Type 2 diabetes (T2D) is one of the main current threats to human health. Both T2D and its numerous clinical complications are related to mitochondrial dysfunction and oxidative stress. Over the past ...decade, great progress has been made in extending our knowledge about the signaling events regulated by mitochondria. However, the links among mitochondrial impairment, oxidative stress, autophagy, endoplasmic reticulum (ER) stress, and activation of the inflammasome still need to be clarified. In light of this deficit, we aim to provide a review of the existing literature concerning the complicated crosstalk between mitochondrial impairment, autophagy, ER stress, and the inflammasome in the molecular pathogenesis of T2D.
Oxidative stress, mitochondrial dysfunction, and type 2 diabetes are closely interconnected.Mitochondrial impairment characteristic for type 2 diabetes is related to changes in the autophagic process, endoplasmic reticulum stress, and inflammation.A new understanding of the pathophysiological mechanisms by which mitochondrial dysfunction and ROS, as essential signaling molecules, relate to other molecular pathways, could help to identify novel therapeutic targets for the treatment of type 2 diabetes.The identification of key molecular targets for type 2 diabetes treatment can widen the pharmacological scope for clinical development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Type 2 diabetes (T2D) is a very prevalent, multisystemic, chronic metabolic disorder closely related to atherosclerosis and cardiovascular diseases. It is characterised by mitochondrial dysfunction ...and the presence of oxidative stress. Metformin is one of the safest and most effective anti-hyperglycaemic agents currently employed as first-line oral therapy for T2D. It has demonstrated additional beneficial effects, unrelated to its hypoglycaemic action, on weight loss and several diseases, such as cancer, cardiovascular disorders and metabolic diseases, including thyroid diseases. Despite the vast clinical experience gained over several decades of use, the mechanism of action of metformin is still not fully understood. This review provides an overview of the existing literature concerning the beneficial mitochondrial and vascular effects of metformin, which it exerts by diminishing oxidative stress and reducing leukocyte-endothelium interactions. Specifically, we describe the molecular mechanisms involved in metformin's effect on gluconeogenesis, its capacity to interfere with major metabolic pathways (AMPK and mTORC1), its action on mitochondria and its antioxidant effects. We also discuss potential targets for therapeutic intervention based on these molecular actions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Ohrid-Prespa lake system is the oldest and most diverse permanent lake system in Europe, dating from the Pliocene era and aged at over 4Ma. Its smaller component is Lake Macro Prespa (thereafter ...called Prespa), shared by North Macedonia, Albania, and Greece. Lake Prespa’s depth was reported as 14 m mean and 48 m maximum before its major water level decline. The lake is highly sensitive to external impacts, including climate change, and has been suffering major water loss for decades. A lake-level decline of almost 10 m was documented between 1950 and 2009 due to restricted precipitation and increased water abstraction for irrigation. This study describes the changes in the surface size of Prespa Lake and the vegetation/land use in the surrounding area in the period 1984–2020 using satellite images (remote sensing, Landsat 5 & 8 images by United States Geological Survey). The lake lost 18.87 km2 of surface in this period (6.9% of its size, dropping from 273.38 km2 to 254.51 km2). Water loss was greater in the period 1987–1993 and 1998–2004. The Analysis of Normalized Difference Vegetation Index (NDVI) in the area (app. 4950 km2) surrounding Lake Prespa revealed an increase in the mean NDVI values over the period studied (1984–2020), pointing to a general increase in vegetation. Areas with NDVI > 0.13 increased from 78% in 1984 to 86% in 2020, while those with the highest vegetation intensity (NDVI > 0.45) increased by 40%. These changes in vegetation may be related to the water loss of the lake.
Chronic liver disease (CLD) constitutes a growing global health issue, with no effective treatments currently available. Oxidative stress closely interacts with other cellular and molecular processes ...to trigger stress pathways in different hepatic cells and fuel the development of liver fibrosis. Therefore, inhibition of reactive oxygen species (ROS)-mediated effects and modulation of major antioxidant responses to counteract oxidative stress-induced damage have emerged as interesting targets to prevent or ameliorate liver injury. Although many preclinical studies have shown that dietary supplements with antioxidant properties can significantly prevent CLD progression in animal models, this strategy has not proved effective to significantly reduce fibrosis when translated into clinical trials. Novel and more specific therapeutic approaches are thus required to alleviate oxidative stress and reduce liver fibrosis. We have reviewed the relevant literature concerning the crucial role of alterations in redox homeostasis in different hepatic cell types during the progression of CLD and discussed current pharmacological approaches to ameliorate fibrosis by reducing oxidative stress focusing on selective modulation of enzymatic oxidant sources, antioxidant systems and ROS-mediated pathogenic processes.
As the main extracellular matrix-producing cells, activated hepatic stellate cells (HSC) are fundamental mediators of liver fibrosis (LF), and understanding their activation/inactivation mechanisms ...is paramount to the search for novel therapeutics. The antiretroviral drug Rilpivirine (RPV) has demonstrated a hepatoprotective effect in several animal models of chronic liver injury that is related to its antifibrogenic and apoptotic action in HSC. In the present study, we evaluated whether autophagy is implicated in the hepatoprotective action of RPV, as autophagy plays an important role in HSC transdifferentiation. We employed two standard mouse models of chronic liver injury - fatty liver disease and carbon tetrachloride (CCl
)-induced hepatotoxicity -and cultured HSC activated with the profibrotic cytokine TGF-β. RPV enhanced autophagy in the whole liver of both mouse models and in activated HSC, evident in the protein expression of autophagy markers, increased autophagosome content and lysosomal mass. Moreover, increased autophagic flux was observed in RPV-exposed HSC as revealed by tandem fluorescence-tagged LC3 and p62 and analysis of LC3-II accumulation in cells exposed to the lysosomal inhibitor chloroquine. Importantly, autophagy was involved in the cytotoxic effect of RPV on HSC, though in a differential manner. Pharmacological inhibition of autophagy by 3-methyladenine (3-MA) did not affect the diminishing effect of RPV on viability, while treatment with wortmannin or depletion of specific autophagy proteins (ATG5, Beclin-1 and SQSTM1/p62) rescued the detrimental effect of high concentrations of RPV on the viability of activated HSC. Finally, we also provide evidence that RPV compromises the viability of TGF-β-induced HSC independently of its antifibrogenic effect, observed as reduced collagen 1A1 synthesis, and that this effect does not include RPV´s modulation of autophagy. In summary, as a contributor to the mechanisms involved in the hepatoprotective action of RPV, autophagy may be a good candidate to explore when developing novel therapeutics for LF.
Type 2 diabetes is a chronic metabolic disease that affects mitochondrial function. In this context, the rescue mechanisms of mitochondrial health, such as mitophagy and mitochondrial biogenesis, are ...of crucial importance. The gold standard for the treatment of type 2 diabetes is metformin, which has a beneficial impact on the mitochondrial metabolism. In this study, we set out to describe the effect of metformin treatment on mitochondrial function and mitophagy in peripheral blood mononuclear cells (PBMCs) from type 2 diabetic patients. We performed a preliminary cross-sectional observational study complying with CONSORT requirements, for which we recruited 242 subjects, divided into 101 healthy volunteers, 93 metformin-treated type 2 diabetic patients and 48 non-metformin-treated type 2 diabetic patients. Mitochondria from the type 2 diabetic patients not treated with metformin displayed more reactive oxygen species (ROS) than those from healthy or metformin-treated subjects. Protein expression of the electron transport chain (ETC) complexes was lower in PBMCs from type 2 diabetic patients without metformin treatment than in those from the other two groups. Mitophagy was altered in type 2 diabetic patients, evident in a decrease in the protein levels of PINK1 and Parkin in parallel to that of the mitochondrial biogenesis protein PGC1α, both of which effects were reversed by metformin. Analysis of AMPK phosphorylation revealed that its activation was decreased in the PBMCs of type 2 diabetic patients, an effect which was reversed, once again, by metformin. In addition, there was an increase in the serum levels of TNFα and IL-6 in type 2 diabetic patients and this was reversed with metformin treatment. These results demonstrate that metformin improves mitochondrial function, restores the levels of ETC complexes, and enhances AMPK activation and mitophagy, suggesting beneficial clinical implications in the treatment of type 2 diabetes.
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•Metformin promoted electron transport chain expression on type 2 diabetic patients.•Metformin restored mitophagy levels via PINK1 and PARKIN on type 2 diabetic patients.•Mitochondrial biogenesis was enhanced by metformin on type 2 diabetic patients.•Metformin restored AMPK activation on type 2 diabetic patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Efavirenz (EFV) is a non‐nucleoside reverse transcriptase inhibitor (NNRTI) widely used in human immunodeficiency virus (HIV) infection therapy. It has been associated with hepatotoxic effects and ...alterations in lipid and body fat composition. Given the importance of the liver in lipid regulation, we have evaluated the effects of clinically used concentrations of EFV on the mitochondria and lipid metabolism of human hepatic cells in vitro. Mitochondrial function was rapidly undermined by EFV to an extent that varied with the concentration employed; in particular, respiration and intracellular adenosine triphosphate (ATP) levels were reduced whereas reactive oxygen species (ROS) production increased. Results in isolated mitochondria suggest that the mechanism responsible for these actions was a specific inhibition of complex I of the respiratory chain. The reduction in energy production triggered a compensatory mechanism mediated by the enzyme adenosine monophosphate–activated protein kinase (AMPK), the master switch of cellular bioenergetics. Fluorescence and nuclear magnetic resonance demonstrated a rapid intracellular increase of neutral lipids, usually in the form of droplets. This was prevented by the AMPK inhibitor compound C and by removal of fatty acids from the culture medium. These effects were not reproduced by Nevirapine, another NNRTI. EFV is clinically coadministered with two nucleoside reverse transcriptase inhibitors. Evaluation of one of the most common combination, EFV/Lamivudine/Abacavir, revealed that the effects of EFV on ROS production were enhanced. Conclusion: Clinical concentrations of EFV induce bioenergetic stress in hepatic cells by acutely inhibiting mitochondrial function. This new mechanism of mitochondrial interference leads to an accumulation of lipids in the cytoplasm that is mediated by activation of AMPK. HEPATOLOGY 2010
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease (CLD) worldwide and inflammation is key to its progression/resolution. As we have previously described that ...rilpivirine (RPV) is hepatoprotective in murine models of CLD, here we determine the molecular mechanisms involved, focusing on its anti-inflammatory and immunomodulating properties. They were evaluated in vitro (human hepatic cell lines of the major hepatic cell types), in vivo (liver samples from a murine nutritional model of NAFLD) and ex vivo (peripheral blood mononuclear cells -PBMC- from patients with CLD). Transcriptomic analysis of liver samples from NAFLD mice showed RPV down-regulated biological processes associated with the inflammatory response (NF-κB/IκB signaling and mitogen-activated protein kinase -MAPK- activity) and leukocyte chemotaxis and migration. We observed a decrease in Adgre1 and Ccr2 expression and in the number of CCR2 + cells in the periportal areas of RPV-treated NAFLD mice. This RPV-induced effect on the CCL2/CCR2 axis was confirmed in vitro. A similar result was also obtained with CXCL10/IP10, one of the main chemokines in the liver. RPV also diminished activation of MAP kinases p38 and JNK. In addition, RPV inhibited the NLRP3 inflammasome pathway in vitro, decreasing NLRP3 protein expression, caspase-1 activation and IL-1β gene expression. RPV was also proven anti-inflammatory in PBMC from patients with CLD treated ex vivo. In conclusion, beyond its well-described role in antiretroviral therapy, RPV manifests anti-inflammatory and immunoregulatory effects, a finding that could be of great relevance for the search of novel targets or repositioning strategies for CLD.
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•Modified inflammatory and immunomodulating pathways in livers of RPV-treated HFD mice.•RPV diminishes leukocyte migration and recruitment in vivo and in vitro.•Anti-inflammatory effect of RPV ex vivo in PBMC isolated from patients with CLD
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mitochondria are crucial, multifunctional organelles which actively regulate cellular homeostasis. Their complex and diverse role includes maintenance of the cellular energetic balance through ...hosting several catabolic pathways which result in the process of oxidative phosphorylation, as well as enabling various fundamental anabolic processes and controlling Ca2+ distribution. Moreover, mitochondria are the main cellular generator of reactive oxygen species, which act as second messengers and when over-produced provoke a state of oxidative stress, a condition implicated in many pathologies. Importantly, mitochondria are directly involved in triggering different and complexly interconnected programs promoting cell survival or death. The aim of this review is to summarize the current understanding regarding mitochondrial implication in the main cellular pathways controlling cell "fate" such as apoptosis, autophagy (mitophagy), mitoptosis and necrosis with particular emphasis on the role that reactive oxygen species and oxidative stress may play in these phenomena. The literature extensively covers the topic of reactive oxygen species and apoptosis, fewer articles however deal with mitophagy or mitochondrial dynamics and very few mention the implication oxidative stress and redox modifications have for mitoptosis or necrosis. This review offers a global picture of the complex role of mitochondria in the regulation of cell "fate", referring specifically to the interconnection and balance between different cellular pathways of death and survival. Current knowledge regarding the involvement of these processes in particular human pathologies, specifically with respect to the implication of reactive oxygen species and oxidative stress, is also discussed.
Type 2 diabetes (T2D) is linked to metabolic, mitochondrial and inflammatory alterations, atherosclerosis development and cardiovascular diseases (CVDs). The aim was to investigate the potential ...therapeutic benefits of GLP-1 receptor agonists (GLP-1 RA) on oxidative stress, mitochondrial respiration, leukocyte-endothelial interactions, inflammation and carotid intima–media thickness (CIMT) in T2D patients.
Type 2 diabetic patients (255) and control subjects (175) were recruited, paired by age and sex, and separated into two groups: without GLP-1 RA treatment (196) and treated with GLP-1 RA (59). Peripheral blood polymorphonuclear leukocytes (PMNs) were isolated to measure reactive oxygen species (ROS) production by flow cytometry and oxygen consumption with a Clark electrode. PMNs were also used to assess leukocyte-endothelial interactions. Circulating levels of adhesion molecules and inflammatory markers were quantified by Luminex's technology, and CIMT was measured as surrogate marker of atherosclerosis.
Treatment with GLP-1 RA reduced ROS production and recovered mitochondrial membrane potential, oxygen consumption and MPO levels. The velocity of leukocytes rolling over endothelial cells increased in PMNs from GLP-1 RA-treated patients, whereas rolling and adhesion were diminished. ICAM-1, VCAM-1, IL-6, TNFα and IL-12 protein levels also decreased in the GLP-1 RA-treated group, while IL-10 increased. CIMT was lower in GLP-1 RA-treated T2D patients than in T2D patients without GLP-1 RA treatment.
GLP-1 RA treatment improves the redox state and mitochondrial respiration, and reduces leukocyte-endothelial interactions, inflammation and CIMT in T2D patients, thereby potentially diminishing the risk of atherosclerosis and CVDs.
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•Risk of atherosclerosis and cardiovascular diseases is higher in type 2 diabetes.•The question was to investigate GLP-1 RA benefits on diabetes-related factors.•GLP-1 RA improved the redox state and mitochondrial respiration of leukocytes.•GLP-1 RA diminished leukocyte-endothelial interactions, inflammation and CIMT.•The risk of cardiovascular diseases could be reduced with GLP-1 RA treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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