The mutation of Japanese encephalitis virus envelope protein residue 389 attenuates viral neuroinvasiveness.

The envelope (E) protein of the Japanese encephalitis virus (JEV) is a key protein for virus infection and adsorption of host cells, which determines the virulence of the virus and regulates the intensity of inflammatory response. The mutation of multiple aa residues in the E protein plays a critical role in the attenuated strain of JEV. This study demonstrated that the Asp to Gly, Ser, and His mutation of the E389 site, respectively, the replication ability of the viruses in cells was significantly reduced, and the viral neuroinvasiveness was attenuated to different degrees. Among them, the mutation at E389 site enhanced the E protein flexibility contributed to the attenuation of neuroinvasiveness. In contrast, less flexibility of E protein enhanced the neuroinvasiveness of the strain. Our results indicate that the mechanism of attenuation of E389 aa mutation attenuates neuroinvasiveness is related to increased flexibility of the E protein. In addition, the increased flexibility of E protein enhanced the viral sensitivity to heparin inhibition in vitro, which may lead to a decrease in the viral load entering brain. These results suggest that E389 residue is a potential site affecting JEV virulence, and the flexibility of the E protein of aa at this site plays an important role in the determination of neuroinvasiveness.

Prevalence of Malnutrition in Patients with Hepatocellular Carcinoma: A Comparative Study of GLIM Criteria, NRS2002, and PG-SGA, and Identification of Independent Risk Factors.

AIM: Malnutrition is prevalent in hepatocellular carcinoma (HCC) patients, linked to poor outcomes, necessitating early intervention. This study aimed to investigate malnutrition in HCC patients, assess Nutrition Risk Screening 2002 (NRS-2002) and Patient-Generated Subjective Global Assessment (PG-SGA) vs. Global Leadership Initiative on Malnutrition (GLIM) criteria, and identify independent risk factors. METHOD: A cross-sectional retrospective study was conducted on 207 patients with HCC. Nutritional screening/assessment results and blood samples were collected within 72 h of admission. This study assessed the prevalence of malnutrition using the NRS-2002 and PG-SGA and retrospectively using the GLIM criteria. The performance of the screening tools was evaluated using kappa (K) values. Logistic regression analyses were performed to determine whether laboratory parameters were associated with malnutrition as identified by the GLIM criteria. RESULTS: Of the participants, 30.4% were at risk of malnutrition according to NRS-2002. The agreement between the NRS-2002 and GLIM criteria was substantial. The GLIM criteria and PG-SGA diagnosed malnutrition in 43 and 54.6% of the participants, respectively. Age, anemia, and ascites correlated with malnutrition in regression. CONCLUSION: The GLIM criteria, along with NRS-2002 and PG-SGA, aid in diagnosing malnutrition in HCC patients. Recognizing risk factors improves accuracy, enabling timely interventions for better outcomes.

OSMAC Strategy: A promising way to explore microbial cyclic peptides.

Microbial secondary metabolites are pivotal for the development of novel drugs. However, conventional culture techniques, have left a vast array of unexpressed biosynthetic gene clusters (BGCs) in microorganisms, hindering the discovery of metabolites with distinct structural features and diverse biological functions. To address this limitation, several innovative strategies have been emerged. The "One Strain Many Compounds" (OSMAC) strategy, which involves altering microbial culture conditions, has proven to be particularly effective in mining numerous novel secondary metabolites for the past few years. Among these, microbial cyclic peptides stand out. These peptides often comprise rare amino acids, unique chemical structures, and remarkable biological function. With the advancement of the OSMAC strategy, a plethora of new cyclic peptides have been identified from diverse microbial genera. This work reviews the progress in mining novel compounds using the OSMAC strategy and the applications of this strategy in discovering 284 microbial cyclic peptides from 63 endophytic strains, aiming to offer insights for the further explorations into novel active cyclic peptides.

CircMap4k2 reactivated by aneurysm plication alleviates residual cardiac remodeling after SVR by enhancing cardiomyocyte proliferation in post-MI mice.

INTRODUCTION: Surgical ventricular reconstruction (SVR) is an alternative therapeutic approach in patients with refractory heart failure (HF), but residual remodeling after SVR limits the improvement of HF. Recently, we reported that SVR may act as an environmental cue to reactivate endogenous proliferation of cardiomyocytes; however, it is unclear whether enhancing endogenous cardiomyocyte regeneration further improves HF after SVR. OBJECTIVES: We aimed to explore whether circular RNAs (circRNAs) would involved in SVR and their mechanisms. METHODS: Male C57BL/6 mice were subjected to myocardial infarction (MI) or sham surgery. Four weeks later, MI mice with a large ventricular aneurysm underwent SVR or a second open-chest operation only. Echocardiography and histological analysis were used to evaluate heart function, cardiac remodeling, and myocardial regeneration. Sequencing of circular RNAs, RNA immunoprecipitation, RNA pulldown, and luciferase reporter assay were used to explore the underlying mechanisms. RESULTS: SVR markedly attenuated cardiac remodeling and induced cardiomyocyte regeneration, as evidenced by positive staining of Ki-67, phospho-histone H3 (pH3), and Aurora B in the plication zone, but significant residual remodeling still existed in comparison with the sham group. Sequencing results showed that SVR altered the expression profile of cardiac circRNAs, and circMap4k2 was identified as the most upregulated one. After characterizing circMap4k2, we noted that overexpression of circMap4k2 significantly promoted proliferation of cardiomyocytes in cultured neonatal rat cardiomyocytes and silencing of circMap4k2 significantly inhibited it; similar results were obtained in SVR-treated MI mice but not in MI mice without SVR treatment. Residual cardiac remodeling after SVR was further attenuated by circMap4k2 overexpression. CircMap4k2 bound with miR-106a-3p and inhibited cardiomyocyte proliferation by targeting a downstream effector of the antizyme inhibitor 1 (Azin1) gene. CONCLUSIONS: CircMap4k2 acts as an environmental cue and targets the miR-106a-3p/Azin1 pathway to increase cardiac regeneration in the plication zone and attenuate residual remodeling after SVR.

Oridonin Promotes Apoptosis in Rheumatoid Arthritis Fibroblast-like Synoviocytes Through PERK/eIF2α/CHOP of Endoplasmic Reticulum Stress Pathway.

Oridonin (ORI), derived from Chinese herbs Rabdosia rubescens, has anti-inflammatory, proapoptotic, anticancer effects. Previous studies have found that ORI induces apoptosis in rheumatoid arthritis fibroblast synovial cells (RA-FLSs), but this mechanism is not clear. We will investigate the apoptosis mechanism of ORI on RA-FLSs. RA-FLSs were treated with various concentrations of ORI (0, 5, 10, 15, 20, 25, and 30 µM) for 24 h. CCK8, LDH, and hochest/PI assay determined the viability, cytotoxicity, and death of ORI on RA-FLSs. The endoplasmic reticulum probe was used to observe structural changes of endoplasmic reticulum in RA-FLSs. RNA expression was detected with RNA sequencing analysis and quantitative real-time PCR. The PERK/eIF2α/CHOP pathway protein of the endoplasmic reticulum was verified with Western Blot. Our results show that ORI induced the apoptosis of RA-FLSs from CCK8, LDH, and Hochest/PI. The endoplasmic reticulum distribution was altered in RA-FLSs after being treated with ORI. Bioinformatics analysis of RNA sequencing data found that 1453 genes were elevated. The PERK/eIF2α/CHOP pathway of the endoplasmic reticulum was regulated from the Gene ontology and KEGG analysis. The results of quantitative real-time PCR and Western blot analysis verified the regulation of PERK/eIF2α/CHOP pathway in RA-FLSs. Our data imply that the endoplasmic reticulum's PERK/eIF2α/CHOP signaling pathway is certainly implicated in the induction of RA-FLS apoptosis by ORI. This study has important implications for the pharmacological effects of ORI and the treatment of RA.

Noninvasive Methods for Detecting Advanced Liver Fibrosis and Cirrhosis in Patients with Chronic Hepatitis B: A Single-Center Retrospective Study.

Background and Aims: The performance of noninvasive assessments to rule-in or rule-out fibrosis may improve when combined. We aimed to evaluate the efficiencies of sequential algorithms based on the aspartate aminotransferase-to-platelet ratio index (APRI), the fibrosis index based on four factors (FIB-4), and transient elastography (TE) for the assessment of advanced fibrosis (AF) and cirrhosis. Methods: This study enrolled 179 CHB subjects who underwent liver biopsy (LB) before antiviral treatment. Results: AF and cirrhosis were identified in 71 (39.7%) and 28 (15.7%) patients, respectively. Compared with TE alone, sequential FIB-4-TE and APRI-TE algorithms saved a slightly higher number of liver biopsies for the identification of advanced fibrosis (69.3% or 68.2% vs 63.7%, P=0.263 or P=0.372, respectively). For the identification of cirrhosis, sequential FIB-4-TE and APRI-TE algorithms saved a significantly higher number of liver biopsies than TE alone (83.2% or 88.3% vs 69.8%, P=0.003 or P=0.000, respectively). No significant difference was found between the sequential algorithms and TE alone in the diagnostic accuracy for the detection of AF and cirrhosis. Conclusion: The sequential algorithms could significantly reduce the need for liver biopsy with high accuracy for diagnosis of AF and cirrhosis in CHB patients, which would be optimal especially in resource-limited areas.

Impact of stress hyperglycemia ratio on mortality in patients with critical acute myocardial infarction: insight from american MIMIC-IV and the chinese CIN-II study.

BACKGROUND: Among patients with acute coronary syndrome and percutaneous coronary intervention, stress hyperglycemia ratio (SHR) is primarily associated with short-term unfavorable outcomes. However, the relationship between SHR and long-term worsen prognosis in acute myocardial infarction (AMI) patients admitted in intensive care unit (ICU) are not fully investigated, especially in those with different ethnicity. This study aimed to clarify the association of SHR with all-cause mortality in critical AMI patients from American and Chinese cohorts. METHODS: Overall 4,337 AMI patients with their first ICU admission from the American Medical Information Mart for Intensive Care (MIMIC)-IV database (n = 2,166) and Chinese multicenter registry cohort Cardiorenal ImprovemeNt II (CIN-II, n = 2,171) were included in this study. The patients were divided into 4 groups based on quantiles of SHR in both two cohorts. RESULTS: The total mortality was 23.8% (maximum follow-up time: 12.1 years) in American MIMIC-IV and 29.1% (maximum follow-up time: 14.1 years) in Chinese CIN-II. In MIMIC-IV cohort, patients with SHR of quartile 4 had higher risk of 1-year (adjusted hazard radio [aHR] = 1.87; 95% CI: 1.40-2.50) and long-term (aHR = 1.63; 95% CI: 1.27-2.09) all-cause mortality than quartile 2 (as reference). Similar results were observed in CIN-II cohort (1-year mortality: aHR = 1.44; 95%CI: 1.03-2.02; long-term mortality: aHR = 1.32; 95%CI: 1.05-1.66). In both two group, restricted cubic splines indicated a J-shaped correlation between SHR and all-cause mortality. In subgroup analysis, SHR was significantly associated with higher 1-year and long-term all-cause mortality among patients without diabetes in both MIMIC-IV and CIN-II cohort. CONCLUSION: Among critical AMI patients, elevated SHR is significantly associated with and 1-year and long-term all-cause mortality, especially in those without diabetes, and the results are consistently in both American and Chinese cohorts.

Relationship between stress hyperglycemia and worsening heart failure in patients with significant secondary mitral regurgitation.

BACKGROUND AND AIMS: Secondary mitral regurgitation (sMR), a major valvular disease, is prevalent in patients with coronary artery disease (CAD), and is associated with higher incidence of heart failure (HF) and mortality when present in combination with abnormal glucose metabolism. We aimed to evaluate the relationship between stress hyperglycemia ratio (SHR) and worsening HF in CAD patients with significant (grade ≥2) sMR. METHODS: We performed a multi-center observational study of 874 participants with significant sMR following percutaneous coronary intervention (PCI) in the Cardiorenal Improvement-II (CIN-II) cohort. Patients with glucose and glycated hemoglobin (HbA1c) data at admission were included in the analysis, and categorized according to the SHR, the ratio of mmol/L blood glucose to % HbA1c, as quartiles: Q1: <0.74; Q2: 0.74-0.91; Q3: 0.91-1.14; and Q4: ≥1.14. The primary clinical endpoint was worsening HF and the secondary endpoint was major adverse cardiac events (MACE). RESULTS: Of the 874 participants (64.1 ± 10.8 years, 80% male), 174 showed worsening HF and 226 developed MACE during a median follow-up of 3.7 years (interquartile range: 1.8-6.2 years). Compared to participants in the lowest quartile (Q1) of SHR, the highest quartile group (Q4) was at significantly higher risks of worsening HF (adjusted hazard ratio, 2.44; 95% confidence interval, 1.51-3.94; p< 0.001), while this was not associated with increased risk of MACE (p>0.05) after adjustment for potential covariates. For worsening HF, the results obtained for the normal glucose regulation subgroup may be more meaningful than those for the diabetes mellitus (DM) and pre-DM groups (p-interaction<0.001). For MACE, the acute myocardial infarction (AMI) (Q4 vs. Q1; HR: 0.65, 95%CI: 0.26-1.59) and non-AMI (Q4 vs. Q1; HR: 2.20, 95%CI: 1.36-3.54) subgroups differed significantly on MACE (p-interaction = 0.006). CONCLUSIONS: Increasing SHR is associated with a higher risk of worsening of HF in patients with significant sMR, especially in those with normoglycemia.

Increased SLAMF7+CD8+ T cells are associated with the pathogenesis of experimental autoimmune pancreatitis in mice.

BACKGROUND: IgG4-related autoimmune pancreatitis (AIP) is considered to be a T cell-mediated autoimmune disease. However, CD8+ T cells have only received brief mention, and have yet to be completely studied. The study aimed to investigate the expression of signaling lymphocytic activation molecule family 7 (SLAMF7) on CD8+ T cells and the features of SLAMF7+CD8+ T cells in MRL/Mp mice with AIP. METHODS: A murine model of AIP was established by intraperitoneal injection with polyinosinic:polycytidylic acid (poly I:C) for 8 weeks. Dexamethasone treatment was daily administrated for the last 2 weeks during a 6-week course of poly I:C. SLAMF7 expression on CD8+ T cells in the spleen and pancreas was detected by flow cytometry. Granzyme B (GZMB) and cytokines including IFN-γ, TNF-α, and IL-2, were monitored in an in vitro T cell activation assay. Dexamethasone suppression assays were performed to downregulate SLAMF7 expression on T cells upon T cell receptor stimulation. RESULTS: AIP in MRL/Mp mice was induced by repeated intraperitoneal administration of poly I:C and CD8+ T cells were increased in the inflamed pancreas. SLAMF7+CD8+ T cells were elevated in the spleen and pancreas of AIP mice. SLAMF7+CD8+ T subsets produced more GZMB, IFN-γ, TNF-α and IL-2 than SLAMF7-CD8+ T subsets. Dexamethasone treatment ameliorated pancreatic inflammatory and fibrosis of AIP. Dexamethasone could downregulate SLAMF7+CD8+ T cells and reduce GZMB, IFN-γ and TNF-α levels both in vitro and in vivo. CONCLUSIONS: Increased SLAMF7+CD8+ T cells exhibit enhanced cytotoxicity and cytokines secretion capacity, which may be involved in the pathogenesis of AIP.

Proportion and number of incident cancer deaths in coronary artery disease.

BACKGROUND: Globally, coronary artery disease (CAD) and cancer are the leading causes of death. Studies focusing on the proportion and spectrum of cancer mortality among CAD patients are lacking. We aim to characterize the proportion and spectrum of cancer-specific mortality among patients with CAD. METHODS: We analyzed 93,797 hospitalized survivors with angiographically documented CAD between 2007 and 2020 (mean age: 62.8 ± 11.1 years, 24.7% female) from Cardiorenal ImprovemeNt II (CIN-II) cohort. RESULTS: During the median follow-up of 4.8 years (IQR: 2.6-7.5), 13,162 (14.0%) patients died after discharge. A total of 1223/7703 (15.8% of cause-specific death) CAD patients died of cancer. The three most common types of cancer-specific death were lung (36.1%), liver (13.3%), and colorectum cancer (12.8%). Furthermore, male (adjusted HR 2.38, 95% CI: 1.99-2.85) and older (≥60 vs. <60 years, adjusted HR 3.25, 95%CI 2.72-3.88) patients had a significantly increased cancer-specific mortality. CONCLUSIONS: Our data suggest that nearly one-sixth of death is accounted for cancer among CAD patients within a median follow-up of 4.8 years. Lung, liver, and colorectum cancer are top three cancer-specific mortality. Further studies are needed to reduce cancer mortality for CAD patients, especially in older and male ones. TRAIL REGISTRATION: (ClinicalTrials.gov NCT05050877).

Effect of cumulative radiation exposure from Coronary catheterization on lung cancer mortality.

BACKGROUND: Coronary catheterization (CC) procedure inevitably exposes patients with cardiovascular disease (CVD) to radiation, while cumulative radiation exposure may lead to higher risk of cancer. METHODS: This multi-center, retrospective study was based on the CC procedure in Cardiorenal ImprovemeNt II cohort (CIN-II, NCT05050877) among five regional central tertiary teaching hospitals in China between 2007 and 2020. Patients without known cancer were stratified according to the times they received CC procedure. Baseline information from their last CC procedure was analyzed. Cox regression and Fine-Gray competing risk models were used to assess the relationship between cumulative radiation exposure from CC procedures and cancer-specific, all-cause and cardiovascular mortality. RESULTS: Of 136,495 hospitalized survivors without cancer at baseline (mean age: 62.3 ± 11.1 years, 30.9% female), 116,992 patients (85.7%) underwent CC procedure once, 15,184 patients (11.1%) on twice, and 4,319 patients (3.2%) underwent CC procedure more than three times. During the median follow-up of 4.7 years (IQR: 2.5 to 7.4), totally 18,656 patients (13.7%) died after discharge, of which 617 (0.5%) died of lung cancer. Compared with the patients who underwent CC procedure once, the risk of lung cancer mortality increased significantly with the increase of the number of CC procedure (CC 2 times vs. 1 time: HR 1.42, 95% CI 1.13 to 1.78, P < 0.001; CC ≥ 3 times vs. 1 time: HR 1.64, 95%CI 1.13 to 2.39, P < 0.05). Similar results were observed in all-cause mortality and cardiovascular mortality, but not in other cancer-specific mortality. CONCLUSIONS: Our data suggest that substantial proportion of CVD patients are exposed to multiple high levels of low-dose ionizing radiation from CC procedure, which is associated with an increased risk of cancer mortality in this population. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05050877; URL: http://www. CLINICALTRIALS: gov ; 21/09/2021.

Simplified Rapid Hydration Prevents Contrast-Associated Acute Kidney Injury Among CKD Patients Undergoing Coronary Angiography.

BACKGROUND: Patients with chronic kidney disease (CKD) undergoing coronary angiography (CAG) are at high risk of contrast-associated acute kidney injury (CA-AKI) and mortality. Therefore, there is a clinical need to explore safe, convenient, and effective strategies for preventing CA-AKI. OBJECTIVES: This study sought to assess whether simplified rapid hydration is noninferior to standard hydration for CA-AKI prevention in patients with CKD. METHODS: This multicenter, open-label, randomized controlled study was conducted across 21 teaching hospitals and included 1,002 patients with CKD. Patients were randomized to either simplified hydration (SH) (SH group, with normal saline from 1 hour before to 4 hours after CAG at a rate of 3 mL/kg/h) or standard hydration (control group, with normal saline 12 hours before and 12 hours after CAG at a rate of 1 mL/kg/h). The primary endpoint of CA-AKI was a ≥25% or 0.5-mg/dL rise in serum creatinine from baseline within 48 to 72 hours. RESULTS: CA-AKI occurred in 29 of 466 (6.2%) patients in the SH group and in 38 of 455 (8.4%) patients in the control group (relative risk: 0.8; 95% CI: 0.5-1.2; P = 0.216). In addition, the risk of acute heart failure and 1-year major adverse cardiovascular events did not differ significantly between the groups. However, the median hydration duration was significantly shorter in the SH group than in the control group (6 vs 25 hours; P < 0.001). CONCLUSIONS: In CKD patients undergoing CAG, SH is noninferior to standard hydration in preventing CA-AKI with a shorter hydration duration.

Mesenchymal Stem Cells Pretreated with Collagen Promote Skin Wound-Healing.

The existing treatment modalities for skin injuries mainly include dressings, negative-pressure wound treatment, autologous skin grafting, and high-pressure wound treatment. All of these therapies have limitations such as high time cost, the inability to remove inactivated tissue in a timely manner, surgical debridement, and oxygen toxicity. Mesenchymal stem cells have a unique self-renewal ability and wide differentiation potential, and they are one of the most promising stem cell types in cell therapy and have great application prospects in the field of regenerative medicine. Collagen exerts structural roles by promoting the molecular structure, shape, and mechanical properties of cells, and adding it to cell cultures can also promote cell proliferation and shorten the cell doubling time. The effects of collagen on MSCs were examined using Giemsa staining, EdU staining, and growth curves. Mice were subjected to allogeneic experiments and autologous experiments to reduce individual differences; all animals were separated into four groups. Neonatal skin sections were detected by HE staining, Masson staining, immunohistochemical staining, and immunofluorescence staining. We found that the MSCs pretreated with collagen accelerated the healing of skin wounds in mice and canines by promoting epidermal layer repair, collagen deposition, hair follicle angiogenesis, and an inflammatory response. Collagen promotes the secretion of the chemokines and growth factors associated with skin healing by MSCs, which positively influences skin healing. This study supports the treatment of skin injuries with MSCs cultured in medium with collagen added.

The Natural Alkaloid (-)-N-Hydroxyapiosporamide Suppresses Colorectal Tumor Progression as an NF-κB Pathway Inhibitor by Targeting the TAK1-TRAF6 Complex.

Colorectal cancer (CRC) is an exceptionally deadly disease, whereas effective therapeutic drugs for CRC have declined over the past few decades. Natural products have become a reliable source of anticancer drugs. Previously we isolated an alkaloid named (-)-N-hydroxyapiosporamide (NHAP), which exerts potent antitumor effects, but its effect and mechanism in CRC remain unclear. This study aimed to reveal the antitumor target of NHAP and identify NHAP as a promising lead compound for CRC. Various biochemical methods and animal models were used to investigate the antitumor effect and molecular mechanism for NHAP. These results showed that NHAP exhibited potent cytotoxicity, induced both apoptosis and autophagic cell death of CRC cells, and inhibited the NF-κB signaling pathway by blocking the interaction of the TAK1-TRAF6 complex. NHAP also markedly inhibited CRC tumor growth in vivo without obvious toxicities and possessed good pharmacokinetic characteristics. These findings identify, for the first time, that NHAP is an NF-κB inhibitor with potent antitumor activity in vitro and in vivo. This study clarifies the antitumor target of NHAP against CRC, which will contribute to the future development of NHAP as a novel therapeutic lead compound for CRC.

Renal Insufficiency Increases the Combined Risk of Left Ventricular Hypertrophy and Dysfunction in Patients at High Risk of Cardiovascular Diseases.

BACKGROUND: The identification of asymptomatic structural and functional cardiac abnormalities can help us to recognize early and intervene in patients at pre-heart failure (HF). However, few studies have adequately evaluated the associations of renal function and left ventricular (LV) structure and function in patients at high risk of cardiovascular diseases (CVD). METHODS: Patients undergoing coronary angiography and/or percutaneous coronary interventions were enrolled from the Cardiorenal ImprovemeNt II (CIN-II) cohort study, and their echocardiography and renal function were assessed at admission. Patients were divided into five groups according to their estimated glomerular filtration rate (eGFR). Our outcomes were LV hypertrophy and LV systolic and diastolic dysfunction. Multivariable logistic regression analyses were conducted to investigate the associations of eGFR with LV hypertrophy and LV systolic and diastolic dysfunction. RESULTS: A total of 5610 patients (mean age: 61.6 ± 10.6 years; 27.3% female) were included in the final analysis. The prevalence of LV hypertrophy assessed by echocardiography was 29.0%, 34.8%, 51.9%, 66.7%, and 74.3% for the eGFR categories >90, 61-90, 31-60, 16-30, and ≤15 mL/min per 1.73 m2 or for patients needing dialysis, respectively. Multivariate logistic regression analysis showed that subjects with eGFR levels of ≤15 mL/min per 1.73 m2 or needing dialysis (OR: 4.66, 95% CI: 2.96-7.54), as well as those with eGFR levels of 16-30 (OR: 3.87, 95% CI: 2.43-6.24), 31-60 (OR: 2.00, 95% CI: 1.64-2.45), and 61-90 (OR: 1.23, 95% CI: 1.07-1.42), were significantly associated with LV hypertrophy. This reduction in renal function was also significantly associated with LV systolic and diastolic dysfunction (all P for trend <0.001). In addition, a per one unit decrease in eGFR was associated with a 2% heightened combined risk of LV hypertrophy and systolic and diastolic dysfunction. CONCLUSIONS: Among patients at high risk of CVD, poor renal function was strongly associated with cardiac structural and functional abnormalities. In addition, the presence or absence of CAD did not change the associations. The results may have implications for the pathophysiology behind cardiorenal syndrome.

Influence of FOSL1 Inhibition on Vascular Calcification and ROS Generation through Ferroptosis via P53-SLC7A11 Axis.

BACKGROUND: Vascular calcification during aging is highly prevalent in patients with cardiovascular disease; however, there is still no improvement in clarifying the development of vascular calcification. FOSL1 is a transcription regulator belonging to the AP-1 family, which has a unique function in vascular senescence, but its role in vascular calcification needs to be further explored. METHODS: Primary mouse vascular smooth muscle cells were isolated and used to construct a calcification model in vitro. Seven-week-old male C57BL/6 mice were used to build the vitD3-induced calcification model in vivo. qRT-PCR and western blot were used to verify the expression of FOSL1 and other genes expressed in vascular smooth muscle cells and aortas. The level of calcification was determined by Alizarin Red S (ARS) staining and the calcium content assay. The level of cellular GSH was detected by the GSH assay kit. RESULTS: Here, we report that FOSL1 was up-regulated after high-calcium/phosphate treatment in both the in vivo and in vitro vascular calcification models. Functional studies have shown that the reduction of FOSL1 attenuates ferroptosis and calcification in vascular smooth muscle cells, as indicated by ARS staining, calcium content assay, and western blot. The inhibition of FOSL1 downregulated the expression of bone-related molecules including Msh Homeobox 2 (MSX2) and tumor necrosis factor receptor superfamily, member 11b/osteoprotegerin (OPG), suggesting that FOSL1 promoted osteogenic differentiation of vascular smooth muscle cells. Furthermore, we found that the ferroptosis-inducing drug erastin can significantly accelerate calcification in the aortic ring while Ferrostatin-1 (fer-1), a drug to protect cells from ferroptosis, can alleviate calcification. Further experiments have shown that inhibiting FOSL1 can promote the expression of ferroptosis-related genes and attenuate calcification. Functionally, cellular GSH levels were increased after the reduction of FOSL1. CONCLUSIONS: In this study, we observed a significant protective effect when we reduced the expression of FOSL1 during vascular calcification, and this effect might regulate ferroptosis to a great extent.

Association between triglyceride glucose index and worsening heart failure in significant secondary mitral regurgitation following percutaneous coronary intervention.

BACKGROUND: The triglyceride glucose (TyG) index is an alternative to insulin resistance (IR) as an early indicator of worsening heart failure (HF). Patients with secondary mitral regurgitation (sMR) often experience progressive deterioration of cardiac function. This study aimed to investigate the relationship between the TyG index and worsening of HF in significant sMR (grade ≥ 2) following percutaneous coronary intervention (PCI). METHODS: This study enrolled participants with significant sMR following PCI from a multicenter cohort study. The patients were divided into the following 3 groups according to tertiles of TyG index: T1, TyG ≤ 8.51; T2, TyG > 8.51 to ≤ 8.98; and T3, TyG > 8.98. The main clinical outcome was worsening HF including unplanned rehospitalization or unscheduled physician office/emergency department visit due to HF and unplanned mitral valve surgery. RESULTS: A total of 922 patients (mean ± SD age, 64.1 ± 11.0 years; 79.6% male) were enrolled. The incidence of worsening HF was 15.5% in T1, 15.7% in T2, and 26.4% in T3. In the multivariable model, the highest TyG tertile (T3 group) was more strongly correlated with worsening HF than the lowest tertile (T1 group) after adjusting for confounders (adjusted hazard ratio, 2.44; 95% confidence interval, 1.59-3.72; P < 0.001). The addition of TyG to risk factors such as N-terminal pro brain natriuretic peptide and clinical models improved the predictive ability of TyG for worsening HF. CONCLUSIONS: Elevated preprocedural TyG index is a significant and independent risk factor for worsening HF in sMR following PCI that can be used for risk stratification.

Liquid-Liquid Phase Separation in Cardiovascular Diseases.

Liquid-liquid phase separation (LLPS) is a biochemical process in cells that can drive proteins, RNA, and other molecules to concentrate into droplets. These droplets do not have a lipid membrane but rather exist as distinct organelles relative to the surrounding environment, and act as biochemical reaction chambers. In recent years, significant progress has been made in the study of LLPS, especially in the neurodegenerative disease, cancer, and virology fields, but little is known about LLPS in cardiovascular disease (CVD). In this review, we discuss the current understanding of the mechanism and biological functions of LLPS, particularly its roles in regulating CVD.

Prognosis and Risk Factors of Recurrence in HBV-Related Small Hepatocellular Carcinoma After Stereotactic Body Radiation Therapy.

Objective: The role of stereotactic body radiation therapy (SBRT) for treating small hepatocellular carcinoma (sHCC) has gained increasing recognition. However, the prognosis and risk factors for recurrence in patients with sHCC remain unclear. This study investigated the risk factors for the recurrence of hepatitis B virus (HBV)-related sHCC after SBRT. Methods: A total of 240 HBV-related sHCC patients treated with SBRT between March 2011 and March 2020 were retrospectively analyzed. The cumulative probability of recurrence was calculated according to the Kaplan-Meier method. Univariate and multivariate analyses were performed with Cox proportional hazard models. Results: Recurrent hepatocellular carcinoma developed in 134 (55.8%) patients at a median time of 27 months after SBRT. The one- and two-year rates of recurrence were 20.9 and 45.0%, respectively. The median follow-up time was 30 months. The Cox multivariate analysis indicated that age (P = 0.029, HR [1.019, 1.002-1.037]), tumor size (P = 0.012, HR [1.227, 1.045-1.440]), and aspartate aminotransferase-to-platelet ratio index (APRI) (P = 0.005, HR [1.911, 1.221-2.989]) were independent risk factors for recurrence. Conclusion: Patients receiving SBRT for HBV-related sHCC may be at greater risk of recurrence if they have a high APRI score combined with advanced age and large tumor size.

Sex Differences in Characteristics, Treatments, and In-hospital Outcomes of Patients Undergoing Coronary Angiography or Intervention.

Background: Whether women have a higher risk of adverse events compared with men following coronary angiography (CAG) and percutaneous coronary intervention (PCI) remains controversial. We aimed to investigate the sex differences in characteristics, treatments and outcomes among patients undergoing CAG and PCI in a large Chinese cohort. Methods: We analyzed patients undergoing CAG and/or PCI in this multi-center registry cohort study Cardiorenal ImprovemeNt II (CIN-II) in 5 Chinese tertiary hospitals from 2007 to 2020. Clinical characteristics, treatment (discharge medication and PCI) and in-hospital outcomes (mortality and major bleeding) were compared between women and men. Results: Totally 141,459 patients underwent CAG (44,362 [31.4%] women), of which 69,345 patients underwent PCI (15,376 [22.2%] women). Women were older (64.4 vs. 60.8 years), had more chronic comorbidities and lower PCI rate for stable coronary artery disease (CAD) than men (52.8 vs. 64.2%). Women received less CAG and PCI procedures. Among women undergoing PCI they received similar discharge medication treatment. In addition, women undergoing PCI had mildly lower rate of major bleeding (0.2 vs. 0.3%, P = 0.033) but higher in-hospital mortality (1.2 vs. 0.8%, P < 0.001). After adjustment, women had a higher risk in the major bleeding (adjusted odds ratio, 2.04 [95% CI: 1.07 to 3.62]), and the in-hospital mortality (adjusted odds ratio, 1.87 [95% CI: 1.36 to 2.56]). Conclusion: Among our Chinese cohort, women are older with more chronic comorbidities, receiving less PCI procedure and similar discharge medication treatment. Women have nearly 90% higher risk of in-hospital mortality and over 1-fold increased risk of major bleeding after PCI compared with men.