Endothelial dysfunction is an important risk factor for cardiovascular disease, and it represents the initial step in the pathogenesis of atherosclerosis. Failure to protect against oxidative ...stress-induced cellular damage accounts for endothelial dysfunction in the majority of pathophysiological conditions. Numerous antioxidant pathways are involved in cellular redox homeostasis, among which the nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway is perhaps the most prominent. Nrf2, a transcription factor with a high sensitivity to oxidative stress, binds to AREs in the nucleus and promotes the transcription of a wide variety of antioxidant genes. Nrf2 is located in the cytoskeleton, adjacent to Keap1. Keap1 acts as an adapter for cullin 3/ring-box 1-mediated ubiquitination and degradation of Nrf2, which decreases the activity of Nrf2 under physiological conditions. Oxidative stress causes Nrf2 to dissociate from Keap1 and to subsequently translocate into the nucleus, which results in its binding to ARE and the transcription of downstream target genes. Experimental evidence has established that Nrf2-driven free radical detoxification pathways are important endogenous homeostatic mechanisms that are associated with vasoprotection in the setting of aging, atherosclerosis, hypertension, ischemia, and cardiovascular diseases. The aim of the present review is to briefly summarize the mechanisms that regulate the Nrf2/Keap1-ARE signaling pathway and the latest advances in understanding how Nrf2 protects against oxidative stress-induced endothelial injuries. Further studies regarding the precise mechanisms by which Nrf2-regulated endothelial protection occurs are necessary for determining whether Nrf2 can serve as a therapeutic target in the treatment of cardiovascular diseases.
•Descripting the dysregulation of mitochondrial biogenesis in the development of aging and aging-related diseases.•Completed description of the transcriptional and post-translational regulation of ...SIRT1 in aging process.•Regulation of mitochondrial biogenesis via SIRT1-PGC1α dependent and independent pathway have been elaborated in this paper.
Aging is a degenerative process associated with cumulative damage, which leads to cellular dysfunction, tissue failure, and disorders of body function. Silent information regulator-1, also known as sirtuin 1 (SIRT1), has been reported to be involved in the regulation of various important biological processes, including inflammation, mitochondrial biogenesis, as well as cell senescence and consequent aging. The level of SIRT1 is decreased in both transcriptional and postranscriptional conditions during aging, accompanied by attenuated mitochondrial biogenesis, an important component of aging-related diseases. Over the last decade, extensive studies have demonstrated that SIRT1 can activate several transcriptional factors, such as peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α) and hypoxia-inducible factor 1α (HIF-1α) resulting in ameliorated mitochondria biogenesis and extended life span. In this review, we focus on the molecular regulation of SIRT1 and its role in mitochondrial biogenesis during in the context of aging and aging-related diseases.
Ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-AKI) is characterized by elevated levels of reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation, but the ...potential link among these features remains unclear. In this study, we aimed to investigate the specific role of mitochondrial ROS (mtROS) in initiating mitochondrial DNA (mtDNA) damage and inflammation during IRI-AKI.
The changes in renal function, mitochondrial function, and inflammation in IRI-AKI mice with or without mtROS inhibition were analyzed
. The impact of mtROS on TFAM (mitochondrial transcription factor A), Lon protease, mtDNA, mitochondrial respiration, and cytokine release was analyzed in renal tubular cells
. The effects of TFAM knockdown on mtDNA, mitochondrial function, and cytokine release were also analyzed
. Finally, changes in TFAM and mtDNA nucleoids were measured in kidney samples from IRI-AKI mice and patients.
Decreasing mtROS levels attenuated renal dysfunction, mitochondrial damage, and inflammation in IRI-AKI mice. Decreasing mtROS levels also reversed the decrease in TFAM levels and mtDNA copy number that occurs in HK2 cells under oxidative stress. mtROS reduced the abundance of mitochondrial TFAM in HK2 cells by suppressing its transcription and promoting Lon-mediated TFAM degradation. Silencing of TFAM abolished the Mito-Tempo (MT)-induced rescue of mitochondrial function and cytokine release in HK2 cells under oxidative stress. Loss of TFAM and mtDNA damage were found in kidneys from IRI-AKI mice and AKI patients.
mtROS can promote renal injury by suppressing TFAM-mediated mtDNA maintenance, resulting in decreased mitochondrial energy metabolism and increased cytokine release. TFAM defects may be a promising target for renal repair after IRI-AKI.
Biometrics authenticated schemes using smart cards have attracted much attention in multi-server environments. Several schemes of this type where proposed in the past. However, many of them were ...found to have some design flaws. This paper concentrates on the security weaknesses of the three-factor authentication scheme by Mishra et al. After careful analysis, we find their scheme does not really resist replay attack while failing to provide an efficient password change phase. We further propose an improvement of Mishra et al.'s scheme with the purpose of preventing the security threats of their scheme. We demonstrate the proposed scheme is given to strong authentication against several attacks including attacks shown in the original scheme. In addition, we compare the performance and functionality with other multi-server authenticated key schemes.
Aim
This study aims to demonstrate the protective effects of monounsaturated oleic acid (OA) against saturated palmitic acid (PA) induced cellular lipotoxicity in hepatocytes and rats with ...non-alcoholic steatohepatitis (NASH).
Human hepatoma cell line HepG2 cells and neonatal rat primary hepatocytes were treated with PA or/and OA for 24 h. SD rats were fed with high fat diet (HFD) to induce NASH. From the 16th w, the HFD was full or half replaced by olive oil to observe the protective effects.
In vitro, OA substantially alleviated PA induced cellular apoptosis, oxidative stress, ER stress, mitochondrial dysfunction, as well as inflammation in hepatocytes. In vivo, only olive oil supplementation had no detrimental effects, while HFD developed NASH in normal rats. Full replacement of HFD with olive oil had profoundly reversed NASH. Noteworthily, half replacement of HFD with olive oil (a mixed diet) has ameliorated NASH injury as well. It strikingly changed the hepatic histology from macrovesicular-steatosis into entire microvesicular-steatosis, and significantly reduced inflammation, ballooning and fibrosis.
Our study has demonstrated in both hepatocytes and NASH rats that oleic acids had great potential to combat the saturated fatty acids induced hepatic lipotoxicity. Only half replacement of HFD by monounsaturated fatty acids rich diet still had significant therapeutic outcome in NASH rats. Redirecting the toxic saturated fatty acids into triglyceride storage and reduction of cholesterol accumulation might be the possible explanation of OA driven protection in this scenario.
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Diabetic nephropathy (DN) is a serious complication of diabetes mellitus (DM), which is a major public health problem in the world. To reveal the metabolic changes associated with DN, we analyzed the ...serum, urine, and renal extracts obtained from control and streptozotocin (STZ)-induced DN rats by
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H NMR-based metabonomics and multivariate data analysis. A significant difference between control and DN rats was revealed in metabolic profiles, and we identified several important DN-related metabolites including increased levels of allantoin and uric acid (UA) in the DN rats, suggesting that disturbed purine metabolism may be involved in the DN. Combined with conventional histological and biological methods, we further demonstrated that xanthine oxidase (XO), a key enzyme for purine catabolism, was abnormally activated in the kidney of diabetic rats by hyperglycemia. The highly activated XO increased the level of intracellular ROS, which caused renal injury by direct oxidative damage to renal cells, and indirect inducing inflammatory responses via activating NF-κB signaling pathway. Our study highlighted that metabonomics is a promising tool to reveal the metabolic changes and the underlying mechanism involved in the pathogenesis of DN.
Graphical Abstract
In this study, we performed
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H NMR-based metabonomic to analyze the serum, urine, and renal extracts in a rat model of diabetic nephropathy (DN), and identified the disturbed purine metabolism and its underlying xanthine oxidase induced oxidative stress and inflammation was involved in the pathogenesis of DN
WSNs (Wireless sensor networks) are nowadays viewed as a vital portion of the IoTs (Internet of Things). Security is a significant issue in WSNs, especially in resource-constrained environments. AKA ...(Authentication and key agreement) enhances the security of WSNs against adversaries attempting to get sensitive sensor data. Various AKA schemes have been developed for verifying the legitimate users of a WSN. Firstly, we scrutinize Amin-Biswas's currently scheme and demonstrate the major security loopholes in their works. Next, we propose a lightweight AKA scheme, using symmetric key cryptography based on smart card, which is resilient against all well known security attacks. Furthermore, we prove the scheme accomplishes mutual handshake and session key agreement property securely between the participates involved under BAN (Burrows, Abadi and Needham) logic. Moreover, formal security analysis and simulations are also conducted using AVISPA(Automated Validation of Internet Security Protocols and Applications) to show that our scheme is secure against active and passive attacks. Additionally, performance analysis shows that our proposed scheme is secure and efficient to apply for resource-constrained WSNs.
Aims: Cisplatin, an anticancer drug, always leads to nephrotoxicity by causing mitochondrial dysfunction. As a major mechanism for cellular self-degradation, autophagy has been proven to protect ...against cisplatin-induced acute kidney injury (AKI). Based on the activation of autophagy induced by trehalose, we aimed to investigate the nephroprotective effects of trehalose on cisplatin-induced AKI and its underlying mechanisms. Results: Due to the activation of autophagy, mitochondrial dysfunction (mitochondrial fragmentation, depolarization, reactive oxygen species (ROS), and reduced ATP generation) and apoptosis induced by cisplatin were markedly inhibited in trehalose-treated HK2 cells in vitro. Based on the transcriptional regulation role of transcription factor EB (TFEB) in autophagy and lysosome, we characterized trehalose-induced nuclear translocation of TFEB. Furthermore, consistent with trehalose treatment, overexpression of TFEB inhibited cell injury induced by cisplatin. However, the protective effects of trehalose were largely abrogated in tfeb-knockdown cells. In vivo, cisplatin injection resulted in severe kidney dysfunction and histological damage in mice. Trehalose administration activated TFEB-mediated autophagy, alleviated mitochondrial dysfunction and kidney injury in AKI mice. Innovation and conclusion: Our data suggest that trehalose treatment preserves mitochondria function via activation of TFEB-mediated autophagy and attenuates cisplatin-induced kidney injury.
Increasing evidence indicates that obesity is highly associated with chronic kidney disease (CKD). GLP-1 receptor (GLP-1R) agonist has shown benefits on kidney diseases, but its direct role on kidney ...metabolism in obesity is still not clear. This study aims to investigate the protection and metabolic modulation role of liraglutide (Lira) on kidney of obesity. Rats were induced obese by high-fat diet (HFD), and renal function and metabolism changes were evaluated by metabolomic, biological and histological methods. HFD rats exhibited systemic metabolic disorders such as obesity, hyperlipidemia and impaired glucose tolerance, as well as renal histological and function damages, while Lira significantly ameliorated these adverse effects in HFD rats. Metabolomic data showed that Lira directly reduced renal lipids including fatty acid residues, cholesterol, phospholipids and triglycerides, and improved mitochondria metabolites such as succinate, citrate, taurine, fumarate and nicotinamide adenine dinucleotide (NAD+) in the kidney of HFD rats. Furthermore, we revealed that Lira inhibited renal lipid accumulation by coordinating lipogenic and lipolytic signals, and partly rescued renal mitochondria function via Sirt1/AMPK/PGC1α pathways in HFD rats. This study suggested that Lira alleviated HFD-induced kidney injury at least partly via directly restoring renal metabolism, thus GLP-1R agonist is a promising therapy for obesity-associated CKD.
Senescence of bone marrow-derived mesenchymal stem cells (BMSCs) has been widely reported to be closely correlated with aging-related diseases, including osteoporosis (OP). Moreover, the beneficial ...functions of BMSCs decline with age, limiting their therapeutic efficacy in OP. In the present study, using RNA sequencing (RNA-Seq), we found that leucine-rich repeat containing 17 (LRRc17) expression in BMSCs was highly positively correlated with age. Therefore, we investigated whether LRRc17 knockdown could rejuvenate aged MSCs and increase their therapeutic efficacy in OP. Consistent with the RNA-Seq results, the protein expression of LRRc17 in senescent BMSCs was significantly increased, whereas LRRc17 knockdown inhibited cell apoptosis and reduced the expression of age-related proteins and G2 and S phase quiescence. Furthermore, LRRc17 knockdown shifted BMSCs from adipogenic to osteogenic differentiation, indicating the critical role of LRRc17 in BMSC senescence and differentiation. Additionally, similar to rapamycin (RAPA) treatment, LRRc17 knockdown activated mitophagy via inhibition of the mTOR/PI3K pathway, which consequently reduced mitochondrial dysfunction and inhibited BMSC senescence. However, the effects of LRRc17 knockdown were significantly blocked by the autophagy inhibitor hydroxychloroquine (HCQ), demonstrating that LRRc17 knockdown prevented BMSC senescence by activating mitophagy. In vivo, compared with untransfected aged mouse-derived BMSCs (O-BMSCs), O-BMSCs transfected with sh-LRRc17 showed effective amelioration of ovariectomy (OVX)-induced bone loss. Collectively, these results indicated that LRRc17 knockdown rejuvenated senescent BMSCs and thus enhanced their therapeutic efficacy in OP by activating autophagy.
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