Mangiferin alleviates cisplatin-induced ototoxicity in sensorineural hearing loss.

Mangiferin(MGF) exhibits crucial biological roles, including antioxidant and anti-inflammatory functions. However, how to clearly elucidate the functioning mechanism of MGF for inhibiting cisplatin-induced hearing loss requires in-depth investigation. In this work, we aimed at gaining insight into how MGF functions as the protective agent against cisplatin-triggered ototoxicity using various assays. The variation for reactive oxygen species (ROS) concentrations was determined with MitoSOX-Red and 2',7'-Dichlorodihydrofluorescein diacetate staining (DCFH-DA). The protective function and corresponding mechanism of MGF in hair cell survival in the House Ear Institute-Organ of Corti (HEI-OC1) cell line were assessed using RNA sequencing (RNA-Seq). Our findings demonstrated that MGF significantly alleviated cisplatin-induced injury to hair cells in vitro, encompassing cell lines and cochlear explants, as well as in vivo models, including C57BL/6 J mice and zebrafish larvae. Mechanistic studies revealed that MGF reversed the increased accumulation of ROS and inhibited cell apoptosis through mitochondrial-mediated intrinsic pathway. Moreover, real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting data indicated MGF protected against cisplatin-mediated ototoxicity via the mitogen-activated protein kinase pathway (MAPK). These findings demonstrated MGF has significant potential promise in combating cisplatin-induced ototoxicity, offering a foundation for expanded investigation into therapeutic approaches for auditory protection.

A risk score for predicting in-stent restenosis in patients with premature acute myocardial infarction undergoing percutaneous coronary intervention with drug-eluting stent.

Background: This study aimed at developing and validating a risk score to predict in-stent restenosis (ISR) in patients with premature acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) with drug-eluting stent (DES). Methods: This was a two-center retrospective study. A total of 2185 patients firstly diagnosed with premature AMI (age ≥18 years and <55 years in men, <65 years in women) from Xinjiang cohort were retrospectively analyzed. After filtering by exclusion criteria, patients were randomly divided into training cohort (n = 434) and internal validation cohort (n = 186) at a 7:3 ratio. Several candidate variables associated with ISR in the training cohort were assessed by the least absolute shrinkage and selection operator and logistic regression analysis. The ISR risk nomogram score based on the superior predictors was finally developed, and then validated in the internal validation cohort and in an independent Chengdu external validation cohort (n = 192). The higher total nomogram score, the greater the ISR risk. Results: The eight variables in the final risk nomogram score, cardiovascular-kidney-metabolic (CKM) score included age, diabetes mellitus (DM), body mass index (BMI), systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDLC), estimated glomerular filtration rate (eGFR), stent in left anterior descending coronary artery, minimum stent diameter <3 mm. The areas under the curve (AUC) and C-statistics [training cohort: 0.834 (95%CI: 0.787 to 0.882); internal validation cohort: 0.852 (95%CI: 0.784 to 0.921); Chengdu external validation cohort: 0.787 (95%CI: 0.692 to 0.882), respectively)] demonstrated the good discrimination of the CKM score. The Hosmer-Lemeshow test (χ2 = 7.86, P = 0.448; χ2 = 5.17, P = 0.740; χ2 = 6.35, P = 0.608, respectively) and the calibration curve confirmed the good calibration of the CKM score. Decision curve analysis (DCA) testified the clinical net benefit of the CKM score in the training and validation cohort. Conclusion: This study provided a well-developed and validated risk nomogram score, the CKM score to predict ISR in patients with premature AMI undergoing PCI with DES. Given that these variables are readily available and practical, the CKM score should be widely adopted for individualized assessment and management of premature AMI.

Adenosine kinase inhibition protects mice from abdominal aortic aneurysm via epigenetic modulation of VSMC inflammation.

AIM: Abdominal aortic aneurysm (AAA) is a common, serious vascular disease with no effective pharmacological treatment. The nucleoside adenosine plays an important role in modulating vascular homeostasis, which prompted us to determine whether adenosine kinase (ADK), an adenosine metabolizing enzyme, modulates AAA formation via control of intracellular adenosine level, and to investigate the underlying mechanisms. METHODS AND RESULTS: We used a combination of genetic and pharmacological approaches in murine models of AAA induced by calcium chloride (CaCl2) application or angiotensin II (Ang II) infusion to study the role of ADK in the development of AAA. In vitro functional assays were performed by knocking down ADK with adenovirus-short hairpin RNA in human vascular smooth muscle cells (VSMCs), and the molecular mechanisms underlying ADK function were investigated using RNA-sequencing, isotope tracing and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). Heterozygous deficiency of Adk protected mice from CaCl2- and Ang II-induced AAA formation. Moreover, specific knockout of Adk in VSMCs prevented Ang II-induced AAA formation, as evidenced by reduced aortic extracellular elastin fragmentation, neovascularization and aortic inflammation. Mechanistically, ADK knockdown in VSMCs markedly suppressed the expression of inflammatory genes associated with AAA formation, and these effects were independent of adenosine receptors. Metabolic flux and ChIP-qPCR results showed that ADK knockdown in VSMCs decreased S-adenosylmethionine (SAM)-dependent transmethylation, thereby reducing H3K4me3 binding to the promoter regions of the genes that are associated with inflammation, angiogenesis and extracellular elastin fragmentation. Furthermore, the ADK inhibitor ABT702 protected mice from CaCl2-induced aortic inflammation, extracellular elastin fragmentation and AAA formation. CONCLUSION: Our findings reveal a novel role for ADK inhibition in attenuating AAA via epigenetic modulation of key inflammatory genes linked to AAA pathogenesis.

Implications of bacteria‒bacteria interactions within the plant microbiota for plant health and productivity. / 植物微生物群落中细菌-细菌互作对植物健康和生产力的影响.

Crop production currently relies on the widespread use of agrochemicals to ensure food security. This practice is considered unsustainable, yet has no viable alternative at present. The plant microbiota can fulfil various functions for its host, some of which could be the basis for developing sustainable protection and fertilization strategies for plants without relying on chemicals. To harness such functions, a detailed understanding of plant‒microbe and microbe‒microbe interactions is necessary. Among interactions within the plant microbiota, those between bacteria are the most common ones; they are not only of ecological importance but also essential for maintaining the health and productivity of the host plants. This review focuses on recent literature in this field and highlights various consequences of bacteria‒bacteria interactions under different agricultural settings. In addition, the molecular and genetic backgrounds of bacteria that facilitate such interactions are emphasized. Representative examples of commonly found bacterial metabolites with bioactive properties, as well as their modes of action, are given. Integrating our understanding of various binary interactions into complex models that encompass the entire microbiota will benefit future developments in agriculture and beyond, which could be further facilitated by artificial intelligence-based technologies.

RIPK3 signaling and its role in regulated cell death and diseases.

Receptor-interacting protein kinase 3 (RIPK3), a member of the receptor-interacting protein kinase (RIPK) family with serine/threonine protein kinase activity, interacts with RIPK1 to generate necrosomes, which trigger caspase-independent programmed necrosis. As a vital component of necrosomes, RIPK3 plays an indispensable role in necroptosis, which is crucial for human life and health. In addition, RIPK3 participates in the pathological process of several infections, aseptic inflammatory diseases, and tumors (including tumor-promoting and -suppressive activities) by regulating autophagy, cell proliferation, and the metabolism and production of chemokines/cytokines. This review summarizes the recent research progress of the regulators of the RIPK3 signaling pathway and discusses the potential role of RIPK3/necroptosis in the aetiopathogenesis of various diseases. An in-depth understanding of the mechanisms and functions of RIPK3 may facilitate the development of novel therapeutic strategies.

Blockade of endothelial adenosine receptor 2 A suppresses atherosclerosis in vivo through inhibiting CREB-ALK5-mediated endothelial to mesenchymal transition.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and morbidity and mortality rates continue to rise. Atherosclerosis constitutes the principal etiology of CVDs. Endothelial injury, inflammation, and dysfunction are the initiating factors of atherosclerosis. Recently, we reported that endothelial adenosine receptor 2 A (ADORA2A), a G protein-coupled receptor (GPCR), plays critical roles in neovascularization disease and cerebrovascular disease. However, the precise role of endothelial ADORA2A in atherosclerosis is still not fully understood. Here, we showed that ADORA2A expression was markedly increased in the aortic endothelium of humans with atherosclerosis or Apoe-/- mice fed a high-cholesterol diet. In vivo studies unraveled that endothelial-specific Adora2a deficiency alleviated endothelial-to-mesenchymal transition (EndMT) and prevented the formation and instability of atherosclerotic plaque in Apoe-/- mice. Moreover, pharmacologic inhibition of ADORA2A with KW6002 recapitulated the anti-atherogenic phenotypes observed in genetically Adora2a-deficient mice. In cultured human aortic endothelial cells (HAECs), siRNA knockdown of ADORA2A or KW6002 inhibition of ADORA2A decreased EndMT, whereas adenoviral overexpression of ADORA2A induced EndMT. Mechanistically, ADORA2A upregulated ALK5 expression via a cAMP/PKA/CREB axis, leading to TGFß-Smad2/3 signaling activation, thereby promoting EndMT. In conclusion, these findings, for the first time, demonstrate that blockade of ADORA2A attenuated atherosclerosis via inhibition of EndMT induced by the CREB1-ALK5 axis. This study discloses a new link between endothelial ADORA2A and EndMT and indicates that inhibiting endothelial ADORA2A could be an effective novel strategy for the prevention and treatment of atherosclerotic CVDs.

Inactivation of adenosine receptor 2A suppresses endothelial-to-mesenchymal transition and inhibits subretinal fibrosis in mice.

Anti-vascular endothelial growth factor therapy has had a substantial impact on the treatment of choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (nAMD), the leading cause of vision loss in older adults. Despite treatment, many patients with nAMD still develop severe and irreversible visual impairment because of the development of subretinal fibrosis. We recently reported the anti-inflammatory and antiangiogenic effects of inhibiting the gene encoding adenosine receptor 2A (Adora2a), which has been implicated in cardiovascular disease. Here, using two mouse models of subretinal fibrosis (mice with laser injury-induced CNV or mice with a deficiency in the very low-density lipoprotein receptor), we found that deletion of Adora2a either globally or specifically in endothelial cells reduced subretinal fibrosis independently of angiogenesis. We showed that Adora2a-dependent endothelial-to-mesenchymal transition contributed to the development of subretinal fibrosis in mice with laser injury-induced CNV. Deficiency of Adora2a in cultured mouse and human choroidal endothelial cells suppressed induction of the endothelial-to-mesenchymal transition. A metabolomics analysis of cultured human choroidal endothelial cells showed that ADORA2A knockdown with an siRNA reversed the increase in succinate because of decreased succinate dehydrogenase B expression under fibrotic conditions. Pharmacological inhibition of ADORA2A with a small-molecule KW6002 in both mouse models recapitulated the reduction in subretinal fibrosis observed in mice with genetic deletion of Adora2a. ADORA2A inhibition may be a therapeutic approach to treat subretinal fibrosis associated with nAMD.

Methane production and lignocellulosic degradation of wastes from rice, corn and sugarcane by natural anaerobic fungi-methanogens co-culture.

Biomass from agriculture, forestry, and urban wastes is a potential renewable organic resource for energy generation. Many investigations have demonstrated that anaerobic fungi and methanogens could be co-cultured to degrade lignocellulose for methane generation. Thus, this study aimed to evaluate the effect of natural anaerobic fungi-methanogens co-culture on the methane production and lignocellulosic degradation of wastes from rice, corn and sugarcane. Hu sheep rumen digesta was used to develop a natural anaerobic fungi-methanogen co-culture. The substrates were rice straw (RS), rich husk (RH), corn stover (CS), corn cobs (CC), and sugarcane baggage (SB). Production of total gas and methane, metabolization rate of reducing sugar, glucose, and xylose, digestibility of hemicellulose and cellulose, activity of carboxymethylcellulase and xylanase, and concentrations of total acid and acetate were highest (P < 0.05) in CC, moderate (P < 0.05) in RS and CS, and lowest (P < 0.05) in SB and RH. The pH, lactate and ethanol were lowest (P < 0.05) in CC, moderate (P < 0.05) in RS and CS, and lowest (P < 0.05) SB and RH. Formate was lowest (P < 0.05) in CC, RS and CS, moderate (P < 0.05) in SB, and lowest (P < 0.05) in RH. Therefore, this study indicated that the potential of methane production and lignocellulosic degradation by natural anaerobic fungi-methanogens co-culture were highest in CC, moderate in RS and CS, and lowest in SB and RH.

Dynamic changes of rumen microbiota and serum metabolome revealed increases in meat quality and growth performances of sheep fed bio-fermented rice straw.

BACKGROUND: Providing high-quality roughage is crucial for improvement of ruminant production because it is an essential component of their feed. Our previous study showed that feeding bio-fermented rice straw (BF) improved the feed intake and weight gain of sheep. However, it remains unclear why feeding BF to sheep increased their feed intake and weight gain. Therefore, the purposes of this research were to investigate how the rumen microbiota and serum metabolome are dynamically changing after feeding BF, as well as how their changes influence the feed intake, digestibility, nutrient transport, meat quality and growth performances of sheep. Twelve growing Hu sheep were allocated into 3 groups: alfalfa hay fed group (AH: positive control), rice straw fed group (RS: negative control) and BF fed group (BF: treatment). Samples of rumen content, blood, rumen epithelium, muscle, feed offered and refusals were collected for the subsequent analysis. RESULTS: Feeding BF changed the microbial community and rumen fermentation, particularly increasing (P < 0.05) relative abundance of Prevotella and propionate production, and decreasing (P < 0.05) enteric methane yield. The histomorphology (height, width, area and thickness) of rumen papillae and gene expression for carbohydrate transport (MCT1), tight junction (claudin-1, claudin-4), and cell proliferation (CDK4, Cyclin A2, Cyclin E1) were improved (P < 0.05) in sheep fed BF. Additionally, serum metabolome was also dynamically changed, which led to up-regulating (P < 0.05) the primary bile acid biosynthesis and biosynthesis of unsaturated fatty acid in sheep fed BF. As a result, the higher (P < 0.05) feed intake, digestibility, growth rate, feed efficiency, meat quality and mono-unsaturated fatty acid concentration in muscle, and the lower (P < 0.05) feed cost per kg of live weight were achieved by feeding BF. CONCLUSIONS: Feeding BF improved the growth performances and meat quality of sheep and reduced their feed cost. Therefore, bio-fermentation of rice straw could be an innovative way for improving ruminant production with minimizing production costs.