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Al-Kuraishy HM, Sulaiman GM, Mohsin MH, Mohammed HA, Dawood RA, Albuhadily AK, Al-Gareeb AI, Albukhaty S, Abomughaid MM. Targeting of AMPK/MTOR signaling in the management of atherosclerosis: Outmost leveraging. Int J Biol Macromol 2025; 309:142933. [PMID: 40203916 DOI: 10.1016/j.ijbiomac.2025.142933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 04/05/2025] [Accepted: 04/06/2025] [Indexed: 04/11/2025]
Abstract
Atherosclerosis (AS) is a chronic vascular disorder that is characterized by the thickening and narrowing of arteries due to the development of atherosclerotic plaques. The traditional risk factors involved in AS are obesity, type 2 diabetes (T2D), dyslipidemia, hypertension, and smoking. Furthermore, non-traditional risk factors for AS, such as inflammation, sleep disturbances, physical inactivity, air pollution, and alterations of gut microbiota, gained attention in relation to the pathogenesis of AS. Interestingly, the pathogenesis of AS, is complex and related to different abnormalities of cellular and sub-cellular signaling pathways. It has been illustrated that AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (MTOR) pathways are involved in AS pathogenesis. Mounting evidence indicated that AMPK plays a critical role in attenuating the development of AS by activating autophagy, which is impaired during atherogenesis. AMPK has a vasculoprotective effect by reducing lipid accumulation, inflammatory cell proliferation, and the release of pro-inflammatory cytokines, as well as decreasing inflammatory cell adhesion to the vascular endothelium. AMPK activation by metformin inhibits the migration of vascular smooth muscle cells (VSMCs) and AS development. However, the MTOR pathway contributes to AS by inhibiting autophagy, highlighting autophagy as a crucial link between the AMPK and MTOR pathways in AS pathogenesis. The MTOR is a key inducer of endothelial dysfunction and is involved in the development of AS. Therefore, both the AMPK and MTOR pathways play a crucial role in the pathogenesis of AS. However, the exact role of AMPK and MTOR pathways in the pathogenesis of AS is not fully clarified. Therefore, this review aims to discuss the potential role of the AMPK/MTOR signaling pathway in AS, and how AMPK activators and MTOR inhibitors influence the development and progression of AS. In conclusion, AMPK activators and MTOR inhibitors have vasculoprotective effects against the development and progression of AS.
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Affiliation(s)
- Hayder M Al-Kuraishy
- Department of Clinical pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | - Ghassan M Sulaiman
- Department of Applied Sciences, University of Technology, Baghdad, Iraq.
| | - Mayyadah H Mohsin
- Department of Applied Sciences, University of Technology, Baghdad, Iraq
| | - Hamdoon A Mohammed
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia
| | - Retaj A Dawood
- Department of Biology, College of Science, Al-Mustaqbal University, Hilla 51001, Iraq
| | - Ali K Albuhadily
- Department of Clinical pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Jabir ibn Hayyan Medical University, Al-Ameer Qu, PO.Box13 Kufa, Najaf, Iraq
| | | | - Mosleh M Abomughaid
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, 255, Bisha 67714, Saudi Arabia
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Berlind JE, Lai JD, Lie C, Vicente J, Lam K, Guo S, Chang J, Yu V, Ichida JK. KCTD20 suppression mitigates excitotoxicity in tauopathy patient organoids. Neuron 2025; 113:1169-1189.e7. [PMID: 40049159 PMCID: PMC12005969 DOI: 10.1016/j.neuron.2025.02.001] [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: 05/07/2024] [Revised: 12/13/2024] [Accepted: 02/04/2025] [Indexed: 04/19/2025]
Abstract
Excitotoxicity is a major pathologic mechanism in patients with tauopathy and other neurodegenerative diseases. However, the key neurotoxic drivers and the most effective strategies for mitigating these degenerative processes are unclear. Here, we show that glutamate treatment of induced pluripotent stem cell (iPSC)-derived cerebral organoids induces tau oligomerization and neurodegeneration and that these phenotypes are enhanced in organoids derived from tauopathy patients. Using a genome-wide CRISPR interference (CRISPRi) screen, we find that the suppression of KCTD20 potently ameliorates tau pathology and neurodegeneration in glutamate-treated organoids and mice, as well as in transgenic mice overexpressing mutant human tau. KCTD20 suppression reduces oligomeric tau and improves neuron survival by activating lysosomal exocytosis, which clears pathological tau. Our results show that glutamate signaling can induce neuronal tau pathology and identify KCTD20 suppression and lysosomal exocytosis as effective strategies for clearing neurotoxic tau species.
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Affiliation(s)
- Joshua E Berlind
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA
| | - Jesse D Lai
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA; Department of Neuroscience, Amgen Inc., Cambridge, MA, USA; Neurological & Rare Diseases, Dewpoint Therapeutics, Boston, MA, USA.
| | - Cecilia Lie
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA
| | - Jokabeth Vicente
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA
| | - Kelsey Lam
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA
| | - Sheron Guo
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA
| | - Jonathan Chang
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA
| | - Violeta Yu
- Neurological & Rare Diseases, Dewpoint Therapeutics, Boston, MA, USA
| | - Justin K Ichida
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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Jurca AA, Jurca AD, Petchesi CD, Bembea D, Jurca CM, Severin E, Jurca S, Vesa CM. Tuberous Sclerosis Complex: New Insights into Pathogenesis and Therapeutic Breakthroughs. Life (Basel) 2025; 15:368. [PMID: 40141713 PMCID: PMC11944049 DOI: 10.3390/life15030368] [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: 12/30/2024] [Revised: 02/12/2025] [Accepted: 02/24/2025] [Indexed: 03/28/2025] Open
Abstract
Background/Objectives: Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disorder caused by mutations in the TSC1 and TSC2 genes, which disrupt the regulation of the mammalian target of rapamycin (mTOR) pathway, a critical regulator of cellular growth. The disorder presents as a multisystem condition, with benign tumors (hamartomas) developing in organs such as the brain, skin, heart, kidneys, and lungs, leading to significant clinical variability and impact on quality of life. This review aims to summarize recent advances in the understanding of TSC pathogenesis and clinical variability and evaluate the therapeutic breakthroughs in targeted treatments. Methods: A narrative review was conducted using various available databases. We applied objective evaluation metrics, such as the impact factor of the journals and the citation count, to assess the quality of the studies. Results: Targeted therapies, particularly mTOR inhibitors (mTORis), have shown efficacy in reducing hamartoma size, improving neuropsychiatric symptoms, and enhancing patient outcomes. Despite these advances, variability in disease expression poses challenges in diagnosis and individualized management strategies. Conclusions: Challenges such as early diagnosis, optimizing long-term outcomes, and addressing residual unmet needs remain critical. Future research should prioritize precision medicine approaches and patient-centered care models within centers of expertise to improve treatment efficacy and quality of life for individuals with TSC.
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Affiliation(s)
- Aurora Alexandra Jurca
- Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania;
| | - Alexandru Daniel Jurca
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 1 December Sq., 410081 Oradea, Romania; (C.D.P.); (D.B.); (C.M.J.); (C.M.V.)
| | - Codruta Diana Petchesi
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 1 December Sq., 410081 Oradea, Romania; (C.D.P.); (D.B.); (C.M.J.); (C.M.V.)
- Regional Center of Medical Genetics Bihor, County Emergency Clinical Hospital Oradea (Part of ERN THACA), 410469 Oradea, Romania
| | - Dan Bembea
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 1 December Sq., 410081 Oradea, Romania; (C.D.P.); (D.B.); (C.M.J.); (C.M.V.)
| | - Claudia Maria Jurca
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 1 December Sq., 410081 Oradea, Romania; (C.D.P.); (D.B.); (C.M.J.); (C.M.V.)
- Regional Center of Medical Genetics Bihor, County Emergency Clinical Hospital Oradea (Part of ERN THACA), 410469 Oradea, Romania
| | - Emilia Severin
- Department of Genetics, University of Medicine and Pharmacy “Carol Davila”, Dionisie Lupu Street, Number 37, District 2, 020021 Bucharest, Romania
| | - Sanziana Jurca
- Faculty of Medicine and Pharmacy, University of Oradea, December Sq., 410081 Oradea, Romania;
| | - Cosmin Mihai Vesa
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 1 December Sq., 410081 Oradea, Romania; (C.D.P.); (D.B.); (C.M.J.); (C.M.V.)
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Tyler AL, Mahoney JM, Keller MP, Baker CN, Gaca M, Srivastava A, Gerdes Gyuricza I, Braun MJ, Rosenthal NA, Attie AD, Churchill GA, Carter GW. Transcripts with high distal heritability mediate genetic effects on complex metabolic traits. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.26.613931. [PMID: 39386475 PMCID: PMC11463413 DOI: 10.1101/2024.09.26.613931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
Although many genes are subject to local regulation, recent evidence suggests that complex distal regulation may be more important in mediating phenotypic variability. To assess the role of distal gene regulation in complex traits, we combined multi-tissue transcriptomes with physiological outcomes to model diet-induced obesity and metabolic disease in a population of Diversity Outbred mice. Using a novel high-dimensional mediation analysis, we identified a composite transcriptome signature that summarized genetic effects on gene expression and explained 30% of the variation across all metabolic traits. The signature was heritable, interpretable in biological terms, and predicted obesity status from gene expression in an independently derived mouse cohort and multiple human studies. Transcripts contributing most strongly to this composite mediator frequently had complex, distal regulation distributed throughout the genome. These results suggest that trait-relevant variation in transcription is largely distally regulated, but is nonetheless identifiable, interpretable, and translatable across species.
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Stanciu SM, Jinga M, Miricescu D, Stefani C, Nica RI, Stanescu-Spinu II, Vacaroiu IA, Greabu M, Nica S. mTOR Dysregulation, Insulin Resistance, and Hypertension. Biomedicines 2024; 12:1802. [PMID: 39200267 PMCID: PMC11351979 DOI: 10.3390/biomedicines12081802] [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: 07/06/2024] [Revised: 08/04/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Worldwide, diabetes mellitus (DM) and cardiovascular diseases (CVDs) represent serious health problems associated with unhealthy diet and sedentarism. Metabolic syndrome (MetS) is characterized by obesity, dyslipidemia, hyperglycemia, insulin resistance (IR) and hypertension. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase with key roles in glucose and lipid metabolism, cell growth, survival and proliferation. mTOR hyperactivation disturbs glucose metabolism, leading to hyperglycemia and further to IR, with a higher incidence in the Western population. Metformin is one of the most used hypoglycemic drugs, with anti-inflammatory, antioxidant and antitumoral properties, having also the capacity to inhibit mTOR. mTOR inhibitors such as rapamycin and its analogs everolimus and temsirolimus block mTOR activity, decrease the levels of glucose and triglycerides, and reduce body weight. The link between mTOR dysregulation, IR, hypertension and mTOR inhibitors has not been fully described. Therefore, the main aim of this narrative review is to present the mechanism by which nutrients, proinflammatory cytokines, increased salt intake and renin-angiotensin-aldosterone system (RAAS) dysregulation induce mTOR overactivation, associated further with IR and hypertension development, and also mTOR inhibitors with higher potential to block the activity of this protein kinase.
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Affiliation(s)
- Silviu Marcel Stanciu
- Department of Internal Medicine and Gastroenterology, Carol Davila University of Medicine and Pharmacy, Central Military Emergency University Hospital, “Dr. Carol Davila”, 010825 Bucharest, Romania; (S.M.S.); (M.J.)
| | - Mariana Jinga
- Department of Internal Medicine and Gastroenterology, Carol Davila University of Medicine and Pharmacy, Central Military Emergency University Hospital, “Dr. Carol Davila”, 010825 Bucharest, Romania; (S.M.S.); (M.J.)
| | - Daniela Miricescu
- Discipline of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania;
| | - Constantin Stefani
- Department of Family Medicine and Clinical Base, Central Military Emergency University Hospital, “Dr. Carol Davila”, 010825 Bucharest, Romania;
| | - Remus Iulian Nica
- Surgery Department, Central Military Emergency University Hospital, “Dr. Carol Davila”, 010825 Bucharest, Romania;
- Discipline of General Surgery, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanotari Blvd, 054474 Bucharest, Romania
| | - Iulia-Ioana Stanescu-Spinu
- Discipline of Physiology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
| | - Ileana Adela Vacaroiu
- Department of Nephrology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Maria Greabu
- Discipline of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania;
| | - Silvia Nica
- Emergency Discipline, University Hospital of Bucharest, 050098 Bucharest, Romania;
- Department of Emergency and First Aid, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
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Kirchner VA, Badshah JS, Kyun Hong S, Martinez O, Pruett TL, Niedernhofer LJ. Effect of Cellular Senescence in Disease Progression and Transplantation: Immune Cells and Solid Organs. Transplantation 2024; 108:1509-1523. [PMID: 37953486 PMCID: PMC11089077 DOI: 10.1097/tp.0000000000004838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2023]
Abstract
Aging of the world population significantly impacts healthcare globally and specifically, the field of transplantation. Together with end-organ dysfunction and prolonged immunosuppression, age increases the frequency of comorbid chronic diseases in transplant candidates and recipients, contributing to inferior outcomes. Although the frequency of death increases with age, limited use of organs from older deceased donors reflects the concerns about organ durability and inadequate function. Cellular senescence (CS) is a hallmark of aging, which occurs in response to a myriad of cellular stressors, leading to activation of signaling cascades that stably arrest cell cycle progression to prevent tumorigenesis. In aging and chronic conditions, senescent cells accumulate as the immune system's ability to clear them wanes, which is causally implicated in the progression of chronic diseases, immune dysfunction, organ damage, decreased regenerative capacity, and aging itself. The intimate interplay between senescent cells, their proinflammatory secretome, and immune cells results in a positive feedback loop, propagating chronic sterile inflammation and the spread of CS. Hence, senescent cells in organs from older donors trigger the recipient's alloimmune response, resulting in the increased risk of graft loss. Eliminating senescent cells or attenuating their inflammatory phenotype is a novel, potential therapeutic target to improve transplant outcomes and expand utilization of organs from older donors. This review focuses on the current knowledge about the impact of CS on circulating immune cells in the context of organ damage and disease progression, discusses the impact of CS on abdominal solid organs that are commonly transplanted, and reviews emerging therapies that target CS.
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Affiliation(s)
- Varvara A. Kirchner
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, CA
| | - Joshua S. Badshah
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, CA
| | - Suk Kyun Hong
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, CA
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Olivia Martinez
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, CA
| | - Timothy L. Pruett
- Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN
| | - Laura J. Niedernhofer
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, MN
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Lüftner D, Schuetz F, Schneeweiss A, Hartkopf A, Bloch W, Decker T, Uleer C, Stötzer O, Foerster F, Schmidt M, Mundhenke C, Tesch H, Jackisch C, Fischer T, Kreuzeder J, Guderian G, Fasching PA. Efficacy and safety of everolimus plus exemestane in patients with hormone receptor-positive, HER-2-negative advanced breast cancer: Results from the open-label, multicentre, non-interventional BRAWO study. Int J Cancer 2024; 155:128-138. [PMID: 38447007 DOI: 10.1002/ijc.34912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 02/07/2024] [Accepted: 02/08/2024] [Indexed: 03/08/2024]
Abstract
BRAWO, a real-world study, assessed the efficacy, quality of life (QoL) and safety of EVE + EXE in postmenopausal women with HR+/HER2- advanced breast cancer (ABC) in routine clinical practice. Postmenopausal women with HR+/HER2-ABC with recurrence or progression after a NSAI were included. Primary Observation parameters included the evaluation of the effectiveness of EVE + EXE. A multivariate-analysis using Cox proportional hazard model was built to identify predictors of progression. Overall, 2100 patients were enrolled (August 2012-December 2017); 2074 were evaluable for efficacy and safety analyses. Majority of patients (60.6%) received EVE + EXE as first (28.7%) or second-line (31.9%) therapy. Visceral metastases were present in 54.1% patients. Median progression-free survival (mPFS) reported as 6.6 months (95%CI: 6.3-7.0). Multivariate-analysis in a subset of patients (n = 1837) found higher body mass index (BMI) and non-visceral metastases to be independent predictors of favorable PFS. Patients with a BMI of 20 to <25 had a mPFS of 6.0 (95%CI: 5.4-6.4) and those with a BMI ≥30 had mPFS of 8.5 (95%CI: 6.9-9.9). 41.2% patients achieved stable disease and 7.3% partial response. No major changes were observed QoL; 86.4% patients received stomatitis prophylaxis and 41.4% experienced EVE related AEs of stomatitis, mainly low grade. AEs occurred in 91.2% of patients, of which stomatitis (42.6%) and fatigue (19.8%) were most frequent. The BRAWO study provides real-world evidence of efficacy and safety of EVE + EXE in patients with HR+, HER2- ABC. A high BMI and the absence of visceral metastases were independent predictors of PFS in this cohort of patients.
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Affiliation(s)
- Diana Lüftner
- Medical University of Brandenburg Theodor Fontane, Campus Rüdersdorf and Immanuel Hospital Märkische Schweiz, Buckow, Germany
| | | | - Andreas Schneeweiss
- Division of Gynecologic Oncology, National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany
| | - Andreas Hartkopf
- Department of Women's Health, Universitäts-Frauenklinik Tubingen, Eberhard Karls University, Tubingen, Germany
- Department of Gynecology and Obstetrics, University of Ulm, Ulm, Germany
| | | | - Thomas Decker
- Studienzentrum Onkologie Ravensburg, Ravensburg, Germany
| | - Christoph Uleer
- Gyn.-onkologische Gemeinschaftspraxis Hildesheim, Hildesheim, Germany
| | | | | | - Marcus Schmidt
- Department of Obstetrics and Gynecology, University Medical Center, Johannes Gutenberg University, Mainz, Germany
| | | | - Hans Tesch
- Oncological Practice Bethanien, Frankfurt, Germany
| | | | | | | | | | - Peter A Fasching
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
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Qu W, Zhou X, Jiang X, Xie X, Xu K, Gu X, Na R, Piao M, Xi X, Sun N, Wang X, Peng X, Xu J, Tian J, Zhang J, Guo J, Zhang M, Zhang Y, Pan Z, Wang K, Yu B, Sun B, Li S, Tian J. Long Noncoding RNA Gpr137b-ps Promotes Advanced Atherosclerosis via the Regulation of Autophagy in Macrophages. Arterioscler Thromb Vasc Biol 2023; 43:e468-e489. [PMID: 37767704 DOI: 10.1161/atvbaha.123.319037] [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: 05/05/2023] [Accepted: 08/28/2023] [Indexed: 09/29/2023]
Abstract
BACKGROUND Current therapies cannot completely reverse advanced atherosclerosis. High levels of amino acids, induced by Western diet, stimulate mTORC1 (mammalian target of rapamycin complex 1)-autophagy defects in macrophages, accelerating atherosclerotic plaque progression. In addition, autophagy-lysosomal dysfunction contributes to plaque necrotic core enlargement and lipid accumulation. Therefore, it is essential to investigate the novel mechanism and molecules to reverse amino acid-mTORC1-autophagy signaling dysfunction in macrophages of patients with advanced atherosclerosis. METHODS We observed that Gpr137b-ps (G-protein-coupled receptor 137B, pseudogene) was upregulated in advanced atherosclerotic plaques. The effect of Gpr137b-ps on the progression of atherosclerosis was studied by generating advanced plaques in ApoE-/- mice with cardiac-specific knockout of Gpr137b-ps. Bone marrow-derived macrophages and mouse mononuclear macrophage cell line RAW264.7 cells were subjected to starvation or amino acid stimulation to study amino acid-mTORC1-autophagy signaling. Using both gain- and loss-of-function approaches, we explored the mechanism of Gpr137b-ps-regulated autophagy. RESULTS Our results demonstrated that Gpr137b-ps deficiency led to enhanced autophagy in macrophages and reduced atherosclerotic lesions, characterized by fewer necrotic cores and less lipid accumulation. Knockdown of Gpr137b-ps increased autophagy and prevented amino acid-induced mTORC1 signaling activation. As the downstream binding protein of Gpr137b-ps, HSC70 (heat shock cognate 70) rescued the impaired autophagy induced by Gpr137b-ps. Furthermore, Gpr137b-ps interfered with the HSC70 binding to G3BP (Ras GTPase-activating protein-binding protein), which tethers the TSC (tuberous sclerosis complex) complex to lysosomes and suppresses mTORC1 signaling. In addition to verifying that the NTF2 (nuclear transport factor 2) domain of G3BP binds to HSC70 by in vitro protein synthesis, we further demonstrated that HSC70 binds to the NTF2 domain of G3BP through its W90-F92 motif by using computational modeling. CONCLUSIONS These findings reveal that Gpr137b-ps plays an essential role in the regulation of macrophage autophagy, which is crucial for the progression of advanced atherosclerosis. Gpr137b-ps impairs the interaction of HSC70 with G3BP to regulate amino acid-mTORC1-autophagy signaling, and these results provide a new potential therapeutic direction for the treatment of advanced atherosclerosis.
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Affiliation(s)
- Wenbo Qu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian)
- The Key Laboratory of Myocardial Ischemia, Ministry of Education (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian), Harbin Medical University, China
| | - Xin Zhou
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian)
- The Key Laboratory of Myocardial Ischemia, Ministry of Education (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian), Harbin Medical University, China
| | - Xinjian Jiang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian)
- The Key Laboratory of Myocardial Ischemia, Ministry of Education (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian), Harbin Medical University, China
| | - Xianwei Xie
- Department of Cardiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China (X. Xie)
| | - Kaijian Xu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian)
- The Key Laboratory of Myocardial Ischemia, Ministry of Education (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian), Harbin Medical University, China
| | - Xia Gu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian)
- The Key Laboratory of Myocardial Ischemia, Ministry of Education (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian), Harbin Medical University, China
| | - Ruisi Na
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Heilongjiang, China (R.N.)
| | - Minghui Piao
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian)
- The Key Laboratory of Myocardial Ischemia, Ministry of Education (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian), Harbin Medical University, China
| | - Xiangwen Xi
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian)
- The Key Laboratory of Myocardial Ischemia, Ministry of Education (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian), Harbin Medical University, China
| | - Na Sun
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian)
- The Key Laboratory of Myocardial Ischemia, Ministry of Education (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian), Harbin Medical University, China
| | - Xueyu Wang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian)
- The Key Laboratory of Myocardial Ischemia, Ministry of Education (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian), Harbin Medical University, China
| | - Xiang Peng
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian)
- The Key Laboratory of Myocardial Ischemia, Ministry of Education (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian), Harbin Medical University, China
| | - Junyan Xu
- Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China (J.X.)
- Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, Cardiovascular Diseases Institute of the First Affiliated Hospital, Key Laboratory of Emergency and Trauma, Ministry of Education, College of Emergency and Trauma, Hainan Medical University, Haikou, China (J.X., J.G.)
| | - Jiangtian Tian
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian)
- The Key Laboratory of Myocardial Ischemia, Ministry of Education (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian), Harbin Medical University, China
| | - Jian Zhang
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology (J.Z.)
| | - Junli Guo
- Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, Cardiovascular Diseases Institute of the First Affiliated Hospital, Key Laboratory of Emergency and Trauma, Ministry of Education, College of Emergency and Trauma, Hainan Medical University, Haikou, China (J.X., J.G.)
| | - Maomao Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian)
- The Key Laboratory of Myocardial Ischemia, Ministry of Education (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian), Harbin Medical University, China
| | - Yao Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian)
- The Key Laboratory of Myocardial Ischemia, Ministry of Education (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian), Harbin Medical University, China
| | - Zhenwei Pan
- College of Pharmacy (Z.P., B.S.), Harbin Medical University, China
| | - Kun Wang
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, China (K.W.)
| | - Bo Yu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian)
- The Key Laboratory of Myocardial Ischemia, Ministry of Education (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian), Harbin Medical University, China
| | - Bin Sun
- College of Pharmacy (Z.P., B.S.), Harbin Medical University, China
| | - Shuijie Li
- Department of Biopharmaceutical Sciences, College of Pharmacy (S.L.), Harbin Medical University, China
- State Key Laboratory of Frigid Zone Cardiovascular Diseases Harbin Medical University, China (S.L.)
- Department of Biopharmaceutical Sciences, College of Pharmacy Harbin Medical University, China (S.L.)
| | - Jinwei Tian
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian)
- The Key Laboratory of Myocardial Ischemia, Ministry of Education (W.Q., X.Z., X.J., K.X., X.G., M.P., X. Xi, N.S., X.W., X.P., Jiangtian Tian, M.Z., Y.Z., B.Y., Jinwei Tian), Harbin Medical University, China
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9
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Zhang X, Evans TD, Chen S, Sergin I, Stitham J, Jeong SJ, Rodriguez-Velez A, Yeh YS, Park A, Jung IH, Diwan A, Schilling JD, Rom O, Yurdagul A, Epelman S, Cho J, Lodhi IJ, Mittendorfer B, Razani B. Loss of Macrophage mTORC2 Drives Atherosclerosis via FoxO1 and IL-1β Signaling. Circ Res 2023; 133:200-219. [PMID: 37350264 PMCID: PMC10527041 DOI: 10.1161/circresaha.122.321542] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 06/12/2023] [Indexed: 06/24/2023]
Abstract
BACKGROUND The mTOR (mechanistic target of rapamycin) pathway is a complex signaling cascade that regulates cellular growth, proliferation, metabolism, and survival. Although activation of mTOR signaling has been linked to atherosclerosis, its direct role in lesion progression and in plaque macrophages remains poorly understood. We previously demonstrated that mTORC1 (mTOR complex 1) activation promotes atherogenesis through inhibition of autophagy and increased apoptosis in macrophages. METHODS Using macrophage-specific Rictor- and mTOR-deficient mice, we now dissect the distinct functions of mTORC2 pathways in atherogenesis. RESULTS In contrast to the atheroprotective effect seen with blockade of macrophage mTORC1, macrophage-specific mTORC2-deficient mice exhibit an atherogenic phenotype, with larger, more complex lesions and increased cell death. In cultured macrophages, we show that mTORC2 signaling inhibits the FoxO1 (forkhead box protein O1) transcription factor, leading to suppression of proinflammatory pathways, especially the inflammasome/IL (interleukin)-1β response, a key mediator of vascular inflammation and atherosclerosis. In addition, administration of FoxO1 inhibitors efficiently rescued the proinflammatory response caused by mTORC2 deficiency both in vitro and in vivo. Interestingly, collective deletion of macrophage mTOR, which ablates mTORC1- and mTORC2-dependent pathways, leads to minimal change in plaque size or complexity, reflecting the balanced yet opposing roles of these signaling arms. CONCLUSIONS Our data provide the first mechanistic details of macrophage mTOR signaling in atherosclerosis and suggest that therapeutic measures aimed at modulating mTOR need to account for its dichotomous functions.
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Affiliation(s)
- Xiangyu Zhang
- Department of Medicine and Vascular Medicine Institute, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
- Cardiovascular Division, Washington University School of Medicine, St Louis, MO, USA
| | - Trent D. Evans
- Cardiovascular Division, Washington University School of Medicine, St Louis, MO, USA
| | - Sunny Chen
- Cardiovascular Division, Washington University School of Medicine, St Louis, MO, USA
| | - Ismail Sergin
- Cardiovascular Division, Washington University School of Medicine, St Louis, MO, USA
| | - Jeremiah Stitham
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St Louis, MO, USA
| | - Se-Jin Jeong
- Cardiovascular Division, Washington University School of Medicine, St Louis, MO, USA
| | | | - Yu-Sheng Yeh
- Department of Medicine and Vascular Medicine Institute, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
- Cardiovascular Division, Washington University School of Medicine, St Louis, MO, USA
| | - Arick Park
- Cardiovascular Division, Washington University School of Medicine, St Louis, MO, USA
| | - In-Hyuk Jung
- Cardiovascular Division, Washington University School of Medicine, St Louis, MO, USA
| | - Abhinav Diwan
- Cardiovascular Division, Washington University School of Medicine, St Louis, MO, USA
- John Cochran VA Medical Center, St. Louis, MO, USA
| | - Joel D. Schilling
- Cardiovascular Division, Washington University School of Medicine, St Louis, MO, USA
| | - Oren Rom
- Department of Pathology and Translational Pathobiology and Department of Molecular and Cellular Physiology, Louisiana State University, Shreveport, LA
| | - Arif Yurdagul
- Department of Pathology and Translational Pathobiology and Department of Molecular and Cellular Physiology, Louisiana State University, Shreveport, LA
| | - Slava Epelman
- Ted Rogers Centre for Heart Research, Peter Munk Cardiac Center, Toronto General Hospital Research Institute, University Health Network and University of Toronto, Toronto, Canada
| | - Jaehyung Cho
- Division of Hematology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
- Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - Irfan J. Lodhi
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St Louis, MO, USA
| | - Bettina Mittendorfer
- Division of Geriatrics and Nutritional Science, and Washington University School of Medicine, St Louis, MO, USA
| | - Babak Razani
- Department of Medicine and Vascular Medicine Institute, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
- Pittsburgh VA Medical Center, Pittsburgh, PA
- Cardiovascular Division, Washington University School of Medicine, St Louis, MO, USA
- Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO, USA
- John Cochran VA Medical Center, St. Louis, MO, USA
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10
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Jurca CM, Kozma K, Petchesi CD, Zaha DC, Magyar I, Munteanu M, Faur L, Jurca A, Bembea D, Severin E, Jurca AD. Tuberous Sclerosis, Type II Diabetes Mellitus and the PI3K/AKT/mTOR Signaling Pathways-Case Report and Literature Review. Genes (Basel) 2023; 14:433. [PMID: 36833359 PMCID: PMC9957184 DOI: 10.3390/genes14020433] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/23/2023] [Accepted: 02/05/2023] [Indexed: 02/11/2023] Open
Abstract
Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurocutaneous syndrome. It is manifested mainly in cutaneous lesions, epilepsy and the emergence of hamartomas in several tissues and organs. The disease sets in due to mutations in two tumor suppressor genes: TSC1 and TSC2. The authors present the case of a 33-year-old female patient registered with the Bihor County Regional Center of Medical Genetics (RCMG) since 2021 with a TSC diagnosis. She was diagnosed with epilepsy at eight months old. At 18 years old she was diagnosed with tuberous sclerosis and was referred to the neurology department. Since 2013 she has been registered with the department for diabetes and nutritional diseases with a type 2 diabetes mellitus (T2DM) diagnosis. The clinical examination revealed: growth delay, obesity, facial angiofibromas, sebaceous adenomas, depigmented macules, papillomatous tumorlets in the thorax (bilateral) and neck, periungual fibroma in both lower limbs, frequent convulsive seizures; on a biological level, high glycemia and glycated hemoglobin levels. Brain MRI displayed a distinctive TS aspect with five bilateral hamartomatous subependymal nodules associating cortical/subcortical tubers with the frontal, temporal and occipital distribution. Molecular diagnosis showed a pathogenic variant in the TSC1 gene, exon 13, c.1270A>T (p. Arg424*). Current treatment targets diabetes (Metformin, Gliclazide and the GLP-1 analog semaglutide) and epilepsy (Carbamazepine and Clonazepam). This case report presents a rare association between type 2 diabetes mellitus and Tuberous Sclerosis Complex. We suggest that the diabetes medication Metformin may have positive effects on both the progression of the tumor associated with TSC and the seizures specific to TSC and we assume that the association of TSC and T2DM in the presented cases is accidental, as there are no similar cases reported in the literature.
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Affiliation(s)
- Claudia Maria Jurca
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
- Regional Center of Medical Genetics Bihor, County Emergency Clinical Hospital Oradea (Part of ERN-ITHACA), 410469 Oradea, Romania
| | - Kinga Kozma
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
- Regional Center of Medical Genetics Bihor, County Emergency Clinical Hospital Oradea (Part of ERN-ITHACA), 410469 Oradea, Romania
| | - Codruta Diana Petchesi
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
- Regional Center of Medical Genetics Bihor, County Emergency Clinical Hospital Oradea (Part of ERN-ITHACA), 410469 Oradea, Romania
| | - Dana Carmen Zaha
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
| | - Ioan Magyar
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
| | - Mihai Munteanu
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
| | - Lucian Faur
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
| | - Aurora Jurca
- Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
| | - Dan Bembea
- Faculty of Medicine, University of Medicine and Pharmacy ”Iuliu Hațieganu”, 400012 Cluj Napoca, Romania
| | - Emilia Severin
- Department of Genetics, University of Medicine and Pharmacy ”Carol Davila”, 020021 Bucharest, Romania
| | - Alexandru Daniel Jurca
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
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11
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Battistella S, D’Arcangelo F, Grasso M, Zanetto A, Gambato M, Germani G, Senzolo M, Russo FP, Burra P. Liver transplantation for non-alcoholic fatty liver disease: indications and post-transplant management. Clin Mol Hepatol 2023; 29:S286-S301. [PMID: 36577425 PMCID: PMC10029965 DOI: 10.3350/cmh.2022.0392] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/30/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently the fastest growing indication to liver transplantation (LT) in Western Countries, both for end stage liver disease and hepatocellular carcinoma. NAFLD/non-alcoholic steatohepatitis (NASH) is often expression of a systemic metabolic syndrome; therefore, NAFLD/NASH patients require a multidisciplinary approach for a proper pre-surgical evaluation, which is important to achieve a post-transplant outcome comparable to that of other indications to LT. NAFLD/NASH patients are also at higher risk of post-transplant cardiovascular events, diabetes, dyslipidemia, obesity, renal impairment and recurrent NASH. Lifestyle modifications, included diet and physical activity, are key to improve survival and quality of life after transplantation. A tailored immunosuppressive regimen may be proposed in selected patients. Development of new drugs for the treatment of recurrent NASH is awaited.
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Affiliation(s)
- Sara Battistella
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, University of Padua, Padua,
Italy
| | - Francesca D’Arcangelo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, University of Padua, Padua,
Italy
| | - Marco Grasso
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, University of Padua, Padua,
Italy
| | - Alberto Zanetto
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, University of Padua, Padua,
Italy
| | - Martina Gambato
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, University of Padua, Padua,
Italy
| | - Giacomo Germani
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, University of Padua, Padua,
Italy
| | - Marco Senzolo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, University of Padua, Padua,
Italy
| | - Francesco Paolo Russo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, University of Padua, Padua,
Italy
| | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, University of Padua, Padua,
Italy
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12
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Paez-Mayorga J, Campa-Carranza JN, Capuani S, Hernandez N, Liu HC, Chua CYX, Pons-Faudoa FP, Malgir G, Alvarez B, Niles JA, Argueta LB, Shelton KA, Kezar S, Nehete PN, Berman DM, Willman MA, Li XC, Ricordi C, Nichols JE, Gaber AO, Kenyon NS, Grattoni A. Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats. Nat Commun 2022; 13:7951. [PMID: 36572684 PMCID: PMC9792517 DOI: 10.1038/s41467-022-35629-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 12/14/2022] [Indexed: 12/27/2022] Open
Abstract
Pancreatic islet transplantation efficacy for type 1 diabetes (T1D) management is limited by hypoxia-related graft attrition and need for systemic immunosuppression. To overcome these challenges, we developed the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, which integrates direct vascularization for facile mass transfer and localized immunosuppressant delivery for islet rejection prophylaxis. Here, we investigated NICHE efficacy for allogeneic islet transplantation and long-term diabetes reversal in an immunocompetent, male rat model. We demonstrated that allogeneic islets transplanted within pre-vascularized NICHE were engrafted, revascularized, and functional, reverting diabetes in rats for over 150 days. Notably, we confirmed that localized immunosuppression prevented islet rejection without inducing toxicity or systemic immunosuppression. Moreover, for translatability efforts, we showed NICHE biocompatibility and feasibility of deployment as well as short-term allogeneic islet engraftment in an MHC-mismatched nonhuman primate model. In sum, the NICHE holds promise as a viable approach for safe and effective islet transplantation and long-term T1D management.
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Affiliation(s)
- Jesus Paez-Mayorga
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
- School of Medicine and Health Sciences, Tecnologico de Monterrey, Monterrey, NL, Mexico
| | - Jocelyn Nikita Campa-Carranza
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
- School of Medicine and Health Sciences, Tecnologico de Monterrey, Monterrey, NL, Mexico
| | - Simone Capuani
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
- University of the Chinese Academy of Sciences (UCAS), Shijingshan, Beijing, China
| | - Nathanael Hernandez
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
| | - Hsuan-Chen Liu
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
| | | | | | - Gulsah Malgir
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
| | - Bella Alvarez
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
- School of Medicine and Health Sciences, Tecnologico de Monterrey, Monterrey, NL, Mexico
| | - Jean A Niles
- Center for Tissue Engineering, Houston Methodist Research Institute, Houston, TX, USA
| | - Lissenya B Argueta
- Center for Tissue Engineering, Houston Methodist Research Institute, Houston, TX, USA
| | - Kathryn A Shelton
- Department of Comparative Medicine, Michael E. Keeling Center for Comparative Medicine and Research, MD Anderson Cancer Center, Bastrop, TX, USA
| | - Sarah Kezar
- Department of Comparative Medicine, Michael E. Keeling Center for Comparative Medicine and Research, MD Anderson Cancer Center, Bastrop, TX, USA
| | - Pramod N Nehete
- Department of Comparative Medicine, Michael E. Keeling Center for Comparative Medicine and Research, MD Anderson Cancer Center, Bastrop, TX, USA
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA
| | - Dora M Berman
- Diabetes Research Institute, University of Miami, Miami, FL, USA
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | - Xian C Li
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
- Immunobiology and Transplant Science Center, Houston Methodist Hospital, Houston, TX, USA
| | - Camillo Ricordi
- Diabetes Research Institute, University of Miami, Miami, FL, USA
| | - Joan E Nichols
- Center for Tissue Engineering, Houston Methodist Research Institute, Houston, TX, USA
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
| | - A Osama Gaber
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
| | - Norma S Kenyon
- Diabetes Research Institute, University of Miami, Miami, FL, USA
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL, USA
- Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL, USA
| | - Alessandro Grattoni
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA.
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA.
- Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL, USA.
- Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX, USA.
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13
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Toro C, Felmingham B, Jessop S, Celermajer DS, Kotecha RS, Govender D, Terese Hanna DM, O'Connor M, Manudhane R, Ayer J, O'Sullivan J, Sullivan M, Costello B, La Gerche A, Walwyn T, Horvath L, Mateos MK, Fulbright J, Jadhav M, Cheung M, Eisenstat D, Elliott DA, Conyers R. Cardio-Oncology Recommendations for Pediatric Oncology Patients: An Australian and New Zealand Delphi Consensus. JACC. ADVANCES 2022; 1:100155. [PMID: 38939459 PMCID: PMC11198111 DOI: 10.1016/j.jacadv.2022.100155] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/07/2022] [Accepted: 10/25/2022] [Indexed: 06/29/2024]
Abstract
Cardio-oncology is a new multidisciplinary area of expertise that seeks to pre-emptively and proactively address cardiac complications that emerge during and following cancer therapy. Modern therapies including molecular targeted therapy and immunotherapy have broadened the agents that can cause cardiac sequelae, often with complications arising within days to weeks of therapy. Several international guidelines have been developed for the acute monitoring of cardio-oncology side effects. However, none are specific to pediatrics. We have addressed this gap in the literature by undertaking a rigorous Delphi consensus approach across 11 domains of cardio-oncology care using an Australian and New Zealand expert group. The expert group consisted of pediatric and adult cardiologists and pediatric oncologists. This Delphi consensus provides an approach to perform risk and baseline assessment, screening, and follow-up, specific to the cancer therapeutic. This review is a useful tool for clinicians involved in the cardio-oncology care of pediatric oncology patients.
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Affiliation(s)
- Claudia Toro
- Cardiac Regeneration Laboratory, Murdoch Children’s Research Institute, Parkville, Melbourne, Australia
- Children’s Cancer Centre, The Royal Children’s Hospital, Parkville, Melbourne, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Australia
| | - Ben Felmingham
- Cardiac Regeneration Laboratory, Murdoch Children’s Research Institute, Parkville, Melbourne, Australia
- Children’s Cancer Centre, The Royal Children’s Hospital, Parkville, Melbourne, Australia
| | - Sophie Jessop
- Michael Rice Centre for Haematology and Oncology, Women’s and Children’s Hospital, Adelaide, South Australia, Australia
| | - David S. Celermajer
- Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
- Department of Cardiology, RPA Hospital, Camperdown, New South Wales, Australia
| | - Rishi S. Kotecha
- Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children’s Hospital, Perth, Australia
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia
- Curtin Medical School, Curtin University, Perth, Australia
| | - Dinisha Govender
- Cancer Centre for Children, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
| | - Diane Marie Terese Hanna
- Children’s Cancer Centre, The Royal Children’s Hospital, Parkville, Melbourne, Australia
- Murdoch Children's Research Institute, Melbourne University, Parkville, Victoria, Australia
- The Walter & Eliza Hall Institute, Parkville, Victoria, Australia
| | - Matthew O'Connor
- Michael Rice Centre for Haematology and Oncology, Women’s and Children’s Hospital, Adelaide, South Australia, Australia
| | - Rebecca Manudhane
- Michael Rice Centre for Haematology and Oncology, Women’s and Children’s Hospital, Adelaide, South Australia, Australia
| | - Julian Ayer
- Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
- The Heart Centre for Children, The Sydney Children’s Hospital Network Children’s Hospital at Westmead, Westmead, New South Wales, Australia
| | - John O'Sullivan
- Department of Cardiology, RPA Hospital, Camperdown, New South Wales, Australia
- Heart Institute, Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia
| | - Michael Sullivan
- Children’s Cancer Centre, The Royal Children’s Hospital, Parkville, Melbourne, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Australia
| | - Ben Costello
- Clinical Research Domain, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - André La Gerche
- Clinical Research Domain, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Thomas Walwyn
- Department of Paediatric Oncology, Haematology and Bone Marrow Transplantation, Perth Children’s Hospital, Nedlands, Western Australia, Australia
- Discipline of Paediatrics, Medical School, University of Western Australia, Perth, Western Australia, Australia
| | - Lisa Horvath
- Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia
| | - Marion K. Mateos
- Kids Cancer Centre, Sydney Children’s Hospital Randwick, Sydney, Australia
- Discipline of Paediatrics and Child Health, School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, New South Wales, Australia
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia
| | - Joy Fulbright
- Division of Pediatric Hematology/Oncology, Children’s Mercy Kansas City, Kansas City, Missouri, USA
| | - Mangesh Jadhav
- Cardiology Department, The Royal Children’s Hospital, Melbourne, Australia
| | - Michael Cheung
- Cardiac Regeneration Laboratory, Murdoch Children’s Research Institute, Parkville, Melbourne, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Australia
- Cardiology Department, The Royal Children’s Hospital, Melbourne, Australia
| | - David Eisenstat
- Children’s Cancer Centre, The Royal Children’s Hospital, Parkville, Melbourne, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Australia
| | - David A. Elliott
- Cardiac Regeneration Laboratory, Murdoch Children’s Research Institute, Parkville, Melbourne, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Australia
| | - Rachel Conyers
- Cardiac Regeneration Laboratory, Murdoch Children’s Research Institute, Parkville, Melbourne, Australia
- Children’s Cancer Centre, The Royal Children’s Hospital, Parkville, Melbourne, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Australia
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14
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Ramasubbu K, Devi Rajeswari V. Impairment of insulin signaling pathway PI3K/Akt/mTOR and insulin resistance induced AGEs on diabetes mellitus and neurodegenerative diseases: a perspective review. Mol Cell Biochem 2022; 478:1307-1324. [PMID: 36308670 DOI: 10.1007/s11010-022-04587-x] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 10/12/2022] [Indexed: 12/01/2022]
Abstract
Insulin resistance is common in type 2 diabetes mellitus (T2DM), neurodegenerative diseases, cardiovascular diseases, kidney diseases, and polycystic ovary syndrome. Impairment in insulin signaling pathways, such as the PI3K/Akt/mTOR pathway, would lead to insulin resistance. It might induce the synthesis and deposition of advanced glycation end products (AGEs), reactive oxygen species, and reactive nitrogen species, resulting in stress, protein misfolding, protein accumulation, mitochondrial dysfunction, reticulum function, and metabolic syndrome dysregulation, inflammation, and apoptosis. It plays a huge role in various neurodegenerative diseases like Parkinson's disease, Alzheimer's disease, Huntington's disease, and Amyloid lateral sclerosis. In this review, we intend to focus on the possible effect of insulin resistance in the progression of neurodegeneration via the impaired P13K/Akt/mTOR signaling pathway, AGEs, and receptors for AGEs.
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Affiliation(s)
- Kanagavalli Ramasubbu
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Tamil Nadu, Vellore, 632014, India
| | - V Devi Rajeswari
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Tamil Nadu, Vellore, 632014, India.
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15
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Ge X, Wang L, Fei A, Ye S, Zhang Q. Research progress on the relationship between autophagy and chronic complications of diabetes. Front Physiol 2022; 13:956344. [PMID: 36003645 PMCID: PMC9393249 DOI: 10.3389/fphys.2022.956344] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/11/2022] [Indexed: 12/01/2022] Open
Abstract
Diabetes is a common metabolic disease whose hyperglycemic state can induce diverse complications and even threaten human health and life security. Currently, the treatment of diabetes is restricted to drugs that regulate blood glucose and have certain accompanying side effects. Autophagy, a research hotspot, has been proven to be involved in the occurrence and progression of the chronic complications of diabetes. Autophagy, as an essential organismal defense mechanism, refers to the wrapping of cytoplasmic proteins, broken organelles or pathogens by vesicles, which are then degraded by lysosomes to maintain the stability of the intracellular environment. Here, we review the relevant aspects of autophagy and the molecular mechanisms of autophagy in diabetic chronic complications, and further analyze the impact of improving autophagy on diabetic chronic complications, which will contribute to a new direction for further prevention and treatment of diabetic chronic complications.
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Affiliation(s)
- Xia Ge
- Department of Endocrinology, The Second Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Ling Wang
- Graduate School of Anhui University of Chinese Medicine, Hefei, China
| | - Aihua Fei
- Department of Endocrinology, The Second Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Shandong Ye
- Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- *Correspondence: Shandong Ye, ; Qingping Zhang,
| | - Qingping Zhang
- College of Acupuncture-Moxibustion and Tuina, Anhui University of Chinese Medicine, Hefei, China
- *Correspondence: Shandong Ye, ; Qingping Zhang,
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16
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Culig L, Chu X, Bohr VA. Neurogenesis in aging and age-related neurodegenerative diseases. Ageing Res Rev 2022; 78:101636. [PMID: 35490966 PMCID: PMC9168971 DOI: 10.1016/j.arr.2022.101636] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 04/14/2022] [Accepted: 04/25/2022] [Indexed: 12/11/2022]
Abstract
Adult neurogenesis, the process by which neurons are generated in certain areas of the adult brain, declines in an age-dependent manner and is one potential target for extending cognitive healthspan. Aging is a major risk factor for neurodegenerative diseases and, as lifespans are increasing, these health challenges are becoming more prevalent. An age-associated loss in neural stem cell number and/or activity could cause this decline in brain function, so interventions that reverse aging in stem cells might increase the human cognitive healthspan. In this review, we describe the involvement of adult neurogenesis in neurodegenerative diseases and address the molecular mechanistic aspects of neurogenesis that involve some of the key aggregation-prone proteins in the brain (i.e., tau, Aβ, α-synuclein, …). We summarize the research pertaining to interventions that increase neurogenesis and regulate known targets in aging research, such as mTOR and sirtuins. Lastly, we share our outlook on restoring the levels of neurogenesis to physiological levels in elderly individuals and those with neurodegeneration. We suggest that modulating neurogenesis represents a potential target for interventions that could help in the fight against neurodegeneration and cognitive decline.
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Affiliation(s)
- Luka Culig
- Section on DNA Repair, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Xixia Chu
- Section on DNA Repair, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Vilhelm A Bohr
- Section on DNA Repair, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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17
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Poznyak AV, Sukhorukov VN, Zhuravlev A, Orekhov NA, Kalmykov V, Orekhov AN. Modulating mTOR Signaling as a Promising Therapeutic Strategy for Atherosclerosis. Int J Mol Sci 2022; 23:ijms23031153. [PMID: 35163076 PMCID: PMC8835022 DOI: 10.3390/ijms23031153] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 12/14/2022] Open
Abstract
For more than a decade, atherosclerosis has been one of the leading causes of death in developed countries. The issue of treatment and prevention of the disease is especially acute. Despite the huge amount of basic and clinical research, a significant number of gaps remain in our understanding of the pathogenesis of atherosclerosis, and only their closure will bring us closer to understanding the causes of the disease at the cellular and molecular levels and, accordingly, to the development of an effective treatment. One of the seemingly well-studied elements of atherogenesis is the mTOR signaling pathway. However, more and more new details are still being clarified. Therapeutic strategies associated with rapamycin have worked well in a number of different diseases, and there is every reason to believe that targeting components of the mTOR pathway may pay off in atherosclerosis as well.
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Affiliation(s)
- Anastasia V. Poznyak
- Skolkovo Innovative Center, Institute for Atherosclerosis Research, Osennyaya Street 4-1-207, 121609 Moscow, Russia;
- Correspondence: (A.V.P.); (A.N.O.)
| | - Vasily N. Sukhorukov
- AP Avtsyn Research Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia; (V.N.S.); (A.Z.); (V.K.)
- National Medical Research Center of Cardiology, Institute of Experimental Cardiology, 15A 3-rd Cherepkovskaya Street, 121552 Moscow, Russia
| | - Alexander Zhuravlev
- AP Avtsyn Research Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia; (V.N.S.); (A.Z.); (V.K.)
| | - Nikolay A. Orekhov
- Skolkovo Innovative Center, Institute for Atherosclerosis Research, Osennyaya Street 4-1-207, 121609 Moscow, Russia;
| | - Vladislav Kalmykov
- AP Avtsyn Research Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia; (V.N.S.); (A.Z.); (V.K.)
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia
| | - Alexander N. Orekhov
- Skolkovo Innovative Center, Institute for Atherosclerosis Research, Osennyaya Street 4-1-207, 121609 Moscow, Russia;
- AP Avtsyn Research Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia; (V.N.S.); (A.Z.); (V.K.)
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia
- Correspondence: (A.V.P.); (A.N.O.)
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18
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Xu G, Fang J, Xu J, Shen Z, Huang C, Jiang Y. Expression and significance of mammalian target of rapamycin in cutaneous squamous cell carcinoma and precancerous lesions. Bioengineered 2021; 12:9930-9938. [PMID: 34874800 PMCID: PMC8810078 DOI: 10.1080/21655979.2021.1984719] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
The aim of this study is to explore the role of mammalian target of rapamycin (mTOR) in cutaneous squamous cell carcinoma (CSCC), Bowen’s disease (BD), and actinic keratosis (AK) with squamous cell differentiation abnormality and its relationship with the degree of tumor proliferation. Thirty cases of clinical paraffin specimens of CSCC, BD, and AK were each collected from Jinhua Fifth Hospital, while 30 cases of normal skin specimens surgically resected in Department of Plastic Surgery were selected as controls. The expressions of mTOR and Ki-67 in tissues were detected by immunohistochemical staining. The positive expression rate of mTOR in the CSCC group was higher than those in the BD group and AK group (P < 0.05), while it was higher in the BD group and AK group than in the normal skin group (P < 0.05). The CSCC group had a higher positive expression rate of Ki-67 than the AK group (P < 0.01). The results of logistic regression analysis showed that the pathogenic site [odds ratio (OR) = 1.189, 95% confidence interval (95%CI): 1.028–1.381, P = 0.021], course of disease (OR = 2.059, 95%CI: 1.036–4.087, P = 0.043), and differentiation degree (OR = 1.325, 95%CI: 1.169–1.512, P = 0.001) were independent factors for the positive expression of mTOR. OR>1, indicating that the factor is a risk factor. The expression levels of mTOR in CSCC, BD, and AK were positively correlated with the expression level of Ki-67 (r = 0.827, P < 0.01, r = 0.608, P < 0.01, r = 0.368, P = 0.045). These results suggest that mTOR may be involved in the pathogenesis of CSCC, and related to the proliferation degree of CSCC, as an index reflecting the proliferation status of CSCC.
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Affiliation(s)
- Gongjun Xu
- Department of Dermatology,Jinhua Fifth Hospital, JinHua, ZheJiang,China
| | - Jinxian Fang
- Department of Dermatology,Jinhua Fifth Hospital, JinHua, ZheJiang,China
| | - Jinlun Xu
- Department of Dermatology,Jinhua Fifth Hospital, JinHua, ZheJiang,China
| | - Zhen Shen
- Department of Dermatology,Jinhua Fifth Hospital, JinHua, ZheJiang,China
| | - Chiqing Huang
- Department of Dermatology,Jinhua Fifth Hospital, JinHua, ZheJiang,China
| | - Yixiu Jiang
- Department of Dermatology,Jinhua Fifth Hospital, JinHua, ZheJiang,China
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19
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Kotha S, Lawendy B, Asim S, Gomes C, Yu J, Orchanian-Cheff A, Tomlinson G, Bhat M. Impact of immunosuppression on incidence of post-transplant diabetes mellitus in solid organ transplant recipients: Systematic review and meta-analysis. World J Transplant 2021; 11:432-442. [PMID: 34722172 PMCID: PMC8529944 DOI: 10.5500/wjt.v11.i10.432] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/27/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Solid organ transplantation is a life-saving intervention for end-stage organ disease. Post-transplant diabetes mellitus (PTDM) is a common complication in solid organ transplant recipients, and significantly compromises long-term survival beyond a year.
AIM To perform a systematic review and meta-analysis to estimate incidence of PTDM and compare the effects of the 3 major immunosuppressants on incidence of PTDM.
METHODS Two hundred and six eligible studies identified 75595 patients on Tacrolimus, 51242 on Cyclosporine and 3020 on Sirolimus. Random effects meta-analyses was used to calculate incidence.
RESULTS Network meta-analysis estimated the overall risk of developing PTDM was higher with tacrolimus (OR = 1.4 95%CI: 1.0–2.0) and sirolimus (OR = 1.8; 95%CI: 1.5–2.2) than with Cyclosporine. The overall incidence of PTDM at years 2-3 was 17% for kidney, 19% for liver and 22% for heart. The risk factors for PTDM most frequently identified in the primary studies were age, body mass index, hepatitis C, and African American descent.
CONCLUSION Tacrolimus tends to exhibit higher diabetogenicity in the short-term (2-3 years post-transplant), whereas sirolimus exhibits higher diabetogenicity in the long-term (5-10 years post-transplant). This study will aid clinicians in recognition of risk factors for PTDM and encourage careful evaluation of the risk/benefit of different immunosuppressant regimens in transplant recipients.
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Affiliation(s)
- Sreelakshmi Kotha
- Department of Gastroenterology, Guy's and St Thomas' Hospital, London SE1 7JD, United Kingdom
| | - Bishoy Lawendy
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Saira Asim
- Multi Organ Transplant Program, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Charlene Gomes
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Jeffrey Yu
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Ani Orchanian-Cheff
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - George Tomlinson
- Dalla Lana School of Public Health, Department of Medicine, University Health Network - Toronto General Hospital, University of Toronto, Toronto M5G 2C4, Canada
| | - Mamatha Bhat
- Multi-organ Transplant, Toronto General Hospital, Toronto M5G 2C4, Canada
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20
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Dankó T, Petővári G, Sztankovics D, Moldvai D, Raffay R, Lőrincz P, Visnovitz T, Zsiros V, Barna G, Márk Á, Krencz I, Sebestyén A. Rapamycin Plus Doxycycline Combination Affects Growth Arrest and Selective Autophagy-Dependent Cell Death in Breast Cancer Cells. Int J Mol Sci 2021; 22:ijms22158019. [PMID: 34360785 PMCID: PMC8347279 DOI: 10.3390/ijms22158019] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 07/20/2021] [Accepted: 07/22/2021] [Indexed: 12/22/2022] Open
Abstract
Metabolic alteration is characteristic during tumour growth and therapy; however, targeting metabolic rewiring could overcome therapy resistance. mTOR hyperactivity, autophagy and other metabolic processes, including mitochondrial functions, could be targeted in breast cancer progression. We investigated the growth inhibitory mechanism of rapamycin + doxycycline treatment in human breast cancer model systems. Cell cycle and cell viability, including apoptotic and necrotic cell death, were analysed using flow cytometry, caspase activity measurements and caspase-3 immunostainings. mTOR-, autophagy-, necroptosis-related proteins and treatment-induced morphological alterations were analysed by WesTM, Western blot, immunostainings and transmission electron microscopy. The rapamycin + doxycycline combination decreased tumour proliferation in about 2/3rd of the investigated cell lines. The continuous treatment reduced tumour growth significantly both in vivo and in vitro. The effect after short-term treatment was reversible; however, autophagic vacuoles and degrading mitochondria were detected simultaneously, and the presence of mitophagy was also observed after the long-term rapamycin + doxycycline combination treatment. The rapamycin + doxycycline combination did not cause apoptosis or necrosis/necroptosis, but the alterations in autophagy- and mitochondria-related protein levels (LC3-B-II/I, p62, MitoTracker, TOM20 and certain co-stainings) were correlated to autophagy induction and mitophagy, without mitochondria repopulation. Based on these results, we suggest considering inducing metabolic stress and targeting mTOR hyperactivity and mitochondrial functions in combined anti-cancer treatments.
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Affiliation(s)
- Titanilla Dankó
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary; (T.D.); (G.P.); (D.S.); (D.M.); (R.R.); (G.B.); (Á.M.); (I.K.)
| | - Gábor Petővári
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary; (T.D.); (G.P.); (D.S.); (D.M.); (R.R.); (G.B.); (Á.M.); (I.K.)
| | - Dániel Sztankovics
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary; (T.D.); (G.P.); (D.S.); (D.M.); (R.R.); (G.B.); (Á.M.); (I.K.)
| | - Dorottya Moldvai
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary; (T.D.); (G.P.); (D.S.); (D.M.); (R.R.); (G.B.); (Á.M.); (I.K.)
| | - Regina Raffay
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary; (T.D.); (G.P.); (D.S.); (D.M.); (R.R.); (G.B.); (Á.M.); (I.K.)
| | - Péter Lőrincz
- Department of Anatomy, Cell and Developmental Biology, Eotvos Lorand University, Pázmány Péter sétány 1/c, H-1117 Budapest, Hungary;
| | - Tamás Visnovitz
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary;
| | - Viktória Zsiros
- Department of Anatomy, Histology and Embryology, Semmelweis University, Tűzoltó utca 58, H-1094 Budapest, Hungary;
| | - Gábor Barna
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary; (T.D.); (G.P.); (D.S.); (D.M.); (R.R.); (G.B.); (Á.M.); (I.K.)
| | - Ágnes Márk
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary; (T.D.); (G.P.); (D.S.); (D.M.); (R.R.); (G.B.); (Á.M.); (I.K.)
| | - Ildikó Krencz
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary; (T.D.); (G.P.); (D.S.); (D.M.); (R.R.); (G.B.); (Á.M.); (I.K.)
| | - Anna Sebestyén
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary; (T.D.); (G.P.); (D.S.); (D.M.); (R.R.); (G.B.); (Á.M.); (I.K.)
- Correspondence:
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21
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Che X, Qi X, Xu Y, Wang Q, Wu G. Genomic and Transcriptome Analysis to Identify the Role of the mTOR Pathway in Kidney Renal Clear Cell Carcinoma and Its Potential Therapeutic Significance. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6613151. [PMID: 34194607 PMCID: PMC8203410 DOI: 10.1155/2021/6613151] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 04/06/2021] [Accepted: 04/28/2021] [Indexed: 12/20/2022]
Abstract
The mTOR pathway, a major signaling pathway, regulates cell growth and protein synthesis by activating itself in response to upstream signals. Overactivation of the mTOR pathway may affect the occurrence and development of cancer, but no specific treatment has been proposed for targeting the mTOR pathway. In this study, we explored the expression of mTOR pathway genes in a variety of cancers and the potential compounds that target the mTOR pathway and focused on an abnormal type of cancer, kidney renal clear cell carcinoma (KIRC). Based on the mRNA expression of the mTOR pathway gene, we divided KIRC patient samples into three clusters. We explored possible therapeutic targets of the mTOR pathway in KIRC. We predicted the IC50 of some classical targeted drugs to analyze their correlation with the mTOR pathway. Subsequently, we investigated the correlation of the mTOR pathway with histone modification and immune infiltration, as well as the response to anti-PD-1 and anti-CTLA-4 therapy. Finally, we used a LASSO regression analysis to construct a model to predict the survival of patients with KIRC. This study shows that mTOR scores can be used as tools to study various treatments targeting the mTOR pathway and that we can predict the recovery of KIRC patients through the expression of mTOR pathway genes. These research results can provide a reference for future research on KIRC patient treatment strategies.
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Affiliation(s)
- Xiangyu Che
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China
| | - Xiaochen Qi
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China
| | - Yingkun Xu
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Qifei Wang
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China
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22
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Mohammad K, Titorenko VI. Caloric restriction creates a metabolic pattern of chronological aging delay that in budding yeast differs from the metabolic design established by two other geroprotectors. Oncotarget 2021; 12:608-625. [PMID: 33868583 PMCID: PMC8021023 DOI: 10.18632/oncotarget.27926] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/15/2021] [Indexed: 12/19/2022] Open
Abstract
Caloric restriction and the tor1Δ mutation are robust geroprotectors in yeast and other eukaryotes. Lithocholic acid is a potent geroprotector in Saccharomycescerevisiae. Here, we used liquid chromatography coupled with tandem mass spectrometry method of non-targeted metabolomics to compare the effects of these three geroprotectors on the intracellular metabolome of chronologically aging budding yeast. Yeast cells were cultured in a nutrient-rich medium. Our metabolomic analysis identified and quantitated 193 structurally and functionally diverse water-soluble metabolites implicated in the major pathways of cellular metabolism. We show that the three different geroprotectors create distinct metabolic profiles throughout the entire chronological lifespan of S. cerevisiae. We demonstrate that caloric restriction generates a unique metabolic pattern. Unlike the tor1Δ mutation or lithocholic acid, it slows down the metabolic pathway for sulfur amino acid biosynthesis from aspartate, sulfate and 5-methyltetrahydrofolate. Consequently, caloric restriction significantly lowers the intracellular concentrations of methionine, S-adenosylmethionine and cysteine. We also noticed that the low-calorie diet, but not the tor1Δ mutation or lithocholic acid, decreases intracellular ATP, increases the ADP:ATP and AMP:ATP ratios, and rises intracellular ADP during chronological aging. We propose a model of how the specific remodeling of cellular metabolism by caloric restriction contributes to yeast chronological aging delay.
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Affiliation(s)
- Karamat Mohammad
- Department of Biology, Concordia University, Montreal, Quebec H4B 1R6, Canada
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23
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Chang GR, Hou PH, Wang CM, Wu CF, Su HK, Liao HJ, Chen TP. Chronic everolimus treatment of high-fat diet mice leads to a reduction in obesity but impaired glucose tolerance. Pharmacol Res Perspect 2021; 9:e00732. [PMID: 33715287 PMCID: PMC7955951 DOI: 10.1002/prp2.732] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/21/2021] [Accepted: 01/27/2021] [Indexed: 12/13/2022] Open
Abstract
Everolimus, which inhibits mTOR kinase activity and is clinically used in graft rejection treatment, may have a two‐sided influence on metabolic syndrome; its role in obesity and hyperglycemic in animals and humans, however, has been explored insufficiently. This study further determined how continual everolimus treatment affects glucose homeostasis and body weight control in C57BL6/J mice with obesity. An obesity mouse model was developed by administering a high‐fat diet (HFD) to C57BL6/J mice over 12 weeks. The experimental group, while continuing their HFD consumption, were administered everolimus daily for 8 weeks. Metabolic parameters, glucose tolerance, fatty liver score, endocrine profile, insulin sensitivity index (ISI), insulin resistance (IR) index, and Akt phosphorylation, GLUT4, TNF‐α, and IL‐1 levels were measured in vivo. Compared with the control group, the everolimus group gained less body weight and had smaller adipocytes and lower fat pad weight; triglyceride (serum and hepatic), patatin‐like phospholipase domain‐containing 3, and fatty acid synthase levels; fatty liver scores; and glucose tolerance test values—all despite consuming more food. However, the everolimus group exhibited decreased ISI and muscle Akt phosphorylation and GLUT4 expression as well as impaired glucose tolerance and serum TNF‐α and IL‐1β levels—even when insulin levels were high. In conclusion, continual everolimus treatment may lead to diabetes with glucose intolerance and IR.
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Affiliation(s)
- Geng-Ruei Chang
- Department of Veterinary Medicine, National Chiayi University, Chiayi, Taiwan
| | - Po-Hsun Hou
- Department of Psychiatry, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chao-Min Wang
- Department of Veterinary Medicine, National Chiayi University, Chiayi, Taiwan
| | - Ching-Feng Wu
- Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Chang Gung University, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Huang-Kai Su
- Department of Veterinary Medicine, National Chiayi University, Chiayi, Taiwan
| | - Huei-Jyuan Liao
- Department of Veterinary Medicine, National Chiayi University, Chiayi, Taiwan
| | - To-Pang Chen
- Division of Endocrinology and Metabolism, Show Chwan Memorial Hospital, Changhua, Taiwan
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Li Y, Xu Y, Liu X, Yan X, Lin Y, Tan Q, Hou Y. mTOR inhibitor INK128 promotes wound healing by regulating MDSCs. Stem Cell Res Ther 2021; 12:170. [PMID: 33691762 PMCID: PMC7944919 DOI: 10.1186/s13287-021-02206-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 02/02/2021] [Indexed: 12/15/2022] Open
Abstract
Background Skin wounds in diabetic patients hardly recover. Accumulating evidence has shown that mammalian target of rapamycin (mTOR) pathway and myeloid-derived suppressor cells (MDSCs) are involved in inflammatory-related response. INK128 is a novel mTOR kinase inhibitor in clinical development. However, the exact roles of MDSCs and INK128 in healing wound of diabetic patients are unclear. Methods Mice models of normal, diabetic, and diabetic+INK128 were constructed. Bone marrow (BM)-derived macrophages and RAW264.7 cell line co-cultured with MDSCs, which were induced at different conditions. Flow cytometry, western blot, quantitative real-time PCR, and immunohistochemical analysis were performed. Results Diabetic mice (DM) had a slower recovery rate, thinner epidermis and dermis, and less blood vessels than those of normal mice. MDSCs were abnormally accumulated in DM, mTOR was activated in MDSCs of DM, and the cells were treated with high glucose. Moreover, mTOR signaling inhibitor INK128 could promote wound healing through reducing the MDSCs. MDSC function was disordered in DM and high-glucose environments, while INK128 could help retrieve their function. Furthermore, high glucose and other factors in DM could promote M-MDSC differentiation to M1 pro-inflammatory macrophage cells, thus inhibiting wound healing. The differentiation, which was dependent on mTOR signaling, could be reversed by INK128. Conclusion INK128 is potential to be developed as a clinical strategy to promote wound healing of diabetic patients.
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Affiliation(s)
- Yi Li
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, People's Republic of China.,The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Yujun Xu
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Xinghan Liu
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Xin Yan
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, People's Republic of China
| | - Yue Lin
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, People's Republic of China
| | - Qian Tan
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, People's Republic of China.
| | - Yayi Hou
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China. .,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, People's Republic of China.
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25
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In silico analysis of non-coding RNAs and putative target genes implicated in metabolic syndrome. Comput Biol Med 2021; 130:104229. [PMID: 33516961 DOI: 10.1016/j.compbiomed.2021.104229] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 01/12/2023]
Abstract
Regulation of gene expression is vital to maintain normal cellular functions and its dysregulation leads to molecular pathogenesis of many diseases and disorders. Non-coding RNAs regulate the expression of approximately 60% of protein-coding genes and their malfunction contribute to the development of numerous diseases. The involvement of variant forms of circulating non-coding RNAs in diseases has been established. However, their function as biomarkers or therapeutic targets in metabolic disorders are underexploited. The aim of this study was to predict therapeutic targets and construction of biomarker panel for early detection of metabolic syndrome (MS). Non-coding RNAs including circular RNAs (circRNAs), long chain non-coding RNAs (lncRNA) and micro RNAs (miRNAs) were extracted from intensive literature search and experimentally supported databases. Raw data of gene expression profiles of MS were obtained from the GEO dataset and analyzed to get differentially expressed genes (DEGs). Functional enrichment analysis, network illustration of non-coding RNAs and predicted target DEGs were performed. Furthermore, a few numbers of miRNAs targeted DEGs were subjected to homology study. The strong association of hsa-miR-548c-3p, hsa-miR-579-3p, hsa-miR-17-5p and hsa-miR-320a was observed with the pathogenesis of MS. It includes the regulation of genes in glucose and lipid homeostasis, MAPKK activity, regulation of inflammatory responses and many signaling pathways such as insulin resistance, JAK/STAT and mTOR. Finally, interactions of hsa-miR-17-5p:STAT3, hsa-miR-320:JAK2, hsa-miR-320:S6K and hsa-let-7:DVL hybrids were predicted. Results of this study suggest the designing of a biomarker panel to detect early onset and molecular approach for the management of MS.
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Chevallier E, Jouve T, Rostaing L, Malvezzi P, Noble J. pre-existing diabetes and PTDM in kidney transplant recipients: how to handle immunosuppression. Expert Rev Clin Pharmacol 2020; 14:55-66. [PMID: 33196346 DOI: 10.1080/17512433.2021.1851596] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Preexisting diabetes (PD) and post-transplant diabetes mellitus (PTDM) are common and severe comorbidities posttransplantation. The immunosuppressive regimens are modifiable risk factors. AREAS COVERED We reviewed Pubmed and Cochrane database and we summarize the mechanisms and impacts of available immunosuppressive treatments on the risk of PD and PTDM. We also assess the possible management of these drugs to improve glycemic parameters while considering risks inherent in transplantation. EXPERT OPINION PD i) increases the risk of sepsis, ii) is an independent risk factor for infection-related mortality, and iii) increases acute rejection risk. Regarding PTDM development i) immunosuppressive strategies without corticosteroids significantly reduce the risk but the price may be a higher incidence of rejection; ii) minimization or rapid withdrawal of steroids are two valuable approaches; iii) the diabetogenic role of calcineurin inhibitors(CNIs) is also well-described and is more important for tacrolimus than for cyclosporine. Reducing tacrolimus-exposure may improve glycemic parameters but also has a higher risk of rejection. PTDM risk is higher in patients that receive sirolimus compared to mycophenolate mofetil. Finally, conversion from CNIs to belatacept may offer the best benefits to PTDM-recipients in terms of glycemic parameters, graft and patient-outcomes.
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Affiliation(s)
- Eloi Chevallier
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
| | - Thomas Jouve
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France.,Université Grenoble Alpes , Grenoble, France
| | - Lionel Rostaing
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France.,Université Grenoble Alpes , Grenoble, France
| | - Paolo Malvezzi
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
| | - Johan Noble
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
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Yan X, Hu Y, Wang B, Wang S, Zhang X. Metabolic Dysregulation Contributes to the Progression of Alzheimer's Disease. Front Neurosci 2020; 14:530219. [PMID: 33250703 PMCID: PMC7674854 DOI: 10.3389/fnins.2020.530219] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 09/25/2020] [Indexed: 12/15/2022] Open
Abstract
Alzheimer's disease (AD) is an incurable neurodegenerative disease. Numerous studies have demonstrated a critical role for dysregulated glucose metabolism in its pathogenesis. In this review, we summarize metabolic alterations in aging brain and AD-related metabolic deficits associated with glucose metabolism dysregulation, glycolysis dysfunction, tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS) deficits, and pentose phosphate pathway impairment. Additionally, we discuss recent treatment strategies targeting metabolic defects in AD, including their limitations, in an effort to encourage the development of novel therapeutic strategies.
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Affiliation(s)
- Xu Yan
- The VIP Department, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Yue Hu
- The VIP Department, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Biyao Wang
- The VIP Department, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Sijian Wang
- Center of Implant Dentistry, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Xinwen Zhang
- Center of Implant Dentistry, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
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28
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Obesity and Related Type 2 Diabetes: A Failure of the Autonomic Nervous System Controlling Gastrointestinal Function? GASTROINTESTINAL DISORDERS 2020. [DOI: 10.3390/gidisord2040039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The pandemic spread of obesity and type 2 diabetes is a serious health problem that cannot be contained with common therapies. At present, the most effective therapeutic tool is metabolic surgery, which substantially modifies the gastrointestinal anatomical structure. This review reflects the state of the art research in obesity and type 2 diabetes, describing the probable reason for their spread, how the various brain sectors are involved (with particular emphasis on the role of the vagal system controlling different digestive functions), and the possible mechanisms for the effectiveness of bariatric surgery. According to the writer’s interpretation, the identification of drugs that can modulate the activity of some receptor subunits of the vagal neurons and energy-controlling structures of the central nervous system (CNS), and/or specific physical treatment of cortical areas, could reproduce, non-surgically, the positive effects of metabolic surgery.
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29
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Zhang Y, Liang Y, Liu H, Huang Y, Li H, Chen B. Paeoniflorin attenuates gestational diabetes via Akt/mTOR pathway in a rat model. Food Nutr Res 2020; 64:4362. [PMID: 33240030 PMCID: PMC7672451 DOI: 10.29219/fnr.v64.4362] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 06/07/2020] [Accepted: 06/16/2020] [Indexed: 12/15/2022] Open
Abstract
Background Gestational diabetes mellitus (GDM) is a type of diabetes associated with pregnancy and may impose risks on both mother and fetus. Akt paeoniflorin was shown to have anti-inflammatory and anti-hyperglycemia properties and has a potential ability to suppress mammalian target of rapamycin (mTOR) signaling. The current study aimed to study the effect of paeoniflorin on GDM maternal, fetal, and placental characteristics in vivo. Methods Streptozotocin (STZ)-induced gestational diabetes rat model was used in our study. The expression levels of phosphorylation (p-) and total protein expression levels of protein kinase B (Akt), mTOR, serum/glucocorticoid regulated kinase 1 (SGK1), and eIF4E-binding protein 1 (4E-BP1) in the placenta were determined by Western blot assay. The blood glucose, insulin, and leptin levels were assessed using enzyme-linked immunosorbent assay (ELISA). Results We found that placental Akt/mTOR signaling was substantially upregulated in GDM patients compared with healthy donors. Paeoniflorin administration alleviates the dysregulation of blood glucose, leptin, and insulin levels in both maternal and fetal GDM rats. Paeoniflorin treatment suppressed the overactivation of Akt/mTOR signaling in placental tissues. More importantly, administration of paeoniflorin was beneficial for normalization of fetal size and body weight in the GDM rats. Conclusion Our study suggested that application of paeoniflorin may serve as a potential therapeutical strategy for patients with GDM.
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Affiliation(s)
- Yonghua Zhang
- Department of Obstetrics and Gynecology, Heze Municipal Hospital of Shandong Province, Heze, Shandong, China
| | - Yulin Liang
- Department of Obstetrics and Gynecology, Heze Municipal Hospital of Shandong Province, Heze, Shandong, China
| | - Huiqiao Liu
- Department of Obstetrics and Gynecology, Heze Municipal Hospital of Shandong Province, Heze, Shandong, China
| | - Ying Huang
- Department of Obstetrics and Gynecology, Heze Municipal Hospital of Shandong Province, Heze, Shandong, China
| | - Hongmei Li
- Department of Obstetrics and Gynecology, Heze Municipal Hospital of Shandong Province, Heze, Shandong, China
| | - Bo Chen
- Department of Obstetrics and Gynecology, Heze Municipal Hospital of Shandong Province, Heze, Shandong, China
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30
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Zemel MB. Modulation of Energy Sensing by Leucine Synergy with Natural Sirtuin Activators: Effects on Health Span. J Med Food 2020; 23:1129-1135. [PMID: 32758058 DOI: 10.1089/jmf.2020.0105] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Sirt1 and 5' adenosine monophosphate-activated protein kinase (AMPK) are energy-sensing systems that work cooperatively and regulate mitochondrial biogenesis and fuel metabolism, and mediate, in part, the salutary effects of caloric restriction on lifespan and healthspan. We have shown that leucine activates Sirt1 and enables synergy with sirtuin co-activators. Resveratrol is a widely recognized activator of Sirt1; however, poor bioavailability and rapid metabolism limit effective clinical translation of promising animal data. However, we found that combining low resveratrol doses with leucine increased skeletal muscle and adipocyte Sirt1 activity, mitochondrial biogenesis and fatty acid oxidation; these effects result in increased lifespan and marked reductions in insulin resistance, inflammatory markers, body weight, and visceral adiposity in preclinical models. To translate these data to humans, we assessed the effects of resveratrol (50 mg)/leucine (1.11 g) on glucose dynamics in a 4-week placebo-controlled trial of 36 prediabetic subjects. Leucine-resveratrol reduced insulin resistance (homeostatic model assessment for insulin resistance) 33% with corresponding reductions in glucose and insulin area under the curve in oral glucose tolerance tests. We extended these concepts in preclinical studies using both direct Sirt1 activators and Sirt1 pathway activators. Low-dose (10 nM) NAD+ precursors (nicotinic acid, nicotinamide mononucleotide, and nicotinamide riboside) synergized with leucine to increase Sirt1 activity in adipocytes, hepatocytes, and muscle cells (30-100%, P < .01) and lifespan in Caenorhabditis elegans (25%, P = .025) and to significantly regress atherosclerotic lesion size and macrophage infiltration in a mouse model of atherosclerosis. Thus, synergistic activation of Sirt1 using leucine and a co-activator exerts pleiotropic effects impacting cardiometabolic endpoints.
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Affiliation(s)
- Michael B Zemel
- NuSirt Biopharma, Research and Development, Knoxville, Tennessee, USA
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31
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Mathiyazhagan J, Kodiveri Muthukaliannan G. The role of mTOR and oral intervention of combined Zingiber officinale-Terminalia chebula extract in type 2 diabetes rat models. J Food Biochem 2020; 44:e13250. [PMID: 32462682 DOI: 10.1111/jfbc.13250] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 03/20/2020] [Accepted: 03/31/2020] [Indexed: 11/29/2022]
Abstract
The present study examined the potential of Zingiber officinale-Terminalia chebula extract alone (ZO and TC) and in combination (ZOTC) against type 2 diabetes via downregulation of mechanistic target of rapamycin (mTOR). The 1:4 (ZOTC) ratio showed high cell survival percentage against the rat insulinoma cell line (RIN-5F) when compared to other possible ratios of ZOTC. Oral administration of ZO alone, TC alone, combined ZOTC (1:4), and the positive control metformin (Met) in fructose-streptozotocin (STZ) -induced diabetic rats showed reduced blood glucose levels, reduced insulin resistance (HOMA-IR), increased insulin levels, and increased pancreatic beta cell function (HOMA-β). ZOTC treatment in diabetic rats ameliorated the antioxidant status without affecting liver and serum parameters. Histological evaluation of the pancreas was performed to find pathological changes; the transcriptional and immunohistochemistry results showed reduced mTOR expression in the pancreas during ZOTC treatment. Conclusively, the results obtained suggest that ZOTC treatment against fructose-STZ-induced type 2 diabetes rat models can help regulate blood glucose, insulin levels, and normalize pancreatic β cell damage. PRACTICAL APPLICATIONS: Type 2 diabetes is a chronic metabolic disorder that affects a large number of populations worldwide. Zingiber officinale (ZO) and Terminalia chebula (TC) has been used in traditional medicine since ancient times against various ailments, including diabetes. In this study, we reported the effect of the combined ZOTC that showed significant blood glucose reduction and increased insulin levels via mTOR when compared to individual treatments. This finding is valuable for food technologists and alternative medicine practitioners to know the antidiabetic effect of the ZOTC combination.
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Ellingson BM, Yao J, Raymond C, Nathanson DA, Chakhoyan A, Simpson J, Garner JS, Olivero AG, Mueller LU, Rodon J, Gerstner E, Cloughesy TF, Wen PY. Multiparametric MR-PET Imaging Predicts Pharmacokinetics and Clinical Response to GDC-0084 in Patients with Recurrent High-Grade Glioma. Clin Cancer Res 2020; 26:3135-3144. [PMID: 32269051 DOI: 10.1158/1078-0432.ccr-19-3817] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 02/14/2020] [Accepted: 04/03/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE GDC-0084 is an oral, brain-penetrant small-molecule inhibitor of PI3K and mTOR. Because these two targets alter tumor vascularity and metabolism, respectively, we hypothesized multiparametric MR-PET could be used to quantify the response, estimate pharmacokinetic (PK) parameters, and predict progression-free survival (PFS) in patients with recurrent malignant gliomas. PATIENTS AND METHODS Multiparametric advanced MR-PET imaging was performed to evaluate physiologic response in a first-in-man, multicenter, phase I, dose-escalation study of GDC-0084 (NCT01547546) in 47 patients with recurrent malignant glioma. RESULTS Measured maximum concentration (C max) was associated with a decrease in enhancing tumor volume (P = 0.0287) and an increase in fractional anisotropy (FA; P = 0.0418). Posttreatment tumor volume, 18F-FDG uptake, Ktrans, and relative cerebral blood volume (rCBV) were all correlated with C max. A linear combination of change in 18F-FDG PET uptake, apparent diffusion coefficient (ADC), FA, Ktrans, vp, and rCBV was able to estimate both C max (R2 = 0.4113; P < 0.0001) and drug exposure (AUC; R2 = 0.3481; P < 0.0001). Using this composite multiparametric MR-PET imaging response biomarker to predict PK, patients with an estimated C max > 0.1 μmol/L and AUC > 1.25 μmol/L*hour demonstrated significantly longer PFS compared with patients with a lower estimated concentration and exposure (P = 0.0039 and P = 0.0296, respectively). CONCLUSIONS Results from this study suggest composite biomarkers created from multiparametric MR-PET imaging targeting metabolic and/or physiologic processes specific to the drug mechanism of action may be useful for subsequent evaluation of treatment efficacy for larger phase II-III studies.
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Affiliation(s)
- Benjamin M Ellingson
- UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California. .,Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.,Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, California.,Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.,Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.,UCLA Neuro-Oncology Program, University of California, Los Angeles, Los Angeles, California
| | - Jingwen Yao
- UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California.,Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.,Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, California
| | - Catalina Raymond
- UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California.,Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - David A Nathanson
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Ararat Chakhoyan
- UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California.,Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Jeremy Simpson
- Kazia Therapeutics Limited, Sydney, New South Wales, Australia
| | - James S Garner
- Kazia Therapeutics Limited, Sydney, New South Wales, Australia
| | | | | | - Jordi Rodon
- Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Elizabeth Gerstner
- Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts
| | - Timothy F Cloughesy
- UCLA Neuro-Oncology Program, University of California, Los Angeles, Los Angeles, California.,Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Patrick Y Wen
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
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Tiedemann K, Hussein O, Komarova SV. Role of Altered Metabolic Microenvironment in Osteolytic Metastasis. Front Cell Dev Biol 2020; 8:435. [PMID: 32582711 PMCID: PMC7290111 DOI: 10.3389/fcell.2020.00435] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 05/08/2020] [Indexed: 12/17/2022] Open
Abstract
Metastatic bone disease is generally incurable and leads to pathological fractures, pain, hypercalcemia, spinal cord compression and decreased mobility. The skeleton is the major site of bone metastases from solid cancers, including breast and prostate carcinoma. Bone metastasis is facilitated by activation of bone-resorbing osteoclasts, terminally differentiated multinucleated cells formed by fusion from monocytic precursors. Cancer cells are known to produce specific factors that stimulate osteoclast differentiation and function. Of interest, cancer cells are also known to alter their own bioenergetics increasing the use of glycolysis for their survival and function. Such change in energy utilization by cancer cells would result in altered levels of cell-permeable metabolites, including glucose, lactate, and pyruvate. Osteoclast resorption is energy-expensive, and we have previously demonstrated that during differentiation osteoclasts actively adapt to their bioenergetics microenvironment. We hypothesize that altered bioenergetics state of cancer cells will also modify the bioenergetics substrate availability for the tissue-resident bone cells, potentially creating a favorable milieu for pathological osteolysis. The goals of this review are to analyze how metastasizing cancer cells change the availability of energy substrates in bone microenvironment; and to assess how the altered bioenergetics may affect osteoclast differentiation and activity.
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Affiliation(s)
- Kerstin Tiedemann
- Faculty of Dentistry, McGill University, Montréal, QC, Canada.,Shriners Hospitals for Children - Canada, Montréal, QC, Canada
| | - Osama Hussein
- Department of Surgery, Mansoura University Cancer Center, Mansoura, Egypt
| | - Svetlana V Komarova
- Faculty of Dentistry, McGill University, Montréal, QC, Canada.,Shriners Hospitals for Children - Canada, Montréal, QC, Canada
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Hersi F, Omar HA, Al-Qawasmeh RA, Ahmad Z, Jaber AM, Zaher DM, Al-Tel TH. Design and synthesis of new energy restriction mimetic agents: Potent anti-tumor activities of hybrid motifs of aminothiazoles and coumarins. Sci Rep 2020; 10:2893. [PMID: 32076009 PMCID: PMC7031302 DOI: 10.1038/s41598-020-59685-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 02/03/2020] [Indexed: 11/09/2022] Open
Abstract
The incidence of obesity-related diseases like diabetes, cardiovascular diseases, and different types of cancers shed light on the importance of dietary control as preventive and treatment measures. However, long-term dietary control is challenging to achieve in most individuals. The use of energy restriction mimetic agents (ERMAs) as an alternative approach to affect the energy machinery of cancer cells has emerged as a promising approach for cancer therapy. ERMAs limit the high need for energy in rapidly growing tumor cells, with their survival rate strongly dependent on the robust availability of energy. In this context, initial phenotypic screening of an in-house pilot compound library identified a new class of aminothiazole anchored on coumarin scaffold as potent anticancer lead drug candidates with potential activity as ERMA. The identified chemotypes were able to inhibit glucose uptake and increase ROS content in cancer cells. Compounds 9b, 9c, 9i, 11b, and 11c were highly active against colorectal cancer cell lines, HCT116 and HT-29, with half-maximal inhibitory concertation (IC50) range from 0.25 to 0.38 µM. Further biological evaluations of 9b and 9f using Western blotting, caspase activity, glucose uptake, ROS production, and NADPH/NADP levels revealed the ability of these lead drug candidates to induce cancer cell death via, at least in part, energy restriction. Moreover, the assessment of 9b and 9f synergistic activity with cisplatin showed promising outcomes. The current work highlights the significant potential of the lead compounds, 9b, and 9f as potential anticancer agents via targeting the cellular energy machinery in cancer cells.
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Affiliation(s)
- Fatema Hersi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates.,College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Hany A Omar
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates. .,College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates. .,Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
| | - Raed A Al-Qawasmeh
- Department of Chemistry, Faculty of Science, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Zainab Ahmad
- Department of Chemistry, Faculty of Science, The University of Jordan, Amman, 11942, Jordan
| | - Areej M Jaber
- Department of Chemistry, Faculty of Science, The University of Jordan, Amman, 11942, Jordan
| | - Dana M Zaher
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates.,College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Taleb H Al-Tel
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates. .,College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates.
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Yaribeygi H, Ashrafizadeh M, Henney NC, Sathyapalan T, Jamialahmadi T, Sahebkar A. Neuromodulatory effects of anti-diabetes medications: A mechanistic review. Pharmacol Res 2020; 152:104611. [PMID: 31863868 DOI: 10.1016/j.phrs.2019.104611] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 12/06/2019] [Accepted: 12/17/2019] [Indexed: 12/14/2022]
Abstract
Diabetes mellitus is a potent upstream event in the molecular pathophysiology which gives rise to various diabetes-related complications. There are several classes of anti-diabetic medications that have been developed to normalize blood glucose concentrations through a variety of molecular mechanisms. Beyond glucose-lowering effects, these agents may also provide further therapeutic potential. For instance, there is a high incidence of diabetes-induced neuronal disorders among patients with diabetes, who may also develop neurodegenerative and psychological complications. If anti-diabetic agents can modify the molecular mechanisms involved in the pathophysiology of neuronal comorbidities, this could potentially be translated to reducing the risk of other neurological conditions such as Alzheimer's disease, Parkinson's disease, depression, memory deficits and cognition impairments among patients with diabetes. This review aimed to shed light on some of the potentially beneficial aspects of anti-diabetic agents in lowering the risk or treating neuronal disorders by reviewing the molecular mechanisms by which these agents can potentially modulate neuronal behaviors.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Neil C Henney
- Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
| | - Thozhukat Sathyapalan
- Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, UK
| | - Tannaz Jamialahmadi
- Halal Research Center of IRI, FDA, Tehran, Iran; Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Eguia A, Bagán-Debón L, Cardona F. Review and update on drugs related to the development of osteonecrosis of the jaw. Med Oral Patol Oral Cir Bucal 2020; 25:e71-e83. [PMID: 31880288 PMCID: PMC6982985 DOI: 10.4317/medoral.23191] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 07/07/2019] [Indexed: 02/07/2023] Open
Abstract
Background Medication-related osteonecrosis of the jaw (MRONJ) is a rare, but serious adverse effect of certain drugs, of which bisphosphonates are the most widely known. This pathology is also associated with other medications such as the biologic antiresorptive agent, denosumab and some antiangiogenics such as sunitinib, bevacizumab or aflibercept. Very recently, new medications have also been associated with osteonecrosis of the jaw (ONJ). The objectives were to update the list of medications associated with ONJ, to analyze the fundamental aspects of this list and to describe the level of evidence available.
Material and Methods A narrative bibliographic review was made, using the PubMed-MedLine, DOAJ and SCIELO databases. Additional information was obtained through the online Medication Information Centre of the Spanish Agency of Medicines and Medical Devices (AEMPS – CIMA), the websites of the US Food & Drugs Administration (Drugs@FDA) and the European Medicines Agency (EMA).
Results The latest drugs identified as potential facilitators of this pathology include a number of anti-VEGF based antiangiogenic drugs and anti-TKI and different types of immunomodulators. Neither the level of evidence in this association nor the risk are equal for all these drugs. On the other hand, over the coming years, new drugs will be marketed with similar action mechanisms to those that are recognized as having this adverse effect.
Conclusions No effective therapy is currently known for the treatment of ONJ. Therefore, in order to prevent new cases of MRONJ, it is essential for all oral healthcare professionals to be fully up-to-date with the etiopathogenic aspects of this pathology and to be aware of those drugs considered to be a risk. Key words:Osteonecrosis of the jaw, MRONJ, bisphosphonates, antiresorptives, antiangiogenics.
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Affiliation(s)
- A Eguia
- Departamento de Inmunología, Microbiología y Parasitología Facultad de Medicina y Enfermería Universidad del País Vasco/Euskal Herriko Unibertsitatea UPV/EHU Apartado 699, 48080 Bilbao, Spain
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Lin J, Jiao A, Lv W, Zhang C, Shi Y, Yang Z, Sun N, Li X, Zhang J. Pentapeptide Protects INS-1 Cells From hIAPP-Mediated Apoptosis by Enhancing Autophagy Through mTOR Pathway. Front Pharmacol 2019; 10:896. [PMID: 31447682 PMCID: PMC6697068 DOI: 10.3389/fphar.2019.00896] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 07/16/2019] [Indexed: 12/18/2022] Open
Abstract
The human islet amyloid polypeptide (hIAPP), the major component of islet amyloid deposition, is one of the amyloidogenic peptides and has been associated with β cell loss and dysfunction in type 2 diabetes (T2D). Autophagy plays a central role in the clearance of hIAPP aggregates, thereby diminishing the hIAPP-induced cytotoxicity. Conversely, hIAPP has been reported to have interfering effects on the autophagy. The pentapeptide FLPNF developed in our previous study has been shown to have effects on the level of the downstream proteins of mTOR and autophagy–lysosome pathway. In the present study, the peptide FLPNF-mediated increase in autophagy flux and its underlying mechanisms, as well as its protecting effect on INS-1 cells, were investigated. Autophagy flux in INS-1 cells overexpressing hIAPP (hIAPP-INS-1 cells) markedly increased after exposure to peptide FLPNF for 24 h and peaked at a concentration of 200 µM. Peptide FLPNF enhanced the autophagy by inhibiting the mTORC1 activity. Flow cytometry results showed the peptide FLPNF bind to mammalian target of rapamycin (mTOR), and further molecular docking analysis revealed a direct interaction between peptide FLPNF and the FRB domain of mTOR. Meanwhile, both peptide FLPNF and rapamycin significantly decreased the hIAPP-induced apoptosis, whereas 3-MA increased the apoptosis. Furthermore, peptide FLPNF reduced the hIAPP oligomer and improved the hIAPP-INS-1 cells insulin release function at high glucose concentration. Taken together, the peptide FLPNF decreased the hIAPP oligomer via upregulating autophagy by inhibiting mTORC1 activity, thus protecting the INS-1 cells from hIAPP-induced apoptosis and improving the insulin release function of INS-1 cells.
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Affiliation(s)
- Jianzhen Lin
- Hepatobiliary Surgery Department and Unit of Organ Transplantation, The First Hospital of China Medical University, Shenyang, China
| | - Ao Jiao
- Hepatobiliary Surgery Department and Unit of Organ Transplantation, The First Hospital of China Medical University, Shenyang, China.,Department of General Surgery, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Wu Lv
- Department of General Surgery, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Chengshuo Zhang
- Hepatobiliary Surgery Department and Unit of Organ Transplantation, The First Hospital of China Medical University, Shenyang, China
| | - Yue Shi
- Hepatobiliary Surgery Department and Unit of Organ Transplantation, The First Hospital of China Medical University, Shenyang, China
| | - Zhaoming Yang
- Hepatobiliary Surgery Department and Unit of Organ Transplantation, The First Hospital of China Medical University, Shenyang, China
| | - Ning Sun
- Hepatobiliary Surgery Department and Unit of Organ Transplantation, The First Hospital of China Medical University, Shenyang, China
| | - Xiaohang Li
- Hepatobiliary Surgery Department and Unit of Organ Transplantation, The First Hospital of China Medical University, Shenyang, China
| | - Jialin Zhang
- Hepatobiliary Surgery Department and Unit of Organ Transplantation, The First Hospital of China Medical University, Shenyang, China
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Early Cellular Responses of Prostate Carcinoma Cells to Sepantronium Bromide (YM155) Involve Suppression of mTORC1 by AMPK. Sci Rep 2019; 9:11541. [PMID: 31395901 PMCID: PMC6687778 DOI: 10.1038/s41598-019-47573-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 07/18/2019] [Indexed: 02/07/2023] Open
Abstract
The imidazolium compound YM155, first discovered as a potent inhibitor of Survivin, effectively kills many carcinomas in preclinical models. However, the upstream signaling mechanism triggered by YM155 remains unclear. Here we studied early signaling responses in vitro in prostate and renal cancer cell lines in a dose-dependent manner. We found that YM155 rapidly activates the retinoblastoma protein, correlating with the loss of expression of all three Cyclin Ds. Using Western blot, various selective chemical inhibitors and q-PCR, we show that YM155-mediated decrease in protein levels of Cyclin Ds, Survivin and Mcl-1 is independent of transcription or proteasomal control mechanisms. Moreover, we provide the first evidence that YM155 changes the phosphorylation status of known mTOR-target proteins involved in translational control, namely ribosomal protein S6 (rS6) and 4E-BP1. Our data support that YM155 achieves this by blocking mTORC1 via the phosphorylation of Raptor at S792 through activated AMPKα (T172). Furthermore, we also used a polysome profile, supporting that YM155 markedly suppresses cap-dependent translation of mRNAs which include Survivin, Cyclin D1 and Mcl-1. We provide the first evidence that YM155 functions as a potent activator of AMPKα, a robust suppressor of mTORC1 and an attenuator of global protein synthesis.
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Chamcheu JC, Roy T, Uddin MB, Banang-Mbeumi S, Chamcheu RCN, Walker AL, Liu YY, Huang S. Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy. Cells 2019; 8:cells8080803. [PMID: 31370278 PMCID: PMC6721560 DOI: 10.3390/cells8080803] [Citation(s) in RCA: 137] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 07/26/2019] [Accepted: 07/29/2019] [Indexed: 12/16/2022] Open
Abstract
The mammalian or mechanistic target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) pathways regulate cell growth, differentiation, migration, and survival, as well as angiogenesis and metabolism. Dysregulation of these pathways is frequently associated with genetic/epigenetic alterations and predicts poor treatment outcomes in a variety of human cancers including cutaneous malignancies like melanoma and non-melanoma skin cancers. Recently, the enhanced understanding of the molecular and genetic basis of skin dysfunction in patients with skin cancers has provided a strong basis for the development of novel therapeutic strategies for these obdurate groups of skin cancers. This review summarizes recent advances in the roles of PI3K/Akt/mTOR and their targets in the development and progression of a broad spectrum of cutaneous cancers and discusses the current progress in preclinical and clinical studies for the development of PI3K/Akt/mTOR targeted therapies with nutraceuticals and synthetic small molecule inhibitors.
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Affiliation(s)
| | - Tithi Roy
- College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209-0497, USA
| | | | - Sergette Banang-Mbeumi
- College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209-0497, USA
- Division for Research and Innovation, POHOFI Inc., P.O. Box 44067, Madison, WI 53744, USA
- School of Nursing and Allied Health Sciences, Louisiana Delta Community College, Monroe, LA 71203, USA
| | | | - Anthony L Walker
- College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209-0497, USA
| | - Yong-Yu Liu
- College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209-0497, USA
| | - Shile Huang
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA
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Effect of Konjac Mannan Oligosaccharides on Glucose Homeostasis via the Improvement of Insulin and Leptin Resistance In Vitro and In Vivo. Nutrients 2019; 11:nu11081705. [PMID: 31344867 PMCID: PMC6723648 DOI: 10.3390/nu11081705] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Revised: 07/20/2019] [Accepted: 07/22/2019] [Indexed: 12/15/2022] Open
Abstract
Functional oligosaccharides, particularly konjac mannan oligosaccharides (KMOS), can regulate glucose metabolism. However, the molecular mechanisms involved in the hypoglycemic effect of KMOS remain largely unknown. Here, the effect of KMOS supplementation on glucose homeostasis was evaluated in both high-fat diet (HFD)-fed C57BL/6J mice and high-glucosamine-induced HepG2 cells. KMOS supplementation remarkably ameliorated the fasting blood glucose, glucose tolerance, and insulin tolerance of HFD-fed mice. Abnormalities of triglyceride and glycogen metabolism in the liver induced by the HFD were reversed by KMOS supplementation. The insulin signaling pathway was activated by KMOS, with stimulation of GLUT2 membrane translocation and glucose uptake in HepG2 cells via the AMPK pathway. Moreover, KMOS suppressed p-mTOR expression and stimulated the GSK-3β/CREB pathway via the AMPK pathway. KMOS significantly upregulated leptin receptor expression and downregulated PTP1B and SOCS3 levels in the liver and brain, with a decreased serum leptin concentration. Phosphorylation of JAK2 and STAT3 in the liver was activated by KMOS supplementation, while the expressions of Sirt1, Tfam, and Pgc1-α in the brain were elevated. Conclusively, KMOS attenuated HFD-induced glucose metabolism dysfunction through the regulation of insulin resistance and leptin resistance. This finding indicates that KMOS have potential value as an anti-hyperglycemic dietary supplement.
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Subirada PV, Paz MC, Ridano ME, Lorenc VE, Fader CM, Chiabrando GA, Sánchez MC. Effect of Autophagy Modulators on Vascular, Glial, and Neuronal Alterations in the Oxygen-Induced Retinopathy Mouse Model. Front Cell Neurosci 2019; 13:279. [PMID: 31297049 PMCID: PMC6608561 DOI: 10.3389/fncel.2019.00279] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 06/11/2019] [Indexed: 12/25/2022] Open
Abstract
Hypoxia is one of the main insults in proliferative retinopathies, leading to neovascularization and neurodegeneration. To maintain homeostasis, neurons require efficient degradation and recycling systems. Autophagy participates in retinal cell death, but it is also a cell survival mechanism. Here, we analyzed the role of autophagy at the three characteristic time periods in the oxygen-induced retinopathy (OIR) mouse model and determined if its modulation can improve vascular and non-vascular alterations. Experiments were performed with chloroquine (CQ) in order to monitor autophagosome accumulation by lysosomal blockade. Post natal day (P)17 OIR mouse retinas showed a significant increase in autophagy flux. In particular, an intense LC3B and p62 staining was observed in inner layers of the retina, mainly proliferating endothelial cells. After a single intraocular injection of Rapamycin at P12 OIR, a decreased neovascular area and vascular endothelial growth factor (VEGF) protein expression were observed at P17 OIR. In addition, whereas the increased expression of glial fibrillary acidic protein (GFAP) was reversed at P26 OIR, the functional alterations persisted. Using a similar therapeutic schedule, we analyzed the effect of anti-VEGF therapy on autophagy flux. Like Rapamycin, VEGF inhibitor treatment not only reduced the amount of neovascular tufts, but also activated autophagy flux at P17 OIR, mainly in ganglion cell layer and inner nuclear layer. Finally, the effects of the disruption of autophagy by Spautin-1, were evaluated at vascular, glial, and neuronal levels. After a single dose of Spautin-1, Western blot analysis showed a significant decrease in LC3B II and p62 protein expression at P13 OIR, returning both autophagy markers to OIR control levels at P17. In addition, neither gliosis nor functional alterations were attenuated. In line with these results, TUNEL staining showed a slight increase in the number of positive cells in the outer nuclear layer at P17 OIR. Overall, our results demonstrate that all treatments of induction or inhibition of the autophagic flux reduced neovascular area but were unable to completely reverse the neuronal damage. Besides, compared to current treatments, rapamycin provides a more promising therapeutic strategy as it reduces both neovascular tufts and persistent gliosis.
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Affiliation(s)
- Paula V Subirada
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Córdoba, Argentina
| | - María C Paz
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Córdoba, Argentina
| | - Magali E Ridano
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Córdoba, Argentina
| | - Valeria E Lorenc
- Nanomedicine and Vision Group, Facultad de Ciencias Biomédicas, Instituto de Investigaciones en Medicina Traslacional, Universidad Austral, Consejo Nacional de Investigaciones en Ciencia y Tecnología (CONICET), Pilar, Argentina
| | - Claudio M Fader
- Facultad de Odontología Mendoza, Universidad Nacional de Cuyo, Mendoza, Argentina.,Instituto de Histología y Embriología (IHEM), Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mendoza, Argentina
| | - Gustavo A Chiabrando
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Córdoba, Argentina
| | - María C Sánchez
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Córdoba, Argentina
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Formononetin Enhances the Tumoricidal Effect of Everolimus in Breast Cancer MDA-MB-468 Cells by Suppressing the mTOR Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2019:9610629. [PMID: 31007702 PMCID: PMC6441524 DOI: 10.1155/2019/9610629] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 02/27/2019] [Indexed: 12/25/2022]
Abstract
Background Formononetin, an active ingredient isolated from the traditional Chinese medicinal herb Astragalus membranaceus, has anticancer and chemoresistance-reducing biological activities. We evaluated the efficacy of formononetin in improving the tumoricidal effect of everolimus by suppressing the mTOR pathway in breast cancer cells. Methods Cell survival was assessed using an MTT assay. Apoptosis was detected using flow cytometry. Proteins related to the mTOR pathway were detected and assessed using real-time PCR and Western blot analysis. Results. The results showed that formononetin enhances the efficacy of everolimus in suppressing breast cancer cell growth both in vitro and in vivo. The combination of formononetin and everolimus resulted in a 2-fold decrease in tumor volume and a 21.6% decrease in cell survival. The apoptosis ratio in cells treated with formononetin and everolimus increased by 27.9%. Formononetin and everolimus also inhibited the expression of p-mTOR and p-P70S6K and increased the expression of PTEN and p-4EBP-1. Notably, formononetin alone inhibited p-Akt expression but not everolimus. Conclusions Formononetin enhances the tumoricidal effect of everolimus by inhibiting the activity of Akt.
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