Melatonin suppresses ER stress-dependent proapoptotic effects via AMPK in bone mesenchymal stem cells during mitochondrial oxidative damage.

BACKGROUND: Bone marrow mesenchymal stem cells (BMSCs) have been used as important cell-based tools for clinical applications. Oxidative stress-induced apoptosis causes a low survival rate after transplantation, and the underlying mechanisms remain unknown. The endoplasmic reticulum (ER) and mitochondria are vital organelles regulated by adenosine monophosphate (AMP)-activated protein kinase (AMPK), especially during oxidative stress injury. Melatonin exerts an antioxidant effect by scavenging free radicals. Here, we aimed to explore whether cytoprotective melatonin relieves ER stress-mediated mitochondrial dysfunction through AMPK in BMSCs after oxidative stress injury. METHODS: Mouse BMSCs were isolated and exposed to H2O2 in the absence or presence of melatonin. Thereafter, cell damage, oxidative stress levels, mitochondrial function, AMPK activity, ER stress-related proteins, and apoptotic markers were measured. Additionally, the involvement of AMPK and ER stress in the melatonin-mediated protection of BMSCs against H2O2-induced injury was investigated using pharmacologic agonists and inhibitors. RESULTS: Melatonin improved cell survival and restored mitochondrial function. Moreover, melatonin intimately regulated the phosphorylation of AMPK and molecules associated with ER stress pathways. AMPK activation and ER stress inhibition following melatonin administration improved the mitochondrial membrane potential (MMP), reduced mitochondria-initiated oxidative damage, and ultimately suppressed apoptotic signaling pathways in BMSCs. Cotreatment with N-acetyl-L-cysteine (NAC) significantly enhanced the antioxidant effect of melatonin. Importantly, pharmacological AMPK activation/ER stress inhibition promoted melatonin-induced cytoprotection, while pharmacological AMPK inactivation/ER stress induction conferred resistance to the effect of melatonin against H2O2 insult. CONCLUSIONS: Our data also reveal a new, potentially therapeutic mechanism by which melatonin protects BMSCs from oxidative stress-mediated mitochondrial apoptosis, possibly by regulating the AMPK-ER stress pathway.

C1q/tumor necrosis factor-related protein-3-engineered mesenchymal stromal cells attenuate cardiac impairment in mice with myocardial infarction.

Mesenchymal stromal cells (MSCs) transplantation offers an attractive alternative in myocardial infarctive therapy. However, poor cell engraftment and survival limit their restorative capacity. C1q/tumor necrosis factor-related protein-3 (CTRP3) inhibits reverse remodeling after myocardial infarction (MI) and was found to be secreted by MSCs in our preliminary experiments. We examined whether the overexpression of CTRP3 improved the survival of transplanted MSCs and augmented their efficacy on MI and whether silencing CTRP3 attenuated these effects. For gain-of-function analysis, MSCs overexpressing CTRP3 (LvC3-MSCs), control virus-transfected MSCs (LvNull-MSCs), MSCs alone, or phosphate-buffered saline (PBS) were injected into the peripheral areas of the infarction immediately after coronary artery ligation. For loss-of-function analysis, mice subjected to MI were randomized into groups and administered CTRP3-knockdown MSCs (LvshC3-MSCs), Lvshctrl-MSCs, MSCs, or PBS. Survival rates, cardiac function, and myocardial remodeling in mice were evaluated after 4 weeks. Injection of MSCs or LvNull-MSCs improved the left ventricular ejection fraction, inhibited cardiac fibrosis, and regulated cellular profiles of the infarction border zone 4 weeks after MI compared with those in the PBS group. Furthermore, overexpression of hCTRP3 promoted the efficacy of MSCs in the treatment of MI. However, knocking down CTRP3 impaired that. Coculture experiments confirmed that hCTRP3-enriched conditioned medium (CM) promoted MSCs migration and protected against H2O2-induced cell damage. Conversely, CM from C3-/- MSCs (CTRP3 knock out) significantly reduced the migration and antioxidative effects of MSCs. CTRP3 protein alone promoted MSCs proliferation and migration by upregulating matrix metalloproteinase 9 (MMP9) and protecting against oxidation by increasing superoxide dismutase 2 (SOD2) and metallothionein 1/2 (MT1/2) expression; and these effects were blocked by pretreatment with the extracellular signal-regulated kinase (ERK1/2) inhibitor U0126. Overexpression of CTRP3 significantly improved the MSCs-based efficacy on MI by increasing cell survival and retention via a mechanism involving ERK1/2-MMP9 and ERK1/2-SOD2/MT1/2 signaling.

PERK/eIF-2α/CHOP Pathway Dependent ROS Generation Mediates Butein-induced Non-small-cell Lung Cancer Apoptosis and G2/M Phase Arrest.

Butein, a member of the chalcone family, is a potent anticarcinogen against multiple cancers, but its specific anti-NSCLC mechanism remains unknown. The present study examined the effects of butein treatment on NSCLC cell lines and NSCLC xenografts. Butein markedly decreased NSCLC cell viability; inhibited cell adhesion, migration, invasion, and colony forming ability; and induced cell apoptosis and G2/M phase arrest in NSCLC cells. Moreover, butein significantly inhibited PC-9 xenograft growth. Both in vivo and in vitro studies verified that butein exerted anti-NSCLC effect through activating endoplasmic reticulum (ER) stress-dependent reactive oxygen species (ROS) generation. These pro-apoptotic effects were reversed by the use of 4- phenylbutyric acid (4-PBA), CHOP siRNA, N-acetyl-L-cysteine (NAC) and Z-VAD-FMK (z-VAD) in vitro. Moreover, inhibition of ER stress markedly reduced ROS generation. In addition, in vivo studies further confirmed that inhibition of ER stress or oxidative stress partially abolished the butein-induced inhibition of tumor growth. Therefore, butein is a potential therapeutic agent for NSCLC, and its anticarcinogenic action might be mediated by ER stress-dependent ROS generation and the apoptosis pathway.

Berberine ameliorates lipopolysaccharide-induced acute lung injury via the PERK-mediated Nrf2/HO-1 signaling axis.

A fundamental element of acute lung injury (ALI) is the inflammatory response, which can affect the entire respiratory system, including the respiratory tract and alveoli. Berberine has gained attention because of its anti-inflammatory effects. Nuclear factor-erythroid 2-related factor 2 (Nrf2) and endoplasmic reticulum (ER) stress are involved in lung injury. Nrf2 also acts as a protein kinase-like ER kinase (PERK) substrate in heart disease. Therefore, this study investigated the effect of berberine against lipopolysaccharide (LPS)-induced ALI and the role of the PERK-mediated Nrf2/HO-1 signaling axis. Berberine promoted Nrf2 nuclear translocation and phosphorylation in vitro. After LPS stimulation, this effect was further enhanced, whereas inflammatory factor (IL-6 and IL-8) release and reactive oxygen species generation were significantly decreased. Berberine effectively alleviated lung injury by reducing lung edema and neutrophil infiltration. Berberine also significantly reduced histopathological inflammatory changes via inhibition of ER stress and activation of Nrf2 signaling. Thapsigargin-induced ER stress and small interference RNA (siRNA)-mediated Nrf2 inhibition abrogated the protective effects of berberine in vitro, whereas siRNA-mediated suppression of ER stress and sulforaphane-induced Nrf2 activation further improved those effects. Importantly, ER stress induction led to Nrf2 activation, whereas PERK depletion partly reduced the level of Nrf2 phosphorylation and translocation in LPS-induced cells. Therefore, berberine inhibits LPS-induced ALI through the PERK-mediated Nrf2/HO-1 signaling axis.

Icariin protects cardiomyocytes against ischaemia/reperfusion injury by attenuating sirtuin 1-dependent mitochondrial oxidative damage.

BACKGROUND AND PURPOSE: Icariin, a major active ingredient in traditional Chinese medicines, is attracting increasing attention because of its unique pharmacological effects against ischaemic heart disease. The histone deacetylase, sirtuin-1, plays a protective role in ischaemia/reperfusion (I/R) injury, and this study was designed to investigate the protective role of icariin in models of cardiac I/R injury and to elucidate the potential involvement of sirtuin-1. EXPERIMENTAL APPROACH: I/R injury was simulated in vivo (mouse hearts), ex vivo (isolated rat hearts) and in vitro (neonatal rat cardiomyocytes and H9c2 cells). Prior to I/R injury, animals or cells were exposed to icariin, with or without inhibitors of sirtuin-1 (sirtinol and SIRT1 siRNA). KEY RESULTS: In vivo and in vitro, icariin given before I/R significantly improved post-I/R heart contraction and limited the infarct size and leakage of creatine kinase-MB and LDH from the damaged myocardium. Icariin also attenuated I/R-induced mitochondrial oxidative damage, decreasing malondialdehyde content and increasing superoxide dismutase activity and expression of Mn-superoxide dismutase. Icariin significantly improved mitochondrial membrane homeostasis by increasing mitochondrial membrane potential and cytochrome C stabilization, which further inhibited cell apoptosis. Sirtuin-1 was significantly up-regulated in hearts treated with icariin, whereas Ac-FOXO1 was simultaneously down-regulated. Importantly, sirtinol and SIRT1 siRNA either blocked icariin-induced cardioprotection or disrupted icariin-mediated mitochondrial homeostasis. CONCLUSIONS AND IMPLICATIONS: Pretreatment with icariin protected cardiomyocytes from I/R-induced oxidative stress through activation of sirtuin-1 /FOXO1 signalling.

Pterostilbene exerts anticancer activity on non-small-cell lung cancer via activating endoplasmic reticulum stress.

Pterostilbene (PT), the natural dimethylated analog of resveratrol (RSV), is a potent anticarcinogen for non-small-cell lung cancer (NSCLC), but its anti-NSCLC mechanisms remain unclear. In this study, we show that PT treatment time- and dose-dependently enhanced the endoplasmic reticulum stress (ERS) signaling (i.e., p-PERK, IRE1, ATF4, CHOP), thus decreasing the cell viability and inducing apoptosis in human PC9 and A549 NSCLC cell lines. Moreover, the decreased migratory and adhesive abilities, downregulation of intracellular glutathione (GSH) level, enhanced reactive oxygen species (ROS) generation, Caspase 3 activity and mitochondrial membrane depolarization were observed in NSCLC cells treated with PT. These effects were reversed by CHOP siRNA which inhibited the ERS signaling pathway, but were promoted by thapsigargin (a classical ERS inducer) in vitro. Besides, in vivo studies also verify that PT exerted anticancer activity by mobilizing ERS signaling and apoptosis-related proteins, and these effects were enhanced by thapsigargin. Therefore, ERS activation may represent a new mechanism of anti-NSCLC action by PT, and a novel therapeutic intervention for lung cancer.

Molecular insights of Gas6/TAM in cancer development and therapy.

Since growth arrest-specific gene 6 (Gas6) was discovered in 1988, numerous studies have highlighted the role of the Gas6 protein and its receptors Tyro3, Axl and Mer (collectively referred to as TAM), in proliferation, apoptosis, efferocytosis, leukocyte migration, sequestration and platelet aggregation. Gas6 has a critical role in the development of multiple types of cancers, including pancreatic, prostate, oral, ovarian and renal cancers. Acute myelocytic leukaemia (AML) is a Gas6-dependent cancer, and Gas6 expression predicts poor prognosis in AML. Interestingly, Gas6 also has a role in establishing tumour dormancy in the bone marrow microenvironment and in suppressing intestinal tumorigenesis. Numerous studies regarding cancer therapy have targeted Gas6 and TAM receptors with good results. However, some findings have suggested that Gas6 is associated with the development of resistance to cancer therapies. Concerning these significant effects of Gas6 in numerous cancers, we discuss the roles of Gas6 in cancer development in this review. First, we introduce basic knowledge on Gas6 and TAM receptors. Next, we describe and discuss the involvement of Gas6 and TAM receptors in cancers from different organ systems. Finally, we highlight the progress in therapies targeting Gas6 and TAM receptors. This review presents the significant roles of Gas6 in cancers from different systems and may contribute to the continued promotion of Gas6 as a therapeutic target.

Utilizing melatonin to combat bacterial infections and septic injury.

Melatonin, also known as N-acetyl-5-methoxytryptamine, is a ubiquitously acting molecule that is produced by the pineal gland and other organs of animals, including humans. As melatonin and its metabolites are potent antioxidants and free radical scavengers, they are protective against a variety of disorders. Moreover, multiple molecular targets of melatonin have been identified, and its actions are both receptor-mediated and receptor-independent. Recent studies have shown that melatonin may be useful in fighting against sepsis and septic injury due to its antioxidative and anti-inflammatory actions; the results generally indicate a promising therapeutic application for melatonin in the treatment of sepsis. To provide a comprehensive understanding regarding the protective effects of melatonin against septic injury, in the present review we have evaluated the published literature in which melatonin has been used to treat experimental and clinical sepsis. Firstly, we present the evidence from studies that have used melatonin to resist bacterial pathogens. Secondly, we illustrate the protective effect of melatonin against septic injury and discuss the possible mechanisms. Finally, the potential directions for future melatonin research against sepsis are summarized.

Pterostilbene attenuates high glucose-induced oxidative injury in hippocampal neuronal cells by activating nuclear factor erythroid 2-related factor 2.

In the present study, neuroblastoma (SH-SY5Y) cells were used to investigate the mechanisms mediating the potential protective effects of pterostilbene (PTE) against mitochondrial metabolic impairment and oxidative stress induced by hyperglycemia for mimicking the diabetic encephalopathy. High glucose medium (100mM) decreased cellular viability after 24h incubation which was evidenced by: (i) reduced mitochondrial complex I and III activities; (ii) reduced mitochondrial cytochrome C; (iii) increased reactive oxygen species (ROS) generation; (iv) decreased mitochondrial membrane potential (ΔΨm); and (v) increased lactate dehydrogenase (LDH) levels. PTE (2.5, 5, and 10µM for 24h) was nontoxic and induced the nuclear transition of Nrf2. Pretreatment of PTE (2.5, 5, and 10µM for 2h) displayed a dose-dependently neuroprotective effect, as indicated by significantly prevented high glucose-induced loss of cellular viability, generation of ROS, reduced mitochondrial complex I and III activities, reduced mitochondrial cytochrome C, decreased ΔΨm, and increased LDH levels. Moreover, the levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and glutathione S-transferase (GST) were elevated after PTE treatment. In addition, the elevation of nuclear Nrf2 by PTE treatment (10µM for 2h) was abolished by Nrf2 siRNA. Importantly, Nrf2 siRNA induced the opposite changes in mitochondrial complex I and III activities, mitochondrial cytochrome C, reactive species generation, ΔΨm, and LDH. Overall, the present findings were the first to show that pterostilbene attenuated high glucose-induced central nervous system injury in vitro through the activation of Nrf2 signaling, displaying protective effects against mitochondrial dysfunction-derived oxidative stress.

Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1α-SIRT3 signaling.

Enhancing mitochondrial biogenesis and reducing mitochondrial oxidative stress have emerged as crucial therapeutic strategies to ameliorate diabetic myocardial ischemia/reperfusion (MI/R) injury. Melatonin has been reported to be a safe and potent cardioprotective agent. However, its role on mitochondrial biogenesis or reactive oxygen species (ROS) production in type 1 diabetic myocardium and the underlying mechanisms remain unknown. We hypothesize that melatonin ameliorates MI/R injury in type 1 diabetic rats by preserving mitochondrial function via AMPK-PGC-1α-SIRT3 signaling pathway. Both our in vivo and in vitro data showed that melatonin reduced MI/R injury by improving cardiac function, enhancing mitochondrial SOD activity, ATP production and oxidative phosphorylation complex (II, III and IV), reducing myocardial apoptosis and mitochondrial MDA, H2O2 generation. Importantly, melatonin also activated AMPK-PGC-1α-SIRT3 signaling and increased SOD2, NRF1 and TFAM expressions. However, these effects were abolished by Compound C (a specific AMPK signaling blocker) administration. Additionally, our cellular experiment showed that SIRT3 siRNA inhibited the cytoprotective effect of melatonin without affecting p-AMPK/AMPK ratio and PGC-1α expression. Taken together, we concluded that melatonin preserves mitochondrial function by reducing mitochondrial oxidative stress and enhancing its biogenesis, thus ameliorating MI/R injury in type 1 diabetic state. AMPK-PGC1α-SIRT3 axis plays an essential role in this process.

A new flavonoid glycoside (APG) isolated from Clematis tangutica attenuates myocardial ischemia/reperfusion injury via activating PKCε signaling.

Clematis tangutica has been shown to be beneficial for the heart; however, the mechanism of this effectremains unknown. Apigenin-7-O-ß-D-(-6″-p-coumaroyl)-glucopyranoside (APG) is a new flavonoid glycoside isolated from Clematis tangutica. This study investigates the effects of APG on myocardial ischemia/reperfusion (IR) injury (IRI). An IRI model of primary myocardial cells and mice was used in this study. Compared with the IR group, APG preconditioning is protective against IRI in primary myocardial cells and in mice hearts in a dose-dependent manner. The cardioprotective mechanisms of APG may involve a significant PKCε translocation into the mitochondria and an activation of the Nrf2/HO-1 pathway, which respectively suppressesmitochondrial oxidative stress and inhibits apoptosis. In addition, PKCε-targeted siRNA and a PKCε specialized inhibitor (ε-V1-2) were used to inhibit PKCε expression and activity. The inhibition of PKCε reversed the cardioprotective effect of APG, with an inhibition of Nrf2/HO-1 activation and increased mitochondrial oxidative stress and cardiomyocyte apoptosis. In conclusion, PKCε activation plays an important role in the cardioprotective effects of APG. PKCε activation induced by APG preconditioning reduces mitochondrial oxidative stress and promotes Nrf2/HO-1-mediated anti-apoptosis signaling.

Tackling myocardial ischemic injury: the signal transducer and activator of transcription 3 (STAT3) at a good site.

INTRODUCTION: Myocardial ischemia is one of the main causes of cardiac remodeling and heart failure. As a highly evolutionarily conserved pathway, the signal transducer and activator of transcription 3 (STAT3) signaling controls intercellular communication, signaling transduction and gene transcription. Interestingly, STAT3 signaling has been demonstrated to take part in myocardial ischemia. Furthermore, activation of STAT3 signaling contributes to the protective efficacy of various interventions, including pharmacological and non-pharmacological treatment of myocardial ischemic injury. Areas covered: We first introduce the protective mechanisms of STAT3. We then discuss STAT3 signaling in various cells and the roles of STAT3 in myocardial processes during myocardial ischemia. Finally, the roles of STAT3 in myocardial ischemia and the upstream regulators of STAT3 activation are summarized. Expert opinion: In various animal experiments, STAT3 has been demonstrated to take part in myocardial responses to myocardial ischemic injury and to be activated during various modes of protection against myocardial ischemia and ischemia/reperfusion (I/R) injury. However, further clinical evidence on the role of STAT3 in such protection is needed. Treatments targeting STAT3 as a means of reducing myocardial ischemic injury need to be tested in a clinical setting. Furthermore, biotechnology can be used to develop effective drugs for this purpose.

FOXOs in the impaired heart: New therapeutic targets for cardiac diseases.

Cardiac diseases have a high morbidity and mortality and affect the global population. Based on recent accumulating evidence, Forkhead box O (FOXOs) play important roles in cardiac diseases. Therefore, a summary of the current literature on the molecular mechanisms and roles of FOXOs in the heart will provide valuable information. In this review, we first briefly introduce the molecular features of FOXOs. Then, we discuss the regulation and cardiac actions of the FOXO pathways. Based on this background, we expand our discussion to the roles of FOXOs in several major cardiac diseases, such as ischemic cardiac diseases, diabetic cardiomyopathy and myocardial hypertrophy. Then, we describe some methodological problems associated with the FOXO gene-modified animal models. Finally, we discuss potential future directions. The information reviewed here may be significant for the design of future studies and may increase the potential of FOXOs as therapeutic targets.

Nrf2 Weaves an Elaborate Network of Neuroprotection Against Stroke.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a neuroprotective transcription factor that has recently attracted increased attention. Stroke, a common and serious neurological disease, is currently a leading cause of death in the USA so far. It is therefore of vital importance to explore how Nrf2 behaves in stroke. In this review, we first introduce the structural features of Nrf2 and Kelch-like ECH-associated protein 1 (Keap1) and briefly depict the activation, inactivation, and regulation processes of the Nrf2 pathway. Next, we discuss the physiopathological mechanisms, upstream modulators, and downstream targets of the Nrf2 pathway. Following this background, we expand our discussion to the roles of Nrf2 in ischemic and hemorrhagic stroke and provide several potential future directions. The information presented here may be useful in the design of future experimental research and increase the likelihood of using Nrf2 as a therapeutic target for stroke in the future.

Liver X Receptors and their Agonists: Targeting for Cholesterol Homeostasis and Cardiovascular Diseases.

Liver X receptors α (LXRα) and ß (LXRß) are essential for protection against cardiovascular diseases. LXRs are members of the nuclear receptor superfamily of DNA-binding transcription factors and act as sensors of cholesterol homeostasis. In this review, we introduce LXRs and briefly describe the roles of LXRs in reverse cholesterol transport and trans-intestinal cholesterol efflux. We discuss LXR agonists and the downstream genes of LXRs that are involved in the regulation of cholesterol transport. In addition, we describe the cardioprotective effects of LXRs against atherosclerosis, myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, and myocardial hypertrophy. Finally, we expand our discussion to the actions of LXRs in atherosclerosis and suggest several potential research avenues that may be of interest to clinicians and basic scientists. The information included herein may be useful for the design of future experimental research studies and may advance the investigation of LXRs as therapeutic targets.

Melatonin rescues cardiac thioredoxin system during ischemia-reperfusion injury in acute hyperglycemic state by restoring Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner.

Stress hyperglycemia is commonly observed in patients suffering from ischemic heart disease. It not only worsens cardiovascular prognosis but also attenuates the efficacies of various cardioprotective agents. This study aimed to investigate the protective effect of melatonin against myocardial ischemia-reperfusion (MI/R) injury in acute hyperglycemic state with a focus on Notch1/Hes1/Akt signaling and intracellular thioredoxin (Trx) system. Sprague Dawley rats were subjected to MI/R surgery and high-glucose (HG, 500 g/L) infusion (4 mL/kg/h) to induce temporary hyperglycemia. Rats were treated with or without melatonin (10 mg/kg/d) during the operation. Furthermore, HG (33 mmol/L)-incubated H9c2 cardiomyoblasts were treated in the presence or absence of luzindole (a competitive melatonin receptor antagonist), DAPT (a γ-secretase inhibitor), LY294002 (a PI3-kinase/Akt inhibitor), or thioredoxin-interacting protein (Txnip) adenoviral vectors. We found that acute hyperglycemia aggravated MI/R injury by suppressing Notch1/Hes1/Akt signaling and intracellular Trx activity. Melatonin treatment effectively ameliorated MI/R injury by reducing infarct size, myocardial apoptosis, and oxidative stress. Moreover, melatonin also markedly enhanced Notch1/Hes1/Akt signaling and rescued intracellular Trx system by upregulating Notch1, N1ICD, Hes1, and p-Akt expressions, increasing Trx activity, and downregulating Txnip expression. However, these effects were blunted by luzindole, DAPT, or LY294002. Additionally, Txnip overexpression not only decreased Trx activity, but also attenuated the cytoprotective effect of melatonin. We conclude that impaired Notch1 signaling aggravates MI/R injury in acute hyperglycemic state. Melatonin rescues Trx system by reducing Txnip expression via Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner. Its role as a prophylactic/therapeutic drug deserves further clinical study.

An overview of the mechanisms and novel roles of Nrf2 in cardiovascular diseases.

INTRODUCTION: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a basic leucine zipper (bZIP) transcription factor of the cap'n'collar (CNC) family that is present in various organs. The cardiovascular system (CVS) is susceptible to a spectrum of diseases that are strongly associated with increased risks of mortality and morbidity, and studies have demonstrated that Nrf2 has a pivotal role in protection against cardiovascular diseases (CVDs). Areas covered: Nrf2 is a basic protective molecule that guards against CVD by attenuating oxidative stress, mitochondrial dysfunction, and inflammation. Initially, we briefly introduce the biological characteristics of Nrf2 and the newly discovered Neh7 domain. Next, we discuss the concrete roles of Nrf2 in the CVS and enumerate some related upstream molecules and downstream targets. Lastly, we expand our focus to the behaviors of Nrf2 in CVDs and discuss potential research directions. Expert opinion: Although certain studies have cast doubt on the positive actions of Nrf2 in the CVS, Nrf2 is a pivotal endogenous molecule for defense against CVD. The review compiled here may serve as a broad and comprehensive reference for the roles of Nrf2 in the CVS, with the aim of facilitating the design of new drugs and clinical therapies for CVDs.

C1q/TNF-Related Protein 9 Protects Diabetic Rat Heart against Ischemia Reperfusion Injury: Role of Endoplasmic Reticulum Stress.

As a newly identified adiponectin paralog, C1q/TNF-related protein 9 (CTRP9) reduces myocardial ischemia reperfusion (IR) injury through partially understood mechanisms. In the present study, we sought to identify the role of endoplasmic reticulum stress (ERS) in CTRP9 induced cardioprotection in diabetic heart. Isolated hearts from high-fat-diet (HFD) induced type 2 diabetic Sprague-Dawley rats were subjected to ex vivo IR protocol via a Langendorff apparatus at the presence of globular CTRP9. CTRP9 significantly improved post-IR heart function and reduced cardiac infarction, cardiomyocytes apoptosis, Caspase-3, Caspase-9, Caspase-12, TNF-α expression, and lactate dehydrogenase activity. The cardioprotective effect of CTRP9 was associated with reduced ERS and increased expression of disulfide-bond A oxidoreductase-like protein (DsbA-L) in diabetic heart. CTRP9 reduced ERS in thapsigargin (TG) treated cardiomyocytes and protected endoplasmic reticulum (ER) stressed H9c2 cells against simulated ischemia reperfusion (SIR) injury, concurrent with increased expression of DsbA-L. Knockdown of DsbA-L increased ERS and attenuated CTRP9 induced protection against SIR injury in H9c2 cells. Our findings demonstrated for the first time that CTRP9 exerts cardioprotection by reducing ERS in diabetic heart through increasing DsbA-L.

Snapshot: implications for melatonin in endoplasmic reticulum homeostasis.

The endoplasmic reticulum (ER) is an important intracellular membranous organelle. Previous studies have demonstrated that the ER is responsible for protein folding and trafficking, lipid synthesis and the maintenance of calcium homeostasis. Interestingly, the morphology and structure of the ER were recently found to be important. Melatonin is a hormone that anticipates the daily onset of darkness in mammals, and it is well known that melatonin acts as an antioxidant by scavenging free radicals and increasing the activity of antioxidant enzymes in the body. Notably, the existing evidence demonstrates that melatonin is involved in ER homeostasis, particularly in the morphology of the ER, indicating a potential protective role of melatonin. This review discusses the existing knowledge regarding the implications for the involvement of melatonin in ER homeostasis.