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Dong R, Najjar G, Günes C, Lechel A. Aberrant TERT expression: linking chronic inflammation to hepatocellular carcinoma †. J Pathol 2025; 266:130-133. [PMID: 40213897 PMCID: PMC12056276 DOI: 10.1002/path.6421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 02/21/2025] [Accepted: 02/24/2025] [Indexed: 05/08/2025]
Abstract
Telomerase reverse transcriptase (TERT), the catalytic enzyme component of telomerase, plays multiple roles in cellular biology. Its canonical function is primarily associated with telomere maintenance and genomic stability. In addition, several studies revealed critical non-canonical extra-telomeric functions of TERT in various cellular processes, including cell proliferation and survival, DNA damage response, transcription, signal transduction, and metabolic regulation, both in normal and in cancer cells. Notably, TERT is aberrantly upregulated in more than 80% of hepatocellular carcinoma (HCC) cases, making it an important target in liver cancer research. However, due to the diversity and complexity of TERT's functions in vivo, the precise mechanisms by which TERT contributes to the initiation and progression of HCC remain unclear. A recent study published in The Journal of Pathology using the Alb-Cre;TertTg mouse model and clinical HCC samples addresses the role of TERT in hepatocarcinogenesis. The study demonstrates that TERT promotes cell cycle progression and hepatocarcinogenesis by enhancing NF-κB promoter activity and facilitating the ubiquitination of p21. Notably, absence of functional p53 accelerates liver tumor development in TERT transgenic mice. These findings further underscore the critical role of TERT in inflammation-driven hepatocarcinogenesis and provide new insights into its underlying mechanisms. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Rui Dong
- Department of Internal Medicine IUniversity Hospital UlmUlmGermany
| | | | - Cagatay Günes
- Department of UrologyUniversity Hospital UlmUlmGermany
| | - André Lechel
- Department of Internal Medicine IUniversity Hospital UlmUlmGermany
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2
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Chen C, Wang L. Aging and metabolic dysfunction-associated steatotic liver disease: a bidirectional relationship. Front Med 2025:10.1007/s11684-025-1133-7. [PMID: 40316793 DOI: 10.1007/s11684-025-1133-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/09/2025] [Indexed: 05/04/2025]
Abstract
In recent years, aging and cellular senescence have triggered an increased interest in corresponding research fields. Evidence shows that the complex aging process is involved in the development of many chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In fact, aging has a tremendous effect on the liver, leading to a gradual decline in the metabolism, detoxification and immune functions of the liver, which in turn increases the risk of liver disease. These changes can be based on the aging of liver cells (hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells). Similarly, patients with liver diseases exhibit increases in the aging phenotype and aging cells, often manifesting as faster physical functional decline, which is closely related to the promoting effect of liver disease on aging. This review summarizes the interplay between MASLD/MASH development and aging, aiming to reveal the complex relationships that exacerbate one another. Moreover, the corresponding schemes for delaying aging or treating diseases are discussed to provide a basis for the development of effective prevention and treatment strategies in the future.
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Affiliation(s)
- Chen Chen
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
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3
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Wang M, Chen D, Liu J, Huang T, Du Y, Ming S, Zong S. Isolation, characterization and palliative effect of D-gal-induced liver injury of Stropharia rugosoannulata exopolysaccharide. Int J Biol Macromol 2025; 308:142457. [PMID: 40147650 DOI: 10.1016/j.ijbiomac.2025.142457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 03/29/2025]
Abstract
In this study, a homogeneous polysaccharide component, namely SREP-1, was purified from Stropharia rugosoannulata fermentation broth. SREP-1 was identified as a novel water-soluble neutral polysaccharide, with a molecular weight of 9.6 kDa. Monosaccharide composition analysis showed that SREP-1 was composed of glucose, galactose and mannose in a molar ratio of 78.6: 13.6: 7.8. The primary structure was elucidated through FT-IR, methylation analysis and NMR spectroscopy, revealing a backbone of →4)-α-D-Glcp-(1 → and →4,6)-α-D-Glcp-(1 → residues, and →6)-α-D-Galp-(1→, β-D-Manp-(1 → and α-D-Glcp-(→1 residues for the branched chains. Results indicated that SREP-1 possessed an amorphous globular-like structure, good thermally stability and triple-helix conformation in water. In vivo results showed that SREP-1 reversed D-galactose (D-gal)-induced body weight and organ indexes decrease, and alleviated liver damage according to improved histopathology and declined indicators in serum. Amelioration of oxidative stress and abnormal inflammation of aging liver might be due to the elevated nuclear factor-erythroid 2-related factor 2 (Nrf2) expression and decreased that of nuclear factor-κB p65 (NF-κB p65). Interestingly, the beneficial effects of SREP-1 were abolished after pretreatment with antibiotics. Our findings demonstrated that the role of SREP-1 in attenuating aging-related liver injury might involve the regulation of Nrf2-NF-κB signaling pathway and its prebiotic effect.
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Affiliation(s)
- Mengmeng Wang
- College of Food Science and Engineering, Yangzhou University, Yangzhou 225127, China
| | - Dan Chen
- College of Food Science and Engineering, Yangzhou University, Yangzhou 225127, China
| | - Jun Liu
- College of Food Science and Engineering, Yangzhou University, Yangzhou 225127, China
| | - Tiantian Huang
- Jiangsu Alphay Bio-technology Co., Ltd., Nantong 226009, China
| | - Yuguang Du
- State Key Laboratory of Biochemical Engineering and Key Laboratory of Biopharmaceutical Production & Formulation Engineering, PLA, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
| | - Song Ming
- Jiangsu Zhongnongke Food Engineering Co., Ltd, Suqian 223814, China
| | - Shuai Zong
- College of Food Science and Engineering, Yangzhou University, Yangzhou 225127, China.
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Asthana S, Verma A, Bhattacharya B, Nath A, Sajeev N, Maan K, Nair RR, Ayappa KG, Saini DK. Oxysterols Modulate Protein-Sterol Interactions to Impair CXCR4 Signaling in Aging Cells. Biochemistry 2025; 64:1606-1623. [PMID: 40099855 DOI: 10.1021/acs.biochem.4c00617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
Organismal aging is accompanied by the accumulation of senescent cells in the body, which drives tissue dysfunction. Senescent cells have a distinctive profile, including proliferation arrest, resistance to apoptosis, altered gene expression, and high inflammation. Despite global signaling and metabolic dysregulation during senescence, the underlying reasons for changes in signaling remain unclear. GPCRs are pivotal in cellular signaling, dynamically mediating the complex interplay between cells and their surrounding environment to maintain cellular homeostasis. The chemokine receptor CXCR4 plays a crucial role in modulating immune responses and inflammation. It has been shown that the expression of CXCR4 increases in cells undergoing senescence, which enhances inflammation postactivation. Here, we examine CXCR4 signaling in deeply senescent cells (aged cells), where cholesterol and its oxidized derivatives, oxysterols, affect receptor function. We report elevated oxysterol levels in senescent cells, which altered classical CXCL12-mediated CXCR4 signaling. Tail-oxidized sterols disrupted signaling more than ring-oxidized counterparts. Molecular dynamics simulations revealed that 27-hydroxycholesterol displaces cholesterol and binds strongly to alter the conformation of critical signaling residues, modifying the sterol-CXCR4 interaction landscape. Our study provides a molecular view of the observed mitigated GPCR signaling in the presence of oxysterols, which switched G-protein signaling from Gαi/o to Gαs class. Overall, we present an altered paradigm of GPCR signaling, where cholesterol oxidation alters the signaling outcome in aged cells.
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Affiliation(s)
- Suramya Asthana
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bengaluru 560012, India
- Longevity India, Indian Institute of Science, Bengaluru 560012, India
| | - Anant Verma
- Department of Chemical Engineering, Indian Institute of Science, Bengaluru 560012, India
| | - Baivabi Bhattacharya
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bengaluru 560012, India
| | - Arnab Nath
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bengaluru 560012, India
| | | | | | - Raji R Nair
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bengaluru 560012, India
| | - K Ganapathy Ayappa
- Department of Chemical Engineering, Indian Institute of Science, Bengaluru 560012, India
| | - Deepak Kumar Saini
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bengaluru 560012, India
- Longevity India, Indian Institute of Science, Bengaluru 560012, India
- Department of Bioengineering, Indian Institute of Science, Bengaluru 560012, India
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Sasaki M, Sato Y, Nakanuma Y. A heterogeneous subtype of biliary epithelial senescence may be involved in the pathogenesis of primary biliary cholangitis. Clin Res Hepatol Gastroenterol 2025; 49:102512. [PMID: 39662730 DOI: 10.1016/j.clinre.2024.102512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 12/05/2024] [Accepted: 12/07/2024] [Indexed: 12/13/2024]
Abstract
BACKGROUND & AIMS Biliary epithelial senescence is involved in the pathogenesis of primary biliary cholangitis (PBC). We hypothesized that a unique subtype of programmed death-ligand 1 (PD-L1)-positive senescent biliary epithelial cells (BECs) may be related to the pathogenesis of PBC in association with cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) pathway. APPROACH & RESULTS The expression of PD-L1, STING and their association with senescent markers p16INK4a and p21WAF1/Cip1 were immunohistochemically determined in livers taken from the patients with PBC (n = 87) and 97 diseased and normal control livers. The expression of PD-L1 was significantly increased in a part of senescent BECs with p21WAF1/Cip1 expression in BECs in the damaged small bile ducts in PBC, compared to control livers (p < 0.01). In contrast, PD-L1 was not expressed in BECs in ductular reactions. The expression of STING was significantly increased in BECs in small bile ducts and ductular reactions in PBC, compared to control livers (p < 0.01). The expression of PD-L1, STING and senescence associated secretory phenotypes (SASPs) including interferon (IFN)-beta was significantly increased in senescent BECs induced by a treatment with serum depletion or glycochenodeoxycholic acid (GCDC) for 4-7 days (p < 0.01) and the increase was significantly suppressed by a knockdown of STING using siRNA (p < 0.01). Induction of cellular senescence induced by a treatment with serum depletion or GCDC was significantly suppressed by a knockdown of STING in BECs. (p < 0.01). CONCLUSION A unique subtype of senescent BECs with PD-L1 expression associated with cGAS-STING pathway may be involved in the pathogenesis of PBC.
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Affiliation(s)
- Motoko Sasaki
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan.
| | - Yasunori Sato
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
| | - Yasuni Nakanuma
- Department of Pathology, Fukui Saiseikai Hospital, Fukui 918-8503, Japan
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Xie JW, Wang HL, Lin LQ, Guo YF, Wang M, Zhu XZ, Niu JJ, Lin LR. Telomere-methylation genes: Novel prognostic biomarkers for hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2025; 49:102516. [PMID: 39675625 DOI: 10.1016/j.clinre.2024.102516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 12/06/2024] [Accepted: 12/13/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND Since telomere length and DNA methylation both correlate with hepatocellular carcinoma (HCC) prognosis, telomere-methylation genes could be novel prognostic markers for HCC. METHOD This study first investigated the interaction between telomere length and DNA methylation in HCC through Mendelian randomization analysis. Then, this study identified telomere-methylation genes in HCC by employing the TCGA-LIHC cohort, and explored the expression patterns of these genes in the tumor microenvironment of HCC and potential underlying mechanisms. Finally, the HCC risk-scoring model and prognostic model based on these genes were established, and the performance of the model was assessed. RESULT The findings revealed a bidirectional relationship between telomere length and DNA methylation in HCC. Fifty telomere-methylation genes were identified, and the prognosis-related telomere-methylation genes were closely associated with Treg and Tprolif cell subsets within the HCC tumor microenvironment. Telomere-methylation genes could potentially impact the prognosis of HCC patients by modulating chromosome stability and regulating the cell cycle. Additionally, the constructed risk scoring model and prognostic prediction model showcased compelling clinical applicability, as evidenced by the receiver operating characteristic curve, the decision curve analysis, and the calibration curves. CONCLUSION This study elucidated the potential of telomere-methylation genes as prognostic biomarkers for HCC and paves the way for novel approaches in prognostication and treatment management for HCC patients.
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Affiliation(s)
- Jia-Wen Xie
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China
| | - Hui-Ling Wang
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Ling-Qing Lin
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
| | - Yin-Feng Guo
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China
| | - Mao Wang
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China; Department of Pathology, Chengdu Wenjiang District People's Hospital, Chengdu, China
| | - Xiao-Zhen Zhu
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China.
| | - Jian-Jun Niu
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China.
| | - Li-Rong Lin
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China.
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Zhang F, Yan Y, Li B, Ge C. Frailty serves as an adverse predictor for mortality in liver transplant candidates: A systematic review and meta-analysis. Transplant Rev (Orlando) 2024; 38:100884. [PMID: 39396446 DOI: 10.1016/j.trre.2024.100884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/29/2024] [Accepted: 10/02/2024] [Indexed: 10/15/2024]
Abstract
BACKGROUND Physical frailty increases susceptibility to stressors and has been associated with increased mortality among liver transplant candidates. However, evidence about this population's frailty prevalence and mortality is inconsistent and needs to be clarified. This study aimed to quantitatively synthesize the prevalence of frailty and the role of frailty on mortality in liver transplant candidates. METHODS All eligible studies published in Embase, PubMed, Scopus, and Web of Science from inception until March 5, 2024, were included. The pooled prevalence and hazard ratio (HR) corresponding to 95 % confidence intervals (CI) in mortality estimates were conducted. The random-effects model was used for the calculations. RESULTS A total of 17 studies containing 4509 patients with liver transplant waitlist candidates were included. The prevalence of frailty in liver transplant waitlist candidates was 32 % (95 % CI = 25-38; p < 0.01). In this population, frailty was associated with an increased hazard ratio for mortality (8 studies) (HR = 2.49; 95 % CI = 1.77-3.51; p < 0.01). Furthermore, subgroup analysis showed that frailty was associated with a higher mortality in the USA (HR = 4.03; 95 % CI = 1.77-3.51; p < 0.01) compared with the non-USA area (HR = 2.03; 95 % CI = 1.51-2.72; p < 0.01). CONCLUSION Our results suggest that frailty is prevalent in patients awaiting liver transplants, which strongly predicts waitlist mortality among this population. These findings highlight the importance of frailty in the decision of transplantation and in designing studies that consider frailty. Reducing the severity or impact of frailty on this population may improve prognosis.
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Affiliation(s)
- Fei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Ying Yan
- Department of Urinary Surgery, Northeast International Hospital, Shenyang, 110623, China
| | - Baifeng Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Chunlin Ge
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of China Medical University, Shenyang 110001, China
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Wang X, Jia JK, Wang Q, Gong JW, Li A, Su J, Zhou P. Myotis bat STING attenuates aging-related inflammation in female mice. Zool Res 2024; 45:961-971. [PMID: 39016174 PMCID: PMC11491773 DOI: 10.24272/j.issn.2095-8137.2024.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 04/12/2024] [Indexed: 07/18/2024] Open
Abstract
Bats, notable as the only flying mammals, serve as natural reservoir hosts for various highly pathogenic viruses in humans (e.g., SARS-CoV and Ebola virus). Furthermore, bats exhibit an unparalleled longevity among mammals relative to their size, particularly the Myotis bats, which can live up to 40 years. However, the mechanisms underlying these distinctive traits remain incompletely understood. In our prior research, we demonstrated that bats exhibit dampened STING-interferon activation, potentially conferring upon them the capacity to mitigate virus- or aging-induced inflammation. To substantiate this hypothesis, we established the first in vivo bat-mouse model for aging studies by integrating Myotis davidii bat STING ( MdSTING) into the mouse genome. We monitored the genotypes of these mice and performed a longitudinal comparative transcriptomic analysis on MdSTING and wild-type mice over a 3-year aging process. Blood transcriptomic analysis indicated a reduction in aging-related inflammation in female MdSTING mice, as evidenced by significantly lower levels of pro-inflammatory cytokines and chemokines, immunopathology, and neutrophil recruitment in aged female MdSTING mice compared to aged wild-type mice in vivo. These results indicated that MdSTING knock-in attenuates the aging-related inflammatory response and may also improve the healthspan in mice in a sex-dependent manner. Although the underlying mechanism awaits further study, this research has critical implications for bat longevity research, potentially contributing to our comprehension of healthy aging in humans.
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Affiliation(s)
- Xi Wang
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510005, China
- University of Chinese Academy of Sciences, Beijing 100000, China
| | - Jing-Kun Jia
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510005, China
- University of Chinese Academy of Sciences, Beijing 100000, China
| | - Qi Wang
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510005, China
- University of Chinese Academy of Sciences, Beijing 100000, China
| | - Jing-Wen Gong
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China
| | - Ang Li
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510005, China
- State Key Laboratory of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical School, Guangzhou, Guangdong 510005, China
| | - Jia Su
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510005, China
- University of Chinese Academy of Sciences, Beijing 100000, China
| | - Peng Zhou
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510005, China
- State Key Laboratory of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical School, Guangzhou, Guangdong 510005, China. E-mail:
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Chatterjee N, Sharma R, Kale PR, Trehanpati N, Ramakrishna G. Is the liver resilient to the process of ageing? Ann Hepatol 2024; 30:101580. [PMID: 39276981 DOI: 10.1016/j.aohep.2024.101580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 08/15/2024] [Accepted: 08/21/2024] [Indexed: 09/17/2024]
Abstract
The liver's unique regenerative capacity, immunotolerant feature, and polyploidy status distinguish it as a metabolic organ unlike any other in the body. Despite aging, the liver generally exhibits fewer pathological abnormalities than other organs (such as the kidney), maintaining its functions near-normal balanced manner. Subtle changes in the liver, including reduced blood flow, detoxification alterations, pseudo-capillarization, and lipofuscin deposition, may occur with chronological age. Research indicates that carefully selected liver grafts from octogenarian donors can perform well post-transplant, emphasizing instances where age doesn't necessarily compromise liver function. Notably, a recent report suggests that the liver is a youthful organ, with hepatocytes averaging an age of only 3 years. Despite the liver's impressive regenerative capabilities and cellular reserve, a lingering question persists: how does the liver maintain its youthful characteristic amidst the chronological aging of the entire organism? The various adaptive mechanism possibly include:(a) cellular hypertrophy to maintain physiological capacity even before proliferation initiates, (b) the "ploidy conveyor" as a genetic adaptation to endure aging-related stress, (c) sustained telomere length indicative of youthfulness (d) active extracellular matrix remodelling for normal cellular functioning, (e) Mitochondria-Endoplasmic Reticulum based metabolic adaptation and (c) cellular plasticity as fitness mechanisms for healthy aging. However, it is crucial to note that aged livers may have compromised regenerative capacity and chronic liver disease is often associated with declining function due to premature hepatocyte senescence. This review delves into varied cellular adaptations sustaining liver homeostasis with chronological aging and briefly explores the role of accelerated hepatocyte aging as a precursor to chronic liver disease.
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Affiliation(s)
- Nirupama Chatterjee
- Artemis Education and Research Foundation, Artemis Health Institute, Sector 51 Gurugram, India
| | - Rishabh Sharma
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana Amity Education Valley, Panchgaon, Manesar Gurugram, HR 122413, India
| | - Pratibha R Kale
- Department of Clinical Microbiology, Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, India
| | - Nirupma Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, India
| | - Gayatri Ramakrishna
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, India.
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Coukos A, Saglietti C, Sempoux C, Haubitz M, Greuter T, Mittaz-Crettol L, Maurer F, Mdawar-Bailly E, Moradpour D, Alberio L, Good JM, Baerlocher GM, Fraga M. High prevalence of short telomeres in idiopathic porto-sinusoidal vascular disorder. Hepatol Commun 2024; 8:e0500. [PMID: 39037376 PMCID: PMC11265777 DOI: 10.1097/hc9.0000000000000500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 06/01/2024] [Indexed: 07/23/2024] Open
Abstract
BACKGROUND Telomeres prevent damage to coding DNA as end-nucleotides are lost during mitosis. Mutations in telomere maintenance genes cause excessive telomere shortening, a condition known as short telomere syndrome (STS). One hepatic manifestation documented in STS is porto-sinusoidal vascular disorder (PSVD). METHODS As the etiology of many cases of PSVD remains unknown, this study explored the extent to which short telomeres are present in patients with idiopathic PSVD. RESULTS This monocentric cross-sectional study included patients with histologically defined idiopathic PSVD. Telomere length in 6 peripheral blood leukocyte subpopulations was assessed using fluorescent in situ hybridization and flow cytometry. Variants of telomere-related genes were identified using high-throughput exome sequencing. In total, 22 patients were included, of whom 16 (73%) had short (9/22) or very short (7/22) telomeres according to age-adjusted reference ranges. Fourteen patients (64%) had clinically significant portal hypertension. Shorter telomeres were more frequent in males (p = 0.005) and patients with concomitant interstitial lung disease (p < 0.001), chronic kidney disease (p < 0.001), and erythrocyte macrocytosis (p = 0.007). Portal hypertension (p = 0.021), low serum albumin level (p < 0.001), low platelet count (p = 0.007), and hyperbilirubinemia (p = 0.053) were also associated with shorter telomeres. Variants in known STS-related genes were identified in 4 patients with VSTel and 1 with STel. CONCLUSIONS Short and very short telomeres were highly prevalent in patients with idiopathic PSVD, with 31% presenting with variants in telomere-related genes. Telomere biology may play an important role in vascular liver disease development. Clinicians should consider measuring telomeres in any patient presenting with PSVD.
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Affiliation(s)
- Alexander Coukos
- Divisions of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Chiara Saglietti
- Institute of Pathology, Department of Laboratory Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Christine Sempoux
- Institute of Pathology, Department of Laboratory Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Monika Haubitz
- Department of Biomedical Research, Laboratory for Hematopoiesis and Molecular Genetics, University of Bern, Bern, Switzerland
| | - Thomas Greuter
- Divisions of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Division of Gastroenterology and Hepatology, Department of Medicine, GZO-Zurich Regional Health Center, Wetzikon, Switzerland
| | - Laureane Mittaz-Crettol
- Genetic Medicine, Department of Laboratory Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Fabienne Maurer
- Genetic Medicine, Department of Laboratory Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Elise Mdawar-Bailly
- Divisions of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Darius Moradpour
- Divisions of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Lorenzo Alberio
- Department of Oncology, Hematology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Jean-Marc Good
- Genetic Medicine, Department of Laboratory Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Gabriela M. Baerlocher
- Department of Biomedical Research, Laboratory for Hematopoiesis and Molecular Genetics, University of Bern, Bern, Switzerland
| | - Montserrat Fraga
- Divisions of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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11
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Zhang J, Yang XY, Chen J, Zhou Q, Pan G, Wang Y, Luo W, Hou J, Bao H, Xu G, Tang G, Bai H, Yu R. A Poly(amino acid)-Based Nanomedicine Strategy: Telomere-Telomerase Axis Targeting and Magnetic Resonance Imaging in Hepatocellular Carcinoma Treatment. NANO LETTERS 2024; 24:8351-8360. [PMID: 38916238 DOI: 10.1021/acs.nanolett.4c01767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Targeting telomere maintenance has emerged as a promising strategy for hepatocellular carcinoma (HCC) treatment. However, given the duality of the telomere-telomerase axis in telomere maintenance, a comprehensive strategy is urgently needed. Herein, we develop a poly(amino acid) (D-PAAs)-based strategy for spatiotemporal codelivery of telomerase inhibitor, BIBR1523, and AKT inhibitor, isobavachalcone. By leveraging D-PAAs' modifiability, we synthesize polymer-inhibitor conjugates (PB and PI) and a folic acid-decorated tumor-targeting vector (PF). These building blocks undergo micellization to fabricate a codelivery nanomedicine (P-BI@P-FA) by exploiting D-PAAs' noncovalent assembly. P-BI@P-FA improves the pharmacokinetics, tumor selectivity, and bioavailability of small molecule inhibitors and initiates a dual telomere-specific inhibition by combining telomerase deactivation with telomere disruption. Furthermore, a hybrid tumor-targeting magnetic nanosystem is designed using D-PAAs and manganese dioxide to showcase magnetic resonance imaging capacities. Our D-PAAs-based strategy addresses the pressing need for telomere-specific HCC treatment while allowing for diagnostic application, presenting a promising avenue for nanomedicine design.
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Affiliation(s)
- Jinguo Zhang
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Xiao-Yan Yang
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Jiayi Chen
- Department of Chemistry, Zhejiang University, Hangzhou 310028, People's Republic of China
| | - Qiaomei Zhou
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Guohua Pan
- Department of Chemistry, Zhejiang University, Hangzhou 310028, People's Republic of China
| | - Yining Wang
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Wangping Luo
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Jue Hou
- Department of Chemistry, Zhejiang University, Hangzhou 310028, People's Republic of China
| | - Hanxiao Bao
- Department of Chemistry, Zhejiang University, Hangzhou 310028, People's Republic of China
| | - Guoqiao Xu
- Department of Chemistry, Zhejiang University, Hangzhou 310028, People's Republic of China
| | - Guping Tang
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
- Department of Chemistry, Zhejiang University, Hangzhou 310028, People's Republic of China
| | - Hongzhen Bai
- Department of Chemistry, Zhejiang University, Hangzhou 310028, People's Republic of China
| | - Risheng Yu
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
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12
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Sanfeliu-Redondo D, Gibert-Ramos A, Gracia-Sancho J. Cell senescence in liver diseases: pathological mechanism and theranostic opportunity. Nat Rev Gastroenterol Hepatol 2024; 21:477-492. [PMID: 38485755 DOI: 10.1038/s41575-024-00913-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/12/2024] [Indexed: 06/30/2024]
Abstract
The liver is not oblivious to the passage of time, as ageing is a major risk factor for the development of acute and chronic liver diseases. Ageing produces alterations in all hepatic cells, affecting their phenotype and function and worsening the prognosis of liver disease. The ageing process also implies the accumulation of a cellular state characterized by a persistent proliferation arrest and a specific secretory phenotype named cellular senescence. Indeed, senescent cells have key roles in many physiological processes; however, their accumulation owing to ageing or pathological conditions contributes to the damage occurring in chronic diseases. The aim of this Review is to provide an updated description of the pathophysiological events in which hepatic senescent cells are involved and their role in liver disease progression. Finally, we discuss novel geroscience therapies that could be applied to prevent or improve liver diseases and age-mediated hepatic deregulations.
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Affiliation(s)
- David Sanfeliu-Redondo
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain
| | - Albert Gibert-Ramos
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain.
- Department of Visceral Surgery and Medicine, Inselspital - University of Bern, Bern, Switzerland.
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13
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Wahid RM, Hassan NH, Samy W, Abdelhadi AA, Saadawy SF, Elsayed SF, Seada SG, Mohamed SRA. Unraveling the hepatic stellate cells mediated mechanisms in aging's influence on liver fibrosis. Sci Rep 2024; 14:13473. [PMID: 38866800 PMCID: PMC11169484 DOI: 10.1038/s41598-024-63644-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 05/30/2024] [Indexed: 06/14/2024] Open
Abstract
Aging enhances numerous processes that compromise homeostasis and pathophysiological processes. Among these, activated HSCs play a pivotal role in advancing liver fibrosis. This research delved into how aging impacts liver fibrosis mechanisms. The study involved 32 albino rats categorized into four groups: Group I (young controls), Group II (young with liver fibrosis), Group III (old controls), and Group IV (old with liver fibrosis). Various parameters including serum ALT, adiponectin, leptin, and cholesterol levels were evaluated. Histopathological analysis was performed, alongside assessments of TGF-β, FOXP3, and CD133 gene expressions. Markers of fibrosis and apoptosis were the highest in group IV. Adiponectin levels significantly decreased in Group IV compared to all other groups except Group II, while cholesterol levels were significantly higher in liver fibrosis groups than their respective control groups. Group III displayed high hepatic expression of desmin, α-SMA, GFAP and TGF- β and in contrast to Group I. Increased TGF-β and FOXP3 gene expressions were observed in Group IV relative to Group II, while CD133 gene expression decreased in Group IV compared to Group II. In conclusion, aging modulates immune responses, impairs regenerative capacities via HSC activation, and influences adipokine and cholesterol levels, elevating the susceptibility to liver fibrosis.
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Affiliation(s)
- Reham M Wahid
- Medical Physiology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Nancy Husseiny Hassan
- Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Walaa Samy
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Amina A Abdelhadi
- Medical Microbiology and Immunology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
| | - Sara F Saadawy
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Sherein F Elsayed
- Medical Physiology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Sara G Seada
- Medical Physiology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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14
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Xu L, Yang T, Wen M, Wen D, Jin C, An M, Wang L, Liu Y, Fan J. Frontiers in the Etiology and Treatment of Preterm Premature Rupture of Membrane: From Molecular Mechanisms to Innovative Therapeutic Strategies. Reprod Sci 2024; 31:917-931. [PMID: 37989803 DOI: 10.1007/s43032-023-01411-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 11/09/2023] [Indexed: 11/23/2023]
Abstract
Preterm premature rupture of membranes (pPROM) poses a significant threat to fetal viability and increases the risk for newborn morbidities. The perinatal period of preterm infants affected by pPROM is often characterized by higher rates of mortality and morbidity, with associated risks of cerebral palsy, developmental delays, compromised immune function, respiratory diseases, and sensory impairments. pPROM is believed to result from a variety of causes, including but not limited to microbially induced infections, stretching of fetal membranes, oxidative stress, inflammatory responses, and age-related changes in the fetal-placental interface. Maternal stress, nutritional deficiencies, and medically induced procedures such as fetoscopy are also considered potential contributing factors to pPROM. This comprehensive review explores the potential etiologies leading to pPROM, delves into the intricate molecular mechanisms through which these etiologies cause membrane ruptures, and provides a concise overview of diagnostic and treatment approaches for pPROM. Based on available therapeutic options, this review proposes and explores the possibilities of utilizing a novel composite hydrogel composed of amniotic membrane particles for repairing ruptured fetal membranes, thereby holding promise for its clinical application.
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Affiliation(s)
- Ludan Xu
- Institute of Biomedical Engineering, College of Biomedical Engineering, Shanxi Key Laboratory of Material Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, Shanxi, China
| | - Tiantian Yang
- Institute of Biomedical Engineering, College of Biomedical Engineering, Shanxi Key Laboratory of Material Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, Shanxi, China
| | - Meiling Wen
- Institute of Biomedical Engineering, College of Biomedical Engineering, Shanxi Key Laboratory of Material Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, Shanxi, China
- Research Center for Nanobiomaterials & Regenerative Medicine, College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan, Shanxi, China
| | - Dawei Wen
- Institute of Biomedical Engineering, College of Biomedical Engineering, Shanxi Key Laboratory of Material Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, Shanxi, China
| | - Chaoyang Jin
- Institute of Biomedical Engineering, College of Biomedical Engineering, Shanxi Key Laboratory of Material Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, Shanxi, China
| | - Meiwen An
- Institute of Biomedical Engineering, College of Biomedical Engineering, Shanxi Key Laboratory of Material Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, Shanxi, China
| | - Li Wang
- Institute of Biomedical Engineering, College of Biomedical Engineering, Shanxi Key Laboratory of Material Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, Shanxi, China
| | - Yang Liu
- Institute of Biomedical Engineering, College of Biomedical Engineering, Shanxi Key Laboratory of Material Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, Shanxi, China.
- Research Center for Nanobiomaterials & Regenerative Medicine, College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan, Shanxi, China.
- Department of Nuclear Medicine, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
| | - Junmei Fan
- Department of Reproductive Medicine Center, Children's Hospital of Shanxi and Women Health Center of Shanxi, Affiliated of Shanxi Medical University, Taiyuan, Shanxi, China.
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15
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Lin Y, Liu S, Sun Y, Chen C, Yang S, Pei G, Lin M, Yu J, Liu X, Wang H, Long J, Yan Q, Liang J, Yao J, Yi F, Meng L, Tan Y, Chen N, Yang Y, Ai Q. CCR5 and inflammatory storm. Ageing Res Rev 2024; 96:102286. [PMID: 38561044 DOI: 10.1016/j.arr.2024.102286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 03/15/2024] [Accepted: 03/25/2024] [Indexed: 04/04/2024]
Abstract
Chemokines and their corresponding receptors play crucial roles in orchestrating inflammatory and immune responses, particularly in the context of pathological conditions disrupting the internal environment. Among these receptors, CCR5 has garnered considerable attention due to its significant involvement in the inflammatory cascade, serving as a pivotal mediator of neuroinflammation and other inflammatory pathways associated with various diseases. However, a notable gap persists in comprehending the intricate mechanisms governing the interplay between CCR5 and its ligands across diverse and intricate inflammatory pathologies. Further exploration is warranted, especially concerning the inflammatory cascade instigated by immune cell infiltration and the precise binding sites within signaling pathways. This study aims to illuminate the regulatory axes modulating signaling pathways in inflammatory cells by providing a comprehensive overview of the pathogenic processes associated with CCR5 and its ligands across various disorders. The primary focus lies on investigating the pathomechanisms associated with CCR5 in disorders related to neuroinflammation, alongside the potential impact of aging on these processes and therapeutic interventions. The discourse culminates in addressing current challenges and envisaging potential future applications, advocating for innovative research endeavors to advance our comprehension of this realm.
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Affiliation(s)
- Yuting Lin
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Shasha Liu
- Department of Pharmacy, Changsha Hospital for Matemal&Child Health Care Affiliated to Hunan Normal University, Changsha 410007, China
| | - Yang Sun
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Chen Chen
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Songwei Yang
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Gang Pei
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Meiyu Lin
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Jingbo Yu
- Technology Innovation Center/National Key Laboratory Breeding Base of Chinese Medicine Powders and Innovative Drugs, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Xuan Liu
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Huiqin Wang
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Junpeng Long
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Qian Yan
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Jinping Liang
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Jiao Yao
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Fan Yi
- Key Laboratory of Cosmetic, China National Light Industry, Beijing Technology and Business University, Beijing 100048, China
| | - Lei Meng
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Yong Tan
- Nephrology Department, Xiangtan Central Hospital, Xiangtan 411100, China
| | - Naihong Chen
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
| | - Yantao Yang
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China.
| | - Qidi Ai
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China.
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16
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Liu Y, Xiao J, Cai J, Li R, Sui X, Zhang J, Lu T, Chen H, Chen G, Li H, Jiang C, Zhao X, Xiao C, Lei Y, Yao J, Lv G, Liang J, Zhang Y, Yang JR, Zheng J, Yang Y. Single-cell immune profiling of mouse liver aging reveals Cxcl2+ macrophages recruit neutrophils to aggravate liver injury. Hepatology 2024; 79:589-605. [PMID: 37695548 PMCID: PMC10871588 DOI: 10.1097/hep.0000000000000590] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 07/21/2023] [Indexed: 09/12/2023]
Abstract
BACKGROUND AND AIMS Immune cells play a crucial role in liver aging. However, the impact of dynamic changes in the local immune microenvironment on age-related liver injury remains poorly understood. We aimed to characterize intrahepatic immune cells at different ages to investigate key mechanisms associated with liver aging. APPROACH AND RESULTS We carried out single-cell RNA sequencing on mouse liver tissues at 4 different ages, namely, the newborn, suckling, young, and aged stages. The transcriptomic landscape, cellular classification, and intercellular communication were analyzed. We confirmed the findings by multiplex immunofluorescence staining, flow cytometry, in vitro functional experiments, and chimeric animal models. Nine subsets of 89,542 immune cells with unique properties were identified, of which Cxcl2+ macrophages within the monocyte/macrophage subset were preferentially enriched in the aged liver. Cxcl2+ macrophages presented a senescence-associated secretory phenotype and recruited neutrophils to the aged liver through the CXCL2-CXCR2 axis. Through the secretion of IL-1β and TNF-α, Cxcl2+ macrophages stimulated neutrophil extracellular traps formation. Targeting the CXCL2-CXCR2 axis limited the neutrophils migration toward the liver and attenuated age-related liver injury. Moreover, the relationship between Cxcl2+ macrophages and neutrophils in age-related liver injury was further validated by human liver transplantation samples. CONCLUSIONS This in-depth study illustrates that the mechanism of Cxcl2+ macrophage-driven neutrophil activation involves the CXCL2-CXCR2 axis and provides a potential therapeutic strategy for age-related liver injury.
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Affiliation(s)
- Yasong Liu
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine; Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Jiaqi Xiao
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine; Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Jianye Cai
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine; Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Rong Li
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Xin Sui
- Surgical ICU, The Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Jiebin Zhang
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine; Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Tongyu Lu
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine; Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Haitian Chen
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine; Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Guihua Chen
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine; Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Haibo Li
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine; Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Chenhao Jiang
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine; Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Xuegang Zhao
- Surgical ICU, The Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Cuicui Xiao
- Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-Sen University; Guangzhou, China
| | - Yunguo Lei
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine; Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Jia Yao
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine; Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Guo Lv
- Biological Treatment Center, The Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Jinliang Liang
- Organ Transplantation Research Center of Guangdong Province Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yingcai Zhang
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine; Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Jian-Rong Yang
- Department of Genetics and Biomedical Informatics, Zhongshan School of Medicine, Sun Yat-sen University; Guangzhou, China
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University; Guangzhou, China
| | - Jun Zheng
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine; Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
| | - Yang Yang
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine; Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University; Guangzhou, China
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17
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Aging Biomarker Consortium, Jiang M, Zheng Z, Wang X, Chen Y, Qu J, Ding Q, Zhang W, Liu YS, Yang J, Tang W, Hou Y, He J, Wang L, Huang P, Li LC, He Z, Gao Q, Lu Q, Wei L, Wang YJ, Ju Z, Fan JG, Ruan XZ, Guan Y, Liu GH, Pei G, Li J, Wang Y. A biomarker framework for liver aging: the Aging Biomarker Consortium consensus statement. LIFE MEDICINE 2024; 3:lnae004. [PMID: 39872390 PMCID: PMC11749002 DOI: 10.1093/lifemedi/lnae004] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/29/2024] [Indexed: 01/11/2025]
Abstract
In human aging, liver aging per se not only increases susceptibility to liver diseases but also increases vulnerability of other organs given its central role in regulating metabolism. Total liver function tends to be well maintained in the healthy elderly, so liver aging is generally difficult to identify early. In response to this critical challenge, the Aging Biomarker Consortium of China has formulated an expert consensus on biomarkers of liver aging by synthesizing the latest scientific literature, comprising insights from both scientists and clinicians. This consensus provides a comprehensive assessment of biomarkers associated with liver aging and presents a systematic framework to characterize these into three dimensions: functional, imaging, and humoral. For the functional domain, we highlight biomarkers associated with cholesterol metabolism and liver-related coagulation function. For the imaging domain, we note that hepatic steatosis and liver blood flow can serve as measurable biomarkers for liver aging. Finally, in the humoral domain, we pinpoint hepatokines and enzymatic alterations worthy of attention. The aim of this expert consensus is to establish a foundation for assessing the extent of liver aging and identify early signs of liver aging-related diseases, thereby improving liver health and the healthy life expectancy of the elderly population.
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Affiliation(s)
| | - Mengmeng Jiang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
| | - Zhuozhao Zheng
- Department of Radiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Xuan Wang
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Yanhao Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Qiurong Ding
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Weiqi Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China
| | - You-Shuo Liu
- Department of Geriatrics, the Second Xiangya Hospital, and the Institute of Aging and Geriatrics, Central South University, Changsha 410011, China
| | - Jichun Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
| | - Weiqing Tang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, China
| | - Yunlong Hou
- Yiling Pharmaceutical Academician Workstation, Shijiazhuang 050035, China
| | - Jinhan He
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Pengyu Huang
- State Key Laboratory of Advanced Medical Materials and Devices, Engineering Research Center of Pulmonary and Critical Care Medicine Technology and Device (Ministry of Education), Institute of Biomedical Engineering, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, China
| | - Lin-Chen Li
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
| | - Zhiying He
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200092, China
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qian Lu
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
- Key Laboratory of Digital Intelligence Hepatology (Ministry of Education), School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Lai Wei
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Yan-Jiang Wang
- Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xiong Zhong Ruan
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Youfei Guan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Gang Pei
- Collaborative Innovation Center for Brain Science, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Jian Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, China
| | - Yunfang Wang
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
- Key Laboratory of Digital Intelligence Hepatology (Ministry of Education), School of Clinical Medicine, Tsinghua University, Beijing 102218, China
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing 102218, China
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Rayginia TP, Keerthana CK, Shifana SC, Pellissery MJ, Abhishek A, Anto RJ. Phytochemicals as Potential Lead Molecules against Hepatocellular Carcinoma. Curr Med Chem 2024; 31:5199-5221. [PMID: 38213177 DOI: 10.2174/0109298673275501231213063902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 10/31/2023] [Accepted: 11/16/2023] [Indexed: 01/13/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, accounting for 85-90% of liver cancer cases and is a leading cause of cancer-related mortality worldwide. The major risk factors for HCC include hepatitis C and B viral infections, along with chronic liver diseases, such as cirrhosis, fibrosis, and non-alcoholic steatohepatitis associated with metabolic syndrome. Despite the advancements in modern medicine, there is a continuous rise in the annual global incidence rate of HCC, and it is estimated to reach >1 million cases by 2025. Emerging research in phytomedicine and chemotherapy has established the anti-cancer potential of phytochemicals, owing to their diverse biological activities. In this review, we report the major phytochemicals that have been explored in combating hepatocellular carcinoma and possess great potential to be used as an alternative or in conjunction with the existing HCC treatment modalities. An overview of the pre-clinical observations, mechanism of action and molecular targets of some of these phytochemicals is also incorporated.
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Affiliation(s)
- Tennyson Prakash Rayginia
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
- Department of Biotechnology, University of Kerala, Thiruvananthapuram, Kerala, 695011, India
| | - Chenicheri Kizhakkeveettil Keerthana
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
- Department of Biotechnology, University of Kerala, Thiruvananthapuram, Kerala, 695011, India
| | | | - Maria Joy Pellissery
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
| | - Ajmani Abhishek
- Molecular Bioassay Laboratory, Institute of Advanced Virology, Thiruvananthapuram, Kerala, 695317, India
| | - Ruby John Anto
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
- Molecular Bioassay Laboratory, Institute of Advanced Virology, Thiruvananthapuram, Kerala, 695317, India
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19
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Lin Y, Li Q, Liang G, Xiao N, Yang J, Yang X, Zhang H, Zhang C, Liu A. Overview of Innate Immune Cell Landscape in Liver Aging. Int J Mol Sci 2023; 25:181. [PMID: 38203352 PMCID: PMC10778796 DOI: 10.3390/ijms25010181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 12/06/2023] [Accepted: 12/13/2023] [Indexed: 01/12/2024] Open
Abstract
Aging is a biological process with a gradual decline in functional capacity, and this process often enhances the risk of chronic disease morbidity and mortality. With advanced age, the immune system undergoes a process of remodeling that can lead to a chronic inflammatory state, termed immunosenescence and inflammaging, respectively. Immunosenescence is accompanied by changes in the number, proportion, and functional capacity of the innate immune cells. The accumulation of dysfunctional immune cells and the presence of low-grade inflammation can lead to organ damage and expedite the aging process. The liver, crucial in regulating the body's metabolism and immune function, is not exempt from these effects. Age-related modifications affect its immune function and regenerative abilities, potentially increasing the prevalence of age-related liver diseases. While aging's impact on the liver is relatively less severe compared to other organ systems, it still experiences an infiltration of innate immune cells and heightened inflammation levels. This review will elaborate on how aging affects the liver's innate immune cells, such as neutrophils, macrophages, dendritic cells, mast cells, and innate lymphoid cells. It will also explore potential strategies for delaying immunosenescence to alleviate these age-related changes.
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Affiliation(s)
- Yan Lin
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qiao Li
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Guangyu Liang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Nanyin Xiao
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jiankun Yang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiao Yang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Heng Zhang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Cuntai Zhang
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Anding Liu
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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20
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Yang X, Zong C, Feng C, Zhang C, Smirnov A, Sun G, Shao C, Zhang L, Hou X, Liu W, Meng Y, Zhang L, Shao C, Wei L, Melino G, Shi Y. Hippo Pathway Activation in Aged Mesenchymal Stem Cells Contributes to the Dysregulation of Hepatic Inflammation in Aged Mice. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300424. [PMID: 37544916 PMCID: PMC10520691 DOI: 10.1002/advs.202300424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 07/14/2023] [Indexed: 08/08/2023]
Abstract
Aging is always accompanied by chronic diseases which probably attribute to long-term chronic inflammation in the aging body. Whereas, the mechanism of chronic inflammation in aging body is still obscure. Mesenchymal stem cells (MSCs) are capable of local chemotaxis to sites of inflammation and play a powerful role in immune regulation. Whether degeneration of MSCs in the aging body is associated with unbalanced inflammation is still not clear. In this study, immunosuppressive properties of aged MSCs are found to be repressed. The impaired immunosuppressive function of aged MSCs is associated with lower expression of the Hippo effector Yes-associated protein 1 (YAP1) and its target gene signal transducer and activator of transcription 1 (STAT1). YAP1 regulates the transcription of STAT1 through binding with its promoter. In conclusion, a novel YAP1/STAT1 axis maintaining immunosuppressive function of MSCs is revealed and impairment of this signal pathway in aged MSCs probably resulted in higher inflammation in aged mice liver.
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Affiliation(s)
- Xue Yang
- The Third Affiliated Hospital of Soochow UniversityInstitutes for Translational MedicineState Key Laboratory of Radiation Medicine and ProtectionKey Laboratory of Stem Cells and Medical Biomaterials of Jiangsu ProvinceMedical College of Soochow UniversitySoochow UniversitySuzhou215000China
- Department of Experimental MedicineTORUniversity of Rome Tor VergataRome00133Italy
- Department of Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438China
- Department of immunology and metabolismNational Center for Liver CancerShanghai201805China
| | - Chen Zong
- Department of Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438China
- Department of immunology and metabolismNational Center for Liver CancerShanghai201805China
| | - Chao Feng
- The Third Affiliated Hospital of Soochow UniversityInstitutes for Translational MedicineState Key Laboratory of Radiation Medicine and ProtectionKey Laboratory of Stem Cells and Medical Biomaterials of Jiangsu ProvinceMedical College of Soochow UniversitySoochow UniversitySuzhou215000China
- Department of Experimental MedicineTORUniversity of Rome Tor VergataRome00133Italy
| | - Cangang Zhang
- Department of Pathogenic Microbiology and ImmunologySchool of Basic Medical SciencesXi'an Jiaotong UniversityXi'anShaanxi710061China
| | - Artem Smirnov
- Department of Experimental MedicineTORUniversity of Rome Tor VergataRome00133Italy
| | - Gangqi Sun
- Department of Clinical PharmacologyThe Second Hospital of Anhui Medical UniversityHefei230601China
| | - Changchun Shao
- Department of OncologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiAnhui230022China
| | - Luyao Zhang
- Department of Clinical PharmacologyThe Second Hospital of Anhui Medical UniversityHefei230601China
| | - Xiaojuan Hou
- Department of Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438China
- Department of immunology and metabolismNational Center for Liver CancerShanghai201805China
| | - Wenting Liu
- Department of Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438China
- Department of immunology and metabolismNational Center for Liver CancerShanghai201805China
| | - Yan Meng
- Department of Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438China
- Department of immunology and metabolismNational Center for Liver CancerShanghai201805China
| | - Liying Zhang
- The Third Affiliated Hospital of Soochow UniversityInstitutes for Translational MedicineState Key Laboratory of Radiation Medicine and ProtectionKey Laboratory of Stem Cells and Medical Biomaterials of Jiangsu ProvinceMedical College of Soochow UniversitySoochow UniversitySuzhou215000China
| | - Changshun Shao
- The Third Affiliated Hospital of Soochow UniversityInstitutes for Translational MedicineState Key Laboratory of Radiation Medicine and ProtectionKey Laboratory of Stem Cells and Medical Biomaterials of Jiangsu ProvinceMedical College of Soochow UniversitySoochow UniversitySuzhou215000China
| | - Lixin Wei
- Department of Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438China
- Department of immunology and metabolismNational Center for Liver CancerShanghai201805China
| | - Gerry Melino
- Department of Experimental MedicineTORUniversity of Rome Tor VergataRome00133Italy
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow UniversityInstitutes for Translational MedicineState Key Laboratory of Radiation Medicine and ProtectionKey Laboratory of Stem Cells and Medical Biomaterials of Jiangsu ProvinceMedical College of Soochow UniversitySoochow UniversitySuzhou215000China
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Ge T, Shao Y, Bao X, Xu W, Lu C. Cellular senescence in liver diseases: From mechanisms to therapies. Int Immunopharmacol 2023; 121:110522. [PMID: 37385123 DOI: 10.1016/j.intimp.2023.110522] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 06/05/2023] [Accepted: 06/14/2023] [Indexed: 07/01/2023]
Abstract
Cellular senescence is an irreversible state of cell cycle arrest, characterized by a gradual decline in cell proliferation, differentiation, and biological functions. Cellular senescence is double-edged for that it can provoke organ repair and regeneration in physiological conditions but contribute to organ and tissue dysfunction and prime multiple chronic diseases in pathological conditions. The liver has a strong regenerative capacity, where cellular senescence and regeneration are closely involved. Herein, this review firstly introduces the morphological manifestations of senescent cells, the major regulators (p53, p21, and p16), and the core pathophysiologic mechanisms underlying senescence process, and then specifically generalizes the role and interventions of cellular senescence in multiple liver diseases, including alcoholic liver disease, nonalcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. In conclusion, this review focuses on interpreting the importance of cellular senescence in liver diseases and summarizes potential senescence-related regulatory targets, aiming to provide new insights for further researches on cellular senescence regulation and therapeutic developments for liver diseases.
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Affiliation(s)
- Ting Ge
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Yunyun Shao
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Xiaofeng Bao
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Wenxuan Xu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China.
| | - Chunfeng Lu
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China.
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22
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Zhang S, Zheng Y, Li X, Zhang S, Hu H, Kuang W. Cellular senescence-related gene signature as a valuable predictor of prognosis in hepatocellular carcinoma. Aging (Albany NY) 2023; 15:3064-3093. [PMID: 37059592 DOI: 10.18632/aging.204658] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 03/28/2023] [Indexed: 04/16/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a lethal tumor. Its prognosis prediction remains a challenge. Meanwhile, cellular senescence, one of the hallmarks of cancer, and its related prognostic genes signature can provide critical information for clinical decision-making. METHOD Using bulk RNA sequencing and microarray data of HCC samples, we established a senescence score model via multi-machine learning algorithms to predict the prognosis of HCC. Single-cell and pseudo-time trajectory analyses were used to explore the hub genes of the senescence score model in HCC sample differentiation. RESULT A machine learning model based on cellular senescence gene expression profiles was identified in predicting HCC prognosis. The feasibility and accuracy of the senescence score model were confirmed in external validation and comparison with other models. Moreover, we analyzed the immune response, immune checkpoints, and sensitivity to immunotherapy drugs of HCC patients in different prognostic risk groups. Pseudo-time analyses identified four hub genes in HCC progression, including CDCA8, CENPA, SPC25, and TTK, and indicated related cellular senescence. CONCLUSIONS This study identified a prognostic model of HCC by cellular senescence-related gene expression and insight into novel potential targeted therapies.
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Affiliation(s)
- Shuqiao Zhang
- First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yilu Zheng
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xinyu Li
- Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Shijun Zhang
- Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hao Hu
- First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Weihong Kuang
- Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, The First Dongguan Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Dongguan, Guangdong, China
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23
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Liu S, Nong W, Ji L, Zhuge X, Wei H, Luo M, Zhou L, Chen S, Zhang S, Lei X, Huang H. The regulatory feedback of inflammatory signaling and telomere/telomerase complex dysfunction in chronic inflammatory diseases. Exp Gerontol 2023; 174:112132. [PMID: 36849001 DOI: 10.1016/j.exger.2023.112132] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 02/18/2023] [Accepted: 02/21/2023] [Indexed: 03/01/2023]
Abstract
Inflammation is believed to play a role in the progression of numerous human diseases. Research has shown that inflammation and telomeres are involved in a feedback regulatory loop: inflammation increases the rate of telomere attrition, leading to telomere dysfunction, while telomere components also participate in regulating the inflammatory response. However, the specific mechanism behind this feedback loop between inflammatory signaling and telomere/telomerase complex dysfunction has yet to be fully understood. This review presents the latest findings on this topic, with a particular focus on the detailed regulation and molecular mechanisms involved in the progression of aging, various chronic inflammatory diseases, cancers, and different stressors. Several feedback loops between inflammatory signaling and telomere/telomerase complex dysfunction, including NF-κB-TERT feedback, NF-κB-RAP1 feedback, NF-κB-TERC feedback, STAT3-TERT feedback, and p38 MAPK-shelterin complex-related gene feedback, are summarized. Understanding the latest discoveries of this feedback regulatory loop can help identify novel potential drug targets for the suppression of various inflammation-associated diseases.
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Affiliation(s)
- Shun Liu
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Weihua Nong
- Department of Obstetrics and Gynecology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533300, China
| | - Lin Ji
- Reproductive Hospital of Guangxi Zhuang Autonomous Region, 530021 Nanning, China
| | - Xiuhong Zhuge
- Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China
| | - Huimei Wei
- Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China
| | - Min Luo
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Leguang Zhou
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Shenghua Chen
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
| | - Shun Zhang
- Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China.
| | - Xiaocan Lei
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
| | - Hua Huang
- Reproductive Hospital of Guangxi Zhuang Autonomous Region, 530021 Nanning, China.
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Machado IF, Palmeira CM, Rolo AP. Preservation of Mitochondrial Health in Liver Ischemia/Reperfusion Injury. Biomedicines 2023; 11:948. [PMID: 36979927 PMCID: PMC10046671 DOI: 10.3390/biomedicines11030948] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/06/2023] [Accepted: 03/16/2023] [Indexed: 03/22/2023] Open
Abstract
Liver ischemia-reperfusion injury (LIRI) is a major cause of the development of complications in different clinical settings such as liver resection and liver transplantation. Damage arising from LIRI is a major risk factor for early graft rejection and is associated with higher morbidity and mortality after surgery. Although the mechanisms leading to the injury of parenchymal and non-parenchymal liver cells are not yet fully understood, mitochondrial dysfunction is recognized as a hallmark of LIRI that exacerbates cellular injury. Mitochondria play a major role in glucose metabolism, energy production, reactive oxygen species (ROS) signaling, calcium homeostasis and cell death. The diverse roles of mitochondria make it essential to preserve mitochondrial health in order to maintain cellular activity and liver integrity during liver ischemia/reperfusion (I/R). A growing body of studies suggest that protecting mitochondria by regulating mitochondrial biogenesis, fission/fusion and mitophagy during liver I/R ameliorates LIRI. Targeting mitochondria in conditions that exacerbate mitochondrial dysfunction, such as steatosis and aging, has been successful in decreasing their susceptibility to LIRI. Studying mitochondrial dysfunction will help understand the underlying mechanisms of cellular damage during LIRI which is important for the development of new therapeutic strategies aimed at improving patient outcomes. In this review, we highlight the progress made in recent years regarding the role of mitochondria in liver I/R and discuss the impact of liver conditions on LIRI.
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Affiliation(s)
- Ivo F. Machado
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal
- IIIUC—Institute of Interdisciplinary Research, University of Coimbra, 3000 Coimbra, Portugal
| | - Carlos M. Palmeira
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal
- Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal
| | - Anabela P. Rolo
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal
- Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal
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25
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An involvement of Hippo-yes-associated protein pathway in biliary epithelial senescence in primary biliary cholangitis. Clin Res Hepatol Gastroenterol 2023; 47:102106. [PMID: 36849079 DOI: 10.1016/j.clinre.2023.102106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 02/03/2023] [Accepted: 02/24/2023] [Indexed: 03/01/2023]
Abstract
BACKGROUND & AIMS Accumulating evidence suggest that Hippo-yes-associated protein (YAP) pathway plays important roles in development and repair after injuries in biliary system. We disclosed that senescent biliary epithelial cells (BECs) participate in the pathogenesis of primary biliary cholangitis (PBC). We hypothesized that dysregulation of Hippo-YAP pathway may be associated with biliary epithelial senescence in pathogenesis of PBC. APPROACH & RESULTS Cellular senescence was induced in cultured BECs by treatment with serum depletion or glycochenodeoxycholic acid. The expression and activity of YAP1 were significantly decreased in senescent BECs (p<0.01). Cellular senescence and apoptosis were significantly increased (p<0.01) and a proliferation activity and a 3D-cyst formation activity were significantly decreased (p<0.01) by a knockdown of YAP1 in BECs. The expression of YAP1 were immunohistochemically determined in livers taken from the patients with PBC (n = 79) and 79 control diseased and normal livers and its association with senescent markers p16INK4a and p21WAF1/Cip1 was analyzed. The nuclear expression of YAP1, which indicates activation of YAP1, was significantly decreased in BECs in small bile ducts involved in cholangitis and ductular reactions in PBC, compared to control livers (p<0.01). The decreased expression of YAP1 was seen in senescent BECs showing expression of p16INK4a and p21WAF1/Cip1 in bile duct lesions. CONCLUSION Dysregulation of Hippo-YAP1 pathway may be involved in the pathogenesis of PBC in association with biliary epithelial senescence.
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26
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Wuestefeld A, Iakovleva V, Yap SXL, Ong ABL, Huang DQ, Shuen TWH, Toh HC, Dan YY, Zender L, Wuestefeld T. A Pro-Regenerative Environment Triggers Premalignant to Malignant Transformation of Senescent Hepatocytes. Cancer Res 2023; 83:428-440. [PMID: 36449018 PMCID: PMC9896023 DOI: 10.1158/0008-5472.can-22-1477] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/16/2022] [Accepted: 11/23/2022] [Indexed: 02/04/2023]
Abstract
Unfortunately, available liver cancer treatments are associated with modest survival advantage. The biggest factor improving survival is early detection, but the current understanding of early transformation events is limited. Therefore, we set up a model to study these early events and investigated the relationship of premalignant, senescent hepatocytes, a regenerative environment, and the influence of secreted factors on liver tumorigenesis. Oncogene-induced senescence (OIS) was triggered in a subset of mouse hepatocytes, which under normal conditions, are eliminated by immunosurveillance. Inducing liver damage and regeneration was sufficient to trigger immunosurveillance escape of OIS hepatocytes, resulting in premalignant to malignant transformation and hepatocellular tumor development. Trefoil factor 3 (TFF3) was found to be overexpressed in OIS hepatocytes and in hepatocellular carcinoma. TFF3 deficiency strongly attenuated malignant transformation by increasing insulin-like growth factor binding protein 5 (IGFBP5) expression, which consequently dampened IGF receptor signaling. Furthermore, analysis of precancerous liver tissue validated TFF3 as an early liver cancer biomarker. Altogether, these findings provide mechanistic insights into early transformation and immunosurveillance escape in liver cancer, revealing TFF3 and IGFBP5 to be important players with opposite roles in tumorigenesis. SIGNIFICANCE Liver damage induces a compensatory regenerative response that can drive premalignant to malignant transformation of senescent hepatocytes.
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Affiliation(s)
- Anna Wuestefeld
- Laboratory of In Vivo Genetics & Gene Therapy, Genome Institute of Singapore, Singapore
| | - Viktoriia Iakovleva
- Laboratory of In Vivo Genetics & Gene Therapy, Genome Institute of Singapore, Singapore
| | - Shirlyn Xue Ling Yap
- Laboratory of In Vivo Genetics & Gene Therapy, Genome Institute of Singapore, Singapore
| | - Agnes Bee Leng Ong
- Laboratory of In Vivo Genetics & Gene Therapy, Genome Institute of Singapore, Singapore
| | - Daniel Q. Huang
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Hospital, Singapore
| | | | - Han Chong Toh
- Department of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - Yock Young Dan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Hospital, Singapore
| | - Lars Zender
- Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tuebingen, Tübingen, Germany.,Cluster of Excellence 'Image Guided and Functionally Instructed Tumor Therapies' (iFIT), Eberhard Karls University of Tübingen, Tübingen, Germany.,German Consortium for Translational Cancer Research (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Torsten Wuestefeld
- Laboratory of In Vivo Genetics & Gene Therapy, Genome Institute of Singapore, Singapore.,National Cancer Centre Singapore, Singapore.,Nanyang Technological University, School of Biological Sciences, Singapore.,Corresponding Author: Torsten Wuestefeld, Laboratory of In Vivo Genetics & Gene Therapy, Genome Institute of Singapore, Singapore. Phone: 656-808-8218; E-mail:
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He Y, Su Y, Duan C, Wang S, He W, Zhang Y, An X, He M. Emerging role of aging in the progression of NAFLD to HCC. Ageing Res Rev 2023; 84:101833. [PMID: 36565959 DOI: 10.1016/j.arr.2022.101833] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 12/10/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022]
Abstract
With the aging of global population, the incidence of nonalcoholic fatty liver disease (NAFLD) has surged in recent decades. NAFLD is a multifactorial disease that follows a progressive course, ranging from simple fatty liver, nonalcoholic steatohepatitis (NASH) to liver cirrhosis and hepatocellular carcinoma (HCC). It is well established that aging induces pathological changes in liver and potentiates the occurrence and progression of NAFLD, HCC and other age-related liver diseases. Studies of senescent cells also indicate a pivotal engagement in the development of NAFLD via diverse mechanisms. Moreover, nicotinamide adenine dinucleotide (NAD+), silence information regulator protein family (sirtuins), and mechanistic target of rapamycin (mTOR) are three vital and broadly studied targets involved in aging process and NAFLD. Nevertheless, the crucial role of these aging-associated factors in aging-related NAFLD remains underestimated. Here, we reviewed the current research on the roles of aging, cellular senescence and three aging-related factors in the evolution of NAFLD to HCC, aiming at inspiring promising therapeutic targets for aging-related NAFLD and its progression.
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Affiliation(s)
- Yongyuan He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yinghong Su
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengcheng Duan
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Siyuan Wang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China; School of Basic Medicine, Kunming Medical University, China
| | - Yingting Zhang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaofei An
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Ming He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
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28
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Jiang S, Yu D, He H, Sun H, Sun Y, Zhou L, Wu Z, Gu Q. Short- and Long-Term Outcomes in Laparoscopic Versus Open Hepatectomy for Hepatocellular Carcinoma in Elderly Patients: A Systematic Review and Meta-Analysis. J Laparoendosc Adv Surg Tech A 2023; 33:321-334. [PMID: 36716177 DOI: 10.1089/lap.2022.0524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Background: Laparoscopic hepatectomy (LH) is considered a safe and feasible treatment for patients with hepatocellular carcinoma (HCC) in recent studies. However, in elderly patients, application of LH still remains controversial, and the outcomes of LH versus open hepatectomy (OH) have not been fully evaluated. Our objective is to compare the short- and long-term outcomes of LH with OH in elderly patients with HCC. Materials and Methods: All studies comparing LH and OH in elderly patients with HCC were systematically searched in the databases of PubMed, EmBase, and Web of Science. Statistical analysis was conducted using Review Manager 5.3 (Cochrane Collaboration, 2014). The last search was performed on March 20, 2022. Short-term outcomes include blood loss, operation time, blood transfusion, overall and major postoperative complications, mortality, hospital stay, tumor size, and surgical margin. Long-term outcomes include 1-, 3-, and 5-year overall survival (OS); 1-, 3-, and 5-year disease-free survival (DFS); and 1-, 3-, and 5-year recurrence-free survival (RFS). Results: Fourteen studies involving 1596 patients were included in this meta-analysis. The short-term outcomes of LH were a shorter postoperative hospital stay and fewer overall and major postoperative complications (all P < .00001). However, there were no significant differences in operation time, blood loss, blood transfusion rate, surgical margin, tumor size, and mortality. For the long-term outcomes, LH is comparable with OH in terms of 1-, 3-, and 5-year OS; 1-, 3-, and 5-year DFS; and 1-, 3-, and 5-year RFS. Conclusions: Compared with OH, LH is a safe and feasible treatment for elderly patients with HCC.
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Affiliation(s)
- Song Jiang
- Department of Hepatobiliary Surgery, Jinshan Branch of Shanghai Sixth People's Hospital, Shanghai, China
| | - Dong Yu
- Department of Hepatobiliary Surgery, Jinshan Branch of Shanghai Sixth People's Hospital, Shanghai, China
| | - Hongwei He
- Department of Hepatobiliary Surgery, Jinshan Branch of Shanghai Sixth People's Hospital, Shanghai, China
| | - Haijian Sun
- Department of Hepatobiliary Surgery, Jinshan Branch of Shanghai Sixth People's Hospital, Shanghai, China
| | - Yan Sun
- Department of Hepatobiliary Surgery, Jinshan Branch of Shanghai Sixth People's Hospital, Shanghai, China
| | - Longxiang Zhou
- Department of Hepatobiliary Surgery, Jinshan Branch of Shanghai Sixth People's Hospital, Shanghai, China
| | - Zhongxin Wu
- Department of Hepatobiliary Surgery, Jinshan Branch of Shanghai Sixth People's Hospital, Shanghai, China
| | - Qiyun Gu
- Department of Hepatobiliary Surgery, Jinshan Branch of Shanghai Sixth People's Hospital, Shanghai, China
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29
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Hepatoprotective Efficacy of Cycloastragenol Alleviated the Progression of Liver Fibrosis in Carbon-Tetrachloride-Treated Mice. Biomedicines 2023; 11:biomedicines11010231. [PMID: 36672739 PMCID: PMC9855659 DOI: 10.3390/biomedicines11010231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/12/2023] [Accepted: 01/13/2023] [Indexed: 01/19/2023] Open
Abstract
The continuous death of hepatocytes induced by various etiologies leads to an aberrant tissue healing process and promotes the progression of liver fibrosis and ultimately chronic liver diseases. To date, effective treatments to delay this harmful process remain an unmet clinical need. Cycloastragenol is an active phytochemical substance isolated from Astragalus membranaceus, a plant used in traditional Chinese medicine to protect the liver. Therefore, our study aimed to elucidate the efficacy of cycloastragenol on carbon-tetrachloride (CCl4)-induced liver fibrosis in mice. We found that cycloastragenol at 200 mg/kg dosage exhibited anti-fibrotic efficacy as demonstrated by a decrease in collagen deposition, downregulation of mRNA expression of collagen type 1, and a reduction in the content of total collagens. In addition, cycloastragenol further augmented the levels of anti-fibrotic matrix metalloproteinases (Mmps), that is, Mmp8, proMmp9, and Mmp12, which play a pivotal role in fibrosis resolution. According to histological analysis and serum markers of hepatotoxicity, cycloastragenol protected the livers from damage and mitigated the increment of serum alanine aminotransferase and bilirubin implicating hepatoprotective efficacy against CCl4. Moreover, cycloastragenol upregulated the mRNA expression of interleukin 6, a pleiotropic cytokine plays a vital role in the promotion of hepatocyte regeneration. In conclusion, cycloastragenol alleviated the progression of liver fibrosis in CCl4-treated mice and its anti-fibrotic efficacy was mainly due to the hepatoprotective efficacy.
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30
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Graça AL, Gomez-Florit M, Gomes ME, Docheva D. Tendon Aging. Subcell Biochem 2023; 103:121-147. [PMID: 37120467 DOI: 10.1007/978-3-031-26576-1_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2023]
Abstract
Tendons are mechanosensitive connective tissues responsible for the connection between muscles and bones by transmitting forces that allow the movement of the body, yet, with advancing age, tendons become more prone to degeneration followed by injuries. Tendon diseases are one of the main causes of incapacity worldwide, leading to changes in tendon composition, structure, and biomechanical properties, as well as a decline in regenerative potential. There is still a great lack of knowledge regarding tendon cellular and molecular biology, interplay between biochemistry and biomechanics, and the complex pathomechanisms involved in tendon diseases. Consequently, this reflects a huge need for basic and clinical research to better elucidate the nature of healthy tendon tissue and also tendon aging process and associated diseases. This chapter concisely describes the effects that the aging process has on tendons at the tissue, cellular, and molecular levels and briefly reviews potential biological predictors of tendon aging. Recent research findings that are herein reviewed and discussed might contribute to the development of precision tendon therapies targeting the elderly population.
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Affiliation(s)
- Ana Luísa Graça
- 3B's Research Group, I3Bs-Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Manuel Gomez-Florit
- Health Research Institute of the Balearic Islands (IdISBa), Palma de Mallorca, Spain
| | - Manuela Estima Gomes
- 3B's Research Group, I3Bs-Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Denitsa Docheva
- Department of Musculoskeletal Tissue Regeneration, Orthopaedic Hospital König-Ludwig-Haus, University of Würzburg, Würzburg, Germany.
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31
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Ferreira-Gonzalez S, Man TY, Esser H, Aird R, Kilpatrick AM, Rodrigo-Torres D, Younger N, Campana L, Gadd VL, Dwyer B, Aleksieva N, Boulter L, Macmillan MT, Wang Y, Mylonas KJ, Ferenbach DA, Kendall TJ, Lu WY, Acosta JC, Kurian D, O'Neill S, Oniscu GC, Banales JM, Krimpenfort PJ, Forbes SJ. Senolytic treatment preserves biliary regenerative capacity lost through cellular senescence during cold storage. Sci Transl Med 2022; 14:eabj4375. [PMID: 36475903 DOI: 10.1126/scitranslmed.abj4375] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Liver transplantation is the only curative option for patients with end-stage liver disease. Despite improvements in surgical techniques, nonanastomotic strictures (characterized by the progressive loss of biliary tract architecture) continue to occur after liver transplantation, negatively affecting liver function and frequently leading to graft loss and retransplantation. To study the biological effects of organ preservation before liver transplantation, we generated murine models that recapitulate liver procurement and static cold storage. In these models, we explored the response of cholangiocytes and hepatocytes to cold storage, focusing on responses that affect liver regeneration, including DNA damage, apoptosis, and cellular senescence. We show that biliary senescence was induced during organ retrieval and exacerbated during static cold storage, resulting in impaired biliary regeneration. We identified decoy receptor 2 (DCR2)-dependent responses in cholangiocytes and hepatocytes, which differentially affected the outcome of those populations during cold storage. Moreover, CRISPR-mediated DCR2 knockdown in vitro increased cholangiocyte proliferation and decreased cellular senescence but had the opposite effect in hepatocytes. Using the p21KO model to inhibit senescence onset, we showed that biliary tract architecture was better preserved during cold storage. Similar results were achieved by administering senolytic ABT737 to mice before procurement. Last, we perfused senolytics into discarded human donor livers and showed that biliary architecture and regenerative capacities were better preserved. Our results indicate that cholangiocytes are susceptible to senescence and identify the use of senolytics and the combination of senotherapies and machine-perfusion preservation to prevent this phenotype and reduce the incidence of biliary injury after transplantation.
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Affiliation(s)
- Sofia Ferreira-Gonzalez
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Tak Yung Man
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Hannah Esser
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
- Department of Visceral, Transplant and Thoracic Surgery, Centre of Operative Medicine, Innsbruck Medical University, Anichstrasse 35, Innsbruck 6020, Austria
| | - Rhona Aird
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Alastair M Kilpatrick
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Daniel Rodrigo-Torres
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Nicholas Younger
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Lara Campana
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Victoria L Gadd
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Benjamin Dwyer
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Niya Aleksieva
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Mark T Macmillan
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Yinmiao Wang
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Katie J Mylonas
- Centre for Inflammation Research (CIR), University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - David A Ferenbach
- Centre for Inflammation Research (CIR), University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Timothy J Kendall
- Centre for Inflammation Research (CIR), University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Wei-Yu Lu
- Centre for Inflammation Research (CIR), University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Juan Carlos Acosta
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Cancer, University of Edinburgh, Crewe Road, Edinburgh EH4 2XR, UK
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria-SODERCAN, C/ Albert Einstein 22, Santander, 39011, Spain
| | - Dominic Kurian
- Proteomic and Metabolomics Unit, Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UK
| | - Stephen O'Neill
- Department of Transplant Surgery, Belfast City Hospital, 51 Lisburn Road, Belfast BT9 7AB, UK
- Centre for Public Health, Queen's University Belfast, Institute of Clinical Science, Block A, Royal Victoria Hospital, Belfast BT12 6BA, UK
| | - Gabriel C Oniscu
- Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK
- Department of Clinical Surgery, University of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastian 20014, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31009 Pamplona, Spain
| | | | - Stuart J Forbes
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
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Dutta RK, Lee JN, Maharjan Y, Park C, Choe SK, Ho YS, Kwon HM, Park R. Catalase-deficient mice induce aging faster through lysosomal dysfunction. Cell Commun Signal 2022; 20:192. [PMID: 36474295 PMCID: PMC9724376 DOI: 10.1186/s12964-022-00969-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 09/03/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Lysosomes are a central hub for cellular metabolism and are involved in the regulation of cell homeostasis through the degradation or recycling of unwanted or dysfunctional organelles through the autophagy pathway. Catalase, a peroxisomal enzyme, plays an important role in cellular antioxidant defense by decomposing hydrogen peroxide into water and oxygen. In accordance with pleiotropic significance, both impaired lysosomes and catalase have been linked to many age-related pathologies with a decline in lifespan. Aging is characterized by progressive accumulation of macromolecular damage and the production of high levels of reactive oxygen species. Although lysosomes degrade the most long-lived proteins and organelles via the autophagic pathway, the role of lysosomes and their effect on catalase during aging is not known. The present study investigated the role of catalase and lysosomal function in catalase-knockout (KO) mice. METHODS We performed experiments on WT and catalase KO younger (9 weeks) and mature adult (53 weeks) male mice and Mouse embryonic fibroblasts isolated from WT and KO mice from E13.5 embryos as in vivo and in ex-vivo respectively. Mouse phenotyping studies were performed with controls, and a minimum of two independent experiments were performed with more than five mice in each group. RESULTS We found that at the age of 53 weeks (mature adult), catalase-KO mice exhibited an aging phenotype faster than wild-type (WT) mice. We also found that mature adult catalase-KO mice induced leaky lysosome by progressive accumulation of lysosomal content, such as cathespin D, into the cytosol. Leaky lysosomes inhibited autophagosome formation and triggered impaired autophagy. The dysregulation of autophagy triggered mTORC1 (mechanistic target of rapamycin complex 1) activation. However, the antioxidant N-acetyl-L-cysteine and mTORC1 inhibitor rapamycin rescued leaky lysosomes and aging phenotypes in catalase-deficient mature adult mice. CONCLUSIONS This study unveils the new role of catalase and its role in lysosomal function during aging. Video abstract.
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Affiliation(s)
- Raghbendra Kumar Dutta
- grid.61221.360000 0001 1033 9831Department of Biomedical Science and Engineering, Institute of AI-Medical Science, GRI, Gwangju Institute of Science and Technology, Gwangju, 61005 Republic of Korea
| | - Joon No Lee
- grid.61221.360000 0001 1033 9831Department of Biomedical Science and Engineering, Institute of AI-Medical Science, GRI, Gwangju Institute of Science and Technology, Gwangju, 61005 Republic of Korea
| | - Yunash Maharjan
- grid.61221.360000 0001 1033 9831Department of Biomedical Science and Engineering, Institute of AI-Medical Science, GRI, Gwangju Institute of Science and Technology, Gwangju, 61005 Republic of Korea
| | - Channy Park
- grid.61221.360000 0001 1033 9831Department of Biomedical Science and Engineering, Institute of AI-Medical Science, GRI, Gwangju Institute of Science and Technology, Gwangju, 61005 Republic of Korea
| | - Seong-Kyu Choe
- grid.410899.d0000 0004 0533 4755Department of Microbiology and Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan, Jeonbuk 54538 Republic of Korea
| | - Ye-Shih Ho
- grid.254444.70000 0001 1456 7807Institute of Environmental Health Sciences and Department of Biochemistry and Molecular Biology, Wayne State University, Detroit, MI USA
| | - Hyug Moo Kwon
- grid.42687.3f0000 0004 0381 814XSchool of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Raekil Park
- grid.61221.360000 0001 1033 9831Department of Biomedical Science and Engineering, Institute of AI-Medical Science, GRI, Gwangju Institute of Science and Technology, Gwangju, 61005 Republic of Korea
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Radonjić T, Dukić M, Jovanović I, Zdravković M, Mandić O, Popadić V, Popović M, Nikolić N, Klašnja S, Divac A, Todorović Z, Branković M. Aging of Liver in Its Different Diseases. Int J Mol Sci 2022; 23:13085. [PMID: 36361873 PMCID: PMC9656219 DOI: 10.3390/ijms232113085] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/24/2022] [Accepted: 10/01/2022] [Indexed: 09/05/2023] Open
Abstract
The proportion of elderly people in the world population is constantly increasing. With age, the risk of numerous chronic diseases and their complications also rises. Research on the subject of cellular senescence date back to the middle of the last century, and today we know that senescent cells have different morphology, metabolism, phenotypes and many other characteristics. Their main feature is the development of senescence-associated secretory phenotype (SASP), whose pro-inflammatory components affect tissues and organs, and increases the possibility of age-related diseases. The liver is the main metabolic organ of our body, and the results of previous research indicate that its regenerative capacity is greater and that it ages more slowly compared to other organs. With age, liver cells change under the influence of various stressors and the risk of developing chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH) and hepatocellular carcinoma (HCC) increases. It has been proven that these diseases progress faster in the elderly population and in some cases lead to end-stage liver disease that requires transplantation. The treatment of elderly people with chronic liver diseases is a challenge and requires an individual approach as well as new research that will reveal other safe and effective therapeutic modalities.
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Affiliation(s)
- Tijana Radonjić
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Marija Dukić
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Igor Jovanović
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Marija Zdravković
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Olga Mandić
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Višeslav Popadić
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Maja Popović
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Novica Nikolić
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Slobodan Klašnja
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Anica Divac
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Zoran Todorović
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Marija Branković
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
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Widmer J, Eden J, Carvalho MF, Dutkowski P, Schlegel A. Machine Perfusion for Extended Criteria Donor Livers: What Challenges Remain? J Clin Med 2022; 11:5218. [PMID: 36079148 PMCID: PMC9457017 DOI: 10.3390/jcm11175218] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 08/30/2022] [Indexed: 11/28/2022] Open
Abstract
Based on the renaissance of dynamic preservation techniques, extended criteria donor (ECD) livers reclaimed a valuable eligibility in the transplantable organ pool. Being more vulnerable to ischemia, ECD livers carry an increased risk of early allograft dysfunction, primary non-function and biliary complications and, hence, unveiled the limitations of static cold storage (SCS). There is growing evidence that dynamic preservation techniques-dissimilar to SCS-mitigate reperfusion injury by reconditioning organs prior transplantation and therefore represent a useful platform to assess viability. Yet, a debate is ongoing about the advantages and disadvantages of different perfusion strategies and their best possible applications for specific categories of marginal livers, including organs from donors after circulatory death (DCD) and brain death (DBD) with extended criteria, split livers and steatotic grafts. This review critically discusses the current clinical spectrum of livers from ECD donors together with the various challenges and posttransplant outcomes in the context of standard cold storage preservation. Based on this, the potential role of machine perfusion techniques is highlighted next. Finally, future perspectives focusing on how to achieve higher utilization rates of the available donor pool are highlighted.
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Affiliation(s)
- Jeannette Widmer
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zürich, Switzerland
| | - Janina Eden
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zürich, Switzerland
| | - Mauricio Flores Carvalho
- Hepatobiliary Unit, Department of Clinical and Experimental Medicine, University of Florence, AOU Careggi, 50139 Florence, Italy
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zürich, Switzerland
| | - Andrea Schlegel
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zürich, Switzerland
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Centre of Preclinical Research, 20122 Milan, Italy
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35
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Chen Z, Chen P, Zheng M, Gao J, Liu D, Wang A, Zheng Q, Leys T, Tai A, Zheng M. Challenges and perspectives of tendon-derived cell therapy for tendinopathy: from bench to bedside. Stem Cell Res Ther 2022; 13:444. [PMID: 36056395 PMCID: PMC9438319 DOI: 10.1186/s13287-022-03113-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/03/2022] [Indexed: 11/18/2022] Open
Abstract
Tendon is composed of dense fibrous connective tissues, connecting muscle at the myotendinous junction (MTJ) to bone at the enthesis and allowing mechanical force to transmit from muscle to bone. Tendon diseases occur at different zones of the tendon, including enthesis, MTJ and midsubstance of the tendon, due to a variety of environmental and genetic factors which consequently result in different frequencies and recovery rates. Self-healing properties of tendons are limited, and cell therapeutic approaches in which injured tendon tissues are renewed by cell replenishment are highly sought after. Homologous use of individual’s tendon-derived cells, predominantly differentiated tenocytes and tendon-derived stem cells, is emerging as a treatment for tendinopathy through achieving minimal cell manipulation for clinical use. This is the first review summarizing the progress of tendon-derived cell therapy in clinical use and its challenges due to the structural complexity of tendons, heterogeneous composition of extracellular cell matrix and cells and unsuitable cell sources. Further to that, novel future perspectives to improve therapeutic effect in tendon-derived cell therapy based on current basic knowledge are discussed.
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Affiliation(s)
- Ziming Chen
- Division of Surgery, Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia
| | - Peilin Chen
- Division of Surgery, Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia
| | - Monica Zheng
- Department of Orthopaedic Surgery, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia
| | - Junjie Gao
- Perron Institute for Neurological and Translational Science, Nedlands, WA, 6009, Australia.,Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Shanghai Sixth People's Hospital, Shanghai, 200233, China
| | - Delin Liu
- Division of Surgery, Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia.,Perron Institute for Neurological and Translational Science, Nedlands, WA, 6009, Australia
| | - Allan Wang
- Division of Surgery, Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia
| | - Qiujian Zheng
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510000, Guangdong, China.,Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510000, Guangdong, China
| | - Toby Leys
- Department of Orthopaedic Surgery, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia
| | - Andrew Tai
- Perron Institute for Neurological and Translational Science, Nedlands, WA, 6009, Australia.
| | - Minghao Zheng
- Division of Surgery, Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia. .,Perron Institute for Neurological and Translational Science, Nedlands, WA, 6009, Australia.
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36
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Zhang S, Paul S, Kundu P. NF-κB Regulation by Gut Microbiota Decides Homeostasis or Disease Outcome During Ageing. Front Cell Dev Biol 2022; 10:874940. [PMID: 35846362 PMCID: PMC9285657 DOI: 10.3389/fcell.2022.874940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 06/13/2022] [Indexed: 11/15/2022] Open
Abstract
Human beings and their indigenous microbial communities have coexisted for centuries, which led to the development of co-evolutionary mechanisms of communication and cooperation. Such communication machineries are governed by sophisticated multi-step feedback loops, which typically begin with the recognition of microbes by pattern recognition receptors (PRRs), followed by a host transcriptional response leading to the release of effector molecules. Our gastrointestinal tract being the main platform for this interaction, a variety of host intestinal cells tightly regulate these loops to establish tolerance towards the microbial communities of the gut and maintain homeostasis. The transcription factor, nuclear factor kappa B (NF-κB) is an integral component of such a communication apparatus, which plays a critical role in determining the state of homeostasis or inflammation associated with dysbiosis in the host. Here we outline the crucial role of NF-κB in host response to microbial cues in the context of ageing and associated diseases.
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Affiliation(s)
- Shuning Zhang
- Laboratory for Microbiota-Host Interactions, The Center for Microbes, Development and Health, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Soumyajeet Paul
- Laboratory for Microbiota-Host Interactions, The Center for Microbes, Development and Health, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Parag Kundu
- Laboratory for Microbiota-Host Interactions, The Center for Microbes, Development and Health, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
- *Correspondence: Parag Kundu,
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37
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Marti-Aguado D, Clemente-Sanchez A, Bataller R. Cigarette smoking and liver diseases. J Hepatol 2022; 77:191-205. [PMID: 35131406 DOI: 10.1016/j.jhep.2022.01.016] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 01/14/2022] [Accepted: 01/25/2022] [Indexed: 01/27/2023]
Abstract
Cigarette smoking is a preventable risk factor for premature morbidity and mortality. A history of smoking is observed in approximately 40% of patients with liver disease, while a growing number of studies are investigating the potential impact of smoking in chronic liver diseases. This review discusses the effects of smoking on liver diseases, at multiple levels, with a focus on its potential causal role. Clinical evidence indicates that cigarette smoking negatively impacts the incidence and severity of fatty liver disease, fibrosis progression, hepatocellular carcinoma development, and the outcomes of patients with advanced liver disease. The underlying mechanisms are complex and involve different pathophysiological pathways including oxidative stress and oncogenic signals. Importantly, smoking promotes cardiovascular disease and extrahepatic cancers in patients with steatohepatitis and in transplant recipients. We discuss how promoting smoking cessation could improve the rates of treatment response (in clinical trials) and fibrosis regression, while reducing the risk of hepatocellular carcinoma and improving liver transplant outcomes. Finally, we discuss current challenges such as the referral of smokers to specialised units for smoking cessation.
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Affiliation(s)
- David Marti-Aguado
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, Spain; Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Ana Clemente-Sanchez
- Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Liver Unit and Digestive Department, Hospital General Universitario Gregorio Marañon, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Ramon Bataller
- Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
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Zanotti S, Boot GF, Coto-Llerena M, Gallon J, Hess GF, Soysal SD, Kollmar O, Ng CKY, Piscuoglio S. The Role of Chronic Liver Diseases in the Emergence and Recurrence of Hepatocellular Carcinoma: An Omics Perspective. Front Med (Lausanne) 2022; 9:888850. [PMID: 35814741 PMCID: PMC9263082 DOI: 10.3389/fmed.2022.888850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 05/23/2022] [Indexed: 12/02/2022] Open
Abstract
Hepatocellular carcinoma (HCC) typically develops from a background of cirrhosis resulting from chronic inflammation. This inflammation is frequently associated with chronic liver diseases (CLD). The advent of next generation sequencing has enabled extensive analyses of molecular aberrations in HCC. However, less attention has been directed to the chronically inflamed background of the liver, prior to HCC emergence and during recurrence following surgery. Hepatocytes within chronically inflamed liver tissues present highly activated inflammatory signaling pathways and accumulation of a complex mutational landscape. In this altered environment, cells may transform in a stepwise manner toward tumorigenesis. Similarly, the chronically inflamed environment which persists after resection may impact the timing of HCC recurrence. Advances in research are allowing an extensive epigenomic, transcriptomic and proteomic characterization of CLD which define the emergence of HCC or its recurrence. The amount of data generated will enable the understanding of oncogenic mechanisms in HCC from the CLD perspective and provide the possibility to identify robust biomarkers or novel therapeutic targets for the treatment of primary and recurrent HCC. Importantly, biomarkers defined by the analysis of CLD tissue may permit the early detection or prevention of HCC emergence and recurrence. In this review, we compile the current omics based evidence of the contribution of CLD tissues to the emergence and recurrence of HCC.
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Affiliation(s)
- Sofia Zanotti
- Anatomic Pathology Unit, IRCCS Humanitas University Research Hospital, Milan, Italy
| | - Gina F. Boot
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Mairene Coto-Llerena
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - John Gallon
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Gabriel F. Hess
- Clarunis, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Savas D. Soysal
- Clarunis, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Otto Kollmar
- Clarunis, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Charlotte K. Y. Ng
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- Bern Center for Precision Medicine, Bern, Switzerland
| | - Salvatore Piscuoglio
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
- *Correspondence: Salvatore Piscuoglio
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Nutrition Interventions of Herbal Compounds on Cellular Senescence. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:1059257. [PMID: 35528514 PMCID: PMC9068308 DOI: 10.1155/2022/1059257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 11/01/2021] [Accepted: 04/02/2022] [Indexed: 01/10/2023]
Abstract
When cells undergo large-scale senescence, organ aging ensues, resulting in irreversible organ pathology and organismal aging. The study of senescence in cells provides an important avenue to understand the factors that influence aging and can be used as one of the useful tools for examining age-related human diseases. At present, many herbal compounds have shown effects on delaying cell senescence. This review summarizes the main characteristics and mechanisms of cell senescence, age-related diseases, and the recent progress on the natural products targeting cellular senescence, with the aim of providing insights to aid the clinical management of age-related diseases.
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Complex Positive Effects of SGLT-2 Inhibitor Empagliflozin in the Liver, Kidney and Adipose Tissue of Hereditary Hypertriglyceridemic Rats: Possible Contribution of Attenuation of Cell Senescence and Oxidative Stress. Int J Mol Sci 2021; 22:ijms221910606. [PMID: 34638943 PMCID: PMC8508693 DOI: 10.3390/ijms221910606] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/26/2021] [Accepted: 09/28/2021] [Indexed: 12/18/2022] Open
Abstract
(1) Background: empagliflozin, sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is an effective antidiabetic agent with strong cardio- and nephroprotective properties. The mechanisms behind its cardio- and nephroprotection are still not fully clarified. (2) Methods: we used male hereditary hypertriglyceridemic (hHTG) rats, a non-obese model of dyslipidaemia, insulin resistance, and endothelial dysfunction fed standard diet with or without empagliflozin for six weeks to explore the molecular mechanisms of empagliflozin effects. Nuclear magnetic resonance (NMR)-based metabolomics; quantitative PCR of relevant genes involved in lipid and glucose metabolism, or senescence; glucose and palmitic acid oxidation in isolated tissues and cell lines of adipocytes and hepatocytes were used. (3) Results: empagliflozin inhibited weight gain and decreased adipose tissue weight, fasting blood glucose, and triglycerides and increased HDL-cholesterol. It also improved insulin sensitivity in white fat. NMR spectroscopy identified higher plasma concentrations of ketone bodies, ketogenic amino acid leucine and decreased levels of pyruvate and alanine. In the liver, adipose tissue and kidney, empagliflozin up-regulated expression of genes involved in gluconeogenesis and down-regulated expression of genes involved in lipogenesis along with reduction of markers of inflammation, oxidative stress and cell senescence. (4) Conclusion: multiple positive effects of empagliflozin, including reduced cell senescence and oxidative stress, could contribute to its long-term cardio- and nephroprotective actions.
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Biomarkers of cellular aging during a controlled human malaria infection. Sci Rep 2021; 11:18733. [PMID: 34548530 PMCID: PMC8455531 DOI: 10.1038/s41598-021-97985-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 08/23/2021] [Indexed: 11/08/2022] Open
Abstract
Cellular aging is difficult to study in individuals with natural infection, given the diversity of symptom duration and clinical presentation, and the high interference of aging-related processes with host and environmental factors. To address this challenge, we took advantage of the controlled human malaria infection (CHMI) model. This approach allowed us to characterize the relationship among cellular aging markers prior, during and post malaria pathophysiology in humans, controlling for infection dose, individual heterogeneity, previous exposure and co-infections. We demonstrate that already low levels of Plasmodium falciparum impact cellular aging by inducing high levels of inflammation and redox-imbalance; and that cellular senescence reversed after treatment and parasite clearance. This study provides insights into the complex relationship of telomere length, cellular senescence, telomerase expression and aging-related processes during a single malaria infection.
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Govindasamy V, Rajendran A, Lee ZX, Ooi GC, Then KY, Then KL, Gayathri M, Kumar Das A, Cheong SK. The potential role of mesenchymal stem cells in modulating antiageing process. Cell Biol Int 2021; 45:1999-2016. [PMID: 34245637 DOI: 10.1002/cbin.11652] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 05/24/2021] [Accepted: 06/17/2021] [Indexed: 12/19/2022]
Abstract
Ageing and age-related diseases share some basic origin that largely converges on inflammation. Precisely, it boils down to a common pathway characterised by the appearance of a fair amount of proinflammatory cytokines known as inflammageing. Among the proposed treatment for antiageing, MSCs gained attention in recent years. Since mesenchymal stem cells (MSCs) can differentiate itself into a myriad of terminal cells, previously it was believed that these cells migrate to the site of injury and perform their therapeutic effect. However, with the more recent discovery of huge amounts of paracrine factors secreted by MSCs, it is now widely accepted that these cells do not engraft upon transplantation but rather unveil their benefits through excretion of bioactive molecules namely those involved in inflammatory and immunomodulatory activities. Conversely, the true function of these paracrine changes has not been thoroughly investigated all these years. Hence, this review will describe in detail on ways MSCs may capitalize its paracrine properties in modulating antiageing process. Through a comprehensive literature search various elements in the antiageing process, we aim to provide a novel treatment perspective of MSCs in antiageing related clinical conditions.
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Affiliation(s)
- Vijayendran Govindasamy
- Research and Development Department, CryoCord Sdn Bhd, Bio-X Centre, Cyberjaya, Selangor, Malaysia
| | - Abilashini Rajendran
- Research and Development Department, CryoCord Sdn Bhd, Bio-X Centre, Cyberjaya, Selangor, Malaysia
| | - Zhi-Xin Lee
- Research and Development Department, CryoCord Sdn Bhd, Bio-X Centre, Cyberjaya, Selangor, Malaysia
| | - Ghee-Chien Ooi
- Research and Development Department, CryoCord Sdn Bhd, Bio-X Centre, Cyberjaya, Selangor, Malaysia
| | - Kong-Yong Then
- Research and Development Department, CryoCord Sdn Bhd, Bio-X Centre, Cyberjaya, Selangor, Malaysia.,Brighton Healthcare (Bio-X Healthcare Sdn Bhd), Bio-X Centre, Cyberjaya, Selangor, Malaysia
| | - Khong-Lek Then
- Research and Development Department, CryoCord Sdn Bhd, Bio-X Centre, Cyberjaya, Selangor, Malaysia
| | - Merilynn Gayathri
- Brighton Healthcare (Bio-X Healthcare Sdn Bhd), Bio-X Centre, Cyberjaya, Selangor, Malaysia
| | - Anjan Kumar Das
- Deparment of Surgery, IQ City Medical College, Durgapur, West Bengal, India
| | - Soon-Keng Cheong
- Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman (UTAR), Kajang, Selangor, Malaysia
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Baiocchi L, Glaser S, Francis H, Kennedy L, Felli E, Alpini G, Gracia‐Sancho J. Impact of Aging on Liver Cells and Liver Disease: Focus on the Biliary and Vascular Compartments. Hepatol Commun 2021; 5:1125-1137. [PMID: 34278165 PMCID: PMC8279468 DOI: 10.1002/hep4.1725] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/26/2021] [Accepted: 03/16/2021] [Indexed: 12/11/2022] Open
Abstract
The aging process is represented by the time-dependent decay in physiologic functions of living beings. Major interest has been focused in recent years on the determinants of this progressive condition due to its correlative relationship with the onset of diseases. Several hallmark features have been observed in aging, such as genetic alterations, mitochondrial impairment, and telomere shortening. At the cellular level, a senescent phenotype has been identified in response to aging that is characterized by a flat appearance, proliferative arrest, and production of specific molecules. The net effect of these cells in the course of diseases is an argument of debate. In fact, while the onset of a senescent phenotype may prevent tumor spreading, these cells appear to support pathological processes in some conditions. Several studies are now focused on clarifying the specific molecular pathways of aging/senescence in different cells, tissues, or organs. Biliary and vascular components, within the liver, have emerged as important determinants of some form of liver disease. In this review we summarize the most recent achievements on aging/senescence, focusing on the biliary and vascular liver system. Conclusion: Several findings, in both preclinical animal models and on human liver specimens, converge in supporting the presence of specific aging hallmarks in the diseases involving these hepatic compartments.
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Affiliation(s)
- Leonardo Baiocchi
- Hepatology UnitDepartment of MedicineUniversity of Tor VergataRomeItaly
| | - Shannon Glaser
- Medical PhysiologyTexas A&M College of MedicineBryanTXUSA
| | - Heather Francis
- Hepatology and MedicineIndiana UniversityIndianapolisINUSA
- Richard L. Roudebush VA Medical CenterIndianapolisINUSA
| | - Lindsey Kennedy
- Hepatology and MedicineIndiana UniversityIndianapolisINUSA
- Richard L. Roudebush VA Medical CenterIndianapolisINUSA
| | - Eric Felli
- HepatologyDepartment of Biomedical ResearchInselspitalBernSwitzerland
| | - Gianfranco Alpini
- Hepatology and MedicineIndiana UniversityIndianapolisINUSA
- Richard L. Roudebush VA Medical CenterIndianapolisINUSA
| | - Jordi Gracia‐Sancho
- Liver Vascular BiologyIDIBAPS Biomedical Research Institute and CIBEREHDBarcelonaSpain
- HepatologyDepartment of Biomedical ResearchInselspitalBernSwitzerland
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Amevor FK, Cui Z, Du X, Ning Z, Shu G, Jin N, Deng X, Tian Y, Zhang Z, Kang X, Xu D, You G, Zhang Y, Li D, Wang Y, Zhu Q, Zhao X. Combination of Quercetin and Vitamin E Supplementation Promotes Yolk Precursor Synthesis and Follicle Development in Aging Breeder Hens via Liver-Blood-Ovary Signal Axis. Animals (Basel) 2021; 11:ani11071915. [PMID: 34203138 PMCID: PMC8300405 DOI: 10.3390/ani11071915] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 06/20/2021] [Accepted: 06/21/2021] [Indexed: 12/28/2022] Open
Abstract
Simple Summary This study evaluated the capacity of dietary quercetin, vitamin E and their combination to promote follicle development and attenuate organ inflammation by improving the antioxidant capacity of the liver–blood–ovary signal axis of aging broiler breeder hens. The results from this study showed that the combination of quercetin and vitamin E synergistically improved the chicken’s reproductive organ characteristics, and also showed protective effects on liver morphology and histology. Moreover, the antioxidant parameters, reproductive hormones and receptors, liver lipid synthesis, and the levels of mRNAs related to yolk precursor synthesis (very low density apolipoprotein-II and vitellogenin-II), lipid transport (microsomal triglyceride transport protein), lipogenesis (fatty acid synthase), and follicle developments were increased remarkably by the combination of quercetin and vitamin E. The results obtained in this study provide an important reference for the combination of quercetin and vitamin E as a functional feed additive for promoting the functions of the liver–blood–ovary axis, and also as a potential chemopreventive and chemotherapeutic agent for improving liver and ovary functions in chickens by acting as a hepatoprotective and oviprotective agent. This could facilitate the transport and exchange of synthetic substances (including hormones, yolk precursors, and other biochemical substances) among the liver–blood–ovary alliances to ensure the synchronous development and functional coordination between the liver and ovary in aging breeder hens. Abstract The fertility of female animals is negatively correlated with increasing chronological age. In aging broiler breeder hens, there is a decline in the functionality of the ovary and liver accompanied by hormonal or endocrine changes, a reduction in antioxidant capacity, and a decrease in folliculogenesis. Therefore, improving the reproductive function in aging breeder hens using dietary strategies is of great concern to the poultry breeder. This study evaluated the capacity of dietary quercetin (Q), vitamin E (VE), and their combination (Q + VE) to promote follicle development and attenuate organ inflammation by improving the antioxidant capacity of aging breeder hens. In this study, 400 broiler breeder hens (Tianfu broilers breeder hens, 435 days old) were allotted into four groups (100 birds each) with four replicates each (25 birds each). They were fed diets containing Q (0.4 g/kg), VE (0.2 g/kg), Q + VE (0.4 g/kg + 0.2 g/kg), and a basal diet for 10 weeks. The results showed that Q + VE improved the organ characteristics (p < 0.05), and also that Q + VE showed protective effects on the liver against injury, as well as increasing the antioxidant capacity of the liver, serum, and ovary (p < 0.05). Furthermore, liver lipid synthesis was increased remarkably, as indicated by the changes in triglyceride levels in hens fed Q + VE (p < 0.05). Levels of E2, FSH, and LH, their receptors, and mRNAs related to yolk precursor synthesis were increased by the Q + VE (p < 0.05). Therefore, the combination of quercetin and vitamin E synergistically promotes and regulates the transportation and exchange of synthetic substances among the liver–blood–ovary alliances to ensure the synchronous development and functional coordination between the liver and ovary in aging breeder hens.
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Affiliation(s)
- Felix Kwame Amevor
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (F.K.A.); (Z.C.); (X.D.); (Z.N.); (N.J.); (X.D.); (Y.T.); (Z.Z.); (X.K.); (G.Y.); (Y.Z.); (D.L.); (Y.W.); (Q.Z.)
| | - Zhifu Cui
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (F.K.A.); (Z.C.); (X.D.); (Z.N.); (N.J.); (X.D.); (Y.T.); (Z.Z.); (X.K.); (G.Y.); (Y.Z.); (D.L.); (Y.W.); (Q.Z.)
| | - Xiaxia Du
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (F.K.A.); (Z.C.); (X.D.); (Z.N.); (N.J.); (X.D.); (Y.T.); (Z.Z.); (X.K.); (G.Y.); (Y.Z.); (D.L.); (Y.W.); (Q.Z.)
| | - Zifan Ning
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (F.K.A.); (Z.C.); (X.D.); (Z.N.); (N.J.); (X.D.); (Y.T.); (Z.Z.); (X.K.); (G.Y.); (Y.Z.); (D.L.); (Y.W.); (Q.Z.)
| | - Gang Shu
- Department of Basic Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (G.S.); (D.X.)
| | - Ningning Jin
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (F.K.A.); (Z.C.); (X.D.); (Z.N.); (N.J.); (X.D.); (Y.T.); (Z.Z.); (X.K.); (G.Y.); (Y.Z.); (D.L.); (Y.W.); (Q.Z.)
| | - Xun Deng
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (F.K.A.); (Z.C.); (X.D.); (Z.N.); (N.J.); (X.D.); (Y.T.); (Z.Z.); (X.K.); (G.Y.); (Y.Z.); (D.L.); (Y.W.); (Q.Z.)
| | - Yaofu Tian
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (F.K.A.); (Z.C.); (X.D.); (Z.N.); (N.J.); (X.D.); (Y.T.); (Z.Z.); (X.K.); (G.Y.); (Y.Z.); (D.L.); (Y.W.); (Q.Z.)
| | - Zhichao Zhang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (F.K.A.); (Z.C.); (X.D.); (Z.N.); (N.J.); (X.D.); (Y.T.); (Z.Z.); (X.K.); (G.Y.); (Y.Z.); (D.L.); (Y.W.); (Q.Z.)
| | - Xincheng Kang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (F.K.A.); (Z.C.); (X.D.); (Z.N.); (N.J.); (X.D.); (Y.T.); (Z.Z.); (X.K.); (G.Y.); (Y.Z.); (D.L.); (Y.W.); (Q.Z.)
| | - Dan Xu
- Department of Basic Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (G.S.); (D.X.)
| | - Guishuang You
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (F.K.A.); (Z.C.); (X.D.); (Z.N.); (N.J.); (X.D.); (Y.T.); (Z.Z.); (X.K.); (G.Y.); (Y.Z.); (D.L.); (Y.W.); (Q.Z.)
| | - Yao Zhang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (F.K.A.); (Z.C.); (X.D.); (Z.N.); (N.J.); (X.D.); (Y.T.); (Z.Z.); (X.K.); (G.Y.); (Y.Z.); (D.L.); (Y.W.); (Q.Z.)
| | - Diyan Li
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (F.K.A.); (Z.C.); (X.D.); (Z.N.); (N.J.); (X.D.); (Y.T.); (Z.Z.); (X.K.); (G.Y.); (Y.Z.); (D.L.); (Y.W.); (Q.Z.)
| | - Yan Wang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (F.K.A.); (Z.C.); (X.D.); (Z.N.); (N.J.); (X.D.); (Y.T.); (Z.Z.); (X.K.); (G.Y.); (Y.Z.); (D.L.); (Y.W.); (Q.Z.)
| | - Qing Zhu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (F.K.A.); (Z.C.); (X.D.); (Z.N.); (N.J.); (X.D.); (Y.T.); (Z.Z.); (X.K.); (G.Y.); (Y.Z.); (D.L.); (Y.W.); (Q.Z.)
| | - Xiaoling Zhao
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (F.K.A.); (Z.C.); (X.D.); (Z.N.); (N.J.); (X.D.); (Y.T.); (Z.Z.); (X.K.); (G.Y.); (Y.Z.); (D.L.); (Y.W.); (Q.Z.)
- Correspondence:
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A Senescence-Like Cellular Response Inhibits Bovine Ephemeral Fever Virus Proliferation. Vaccines (Basel) 2021; 9:vaccines9060601. [PMID: 34200003 PMCID: PMC8227762 DOI: 10.3390/vaccines9060601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/23/2021] [Accepted: 05/31/2021] [Indexed: 01/10/2023] Open
Abstract
During industrial-scale production of viruses for vaccine manufacturing, anti-viral response of host cells can dampen maximal viral antigen yield. In addition to interferon responses, many other cellular responses, such as the AMPK signaling pathway or senescence-like response may inhibit or slow down virus amplification in the cell culture system. In this study, we first performed a Gene Set Enrichment Analysis of the whole-genome mRNA transcriptome and found a senescence-like cellular response in BHK-21 cells when infected with bovine ephemeral fever virus (BEFV). To demonstrate that this senescence-like state may reduce virus growth, BHK-21 subclones showing varying degrees of a senescence-like state were infected with BEFV. The results showed that the BHK-21 subclones showing high senescence staining could inhibit BEFV replication while low senescence-staining subclones are permissive to virus replication. Using a different approach, a senescence-like state was induced in BHK-21 using a small molecule, camptothecin (CPT), and BEFV susceptibility were examined. The results showed that CPT-treated BHK-21 is more resistant to virus infection. Overall, these results indicate that a senescence-like response may be at play in BHK-21 upon virus infection. Furthermore, cell clone selection and modulating treatments using small molecules may be tools in countering anti-viral responses.
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Sasaki M, Sato Y, Nakanuma Y. Interferon-induced protein with tetratricopeptide repeats 3 may be a key factor in primary biliary cholangitis. Sci Rep 2021; 11:11413. [PMID: 34075171 PMCID: PMC8169865 DOI: 10.1038/s41598-021-91016-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 05/20/2021] [Indexed: 12/13/2022] Open
Abstract
Accumulating studies suggest that senescent biliary epithelial cells (BECs) produce senescence-associated secretory phenotypes (SASPs) and play various roles in the pathogenesis of primary biliary cholangitis (PBC) and other cholangiopathies. We examined comprehensive profiles of senescent BECs and its contribution to the pathogenesis of PBC taking advantage of microarray analysis. cDNA microarray analysis revealed that 1841 genes including CCL2, IFIT3, CPQ were commonly up-regulated in senescent BECs cultured in serum depleted media or media with glycochenodeoxycholic acid. Knockdown of IFIT3 significantly suppressed cellular senescence (p < 0.01) and significantly increased apoptosis (p < 0.01) in BECs treated with serum depletion or glycochenodeoxycholic acid. Significantly increased expression of IFIT3 was seen in senescent BECs in small bile ducts showing cholangitis and in ductular reactions in PBC, compared to control livers (p < 0.01). An inadequate response to UDCA was inversely correlated to the increased expression of IFIT3 in small bile duct in PBC (p < 0.05). In conclusion, the expression of various genes related to immunity and inflammation including SASPs were increased in senescent BECs. Upregulated IFIT3 in senescent BECs may be associated with the pathogenesis of PBC and may be a possible therapeutic target in PBC.
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Affiliation(s)
- Motoko Sasaki
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan.
| | - Yasunori Sato
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
| | - Yasuni Nakanuma
- Department of Pathology, Fukui Saiseikai Hospital, Fukui, 918-8503, Japan
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Alswady-Hoff M, Erdem JS, Phuyal S, Knittelfelder O, Sharma A, Fonseca DDM, Skare Ø, Slupphaug G, Zienolddiny S. Long-Term Exposure to Nanosized TiO 2 Triggers Stress Responses and Cell Death Pathways in Pulmonary Epithelial Cells. Int J Mol Sci 2021; 22:ijms22105349. [PMID: 34069552 PMCID: PMC8161419 DOI: 10.3390/ijms22105349] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/14/2021] [Accepted: 05/17/2021] [Indexed: 02/03/2023] Open
Abstract
There is little in vitro data available on long-term effects of TiO2 exposure. Such data are important for improving the understanding of underlying mechanisms of adverse health effects of TiO2. Here, we exposed pulmonary epithelial cells to two doses (0.96 and 1.92 µg/cm2) of TiO2 for 13 weeks and effects on cell cycle and cell death mechanisms, i.e., apoptosis and autophagy were determined after 4, 8 and 13 weeks of exposure. Changes in telomere length, cellular protein levels and lipid classes were also analyzed at 13 weeks of exposure. We observed that the TiO2 exposure increased the fraction of cells in G1-phase and reduced the fraction of cells in G2-phase, which was accompanied by an increase in the fraction of late apoptotic/necrotic cells. This corresponded with an induced expression of key apoptotic proteins i.e., BAD and BAX, and an accumulation of several lipid classes involved in cellular stress and apoptosis. These findings were further supported by quantitative proteome profiling data showing an increase in proteins involved in cell stress and genomic maintenance pathways following TiO2 exposure. Altogether, we suggest that cell stress response and cell death pathways may be important molecular events in long-term health effects of TiO2.
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Affiliation(s)
- Mayes Alswady-Hoff
- National Institute of Occupational Health, NO-0033 Oslo, Norway; (M.A.-H.); (J.S.E.); (S.P.); (Ø.S.)
| | - Johanna Samulin Erdem
- National Institute of Occupational Health, NO-0033 Oslo, Norway; (M.A.-H.); (J.S.E.); (S.P.); (Ø.S.)
| | - Santosh Phuyal
- National Institute of Occupational Health, NO-0033 Oslo, Norway; (M.A.-H.); (J.S.E.); (S.P.); (Ø.S.)
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, NO-0316 Oslo, Norway
| | | | - Animesh Sharma
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway; (A.S.); (D.d.M.F.); (G.S.)
- Proteomics and Metabolomics Core Facility (PROMEC), Norwegian University of Science and Technology and the Central Norway Regional Health Authority, NO-7491 Trondheim, Norway
| | - Davi de Miranda Fonseca
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway; (A.S.); (D.d.M.F.); (G.S.)
- Proteomics and Metabolomics Core Facility (PROMEC), Norwegian University of Science and Technology and the Central Norway Regional Health Authority, NO-7491 Trondheim, Norway
| | - Øivind Skare
- National Institute of Occupational Health, NO-0033 Oslo, Norway; (M.A.-H.); (J.S.E.); (S.P.); (Ø.S.)
| | - Geir Slupphaug
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway; (A.S.); (D.d.M.F.); (G.S.)
- Proteomics and Metabolomics Core Facility (PROMEC), Norwegian University of Science and Technology and the Central Norway Regional Health Authority, NO-7491 Trondheim, Norway
| | - Shanbeh Zienolddiny
- National Institute of Occupational Health, NO-0033 Oslo, Norway; (M.A.-H.); (J.S.E.); (S.P.); (Ø.S.)
- Correspondence: ; Tel.: +47-23195284
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Ningarhari M, Caruso S, Hirsch TZ, Bayard Q, Franconi A, Védie AL, Noblet B, Blanc JF, Amaddeo G, Ganne N, Ziol M, Paradis V, Guettier C, Calderaro J, Morcrette G, Kim Y, MacLeod AR, Nault JC, Rebouissou S, Zucman-Rossi J. Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target. J Hepatol 2021; 74:1155-1166. [PMID: 33338512 DOI: 10.1016/j.jhep.2020.11.052] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 11/17/2020] [Accepted: 11/20/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. Thus, we aimed to elucidate the role of telomere length maintenance during liver carcinogenesis. METHODS Telomere length was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, as well as clinical and molecular (analyzed by genome, exome, targeted and/or RNA-sequencing) features of HCC. The preclinical efficacy of anti-TERT antisense oligonucleotides (ASO) was assessed in vitro in 26 cell lines and in vivo in a xenograft mouse model. RESULTS Aging, liver fibrosis, male sex and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC that developed in livers with long telomeres frequently had wild-type TERT with progenitor features and BAP1 mutations. In contrast, HCC that developed on livers with short telomeres were enriched in the non-proliferative HCC class and frequently had somatic TERT promoter mutations. In HCCs, telomere length is stabilized in a narrow biological range around 5.7 kb, similar to non-tumor livers, by various mechanisms that activate TERT expression. Long telomeres are characteristic of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with ASO was efficient in highly proliferative and poorly differentiated cells. Treatment for 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and activation of apoptosis. The therapeutic effect was also obtained in a xenograft mouse model. CONCLUSIONS Telomere maintenance in HCC carcinogenesis is diverse, and is associated with tumor progression and aggressiveness. The efficacy of anti-TERT ASO treatment in cell lines revealed the oncogenic addiction to TERT in HCC, providing a preclinical rationale for anti-TERT ASO treatment in HCC clinical trials. LAY SUMMARY Telomeres are repeated DNA sequences that protect chromosomes and naturally shorten in most adult cells because of the inactivation of the TERT gene, coding for the telomerase enzyme. Here we show that telomere attrition in the liver, modulated by aging, sex, fibrosis and alcohol, associates with specific clinical and molecular features of hepatocellular carcinoma, the most frequent primary liver cancer. We also show that liver cancer is dependent on TERT reactivation and telomere maintenance, which could be targeted through a novel therapeutic approach called antisense oligonucleotides.
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Affiliation(s)
- Massih Ningarhari
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France
| | - Stefano Caruso
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France
| | - Théo Z Hirsch
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France
| | - Quentin Bayard
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France
| | - Andrea Franconi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France
| | - Anne-Laure Védie
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France
| | - Bénédicte Noblet
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France
| | - Jean-Frédéric Blanc
- Service Hépato-Gastroentérologie et Oncologie Digestive, Hôpital Haut-Lévêque, CHU de Bordeaux, F-33000, Bordeaux, France; Service de Pathologie, Hôpital Pellegrin, CHU de Bordeaux, F-33076, Bordeaux, France; Université Bordeaux, Inserm, Research in Translational Oncology, BaRITOn, F-33076, Bordeaux, France
| | - Giuliana Amaddeo
- Service d'Hépato-Gastro-Entérologie, Hôpital Henri Mondor, APHP, Université Paris Est Créteil, Inserm U955, Institut Mondor de Recherche Biomédicale, F-94010, Créteil, France
| | - Nathalie Ganne
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Service d'Hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, APHP, F-93140, Bondy, France
| | - Marianne Ziol
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Service d'Anatomo-Pathologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, APHP, F-93140, Bondy, France
| | - Valérie Paradis
- Service de Pathologie, Hôpital Beaujon, APHP, F-92110, Clichy, France; Université Paris Diderot, CNRS, Centre de Recherche sur l'Inflammation (CRI), Paris, F-75890, France
| | - Catherine Guettier
- Service d'Anatomie Pathologique, CHU Bicêtre, APHP, F-94270, Le Kremlin-Bicêtre, France
| | - Julien Calderaro
- Service d'Anatomopathologie, Hôpital Henri Mondor, APHP, Institut Mondor de Recherche Biomédicale, F-94010, Créteil, France
| | - Guillaume Morcrette
- Service de Pathologie Pédiatrique, Assistance Publique Hôpitaux de Paris, Hôpital Robert Debré, F-75019, Paris, France
| | | | | | - Jean-Charles Nault
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Service d'Hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, APHP, F-93140, Bondy, France.
| | - Sandra Rebouissou
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France.
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Hôpital Européen Georges Pompidou, APHP, F-75015, Paris, France.
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Nah EH, Cho S, Kim S, Chu J, Kwon E, Cho HI. Prevalence of liver fibrosis and associated risk factors in the Korean general population: a retrospective cross-sectional study. BMJ Open 2021; 11:e046529. [PMID: 33762246 PMCID: PMC7993338 DOI: 10.1136/bmjopen-2020-046529] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES The health burden of chronic liver disease is increasing worldwide. Its main histological consequence is liver fibrosis, and eventually cirrhosis. This process is rarely diagnosed at the pre-cirrhotic stage due to it being asymptomatic. Little is known about the prevalence of liver fibrosis and associated risk factors in the general population. The aims of this study were to determine the prevalence and distribution of liver fibrosis using magnetic resonance elastography (MRE), as well as the risk factors associated with liver fibrosis in the asymptomatic general population. DESIGN, SETTING AND PARTICIPANTS This cross-sectional retrospective study consecutively selected subjects who underwent health check-ups including MRE at 13 health promotion centres in Korea between 2018 and 2020. Liver fibrosis was estimated using MRE with cut-off values for significant and advanced liver fibrosis of 2.90 and 3.60 kPa, respectively. PRIMARY AND SECONDARY OUTCOME MEASURES The Χ2 test was used to compare the prevalence of liver fibrosis according to sex and age groups. Multivariable logistic regression analyses were performed to identify the factors for significant and advanced liver fibrosis. RESULTS Among the 8183 subjects, 778 (9.5%) had ≥significant fibrosis (≥2.9 kPa), which included 214 (2.6%) subjects with ≥advanced fibrosis (≥3.6 kPa). Multivariable analysis revealed that liver fibrosis was associated with age (OR=1.34, 95% CI=1.18 to 1.51), male sex (OR=3.18, 95% CI=1.97 to 5.13), diabetes (OR=2.43, 95% CI=1.8 to 3.28), HBsAg positivity (OR=3.49, 95% CI=2.55 to 4.79), abnormal liver function test (OR=1.9, 95% CI=1.49 to 2.42) and obesity (OR=1.77, 95% CI=1.35 to 2.32) (all p<0.001), as well as metabolic syndrome (OR=1.4, 95% CI=1.05 to 1.87) (p=0.024). CONCLUSIONS The prevalence of significant or more liver fibrosis was high in the Korean general population and much higher among individuals with risk factors. This suggests that screening of liver fibrosis should be considered in general population, especially among high-risk groups.
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Affiliation(s)
- Eun-Hee Nah
- Health Promotion Research Institute, Korea Association of Health Promotion, Seoul, South Korea
| | - Seon Cho
- Health Promotion Research Institute, Korea Association of Health Promotion, Seoul, South Korea
| | - Suyoung Kim
- Health Promotion Research Institute, Korea Association of Health Promotion, Seoul, South Korea
| | - Jieun Chu
- Health Promotion Research Institute, Korea Association of Health Promotion, Seoul, South Korea
| | - Eunjoo Kwon
- Health Promotion Research Institute, Korea Association of Health Promotion, Seoul, South Korea
| | - Han-Ik Cho
- MEDIcheck LAB, Korea Association of Health Promotion, Seoul, South Korea
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50
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Łysek-Gładysińska M, Wieczorek A, Jóźwik A, Walaszczyk A, Jelonek K, Szczukiewicz-Markowska G, Horbańczuk OK, Pietrowska M, Widłak P, Gabryś D. Aging-Related Changes in the Ultrastructure of Hepatocytes and Cardiomyocytes of Elderly Mice Are Enhanced in ApoE-Deficient Animals. Cells 2021; 10:cells10030502. [PMID: 33652838 PMCID: PMC7996907 DOI: 10.3390/cells10030502] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/18/2021] [Accepted: 02/22/2021] [Indexed: 01/08/2023] Open
Abstract
Biological aging is associated with various morphological and functional changes, yet the mechanisms of these phenomena remain unclear in many tissues and organs. Hyperlipidemia is among the factors putatively involved in the aging of the liver and heart. Here, we analyzed morphological, ultrastructural, and biochemical features in adult (7-month-old) and elderly (17-month-old) mice, and then compared age-related features between wild type (C57Bl/6 strain) and ApoE-deficient (transgenic ApoE−/−) animals. Increased numbers of damaged mitochondria, lysosomes, and lipid depositions were observed in the hepatocytes of elderly animals. Importantly, these aging-related changes were significantly stronger in hepatocytes from ApoE-deficient animals. An increased number of damaged mitochondria was observed in the cardiomyocytes of elderly animals. However, the difference between wild type and ApoE-deficient mice was expressed in the larger size of mitochondria detected in the transgenic animals. Moreover, a few aging-related differences were noted between wild type and ApoE-deficient mice at the level of plasma biochemical markers. Levels of cholesterol and HDL increased in the plasma of elderly ApoE−/− mice and were markedly higher than in the plasma of elderly wild type animals. On the other hand, the activity of alanine transaminase (ALT) decreased in the plasma of elderly ApoE−/− mice and was markedly lower than in the plasma of elderly wild type animals.
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Affiliation(s)
- Małgorzata Łysek-Gładysińska
- Division of Medical Biology, Institute of Biology, University of Jan Kochanowski, Uniwersytecka 7, 25-406 Kielce, Poland;
- Correspondence: (M.Ł.-G.); (A.J.)
| | - Anna Wieczorek
- Division of Medical Biology, Institute of Biology, University of Jan Kochanowski, Uniwersytecka 7, 25-406 Kielce, Poland;
| | - Artur Jóźwik
- Institute of Genetics and Animal Biotechnology PAS, Jastrzębiec, Postępu 36A, 05-552 Magdalenka, Poland
- Correspondence: (M.Ł.-G.); (A.J.)
| | - Anna Walaszczyk
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE1 7RU, UK;
| | - Karol Jelonek
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeże Armii Krajowej 15, 44-101 Gliwice, Poland; (K.J.); (M.P.); (P.W.)
| | - Grażyna Szczukiewicz-Markowska
- Department of Surgical Medicine with the Laboratory of Medical Genetics, Collegium Medicum, University of Jan Kochanowski, al. IX Wieków Kielc 19A, 25-317 Kielce, Poland;
| | - Olaf K. Horbańczuk
- Faculty of Human Nutrition, Warsaw University of Life Sciences, Nowoursynowska 159 C, 02-776 Warsaw, Poland;
| | - Monika Pietrowska
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeże Armii Krajowej 15, 44-101 Gliwice, Poland; (K.J.); (M.P.); (P.W.)
| | - Piotr Widłak
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeże Armii Krajowej 15, 44-101 Gliwice, Poland; (K.J.); (M.P.); (P.W.)
| | - Dorota Gabryś
- Department of Radiotherapy, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej 15, 44-101 Gliwice, Poland;
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