Search Results (235)

Background and Objectives: Effective myocardial protection is essential for successful cardiac surgery outcomes, especially in complex and prolonged procedures. To this end, Del Nido (DN) and histidine-tryptophan-ketoglutarate (HTK) cardioplegia solutions are widely used; however, their comparative efficacy in adult surgeries with prolonged aortic cross-clamp (ACC) times remains unclear. This study aimed to compare the efficacy and safety of DN and HTK for myocardial protection during prolonged ACC times in adult cardiac surgery and to define clinically relevant thresholds. Materials and Methods: This retrospective study included a total of 320 adult patients who underwent cardiac surgery under cardiopulmonary bypass (CPB) with an aortic cross-clamp time ≥ 90 min. Data were collected from the medical records of elective adult cardiac surgery cases performed at a single center between 2019 and 2025. Patients were categorized into two groups based on the type of cardioplegia received: Del Nido (n = 160) and HTK (n = 160). The groups were compared using 1:1 propensity score matching. Clinical and biochemical outcomes—including troponin I (TnI), CK-MB, lactate levels, incidence of low cardiac output syndrome (LCOS), and need for mechanical circulatory support—were analyzed between the two cardioplegia groups. Subgroup analyses were performed according to ACC duration (90–120, 120–150, 150–180 and >180 min). The predictive threshold of ACC duration for each complication was determined by ROC analysis, followed by the analysis of independent predictors of each endpoint by multivariate logistic regression. Results: Intraoperative cardioplegia volume and transfusion requirements were lower in the DN group (p < 0.05). HTK was associated with lower TnI levels and less intra-aortic balloon pump (IABP) requirement at ACC times exceeding 180 min. Markers of myocardial injury were lower in patients with an ACC duration of 120–150 min in favor of HTK. The propensity for ventricular fibrillation after ACC was significantly lower in the DN group. Significantly lower postoperative sodium levels were observed in the HTK group. Prolonged ACC duration was an independent risk factor for LCOS (odds ratio [OR]: 1.023, p < 0.001), VIS > 15 (OR, 1.015; p < 0.001), IABP requirement (OR: 1.020, p = 0.002), and early mortality (OR: 1.016, p = 0.048). Postoperative ejection fraction (EF), troponin I, and CK-MB levels were associated with the development of LCOS and a VIS > 15. Furthermore, according to ROC analysis, HTK cardioplegia was able to tolerate ACC for up to a longer duration in terms of certain complications, suggesting a higher physiological tolerance to ischemia. Conclusions: ACC duration is a strong predictor of major adverse outcomes in adult cardiac surgeries. Although DN cardioplegia is effective and economically advantageous for shorter procedures, HTK may provide superior myocardial protection in operations with long ACC duration. This study supports the need to individualize cardioplegia choice according to ACC duration. Further prospective studies are needed to establish standard dosing protocols and to optimize cardioplegia selection according to surgical duration and complexity. Full article

Hypothermia-related deaths present significant diagnostic challenges due to non-specific and often inconsistent autopsy findings. This study investigated the histological and immunohistochemical alterations associated with primary and secondary hypothermia in an experimental Rattus norvegicus model, focusing on the effects of benzodiazepine and alcohol ingestion. Twenty-one male rats were divided into three groups: control (K), benzodiazepine-treated (B), and alcohol-treated (A). After two weeks of substance administration, hypothermia was induced and multiple organ samples were analyzed. Histologically, renal tissue showed hydropic and vacuolar degeneration, congestion, and acute tubular injury across all groups, with no significant differences in E-cadherin expression. Lung samples revealed congestion, emphysema, and hemorrhage, with more pronounced vascular congestion in the alcohol and benzodiazepine groups. Cardiac tissue exhibited vacuolar degeneration and protein denaturation, particularly in substance-exposed animals. The spleen showed preserved architecture but increased erythrocyte infiltration and significantly elevated myeloperoxidase (MPO)-positive granulocytes in the intoxicated groups. Liver samples demonstrated congestion, focal necrosis, and subcapsular hemorrhage, especially in the alcohol group. Immunohistochemical analysis revealed statistically significant differences in MPO expression in both lung and spleen tissues, with the highest levels observed in the benzodiazepine group. Similarly, CK7 and CK20 expression in the gastroesophageal junction was significantly elevated in both alcohol- and benzodiazepine-treated animals compared to the controls. In contrast, E-cadherin expression in the kidney did not differ significantly among the groups. These findings suggest that specific histological and immunohistochemical patterns, particularly involving pulmonary, cardiac, hepatic, and splenic tissues, may help differentiate primary hypothermia from substance-related secondary hypothermia. The study underscores the value of integrating toxicological, histological, and molecular analyses to enhance the forensic assessment of hypothermia-related fatalities. Future research should aim to validate these markers in human autopsy series and explore additional molecular indicators to refine diagnostic accuracy in forensic pathology. Full article

The insulin-like growth factor binding protein, acid-labile subunit (IGFALS), plays a crucial role in glucose metabolism and immune regulation, key processes in recovery from surgery. Here, we studied the perioperative serum IGFALS dynamics and explored potential clinical implications. A total of 79 patients undergoing elective cardiac surgery with implementation of cardiopulmonary bypass had their serum isolated at baseline, 24 h, seven days, and three months postoperatively to assess serum concentrations of IGFALS and insulin growth factor 1 (IGF-1). Markers of perioperative injury included troponin I (TnI), high-mobility group box 1 (HMGB-1), and heat shock protein 60 (Hsp-60). Inflammatory status was assessed via interleukin-6 (IL-6) and interleukin-8 (IL-8). Additionally, we measured in vitro cytokine production to viral stimulation of whole blood and monocytes. Surrogates of neuronal distress included neurofilament light chain (NF-L), total tau (τ), phosphorylated tau at threonine 181 (τp181), and amyloid β40 and β42. Renal impairment was defined by RIFLE criteria. Cardiac dysfunction was denoted by serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Serum IGFALS levels declined significantly after surgery and remained depressed even at 3 months. Administration of acetaminophen and acetylsalicylic acid differentiated IGFALS levels at the 24 h postoperatively. Serum IGFALS 24 h post-operatively correlated with production of cytokines by leukocytes after in vitro viral stimulation. Serum amyloid-β1-42 was significantly associated with IGFALS at baseline and 24 h post-surgery Patients discharged home had higher IGFALS levels at 28 days and 3 months than those discharged to healthcare facilities or who died. These findings suggest that IGFALS may serve as a prognostic biomarker for recovery trajectory and postoperative outcomes in cardiac surgery patients. Full article

Background: We investigated the role of a high-sensitive cardiac troponin T (hsTnT) increase below the upper limit of normal (ULN) in patients with breast cancer (BC). hsTnT assays accurately quantify very low plasma troponin concentrations and enable the early detection of cardiomyocyte injury before a drop in the left ventricular ejection fraction (LVEF). The increase in hsTnT below the ULN in response to chemotherapy has not previously been studied. Method: This was an open-label pilot study. Female patients with newly diagnosed BC scheduled to receive systemic cancer treatment were recruited. Blood sampling and echocardiography were performed at baseline, at 3 and 6 months of cancer treatment. hsTnT concentrations were measured using the Elecsys TnT hs assay (Roche Diagnostics). The limit of blank and 99th percentile cutoff values for the hsTnT assay were 3 and 14 ng/L. We calculated the rise in hsTnT (ΔhsTnT) by the difference (%) between its baseline level and during follow-up (FU) in each patient. Results: Among eligible subjects, we excluded 4 patients before the start of treatment and 17 patients during the follow-up with values for the hsTnT >14 ng/L. Finally, 60 women with a median age of 48.6 ± 1.3 years were included in the study. The median baseline hsTnT concentration was 5.5 ± 1.4 ng/L. During 6 months of cancer treatment, hsTnT increased in all patients by up to 10–305% from baseline, with an average of 94.2%. LV EF was normal at baseline and decreased significantly compared to the value before cancer treatment (61.9 ± 3.3% vs. 56.3 ± 7.0%; p < 0.045). We correlated the hsTnT rise with a drop in LV EF ≥ 10% from its baseline level. Logistic regression analysis showed that Δ hsTnT has a good predictive value for LV dysfunction, 0.78 (p = 0.05), 95% CI (0.67–0.90). The increase in hsTnT > 81% was determined as the optimal threshold value for detecting early biochemical cardiotoxicity. Conclusion: It was investigated that hsTnT rise within the cutoff < 14 ng/L can be used as a marker of early biochemical cardiotoxicity and is valuable for predicting LV drop in 6 months of FU. We conclude that BC patients with increased hsTnT plasma concentration > 81% from the baseline value should be considered as high-risk patients for cardiotoxicity and need more precise cardiac monitoring and early preventive medical intervention strategies. Full article

Background: Coronavirus disease 2019 (COVID-19) is frequently complicated by cardiovascular involvement. Soluble growth stimulation-expressed gene 2 (sST2) is a promising cardiovascular biomarker, but its prognostic value in COVID-19 remains unclear. Methods: This retrospective cohort study included 314 hospitalized COVID-19 patients classified into mild/moderate (n = 168) and severe/critical (n = 146). Plasma sST2 were measured using an enzyme-linked immunosorbent assay. Correlation analyses evaluated associations between sST2 and clinical parameters. Cox regression assessed the independent predictive value for cardiovascular events and all-cause mortality. Results: sST2 levels were significantly higher in severe/critical patients (16.877 ng/mL) than in mild/moderate cases (6.189 ng/mL) and healthy controls (4.003 ng/mL). sST2 positively correlated with cardiac injury markers (cTnI, CK-Mb, NT-proBNP), inflammatory indices (IL-1β, hsCRP), D-dimer, and inversely correlated with a left ventricular ejection fraction (r = −0.86). Elevated sST2 independently predicted cardiovascular events (HR = 2.972) and mortality (HR = 4.681). The Kaplan–Meier survival analysis demonstrated higher cardiovascular event rates and lower survival probabilities in patients with elevated sST2. The ROC curve indicated sST2 outperformed cTnI and NT-proBNP in predicting cardiovascular events (AUC = 0.898) and mortality (AUC = 0.871). Conclusion: Elevated sST2 is associated with myocardial injury, inflammation, and poor prognosis in COVID-19, supporting its value for risk stratification. Full article

Myocardial injury following polytrauma is a significant yet often underdiagnosed condition that contributes to acute cardiac dysfunction and long-term cardiovascular complications. This review examines the role of systemic inflammation, oxidative stress, neuro-hormonal activation, and immune dysregulation in trauma-induced myocardial damage. Key immunological markers, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), monocyte chemoattractant protein-1 (MCP-1), and adhesion molecules (ICAM-1, VCAM-1), are implicated in endothelial dysfunction, myocardial apoptosis, and ventricular remodeling. The interplay between these factors potentially exacerbates cardiac injury, increasing the risk of heart failure. Biomarker-guided approaches for early detection, combined with advanced imaging techniques such as speckle-tracking echocardiography and cardiac MRI, offer promising avenues for risk stratification and targeted interventions. Anti-inflammatory and oxidative stress-modulating therapies may mitigate myocardial damage and improve outcomes. This article highlights the clinical relevance of integrating immunological markers into diagnostic and therapeutic strategies to enhance the management of trauma-related cardiac dysfunction and reduce long-term morbidity. Full article

Acute heart failure (AHF) is a clinical syndrome characterized by the sudden onset or rapid worsening of heart failure signs and symptoms, frequently triggered by myocardial ischemia, pressure overload, or cardiotoxic injury. A central component of its pathophysiology is the activation of intracellular signal transduction cascades that translate extracellular stress into cellular responses. Among these, the mitogen-activated protein kinase (MAPK) pathways have received considerable attention due to their roles in mediating inflammation, apoptosis, hypertrophy, and adverse cardiac remodeling. The canonical MAPK cascades—including extracellular signal-regulated kinases (ERK1/2), p38 MAPK, and c-Jun N-terminal kinases (JNK)—are activated by upstream stimuli such as angiotensin II (Ang II), aldosterone, endothelin-1 (ET-1), and sustained catecholamine release. Additionally, emerging evidence highlights the role of receptor-mediated signaling, cellular stress, and myeloid cell-driven coagulation events in linking MAPK activation to fibrotic remodeling following myocardial infarction. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade plays a central role in regulating cardiomyocyte survival, hypertrophy, energy metabolism, and inflammation. Activation of the PI3K/Akt pathway has been shown to confer cardioprotective effects by enhancing anti-apoptotic and pro-survival signaling; however, aberrant or sustained activation may contribute to maladaptive remodeling and progressive cardiac dysfunction. In the context of AHF, understanding the dual role of this pathway is crucial, as it functions both as a marker of compensatory adaptation and as a potential therapeutic target. Recent reviews and preclinical studies have linked PI3K/Akt activation with reduced myocardial apoptosis and attenuation of pro-inflammatory cascades that exacerbate heart failure. Among the multiple signaling pathways involved, glycogen synthase kinase-3β (GSK-3β) has emerged as a key regulator of apoptosis, inflammation, metabolic homeostasis, and cardiac remodeling. Recent studies underscore its dual function as both a negative regulator of pathological hypertrophy and a modulator of cell survival, making it a compelling therapeutic candidate in acute cardiac settings. While earlier investigations focused primarily on chronic heart failure and long-term remodeling, growing evidence now supports a critical role for GSK-3β dysregulation in acute myocardial stress and injury. This comprehensive review discusses recent advances in our understanding of the MAPK signaling pathway, the PI3K/Akt cascade, and GSK-3β activity in AHF, with a particular emphasis on mechanistic insights, preclinical models, and emerging therapeutic targets. Full article

Introduction: Postoperative delirium (POD) remains a major complication in geriatric surgical care, with poorly understood molecular mechanisms. Emerging evidence links cardiac surgery to elevated markers of neurologic injury, even in cognitively intact individuals. While neuroinflammation is the prevailing model, a more detailed characterization of the systemic inflammatory and metabolic response to surgery may offer deeper insights into POD pathogenesis. Methods: We used the 7K SomaLogic proteomic platform to analyze preoperative and postoperative day-one serum samples from 78 patients undergoing cardiac surgery with cardiopulmonary bypass. We compared proteomic profiles within individuals (pre- vs. post-surgery) and between those who developed POD and those who did not. Functional analyses were performed to identify relevant biological pathways. A composite metabo-inflammatory score (MIF) was derived to quantify systemic derangement. We modeled the association between POD and age, sex, baseline cognition, and MIF score. Results: Cardiac surgery with CPB was associated with marked inflammatory responses across all subjects, including increased IL-6, CRP, and serum amyloid A. Compared to controls, POD cases showed greater metabo-inflammatory shifts from baseline (average logFC = 2.56, p < 0.001). Lower baseline cognitive scores (OR = 0.74, p = 0.019) and higher MIF scores (OR = 1.03, p = 0.013) were independently associated with increased POD risk. Conclusions: Cardiac surgery with CPB elicits a significant metabo-inflammatory response in all patients. However, those who develop POD exhibit disproportionately greater dysregulation. Full article

Background: Quasipaa spinosa crude extract (QSce), a natural source rich in proteins such as parvalbumin (PV), has been traditionally used to promote physical recovery. However, its mechanisms in mitigating exercise-induced fatigue remain unclear. Methods: Using a murine treadmill exhaustion model, we evaluated the effects of QS-derived Parvalbumin (QsPV) (30 and 150 mg/kg/day) on endurance capacity, oxidative stress, tissue injury, and muscle function. Indicators measured included time to exhaustion, intracellular calcium levels, antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px)], lipid peroxidation (malondialdehyde, MDA), injury markers [creatine kinase (CK), lactate dehydrogenase (LDH), cardiac troponin I (cTnI)], renal function (blood urea), and muscle force. Results: QsPV-150 significantly increased time to exhaustion by 34.6% compared to the exercise-only group (p < 0.01). It reduced MDA by 41.2% in skeletal muscle and increased SOD and GSH-Px levels by 35.4% and 28.1%, respectively. Serum CK, LDH, and cTnI were reduced by 39.5%, 31.7%, and 26.8%, respectively, indicating protection against muscle and cardiac injury. QsPV also decreased blood urea by 22.3% and improved renal histology, with reduced glomerular damage and tubular lesions. At the molecular level, QsPV restored calcium balance and downregulated calpain-1/2 and atrophy-related genes (MuRF-1, MAFbx-32). Muscle contractile force (GAS and SOL) improved by 12.2–20.3%. Conclusions: QsPV attenuates exercise-induced fatigue through multi-organ protection involving calcium buffering, oxidative stress reduction, and anti-atrophy effects. These findings support its potential as a natural recovery-enhancing supplement, pending further clinical and pharmacokinetic studies. Full article

Cardiovascular injury caused by fine particulate matter (PM2.5) exposure is an escalating public health concern due to its role in triggering systemic inflammation and oxidative stress. This study elucidates the sirtuin 1 (SIRT1)-mediated epigenetic mechanisms underlying the protective effects of phytosome-encapsulated Zea mays L. var. ceratina tassel extract (PZT) in a rat model of PM2.5-induced cardiovascular inflammation. Male Wistar rats were pretreated with PZT (100, 200, and 400 mg/kg body weight) for 21 days before and throughout a 27-day PM2.5 exposure period. SIRT1 expression and associated inflammatory and oxidative stress markers were evaluated in cardiac and vascular tissues. The findings revealed that PZT significantly upregulated SIRT1 expression, a key epigenetic regulator known to modulate inflammatory and antioxidant pathways. The activation of SIRT1 inhibited the nuclear factor-kappa B (NF-κB) signaling pathway, leading to a reduction in pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) within cardiac tissue. In vascular tissue, treatment with PZT reduced the levels of tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β), thereby mitigating inflammatory and fibrotic responses. Furthermore, SIRT1 activation by PZT enhanced the antioxidant defense system by upregulating superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), which was associated with a decrease in malondialdehyde (MDA), a marker of lipid peroxidation. Collectively, these results demonstrate that PZT confers cardiovascular protection through SIRT1-dependent epigenetic modulation, mitigating PM2.5-induced inflammation, oxidative stress, and tissue remodeling. The dual anti-inflammatory and antioxidant actions of PZT via SIRT1 activation highlight its potential as a functional food-based preventative agent for reducing cardiovascular risk in polluted environments. Full article

Background: Estrogens play a protective role during the early stages of life. However, endogenous 17β-estradiol (E2) can accelerate atherosclerosis progression. Aim: The purpose of this study was to test for the significance of the sex-specific associations of gonadal hormones with the extent of the inflammatory response, myocardial damage, and ventricular arrhythmia risk in acute myocardial infarction (MI). Materials and Methods: Study design: single-center cohort study. Blood samples for the assessment of sex steroids (E2, total testosterone [T]), oxidized low-density lipoproteins, high-sensitivity C-reactive protein (CRP), white blood cell (WBC) counts, and cardiac enzymes were collected 48 h after the onset of symptoms (and within 6 h after PCI) from 111 patients (37% women) with acute MI. Coronary disease severity, left ventricular systolic function (LV), and indices of ventricular repolarization were assessed using coronary angiography, echocardiography, and a conventional electrocardiogram, respectively. Results: In men with acute MI, peak cardiac enzyme levels were predicted by post-percutaneous coronary intervention (PCI) E2 plasma levels, peak WBC count, and peak CRP plasma levels. T levels and the E2/T ratio were associated with post-PCI CRP in these men. For women, peak WBC count was a marker of highest testosterone, and only WBC count was a significant indicator of myocardial injury extent. The incidence of acute ventricular tachycardia detected in AMI was significantly associated with left ventricular ejection fraction and with peak WBC count (as a tendency) regardless of sex. A longer duration of cardiac repolarization prior to PCI was predicted by lower ejection fractions in men and by age, CRP, and testosterone levels in female patients. Conclusions: During acute MI, elevated endogenous estradiol levels in men and increased leukocytes in women indicate acute myocardial damage. Post-PCI plasma inflammatory markers are sex-specific confounding factors for acute endogenous E2 levels, T levels, and the E2/T ratio. LV systolic function in men and, characteristically, the acute inflammatory response and testosterone levels in women are predictors of longer ventricular repolarization and arrhythmia risk. Full article

Objective: Study the mechanism of ginsenoside Rg₁ in ameliorating hyperuricemia (HUA) induced by high-purine diet. Methods: Rats were randomly divided into groups, and the HUA model was established by administering a high-purine diet containing potassium oxonate combined with yeast. After the experiment, blood was collected via cardiac puncture, and the organ indices of the rats were calculated. Serum biochemical markers including aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), total cholesterol (TC), xanthine oxidase (XOD), creatinine (CREA), uric acid (UA), and blood urea nitrogen (BUN) were measured. Histopathological sections of the kidney and intestine were prepared. Western blot was used to assess the expression levels of intestinal occludin and zonula occludens-1 barrier proteins and key proteins in IL-17/NF-κB inflammatory pathways. After the experiment, fecal samples were collected from the rats. The gut microbiota of HUA-induced rats was analyzed via 16S rRNA sequencing, and the levels of short-chain fatty acids in the fecal samples were quantified using gas chromatography–mass spectrometry. Results: Ginsenoside Rg₁ significantly increased body weight and organ indexes as well as reduced serum levels of BUN, CREA, ALT, AST, XOD, and UA. Pathologic analysis showed that ginsenoside Rg₁ improved renal cell injury, glomerulosclerosis, and renal interstitial fibrosis while restoring intestinal barrier function. Ginsenoside Rg₁ down-regulated the expression of inflammatory proteins and up-regulated the levels of intestinal barrier proteins. The results of 16S rRNA sequencing showed that ginsenoside Rg₁ significantly increased the diversity index of gut microbiota and enhanced the number of beneficial bacteria in HUA rats. Short-chain fatty acids analysis demonstrated that ginsenoside Rg₁ markedly elevated the levels of acetate, propionate, butyrate, and valerate in HUA rats. Conclusions: Ginsenoside Rg₁ ameliorates and treats HUA by improving the composition of intestinal flora and inhibiting the IL-17/NF-κB signaling pathway to reduce inflammatory factors in the intestinal tract in HUA rats. Full article

Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized as a systemic disorder, often coexisting with chronic obstructive pulmonary disease (COPD). This study aims to identify the shared pathogenic mechanisms between HFpEF and COPD and validate them in an experimental HFpEF model. Transcriptomic datasets from HFpEF cardiac tissue and COPD lung tissue were analyzed using differentially expressed gene (DEG) analysis, weighted gene co-expression network analysis (WGCNA), and functional enrichment analysis. Key genes were identified through least absolute shrinkage and selection operator (LASSO) regression. Immune cell infiltration was assessed using xCell and CIBERSORT, and single-cell RNA sequencing (scRNA-seq) was utilized to determine gene expression patterns across different cell populations. A high-fat diet and N[w]-nitro-L-arginine methyl ester (L-NAME)-induced HFpEF mouse model was established, and the expression of SESN3 and autophagy-related markers was evaluated in both cardiac and pulmonary tissues using immunofluorescence, quantitative PCR (qPCR), Western blotting (WB), and transmission electron microscopy. DEG and WGCNA analyses identified 1243 and 131 core genes in HFpEF and COPD, respectively. Functional enrichment analysis highlighted autophagy as a common regulatory pathway in both conditions. Among the nine intersecting genes, SESN3 was identified as a key candidate through LASSO regression. Immune infiltration analysis and scRNA-seq further demonstrated the involvement of SESN3 in both cardiac and pulmonary pathophysiology. In vivo experiments showed that HFpEF mice exhibited significant lung injury. Furthermore, SESN3 upregulation and autophagy dysregulation were observed in both heart and lung tissues, supporting a potential systemic role of SESN3-mediated autophagy in HFpEF-related pulmonary alterations. This study suggests that SESN3-mediated autophagy may represent a shared mechanism between HFpEF and COPD. Our findings suggest that HFpEF may be associated with pulmonary alterations beyond cardiac dysfunction alone. These results provide novel insights into the potential multi-organ involvement in HFpEF and support the role of SESN3 as a shared molecular target in both cardiac and pulmonary pathologies. Full article

Purpose: Doxorubicin (DOX) is a broad-spectrum anti-tumor anthracycline drug. However, its clinical application is greatly limited due to the side effect of cardiotoxicity. Caffeic acid phenethyl ester (CAPE) is one of the major biologically active compounds isolated from propolis, which is effective in the treatment of cardiovascular diseases. The purpose of this study aimed to explore the possible mechanism of CAPE’s protective effect on DOX-induced cardiotoxicity (DIC). Methods: In vivo, a DIC model was established by the intraperitoneal injection of 3 mg/kg DOX. The cardiac function of mice was monitored by electrocardiograms. Histopathological changes in myocardial tissue were detected by H&E staining. Serum samples were tested for the level of markers of myocardial injury. In vitro, transmission electron microscopy was used to assess the mitochondrial damage. Oxidative stress was measured by flow cytometry and mitochondrial respiration analysis. Necroptosis pathway changes were detected by Western blotting. Furthermore, the overexpression plasmid of a key necroptosis gene, necroptosis inhibitor or ROS inducer/inhibitor was applied to H9c2 and AC16 cells to explore whether CAPE exerted a protective effect against DIC through the cross-talk mediated by ROS and MLKL. Results: CAPE could improve the cardiac function and protect against myocardial tissue. CAPE pre-administration treatment attenuated the DOX-induced generation of ROS, protected mitochondrial functions and inhibited necroptosis. Moreover, there was cross-talk between the ROS and necroptosis. CAPE could protect against DIC by inhibiting the ROS-MLKL signaling that regulated the cross-talk. Conclusions: CAPE alleviated the oxidative stress and necroptosis of DIC, indicating that the cross-talk mediated by ROS-MLKL signaling may be a potential therapeutic mechanism for clinical DIC. Full article

Heat stress has become a significant challenge in animal husbandry and human health, posing significant threats to both livestock and human health and profoundly impacting agricultural productivity. Sheng Mai San has been shown to effectively alleviate heat stress, yet the underlying mechanisms remain unclear. Therefore, this study established a heat stress model and employed Sheng Mai San as an intervention, with NAC as the positive control. Using histopathological analysis, Western blotting, ELISA, and 16S rDNA sequencing, we investigated the protective effects of Sheng Mai San against heat-stress-induced cardiac and intestinal injuries, as well as gut microbiota dysbiosis. The results demonstrated that heat stress-induced cardiac injury primarily occurred within 6–12 h of the cessation of heat stress. This injury was manifested by a significant elevation in the cardiac index, accompanied by attenuated expression of cardiac antioxidants (GSH, SOD, CAT, and T-AOC) and increased MDA content. Following Sheng Mai San intervention, the cardiac index was reduced, antioxidant indices (GSH, SOD, and CAT) were significantly elevated, and MDA and inflammatory markers (IL-1β, IL-6, and TNF-α) were markedly decreased. Additionally, Sheng Mai San was found to activate the Keap1-Nrf2 signaling pathway in the heart. Sheng Mai San demonstrated significant protective effects on small intestinal morphology, attenuating pathological alterations while promoting goblet cell proliferation. Analysis of the gut microbiota revealed that Sheng Mai San increased the Chao1, ACE, Shannon, and Simpson indices while reducing the abundance of harmful bacteria, such as g_Globicatella, g_Thermoactinomyces, g_Staphylococcus, g_Gemella, and g_Veillonella. Additionally, it promoted the expression of beneficial bacteria, including g_Lactobacillus and g_Ruminococcaceae. In summary, Sheng Mai San alleviates heat stress-induced cardiac hypertrophy and restores the oxidative stress balance in the heart. It also mitigates pathological damage in the small intestine, enhances the diversity and richness of the gut microbiota, and ameliorates gut microbiota dysbiosis. These findings highlight the significance of the heart-small intestine-gut microbiota axis in the protective effects of Sheng Mai San against heat stress injury. This study provides a potential therapeutic approach for heat-stress-related diseases and offers insights into the development of anti-heat-stress drugs. Full article