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Raju C, Sankaranarayanan K. Insights on post-translational modifications in fatty liver and fibrosis progression. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167659. [PMID: 39788217 DOI: 10.1016/j.bbadis.2025.167659] [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: 09/06/2024] [Revised: 12/20/2024] [Accepted: 01/02/2025] [Indexed: 01/12/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease [MASLD] is a pervasive multifactorial health burden. Post-translational modifications [PTMs] of amino acid residues in protein domains demonstrate pivotal roles for imparting dynamic alterations in the cellular micro milieu. The crux of identifying novel druggable targets relies on comprehensively studying the etiology of metabolic disorders. This review article presents how different chemical moieties of various PTMs like phosphorylation, methylation, ubiquitination, glutathionylation, neddylation, acetylation, SUMOylation, lactylation, crotonylation, hydroxylation, glycosylation, citrullination, S-sulfhydration and succinylation presents the cause-effect contribution towards the MASLD spectra. Additionally, the therapeutic prospects in the management of liver steatosis and hepatic fibrosis via targeting PTMs and regulatory enzymes are also encapsulated. This review seeks to understand the function of protein modifications in progression and promote the markers discovery of diagnostic, prognostic and drug targets towards MASLD management which could also halt the progression of a catalogue of related diseases.
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Affiliation(s)
- Chithra Raju
- Ion Channel Biology Laboratory, AU-KBC Research Centre, Madras Institute of Technology Campus, Anna University, Chrompet, Chennai 600 044, Tamil Nadu, India
| | - Kavitha Sankaranarayanan
- Ion Channel Biology Laboratory, AU-KBC Research Centre, Madras Institute of Technology Campus, Anna University, Chrompet, Chennai 600 044, Tamil Nadu, India.
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Abasilim C, Persky V, Sargis RM, Day T, Tsintsifas K, Daviglus M, Cai J, Freels S, Grieco A, Peters BA, Isasi CR, Talavera GA, Thyagarajan B, Davis M, Jones R, Sjodin A, Turyk ME. Persistent organic pollutants and endogenous sex-related hormones in Hispanic/Latino adults: The Hispanic Community health study/study of Latinos (HCHS/SOL). ENVIRONMENTAL RESEARCH 2025; 267:120742. [PMID: 39743011 DOI: 10.1016/j.envres.2024.120742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 12/05/2024] [Accepted: 12/30/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND Previous studies have demonstrated associations of persistent organic pollutants (POPs) with sex-related hormones; however, findings were inconsistent. Sex-specific impacts and pathways through which adiposity influences associations are not completely understood. We sought to evaluate sex-specific associations of POPs serum concentration with sex-related hormones and to explore pathways through which adiposity may modify associations. METHODS We studied 1073 men and 716 postmenopausal women participating in the "Persistent Organic Pollutants, Endogenous Hormones, and Diabetes in Latinos" ancillary study which is a subcohort of the "Hispanic Community Health Study/Study of Latinos." We use baseline examination data collected from 2008 to 2011 to investigate associations between eight organochlorine pesticides (OCPs), five polychlorinated biphenyls (PCB) groups, sum of polybrominated diphenyl ethers and polybrominated biphenyl 153 on sex hormone binding globulin (SHBG) and various sex-related hormone levels. We examined associations cross-sectionally using linear and logistic regression models adjusted for complex survey design and confounders. RESULTS PCBs and select OCPs were associated with increased SHBG in women and decreased estradiol (E2) and/or bioavailable E2 in men. For instance, per quartile increase in serum concentrations of ∑PCBs and oxychlordane were associated with decreased levels of E2 (β = -6.36 pmol/L; 95% CI: 10.7,-2.02 and β = -5.08 pmol/L; 95% CI: 8.11,-2.05) and bioavailable E2 (β = -4.48 pmol/L; 95% CI: 7.22,-1.73 and β = -4.23 pmol/L; 95% CI: 6.17,-2.28), respectively, in men, and increased levels of SHBG (β = 7.25 nmol/L; 95% CI:2.02,12.8 and β = 9.42 nmol/L; 95% CI:4.08,15.0), respectively, in women. p,p'-DDT and β-HCCH, and o,p'-DDT were also associated with decreased testosterone (T) and bioavailable T (ng/dL) levels in men. Adiposity modified associations in men, revealing stronger inverse associations of PCBs, PBDEs, and several OCPs with LH, SHBG, E2, bioavailable E2, T, and the ratios of LH to FSH and E2 to T in those with below median body mass index and waist-to-hip ratio. CONCLUSION Distinct patterns of hormone dysregulation with increasing POPs serum concentration were identified in men and post-menopausal women. In men but less so in postmenopausal women, adiposity modified associations of POPs serum concentration with sex-related hormones.
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Affiliation(s)
- Chibuzor Abasilim
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois Chicago, USA; Division of Environmental and Occupational Health Sciences, School of Public Health, University of Illinois Chicago, USA.
| | - Victoria Persky
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois Chicago, USA
| | - Robert M Sargis
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois Chicago and Medical Service, Jesse Brown VA Medical Center, USA
| | - Tessa Day
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois Chicago, USA
| | - Konstantina Tsintsifas
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois Chicago, USA
| | - Martha Daviglus
- Institute for Minority Health Research, University of Illinois Chicago, USA
| | - Jianwen Cai
- Department of Biostatistics, University of North Carolina at Chapel Hill, USA
| | - Sally Freels
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois Chicago, USA
| | - Arielle Grieco
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois Chicago, USA
| | - Brandilyn A Peters
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, USA
| | - Carmen R Isasi
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, USA
| | | | - Bharat Thyagarajan
- Department of Laboratory Medicine and Pathology, University of Minnesota, USA
| | - Mark Davis
- Persistent Pollutants Biomonitoring Laboratory, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Richard Jones
- Persistent Pollutants Biomonitoring Laboratory, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Andreas Sjodin
- Persistent Pollutants Biomonitoring Laboratory, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Mary E Turyk
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois Chicago, USA
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Jin Y, Sun G, Chen B, Feng S, Tang M, Wang H, Zhang Y, Wang Y, An Y, Xiao Y, Liu Z, Liu P, Tian Z, Yin H, Zhang S, Luan X. Delivering miR-23b-3p by small extracellular vesicles to promote cell senescence and aberrant lipid metabolism. BMC Biol 2025; 23:41. [PMID: 39934790 DOI: 10.1186/s12915-025-02143-9] [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: 03/30/2024] [Accepted: 01/23/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Aging is a natural process that affects the majority of organs within the organism. The liver, however, plays a pivotal role in maintaining the organism's homeostasis due to its robust regenerative and metabolic capabilities. Nevertheless, the liver also undergoes the effects of aging, which can result in a range of metabolic disorders. The function of extracellular vesicles and the signals they convey represent a significant area of interest within the field of ageing research. However, research on liver ageing from the perspective of EVs remains relatively limited. RESULTS In the present study, we extracted liver tissue small extracellular vesicles (sEVs) of mice at different ages and performed transcriptome and proteome analyses to investigate the senescence-associated secretory phenotype (SASP) and mechanisms. sEVs in the older group were rich in miR-23b-3p, which was abundant in the sEVs of induced aging cells and promoted cell senescence by targeting TNF alpha induced protein 3 (Tnfaip3). After injecting adeno-associated virus (AAV) expressing miR-23b-3p into mice, the liver of mice in the experimental group displayed a more evident inflammatory response than that in the control group. Additionally, we found elevated miR-23b-3p in blood-derived-sEVs from patients with familial hypercholesterolemia. CONCLUSIONS Our findings suggest that miR-23b-3p plays a pivotal role in liver aging and is associated with abnormal lipid metabolism. The upregulation of miR-23b-3p in liver EVs may serve as a potential biomarker for aging and metabolic disorders. Targeting miR-23b-3p could provide new therapeutic strategies for ameliorating age-related liver dysfunction and associated metabolic abnormalities.
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Affiliation(s)
- Ye Jin
- Rare Disease Medical Center, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
- Center for Digital Medicine and Artificial Intelligence, National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
| | - Gaoge Sun
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Binxian Chen
- Rare Disease Medical Center, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
- School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Siqin Feng
- Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
| | - Muyun Tang
- Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
| | - Hui Wang
- Department of Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
| | - Ying Zhang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Yuan Wang
- Echo Biotech Co., Ltd, Beijing, 102627, China
| | - Yang An
- GemPharmatech Co., Ltd, Nanjing, 210000, China
| | - Yu Xiao
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
- Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084, China
- Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China
- Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510260, China
| | - Zihan Liu
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Peng Liu
- Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
| | - Zhuang Tian
- Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China.
| | - Hang Yin
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
- Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084, China.
- Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China.
| | - Shuyang Zhang
- Rare Disease Medical Center, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China.
- School of Medicine, Tsinghua University, Beijing, 100084, China.
- Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China.
| | - Xiaodong Luan
- Rare Disease Medical Center, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China.
- Center for Drug Research and Evaluation, National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China.
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Sarmento-Cabral A, Fuentes-Fayos AC, Ordoñez FM, León-González AJ, Martínez-Fuentes AJ, Gahete MD, Luque RM. From pituitary cells to prostate gland in health and disease: direct and indirect endocrine connections. Rev Endocr Metab Disord 2025:10.1007/s11154-025-09948-7. [PMID: 39910005 DOI: 10.1007/s11154-025-09948-7] [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] [Accepted: 01/27/2025] [Indexed: 02/07/2025]
Abstract
The prostate gland is an endocrine-sensitive organ responding to multiple stimuli. Its development and function are regulated by multiple hormones (i.e. steroids such as androgens, estrogens and glucocorticoids) but also by other key hormonal systems such as those comprised by insulin-like growth factor 1 and insulin, which are sourced by different tissues [e.g. testicles/adrenal-gland/adipose-tissue/liver/pancreas, etc.). Particularly important for the endocrine control of prostatic pathophysiology and anatomy are hormones produced and/or secreted by different cell types of the pituitary gland [growth-hormone, luteinizing-hormone, follicle-stimulating hormone, and prolactin, oxytocin, arginine-vasopressin and melanocyte-stimulating hormone], which affect prostate gland function either directly or indirectly under physiological and pathophysiological conditions [e.g. metabolic dysregulation (e.g. obesity), and prostate transformations (e.g. prostate cancer)]. This review summarizes the impact of all pituitary hormone types on prostate gland under these diverse conditions including in vivo and in vitro studies.
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Affiliation(s)
- André Sarmento-Cabral
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Avda. Menéndez Pidal s/n., Cordoba, 14004, Spain.
- Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Cordoba, 14014, Spain.
- Reina Sofia University Hospital (HURS), Cordoba, 14004, Spain.
| | - Antonio C Fuentes-Fayos
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Avda. Menéndez Pidal s/n., Cordoba, 14004, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Cordoba, 14014, Spain
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Fernando Mata Ordoñez
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Avda. Menéndez Pidal s/n., Cordoba, 14004, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Cordoba, 14014, Spain
- Reina Sofia University Hospital (HURS), Cordoba, 14004, Spain
- Faculty of Health Sciences, Alfonso X el Sabio University, Villanueva de la Cañada, 28691, Spain
| | - Antonio J León-González
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Avda. Menéndez Pidal s/n., Cordoba, 14004, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Cordoba, 14014, Spain
- Reina Sofia University Hospital (HURS), Cordoba, 14004, Spain
- Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, 41012, Spain
| | - Antonio J Martínez-Fuentes
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Avda. Menéndez Pidal s/n., Cordoba, 14004, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Cordoba, 14014, Spain
- Reina Sofia University Hospital (HURS), Cordoba, 14004, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, 14004, Spain
| | - Manuel D Gahete
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Avda. Menéndez Pidal s/n., Cordoba, 14004, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Cordoba, 14014, Spain
- Reina Sofia University Hospital (HURS), Cordoba, 14004, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, 14004, Spain
| | - Raúl M Luque
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Avda. Menéndez Pidal s/n., Cordoba, 14004, Spain.
- Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Cordoba, 14014, Spain.
- Reina Sofia University Hospital (HURS), Cordoba, 14004, Spain.
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, 14004, Spain.
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Uddin J, Akhter S, Asad MJ, Irfan M, Qayyum M, Aijaz M, Aslam S. Effect of Hepatitis C Infection on Semen Parameters of Men From Rawalpindi and Islamabad, Punjab, Pakistan. Am J Mens Health 2025; 19:15579883251316564. [PMID: 39981641 PMCID: PMC11843681 DOI: 10.1177/15579883251316564] [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: 11/01/2024] [Revised: 12/19/2024] [Accepted: 01/08/2025] [Indexed: 02/22/2025] Open
Abstract
Hepatitis C virus (HCV) poses a global health challenge, especially due to its genetic diversity and capacity to infect 71 million people worldwide. This infection is prevalent in Pakistan, with 15% of the population affected, with varying rates across provinces. HCV primarily targets liver cells but can also impact other bodily systems, including the reproductive system. Liver infection, oxidative stress, and inflammation may directly or indirectly affect the production, transport, and functions of reproductive hormones and sperm. This study hypothesized that HCV infection may reduce male fertility in the patients. In this case-control study, 74 HCV-infected men and 12 healthy controls from Rawalpindi and Islamabad were compared for semen quality. Participants provided semen samples following strict guidelines, ensuring the reliability of results. The semen analysis, conducted using manual and computer-assisted techniques, revealed significant (p < .05) reductions in volume, concentration, motility, and morphology among HCV-infected men compared to the control group. In addition, a weak negative correlation between virus load and semen parameters was observed. These findings reveal broader health implications of HCV beyond liver damage, highlighting the need for targeted reproductive health interventions for affected men. Improved fertility preservation options and informed reproductive guidance for HCV-infected men could significantly benefit those undergoing treatment.
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Affiliation(s)
- Jamal Uddin
- Department of Zoology, Wildlife and Fisheries, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, Rawalpindi, Pakistan
| | - Shamim Akhter
- Department of Zoology, Wildlife and Fisheries, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, Rawalpindi, Pakistan
| | - Muhammad Javaid Asad
- University Institute of Biochemistry and Biotechnology, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, Rawalpindi, Pakistan
| | - Muhammad Irfan
- Department of Zoology, Wildlife and Fisheries, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, Rawalpindi, Pakistan
| | - Mazhar Qayyum
- Department of Zoology, Wildlife and Fisheries, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, Rawalpindi, Pakistan
| | - Majid Aijaz
- Department of Zoology, Wildlife and Fisheries, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, Rawalpindi, Pakistan
| | - Shahzad Aslam
- Department of Zoology, Wildlife and Fisheries, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, Rawalpindi, Pakistan
- Department of Zoology, Islamabad College for Boys G-6/3, Islamabad, Pakistan
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Moon JH, Roh HS, Park YJ, Song HH, Choi J, Jung DW, Park SJ, Park HJ, Park SH, Kim DE, Kim G, Auh JH, Bhang DH, Lee HJ, Lee DY. A three-dimensional mouse liver organoid platform for assessing EDCs metabolites simulating liver metabolism. ENVIRONMENT INTERNATIONAL 2025; 195:109184. [PMID: 39798515 DOI: 10.1016/j.envint.2024.109184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 10/23/2024] [Accepted: 12/03/2024] [Indexed: 01/15/2025]
Abstract
Hepatic metabolism is an important process for evaluate the potential activity and toxicity of endocrine disrupting chemicals (EDCs) metabolites. Organization for Economic Co-operation and Development (OECD) has advocated the development of in vitro assays that mimic in vivo hepatic metabolism to eventually replace classical animal tests. In response to this need, we established a 3D mouse liver organoid (mLO) platform that mimics the animal model and is distinct from existing models. We evaluated the effects the activity of EDC metabolites generated through mLOs based on human cell-based reporter gene assays in addition to existing models. This study emphasizes the importance of hepatic ex-vivo and suggests the need a new metabolic model through a 3D mLOs platform. These results indicate that mLOs provides a novel biological method to screen for potential endocrine-disrupting activities of EDC metabolites.
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Affiliation(s)
- Ji Hyun Moon
- Department of Agricultural Biotechnology, Seoul National University, Seoul 00826, Republic of Korea
| | - Hyun-Soo Roh
- Department of Molecular and Cellular Biology, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 16419, Republic of Korea; Attislab Inc., Anyang, Gyeonggi-Do 14059, Republic of Korea
| | - Young Jae Park
- Department of Agricultural Biotechnology, Seoul National University, Seoul 00826, Republic of Korea
| | - Hyun Ho Song
- Department of Agricultural Biotechnology, Seoul National University, Seoul 00826, Republic of Korea
| | - Jieun Choi
- Department of Agricultural Biotechnology, Seoul National University, Seoul 00826, Republic of Korea
| | - Da Woon Jung
- Department of Agricultural Biotechnology, Seoul National University, Seoul 00826, Republic of Korea
| | - Soo Jin Park
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Ho Jin Park
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - So-Hyeon Park
- Department of Food Science and Biotechnology, Chung-Ang University, Anseong 17546, South Korea
| | - Da-Eun Kim
- Department of Molecular and Cellular Biology, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 16419, Republic of Korea
| | - Gahee Kim
- Department of Molecular and Cellular Biology, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 16419, Republic of Korea; Attislab Inc., Anyang, Gyeonggi-Do 14059, Republic of Korea
| | - Joong-Hyuck Auh
- Department of Food Science and Biotechnology, Chung-Ang University, Anseong 17546, South Korea
| | - Dong Ha Bhang
- Department of Molecular and Cellular Biology, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 16419, Republic of Korea; Attislab Inc., Anyang, Gyeonggi-Do 14059, Republic of Korea
| | - Hong Jin Lee
- Department of Food Science and Biotechnology, Chung-Ang University, Anseong 17546, South Korea
| | - Do Yup Lee
- Department of Agricultural Biotechnology, Seoul National University, Seoul 00826, Republic of Korea; Department of Food and Animal Biotechnology, Seoul National University, Seoul 00826, Republic of Korea; Center for Food and Bioconvergence, Research Institute for Agricultural and Life Sciences, Interdisciplinary Programs in Agricultural Genomics, Seoul National University, Seoul 00826, Republic of Korea; Green Bio Science & Technology, Bio-Food Industrialization, Seoul National University, 1447 Pyeongchang-daero, Daehwa-myeon, Pyeongchang-gun, Gangwon-do 25354, Republic of Korea.
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Scheun J, Ganswindt A, Jansen R, Labuschagne K. Validating enzyme immunoassays for non-invasive reproductive hormone monitoring in Temminck's pangolin. CONSERVATION PHYSIOLOGY 2024; 12:coae079. [PMID: 39544460 PMCID: PMC11562634 DOI: 10.1093/conphys/coae079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 10/22/2024] [Accepted: 10/23/2024] [Indexed: 11/17/2024]
Abstract
Gonadal hormones play a central role in reproductive function and success. As such, quantifying reproductive hormones non-invasively in threatened, vulnerable and endangered wildlife species offers an ideal tool for assessing general and individual reproductive patterns in situ. Whilst the use of faeces as a hormone matrix is often preferred in these cases, the required enzyme immunoassays (EIAs) for measuring faecal androgen (fAM), oestrogen (fEM) and progestagen metabolite (fPM) concentrations must first be validated if a species gets investigated for the first time to ensure biologically relevant patterns can be observed. In this study we aimed to biologically validate the EIAs for monitoring fAM, fEM and fPM concentrations in Temminck's pangolin, Smutsia temminckii. Hormone metabolite concentrations derived from each EIA tested were compared between different age and sex classes. An epiandrosterone EIA effectively measured androgen levels in males, distinguishing between adult and juvenile individuals, as well as both female age classes. Similarly, the tested oestrogen EIA successfully distinguished between adult and juvenile female fEM concentrations, and both tested progestagen EIAs demonstrated adequate differences between fPM concentrations of adult and juvenile females. The now-validated EIAs offer robust tools for a non-invasive monitoring of reproductive activity in Temminck's pangolin. The development of such techniques will allow researchers to assess reproductive hormone patterns of the species in situ, whilst also paving the way for further studies in this field. Despite the small sample size due to the species' conservation status, the study provides a foundation for future research using a robust, validated, non-invasive monitoring tool. The latter can now be implemented in long-term monitoring with larger sample sizes to yield more comprehensive data, aiding in the conservation of Temminck's pangolin.
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Affiliation(s)
- Juan Scheun
- Department Nature Conservation, Tshwane University of Technology, Staatsartillerie Rd, Pretoria West, Pretoria 0183, South Africa
- Faculty of Natural and Agricultural Sciences, Mammal Research Institute, University of Pretoria, Lynnwood Rd, Hatfield, Pretoria 0002, South Africa
| | - Andre Ganswindt
- Faculty of Natural and Agricultural Sciences, Mammal Research Institute, University of Pretoria, Lynnwood Rd, Hatfield, Pretoria 0002, South Africa
| | - Raymond Jansen
- Department of Environmental, Water and Earth Science, Tshwane University of Technology, Staatsartillerie Rd, Pretoria West, Pretoria 0183, South Africa
- IUCN SSC Pangolin Specialist Group, c/o Zoological Society of London, London NW1 4RY, UK
| | - Kim Labuschagne
- SANBI Wildlife Biobank, South African National Biodiversity Institute, 232 Boom St, Daspoort 319-Jr, Pretoria 0001, South Africa
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Kim EY, Lee YJ, Kwon YJ, Lee JW. Age at menopause and risk of metabolic dysfunction-associated fatty liver disease: A 14-year cohort study. Dig Liver Dis 2024; 56:1880-1886. [PMID: 38763798 DOI: 10.1016/j.dld.2024.05.003] [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: 01/30/2024] [Revised: 05/02/2024] [Accepted: 05/07/2024] [Indexed: 05/21/2024]
Abstract
BACKGROUNDS & AIMS Menopause, characterized by a sudden decline in estrogen levels, has significant effects on women's health, especially when it occurs early. This study aimed to investigate the associations between menopausal age and incidence of metabolic dysfunction-associated fatty liver disease (MAFLD) using a large cohort and a long-term follow-up. METHODS Menopausal age was categorized into four groups (G1-4 [<40, 40-44, 45-49, and ≥50 years, respectively]). Cox proportional hazards regression analysis was used to assess the risk of developing MAFLD during the follow-up period according to the menopausal age categories. RESULTS A total of 1,888 participants were included in the final analysis and followed for a median period of 12.3 years. The unadjusted hazard ratios (95 % CIs) for the incidence of new-onset MAFLD were 1.11 (0.93-1.32), 1.15 (0.90-1.47), and 1.52 (1.12-2.07) in G3, G2, and G1, respectively, compared with that in G4. After adjusting for confounders, the hazard ratio (95 % CIs) for the incidence of new-onset MAFLD was 1.40 (1.00-1.95) in G1 compared with that in G4. CONCLUSION The risk of developing MAFLD was higher in women with premature menopause (<40 years) than in those with menopause aged ≥50 years.
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Affiliation(s)
- Ehn-Young Kim
- Department of Family Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea
| | - Yae-Ji Lee
- Department of Biostatistics and Computing, Yonsei University, Seoul 03722, Korea
| | - Yu-Jin Kwon
- Department of Family Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, 363, Dongbaekjukjeon-daero, Giheung-gu, Yongin-si 16995, Gyeonggi-do, Korea.
| | - Ji-Won Lee
- Department of Family Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea; Institute for Innovation in Digital Healthcare, Yonsei University, Seoul 03722, Republic of Korea.
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9
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Nayak SPRR, Boopathi S, Chandrasekar M, Panda SP, Manikandan K, Chitra V, Almutairi BO, Arokiyaraj S, Guru A, Arockiaraj J. Indole-3-acetic acid exposure leads to cardiovascular inflammation and fibrosis in chronic kidney disease rat model. Food Chem Toxicol 2024; 192:114917. [PMID: 39128690 DOI: 10.1016/j.fct.2024.114917] [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: 02/22/2024] [Revised: 07/24/2024] [Accepted: 08/08/2024] [Indexed: 08/13/2024]
Abstract
Indole-3-acetic acid (IAA), a protein-bound uremic toxin, has been linked to cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. This study explores the influence of IAA (125 mg/kg) on cardiovascular changes in adenine sulfate-induced CKD rats. HPLC analysis revealed that IAA-exposed CKD rats had lower excretion and increased circulation of IAA compared to both CKD and IAA control groups. Moreover, echocardiography indicated that CKD rats exposed to IAA exhibited heart enlargement, thickening of the myocardium, and cardiac hypertrophy in contrast to CKD or IAA control group. Biochemical analyses supported the finding that IAA-induced CKD rats had elevated serum levels of c-Tn-I, CK-MB, and LDH; there was also evidence of oxidative stress in cardiac tissues, with a significant decrease in SOD and CAT levels, as well as an increase in MDA levels. The gene expression analysis found significant increases in ANP, BNP, β-MHC, TNF-α, IL-1β, and NF-κB levels in IAA-exposed CKD groups in contrast to the CKD or IAA control group. In addition, higher cardiac fibrosis markers, including Col-I and Col-III. The findings of this study indicate that IAA could trigger cardiovascular inflammation and fibrosis in CKD conditions.
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Affiliation(s)
- S P Ramya Ranjan Nayak
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India
| | - Seenivasan Boopathi
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India
| | - Munisamy Chandrasekar
- Resident Veterinary Services Section, Madras Veterinary College, Chennai, 600007, Tamil Nadu, India
| | - Siva Prasad Panda
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttarpradesh, India
| | - K Manikandan
- Department of Pharmaceutical Analysis, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India
| | - Vellapandian Chitra
- Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India
| | - Bader O Almutairi
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
| | - Selvaraj Arokiyaraj
- Department of Food Science & Biotechnology, Sejong University, Seoul, 05006, South Korea
| | - Ajay Guru
- Department of Cariology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
| | - Jesu Arockiaraj
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India.
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10
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Krüger P, Schroll M, Fenzl F, Lederer EM, Hartinger R, Arnold R, Cagla Togan D, Guo R, Liu S, Petry A, Görlach A, Djabali K. Inflammation and Fibrosis in Progeria: Organ-Specific Responses in an HGPS Mouse Model. Int J Mol Sci 2024; 25:9323. [PMID: 39273272 PMCID: PMC11395088 DOI: 10.3390/ijms25179323] [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: 08/10/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder that causes accelerated aging, due to a pathogenic variant in the LMNA gene. This pathogenic results in the production of progerin, a defective protein that disrupts the nuclear lamina's structure. In our study, we conducted a histopathological analysis of various organs in the LmnaG609G/G609G mouse model, which is commonly used to study HGPS. The objective of this study was to show that progerin accumulation drives systemic but organ-specific tissue damage and accelerated aging phenotypes. Our findings show significant fibrosis, inflammation, and dysfunction in multiple organ systems, including the skin, cardiovascular system, muscles, lungs, liver, kidneys, spleen, thymus, and heart. Specifically, we observed severe vascular fibrosis, reduced muscle regeneration, lung tissue remodeling, depletion of fat in the liver, and disruptions in immune structures. These results underscore the systemic nature of the disease and suggest that chronic inflammation and fibrosis play crucial roles in the accelerated aging seen in HGPS. Additionally, our study highlights that each organ responds differently to the toxic effects of progerin, indicating that there are distinct mechanisms of tissue-specific damage.
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Affiliation(s)
- Peter Krüger
- Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, Germany
| | - Moritz Schroll
- Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, Germany
| | - Felix Fenzl
- Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, Germany
| | - Eva-Maria Lederer
- Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, Germany
| | - Ramona Hartinger
- Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, Germany
| | - Rouven Arnold
- Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, Germany
- Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Deniz Cagla Togan
- Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, Germany
| | - Runjia Guo
- Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, Germany
| | - Shiyu Liu
- Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, Germany
| | - Andreas Petry
- Experimental and Molecular Pediatric Cardiology, Department of Pediatric Cardiology and Congenital, Heart Diseases, German Heart Center Munich, Technical University Munich, 80636 Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, 80636 Munich, Germany
| | - Agnes Görlach
- Experimental and Molecular Pediatric Cardiology, Department of Pediatric Cardiology and Congenital, Heart Diseases, German Heart Center Munich, Technical University Munich, 80636 Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, 80636 Munich, Germany
| | - Karima Djabali
- Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, Germany
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11
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Mușat MI, Militaru F, Udriștoiu I, Mitran SI, Cătălin B. Alcohol Consumption Is a Coping Mechanism for Male Patients with Severe Anxiety Disorders Treated with Antidepressants Monotherapy. J Clin Med 2024; 13:2723. [PMID: 38731251 PMCID: PMC11084266 DOI: 10.3390/jcm13092723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 04/30/2024] [Accepted: 05/02/2024] [Indexed: 05/13/2024] Open
Abstract
Background: Anxiety disorders are prevalent mental health conditions often accompanied by various comorbidities. The association between anxiety and liver disease, as well as fluctuations in blood sugar levels, highlights the importance of carefully evaluating patients with anxiety undergoing antidepressant therapy. The aim of this study was to conduct a comparative assessment of liver function and blood glucose levels in patients diagnosed with anxiety disorders while considering potential gender-specific differences. Methods: An analysis was conducted over a 24-month period. This study included 88 patients diagnosed with anxiety disorders, with symptoms severe enough to require hospitalization, aged 18 or older, undergoing antidepressant monotherapy, without any additional pathologies. Liver enzymes (AST, ALT, GGT), AST/ALT ratio, and blood glucose levels were measured and compared. Results: While no significant differences were found between antidepressant classes, increased GGT levels were observed in men older than 40 years compared to women of the same age, suggesting that alcohol consumption may be a coping mechanism for anxiety. This gender difference was not observed among young patients. Conclusions: Early detection of alcohol consumption is essential in patients with anxiety disorders in order to prevent alcohol-related liver damage and to adjust the management of both conditions accordingly.
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Affiliation(s)
- Mădălina Iuliana Mușat
- U.M.F. Doctoral School Craiova, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
- Experimental Research Centre for Normal and Pathological Aging, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Felicia Militaru
- Department of Psychiatry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Ion Udriștoiu
- Department of Psychiatry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Smaranda Ioana Mitran
- Experimental Research Centre for Normal and Pathological Aging, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
- Department of Physiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Bogdan Cătălin
- Experimental Research Centre for Normal and Pathological Aging, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
- Department of Physiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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12
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Nam SY, Jo J, Cho CM. A population-based cohort study of longitudinal change of high-density lipoprotein cholesterol impact on gastrointestinal cancer risk. Nat Commun 2024; 15:2923. [PMID: 38575589 PMCID: PMC10994902 DOI: 10.1038/s41467-024-47193-9] [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: 05/17/2023] [Accepted: 03/19/2024] [Indexed: 04/06/2024] Open
Abstract
High-density Lipoprotein Cholesterol (HDL-C) levels have been associated with cancer. In this observational population-based cohort study using data from the Korean National Health Insurance Service system, we investigate the impact of longitudinal changes in HDL-C levels on gastrointestinal cancer risk. Individuals who underwent health examinations in 2010 and 2014 were followed-up through 2021. Among 3.131 million, 40696 gastric, 35707 colorectal, 21309 liver, 11532 pancreatic, 4225 gallbladder, and 7051 biliary cancers are newly detected. The persistent low HDL-C group increases the risk of gastric, liver, and biliary cancer comparing to persistent normal HDL-C group. HDL-C change from normal to low level increases the risk for gastric, colorectal, liver, pancreatic, gallbladder, and biliary cancers. Effects of HDL-C change on the gastrointestinal cancer risk are also modified by sex and smoking status. HDL-C changes affect the gastric and gallbladder cancer risk in age ≥60 years and the pancreatic and biliary cancer risk in age <60 years. Here, we show persistently low HDL-C and normal-to-low HDL-C change increase gastrointestinal cancer risk with discrepancies by sex, smoking status, and age.
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Affiliation(s)
- Su Youn Nam
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, South Korea.
- Division of Gastroenterology, Kyungpook National University Chilgok Hospital, Daegu, South Korea.
| | - Junwoo Jo
- Department of Statistics, Kyungpook National University, Daegu, South Korea
| | - Chang-Min Cho
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, South Korea
- Division of Gastroenterology, Kyungpook National University Chilgok Hospital, Daegu, South Korea
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13
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Szydlowska-Gladysz J, Gorecka AE, Stepien J, Rysz I, Ben-Skowronek I. IGF-1 and IGF-2 as Molecules Linked to Causes and Consequences of Obesity from Fetal Life to Adulthood: A Systematic Review. Int J Mol Sci 2024; 25:3966. [PMID: 38612776 PMCID: PMC11012406 DOI: 10.3390/ijms25073966] [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: 02/20/2024] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/14/2024] Open
Abstract
This study examines the impact of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2) on various aspects of children's health-from the realms of growth and puberty to the nuanced characteristics of metabolic syndrome, diabetes, liver pathology, carcinogenic potential, and cardiovascular disorders. A comprehensive literature review was conducted using PubMed, with a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method employing specific keywords related to child health, obesity, and insulin-like growth factors. This study reveals associations between insulin-like growth factor 1 and birth weight, early growth, and adiposity. Moreover, insulin-like growth factors play a pivotal role in regulating bone development and height during childhood, with potential implications for puberty onset. This research uncovers insulin-like growth factor 1 and insulin-like growth factor 2 as potential biomarkers and therapeutic targets for metabolic dysfunction-associated liver disease and hepatocellular carcinoma, and it also highlights the association between insulin-like growth factors (IGFs) and cancer. Additionally, this research explores the impact of insulin-like growth factors on cardiovascular health, noting their role in cardiomyocyte hypertrophy. Insulin-like growth factors play vital roles in human physiology, influencing growth and development from fetal stages to adulthood. The impact of maternal obesity on children's IGF levels is complex, influencing growth and carrying potential metabolic consequences. Imbalances in IGF levels are linked to a range of health conditions (e.g., insulin resistance, glucose intolerance, metabolic syndrome, and diabetes), prompting researchers to seek novel therapies and preventive strategies, offering challenges and opportunities in healthcare.
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Affiliation(s)
- Justyna Szydlowska-Gladysz
- Department of Pediatric Endocrinology and Diabetology with Endocrine-Metabolic Laboratory, Medical University in Lublin, 20-093 Lublin, Poland
| | | | | | | | - Iwona Ben-Skowronek
- Department of Pediatric Endocrinology and Diabetology with Endocrine-Metabolic Laboratory, Medical University in Lublin, 20-093 Lublin, Poland
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14
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Zhang K, Jiang L, Xue L, Wang Y, Sun Y, Fan M, Qian H, Wang L, Li Y. 5-Heptadecylresorcinol Improves Aging-Associated Hepatic Fatty Acid Oxidation Dysfunction via Regulating Adipose Sirtuin 3. Nutrients 2024; 16:978. [PMID: 38613012 PMCID: PMC11013747 DOI: 10.3390/nu16070978] [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: 03/02/2024] [Revised: 03/23/2024] [Accepted: 03/26/2024] [Indexed: 04/14/2024] Open
Abstract
Aging-associated hepatic fatty acid (FA) oxidation dysfunction contributes to impaired adaptive thermogenesis. 5-Heptadecylresorcinol (AR-C17) is a prominent functional component of whole wheat and rye, and has been demonstrated to improve the thermogenic capacity of aged mice via the regulation of Sirt3. However, the effect of AR-C17 on aging-associated hepatic FA oxidation dysfunction remains unclear. Here, 18-month-old C57BL/6J mice were orally administered with AR-C17 at a dose of 150 mg/kg/day for 8 weeks. Systemic glucose and lipid metabolism, hepatic FA oxidation, and the lipolysis of white adipose tissues (WAT) were measured. The results showed that AR-C17 improved the hepatic FA oxidation, and especially acylcarnitine metabolism, of aged mice during cold stimulation, with the enhancement of systemic glucose and lipid metabolism. Meanwhile, AR-C17 improved the WAT lipolysis of aged mice, promoting hepatic acylcarnitine production. Furthermore, the adipose-specific Sirt3 knockout mice were used to investigate and verify the regulation mechanism of AR-C17 on aging-associated hepatic FA oxidation dysfunction. The results showed that AR-C17 failed to improve the WAT lipolysis and hepatic FA oxidation of aged mice in the absence of adipose Sirt3, indicating that AR-C17 might indirectly influence hepatic FA oxidation via regulating WAT Sirt3. Our findings suggest that AR-C17 might improve aging-associated hepatic FA oxidation dysfunction via regulating adipose Sirt3.
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Affiliation(s)
| | | | | | | | | | | | | | - Li Wang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (K.Z.); (L.J.); (L.X.); (Y.W.); (Y.S.); (M.F.); (H.Q.)
| | - Yan Li
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (K.Z.); (L.J.); (L.X.); (Y.W.); (Y.S.); (M.F.); (H.Q.)
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15
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Chauhan HM, Modi HH, Rathod JB, Prajapati HK. Morphological Study of Human Cadaveric Livers and Its Clinical Significance. Cureus 2024; 16:e53873. [PMID: 38465106 PMCID: PMC10924653 DOI: 10.7759/cureus.53873] [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] [Accepted: 02/07/2024] [Indexed: 03/12/2024] Open
Abstract
Introduction The liver is the largest gland in the body and shows wide variation in surface features. Knowledge of external features is essential for radiological investigations and during abdominal surgeries. Morphological variation of the liver should be considered for better patient outcomes. Segmental anatomy has received more attention for segmental resection and transplant surgery. The present study aimed to determine variations in external features of the liver and indicate its clinical importance. Materials and method A cross-sectional observational study was conducted on 52 specimens of human cadaveric livers, obtained during routine dissection in the anatomy departments of various medical colleges of Gujarat, India. Livers were examined for their morphology (lobes, notches, fissures, grooves), including their variations; pictures were taken; and results were tabulated. Result In the present study, 28 (53.84%) livers were normal in appearance in reference to surfaces, borders, lobes, and fissures. Specifically, 3.84% of livers were found with a very small left lobe, and 1.92% of livers with a large saddle-shaped left lobe. Five (9.61%) livers show the presence of Riedel's lobe, three (5.76%) livers show deep renal impression, and 13 (25%) livers show grooves on its antero-superior surface. One or two extra fissures were present in 28 livers, either present on the visceral surface of the right lobe, between the caudate process and papillary process of the caudate lobe or quadrate lobe. Pons hepatis was found in 10 (19.22%) livers. Tongue-like projection of the right lobe of the liver was observed in five (9.61%) livers, while an elongated left lobe was observed in three (5.76%) livers. Conclusion Livers show wide variations in their surface features. The variations observed in the present study will be of great help to anatomists, radiologists, and surgeons during diagnosis or surgical procedures.
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Affiliation(s)
| | - Hetal H Modi
- Anatomy, G.M.E.R.S. Medical College, Himmatnagar, Himmatnagar, IND
| | - Jinesh B Rathod
- Obstetrics and Gynaecology, Tirth Hospital, Himmatnagar, IND
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16
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Yang S, Liu C, Jiang M, Liu X, Geng L, Zhang Y, Sun S, Wang K, Yin J, Ma S, Wang S, Belmonte JCI, Zhang W, Qu J, Liu GH. A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes. Protein Cell 2024; 15:98-120. [PMID: 37378670 PMCID: PMC10833472 DOI: 10.1093/procel/pwad039] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 05/19/2023] [Indexed: 06/29/2023] Open
Abstract
Aging increases the risk of liver diseases and systemic susceptibility to aging-related diseases. However, cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely characterized. Here, we constructed the first single-nucleus transcriptomic landscape of primate liver aging, in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche cells. Upon in-depth dissection of this rich dataset, we identified impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during aging. In particular, hyperactivated sterol regulatory element-binding protein (SREBP) signaling was a hallmark of the aged liver, and consequently, forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes, manifesting as impaired detoxification and accelerated cellular senescence. This study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.
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Affiliation(s)
- Shanshan Yang
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Xuanwu Hospital Capital Medical University, Beijing 100053, China
| | - Chengyu Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - 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
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Xiaoqian Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Lingling Geng
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Yiyuan Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Shuhui Sun
- 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
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Kang Wang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jian Yin
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shuai Ma
- 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
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, 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
- University of Chinese Academy of Sciences, Beijing 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Aging Biomarker Consortium, Beijing 100101, China
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Aging Biomarker Consortium, Beijing 100101, China
| | - Guang-Hui Liu
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Xuanwu Hospital Capital Medical University, Beijing 100053, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Aging Biomarker Consortium, Beijing 100101, China
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17
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Evangelista S, Vazakidou P, Koekkoek J, Heinzelmann MT, Lichtensteiger W, Schlumpf M, Tresguerres JAF, Linillos-Pradillo B, van Duursen MBM, Lamoree MH, Leonards PEG. High throughput LC-MS/MS method for steroid hormone analysis in rat liver and plasma - unraveling methodological challenges. Talanta 2024; 266:124981. [PMID: 37516072 DOI: 10.1016/j.talanta.2023.124981] [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: 02/21/2023] [Revised: 07/20/2023] [Accepted: 07/22/2023] [Indexed: 07/31/2023]
Abstract
Comprehensive reference data for steroid hormones are lacking in rat models, particularly for early developmental stages and unconventional matrices as the liver. Therefore, we developed and validated an enzymatic, solid-phase extraction (SPE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify a panel of 23 steroid hormones in liver and plasma from adult and neonatal rats. Our approach tackles methodological challenges, focusing on undesired byproducts associated with specific enzymatic treatment, and enables a thorough assessment of potential interferences in complex matrices by utilizing unstripped plasma and liver. We propose an optimized enzymatic hydrolysis protocol using a recombinant β-glucuronidase/sulfatase mix (BGS mix) to efficiently deconjugate steroid phase II conjugates. The streamlined sample preparation and high-throughput solid phase extraction in a 96-well plate significantly accelerate sample processing for complex matrices and alarge number of samples. We were able to achieve the necessary sensitivity for accurately measuring the target analytes, particularly estrogens, in small sample sizes of 5-20 mg of liver tissue and 100 μL of plasma. Through the analysis of liver and plasma samples from adult and neonatal rats, including both sexes, our study showed a novel set of steroid hormone reference intervals. This study provides a reliable diagnostic tool for the quantification of steroids in rat models and gives insight in liver and plasma-related steroid hormone dynamics at early developmental stages. In addition, the method covers several pathway intermediates and extend the list of steroid hormones to be investigated.
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Affiliation(s)
- Sara Evangelista
- Amsterdam Institute for Life and Environment (A-LIFE), Faculty of Science, Vrije Universiteit Amsterdam, the Netherlands.
| | - Paraskevi Vazakidou
- Amsterdam Institute for Life and Environment (A-LIFE), Faculty of Science, Vrije Universiteit Amsterdam, the Netherlands
| | - Jacco Koekkoek
- Amsterdam Institute for Life and Environment (A-LIFE), Faculty of Science, Vrije Universiteit Amsterdam, the Netherlands
| | - Manuel T Heinzelmann
- Amsterdam Institute for Life and Environment (A-LIFE), Faculty of Science, Vrije Universiteit Amsterdam, the Netherlands
| | - Walter Lichtensteiger
- GREEN Tox and Institute of Veterinary Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
| | - Margret Schlumpf
- GREEN Tox and Institute of Veterinary Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
| | - Jesus A F Tresguerres
- Departments of Physiology and of Biochemistry and Molecular Biology, Complutense University of Madrid, Madrid, Spain
| | - Beatriz Linillos-Pradillo
- Departments of Physiology and of Biochemistry and Molecular Biology, Complutense University of Madrid, Madrid, Spain
| | - Majorie B M van Duursen
- Amsterdam Institute for Life and Environment (A-LIFE), Faculty of Science, Vrije Universiteit Amsterdam, the Netherlands
| | - Marja H Lamoree
- Amsterdam Institute for Life and Environment (A-LIFE), Faculty of Science, Vrije Universiteit Amsterdam, the Netherlands
| | - Pim E G Leonards
- Amsterdam Institute for Life and Environment (A-LIFE), Faculty of Science, Vrije Universiteit Amsterdam, the Netherlands
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18
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McLin VA, Franchi-Abella S, Brütsch T, Bahadori A, Casotti V, de Ville de Goyet J, Dumery G, Gonzales E, Guérin F, Hascoet S, Heaton N, Kuhlmann B, Lador F, Lambert V, Marra P, Plessier A, Quaglia A, Rougemont AL, Savale L, Sarma MS, Sitbon O, Superina RA, Uchida H, van Albada M, van der Doef HPJ, Vilgrain V, Wacker J, Zwaveling N, Debray D, Wildhaber BE. Expert management of congenital portosystemic shunts and their complications. JHEP Rep 2024; 6:100933. [PMID: 38234409 PMCID: PMC10792643 DOI: 10.1016/j.jhepr.2023.100933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 09/18/2023] [Accepted: 09/25/2023] [Indexed: 01/19/2024] Open
Abstract
Congenital portosystemic shunts are often associated with systemic complications, the most challenging of which are liver nodules, pulmonary hypertension, endocrine abnormalities, and neurocognitive dysfunction. In the present paper, we offer expert clinical guidance on the management of liver nodules, pulmonary hypertension, and endocrine abnormalities, and we make recommendations regarding shunt closure and follow-up.
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Affiliation(s)
- Valérie Anne McLin
- Swiss Pediatric Liver Center, Gastroenterology, Hepatology and Pediatric
Nutrition Unit, Department of Pediatrics, Gynecology and Obstetrics, University
of Geneva, Geneva, Switzerland
- ERN RARE LIVER
| | - Stéphanie Franchi-Abella
- Université Paris-Saclay, Faculté de médecine, Le Kremlin-Bicêtre,
France
- AP-HP, Centre de référence des maladies rares du foie de l’enfant,
Service de radiologie pédiatrique diagnostique et interventionnelle, Hôpital
Bicêtre, Le Kremlin-Bicêtre, France
- BIOMAPS UMR 9011 CNRS, INSERM, CEA, Orsay, France
- ERN RARE LIVER
- ERN Transplant Child
| | | | - Atessa Bahadori
- Department of Pediatrics, Gynecology and Obstetrics, University of
Geneva, Geneva, Switzerland
| | - Valeria Casotti
- ERN Transplant Child
- Pediatric Hepatology, Gastroenterology and Transplant Centre, ASST Papa
Giovanni XXIII Hospital, Bergamo, Italy
| | - Jean de Ville de Goyet
- Pediatric Department for the Treatment and Study of Abdominal Diseases
and Abdominal Transplantation, ISMETT UPMC, Palermo, Italy
| | - Grégoire Dumery
- Université Paris-Saclay, Faculté de médecine, Le Kremlin-Bicêtre,
France
- AP-HP, Service de gynécologie et d’obstétrique, Hôpital Bicêtre, Le
Kremlin-Bicêtre, France
| | - Emmanuel Gonzales
- Université Paris-Saclay, Faculté de médecine, Le Kremlin-Bicêtre,
France
- ERN RARE LIVER
- ERN Transplant Child
- AP-HP, Centre de référence des maladies rares du foie de l’enfant, FHU
Hepatinov, Service d’hépatologie et transplantation hépatique pédiatriques,
Hôpital Bicêtre, Le Kremlin-Bicêtre, France
- INSERM UMRS_1193, Orsay, France
| | - Florent Guérin
- Université Paris-Saclay, Faculté de médecine, Le Kremlin-Bicêtre,
France
- ERN RARE LIVER
- ERN Transplant Child
- AP-HP, Service de chirurgie pédiatrique, Hôpital Bicêtre, Le
Kremlin-Bicêtre, France
| | - Sebastien Hascoet
- Department of Congenital Heart Diseases, Hôpital Marie Lannelongue,
France
- INSERM UMR_S 999, Université Paris, France
| | - Nigel Heaton
- Institute of Liver Studies, Kings College Hospital, London,
England
| | - Béatrice Kuhlmann
- Pediatric Endocrinology, Cantonal Hospital Aarau KSA, Aarau,
Switzerland
| | - Frédéric Lador
- Service de Pneumologie, University of Geneva, Geneva,
Switzerland
| | - Virginie Lambert
- AP-HP, Centre de référence des maladies rares du foie de l’enfant,
Service de radiologie pédiatrique diagnostique et interventionnelle, Hôpital
Bicêtre, Le Kremlin-Bicêtre, France
- Cardiologie congénitale, Institut Mutualiste Montsouris, Paris,
France
| | - Paolo Marra
- Department of Radiology, Papa Giovanni XXIII Hospital, School of Medicine
and Surgery - University of Milano-Bicocca, Bergamo, Italy
| | - Aurélie Plessier
- ERN RARE LIVER
- Centre de référence des maladies vasculaires du foie, Service
d’hépatologie Hôpital Beaujon, Clichy, France
- VALDIG
| | - Alberto Quaglia
- Department of Cellular Pathology, Royal Free London NHS Foundation
Trust/UCL Cancer Institute, London, England
| | - Anne-Laure Rougemont
- Swiss Pediatric Liver Center, Division of Clinical Pathology, Diagnostic
Department, University of Geneva, Geneva, Switzerland
| | - Laurent Savale
- Université Paris-Saclay, Faculté de médecine, Le Kremlin-Bicêtre,
France
- AP-HP, Centre de référence de l’hypertension pulmonaire, Service de
pneumologie et soins intensifs respiratoires, Hôpital Bicêtre, Le
Kremlin-Bicêtre, France
- INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson,
France
- ERN Lung
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate
Institute of Medical Sciences, Lucknow, India
| | - Olivier Sitbon
- Université Paris-Saclay, Faculté de médecine, Le Kremlin-Bicêtre,
France
- AP-HP, Centre de référence de l’hypertension pulmonaire, Service de
pneumologie et soins intensifs respiratoires, Hôpital Bicêtre, Le
Kremlin-Bicêtre, France
- INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson,
France
- ERN Lung
| | - Riccardo Antonio Superina
- Northwestern University Feinberg School of Medicine, Ann & Robert H.
Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA
| | - Hajime Uchida
- Organ Transplantation Center, National Center for Child Health and
Development, Tokyo, Japan
| | - Mirjam van Albada
- Department of paediatric and congenital cardiology, University Medical
Center Groningen, University of Groningen, The Netherlands
| | - Hubert Petrus Johannes van der Doef
- Division of paediatric gastroenterology and hepatology, Department of
paediatrics, University Medical Center Groningen, Groningen, The
Netherlands
| | - Valérie Vilgrain
- ERN RARE LIVER
- VALDIG
- Université Paris Cité, CRI, INSERM, Paris, France
- AP-HP, Département de Radiologie, Hôpital Beaujon. Nord, Clichy,
France
| | - Julie Wacker
- Pediatric Cardiology Unit, Department of pediatrics, Gynecology and
Obstetrics, University of Geneva, Geneva, Switzerland
- Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque
Pédiatrique, University of Geneva and Lausanne, Switzerland
| | - Nitash Zwaveling
- Department of Pediatric Endocrinology, Amsterdam University Medical
Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Dominique Debray
- ERN RARE LIVER
- ERN Transplant Child
- AP-HP, Unité d’hépatologie pédiatrique et transplantation hépatique,
Hôpital Necker, Paris, France
- Centre de Référence des maladies rares du foie de l’enfant, FILFOIE,
France
| | - Barbara Elisabeth Wildhaber
- ERN RARE LIVER
- Swiss pediatric Liver Center, Division of pediatric surgery, Department
of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva,
Switzerland
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19
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Wu J, Duan C, Yang Y, Wang Z, Tan C, Han C, Hou X. Insights into the liver-eyes connections, from epidemiological, mechanical studies to clinical translation. J Transl Med 2023; 21:712. [PMID: 37817192 PMCID: PMC10566185 DOI: 10.1186/s12967-023-04543-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 09/19/2023] [Indexed: 10/12/2023] Open
Abstract
Maintenance of internal homeostasis is a sophisticated process, during which almost all organs get involved. Liver plays a central role in metabolism and involves in endocrine, immunity, detoxification and storage, and therefore it communicates with distant organs through such mechanisms to regulate pathophysiological processes. Dysfunctional liver is often accompanied by pathological phenotypes of distant organs, including the eyes. Many reviews have focused on crosstalk between the liver and gut, the liver and brain, the liver and heart, the liver and kidney, but with no attention paid to the liver and eyes. In this review, we summarized intimate connections between the liver and the eyes from three aspects. Epidemiologically, we suggest liver-related, potential, protective and risk factors for typical eye disease as well as eye indicators connected with liver status. For molecular mechanism aspect, we elaborate their inter-organ crosstalk from metabolism (glucose, lipid, proteins, vitamin, and mineral), detoxification (ammonia and bilirubin), and immunity (complement and inflammation regulation) aspect. In clinical application part, we emphasize the latest advances in utilizing the liver-eye axis in disease diagnosis and therapy, involving artificial intelligence-deep learning-based novel diagnostic tools for detecting liver disease and adeno-associated viral vector-based gene therapy method for curing blinding eye disease. We aim to focus on and provide novel insights into liver and eyes communications and help resolve existed clinically significant issues.
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Affiliation(s)
- Junhao Wu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Caihan Duan
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Yuanfan Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Centre, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Zhe Wang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Chen Tan
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Chaoqun Han
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
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20
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Agrawal S, Bisen AC, Sanap SN, Biswas A, Choudhury AD, Verma SK, Bhatta RS. LC-MS/MS based quantification of steroidal biomarkers in polycystic ovary syndrome induced rats. J Pharm Biomed Anal 2023; 234:115484. [PMID: 37453143 DOI: 10.1016/j.jpba.2023.115484] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/12/2023] [Accepted: 05/23/2023] [Indexed: 07/18/2023]
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine disorder that causes reproductive hormones imbalance, missed periods, infertility and distributed steroidogenesis. Reportedly, during PCOS, the endogenous levels of P4 (Progesterone), 17OHP4 (17-α hydroxy progesterone), and T4 (Testosterone) were significantly altered. Thus, quantification of steroid biomarkers involved in the steroidogenesis pathway of PCOS, such as P4, 17OHP4, and T4, holds significant importance. One important drawback of current methods is steroid metabolome traceability. Without adequate traceability, the findings of these techniques will be less reliable for identifying P4, 17OHP4, and T4. These methods also need a high sample size, especially for the most important biomarker that initiates steroidogenesis. To address these challenges, we require a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for steroid biomarker analysis. Herein the present work, using validated LC-MS/MS, PCOS biomarkers were measured and compared between normal control rats and PCOS-induced rats before and after analyte administration. The experiment utilized an isocratic separation method employing an analytical C18 column. The mobile phase consisted of acetonitrile (ACN) and aqueous 0.1% formic acid (FA) in a ratio of 90:10 (v/v). The plasma samples were processed with protein precipitation (PPT) followed by the liquid-liquid extraction (LLE) method. The lower limit of quantification (LLOQ) was 0.5 ng/mL in plasma. According to USFDA criteria, the method's systematic validation took into account linearity (r2 > 0.99), accuracy and precision of intra- and inter-batch measurements, stability, biomarker recovery (60-85%) and matrix effect (<± 15%), all of which were determined to be within range ( ± 15%). The pharmacokinetic data showed that, as compared to normal rats, PCOS-induced animals had significantly higher Cmax values for 17OHP4 and T4 (∼2 fold), while lower Cmax values for P4 (∼2 fold). The present work is novel and provides scientific information to explore systematic processes involved in steroidogenesis and boost clinical applicability for PCOS therapy.
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Affiliation(s)
- Sristi Agrawal
- Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Amol Chhatrapati Bisen
- Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Sachin Nashik Sanap
- Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Arpon Biswas
- Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Abhijit Deb Choudhury
- Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Sarvesh Kumar Verma
- Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Rabi Sankar Bhatta
- Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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21
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Kondashevskaya MV, Mikhaleva LM, Artem’yeva KA, Aleksankina VV, Areshidze DA, Kozlova MA, Pashkov AA, Manukhina EB, Downey HF, Tseilikman OB, Yegorov ON, Zhukov MS, Fedotova JO, Karpenko MN, Tseilikman VE. Unveiling the Link: Exploring Mitochondrial Dysfunction as a Probable Mechanism of Hepatic Damage in Post-Traumatic Stress Syndrome. Int J Mol Sci 2023; 24:13012. [PMID: 37629192 PMCID: PMC10455150 DOI: 10.3390/ijms241613012] [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: 06/10/2023] [Revised: 08/14/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023] Open
Abstract
PTSD is associated with disturbed hepatic morphology and metabolism. Neuronal mitochondrial dysfunction is considered a subcellular determinant of PTSD, but a link between hepatic mitochondrial dysfunction and hepatic damage in PTSD has not been demonstrated. Thus, the effects of experimental PTSD on the livers of high anxiety (HA) and low anxiety (LA) rats were compared, and mitochondrial determinants underlying the difference in their hepatic damage were investigated. Rats were exposed to predator stress for 10 days. Then, 14 days post-stress, the rats were evaluated with an elevated plus maze and assigned to HA and LA groups according to their anxiety index. Experimental PTSD caused dystrophic changes in hepatocytes of HA rats and hepatocellular damage evident by increased plasma ALT and AST activities. Mitochondrial dysfunction was evident as a predominance of small-size mitochondria in HA rats, which was positively correlated with anxiety index, activities of plasma transaminases, hepatic lipids, and negatively correlated with hepatic glycogen. In contrast, LA rats had a predominance of medium-sized mitochondria. Thus, we show links between mitochondrial dysfunction, hepatic damage, and heightened anxiety in PTSD rats. These results will provide a foundation for future research on the role of hepatic dysfunction in PTSD pathogenesis.
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Affiliation(s)
- Marina V. Kondashevskaya
- A.P. Avtsyn Research Institute of Human Morphology, B.V. Petrovsky National Research Center of Surgery, Moscow 119991, Russia (L.M.M.)
| | - Lyudmila M. Mikhaleva
- A.P. Avtsyn Research Institute of Human Morphology, B.V. Petrovsky National Research Center of Surgery, Moscow 119991, Russia (L.M.M.)
| | - Kseniya A. Artem’yeva
- A.P. Avtsyn Research Institute of Human Morphology, B.V. Petrovsky National Research Center of Surgery, Moscow 119991, Russia (L.M.M.)
| | - Valentina V. Aleksankina
- A.P. Avtsyn Research Institute of Human Morphology, B.V. Petrovsky National Research Center of Surgery, Moscow 119991, Russia (L.M.M.)
| | - David A. Areshidze
- A.P. Avtsyn Research Institute of Human Morphology, B.V. Petrovsky National Research Center of Surgery, Moscow 119991, Russia (L.M.M.)
| | - Maria A. Kozlova
- A.P. Avtsyn Research Institute of Human Morphology, B.V. Petrovsky National Research Center of Surgery, Moscow 119991, Russia (L.M.M.)
| | - Anton A. Pashkov
- Scientific and Educational Center ‘Biomedical Technologies’, School of Medical Biology, South Ural State University, Chelyabinsk 454080, Russia
- Federal Neurosurgical Center, Novosibirsk 630048, Russia
| | - Eugenia B. Manukhina
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
- Institute of General Pathology and Pathophysiology, Moscow 125315, Russia
| | - H. Fred Downey
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Olga B. Tseilikman
- Scientific and Educational Center ‘Biomedical Technologies’, School of Medical Biology, South Ural State University, Chelyabinsk 454080, Russia
- Faculty of Basic Medicine, Chelyabinsk State University, Chelyabinsk 454080, Russia
| | - Oleg N. Yegorov
- Faculty of Basic Medicine, Chelyabinsk State University, Chelyabinsk 454080, Russia
| | - Maxim S. Zhukov
- A.P. Avtsyn Research Institute of Human Morphology, B.V. Petrovsky National Research Center of Surgery, Moscow 119991, Russia (L.M.M.)
| | - Julia O. Fedotova
- Laboratory of Neuroendocrinology, Pavlov Institute of Physiology, Saint Petersburg 199034, Russia
| | - Marina N. Karpenko
- Department of Physiology, Pavlov Institute of Experimental Medicine, Saint Petersburg 197376, Russia
| | - Vadim E. Tseilikman
- Scientific and Educational Center ‘Biomedical Technologies’, School of Medical Biology, South Ural State University, Chelyabinsk 454080, Russia
- Zelman Institute of Medicine and Psychology, Novosibirsk State University, Novosibirsk 630090, Russia
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22
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van Albada ME, Shah P, Derks TGJ, Fuchs S, Jans JJM, McLin V, van der Doef HPJ. Abnormal glucose homeostasis and fasting intolerance in patients with congenital porto-systemic shunts. Front Endocrinol (Lausanne) 2023; 14:1190473. [PMID: 37664849 PMCID: PMC10471981 DOI: 10.3389/fendo.2023.1190473] [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: 03/20/2023] [Accepted: 08/04/2023] [Indexed: 09/05/2023] Open
Abstract
In physiological glucose homeostasis, the liver plays a crucial role in the extraction of glucose from the portal circulation and storage as glycogen to enable release through glycogenolysis upon fasting. In addition, insulin secreted by the pancreas is partly eliminated from the systemic circulation by hepatic first-pass. Therefore, patients with a congenital porto-systemic shunt present a unique combination of (a) postabsorptive hyperinsulinemic hypoglycaemia (HH) because of decreased insulin elimination and (b) fasting (ketotic) hypoglycaemia because of decreased glycogenolysis. Patients with porto-systemic shunts therefore provide important insight into the role of the portal circulation and hepatic function in different phases of glucose homeostasis.
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Affiliation(s)
- Mirjam E. van Albada
- Department of Pediatric Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Pratik Shah
- Department of Pediatric Endocrinology, The Royal London Childrens Hospital, Barts Health National Health Service (NHS) Trust and William Harvey Research Institute, Queen Mary University London, London, United Kingdom
| | - Terry G. J. Derks
- Department of Metabolic Diseases, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Sabine Fuchs
- Department of Metabolic Diseases, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, Netherlands
| | - Judith J. M. Jans
- Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Utrecht, Netherlands
| | - Valérie McLin
- Swiss Pediatric Liver Center, Department of Pediatrics, Obstetrics, and Gynecology, University of Geneva, Geneva, Switzerland
| | - Hubert P. J. van der Doef
- Department of Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
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23
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Wahlang B. RISING STARS: Sex differences in toxicant-associated fatty liver disease. J Endocrinol 2023; 258:e220247. [PMID: 37074385 PMCID: PMC10330380 DOI: 10.1530/joe-22-0247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 04/19/2023] [Indexed: 04/20/2023]
Abstract
Based on biological sex, the consequential health outcomes from exposures to environmental chemicals or toxicants can differ in disease pathophysiology, progression, and severity. Due to basal differences in cellular and molecular processes resulting from sexual dimorphism of organs including the liver and additional factors influencing 'gene-environment' interactions, males and females can exhibit different responses to toxicant exposures. Associations between environmental/occupational chemical exposures and fatty liver disease (FLD) have been well-acknowledged in human epidemiologic studies and their causal relationships demonstrated in experimental models. However, studies related to sex differences in liver toxicology are still limited to draw any inferences on sex-dependent chemical toxicity. The purpose of this review is to highlight the present state of knowledge on the existence of sex differences in toxicant-associated FLD (TAFLD), discuss potential underlying mechanisms driving these differences, implications of said differences on disease susceptibility, and emerging concepts. Chemicals of interest include various categories of pollutants that have been investigated in TAFLD, namely persistent organic pollutants, volatile organic compounds, and metals. Insight into research areas requiring further development is also discussed, with the objective of narrowing the knowledge gap on sex differences in environmental liver diseases. Major conclusions from this review exercise are that biological sex influences TAFLD risks, in part due to (i) toxicant disruption of growth hormone and estrogen receptor signaling, (ii) basal sex differences in energy mobilization and storage, and (iii) differences in chemical metabolism and subsequent body burden. Finally, further sex-dependent toxicological assessments are warranted for the development of sex-specific intervention strategies.
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Affiliation(s)
- Banrida Wahlang
- Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, 40202, USA
- UofL Superfund Research Center, University of Louisville, Louisville, KY, 40202, USA
- The Center for Integrative Environmental Health Sciences, University of Louisville, Louisville, KY, 40202, USA
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24
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Martin-Grau M, Monleon D. Sex dimorphism and metabolic profiles in management of metabolic-associated fatty liver disease. World J Clin Cases 2023; 11:1236-1244. [PMID: 36926130 PMCID: PMC10013124 DOI: 10.12998/wjcc.v11.i6.1236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/30/2022] [Accepted: 02/02/2023] [Indexed: 02/23/2023] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) refers to the build-up of fat in the liver associated with metabolic dysfunction and has been estimated to affect a quarter of the population worldwide. Although metabolism is highly influenced by the effects of sex hormones, studies of sex differences in the incidence and progression of MAFLD are scarce. Metabolomics represents a powerful approach to studying these differences and identifying potential biomarkers and putative mechanisms. First, metabolomics makes it possible to obtain the molecular phenotype of the individual at a given time. Second, metabolomics may be a helpful tool for classifying patients according to the severity of the disease and obtaining diagnostic biomarkers. Some studies demonstrate associations between circulating metabolites and early and established MAFLD, but little is known about how metabolites relate to and encompass sex differences in disease progression and risk management. In this review, we will discuss the epidemiological metabolomic studies for sex differences in the development and progression of MAFLD, the role of metabolic profiles in understanding mechanisms and identifying sex-dependent biomarkers, and how this evidence may help in the future management of the disease.
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Affiliation(s)
- Maria Martin-Grau
- Department of Pathology, University of Valencia, Valencia 46010, Spain
| | - Daniel Monleon
- Department of Pathology, University of Valencia, Valencia 46010, Spain
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25
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Stefan N, Schick F, Birkenfeld AL, Häring HU, White MF. The role of hepatokines in NAFLD. Cell Metab 2023; 35:236-252. [PMID: 36754018 PMCID: PMC10157895 DOI: 10.1016/j.cmet.2023.01.006] [Citation(s) in RCA: 110] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/18/2022] [Accepted: 01/13/2023] [Indexed: 02/09/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is not only a consequence of insulin resistance, but it is also an important cause of insulin resistance and major non-communicable diseases (NCDs). The close relationship of NAFLD with visceral obesity obscures the role of fatty liver from visceral adiposity as the main pathomechanism of insulin resistance and NCDs. To overcome this limitation, in analogy to the concept of adipokines, in 2008 we introduced the term hepatokines to describe the role of fetuin-A in metabolism. Since then, several other hepatokines were tested for their effects on metabolism. Here we address the dysregulation of hepatokines in people with NAFLD. Then, we discuss pathophysiological mechanisms of cardiometabolic diseases specifically related to NAFLD by focusing on hepatokine-related organ crosstalk. Finally, we propose how the determination of major hepatokines and adipokines can be used for pathomechanism-based clustering of insulin resistance in NAFLD and visceral obesity to better implement precision medicine in clinical practice.
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Affiliation(s)
- Norbert Stefan
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Otfried-Müller Str. 10, 72076 Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
| | - Fritz Schick
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Section of Experimental Radiology, Department of Radiology, University Hospital of Tübingen, Tübingen, Germany
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Otfried-Müller Str. 10, 72076 Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Otfried-Müller Str. 10, 72076 Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Morris F White
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
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26
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Yeo XY, Tan LY, Chae WR, Lee DY, Lee YA, Wuestefeld T, Jung S. Liver's influence on the brain through the action of bile acids. Front Neurosci 2023; 17:1123967. [PMID: 36816113 PMCID: PMC9932919 DOI: 10.3389/fnins.2023.1123967] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 01/18/2023] [Indexed: 02/05/2023] Open
Abstract
The liver partakes as a sensor and effector of peripheral metabolic changes and a regulator of systemic blood and nutrient circulation. As such, abnormalities arising from liver dysfunction can influence the brain in multiple ways, owing to direct and indirect bilateral communication between the liver and the brain. Interestingly, altered bile acid composition resulting from perturbed liver cholesterol metabolism influences systemic inflammatory responses, blood-brain barrier permeability, and neuron synaptic functions. Furthermore, bile acids produced by specific bacterial species may provide a causal link between dysregulated gut flora and neurodegenerative disease pathology through the gut-brain axis. This review will cover the role of bile acids-an often-overlooked category of active metabolites-in the development of neurological disorders associated with neurodegeneration. Further studies into bile acid signaling in the brain may provide insights into novel treatments against neurological disorders.
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Affiliation(s)
- Xin Yi Yeo
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore,Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Li Yang Tan
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore,Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Woo Ri Chae
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore,Department of BioNano Technology, Gachon University, Seongnam, South Korea
| | - Dong-Yup Lee
- School of Chemical Engineering, Sungkyunkwan University, Suwon, South Korea
| | - Yong-An Lee
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore,*Correspondence: Yong-An Lee,
| | - Torsten Wuestefeld
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore,School of Biological Sciences, Nanyang Technological University, Singapore, Siingapore,National Cancer Centre Singapore, Singapore, Singapore,Torsten Wuestefeld,
| | - Sangyong Jung
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore,Sangyong Jung,
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27
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Cumhur Cure M, Cure E. Severe acute respiratory syndrome coronavirus 2 may cause liver injury via Na +/H + exchanger. World J Virol 2023; 12:12-21. [PMID: 36743661 PMCID: PMC9896593 DOI: 10.5501/wjv.v12.i1.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 10/03/2022] [Accepted: 11/22/2022] [Indexed: 01/18/2023] Open
Abstract
The liver has many significant functions, such as detoxification, the urea cycle, gluconeogenesis, and protein synthesis. Systemic diseases, hypoxia, infections, drugs, and toxins can easily affect the liver, which is extremely sensitive to injury. Systemic infection of severe acute respiratory syndrome coronavirus 2 can cause liver damage. The primary regulator of intracellular pH in the liver is the Na+/H+ exchanger (NHE). Physiologically, NHE protects hepatocytes from apoptosis by making the intracellular pH alkaline. Severe acute respiratory syndrome coronavirus 2 increases local angiotensin II levels by binding to angiotensin-converting enzyme 2. In severe cases of coronavirus disease 2019, high angi-otensin II levels may cause NHE overstimulation and lipid accumulation in the liver. NHE overstimulation can lead to hepatocyte death. NHE overstimulation may trigger a cytokine storm by increasing proinflammatory cytokines in the liver. Since the release of proinflammatory cytokines such as interleukin-6 increases with NHE activation, the virus may indirectly cause an increase in fibrinogen and D-dimer levels. NHE overstimulation may cause thrombotic events and systemic damage by increasing fibrinogen levels and cytokine release. Also, NHE overstimulation causes an increase in the urea cycle while inhibiting vitamin D synthesis and gluconeogenesis in the liver. Increasing NHE3 activity leads to Na+ loading, which impairs the containment and fluidity of bile acid. NHE overstimulation can change the gut microbiota composition by disrupting the structure and fluidity of bile acid, thus triggering systemic damage. Unlike other tissues, tumor necrosis factor-alpha and angiotensin II decrease NHE3 activity in the intestine. Thus, increased luminal Na+ leads to diarrhea and cytokine release. Severe acute respiratory syndrome coronavirus 2-induced local and systemic damage can be improved by preventing virus-induced NHE overstimulation in the liver.
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Affiliation(s)
- Medine Cumhur Cure
- Department of Biochemistry, Private Tanfer Hospital, Istanbul 34394, Turkey
| | - Erkan Cure
- Department of Internal Medicine, Bagcilar Medilife Hospital, Istanbul 34200, Turkey
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Carson MD, Warner AJ, Hathaway-Schrader JD, Geiser VL, Kim J, Gerasco JE, Hill WD, Lemasters JJ, Alekseyenko AV, Wu Y, Yao H, Aguirre JI, Westwater C, Novince CM. Minocycline-induced disruption of the intestinal FXR/FGF15 axis impairs osteogenesis in mice. JCI Insight 2023; 8:160578. [PMID: 36413391 PMCID: PMC9870091 DOI: 10.1172/jci.insight.160578] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 11/16/2022] [Indexed: 11/24/2022] Open
Abstract
Antibiotic-induced shifts in the indigenous gut microbiota influence normal skeletal maturation. Current theory implies that gut microbiota actions on bone occur through a direct gut/bone signaling axis. However, our prior work supports that a gut/liver signaling axis contributes to gut microbiota effects on bone. Our purpose was to investigate the effects of minocycline, a systemic antibiotic treatment for adolescent acne, on pubertal/postpubertal skeletal maturation. Sex-matched specific pathogen-free (SPF) and germ-free (GF) C57BL/6T mice were administered a clinically relevant minocycline dose from age 6-12 weeks. Minocycline caused dysbiotic shifts in the gut bacteriome and impaired skeletal maturation in SPF mice but did not alter the skeletal phenotype in GF mice. Minocycline administration in SPF mice disrupted the intestinal farnesoid X receptor/fibroblast growth factor 15 axis, a gut/liver endocrine axis supporting systemic bile acid homeostasis. Minocycline-treated SPF mice had increased serum conjugated bile acids that were farnesoid X receptor (FXR) antagonists, suppressed osteoblast function, decreased bone mass, and impaired bone microarchitecture and fracture resistance. Stimulating osteoblasts with the serum bile acid profile from minocycline-treated SPF mice recapitulated the suppressed osteogenic phenotype found in vivo, which was mediated through attenuated FXR signaling. This work introduces bile acids as a potentially novel mediator of gut/liver signaling actions contributing to gut microbiota effects on bone.
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Affiliation(s)
- Matthew D Carson
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Pediatrics, Division of Endocrinology, College of Medicine.,Department of Stomatology, Division of Periodontics, College of Dental Medicine
| | - Amy J Warner
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Pediatrics, Division of Endocrinology, College of Medicine.,Department of Stomatology, Division of Periodontics, College of Dental Medicine
| | - Jessica D Hathaway-Schrader
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Pediatrics, Division of Endocrinology, College of Medicine.,Department of Stomatology, Division of Periodontics, College of Dental Medicine
| | - Vincenza L Geiser
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Pediatrics, Division of Endocrinology, College of Medicine.,Department of Stomatology, Division of Periodontics, College of Dental Medicine
| | - Joseph Kim
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Pediatrics, Division of Endocrinology, College of Medicine.,Department of Stomatology, Division of Periodontics, College of Dental Medicine
| | - Joy E Gerasco
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Drug Discovery & Biomedical Sciences, College of Pharmacy
| | - William D Hill
- Department of Pathology and Laboratory Medicine, College of Medicine
| | - John J Lemasters
- Department of Drug Discovery & Biomedical Sciences, College of Pharmacy.,Department of Biochemistry & Molecular Biology, College of Medicine
| | - Alexander V Alekseyenko
- Department of Oral Health Sciences, College of Dental Medicine.,Biomedical Informatics Center, Program for Human Microbiome Research, Department of Public Health Sciences, College of Medicine.,Department of Healthcare Leadership and Management, College of Health Professions; and
| | - Yongren Wu
- Department of Orthopedics & Physical Medicine, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.,Department of Bioengineering, College of Engineering, Clemson University, Clemson, South Carolina, USA
| | - Hai Yao
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Bioengineering, College of Engineering, Clemson University, Clemson, South Carolina, USA
| | - J Ignacio Aguirre
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida, USA
| | - Caroline Westwater
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Chad M Novince
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Pediatrics, Division of Endocrinology, College of Medicine.,Department of Stomatology, Division of Periodontics, College of Dental Medicine
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29
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Merbach M, Ramchandran R, Spearman AD. Hepatic factor may not originate from hepatocytes. Front Cardiovasc Med 2022; 9:999315. [PMID: 36148055 PMCID: PMC9486074 DOI: 10.3389/fcvm.2022.999315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 08/18/2022] [Indexed: 01/25/2023] Open
Abstract
Pulmonary arteriovenous malformations (PAVMs) develop universally in patients with univentricular congenital heart disease. They are believed to form due to lack of an unidentified factor from hepatocytes that perfuses the lungs to maintain vascular homeostasis and prevent PAVM formation. This unidentified factor is termed hepatic factor; however, the identity, mechanism, and origin of hepatic factor are unknown. Several hepatic factor candidates have been previously proposed, but few data are available to support previous hypotheses. Recent data showed that soluble vascular endothelial growth factor receptor 1 (sVEGFR1) is enriched in hepatic vein blood and may be a potential hepatic factor candidate. We used imaging and molecular approaches with wild-type mice to determine whether sVEGFR1 originates from hepatocytes in the liver. To our surprise, we identified that sVEGFR1 is negligibly expressed by hepatocytes but is robustly expressed by the non-parenchymal cell population of the liver. This suggests that hepatic factor may not originate from hepatocytes and alternative hypotheses should be considered. We believe it is necessary to consider hepatic factor candidates more broadly to finally identify hepatic factor and develop targeted therapies for CHD-associated PAVMs.
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Affiliation(s)
- Monica Merbach
- Division of Cardiology, Department of Pediatrics, Medical College of Wisconsin, Children's Wisconsin, Herma Heart Institute, Milwaukee, WI, United States
| | - Ramani Ramchandran
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States,Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Children's Wisconsin, Milwaukee, WI, United States
| | - Andrew D. Spearman
- Division of Cardiology, Department of Pediatrics, Medical College of Wisconsin, Children's Wisconsin, Herma Heart Institute, Milwaukee, WI, United States,Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States,*Correspondence: Andrew D. Spearman
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30
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Wang TY, Tao SY, Wu YX, An T, Lv BH, Liu JX, Liu YT, Jiang GJ. Quinoa Reduces High-Fat Diet-Induced Obesity in Mice via Potential Microbiota-Gut-Brain-Liver Interaction Mechanisms. Microbiol Spectr 2022; 10:e0032922. [PMID: 35583337 PMCID: PMC9241864 DOI: 10.1128/spectrum.00329-22] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/21/2022] [Indexed: 01/04/2023] Open
Abstract
The gut microbiota is important in the occurrence and development of obesity. It can not only via its metabolites, but also through microbiota-gut-brain-liver interactions, directly or indirectly, influence obesity. Quinoa, known as one kind of pseudocereals and weight loss food supplements, has been high-profile for its high nutritional value and broad applications. In this context, we produced high-fat diet-induced (HFD) obese mouse models and assessed the efficacy of quinoa with saponin and quinoa without saponin on obesity. We explored the potential therapeutic mechanisms of quinoa using methods such as 16S rRNA, Western blotting, Immunohistochemical (IHC). Our results indicated that quinoa can improve the obese symptoms significantly on HFD mice, as well as aberrant glucose and lipid metabolism. Further analyses suggest that quinoa can regulate microbiota in the colon and have predominantly regulation on Bacteroidetes, Actinobacteria and Desulfovibrio, meanwhile can decrease the F/B ratio and the abundance of Blautia. Contemporaneously, quinoa can upregulate the expression of TGR5 in the colon and brain, as well as GLP-1 in the colon, liver and brain. while downregulate the expression of TLR4 in the colon and liver, as well as markers of ER stress and oxidative stress in livers and serums. Beyond this, tight junctional proteins in colons and brains are also increased in response to quinoa. Therefore, quinoa can effectively reduce obesity and may possibly exert through microbiota-gut-brain-liver interaction mechanisms. IMPORTANCE Gut microbiota has been investigated extensively, as a driver of obesity as well as a therapeutic target. Studies of its mechanisms are predominantly microbiota-gut-brain axis or microbiota-gut-liver axis. Recent studies have shown that there is an important correlation between the gut-brain-liver axis and the energy balance of the body. Our research focus on microbiota-gut-brain-liver axis, as well as influences of quinoa in intestinal microbiota. We extend this study to the interaction between microbiota and brains, and the result shows obvious differences in the composition of the microbiome between the HFD group and others. These observations infer that besides the neurotransmitter and related receptors, microbiota itself may be a mediator for regulating bidirectional communication, along the gut-brain-liver axis. Taken together, these results also provide strong evidence for widening the domain of applicability of quinoa.
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Affiliation(s)
- Ting-Ye Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Si-Yu Tao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yan-Xiang Wu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Tian An
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Bo-Han Lv
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jia-Xian Liu
- Zhong Li Science and Technology Limited Company, Beijing, China
| | - Yu-Tong Liu
- Gansu Pure High-Land Agricultural Science and Technology Limited Company, Lanzhou, Gansu, China
| | - Guang-Jian Jiang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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31
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Langlois A, Dumond A, Vion J, Pinget M, Bouzakri K. Crosstalk Communications Between Islets Cells and Insulin Target Tissue: The Hidden Face of Iceberg. Front Endocrinol (Lausanne) 2022; 13:836344. [PMID: 35185804 PMCID: PMC8851682 DOI: 10.3389/fendo.2022.836344] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/06/2022] [Indexed: 12/11/2022] Open
Abstract
The regulation of insulin secretion is under control of a complex inter-organ/cells crosstalk involving various metabolites and/or physical connections. In this review, we try to illustrate with current knowledge how β-cells communicate with other cell types and organs in physiological and pathological contexts. Moreover, this review will provide a better understanding of the microenvironment and of the context in which β-cells exist and how this can influence their survival and function. Recent studies showed that β-cell insulin secretion is regulated also by a direct and indirect inter-organ/inter-cellular communication involving various factors, illustrating the idea of "the hidden face of the iceberg". Moreover, any disruption on the physiological communication between β-cells and other cells or organs can participate on diabetes onset. Therefore, for new anti-diabetic treatments' development, it is necessary to consider the entire network of cells and organs involved in the regulation of β-cellular function and no longer just β-cell or pancreatic islet alone. In this context, we discuss here the intra-islet communication, the β-cell/skeletal muscle, β-cell/adipose tissue and β-cell/liver cross talk.
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