Salvia miltiorrhiza suppresses cardiomyocyte ferroptosis after myocardial infarction by activating Nrf2 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Ferroptosis, a recently identified non-apoptotic form of cell death reliant on iron, is distinguished by an escalation in lipid reactive oxygen species (ROS) that are iron-dependent. This phenomenon has a strong correlation with irregularities in iron metabolism and lipid peroxidation. Salvia miltiorrhiza Bunge (DS), a medicinal herb frequently utilized in China, is highly esteemed for its therapeutic effectiveness in enhancing blood circulation and ameliorating blood stasis, particularly during the treatment of cardiovascular diseases (CVDs). Numerous pharmacological studies have identified that DS manifests antioxidative stress effects as well as inhibits lipid peroxidation. However, ambiguity persists regarding the potential of DS to impede ferroptosis in cardiomyocytes and subsequently improve myocardial damage post-myocardial infarction (MI). AIM OF THE STUDY: The present work focused on investigating whether DS could be used to prevent the ferroptosis of cardiomyocytes and improve post-MI myocardial damage. MATERIALS AND METHODS: In vivo experiments: Through ligation of the left anterior descending coronary artery, we constructed both a wild-type (WT) and NF-E2 p45-related factor 2 knockout (Nrf2-/-) mouse model of MI. Effects of DS and ferrostatin-1 (Fer-1) on post-MI cardiomyocyte ferroptosis were examined through detecting ferroptosis and myocardial damage-related indicators as well as Nrf2 signaling-associated protein levels. In vitro experiments: Erastin was used for stimulating H9C2 cardiomyocytes to construct an in vitro ferroptosis cardiomyocyte model. Effects of DS and Fer-1 on cardiomyocyte ferroptosis were determined based on ferroptosis-related indicators and Nrf2 signaling-associated protein levels. Additionally, inhibitor and activator of Nrf2 were used for confirming the impact of Nrf2 signaling on DS's effect on cardiomyocyte ferroptosis. RESULTS: In vivo: In comparison to the model group, DS suppressed ferroptosis in cardiomyocytes post-MI and ameliorated myocardial damage by inducing Nrf2 signaling-related proteins (Nrf2, xCT, GPX4), diminishing tissue ferrous iron and malondialdehyde (MDA) content. Additionally, it enhanced glutathione (GSH) levels and total superoxide dismutase (SOD) activity, effects that are aligned with those of Fer-1. Moreover, the effect of DS on alleviating cardiomyocyte ferroptosis after MI could be partly inhibited through Nrf2 knockdown. In vitro: Compared with the erastin group, DS inhibited cardiomyocyte ferroptosis by promoting the expression of Nrf2 signaling-related proteins, reducing ferrous iron, ROS, and MDA levels, but increasing GSH content and SOD activity, consistent with the effect of Fer-1. Additionally, Nrf2 inhibition increased erastin-mediated ferroptosis of cardiomyocytes through decreasing Nrf2 signaling-related protein expressions. Co-treatment with DS and Nrf2 activator failed to further enhance the anti-ferroptosis effect of DS. CONCLUSION: MI is accompanied by cardiomyocyte ferroptosis, whose underlying mechanism is probably associated with Nrf2 signaling inhibition. DS possibly suppresses ferroptosis of cardiomyocytes and improves myocardial damage after MI through activating Nrf2 signaling.

Ferrostatin-1 suppresses cardiomyocyte ferroptosis after myocardial infarction by activating Nrf2 signaling.

OBJECTIVES: Ferroptosis, a new regulated cell death pathway, plays a crucial part in the development of cardiovascular disease. However, the precise underlying mechanism remains unclear. Therefore, this study aimed to elucidate this. METHODS: Herein, an erastin-induced H9C2 cell ferroptosis in vitro model and a myocardial infarction murine model, which was created by ligating the left anterior descending coronary artery, were established. Ferroptosis-related indicators, myocardial injury-related indicators, and Nrf2 signaling-related proteins expression were analyzed to explore the potential mechanism underlying cardiomyocyte ferroptosis-mediated cardiovascular disease development. RESULTS: We demonstrated that Nrf2 downregulation in myocardial tissue, accompanied by ferroptotic events and changes in xCT and GPX4 expressions, induced cardiomyocyte ferroptosis and myocardial injury after myocardial infarction. These events, including ferroptosis and changes in Nrf2, xCT, and GPX4 expressions, were improved by ferrostatin-1 in vivo and in vitro. Besides, Nrf2 deficiency or inhibition aggravated myocardial infarction-induced cardiomyocyte ferroptosis by decreasing xCT and GPX4 expressions in vivo and in vitro. Moreover, ferrostatin-1 directly targeted Nrf2, as evidenced by surface plasmon resonance analysis. CONCLUSIONS: These results indicated that myocardial infarction is accompanied by cardiomyocyte ferroptosis and that Nrf2 signaling plays a crucial part in regulating cardiomyocyte ferroptosis after myocardial infarction.

Association between polymorphisms in connexin 40 gene (Cx40) and risk of atrial fibrillation: a meta-analysis based on 3,452 subjects.

INTRODUCTION: Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with heart failure and stroke, leading sometimes to death. But the pathogenesis of AF remains unclear. Numerous studies have investigated whether the connexin 40 (Cx40) polymorphisms influences the risk of AF, but the results are controversial. METHODS: We searched English and Chinese databases and calculated the odds ratio (OR) and 95% confidence interval (CI) to examine the existence of genetic associations between the Cx40 polymorphisms and the risk of AF. All relevant studies were screened and meta-analyzed using Review Manager 5.0. RESULTS: A total of 12 studies, including 10 studies for -44 polymorphism (rs35594137) and 4 studies for -26 polymorphism (rs10465885), were identified for the meta-analysis. For -44 polymorphism, the results showed a significantly increased risk of AF in the five genetic models in the overall analysis. Furthermore, in subgroup analysis, increased AF risks were also observed in Asian and non-Asian populations. For -26 polymorphism, the overall OR revealed an increased risk of AF in dominant model. In subgroup analysis, increased AF risk was only found in recessive genetic model of the Asian population. CONCLUSIONS: The Cx40 polymorphisms were positively associated with AF in both populations, especially on -44 polymorphism.

MiR-199a-5p promotes ferroptosis-induced cardiomyocyte death responding to oxygen-glucose deprivation/reperfusion injury via inhibiting Akt/eNOS signaling pathway.

Myocardial ischemia/reperfusion (I/R) injury is associated with the poor outcome and higher mortality after myocardial infarction. Recent studies have revealed that miR-199a-5p participates in the process of myocardial I/R injury, but the precise roles and molecular mechanisms of miR-199a-5p in myocardial I/R injury remain not well-studied. Ferroptosis has been proposed to promote cardiomyocyte death, closely associated with myocardial I/R injury. Herein, the present study aimed to explore the function and mechanisms by which miR-199a-5p regulates whether miR-199a-5p contributes to ferroptosis-induced cardiomyocyte death responding to oxygen-glucose deprivation/reoxygenation (OGD/R) injury, an in vitro model of myocardial I/R injury focusing on Akt/eNOS signaling pathway. The results found that ferroptosis-induced cardiomyocyte death occurs and is accompanied by an increase in miR-199a-5p level in OGD/R-treated H9c2 cells. MiR-199a-5p inhibitor ameliorated ferroptosis-induced cardiomyocyte death as evidenced by the increased cell viability, the reduced reactive oxygen species (ROS) generation, lactate dehydrogenase (LDH) activity, malondialdehyde (MDA) and Fe2+ contents, and the up-regulated glutathione (GSH)/glutathione disulphide (GSSG) ratio as well as glutathione peroxidase 4 (Gpx4) protein expression in H9c2 cells-exposed to OGD/R, while miR-199a-5p mimic had the opposite effects. In addition, OGD/R led to the inhibition of Akt/eNOS signaling pathway, which was also blocked by miR-199a-5p inhibitor and aggravated by miR-199a-5p mimic. Furthermore, LY294002, an inhibitor of Akt/eNOS signaling pathway, abrogated miR-199a-5p inhibitor-induced the reduction of ferroptosis-induced cardiomyocyte death. In summary, our findings demonstrated that miR-199a-5p plays a central role in stimulating ferroptosis-induced cardiomyocyte death during ischemic/hypoxic injury via inhibiting Akt/eNOS signaling pathway.

Clinical Characteristics of Minor Hallucinations in Chinese Parkinson's Disease Patients.

BACKGROUND: Psychotic symptoms are common in Parkinson's disease (PD). However, the clinical characteristics of PD psychosis (PDP) have been rarely reported in Chinese PD patients. We aimed to categorize PDP in a PD cohort and its relationship to other clinical characteristics. METHODS: A total of 149 Chinese PD patients were consecutively enrolled, and idiopathic PD patients were recruited in the study. The symptoms of PDP were assessed with the enhanced Scale for the Assessment of Positive Symptoms in PD. Then, the patients were classified into a PD-control group, isolated minor hallucination (MH) group, and complex MH group, and clinical and demographic data of different groups were compared. RESULTS: Parkinson's disease psychosis was present in 40.3% (60/149) of our patients. The most common PDPs were MHs, present in 32.9% (49 of 149) of the cohort. Compared to patients without MHs, patients with MHs were older, had a longer disease duration, a higher levodopa equivalent daily dose, more severe motor symptoms, dyskinesia, a higher rate of rapid eye movement sleep behavior disorders, frontal lobe function impairments, and a higher percentage of cognitive impairment. Logistic regression analysis showed that advanced Hoehn-Yahr stage [odds ratio (OR): 2.697, p = 0.007)] and frontal lobe function impairment (OR: 0.684, p = 0.003) were independent risk factors for MHs. CONCLUSION: MHs were frequent non-motor symptoms in PD patients. It was associated with increased motor and non-motor symptom burdens and reduced quality of life. MHs have been called "minor," but they have major clinical and prognostic implications and need early screening.

White matter hyperintensities: a marker for apathy in Parkinson's disease without dementia?

OBJECTIVE: The objective of this study was to assess the relationship between white matter hyperintensities (WMH) and the occurrence and progression of apathy in Parkinson's disease (PD). METHODS: We recruited patients with PD who underwent baseline evaluation, which included apathy assessment and magnetic resonance imaging (MRI) head scans. After 2.5 years of follow-up, we re-evaluated patient apathy symptoms. The severity and location of WMH were assessed with fluid-attenuated inversion recovery (FLAIR) sequences using the Fazekas visual rating scale. Logistic regression and linear regression analyses of baseline WMH characteristics were conducted to explore the potential association between apathy and WMH. RESULTS: A total of 141 PD patients were recruited. The apathy group had a higher proportion of male patients, advanced disease, and depression, which was coupled with a lower quality of life. Morever, higher WMH severity was significantly associated with apathy. Logistic regression analyses demonstrated that WMH severity was a risk factor for apathy. In addition, linear regression analysis also suggests that apathy severity is positively correlated with baseline WMH Fazekas scales (ϐ = 0.959, P < 0.001). Baseline WMH severity was also a risk factor for apathy progression. INTERPRETATION: WMH is associated with apathy and could be a promising marker to predict apathy progression in PD.

Distribution of yeast isolates from invasive infections and their in vitro susceptibility to antifungal agents: evidence from 299 cases in a 3-year (2010 to 2012) surveillance study.

Invasive yeast infections cause significant morbidity and mortality. Surveillance for the infection is necessary to detect trends in species distribution and antifungal resistance. We performed this retrospective study of yeast infection at Jinling Hospital, Nanjing in China, from year of 2010 to 2012. A total of 341 yeast isolates were obtained from patients with invasive infections in the period. Among these isolates, Candida spp. comprised of the highest percentage of yeast strains (91.8 %), followed by Cryptococcus neoformans (5.9 %) and other non-Candida yeast strains (2.3 %). Bloodstream isolates made up 41.3 % of yeast strains and the isolates from CVC made up 17.3 %. Among Candida spp., C. albicans was the most common species identified from non-blood clinical specimens (42.9 %), but appeared in only 20.8 % of blood isolates (P < 0.001). C. tropicalis was the most prevalent Candida species in the blood samples (28.5 %). Candida spp. was mainly isolated from specimens of the ICU patients, while C. neoformans was mainly isolated from specimens in medical wards. Resistance to FLC occurred in 3.7 % of C. albicans, 9.9 % of C. tropicalis, 74.0 % of C. glabrata, and 4.4 % of C. parapsilosis. Most (>92 %) isolates of C. albicans, C. tropicalis, C. parapsilosis, and C. neoformans strains were susceptible to VRC; However, 26.7 % of isolates of C. glabrata were VRC resistant.

Control for a synchronization-desynchronization switch.

How to freely enhance or suppress synchronization of networked dynamical systems is of great importance in many disciplines. A unified precise control method for a synchronization-desynchronization switch, called the pull-push control method, is suggested. Namely, synchronization can be achieved when the original systems are desynchronous by pulling (or protecting) one node or a certain subset of nodes, whereas desynchronization can be accomplished when the systems are already synchronous by pushing (or kicking) one node or a certain subset of nodes. With this method, the controlled nodes should be chosen by the generalized eigenvector centrality of the critical synchronization mode of the Laplacian matrix. Compared with existing control methods for synchronization, it displays high efficiency, flexibility, and precision as well.

Four-state rock-paper-scissors games in constrained Newman-Watts networks.

We study the cyclic dominance of three species in two-dimensional constrained Newman-Watts networks with a four-state variant of the rock-paper-scissors game. By limiting the maximal connection distance Rmax in Newman-Watts networks with the long-range connection probability p , we depict more realistically the stochastic interactions among species within ecosystems. When we fix mobility and vary the value of p or Rmax, the Monte Carlo simulations show that the spiral waves grow in size, and the system becomes unstable and biodiversity is lost with increasing p or Rmax. These results are similar to recent results of Reichenbach et al. [Nature (London) 448, 1046 (2007)], in which they increase the mobility only without including long-range interactions. We compared extinctions with or without long-range connections and computed spatial correlation functions and correlation length. We conclude that long-range connections could improve the mobility of species, drastically changing their crossover to extinction and making the system more unstable.