Inter-leg systolic blood pressure difference has been associated with all-cause and cardiovascular mortality: analysis of NHANES 1999-2004.

BACKGROUND: Inter-leg systolic blood pressure difference (ILSBPD) has emerged as a novel cardiovascular risk factor. This study aims to investigate the predictive value of ILSBPD on all-cause and cardiovascular mortality in general population. METHODS: We combined three cycles (1999-2004) of the National Health and Nutrition Examination Survey (NHANES) data. Levels of ILSBPD were calculated and divided into four groups based on three cut-off values of 5, 10 and 15mmHg. Time-to-event curves were estimated with the use of the Kaplan-Meier method, and two multivariable Cox proportional hazards regression models were conducted to assess the hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause and cardiovascular mortality associated with ILSBPD. RESULTS: A total of 6 842 subjects were included, with the mean (SD) age of 59.5 (12.8) years. By December 31, 2019, 2 544 and 648 participants were identified all-cause and cardiovascular mortality respectively during a median follow-up of 16.6 years. Time-to-event analyses suggested that higher ILSBPD was associated with increased all-cause and cardiovascular mortality (logrank, p < 0.001). Every 5mmHg increment of ILSBPD brings about 5% and 7% increased risk of all-cause and cardiovascular mortality, and individuals with an ILSBPD ≥ 15mmHg were significantly associated with higher incidence of all-cause mortality (HR 1.43, 95%CI 1.18-1.52, p < 0.001) and cardiovascular mortality (HR 1.73, 95%CI 1.36-2.20, p < 0.001) when multiple confounding factors were adjusted. Subgroup and sensitivity analysis confirmed the relationship. CONCLUSIONS: Our findings suggest that the increment of ILSBPD was significantly associated with higher risk of all-cause and cardiovascular mortality in general population.

Development of (2-(Benzyloxy)phenyl)methanamine Derivatives as Potent and Selective Inhibitors of CARM1 for the Treatment of Melanoma.

Coactivator-associated arginine methyltransferase 1 (CARM1), an important member of type I protein arginine methyltransferases (PRMTs), has emerged as a promising therapeutic target for various cancer types. In our previous study, we have identified a series of type I PRMT inhibitors, among which ZL-28-6 (6) exhibited increased activity against CARM1 while displaying decreased potency against other type I PRMTs. In this work, we conducted chemical modifications on compound 6, resulting in a series of (2-(benzyloxy)phenyl)methanamine derivatives as potent inhibitors of CARM1. Among them, compound 17e displayed remarkable potency and selectivity for CARM1 (IC50 = 2 ± 1 nM), along with notable antiproliferative effects against melanoma cell lines. Cellular thermal shift assay and western blot experiments confirmed that compound 6 effectively targets CARM1 within cells. Furthermore, compound 17e displayed good antitumor efficacy in a melanoma xenograft model, indicating that this compound warrants further investigation as a potential anticancer agent.

Unraveling varying spatiotemporal patterns of dengue and associated exposure-response relationships with environmental variables in Southeast Asian countries before and during COVID-19.

The enforcement of COVID-19 interventions by diverse governmental bodies, coupled with the indirect impact of COVID-19 on short-term environmental changes (e.g. plant shutdowns lead to lower greenhouse gas emissions), influences the dengue vector. This provides a unique opportunity to investigate the impact of COVID-19 on dengue transmission and generate insights to guide more targeted prevention measures. We aim to compare dengue transmission patterns and the exposure-response relationship of environmental variables and dengue incidence in the pre- and during-COVID-19 to identify variations and assess the impact of COVID-19 on dengue transmission. We initially visualized the overall trend of dengue transmission from 2012-2022, then conducted two quantitative analyses to compare dengue transmission pre-COVID-19 (2017-2019) and during-COVID-19 (2020-2022). These analyses included time series analysis to assess dengue seasonality, and a Distributed Lag Non-linear Model (DLNM) to quantify the exposure-response relationship between environmental variables and dengue incidence. We observed that all subregions in Thailand exhibited remarkable synchrony with a similar annual trend except 2021. Cyclic and seasonal patterns of dengue remained consistent pre- and during-COVID-19. Monthly dengue incidence in three countries varied significantly. Singapore witnessed a notable surge during-COVID-19, particularly from May to August, with cases multiplying several times compared to pre-COVID-19, while seasonality of Malaysia weakened. Exposure-response relationships of dengue and environmental variables show varying degrees of change, notably in Northern Thailand, where the peak relative risk for the maximum temperature-dengue relationship rose from about 3 to 17, and the max RR of overall cumulative association 0-3 months of relative humidity increased from around 5 to 55. Our study is the first to compare dengue transmission patterns and their relationship with environmental variables before and during COVID-19, showing that COVID-19 has affected dengue transmission at both the national and regional level, and has altered the exposure-response relationship between dengue and the environment.

Metal-Free Electron Donor-Acceptor Pair Enabled Long-Term Stability of Li-CO2 Battery.

The challenges of Lithium-carbon dioxide (Li-CO2) batteries for ensuring long-term cycling stability arise from the thermodynamically stable and electrically insulating discharge products (e.g., Li2CO3), which primarily rely on their interaction with the active materials. To achieve the optimized intermediates, the bifunctional electron donor-acceptor (D-A) pairs are proposed in cathode design to adjust such interactions in the case of B-O pairs. The inclusion of BC2O sites allows for the optimized redistribution of electrons via p-π conjugation. The as-obtained DO-AB pairs endow the enhanced interactions with Li+, CO2, and various intermediates, accompanied by the adjustable growth mode of Li2CO3. The shift from solvation-mediated mode into surface absorption mode in turn manipulates the morphology and decomposition kinetics of Li2CO3. Therefore, the corresponding Li-CO2 battery got twofold improved in both the capacity and reversibility. The cycling prolongs exceed 1300 h and well operates at a wide temperature range (20-50 °C) and different folding angles (0-180°). Such a strategy of introducing electron donor-acceptor pairs provides a distinct direction to optimize the lifetime of Li-CO2 battery from local structure regulation at the atomic scale, further inspiring in-depth understandings for developing electrochemical energy storage and carbon capture technologies.

Preclinical Pharmacokinetics and Pharmacology Study of RC98: A Programmed Cell Death Ligand 1 Monoclonal Antibody in Cynomolgus Monkeys.

INTRODUCTION: RC98 is the monoclonal antibody against Programmed Cell Death Ligand 1 (PD-L1). Relevant reports have confirmed that the influence of PD-L1 expressed by tumor cells on antitumor CD8+ T cell responses is well characterized, but the impact of PD-L1 expressed by immune cells has not been well defined. OBJECTIVE: This study aimed to design a Pharmacokinetics/Pharmacology (PK/PD) study of RC98 in normal cynomolgus monkeys to research the effect on the immune system. METHODS: RC98 and vehicle were administered to cynomolgus monkeys at 15 mg/kg via intravenous infusion once a week for 4 weeks to evaluate the relationship between PK and PD. The pharmacodynamic activity was measured by the PD-L1 receptor occupancy (RO) in CD3+ T cells, A T-cell-dependent antibody response (TDAR), and the concentration of soluble PD-L1. RESULTS: The pharmacokinetic result showed that the exposure from the last administration was lower than that of the first administration, probably due to immunogenicity production. There was a strong correlation between systemic exposure and RO in CD3+ T cells but decreased RO levels after the last dose, which indirectly reflected the activation of T cells. The keyhole limpet hemocyanin (KLH)-induced TDAR in the RC98 group was higher than in the vehicle group. The concentration of soluble PD-L1 had increased feedback with RC98, and the concentration of soluble PD-L1 was maintained at a higher level after multiple doses than before dosing. CONCLUSION: These data indicate that the immune system was clearly activated. In addition, the non-clinical data could provide a basis for its efficacy evaluation in clinical trials.

B(a)P induces ovarian granulosa cell apoptosis via TRAF2-NFκB-Caspase1 axis during early pregnancy.

Benzo(a)pyrene [B(a)P] is an environmental endocrine disruptor with reproductive toxicity. The corpus luteum (CL) of the ovary plays an important role in embryo implantation and pregnancy maintenance. Our previous studies have shown that B(a)P exposure affects embryo implantation and endometrial decidualization in mouse, but its effects and mechanisms on CL function remain unclear. In this study, we explore the mechanism of ovarian toxicity of B(a)P using a pregnant mouse model and an in vitro model of human ovarian granulosa cells (GCs) KGN. Pregnant mice were gavaged with corn oil or 0.2 mg/kg.bw B(a)P from pregnant day 1 (D1) to D7, while KGN cells were treated with DMSO, 1.0IU/mL hCG, or 1.0IU/mL hCG plus benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), a B(a)P metabolite. Our findings revealed that B(a)P exposure damaged embryo implantation and reduced estrogen and progesterone levels in early pregnant mice. Additionally, in vitro, BPDE impaired luteinization in KGN cells. We observed that B(a)P/BPDE promoted oxidative stress (OS) and inflammation, leading to apoptosis rather than pyroptosis in ovaries and luteinized KGN cells. This apoptotic response was mediated by the activation of inflammatory Caspase1 through the cleavage of BID. Furthermore, B(a)P/BPDE inhibited TRAF2 expression and suppressed NFκB signaling pathway activation. The administration of VX-765 to inhibit the Caspase1 activation, over-expression of TRAF2 using TRAF2-pcDNA3.1 (+) plasmid, and BetA-induced activation of NFκB signaling pathway successfully alleviated BPDE-induced apoptosis and cellular dysfunction in luteinized KGN cells. These findings were further confirmed in the KGN cell treated with H2O2 and NAC. In conclusion, this study elucidated that B(a)P/BPDE induces apoptosis rather than pyroptosis in GCs via TRAF2-NFκB-Caspase1 during early pregnancy, and highlighting OS as the primary contributor to B(a)P/BPDE-induced ovarian toxicity. Our results unveil a novel role of TRAF2-NFκB-Caspase1 in B(a)P-induced apoptosis and broaden the understanding of mechanisms underlying unexplained luteal phase deficiency.

Deubiquitinase USP4 suppresses antitumor immunity by inhibiting IRF3 activation and tumor cell-intrinsic interferon response in colorectal cancer.

Despite the approval of immune checkpoint blockade (ICB) therapy for various tumor types, its effectiveness is limited to only approximately 15% of patients with microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) colorectal cancer (CRC). Approximately 80%-85% of CRC patients have a microsatellite stability (MSS) phenotype, which features a rare T-cell infiltration. Thus, elucidating the mechanisms underlying resistance to ICB in patients with MSS CRC is imperative. In this study, we demonstrate that ubiquitin-specific peptidase 4 (USP4) is upregulated in MSS CRC tumors and negatively regulates the immune response against tumors in CRC. Additionally, USP4 represses the cellular interferon (IFN) response and antigen presentation and impairs PRR signaling-mediated cell death. Mechanistically, USP4 impedes the nuclear localization of interferon regulator Factor 3 (IRF3) by deubiquitinating the K63-polyubiquitin chain of TRAF6 and IRF3. Knockdown of USP4 enhances the infiltration of T cells in CRC tumors and overcomes ICB resistance in an MC38 syngeneic mouse model. Moreover, published datasets revealed that patients showing higher USP4 expression exhibited decreased responsiveness to anti-PD-L1 therapy. These findings highlight an essential role of USP4 in the suppression of antitumor immunity in CRC.

Structure-based discovery of potent CARM1 inhibitors for colorectal cancer therapy.

Coactivator-associated arginine methyltransferase 1 (CARM1) plays an important role in cell proliferation and gene expression, and is highly expressed in a variety of tumor tissues. Guided by our previous reported structure of DCPR049_12, we focused on designing and evaluating selective CARM1 inhibitors, resulting in the identification of compound 11f as a promising lead candidate. Compound 11f displayed potent inhibition of CARM1 (IC50 = 9 nM). Comprehensive evaluations, including in vitro metabolic stability assessments, molecular modelling, cellular studies, and in vivo anti-tumor studies, confirmed that it induced cancer cell apoptosis and specifically inhibited CARM1's methylation function. Notably, compound 11f displayed significant anti-proliferative effects on colorectal cancer cell lines, showcasing its potential for targeted therapies against CARM1-related diseases. This study provides valuable insights for the future development of specific and effective CARM1 inhibitors.

Unveiling the Role of Protein Kinase C θ in Porcine Epidemic Diarrhea Virus Replication: Insights from Genome-Wide CRISPR/Cas9 Library Screening.

Porcine epidemic diarrhea virus (PEDV), a member of the Alpha-coronavirus genus in the Coronaviridae family, induces acute diarrhea, vomiting, and dehydration in neonatal piglets. This study aimed to investigate the genetic dependencies of PEDV and identify potential therapeutic targets by using a single-guide RNA (sgRNA) lentiviral library to screen host factors required for PEDV infection. Protein kinase C θ (PKCθ), a calcium-independent member of the PKC family localized in the cell membrane, was found to be a crucial host factor in PEDV infection. The investigation of PEDV infection was limited in Vero and porcine epithelial cell-jejunum 2 (IPEC-J2) due to defective interferon production in Vero and the poor replication of PEDV in IPEC-J2. Therefore, identifying suitable cells for PEDV investigation is crucial. The findings of this study reveal that human embryonic kidney (HEK) 293T and L929 cells, but not Vero and IPEC-J2 cells, were suitable for investigating PEDV infection. PKCθ played a significant role in endocytosis and the replication of PEDV, and PEDV regulated the expression and phosphorylation of PKCθ. Apoptosis was found to be involved in PEDV replication, as the virus activated the PKCθ-B-cell lymphoma 2 (BCL-2) ovarian killer (BOK) axis in HEK293T and L929 cells to increase viral endocytosis and replication via mitochondrial apoptosis. This study demonstrated the suitability of HEK293T and L929 cells for investigating PEDV infection and identified PKCθ as a host factor essential for PEDV infection. These findings provide valuable insights for the development of strategies and drug targets for PEDV infection.

The regulation of CuSNPs' interface for further enhancing mechanical and photothermal conversion properties of chitosan/@CuSNPs hybrid fibers.

Our previous study has demonstrated that the microstructure of copper sulfide nanoparticles (CuSNPs) can be controlled to enhance mechanical and photothermal conversion properties of chitosan (CS)/CuSNPs hybrid fibers. However, achieving optimal dispersion and compatibility of CuSNPs within a CS matrix remains a challenge, this study aims to improve dispersion and compatibility by modifying the CuSNPs' interface, thereby enhancing mechanical and photothermal conversion properties of hybrid fibers. The interfaces of @CuSNPs (CuS@Xylan NPs, CuS@SA NPs, and CuS@PEG NPs) contain hydroxyl groups, facilitating the hydrogen bonds formation with the CS matrix. The dispersibility is further enhanced by the synergistic effect of xylan and SA's anionic charges with cationic chitosan. Notably, the viscosity of the CS/@CuSNPs hybrid spinning solution is significantly enhanced, resulting in improved breaking strength for initial hybrid fibers. Specifically, the breaking strength of CS/CuS@Xylan NPs hybrid fibers reaches 1.4 cN/dtex, exhibiting a 42.86 % and 20.6 % increase over CS and CS/CuSNPs hybrid fibers. Simultaneously, the CS/CuS@Xylan NPs hybrid fibers exhibit exceptional photothermal conversion performance, surpassing that of CS fibers by 5.2 times and CS/CuSNPs hybrid fibers by 1.4 times. The regulation of interface modification is an efficient approach to enhance the tensile strength and photothermal conversion properties of CS/CuSNPs hybrid fibers.

Efficacy of hepatectomy for hepatolithiasis using 3D visualization combined with ICG fluorescence imaging: A retrospective cohort study.

BACKGROUND: Hepatolithiasis is a complex condition that poses challenges and difficulties in surgical treatment. Three-dimensional visualization technology combined with fluorescence imaging (3DVT-FI) enables accurate preoperative assessment and real-time intraoperative navigation. However, the perioperative outcomes of 3DVT-FI in hepatolithiasis have not been reported. We aim to evaluate the efficacy of 3DVT-FI in the treatment of hepatolithiasis. METHODS: A retrospective analysis was performed on 128 patients who underwent hepatectomy for hepatolithiasis at the Department of Hepatobiliary Surgery, Zhujiang Hospital, between January 2017 and December 2022. Among them, 50 patients underwent hepatectomy using 3DVT-FI (3DVT-FI group), while 78 patients underwent conventional hepatectomy without 3DVT-FI (CH group). The operative data, postoperative liver function indices, complication rates and stone residue were compared between the two groups. RESULTS: There were no significant differences in preoperative baseline data between the two groups (p > 0.05). Compared with the CH group, the 3DVT-FI group exhibited lower intraoperative blood loss (140.00 ± 112.12 vs. 225.99 ± 186.50 mL, p = 0.001), and a lower intraoperative transfusion rate (8.0% vs. 23.1%, p = 0.027). The overall incidence of postoperative complications did not differ significantly (22.0% vs. 35.9%, p = 0.096). The 3DVT-FI group was associated with a lower immediate residual stone rate (16.0% vs. 34.6%, p = 0.021). There were no perioperative deaths in the 3DVT-FI group, while one perioperative death occurred in the CH group. CONCLUSIONS: The 3DVT-FI may offer significant benefits in terms of surgical safety, reduced intraoperative bleeding and decreased stone residue during hepatectomy for hepatolithiasis.

Investigation of shared genetic features and related mechanisms between diabetes and tuberculosis.

OBJECTIVE: This study aimed to integrate bioinformatics technology to explore shared hub genes and related mechanisms between diabetes and tuberculosis and to provide a theoretical basis for revealing the disease mechanisms in patients with both diabetes and tuberculosis. METHODS: Differentially expressed genes and Venn analysis were used to identify shared genes between diabetes and tuberculosis. PPI network analysis was used to screen key hub genes. GO and KEGG analyses were used to analyze the potential biological functions of these key hub genes. Immune infiltration analysis was performed using the ssGSEA algorithm. EnrichR online analysis website was used to explore potential therapeutic drugs. RESULTS: The dataset analysis showed that PSMB9, ISG15, RTP4, CXCL10, GBP2, and GBP3 were six hub genes shared by diabetes and tuberculosis, which not only could distinguish between the two disease samples but also had a high diagnostic rate. GO and KEGG analyses showed that these six genes mainly mediate immune-related biological processes such as interferon, interleukin, and chemokine receptor binding, as well as signaling pathways such as RIG-I-like receptor, NOD-like receptor, and proteasome. Immune infiltration analysis showed that high expression of TIL may mediate the development of both diabetes and tuberculosis. In addition, suloctidil HL60 UP, thioridazine HL60 UP, mefloquine HL60 UP, 1-NITROPYRENE CTD 00001569, and chlorophyllin CTD 00000324 were the candidate drugs predicted by this study that were most likely to target hub genes. CONCLUSION: Six differentially expressed genes shared by both diseases (PSMB9, ISG15, RTP4, CXCL10, GBP2, and GBP3) may play a key role in the disease progression of patients with both diabetes and tuberculosis. Candidate drugs targeting these hub genes have therapeutic potential and are worthy of further research. In summary, this study reveals potential shared pathogenic mechanisms between tuberculosis and diabetes.

Inverse Association between the Global Diet Quality Score and New-Onset Hypertension in Adults: A Nationwide Cohort Study.

BACKGROUND: The Global Diet Quality Score (GDQS) is a simple and practical dietary metric associated with a number of chronic diseases. The GDQS included various foods related to blood pressure, especially diverse plant-based foods that have shown to lower blood pressure. However, studies on the role of the GDQS in reducing the risk of new-onset hypertension and whether its performance differs from that of other dietary metrics are lacking. OBJECTIVE: We aimed to examine the association between the GDQS and new-onset hypertension and to compare its performance with that of other dietary patterns, including the Plant-based Diet Index (PDI), alternate Mediterranean diet (aMED) score, Alternative Healthy Eating Index-2010, and Dietary Approaches to Stop Hypertension (DASH) score in Chinese adults. METHODS: We included a total of 12,002 participants (5644 males and 6358 females) aged >18 y from the China Health and Nutrition Survey (1997-2015). Dietary intake was estimated using average food intakes from 3 consecutive 24-h dietary recalls. Multivariable relative risks (RRs) were computed for hypertension using modified Poisson regression models. RESULTS: With ≤18 y of follow-up (mean 8.7± 5.4 y), we ascertained 4232 incident cases of hypertension. Compared with participants with a low GDQS score (<15), the multivariable-adjusted RR of hypertension was 0.72 [95% confidence interval (CI): 0.62, 0.83] among participants with a high score (≥23). A 25% increment in the GDQS was associated with a 30% (RR, 0.70; 95% CI: 0.64, 0.76) lower risk of new-onset hypertension, which was comparable with the RRs of new-onset hypertension associated with every 25% increment in the PDI (RR, 0.84; 95% CI: 0.76, 0.93), DASH score (RR, 0.84; 95% CI: 0.78, 0.91), and aMED score (RR, 0.89; 95% CI: 0.84, 0.93). CONCLUSION: A higher GDQS was associated with a lower risk of new-onset hypertension, with comparable associations of new-onset hypertension with PDI, DASH, and aMED scores in Chinese adults.

A parameter-independent algorithm of finding maximum clique with Seidel continuous-time quantum walks.

The maximum clique (MC) problem holds significance in network analysis. Quantum-based algorithms have recently emerged as promising approaches for this problem. However, these algorithms heavily depend on parameters of quantum system and vary significantly for different graphs. In order to tackle this issue, we initially demonstrate that continuous-time quantum walks (CTQW) driven by the Seidel matrix offer valuable insights into the clique structure of graphs, outperforming the CTQW driven by adjacency matrix. Specifically, we conduct an in-depth analysis for CTQW of 4 types of graphs, meticulously calculating the amplitudes associated with different vertices. Our findings consistently reveal that vertices belonging to MC exhibit the highest intensity at the largest frequency component of the probability amplitude for these types of graphs. Considering the varying intensities, we propose a parameter-independent algorithm for determining the MC. We compare our algorithm with a typical quantum-based algorithm, the results indicate that our algorithm exhibits greater stability.

Chemical Compositions of Scutellaria baicalensis Georgi. (Huangqin) Extracts and Their Effects on ACE2 Binding of SARS-CoV-2 Spike Protein, ACE2 Activity, and Free Radicals.

The water and ethanol extracts of huangqin, the roots of Scutellaria baicalensis Georgi. with potential antiviral properties and antioxidant activities, were investigated for their chemical profiles and their abilities to interfere with the interaction between SARS-CoV-2 spike protein and ACE2, inhibiting ACE2 activity and scavenging free radicals. A total of 76 compounds were tentatively identified from the extracts. The water extract showed a greater inhibition on the interaction between SARS-CoV-2 spike protein and ACE2, but less inhibition on ACE2 activity than that of the ethanol extract on a per botanical weight concentration basis. The total phenolic content was 65.27 mg gallic acid equivalent (GAE)/g dry botanical and the scavenging capacities against HO●, DPPH●, and ABTS●+ were 1369.39, 334.37, and 533.66 µmol trolox equivalent (TE)/g dry botanical for the water extract, respectively. These values were greater than those of the ethanol extract, with a TPC of 20.34 mg GAE/g, and 217.17, 10.93, and 50.21 µmol TE/g against HO●, DPPH●, and ABTS●+, respectively. The results suggested the potential use of huangqin as a functional food ingredient in preventing COVID-19.

AdipoRon ameliorates the progression of heart failure with preserved ejection fraction via mitigating lipid accumulation and fibrosis.

INTRODUCTION: Obesity and imbalance in lipid homeostasis contribute greatly to heart failure with preserved ejection fraction (HFpEF), the dominant form of heart failure. Few effective therapies exist to control metabolic alterations and lipid homeostasis. OBJECTIVES: We aimed to investigate the cardioprotective roles of AdipoRon, the adiponectin receptor agonist, in regulating lipid accumulation in the two-hit HFpEF model. METHODS: HFpEF mouse model was induced using 60 % high-fat diet plus L-NAME drinking water. Then, AdipoRon (50 mg/kg) or vehicle were administered by gavage to the two-hit HFpEF mouse model once daily for 4 weeks. Cardiac function was evaluated using echocardiography, and Postmortem analysis included RNA-sequencing, untargeted metabolomics, transmission electron microscopy and molecular biology methods. RESULTS: Our study presents the pioneering evidence that AdipoR was downregulated and impaired fatty acid oxidation in the myocardia of HFpEF mice, which was associated with lipid metabolism as indicated by untargeted metabolomics. AdipoRon, orally active synthetic adiponectin receptor agonist, could upregulate AdipoR1/2 (independently of adiponectin) and reduce lipid droplet accumulation, and alleviate fibrosis to restore HFpEF phenotypes. Finally, AdipoRon primarily exerted its effects through restoring the balance of myocardial fatty acid intake, transport, and oxidation via the downstream AMPKα or PPARα signaling pathways. The protective effects of AdipoRon in HFpEF mice were reversed by compound C and GW6471, inhibitors of AMPKα and PPARα, respectively. CONCLUSIONS: AdipoRon ameliorated the HFpEF phenotype by promoting myocardial fatty acid oxidation, decreasing fatty acid transport, and inhibiting fibrosis via the upregulation of AdipoR and the activation of AdipoR1/AMPKα and AdipoR2/PPARα-related downstream pathways. These findings underscore the therapeutic potential of AdipoRon in HFpEF. Importantly, all these parameters get restored in the context of continued mechanical and metabolic stressors associated with HFpEF.

Mast cell stabilizer, an anti-allergic drug, reduces ventricular arrhythmia risk via modulation of neuroimmune interaction.

Mast cells (MCs) are important intermediates between the nervous and immune systems. The cardiac autonomic nervous system (CANS) crucially modulates cardiac electrophysiology and arrhythmogenesis, but whether and how MC-CANS neuroimmune interaction influences arrhythmia remain unclear. Our clinical data showed a close relationship between serum levels of MC markers and CANS activity, and then we use mast cell stabilizers (MCSs) to alter this MC-CANS communication. MCSs, which are well-known anti-allergic agents, could reduce the risk of ventricular arrhythmia (VA) after myocardial infarction (MI). RNA-sequencing (RNA-seq) analysis to investigate the underlying mechanism by which MCSs could affect the left stellate ganglion (LSG), a key therapeutic target for modulating CANS, showed that the IL-6 and γ-aminobutyric acid (GABA)-ergic system may be involved in this process. Our findings demonstrated that MCSs reduce VA risk along with revealing the potential underlying antiarrhythmic mechanisms.

Influence of skeletal muscle and intermuscular fat on postoperative complications and long-term survival in rectal cancer patients.

BACKGROUND: The body composition of patients with rectal cancer potentially affects postoperative outcomes. This study explored the correlations between skeletal muscle and adipose tissue quantified by computed tomography (CT) with postoperative complications and long-term prognosis in patients with rectal cancer after surgical resection. METHODS: This retrospective cohort study included patients with rectal cancer who underwent surgical resection at the Wuhan Union Hospital between 2014 and 2018. CT images within 3 months prior to the surgery were used to quantify the indices of skeletal muscle and adipose tissue at the levels of the third lumbar vertebra (L3) and umbilicus. Optimal cut-off values for each index were defined separately for males and females. Associations between body composition and postoperative complications, overall survival (OS), and disease-free survival (DFS) were evaluated using logistic and Cox proportional hazards models. RESULTS: We included 415 patients (240 males and 175 females; mean age: 57.8 ± 10.5 years). At the L3 level, a high skeletal muscle density (SMD; hazard ratio [HR]: 0.357, 95% confidence interval [CI]: 0.191-0.665, P = 0.001; HR: 0.571, 95% CI: 0.329-0.993, P = 0.047) and a high skeletal muscle index (SMI; HR: 0.435, 95% CI 0.254-0.747, P = 0.003; HR: 0.568, 95% CI: 0.359-0.897, P = 0.015) were independent prognostic factors for better OS and DFS. At the umbilical level, a large intermuscular fat area (IMFA; HR: 1.904, 95% CI: 1.068-3.395, P = 0.029; HR: 2.064, 95% CI: 1.299-3.280, P = 0.002) was an independent predictive factor for worse OS and DFS, and a high SMI (HR: 0.261, 95% CI: 0.132-0.517, P < 0.001; HR: 0.595, 95% CI: 0.387-0.913, P = 0.018) was an independent prognostic factor for better OS and DFS. The models combining body composition and clinical indicators had good predictive abilities for OS. The receiver operating characteristic areas under the curve were 0.848 and 0.860 at the L3 and umbilical levels, respectively (both P < 0.05). CONCLUSIONS: No correlations existed between CT-quantified body composition parameters and postoperative complications. However, a high SMD and high SMI were significantly associated with longer OS and DFS at the L3 level, whereas a large IMFA and low SMI were associated with worse OS and DFS at the umbilical level. Combining CT-quantified body composition and clinical indicators could help physicians predict the prognosis of patients with rectal cancer after surgery.

Cornuside protects against ischemic stroke in rats by suppressing the IL-17F/TRAF6/NF-κB pathway via the brain-gut axis.

Ischemic stroke is a serious neurological disease with limited therapeutic options; thus, it is particularly important to find effective treatments. Restoration of gut microflora diversity is an important factor in the treatment of ischemic stroke, but the mechanism remains unclear. Cornuside is known for its unique anti-inflammatory and circulation-promoting effects; however, whether it can effectively treat ischemic stroke and its therapeutic mechanisms remain unknown. In this study, we used a rat middle cerebral artery occlusion-reperfusion model (MCAO/R) to mimic ischemic stroke in humans and to assess the cerebral protective effects of cornuside in rats with ischemic stroke. Using 16S rRNA sequencing and RNA sequencing, we explored the cornuside mechanism in the brain-gut axis that confers protection against ischemic stroke. In conclusion, cornuside can inhibit the IL-17F/TRAF6/NF-κB pathway by improving the dysregulation of intestinal microflora, and reduce intestinal inflammation and neuroinflammation, which treated ischemic stroke rats.