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Bhatia V, Vikram V, Chandel A, Rattan A. Interplay between PI3k/AKT signaling and caspase pathway in Alzheimer disease: mechanism and therapeutic implications. Inflammopharmacology 2025; 33:1785-1802. [PMID: 40088370 DOI: 10.1007/s10787-025-01715-z] [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: 02/11/2025] [Accepted: 02/21/2025] [Indexed: 03/17/2025]
Abstract
Alzheimer's disease, a neurodegenerative disorder, is characterized by cognitive impairment, neuronal loss, and synaptic dysfunction. The interplay between the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway and the caspase-mediated apoptotic cascade plays a pivotal role in its progression. The signaling pathway responsible for neuronal survival also regulates synaptic plasticity and resistance to oxidative stress, whereas caspase activation accelerates neurodegeneration by triggering cell death and inflammation. Dysregulation of these pathways leads to amyloid-beta (Aβ) accumulation, tau hyperphosphorylation, and mitochondrial dysfunction, creating a negative feedback loop and accelerating disease progression. Emerging treatment methods that target PI3K/AKT activation and caspase inhibition have showed promise in preclinical models, preventing neuronal apoptosis while retaining cognitive function. This review investigates the molecular processes driving PI3K/AKT and caspase crosstalk, their significance in Alzheimer's disease, and prospective therapeutic strategies aiming at regulating these pathways to improve disease outcomes.
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Affiliation(s)
- Vandana Bhatia
- Department of Pharmacology, CT University Ludhiana, Ludhiana, Punjab, 142024, India.
| | - Vir Vikram
- Department of Pharmacology, CT University Ludhiana, Ludhiana, Punjab, 142024, India
| | - Anjali Chandel
- Department of Pharmacology, Laureate Institute of Pharmacy Kathog, Kangra, 177101, India
| | - Aditya Rattan
- Department of Pharmacology, Laureate Institute of Pharmacy Kathog, Kangra, 177101, India
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Lee WJ, Jo JH, Uwamahoro C, Jang SI, Jung EJ, Bae JW, Moon J, Kim DH, Yi JK, Ha JJ, Oh DY, Kwon WS. Role of PI3K/AKT signaling pathway during capacitation. Theriogenology 2025; 235:94-102. [PMID: 39799846 DOI: 10.1016/j.theriogenology.2024.12.026] [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: 09/03/2024] [Revised: 12/02/2024] [Accepted: 12/29/2024] [Indexed: 01/15/2025]
Abstract
Spermatozoa must undergo a complex maturation process within the female genital tract known as capacitation. This process entails the phosphorylation or dephosphorylation of various proteins, and multiple signaling pathways are recognized to play a role. The present study aims to identify alterations in the expression of proteins related to the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) signaling pathway and assess sperm functions during capacitation. Mouse spermatozoa were incubated in a medium supplemented with bovine serum albumin to induce capacitation. Subsequently, we evaluated sperm motility, cell viability, capacitation status, and acrosome reaction. Consequently, we observed a significant increase in several kinematic parameters. Additionally, the capacitation status and acrosome reaction exhibited a time-dependent manner. Furthermore, we confirmed a significant increase in the phosphorylation of PI3K, PDK1, and p-AKT (Thr308), along with activation of PKA and tyrosine phosphorylation. These alterations in protein expression were found to correlate with capacitation status, acrosome reaction, and various kinematic parameters. Therefore, our findings show that the phosphorylation of PKA and PI3K/AKT pathway-related proteins during capacitation may plays a crucial role in regulating sperm function. These findings contribute to a better understanding of the molecular mechanisms and interactions of the PI3K/AKT signaling pathway in the capacitation process.
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Affiliation(s)
- Woo-Jin Lee
- Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, 37224, Republic of Korea
| | - Jae-Hwan Jo
- Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, 37224, Republic of Korea
| | - Claudine Uwamahoro
- Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, 37224, Republic of Korea
| | - Seung-Ik Jang
- Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, 37224, Republic of Korea
| | - Eun-Ju Jung
- Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, 37224, Republic of Korea
| | - Jeong-Won Bae
- Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, 37224, Republic of Korea
| | - Joonho Moon
- Seoul National University Hospital, Seoul 03080, Republic of Korea
| | - Dae-Hyun Kim
- Department of Animal Science, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Jun Koo Yi
- School of Animal Life Convergence Science, Hankyong National University, Anseong, 17579, Republic of Korea
| | - Jae Jung Ha
- Gyeongbuk Livestock Research Institute, Yeongju, 36052, Republic of Korea
| | - Dong Yep Oh
- Gyeongbuk Livestock Research Institute, Yeongju, 36052, Republic of Korea.
| | - Woo-Sung Kwon
- Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, 37224, Republic of Korea; Research Institute for Innovative Animal Science, Kyungpook National University, Sangju, 37224, Republic of Korea.
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Lin HYH, Chen IY, Wang TM, Yen CH, Chen Y, Chen YH, Dai DF, Huang JF, Chiu YW, Yang MY. The Role of Mitochondrial AKT1 Signaling in Renal Tubular Injury of Metabolic Syndrome. Kidney Int Rep 2025; 10:906-920. [PMID: 40225378 PMCID: PMC11993225 DOI: 10.1016/j.ekir.2024.12.021] [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: 07/29/2024] [Revised: 12/02/2024] [Accepted: 12/10/2024] [Indexed: 04/15/2025] Open
Abstract
Introduction Metabolic syndrome (MetS) is increasingly recognized as a contributor to kidney disease, yet the underlying mechanisms remain poorly defined. Recent studies suggest a pivotal role for mitochondrial dysfunction in renal injury. We hypothesized that mitochondrial AKT1 signaling in renal tubules plays a critical role in MetS-related kidney injuries. Methods MetS was induced in a 8-week-old C57BL/6 male mice using a high-fat diet (HFD) for 4 months compared with controls on a standard chow diet. Additional experiments were conducted in DB/DB diabetic mice and their controls (WT and DB/WT) to validate findings. Renal metabolic parameters, mitochondrial AKT1 signaling, and markers of kidney injury were assessed. Results MetS mice exhibited significant weight gain, altered glucose handling, and decreased energy expenditure. Although kidney size and basic renal function (blood urea nitrogen [BUN], creatinine) were unchanged, markers of renal damage, including proteinuria (P = 0.0002) and KIM-1 (P < 0.0001) were elevated. Histological analyses showed increased tubular injury (P < 0.0001) and glomerulosclerosis (P = 0.0004). Transmission electron microscopy revealed aberrant mitochondria (P < 0.001), with reduced cristae length (P = 0.012) and numbers (P < 0.001). Immunohistochemistry, immunofluorescence, and Western blot analysis confirmed increased phosphorylated AKT1 (pAKT1) in the mitochondria of renal tubules (P = 0.0474), findings corroborated in DB/DB mice. This translocation of pAKT1 into mitochondria correlated with decreased cell viability upon inhibition of heat shock protein 90, indicating a dependency on mitochondrial AKT1 for cell survival. Conclusion These findings underscore the mechanistic link between mitochondrial AKT1 signaling and renal tubular injury in MetS. Targeting mitochondrial dysfunction may offer new avenues for preventing and treating kidney diseases in patients with MetS.
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Affiliation(s)
- Hugo Y.-H. Lin
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - I-Ya Chen
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tzu-Ming Wang
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Hung Yen
- Graduate Institute of Natural Product, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yumay Chen
- School of Medicine, University of California, Irvine, California, USA
| | - Yen-Hua Chen
- School of Medicine, Doctoral Program of Clinical and Experimental Medicine, Institute of Biomedical Sciences, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Dao-Fu Dai
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Wen Chiu
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Yu Yang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Lu Y, Zhang X, Guan Z, Ji R, Peng F, Zhao C, Gao W, Gao F. Molecular pathogenesis of Cryptosporidium and advancements in therapeutic interventions. Parasite 2025; 32:7. [PMID: 39902829 PMCID: PMC11792522 DOI: 10.1051/parasite/2025001] [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: 08/07/2024] [Accepted: 01/14/2025] [Indexed: 02/06/2025] Open
Abstract
Cryptosporidiosis, caused by a Cryptosporidium infection, is a serious gastrointestinal disease commonly leading to diarrhea in humans. This disease poses a particular threat to infants, young children, and those with weakened immune systems. The treatment of cryptosporidiosis is challenging due to the current lack of an effective treatment or vaccine. Ongoing research is focused on understanding the molecular pathogenesis of Cryptosporidium and developing pharmacological treatments. In this review, we examine the signaling pathways activated by Cryptosporidium infection within the host and their role in protecting host epithelial cells. Additionally, we also review the research progress of chemotherapeutic targets against cryptosporidia-specific enzymes and anti-Cryptosporidium drugs (including Chinese and Western medicinal drugs), aiming at the development of more effective treatments for cryptosporidiosis.
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Affiliation(s)
- Yilong Lu
- College of Basic Medical Sciences, Shandong Second Medical University Weifang China
| | - Xiaoning Zhang
- College of Basic Medical Sciences, Shandong Second Medical University Weifang China
| | - Zhiyu Guan
- College of Basic Medical Sciences, Shandong Second Medical University Weifang China
| | - Rui Ji
- College of Traditional Chinese Medicine, Shandong Second Medical University Weifang China
| | - Fujun Peng
- College of Basic Medical Sciences, Shandong Second Medical University Weifang China
| | - Chunzhen Zhao
- College of Pharmacy, Shandong Second Medical University Weifang China
| | - Wei Gao
- College of Clinical Medicine, Shandong Second Medical University Weifang China
| | - Feng Gao
- College of Pharmacy, Shandong Second Medical University Weifang China
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Vujovic F, Farahani RM. Thyroid Hormones and Brain Development: A Focus on the Role of Mitochondria as Regulators of Developmental Time. Cells 2025; 14:150. [PMID: 39936942 PMCID: PMC11816491 DOI: 10.3390/cells14030150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 01/16/2025] [Accepted: 01/19/2025] [Indexed: 02/13/2025] Open
Abstract
Thyroid hormones (THs) regulate metabolism in a homeostatic state in an adult organism. During the prenatal period, prior to the establishment of homeostatic mechanisms, THs assume additional functions as key regulators of brain development. Here, we focus on reviewing the role of THs in orchestrating cellular dynamics in a developing brain. The evidence from the reviewed scientific literature suggests that the developmental roles of the hormones are predominantly mediated by non-genomic mitochondrial effects of THs due to attenuation of genomic effects of THs that antagonise non-genomic impacts. We argue that the key function of TH signalling during brain development is to orchestrate the tempo of self-organisation of neural progenitor cells. Further, evidence is provided that major neurodevelopmental consequences of hypothyroidism stem from an altered tempo of cellular self-organisation.
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Affiliation(s)
- Filip Vujovic
- IDR/WSLHD Research and Education Network, Sydney, NSW 2145, Australia
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
| | - Ramin M Farahani
- IDR/WSLHD Research and Education Network, Sydney, NSW 2145, Australia
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
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Palmero Casanova B, Albentosa González L, Maringer K, Sabariegos R, Mas A. A conserved role for AKT in the replication of emerging flaviviruses in vertebrates and vectors. Virus Res 2024; 348:199447. [PMID: 39117146 PMCID: PMC11364138 DOI: 10.1016/j.virusres.2024.199447] [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: 05/29/2024] [Revised: 07/11/2024] [Accepted: 08/05/2024] [Indexed: 08/10/2024]
Abstract
One third of all emerging infectious diseases are vector-borne, with no licensed antiviral therapies available against any vector-borne viruses. Zika virus and Usutu virus are two emerging flaviviruses transmitted primarily by mosquitoes. These viruses modulate different host pathways, including the PI3K/AKT/mTOR pathway. Here, we report the effect on ZIKV and USUV replication of two AKT inhibitors, Miransertib (ARQ-092, allosteric inhibitor) and Capivasertib (AZD5363, competitive inhibitor) in different mammalian and mosquito cell lines. Miransertib showed a stronger inhibitory effect against ZIKV and USUV than Capivasertib in mammalian cells, while Capivasertib showed a stronger effect in mosquito cells. These findings indicate that AKT plays a conserved role in flavivirus infection, in both the vertebrate host and invertebrate vector. Nevertheless, the specific function of AKT may vary depending on the host species. These findings indicate that AKT may be playing a conserved role in flavivirus infection in both, the vertebrate host and the invertebrate vector. However, the specific function of AKT may vary depending on the host species. A better understanding of virus-host interactions is therefore required to develop new treatments to prevent human disease and new approaches to control transmission by insect vectors.
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Affiliation(s)
- Blanca Palmero Casanova
- Instituto de Investigación Biomédica de la UCLM (IB-UCLM), C/Almansa 14, 02008 Albacete, Spain
| | - Laura Albentosa González
- Instituto de Investigación Biomédica de la UCLM (IB-UCLM), C/Almansa 14, 02008 Albacete, Spain; Facultad de farmacia, Universidad de Castilla-La Mancha, Av. Dr. José María Sánchez Ibáñez, s/n, 02008 Albacete, Spain
| | - Kevin Maringer
- The Pirbright Institute, Ash Road, Pirbright, Surrey GU24 0NF, UK
| | - Rosario Sabariegos
- Instituto de Investigación Biomédica de la UCLM (IB-UCLM), C/Almansa 14, 02008 Albacete, Spain; Unidad asociada de Biomedicina UCLM-CSIC. Universidad de Castilla-La Mancha. C/Altagracia 50, 13071 Ciudad Real, Spain; Facultad de Medicina, Universidad de Castilla-La Mancha. C/Almansa 14, 02008 Albacete, Spain
| | - Antonio Mas
- Instituto de Investigación Biomédica de la UCLM (IB-UCLM), C/Almansa 14, 02008 Albacete, Spain; Facultad de farmacia, Universidad de Castilla-La Mancha, Av. Dr. José María Sánchez Ibáñez, s/n, 02008 Albacete, Spain; Unidad asociada de Biomedicina UCLM-CSIC. Universidad de Castilla-La Mancha. C/Altagracia 50, 13071 Ciudad Real, Spain.
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Lukoseviciute M, Need E, Holzhauser S, Dalianis T, Kostopoulou ON. Combined targeted therapy with PI3K and CDK4/6, or FGFR inhibitors show synergistic effects in a neuroblastoma spheroid culture model. Biomed Pharmacother 2024; 177:116993. [PMID: 38889643 DOI: 10.1016/j.biopha.2024.116993] [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: 04/11/2024] [Revised: 06/13/2024] [Accepted: 06/15/2024] [Indexed: 06/20/2024] Open
Abstract
AIM Neuroblastoma (NB) is, in spite of current intensive therapy with severe side effects, still not cured so new therapies are needed. Recently, we showed combining phosphoinositide 3-kinase (PI3K) (BYL719), fibroblast growth factor receptor (FGFR) (JNJ-42756493) and cyclin-dependent kinase 4/6 (CDK4/6) (PD-0332991) inhibitors, in vitro in NB cell lines grown as monolayers had synergistic effects. However, there were variations depending on the combinations used and the targeted NB cell lines. To obtain further information and to mimic more natural circumstances, we investigated the effects of single and combined administrations of the above inhibitors in spheroid NB-cultures. MATERIAL AND METHODS Spheroid cultures of NB cell lines SK-N-AS, SK-N-BE(2)-C, SK-N-FI and SK-N-SH were established and treated with single and combined administrations of BYL719, JNJ-42756493, and PD-0332991 and followed for growth, viability, proliferation, cytotoxicity and migration. KEY FINDINGS Single inhibitor administrations gave dose dependent responses with regard to growth and viability and their combinations were efficient and resulted in a range of additive and synergistic effects. The responses to individual drugs and their various combinations were predominantly alike regardless of whether the cells were cultivated in monolayer or D spheroid NB models. However, in general, slightly higher drug concentrations were necessary in spheroidcultures. SIGNIFICANCE This study provides pre-clinical evidence that single PI3K, FGFR, and CDK4/6, inhibitors exhibit promising anti-NB activity and when combined lower doses of the drugs could be also used in spheroid NB-cultures, supporting the pursuit of further in vitro and in vivo studies in preparation for future potential clinical use.
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Affiliation(s)
- Monika Lukoseviciute
- Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm 171 64, Sweden
| | - Emma Need
- Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm 171 64, Sweden
| | - Stefan Holzhauser
- Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm 171 64, Sweden
| | - Tina Dalianis
- Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm 171 64, Sweden
| | - Ourania N Kostopoulou
- Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm 171 64, Sweden.
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Murgo E, Falco G, Serviddio G, Mazzoccoli G, Colangelo T. Circadian patterns of growth factor receptor-dependent signaling and implications for carcinogenesis. Cell Commun Signal 2024; 22:319. [PMID: 38858728 PMCID: PMC11163765 DOI: 10.1186/s12964-024-01676-w] [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: 03/07/2024] [Accepted: 05/21/2024] [Indexed: 06/12/2024] Open
Abstract
Several different signaling pathways that regulate cell proliferation and differentiation are initiated by binding of ligands to cell-surface and membrane-bound enzyme-linked receptors, such as receptor tyrosine kinases and serine-threonine kinases. They prompt phosphorylation of tyrosine and serine-threonine residues and initiate downstream signaling pathways and priming of intracellular molecules that convey the signal in the cytoplasm and nucleus, with transcriptional activation of specific genes enriching cell growth and survival-related cascades. These cell processes are rhythmically driven by molecular clockworks endowed in every cell type and when deregulated play a crucial role in cancer onset and progression. Growth factors and their matching receptor-dependent signaling are frequently overexpressed and/or dysregulated in many cancer types. In this review we focus on the interplay between biological clocks and Growth Factor Receptor-dependent signaling in the context of carcinogenesis.
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Affiliation(s)
- Emanuele Murgo
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS "Casa Sollievo della Sofferenza",, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo, 71013, Italy
| | - Giorgia Falco
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS "Casa Sollievo della Sofferenza",, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo, 71013, Italy
| | - Gaetano Serviddio
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianluigi Mazzoccoli
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS "Casa Sollievo della Sofferenza",, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo, 71013, Italy.
| | - Tommaso Colangelo
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
- Cancer Cell Signaling Unit, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), San Giovanni Rotondo, Italy.
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Duran P, Yang BA, Plaster E, Eiken M, Loebel C, Aguilar CA. Tracking of Nascent Matrix Deposition during Muscle Stem Cell Activation across Lifespan Using Engineered Hydrogels. Adv Biol (Weinh) 2024; 8:e2400091. [PMID: 38616175 DOI: 10.1002/adbi.202400091] [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: 02/18/2024] [Revised: 03/22/2024] [Indexed: 04/16/2024]
Abstract
Adult stem cells occupy a niche that contributes to their function, but how stem cells rebuild their microenvironment after injury remains an open-ended question. Herein, biomaterial-based systems and metabolic labeling are utilized to evaluate how skeletal muscle stem cells deposit extracellular matrix. Muscle stem cells and committed myoblasts are observed to generate less nascent matrix than muscle resident fibro-adipogenic progenitors. When cultured on substrates that matched the stiffness of physiological uninjured and injured muscles, muscle stem cells increased nascent matrix deposition with activation kinetics. Reducing the ability to deposit nascent matrix by an inhibitor of vesicle trafficking (Exo-1) attenuated muscle stem cell function and mimicked impairments observed from muscle stem cells isolated from old muscles. Old muscle stem cells are observed to deposit less nascent matrix than young muscle stem cells, which is rescued with therapeutic supplementation of insulin-like growth factors. These results highlight the role of nascent matrix production with muscle stem cell activation.
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Affiliation(s)
- Pamela Duran
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
- BioInterfaces Institute, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Benjamin A Yang
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
- BioInterfaces Institute, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Eleanor Plaster
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Madeline Eiken
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Claudia Loebel
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Materials Science & Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Carlos A Aguilar
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
- BioInterfaces Institute, University of Michigan, Ann Arbor, MI, 48109, USA
- Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, 48109, USA
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Chrysafi M, Jacovides C, Papadopoulou SK, Psara E, Vorvolakos T, Antonopoulou M, Dakanalis A, Martin M, Voulgaridou G, Pritsa A, Mentzelou M, Giaginis C. The Potential Effects of the Ketogenic Diet in the Prevention and Co-Treatment of Stress, Anxiety, Depression, Schizophrenia, and Bipolar Disorder: From the Basic Research to the Clinical Practice. Nutrients 2024; 16:1546. [PMID: 38892480 PMCID: PMC11174630 DOI: 10.3390/nu16111546] [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: 05/05/2024] [Revised: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND The ketogenic diet (KD) has been highly developed in the past for the treatment of epileptic pathological states in children and adults. Recently, the current re-emergence in its popularity mainly focuses on the therapy of cardiometabolic diseases. The KD can also have anti-inflammatory and neuroprotective activities which may be applied to the prevention and/or co-treatment of a diverse range of psychiatric disorders. PURPOSE This is a comprehensive literature review that intends to critically collect and scrutinize the pre-existing research basis and clinical data of the potential advantageous impacts of a KD on stress, anxiety, depression, schizophrenia and bipolar disorder. METHODS This literature review was performed to thoroughly represent the existing research in this topic, as well as to find gaps in the international scientific community. In this aspect, we carefully investigated the ultimate scientific web databases, e.g., PubMed, Scopus, and Web of Science, to derive the currently available animal and clinical human surveys by using efficient and representative keywords. RESULTS Just in recent years, an increasing amount of animal and clinical human surveys have focused on investigating the possible impacts of the KD in the prevention and co-treatment of depression, anxiety, stress, schizophrenia, and bipolar disorder. Pre-existing basic research with animal studies has consistently demonstrated promising results of the KD, showing a propensity to ameliorate symptoms of depression, anxiety, stress, schizophrenia, and bipolar disorder. However, the translation of these findings to clinical settings presents a more complex issue. The majority of the currently available clinical surveys seem to be moderate, usually not controlled, and have mainly assessed the short-term effects of a KD. In addition, some clinical surveys appear to be characterized by enormous dropout rates and significant absence of compliance measurement, as well as an elevated amount of heterogeneity in their methodological design. CONCLUSIONS Although the currently available evidence seems promising, it is highly recommended to accomplish larger, long-term, randomized, double-blind, controlled clinical trials with a prospective design, in order to derive conclusive results as to whether KD could act as a potential preventative factor or even a co-treatment agent against stress, anxiety, depression, schizophrenia, and bipolar disorder. Basic research with animal studies is also recommended to examine the molecular mechanisms of KD against the above psychiatric diseases.
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Affiliation(s)
- Maria Chrysafi
- Department of Food Science and Nutrition, School of Environment, University of the Aegean, 81400 Lemnos, Greece; (M.C.); (C.J.); (E.P.); (M.A.); (M.M.); (M.M.)
| | - Constantina Jacovides
- Department of Food Science and Nutrition, School of Environment, University of the Aegean, 81400 Lemnos, Greece; (M.C.); (C.J.); (E.P.); (M.A.); (M.M.); (M.M.)
- Department of Nutritional Sciences and Dietetics, Faculty of Health Sciences, International Hellenic University, 57400 Thessaloniki, Greece; (S.K.P.); (G.V.); (A.P.)
| | - Sousana K. Papadopoulou
- Department of Nutritional Sciences and Dietetics, Faculty of Health Sciences, International Hellenic University, 57400 Thessaloniki, Greece; (S.K.P.); (G.V.); (A.P.)
| | - Evmorfia Psara
- Department of Food Science and Nutrition, School of Environment, University of the Aegean, 81400 Lemnos, Greece; (M.C.); (C.J.); (E.P.); (M.A.); (M.M.); (M.M.)
| | - Theophanis Vorvolakos
- Department of Psychiatry, School of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Marina Antonopoulou
- Department of Food Science and Nutrition, School of Environment, University of the Aegean, 81400 Lemnos, Greece; (M.C.); (C.J.); (E.P.); (M.A.); (M.M.); (M.M.)
| | - Antonios Dakanalis
- Department of Mental Health, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy;
- Department of Medicine and Surgery, University of Milan Bicocca, Via Cadore 38, 20900 Monza, Italy
| | - Mato Martin
- Department of Food Science and Nutrition, School of Environment, University of the Aegean, 81400 Lemnos, Greece; (M.C.); (C.J.); (E.P.); (M.A.); (M.M.); (M.M.)
| | - Gavriela Voulgaridou
- Department of Nutritional Sciences and Dietetics, Faculty of Health Sciences, International Hellenic University, 57400 Thessaloniki, Greece; (S.K.P.); (G.V.); (A.P.)
| | - Agathi Pritsa
- Department of Nutritional Sciences and Dietetics, Faculty of Health Sciences, International Hellenic University, 57400 Thessaloniki, Greece; (S.K.P.); (G.V.); (A.P.)
| | - Maria Mentzelou
- Department of Food Science and Nutrition, School of Environment, University of the Aegean, 81400 Lemnos, Greece; (M.C.); (C.J.); (E.P.); (M.A.); (M.M.); (M.M.)
| | - Constantinos Giaginis
- Department of Food Science and Nutrition, School of Environment, University of the Aegean, 81400 Lemnos, Greece; (M.C.); (C.J.); (E.P.); (M.A.); (M.M.); (M.M.)
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11
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Pasha R, Bashir B, Omed D, Adam S, Kamath A, Elhofy A, Ferdousi M, Azmi S, Soran H. Impact of Lipid-lowering Therapy on Cancer Risk: A Narrative Review. Clin Ther 2024; 46:411-419. [PMID: 38744540 DOI: 10.1016/j.clinthera.2024.03.004] [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: 11/13/2023] [Revised: 02/27/2024] [Accepted: 03/13/2024] [Indexed: 05/16/2024]
Abstract
PURPOSE There are inconsistent reports of an association between low cholesterol, use of lipid-lowering agents, and carcinogenesis. The purpose of this paper was to examine the relationship between cancer, lipids, statin use, and use of other lipid-lowering therapies. METHODS This comprehensive literature review incorporated article searches in electronic databases (Embase, PubMed, OVID) and reference lists of relevant articles, with the authors' expertise in lipidology. This review considered seminal and novel research looking at the relationship between cholesterol, lipid-lowering therapies, and cancer. FINDINGS Statin use has been reported to reduce the risk for incident cancer or progression of cancer; however, it is unknown whether this reduced risk of carcinogenesis is due to the pleotropic properties of statins or the effects of low cholesterol. The effect of ezetimibe on carcinogenesis has been regarded as neutral, despite earlier concerns of increased cancer risk with its use. Proprotein convertase subtilisin/kexin (PCSK)-9 monoclonal antibodies have been shown to have a neutral effect on carcinogenesis. Despite anti-cancer effects of fibrates in vitro, studies in humans have yielded inconsistent outcomes leaning toward protection against the development and progression of cancer. IMPLICATIONS Statins, fibrates, PCSK9 monoclonal antibodies, and ezetimibe have a neutral effect on cancer risk, and the first three may provide some protection. PSCK9 monoclonal antibodies have the potential to enhance the response to checkpoint inhibitor therapy for cancer. Further research is needed to determine which drugs can be issued in adjuvant therapy to improve outcomes in patients undergoing cancer treatment.
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Affiliation(s)
- Raabya Pasha
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; Manchester University NHS Foundation Trust, Manchester, United Kingdom; NIHR/Wellcome Trust Clinical Research Facility, Manchester, United Kingdom
| | - Bilal Bashir
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; Manchester University NHS Foundation Trust, Manchester, United Kingdom; NIHR/Wellcome Trust Clinical Research Facility, Manchester, United Kingdom
| | - Diya Omed
- Faculty of Medicine, University of Kurdistan, Erbil, Iraq
| | - Safwaan Adam
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; Department of Endocrinology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Anoushka Kamath
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
| | - Ahmed Elhofy
- Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Maryam Ferdousi
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; NIHR/Wellcome Trust Clinical Research Facility, Manchester, United Kingdom
| | - Shazli Azmi
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; Diabetes, Endocrinology and Metabolism Centre, Manchester University NHS Trust, Manchester, United Kingdom
| | - Handrean Soran
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; NIHR/Wellcome Trust Clinical Research Facility, Manchester, United Kingdom; Diabetes, Endocrinology and Metabolism Centre, Manchester University NHS Trust, Manchester, United Kingdom.
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12
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Duran P, Yang BA, Plaster E, Eiken M, Loebel C, Aguilar CA. Quantification of local matrix deposition during muscle stem cell activation using engineered hydrogels. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.20.576326. [PMID: 38328131 PMCID: PMC10849481 DOI: 10.1101/2024.01.20.576326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Adult stem cells occupy a niche that contributes to their function, but how stem cells remodel their microenvironment remains an open-ended question. Herein, biomaterials-based systems and metabolic labeling were utilized to evaluate how skeletal muscle stem cells deposit extracellular matrix. Muscle stem cells and committed myoblasts were observed to generate less nascent matrix than muscle resident fibro-adipogenic progenitors. When cultured on substrates that matched the stiffness of physiological uninjured and injured muscles, the increased nascent matrix deposition was associated with stem cell activation. Reducing the ability to deposit nascent matrix in muscle stem cells attenuated function and mimicked impairments observed from muscle stem cells isolated from old aged muscles, which could be rescued with therapeutic supplementation of insulin-like growth factors. These results highlight how nascent matrix production is critical for maintaining healthy stem cell function.
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Affiliation(s)
- Pamela Duran
- Dept. of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
- BioInterfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Benjamin A. Yang
- Dept. of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
- BioInterfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Eleanor Plaster
- Dept. of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Madeline Eiken
- Dept. of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Claudia Loebel
- Dept. of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
- Dept. of Materials Science & Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Carlos A. Aguilar
- Dept. of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
- BioInterfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
- Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA
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13
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Chen L, Lu Y, Zhao M, Xu J, Wang Y, Xu Q, Cao Y, Liu H. A non-canonical role of endothelin converting enzyme 1 (ECE1) in promoting lung cancer development via directly targeting protein kinase B (AKT). J Gene Med 2024; 26:e3612. [PMID: 37897251 DOI: 10.1002/jgm.3612] [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: 07/28/2023] [Revised: 09/19/2023] [Accepted: 09/25/2023] [Indexed: 10/30/2023] Open
Abstract
BACKGROUND Lung cancer is the second most common malignancy in the world, and lung adenocarcinoma (LUAD) in particular is the leading cause of cancer death worldwide. Endothelin converting enzyme 1 (ECE1) is a membrane-bound metalloprotease involved in endothelin-1 (ET-1) processing and regulates vasoconstriction. However, very few studies have reported the involvement of ECE1 in regulating tumor cell proliferation, and the mechanism remains poorly understood. Therefore, we aimed to determine the role of ECE1 in lung cancer development. METHODS The Cancer Genome Atlas database and Kaplan-Meier plotter were used to assess the association between ECE1 and lung cancer. The expression of ECE1 was detected using immunohistochemistry staining and western blotting. A variety of in vitro assays were performed to evaluate the effects of ECE1 on the colony formation, proliferation, migration and invasion using ECE1 knockdown lung cancer cells. The gene expression profiles regulated by ECE1 were investigated by RNA sequencing. An immunoprecipitation assay and immunofluorescence assay were used to evaluate the mechanism underlying the regulatory effect of ECE1 on protein kinase B (AKT). The effect of ECE1 on tumor development was assessed by xenografted lung cancer cells in either C57BL/6 mice or nude mice. RESULTS ECE1 was upregulated in LUAD and correlated with the poor prognosis of patients with LUAD. Functional studies showed that knockdown of ECE1 retarded the progression of tumors formed by lung cancer cells at least partly by inhibiting tumor cell proliferation. Moreover, ECE1 accelerated tumor cell proliferation through promoting AKT activation dispensable of its canonical target ET-1. Mechanically, ECE1 interacted with the pleckstrin homology (PH) domain of AKT and facilitated its translocation to the plasma membrane for activation. Furthermore, the inhibition of AKT activity counteracted the lung cancer cell growth inhibition observed both in vitro and in xenografts caused by ECE1 suppression. CONCLUSIONS The present study reveals a non-canonical function of ECE1 in regulating AKT activation and cell proliferation, which provides the basis for the development of a novel strategy for the intervention of cancer including LUAD by abrogating ECE1-AKT signaling.
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Affiliation(s)
- Li Chen
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yikai Lu
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Mengmeng Zhao
- Research Center of Translational Medicine, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Junfang Xu
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yan Wang
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qinghua Xu
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China
| | - Yajuan Cao
- Department of Integrated Traditional Chinese and Western Medicine, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China
| | - Haipeng Liu
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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14
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Keleş ID, Günel T, Özgör BY, Ülgen E, Gümüşoğlu E, Hosseini MK, Sezerman U, Buyru F, Yeh J, Baştu E. Gene pathway analysis of the endometrium at the start of the window of implantation in women with unexplained infertility and unexplained recurrent pregnancy loss: is unexplained recurrent pregnancy loss a subset of unexplained infertility? HUM FERTIL 2023; 26:1129-1141. [PMID: 36369952 DOI: 10.1080/14647273.2022.2143299] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 06/05/2022] [Indexed: 11/14/2022]
Abstract
This study aims to understand differences/similarities in the genetic profile of the endometrium at the start of window of implantation (WOI) in women with unexplained infertility (UI) and unexplained recurrent pregnancy loss (uRPL). Differentially expressed genes (DEGs) from the endometrium were evaluated using gene expression array and pathway enrichment analysis was performed to analyse gene expression pathways involved in both conditions. We found 2,171 genes arranged in 117 pathways and 730 genes arranged in 33 pathways differentially expressed in endometrium of patients in UI and uRPL, respectively. Complement-coagulation cascades, morphine addiction pathway, and PI3K-Akt signalling pathway were predominantly differentially expressed in UI. Cancer pathways, NF-κB signalling pathway, and actin cytoskeleton regulation pathway showed significant changes in uRPL. Forty-eight percent of DEGs and 84% of differentially expressed pathways in uRPL were found in the endometrium of UI patients. Unexpected close association in gene expression pathways between UI and uRPL is observed supporting the hypothesis 'uRPL is a clinical subset of UI'. Yet 100% DEGs overlap wasn't found suggesting the endometrium has still some different gene expression patterns at start of WOI in UI and uRPL. Lastly, diagnostic tools may be developed for uRPL because more specific genes-pathways are involved compared with UI, which shows broader genetic expression profile.
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Affiliation(s)
- Irem Demiral Keleş
- Department of Obstetrics and Gynecology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Tuba Günel
- Department of Molecular Biology and Genetics, Istanbul University, Istanbul, Turkey
| | - Bahar Yüksel Özgör
- Department of Obstetrics and Gynecology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Ege Ülgen
- Department of Biostatistics and Medical Informatics, Acibadem University School of Medicine, Istanbul, Turkey
| | - Ece Gümüşoğlu
- Department of Molecular Biology and Genetics, Istanbul University, Istanbul, Turkey
| | | | - Uğur Sezerman
- Department of Biostatistics and Medical Informatics, Acibadem University School of Medicine, Istanbul, Turkey
| | - Faruk Buyru
- Department of Obstetrics and Gynecology, Acibadem University School of Medicine, Istanbul, Turkey
| | - John Yeh
- Department of Obstetrics and Gynecology, UMass Memorial Medical Center, Worcester, MA, USA
| | - Ercan Baştu
- Department of Obstetrics and Gynecology, Acibadem University School of Medicine, Istanbul, Turkey
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15
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Nasir NJN, Arifin N, Noordin KBA, Yusop N. Bone repair and key signalling pathways for cell-based bone regenerative therapy: A review. J Taibah Univ Med Sci 2023; 18:1350-1363. [PMID: 37305024 PMCID: PMC10248876 DOI: 10.1016/j.jtumed.2023.05.015] [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: 02/20/2023] [Revised: 04/11/2023] [Accepted: 05/15/2023] [Indexed: 06/13/2023] Open
Abstract
Advances in cell-based regenerative therapy create new opportunities for the treatment of bone-related disorders and injuries, by improving the reparative phase of bone healing. Apart from the classical approach of bone grafting, the application of cell-based therapies, particularly stem cells (SCs), has gained a lot of attention in recent years. SCs play an important role in regenerative therapy due to their excellent ability to differentiate into bone-forming cells. Regeneration of new bone is regulated by a wide variety of signalling molecules and intracellular networks, which are responsible for coordinating cellular processes. The activated signalling cascade is significantly involved in cell survival, proliferation, apoptosis, and interaction with the microenvironment and other types of cells within the healing site. Despite the increasing evidence from studies conducted on signalling pathways associated with bone formation, the exact mechanism involved in controlling the differentiation stage of transplanted cells is not well understood. Identifying the key activated pathways involved in bone regeneration may allow for precise manipulation of the relevant signalling molecules within the progenitor cell population to accelerate the healing process. The in-depth knowledge of molecular mechanisms would be advantageous in improving the efficiency of personalised medicine and targeted therapy in regenerative medicine. In this review, we briefly introduce the theory of bone repair mechanism and bone tissue engineering followed by an overview of relevant signalling pathways that have been identified to play an important role in cell-based bone regenerative therapy.
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Affiliation(s)
- Nur Julia N. Nasir
- Basic and Medical Sciences Department, School of Dental Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia
| | - Norsyahida Arifin
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Penang, Malaysia
| | - Khairul Bariah A.A. Noordin
- Basic and Medical Sciences Department, School of Dental Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia
| | - Norhayati Yusop
- Basic and Medical Sciences Department, School of Dental Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia
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16
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Vujovic F, Shepherd CE, Witting PK, Hunter N, Farahani RM. Redox-Mediated Rewiring of Signalling Pathways: The Role of a Cellular Clock in Brain Health and Disease. Antioxidants (Basel) 2023; 12:1873. [PMID: 37891951 PMCID: PMC10604469 DOI: 10.3390/antiox12101873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/14/2023] [Accepted: 10/15/2023] [Indexed: 10/29/2023] Open
Abstract
Metazoan signalling pathways can be rewired to dampen or amplify the rate of events, such as those that occur in development and aging. Given that a linear network topology restricts the capacity to rewire signalling pathways, such scalability of the pace of biological events suggests the existence of programmable non-linear elements in the underlying signalling pathways. Here, we review the network topology of key signalling pathways with a focus on redox-sensitive proteins, including PTEN and Ras GTPase, that reshape the connectivity profile of signalling pathways in response to an altered redox state. While this network-level impact of redox is achieved by the modulation of individual redox-sensitive proteins, it is the population by these proteins of critical nodes in a network topology of signal transduction pathways that amplifies the impact of redox-mediated reprogramming. We propose that redox-mediated rewiring is essential to regulate the rate of transmission of biological signals, giving rise to a programmable cellular clock that orchestrates the pace of biological phenomena such as development and aging. We further review the evidence that an aberrant redox-mediated modulation of output of the cellular clock contributes to the emergence of pathological conditions affecting the human brain.
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Affiliation(s)
- Filip Vujovic
- IDR/Westmead Institute for Medical Research, Sydney, NSW 2145, Australia; (F.V.); (N.H.)
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
| | | | - Paul K. Witting
- Redox Biology Group, Charles Perkins Centre, Faculty of Medicine and Health, School of Medical Sciences, The University of Sydney, Sydney, NSW 2006, Australia;
| | - Neil Hunter
- IDR/Westmead Institute for Medical Research, Sydney, NSW 2145, Australia; (F.V.); (N.H.)
| | - Ramin M. Farahani
- IDR/Westmead Institute for Medical Research, Sydney, NSW 2145, Australia; (F.V.); (N.H.)
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
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17
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Asghariazar V, Kadkhodayi M, Sarailoo M, Jolfayi AG, Baradaran B. MicroRNA-143 as a potential tumor suppressor in cancer: An insight into molecular targets and signaling pathways. Pathol Res Pract 2023; 250:154792. [PMID: 37689002 DOI: 10.1016/j.prp.2023.154792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 08/25/2023] [Accepted: 09/02/2023] [Indexed: 09/11/2023]
Abstract
MicroRNAs (MiRNAs), which are highly conserved and small noncoding RNAs, negatively regulate gene expression and influence signaling pathways involved in essential biological activities, including cell proliferation, differentiation, apoptosis, and cell invasion. MiRNAs have received much attention in the past decade due to their significant roles in cancer development. In particular, microRNA-143 (miR-143) is recognized as a tumor suppressor and is downregulated in most cancers. However, it seems that miR-143 is upregulated in rare cases, such as prostate cancer stem cells, and acts as an oncogene. The present review will outline the current studies illustrating the impact of miR-143 expression levels on cancer progression and discuss its target genes and their relevant signaling pathways to discover a potential therapeutic way for cancer.
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Affiliation(s)
- Vahid Asghariazar
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Deputy of Research and Technology, Ardabil University of Medical Sciences, Ardabil, Iran.
| | - Mahtab Kadkhodayi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Animal Biology, Faculty of Natural Sciences, The University of Tabriz, Tabriz, Iran
| | - Mehdi Sarailoo
- Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Amir Ghaffari Jolfayi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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18
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Moon DO. A comprehensive review of the effects of resveratrol on glucose metabolism: unveiling the molecular pathways and therapeutic potential in diabetes management. Mol Biol Rep 2023; 50:8743-8755. [PMID: 37642760 DOI: 10.1007/s11033-023-08746-1] [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: 04/15/2023] [Accepted: 08/08/2023] [Indexed: 08/31/2023]
Abstract
Resveratrol, a naturally occurring polyphenolic compound predominantly found in red wine and grapes, has garnered attention for its potential role in regulating carbohydrate digestion, glucose absorption, and metabolism. This review aims to deliver a comprehensive analysis of the molecular mechanisms and therapeutic potential of resveratrol in influencing vital processes in glucose homeostasis. These processes include carbohydrate digestion, glucose absorption, glycogen storage, insulin secretion, glucose metabolism in muscle cells, and triglyceride synthesis in adipocytes.The goal of this review is to offer an in-depth understanding of the multifaceted effects of resveratrol on glucose metabolism. By doing so, it presents valuable insights into its potential applications for preventing and treating metabolic disorders. This comprehensive examination of resveratrol's impact on glucose management will contribute to the growing body of knowledge on this promising natural compound, which may benefit researchers, healthcare professionals, and individuals interested in metabolic disorder prevention and treatment.
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Affiliation(s)
- Dong-Oh Moon
- Department of Biology Education, Daegu University, 201, Daegudae-ro, Gyeongsan-si, 38453, Gyeongsangbuk-do, Republic of Korea.
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19
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Liu Y, Kong H, Cai H, Chen G, Chen H, Ruan W. Progression of the PI3K/Akt signaling pathway in chronic obstructive pulmonary disease. Front Pharmacol 2023; 14:1238782. [PMID: 37799975 PMCID: PMC10548138 DOI: 10.3389/fphar.2023.1238782] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 09/08/2023] [Indexed: 10/07/2023] Open
Abstract
Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory disease characterized by a slow progression and caused by the inhalation of harmful particulate matter. Cigarette smoke and air pollutants are the primary contributing factors. Currently, the pathogenesis of COPD remains incompletely understood. The PI3K/Akt signaling pathway has recently emerged as a critical regulator of inflammation and oxidative stress response in COPD, playing a pivotal role in the disease's progression and treatment. This paper reviews the association between the PI3K/Akt pathway and COPD, examines effective PI3K/Akt inhibitors and novel anti-COPD agents, aiming to identify new therapeutic targets for clinical intervention in this disease.
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Affiliation(s)
- Yanhui Liu
- Department of Clinical Pharmacy, Anhui Provincial Children’s Hospital, Hefei, Anhui, China
| | - Haobo Kong
- Department of Respiratory Intensive Care Unit, Anhui Chest Hospital, Hefei, Anhui, China
| | - Heping Cai
- Department of Clinical Pharmacy, Anhui Provincial Children’s Hospital, Hefei, Anhui, China
| | - Guanru Chen
- Department of Clinical Pharmacy, Anhui Provincial Children’s Hospital, Hefei, Anhui, China
| | - Huiying Chen
- Department of Clinical Pharmacy, Anhui Provincial Children’s Hospital, Hefei, Anhui, China
| | - Wenyi Ruan
- Department of Clinical Pharmacy, Anhui Provincial Children’s Hospital, Hefei, Anhui, China
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20
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Kim M, Kim KY. Wound healing effects of Asparagus lucidus Lindl extract through the phosphorylation of ERK1/2. BMC Complement Med Ther 2023; 23:238. [PMID: 37454069 PMCID: PMC10349518 DOI: 10.1186/s12906-023-04066-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 07/01/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Skin is the outermost part of the human body and is essential in maintaining body homeostasis. In the event of skin injury, rapid wound repair is crucial to protect the body. In this study, we investigated the wound-healing properties of Asparagus lucidus Lindl extract by promoting keratinocyte proliferation. METHODS To evaluate the effect of Asparagus lucidus Lindl extract on skin regeneration, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to measure keratinocyte proliferation, while an in vitro wound-healing assay was performed to evaluate wound closure through keratinocyte re-epithelialization. The intracellular mechanisms of the extract were studied using Western blot analysis to measure the phosphorylated forms of mitogen-activated protein kinases and protein kinase B. The mRNA expression of cell cycle-related genes was analyzed using quantitative real time-PCR analysis. A murine in vivo wound-healing assay was also conducted to observe the effect of the extract on wound closure. RESULTS Asparagus lucidus Lindl extract induced 131.15% keratinocyte proliferation compared to the control in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The in vitro wound-healing assay showed that the extract improved wound closure by 216.94% through keratinocyte re-epithelialization. Western blot analysis revealed that the phosphorylated form of extracellular signal-regulated kinase 1/2 was increased by extract treatment. Quantitative real time-PCR analysis showed a dose-dependent increase in the mRNA expression of c-fos, c-jun, and VEGF. The in vivo wound-healing assay showed a significant increase (22.13%) of wound closure compared to the control on day 5. CONCLUSION Asparagus lucidus Lindl extract promotes keratinocyte proliferation by activating the extracellular signal-regulated kinase 1/2 pathway and up-regulating the mRNA expression of c-fos, c-jun, and vascular endothelial growth factor.
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Affiliation(s)
- Minho Kim
- Graduate School of Biotechnology, Kyung Hee University, Seocheon, Giheung, Yongin-Si, Gyeonggi-do, 446-701, Korea
| | - Ki-Young Kim
- Graduate School of Biotechnology, Kyung Hee University, Seocheon, Giheung, Yongin-Si, Gyeonggi-do, 446-701, Korea.
- Department of Genetics and Biotechnology, College of Life Science, and Graduate School of Biotechnology, Kyung Hee University, Seocheon, Giheung, Yongin-si, Gyeonggi-do, 446-701, Korea.
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21
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Zhao T, Zhu Y, Zhao R, Xiong S, Sun J, Zhang J, Fan D, Deng J, Yang H. Structure-activity relationship, bioactivities, molecular mechanisms, and clinical application of nuciferine on inflammation-related diseases. Pharmacol Res 2023; 193:106820. [PMID: 37315822 DOI: 10.1016/j.phrs.2023.106820] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 05/23/2023] [Accepted: 06/11/2023] [Indexed: 06/16/2023]
Abstract
Nuciferine aporphine alkaloid mainly exists in Nelumbo nucifera Gaertn and is a beneficial to human health, such as anti-obesity, lowering blood lipid, prevention of diabetes and cancer, closely associated with inflammation. Importantly, nuciferine may contribute to its bioactivities by exerting intense anti-inflammatory activities in multiple models. However, no review has summarized the anti-inflammatory effect of nuciferine. This review critically summarized the information regarding the structure-activity relationships of dietary nuciferine. Moreover, biological activities and clinical application on inflammation-related diseases, such as obesity, diabetes, liver, cardiovascular diseases, and cancer, as well as their potential mechanisms, involving oxidative stress, metabolic signaling, and gut microbiota has been reviewed. The current work provides a better understanding of the anti-inflammation properties of nuciferine against multiple diseases, thereby improving the utilization and application of nuciferine-containing plants across functional food and medicine.
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Affiliation(s)
- Tong Zhao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Yuchen Zhu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Rui Zhao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Shiyi Xiong
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Jing Sun
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Juntao Zhang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials, Shaanxi R&D Center of Biomaterials and Fermentation Engineering, Biotech & Biomed Research Institute, School of Chemical Engineering, Northwest University, Xi'an, China
| | - Jianjun Deng
- State Key Laboratory of Vegetable Biobreeding, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing 100081, China; Shaanxi Key Laboratory of Degradable Biomedical Materials, Shaanxi R&D Center of Biomaterials and Fermentation Engineering, Biotech & Biomed Research Institute, School of Chemical Engineering, Northwest University, Xi'an, China.
| | - Haixia Yang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
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Zhang C, Zhong L, Lau YK, Wu M, Yao L, Schaer TP, Mauck RL, Malhotra NR, Qin L, Smith LJ. Single Cell RNA Sequencing Reveals Emergent Notochord-Derived Cell Subpopulations in the Postnatal Nucleus Pulposus. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.21.541589. [PMID: 37292597 PMCID: PMC10245831 DOI: 10.1101/2023.05.21.541589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Intervertebral disc degeneration is a leading cause of chronic low back pain. Cell-based strategies that seek to treat disc degeneration by regenerating the central nucleus pulposus hold significant promise, but key challenges remain. One of these is the inability of therapeutic cells to effectively mimic the performance of native nucleus pulposus cells, which are unique amongst skeletal cell types in that they arise from the embryonic notochord. In this study we use single cell RNA sequencing to demonstrate emergent heterogeneity amongst notochord-derived nucleus pulposus cells in the postnatal mouse disc. Specifically, we established the existence of early and late stage nucleus pulposus cells, corresponding to notochordal progenitor and mature cells, respectively. Late stage cells exhibited significantly higher expression levels of extracellular matrix genes including aggrecan, and collagens II and VI, along with elevated TGF-β and PI3K-Akt signaling. Additionally, we identified Cd9 as a novel surface marker of late stage nucleus pulposus cells, and demonstrated that these cells were localized to the nucleus pulposus periphery, increased in numbers with increasing postnatal age, and co-localized with emerging glycosaminoglycan-rich matrix. Finally, we used a goat model to show the Cd9+ nucleus pulposus cell numbers decrease with moderate severity disc degeneration, suggesting that these cells are associated with maintenance of the healthy nucleus pulposus extracellular matrix. Improved understanding of the developmental mechanisms underlying regulation of ECM deposition in the postnatal NP may inform improved regenerative strategies for disc degeneration and associated low back pain.
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23
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Li H, Zhang X, Shang J, Feng X, Yu L, Fan J, Ren J, Zhang R, Duan X. Identification of NETs-related biomarkers and molecular clusters in systemic lupus erythematosus. Front Immunol 2023; 14:1150828. [PMID: 37143669 PMCID: PMC10151561 DOI: 10.3389/fimmu.2023.1150828] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 04/04/2023] [Indexed: 05/06/2023] Open
Abstract
Neutrophil extracellular traps (NETs) is an important process involved in the pathogenesis of systemic lupus erythematosus (SLE), but the potential mechanisms of NETs contributing to SLE at the genetic level have not been clearly investigated. This investigation aimed to explore the molecular characteristics of NETs-related genes (NRGs) in SLE based on bioinformatics analysis, and identify associated reliable biomarkers and molecular clusters. Dataset GSE45291 was acquired from the Gene Expression Omnibus repository and used as a training set for subsequent analysis. A total of 1006 differentially expressed genes (DEGs) were obtained, most of which were associated with multiple viral infections. The interaction of DEGs with NRGs revealed 8 differentially expressed NRGs (DE-NRGs). The correlation and protein-protein interaction analyses of these DE-NRGs were performed. Among them, HMGB1, ITGB2, and CREB5 were selected as hub genes by random forest, support vector machine, and least absolute shrinkage and selection operator algorithms. The significant diagnostic value for SLE was confirmed in the training set and three validation sets (GSE81622, GSE61635, and GSE122459). Additionally, three NETs-related sub-clusters were identified based on the hub genes' expression profiles analyzed by unsupervised consensus cluster assessment. Functional enrichment was performed among the three NETs subgroups, and the data revealed that cluster 1 highly expressed DEGs were prevalent in innate immune response pathways while that of cluster 3 were enriched in adaptive immune response pathways. Moreover, immune infiltration analysis also revealed that innate immune cells were markedly infiltrated in cluster 1 while the adaptive immune cells were upregulated in cluster 3. As per our knowledge, this investigation is the first to explore the molecular characteristics of NRGs in SLE, identify three potential biomarkers (HMGB1, ITGB2, and CREB5), and three distinct clusters based on these hub biomarkers.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Xinwang Duan
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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24
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Si P, Wang G, Wu W, Hussain S, Guo L, Wu W, Yang Q, Xing F. SakA Regulates Morphological Development, Ochratoxin A Biosynthesis and Pathogenicity of Aspergillus westerdijkiae and the Response to Different Environmental Stresses. Toxins (Basel) 2023; 15:292. [PMID: 37104230 PMCID: PMC10141874 DOI: 10.3390/toxins15040292] [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: 02/28/2023] [Revised: 04/05/2023] [Accepted: 04/14/2023] [Indexed: 04/28/2023] Open
Abstract
Ochratoxin A (OTA), as a common mycotoxin, has seriously harmful effects on agricultural products, livestock and humans. There are reports on the regulation of SakA in the MAPK pathway, which regulates the production of mycotoxins. However, the role of SakA in the regulation of Aspergillus westerdijkiae and OTA production is not clear. In this study, a SakA deletion mutant (ΔAwSakA) was constructed. The effects of different concentrations of D-sorbitol, NaCl, Congo red and H2O2 on the mycelia growth, conidia production and biosynthesis of OTA were investigated in A. westerdijkiae WT and ΔAwSakA. The results showed that 100 g/L NaCl and 3.6 M D-sorbitol significantly inhibited mycelium growth and that a concentration of 0.1% Congo red was sufficient to inhibit the mycelium growth. A reduction in mycelium development was observed in ΔAwSakA, especially in high concentrations of osmotic stress. A lack of AwSakA dramatically reduced OTA production by downregulating the expression of the biosynthetic genes otaA, otaY, otaB and otaD. However, otaC and the transcription factor otaR1 were slightly upregulated by 80 g/L NaCl and 2.4 M D-sorbitol, whereas they were downregulated by 0.1% Congo red and 2 mM H2O2. Furthermore, ΔAwSakA showed degenerative infection ability toward pears and grapes. These results suggest that AwSakA is involved in the regulation of fungal growth, OTA biosynthesis and the pathogenicity of A. westerdijkiae and could be influenced by specific environmental stresses.
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Affiliation(s)
- Peidong Si
- College of Food Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China; (P.S.); (W.W.); (Q.Y.)
- Key Laboratory of Agro-Products Quality and Safety Control in Storage and Transport Process, Ministry of Agriculture and Rural Affairs, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (G.W.); (W.W.); (S.H.); (L.G.)
| | - Gang Wang
- Key Laboratory of Agro-Products Quality and Safety Control in Storage and Transport Process, Ministry of Agriculture and Rural Affairs, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (G.W.); (W.W.); (S.H.); (L.G.)
| | - Wenqing Wu
- Key Laboratory of Agro-Products Quality and Safety Control in Storage and Transport Process, Ministry of Agriculture and Rural Affairs, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (G.W.); (W.W.); (S.H.); (L.G.)
| | - Sarfaraz Hussain
- Key Laboratory of Agro-Products Quality and Safety Control in Storage and Transport Process, Ministry of Agriculture and Rural Affairs, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (G.W.); (W.W.); (S.H.); (L.G.)
| | - Ling Guo
- Key Laboratory of Agro-Products Quality and Safety Control in Storage and Transport Process, Ministry of Agriculture and Rural Affairs, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (G.W.); (W.W.); (S.H.); (L.G.)
| | - Wei Wu
- College of Food Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China; (P.S.); (W.W.); (Q.Y.)
| | - Qingli Yang
- College of Food Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China; (P.S.); (W.W.); (Q.Y.)
| | - Fuguo Xing
- Key Laboratory of Agro-Products Quality and Safety Control in Storage and Transport Process, Ministry of Agriculture and Rural Affairs, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (G.W.); (W.W.); (S.H.); (L.G.)
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25
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Kopp KO, Glotfelty EJ, Li Y, Greig NH. Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment. Pharmacol Res 2022; 186:106550. [PMID: 36372278 PMCID: PMC9712272 DOI: 10.1016/j.phrs.2022.106550] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/03/2022] [Accepted: 11/06/2022] [Indexed: 11/13/2022]
Abstract
Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for such diseases. Interestingly, increased inflammation and neurodegenerative disease risk have been associated with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), suggesting that treatments that mitigate T2DM pathology may be successful in treating neuroinflammatory and neurodegenerative pathology as well. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes healthy insulin signaling, regulates blood sugar levels, and suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs have been developed and approved by the US Food and Drug Administration (FDA) and related global regulatory authorities for the treatment of T2DM. Furthermore, GLP-1R stimulating drugs have been associated with anti-inflammatory, neurotrophic, and neuroprotective properties in neurodegenerative disorder preclinical models, and hence hold promise for repurposing as a treatment for neurodegenerative diseases. In this review, we discuss incretin signaling, neuroinflammatory pathways, and the intersections between neuroinflammation, brain IR, and neurodegenerative diseases, with a focus on AD and PD. We additionally overview current FDA-approved incretin receptor stimulating drugs and agents in development, including unimolecular single, dual, and triple receptor agonists, and highlight those in clinical trials for neurodegenerative disease treatment. We propose that repurposing already-approved GLP-1R agonists for the treatment of neurodegenerative diseases may be a safe, efficacious, and cost-effective strategy for ameliorating AD and PD pathology by quelling neuroinflammation.
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Affiliation(s)
- Katherine O Kopp
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, United States.
| | - Elliot J Glotfelty
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, United States; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Yazhou Li
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, United States
| | - Nigel H Greig
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, United States.
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BPR0C261, An Analogous of Microtubule Disrupting Agent D-24851 Enhances the Radiosensitivity of Human Non-Small Cell Lung Cancer Cells via p53-Dependent and p53-Independent Pathways. Int J Mol Sci 2022; 23:ijms232214083. [PMID: 36430560 PMCID: PMC9692308 DOI: 10.3390/ijms232214083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/23/2022] [Accepted: 09/23/2022] [Indexed: 11/17/2022] Open
Abstract
(1) Destabilization of microtubule dynamics is a primary strategy to inhibit fast growing tumor cells. The low cytotoxic derivative of microtubule inhibitor D-24851, named BPR0C261 exhibits antitumor activity via oral administration. In this study, we investigated if BPR0C261 could modulate the radiation response of human non-small cell lung cancer (NSCLC) cells with or without p53 expression. (2) Different doses of BPR0C261 was used to treat human NSCLC A549 (p53+/+) cells and H1299 (p53-/-) cells. The cytotoxicity, radiosensitivity, cell cycle distribution, DNA damage, and protein expression were evaluated using an MTT assay, a colony formation assay, flow cytometry, a comet assay, and an immunoblotting analysis, respectively. (3) BPR0C261 showed a dose-dependent cytotoxicity on A549 cells and H1299 cells with IC50 at 0.38 μM and 0.86 μM, respectively. BPR0C261 also induced maximum G2/M phase arrest and apoptosis in both cell lines after 24 h of treatment with a dose-dependent manner. The colony formation analysis demonstrated that a combination of low concentration of BPR0C261 and X-rays caused a synergistic radiosensitizing effect on NSCLC cells. Additionally, we found that a low concentration of BPR0C261 was sufficient to induce DNA damage in these cells, and it increased the level of DNA damage induced by a fractionation radiation dose (2 Gy) of conventional radiotherapy. Furthermore, the p53 protein level of A549 cell line was upregulated by BPR0C261. On the other hand, the expression of PTEN tumor suppressor was found to be upregulated in H1299 cells but not in A549 cells under the same treatment. Although radiation could not induce PTEN in H1299 cells, a combination of low concentration of BPR0C261 and radiation could reverse this situation. (4) BPR0C261 exhibits specific anticancer effects on NSCLC cells by the enhancement of DNA damage and radiosensitivity with p53-dependent and p53-independent/PTEN-dependent manners. The combination of radiation and BPR0C261 may provide an important strategy for the improvement of radiotherapeutic treatment.
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27
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Chen CC, Chou YC, Hsu CY, Tsai EM, Er TK. Transcriptome Profiling of Eutopic and Ectopic Endometrial Stromal Cells in Women with Endometriosis Based on High-Throughput Sequencing. Biomedicines 2022; 10:biomedicines10102432. [PMID: 36289693 PMCID: PMC9598494 DOI: 10.3390/biomedicines10102432] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 09/13/2022] [Accepted: 09/26/2022] [Indexed: 11/20/2022] Open
Abstract
Endometriosis is a common gynecological disease that affects approximately 5–10% of reproductive-aged women. However, the etiology and pathophysiology of endometriosis are currently unclear. The objective of this study was to identify a potential pathogenic gene of endometriosis using RNA sequencing (RNA-seq) analysis. Human endometrial stromal cells were isolated from four patients receiving surgical treatment for endometriosis during laparoscopic surgery, and RNA-seq was used to examine differentially expressed genes (DEGs) in eutopic and ectopic endometrial stromal cells. The functional significance of the differentially expressed genes was analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. A total of 1309 upregulated and 663 downregulated genes were identified through the analysis of the transcriptomes of eutopic and ectopic endometrial stromal cells. Furthermore, KEGG analysis indicated that these DEGs were mainly enriched in the PI3K-Akt signaling pathway, cytokine–cytokine receptor interaction, and MAPK signaling pathway. Our study identified differential gene expression in eutopic as compared to ectopic endometrial tissue stromal cells. We strongly believe that our findings can bring new insights into the underlying mechanisms of endometriosis. However, future research is necessary to clarify the roles of the identified genes.
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Affiliation(s)
- Chih-Chieh Chen
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 804, Taiwan
| | - Yung-Che Chou
- Division of Laboratory Medicine, Asia University Hospital, Asia University, Taichung 413, Taiwan
| | - Chia-Yi Hsu
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Eing-Mei Tsai
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Tze-Kiong Er
- Division of Laboratory Medicine, Asia University Hospital, Asia University, Taichung 413, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 413, Taiwan
- Correspondence:
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28
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Campbell IH, Campbell H, Smith DJ. Insulin signaling as a therapeutic mechanism of lithium in bipolar disorder. Transl Psychiatry 2022; 12:350. [PMID: 36038539 PMCID: PMC9424309 DOI: 10.1038/s41398-022-02122-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/09/2022] [Accepted: 08/16/2022] [Indexed: 11/15/2022] Open
Abstract
In this paper, we propose that lithium may exert its therapeutic effect in bipolar disorder by acting on insulin signaling pathways. Specifically, we assess the importance of the phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/Akt) insulin signaling pathway and we assess how the action of lithium on both glycogen synthase kinase-3 (GSK3) and the phosphatidylinositol cycle may lead to mood stabilization mediated by PI3K/Akt insulin signaling. We also highlight evidence that several other actions of lithium (including effects on Akt, Protein kinase C (PKC), and sodium myo-inositol transporters) are putative mediators of insulin signaling. This novel mode of action of lithium is consistent with an emerging consensus that energy dysregulation represents a core deficit in bipolar disorder. It may also provide context for the significant co-morbidity between bipolar disorder, type 2 diabetes, and other forms of metabolic illness characterized by impaired glucose metabolism. It is suggested that developments in assessing neuronal insulin signaling using extracellular vesicles would allow for this hypothesis to be tested in bipolar disorder patients.
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Affiliation(s)
- Iain H. Campbell
- grid.4305.20000 0004 1936 7988Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Harry Campbell
- grid.4305.20000 0004 1936 7988Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Daniel J. Smith
- grid.4305.20000 0004 1936 7988Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
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29
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Reneau JC, Shindiapina P, Braunstein Z, Youssef Y, Ruiz M, Farid S, Hanel W, Brammer JE. Extranodal Natural Killer/T-Cell Lymphomas: Current Approaches and Future Directions. J Clin Med 2022; 11:jcm11102699. [PMID: 35628826 PMCID: PMC9145443 DOI: 10.3390/jcm11102699] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 04/13/2022] [Accepted: 04/29/2022] [Indexed: 11/29/2022] Open
Abstract
Extranodal natural killer/T(NK/T)-cell lymphoma (ENKTL) is a rare subtype of non-Hodgkin lymphoma that typically presents with an isolated nasal mass, but a sizeable minority present with advanced stage disease and have a significantly poorer prognosis. Those with limited disease are standardly treated with chemotherapy and radiation while those with advanced stage disease are treated with L-asparaginase containing chemotherapy regimens. The addition of modern radiation therapy techniques and the incorporation of L-asparaginase into chemotherapy regimens have significantly improved outcomes in this disease, but relapses and death from relapsed disease remain frequent. Given the high rate of relapse, several novel therapies have been evaluated for the treatment of this disease. In this review, we explore the current standard of care for ENKTL as well as novel therapies that have been evaluated for its treatment and the biologic understanding behind these therapies.
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Affiliation(s)
- John C. Reneau
- Division of Hematology, Department of Internal Medicine, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (J.C.R.); (P.S.); (Y.Y.); (M.R.); (S.F.); (W.H.)
| | - Polina Shindiapina
- Division of Hematology, Department of Internal Medicine, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (J.C.R.); (P.S.); (Y.Y.); (M.R.); (S.F.); (W.H.)
| | - Zachary Braunstein
- Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA;
| | - Youssef Youssef
- Division of Hematology, Department of Internal Medicine, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (J.C.R.); (P.S.); (Y.Y.); (M.R.); (S.F.); (W.H.)
| | - Miguel Ruiz
- Division of Hematology, Department of Internal Medicine, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (J.C.R.); (P.S.); (Y.Y.); (M.R.); (S.F.); (W.H.)
| | - Saira Farid
- Division of Hematology, Department of Internal Medicine, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (J.C.R.); (P.S.); (Y.Y.); (M.R.); (S.F.); (W.H.)
| | - Walter Hanel
- Division of Hematology, Department of Internal Medicine, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (J.C.R.); (P.S.); (Y.Y.); (M.R.); (S.F.); (W.H.)
| | - Jonathan E. Brammer
- Division of Hematology, Department of Internal Medicine, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (J.C.R.); (P.S.); (Y.Y.); (M.R.); (S.F.); (W.H.)
- Correspondence:
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30
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Skolariki A, D’Costa J, Little M, Lord S. Role of PI3K/Akt/mTOR pathway in mediating endocrine resistance: concept to clinic. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:172-199. [PMID: 36046843 PMCID: PMC9400772 DOI: 10.37349/etat.2022.00078] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 02/11/2022] [Indexed: 01/06/2023] Open
Abstract
The majority of breast cancers express the estrogen receptor (ER) and for this group of patients, endocrine therapy is the cornerstone of systemic treatment. However, drug resistance is common and a focus for breast cancer preclinical and clinical research. Over the past 2 decades, the PI3K/Akt/mTOR axis has emerged as an important driver of treatment failure, and inhibitors of mTOR and PI3K are now licensed for the treatment of women with advanced ER-positive breast cancer who have relapsed on first-line hormonal therapy. This review presents the preclinical and clinical data that led to this new treatment paradigm and discusses future directions.
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Affiliation(s)
- Aglaia Skolariki
- Department of Oncology, University of Oxford, Churchill Hospital, OX3 7LE Oxford, UK
| | - Jamie D’Costa
- Department of Oncology, University of Oxford, Churchill Hospital, OX3 7LE Oxford, UK
| | - Martin Little
- Department of Oncology, Churchill Hospital, OX3 7LE Oxford, UK
| | - Simon Lord
- Department of Oncology, University of Oxford, Churchill Hospital, OX3 7LE Oxford, UK
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31
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Elimination of Vitamin D Signaling Causes Increased Mortality in a Model of Overactivation of the Insulin Receptor: Role of Lipid Metabolism. Nutrients 2022; 14:nu14071516. [PMID: 35406129 PMCID: PMC9002971 DOI: 10.3390/nu14071516] [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: 03/15/2022] [Revised: 04/01/2022] [Accepted: 04/03/2022] [Indexed: 11/17/2022] Open
Abstract
Vitamin D (VD) deficiency has been associated with cancer and diabetes. Insulin signaling through the insulin receptor (IR) stimulates cellular responses by activating the PI3K/AKT pathway. PTEN is a tumor suppressor and a negative regulator of the pathway. Its absence enhances insulin signaling leading to hypoglycemia, a dangerous complication found after insulin overdose. We analyzed the effect of VD signaling in a model of overactivation of the IR. We generated inducible double KO (DKO) mice for the VD receptor (VDR) and PTEN. DKO mice showed severe hypoglycemia, lower total cholesterol and increased mortality. No macroscopic tumors were detected. Analysis of the glucose metabolism did not show clear differences that would explain the increased mortality. Glucose supplementation, either systemically or directly into the brain, did not enhance DKO survival. Lipidic liver metabolism was altered as there was a delay in the activation of genes related to β-oxidation and a decrease in lipogenesis in DKO mice. High-fat diet administration in DKO significantly improved its life span. Lack of vitamin D signaling increases mortality in a model of overactivation of the IR by impairing lipid metabolism. Clinically, these results reveal the importance of adequate Vitamin D levels in T1D patients.
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32
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Wang C, Yang C, Wang X, Zhou G, Chen C, Han G. ceRNA Network and Functional Enrichment Analysis of Preeclampsia by Weighted Gene Coexpression Network Analysis. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:5052354. [PMID: 35035521 PMCID: PMC8759911 DOI: 10.1155/2022/5052354] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 11/25/2021] [Accepted: 12/08/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND Preeclampsia (PE) is a multisystemic syndrome which has short- and long-term risk to mothers and children and has pluralistic etiology. OBJECTIVE This study is aimed at constructing a competitive endogenous RNA (ceRNA) network for pathways most related to PE using a data mining strategy based on weighted gene coexpression network analysis (WGCNA). METHODS We focused on pathways involving hypoxia, angiogenesis, and epithelial mesenchymal transition according to the gene set variation analysis (GSVA) scores. The gene sets of these three pathways were enriched by gene set enrichment analysis (GSEA). WGCNA was used to study the underlying molecular mechanisms of the three pathways in the pathogenesis of PE by analyzing the relationship among pathways and genes. The soft threshold power (β) and topological overlap matrix allowed us to obtain 15 modules, among which the red module was chosen for the downstream analysis. We chose 10 hub genes that satisfied ∣log2Fold Change | >2 and had a higher degree of connectivity within the module. These candidate genes were subsequently confirmed to have higher gene significance and module membership in the red module. Coexpression networks were established for the hub genes to unfold the connection between the genes in the red module and PE. Finally, ceRNA networks were constructed to further clarify the underlying molecular mechanism involved in the occurrence of PE. 56 circRNAs, 17 lncRNAs, and 20 miRNAs participated in the regulation of the hub genes. Coagulation factor II thrombin receptor (F2R) and lumican (LUM) were considered the most relevant genes, and ceRNA networks of them were constructed. CONCLUSION The microarray data mining process based on bioinformatics methods constructed lncRNA and miRNA networks for ten hub genes that were closely related to PE and focused on ceRNAs of F2R and LUM finally. The results of our study may provide insight into the mechanisms underlying PE occurrence.
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Affiliation(s)
- Chenxu Wang
- The Second Hospital of Nanjing, Medical School of Nanjing University, Nanjing 210003, China
| | - Chaofan Yang
- Model Animal Research Center of Nanjing University, Nanjing 210093, China
| | - Xinying Wang
- Model Animal Research Center of Nanjing University, Nanjing 210093, China
| | - Guanlun Zhou
- The Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, China
| | - Chao Chen
- The Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, China
| | - Guorong Han
- The Second Hospital of Nanjing, Medical School of Nanjing University, Nanjing 210003, China
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Qu H, Gao-Wa H, Hou Y, Ren M, Li J, Jing B, Du Y. TRIM37 interacts with PTEN to promote the growth of human T-cell acute lymphocytic leukemia cells through regulating PI3K/AKT pathway. Front Oncol 2022; 12:1016725. [PMID: 36923153 PMCID: PMC10009101 DOI: 10.3389/fonc.2022.1016725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 12/30/2022] [Indexed: 03/02/2023] Open
Abstract
Background TRIM37 has been reported to be associated with the tumorigenesis of cancers. However, the role of TRIM37 in T-cell acute lymphoblastic leukemia (T-ALL) remains unclear. This study aimed to characterize the effect of TRIM37 on T-ALL. Methods TRIM37 expression in T-ALL patients and T-ALL cell lines was determined by qRT-PCR and Western blot. Knockdown or overexpression of TRIM37 was conducted by transferring small-interfering TRIM37 or lentivirus-mediated transducing into T-ALL cells. CCK-8 assay and flow cytometry assay were conducted to analyze the proliferation and apoptosis of T-ALL cells. Co-immunoprecipitation experiments were conducted to investigate the relationship between TRIM37 and PTEN and the ubiquitination of PTEN. Results Our results suggested that TRIM37 expression was upregulated in the blood of T-ALL patients and T-ALL cell lines. Knockdown of TRIM37 noticeably inhibited the proliferation and promoted apoptosis of T-ALL cells. Ectopic expression of TRIM37 promoted the proliferation and suppressed the apoptosis rate of MOLT-4 cells and enhanced the phosphorylation of AKT. Moreover, TRIM37 interacted with PTEN and accelerated the degradation of PTEN via TRIM37-mediated ubiquitination in T-ALL cells. Moreover, TRIM37 reduced the sensitivity of T-ALL cells to bortezomib treatment. Additionally, PI3K/AKT signaling pathway was involved in the function of TRIM37 in T-ALL. TRIM37 contributed to the proliferation of T-ALL cells and reduced the susceptibility of T-ALL cells to bortezomib treatment through ubiquitination of PTEN and activating PI3K/AKT signaling pathway. Conclusions Our study suggested that TRIM37 could be considered as a therapeutic target for T-ALL.
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Affiliation(s)
- Honglan Qu
- Department of Hematology and Oncology, Inner Mongolia Forestry General Hospital, The Second Clinical Medical College of Inner Mongolia University for Nationalities, Yakeshi, China
| | - Hasen Gao-Wa
- Department of Hematology and Oncology, Inner Mongolia Forestry General Hospital, The Second Clinical Medical College of Inner Mongolia University for Nationalities, Yakeshi, China
| | - Yanyan Hou
- Department of Hematology and Oncology, Inner Mongolia Forestry General Hospital, The Second Clinical Medical College of Inner Mongolia University for Nationalities, Yakeshi, China
| | - Mengwei Ren
- Department of Hematology and Oncology, Inner Mongolia Forestry General Hospital, The Second Clinical Medical College of Inner Mongolia University for Nationalities, Yakeshi, China
| | - Jun Li
- Department of Hematology and Oncology, Inner Mongolia Forestry General Hospital, The Second Clinical Medical College of Inner Mongolia University for Nationalities, Yakeshi, China
| | - Baoshong Jing
- Department of Hematology and Oncology, Inner Mongolia Forestry General Hospital, The Second Clinical Medical College of Inner Mongolia University for Nationalities, Yakeshi, China
| | - YanDan Du
- Department of Hematology and Oncology, Inner Mongolia Forestry General Hospital, The Second Clinical Medical College of Inner Mongolia University for Nationalities, Yakeshi, China
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Nuciferine attenuates the progression of osteoarthritis by targeting PI3K/Akt/NF-κB signaling pathway. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104682] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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Chen J, Cheng J, Zhao C, Zhao B, Mi J, Li W. The Hippo pathway: a renewed insight in the craniofacial diseases and hard tissue remodeling. Int J Biol Sci 2021; 17:4060-4072. [PMID: 34671220 PMCID: PMC8495397 DOI: 10.7150/ijbs.63305] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 09/20/2021] [Indexed: 12/13/2022] Open
Abstract
The Hippo pathway plays an important role in many pathophysiological processes, including cell proliferation and differentiation, cell death, cell migration and invasion. Because of its extensive functions, Hippo pathway is closely related to not only growth and development, but also many diseases, including inflammation and cancer. In this study, the role of Hippo pathway in craniofacial diseases and hard tissue remodeling was reviewed, in attempting to find new research directions.
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Affiliation(s)
- Jun Chen
- Xiangya School of Stomatology, Central South University, Changsha 410008, China.,Xiangya Stomatological Hospital, Central South University, Changsha 410008, China.,Hunan Key Laboratory of Oral Health Research, Hunan 3D Printing Engineering Research Center of Oral Care, Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Central South University, Changsha 410008, China
| | - Jingyi Cheng
- Xiangya School of Stomatology, Central South University, Changsha 410008, China
| | - Cong Zhao
- Xiangya School of Stomatology, Central South University, Changsha 410008, China
| | - Boxuan Zhao
- Xiangya School of Stomatology, Central South University, Changsha 410008, China
| | - Jia Mi
- Xiangya School of Stomatology, Central South University, Changsha 410008, China
| | - Wenjie Li
- Xiangya School of Stomatology, Central South University, Changsha 410008, China.,Xiangya Stomatological Hospital, Central South University, Changsha 410008, China.,Hunan Key Laboratory of Oral Health Research, Hunan 3D Printing Engineering Research Center of Oral Care, Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Central South University, Changsha 410008, China.,National Key Laboratory of Science and Technology on High-strength Structural Materials, Central South University, Changsha 410083, China.,State Key Laboratory of Powder Metallurgy, Central South University, Changsha 410083, China
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Kwon HS, Kim YE, Park HH, Son JW, Choi H, Lee YJ, Kim HY, Lee KY, Koh SH. Neuroprotective Effects of GV1001 in Animal Stroke Model and Neural Cells Subject to Oxygen-Glucose Deprivation/Reperfusion Injury. J Stroke 2021; 23:420-436. [PMID: 34649386 PMCID: PMC8521247 DOI: 10.5853/jos.2021.00626] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 06/16/2021] [Indexed: 12/04/2022] Open
Abstract
Background and Purpose Previous studies have revealed the diverse neuroprotective effects of GV1001. In this study, we investigated the effects of GV1001 on focal cerebral ischemia-reperfusion injury (IRI) in rats and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in neural stem cells (NSCs) and cortical neurons.
Methods Focal cerebral IRI was induced by transient middle cerebral artery occlusion (MCAO). Brain diffusion-weighted imaging (DWI) was performed 2 hours after occlusion, and a total of 37 rats were treated by reperfusion with GV1001 or saline 2 hours after occlusion. Fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging, immunohistochemistry, and neurobehavioral function analyses were performed. Additionally, OGD/R-injured NSCs and cortical neurons were treated with different GV1001 concentrations. Cell viability, proliferation, migration, and oxidative stress were determined by diverse molecular analyses.
Results In the stroke model, GV1001 protected neural cells against IRI. The most effective dose of GV1001 was 60 μM/kg. The infarct volume on FLAIR 48 hours after MCAO compared to lesion volume on DWI showed a significantly smaller ratio in the GV1001-treated group. GV1001-treated rats exhibited better behavioral functions than the saline-treated rats. Treatment with GV1001 increased the viability, proliferation, and migration of the OGD/R-injured NSCs. Free radicals were significantly restored by treatment with GV1001. These neuroprotective effects of GV1001 have also been demonstrated in OGD/R-injured cortical neurons. Conclusions The results suggest that GV1001 has neuroprotective effects against IRI in NSCs, cortical neurons, and the rat brain. These effects are mediated through the induction of cellular proliferation, mitochondrial stabilization, and anti-apoptotic, anti-aging, and antioxidant effects.
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Affiliation(s)
- Hyuk Sung Kwon
- Department of Neurology, Hanyang University Guri Hospital, Hangyang University College of Medicine, Guri, Korea
| | - Ye Eun Kim
- Department of Neurology, Hanyang University Guri Hospital, Hangyang University College of Medicine, Guri, Korea
| | - Hyun-Hee Park
- Department of Neurology, Hanyang University Guri Hospital, Hangyang University College of Medicine, Guri, Korea
| | - Jeong-Woo Son
- Department of Neurology, Hanyang University Guri Hospital, Hangyang University College of Medicine, Guri, Korea
| | - Hojin Choi
- Department of Neurology, Hanyang University Guri Hospital, Hangyang University College of Medicine, Guri, Korea
| | - Young Joo Lee
- Department of Neurology, Hanyang University Guri Hospital, Hangyang University College of Medicine, Guri, Korea
| | - Hyun Young Kim
- Department of Neurology, Hanyang University Seoul Hospital, Hanyang University College of Medicine, Seoul, Korea
| | - Kyu-Yong Lee
- Department of Neurology, Hanyang University Guri Hospital, Hangyang University College of Medicine, Guri, Korea
| | - Seong-Ho Koh
- Department of Neurology, Hanyang University Guri Hospital, Hangyang University College of Medicine, Guri, Korea.,Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Korea
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Chalkiadaki K, Statoulla E, Markou M, Bellou S, Bagli E, Fotsis T, Murphy C, Gkogkas CG. Translational control in neurovascular brain development. ROYAL SOCIETY OPEN SCIENCE 2021; 8:211088. [PMID: 34659781 PMCID: PMC8511748 DOI: 10.1098/rsos.211088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/23/2021] [Indexed: 06/13/2023]
Abstract
The human brain carries out complex tasks and higher functions and is crucial for organismal survival, as it senses both intrinsic and extrinsic environments. Proper brain development relies on the orchestrated development of different precursor cells, which will give rise to the plethora of mature brain cell-types. Within this process, neuronal cells develop closely to and in coordination with vascular cells (endothelial cells (ECs), pericytes) in a bilateral communication process that relies on neuronal activity, attractive or repulsive guidance cues for both cell types and on tight-regulation of gene expression. Translational control is a master regulator of the gene-expression pathway and in particular for neuronal and ECs, it can be localized in developmentally relevant (axon growth cone, endothelial tip cell) and mature compartments (synapses, axons). Herein, we will review mechanisms of translational control relevant to brain development in neurons and ECs in health and disease.
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Affiliation(s)
- Kleanthi Chalkiadaki
- Division of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, University Campus, 45110 Ioannina, Greece
| | - Elpida Statoulla
- Division of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, University Campus, 45110 Ioannina, Greece
| | - Maria Markou
- Division of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, University Campus, 45110 Ioannina, Greece
| | - Sofia Bellou
- Division of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, University Campus, 45110 Ioannina, Greece
| | - Eleni Bagli
- Division of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, University Campus, 45110 Ioannina, Greece
| | - Theodore Fotsis
- Division of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, University Campus, 45110 Ioannina, Greece
| | - Carol Murphy
- Division of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, University Campus, 45110 Ioannina, Greece
| | - Christos G. Gkogkas
- Division of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, University Campus, 45110 Ioannina, Greece
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Boovarahan SR, Kurian GA. Preconditioning the rat heart with 5-azacytidine attenuates myocardial ischemia/reperfusion injury via PI3K/GSK3β and mitochondrial K ATP signaling axis. J Biochem Mol Toxicol 2021; 35:e22911. [PMID: 34462995 DOI: 10.1002/jbt.22911] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 07/22/2021] [Accepted: 08/24/2021] [Indexed: 12/18/2022]
Abstract
5-Azacytidine is well known for its clinical usage in cancer treatments. The present study investigates the role of 5-azacytidine as a cardioprotective agent to ameliorate ischemia/reperfusion (I/R) injury. The cardioprotective effect of 5-azacytidine was evaluated in three experimental models: in vitro, ex vivo, and in vivo. The cardioprotective effect was evaluated via cell viability, hemodynamic indices, infarct size measurement, and assessment of histopathology, oxidative stress, and mitochondrial function. The experiments were repeated in the presence of PI3K/GSK3β and mitochondrial KATP (mtKATP ) cardioprotective signaling pathway inhibitors to understand the underlying mechanism. 5-Azacytidine improved the cell viability by 29% in I/R-challenged H9C2 cells. Both isolated rat heart and LAD ligation model confirmed the infarct sparing effect of 5-azacytidine against I/R. It also provided a beneficial effect by normalizing the altered hemodynamics, reducing the infarct size and cardiac injury markers, reversing the perturbation of mitochondria, reduced oxidative stress, and improved the pPI3K and pAKT protein expression from I/R. In addition, it also augmented the activation of PI3K/AKT and mtKATP signaling pathway, confirmed by using wortmannin (PI3K inhibitor), SB216763 (GSK3β inhibitor), and glibenclamide (mtKATP channel closer). The effectiveness of 5-azacytidine as a cardioprotective agent is attributed to its activation of the PI3K/GSK3β and mtKATP channel signaling axis, thereby preserving mitochondrial function and reducing oxidative stress.
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Affiliation(s)
- Sri Rahavi Boovarahan
- School of Chemical and Biotechnology, Vascular Biology Lab, SASTRA Deemed University, Thanjavur, Tamilnadu, India
| | - Gino A Kurian
- School of Chemical and Biotechnology, Vascular Biology Lab, SASTRA Deemed University, Thanjavur, Tamilnadu, India
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Ibrutinib in patients with atrial fibrillation - the challenge of thromboembolic prophylaxis. ACTA ACUST UNITED AC 2021; 59:270-277. [PMID: 33913303 DOI: 10.2478/rjim-2021-0015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Indexed: 11/20/2022]
Abstract
Ibrutinib is a novel drug used in haematological malignancies. Its use is associated with an increased risk of atrial fibrillation (AF), which, in turn, exposes patients to embolic risk, including stroke. Reducing this risk requires anticoagulant therapy which is a matter of concern in the context of the increased bleeding risk of patients with haematological malignancies. In this context the presence of thrombocytopenia related to haematological disorder, ibrutinib-anticoagulants and ibrutinib-platelets interactions contribute to the amplification of the problem. The correct assessment of the thrombosis vs. haemorrhage balance represents a significant challenge for the clinician. In this paper we discuss practical issues related to anticoagulation in patients treated with ibrutinib and incident AF.
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40
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Lebo DPV, Chirn A, Taylor JD, Levan A, Doerre Torres V, Agreda E, Serizier SB, Lord AK, Jenkins VK, McCall K. An RNAi screen of the kinome in epithelial follicle cells of the Drosophila melanogaster ovary reveals genes required for proper germline death and clearance. G3-GENES GENOMES GENETICS 2021; 11:6080751. [PMID: 33693600 PMCID: PMC8022946 DOI: 10.1093/g3journal/jkaa066] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 12/09/2020] [Indexed: 02/07/2023]
Abstract
Programmed cell death and cell corpse clearance are an essential part of organismal health and development. Cell corpses are often cleared away by professional phagocytes such as macrophages. However, in certain tissues, neighboring cells known as nonprofessional phagocytes can also carry out clearance functions. Here, we use the Drosophila melanogaster ovary to identify novel genes required for clearance by nonprofessional phagocytes. In the Drosophila ovary, germline cells can die at multiple time points. As death proceeds, the epithelial follicle cells act as phagocytes to facilitate the clearance of these cells. We performed an unbiased kinase screen to identify novel proteins and pathways involved in cell clearance during two death events. Of 224 genes examined, 18 demonstrated severe phenotypes during developmental death and clearance while 12 demonstrated severe phenotypes during starvation-induced cell death and clearance, representing a number of pathways not previously implicated in phagocytosis. Interestingly, it was found that several genes not only affected the clearance process in the phagocytes, but also non-autonomously affected the process by which germline cells died. This kinase screen has revealed new avenues for further exploration and investigation.
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Affiliation(s)
- Diane P V Lebo
- Department of Biology, Boston University, Boston, MA 02215, USA
| | - Alice Chirn
- Department of Biology, Boston University, Boston, MA 02215, USA
| | - Jeffrey D Taylor
- Department of Biology, Boston University, Boston, MA 02215, USA.,Program in Biochemistry and Molecular Biology, Boston University, Boston, MA 02215, USA
| | - Andre Levan
- Department of Biology, Boston University, Boston, MA 02215, USA.,Program in Biochemistry and Molecular Biology, Boston University, Boston, MA 02215, USA
| | | | - Emily Agreda
- Department of Biology, Boston University, Boston, MA 02215, USA
| | - Sandy B Serizier
- Department of Biology, Boston University, Boston, MA 02215, USA.,Program in Molecular Biology, Cell Biology, and Biochemistry, Boston University, Boston, MA 02215, USA
| | - Allison K Lord
- Department of Biology, Boston University, Boston, MA 02215, USA
| | | | - Kimberly McCall
- Department of Biology, Boston University, Boston, MA 02215, USA
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Hanel W, Epperla N. Evolving therapeutic landscape in follicular lymphoma: a look at emerging and investigational therapies. J Hematol Oncol 2021; 14:104. [PMID: 34193230 PMCID: PMC8247091 DOI: 10.1186/s13045-021-01113-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 06/04/2021] [Indexed: 02/08/2023] Open
Abstract
Follicular Lymphoma (FL) is the most common subtype of indolent B cell non-Hodgkin lymphoma. The clinical course can be very heterogeneous with some patients being safely observed over many years without ever requiring treatment to other patients having more rapidly progressive disease requiring multiple lines of treatment for disease control. Front-line treatment of advanced FL has historically consisted of chemoimmunotherapy but has extended to immunomodulatory agents such as lenalidomide. In the relapsed setting, several exciting therapies that target the underlying biology and immune microenvironment have emerged, most notable among them include targeted therapies such as phosphoinositide-3 kinase and Enhancer of Zeste 2 Polycomb Repressive Complex 2 inhibitors and cellular therapies including chimeric antigen receptor T cells and bispecific T cell engagers. There are several combination therapies currently in clinical trials that appear promising. These therapies will likely reshape the treatment approach for patients with relapsed and refractory FL in the coming years. In this article, we provide a comprehensive review of the emerging and investigational therapies in FL and discuss how these agents will impact the therapeutic landscape in FL.
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Affiliation(s)
- Walter Hanel
- Division of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State University, 460 W 10th Ave, Columbus, OH 43210 USA
| | - Narendranath Epperla
- Division of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State University, 460 W 10th Ave, Columbus, OH 43210 USA
- The Ohio State University Comprehensive Cancer Center, 1110E Lincoln Tower, 1800 Cannon Drive, Columbus, OH 43210 USA
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Foxo1 selectively regulates static mechanical pain by interacting with Nav1.7. Pain 2021; 162:490-502. [PMID: 32868747 DOI: 10.1097/j.pain.0000000000002055] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 08/14/2020] [Indexed: 02/07/2023]
Abstract
ABSTRACT Mechanical allodynia is a debilitating condition for millions of patients with chronic pain. Mechanical allodynia can manifest in distinct forms, including brush-evoked dynamic and filament-evoked static allodynia. In the nervous system, the forkhead protein Foxo1 plays a critical role in neuronal structures and functions. However, the role of Foxo1 in the somatosensory signal remains unclear. Here, we found that Foxo1 selectively regulated static mechanical pain. Foxo1 knockdown decreased sensitivity to static mechanical stimuli in normal rats and attenuated static mechanical allodynia in rat models for neuropathic, inflammatory, and chemotherapy pain. Conversely, Foxo1 overexpression selectively enhanced sensitivity to static mechanical stimuli and provoked static mechanical allodynia. Furthermore, Foxo1 interacted with voltage-gated sodium Nav1.7 channels and increased the Nav1.7 current density by accelerating activation rather than by changing the expression of Nav1.7 in dorsal root ganglia neurons. In addition, the serum level of Foxo1 was found to be increased in chronic pain patients and to be positively correlated with the severity of chronic pain. Altogether, our findings suggest that serum Foxo1 level could be used as a biological marker for prediction and diagnosis of chronic pain. Moreover, selective blockade of Foxo1/Nav1.7 interaction may offer a new therapeutic approach in patients with mechanical pain.
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Deng S, Jin P, Sherchan P, Liu S, Cui Y, Huang L, Zhang JH, Gong Y, Tang J. Recombinant CCL17-dependent CCR4 activation alleviates neuroinflammation and neuronal apoptosis through the PI3K/AKT/Foxo1 signaling pathway after ICH in mice. J Neuroinflammation 2021; 18:62. [PMID: 33648537 PMCID: PMC7923481 DOI: 10.1186/s12974-021-02112-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/16/2021] [Indexed: 02/07/2023] Open
Abstract
Background Intracerebral hemorrhage (ICH), a devastating subtype of stroke, is associated with high mortality and morbidity. Neuroinflammation is an important factor leading to ICH-induced neurological injuries. C-C Chemokine Receptor 4 (CCR4) plays an important role in enhancing hematoma clearance after ICH. However, it is unclear whether CCR4 activation can ameliorate neuroinflammation and apoptosis of neurons following ICH. The aim of the present study was to examine the effects of recombinant CCL17 (rCCL17)-dependent CCR4 activation on neuroinflammation and neuronal apoptosis in an intrastriatal autologous blood injection ICH model, and to determine whether the PI3K/AKT/Foxo1 signaling pathway was involved. Methods Two hundred twenty-six adult (8-week-old) male CD1 mice were randomly assigned to sham and ICH surgery groups. An intrastriatal autologous blood injection ICH model was used. rCCL17, a CCR4 ligand, was delivered by intranasal administration at 1 h, 3 h, and 6 h post-ICH. CCL17 antibody was administrated by intraventricular injection at 1 h post-ICH. C021, a specific inhibitor of CCR4 and GDC0068, an AKT inhibitor were delivered intraperitoneally 1 h prior to ICH induction. Brain edema, neurobehavioral assessments, western blotting, Fluoro-Jade C staining, terminal deoxynucleotidyl transferase dUTP nick end labeling, and immunofluorescence staining were conducted. Results Endogenous expression of CCL17 and CCR4 were increased following ICH, peaking at 5 days post-induction. CCR4 was found to co-localize with microglia, neurons, and astrocytes. rCCL17 treatment decreased brain water content, attenuated short- and long-term neurological deficits, deceased activation of microglia/macrophages and infiltration of neutrophils, and inhibited neuronal apoptosis in the perihematomal region post-ICH. Moreover, rCCL17 treatment post-ICH significantly increased the expression of CCR4, PI3K, phosphorylated AKT, and Bcl-2, while Foxo1, IL-1β, TNF-α, and Bax expression were decreased. The neuroprotective effects of rCCL17 were reversed with the administration of C021 or GDC0068. Conclusions rCCL17-dependent CCR4 activation ameliorated neurological deficits, reduced brain edema, and ameliorated neuroinflammation and neuronal apoptosis, at least in part, through the PI3K/AKT/Foxo1 signaling pathway after ICH. Thus, activation of CCR4 may provide a promising therapeutic approach for the early management of ICH. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02112-3.
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Affiliation(s)
- Shuixiang Deng
- Department of Critical Care Medicine, HuaShan Hospital, Fudan University, 12 middle WuLuMuQi, Shanghai, 200040, China.,Department of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of Medicine, Risley Hall, Room 219, 11041 Campus Street, Loma Linda, CA, 92350, USA
| | - Peng Jin
- Department of Critical Care Medicine, HuaShan Hospital, Fudan University, 12 middle WuLuMuQi, Shanghai, 200040, China.,Department of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of Medicine, Risley Hall, Room 219, 11041 Campus Street, Loma Linda, CA, 92350, USA
| | - Prativa Sherchan
- Department of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of Medicine, Risley Hall, Room 219, 11041 Campus Street, Loma Linda, CA, 92350, USA
| | - Shengpeng Liu
- Department of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of Medicine, Risley Hall, Room 219, 11041 Campus Street, Loma Linda, CA, 92350, USA.,Department of Pediatrics, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, Guangdong, China
| | - Yuhui Cui
- Department of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of Medicine, Risley Hall, Room 219, 11041 Campus Street, Loma Linda, CA, 92350, USA
| | - Lei Huang
- Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA
| | - John H Zhang
- Department of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of Medicine, Risley Hall, Room 219, 11041 Campus Street, Loma Linda, CA, 92350, USA.,Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA.,Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA
| | - Ye Gong
- Department of Critical Care Medicine, HuaShan Hospital, Fudan University, 12 middle WuLuMuQi, Shanghai, 200040, China. .,Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| | - Jiping Tang
- Department of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of Medicine, Risley Hall, Room 219, 11041 Campus Street, Loma Linda, CA, 92350, USA.
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Veale CGL. Into the Fray! A Beginner's Guide to Medicinal Chemistry. ChemMedChem 2021; 16:1199-1225. [PMID: 33591595 DOI: 10.1002/cmdc.202000929] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Indexed: 12/31/2022]
Abstract
Modern medicinal chemistry is a complex, multidimensional discipline that operates at the interface of the chemical and biological sciences. The medicinal chemistry contribution to drug discovery is typically described in the context of the well-recited linear progression of the drug discovery pipeline. However, compound optimization is idiosyncratic to each project, and clear definitions of hit and lead molecules and the subsequent progress along the pipeline becomes easily blurred. In addition, this description lacks insight into the entangled relationship between chemical and pharmacological properties, and thus provides limited guidance on how innovative medicinal chemistry strategies can be applied to solve optimization problems, regardless of the stage in the pipeline. Through discussion and illustrative examples, this article seeks to provide insights into the finesse of medicinal chemistry and the subtlety of balancing chemical properties pharmacology. In so doing, it aims to serve as an accessible and simple-to-digest guide for anyone who wishes to learn about the underlying principles of medicinal chemistry, in a context that has been decoupled from the pipeline description.
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Affiliation(s)
- Clinton G L Veale
- School of Chemistry and Physics, Pietermaritzburg Campus, University of KwaZulu-Natal, Private Bag X01, Pietermaritzburg, Scottsville, 3209, South Africa
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Wang S, Zheng B, Zhao H, Li Y, Zhang X, Wen J. Downregulation of lncRNA MIR181A2HG by high glucose impairs vascular endothelial cell proliferation and migration through the dysregulation of the miRNAs/AKT2 axis. Int J Mol Med 2021; 47:35. [PMID: 33537821 PMCID: PMC7891834 DOI: 10.3892/ijmm.2021.4868] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 01/04/2021] [Indexed: 01/06/2023] Open
Abstract
Endothelial dysfunction and diabetic vascular disease induced by chronic hyperglycemia involve complex interactions among high glucose, long non-coding RNAs (lncRNAs), microRNAs (miRNAs or miRs) and the Ser/Thr kinase AKT. However, the molecular mechanisms under-lying the regulatory crosstalk between these have not yet been completely elucidated. Thus, the present study aimed to explore the molecular mechanisms whereby high glucose (HG)-induced lncRNA MIR181A2HG modulates human umbilical vein endothelial cell (HUVEC) proliferation and migration by regulating AKT2 expression. The persistent exposure of HUVECs to HG resulted in MIR181A2HG down-regulation and thus reduced its ability to sponge miR-6832-5p, miR-6842-5p and miR-8056, subsequently leading to an increase in miR-6832-5p, miR-6842-5p and miR-8056 levels. Mechanistically, miR-6832-5p, miR-6842-5p and miR-8056 were found to target the 3′UTR of AKT2 mRNA in HUVECs, and the increase in their levels led to a decreased expression of AKT2. Thus, this also led to the suppression of HUVEC proliferation and migration, and the formation of capillary-like structures. Moreover, the suppression of HUVEC proliferation and migration induced by MIR181A2HG downregulation was accompanied by changes in glucose metabolism. On the whole, the present study demonstrates that the downregulation of lncRNA MIR181A2HG by HG impairs HUVEC proliferation and migration by dysregulating the miRNA/AKT2 axis. The MIR181A2HG/miRNA/AKT2 regulatory axis may thus be a potential therapeutic target for HG-induced endothelial dysfunction.
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Affiliation(s)
- Shaohua Wang
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Bin Zheng
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Hongye Zhao
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Yongjun Li
- Department of Clinical Laboratorial Examination, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. Chin
| | - Xinhua Zhang
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Jinkun Wen
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
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46
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Martins BR, Pinto TS, da Costa Fernandes CJ, Bezerra F, Zambuzzi WF. PI3K/AKT signaling drives titanium-induced angiogenic stimulus. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2021; 32:18. [PMID: 33506378 PMCID: PMC7840643 DOI: 10.1007/s10856-020-06473-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 12/10/2020] [Indexed: 05/15/2023]
Abstract
Although osseointegration and clinical success of titanium (Ti)-implanted materials depend on neovascularization in the reactional peri-implant tissue, very little has been achieved considering the Ti-molecules release on the behavior of endothelial cells. To address this issue, we challenged endothelial cells (HUVECs) with Ti-enriched medium obtained from two types of commercial titanium surfaces [presenting or not dual-acid etching (DAE)] up to 72 h to allow molecular machinery analysis. Our data show that the Ti-enriched medium provokes significant stimulus of angiogenesis-related machinery in endothelial cells by upexpressing VEGFR1, VEGFR2, VEGF, eNOS, and iNOS genes, while the PI3K/Akt signaling pathway was also significantly enhanced. As PI3K/AKT signaling was related to angiogenesis in response to vascular endothelial growth factor (VEGF), we addressed the importance of PI3K/Akt upon Ti-enriched medium responses by concomitantly treating the cells with wortmannin, a well-known PI3K inhibitor. Wortmannin suppressed the angiogenic factors, because VEGF, VEGFR1, and eNOS genes were downregulated in those cells, highlighting the importance of PI3K/AKT signaling on driving angiogenic phenotype and angiogenesis performance within the peri-implant tissue reaction. In conjunction, these data reinforce that titanium-implantable devices modify the metabolism of surrounding cells, such as endothelial cells, probably coupling osteogenesis and angiogenesis processes in peri-implant tissue and then contributing to successfully osseointegration of biomedical titanium-based devices.
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Affiliation(s)
- Bruna Rodrigues Martins
- Institute of Biosciences of Botucatu, Department of Chemical and Biological Sciences, UNESP - São Paulo State University, Botucatu, São Paulo, Brazil
| | - Thais Silva Pinto
- Institute of Biosciences of Botucatu, Department of Chemical and Biological Sciences, UNESP - São Paulo State University, Botucatu, São Paulo, Brazil
| | - Célio Junior da Costa Fernandes
- Institute of Biosciences of Botucatu, Department of Chemical and Biological Sciences, UNESP - São Paulo State University, Botucatu, São Paulo, Brazil
| | - Fábio Bezerra
- Institute of Biosciences of Botucatu, Department of Chemical and Biological Sciences, UNESP - São Paulo State University, Botucatu, São Paulo, Brazil
| | - Willian Fernando Zambuzzi
- Institute of Biosciences of Botucatu, Department of Chemical and Biological Sciences, UNESP - São Paulo State University, Botucatu, São Paulo, Brazil.
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The Role of Csmd1 during Mammary Gland Development. Genes (Basel) 2021; 12:genes12020162. [PMID: 33530646 PMCID: PMC7912059 DOI: 10.3390/genes12020162] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/13/2021] [Accepted: 01/21/2021] [Indexed: 12/23/2022] Open
Abstract
The Cub Sushi Multiple Domains-1 (CSMD1) protein is a tumour suppressor which has been shown to play a role in regulating human mammary duct development in vitro. CSMD1 knockdown in vitro demonstrated increased cell proliferation, invasion and motility. However, the role of Csmd1 in vivo is poorly characterised when it comes to ductal development and is therefore an area which warrants further exploration. In this study a Csmd1 knockout (KO) mouse model was used to identify the role of Csmd1 in regulating mammary gland development during puberty. Changes in duct development and protein expression patterns were analysed by immunohistochemistry. This study identified increased ductal development during the early stages of puberty in the KO mice, characterised by increased ductal area and terminal end bud number at 6 weeks. Furthermore, increased expression of various proteins (Stat1, Fak, Akt, Slug/Snail and Progesterone receptor) was shown at 4 weeks in the KO mice, followed by lower expression levels from 6 weeks in the KO mice compared to the wild type mice. This study identifies a novel role for Csmd1 in mammary gland development, with Csmd1 KO causing significantly more rapid mammary gland development, suggesting an earlier adult mammary gland formation.
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48
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Monti N, Masiello MG, Proietti S, Catizone A, Ricci G, Harrath AH, Alwasel SH, Cucina A, Bizzarri M. Survival Pathways Are Differently Affected by Microgravity in Normal and Cancerous Breast Cells. Int J Mol Sci 2021; 22:ijms22020862. [PMID: 33467082 PMCID: PMC7829699 DOI: 10.3390/ijms22020862] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/12/2021] [Accepted: 01/13/2021] [Indexed: 12/16/2022] Open
Abstract
Metazoan living cells exposed to microgravity undergo dramatic changes in morphological and biological properties, which ultimately lead to apoptosis and phenotype reprogramming. However, apoptosis can occur at very different rates depending on the experimental model, and in some cases, cells seem to be paradoxically protected from programmed cell death during weightlessness. These controversial results can be explained by considering the notion that the behavior of adherent cells dramatically diverges in respect to that of detached cells, organized into organoids-like, floating structures. We investigated both normal (MCF10A) and cancerous (MCF-7) breast cells and found that appreciable apoptosis occurs only after 72 h in MCF-7 cells growing in organoid-like structures, in which major modifications of cytoskeleton components were observed. Indeed, preserving cell attachment to the substrate allows cells to upregulate distinct Akt- and ERK-dependent pathways in MCF-7 and MCF-10A cells, respectively. These findings show that survival strategies may differ between cell types but cannot provide sufficient protection against weightlessness-induced apoptosis alone if adhesion to the substrate is perturbed.
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Affiliation(s)
- Noemi Monti
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
- Systems Biology Group Lab, Sapienza University of Rome, 00161 Rome, Italy
| | - Maria Grazia Masiello
- Department of Surgery “Pietro Valdoni”, Sapienza University of Rome, 00161 Rome, Italy; (M.G.M.); (S.P.); (A.C.)
| | - Sara Proietti
- Department of Surgery “Pietro Valdoni”, Sapienza University of Rome, 00161 Rome, Italy; (M.G.M.); (S.P.); (A.C.)
| | - Angela Catizone
- Department of Anatomy, Histology, Forensic-Medicine and Orthopedics, Section of Histology and Embryology, Sapienza University of Rome, 00161 Rome, Italy;
| | - Giulia Ricci
- Department of Experimental Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Abdel Halim Harrath
- Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; (A.H.H.); (S.H.A.)
| | - Saleh H. Alwasel
- Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; (A.H.H.); (S.H.A.)
| | - Alessandra Cucina
- Department of Surgery “Pietro Valdoni”, Sapienza University of Rome, 00161 Rome, Italy; (M.G.M.); (S.P.); (A.C.)
- Azienda Policlinico Umberto I, 00161 Rome, Italy
| | - Mariano Bizzarri
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
- Systems Biology Group Lab, Sapienza University of Rome, 00161 Rome, Italy
- Correspondence: ; Tel.: +39-4976-6606
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Choo J, Heo G, Pothoulakis C, Im E. Posttranslational modifications as therapeutic targets for intestinal disorders. Pharmacol Res 2021; 165:105412. [PMID: 33412276 DOI: 10.1016/j.phrs.2020.105412] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/14/2020] [Accepted: 12/22/2020] [Indexed: 02/08/2023]
Abstract
A variety of biological processes are regulated by posttranslational modifications. Posttranslational modifications including phosphorylation, ubiquitination, glycosylation, and proteolytic cleavage, control diverse physiological functions in the gastrointestinal tract. Therefore, a better understanding of their implications in intestinal diseases, including inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancer would provide a basis for the identification of novel biomarkers as well as attractive therapeutic targets. Posttranslational modifications can be common denominators, as well as distinct biomarkers, characterizing pathological differences of various intestinal diseases. This review provides experimental evidence that identifies changes in posttranslational modifications from patient samples, primary cells, or cell lines in intestinal disorders, and a summary of carefully selected information on the use of pharmacological modulators of protein modifications as therapeutic options.
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Affiliation(s)
- Jieun Choo
- College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea
| | - Gwangbeom Heo
- College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea
| | - Charalabos Pothoulakis
- Section of Inflammatory Bowel Disease & Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
| | - Eunok Im
- College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
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50
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Wu X, Zhang Y, Qiu J, Xu Y, Zhang J, Huang J, Bai J, Huang Z, Qiu X, Xu W. Lipidomics Analysis Indicates Disturbed Hepatocellular Lipid Metabolism in Reynoutria multiflora-Induced Idiosyncratic Liver Injury. Front Pharmacol 2020; 11:569144. [PMID: 33408629 PMCID: PMC7779765 DOI: 10.3389/fphar.2020.569144] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 10/19/2020] [Indexed: 12/14/2022] Open
Abstract
The root of Reynoutria multiflora (Thunb.) Moldenke (syn.: Polygonum multiflorum Thunb., HSW) is a distinguished herb that has been popularly used in traditional Chinese medicine (TCM). Evidence of its potential side effect on liver injury has accumulated and received much attention. The objective of this study was to profile the metabolic characteristics of lipids in injured liver of rats induced by HSW and to find out potential lipid biomarkers of toxic consequence. A lipopolysaccharide (LPS)-induced rat model of idiosyncratic drug-induced liver injury (IDILI) was constructed and evident liver injury caused by HSW was confirmed based on the combination of biochemical, morphological, and functional tests. A lipidomics method was developed for the first time to investigate the alteration of lipid metabolism in HSW-induced IDILI rat liver by using ultra-high-performance liquid chromatography/Q-exactive Orbitrap mass spectrometry coupled with multivariate analysis. A total of 202 characterized lipids, including phosphatidylcholine (PC), lysophosphatidylcholine (LPC), phosphatidylethanolamine (PE), lysophosphatidylethanolamine (LPE), sphingomyelin (SM), phosphatidylinositol (PI), lysophosphatidylinositol (LPI), phosphatidylserine (PS), phosphoglycerols (PG), and ceramide (Cer), were compared among groups of LPS and LPS + HSW. A total of 14 out 26 LPC, 22 out of 47 PC, 19 out of 29 LPE, 16 out of 36 PE, and 10 out of 15 PI species were increased in HSW-treated rat liver, which indicated that HSW may cause liver damage via interfering the phospholipid metabolism. The present work may assist lipid biomarker development of HSW-induced DILI and it also provide new insights into the relationships between phospholipid perturbation and herbal-induced idiosyncratic DILI.
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Affiliation(s)
- Xiaofang Wu
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yating Zhang
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiaqi Qiu
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ya Xu
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jing Zhang
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China.,Key Laboratory of Quality Evaluation of Chinese Medicine of the Guangdong Provincial Medical Products Administration, Guangzhou, China
| | - Juan Huang
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Junqi Bai
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhihai Huang
- Key Laboratory of Quality Evaluation of Chinese Medicine of the Guangdong Provincial Medical Products Administration, Guangzhou, China.,Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Xiaohui Qiu
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China.,Key Laboratory of Quality Evaluation of Chinese Medicine of the Guangdong Provincial Medical Products Administration, Guangzhou, China.,Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.,Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China
| | - Wen Xu
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China.,Key Laboratory of Quality Evaluation of Chinese Medicine of the Guangdong Provincial Medical Products Administration, Guangzhou, China
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