Disruption of the Na+/K+-ATPase-purinergic P2X7 receptor complex in microglia promotes stress-induced anxiety.

Na+/K+-ATPase (NKA) plays an important role in the central nervous system. However, little is known about its function in the microglia. Here, we found that NKAα1 forms a complex with the purinergic P2X7 receptor (P2X7R), an adenosine 5'-triphosphate (ATP)-gated ion channel, under physiological conditions. Chronic stress or treatment with lipopolysaccharide plus ATP decreased the membrane expression of NKAα1 in microglia, facilitated P2X7R function, and promoted microglia inflammatory activation via activation of the NLRP3 inflammasome. Accordingly, global deletion or conditional deletion of NKAα1 in microglia under chronic stress-induced aggravated anxiety-like behavior and neuronal hyperexcitability. DR5-12D, a monoclonal antibody that stabilizes membrane NKAα1, improved stress-induced anxiety-like behavior and ameliorated neuronal hyperexcitability and neurogenesis deficits in the ventral hippocampus of mice. Our results reveal that NKAα1 limits microglia inflammation and may provide a target for the treatment of stress-related neuroinflammation and diseases.

Pharmacology of hydrogen sulfide and its donors in cardiometabolic diseases.

Cardiometabolic diseases (CMDs) are major contributors to global mortality, emphasizing the critical need for novel therapeutic interventions. Hydrogen sulfide (H2S) has garnered enormous attention as a significant gasotransmitter with various physiological, pathophysiological, and pharmacological impacts within mammalian cardiometabolic systems. In addition to its roles in attenuating oxidative stress and inflammatory response, burgeoning research emphasizes the significance of H2S in regulating proteins via persulfidation, a well-known modification intricately associated with the pathogenesis of CMDs This review seeks to investigate recent updates on the physiological actions of endogenous H2S and the pharmacological roles of various H2S donors in addressing diverse aspects of CMDs across cellular, animal, and clinical studies. Of note, advanced methodologies including multi-omics, intestinal microflora analysis, organoid and single-cell sequencing techniques are gaining traction due to their ability to offer comprehensive insights into biomedical research. These emerging approaches hold promise in characterizing the pharmacological roles of H2S in health and diseases. We will critically assesse the current literatures to clarify the roles of H2S in diseases while also delineating the opportunities and challenges they present in H2S-based pharmacotherapy for CMDs. Significance Statement The comprehensive review covers recent developments in H2S biology and pharmacology in CMDs. Endogenous H2S and its donors show great promise for the management of CMDs by regulating numerous proteins and signaling pathways. The emergence of new technologies will considerably advance the pharmacological research and clinical translation of H2S.

o8G Site-Specifically Modified tRF-1-AspGTC: A Novel Therapeutic Target and Biomarker for Pulmonary Hypertension.

BACKGROUND: Hypoxia and oxidative stress contribute to the development of pulmonary hypertension (PH). tRNA-derived fragments play important roles in RNA interference and cell proliferation, but their epitranscriptional roles in PH development have not been investigated. We aimed to gain insight into the mechanistic contribution of oxidative stress-induced 8-oxoguanine in pulmonary vascular remodeling. METHODS: Through small RNA modification array analysis and quantitative polymerase chain reaction, a significant upregulation of the 8-oxoguanine -modified tRF-1-AspGTC was found in the lung tissues and the serum of patients with PH. RESULTS: This modification occurs at the position 5 of the tRF-1-AspGTC (5o8G tRF). Inhibition of the 5o8G tRF reversed hypoxia-induced proliferation and apoptosis resistance in pulmonary artery smooth muscle cells. Further investigation unveiled that the 5o8G tRF retargeted mRNA of WNT5A (Wingless-type MMTV integration site family, member 5A) and CASP3 (Caspase3) and inhibited their expression. Ultimately, BMPR2 (Bone morphogenetic protein receptor 2) -reactive oxygen species/5o8G tRF/WNT5A signaling pathway exacerbated the progression of PH. CONCLUSIONS: Our study highlights the role of site-specific 8-oxoguanine-modified tRF in promoting the development of PH. Our findings present a promising therapeutic avenue for managing PH and propose 5o8G tRF as a potential innovative marker for diagnosing this disease.

ErbB3 Governs Endothelial Dysfunction in Hypoxia-Induced Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension, characterized by vascular remodeling, currently lacks curative therapeutic options. The dysfunction of pulmonary artery endothelial cells plays a pivotal role in the initiation and progression of pulmonary hypertension (PH). ErbB3 (human epidermal growth factor receptor 3), also recognized as HER3, is a member of the ErbB family of receptor tyrosine kinases. METHODS: Microarray, immunofluorescence, and Western blotting analyses were conducted to investigate the pathological role of ErbB3. Blood samples were collected for biomarker examination from healthy donors or patients with hypoxic PH. The pathological functions of ErbB3 were further validated in rodents subjected to chronic hypoxia- and Sugen-induced PH, with or without adeno-associated virus-mediated ErbB3 overexpression, systemic deletion, or endothelial cell-specific ErbB3 knockdown. Primary human pulmonary artery endothelial cells and pulmonary artery smooth muscle cells were used to elucidate the underlying mechanisms. RESULTS: ErbB3 exhibited significant upregulation in the serum, lungs, distal pulmonary arteries, and pulmonary artery endothelial cells isolated from patients with PH compared with those from healthy donors. ErbB3 overexpression stimulated hypoxia-induced endothelial cell proliferation, exacerbated pulmonary artery remodeling, elevated systolic pressure in the right ventricle, and promoted right ventricular hypertrophy in murine models of PH. Conversely, systemic deletion or endothelial cell-specific knockout of ErbB3 yielded opposite effects. Coimmunoprecipitation and proteomic analysis identified YB-1 (Y-box binding protein 1) as a downstream target of ErbB3. ErbB3 induced nuclear translocation of YB-1 and subsequently promoted hypoxia-inducible factor 1/2α transcription. A positive loop involving ErbB3-periostin-hypoxia-inducible factor 1/2α was identified to mediate the progressive development of this disease. MM-121, a human anti-ErbB3 monoclonal antibody, exhibited both preventive and therapeutic effects against hypoxia-induced PH. CONCLUSIONS: Our study reveals, for the first time, that ErbB3 serves as a novel biomarker and a promising target for the treatment of PH.

STING Contributes to Pulmonary Hypertension by Targeting the Interferon and BMPR2 Signaling through Regulating F2RL3.

Pulmonary hypertension (PH) is an incurable disease characterized by pulmonary vascular remodeling. Endothelial injury and inflammation are the key triggers of the disease initiation. Recent findings suggest that STING (stimulator of interferon genes) activation plays a critical role in the endothelial dysfunction and interferon signaling. Here, we investigated the involvement of STING in the pathogenesis of PH. PH patients and rodent PH model samples, Sugen5416/hypoxia (SuHx) PH model, and pulmonary artery endothelial cells (PAECs) were used to evaluate the hypothesis. We found that the cyclic GMP-AMP (cGAS)-STING signaling pathway was activated in the lung tissues from rodent PH models and PH patients, and in the TNF-α induced PAECs in vitro. Specifically, STING expression was significantly elevated in the endothelial cell in PH disease settings. In SuHx mouse model, genetic knockout or pharmacological inhibition of STING prevented the progression of PH. Functionally, knockdown of STING reduced the proliferation and migration in PAECs. Mechanistically, STING transcriptional regulates its binding partner F2RL3 through STING-NF-κB axis, which activated the interferon signaling and repressed the BMPR2 signaling both in vitro and in vivo. Further analysis revealed that F2RL3 expression was increased in PH settings and identified negative feedback regulation of F2RL3/BMPR2 signaling. Accordingly, a positive correlation of expression levels between STING and F2RL3/interferon-stimulated genes (ISGs) was observed in vivo. Our findings suggest that STING activation in PAECs plays a critical role in the pathobiology of PH. Targeting STING may be a promising therapeutic strategy for preventing the development of PH.

GSDMD-mediated NETosis promotes the development of acute respiratory distress syndrome.

Gasdermin D (GSDMD) is a classical molecule involved in pyroptosis. It has been reported to be cleaved into N-terminal fragments to form pores in the neutrophil membrane and promote the release of neutrophil extracellular traps (NETs). However, it remains unclear if GSDMD is involved in neutrophil regulation and NET release during ARDS. The role of neutrophil GSDMD in the development of ARDS was investigated in a murine model of ARDS induced by lipopolysaccharide (LPS) using the neutrophil specific GSDMD-deficient mice. The neutrophil GSDMD cleavage and its relationship with NETosis were also explored in ARDS patients. The cleavage of GSDMD in neutrophils from ARDS patients and mice was upregulated. Inhibition of GSDMD by genetic knockout or inhibitors resulted in reduced production of NET both in vivo and in vitro, and attenuation of LPS-induced lung injury. Moreover, in vitro experiments showed that the inhibition of GSDMD attenuated endothelial injury co-cultured with neutrophils from ARDS patients, while extrinsic NETs reversed the protective effect of GSDMD inhibition. Collectively, our data suggest that the neutrophil GSDMD cleavage is crucial in NET release during ARDS. The NET release maintained by cleaved GSDMD in neutrophils may be a key event in the development of ARDS.

Untargeted metabolomics reveals potential plasma biomarkers for diagnosis of primary aldosteronism using liquid chromatography-mass spectrometry.

Metabolite profiling has the potential to comprehensively bridge phenotypes and complex heterogeneous physiological and pathological states. We performed a metabolomics study using parallel liquid chromatography-mass spectrometry (LC-MS) combined with multivariate data analysis to screen for biomarkers of primary aldosteronism (PA) from a cohort of 111 PA patients and 218 primary hypertension (PH) patients. Hydrophilic interaction chromatography and reversed-phase liquid chromatography separations were employed to obtain a global plasma metabolome of endogenous metabolites. The satisfactory classification between PA and PH patients was obtained using the MVDA model. A total of 35 differential metabolites were screened out and identified. A diagnostic biomarker panel was established using the least absolute shrinkage and selection operator (LASSO) binary logistic regression model and receiver operating characteristic analysis. Joint analysis with clinical indicators, including plasma supine aldosterone level, plasma orthostatic aldosterone level, body mass index, and blood potassium, revealed that the combination of metabolite biomarker panel and plasma supine aldosterone has the best clinical diagnostic efficacy.

Transcriptional landscape of cholangiocarcinoma revealed by weighted gene coexpression network analysis.

Cholangiocarcinoma (CCA) is a type of cancer with limited treatment options and a poor prognosis. Although some important genes and pathways associated with CCA have been identified, the relationship between coexpression and phenotype in CCA at the systems level remains unclear. In this study, the relationships underlying the molecular and clinical characteristics of CCA were investigated by employing weighted gene coexpression network analysis (WGCNA). The gene expression profiles and clinical features of 36 patients with CCA were analyzed to identify differentially expressed genes (DEGs). Subsequently, the coexpression of DEGs was determined by using the WGCNA method to investigate the correlations between pairs of genes. Network modules that were significantly correlated with clinical traits were identified. In total, 1478 mRNAs were found to be aberrantly expressed in CCA. Seven coexpression modules that significantly correlated with clinical characteristics were identified and assigned representative colors. Among the 7 modules, the green and blue modules were significantly related to tumor differentiation. Seventy-eight hub genes that were correlated with tumor differentiation were found in the green and blue modules. Survival analysis showed that 17 hub genes were prognostic biomarkers for CCA patients. In addition, we found five new targets (ISM1, SULT1B1, KIFC1, AURKB and CCNB1) that have not been studied in the context of CCA and verified their differential expression in CCA through experiments. Our results not only promote our understanding of the relationship between the transcriptome and clinical data in CCA but will also guide the development of targeted molecular therapy for CCA.

Unravelling Species Diversity and Pathogenicity of Colletotrichum Associated with Anthracnose on Osmanthus fragrans in Quanjiao, China.

Osmanthus fragrans is a popular ornamental tree species known for its fragrant flowers and is widely cultivated in Asia, Europe, and North America. Anthracnose is a disastrous threat to the growth and development of O. fragrans and has caused significant economic losses. To reveal the potential pathogen diversity of anthracnose, 127 isolates of Colletotrichum were isolated from the symptomatic leaves. Morphological studies and multilocus phylogenetic analyses with the concatenated sequences of the internal transcribed spacer, glyceraldehyde-3-phosphate dehydrogenase, chitin synthase, actin, beta-tubulin, calmodulin, and the intergenic region between Apn2 and Mat1-2-1, as well as a pairwise homoplasy index, test placed the causal fungi as two new species, Colletotrichum anhuiense (two isolates) and C. osmanthicola (12 isolates), and three known taxa, C. fructicola (18 isolates), C. gloeosporioides (62 isolates), and C. karstii (33 isolates). Among them, C. gloeosporioides was the most dominant, and C. anhuiense was occasionally discovered from the host tissues. Pathogenicity tests in vivo on O. fragrans leaves revealed a significant difference in virulence among these species. Of them, C. gloeosporioides, C. osmanthicola, and C. anhuiense were significantly more virulent than C. fructicola and C. karstii, while C. karstii was the least virulent. To our knowledge, this study was the first to report the pathogen diversity of anthracnose on O. fragrans.

A real-world study of the efficacy and safety of anti-PD-1 antibodies plus lenvatinib in patients with advanced gallbladder cancer.

BACKGROUND: Anti-PD-1 antibodies plus lenvatinib therapeutic regimens have demonstrated a relatively high antitumor response in many solid cancers; however, the efficacy and safety of anti-PD-1 antibodies plus lenvatinib in patients with advanced gallbladder cancer (GBC) has not been reported. METHODS: Advanced GBC patients who received anti-PD-1 antibodies plus lenvatinib were retrospectively screened. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), PD-L1 expression and safety were evaluated to identify efficacy biomarkers. RESULTS: A total of 31 GBC patients were included in this study. After a median follow-up of 8 months and 23 deaths were observed. The median PFS was 5.0 months (95% CI: 4.1-8.0 months), and the median OS was 11.3 months (95% CI: 7.5-20.9 months). Overall, the ORR was 32.3%, the DCR was 83.9%, and the CBR was 41.9%. Moreover, after treatment, 3 patients received conventional surgery, in which 1 patient achieved a pathological complete response. All patients (100%) experienced adverse events (AEs), and 58.1% of the patients experienced grade 3 AEs. The most commonly observed grade 3 AEs included fatigue (5/31, 16.1%), decreased appetite (5/31, 16.1%), hypertension (4/31, 12.9%) and bilirubin elevation (4/31, 12.9%). Subgroup analysis revealed that positive PD-L1 expression maybe associate with a longer PFS. CONCLUSION: Anti-PD-1 antibodies plus lenvatinib represent an effective and tolerable therapy for patients with advanced gallbladder cancer.

Periostin: A Potential Therapeutic Target For Pulmonary Hypertension?

RATIONALE: POSTN (Periostin) is an ECM (extracellular matrix) protein involved in tissue remodeling in response to injury and a contributing factor in tumorigenesis, suggesting that POSTN plays a role in the pathogenesis of pulmonary hypertension (PH). OBJECTIVE: We aimed to gain insight into the mechanistic contribution of POSTN in experimental mouse models of PH and correlate these findings with PH in humans. METHODS AND RESULTS: We used genetic epistasis approaches in human pulmonary artery endothelial cells (hPAECs), human pulmonary artery smooth muscle cells, and experimental mouse models of PH (Sugen 5416/hypoxia or chronic hypoxia) to discern the role of POSTN and its relationship to HIF (hypoxia-inducible factor)-1α signaling. We found that POSTN expression was correlated with the extent of PH in mouse models and in humans. Decreasing POSTN improved hemodynamic and cardiac responses in PH mice, blunted the release of growth factors and HIF-1α, and reversed the downregulated BMPR (bone morphogenetic protein receptor)-2 expression in hPAECs from patients with PH, whereas increasing POSTIN had the opposite effects and induced a hyperproliferative and promigratory phenotype in both hPAECs and human pulmonary artery smooth muscle cells. Overexpression of POSTN-induced activation of HIFs and increased the production of ET (endothelin)-1 and VEGF (vascular endothelial growth factor) in hPAECs. SiRNA-mediated knockdown of HIF-1α abolished the proangiogenic effect of POSTN. Blockade of TrkB (tyrosine kinase receptor B) attenuated the effect of POSTN on HIF-1α expression, while inhibition of HIF-1α reduced the expression of POSTN and TrkB. These results suggest that hPAECs produce POSTN via a HIF-1α-dependent mechanism. CONCLUSIONS: Our study reveals that POSTN expression is increased in human and animal models of PH and fosters PH development via a positive feedback loop between HIF-1α and POSTN during hypoxia. We propose that manipulating POSTIN expression may be an efficacious therapeutic target in the treatment of PH. Our results also suggest that POSTN may serve as a biomarker to estimate the severity of PH.

A dilute-and-shoot liquid chromatography-tandem mass spectrometry method for urinary 18-hydroxycortisol quantification and its application in establishing reference intervals.

BACKGROUND: Eighteen-hydroxycortisol (18-OHF) is a potential biomarker for differential diagnosis of the two major primary aldosteronism subtypes, aldosterone-producing adenoma, and idiopathic hyperaldosteronism. METHODS: Urine samples were processed, and the 18-OHF in urine samples were successfully quantified by in-house established dilute-and-shoot liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Separation was accomplished on a Sigma Ascentis Express C18 column with a gradient mixture of phase (A) 0.2% formic acid in water and phase (B) 0.2% formic acid in methanol at a flow rate of 0.4 ml/min. Mass spectrometric detection was performed in positive electrospray ionization mode via a mass spectrometer. RESULTS: The linearity of urinary 18-OHF ranged from 4.28 to 8.77 × 103 nmol/L, with a lower limit of quantification at 4.28 nmol/L. The intra- and inter-precision were both below 3%. The range of analytical recovery was 97.8%-109.2%. The validated dilute-and-shoot LC-MS/MS method was compared with the SPE LC-MS/MS method modified from the one reported in 2013. The results by Passing-Bablok regression analysis and Bland-Altman plotting demonstrated a good agreement between the two methods. The presented method was then applied to establish sex-specific reference intervals from 62 males and 62 females, respectively. The calculated 2.5%-97.5% reference intervals for 24-h urinary 18-OHF were 113-703 nmol/day for males and 71.2-450 nmol/day for females. CONCLUSION: The presented dilute-and-shoot LC-MS/MS method for 18-OHF quantification showed a good performance in the clinical application. Furthermore, the sex-specific reference intervals for 24-h urinary 18-OHF were first established and quite important for its application in primary aldosteronism subtyping.

Cross-cultural adaptation, reliability, and validity of the Chinese version of the Acceptance and Action Questionnaire-Adult Hearing Loss.

OBJECTIVE: Few mental health assessment tools are available for people with hearing loss (HL) in China. The Acceptance and Action Questionnaire-Adult Hearing Loss (AAQ-AHL) has been specifically designed to assess psychological inflexibility in adults with HL and may help assess mental health status promptly for targeted psychological interventions. The study aimed to investigate the cross-cultural validity and reliability of the Chinese version of the AAQ-AHL to assess its applicability to teenagers and adults with HL in China. DESIGN: A descriptive and correlational study of a convenience sample of students aged above 12 years. All participants were invited to complete an online questionnaire. STUDY SAMPLES: Participants included 402 students with HL. RESULTS: The Chinese version of the AAQ-AHL was shown to be an excellent, reliable, and valid instrument that can be used to assess psychological inflexibility in teenagers and adults with HL by clinicians working with Mandarin-speaking populations. CONCLUSION: Although the AAQ-AHL showed very good psychometric properties in hearing-impaired students aged above 12 years, further testing is needed to validate the measure across other age groups and validate its feasibility and utility in clinical applications.

The Fungal Endophyte Epicoccum dendrobii as a Potential Biocontrol Agent Against Colletotrichum gloeosporioides.

Anthracnose caused by Colletotrichum gloeosporioides is one of most serious fungal diseases on Chinese fir (Cunninghamia lanceolata). Eight fungal endophytes were isolated from a young heathy branch of Chinese fir and screened against the pathogen in vitro. One isolate, designated as SMEL1 and subsequently identified as Epicoccum dendrobii based on morphological and phylogenetic analyses, suppressed mycelial growth of Colletotrichum gloeosporioides on dual-culture plates. Additionally, E. dendrobii metabolites significantly decreased the biomass of Colletotrichum gloeosporioides. E. dendrobii was able to enter the internal tissues of the host plant via stomatal cells. Metabolites of E. dendrobii significantly inhibited conidial germination and appressorium formation, which at least partly explained why the endophyte significantly inhibited lesion development caused by Colletotrichum gloeosporioides on various host plants. We further confirmed that some components with antifungal activity could be extracted from E. dendrobii using ethyl acetate as an organic solvent. To our knowledge, this is the first report of E. dendrobii as a potential biocontrol agent against a fungal phytopathogen.

The Role of H2S in the Metabolism of Glucose and Lipids.

Glucose and lipids are essential elements for maintaining the body's homeostasis, and their dysfunction may participate in the pathologies of various diseases, particularly diabetes, obesity, metabolic syndrome, cardiovascular ailments, and cancers. Among numerous endogenous mediators, the gasotransmitter hydrogen sulfide (H2S) plays a central role in the maintenance of glucose and lipid homeostasis. Current evidence from both pharmacological studies and transgenic animal models suggest a complex relationship between H2S and metabolic dysregulation, especially in diabetes and obesity. This notion is achieved through tissue-specific expressions and actions of H2S on target metabolic and hormone organs including the pancreas, skeletal muscle, livers, and adipose. In this chapter, we will summarize the roles and mechanisms of H2S in several metabolic organs/tissues that are necessary for glucose and lipid metabolic homeostasis. In addition, future research directions and valuable therapeutic avenues around the pharmacological regulation of H2S in glycolipid metabolism disorder will be also discussed.

Chronic stress promotes colitis by disturbing the gut microbiota and triggering immune system response.

Chronic stress is known to promote inflammatory bowel disease (IBD), but the underlying mechanism remains largely unresolved. Here, we found chronic stress to sensitize mice to dextran sulfate sodium (DSS)-induced colitis; to increase the infiltration of B cells, neutrophils, and proinflammatory ly6Chi macrophages in colonic lamina propria; and to present with decreased thymus and mesenteric lymph node (MLN) coefficients. Circulating total white blood cells were significantly increased after stress, and the proportion of MLN-associated immune cells were largely changed. Results showed a marked activation of IL-6/STAT3 signaling by stress. The detrimental action of stress was not terminated in IL-6-/- mice. Interestingly, the composition of gut microbiota was dramatically changed after stress, with expansion of inflammation-promoting bacteria. Furthermore, results showed stress-induced deficient expression of mucin-2 and lysozyme, which may contribute to the disorder of gut microbiota. Of note is that, in the case of cohousing, the stress-induced immune reaction and decreased body weight were abrogated, and transferred gut microbiota from stressed mice to control mice was sufficient to facilitate DSS-induced colitis. The important role of gut microbiota was further reinforced by broad-spectrum antibiotic treatment. Taken together, our results reveal that chronic stress disturbs gut microbiota, triggering immune system response and facilitating DSS-induced colitis.

Targeting Lymphocyte Activation Gene 3 to Reverse T-Lymphocyte Dysfunction and Improve Survival in Murine Polymicrobial Sepsis.

BACKGROUND: Lymphocyte activation gene 3 (LAG-3) is one of the immune checkpoint molecules, negatively regulating the T-cell reactions. The present study investigated the role of LAG-3 in sepsis-induced T-lymphocyte disability. METHODS: Mice sepsis was induced by cecal ligation and puncture (CLP). LAG-3 expression on some immune cells were detected 24 hours after CLP. LAG-3 knockout and anti-LAG-3 antibody were applied to investigate the effects on the survival, bacterial clearance. Cytokine levels, T-cell counts, and the presence of apoptosis (in blood, spleen, and thymus) were also determined. In vitro T-cell apoptosis, interferon γ secretion, and proliferation were measured. The expression of interleukin 2 receptor on T cells was also determined after CLP. RESULTS: LAG-3 was up-regulated on CD4+/CD8+ T, CD19+ B, natural killer, CD4+CD25+ regulatory T cells and dendritic cells. Both LAG-3 knockout and anti-LAG-3 antibody had a positive effect on survival and on blood or peritoneal bacterial clearance in mice undergoing CLP. Cytokine levels and T-cell apoptosis decreased in anti-LAG-3 antibody-treated mice. Induced T-cell apoptosis decreased, whereas interferon γ secretion and proliferation were improved by anti-LAG-3 antibody in vitro. Interleukin 2 receptor was up-regulated on T cells in both wild-type and LAG-3-knockout mice undergoing CLP. CONCLUSIONS: LAG-3 knockout or anti-LAG-3 antibody blockade protected mice undergoing CLP from sepsis-associated immunodysfunction and may be a new target for the treatment.

Role of nitroxyl (HNO) in cardiovascular system: From biochemistry to pharmacology.

Cardiovascular diseases are recognized to be a major cause of people morbidity and mortality. A host of stress signals contribute to the pathogenesis of cardiovascular disorders. Deficiency of hydrogen sulfide (H2S) or nitric oxide (NO) coordinately plays essential roles in the development of cardiovascular diseases. Recent studies have shown that interaction between the two gaseostransmitters, H2S and NO, may give rise to nitroxyl (HNO), one-electron-reduced product of NO. HNO is found to exhibit a variety of biological and pharmacological properties including positive inotropy and cardiovascular protective effects, etc. In this review, recent progresses regarding HNO generation, detection, biochemical and pharmacological functions are discussed.

Novel nomograms based on immune and stromal scores for predicting the disease-free and overall survival of patients with hepatocellular carcinoma undergoing radical surgery.

BACKGROUND: Stromal and immune cells play important roles in hepatocellular carcinoma (HCC) development and progression. However, tools for predicting the prognosis of patients with HCC based on stromal and immune scores are not well established. We aimed to develop nomograms that predicted the disease-free survival (DFS) and overall survival (OS) of patients after radical surgery. METHODS: Basic information of 251 patients were retrieved from The Cancer Genome Atlas. Multivariate Cox analyses identified variables predicting the prognosis of patients. DFS and OS nomograms were constructed based on the stromal and immune scores of the training group and verified in the well-matched test group. RESULTS: An intermediate stromal score (hazards ratio [HR] = 3.177; P < .001] was an independent risk factor for DFS. An intermediate immune score independently predicted a longer DFS (HR = 0.323; P = .002) and OS (HR = 0.305; P = .021); a high immune score predicted a longer DFS (HR = 0.289; P = .002). The concordance index (C-index) of nomograms was 0.729 for DFS and 0.696 for OS in the test group. CONCLUSION: Nomograms based on the stromal and immune scores favorably predicted the DFS and OS of patients with HCC after radical surgery.

Exclusion of alternative exon 33 of CaV1.2 calcium channels in heart is proarrhythmogenic.

Alternative splicing changes the CaV1.2 calcium channel electrophysiological property, but the in vivo significance of such altered channel function is lacking. Structure-function studies of heterologously expressed CaV1.2 channels could not recapitulate channel function in the native milieu of the cardiomyocyte. To address this gap in knowledge, we investigated the role of alternative exon 33 of the CaV1.2 calcium channel in heart function. Exclusion of exon 33 in CaV1.2 channels has been reported to shift the activation potential -10.4 mV to the hyperpolarized direction, and increased expression of CaV1.2Δ33 channels was observed in rat myocardial infarcted hearts. However, how a change in CaV1.2 channel electrophysiological property, due to alternative splicing, might affect cardiac function in vivo is unknown. To address these questions, we generated mCacna1c exon 33-/--null mice. These mice contained CaV1.2Δ33 channels with a gain-of-function that included conduction of larger currents that reflects a shift in voltage dependence and a modest increase in single-channel open probability. This altered channel property underscored the development of ventricular arrhythmia, which is reflected in significantly more deaths of exon 33-/- mice from ß-adrenergic stimulation. In vivo telemetric recordings also confirmed increased frequencies in premature ventricular contractions, tachycardia, and lengthened QT interval. Taken together, the significant decrease or absence of exon 33-containing CaV1.2 channels is potentially proarrhythmic in the heart. Of clinical relevance, human ischemic and dilated cardiomyopathy hearts showed increased inclusion of exon 33. However, the possible role that inclusion of exon 33 in CaV1.2 channels may play in the pathogenesis of human heart failure remains unclear.