Pterostilbene protects against H2 O2 -induced oxidative stress by regulating GAS6/Axl signaling in HL-1 cells.

Pterostilbene (PTE, trans-3,5-dimethoxy-4'-hydroxystilbene), a natural plant polyphenol, possesses numerous pharmacological effects, including antioxidant, antidiabetic, antiatherosclerotic, and neuroprotective aspects. This study aims to investigate whether PTE plays a protective role against oxidative stress injury by GAS6/Axl signaling pathway in cardiomyocytes. Hydrogen peroxide (H2 O2 )-induced oxidative stress HL-1 cells were used as models. The mechanism by which PTE protected oxidative stress is investigated by combining cell viability, cell ROS levels, apoptosis assay, molecular docking, quantitative real-time PCR, and western blot analysis. GAS6 shRNA was performed to investigate the involvement of GAS6/Axl pathways in PTE's protective role. The results showed that PTE treatment improved the cell morphology and viability, and inhibited the apoptosis rate and ROS levels in H2 O2 -injured HL-1 cells. Particularly, PTE treatment upregulated the levels of GAS6, Axl, and markers related to oxidative stress, apoptosis, and mitochondrial function related. Molecular docking showed that PTE and GAS6 have good binding ability. Taken together, PTE plays a protective role against oxidative stress injury through inhibiting oxidative stress and apoptosis and improving mitochondrial function. Particularly, GAS6/Axl axis is the surprisingly prominent in the PTE-mediated pleiotropic effects.

Activation of ITLN-1 attenuates oxidative stress injury via activating SIRT1/PGC1-α signaling in neuroblastoma cells.

Cerebral injury is closely associated with enhanced oxidative stress. A newly discovered secretory adipocytokine, intelectin-1 (ITLN-1), has been shown to have beneficial effects in neuroprotection in epidemiological studies. However, the specific molecular mechanism of ITLN-1 in protecting against cerebral oxidative stress needs further investigation. In this study, we hypothesize that ITLN-1 plays a protective role against oxidative stress injury through the SIRT1/PGC1-α signaling pathway in neuromatocytes. We used hydrogen peroxide (H2 O2 ) as a oxidative stress model to simulate oxidative stress injury. Then, small interfering RNAs (siRNAs) was used to knock down SIRT1 in N2a cells with or without ITLN overexpression, followed by H2 O2 -induced injury. We observed that H2 O2 injury significantly decreased the levels of ITLN-1, SIRT1, and PGC-1α. However, ITLN overexpression reversed H2 O2 -induced decline in cell viability and rise in apoptosis and intracellular ROS levels in N2a cells, while ITLN siRNA worsened the neurocyte injury. Furthermore, SIRT1 knockdown reversed the positive effect of ITLN overexpression on oxidative stress injury in N2a cells. Taken together, these findings suggest that ITLN-1 exerts neuroprotective effects against oxidative stress injury primarily through the SIRT1/PGC-1α axis.

Sugar intake and risk of hypertension: a systematic review and dose-response meta-analysis of cohort and cross-sectional studies.

Several epidemiological studies have investigated the association between sugar intake, the levels of systolic blood pressure (SBP) and diastolic blood pressure (DBP) and the risk of hypertension, but findings have been inconsistent. We carried out a systematic review and meta-analysis of observational studies to examine the associations between sugar intake, hypertension risk, and BP levels. Articles published up to February 2, 2021 were sourced through PubMed, EMBASE and Web of Science. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a fixed- or random-effects model. Restricted cubic splines were used to evaluate dose-response associations. Overall, 35 studies were included in the present meta-analysis (23 for hypertension and 12 for BP). Sugar-sweetened beverages (SSBs) and artificially sweetened beverages (ASBs) were positively associated with hypertension risk: 1.26 (95% CI, 1.15-1.37) and 1.10 (1.07-1.13) per 250-g/day increment, respectively. For SBP, only SSBs were significant with a pooled ß value of 0.24 mmHg (95% CI, 0.12-0.36) per 250 g increase. Fructose, sucrose, and added sugar, however, were shown to be associated with elevated DBP with 0.83 mmHg (0.07-1.59), 1.10 mmHg (0.12-2.08), and 5.15 mmHg (0.09-10.21), respectively. Current evidence supports the harmful effects of sugar intake for hypertension and BP level, especially SSBs, ASBs, and total sugar intake.

Protection of melatonin treatment and combination with traditional antibiotics against septic myocardial injury.

BACKGROUND: Heart failure is a common complication of sepsis with a high mortality rate. It has been reported that melatonin can attenuate septic injury due to various properties. On the basis of previous reports, this study will further explore the effects and mechanisms of melatonin pretreatment, posttreatment, and combination with antibiotics in the treatment of sepsis and septic myocardial injury. METHODS AND RESULTS: Our results showed that melatonin pretreatment showed an obvious protective effect on sepsis and septic myocardial injury, which was related to the attenuation of inflammation and oxidative stress, the improvement of mitochondrial function, the regulation of endoplasmic reticulum stress (ERS), and the activation of the AMPK signaling pathway. In particular, AMPK serves as a key effector for melatonin-initiated myocardial benefits. In addition, melatonin posttreatment also had a certain degree of protection, while its effect was not as remarkable as that of pretreatment. The combination of melatonin and classical antibiotics had a slight but limited effect. RNA-seq detection clarified the cardioprotective mechanism of melatonin. CONCLUSION: Altogether, this study provides a theoretical basis for the application strategy and combination of melatonin in septic myocardial injury.

Targeting HMGB1 for the treatment of sepsis and sepsis-induced organ injury.

High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is present in almost all cells and regulates the activity of innate immune responses in both intracellular and extracellular settings. Current evidence suggests that HMGB1 plays a pivotal role in human pathological and pathophysiological processes such as the inflammatory response, immune reactions, cell migration, aging, and cell death. Sepsis is a systemic inflammatory response syndrome (SIRS) that occurs in hosts in response to microbial infections with a proven or suspected infectious etiology and is the leading cause of death in intensive care units worldwide, particularly in the aging population. Dysregulated systemic inflammation is a classic characteristic of sepsis, and suppression of HMGB1 may ameliorate inflammation and improve patient outcomes. Here, we focus on the latest breakthroughs regarding the roles of HMGB1 in sepsis and sepsis-related organ injury, the ways by which HMGB1 are released, and the signaling pathways and therapeutics associated with HMGB1. This review highlights recent advances related to HMGB1: the regulation of HMBG1 might be helpful for both basic research and drug development for the treatment of sepsis and sepsis-related organ injury.

Association between shift work and risk of metabolic syndrome: A systematic review and meta-analysis.

AIMS: A comprehensive assessment of the association of shift work with risk of metabolic syndrome (MetS) through a systematic review and meta-analysis has not been reported. We aimed to evaluate the relationship from observational studies. DATA SYNTHESIS: We searched PubMed, Embase, and Web of Science databases from inception to December 16, 2020. Articles were chosen according to established inclusion criteria. Studies with data on men and women and different types of shift work were treated as independent studies. Relative risks (RRs) and 95% confidence intervals (CIs) were pooled by using random-effects models with heterogeneity (I2) > 50%; otherwise, a fixed-effects model was used. A total of 7192 articles was searched from PubMed, Embase and Web of science. Finally, we included 23 articles (38 studies) in this meta-analysis. The pooled RRs and 95% CI of MetS risk with shift work, 1-shift work, 2-shift work, and 3-shift work versus non-shift work were 1.30 (95% CI 1.19-1.41), 0.95 (95% CI 0.82-1.11), 1.19 (95% CI 0.91-1.56) and 1.17 (95% CI 1.00-1.37), respectively. The results from subgroup analyses stratified by sex, age, and region supported our overall findings that shift work is a risk factor for MetS. CONCLUSIONS: This meta-analysis suggests that shift work increases risk of MetS. Higher risk of MetS was found in the shift workers who were 2-shift or 3-shift or women or Asian workers.

Cardiovascular manifestations in severe and critical patients with COVID-19.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could cause virulent infection leading to Corona Virus Disease 2019 (COVID-19)-related pneumonia as well as multiple organ injuries. HYPOTHESIS: COVID-19 infection may result in cardiovascular manifestations leading to worse clinical outcome. METHODS: Fifty four severe and critical patients with confirmed COVID-19 were enrolled. Risk factors predicting the severity of COVID-19 were analyzed. RESULTS: Of the 54 patients (56.1 ± 13.5 years old, 66.7% male) with COVID-19, 39 were diagnosed as severe and 15 as critical cases. The occurrence of diabetes, the level of D-dimer, inflammatory and cardiac markers in critical cases were significantly higher. Troponin I (TnI) elevation occurred in 42.6% of all the severe and critical patients. Three patients experienced hypotension at admission and were all diagnosed as critical cases consequently. Hypotension was found in one severe case and seven critical cases during hospitalization. Sinus tachycardia is the most common type of arrythmia and was observed in 23 severe patients and all the critical patients. Atrioventricular block and ventricular tachycardia were observed in critical patients at end stage while bradycardia and atrial fibrillation were less common. Mild pericardial effusion was observed in one severe case and five critical cases. Three critical cases suffered new onset of heart failure. Hypotension during treatment, severe myocardial injury and pericardial effusion were independent risk factors predicting the critical status of COVID-19 infection. CONCLUSION: This study has systemically observed the impact of COVID-19 on cardiovascular system, including myocardial injury, blood pressure, arrythmia and cardiac function in severe and critical cases. Monitoring of vital signs and cardiac function of COVID-19 patients and applying potential interventions especially for those with hypotension during treatment, severe myocardial injury or pericardial effusion, is of vital importance.

Inhibition of RAGE by FPS-ZM1 alleviates renal injury in spontaneously hypertensive rats.

The current study was designed to examine the protection of RAGE-specific inhibitor FPS-ZM1 against renal injury in spontaneously hypertensive rats (SHR) and investigate the underlying mechanism. The adult male SHR were treated with FPS-ZM1 via oral gavages for 12 weeks, and age-matched male Wistar-Kyoto rats (WKY) were used as control. Treatment of SHR with FPS-ZM1 slightly reduced blood pressure, and significantly improved baroreflex sensitivity in SHR. Treatment of SHR with FPS-ZM1 improved renal function, evidenced by increased glomerular filtration rate and renal blood flow, and reduced plasma creatinine, blood urea nitrogen and urine albumin excretion rate. Histology results revealed that treatment of SHR with FPS-ZM1 alleviated renal injury and reduced tubulointerstitial fibrosis. Treatment of SHR with FPS-ZM1 suppressed activation of NF-κB and reduced expression of pro-inflammatory cytokines including Tnf, Il6, and Il1b. Treatment of SHR with FPS-ZM1 abated oxidative stress and downregulated mRNA levels of components of NADPH oxidase (Nox) including Cyba, Nox1, Nox2, Nox4 and Ncf1 in kidneys. In addition, treatment of SHR with FPS-ZM1 reduced renal AngII levels, downregulated mRNA expression of Ace and upregulated expression of Agtr2. In conclusion, treatment with FPS-ZM1 alleviated hypertension-related renal dysfunction, possibly by suppressing NF-κB-mediated inflammation, abating Nox-mediated oxidative stress, and improving local renal renin-angiotensin system (RAS).

Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension.

The dysfunction of the renin-angiotensin system (RAS) has been observed in coronavirus infection disease (COVID-19) patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), are associated with clinical outcomes remains unknown. COVID-19 patients with hypertension were enrolled to evaluate the effect of RAS inhibitors. We observed that patients receiving ACEI or ARB therapy had a lower rate of severe diseases and a trend toward a lower level of IL-6 in peripheral blood. In addition, ACEI or ARB therapy increased CD3 and CD8 T cell counts in peripheral blood and decreased the peak viral load compared to other antihypertensive drugs. This evidence supports the benefit of using ACEIs or ARBs to potentially contribute to the improvement of clinical outcomes of COVID-19 patients with hypertension.

Residual flow may increase the risk of adverse events in patients received combined catheter ablation and transcatheter left atrial appendage closure for nonvalvular atrial fibrillation: a meta-analysis.

BACKGROUND: Catheter ablation (CA) and left atrial appendage closure (LAAC) have been combined into a novel one-stop procedure for patients with atrial fibrillation (AF). However, postoperative complications are relatively common in patients undergoing LAAC; the complications, including residual flow, increase in the risk of bleeding, or other adverse events, are unknown in patients receiving one-stop therapy. Therefore, we tried to evaluate the adverse events of CA and LAAC hybrid therapy in patients with nonvalvular AF. METHODS: We performed a meta-analysis and computer-based literature search to identify publications listed in the PubMed, Embase, and Cochrane library databases. Studies were included if patients received CA and LAAC hybrid therapy and reported adverse events. RESULTS: Overall 13 studies involving 952 patients were eligible based on the inclusion criteria. In the periprocedural period, the pooled incidence of pericardial effusion was 3.15%. The rates of bleeding events and residual flow were 5.02 and 9.11%, respectively. During follow-up, the rates of all-cause mortality, embolism events, bleeding events, AF recurrence, and residual flow were 2.15, 5.24, 6.95, 32.89, and 15.35%, respectively. The maximum occurrence probability of residual flow events was 21.87%. Bleeding events were more common in patients with a higher procedural residual flow event rate (P = 0.03). A higher AF recurrence rate indicated higher rates of embolism events (P = 0.04) and residual flow (P = 0.03) during follow-up. CONCLUSIONS: Bleeding events were more common in patients with a higher procedural residual flow event rate. However, combined CA and LAAC therapy is reasonably safe and efficacious in patients with nonvalvular AF. Further studies on the safety and efficacy of CA or LAAC alone are necessary in future.

AMPK-mediated degradation of Nav1.5 through autophagy.

The voltage-gated cardiac sodium channel, Nav1.5, is the key component that controls cardiac excitative electrical impulse and propagation. However, the dynamic alterations of Nav1.5 during cardiac ischemia and reperfusion (I/R) are seldom reported. We found that the protein levels of rat cardiac Nav1.5 were significantly decreased in response to cardiac I/R injury. By simulating I/R injury in cells through activating AMPK by glucose deprivation, AMPK activator treatment, or hypoxia and reoxygenation (H/R), we found that Nav1.5 was down-regulated by AMPK-mediated autophagic degradation. Furthermore, AMPK was found to phosphorylate Nav1.5 at threonine (T) 101, which then regulates the interaction between Nav1.5 and the autophagic adaptor protein, microtubule-associated protein 1 light chain 3 (LC3), by exposing the LC3-interacting region adjacent to T101 in Nav1.5. This study highlights an instrumental role of AMPK in mediating the autophagic degradation of Nav1.5 during cardiac I/R injury.-Liu, X., Chen, Z., Han, Z., Liu, Y., Wu, X., Peng, Y., Di, W., Lan, R., Sun, B., Xu, B., Xu, W. AMPK-mediated degradation of Nav1.5 through autophagy.

Author Correction: Melatonin and mitochondrial function during ischemia/reperfusion injury.

In the original publication, affiliations were incorrectly published for the authors.

PGC-1: The Energetic Regulator in Cardiac Metabolism.

The peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1s (PGC-1s) can induce the expression of several downstream genes that play pivotal roles in the regulation of mitochondrial biogenesis and metabolism in the heart. Moreover, PGC-1 signaling pathways have also been reported to play a critical role in cardioprotection. Given the significance of PGC-1 coactivators, we summarize the current literature on the molecular mechanisms and roles of PGC-1s in cardiac metabolism. Thus, in this review, we first introduce the basic knowledge regarding PGC-1 signaling pathways. We then discuss their roles in heart metabolism. Moreover, we describe several significant treatments that target the PGC-1 signaling pathway. This review presents the significant roles of PGC-1s in cardiac metabolism and may contribute to the promotion of PGC-1 signaling pathway as a novel therapeutic target.

FOXO1: Another avenue for treating digestive malignancy?

Digestive malignancies are the leading cause of mortality among all neoplasms, contributing to estimated 3 million deaths in 2012 worldwide. The mortality rate hassurpassed lung cancer and prostate cancer in recent years. The transcription factor Forkhead Box O1 (FOXO1) is a key member of Forkhead Box family, regulating diverse cellular functions during tumor initiation, progression and metastasis. In this review, we focus on recent studies investigating the antineoplastic role of FOXO1 in digestive malignancy. This review aims to serve as a guide for further research and implicate FOXO1 as a potent therapeutic target in digestive malignancy.

Melatonin: does it have utility in the treatment of haematological neoplasms?

Melatonin, discovered in 1958 in the bovine pineal tissue, is an indoleamine that modulates circadian rhythms and has a wide variety of other functions. Haematological neoplasms are the leading cause of death in children and adolescents throughout the world. Research has demonstrated that melatonin is a low-toxicity protective molecule against experimental haematological neoplasms, but the mechanisms remain poorly defined. Here, we provide an introduction to haematological neoplasms and melatonin, especially as they relate to the actions of melatonin on haematological carcinogenesis. Secondly, we summarize what is known about the mechanisms of action of melatonin in the haematological system, including its pro-apoptotic, pro-oxidative, anti-proliferative and immunomodulatory actions. Thirdly, we discuss the advantages of melatonin in combination with other drugs against haematological malignancy, as well as its other benefits on the haematological system. Finally, we summarize the findings that are contrary to the suppressive effects of melatonin on cancers of haematological origin. We hope that this information will be helpful in the design of studies related to the therapeutic efficacy of melatonin in haematological neoplasms. LINKED ARTICLES: This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc.

Melatonin protects diabetic heart against ischemia-reperfusion injury, role of membrane receptor-dependent cGMP-PKG activation.

It has been demonstrated that the anti-oxidative and cardioprotective effects of melatonin are, at least in part, mediated by its membrane receptors. However, the direct downstream signaling remains unknown. We previously found that melatonin ameliorated myocardial ischemia-reperfusion (MI/R) injury in diabetic animals, although the underlying mechanisms are also incompletely understood. This study was designed to determine the role of melatonin membrane receptors in melatonin's cardioprotective actions against diabetic MI/R injury with a focus on cGMP and its downstream effector PKG. Streptozotocin-induced diabetic Sprague-Dawley rats and high-glucose medium-incubated H9c2 cardiomyoblasts were utilized to determine the effects of melatonin against MI/R injury. Melatonin treatment preserved cardiac function and reduced oxidative damage and apoptosis. Additionally, melatonin increased intracellular cGMP level, PKGIα expression, p-VASP/VASP ratio and further modulated myocardial Nrf-2-HO-1 and MAPK signaling. However, these effects were blunted by KT5823 (a selective inhibitor of PKG) or PKGIα siRNA except that intracellular cGMP level did not changed significantly. Additionally, our in vitro study showed that luzindole (a nonselective melatonin membrane receptor antagonist) or 4P-PDOT (a selective MT2 receptor antagonist) not only blocked the cytoprotective effect of melatonin, but also attenuated the stimulatory effect of melatonin on cGMP-PKGIα signaling and its modulatory effect on Nrf-2-HO-1 and MAPK signaling. This study showed that melatonin ameliorated diabetic MI/R injury by modulating Nrf-2-HO-1 and MAPK signaling, thus reducing myocardial apoptosis and oxidative stress and preserving cardiac function. Importantly, melatonin membrane receptors (especially MT2 receptor)-dependent cGMP-PKGIα signaling played a critical role in this process.

SIRT6 protects against hepatic ischemia/reperfusion injury by inhibiting apoptosis and autophagy related cell death.

Silent information regulator 6 (SIRT6), a class III histone deacetylase, has been revealed to participate in multiple metabolic processes in the liver, and it plays important roles in protecting against ischemia/reperfusion (I/R) injury in multiple organs. In this study, we explored whether SIRT6 is protective against hepatic I/R injury and elucidated the underlying mechanisms. The expression of SIRT6 was significantly decreased during reperfusion compared with the control group. SIRT6-LKO mice exhibited significantly aggravated oxidative stress, mitochondrial dysfunction, inflammatory responses, mitogen-activated protein kinase (MAPK) signaling activation, and apoptosis and autophagy related hepatocyte death compared with control mice. In vitro studies in SIRT6-KO hepatocytes exhibited similar results. In contrast, SIRT6 upregulation alleviated liver damage during hepatic I/R injury. Our study demonstrated for the first time that SIRT6 upregulation effectively protects against hepatic I/R injury. The underlying mechanisms involve the maintenance of oxidative homeostasis and mitochondrial function, which subsequently inhibit the inflammatory responses and MAPK signaling, and finally attenuate apoptosis and autophagy related hepatocyte death. These results suggest that the activation of SIRT6 exerts multifaceted protective effects during hepatic I/R injury, which can provide a novel therapeutic target for hepatic I/R injury.

Diallyl trisulfide exerts cardioprotection against myocardial ischemia-reperfusion injury in diabetic state, role of AMPK-mediated AKT/GSK-3ß/HIF-1α activation.

Diallyl trisulfide (DATS), the major active ingredient in garlic, has been reported to confer cardioprotective effects. However, its effect on myocardial ischemia-reperfusion (MI/R) injury in diabetic state and the underlying mechanism are still unknown. We hypothesize that DATS reduces MI/R injury in diabetic state via AMPK-mediated AKT/GSK-3ß/HIF-1α activation. Streptozotocin-induced diabetic rats received MI/R surgery with or without DATS (20mg/kg) treatment in the presence or absence of Compound C (Com.C, an AMPK inhibitor, 0.25mg/kg) or LY294002 (a PI3K inhibitor, 5mg/kg). We found that DATS significantly improved heart function and reduced myocardial apoptosis. Additionally, in cultured H9c2 cells, DATS (10µM) also attenuated simulated ischemia-reperfusion injury. We found that AMPK and AKT/GSK-3ß/HIF-1α signaling were down-regulated under diabetic condition, while DATS markedly increased the phosphorylation of AMPK, ACC, AKT and GSK-3ß as well as HIF-1α expression in MI/R-injured myocardium. However, these protective actions were all blunted by Com.C administration. Additionally, LY294002 abolished the stimulatory effect of DATS on AKT/GSK-3ß/HIF-1α signaling without affecting AMPK signaling. While 2-methoxyestradiol (a HIF-1α inhibitor) reduced HIF-1α expression without affecting AKT/GSK-3ß signaling. Taken together, these data showed that DATS protected against MI/R injury in diabetic state by attenuating cellular apoptosis via AMPK-mediated AKT/GSK-3ß/HIF-1α signaling. Its cardioprotective effect deserves further study.

AMPK: a novel target for treating hepatic fibrosis.

Fibrosis is a common process of excessive extracellular matrix (ECM) accumulation following inflammatory injury. Fibrosis is involved in the pathogenesis of almost all liver diseases for which there is no effective treatment. 5'-AMP-activated protein kinase (AMPK) is a cellular energy sensor that can ameliorate the process of hepatic fibrogenesis. Given the existing evidence, we first introduce the basic background of AMPK and hepatic fibrosis and the actions of AMPK in hepatic fibrosis. Second, we discuss the three phases of hepatic fibrosis and potential drugs that target AMPK. Third, we analyze possible anti-fibrosis mechanisms and other benefits of AMPK on the liver. Finally, we summarize and briefly explain the current objections to targeting AMPK. This review may aid clinical and basic research on AMPK, which may be a novel drug candidate for hepatic fibrosis.

Melatonin and mitochondrial function during ischemia/reperfusion injury.

Ischemia/reperfusion (IR) injury occurs in many organs and tissues, and contributes to morbidity and mortality worldwide. Melatonin, an endogenously produced indolamine, provides a strong defense against IR injury. Mitochondrion, an organelle for ATP production and a decider for cell fate, has been validated to be a crucial target for melatonin to exert its protection against IR injury. In this review, we first clarify the mechanisms underlying mitochondrial dysfunction during IR and melatonin's protection of mitochondria under this condition. Thereafter, special focus is placed on the protective actions of melatonin against IR injury in brain, heart, liver, and others. Finally, we explore several potential future directions of research in this area. Collectively, the information compiled here will serve as a comprehensive reference for the actions of melatonin in IR injury identified to date and will hopefully aid in the design of future research and increase the potential of melatonin as a therapeutic agent.