Akt2 deficiency alleviates oxidative stress in the heart and liver via up-regulating SIRT6 during high-fat diet-induced obesity.

The present study aims to investigate the role of AKT2 in the pathogenesis of hepatic and cardiac lipotoxicity induced by lipid overload-induced obesity and identify its downstream targets. WT and Akt2 KO mice were fed either normal diet, or high-fat diet (HFD) to induce obesity model in vivo. Human hepatic cell line (L02 cells) and neonatal rat cardiomyocytes (NRCMs) were used as in vitro models. We observed that during HFD-induced obesity, Akt2 loss-of-function mitigated lipid accumulation and oxidative stress in the liver and heart tissue. Mechanistically, down-regulation of Akt2 promotes SIRT6 expression in L02 cells and NRCMs, the latter deacetylates SOD2, which promotes SOD2 activity and therefore alleviates oxidative stress-induced injury of hepatocytes and cardiomyocytes. Furthermore, we also proved that AKT2 inhibitor protects hepatocytes and cardiomyocytes from HFD-induced oxidative stress. Therefore, our work prove that AKT2 plays an important role in the regulation of obesity-induced lipid metabolic disorder in the liver and heart. Our study also indicates AKT2 inhibitor as a potential therapy for obesity-induced hepatic and cardiac injury.

Demethyleneberberine alleviates Pseudomonas aeruginosa-induced acute pneumonia by inhibiting the AIM2 inflammasome and oxidative stress.

BACKGROUND: Acute pneumonia induced by Pseudomonas aeruginosa is characterized by massive infiltration of inflammatory cell and the production of reactive oxygen species (ROS), which lead to severe and transient pulmonary inflammation and acute lung injury. However, P.aeruginosa infection is resistant to multiple antibiotics and causes high mortality in clinic, the search for alternative prophylactic and therapeutic strategies is imperative. PURPOSE: This study was aimed to investigate the anti-inflammatory and antioxidant effects of DMB, a novel derivative of berberine, and explore the role of AIM2 inflammasome in P. aeruginosa-induced acute pneumonia. METHODS: Acute pneumonia mice were established by tracheal injection of P. aeruginosa suspension. Pathological changes of lung tissue were observed by its appearance and H&E staining. The lung coefficient ratio was measured to evaluate pulmonary edema. Inflammatory factors were detected by qRT-PCR, western blotting and immunohistochemistry. ROS and other indicators of oxidative damage were analyzed by flow cytometry and specific kit. Proteins related to AIM2 inflammasome were detected by western blotting. RESULTS: Compared with the P. aeruginosa-induced group, DMB ameliorated pulmonary edema, hyperemia, and pathological damage based on its appearance and H&E staining in DMB groups. First, DMB attenuated the inflammatory response induced by P.aeruginosa. Compared with the P. aeruginosa-induced group, the lung coefficient ratio was decreased by 31.5%, the MPO activity of lung tissue was decreased by 44.0%, the mRNA expression levels of TNF-α, IL-1ß and IL-6 were decreased by 64.8%, 51.2% and 64.0% respectively, and those protein expression levels were decreased by 40.1%, 42.8% and 47.8% respectively, and the number of white blood cells, neutrophils and monocytes were decreased by 53.5%, 29.4% and 13.7% in high dose (200 mg/kg) DMB group. Second, DMB alleviates oxidative stress in the lung tissue during P. aeruginosa-induced acute pneumonia. Compared with the P. aeruginosa-induced group, the level of GSH was increased by 42.5% and MDA was decreased by 49.5% in high dose DMB group. Moreover, the western blotting results showed that DMB markedly suppressed the expression of AIM2, ASC, Cleaved caspase1 and decreased the secretion of IL-1ß. Additionally, these results were also confirmed by in vitro experiments using MH-S and BEAS-2B cell lines. CONCLUSIONS: Taken together, these results indicated that DMB ameliorates P. aeruginosa-induced acute pneumonia through anti-inflammatory, antioxidant effects, and inhibition of AIM2 inflammasome activation.

SIRT6 regulates obesity-induced oxidative stress via ENDOG/SOD2 signaling in the heart.

The sirtuin 6 (SIRT6) participates in regulating glucose and lipid homeostasis. However, the function of SIRT6 in the process of cardiac pathogenesis caused by obesity-associated lipotoxicity remains to be unveiled. This study was designed to elucidate the role of SIRT6 in the pathogenesis of cardiac injury due to nutrition overload-induced obesity and explore the downstream signaling pathways affecting oxidative stress in the heart. In this study, we used Sirt6 cardiac-specific knockout murine models treated with a high-fat diet (HFD) feeding to explore the function and mechanism of SIRT6 in the heart tissue during HFD-induced obesity. We also took advantage of neonatal cardiomyocytes to study the role and downstream molecules of SIRT6 during HFD-induced injury in vitro, in which intracellular oxidative stress and mitochondrial content were assessed. We observed that during HFD-induced obesity, Sirt6 loss-of-function aggravated cardiac injury including left ventricular hypertrophy and lipid accumulation. Our results evidenced that upon increased fatty acid uptake, SIRT6 positively regulated the expression of endonuclease G (ENDOG), which is a mitochondrial-resident molecule that plays an important role in mitochondrial biogenesis and redox homeostasis. Our results also showed that SIRT6 positively regulated superoxide dismutase 2 (SOD2) expression post-transcriptionally via ENDOG. Our study gives a new sight into SIRT6 beneficial role in mitochondrial biogenesis of cardiomyocytes. Our data also show that SIRT6 is required to reduce intracellular oxidative stress in the heart triggered by high-fat diet-induced obesity, involving the control of ENDOG/SOD2.

Obesity induced Ext1 reduction mediates the occurrence of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder with intricate etiology. It is closely associated with metabolic syndrome, insulin resistance and endoplasmic reticulum (ER) stress. Exostosin1 (Ext1) is an ER-resident transmembrane glycosyltransferase, which plays an important role in ER homeostasis. Loss-of-function mutations in Ext1 link to hereditary multiple exostosis (HME). The present research was undertaken to identify the effect of Ext1 in the progress of NAFLD. High-fat-diet induced mice obesity, hepatic steatosis and decreased hepatic Ext1 expression. In consistent with evaluation of NAFLD mice possessing down-regulated Ext1 expression, free fatty acid (FFA) treatment blunted Ext1 expression in hepatocytes. In human subjects, HME patients presented elevated fasting blood glucose-one of the criteria that define insulin resistance. In vitro experiments, Ext1 deficiency promoted FFA-induced insulin resistance in hepatocytes by analysis of glycogen storage and hallmarks of gluconeogenesis, ascertaining its association with insulin resistance. Mechanically, Ext1 silencing exacerbated ER stress triggered by FFA, which severely disrupted autophagy in hepatocytes, and thereby accelerated the progression of NAFLD. In conclusion, our study demonstrates a beneficial role for Ext1 during the development of NAFLD, which establishes a novel correlation between Ext1 and ER stress-induced perturbations of autophagy during NAFLD progression.

IL-6 protects cardiomyocytes from oxidative stress at the early stage of LPS-induced sepsis.

Pro-inflammatory cytokines play important roles in sepsis-induced cardiac injury. Among various cytokines, the function of Interleukin-6 (IL-6) in the regulation of cardiomyocyte injury remains to be elucidated. This study aimed to investigate whether IL-6 plays a key role in the sepsis-induced cardiomyocyte injury and the possible mechanism. Mice deficient for Il-6 exhibited impaired heart rhythm after LPS stimulation. Histological analysis revealed significantly increased oxidative stress after LPS stimulation in the heart with Il-6 knockout. On the contrary, IL-6 supplementation alleviated LPS-induced oxidative stress. Mechanically, IL-6 facilitates Nrf2 expression and its nucleus translocation, which subsequently promotes the expression of antioxidant genes and sustains redox homeostasis in cardiomyocytes, and Nrf2 deletion results in elevated oxidative stress during LPS stimulation and cannot be inverted by IL-6 supplement. Our study presents a new sight for the protective role of IL-6 during the pathological development of LPS-induced cardiac injury, which functions as an anti-oxidant molecule via activating Nrf2 signaling.

Metformin alleviates HFD-induced oxidative stress in hepatocyte via activating SIRT6/PGC-1α/ENDOG signaling.

Metformin is accepted as a first-line drug for the therapy of Type 2 diabetes (T2D), while its mechanism is still controversial. In the present study, by taking advantage of mouse model of high-fat-diet (HFD)-induced obesity and primary mouse hepatocytes (PMHCs) as well as human hepatocyte L02 cell line, we aimed to investigate the involvement of SIRTs during the application of metformin for the therapy of T2D. Our data evidenced that during HFD-induced obesity, there was elevation of nucleus protein acetylation. Analysis of liver tissue showed that among all SIRT members, SIRT6 expression was significantly down-regulated during HFD feeding, which was sustained to regular level with metformin administration. Our result also showed that SIRT6 suppressed intracellular oxidative stress upon FAs stimulation in PMHCs and L02 cells. Mechanistically, SIRT6, but not SIRT1 promoted PGC-1α expression. We further prove that ENDOG is downstream of PGC-1α. In addition, we evidenced that ENDOG protects hepatocytes from lipid-induced oxidative stress, and down-regulation of Endog blunted the protective role of metformin in defending against FAs-induced oxidative stress. Our study established a novel mechanism of metformin in counteracting lipid-induced hepatic injury via activating SIRT6/PGC-1α/ENDOG signaling, thus providing novel targets of metformin in the therapy of T2D.

AKT2 regulates development and metabolic homeostasis via AMPK-depedent pathway in skeletal muscle.

Skeletal muscle is responsible for the majority of glucose disposal in the body. Insulin resistance in the skeletal muscle accounts for 85-90% of the impairment of total glucose disposal in patients with type 2 diabetes (T2D). However, the mechanism remains controversial. The present study aims to investigate whether AKT2 deficiency causes deficits in skeletal muscle development and metabolism, we analyzed the expression of molecules related to skeletal muscle development, glucose uptake and metabolism in mice of 3- and 8-months old. We found that AMP-activated protein kinase (AMPK) phosphorylation and myocyte enhancer factor 2 (MEF2) A (MEF2A) expression were down-regulated in AKT2 knockout (KO) mice, which can be inverted by AMPK activation. We also observed reduced mitochondrial DNA (mtDNA) abundance and reduced expression of genes involved in mitochondrial biogenesis in the skeletal muscle of AKT2 KO mice, which was prevented by AMPK activation. Moreover, AKT2 KO mice exhibited impaired AMPK signaling in response to insulin stimulation compared with WT mice. Our study establishes a new and important function of AKT2 in regulating skeletal muscle development and glucose metabolism via AMPK-dependent signaling.

Pillar[5]arene-Based [2]Rotaxane: Synthesis, Characterization, and Application in a Coupling Reaction.

Mechanically interlocked molecules are a class of smart supramolecular species because of their interesting topological structure and application in various areas, such as biology and nanoscience. In this work, we used "multicomponent reaction" to fabricate a new [2]rotaxane based on pillar[5]arene from different small-sized molecules. The molecular structure of the obtained [2]rotaxane R was confirmed by 1H and 13C NMR, high-resolution electrospray ionization mass spectrometry, two-dimensional nuclear Overhauser effect spectroscopy, and density functional theory studies. Interestingly, the [2]rotaxane-based organometallic cross-linked catalyst (Pd@R) was easily constructed via the coordination between triazole groups and Pd(NO3)2. Pd@R proved to be a good catalyst for the Suzuki-Miyaura coupling reaction with excellent stability and repeatability.

IL-6: A Potential Role in Cardiac Metabolic Homeostasis.

Interleukin-6 (IL-6) is implicated in multiple biological functions including immunity, neural development, and haematopoiesis. Recently, mounting evidence indicates that IL-6 plays a key role in metabolism, especially lipid metabolic homeostasis. A working heart requires a high and constant energy input which is largely generated by fatty acid (FA) ß-oxidation. Under pathological conditions, the precise balance between cardiac FA uptake and metabolism is perturbed so that excessive FA is accumulated, thereby predisposing to myocardial dysfunction (cardiac lipotoxicity). In this review, we summarize the current evidence that suggests the involvement of IL-6 in lipid metabolism. Cardiac metabolic features and consequences of myocardial lipotoxicity are also briefly analyzed. Finally, the roles of IL-6 in cardiac FA uptake (i.e., serum lipid profile and myocardial FA transporters) and FA metabolism (namely, ß-oxidation, mitochondrial function, biogenesis, and FA de novo synthesis) are discussed. Overall, understanding how IL-6 transmits signals to affect lipid metabolism in the heart might allow for development of better clinical therapies for obesity-associated cardiac lipotoxicity.

AKT2 deficiency induces retardation of myocyte development through EndoG-MEF2A signaling in mouse heart.

Protein kinase B2 (AKT2) is implicated in diverse process of cardiomyocyte signaling including survival and metabolism. However, the role of AKT2 in myocardium development and the signaling pathway is rarely understood. Therefore, we sought to determine the effect of AKT2 deletion on heart development and its downstream targets. By using experimental animal models and neonatal rat cardiomyocytes (NRCMs), we observed that AKT2 deficiency induces retardation of heart development and increased systemic blood pressure (BP) without affecting cardiac function. Further investigation suggested that deficiency of AKT2 in myocardium results in diminished MEF2A abundance, which induced decreased size of cardiomyocytes. We additionally confirmed that EndoG, which is also regulated by AKT2, is a suppressor of MEF2A in myocardium. Finally, our results proved that AKT2 deficiency impairs the response to ß-adrenergic stimuli that normally causes hypertrophy in cardiomyocytes by downregulating MEF2A expression. Our data are the first to show the important role of AKT2 in determining the size of myocardium, its deficiency causes retardation of cardiomyocyte development. We also proved a novel pathway of heart development involving EndoG and MEF2A regulated by AKT2.

Interleukin-6 deficiency attenuates angiotensin II-induced cardiac pathogenesis with increased myocyte hypertrophy.

Interleukin-6 (IL-6) signaling is critical for cardiomyocyte hypertrophy, while the role of IL-6 in the pathogenesis of myocardium hypertrophy remains controversial. To determine the essential role of IL-6 signaling for the cardiac development during AngII-induced hypertension, and to elucidate the mechanisms, wild-type (WT) and IL-6 knockout (IL-6 KO) mice were infused subcutaneously with either vehicle or AngII (1.5 µg/h/mouse) for 1 week. Immunohistological and serum studies revealed that the extents of cardiac fibrosis, inflammation and apoptosis were reduced in IL-6 KO heart during AngII-stimulation, while cardiac hypertrophy was obviously induced. To investigate the underlying mechanisms, by using myocardial tissue and neonatal cardiomyocytes, we observed that IL-6/STAT3 signaling was activated under the stimulation of AngII both in vivo and in vitro. Further investigation suggested that STAT3 activation enhances the inhibitory effect of EndoG on MEF2A and hampers cardiomyocyte hypertrophy. Our study is the first to show the important role of IL-6 in regulating cardiac pathogenesis via inflammation and apoptosis during AngII-induced hypertension. We also provide a novel link between IL-6/STAT3 and EndoG/MEF2A pathway that affects cardiac hypertrophy during AngII stimulation.

Interleukin-6 deficiency facilitates myocardial dysfunction during high fat diet-induced obesity by promoting lipotoxicity and inflammation.

OBJECTIVE: Obesity is associated with metabolic disorder and chronic inflammation that plays a crucial role in cardiovascular diseases. IL-6 is involved in regulating obesity-related lipid metabolism and inflammation. In this study, we sought to determine the role of IL-6 in high-fat diet (HFD)-induced cardiomyopathy and explore the signaling pathway. METHODS: Female, 5-week-old IL-6 knockout (KO) and littermate mice were fed a normal diet (ND, 10% fat) or HFD (45% fat) for 14 weeks. At the end of treatment, cardiac function was assessed by echocardiography. Adipose tissues and plasma were collected for further measurement. Immunohistology of CD68 was performed to detect inflammation in the heart. Masson's trichrome staining and Oil Red O staining was applied to evaluated cardiac fibrosis and lipid accumulation. Real-time PCR and Western immunoblotting analyses on heart tissue were used to explore the underlying mechanism. RESULTS: IL-6 KO mice displayed increased insulin resistance compared to WT mice at baseline. When fed HFD, IL-6 KO mice showed decreased gains in body weight and fat mass, increased insulin resistance relative to IL-6 KO mice feed ND. Furthermore, IL-6 KO mice developed cardiac dysfunction during HFD-induced obesity. Histological analysis suggested increased lipid accumulation, fibrosis and inflammation without affecting cardiac morphology during HFD treatment in the heart of IL-6 KO mice. Finally, IL-6 deficiency increased the phosphorylation of AMPK and ACC in the heart during HFD-induced obesity. CONCLUSION: Our results suggest that IL-6 contributes to limit lipid metabolic disorder, cardiac hypertrophy, fibrosis, inflammation and myocardium lipotoxicity during HFD-induced obesity.

Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function.

Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.

AKT2 Blocks Nucleus Translocation of Apoptosis-Inducing Factor (AIF) and Endonuclease G (EndoG) While Promoting Caspase Activation during Cardiac Ischemia.

The AKT (protein kinase B, PKB) family has been shown to participate in diverse cellular processes, including apoptosis. Previous studies demonstrated that protein kinase B2 (AKT2-/-) mice heart was sensitized to apoptosis in response to ischemic injury. However, little is known about the mechanism and apoptotic signaling pathway. Here, we show that AKT2 inhibition does not affect the development of cardiomyocytes but increases cell death during cardiomyocyte ischemia. Caspase-dependent apoptosis of both the extrinsic and intrinsic pathway was inactivated in cardiomyocytes with AKT2 inhibition during ischemia, while significant mitochondrial disruption was observed as well as intracytosolic translocation of cytochrome C (Cyto C) together with apoptosis-inducing factor (AIF) and endonuclease G (EndoG), both of which are proven to conduct DNA degradation in a range of cell death stimuli. Therefore, mitochondria-dependent cell death was investigated and the results suggested that AIF and EndoG nucleus translocation causes cardiomyocyte DNA degradation during ischemia when AKT2 is blocked. These data are the first to show a previous unrecognized function and mechanism of AKT2 in regulating cardiomyocyte survival during ischemia by inducing a unique mitochondrial-dependent DNA degradation pathway when it is inhibited.

A pathway involving HDAC5, cFLIP and caspases regulates expression of the splicing regulator polypyrimidine tract binding protein in the heart.

Polypyrimidine tract binding protein (PTB) regulates pre-mRNA splicing, having special relevance for determining gene expression in the differentiating muscle. We have previously shown that PTB protein abundance is progressively reduced during heart development without reduction of its own transcript. Simultaneous reduction of histone deacetylase (HDAC) expression prompted us to investigate the potential link between these events. HDAC5-deficient mice have reduced cardiac PTB protein abundance, and HDAC inhibition in myocytes causes a reduction in endogenous expression of cellular FLICE-like inhibitory protein (cFLIP) and caspase-dependent cleavage of PTB. In agreement with this, cardiac PTB expression is abnormally high in mice with cardiac-specific executioner caspase deficiency, and cFLIP overexpression prevents PTB cleavage in vitro. Caspase-dependent cleavage triggers further fragmentation of PTB, and these fragments accumulate in the presence of proteasome inhibitors. Experimental modification of the above processes in vivo and in vitro results in coherent changes in the alternative splicing of genes encoding tropomyosin-1 (TPM1), tropomyosin-2 (TPM2) and myocyte enhancer factor-2 (MEF2). Thus, we report a pathway connecting HDAC, cFLIP and caspases regulating the progressive disappearance of PTB, which enables the expression of the adult variants of proteins involved in the regulation of contraction and transcription during cardiac muscle development.

The role of cGAS/STING signaling in ophthalmological diseases.

The eye is one of the most vulnerable parts of the human body. There are many kinds of ophthalmic diseases, which are caused by multiple factors. Generally, ophthalmic diseases have the characteristics of complicated etiology and difficult therapy. With the development of the times, ophthalmic diseases have become a major problem that affects people's lives. Inflammation, a major factor inducing ocular diseases, is one of the most popular research directions. The cGAS/STING pathway is a recently discovered inflammatory signaling pathway, which recognizes double-stranded DNA (dsDNA) as an activation signal to promote the expression of downstream cytokines that promote inflammatory response or autoimmune response. Since most of the current treatments for ophthalmic diseases mainly rely on surgery, it is of positive significance to explore the pathogenesis for the discovery of drug targets. This review summarize the research progress of the cGAS/STING pathway in major ophthalmic diseases by introducing the correlation between classical inflammatory pathway and ophthalmic diseases, in order to predict the research direction and methods targeting the cGAS/STING pathway in the pathogenesis of ophthalmic diseases, and also provide guidance for the mechanism as well as molecular targets of ophthalmic diseases.

The role of Keap1-Nrf2 signaling pathway during the progress and therapy of diabetic retinopathy.

Diabetic retinopathy is a complex and progressive ocular complication of diabetes mellitus and is a leading cause of blindness in people of working age worldwide. The pathophysiology of diabetic retinopathy involves multifactorial processes, including oxidative stress, inflammation and vascular abnormalities. Understanding the underlying molecular mechanisms involved in its pathogenesis is essential for the development of effective therapeutic interventions. One of the pathways receiving increasing attention is the Keap1-Nrf2 signaling pathway, which regulates the cellular response to oxidative stress by activating Nrf2. In this review, we analyze the current evidence linking Keap1-Nrf2 signaling pathway dysregulation to diabetic retinopathy. In addition, we explore the potential therapeutic implications and the challenges of targeting this pathway for disease management. A comprehensive understanding of the molecular mechanisms of diabetic retinopathy and the therapeutic potential of the Keap1-Nrf2 pathway may pave the way for innovative and effective interventions to combat this vision-threatening disease.

Cardiac injury activates STING signaling via upregulating SIRT6 in macrophages after myocardial infarction.

AIMS: This work sought to investigate the mechanism underlying the STING signaling pathway during myocardial infarction (MI), and explore the involvement and the role of SIRT6 in the process. MAIN METHODS: Mice underwent the surgery of permanent left anterior descending (LAD) artery constriction. Primary cardiomyocytes (CMs) and fibroblasts were subjected to hypoxia to mimic MI in vitro. STING expression was assessed in the infarct heart, and the effect of STING inhibition on cardiac fibrosis was explored. This study also evaluated the regulatory effect of STING by SIRT6 in macrophages. KEY FINDINGS: STING protein was increased in the infarct heart tissue, highlighting its involvement in the post-MI inflammatory response. Hypoxia-induced death of CMs and fibroblasts contributed to the upregulation of STING in macrophages, establishing the involvement of STING in the intercellular signaling during MI. Inhibition of STING resulted in a significant reduction of cardiac fibrosis at day 14 after MI. Additionally, this study identified SIRT6 as a key regulator of STING via influencing its acetylation and ubiquitination in macrophages, providing novel insights into the posttranscriptional modification and expression of STING at the acute phase after myocardial infarction. SIGNIFICANCE: This work shows the key role of SIRT6/STING signaling in the pathogenesis of cardiac injury after MI, suggesting that targeting this regulatory pathway could be a promising strategy to attenuate cardiac fibrosis after MI.

AKT2 deficiency alleviates doxorubicin-induced cardiac injury via alleviating oxidative stress in cardiomyocytes.

Doxorubicin (DOX), a widely used chemotherapy agent in cancer treatment, encounters limitations in clinical efficacy due to associated cardiotoxicity. This study aims to explore the role of AKT serine/threonine kinase 2 (AKT2) in mitigating DOX-induced oxidative stress within the heart through both intracellular and extracellular signaling pathways. Utilizing Akt2 knockout (KO) and Nrf2 KO murine models, alongside neonatal rat cardiomyocytes (NRCMs), we systematically investigate the impact of AKT2 deficiency on DOX-induced cardiac injury. Our findings reveal that DOX administration induces significant oxidative stress, a primary contributor to cardiac injury. Importantly, Akt2 deficiency exhibits a protective effect by alleviating DOX-induced oxidative stress. Mechanistically, Akt2 deficiency facilitates nuclear translocation of NRF2, thereby suppressing intracellular oxidative stress by promoting the expression of antioxidant genes. Furthermore, We also observed that AKT2 inhibition facilitates superoxide dismutase 2 (SOD2) expression both inside macrophages and SOD2 secretion to the extracellular matrix, which is involved in lowering oxidative stress in cardiomyocytes upon DOX stimulation. The present study underscores the important role of AKT2 in mitigating DOX-induced oxidative stress through both intracellular and extracellular signaling pathways. Additionally, our findings propose promising therapeutic strategies for addressing DOX-induced cardiomyopathy in clinic.

The role of sirtuins in the regulatin of oxidative stress during the progress and therapy of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and impaired glucose homeostasis. Oxidative stress, arising from an imbalance between reactive oxygen species (ROS) production and antioxidant defense systems, plays a significant role in the development and progression of T2DM. The sirtuin family, particularly Sirt1, Sirt3, and Sirt6, have emerged as key regulators of oxidative stress in various cellular processes. This review aims to explore the role of the sirtuin family in oxidative stress during the progression of T2DM and their potential as therapeutic targets. We discussed the mechanisms through which sirtuins modulate oxidative stress, their impact on insulin sensitivity, and beta-cell function involved in T2DM. Furthermore, we highlight drugs targeting sirtuin activation and related complications in T2DM. This review summarizes the role as well as mechanism of sirtuins in the regulation of oxidative stress in T2DM and available drugs targeting sirtuins in clinic, which may provide novel insights into the mechanism and therapy of T2DM.