Ischemic stroke remains a major contributor to disability and mortality, emphasizing the urgent need for new therapies to enhance reperfusion treatment outcomes. In this study, we systematically investigated the neuroprotective effects of matrine, an alkaloid derived from Sophora flavescens, using both computational and experimental approaches. Initially, a network pharmacology strategy was employed to identify 69 potential targets of matrine relevant to ischemic stroke by integrating data from Swiss Target Prediction, Similarity Ensemble Approach, PharmMapper, and GeneCards. Subsequent protein-protein interaction analyses, along with GO and KEGG pathway enrichment, highlighted the AMPK signaling pathway as a critical mediator. To validate these findings, male C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAO) to induce stroke. Matrine treatment in this model resulted in significant improvements in neurological function, reductions in brain damage, and marked decreases in oxidative stress and apoptosis. Furthermore, molecular docking and molecular dynamics (MD) simulations studies revealed a strong binding affinity between matrine and key targets such as AMPK, CHRNA4, and SLC6A3, with Western blot analyses confirming the involvement of AMPK and its upstream regulator UCP2. Collectively, our results demonstrate that matrine confers neuroprotection in cerebral ischemia-reperfusion injury by modulating the AMPK pathway, suggesting its potential as a novel therapeutic agent for ischemic stroke. The proposed mechanisms of matrine in ischemic stroke are summarized in the graphical abstract.

Previous studies demonstrated that dexmedetomidine (Dex) posttreatment aggravated myocardial dysfunction and reduced survival in septic mice. Yet, whether Dex elicits similar effects in septic patients as defined by Sepsis-3 remains unknown. This study sought to assess the effects of Dex-based sedation on mortality and cardiac dysfunction in septic patients defined by Sepsis-3 and to further reveal the mechanisms in septic rats. In the retrospective cohort study, patients were categorised into sepsis with Dex, other sedatives (propofol or midazolam) or without sedatives, mortality at 28 days were compared, and patients with measurements of cardiovascular biomarkers and echocardiography were used to examine the effect of Dex on cardiac dysfunction. Septic rats and Langendorff-perfused isolated rat hearts were used, cardiac function, mortality and pro-inflammatory mediators were analyzed. The all-cause mortality of septic patients receiving Dex reached to 35.2 % on Day 28, significantly higher than that of patients with other sedatives (16.1 %), while no difference with group of no sedatives (27.3 %). Patients in Dex group showed lower left ventricular EF and lateral mitral annular early diastolic peak velocities, but higher interventricular septum diastolic dimension compared to those with other sedatives. The plasma levels of H-FABP, NT-proBNP and HMGB1 in Dex and other sedative groups showed no difference, while both were significantly lower than the group of no sedative. Notably, Dex posttreatment deteriorated cardiac dysfunction, increasing mortality in septic rats with enhanced systemic and myocardial proinflammatory mediators, including TNF-α, IL-1β, IL-6 and VCAM-1. Mechanistical study by Langendorff-perfusion revealed that Dex directly acted on the heart, aggravating LPS-induced myocardial inflammation and dysfunction. These results suggest that Dex increases mortality and deteriorates myocardial dysfunction compared with other sedatives in septic patients defined by Sepsis 3.0, maybe partly through promoting proinflammatory response via directly acting on the heart.

BACKGROUND:Irreversible electroporation (IRE) represents an innovative localized technique for tumor ablation, possessing the capacity to activate the immune response of the host. However, this method alone is inadequate to halt cancer progression, necessitating the integration of additional strategies to achieve effective immunotherapy. AIM:To investigate the effects and underlying mechanisms of antitumor immunity derived from the synergistic application of IRE and anti-programmed cell death protein 1 (PD-1) therapy within a murine model of hepatocellular carcinoma. METHODS:C57BL-6 mice with tumor growth were divided into four separate cohorts: Control group; IRE group; Anti-PD-1 group; And IRE + anti-PD-1 group. The infiltration levels of T, B, and natural killer cells within the tumors, as well as the plasma concentrations of T helper type 1 cytokines (interleukin-2, interferon-γ, and tumor necrosis factor-β), were evaluated. Real-time polymerase chain reaction was utilized to quantify the expression of cluster of differentiation (CD) 8 (a marker indicative of CD8+ T cells) in the tumor specimens of the mice at various temporal intervals. Tumor growth trajectories were charted. RESULTS:The results indicated that the IRE + anti-PD-1 group exhibited significantly heightened percentages of T lymphocyte infiltration, particularly CD4+ and CD8+ T cells, when compared to the control cohort. Additionally, this group displayed increased infiltration of natural killer and B cells, augmented cytokine levels, and elevated CD8 messenger RNA expression. A marked decrease in tumor volume was noted in the IRE + anti-PD-1 group, indicating enhanced therapeutic efficacy. CONCLUSION:The combined application of IRE and checkpoint blockade elicits an antitumor immune response, leading to a more substantial reduction in tumor volume and improved therapeutic outcomes, thereby establishing a novel avenue for the ablation and immunotherapy of hepatocellular carcinoma.

INTRODUCTION:Doxorubicin (DOX), a potent anthracycline, is widely used in cancer therapy, but its effect is limited by doxorubicin-induced cardiotoxicity (DIC). Increasing evidence suggests that DIC is associated with ferroptosis, a cell death characterized by the iron-dependent accumulation of lipid peroxides. Although aerobic exercise is recommended for chemotherapy-related cardiac dysfunction, the extent to which its protective effects against DIC are mediated through the inhibition of ferroptosis remains largely unclear. The aim of this study was to elucidate the mechanism through which aerobic exercise attenuates DIC and provide theoretical support for promoting scientifically guided exercise in patients with DIC. METHODS:We conducted in vivo experiments involving 8 weeks of aerobic exercise during and after DOX treatment of C57BL/6J male mice, and in vitro experiments, H9c2 cells were treated with DOX and ferrostatin-1 (Fer-1, a ferroptosis inhibitor). Mice were randomly assigned into four groups: Control (C, n = 6), DOX (D, n = 10), aerobic exercise (E, n = 6) and DOX + aerobic exercise (DE, n = 10). Echocardiography was used to measure left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) to assess cardiac function in mice. ELISA kits were used to quantify serum biomarkers of myocardial injury, including cardiac troponin T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP), and lipid peroxidation markers, such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). Hematoxylin and eosin and Masson's trichrome were performed to evaluate myocardial structural damage. Fluorescent probes were used to detect ferrous iron (Fe2+), reactive oxygen species (ROS), and lipid peroxides in H9c2 cells. Western blotting was conducted to analyze ferroptosis-related proteins, including glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), acyl-CoA synthetase long-chain family member 4 (ACSL4), transferrin receptor 1 (TfR1), and ferritin heavy chain 1 (FTH1). RESULTS:DOX treatment significantly induced cardiac damage and dysfunction, as evidenced by disrupted myocardial tissue, increased myocardial fibrosis and cTnT levels, and decreased LVEF and LVFS. However, aerobic exercise effectively reduced cardiac structural and functional damage, and improved the rate of survival in mice. Furthermore, DOX-induced ferroptosis in cardiomyocytes both in vitro and in vivo, as marked by increased levels of Fe2+, ROS, and MDA, along with altered protein expression, including reduced FTH1 and SLC7A11 levels and increased ACSL4 levels. In contrast, aerobic exercise significantly mitigated these changes in vivo, and Fer-1 also effectively inhibited these effects in vitro. CONCLUSION:Collectively, this study demonstrates that aerobic exercise alleviates DIC via the inhibition of ferroptosis.

ABSTRACT β3-adrenergic receptor (β3-AR) has been proposed as a new therapy for several myocardial diseases. However, the effect of β3-AR activation on sepsis-induced myocardial apoptosis is unclear. Here, we investigated the effect of β3-AR activation on the cardiomyocyte apoptosis and cardiac dysfunction in cecal ligation and puncture (CLP)-operated rats and lipopolysaccharide (LPS)-treated cardiomyocytes. We found that β3-AR existed both in adult rat ventricular myocytes (ARVMs) and H9c2 cells. The expression of β3-AR was upregulated in LPS-treated ARVMs and the heart of CLP rats. Pretreatment with β3-AR agonist, BRL37344, inhibited LPS-induced cardiomyocyte apoptosis and caspase-3, -8 and -9 activation in ARVMs. BRL37344 also reduced apoptosis and increased the protein levels of PI3K, p-AktSer473 and p-eNOSSer1177 in LPS-treated H9c2 cells. Inhibition of PI3K using LY294002 abolished the inhibitory effect of BRL37344 on LPS-induced caspase-3, -8, and -9 activation in H9c2 cells. Furthermore, administration of β3-AR antagonist, SR59230A (5 mg/kg), significantly decreased the maximum rate of left ventricular pressure rise (+dP/dt) in CLP-induced septic rats. SR59230A not only increased myocardial apoptosis, reduced p-AktSer473 and Bcl-2 contents, but also increased mitochondrial Bax, cytoplasm cytochrome c, cleaved caspase-9 and cleaved caspase-3 levels of the myocardium in septic rats. These results suggest that endogenous β3-AR activation alleviates sepsis-induced cardiomyocyte apoptosis via PI3K/Akt signaling pathway and maintains intrinsic myocardial systolic function in sepsis.

Cardiomyopathy is particularly common in septic patients. Our previous studies have shown that activation of the alpha 1 adrenergic receptor (α1-AR) on cardiomyocytes inhibits sepsis-induced myocardial dysfunction. However, the role of cardiac endothelial α1-AR in septic cardiomyopathy has not been determined. Here, we identified α1-AR expression in mouse and human endothelial cells and showed that activation of α1-AR with phenylephrine (PE) improved cardiac function and survival by preventing cardiac endothelial injury in septic mice. Mechanistically, activating α1-AR with PE decreased the expression of ICAM-1, VCAM-1, iNOS, E-selectin, and p-p38MAPK, while promoting PKC and ERK1/2 phosphorylation in LPS-treated endothelial cells. These effects were abolished by a PKC inhibitor or α1-AR antagonist. PE also reduced p65 nuclear translocation, but this suppression is not blocked by PKC inhibition. Treatment with U0126 (a specific ERK1/2 inhibitor) reversed the effects of PE on p38MAPK phosphorylation. Our results demonstrate that cardiac endothelial α1-AR activation prevents sepsis-induced myocardial dysfunction in mice by inhibiting the endothelial injury via PKC-ERK/p38MAPK signaling pathway and a PKC-independent inhibition of p65 nuclear translocation. These findings offer a new perspective for septic patients with cardiac dysfunction by inhibiting cardiac endothelial cell injury through α1-AR activation.

Nonalcoholic steatohepatitis (NASH) may soon become the leading cause of end-stage liver disease worldwide with limited treatment options. Liver fibrosis, which is driven by chronic inflammation and hepatic stellate cell (HSC) activation, critically determines morbidity and mortality in patients with NASH. Pyruvate kinase M2 (PKM2) is involved in immune activation and inflammatory liver diseases; however, its role and therapeutic potential in NASH-related fibrosis remain largely unexplored. Bioinformatics screening and analysis of human and murine NASH livers indicated that PKM2 was upregulated in nonparenchymal cells (NPCs), especially macrophages, in the livers of patients with fibrotic NASH. Macrophage-specific PKM2 knockout (PKM2FL/FLLysM-Cre) significantly ameliorated hepatic inflammation and fibrosis severity in three distinct NASH models induced by a methionine- and choline-deficient (MCD) diet, a high-fat high-cholesterol (HFHC) diet, and a western diet plus weekly carbon tetrachloride injection (WD/CCl4). Single-cell transcriptomic analysis indicated that deletion of PKM2 in macrophages reduced profibrotic Ly6Chigh macrophage infiltration. Mechanistically, PKM2-dependent glycolysis promoted NLR family pyrin domain containing 3 (NLRP3) activation in proinflammatory macrophages, which induced HSC activation and fibrogenesis. A pharmacological PKM2 agonist efficiently attenuated the profibrotic crosstalk between macrophages and HSCs in vitro and in vivo. Translationally, ablation of PKM2 in NPCs by cholesterol-conjugated heteroduplex oligonucleotides, representing a novel oligonucleotide drug that preferentially accumulates in the liver, dose-dependently reversed NASH-related fibrosis without causing observable hepatotoxicity. The present study highlights the pivotal role of macrophage PKM2 in advancing NASH fibrogenesis. Thus, therapeutic modulation of PKM2 in a macrophage-specific or liver-specific manner may serve as a novel strategy to combat NASH-related fibrosis.

Background: Dexmedetomidine (DEX) administered before or at 30 min after sepsis induction was reported to alleviate septic cardiomyopathy in experimental models. However, sepsis is a life-threatening organ dysfunction due to infection-induced dysregulated host response, whether DEX treatment in the presence of organ dysfunction affects septic cardiomyopathy is unknown. This study investigated the effect of DEX posttreatment on septic cardiomyopathy.Methods: Male wild-type and alpha 2A-adrenergic receptor (AR) knockout mice were exposed to lipopolysaccharide (LPS) or cecal ligation puncture (CLP), and cultured cardiac endothelial cells were used. Mouse survival, myocardial function, inflammatory response and related signaling pathways were determined.Results: DEX treatment at 6, 9 h after LPS challenge significantly reduced survival rate of LPS-challenged mice, especially at 9 h. DEX administered at 9 h after LPS injection or CLP significantly reduced survival in LPS or CLP-induced sepsis in wild-type mice, but not in alpha 2A-AR knockout mice. LPS treatment for 20 h decreased the left ventricle + dp/dt, increased myocardial interleukin (IL)-1 beta and IL-6 concentrations as well as cardiac endothelial tumor necrosis factor (TNF)-alpha, vascular cell adhesion molecule-1 (VCAM-1) and ICAM-1 expression, which were enhanced by DEX treated at 9 h after LPS injection in wild-type mice, but not in alpha 2A-AR knockout mice. Furthermore, DEX posttreatment increased p38 phosphorylation, c-Fos nuclear translocation and VCAM-1 expression in LPS-treated cardiac endothelial cells, which were eliminated by alpha 2A-AR knockout or PKC inhibitor.Conclusions: DEX posttreatment aggravates LPS-induced cardiac inflammation and myocardial dysfunction, at least in part, via activating cardiac endothelial alpha 2A-AR-mediated PKC signal pathway.

BackgroundIrreversible electroporation (IRE) is a novel local tumor ablation approach with the potential to stimulate an antitumor immune response. However, it is not effective in preventing distant metastasis in isolation. This study aimed to compare the potential of augmenting the antitumor immune response in patients with locally advanced pancreatic cancer (LAPC) who underwent IRE combined with chemotherapy and PD-1/PD-L1 blockade with those who underwent IRE combined with chemotherapy.MethodsA retrospective review was conducted on LAPC patients treated either with IRE in combination with chemotherapy and PD-1/PD-L1 blockade (group A) or with IRE with chemotherapy alone (group B) from July 2015 to June 2021. The primary outcomes were overall survival (OS) and progression-free survival (PFS), with immune responses and adverse events serving as secondary endpoints. Risk factors for OS and PFS were identified using univariate and multivariate analyses.ResultsA total of 103 patients were included in the final analysis, comprising 25 in group A and 78 in group B. The median duration of follow-up was 18.2 months (3.0–38.6 months). Group A patients demonstrated improved survival compared to group B (median OS: 23.6 vs. 19.4 months, p = 0.001; median PFS: 18.2 vs. 14.7 months, p = 0.022). The data suggest a robust immune response in group A, while adverse events related to the treatment were similar in both groups. The multivariate analysis identified the combination of IRE, chemotherapy, and PD-1/PD-L1 blockade as an independent prognostic factor for OS and PFS.ConclusionThe addition of PD-1/PD-L1 blockade to the regimen of IRE combined with chemotherapy enhanced antitumor immunity and extended survival in LAPC patients.

Cardiomyopathy is a common complication and significantly increases the risk of death in septic patients. Our previous study demonstrated that post-treatment with dexmedetomidine (DEX) aggravates septic cardiomyopathy. However, the mechanisms for the side effect of DEX post-treatment on septic cardiomyopathy are not well-defined. Here we employed a cecal ligation and puncture (CLP) model and α2A-adrenoceptor deficient (Adra2a-/-) mice to observe the effects of DEX post-treatment on myocardial metabolic disturbances in sepsis. CLP mice displayed significant cardiac dysfunction, altered mitochondrial dynamics, reduced cardiac lipid and glucose uptake, impaired fatty acid and glucose oxidation, enhanced glycolysis and decreased ATP production in the myocardium, almost all of which were dramatically enhanced by DEX post-treatment in septic mice. In Adra2a-/- mice, DEX post-treatment did not affect cardiac dysfunction and metabolic disruptions in CLP-induced sepsis. Additionally, Adra2a-/- mice exhibited impaired cardiac function, damaged myocardial mitochondrial structures, and disturbed fatty acid metabolism and glucose oxidation. In sum, DEX post-treatment exacerbates metabolic disturbances in septic cardiomyopathy in a α2A-adrenoceptor dependent manner.

Cardiac dysfunction has been recognized as a major contributor to mortality in sepsis, which is closely associated with inflammatory reactions. The carboxy terminus of Hsc70-interacting protein (CHIP), a U-box E3 ubiquitin ligase, defends against cardiac injury caused by other factors, but its role in sepsis-induced cardiac dysfunction has yet to be determined. The present study was designed to investigate the effects of CHIP on cardiac dysfunction caused by sepsis and the molecular mechanisms underlying these processes. We discovered that the CHIP level decreased gradually in the heart at different time points after septic model construction. The decline in CHIP expression of lipopolysaccharide (LPS)-stimulated cardiomyocytes was related to c-Jun activation that inhibited the transcription of CHIP. Functional biology experiments indicated that CHIP bound directly to karyopherin-α 2 (KPNA2) and promoted its degradation through polyubiquitination in cardiomyocytes. CHIP overexpression in cardiomyocytes obviously inhibited LPS-initiated release of TNF-α and IL-6 by promoting KPNA2 degradation, reducing NF-κB translocation into the nucleus. Consistent with the in vitro results, data obtained from animal experiments indicated that septic transgenic mice with heart-specific CHIP overexpression showed a weaker proinflammatory response and reduced cardiac dysfunction than septic control mice. Furthermore, we found that the therapeutic effect of compound YL-109 on cardiac dysfunction in septic mice was due to the upregulation of myocardial CHIP expression. These findings demonstrated that sepsis-initiated the activation of c-Jun suppressed CHIP transcription. CHIP directly promoted ubiquitin-mediated degradation of KPNA2, which reduced the production of proinflammatory cytokines by inhibiting the translocation of NF-κB from the cytoplasm into the nucleus in myocardium, thereby attenuating sepsis-induced cardiac dysfunction.

Sevoflurane, a widely used inhalation anesthetic, has been shown to be cardioprotective in individuals with sepsis and myocardial dysfunction. However, the exact mechanism has not been completely explained. In this study, we performed whole-transcriptome profile analysis in the myocardium of lipopolysaccharide-induced septic mice after sevoflurane pretreatment. RNA transcriptome sequencing showed that 97 protein coding RNAs (mRNAs), 64 long noncoding RNAs (lncRNAs), and 27 microRNAs (miRNAs) were differentially expressed between the lipopolysaccharide and S_L groups. Functional enrichment analysis revealed that target genes for the differentially expressed mRNAs between the 2 groups participated in protein processing in the endoplasmic reticulum, antigen processing and presentation, and the mitogen-activated protein kinase signaling pathway. The bioinformatics study of differentially expressed mRNAs revealed that 13 key genes including Hsph1, Otud1, Manf, Gbp2b, Stip1, Gbp3, Hspa1b, Aff3, Med12, Kdm4a, Gatad1, Cdkn1a, and Ppp1r16b are related to the heart or inflammation. Furthermore, the competing endogenous RNA network revealed that 3 of the 13 key genes established the lncRNA-miRNA-mRNA network (ENSMUST00000192774 --- mmu-miR-7a-5p --- Hspa1b, TCONS_00188587 --- mmu-miR-204-3p --- Aff3 and ENSMUST00000138273 --- mmu-miR-1954 --- Ppp1r16b) may be associated with cardioprotection in septic mice. In general, the findings identified 11 potential essential genes (Hsph1, Otud1, Manf, Gbp2b, Stip1, Gbp3, Hspa1b, Aff3, Med12, Kdm4a, Gatad1, Cdkn1a, and Ppp1r16b) and mitogen-activated protein kinase signaling pathway involved in sevoflurane-induced cardioprotection in septic mice. In particular, sevoflurane may prevent myocardial injury by regulating the lncRNA-miRNA-mRNA network, including (ENSMUST00000192774-mmu-miR-7a-5p-Hspa1b, TCONS_00188587-mmu-miR-204-3p-Aff3, and ENSMUST00000138273-mmu-miR-1954-Ppp1r16b networks), which may be a novel mechanism of sevoflurane-induced cardioprotection.

Intrinsic cardiac adrenergic (ICA) cells regulate both developing and adult cardiac physiological and pathological processes. However, the role of ICA cells in septic cardiomyopathy is unknown. Here we show that norepinephrine (NE) secretion from ICA cells is increased through activation of Toll-like receptor 4 (TLR4) to aggravate myocardial TNF-α production and dysfunction by lipopolysaccharide (LPS). In ICA cells, LPS activated TLR4-MyD88/TRIF-AP-1 signaling that promoted NE biosynthesis through expression of tyrosine hydroxylase, but did not trigger TNF-α production due to impairment of p65 translocation. In a co-culture consisting of LPS-treated ICA cells and cardiomyocytes, the upregulation and secretion of NE from ICA cells activated cardiomyocyte β1-adrenergic receptor driving Ca2+/calmodulin-dependent protein kinase II (CaMKII) to crosstalk with NF-κB and mitogen-activated protein kinase pathways. Importantly, blockade of ICA cell-derived NE prevented LPS-induced myocardial dysfunction. Our findings suggest that ICA cells may be a potential therapeutic target for septic cardiomyopathy.

Occurring independently of cardiac sympathetic nervous system, the intrinsic cardiac adrenergic (ICA) cells have been identified as an important regulator in both of developing and adult cardiac physiological and pathological processes. However, its role in septic cardiomyopathy remains unknown. Herein, we report that lipopolysaccharide (LPS) dose- and time-dependently increased norepinephrine (NE) release from ICA cells, which aggravates myocardial TNF-α production and dysfunction. Inhibition of NE synthesis in ICA cells alleviated LPS-elicited cardiac dysfunction as well as TNF-α production in Langendorff perfusing hearts. Mechanistically, ICA cell expressed Toll-like receptor 4 (TLR4), activated by LPS, to increase the expression of tyrosine hydroxylase, a key enzyme responsible for NE biosynthesis, via AP-1 binding to its promoter. Surprisingly, LPS-TLR4 signaling triggered no TNF-α production in ICA cells due to the elevated Nfkbia and Tnfaip6 expression. In LPS-treated co-culture of ICA cells and cardiomyocytes, the raised NE from ICA cells activated cardiomyocyte β1-adrenergic receptor (β1-AR), driving Ca2+/calmodulin-dependent protein kinase II (CaMKII) to increase the activities of NF-κB and mitogen-activated protein kinase pathways, which were mimicked by dobutamine. Our findings reveal a cell type-specific TLR4 function triggering NE synthesis, but not TNF-α production in inflammatory pathogenesis, and identify ICA cell-derived NE as a paracrine signal in the cross talk among different cardiac cells to enhance myocardial injury during LPS challenge, suggesting that targeting ICA cell-derived NE may be a potential therapeutic strategy for septic cardiomyopathy.

ABSTRACT Dobutamine (DOB) is recommended as an inotrope for septic patients with low cardiac output, but its long-term impact on sepsis-induced cardiomyopathy remains unclear. This study investigated the long-term effect of DOB on septic myocardial dysfunction and injury. Rats were exposed to cecal ligation and puncture (CLP), the intrinsic myocardial function, other organ functions, hemodynamics, inflammatory response, serum myocardial injury biomarkers, myocardial apoptosis, and vascular permeability were determined. At 6 h after CLP, the left ventricular ±dP/dt were significantly depressed, cardiac tumor necrosis factor-α and vascular cell adhesion molecule-1 expression were increased, but not serum cardiac troponin I (cTnI), N-terminal pro-brain natriuretic peptide (NT-proBNP), heart-type fatty acid-binding protein (H-FABP), creatinine, and urea nitrogen concentrations in CLP group compared with controls. At 9 h after CLP, hepatic dysfunction was present in CLP rats compared with controls. At 6 h after CLP, DOB treatment did not affect hemodynamics, the left ventricular ±dP/dt, cytokine levels in serum and myocardium, as well as cardiomyocyte apoptosis and cardiac vascular hyperpermeability at 20 h after CLP. However, DOB (10.0 μg/kg) increased serum IL-10 level and improved survival in septic rats. These results indicate that the intrinsic myocardial depression occurs earlier than hepatic and renal dysfunction in sepsis and serum cTnI, NT-proBNP, and H-FABP are not suitable as early biomarkers for sepsis-induced myocardial dysfunction. Although DOB treatment (10.0 μg/kg) in the presence of myocardial dysfunction improves survival in septic rats, it neither improves myocardial function and hemodynamics nor attenuates myocardial injury at the later stage of sepsis.

Dexmedetomidine (DEX), a selective α2 adrenergic receptor (AR) agonist, is commonly used as a sedative drug during critical illness. In the present study, we explored a novel accelerative effect of DEX on cardiac fibroblast (CF) differentiation mediated by LPS and clarified its potential mechanism. LPS apparently increased the expression of α-SMA and collagen I/III and the phosphorylation of p38 and Smad-3 in the CFs of mice. These effects were significantly enhanced by DEX through increasing α2A-AR expression in CFs after LPS stimulation. The CFs from α2A-AR knockout mice were markedly less sensitive to DEX treatment than those of wild-type mice. Inhibition of protein kinase C (PKC) abolished the enhanced effects of DEX on LPS-induced differentiation of CFs. We also found that the α-SMA level in the second-passage CFs was much higher than that in the nonpassage and first-passage CFs. However, after LPS stimulation, the TNF-α released from the nonpassage CFs was much higher than that in the first- and second-passage CFs. DEX had no effect on LPS-induced release of TNF-α and IL-6 from CFs. Further investigation indicated that DEX promoted cardiac fibrosis and collagen I/III synthesis in mice exposed to LPS for four weeks. Our results demonstrated that DEX effectively accelerated LPS-induced differentiation of CFs to myofibroblasts through the PKC-p38-Smad2/3 signaling pathway by activating α2A-AR.

BackgroundDobutamine (DOB) has been recommended as the first-line inotrope for septic patients with low cardiac output, but its long-term impact on intrinsic myocardial dysfunction during sepsis remains unclear. This study investigated the long-term effect of DOB on intrinsic myocardial function and cardiomyocyte apoptosis in sepsis.MethodsMale Sprague-Dawley rats were randomly divided into sham and cecal ligation and puncture (CLP) groups. The intrinsic myocardial function and other organ functions were measured at different time points, the inflammatory response and serum biomarkers of myocardial injury were also determined. In separate experiments, the effect of DOB (5 or 10 µg/kg) treatment on survival, intrinsic myocardial function, serum and myocardial cytokines and myocardial apoptosis were measured in septic rats.ResultsThe mortality rate of septic rats was 70% on day 10 after CLP. At 6 h after CLP, the left ventricular ± dP/dt were significantly depressed, serum tumor necrosis factor (TNF) –α level, cardiac TNF-α, intercellular adhesion molecule and vascular cell adhesion molecule-1 (VCAM-1) mRNA, and VCAM-1 protein levels were increased, but not serum cTnI, N-terminal pro-brain natriuretic peptide (NT-proBNP), heart-type fatty acid-binding protein (H-FABP), creatinine and urea nitrogen concentrations as well as lung wet-dry weight ratios in CLP group compared with those in sham group. At 9 h after CLP, serum alanine aminotransferase and aspartate aminotransferase activities were higher in CLP rats than controls. At 6 h after CLP, treatment with DOB did not affect the left ventricular ± dP/dt, the levels of TNF-α, interleukin (IL) − 1β and IL-6 in the serum and myocardium as well as cardiomyocyte apoptosis at 20 h after CLP. However, administration of 10.0 µg/kg DOB at 6 h after CLP significantly increased serum IL-10 level and improved survival in septic rats.ConclusionsThe intrinsic myocardial depression occurs earlier than hepatic and renal dysfunction in severe sepsis and serum cTnI, NT-proBNP and H-FABP are not suitable as an early biomarker for this kind of cardiac dysfunction. For septic rats, DOB treatment in the presence of intrinsic myocardial dysfunction neither improves myocardial function nor attenuates myocardial inflammation and cardiomyocyte apoptosis at the later stage of sepsis.

目的:利用脓毒症大鼠模型,比较常规超声和组织多普勒超声指标在早期诊断脓毒症大鼠心肌内在收缩与舒张功能障碍中的价值.方法:利用盲肠结扎穿孔(CLP)建立脓毒症大鼠模型,22只大鼠随机分成CLP组与假手术组,每组11只.利用ELISA和Western blot检测肿瘤坏死因子α(TNF-α)、细胞间黏附分子1(ICAM-1)和血管细胞黏附分子1(VCAM-1)的表达水平;离体心脏灌流、常规超声心动图和心脏组织多普勒成像测定心脏收缩与舒张功能.结果:与假手术组比较,CLP术后6 h,大鼠血清中TNF-α水平及左心室ICAM-1和VCAM-1表达显著升高,左心室±dp/dtmax显著降低,左心室每搏输出量与舒张末期容积显著降低,但左室射血分数的差异没有统计学显著性,二尖瓣血流速度E波峰值和A波峰值显著降低,二尖瓣环舒张早期运动速度E'波峰值和二尖瓣环舒张晚期运动速度A'波峰值显著降低,而E/E'比值的差异没有统计学显著性.相关分析显示,E'波峰值和A'波峰值分别与?dp/dtmax呈正相关(r分别为0.460和0.520,P<0.05).结论:组织多普勒成像可以有效评价脓毒症早期心肌内在舒张功能障碍,E'与A'峰值可以作为检测左室心肌舒张功能障碍的指标.

Polychlorinated biphenyls (PCBs) are a typical class of environmental contaminants recently shown to be metabolism-disrupting chemicals. Lipids are a highly complex group of biomolecules that not only form the structural basis of biofilms but also act as signaling molecules and energy sources. Lipid metabolic disorders contribute to multiple diseases, including obesity, diabetes, fatty liver, and metabolic syndromes. Although previous literature has reported that PCBs can affect lipid metabolism, including lipid synthesis, uptake, and elimination, few systematic summaries of the detailed process of lipid metabolism caused by PCB exposure have been published. Lipid metabolic processes involve many molecules; however, the key factors that are sensitive to PCB exposure have not been fully clarified. Here, we summarize the recent developments in PCB research with a focus on biomarkers of lipid metabolic disorders related to environmental exposures.

Plant growth and development are adversely affected by various environmental stresses. In this study, we investigated the possible function of glycinebetaine (GB) in improving abiotic stress tolerance in maize plants by exogenous application. Results indicated that GB application could effectively improve maize germination percentages, biomass weights and grain yield per plant under abiotic stresses. Moreover, GB-treated plants showed higher reactive oxygen species (ROS)-scavenging capacities, therefore less oxidative destruction than control plants under stresses. In addition, abscisic acid (ABA) levels were increased in GB-treated plants compared to control plants. The comparison of transcriptome profile was performed to analyze the possible mechanism underlying the enhanced tolerance mediated by GB. Many differentially expressed genes (DEGs) between GB-treated and control plants were found to be involved in responses to oxidative stress, abiotic stress and ABA. Taken together, these results indicated that GB might enhance abiotic stress tolerance in maize by regulating ROS-scavenging capacities and ABA-mediated stress-responsive pathways.