BACKGROUND:Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) regulates the expression of clock gene nuclear receptor subfamily 1 group D member 1 (NR1D1) and is closely related to diabetes mellitus and ischemic heart disease. However, the mechanism by which PGC-1α/NR1D1 increases the vulnerability of diabetic myocardium to ischemia/reperfusion (I/R) injury has yet to be elucidated. This study aimed to explore the roles of PGC-1α/NR1D1-mediated regulation of mitochondrial biogenesis in myocardial I/R injury of type 2 diabetic mice. METHODS:Type 2 diabetes was induced in C57BL/6 mice by a high-fat diet and streptozotocin. Diabetic and nondiabetic mice underwent I/R injury, with subsets receiving the NR1D1 agonist SR9009 or cardiac-specific Nr1d1 knockout. In parallel, rat cardiomyocyte-derived cell line H9c2 cardiomyocytes were exposed to high glucose and high fat and hypoxia/reoxygenation insult, with or without Pgc-1α overexpression by Pgc-1α lentivirus. Cardiac function in mice was assessed using an animal ultrasound system. Myocardial infarction size was determined by 2% 2,3,5-triphenyltetrazolium chloride (TTC) staining. Serum levels of troponin I (cTn-I) and lactate dehydrogenase (LDH) were measured by enzyme-linked immunosorbent assay (ELISA). The expression levels of NR1D1, PGC-1α, nuclear respiratory factor 1 (NRF1), transcription factor A (TFAM), ‌autophagy-related protein 4 homolog B (ATG4B), and microtubule-associated protein 1 light chain 3 (LC3) in mouse myocardial tissue were detected by real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting, and immunofluorescence. Meanwhile, the cell viability, apoptosis rate, mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and mitochondrial morphology of H9c2 cardiomyocyte were evaluated using assay kits. RESULTS:Compared with nondiabetic mice, diabetic mice exhibited larger infarct size, higher serum LDH and cTn-I, and severe ultrastructural damage. Cardiac PGC-1α and NR1D1 expression decreased significantly after I/R, accompanied by reduced NRF1 and TFAM levels and impaired mitochondrial biogenesis. Nr1d1 knockout further worsened injury, shown by increased infarct size and decreased left ventricular ejection fraction (LVEF), whereas SR9009 pretreatment restored PGC-1α expression, activated NRF1/TFAM signaling, and reduced infarct size. In vitro, high glucose and high fat plus hypoxia/reoxygenation increased LDH release and apoptosis while decreasing MMP and elevating ROS. Overexpression of Pgc-1α reversed these effects, improving cell viability and reducing ROS by upregulating NR1D1 and NRF1/TFAM. CONCLUSIONS:These results indicate that disruption of PGC-1α/NR1D1 signaling impairs mitochondrial function, exacerbating diabetic myocardial I/R injury. Pharmacological activation of Nr1d1 or Pgc-1α overexpression alleviates injury by restoring mitochondrial function. Targeting this axis represents a promising strategy for cardioprotection in diabetes.

Neuropathic pain (NP) is a chronic pain condition caused by injury to the nervous system. Although alternative splicing dysregulation has been implicated in NP, the contribution of RNA-binding proteins (RBPs) to this process remains unclear. We analysed 12 RNA-seq datasets (GSE217932) using the SUVA pipeline to identify splicing alterations in Sham, chronic constriction injury (CCI) and CCI treated with L-tetrahydropalmatine (CCI_THP) groups. Co-expression and co-disturbance analyses were performed to define splicing-associated RBP networks. Key findings were further validated in a CCI rat model by behavioural testing, junction-specific RT-qPCR, immunohistochemistry and immunofluorescence. Distinct splicing profiles were observed among the three groups. Differentially spliced genes were enriched in pathways related to axonogenesis, cell junction assembly and synapse assembly. Several genes, including Lrrc4c, Shank2, Nefh, and Grid2, showed aberrant splicing in CCI, which was partially reversed by THP treatment. K-means clustering supported a role for THP in restoring synaptic remodelling-related splicing alterations. In addition, Nefh splicing was associated with Rbm47 and Grn expression, and multiple RBPs, including Rbm47, Grn, Lcp2, Plek, Ptpn6 and Hcls1, were significantly upregulated in CCI. These results were supported by in vivo validation of selected splicing events and protein changes. This study provides a transcriptome-wide view of alternative splicing and RBP dysregulation in NP, and suggests that THP may alleviate neuropathic pain partly by modulating aberrant splicing programs. These findings offer insight into NP mechanisms and identify potential therapeutic targets.

Diabetic cardiomyopathy (DCM) is a major cause of mortality in diabetic patients, with impaired mitophagy contributing its pathogenesis. Sirtuin 3 (SIRT3) and caveolin-3 (Cav-3) are protective proteins involved in mitophagy, although their precise mechanisms remain unclear. This study investigated the interplay between SIRT3, Cav-3, and mitophagy in DCM. We found that the diabetic C57BL/6 mice exhibited impaired cardiac structure and function, accompanied by reduced mitophagy and decreased expression of SIRT3 and Cav-3. Cav-3 KO mice with diabetes showed further worsened cardiac dysfunction and mitophagy impairment without further affecting SIRT3 expression. In cultured H9C2 cardiomyocytes, both SIRT3 siRNA and Cav-3 siRNA exacerbated high glucose (HG)-induced cardiomyocyte damage and reduced mitophagy occurrence. Interestingly, SIRT3 siRNA significantly decreased Cav-3 expression, but vice not. Additionally, Cav-3 overexpression rescued HG-induced cardiomyocyte injury and mitophagy impairment without affecting SIRT3 expression. Collectively, our findings suggest that hyperglycemia-induced SIRT3 suppression contributes to DCM by impairing Cav-3-mediated mitophagy.

Heart failure with preserved ejection fraction (HFpEF) is a major heart failure phenotype in type 2 diabetes mellitus, yet therapies directed at its underlying cardiomyocyte mechanisms remain limited. This review focuses on how diabetic metabolic, inflammatory, and structural stress remodel cardiomyocyte Ca2 + handling. Impaired sarcoplasmic reticulum Ca2+ reuptake, enhanced diastolic Ca2+ leak, reduced sarcolemmal Ca2+ extrusion, and disrupted mitochondrial Ca2+-energy coupling collectively delay Ca2+ clearance and sustain elevated end-diastolic cytosolic Ca2+, thereby contributing to impaired diastolic relaxation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors may improve Na+-Ca2+ coupling by reducing sodium-hydrogen exchanger 1 (NHE1)- and late Na+ current-mediated Na+ overload, whereas metabolic interventions such as ketone supplementation and glucagon-like peptide-1 receptor agonists may support mitochondrial energetics and Ca2+ clearance. More direct approaches, including modulation of Ca2+-handling proteins, ryanodine receptor 2 (RyR2) stabilization, sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) restoration, and repair of T-tubule-associated microdomains, remain largely preclinical or early translational. Advancing this field will require human myocardial validation, biomarkers linked to specific Ca2+ defects, and stratification of patients according to the dominant mechanism of Ca2+ dysregulation.

To evaluate the efficacy and safety of NH600001, a novel etomidate derivative, in gastrointestinal endoscopy, as well as its impact on adrenocortical function, two multicenter, double-blind, randomized, controlled clinical trials(NH600001-21 [Phase II trial] and NH600001-31 [Phase III trial]) were conducted in China. In NH600001-21, 160 gastroscopy subjects were randomized 1:1:1:1 to receive NH600001 (0.20, 0.25, or 0.30 mg/kg) and etomidate (0.30 mg/kg). In NH600001-31, 344 gastroscopy or colonoscopy subjects were randomized in a 1:1 ratio to receive NH600001 (0.25 mg/kg) and etomidate (0.30 mg/kg). The primary efficacy outcome was the rate of endoscopic success. Additionally, Safety and effects on adrenocortical function were also assessed. In NH600001-21, the 0.25 mg/kg NH600001 showed non-inferiority to etomidate based on the prespecified non-inferiority margin of -8% (Rate Difference [95% confidence interval], 5.0[-4.49 to 14.49]), whereas the 0.20 mg/kg and 0.30 mg/kg NH600001 did not meet statistical non-inferiority criteria (0[-11.54 to 11.54]; 0[-11.54 to 11.54]). The area under curve (AUC) of plasma cortisol change values within 0-4 h (∆Cortisol AUC0-4h) were significantly higher in the NH600001 treatment groups than in the etomidate group (P < 0.01). In NH600001-31, NH600001 (0.25 mg/kg) showed non-inferiority to etomidate (1.16[-0.44 to 2.76]). ∆Cortisol AUC0-4h in the NH600001 group, versus the etomidate group, were significantly higher (P < 0.001). Furthermore, NH600001 had a safety profile comparable to etomidate and elicited fewer myoclonus adverse events. In Conclusions, NH600001 has a sedative/anesthetic effect comparable to etomidate while reducing the risk of adrenocortical depression with a favorable safety profile. Chictr.org.cn identifier: ChiCTR2300069841, ChiCTR2400084095. Clinical Trial Number and Registry URL: NH60001-21, Identifier, ChiCTR2300069841 (Changsha, China;, principal investigator: Wen Ouyang, first registration date: March 28, 2023), https://www.chictr.org.cn ; NH60001-31, Identifier, ChiCTR2400084095 (Changsha, China, principal investigator: Wen Ouyang, first registration date: May 10, 2024), https://www.chictr.org.cn .

The perilipin (PLIN) protein family serves as key structural and regulatory proteins on the surface of lipid droplets (LDs), which in turn ensures the storage and mobilization of fatty acids (FAs) in cardiac cells, thereby promoting FAs oxidation and playing a central role in the regulation of cardiomyocytes. Cardiovascular diseases (CVDs) are extremely fatal diseases in today's society, and the prevalence of CVDs increases with age. Its pathophysiology is complex, and the occurrence of CVDs is closely associated with abnormalities in lipid metabolism. Members of the PLIN protein family has been shown to be involved in the cellular function and metabolism-related signaling pathways of various diseases. We primarily review the roles of the PLIN protein family in CVDs and their metabolic mechanisms and propose that targeting PLIN directly or indirectly through pharmacological interventions may influence systemic lipid metabolism, offering a promising therapeutic avenue for improving cardiac function and alleviating metabolically disruptive lipotoxicity.

Diabetes mellitus represents a major global health challenge and is strongly associated with cardiovascular complications, among which diabetic cardiomyopathy (DCM) is a major contributor to heart failure. Increasing evidence indicates that mitochondrial dysfunction plays a central role in DCM pathogenesis. However, mitochondrial abnormalities in the diabetic heart reflect not merely cellular injury but a coordinated process of mitochondrial metabolic reprogramming, characterized by altered substrate utilization, impaired oxidative phosphorylation, and disruption of mitochondrial quality control. Under diabetic conditions, chronic hyperglycemia, insulin resistance, and lipid overload induce profound metabolic remodeling in cardiomyocytes. These disturbances promote excessive reactive oxygen species production, mitochondrial DNA damage, and dysfunction of the electron transport chain. Concurrently, cardiomyocytes undergo a shift in substrate preference, including enhanced glycolysis, dysregulated fatty acid oxidation, and altered amino acid metabolism. Such metabolic inflexibility compromises ATP production and contributes to lipotoxicity, oxidative stress, and cardiomyocyte apoptosis. Recent studies have revealed that mitochondrial metabolic reprogramming is governed by complex regulatory networks, including signaling pathways such as AMPK/PGC-1α, PI3K/Akt/mTOR, hypoxia-inducible factor-1α, and TGF-β/Smad, together with epigenetic mechanisms and mitochondrial quality control processes. Disruption of mitochondrial dynamics, mitophagy, and mitochondrial biogenesis further promotes the accumulation of dysfunctional mitochondria and accelerates disease progression. In this review, we summarize current advances in the mechanisms underlying mitochondrial metabolic reprogramming in diabetic cardiomyopathy and discuss emerging therapeutic strategies targeting mitochondrial metabolism. By integrating mitochondrial biology with cardiovascular metabolism, this review provides a comprehensive framework for understanding DCM pathogenesis and highlights potential directions for precision therapeutic intervention.

Following the publication of the above article, an interested reader drew to the authors' attention that, concerning the Masson trichrome‑stained sections of left ventricles shown in Fig. 6A on p. 395, a portion of the panel representing the DM+EGCG group (centre panel) contained an overlapping area with a portion of the panel from the DM group (second panel on the left), which was representative of the experiment that lacked EGCG treatment. Upon investigating this figure, the authors have realized that the affected data panels were inadvertently assembled incorrectly. This error arose due to an oversight in image selection made during figure assembly. A revised version of Fig. 6, now showing the correct data panel for the DM+EGCG group (centre panel) in Fig. 6A, is shown on the next page. Also note that the published version of Fig. 6A did not feature labels portraying the different experimental groups in this figure part, and these are now included in the revised figure to improve its clarity. The authors confirm that the error associated with this figure did not have any significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this Corrigendum; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 40: 389‑399, 2017; DOI: 10.3892/ijmm.2017.3014].

This study evaluated the association between preoperative cognitive performance and postoperative delirium (POD) using a multicenter prospective cohort, and explored potential causality using Mendelian randomization (MR) analysis. We analyzed data from 2257 patients aged ≥ 75 years undergoing elective noncardiac and noncranial surgeries across 16 Chinese medical centers. Preoperative cognitive assessment using Mini-Cog revealed 28.4% of patients had cognitive impairment (score ≤ 2). POD occurred in 9.7% of patients, with higher incidence among those with cognitive impairment. Logistic regression demonstrated that cognitive impairment was significantly associated with increased POD risk (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.55-2.74; p < 0.001). This association persisted after adjustment for demographic, preoperative, and intraoperative factors, and was confirmed through propensity score matching and inverse probability treatment weighting analyses. A nearly linear inverse association was observed between Mini-Cog scores and POD incidence. Complementary MR analysis using 139 SNPs from European ancestry data suggested that higher cognitive performance might be associated with decreased delirium risk (inverse-variance weighted OR, 0.74; 95% CI, 0.59-0.93; p = 0.009). Although these results point to a potential link between preoperative cognition and POD, interpretation of causality should be approached with caution, particularly given differences in populations and genetic datasets.

Postinduction hypotension (PIH) increases the risk of perioperative adverse events. This study aimed to test if low-dose esketamine could significantly decrease the incidence of PIH in elderly patients undergoing elective noncardiac surgery. This was a post hoc analysis of a randomized clinical trial in university-affiliated academic tertiary hospital. Patients (65 to 85 years, ASA physical status classification II or III) randomly received esketamine (0.2 mg/kg) or normal saline intravenous injection before general anesthesia induction. The primary outcome was the incidence of PIH. The secondary outcomes were the profiles of induction and adverse events during postinduction period. Several different definitions of hypotension and postinduction period were prespecified as the sensitivity analysis. The baseline characteristics were comparable between esketamine group (n = 211) and normal saline group (n = 213). The incidence of PIH was significantly lower in esketamine group than that in normal saline group (44.1 vs. 64.8%, P < 0.01). Esketamine pretreatment significantly decreased the consumption of propofol (P < 0.01) and the rate of vasoconstrictor utilization (P = 0.02). There were no significant differences in the incidence of postinduction adverse events between two groups (all P > 0.05). And, no other severe adverse events were observed. The sensitivity analysis displayed the robustness of the conclusion, though the effect size was lower than 0.2 under certain definition of PIH. A low dose of esketamine treatment before general anesthesia induction for elderly patients undergoing noncardiac surgery could significantly reduce the risk of PIH.Trial registration: www.chictr.org.cn (ChiCTR2100051179); registered 15 September 2021. Date of enrolment of the first participant to the trial: 24 February 2022.

Abstract Pharmacological interventions with the inhaled anesthetic sevoflurane, widely used in cardiac surgery, have been reported to mimic the cardioprotection produced by ischemic conditioning against myocardial ischemia–reperfusion injury. Beneficial effects of sevoflurane conditioning vary with dose, time window and duration and have been reported in a variety of studies involving both laboratory experiments and clinical trials. However, sevoflurane conditioning effects are impaired or lost in subjects with diabetes in both laboratory and clinical settings with mechanisms incompletely understood. This article summarizes the major findings investigating sevoflurane-induced myocardial protection. Our aim is to provide a better understanding of the interrelated but poorly described sevoflurane conditioning signaling pathways. Moreover, this may facilitate the development of more effective therapeutic or preventive strategies for myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion injury (MIRI) significantly affects the prognosis of cardiac surgery patients. The anesthetic dexmedetomidine (Dex) has shown protective effects against ischemia-reperfusion injury in cardiomyocytes; however, its exact mechanism remains unclear. In this study, hypoxia/reoxygenation (H/R) and ischemia/reperfusion (I/R) models were used to investigate the effects of Dex on H9c2 cells and MIRI in mice. The roles of the Sirtuin 1/Forkhead box O3a (Sirt1/FoxO3a) pathway in the protective effects of Dex were explored using the Sirt1 inhibitor EX527 and FoxO3a gene silencing. Results showed that H/R significantly reduced H9c2 cell viability, increased Lactate Dehydrogenase (LDH) leakage, and elevated reactive oxygen species (ROS) production. Dex pretreatment reversed these effects. Additionally, Dex significantly reduced the expression of Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2), cleaved caspase-3, Beclin-1, and microtubule-associated protein 1A/1B-light chain 3B (LC3B), inhibiting apoptosis and autophagy while increasing the expression of p62, Sirt1, and FoxO3a. The protective effects of Dex against H/R injury were abolished by EX527 or FoxO3a silencing. In the mouse MIRI model, Dex pretreatment decreased serum LDH and Creatine Kinase-MB (CK-MB) levels, reduced myocardial infarct size and cardiac injury, and significantly improved left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS). These protective effects were markedly reversed by EX527. These findings indicate that Dex alleviates MIRI by restoring Sirt1 expression and activating FoxO3a.

HSK21542, a peripherally restricted kappa opioid receptor agonist, was evaluated for efficacy and safety in patients with postoperative pain following abdominal surgery. This was assessed in two phase 3, multicentre, randomized, double-blind, controlled trials (HSK21542-301 [ClinicalTrials.gov identifier, NCT04738357] and HSK21542-303 [ClinicalTrials.gov identifier, NCT05390905]) in China. HSK21542-301 was a dual-arm study comparing HSK21542 1.0 μg/kg with placebo, while HSK21542-303 involved three arms comparing HSK21542 1.0 μg/kg with tramadol 50 mg/dose and placebo. All treatments were administered intravenously. The primary endpoint was the time-weighted summed pain intensity differences over 24 h (SPID0-24 h). Both HSK21542-301 (least squares [LS] mean [± standard error], -39.1 [1.88] vs -27.4 [1.89]; P < 0.001) and HSK21542-303 (-64.0 [2.25] vs -45.9 [2.25]; P < 0.001) demonstrated superiority of HSK21542 over placebo in terms of SPID0-24 h, while HSK21542-303 showed non-inferiority to tramadol (LS mean difference, -1.1; 95% confidence interval, -7.4 to 5.1; P < 0.001). Furthermore, HSK21542 had a comparable safety profile to placebo, inducing fewer gastrointestinal adverse events compared with tramadol. Grade ≥3 treatment-emergent adverse events occurred in eight (5.9%) and three (2.3%) patients in the HSK21542 arm of HSK21542-301 and HSK21542-303, respectively. In conclusion, HSK21542 showed potent analgesic effect and was well tolerated in patients who underwent abdominal surgery and experienced postoperative pain.

Mitigating myocardial ischemia-reperfusion (IR) injury is essential for enhancing the success of heart transplantation (HT) and improving patient outcomes. During HT, infiltrating neutrophils are influenced and regulated by various other cell types, contributing to myocardial IR injury through the excessive release of neutrophil extracellular traps (NETs). Nonetheless, the precise mechanisms underlying the interactions between neutrophils and other non-cardiomyocytes remain largely unexplored. Single-cell RNA sequencing is employed to characterize the cellular landscape and to explore the crosstalk between neutrophils and other non-cardiomyocytes. The role of AT-rich interactive domain-containing protein 3A (ARID3A) during HT is further examined using myeloid-specific ARID3A-knockout mice. Molecular docking analyses are conducted to identify the target of 4-octyl itaconate (4-OI). These results reveal that M1 macrophages recruited during the reperfusion of HT promote NETs formation and myocardial IR injury through THBS1/CD47 axis, whereas CD47 induces NETosis by activating the p38 MAPK signaling. Exogenous administration of 4-OI specifically inhibits ARID3A in macrophages, thereby suppressing NETosis and alleviating myocardial IR injury. These findings indicate that THBS1/CD47 signaling is a critical bridge mediating the interaction between M1 macrophages and NETs-associated neutrophils, and identify 4-OI as a promising therapeutic candidate for the treatment of myocardial IR injury following HT.

Neutrophil extracellular traps (NETs) and oxidative stress (OS) may be involved in sepsis-associated acute kidney injury (SA-AKI). The aim of this study was to identify potential regulators which modulate NETs and OS in SA-AKI, and to find potential therapeutic agents. SA-AKI-related datasets GSE255281 and GSE225192 were downloaded from Gene Expression Omnibus. Molecular subtypes associated with NETs were identified by unsupervised clustering. The OS-related genes were obtained by weighted gene co-expression network analysis. Differentially expressed genes were screened by “limma” package in R. Least absolute shrinkage and selection operator algorithm was applied to identify the hub genes. Additionally, the biological functions of the hub genes were analyzed with single sample gene set enrichment analysis. NetworkAnalyst database was searched to screen the drugs targeting the hub targets. qRT-PCR was used to analyze the expression of key genes in the peripheral blood mononuclear cells (PBMCs) of the patients with SA-AKI and healthy controls. HK-2 cells and human umbilical vein endothelial cells (HUVECs) were induced by lipopolysaccharide (LPS) to construct a SA-AKI model, and the effects of estradiol and (+)-JQ1 on HK-2 cells and HUVECs were evaluated by CCK-8 assays, flow cytometry and OS indices. Based on NETs-related genes, SA-AKI samples could be divide into two subgroups, and the differentially expressed genes between two subgroups were associated with OS. In silico analyses identified 13 hub targets. The expression of ECT2 and CHRDL1 in PBMCs of SA-AKI patients was significantly lower than that in control group, and the expressions of PTAFR, CSF3 and FOS were significantly higher. Estradiol and (+)-JQ1, which targeted more of the hub targets with good binding affinity, could increase the viability of HK-2 cells and HUVECs induced by LPS and inhibit apoptosis and OS. Formation of NETs, contributes to OS and pathogenesis of SA-AKI. Estradiol and (+)-JQ1, targeting multiple regulators in the formation of NETs, may be potential therapeutic agents for the treatment of SA-AKI. Not applicable.

The hypermetabolic response associated with burns is characterized by skeletal muscle atrophy and an increased incidence of disability and death. Significant remodeling of the gut microbiota occurs after severe burn trauma. However, the specific mechanisms by which gut microbiota contribute to burn-induced muscle atrophy remain unexplored. The results showed that the disruption of the gut microbiota exacerbated skeletal muscle atrophy. Fecal metabolite analysis revealed perturbations, primarily within the tryptophan (Trp) metabolic pathway. Animal models further demonstrated that gut microbiota disorder enhanced the expression of indoleamine 2,3-dioxygenase 1 (IDO-1) in the colon, ultimately resulting in Trp depletion and increased kynurenine (Kyn) levels in the serum and skeletal muscle. Excessive colonic Kyn is released into circulation, transported into skeletal muscle cells, and binds to the aryl hydrocarbon receptor (AHR), consequently triggering AHR nuclear translocation and initiating the transcription of skeletal muscle atrophy-related genes. Notably, serum samples from patients with burns exhibited Trp depletion, and Trp supplementation alleviated skeletal muscle atrophy in rats with burns. This study, for the first time, demonstrates that gut microbiota dysbiosis upregulates colonic IDO-1, promotes Trp-Kyn metabolism, and exacerbates burn-induced skeletal muscle atrophy, suggesting that Trp supplementation may be a potential therapeutic strategy.

Ischemia/reperfusion (I/R) is an inevitable pathophysiological process during heart transplantation, and ferroptosis is an important pathogenic mechanism. Unlike other modes of cell death, ferroptosis depends on the accumulation of iron within the cell and the oxidative degradation of polyunsaturated fatty acids. Dysregulation of this pathway has been linked to the progression of multiple pathological conditions, making it an attractive target for therapeutic intervention. Therefore, this study aims to explore the effect of ferroptosis on I/R during heart transplantation. GEO2R was applied to identify differentially expressed genes (DEGs) obtained from GSE50884 data, which was involved in I/R and heart transplantation. And ferroptosis-related DEGs (FRDEGs) were screened by venn diagram with ferroptosis-related genes downloaded from FerDb database. FRDEGs was enriched and analyzed by GO and KEGG, and hub genes related to ferroptosis were screened by Cytoscape software and database STRING. Additionally, considering the relationship between ferroptosis and immunity, CIBERSORTx was to analyze the infiltration of 22 kinds of immune cells in I/R during heart transplantation, and the correlation between each immune cell and the expression of FRDEGs was also discussed. Finally, the mouse model of heart transplantation with I/R was constructed, and the hub genes was verified by RT-qPCR and western blot. 12 FRDEGs were identified out of 327 DEGs in GSE50844, which were mainly involved in ferroptosis and other pathways. Three hub genes (SLC7A11, PSAT1, ASNS) were obtained by the degree algorithm of cytohubba plug-in. Immunoinfiltration analysis showed that 16 of 22 immune cells changed, and the immune score of heart transplantation with I/R was higher than that without I/R. In addition, hub genes exhibited significant correlation with Eosinophils, NK cells resting, Dendritic cells resting, NK cells activated and T cells CD4 memory activated. We verified the expression of SLC7A11, PSAT1 and ASNS was higher than that in normal tissues using RT-qPCR and western blot in mouse models of heart transplantation with I/R, companied by ferroptosis aggravated is involved. In short, ferroptosis is involved in I/R injury during heart transplantation, which is related to immune cell infiltration. Three hub genes (SLC7A11, PSAT1 and ASNS) identified in this study provide therapeutic targets for ameliorating I/R injury in heart transplantation.

Myocardial ischemia/reperfusion (I/R) injury is a major global health problem with high rates of mortality and disability, which is more severe in patients with diabetes. Substantial researches have documented that diabetic myocardium are more susceptible to I/R injury, but many current intervention strategies against myocardial I/R injury have limited effectiveness in diabetic hearts. Caveolin-3 (Cav-3) is the signature protein of caveolae and serves as a signal integration and transduction platform in the plasma membrane of cardiomyocytes, which plays a vital role in myocardial functions, metabolism and protection of multiple conditioning strategies against I/R injury. Nevertheless, numerous studies have revealed that the expression of Cav-3 is impaired in diabetic hearts, which contributes to increased vulnerability of myocardium to I/R injury and resistance to protective conditioning strategies. In this review, we outline the basic structure and function of Cav-3, emphatically present the unique role of Cav-3 as a signal integration and transduction element in diabetic myocardial I/R injury and discuss its therapeutic perspective in strategies against myocardial I/R injury in diabetes.

Nano- and microplastics (NMPs) have become a serious global environmental threat that causes damage to mammalian organs. In this work, we investigated the potential molecular mechanism underlying the development of liver fibrosis induced by long-term exposure to three different sized polystyrene (PS)-NMPs (80 nm, 0.5 µm and 5 µm) in mice. Liver fibrosis levels were evaluated in mice after chronic exposure to PS-NMPs. Liver inflammation was mainly increased in chronic exposure to 80 nm and 0.5 µm PS-NMPs. Liver lipid deposition was significantly enhanced after PS-NMPs exposure. However, oxidative stress was not changed under PS-NMPs exposure. GO enrichment and KEGG pathway analyses revealed that the DEGs and shared DEGs were mainly enriched in the metabolism of lipids. The mRNA expression levels of genes related to fatty acid oxidation, synthesis and transport were dramatically induced by PS-NMPs exposure. Four hub genes, Acot3, Abcc3, Nr1i3 and Fmo2, were identified by CytoHubba analysis of shared DEGs. The mRNA expression levels of three hub genes, Acot3, Abcc3 and Nr1i3, were significantly augmented under chronic PS-NMPs exposure. Our results suggest that Acot3, Abcc3 and Nr1i3 are potential molecules involved in the development of liver fibrosis under chronic exposure to PS-NMPs.

Sepsis is a systemic inflammatory response syndrome caused by infection, and sepsis-associated acute kidney injury (AKI) markedly increases mortality. Although aspirin's anti-inflammatory properties show therapeutic promise in sepsis, its specific renal protective effects in septic patients remain underexplored. This study investigated the association between aspirin exposure and severe acute kidney injury in septic patients using two databases: MIMIC-IV (73,181 ICU stays, 2008-2022), and eICU (200,859 ICU stays, 2014-2015). Among 45,562 septic patients, cohorts were stratified by aspirin exposure, and outcome variables were compared using multiple statistical adjustment methods including multivariable regression and propensity score analysis. The primary outcome was severe AKI incidence, with secondary outcomes including overall AKI, continuous renal replacement therapy (CRRT), and mortality. Our study suggests that aspirin exposure was associated with significantly lower severe AKI incidence in both databases (adjusted OR 0.35 in MIMIC-IV; 0.84 in eICU), representing risk reductions ranging from 16% to 65%. Secondary outcomes showed that aspirin exposure was associated with reduced kidney injury incidence, mortality rates and continuous renal replacement therapy requirements. These protective associations were consistent with sensitivity analyses and subgroup analyses. Furthermore, these protective effects were observed across different aspirin doses and formulations. However, aspirin may also increase the risk of thrombocytopenia and gastrointestinal bleeding. Our findings suggest that aspirin may be associated with reduced risk of sepsis-related kidney injury and mortality. Nevertheless, prospective randomized controlled trials are needed to confirm these associations, and individualized risk-benefit assessments remain essential before clinical application.