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Wixler V, Boergeling Y, Leite Dantas R, Varga G, Ludwig S. Conversion of dendritic cells into tolerogenic or inflammatory cells depends on the activation threshold and kinetics of the mTOR signaling pathway. Cell Commun Signal 2024; 22:281. [PMID: 38773618 PMCID: PMC11106905 DOI: 10.1186/s12964-024-01655-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 05/08/2024] [Indexed: 05/24/2024] Open
Abstract
BACKGROUND Restoring impaired peripheral immune tolerance is the primary challenge in treating autoimmune diseases. Our previous research demonstrated the effectiveness of small spleen peptides (SSPs), a fraction of low molecular weight proteins, in inhibiting the progression of psoriatic arthritis, even in the presence of high levels of the proinflammatory cytokine TNFα in the bloodstream. When specifically targeting dendritic cells (DCs), SSPs transform them into tolerogenic cells, which efficiently induce the development of regulatory Foxp3+ Treg cells. In this study, we provide further insights into the mechanism of action of SSPs. RESULTS We found that SSPs stimulate the activation of the mTOR signaling pathway in dendritic cells, albeit in a different manner than the classical immunogenic stimulus LPS. While LPS-induced activation is rapid, strong, and sustained, the activity induced by SSPs is delayed, less intense, yet still significant. These distinct patterns of activation, as measured by phosphorylation of key components of the pathway are also observed in response to other immunogenic and tolerogenic stimuli such as GM-CSF + IL-4 or IL-10 and TGFβ. The disparity in mTOR activation between immunogenic and tolerogenic stimuli is quantitative rather than qualitative. In both cases, mTOR activation primarily occurs through the PI3K/Akt signaling axis and involves ERK and GSK3β kinases, with minimal involvement of AMPK or NF-kB pathways. Furthermore, in the case of SSPs, mTOR activation seems to involve adenosine receptors. Additionally, we observed that DCs treated with SSPs exhibit an energy metabolism with high plasticity, which is typical of tolerogenic cells rather than immunogenic cells. CONCLUSION Hence, the decision whether dendritic cells enter an inflammatory or tolerogenic state seems to rely on varying activation thresholds and kinetics of the mTOR signaling pathway.
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Affiliation(s)
- Viktor Wixler
- Institute of Molecular Virology, Centre for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms- University, Von-Esmarch-Str. 56, 48149, Muenster, Germany.
| | - Yvonne Boergeling
- Institute of Molecular Virology, Centre for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms- University, Von-Esmarch-Str. 56, 48149, Muenster, Germany
| | - Rafael Leite Dantas
- Institute of Molecular Virology, Centre for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms- University, Von-Esmarch-Str. 56, 48149, Muenster, Germany
- Department of Mental Health, Westfaelische Wilhelms-University, 48149, Muenster, Germany
| | - Georg Varga
- Pediatric Rheumatology and Immunology, University Children's Hospital Muenster, 48149, Muenster, Germany
| | - Stephan Ludwig
- Institute of Molecular Virology, Centre for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms- University, Von-Esmarch-Str. 56, 48149, Muenster, Germany
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2
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Nguyen LH, Xu Y, Nair M, Bordey A. The mTOR pathway genes MTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function. eLife 2024; 12:RP91010. [PMID: 38411613 PMCID: PMC10942629 DOI: 10.7554/elife.91010] [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] [Indexed: 02/28/2024] Open
Abstract
Brain somatic mutations in various components of the mTOR complex 1 (mTORC1) pathway have emerged as major causes of focal malformations of cortical development and intractable epilepsy. While these distinct gene mutations converge on excessive mTORC1 signaling and lead to common clinical manifestations, it remains unclear whether they cause similar cellular and synaptic disruptions underlying cortical network hyperexcitability. Here, we show that in utero activation of the mTORC1 activator genes, Rheb or MTOR, or biallelic inactivation of the mTORC1 repressor genes, Depdc5, Tsc1, or Pten in the mouse medial prefrontal cortex leads to shared alterations in pyramidal neuron morphology, positioning, and membrane excitability but different changes in excitatory synaptic transmission. Our findings suggest that, despite converging on mTORC1 signaling, mutations in different mTORC1 pathway genes differentially impact cortical excitatory synaptic activity, which may confer gene-specific mechanisms of hyperexcitability and responses to therapeutic intervention.
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Affiliation(s)
- Lena H Nguyen
- Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at DallasRichardsonUnited States
- Departments of Neurosurgery and Cellular & Molecular Physiology, Wu Tsai Institute, Yale University School of MedicineNew HavenUnited States
| | - Youfen Xu
- Departments of Neurosurgery and Cellular & Molecular Physiology, Wu Tsai Institute, Yale University School of MedicineNew HavenUnited States
| | - Maanasi Nair
- Departments of Neurosurgery and Cellular & Molecular Physiology, Wu Tsai Institute, Yale University School of MedicineNew HavenUnited States
| | - Angelique Bordey
- Departments of Neurosurgery and Cellular & Molecular Physiology, Wu Tsai Institute, Yale University School of MedicineNew HavenUnited States
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3
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Baechle JJ, Chen N, Makhijani P, Winer S, Furman D, Winer DA. Chronic inflammation and the hallmarks of aging. Mol Metab 2023; 74:101755. [PMID: 37329949 PMCID: PMC10359950 DOI: 10.1016/j.molmet.2023.101755] [Citation(s) in RCA: 122] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/30/2023] [Accepted: 06/13/2023] [Indexed: 06/19/2023] Open
Abstract
BACKGROUND Recently, the hallmarks of aging were updated to include dysbiosis, disabled macroautophagy, and chronic inflammation. In particular, the low-grade chronic inflammation during aging, without overt infection, is defined as "inflammaging," which is associated with increased morbidity and mortality in the aging population. Emerging evidence suggests a bidirectional and cyclical relationship between chronic inflammation and the development of age-related conditions, such as cardiovascular diseases, neurodegeneration, cancer, and frailty. How the crosstalk between chronic inflammation and other hallmarks of aging underlies biological mechanisms of aging and age-related disease is thus of particular interest to the current geroscience research. SCOPE OF REVIEW This review integrates the cellular and molecular mechanisms of age-associated chronic inflammation with the other eleven hallmarks of aging. Extra discussion is dedicated to the hallmark of "altered nutrient sensing," given the scope of Molecular Metabolism. The deregulation of hallmark processes during aging disrupts the delicate balance between pro-inflammatory and anti-inflammatory signaling, leading to a persistent inflammatory state. The resultant chronic inflammation, in turn, further aggravates the dysfunction of each hallmark, thereby driving the progression of aging and age-related diseases. MAIN CONCLUSIONS The crosstalk between chronic inflammation and other hallmarks of aging results in a vicious cycle that exacerbates the decline in cellular functions and promotes aging. Understanding this complex interplay will provide new insights into the mechanisms of aging and the development of potential anti-aging interventions. Given their interconnectedness and ability to accentuate the primary elements of aging, drivers of chronic inflammation may be an ideal target with high translational potential to address the pathological conditions associated with aging.
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Affiliation(s)
- Jordan J Baechle
- Buck Artificial Intelligence Platform, the Buck Institute for Research on Aging, Novato, CA, USA
| | - Nan Chen
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON, Canada
| | - Priya Makhijani
- Buck Artificial Intelligence Platform, the Buck Institute for Research on Aging, Novato, CA, USA; Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Shawn Winer
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - David Furman
- Buck Artificial Intelligence Platform, the Buck Institute for Research on Aging, Novato, CA, USA; Stanford 1000 Immunomes Project, Stanford University School of Medicine, Stanford, CA, USA; Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral, CONICET, Pilar, Argentina.
| | - Daniel A Winer
- Buck Artificial Intelligence Platform, the Buck Institute for Research on Aging, Novato, CA, USA; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON, Canada; Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
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4
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Lin WR, Liu KH, Ling TC, Wang MC, Lin WH. Role of antidiabetic agents in type 2 diabetes patients with chronic kidney disease. World J Diabetes 2023; 14:352-363. [PMID: 37122432 PMCID: PMC10130897 DOI: 10.4239/wjd.v14.i4.352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/10/2023] [Accepted: 04/04/2023] [Indexed: 04/12/2023] Open
Abstract
Insulin resistance is a condition in which the target tissues have a decreased response to insulin signaling, resulting in glucose uptake defect, and an increased blood sugar level. Pancreatic beta cells thus enhance insulin production to compensate. This situation may cause further beta cell dysfunction and failure, which can lead diabetes mellitus (DM). Insulin resistance is thus an important cause of the development of type 2 DM. Insulin resistance has also been found to have a strong relationship with cardiovascular disease and is common in chronic kidney disease (CKD) patients. The mechanisms of insulin resistance in CKD are complex and multifactorial. They include physical inactivity, inflammation and oxidative stress, metabolic acidosis, vitamin D deficiency, adipose tissue dysfunction, uremic toxins, and renin-angiotensin-aldosterone system activation. Currently, available anti-diabetic agents, such as biguanides, sulfonylureas, thiazolidinediones, alfa-glucosidase inhibitors, glucagon-like peptide-1-based agents, and sodium-glucose co-transporter-2 inhibitors, have different effects on insulin resistance. In this short review, we describe the potential mechanisms of insulin resistance in CKD patients. We also review the interaction of currently available anti-diabetic medications with insulin resistance.
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Affiliation(s)
- Wei-Ren Lin
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Kuan-Hung Liu
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Tsai-Chieh Ling
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Ming-Cheng Wang
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Wei-Hung Lin
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
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5
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Yao J, Wu D, Qiu Y. Adipose tissue macrophage in obesity-associated metabolic diseases. Front Immunol 2022; 13:977485. [PMID: 36119080 PMCID: PMC9478335 DOI: 10.3389/fimmu.2022.977485] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
Adipose tissue macrophage (ATM) has been appreciated for its critical contribution to obesity-associated metabolic diseases in recent years. Here, we discuss the regulation of ATM on both metabolic homeostatsis and dysfunction. In particular, the macrophage polarization and recruitment as well as the crosstalk between ATM and adipocyte in thermogenesis, obesity, insulin resistance and adipose tissue fibrosis have been reviewed. A better understanding of how ATM regulates adipose tissue remodeling may provide novel therapeutic strategies against obesity and associated metabolic diseases.
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Affiliation(s)
- Jingfei Yao
- Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, College of Future Technology, Peking University, Beijing, China
| | - Dongmei Wu
- Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, College of Future Technology, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Yifu Qiu
- Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, College of Future Technology, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
- *Correspondence: Yifu Qiu,
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6
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Backe SJ, Sager RA, Regan BR, Sit J, Major LA, Bratslavsky G, Woodford MR, Bourboulia D, Mollapour M. A specialized Hsp90 co-chaperone network regulates steroid hormone receptor response to ligand. Cell Rep 2022; 40:111039. [PMID: 35830801 PMCID: PMC9306012 DOI: 10.1016/j.celrep.2022.111039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 04/25/2022] [Accepted: 06/10/2022] [Indexed: 12/29/2022] Open
Abstract
Heat shock protein-90 (Hsp90) chaperone machinery is involved in the stability and activity of its client proteins. The chaperone function of Hsp90 is regulated by co-chaperones and post-translational modifications. Although structural evidence exists for Hsp90 interaction with clients, our understanding of the impact of Hsp90 chaperone function toward client activity in cells remains elusive. Here, we dissect the impact of recently identified higher eukaryotic co-chaperones, FNIP1/2 (FNIPs) and Tsc1, toward Hsp90 client activity. Our data show that Tsc1 and FNIP2 form mutually exclusive complexes with FNIP1, and that unlike Tsc1, FNIP1/2 interact with the catalytic residue of Hsp90. Functionally, these co-chaperone complexes increase the affinity of the steroid hormone receptors glucocorticoid receptor and estrogen receptor to their ligands in vivo. We provide a model for the responsiveness of the steroid hormone receptor activation upon ligand binding as a consequence of their association with specific Hsp90:co-chaperone subpopulations.
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Affiliation(s)
- Sarah J Backe
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Rebecca A Sager
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Bethany R Regan
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA; College of Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Julian Sit
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA; College of Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Lauren A Major
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA; College of Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Gennady Bratslavsky
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Mark R Woodford
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Dimitra Bourboulia
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Mehdi Mollapour
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
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7
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Jang D, Jeong H, Kim CE, Leem J. A System-Level Mechanism of Anmyungambi Decoction for Obesity: A Network Pharmacological Approach. Biomolecules 2021; 11:biom11121881. [PMID: 34944525 PMCID: PMC8699029 DOI: 10.3390/biom11121881] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/13/2021] [Accepted: 12/13/2021] [Indexed: 12/18/2022] Open
Abstract
Obesity is a low-grade systemic inflammatory disease involving adipocytokines. As though Anmyungambi decoction (AMGB) showed significant improvement on obesity in a clinical trial, the molecular mechanism of AMGB in obesity remains unknown. Therefore, we explored the potential mechanisms of action of AMGB on obesity through network pharmacological approaches. We revealed that targets of AMGB are significantly associated with obesity-related and adipocyte-elevated genes. Evodiamine, berberine, genipin, palmitic acid, genistein, and quercetin were shown to regulate adipocytokine signaling pathway proteins which mainly involved tumor necrosis factor receptor 1, leptin receptor. In terms of the regulatory pathway of lipolysis in adipocytes, norephedrine, pseudoephedrine, quercetin, and limonin were shown to affect adrenergic receptor-beta, protein kinase A, etc. We also found that AMGB has the potentials to enhance the insulin signaling pathway thereby preventing type II diabetes mellitus. Additionally, AMGB was discovered to be able to control not only insulin-related proteins but also inflammatory mediators and apoptotic regulators and caspases, hence reducing hepatocyte injury in nonalcoholic fatty liver disease. Our findings help develop a better understanding of how AMGB controls obesity.
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Affiliation(s)
- Dongyeop Jang
- Department of Physiology, College of Korean Medicine, Gachon University, Seongnam-si 13121, Korea; (D.J.); (H.J.)
| | - Hayeong Jeong
- Department of Physiology, College of Korean Medicine, Gachon University, Seongnam-si 13121, Korea; (D.J.); (H.J.)
| | - Chang-Eop Kim
- Department of Physiology, College of Korean Medicine, Gachon University, Seongnam-si 13121, Korea; (D.J.); (H.J.)
- Correspondence: (C.-E.K.); (J.L.); Tel.: +82-31-750-5493 (C.-E.K.); +82-63-850-6984 (J.L.)
| | - Jungtae Leem
- Research Center of Traditional Korean Medicine, College of Korean Medicine, Wonkwang University, 460, Iksan-daero, Sin-dong, Iksan 54538, Korea
- Correspondence: (C.-E.K.); (J.L.); Tel.: +82-31-750-5493 (C.-E.K.); +82-63-850-6984 (J.L.)
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8
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Fernandes SA, Demetriades C. The Multifaceted Role of Nutrient Sensing and mTORC1 Signaling in Physiology and Aging. FRONTIERS IN AGING 2021; 2:707372. [PMID: 35822019 PMCID: PMC9261424 DOI: 10.3389/fragi.2021.707372] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 08/12/2021] [Indexed: 01/10/2023]
Abstract
The mechanistic Target of Rapamycin (mTOR) is a growth-related kinase that, in the context of the mTOR complex 1 (mTORC1), touches upon most fundamental cellular processes. Consequently, its activity is a critical determinant for cellular and organismal physiology, while its dysregulation is commonly linked to human aging and age-related disease. Presumably the most important stimulus that regulates mTORC1 activity is nutrient sufficiency, whereby amino acids play a predominant role. In fact, mTORC1 functions as a molecular sensor for amino acids, linking the cellular demand to the nutritional supply. Notably, dietary restriction (DR), a nutritional regimen that has been shown to extend lifespan and improve healthspan in a broad spectrum of organisms, works via limiting nutrient uptake and changes in mTORC1 activity. Furthermore, pharmacological inhibition of mTORC1, using rapamycin or its analogs (rapalogs), can mimic the pro-longevity effects of DR. Conversely, nutritional amino acid overload has been tightly linked to aging and diseases, such as cancer, type 2 diabetes and obesity. Similar effects can also be recapitulated by mutations in upstream mTORC1 regulators, thus establishing a tight connection between mTORC1 signaling and aging. Although the role of growth factor signaling upstream of mTORC1 in aging has been investigated extensively, the involvement of signaling components participating in the nutrient sensing branch is less well understood. In this review, we provide a comprehensive overview of the molecular and cellular mechanisms that signal nutrient availability to mTORC1, and summarize the role that nutrients, nutrient sensors, and other components of the nutrient sensing machinery play in cellular and organismal aging.
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Affiliation(s)
- Stephanie A. Fernandes
- Max Planck Institute for Biology of Ageing (MPI-AGE), Cologne, Germany
- Cologne Graduate School for Ageing Research (CGA), Cologne, Germany
| | - Constantinos Demetriades
- Max Planck Institute for Biology of Ageing (MPI-AGE), Cologne, Germany
- Cologne Graduate School for Ageing Research (CGA), Cologne, Germany
- University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
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9
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Mallela K, Kumar A. Role of TSC1 in physiology and diseases. Mol Cell Biochem 2021; 476:2269-2282. [PMID: 33575875 DOI: 10.1007/s11010-021-04088-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 01/27/2021] [Indexed: 12/15/2022]
Abstract
Since its initial discovery as the gene altered in Tuberous Sclerosis Complex (TSC), an autosomal dominant disorder, the interest in TSC1 (Tuberous Sclerosis Complex 1) has steadily risen. TSC1, an essential component of the pro-survival PI3K/AKT/MTOR signaling pathway, plays an important role in processes like development, cell growth and proliferation, survival, autophagy and cilia development by co-operating with a variety of regulatory molecules. Recent studies have emphasized the tumor suppressive role of TSC1 in several human cancers including liver, lung, bladder, breast, ovarian, and pancreatic cancers. TSC1 perceives inputs from various signaling pathways, including TNF-α/IKK-β, TGF-β-Smad2/3, AKT/Foxo/Bim, Wnt/β-catenin/Notch, and MTOR/Mdm2/p53 axis, thereby regulating cancer cell proliferation, metabolism, migration, invasion, and immune regulation. This review provides a first comprehensive evaluation of TSC1 and illuminates its diverse functions apart from its involvement in TSC genetic disorder. Further, we have summarized the physiological functions of TSC1 in various cellular events and conditions whose dysregulation may lead to several pathological manifestations including cancer.
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Affiliation(s)
- Karthik Mallela
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, 560012, India
| | - Arun Kumar
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, 560012, India.
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10
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Shamshoum H, Vlavcheski F, MacPherson REK, Tsiani E. Rosemary extract activates AMPK, inhibits mTOR and attenuates the high glucose and high insulin-induced muscle cell insulin resistance. Appl Physiol Nutr Metab 2021; 46:819-827. [PMID: 33471600 DOI: 10.1139/apnm-2020-0592] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Impaired action of insulin in skeletal muscle, termed insulin resistance, leads to increased blood glucose levels resulting in compensatory increase in insulin levels. The elevated blood glucose and insulin levels exacerbate insulin resistance and contribute to the pathogenesis of type 2 diabetes mellitus. In previous studies we found attenuation of free fatty acid-induced muscle cell insulin resistance by rosemary extract (RE). In the present study we investigated the effects of RE on high glucose (HG) and high insulin (HI)-induced muscle cell insulin resistance. Exposure of L6 myotubes to 25 mmol/L glucose and 100 nmol/L insulin for 24 h, to mimic hyperglycemia and hyperinsulinemia, abolished the acute insulin-stimulated glucose uptake, increased the serine phosphorylation of IRS-1 and the phosphorylation/activation of mTOR and p70S6K. Treatment with RE significantly improved the insulin-stimulated glucose uptake and increased the acute insulin-stimulated tyrosine phosphorylation while reducing the HG+HI-induced serine phosphorylation of IRS-1 and phosphorylation of mTOR and p70S6K. Additionally, treatment with RE significantly increased the phosphorylation of AMPK, its downstream effector ACC and the plasma membrane GLUT4 levels. Our data indicate a potential of RE to counteract muscle cell insulin resistance and more studies are required to investigate its effectiveness in vivo. Novelty: RE phosphorylated muscle cell AMPK and ACC under both normal and HG+HI conditions. The HG+HI-induced serine phosphorylation of IRS-1 and activation of mTOR and p70S6K were attenuated by RE. RE restored the insulin-stimulated glucose uptake by enhancing GLUT4 glucose transporter translocation to plasma membrane.
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Affiliation(s)
- Hesham Shamshoum
- Department of Health Sciences, Brock University, St. Catharines, ON, Canada.,Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, Canada
| | - Filip Vlavcheski
- Department of Health Sciences, Brock University, St. Catharines, ON, Canada.,Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, Canada
| | - Rebecca E K MacPherson
- Department of Health Sciences, Brock University, St. Catharines, ON, Canada.,Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, Canada
| | - Evangelia Tsiani
- Department of Health Sciences, Brock University, St. Catharines, ON, Canada.,Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, Canada
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11
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Li T, Zhang G, Wang L, Li S, Xu X, Gao Y. Defects in mTORC1 Network and mTORC1-STAT3 Pathway Crosstalk Contributes to Non-inflammatory Hepatocellular Carcinoma. Front Cell Dev Biol 2020; 8:225. [PMID: 32363190 PMCID: PMC7182440 DOI: 10.3389/fcell.2020.00225] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 03/16/2020] [Indexed: 02/05/2023] Open
Abstract
Background and Aims Mammalian target of rapamycin complex 1 (mTORC1) is frequently hyperactivated in hepatocellular carcinoma (HCC). Cases of HCC without inflammation and cirrhosis are not rarely seen in clinics. However, the molecular basis of non-inflammatory HCC remains unclear. Methods Spontaneous non-inflammatory HCC in mice was triggered by constitutive elevation of mTORC1 by liver-specific TSC1 knockout (LTsc1KO). A multi-omics approach was utilized on tumor tissues to better understand the molecular basis for the development of HCC in the LTsc1KO model. Results We showed that LTsc1KO in mice triggered spontaneous non-inflammatory HCC, with molecular characteristics similar to those of diethylnitrosamine-mediated non-cirrhotic HCC. Mitochondrial and autophagy defects, as well as hepatic metabolic disorder were manifested in HCC development by LTsc1KO. mTORC1 activation on its own regulated an oncogenic network (DNA-damage-inducible transcript 4, nuclear protein 1, and fibroblast growth factor 21), and mTORC1-signal transducer and activator of transcription pathway crosstalk that altered specific metabolic pathways contributed to the development of non-inflammatory HCC. Conclusion Our findings reveal the mechanisms of mTORC1-driven non-inflammatory HCC and provide insight into further development of a protective strategy against non-inflammatory HCC.
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Affiliation(s)
- Ting Li
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Guohong Zhang
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, Shantou University Medical College, Shantou, China.,Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Linlin Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Susu Li
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xiaoping Xu
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Artificial Organs and Tissue Engineering Centre of Guangdong Province, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Yi Gao
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Artificial Organs and Tissue Engineering Centre of Guangdong Province, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
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12
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Esch N, Jo S, Moore M, Alejandro EU. Nutrient Sensor mTOR and OGT: Orchestrators of Organelle Homeostasis in Pancreatic β-Cells. J Diabetes Res 2020; 2020:8872639. [PMID: 33457426 PMCID: PMC7787834 DOI: 10.1155/2020/8872639] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/06/2020] [Accepted: 11/24/2020] [Indexed: 02/08/2023] Open
Abstract
The purpose of this review is to integrate the role of nutrient-sensing pathways into β-cell organelle dysfunction prompted by nutrient excess during type 2 diabetes (T2D). T2D encompasses chronic hyperglycemia, hyperlipidemia, and inflammation, which each contribute to β-cell failure. These factors can disrupt the function of critical β-cell organelles, namely, the ER, mitochondria, lysosomes, and autophagosomes. Dysfunctional organelles cause defects in insulin synthesis and secretion and activate apoptotic pathways if homeostasis is not restored. In this review, we will focus on mTORC1 and OGT, two major anabolic nutrient sensors with important roles in β-cell physiology. Though acute stimulation of these sensors frequently improves β-cell function and promotes adaptation to cell stress, chronic and sustained activity disturbs organelle homeostasis. mTORC1 and OGT regulate organelle function by influencing the expression and activities of key proteins, enzymes, and transcription factors, as well as by modulating autophagy to influence clearance of defective organelles. In addition, mTORC1 and OGT activity influence islet inflammation during T2D, which can further disrupt organelle and β-cell function. Therapies for T2D that fine-tune the activity of these nutrient sensors have yet to be developed, but the important role of mTORC1 and OGT in organelle homeostasis makes them promising targets to improve β-cell function and survival.
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Affiliation(s)
- Nicholas Esch
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Seokwon Jo
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Mackenzie Moore
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Surgery, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Emilyn U. Alejandro
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
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13
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The Immunomodulatory Effect of Alpha-Lipoic Acid in Autoimmune Diseases. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8086257. [PMID: 31016198 PMCID: PMC6446120 DOI: 10.1155/2019/8086257] [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: 09/10/2018] [Revised: 02/11/2019] [Accepted: 02/21/2019] [Indexed: 01/08/2023]
Abstract
Αlpha-lipoic acid is a naturally occurring antioxidant in human body and has been widely used as an antioxidant clinically. Accumulating evidences suggested that α-lipoic acid might have immunomodulatory effects on both adaptive and innate immune systems. This review focuses on the evidences and potential targets involved in the immunomodulatory effects of α-lipoic acid. It highlights the fact that α-lipoic acid may have beneficial effects in autoimmune diseases once the immunomodulatory effects can be confirmed by further investigation.
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14
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Regulation of Metabolic Disease-Associated Inflammation by Nutrient Sensors. Mediators Inflamm 2018; 2018:8261432. [PMID: 30116154 PMCID: PMC6079375 DOI: 10.1155/2018/8261432] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 05/21/2018] [Accepted: 06/14/2018] [Indexed: 12/15/2022] Open
Abstract
Visceral obesity is frequently associated with the development of type 2 diabetes (T2D), a highly prevalent chronic disease that features insulin resistance and pancreatic β-cell dysfunction as important hallmarks. Recent evidence indicates that the chronic, low-grade inflammation commonly associated with visceral obesity plays a major role connecting the excessive visceral fat deposition with the development of insulin resistance and pancreatic β-cell dysfunction. Herein, we review the mechanisms by which nutrients modulate obesity-associated inflammation.
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15
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Xia B, Cai GH, Yang H, Wang SP, Mitchell GA, Wu JW. Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice. PLoS Genet 2017; 13:e1007110. [PMID: 29232702 PMCID: PMC5741266 DOI: 10.1371/journal.pgen.1007110] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2017] [Revised: 12/22/2017] [Accepted: 11/08/2017] [Indexed: 02/06/2023] Open
Abstract
Fatty liver is a major health problem worldwide. People with hereditary deficiency of hormone-sensitive lipase (HSL) are reported to develop fatty liver. In this study, systemic and tissue-specific HSL-deficient mice were used as models to explore the underlying mechanism of this association. We found that systemic HSL deficient mice developed fatty liver in an age-dependent fashion between 3 and 8 months of age. To further explore the mechanism of fatty liver in HSL deficiency, liver-specific HSL knockout mice were created. Surprisingly, liver HSL deficiency did not influence liver fat content, suggesting that fatty liver in HSL deficiency is not liver autonomous. Given the importance of adipose tissue in systemic triglyceride metabolism, we created adipose-specific HSL knockout mice and found that adipose HSL deficiency, to a similar extent as systemic HSL deficiency, causes age-dependent fatty liver in mice. Mechanistic study revealed that deficiency of HSL in adipose tissue caused inflammatory macrophage infiltrates, progressive lipodystrophy, abnormal adipokine secretion and systemic insulin resistance. These changes in adipose tissue were associated with a constellation of changes in liver: low levels of fatty acid oxidation, of very low density lipoprotein secretion and of triglyceride hydrolase activity, each favoring the development of hepatic steatosis. In conclusion, HSL-deficient mice revealed a complex interorgan interaction between adipose tissue and liver: the role of HSL in the liver is minimal but adipose tissue deficiency of HSL can cause age-dependent hepatic steatosis. Adipose tissue is a potential target for treating the hepatic steatosis of HSL deficiency. Fatty liver is a major complication of obesity and of type 2 diabetes mellitus. It carries a high risk of cirrhosis and liver cancer. In fatty liver, triglycerides accumulate to high levels in the cytoplasm of hepatocytes. Triglycerides are degraded by lipolysis, which has been most studied in fat cells where its three steps are catalyzed by different enzymes. The second step, hydrolysis of diglyceride to a monoglyceride, can be mediated by hormone-sensitive lipase (HSL). Patients with genetic deficiency of HSL have fatty liver. In this study, we found that systemic HSL deficient mice developed fatty liver with aging. To study the mechanism of steatosis, we made liver-specific HSL-deficient mice. Surprisingly, these mice had normal liver fat content. We then studied mice with HSL deficiency in adipose tissue. Adipose HSL-deficient mice developed hepatic steatosis to a similar extent as mice with systemic HSL deficiency, showing that adipose HSL deficiency is sufficient to cause fatty liver. Furthermore, like reported HSL-deficient humans, mice with adipose HSL deficiency had systemic insulin resistance, reduced fat mass and inflammation in fat tissue. Each of these is known to promote hepatic steatosis. Livers of adipose HSL-deficient mice showed low levels of hepatic fatty acid (FA) oxidation, of very low density lipoprotein (VLDL) secretion and of triglycerides (TG) hydrolase activity, each of which could contribute to fat accumulation in liver. Tissue-selective genetic alterations may help in identifying and understanding the tissues responsible for complex metabolic phenotypes like fatty liver. Our data suggest that at least in mice, strategies for treatment of fatty liver related to HSL deficiency should concentrate on adipose tissue.
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Affiliation(s)
- Bo Xia
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Guo He Cai
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Hao Yang
- Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montréal, QC, Canada
| | - Shu Pei Wang
- Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montréal, QC, Canada
| | - Grant A. Mitchell
- Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montréal, QC, Canada
- * E-mail: (JWW); (GAM)
| | - Jiang Wei Wu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
- Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montréal, QC, Canada
- * E-mail: (JWW); (GAM)
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16
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Zhang Y, Huang B, Wang HY, Chang A, Zheng XFS. Emerging Role of MicroRNAs in mTOR Signaling. Cell Mol Life Sci 2017; 74:2613-2625. [PMID: 28238105 DOI: 10.1007/s00018-017-2485-1] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 02/01/2017] [Accepted: 02/06/2017] [Indexed: 12/15/2022]
Abstract
Mechanistic target of rapamycin (mTOR) is a conserved serine/threonine kinase that plays a critical role in the control of cellular growth and metabolism. Hyperactivation of mTOR pathway is common in human cancers, driving uncontrolled proliferation. MicroRNA (miRNA) is a class of short noncoding RNAs that regulate the expression of a wide variety of genes. Deregulation of miRNAs is a hallmark of cancer. Recent studies have revealed interplays between miRNAs and the mTOR pathway during cancer development. Such interactions appear to provide a fine-tuning of various cellular functions and contribute qualitatively to the behavior of cancer. Here we provide an overview of current knowledge regarding the reciprocal relationship between miRNAs and mTOR pathway: regulation of mTOR signaling by miRNAs and control of miRNA biogenesis by mTOR. Further research in this area may prove important for the diagnosis and therapy of human cancer.
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Affiliation(s)
- Yanjie Zhang
- Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201999, China.
| | - Bo Huang
- Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201999, China
| | - Hui-Yun Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.,Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ, 08854, USA.,Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08903, USA
| | - Augustus Chang
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08903, USA
| | - X F Steven Zheng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China. .,Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ, 08854, USA. .,Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08903, USA.
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17
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Independent and joint effect of type 2 diabetes and gastric and hepatobiliary diseases on risk of pancreatic cancer risk: 10-year follow-up of population-based cohort. Br J Cancer 2014; 111:2180-6. [PMID: 25275365 PMCID: PMC4260037 DOI: 10.1038/bjc.2014.525] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Revised: 08/29/2014] [Accepted: 09/07/2014] [Indexed: 12/13/2022] Open
Abstract
Background: Type 2 diabetes mellitus, gastric and hepatobiliary comorbidities, and cancer share common risk factors: for example, tobacco, obesity, physical inactivity, high calorie intake, and metabolic disorders. Prior studies find type 2 diabetes and gastric and hepatobiliary comorbidities heightening risk of pancreatic cancer. Yet joint association of type 2 diabetes mellitus and gastric and hepatobiliary comorbidities on pancreatic cancer risk has not been assessed. Methods: This study rates independent/joint effects of type 2 diabetes as well as gastric and hepatobiliary comorbidity on pancreatic cancer risk for a retrospective population-based cohort of 166 850 type 2 diabetics identified in 1997–1998 and followed for 10–11 years, comparing their cancer incidence with that of 166 850 non-diabetics matched for age, gender, and locale. Time-dependent Cox's proportional hazards model evaluted joint association of type 2 diabetes and chronic conditions on pancreatic cancer risk. Results: A total of 1178 subjects were newly diagnosed with pancreatic cancer during follow-up, with incidence rates of 0.49 per 1000 person-years in type 2 diabetes and 0.26 per 1000 person-years in the non-diabetics. We observed greater magnitude of hazard ratios (HRs) of pancreatic cancer for patients with type 2 diabetes along with acute alcoholic hepatitis, acute pancreatitis, cholecystitis, and gastric ulcer compared with patients without type 2 diabetes or counterpart comorbidity (HR: 1.36, 95% confidence interval (CI): 1.19–1.56; 1.74, 1.23–2.45; 9.18, 7.44–11.33; and 2.31, 1.98–2.70, respectively). Main effects of type 2 diabetes were all statistically with narrow 95% CI and remained similar across risk stratification with various comorbidities: range 1.59–1.80. Conclusions: Our study demonstrates that pre-existing type 2 diabetes, acute alcoholic hepatitis, acute pancreatitis, cholecystitis, and gastric ulcer independently or jointly predict subsequent pancreatic cancer risk. Clinicians must recognise burden of these gastric and hepatobiliary comorbidities and keep clinically vigilant for their diagnosis.
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18
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Jenwitheesuk A, Nopparat C, Mukda S, Wongchitrat P, Govitrapong P. Melatonin regulates aging and neurodegeneration through energy metabolism, epigenetics, autophagy and circadian rhythm pathways. Int J Mol Sci 2014; 15:16848-84. [PMID: 25247581 PMCID: PMC4200827 DOI: 10.3390/ijms150916848] [Citation(s) in RCA: 117] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 09/03/2014] [Accepted: 09/12/2014] [Indexed: 12/19/2022] Open
Abstract
Brain aging is linked to certain types of neurodegenerative diseases and identifying new therapeutic targets has become critical. Melatonin, a pineal hormone, associates with molecules and signaling pathways that sense and influence energy metabolism, autophagy, and circadian rhythms, including insulin-like growth factor 1 (IGF-1), Forkhead box O (FoxOs), sirtuins and mammalian target of rapamycin (mTOR) signaling pathways. This review summarizes the current understanding of how melatonin, together with molecular, cellular and systemic energy metabolisms, regulates epigenetic processes in the neurons. This information will lead to a greater understanding of molecular epigenetic aging of the brain and anti-aging mechanisms to increase lifespan under healthy conditions.
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Affiliation(s)
- Anorut Jenwitheesuk
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakornpathom 73170, Thailand.
| | - Chutikorn Nopparat
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakornpathom 73170, Thailand.
| | - Sujira Mukda
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakornpathom 73170, Thailand.
| | - Prapimpun Wongchitrat
- Center for Innovation Development and Technology Transfer, Faculty of Medical Technology, Mahidol University, Salaya, Nakornpathom 73170, Thailand.
| | - Piyarat Govitrapong
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakornpathom 73170, Thailand.
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19
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Potter WB, Basu T, O'Riordan KJ, Kirchner A, Rutecki P, Burger C, Roopra A. Reduced juvenile long-term depression in tuberous sclerosis complex is mitigated in adults by compensatory recruitment of mGluR5 and Erk signaling. PLoS Biol 2013; 11:e1001627. [PMID: 23966835 PMCID: PMC3742461 DOI: 10.1371/journal.pbio.1001627] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2012] [Accepted: 07/05/2013] [Indexed: 02/07/2023] Open
Abstract
A mouse model of the human genetic disorder tuberous sclerosis complex fails to undergo developmental down-regulation of mGluR5 expression and activation of Erk signaling, probably contributing to the aberrant plasticity and epilepsy in this disease. Tuberous sclerosis complex (TSC) is a multisystem genetic disease that manifests with mental retardation, tumor formation, autism, and epilepsy. Heightened signaling through the mammalian target of rapamycin (mTOR) pathway is involved in TSC pathology, however it remains unclear how other signaling pathways are perturbed and contribute to disease symptoms. Reduced long-term depression (LTD) was recently reported in TSC mutant mice. We find that although reduced LTD is a feature of the juvenile mutant hippocampus, heightened expression of metabotropic glutamate receptor 5 and constitutively activated Erk signaling in the adult hippocampus drives wild-type levels of LTD. Increased mGluR5 and Erk results in a novel mTOR-independent LTD in CA1 hippocampus of adult mice, and contributes to the development of epileptiform bursting activity in the TSC2+/− CA3 region of the hippocampus. Inhibition of mGluR5 or Erk signaling restores appropriate mTOR-dependence to LTD, and significantly reduces epileptiform bursting in TSC2+/− hippocampal slices. We also report that adult TSC2+/− mice exhibit a subtle perseverative behavioral phenotype that is eliminated by mGluR5 antagonism. These findings highlight the potential of modulating the mGluR5-Erk pathway in a developmental stage-specific manner to treat TSC. Tuberous sclerosis complex (TSC) is a genetic disorder that afflicts around 1 in 6,000 people and results from a mutation in one of two genes, TSC1 or TSC2. TSC patients suffer a number of neuronal symptoms including various degrees of autism, mental retardation, and epilepsy, the latter found in more than 80% of cases within the first year of life. In the TSC mutant mice that are used to model the disease, a region of the brain called the hippocampus fails to undergo long-term depression (LTD), a neuronal process that is important for learning and memory. We find that while this is the case in juvenile mutant mice, adult mice appear to have fixed this deficit. The “fix” involves the ramping up of signaling pathways involving mGluR5 and Erk. Although increased mGluR5 and Erk signaling outwardly fixes the problem of diminished LTD in adulthood, it renders the brain insensitive to the cues and inputs that normally work to control LTD. Moreover, the hippocampus in adult TSC mice is prone to seizures and impaired in learning and memory tasks. We find that drugs that target mGluR5 or Erk signaling repair the problems with excitability and learning deficits.
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Affiliation(s)
- Wyatt B. Potter
- Department of Neuroscience, Medical Science Center, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
- Neuroscience Training Program, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Trina Basu
- Department of Neuroscience, Medical Science Center, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
- Neuroscience Training Program, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Kenneth J. O'Riordan
- Department of Neurology, William S. Middleton Memorial VA Hospital and University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Allison Kirchner
- Department of Neuroscience, Medical Science Center, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Paul Rutecki
- Department of Neurology, William S. Middleton Memorial VA Hospital and University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Corinna Burger
- Department of Neurology, William S. Middleton Memorial VA Hospital and University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Avtar Roopra
- Department of Neuroscience, Medical Science Center, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
- * E-mail:
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20
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Resistance exercise, but not endurance exercise, induces IKKβ phosphorylation in human skeletal muscle of training-accustomed individuals. Pflugers Arch 2013; 465:1785-95. [PMID: 23838844 DOI: 10.1007/s00424-013-1318-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Revised: 06/11/2013] [Accepted: 06/18/2013] [Indexed: 12/20/2022]
Abstract
The mammalian target of rapamycin complex 1 (mTORC1) is considered an important role in the muscular adaptations to exercise. It has been proposed that exercise-induced signaling to mTORC1 do not require classic growth factor PI3K/Akt signaling. Activation of IKKβ and the mitogen-activated protein kinases (MAPKs) Erk1/2 and p38 has been suggested to link inflammation and cellular stress to activation of mTORC1 through the tuberous sclerosis 1 (TSC1)/tuberous sclerosis 2 (TSC2) complex. Consequently, activation of these proteins constitutes potential alternative mechanisms of mTORC1 activation following exercise. Previously, we demonstrated that mTOR is preferentially activated in response to resistance exercise compared to endurance exercise in trained individuals without concomitant activation of Akt. In the present study, we extended this investigation by examining IκB kinase complex (IKK), TSC1, MAPK, and upstream Akt activators, along with gene expression of selected cytokines, in skeletal muscles from these subjects. Biopsies were sampled prior to, immediately after, and in the recovery period following resistance exercise, endurance exercise, and control interventions. The major finding was that IKKβ phosphorylation increased exclusively after resistance exercise. No changes in TSC1, Erk1/2, insulin receptor, or insulin receptor substrate 1 phosphorylation were observed in any of the groups, while p38 phosphorylation was higher in the resistance exercise group compared to both other groups immediately after the intervention. Resistance and endurance exercise increased IL6, IL8, and TNFα gene expression immediately after exercise. The non-exercise control group demonstrated that cytokine gene expression is also sensitive to repeated biopsy sampling, whereas no effect of repeated biopsy sampling on protein expression and phosphorylation was observed. In conclusion, resistance exercise, but not endurance exercise, increases IKKβ phosphorylation in trained human subjects, which support the idea that IKKβ can influence the activation of mTORC1 in human skeletal muscle.
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21
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Radhakrishnan P, Bryant VC, Blowers EC, Rajule RN, Gautam N, Anwar MM, Mohr AM, Grandgenett PM, Bunt SK, Arnst JL, Lele SM, Alnouti Y, Hollingsworth MA, Natarajan A. Targeting the NF-κB and mTOR pathways with a quinoxaline urea analog that inhibits IKKβ for pancreas cancer therapy. Clin Cancer Res 2013; 19:2025-35. [PMID: 23444213 DOI: 10.1158/1078-0432.ccr-12-2909] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE The presence of TNF-α in approximately 50% of surgically resected tumors suggests that the canonical NF-κB and the mTOR pathways are activated. Inhibitor of IκB kinase β (IKKβ) acts as the signaling node that regulates transcription via the p-IκBα/NF-κB axis and regulates translation via the mTOR/p-S6K/p-eIF4EBP axis. A kinome screen identified a quinoxaline urea analog 13-197 as an IKKβ inhibitor. We hypothesized that targeting the NF-κB and mTOR pathways with 13-197 will be effective in malignancies driven by these pathways. EXPERIMENTAL DESIGN Retrospective clinical and preclinical studies in pancreas cancers have implicated NF-κB. We examined the effects of 13-197 on the downstream targets of the NF-κB and mTOR pathways in pancreatic cancer cells, pharmacokinetics, toxicity and tumor growth, and metastases in vivo. RESULTS 13-197 inhibited the kinase activity of IKKβ in vitro and TNF-α-mediated NF-κB transcription in cells with low-μmol/L potency. 13-197 inhibited the phosphorylation of IκBα, S6K, and eIF4EBP, induced G1 arrest, and downregulated the expression of antiapoptotic proteins in pancreatic cancer cells. Prolonged administration of 13-197 did not induce granulocytosis and protected mice from lipopolysaccharide (LPS)-induced death. Results also show that 13-197 is orally available with extensive distribution to peripheral tissues and inhibited tumor growth and metastasis in an orthotopic pancreatic cancer model without any detectable toxicity. CONCLUSION These results suggest that 13-197 targets IKKβ and thereby inhibits mTOR and NF-κB pathways. Oral availability along with in vivo efficacy without obvious toxicities makes this quinoxaline urea chemotype a viable cancer therapeutic.
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Affiliation(s)
- Prakash Radhakrishnan
- Eppley Institute for Cancer Research and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
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22
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Irazabal MV, Torres VE. Experimental therapies and ongoing clinical trials to slow down progression of ADPKD. Curr Hypertens Rev 2013; 9:44-59. [PMID: 23971644 PMCID: PMC4067974 DOI: 10.2174/1573402111309010008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Revised: 10/19/2012] [Accepted: 11/30/2012] [Indexed: 12/19/2022]
Abstract
The improvement of imaging techniques over the years has contributed to the understanding of the natural history of autosomal dominant polycystic kidney disease, and facilitated the observation of its structural progression. Advances in molecular biology and genetics have made possible a greater understanding of the genetics, molecular, and cellular pathophysiologic mechanisms responsible for its development and have laid the foundation for the development of potential new therapies. Therapies targeting genetic mechanisms in ADPKD have inherent limitations. As a result, most experimental therapies at the present time are aimed at delaying the growth of the cysts and associated interstitial inflammation and fibrosis by targeting tubular epithelial cell proliferation and fluid secretion by the cystic epithelium. Several interventions affecting many of the signaling pathways disrupted in ADPKD have been effective in animal models and some are currently being tested in clinical trials.
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Affiliation(s)
- Maria V. Irazabal
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester MN, USA
| | - Vicente E. Torres
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester MN, USA
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23
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Copps KD, White MF. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 2012; 55:2565-2582. [PMID: 22869320 PMCID: PMC4011499 DOI: 10.1007/s00125-012-2644-8] [Citation(s) in RCA: 733] [Impact Index Per Article: 56.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 04/23/2012] [Indexed: 12/11/2022]
Abstract
The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. Tissues from insulin-resistant and diabetic humans exhibit defects in IRS-dependent signalling, implicating their dysregulation in the initiation and progression of metabolic disease. However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). An emerging view is that the positive/negative regulation of IRS by autologous pathways is subverted/co-opted in disease by increased basal and other temporally inappropriate S/T phosphorylation. Compensatory hyperinsulinaemia may contribute strongly to this dysregulation. Here, we examine the links between altered patterns of IRS S/T phosphorylation and the emergence of insulin resistance and diabetes.
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Affiliation(s)
- K D Copps
- Howard Hughes Medical Institute, Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, CLS 16020, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - M F White
- Howard Hughes Medical Institute, Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, CLS 16020, 300 Longwood Avenue, Boston, MA, 02115, USA.
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24
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Liao MT, Sung CC, Hung KC, Wu CC, Lo L, Lu KC. Insulin resistance in patients with chronic kidney disease. J Biomed Biotechnol 2012; 2012:691369. [PMID: 22919275 PMCID: PMC3420350 DOI: 10.1155/2012/691369] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Accepted: 07/15/2012] [Indexed: 02/06/2023] Open
Abstract
Metabolic syndrome and its components are associated with chronic kidney disease (CKD) development. Insulin resistance (IR) plays a central role in the metabolic syndrome and is associated with increased risk for CKD in nondiabetic patients. IR is common in patients with mild-to-moderate stage CKD, even when the glomerular filtration rate is within the normal range. IR, along with oxidative stress and inflammation, also promotes kidney disease. In patients with end stage renal disease, IR is an independent predictor of cardiovascular disease and is linked to protein energy wasting and malnutrition. Systemic inflammation, oxidative stress, elevated serum adipokines and fetuin-A, metabolic acidosis, vitamin D deficiency, depressed serum erythropoietin, endoplasmic reticulum stress, and suppressors of cytokine signaling all cause IR by suppressing insulin receptor-PI3K-Akt pathways in CKD. In addition to adequate renal replacement therapy and correction of uremia-associated factors, thiazolidinedione, ghrelin, protein restriction, and keto-acid supplementation are therapeutic options. Weight control, reduced daily prednisolone dosage, and the use of cyclosporin decrease the risk of developing new-onset diabetes after kidney transplantation. Improved understanding of the pathogenic mechanisms underlying IR in CKD may lead to more effective therapeutic strategies to reduce uremia-associated morbidity and mortality.
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Affiliation(s)
- Min-Tser Liao
- Department of Pediatrics, Taoyuan Armed Forces General Hospital, Taoyuan 325, Taiwan
- Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Chih-Chien Sung
- Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Kuo-Chin Hung
- Division of Nephrology, Department of Medicine, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Chia-Chao Wu
- Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Lan Lo
- Division of Nephrology, Department of Medicine, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Kuo-Cheng Lu
- Division of Nephrology, Department of Medicine, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
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Chen CT, Du Y, Yamaguchi H, Hsu JM, Kuo HP, Hortobagyi GN, Hung MC. Targeting the IKKβ/mTOR/VEGF signaling pathway as a potential therapeutic strategy for obesity-related breast cancer. Mol Cancer Ther 2012; 11:2212-21. [PMID: 22826466 DOI: 10.1158/1535-7163.mct-12-0180] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Clinical correlation studies have clearly shown that obesity is associated with breast cancer risk and patient survival. Although several potential mechanisms linking obesity and cancers have been proposed, the detailed molecular mechanism of obesity-mediated breast tumorigenesis has not yet been critically evaluated. In this study, we evaluated the effects of obesity on mammary tumor initiation and progression using mice with genetic and diet-induced obesity bearing mammary tumor xenografts and mouse mammary tumor virus-neu transgenic mice that were fed a high-fat diet. We show that obesity promoted mammary tumor growth and development in these animal models. Moreover, the expressions of TNFα, VEGF, IKKβ, and mTOR are upregulated in mammary tumors of obese mice, suggesting that the IKKβ/mTOR/VEGF signaling pathway is activated by TNFα in the tumors of obese mice. More importantly, inhibitors (rapamycin, bevacizumab, and aspirin) that target members of the pathway suppressed tumorigenesis and prolonged survival more effectively in obese mice than in nonobese mice. Here, we not only identified a specific signaling pathway that contributes to mammary tumorigenesis in obese mice but also a strategy for treating obesity-mediated breast cancer.
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Affiliation(s)
- Chun-Te Chen
- Department of Molecular and Cellular Oncology, Unit 0079, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
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Tanti JF, Ceppo F, Jager J, Berthou F. Implication of inflammatory signaling pathways in obesity-induced insulin resistance. Front Endocrinol (Lausanne) 2012; 3:181. [PMID: 23316186 PMCID: PMC3539134 DOI: 10.3389/fendo.2012.00181] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Accepted: 12/19/2012] [Indexed: 12/12/2022] Open
Abstract
Obesity is characterized by the development of a low-grade chronic inflammatory state in different metabolic tissues including adipose tissue and liver. This inflammation develops in response to an excess of nutrient flux and is now recognized as an important link between obesity and insulin resistance. Several dietary factors like saturated fatty acids and glucose as well as changes in gut microbiota have been proposed as triggers of this metabolic inflammation through the activation of pattern-recognition receptors (PRRs), including Toll-like receptors (TLR), inflammasome, and nucleotide oligomerization domain (NOD). The consequences are the production of pro-inflammatory cytokines and the recruitment of immune cells such as macrophages and T lymphocytes in metabolic tissues. Inflammatory cytokines activate several kinases like IKKβ, mTOR/S6 kinase, and MAP kinases as well as SOCS proteins that interfere with insulin signaling and action in adipocytes and hepatocytes. In this review, we summarize recent studies demonstrating that PRRs and stress kinases are important integrators of metabolic and inflammatory stress signals in metabolic tissues leading to peripheral and central insulin resistance and metabolic dysfunction. We discuss recent data obtained with genetically modified mice and pharmacological approaches suggesting that these inflammatory pathways are potential novel pharmacological targets for the management of obesity-associated insulin resistance.
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Affiliation(s)
- Jean-François Tanti
- INSERM U1065, Mediterranean Center of Molecular Medicine (C3M), Team “Molecular and Cellular Physiopathology of Obesity and Diabetes”Nice, France
- Faculty of Medicine, University of Nice Sophia-AntipolisNice, France
- *Correspondence: Jean-François Tanti, INSERM U1065, Centre Méditerranéen de Médecine Moléculaire, Bâtiment Archimed, 151, route de St. Antoine de Ginestière, BP 2 3194, 06204, Nice Cedex 3, France. e-mail:
| | - Franck Ceppo
- INSERM U1065, Mediterranean Center of Molecular Medicine (C3M), Team “Molecular and Cellular Physiopathology of Obesity and Diabetes”Nice, France
- Faculty of Medicine, University of Nice Sophia-AntipolisNice, France
| | - Jennifer Jager
- INSERM U1065, Mediterranean Center of Molecular Medicine (C3M), Team “Molecular and Cellular Physiopathology of Obesity and Diabetes”Nice, France
- Faculty of Medicine, University of Nice Sophia-AntipolisNice, France
| | - Flavien Berthou
- INSERM U1065, Mediterranean Center of Molecular Medicine (C3M), Team “Molecular and Cellular Physiopathology of Obesity and Diabetes”Nice, France
- Faculty of Medicine, University of Nice Sophia-AntipolisNice, France
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Rapamycin induces glucose intolerance in mice by reducing islet mass, insulin content, and insulin sensitivity. J Mol Med (Berl) 2011; 90:575-85. [PMID: 22105852 PMCID: PMC3354320 DOI: 10.1007/s00109-011-0834-3] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Revised: 10/15/2011] [Accepted: 11/07/2011] [Indexed: 11/13/2022]
Abstract
Rapamycin, a specific inhibitor for mTOR complex 1, is an FDA-approved immunosuppressant for organ transplant. Recent developments have raised the prospect of using rapamycin to treat cancer or diabetes and to delay aging. It is therefore important to assess how rapamycin treatment affects glucose homeostasis. Here, we show that the same rapamycin treatment reported to extend mouse life span significantly impaired glucose homeostasis of aged mice. Moreover, rapamycin treatment of lean C57B/L6 mice reduced glucose-stimulated insulin secretion in vivo and ex vivo as well as the insulin content and beta cell mass of pancreatic islets. Confounding the diminished capacity for insulin release, rapamycin decreased insulin sensitivity. The multitude of rapamycin effects thus all lead to glucose intolerance. As our findings reveal that chronic rapamycin treatment could be diabetogenic, monitoring glucose homeostasis is crucial when using rapamycin as a therapeutic as well as experimental reagent.
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Feng X, Wang W, Liu J, Liu Y. β-Arrestins: multifunctional signaling adaptors in type 2 diabetes. Mol Biol Rep 2010; 38:2517-28. [PMID: 21086182 DOI: 10.1007/s11033-010-0389-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2010] [Accepted: 11/08/2010] [Indexed: 02/06/2023]
Abstract
β-arrestins are not only well-known negative regulators of G protein-coupled receptor (GPCR) signaling, but also important adaptors in modulating the strength and duration of cellular signaling by scaffolding and interacting with a lot of cytoplasmic proteins. While β-arrestins are rather well described signal-mediated molecules, they are not generally associated with insulin signaling. But recent work has confirmed the difference from original thought. The current review aims to explore the emerging roles for β-arrestins in regulating insulin action, inflammatory signal pathway and other cellular signaling which are associated with type 2 diabetes.
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Affiliation(s)
- Xiaotao Feng
- Institute of Chinese Integrative Medicine, Huashan Hospital, Fudan University, No.12 Wulumuqi Zhong Road, Shanghai, 200040, China
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Gammadelta T cells are reduced and rendered unresponsive by hyperglycemia and chronic TNFalpha in mouse models of obesity and metabolic disease. PLoS One 2010; 5:e11422. [PMID: 20625397 PMCID: PMC2896399 DOI: 10.1371/journal.pone.0011422] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2010] [Accepted: 06/11/2010] [Indexed: 11/23/2022] Open
Abstract
Epithelial cells provide an initial line of defense against damage and pathogens in barrier tissues such as the skin; however this balance is disrupted in obesity and metabolic disease. Skin γδ T cells recognize epithelial damage, and release cytokines and growth factors that facilitate wound repair. We report here that hyperglycemia results in impaired skin γδ T cell proliferation due to altered STAT5 signaling, ultimately resulting in half the number of γδ T cells populating the epidermis. Skin γδ T cells that overcome this hyperglycemic state are unresponsive to epithelial cell damage due to chronic inflammatory mediators, including TNFα. Cytokine and growth factor production at the site of tissue damage was partially restored by administering neutralizing TNFα antibodies in vivo. Thus, metabolic disease negatively impacts homeostasis and functionality of skin γδ T cells, rendering host defense mechanisms vulnerable to injury and infection.
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Xia S, Yu S, Fu Q, Liu F, Zheng W, Fu X, Zhao Y. Inhibiting PI3K/Akt pathway increases DNA damage of cervical carcinoma HeLa cells by drug radiosensitization. ACTA ACUST UNITED AC 2010; 30:360-4. [PMID: 20556582 DOI: 10.1007/s11596-010-0357-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2009] [Indexed: 01/14/2023]
Abstract
This study examined the role of PI3K/Akt pathway in radiosensitization of DNA damage of cervical carcinoma cells. The 50% inhibition concentration (IC50) of cisplatin and docetaxel in HeLa cells was detected by Mono-nuclear cell direct cytotoxicity assay (MTT) in vitro. HeLa cells were treated by cisplatin/docetaxel of 10 percent of IC20 alone or combined with LY294002 for 24 h, and then radiated by different doses of X-ray. The cell survival ratio was obtained by means of clone formation. One-hit multi-target model was fitted to the cell survival curve to calculate dose quasithreshold (Dq), mean lethal dose (D0), 2Gy survival fraction (SF2) and sensitization enhancement ratio (SER). The pAkt and total Akt expression was detected by Western blotting and DNA damage by neutro-comet electrophoresis. The HeLa cells were randomly divided into 7 groups in terms of different treatments: Control; radiation treatment (RT) group; LY294002+RT group; cisplatin+RT group; docetaxel+RT group; LY294002+cisplatin+RT group; LY294002+docetaxel+RT group. The apoptosis ratio of each group was measured by flow cytometry. The results showed that docetaxel and cisplatin significantly enhanced the phosphorylation of Akt in radiation-treated HeLa cells. The Dq, D0 and SF2 in LY294002-contained groups were lower than those in docetaxel or cisplatin+RT group. The SER in the LY294002+docetaxel+RT group was 1.35 times that of the docetaxel+RT group, and that in the LY294002+cisplatin+RT group 1.26 times that of the cisplatin+RT group. The Comet electrophoresis showed that tail distance in the LY294002+cisplatin+RT group or LY294002+docetaxel+ RT group was longer than in the cisplatin+RT group or docetaxel+RT group. The apoptosis ratio in the LY294002+cisplatin+RT group or LY294002+docetaxel +RT group was higher than in the cisplatin+RT group or docetaxel+RT group. It was concluded that inhibiting PI3K/Akt pathway can increase the effect of docetaxel and cisplatin on the radiosensitivity of HeLa cells and DNA damage resulted from radiation.
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Affiliation(s)
- Shu Xia
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Torres VE. Treatment strategies and clinical trial design in ADPKD. Adv Chronic Kidney Dis 2010; 17:190-204. [PMID: 20219622 DOI: 10.1053/j.ackd.2010.01.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2009] [Revised: 01/06/2010] [Accepted: 01/06/2010] [Indexed: 12/22/2022]
Abstract
More frequent utilization and continuous improvement of imaging techniques has enhanced appreciation of the high phenotypic variability of autosomal dominant polycystic kidney disease, improved understanding of its natural history, and facilitated the observation of its structural progression. At the same time, identification of the PKD1 and PKD2 genes has provided clues to how the disease develops when they (genetic mechanisms) and their encoded proteins (molecular mechanisms) are disrupted. Interventions designed to rectify downstream effects of these disruptions have been examined in animal models, and some are currently tested in clinical trials. Efforts are underway to determine whether interventions capable to slow down, stop, or reverse structural progression of the disease will also prevent decline of renal function and improve clinically significant outcomes.
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Affiliation(s)
- Mathieu Laplante
- Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA
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Abstract
Autosomal dominant polycystic kidney disease is the most prevalent, potentially lethal monogenic disorder. It has large inter- and intra-familial variability explained to a large extent by its genetic heterogeneity and modifier genes. An increased understanding of its underlying genetic, molecular, and cellular mechanisms and a better appreciation of its progression and systemic manifestations have laid out the foundation for the development of clinical trials and potentially effective therapies. The purpose of this review is to update the core of knowledge in this area with recent publications that have appeared during 2006-2009.
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Affiliation(s)
- Vicente E Torres
- Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
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