Dexmedetomidine post-treatment exacerbates metabolic disturbances in septic cardiomyopathy via α2A-adrenoceptor.

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.

Effectiveness evaluation of flipped classroom in emergency medicine online teaching for medical undergraduates.

INTRODUCTION: Due to policy changes in the context of COVID-19 pandemic, online teaching has become the main form of class in many Chinese universities. Flipped classroom has been widely used in other disciplines, but there is a dearth of evidence available about the use in online teaching of emergency medicine. This study aimed to develop a flipped classroom for online emergency medicine teaching and evaluate its effectiveness by comparing it with traditional lecture-based online teaching. METHODS: A total of 62 clinical medical undergraduates from Jinan University participated in this study from September to December in 2022. An online flipped classroom approach was developed (FC group, n = 31). Traditional lecture-based online teaching was applied as a contrast (LBT group, n = 31). The undergraduates completed examinations and questionnaires at the end of the course. A course experience questionnaire and course examination score were used to evaluate the effectiveness of the flipped classroom approach. RESULTS: Regarding the five dimensions of the course experience questionnaire, the scores for good teaching (3.47 ± 0.50 vs. 2.34 ± 0.48, p < .001), appropriate assessment (3.31 ± 0.68 vs. 2.95 ± 0.71, p = .043) and generic skills (3.16 ± 0.60 vs. 2.72 ± 0.39, p < .001) were higher for the FC group than for the LBT group. There was no significant difference between the two groups in clear goals and standards, and appropriate workload. The undergraduates in the FC group showed significantly higher overall satisfaction than those in the LBT group (3.52 ± 0.1.03 vs. 2.87 ± 0.92, p = .012). The examination scores (77.936 ± 11.573 vs. 70.484 ± 7.434, p < .001), especially the scores for questions related to case analysis (33.032 ± 5.363 vs. 26.968 ± 7.657, p < .001), were significantly higher in the FC group than in the LBT group. CONCLUSIONS: The flipped classroom for online teaching was efficient in improving undergraduates' emergency medical academic performance and promoting the development of clinical case analysis ability. These findings provide an alternative flipped classroom approach for online teaching of emergency medicine.

Berberine Alleviates Doxorubicin-Induced Myocardial Injury and Fibrosis by Eliminating Oxidative Stress and Mitochondrial Damage via Promoting Nrf-2 Pathway Activation.

Doxorubicin (DOX)-related cardiotoxicity has been recognized as a serious complication of cancer chemotherapy. Effective targeted strategies for myocardial protection in addition to DOX treatment are urgently needed. The purpose of this paper was to determine the therapeutic effect of berberine (Ber) on DOX-triggered cardiomyopathy and explore the underlying mechanism. Our data showed that Ber markedly prevented cardiac diastolic dysfunction and fibrosis, reduced cardiac malondialdehyde (MDA) level and increased antioxidant superoxide dismutase (SOD) activity in DOX-treated rats. Moreover, Ber effectively rescued the DOX-induced production of reactive oxygen species (ROS) and MDA, mitochondrial morphological damage and membrane potential loss in neonatal rat cardiac myocytes and fibroblasts. This effect was mediated by increases in the nuclear accumulation of nuclear erythroid factor 2-related factor 2 (Nrf2) and levels of heme oxygenase-1 (HO-1) and mitochondrial transcription factor A (TFAM). We also found that Ber suppressed the differentiation of cardiac fibroblasts (CFs) into myofibroblasts, as indicated by decreased expression of α-smooth muscle actin (α-SMA), collagen I and collagen III in DOX-treated CFs. Pretreatment with Ber inhibited ROS and MDA production and increased SOD activity and the mitochondrial membrane potential in DOX-challenged CFs. Further investigation indicated that the Nrf2 inhibitor trigonelline reversed the protective effect of Ber on both cardiomyocytes and CFs after DOX stimulation. Taken together, these findings demonstrated that Ber effectively alleviated DOX-induced oxidative stress and mitochondrial damage by activating the Nrf2-mediated pathway, thereby leading to the prevention of myocardial injury and fibrosis. The current study suggests that Ber is a potential therapeutic agent for DOX-induced cardiotoxicity that exerts its effects by activating Nrf2.

Posttreatment with dexmedetomidine aggravates LPS-induced myocardial dysfunction partly via activating cardiac endothelial α2A-AR in mice.

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 α2A-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 α2A-AR knockout mice. LPS treatment for 20 h decreased the left ventricle + dp/dt, increased myocardial interleukin (IL)-1ß and IL-6 concentrations as well as cardiac endothelial tumor necrosis factor (TNF)-α, 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 α2A-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 α2A-AR knockout or PKC inhibitor. CONCLUSIONS: DEX posttreatment aggravates LPS-induced cardiac inflammation and myocardial dysfunction, at least in part, via activating cardiac endothelial α2A-AR-mediated PKC signal pathway.

The E3 ubiquitin ligase CHIP protects against sepsis-induced myocardial dysfunction by inhibiting NF-κB-mediated inflammation via promoting ubiquitination and degradation of karyopherin-α 2.

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.

Intrinsic cardiac adrenergic cells contribute to LPS-induced myocardial dysfunction.

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 ß1-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.

Associations between serum total bilirubin, obesity and type 2 diabetes.

BACKGROUND: This study aims to examine the cross-sectional association between serum total bilirubin (STB) and type 2 diabetes (T2D) risk in the general population, and whether obesity could moderate this association. METHODS: We used data from the 1999-2018 National Health and Nutrition Examination Surveys (NHANES), including a total of 38,641 US adult participants who were 18 years or older. The STB was classified as the low, moderate, and high groups according to tertiles. RESULTS: We found that participants with lower STB had a significantly higher risk of T2D than those with moderate (OR = 0.81; 95% CI 0.74, 0.89; P < 0.001) and high (OR = 0.65; 95% CI 0.59, 0.73; P < 0.001) STB. Also, a significant interaction between body mass index (BMI) and STB on T2D was observed (P < 0.001). Stratified analysis showed that low STB was associated with a 20% and 27% decrease of T2D risk for moderate and high STB groups in obese patients, however, these effect estimates were smaller in the population with lower BMI (< 30 kg/m2). Similar associations of STB with glycohemoglobin and insulin resistance were observed. CONCLUSION: This study suggests that STB is associated with an elevated risk of T2D. More importantly, we reported for the first time that BMI may moderate the association between bilirubin and T2D.

Dexmedetomidine Promotes Lipopolysaccharide-Induced Differentiation of Cardiac Fibroblasts and Collagen I/III Synthesis through α2A Adrenoreceptor-Mediated Activation of the PKC-p38-Smad2/3 Signaling Pathway in Mice.

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.

The Long-term Effect of Dobutamine on Intrinsic Myocardial Function and Myocardial Injury in Septic Rats with Myocardial Dysfunction.

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.

The Effects of Chloroquine and Hydroxychloroquine on ACE2-Related Coronavirus Pathology and the Cardiovascular System: An Evidence-Based Review.

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to global public health and there is currently no effective antiviral therapy. It has been suggested that chloroquine (CQ) and hydroxychloroquine (HCQ), which were primarily employed as prophylaxis and treatment for malaria, could be used to treat COVID-19. CQ and HCQ may be potential inhibitors of SARS-CoV-2 entry into host cells, which are mediated via the angiotensin-converting enzyme 2 (ACE2), and may also inhibit subsequent intracellular processes which lead to COVID-19, including damage to the cardiovascular (CV) system. However, paradoxically, CQ and HCQ have also been reported to cause damage to the CV system. In this review, we provide a critical examination of the published evidence. CQ and HCQ could potentially be useful drugs in the treatment of COVID-19 and other ACE2 involved virus infections, but the antiviral effects of CQ and HCQ need to be tested in more well-designed clinical randomized studies and their actions on the CV system need to be further elucidated. However, even if it were to turn out that CQ and HCQ are not useful drugs in practice, further studies of their mechanism of action could be helpful in improving our understanding of COVID-19 pathology.

A new method for neonatal rat ventricular myocyte purification using superparamagnetic iron oxide particles.

BACKGROUND: Neonatal rat ventricular myocytes (NRVMs) have proven to be an ideal research model for cardiac disease. However, the current methods to purify NRVMs have a limitation to obtain high purity. The purpose of this study was to develop a NRVM purification method by using superparamagnetic iron oxide particles (SIOP). METHODS: NRVMs were purified by using SIOP (SIOP group). The differential attachment with or without bromodeoxyuridine (BrdU) treatment served as control and BrdU groups, respectively. The Percoll gradient (Percoll) and magnetic-activated cell sorting (MACS) methods were performed to compare the purity and viability of NRVMs with SIOP method. RESULTS: The SIOP group enriched NRVMs up to 93.9 ±â€¯2.0% purity determined by flow cytometry (FCM) and 95.6 ±â€¯1.3% by immunofluorescence count (IF). In contrast, the control group gave purities of 71.9 ±â€¯2.9% (by FCM) and 66.8 ±â€¯8.9% (by IF), and the BrdU group obtained 82.0 ±â€¯1.3% (by FCM) and 83.1 ±â€¯2.4% (by IF). The purity of SIOP-isolated NRVMs was not different from that of Percoll and MACS groups. However, the cardiomyocytes separated by these methods, except SIOP protocol, were mixed with intrinsic cardiac adrenergic cells. NRVMs purified by SIOP shaped the similar three-dimensional morphology, with no difference in cell yield, viability and cytosolic Ca2+ homeostasis at 24 h after isolation compared with NRVMs in other groups. Furthermore, SIOP-purified NRVMs retained the responses to phenylephrine and lipopolysaccharide challenge. CONCLUSION: We first reported an efficient and novel method to purify NRVMs using SIOP, which may help accelerate innovative research in the field of cardiomyocyte biology.

α2A-adrenergic blockade attenuates septic cardiomyopathy by increasing cardiac norepinephrine concentration and inhibiting cardiac endothelial activation.

Cardiomyopathy is a common complication associated with increased mortality in sepsis, but lacks specific therapy. Here, using genetic and pharmacological approaches, we explored the therapeutic effect of α2A-adrenergic receptor (AR) blockade on septic cardiomyopathy. CLP-induced septic rats were treated with BRL44408 (α2A-AR antagonist), prazosin (α1-AR antagonist) and/or reserpine. CLP-induced cardiomyopathy, indicated by reduced dP/dt and increased cardiac troponin I phosphorylation, was attenuated by BRL44408, this was associated with reduced cardiac TNF-α and endothelial VCAM-1 expression, cardiomyocyte apoptosis and related signal molecule phosphorylation. BRL44408 increased cardiac norepinephrine (NE) concentration in CLP rats. Pretreatment with reserpine that exhausts cardiac NE without affecting the circulating NE concentration or with prazosin partially abolished the cardioprotection of BRL44408 and reversed its inhibitory effects on myocardial TNF-α, apoptosis and related signal molecule phosphorylation, but not on VCAM-1 expression in septic rats. These effects of BRL44408 were confirmed by α2A-AR gene deletion in septic mice. Furthermore, α2-AR agonist not only enhanced LPS-induced TNF-α and VCAM-1 expression in cardiac endothelial cells that express α2A-AR, but also enhanced LPS-induced cardiac dysfunction in isolated rat hearts. Our data indicate that α2A-AR blockade attenuates septic cardiomyopathy by promoting cardiac NE release that activates myocardial α1-AR and suppressing cardiac endothelial activation.

Efficient Expression of Glutathione Peroxidase with Chimeric tRNA in Amber-less Escherichia coli.

The active center of selenium-containing glutathione peroxidase (GPx) is selenocysteine (Sec), which is is biosynthesized on its tRNA in organisms. The decoding of Sec depends on a specific elongation factor and a Sec Insertion Sequence (SECIS) to suppress the UGA codon. The expression of mammalian GPx is extremely difficult with traditional recombinant DNA technology. Recently, a chimeric tRNA (tRNAUTu) that is compatible with elongation factor Tu (EF-Tu) has made selenoprotein expression easier. In this study, human glutathione peroxidase (hGPx) was expressed in amber-less Escherichia coli C321.ΔA.exp using tRNAUTu and seven chimeric tRNAs that were constructed on the basis of tRNAUTu. We found that chimeric tRNAUTu2, which substitutes the acceptor stem and T-stem of tRNAUTu with those from tRNASec, enabled the expression of reactive hGPx with high yields. We also found that chimeric tRNAUTuT6, which has a single base change (A59C) compared to tRNAUTu, mediated the highest reactive expression of hGPx1. The hGPx1 expressed exists as a tetramer and reacts with positive cooperativity. The SDS-PAGE analysis of hGPx2 produced by tRNAUTuT6 with or without sodium selenite supplementation showed that the incorporation of Sec is nearly 90%. Our approach enables efficient selenoprotein expression in amber-less Escherichia coli and should enable further characterization of selenoproteins in vitro.

An unusual porous cationic metal-organic framework based on a tetranuclear hydroxyl-copper(ii) cluster for fast and highly efficient dichromate trapping through a single-crystal to single-crystal process.

An unusual porous cationic metal-organic framework based on a tetranuclear hydroxy-copper(ii) cluster displays fast and highly efficient dichromate trapping through a single-crystal to single-crystal process.

Berberine promotes antiproliferative effects of epirubicin in T24 bladder cancer cells by enhancing apoptosis and cell cycle arrest
.

OBJECTIVE: The present study was aimed to observe the effect of berberine (Ber) on epirubicin (EPI)-induced growth inhibition, apoptosis, and cell cycle arrest in T24 bladder cancer cells. METHODS: The cancer cells were exposed to EPI, with or without different concentrations of Ber. The viability of the cancer cells was measured by cell counting Kit-8, the apoptosis was determined by Hoechst 33258 staining and the expression of cleaved caspase-3, cleaved caspase-9, Bcl-2, Bax, and P53 proteins were detected by Western blot assay. In addition, cell cycle arrest and the production of reactive oxygen species (ROS) were also measured. RESULTS: We found that Ber enhanced the inhibitory effect of EPI on the viability of T24 cells and promoted EPI-induced cell cycle arrest at G0/G1 and apoptosis in T24 cells. EPI increased the expression of cleaved caspase-3, cleaved caspase-9, Bax, P53, and P21 proteins, all of which were enhanced by treatment with Ber. In contrast, Ber exposure further decreased the expression of Bcl-2 in EPI-treated T24 cells. Furthermore, we also demonstrated that Ber significantly increased ROS production in EPI-treated T24 cells. CONCLUSIONS: These data indicate that Ber enhances the antiproliferative effects of EPI in bladder cancer cells by promoting apoptosis and cell cycle arrest.
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A new strategy to obtain tetranuclear cobalt(ii) metal-organic frameworks based on the [Co4(µ3-OH)2] cluster: synthesis, structures and properties.

Three metal-organic frameworks (MOFs) {[Co4(OH)2(adc)6(H2O)5][Co2(OH)(btrb)]2·8H2O}n (1), {[Co4(OH)2(btrb)(nip)3(H2O)3]·4H2O}n (2·4H2O) and {[Co4(OH)2(btrb)(btc)2(H2O)2]·9H2O}n (3·9H2O) (btrb = 1,4-bis(1,2,4-triazol-4-ylmethyl)benzene, H2adc = 1,3-adamantanedicarboxylic acid, H2nip = 5-nitroisophthalic acid and H3btc = 1,3,5-benzenetricarboxylic acid) were synthesized by a hydrothermal method. 1 shows an unusual (3,4)-connected 2D network with a point symbol of (4·62)2(42·62·82) based on [Co4(µ3-OH)2] and [Co2(µ3-OH)] units. 2 is a 6-connected pcu topology based on the [Co4(µ3-OH)2] unit. 3 is a rare (3,8)-connected 3D framework with a rare point symbol of (4·5·6)2(42·56·616·72·82) based on the [Co4(µ3-OH)2] unit. The magnetic measurements reveal that 1-3 exhibit antiferromagnetic interactions between the adjacent cobalt(ii) centers. 1-3 are good photocatalysts for the degradation of methylene blue (MB). The 1,2-position nitrogen atoms of the 4-substituted 1,2,4-triazole ligand act as strong σ-donators to form a quite stable coordination quadrangle with two metal ions. The btrb ligand containing two 4-substituted 1,2,4-triazole rings is favorable to form tetranuclear metal units. By the regulation of the multicarboxylate ligands, the connection number of [Co4(µ3-OH)2] clusters increases from 4 in 1 to 6 in 2 and then 8 in 3. This work presents a novel but effective method to design and regulate the connection number (4, 6 and 8 connected in this work) of MOFs with 4-substituted 1,2,4-triazole and rigid multicarboxylate ligands.

Pathophysiology of sepsis-induced myocardial dysfunction.

Sepsis-induced myocardial dysfunction is a common complication in septic patients and is associated with increased mortality. In the clinical setting, it was once believed that myocardial dysfunction was not a major pathological process in the septic patients, at least in part, due to the unavailability of suitable clinical markers to assess intrinsic myocardial function during sepsis. Although sepsis-induced myocardial dysfunction has been studied in clinical and basic research for more than 30 years, its pathophysiology is not completely understood, and no specific therapies for this disorder exist. The purpose of this review is to summarize our current knowledge of sepsis-induced myocardial dysfunction with a special focus on pathogenesis and clinical characteristics.

Berberine in combination with yohimbine attenuates sepsis-induced neutrophil tissue infiltration and multiorgan dysfunction partly via IL-10-mediated inhibition of CCR2 expression in neutrophils.

Infiltration of activated neutrophils into the vital organs contributes to the multiple organ dysfunctions in sepsis. In the present study, we investigated the effects of berberine in combination with yohimbine (BY) on neutrophil tissue infiltration and multiple organ damage during sepsis, and further elucidated the involved mechanisms. Sepsis was induced in mice by cecal ligation and puncture (CLP). BY or CCR2 antagonist was administered 2h after CLP, and anti-IL-10 antibody (IL-10 Ab) or control IgG was injected intraperitoneally just before BY treatment. We found that IL-10 production was enhanced by BY therapy in septic mice. BY significantly attenuated neutrophil tissue infiltration and multiple organ injury in CLP-challenged mice, all of which were completely reversed by IL-10 Ab pretreatment. The levels of KC, MCP-1, MIP-1α and MIP-2 in the lung, liver and kidney were markedly increased 6h after CLP. BY reduced the tissue concentrations of these chemokines in septic mice, but IL-10 Ab pretreatment did not completely eliminate these inhibitory effects of BY. Particularly, dramatically increased CCR2 expression in circulating neutrophils of septic mice was reduced by BY and this effect was completely abolished by IL-10 Ab pretreatment. Furthermore, CCR2 antagonist also inhibited lung and renal injury and neutrophil infiltration in septic mice. Taken together, our data strongly suggest that BY therapy attenuates neutrophil tissue infiltration and multiple organ injury in septic mice, at least in part, via IL-10-mediated inhibition of CCR2 expression in circulating neutrophils.

ß1-adrenoceptor stimulation promotes LPS-induced cardiomyocyte apoptosis through activating PKA and enhancing CaMKII and IκBα phosphorylation.

INTRODUCTION: Caspase activation and cardiomyocyte apoptosis have been implicated in lipopolysaccharide (LPS)-induced cardiac contractile dysfunction. We have recently demonstrated that ß1-adrenoceptor (AR) activation by endogenous norepinephrine contributes to cardiomyocyte apoptosis in endotoxemic mice. Here, we further investigated the molecular mechanisms for the enhancing effect of ß1-AR activation on LPS-induced cardiomyocyte apoptosis. METHODS: The adult mouse ventricular myocytes were exposed to LPS, dobutamine, protein kinase A (PKA) inhibitor or/and nifedipine, an L-type Ca(2+) channel blocker. Male BALB/c mice were treated with LPS or/ and ß1-AR antagonist, atenolol. Cardiomyocyte apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) assay and apoptosis-associated molecules were detected. RESULTS: LPS induced apoptosis in adult mouse ventricular myocytes, dobutamine (DOB), a ß1-AR agonist, promoted apoptosis, caspase-8, 9 and 3 activation and increased cytosolic Ca(2+) concentration in LPS-challenged cardiomyocytes. DOB also up-regulated TNF-α expression, decreased Bcl-2 levels, promoted Bax translocation to mitochondria, mitochondrial membrane potential loss and cytochrome c release as well as IκBα, p38 MAPK, JNK and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylation in LPS-treated cardiomyocytes. PKA inhibitor abolished the effects of DOB on caspase-9 activation, Bcl-2 levels as well as JNK and p38 MAPK phosphorylation, but not on IκBα phosphorylation, TNF-α expression and caspase-8 activation in LPS-stimulated cardiomyocytes. Pretreatment with nifedipine not only significantly blocked the enhancing effects of DOB on LPS-induced elevation in cytosolic Ca(2+) concentration and CaMKII phosphorylation in cardiomyocytes, but also partly reversed the effects of DOB on caspase-9 and caspase-3/7 activities in LPS-treated cardiomyocytes. Furthermore, atenolol suppressed TNF-α expression, JNK, p38 MAPK and CaMKII phosphorylation, increased Bcl-2 expression, and inhibited cytochrome c release and cardiomyocyte apoptosis in the myocardium of endotoxemic mice. CONCLUSIONS: ß1-AR activation promotes LPS-induced apoptosis through activating PKA, increasing CaMKII phosphorylation as well as enhancing IκBα phosphorylation and TNF-α expression in cardiomyocytes.

Neuromagnetic coherence of epileptic activity: an MEG study.

PURPOSE: This study was undertaken to test the hypothesis that patients with epilepsy have abnormal imaginary coherence compared with control subjects. METHODS: Thirty patients with seizures underwent magnetoencephalography (MEG) recording using a whole cortex MEG system. Conventional equivalent current dipoles (ECDs) and synthetic aperture magnetometry (SAM) were used to analyze MEG data. Neural synchronization was studied using imaginary coherence to analyze resting-state MEG data. The ECDs, SAM, and MEG results were then compared with intra/extra-operative EEG. RESULTS: Abnormal imaginary coherence was identified in all patients (30/30, 100%). The locations of abnormal imaginary coherence were in agreement with the ECDs locations of spikes in 23 patients (23/30, 76.7%). The ECD locations in 5 patients were scattered or located bilaterally. The locations of abnormal imaginary coherence were in agreement with SAM locations in 26 patients (26/30, 86.7%). One case of imaginary coherence was located in two lobes. The ECDs fit locations were in agreement with SAM locations in 21 patients (21/30, 70.0%). The locations of abnormal imaginary coherence, ECDs, and SAM were in agreement with intra/extra-operative EEG in 23 patients (23/30, 76.7%), 17 patients (17/30, 56.7%), and 20 patients (20/30, 66.7%), respectively. The results of ECDs location, SAM location, imaginary coherence, and intracranial EEG (iEEG) were consistent in 15 patients (15/30, 50%). CONCLUSIONS: The results show that patients with epilepsy have abnormal imaginary coherence, and suggest that the location and coherence of epileptic activity could be quantitatively identified and analyzed using neuromagnetic signals.