Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. Kaempferol shows potential in suppressing HCC progression via glycolysis regulation, yet its molecular targets and mechanisms are unclear. Transcriptomic data were analyzed to identify HCC-related DEGs. Intersection with kaempferol's glycolysis-related targets yielded candidate genes. A prognostic risk model was constructed and validated by ROC curves and survival analysis. GSEA and single-cell RNA sequencing explored mechanisms and cellular heterogeneity. Mendelian randomization assessed causality between prognostic genes and HCC. After HCC cells were treated with different concentrations of kaempferol, the effects of kaempferol on proliferation, invasion, and migration of HCC cells were detected by CCK-8, cell clone formation, and Transwell cell scratch healing experiments. The expression levels of key proteins in the AKT-mTOR signaling pathway and glycolytic rate-limiting enzymes were detected by Western blot. The spectrophotometric method was used to detect the effect of kaempferol on glucose uptake and lactate production of HCC cells. Finally, the impact of knocking down CA9 on glucose uptake and lactic acid production in liver cancer cells was analyzed. The prognostic risk model identified GRK6, ABCC1, CA9, and CDK5R1 as prognostic genes. GSEA implicated cell cycle and PI3K-Akt pathways in HCC progression driven by these genes. Single-cell analysis revealed pronounced upregulation of prognostic genes in hepatocytes. Finally, MR analysis confirmed that CDK5R1 was a risk factor for the incidence of HCC. Kaempferol significantly inhibited the proliferation, invasion, and migration of MHCC97H and Huh7 cells, as well as the expression levels of PKM2, HK2, p-AKT, p-mTOR, and p-RPS6. Kaempferol significantly reduced glucose uptake and lactic acid production in MHCC97H and Huh7 cells. Knockdown of CA9 inhibited the uptake of glucose and lactic acid production, along with suppressing the expression of HK2 and PKM2 in MHCC97H and Huh7 cells. This study found that kaempferol targeted the AKT-mTOR pathway and downregulated the CA9 gene, thereby modulating glycolysis and ultimately suppressing the proliferation, invasion, and migration of hepatocellular carcinoma.

Objective To explore the inhibitory effects of mulberry leaf flavonoid extract (MFE) on high glucose-induced diabetic encephalopathy (DE) in a cell model, and to investigate the underlying mechanisms combined with network pharmacology prediction and experimental validation. Methods A DE cell model was established by chronic high glucose stimulation of HT22 mouse hippocampal neuronal cells. Following intervention with MFE, cell viability, advanced glycation end products (AGEs) content, and ferroptosis-related indices were detected. Network pharmacology was used to screen potential signaling pathways and key targets of MFE, while Western blotting validated the expression of proteins related to the screened pathways and targets. Results Network pharmacology screening identified Akt1, ALB, TNF, IL-1B, and IL-6 as the top-ranked targets. Molecular docking confirmed stable binding between major MFE components and these potential targets. MFE treatment markedly upregulated ferritin heavy chain (FTH) and ferroportin (FPN) levels while decreasing transferrin receptor (TFRC) levels, attenuating iron overload in DE cells. It also suppressed AGEs accumulation, which activated the downstream PI3K/Akt/Nrf2/SLC7A11/GPX4 ferroptosis regulatory pathway to mitigate oxidative stress and inhibit ferroptosis. Additionally, MFE activated Akt, leading to p38 MAPK deactivation, reduced Bax/Bcl-2 ratio, and decreased Caspase-3 levels, blocking the apoptosis pathway. It alleviated inflammatory injury by suppressing the p38 MAPK/NF-κB pathway, thereby reducing TNF-α, IL-1β, and IL-6 protein levels. Conclusion MFE inhibits ferroptosis by upregulating the PI3K/Akt/Nrf2/GPX4 signaling pathway. This study provides valuable insights into the therapeutic application of MFE for DE.

Recent studies have indicated that Lactococcus petauri LZys1 (L. petauri LZys1), isolated from healthy human feces, exhibits a promising probiotic profile in vitro. However, its impact on the physiological status of the host in vivo remains uncertain. The objective of our study was to investigate the effects and mechanisms of orally administering L. petauri LZys1 on gut microbiota and liver function in mice. We administered L. petauri LZys1 through daily oral gavage to C57BL/6 male mice. Subsequently, we analyzed changes in gut microbiota composition using 16S rRNA sequencing and quantified alterations in hepatic-intestinal bile acid (BA) profile. Serum biochemical parameters were assessed to evaluate liver function. Our findings revealed that L. petauri LZys1 led to an increase in body weight, liver mass, and serum aminotransferase levels. Oral administration altered the gut microbiota composition, resulting in reduced diversity and abundance of intestinal bacteria. Additionally, the profiles of BAs were suppressed across organs, associated with the downregulation of the ileum's farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF15) signaling pathway. The decrease in circulating FGF15 mediated the downregulation of hepatic fibroblast growth factor receptor 4 (FGFR4)/FXR, disrupting BA metabolism and fatty acid oxidation. Our findings suggest that L. petauri LZys1 may impact liver function by influencing the gut microbiota-mediated ileal FXR-FGF15 axis and inhibiting hepatic bile acid metabolism. IMPORTANCE:This work elucidated the impact of L. petauri LZys1 on host gut microbiota metabolism and hepatic physiological metabolism. We observed that L. petauri LZys1 administration induced liver weight gain and biochemical parameters changes, in addition to a altered gut microbiota and suppressed bile acid (BA) profiles. Furthermore, we propose that changes in liver status are related to the enterohepatic farnesoid X receptor-fibroblast growth factor axis, which alters bile acid metabolism and disrupts liver function. The above findings suggest that attention should be paid to the effect of probiotics on liver function.

Aging-related frailty increases the risk of falls, disability, and mortality. Frailty is linked to abnormalities in whole-body metabolism. However, the causal relationship between circulating metabolic traits and frailty remains unclear. This study aims to clarify the causal effects of circulating metabolites on frailty. We used bidirectional two sample and multivariable Mendelian Randomization (MVMR) methods to assess associations between circulating metabolites and the Frailty Index (FI). Genetic data on relevant single-nucleotide polymorphisms (SNPs) were obtained from publicly available genome-wide association studies (GWAS). Five MR methods were employed: Inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods were used for Mendelian Randomization (MR) analysis. MVMR analyses examined the effects of selected circulating metabolites (identified via multivariate LASSO regression), obesity, alcohol consumption, and sleep disorders on FI. Preliminary analyses identified 12 circulating metabolites as potential frailty risk factors, while secondary analyses revealed 25 circulating metabolites. Notably, MVMR established a causal relationship between free cholesterol in large low-density lipoprotein (LDL) and frailty. This study establishes a causal link between free cholesterol in large LDL and frailty risk based on genetic evidence, potentially guiding targeted prevention strategies.

Phenyllactic acid (PLA) is a natural antibiotic-like compound derived from certain foods and probiotics. PLA levels have been associated with age-related sarcopenia and provide benefits to metabolic health when derived from probiotics. However, the specific regulatory effects of PLA in aging remain largely unexplored. In this study, aging mice were administered PLA via gavage, followed by fecal 16S rRNA sequencing, measurements of targeted metabolites, glucose metabolism monitoring, and physical performance assessments. Our results indicate that PLA administration significantly altered gut microbiota composition, increased the abundance of short-chain fatty acids (SCFAs) and succinate producing microbiota, and enhanced gut integrity in aging mice. Furthermore, PLA treatment raised fasting blood glucose levels and improved physical activity. Mechanistically, PLA intake elevated the levels of circulating SCFAs and succinate, promoting glycogen metabolic homeostasis and maintaining skeletal muscle oxidative capacity. This study provides evidence that PLA modulates the gut microbiota in aging mice, supports intestinal health, promotes glucose homeostasis, and enhances physical activity.

BACKGROUND:Aging-related energy homeostasis significantly affects normal heart function and disease development. The relationship between the gut microbiota and host energy metabolism has been well established. However, the influence of an aged microbiota on energy metabolism in the heart remains unclear. OBJECTIVE:The objective of this was to explore the effects of age-related microbiota composition on energy metabolism in the heart. METHODS:In this study, we used the fecal microbiota transplantation (FMT) method. The fecal microbiota from young (2-3 mo) and aged (18-22 mo) donor mice were transplanted into separate groups of young (2-3 mo) recipient mice. The analysis utilized whole 16S rRNA sequencing and plasma metabolomics to assess changes in the gut microbiota composition and metabolic potential. Energy changes were monitored by performing an oral glucose tolerance test, biochemical testing, body composition analysis, and metabolic cage measurements. Metabolic markers and markers of DNA damage were assessed in heart samples. RESULTS:FMT of an aged microbiota changed the composition of the recipient's gut microbiota, leading to an elevated Firmicutes-to-Bacteroidetes ratio. It also affected overall energy metabolism, resulting in elevated plasma glucose concentrations, impaired glucose tolerance, and epididymal fat accumulation. Notably, FMT of an aged microbiota increased the heart weight and promoted cardiac hypertrophy. Furthermore, there were significant associations between heart weight and cardiac hypertrophy indicators, epididymal fat weight, and fasting glucose concentrations. Mechanistically, FMT of an aged microbiota modulated the glucose metabolic pathway and induced myocardial oxidative damage. CONCLUSIONS:Our findings suggested that an aged microbiota can modulate metabolism and induce cardiac injury. This highlights the possible role of the gut microbiota in age-related metabolic disorders and cardiac dysfunction.

The dysbiosis of gut microbiota with aging has been extensively studied, revealing its substantial contribution to variety of diseases. However, the impact of aged microbiota in heart failure (HF) remains unclear. In this study, we employed the method of fecal microbiota transplantation (FMT) from aged donors to investigate its role in the context of HF. Our results demonstrate that FMT from aged donors alters the recipient's gut microbiota composition and abundance. Furthermore, FMT impairs cardiac function and physical activity in HF mice. Aged FMT induces metabolic alterations, leading to body weight gain, impaired glucose tolerance, increased respiratory exchange ratio (RER), and enhanced fat accumulation. The epicardium of aged FMT recipients shows fat accumulation, accompanied by cardiomyocyte hypertrophy, cardiac fibrosis and increased cellular apoptosis. Mechanistically, aged FMT suppresses the PPARα/PGC1α signaling pathway in HF. Notably, activation of PPARα effectively rescues the metabolic changes and myocardial injury caused by aged FMT. In conclusion, our study emphasizes the role of the PPARα/PGC1α signaling pathway in aged FMT-mediated HF.

The gut microbiota is closely related to aging, but the genetic relationship between gut microbiota and aging has not been well investigated. The aim of the study was to explore the association of microbiota with epigenetic age acceleration (EAA) using the Mendelian randomization. The independent genetic instruments of gut microbiota were obtained from MiBioGen consortium and the Dutch Microbiome Project. EAA data were derived from genome-wide association study. To assess the causal relationship between gut microbiota and EAA, we applied four different methods of Mendelian Randomization (MR) analysis: the inverse variance weighted method (IVW), the MR-Egger regression, the weighted median analysis (WMA), and the weighted mode. Furthermore, sensitivity analyses were conducted to evaluate heterogeneity and horizontal pleiotropy. We identified potential causal associations between 12 bacterial taxa and EAA (PIVW and PWMA < 0.05). Among them, species Holdemania_unclassified (OR: 1.31, 95

Myocardial fibrosis (MF) is a pathophysiological condition that accompanies various myocardial diseases and comprises a damaged myocardial matrix repair process. Although fibrosis plays a vital role in repair, it ultimately alters cardiac systolic and diastolic functions. The gut microbiota is a complex and dynamic ecosystem with billions of microorganisms that produce bioactive compounds that influence host health and disease progression. Intestinal microbiota has been shown to correlate with cardiovascular disease, and dysbiosis of the intestinal microbiota is involved in the development of MF. In this review, we discuss the role of intestinal microbiota in the process of MF, including alterations in microbiota composition and the effects of metabolites. We also discuss how diet and medicines can affect cardiac fibrosis by influencing the gut microbiota, and potential future therapies targeting the gut-heart axis. A healthy gut microbiota can prevent disease, but dysbiosis can lead to various symptoms, including the induction of heart disease. In this review, we discuss the relevance of the gut-heart axis and the multiple pathways by which gut microbiota may affect cardiac fibrosis, including inflammatory factors, immune cells, and gut microbiota metabolites, such as trimethylamine-N-oxide (TMAO) and short-chain fatty acids (SCFAs). Finally, we discuss the involvement of gut microbiota in the treatment of cardiac fibrosis, including drugs, fecal microbiota transplantation, and oral probiotics or prebiotics. With future studies on the relationship between the heart and gut microbiota, we hope to find better ways to improve MF through the gut-heart axis.

To estimate the cardioprotective mechanism of cordycepin on myocardial ischemia/reperfusion (I/R) injury. The left anterior descending artery of mice was ligated transiently to establish the myocardial I/R model. TTC/Evans Blue staining and TUNEL assay were performed to quantify the infarct size and apoptosis index. The cardiac function was evaluated by echocardiography. Neonatal rat ventricular cardiomyocytes (NRVCs) underwent hypoxia and reoxygenation (H/R). MTS and LDH were detected to measured cell viability and necrosis respectively. The results suggested that cordycepin could markedly decrease apoptosis, reduce infarct size, and improve cardiac function in mice subjected to I/R injury, alongside with enhanced autophagy. In NRVCs, cordycepin treatment obviously reduced ROS production. In addition, cordycepin partly promoted autophagy in the context of H/R injury by regulating AMPK/mTOR pathway. Our data demonstrated that cordycepin exerts cardio-protective effect and promotes cardiac functional recovery following myocardial I/R by enhancing autophagy via AMPK-mTOR signaling pathway.

Previous studies have shown that stromal interaction molecule1 (STIM1)-mediated store-operated Ca2+ entry (SOCE) contributes to intracellular Ca2+ accumulation in H9C2 cells subjected to hypoxia/reoxygenation(H/R) injury. The aim of the present study was to investigate the effect of resveratrol on STIM1-mediated intracellular Ca2+ accumulation and subsequent cell death in the context of myocardial ischemia/reperfusion (I/R) injury. C57 BL/6 mice were fed with either saline or resveratrol (50 mg/kg daily for 2 weeks) and then subjected to myocardial I/R injury. TTC/Evans Blue staining and TUNEL assay were performed to quantify the infarct size and apoptosis index. The cardiac function was evaluated by echocardiography. Neonatal rat ventricular cardiomyocytes (NRVCs) underwent hypoxia/reoxygenation (H/R) to establish the in vitro model. To achieve over-expression, NRVCs were transfected with STIM1-adenovirus vector. Apoptosis was analyzed by TUNEL assay. Cell viability was measured using MTS assay and cell necrosis was determined by LDH release assay. Intracellular Ca2+ concentration was detected by laser scanning confocal microscopy using a Fluo-3AM probe. Resveratrol significantly reduced apoptosis, decreased infarct size, and improved cardiac function in mice subjected to myocardial I/R injury. In NRVCs, resveratrol also downregulated STIM1 expression accompanied by decreased intracellular Ca2+ accumulation elicited by H/R injury. In addition, resveratrol reduced cell apoptosis, upregulated the Bcl-2, decreased Bax, and cleaved caspase-3 expression. Furthermore, the effects of resveratrol on STIM1-mediated intracellular Ca2+ accumulation, apoptotic proteins, and H/R-induced cell injury were exacerbated by STIM1 over-expression and were partly abolished by SOCE inhibitor SKF96365 in NRVCs in vitro. Our findings demonstrate that resveratrol exerts anti-apoptotic activity and improves cardiac functional recovery following myocardial I/R by inhibiting STIM1-induced intracellular Ca2+ accumulation.

目的 本研究旨在探索白藜芦醇对心肌细胞缺氧复氧过程中STIM 1介导的细胞内Ca2+积累及对细胞生存的影响.方法 新生大鼠心室心肌细胞采用缺氧复氧(H/R)建立体外模型,将STIM 1-腺病毒载体转染心肌细胞.MTS法测定细胞活力,LDH释放法测定细胞坏死.用Fluo-3/AM探针检测细胞内Ca2+浓度.结果 白藜芦醇能明显减少心肌细胞缺氧复氧中的凋亡,也下调了STIM1的表达,并减少了H/R损伤引起的细胞内Ca2+积累.白藜芦醇对STIM1介导的细胞内Ca2+积累、凋亡蛋白和H/R诱导的细胞损伤的影响因STIM1过表达而加重.结论 我们的研究结果表明,白藜芦醇通过抑制STIM 1诱导的细胞内Ca2+积累,发挥抗凋亡作用.

The herbal medicine Ipomoea stolonifera (I. stolonifera) has previously been shown to have considerable anti-inflammatory potential in vivo and in vitro. To establish a method for exploring the synergistic effects of multiple compounds, we study the compatibility and dose optimization of compounds isolated from n-butanol extract of I. stolonifera (BE-IS). Raw264.7 cell was treated with lipopolysaccharide (LPS) in the presence of compounds from BE-IS, namely scopoletin, umbelliferone, esculetin, hesperetin and curcumin, using the orthogonal design, uniform design and median-effect method. To verify the best efficacy of principal constituents in vivo, the uniform design was used in the croton oil-induced mouse ear edema model. The results from LPS-induced the production of prostaglandin E2 (PGE2) show that, esculetin, curcumin and hesperetin were the principal constituents that had synergistic effects when used at the optimal ratio. Additionally, the principal constituents were found to work synergistically in the croton oil-induced mouse ear edema model at low doses. It turned out that the three experimental optimization and analysis methods (orthogonal design, uniform design and median-effect method) can be effectively used to solve both compatibility and dose optimization for combined use of multiple compounds.

N-n-butyl haloperidol iodide (F2), a novel compound derived from haloperidol, protects against the damaging effects of ischemia/reperfusion (I/R) injury in vitro and in vivo. In this study, we hypothesized the myocardial protection of F2 on cardiomyocyte hypoxia/reoxygenation (H/R) injury is mediated by inhibiting autophagy in H9c2 cells. The degree of autophagy by treatment with F2 exposed to H/R in H9c2 cell was characterized by monodansylcadaverine, transmission electron microscopy, and expression of autophagy marker protein LC3. Our results indicated that treatment with F2 inhibited autophagy in H9c2 cells exposed to H/R. 3-methyladenine, an inhibitor of autophagy, suppressed H/R-induced autophagy, and decreased apoptosis, whereas rapamycin, a classical autophagy sensitizer, increased autophagy and apoptosis. Mechanistically, macrophage migration inhibitory factor (MIF) was inhibited by F2 treatment after H/R. Accordingly, small interfering RNA (siRNA)-mediated MIF knockdown decreased H/R-induced autophagy. In summary, F2 protects cardiomyocytes during H/R injury through suppressing autophagy activation. Our results provide a new mechanistic insight into a functional role of F2 against H/R-induced cardiomyocyte injury and death.

Reactive oxygen species (ROS)-induced oxidative stress in cells is an important pathophysiological process during myocardial ischemia/reperfusion (I/R) injury, and the transcription factor Egr-1 is a master switch for various damage pathways during reperfusion injury. An in vitro model of myocardial I/R injury and H9c2 cardiomyoblast cells hypoxia/reoxygenation (H/R) was used to assess whether there is abnormal intracellular ROS/JNK/Egr-1 signaling. We also assessed whether N-n-butyl haloperidol (F2), which exerts protective effects during myocardial I/R injury, can modulate this pathway. H/R induced ROS generation, JNK activation, and increased the expression of Egr-1 protein in H9c2 cells. The ROS scavengers edaravone (EDA) and N-acetyl-L-cysteine (NAC) reduced ROS level, downregulated JNK activation, and Egr-1 expression in H9c2 cells after H/R. The JNK inhibitor SP600125 inhibited Egr-1 overexpression in H9c2 cells caused by H/R. F2 could downregulate H/R-induced ROS level, JNK activation, and Egr-1 expression in H9c2 cells in a dose-dependent manner. The ROS donor hypoxanthine-xanthine oxidase (XO/HX) and the JNK activator ANISO antagonized the effects of F2. Therefore, H/R activates ROS/Egr-1 signaling pathway in H9c2 cells, and JNK activation plays an important role in this pathway. F2 regulates H/R-induced ROS/JNK/Egr-1 signaling, which might be an important mechanism by which it antagonizes myocardial I/R injury.

BACKGROUND AND PURPOSE:Calcium antagonists play an important role in clinical practice. However, most of them have serious side effects. We have synthesized a series of novel calcium antagonists, quaternary ammonium salt derivatives of haloperidol with N-p-methoxybenzyl (X1), N-m-methoxybenzyl (X2) and N-o-methoxybenzyl (X3) groups. The objective of this study was to investigate the bioactivity of these novel calcium antagonists, especially the vasodilation activity and cardiac side-effects. The possible working mechanisms of these haloperidol derivatives were also explored.EXPERIMENTAL APPROACH:Novel calcium antagonists were synthesized by amination. Compounds were screened for their activity of vasodilation on isolated thoracic aortic ring of rats. Their cardiac side effects were explored. The patch-clamp, confocal laser microscopy and the computer-fitting molecular docking experiments were employed to investigate the possible working mechanisms of these calcium antagonists.RESULTS:The novel calcium antagonists, X1, X2 and X3 showed stronger vasodilation effect and less cardiac side effect than that of classical calcium antagonists. They blocked L-type calcium channels with an potent effect order of X1 > X2 > X3. Consistently, X1, X2 and X3 interacted with different regions of Ca2+-CaM-CaV1.2 with an affinity order of X1 > X2 > X3.CONCLUSIONS:The new halopedidol derivatives X1, X2 and X3 are novel calcium antagonists with stronger vasodilation effect and less cardiac side effect. They could have wide clinical application.

N-n-butyl haloperidol iodide (F2) has been shown to antagonize myocardial ischemia/reperfusion injury by blocking calcium channels. This study explores the biological functions of ERK pathway in cardiomyocytes hypoxia/reoxygenation injury and clarifies the mechanisms by which F2 ameliorates cardiomyocytes hypoxia/reoxygenation injury through the extracellular-calcium-dependent and -independent ERK1/2-related pathways. In extracellularcalcium-containing hypoxia/reoxygenation cardiomyocytes, PKCα and ERK1/2 were activated, Egr-1 protein level and cTnI leakage increased, and cell viability decreased. The ERK1/2 inhibitors suppressed extracellular-calcium-containing-hypoxia/reoxygenation-induced Egr-1 overexpression and cardiomyocytes injury. PKCα inhibitor downregulated extracellularcalcium-containing-hypoxia/reoxygenation-induced increase in p-ERK1/2 and Egr-1 expression. F2 downregulated hypoxia/reoxygenation-induced elevation of p-PKCα, p-ERK1/2, and Egr-1 expression and inhibited cardiomyocytes damage. The ERK1/2 and PKCα activators antagonized F2's effects. In extracellular-calcium-free-hypoxia/reoxygenation cardiomyocytes, ERK1/2 was activated, LDH and cTnI leakage increased, and cell viability decreased. F2 and ERK1/2 inhibitors antagonized extracellular-calcium-free-hypoxia/reoxygenation-induced ERK1/2 activation and suppressed cardiomyocytes damage. The ERK1/2 activator antagonized F2's above effects. F2 had no effect on cardiomyocyte cAMP content or PKA and Egr-1 expression. Altogether, ERK activation in extracellular-calcium-containing and extracellular-calcium-free hypoxia/reoxygenation leads to cardiomyocytes damage. F2 may ameliorate cardiomyocytes hypoxia/reoxygenation injury by regulating the extracellular-calcium-dependent PKCα/ERK1/2/Egr-1 pathway and through the extracellular-calcium-independent ERK1/2 activation independently of the cAMP/PKA pathway or Egr-1 overexpression.

We have previously shown that N-n-butyl haloperidol iodide (F(2)), a newly synthesized compound, reduces ischemia/reperfusion (I/R) injury by preventing intracellular Ca(2+) overload through inhibiting L-type calcium channels and outward current of Na(+)/Ca(2+) exchanger. This study was to investigate the effects of F(2) on activity and protein expression of the rat myocardial sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) during I/R to discover other molecular mechanisms by which F(2) maintains intracellular Ca(2+) homeostasis. In an in vivo rat model of myocardial I/R achieved by occluding coronary artery for 30-60 min followed by 0-120 min reperfusion, treatment with F(2) (0.25, 0.5, 1, 2 and 4 mg/kg, respectively) dose-dependently inhibited the I/R-induced decrease in SERCA activity. However, neither different durations of I/R nor different doses of F(2) altered the expression levels of myocardial SERCA2a protein. These results indicate that F(2) exerts cardioprotective effects against I/R injury by inhibiting I/R-mediated decrease in SERCA activity by a mechanism independent of SERCA2a protein levels modulation.