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Summary: The association between anti-obesity medications (AOMs) as well as their weight-loss effects and cardiovascular outcomes need to be comprehensively investigated. We searched PubMed, Embase, the Cochrane Center Register of Controlled Trials for Studies, and Clinicaltrial.gov website from the inception to April 2024 and included 129 randomized controlled trials (RCTs) of AOMs. When compared with placebo, every 5 kg weight reduction mediated by AOMs was associated with the reduced risks of 3-point major adverse cardiovascular events (relative risk [RR] 0.72, 95% confidence interval [CI] 0.60–0.85), myocardial infarction (RR 0.75, 95% CI 0.60–0.95), stroke (RR 0.60, 95% CI 0.42–0.85), and heart failure (RR 0.71, 95% CI 0.54–0.95). As for glucagon-like peptide 1 receptor agonist (GLP-1RA)-users, similar cardiovascular benefits were also observed with 5 kg weight loss. This study indicated that the weight reductions mediated by AOMs were associated with cardiovascular benefits observed in AOM-users.

Saccharina japonica is a commercially important species in the seaweed industry, with a long history of cultivation. Understanding the differences in the integrated quality of S. japonica across major production regions is necessary for achieving high-quality output and maximizing resource utilization efficiency. However, to date, comprehensive analyses and evaluations of S. japonica have received limited attention. In this study, we analyzed variations and characteristics of 17 physical and chemical indices of S. japonica from nine cultivated populations across the three primary producing provinces in China, namely Fujian, Liaoning and Shandong. Correlation and path analysis were used to explore the interrelationships among the indices, while hierarchical cluster analysis was used to further identify similarities and differences among populations. We employed two comprehensive analysis methods: grey correlation degree analysis (GCDA) and dynamic technique for order preference by similarity to ideal solution (DTOPSIS) to evaluate the integrated quality of S. japonica. The results showed that coefficients of variation for all physical and chemical indices were 9.4 %–54.6 %, with the color index b* exhibiting the greatest variability. Significant correlations were observed among the physical and chemical indices, and blade length and width were identified as key determinants of fresh weight. Moreover, physical and chemical indices showed significant differences among populations and producing provinces. S. japonica from Liaoning exhibited superior morphological traits, while samples from Shandong displayed better appearance color and higher mannitol content. According to the ranking from the two comprehensive analysis methods, S. japonica from Liaoning had the best overall integrated quality. These findings provide a foundation for the scientific evaluation of the integrated quality of cultivated S. japonica, offering insights for breeding and cultivation strategies, and promoting the high-value utilization of S. japonica.

Background Neoadjuvant anti-programmed cell death protein-1 (PD-1) therapy exhibits potential in treating resectable non-small cell lung cancer (NSCLC). Previously, we have reported the 3-year clinical outcomes of this trial, implying the effectiveness and feasibility of neoadjuvant sintilimab monotherapy. However, the long-term prognosis of patients receiving neoadjuvant mono-immunotherapy has yet to be elucidated.Methods For patients with stage IA-IIIB NSCLC, two doses of sintilimab (200 mg) were administered intravenously in the neoadjuvant setting. The 5-year event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) were assessed in these updated results. The predictive role of specific biomarkers in neoadjuvant immunotherapy was also explored.Results With a median follow-up of 61.0 months, 5-year DFS and OS rates of patients who underwent R0 resection were 65.7% and 80.4%, respectively. The 5-year DFS and OS rates of patients with positive programmed death-ligand 1 (PD-L1) expression were 71.9% and 90.9%, respectively. The presence of PD-L1 positivity (tumor proportion score ≥1%) showed a tendency toward the promising prognosis (OS, HR, 0.143; 95% CI: 0.027 to 0.743), especially for those who did not achieve pathological complete response (pCR). In addition, tumor mutation burden was positively correlated with a favorable prognosis. A total of 10 recurrences and 5 subsequent deaths were identified within the 5-year follow-up, with lung metastasis being the predominant.Conclusions These updated analyses were the first to unveil the 5-year survival benefits of neoadjuvant sintilimab monotherapy, implying the potential value of PD-1 inhibitors in neoadjuvant therapy.

Abstract Copper ions play a crucial role as cofactors for essential enzymes in cellular processes. However, when the intracellular concentration of copper ions exceeds the homeostatic threshold, they become toxic to cells. In our study, we demonstrated that elesclomol, as a carrier of copper ions, caused an upregulation of protein phosphatase 1 regulatory subunit 15 A (PPP1R15A), which plays a role in regulating substrate selectivity of protein phosphatase 1 during cuproptosis. Mechanistically, we investigated that PPP1R15A activated translation initiation by dephosphorylating eukaryotic translation initiation factor 2 subunit alpha at the S51 residue through protein phosphatase 1 and phosphorylating eukaryotic translation initiation factor 4E binding protein 1 at the T70 residue. In addition, PPP1R15A reduced H3K4 methylation by altering the phosphorylation of histone methyltransferases, which led to the silencing of MYC and G2M phase arrest.

Abstract Aims Whether sodium‐glucose co‐transporter 2 inhibitors are effective for heart failure caused by ATTR‐CA (transthyretin cardiac amyloidosis) remains uncertain. The aim of this study is to investigate the cardiovascular prognosis in ATTR‐CA mice model with dapagliflozin treatment. Methods and results Humanized RBP4/TTRVal50Met and RBP4/TTR mice models were constructed with clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR‐Cas9) techniques and multiple generations breeding. A total of 6 RBP4/TTR mice received placebo treatment, when 12 RBP4/TTRVal50Met received dapagliflozin (1 mg/kg/day, 6 mice) and placebo (6 mice) treatment. Fasting glucose, intraperitoneal glucose tolerance test, and plasma brain natriuretic peptide (BNP) concentration were measured at Day 0, Week 2, and Week 4. BNP, transforming growth factor‐beta (TGF‐β), collagen type I alpha 1 (COL1A1) protein levels, and Cola1, TGFβ1, TNFα, IL‐1β, BNP relative quantities in cardiac, along with cardiac pathology examination including right ventricular collagen percentage, ventricular septum thickness, left ventricular wall thickness, and left ventricular internal diameter were measured at Week 4 after treatment procedure. All 18 mice completed the experiment. The baseline characteristics were balanced among three treatment groups. In placebo‐treated mice, the cardiac BNP relative quantity was significantly higher in RBP4/TTRVal50Met mice than RBP4/TTR mice (RBP4[KI/KI], TTR [KI/KI]: 0.72 ± 0.46, RBP4[KI/KI], TTRVal50Met[KI/KI]: 1.44 ± 0.60, P = 0.043), indicating more significant heart failure progression in ATTR‐CA mice than normal mice. In ATTR‐CA mice, the cardiovascular prognosis measurements including heart failure (plasma BNP concentration and relative quantities of BNP), cardiac inflammation (relative quantities of Cola1, TGFβ1, TNFα, and IL‐1β), and pathological changes (right ventricular collagen percentage, ventricular septum thickness, left ventricular wall thickness, and left ventricular internal diameter) were statistically comparable between those under dapagliflozin and placebo treatment. Conclusions Dapagliflozin did not improve cardiovascular prognosis including the progression of heart failure, cardiac inflammation, and pathological changes in ATTR‐CA mice compared with placebo. The results of this study were not in support of dapagliflozin's therapeutic effects for ATTR‐CA. More pre‐clinical and clinical researches to validate these findings and demonstrate the underlying mechanisms are still required.

Background: The chondrogenic differentiation of mesenchymal stem cells (MSCs) to enhance cartilage repair and regeneration is a promising strategy to alleviate osteoarthritis (OA) progression. Method: The potency of JD-312 in inducing chondrogenic differentiation of MSCs was assessed and verified. The efficacy of JD-312-treated MSCs was evaluated using a Sprague–Dawley rat DMM model. Additionally, the capacity of JD-312 to successfully recruit bone marrow-derived mesenchymal stem cells (BMSCs) for the treatment of OA in vitro was confirmed via intra-articular injection. The repair status of the articular cartilage was analyzed in vivo through histological examination. Result: In this study, we identify JD-312 as a novel non-toxic small molecule that can promote chondrogenic differentiation in human umbilical cord-derived MSCs (hUCMSCs) and human bone marrow MSCS (hBMSCs) in vitro. We also show that transient differentiation of MSCs with JD-312 prior to in vivo administration remarkably improves the regeneration of cartilage and promotes Col2a1 and Acan expression in rat models of DMM, in comparison to kartogenin (KGN) pre-treatment or MSCs alone. Furthermore, direct intra-articular injection of JD-312 in murine model of OA showed reduced loss of articular cartilage and improved pain parameters. Lastly, we identified that the effects of JD-312 are at least in part mediated via upregulation of genes associated with the focal adhesion, PI3K-Akt signaling and the ECM-receptor interaction pathways, and specifically cartilage oligomeric matrix protein (COMP) may play a vital role. Conclusion: Our study demonstrated that JD-312 showed encouraging repair effects for OA in vivo. The translational potential of this article: Together, our findings demonstrate that JD-312 is a promising new therapeutic molecule for cartilage regeneration with clinical potential.

Background/Objectives: Metabolic-associated fatty liver disease (MAFLD) is one of the most common liver disorders associated with obesity and metabolic syndrome, and poses a significant global health burden with limited effective treatments. The aim of this study was to assess the protective effects of mulberry twig alkaloids (SZ-A) on MAFLD and to further investigate the underlying mechanisms including the specific targets or pathways. Methods: Diet-induced obesity (DIO) and normal mouse models were established by feeding C57Bl/6J mice with a high-fat diet (HFD) or common diet for 12 weeks. SZ-A, dapagliflozin, and placebo were administered to corresponding mouse groups for 8 weeks. Data of fasting blood glucose, glucose tolerance, insulin tolerance, and the body weight of mice were collected at the baseline and termination of the experiment. Serum liver enzymes and lipids were measured by ELISA. Western blotting, qPCR, and pathological section staining were implemented to evaluate the degrees of liver steatosis, fibrosis, and oxidative stress in mice. Results: In DIO mouse models, high-dose SZ-A (800 mg/kg/d) treatment significantly inhibited HFD-induced weight gain, improved insulin tolerance, and reduced serum alanine aminotransferase, total cholesterol, and triglyceride levels compared with placebo. In DIO mice, SZ-A could alleviate the pathological changes of hepatic steatosis and fibrosis compared with placebo. Lipid catabolism and antioxidant stress-related proteins were significantly increased in the livers of the high-dose SZ-A group (p < 0.05). Inhibition of PGC1α could inhibit the function of SZ-A to enhance lipid metabolism in hepatocytes. PGC1α might interact with NRF2 to exert MAFLD-remedying effects. Conclusions: By regulating the expression of PGC1α and its interacting KEAP1/NRF2 pathway in mouse liver cells, SZ-A played important roles in regulating lipid metabolism, inhibiting oxidative stress, and postponing liver fibrosis in mice with MAFLD.

There are multiple disease-modifying immunotherapies showing the potential of preventing or delaying the progression of type 1 diabetes (T1D). We designed and performed this systematic review and meta-analysis to gain an overview of what a role immunotherapy plays in the treatment of T1D. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to December 2023. We included clinical trials of immunotherapy conducted in patients with T1D that reported the incidence of hypoglycemia or changes from baseline in at least one of following outcomes: 2 h and 4 h mixed-meal-stimulated C-peptide area under the curve (AUC), fasting C-peptide, daily insulin dosage, glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). The results were computed as the weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CIs) in random-effect model. In all, 34 clinical trials were included. When compared with control groups, 2 h C-peptide AUC was marginally higher in patient treated with nonantigen-based immunotherapies (WMD, 0.04nmol/L, 95% CI, 0.00–0.09 nmol/L, P=0.05), which was mainly driven by the effects of T cell-targeted therapy. A greater preservation in 4 h C-peptide AUC was observed in patients with nonantigen-based immunotherapies (WMD, 0.10nmol/L, 95% CI, 0.04–0.16 nmol/L, P=0.0007), which was mainly driven by the effects of tumor necrosis factor α (TNF-α) inhibitor and T cell-targeted therapy. After excluding small-sample trials, less daily insulin dosage was observed in patient treated with nonantigen-based immunotherapies when compared with control groups (WMD, −0.07units/kg/day, 95% CI, −0.11 to −0.03units/kg/day, P=0.0004). The use of antigen-based immunotherapies was also associated with a lower daily insulin dosage versus control groups (WMD, −0.11units/kg/day, 95% CI, −0.23 to −0.00units/kg/day, P=0.05). However, changes of HbA1c or FPG were comparable between nonantigen-based immunotherapies or antigen-based immunotherapies and control groups. The risk of hypoglycemia was not increased in patients treated with nonantigen-based immunotherapies or patients treated with antigen-based immunotherapies when compared with control groups. In conclusion, nonantigen-based immunotherapies were associated with a preservation of 2 h and 4 h C-peptide AUC in patients with T1D when compared with the controls, which was mainly driven by the effects of TNF-a inhibitor and T cell-targeted therapy. Both nonantigen-based immunotherapies and antigen-based immunotherapies tended to reduce the daily insulin dosage in patients with T1D when compared with the controls. However, they did not contribute to a substantial improvement in HbA1c or FPG. Both nonantigen-based immunotherapies and antigen-based immunotherapies were well tolerated with not increased risk of hypoglycemia in patients with T1D.

Grouting is an effective method to solve the problem of water inrush in tunnel and underground engineering. However, rock fractures are often simplified as horizontal and smooth fractures in most grouting studies, while studies on vertical inclined fractures are still rare. To investigate the diffusion law in vertical inclined fractures, a vertical inclined fracture grouting simulation device was developed. A new type of cement slurry with low weight and high flowing water resistance was developed by combining carbon nanotube (CNT) slurry with foamed cement. Physical simulation experiments were conducted to investigate various factors (initial flowing water, inclination angle, sand content, and grouting rate) on the sealing efficiency of grouting. Results show that the high foam content has a negative effect on the compressive strength of the slurry, and has a positive effect on the fluidity and water resistance. The optimum ratio of slurry is 30% foam content, 1.0% CNT content, 1.3 water/cement ratio, and 3% additive content. The inclination angle and inclination direction of the fracture have a great influence on the sealing efficiency of grouting. Foam-CNT composite grouts can meet the requirement of flowing water grouting in vertical inclined fractures.

Abstract Introduction To evaluate the association of sensitivity to thyroid hormone with metabolic syndrome (MetS) and its components in a Chinese euthyroid population. Methods A total of 3573 participants from Pinggu Metabolic Disease Study were analyzed. Serum‐free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin (TSH), total adipose tissue (TAT), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) area of abdominal, and lumbar skeletal muscle area (SMA) were measured. Central thyroid hormone resistance was calculated by the Thyroid Feedback Quantile‐based Index (TFQI) and Chinese‐referenced Parametric TFQI (PTFQI), Thyrotroph T4 Resistance Index (TT4RI) and TSH Index (TSHI). Peripheral thyroid hormone resistance was assessed by FT3/FT4 ratio. Results Higher values of TSHI (odds ratio [OR] = 1.167, 95% confidence interval [CI]: 1.079–1.262, p

Abstract Multimodal epigenetic characterization of cell-free DNA (cfDNA) could improve the performance of blood-based early cancer detection. However, integrative profiling of cfDNA methylome and fragmentome has been technologically challenging. Here, we adapt an enzyme-mediated methylation sequencing method for comprehensive analysis of genome-wide cfDNA methylation, fragmentation, and copy number alteration (CNA) characteristics for enhanced cancer detection. We apply this method to plasma samples of 497 healthy controls and 780 patients of seven cancer types and develop an ensemble classifier by incorporating methylation, fragmentation, and CNA features. In the test cohort, our approach achieves an area under the curve value of 0.966 for overall cancer detection. Detection sensitivity for early-stage patients achieves 73% at 99% specificity. Finally, we demonstrate the feasibility to accurately localize the origin of cancer signals with combined methylation and fragmentation profiling of tissue-specific accessible chromatin regions. Overall, this proof-of-concept study provides a technical platform to utilize multimodal cfDNA features for improved cancer detection.

Pesticides play a crucial role in agricultural production by preventing diseases and pests and ensuring food yield. However, the irrational use of pesticides can lead to numerous issues that compromise crop quality and counteract the original intentions of their application. Therefore, it is necessary to identify more effective methods to counteract pesticide stress. Here we review the impacts of herbicides, insecticides, and fungicides on plants and the measures taken to reduce pesticide residues on plants. We have found that despite the substantial differences in the mechanisms of action of the aforementioned three types of pesticides, the adverse effects they inflict on plants are similar, and at certain dosages, they can severely constrain plant growth and disrupt physiological functions. Also, most current research on using exogenous growth regulators to alleviate pesticide stress still focuses on photosynthesis, the antioxidant system, three-stage detoxification, and secondary metabolites, neglecting the search for genes that respond to pesticide stress. We believe that by combining biological protection with post-harvest treatment techniques and exploring potential genes that are responsive to pesticide stress, a better strategy for dealing with pesticide stress can be found, thereby promoting sustainable agricultural development.

Muscle-invasive and metastatic bladder cancer indicates extra worse prognosis. Accumulating evidence roots for the prominent role of circular RNAs(circRNAs) in bladder cancer, while the mechanisms linking circRNAs and bladder cancer metastasis remain limitedly investigated. Here, we identified a significantly upregulated circRNA candidate, hsa_circ_0001583, from online datasets. Validated by qRT-PCR, PCR, sanger sequencing, actinomycin D and RNase R digestion experiments, hsa_circ_0001583 was proved to be a genuine circular RNA with higher expression levels in bladder cancer tissue. Through gain and loss of function experiments, hsa_circ_0001583 exhibited potent migration and invasion powers both in vitro and in vivo. The staphylococcal nuclease and Tudor domain containing 1 (SND1) was identified as an authentic binding partner for hsa_circ_0001583 through RNA pulldown and RIP experiments. Elevated levels of hsa_circ_0001583 could bind more to SND1 and protect the latter from degradation. Rescue experiments demonstrated that such interaction-induced increased in SND1 levels in bladder cancer cells enabled the protein to pump its endonuclease activity, leading to the degradation of tumor-suppressing MicroRNAs (miRNAs) including miR-126-3p, the suppressor of Disintegrin And Metalloproteinase Domain-Containing Protein 9 (ADAM9), ultimately driving cells into a highly migrative and invasive state. In summary, our study is the first to highlight the upregulation of hsa_circ_0001583 in bladder cancer and its role in downregulating miR-126-3p by binding to and stabilizing the SND1 protein, thereby promoting bladder cancer cell migration and invasion. This study adds hsa_circ_0001583 to the pool of bladder cancer metastasis biomarkers and therapeutic targets.

Marine-derived Penicillium fungi are productive sources of structurally unique and diverse bioactive secondary metabolites, representing a hot topic in natural product research. This review describes structural diversity, bioactivities and statistical research of 452 new natural products from marine-derived Penicillium fungi covering 2021 to 2023. Sediments are the main sources of marine-derived Penicillium fungi for producing nearly 56% new natural products. Polyketides, alkaloids, and terpenoids displayed diverse biological activities and are the major contributors to antibacterial activity, cytotoxicity, anti-inflammatory and enzyme inhibitory capacities. Polyketides had higher proportions of new bioactive compounds in new compounds than other chemical classes. The characteristics of studies in recent years are presented.

Neoadjuvant immunotherapy has brought new hope for patients with non-small cell lung cancer (NSCLC). However, limited by the lack of clinically feasible markers, it is still difficult to select NSCLC patients who respond well and to predict patients’ clinical outcomes before the treatment. Before the treatment, we isolated plasma extracellular vesicles (EVs) from three cohorts (discovery, training and validation) of 78 NSCLC patients treated with neoadjuvant immunotherapy. To identify differentially-expressed EV long RNAs (exLRs), we employed RNA-seq in the discovery cohort. And we subsequently used qRT-PCR to establish and validate the predictive signature in the other two cohorts. We have identified 8 candidate exLRs from 27 top-ranked exLRs differentially expressed between responders and non-responders, and tested their expression with qRT-PCR in the training cohort. We finally identified H3C2 (P = 0.029), MALAT1 (P = 0.043) and RPS3 (P = 0.0086) significantly expressed in responders for establishing the predictive signature. Integrated with PD-L1 expression, our signature performed well in predicting immunotherapeutic responses in the training (AUC=0.892) and validation cohorts (AUC=0.747). Furthermore, our signature was proven to be a predictor for favorable prognosis of patients treated with neoadjuvant immunotherapy, which demonstrates the feasibility of our signature in clinical practices (P = 0.048). Our results demonstrate that the exLR-based signature could accurately predict responses to neoadjuvant immunotherapy and prognosis in NSCLC patients.

ObjectiveThis study sought to assess the efficacy and safety of immunotherapy combined with single-agent chemotherapy as a second- or later-line setting for metastatic non-small cell lung cancer (NSCLC) and to provide clinical evidence for this treatment regimen. The predictive value of extracellular vesicle (EV) membrane proteins was explored in patients who underwent this treatment.MethodsClinical data from patients diagnosed with metastatic NSCLC who received immunotherapy plus single-agent chemotherapy as a second- or later-line setting were retrospectively collected between March 2019 and January 2022. A total of 30 patients met the inclusion criteria, and all were pathologically confirmed to have NSCLC. Short-term efficacy, progression-free survival (PFS), EV markers for response prediction, and adverse events were assessed.ResultsEfficacy data were available for all 30 patients and included a partial response in 5 patients, stable disease in 18 patients, and disease progression in 7 patients. The objective response rate was 16.7%, the disease control rate was 76.7%, and the median PFS was 3.2 months. Univariate analysis showed that PFS was not associated with sex, age, smoking status, treatment lines, prior use of immunotherapy, or prior use of antiangiogenic drugs. The EV membrane proteins MET proto-oncogene, receptor tyrosine kinase (c-MET), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptor 2 (VEGFR2) at baseline were associated with poor prognosis and correlated with the efficacy of immunotherapy plus chemotherapy. According to the receiver operating characteristics and Kaplan–Meier curve analyses, patients with high c-MET, EGFR, and VEGFR2 expression at baseline had significantly shorter PFS than those with low expression. In addition, VEGFR2 expression was increased after combined immunotherapy in responders, which was decreased in non-responders. The most common grade 2 or higher adverse events were neutropenia, gastrointestinal reactions, and thyroid dysfunction, all of which were tolerated.ConclusionsImmunotherapy plus single-agent chemotherapy as a second- or later-line treatment is safe, effective, and tolerable for metastatic NSCLC. EV markers can be used as predictive markers of efficacy in patients with metastatic NSCLC treated with immunotherapy plus chemotherapy to help monitor treatment efficacy and guide treatment decisions.

Abstract Recent research has shown that ferroptosis, the iron-dependent accumulation of lipid peroxides that leads to cell death, suppresses cancer metastasis. However, the role of ferroptosis in prostate cancer metastasis has not been completely elucidated. In the current study, we identified the essential role of serum/glucocorticoid regulated kinase 2 (SGK2) in promoting prostate cancer metastasis by inhibiting ferroptosis. We found that the expression of SGK2 was higher in metastatic prostate cancer and predicted poor clinical outcomes. SGK2 knockdown inhibited the metastatic capacity of prostate cancer cells in vivo and in vitro, while SGK2 overexpression inhibited ferroptosis and facilitated prostate cancer metastasis by phosphorylating the Thr-24 and Ser-319 sites of forkhead box O1 (FOXO1). This process induced the translocation of FOXO1 from the nucleus to the cytoplasm, relieving the inhibitory effect of FOXO1 on glutathione peroxidase 4 (GPX4). These findings delineated a novel role of SGK2 in ferroptosis regulation of prostate cancer metastasis, identifying a new key pathway driving prostate cancer metastasis and potentially providing new treatment strategies for metastatic prostate cancer.

Abstract Background Circular RNAs (circRNAs) are essential participants in the development and progression of various malignant tumors. Previous studies have shown that cell migration-inducing protein (CEMIP) accelerates prostate cancer (PCa) anoikis resistance (AR) by activating autophagy. This study focused on the effect of circCEMIP on PCa metastasis. Methods This study gradually revealed the role of circ_0004585 in PCa anoikis resistance via quantitative real-time PCR (qRT-PCR) analysis, western blotting, pull-down assays, and dual fluorescence reporter assays. Results Functionally, circ_0004585 promoted PCa cells invasion and metastasis both in vitro and in vivo. Mechanistically, circ_0004585 directly interacted with miR-1248 to upregulate target gene expression. Furthermore, target prediction and dual-luciferase reporter assays identified transmembrane 9 superfamily member 4 (TM9SF4) as a potential miR-1248 target. Pathway analysis revealed that TM9SF4 activated autophagy to promote PCa cells anoikis resistance via mTOR phosphorylation. Conclusions These results demonstrated that circ_0004585 played an oncogenic role during PCa invasion and metastasis by targeting the miR-1248/TM9SF4 axis while providing new insight into therapeutic strategy development for metastatic PCa.

IntroductionRheumatoid arthritis (RA) is a multifactorial autoimmune disease. Recently, growing evidence demonstrates that gut microbiota (GM) plays an important role in RA. But so far, no bibliometric studies pertaining to GM in RA have ever been published. This study attempts to depict the knowledge framework in this field from a holistic and systematic perspective based on the bibliometric analysis.MethodsLiterature related to the involvement of GM in RA was searched and picked from the Web of Science Core Collection (WOSCC) database. The annual output, cooperation, hotspots, research status and development trend of this field were analyzed by bibliometric software (VOSviewer and Bibliometricx).Results255 original research articles and 204 reviews were included in the analysis. The articles in this field that can be retrieved in WOSCC were first published in 2004 and increased year by year since then. 2013 is a growth explosion point. China and the United States are the countries with the most contributions, and Harvard University is the affiliation with the most output. Frontiers in Immunology (total citations = 603) is the journal with the most publications and the fastest growth rate. eLife is the journal with the most citations (total citations = 1248). Scher, Jose U. and Taneja, Veena are the most productive and cited authors. The research in this field is mainly distributed in the evidence, mechanism and practical application of GM participating in RA through the analysis of keywords and documents. There is sufficient evidence to prove the close relationship between GM and RA, which lays the foundation for this field. This extended two colorful and tender branches of mechanism research and application exploration, which have made some achievements but still have broad exploration space. Recently, the keywords ”metabolites“, ”metabolomics“, ”acid“, ”b cells“, ”balance“, ”treg cells“, ”probiotic supplementation“ appeared most frequently, which tells us that research on the mechanism of GM participating in RA and exploration of its application are the hotspots in recent years.DiscussionTaken together, these results provide a data-based and objective introduction to the GM participating in RA, giving readers a valuable reference to help guide future research.

Summary: Background: Curbing or reversing high glycated hemoglobin (HbA1c) and body mass index (BMI) are two essential parts in the clinical management of type 2 diabetes (T2D). We delineated the changing patterns of the baseline HbA1c and BMI in patients with T2D from placebo-controlled randomised trials to reflect the unmet clinical needs. Methods: PubMed, Medline, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched from inception to December 19, 2022. Placebo-controlled trials of T2D with reports of baseline HbA1c and BMI were included, of which summary data from published reports were extracted. Pooled effect sizes of baseline HbA1c and BMI of from studies published in the same year were computed in Random-effects model due to the high level of heterogeneity among studies. The main outcome was correlations between the pooled baseline HbA1c, the pooled baseline BMI, and study years. This study was registered in PROSPERO as CRD42022350482. Findings: We identified 6102 studies, of which 427 placebo-controlled trials with 261, 462 participants were finally included in the study. Baseline HbA1c level declined with time (Rs = −0.665, P ＜ 0.0001, I2 = 99.4%). Baseline BMI increased over the past 35 years (R = 0.464, P = 0.0074, I2 = 99.4%), rising by around 0.70 kg/m2 per decade. Patients with BMI ≤25.0 kg/m2 dropped substantially from the half in 1996 to none in 2022. Patients with BMI ranging from 25 kg/m2 to 30 kg/m2 stabilized at 30–40% since 2000. Interpretation: A substantial decline in baseline HbA1c levels and a constant increase in baseline BMI levels was found in placebo-controlled trials through the past 35 years, which indicated the improvement in glycemic control and the urgency for the management of obesity in T2D. Funding: National Natural Science Foundation of China (No.81970698), Beijing Natural Science Foundation (No.7202216) and National Natural Science Foundation of China (No.81970708).

While material defect sites are active for chemical reactions, it is important to understand how different defect types impact reactivity. Here, authors prepare Frenkel-defected MoS2 monolayers and demonstrate improved performances for H2 evolution electrocatalysis than pristine or doped MoS2.

Abstract The survival of cancer cells after detaching from the extracellular matrix (ECM) is essential for the metastatic cascade. The programmed cell death after detachment is known as anoikis, acting as a metastasis barrier. However, the most aggressive cancer cells escape anoikis and other cell death patterns to initiate the metastatic cascade. This study revealed the role of cell migration-inducing protein (CEMIP) in autophagy modulation and anoikis resistance during ECM detachment. CEMIP amplification during ECM detachment resulted in protective autophagy induction via a mechanism dependent on the dissociation of the B-cell lymphoma-2 (Bcl-2)/Beclin1 complex. Additional investigation revealed that acting transcription factor 4 (ATF4) triggered CEMIP transcription and enhanced protein kinase C alpha (PKCα) membrane translocation, which regulated the serine70 phosphorylation of Bcl-2, while the subsequent dissociation of the Bcl-2/Beclin1 complex led to autophagy. Therefore, CEMIP antagonization attenuated metastasis formation in vivo. In conclusion, inhibiting CEMIP-mediated protective autophagy may provide a therapeutic strategy for metastatic prostate cancer (PCa). This study delineates a novel role of CEMIP in anoikis resistance and provides new insight into seeking therapeutic strategies for metastatic PCa.

Abstract Impaired angiogenesis is one of the predominant reasons for non-healing diabetic wounds. Herein, a nanofiber/hydrogel core–shell scaffold with three-dimensional (3D) multilayer patterned structure (3D-PT-P/GM) was introduced for promoting diabetic wound healing with improved angiogenesis. The results showed that the 3D-PT-P/GM scaffolds possessed multilayered structure with interlayer spacing of about 15–80 μm, and the hexagonal micropatterned structures were uniformly distributed on the surface of each layer. The nanofibers in the scaffold exhibited distinct core–shell structures with Gelatin methacryloyl (GelMA) hydrogel as the shell and Poly (d, l-lactic acid) (PDLLA) as the core. The results showed that the porosity, water retention time and water vapor permeability of the 3D-PT-P/GM scaffolds increased to 1.6 times, 21 times, and 1.9 times than that of the two-dimensional (2D) PDLLA nanofibrous scaffolds, respectively. The in vitro studies showed that the 3D-PT-P/GM scaffolds could significantly promote cell adhesion, proliferation, infiltration and migration throughout the scaffolds, and the expression of cellular communication protein-related genes, as well as angiogenesis-related genes in the same group, was remarkably upregulated. The in vivo results further demonstrated that the 3D-PT-P/GM scaffolds could not only effectively absorb exudate and provide a moist environment for the wound sites, but also significantly promote the formation of a 3D network of capillaries. As a result, the healing of diabetic wounds was accelerated with enhanced angiogenesis, granulation tissue formation, and collagen deposition. These results indicate that nanofiber/hydrogel core–shell scaffolds with 3D multilayer patterned structures could provide a new strategy for facilitating chronic wound healing. Graphical Abstract

In-situ stress is an important indicator for the preferential selection of coalbed methane (CBM) exploration dessert zones, and is a key factor affecting the production capacity of coalbed methane wells. Coal reservoir permeability is one of the key parameters to evaluate the recoverability and modifiability of coalbed methane and reflects the seepage capacity of coal reservoirs. In this study, in situ stress data were collected from multiple injection/fall-off tests of multiple parameter wells in western Guizhou province, China The relationships among parameters such as pore pressure (Pp), closure pressure (Pc), breakdown pressure (Pb), in situ stress, coal permeability, and depth were explore. Using Anderson’s classification method, the distribution of three different in situ stress states was counted. A new simplified model diagram of triaxial principal stress and depth in the study area is proposed by linearly fitting the triaxial principal stress and burial depth. The envelope equation and median equation of the lateral pressure coefficient k-value stress ratio with depth of burial obtained by Brown and Hoek method were calculated using hyperbolic regression algorithm. The k-values were found to be discrete at shallower depths and converge at deeper depths, gradually converging to .65. The control of in situ stress on the permeability of coal reservoirs was explored, and a strong positive correlation was found between the permeability and the Z-shaped variation of the lateral pressure coefficient k-values at shallow depths of 1,000 m. Also, the distribution pattern of vertical permeability basically corresponds to the stress transition zone from the strike-slip fault mode to the normal fault mode. The coal seam permeability has a strong sensitivity to effective in situ stress (EIS). In this study, the least squares method with multiple fitting of power exponents is applied to analyze the control mechanism of EIS on permeability in depth and reveal a new relationship between permeability and EIS that is different from that considered by previous authors. Summarizing the above research results, the vertical CBM in western Guizhou is divided into three development potential zones, and 400–1,000 m burial depth is the most favorable vertical development zone.

Objective:Curcumae Rhizoma–Sparganii Rhizoma (CR-SR) is a traditional botanical drug pair that can promote blood circulation, remove blood stasis, and treat tumors in clinics. The aim of the present study was to investigate the therapeutic material basis and potential mechanisms of CR-SR, CR, and SR for the treatment of liver cancer.Method: The chemical profile analyses of CR-SR, CR, and SR were performed by molecular networking and UPLC-LTQ-Orbitrap MSn. The anti-liver cancer activities of CR-SR, CR, and SR were assessed by using a zebrafish xenograft model in vivo for the first time and detected by the HepG2 cell model in vitro. Combining the network analysis and molecular docking, real-time quantitative polymerase chain reaction (RT-qPCR) experiments were undertaken to further explore the mechanisms of CR-SR, CR, and SR for the treatment of liver cancer.Results: In total, 65 components were identified in CR-SR, CR, and SR. Based on the clusters of molecular networking, a total of 12 novel diarylheptanoids were identified from CR-SR and CR. By combining our results with information from the literature, 32 sesquiterpenoids and 21 cyclic dipeptides were identified from CR-SR, CR, and SR. The anti-liver cancer activities were observed in both the drug pair and the single botanical drugs in vitro and in vivo, and the order of activity was CR-SR > CR > SR. They could downregulate the expression of proto-oncogene tyrosine-protein kinase Src (SRC), epidermal growth factor receptor (EGFR), estrogen receptor-α (ESR1), prostaglandin endoperoxide synthase 2 (PTGS2), and amyloid precursor protein (APP).Conclusion: Taken together, the present study provided an experimental basis for the therapeutic material basis and potential molecular mechanisms of CR-SR, CR, and SR. This study provided a novel insight for objective clinical treatment of liver cancer.

ctDNA has been shown to identify minimal residual disease (MRD) and is thus dynamically monitored in different types of tumours. Here, the authors show that serial longitudinal ctDNA analysis can be used as a tool to detect MRD, inform the use of adjuvant therapy, and predict recurrence risk in lung cancer.

Background: The pleiotropic efficacy of SGLT2is in patients with different eGFR levels has not been well-understood. This systematic review and meta-analysis assessed the disparities in the efficacy and safety of SGLT2i treatment across stratified renal function.Methods: We searched four databases from inception to December 2021. We included randomized controlled trials (RCTs) with reported baseline eGFR levels and absolute changes from baseline in at least one of the following outcomes: HbA1c, body weight, blood pressure, and eGFR. Continuous outcomes were evaluated as the weighted mean differences (WMDs) and 95% confidence intervals (CIs). Categorical outcomes were evaluated as odds ratios (ORs) and accompanying 95% CIs.Results: In total, 86 eligible RCTs were included. SGLT2is produces a substantial benefit in glycemic control, weight control, and blood pressure control even in patients with impaired renal function. HbA1c and weight reductions observed in SGLT2i users were generally parallel with the renal function levels, although there was an augmented weight reduction in severe renal dysfunction stratum [HbA1c: −0.49% (−0.58 to −0.39%) for normal renal function, −0.58% (−0.66 to −0.50%) for mild renal function impairment, −0.22% (−0.35 to −0.09%) for moderate renal function impairment, and −0.13% (−0.67 to 0.42%) for severe renal function impairment (p < 0.001 for subgroup differences); weight: −2.12 kg (−2.66 to −1.59 kg) for normal renal function, −2.06 kg (−2.31 to −1.82 kg) for mild renal function impairment; −1.23 kg (−1.59 to −0.86 kg) for moderate renal function impairment; −1.88 kg (−3.04 to −0.72 kg) for severe renal function impairment (p = 0.002 for subgroup differences)]. However, the blood pressure reduction observed in SGLT2i users was independent of renal function. When compared with the placebo, the occurrence of hypoglycemia was more frequent in patients with favorable renal function rather than in those with substantial renal dysfunction.Conclusion: The HbA1c and body weight reductions observed in SGLT2i users were generally parallel with their baseline eGFR levels, while blood pressure reductions in SGLT2i users were independent of their baseline eGFR levels. Consistently, when compared with the placebo, hypoglycemia was more frequent in patients with favorable renal function, where the HbA1c reduction was profound.

AimsThe aim of the study was to evaluate the association between evening chronotype and social jetlag (SJL) with obesity, blood glucose and lipid levels in non-shift working adults.MethodsThe databases of MEDLINE, EMBASE and Cochrane Reviews were searched for studies analyzing the metabolic parameters among groups of different chronotypes or SJL until Feb 2022. Weighted mean difference (WMD) and 95% confidence intervals (CI) were used to analyze the association between these parameters and chronotypes or SJL.ResultsA total of 27 studies were included in this meta-analysis. Compared with morning chronotype, the participants with evening chronotype had higher body mass index (BMI) (WMD= 0.44 kg/m2, 95%CI, 0.30 to 0.57 kg/m2, p

Electrocatalytic NO reduction reaction to generate NH3 under ambient conditions offers an attractive alternative to the energy-extensive Haber–Bosch route; however, the challenge still lies in the development of cost-effective and high-performance electrocatalysts. Herein, nanoporous VN film is first designed as a highly selective and stable electrocatalyst for catalyzing reduction of NO to NH3 with a maximal Faradaic efficiency of 85% and a peak yield rate of 1.05 × 10–7 mol·cm–2·s–1 (corresponding to 5,140.8 μg·h–1·mgcat.–1) at –0.6 V vs. reversible hydrogen electrode in acid medium. Meanwhile, this catalyst maintains an excellent activity with negligible current density and NH3 yield rate decays over 40 h. Moreover, as a proof-of-concept of Zn–NO battery, it delivers a high power density of 2.0 mW·cm–2 and a large NH3 yield rate of 0.22 × 10–7 mol·cm–2·s–1 (corresponding to 1,077.1 μg·h–1·mgcat.–1), both of which are comparable to the best-reported results. Theoretical analyses confirm that the VN surface favors the activation and hydrogenation of NO by suppressing the hydrogen evolution. This work highlights that the electrochemical NO reduction is an eco-friendly and energy-efficient strategy to produce NH3.

High urban temperatures affect city livability and may be harmful for inhabitants. Analyzing spatial and temporal differences in surface temperature and the thermal impact of urban morphological heterogeneity can promote strategies to improve the insulation of the urban thermal environment. Therefore, we analyzed the diurnal variation of land surface temperature (LST) and seasonal differences in the Fifth Ring Road area of Beijing from the perspective of the Local Climate Zone (LCZ) using latest ECOSTRESS data. We used ECOSTRESS LST data with a resolution of 70 m to accurately interpret the effects of urban morphology on the local climate. The study area was dominated by the LCZ9 type (sparse low-rise buildings) and natural LCZ types, such as LCZA/B (woodland), LCZD (grassland), and LCZG (water body), mainly including park landscapes. There were significant differences in LST observed in different seasons as well as day and night. During daytime, LST was ranked as follows: summer > spring > autumn > winter. During night-time, it was ranked as follows: summer > autumn > spring > winter. All data indicated that the highest and lowest LST was observed in summer and winter, respectively. LST was consistent with LCZ in terms of spatial distribution. Overall, the LST of each LCZ during daytime was higher than that of night-time during different seasons (except winter), and the average LST of each LCZ during the diurnal period in summer was higher than that of other seasons. The LST of each LCZ during daytime in winter was lower than that of the corresponding night-time, which indicates that it is colder in the daytime during winter. The results presented herein can facilitate improved analysis of spatial and temporal differences in surface temperature in urban areas, leading to the development of strategies aimed at improving livability and public health in cities.

Abstract Abiraterone, a novel androgen synthesis inhibitor, has been approved for castration-resistant prostate cancer (CRPC) treatment. However, most patients eventually acquire resistance to this agent, and the underlying mechanisms related to this resistance remain largely unelucidated. Lysine acetyltransferase 2 A (KAT2A) has been reported to enhance transcriptional activity for certain histone or non-histone proteins through the acetylation and post-translational modification of the androgen receptor (AR). Therefore, we hypothesised that KAT2A might play a critical role in the resistance of prostate tumours to hormonal treatment. In this study, we found that KAT2A expression was increased in abiraterone-resistant prostate cancer C4-2 cells (C4-2-AbiR). Consistently, elevated expression of KAT2A was observed in patients with prostate cancer exhibiting high-grade disease or biochemical recurrence following radical prostatectomy, as well as in those with poor clinical survival outcomes. Moreover, KAT2A knockdown partially re-sensitised C4-2-AbiR cells to abiraterone, whereas KAT2A overexpression promoted abiraterone resistance in parental C4-2 cells. Consistent with this finding, KAT2A knockdown rescued abiraterone sensitivity and inhibited the proliferation of C4-2-AbiR cells in a mouse model. Mechanistically, KAT2A directly acetylated the hinge region of the AR, and induced AR translocation from the cytoplasm to the nucleus, resulting in increased transcriptional activity of the AR-targeted gene prostate specific antigen (PSA) leading to resistance to the inhibitory effect of abiraterone on proliferation. Taken together, our findings demonstrate a substantial role for KAT2A in the regulation of post-translational modifications in AR affecting CRPC development, suggesting that targeting KAT2A might be a potential strategy for CRPC treatment.

Abstract It has been suggested that the heterogeneity of TAAs in lung cancer may affect the therapeutic response and disease progression. Up to now, several tumor-associated antigen (TAA)-based cancer vaccines have been investigated in lung adenocarcinoma (LUAD); however, most of them have failed at the stage of clinical trials. The present study suggests that inter-tumoral heterogeneity of TAAs is large at single-cell resolution, while the communication between tumor cells and infiltrating T cells is closely related to the expression profile of TAAs.

An amendment to this paper has been published and can be accessed via the original article.

Objectives: To investigate the effect of biologic therapy on risk of fracture in selected rheumatic and autoimmune diseases. Methods: The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to June 4, 2021. Randomized clinical trials (RCTs) comparing biological disease-modifying antirheumatic drugs (bDMARDs) with non-bDMARDs or placebo in patients with five selected rheumatic and autoimmune diseases were included. Meta-analyses were conducted to calculate the odds ratio (OR) with 95 % confidence intervals (CIs) for major osteoporotic fracture, hip fracture, osteoporotic non-vertebral fracture, and total fracture. Results: A total of 100 RCTs involving 51,413 participants fulfilled the inclusion criteria. In patients with psoriasis (Ps), and psoriatic arthritis (PsA), compared with placebo or non-bDMARDs therapy, the risk of major osteoporotic fracture (OR, 0.34 [95 %Cl, 0.15–0.76], p = 0.009), hip fracture (OR, 0.22 [95 %Cl, 0.05–0.89], p = 0.03), and osteoporotic non-vertebral fracture (OR, 0.26 [95 %Cl, 0.10–0.62], p = 0.003) were significantly decreased with the use of bDMARDs. In patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), systemic lupus erythematosus (SLE), and inflammatory bowel diseases (IBD), the risk of fracture were not changed with biologic treatment. Conclusions: The existing evidence from RCTs indicated the use of bDMARDs was associated with a low risk of major osteoporotic fracture, hip fracture, and osteoporotic non-vertebral fracture in patients with Ps and PsA. There are still urgent needs for studies regarding the actions of biologic therapies on the risk of bone fractures in systemic inflammatory diseases.

Abstract Background To exam the associations between the use of sodium glucose co-transporter 2 inhibitor (SGLT2i) and the risk of lower limb complications, and to analyze the associated factors. Methods Pubmed, Medline, Embase, the Cochrane Center Register of Controlled Trials for Studies and Clinicaltrial.gov were searched from the inception to November 2020. Randomized controlled trials of SGLT2i conducted in population containing diabetic patients with reports of amputation, peripheral arterial disease (PAD) and diabetic foot (DF) events were included. Random-effect model, fixed-effect model and meta-regression analysis were accordingly used. Result The numbers of SGLT2i users versus non-SGLT2i users in the analyses of amputation, PAD and DF were 40,925/33,414, 36,446/28,685 and 31,907/25,570 respectively. Compared with non-SGLT2i users, the risks of amputation and PAD were slightly increased in patients with canagliflozin treatment (amputation: OR = 1.60, 95% CI 1.04 to 2.46; PAD: OR = 1.53, 95 % CI 1.14 to 2.05). Meta-regression analyses indicated that greater weight reduction in SGLT2i users was significantly associated with the increased risks of amputation (β = − 0.461, 95% CI − 0.726 to − 0.197), PAD (β = − 0.359, 95% CI − 0.545 to − 0.172) and DF (β = − 0.476, 95% CI − 0.836 to − 0.116). Lower baseline diastolic blood pressure (β = − 0.528, 95% CI − 0.852 to − 0.205), more systolic blood pressure reduction (β = − 0.207, 95% CI − 0.390 to − 0.023) and more diastolic blood pressure reduction (β = − 0.312, 95% CI − 0.610 to − 0.015) were significantly associated with the increased risks of amputation, PAD and DF respectively in patients with SGLT2i treatment. Conclusions The risks of amputation and PAD were slightly increased in patients with canagliflozin treatment. Reductions in body weight and blood pressure were associated with lower limb complications in patients with SGLT2i treatment.

Aims: To estimate the sex differences in the prevalence of overweight and obesity aged 20–89 in Chinese patients with type 2 diabetes (T2D). Methods: 811,264 patients with T2D from six hospital-based, cross-secti onal studies, and 46,053 subjects from the general population were included in ou r analysis. Prevalence of underweight, overweight, obesity were calculated in each sex. Results: In patients with T2D, the standardized prevalence of underweig ht (BMI

IntroductionBody composition is closely related to metabolic health status. Visceral adipose tissue (VAT) dysfunction contributes to metabolic syndrome. However, results regarding subcutaneous adipose tissue (SAT) and skeletal muscle are controversial. We aimed to determine the association of indices of body composition with abnormal metabolic phenotype in China.MethodsA total of 3, 954 subjects (age 50.2 ± 11.7 years) with body mass index (BMI) more than 18.5 kg/m2 from Pinggu Metabolic Disease Study were analyzed. Quantitative computed tomography (QCT) was performed to measure total adipose tissue (TAT), VAT, SAT area, and lumbar skeletal muscle area (SMA). Participants were divided into six groups on the basis of BMI category (normal weight/overweight/obesity) and metabolic status (healthy/unhealthy), as defined by the presence or absence of components of the metabolic syndrome by Chinese Diabetes Society criteria.Results63.4%, 39.5%, and 23.3% participants were classified as metabolically healthy phenotype in individuals with normal weight, overweight and obese, respectively. Individuals in the highest TAT, VAT, and VAT/TAT ratio category had higher risk of being metabolically unhealthy than individuals in the lowest group (all p0.05). The VAT and VAT/TAT ratio were better diagnostic values of indicators to differentiate metabolically unhealthy subjects from controls compared with other indicators, such as TAT, SAT, SMI, SMA/TAT ratio.ConclusionsHigher visceral adipose tissue was closely associated with metabolically unhealthy phenotype in Chinese adults. Subcutaneous adipose tissue might be a protective factor for metabolic health status only in obese individuals.

Abstract Numerous studies have reported the association of long non-coding RNAs (lncRNAs) in cancers, yet the function of lncRNA high expressed in hepatocellular carcinoma (HEIH) in esophageal carcinoma (EC) has seldom been explored. Here, we aimed to explore the mechanism of HEIH on EC via microRNA-185 (miR-185)/kallikrein-related peptidase 5 (KLK5) modulation. Cancer and non-tumoral tissues were collected, in which HEIH, miR-185 and KLK5 expression were detected, as well as their correlations. Also, the relation between the prognosis of EC patients and HEIH/miR-185/KLK5 expression was clarified. EC cells (KYSE-30 and TE-1) were screened for subsequent gain- and loss-of-function assays and their biological functions were further monitored. Tumor volume and weight in EC mice were also measured. Results from this study indicated that HEIH and KLK5 were elevated and miR-185 was declined in EC. The positive correlation was seen in HEIH and KLK5 expression, while the negative correlation was observed in HEIH or KLK5 and miR-185 expression. High HEIH and KLK5 indicated worse prognosis and high miR-185 suggested better prognosis of EC patients. Depleting HEIH or restoring miR-185 suppressed the malignant phenotypes of EC cells, and delayed tumor growth in EC mice. HEIH was found to bind with miR-185 to regulate KLK5 expression. Overexpressing KLK5 alone promoted EC cell progression while up-regulating miR-185 reversed such effects on EC cells. Collectively, we reveal that HEIH depletion dampens EC progression by upregulating miR-185 and downregulating KLK5, which provides novel treatments for EC.

Abstract Background The placebo response in patients with diabetes mellitus is very common. A systematic evaluation needs to be updated with the current evidence about the placebo response in diabetes mellitus and the associated factors in clinical trials of anti-diabetic medicine. Methods Literature research was conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for studies published between the date of inception and June 2019. Randomized placebo-controlled trials conducted in type 1and type 2 diabetes mellitus (T1DM/T2DM) were included. Random-effects model and meta-regression analysis were accordingly used. This meta-analysis was registered in PROSPERO as CRD42014009373. Results Significantly weight elevation (effect size (ES) = 0.33 kg, 95% CI, 0.03 to 0.61 kg) was observed in patients with placebo treatments in T1DM subgroup while significantly HbA1c reduction (ES = − 0.12%, 95% CI, − 0.16 to − 0.07%) and weight reduction (ES = − 0.40 kg, 95% CI, − 0.50 to − 0.29 kg) were observed in patients with placebo treatments in T2DM subgroup. Greater HbA1c reduction was observed in patients with injectable placebo treatments (ES = − 0.22%, 95% CI, − 0.32 to − 0.11%) versus oral types (ES = − 0.09%, 95% CI, − 0.14 to − 0.04%) in T2DM (P = 0.03). Older age (β = − 0.01, 95% CI, − 0.02 to − 0.01, P

Abstract Background Iodine intake is essential in the production of thyroid hormone but very few foods are rich in it. Iodine deficiency or excess iodine level may both lead to thyroid disorders, which further affects human fertility function. The objective of this study is to investigate the relationship between iodine intake and seminal parameters among fertile men in China. Methods A total of 1098 couples were recruited by trained physicians at different family planning service stations in 2015. Semen and iodine samples were obtained from male respondents. A questionnaire survey inquired about demographic information from couples. The main outcome variables of semen quality were semen volume, semen concentration, semen motility, and sperm count, and time to pregnancy. Urinary iodine concentration (UIC) was used to measure iodine levels for male respondents. Ordinary least squared regressions and logistic regressions were performed to estimate the association between iodine intake level and semen quality parameters. Results Male respondents with deficient or excess iodine levels had a 5% higher semen volume relative to those with optimal iodine intake (p

ObjectiveTo establish a system for evaluation of semen quality in fertile men by factor analysis (FA).MethodsThe FA method was used to analyze five sperm test indicators for fertile men (sperm pH, sperm motility, sperm progressive motility, semen density, and total sperm number) to determine the evaluation standard of semen quality. Pearson analysis was adopted for correlation testing.ResultsThe comprehensive score formula for semen quality of normal fertile men was as follows: comprehensive score of semen quality = (0.38272 F1 + 0.36359 F2 + 0.20018 F3)/94.699. Across the whole fertile population, semen quality was found to be correlated with abstinence period, age of first spermatorrhea, and frequency of intercourse. Smoking, drinking, and place of residence were correlated with semen quality in the high semen quality population. In the population with medium semen quality, only the abstinence period was associated with semen quality.ConclusionIt is feasible to evaluate the semen quality of fertile men using the FA method. The comprehensive indicators of semen volume, sperm motility, and semen pH can be used as evaluative measures. Across the whole fertile population, the abstinence period and age of first spermatorrhea were correlated with semen quality. In the high semen quality population, smoking and drinking were negatively correlated with semen quality, and participants living in rural areas had better semen quality.

ObjectivePrevious evidence suggested that sodium–glucose cotransporter 2 inhibitor (SGLT2i)-mediated urinary glucose excretion (UGE) appeared to be reduced with a decrease in glomerular filtration rate. Thus, we conducted a systematic review and meta‐analysis to compare SGLT2i-mediated UGE among individuals with different levels of renal function.MethodsWe conducted systematic searches in PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrial.gov from inception to May 2021. Clinical studies of SGLT2i with reports of UGE changes in predefined different levels of renal function were included. The results were expressed as pooled effect sizes with 95% confidence interval (CI). A random-effects model was used to calculate the pooled effect sizes.ResultsIn total, eight eligible studies were included. Significant differences were observed in the post-treatment UGE level among subgroups stratified by renal function (P

Three new phenolic compounds, epicocconigrones C–D (1–2) and flavimycin C (3), together with six known phenolic compounds: epicocconigrone A (4); 2-(10-formyl-11,13-dihydroxy-12-methoxy-14-methyl)-6,7-dihydroxy-5-methyl-4-benzofurancarboxaldehyde (5); epicoccolide B (6); eleganketal A (7); 1,3-dihydro-5-methoxy-7-methylisobenzofuran (8); and 2,3,4-trihydroxy-6-(hydroxymethyl)-5-methylbenzyl-alcohol (9), were isolated from fermentation cultures of a deep-sea sediment-derived fungus, Aspergillus insulicola. Their planar structures were elucidated based on the 1D and 2D NMR spectra and HRESIMS data. The absolute configurations of compounds 1–3 were determined by ECD calculations. Compound 3 represented a rare fully symmetrical isobenzofuran dimer. All compounds were evaluated for their α-glucosidase inhibitory activity, and compounds 1, 4–7, and 9 exhibited more potent α-glucosidase inhibitory effect with IC50 values ranging from 17.04 to 292.47 μM than positive control acarbose with IC50 value of 822.97 μM, indicating that these phenolic compounds could be promising lead compounds of new hypoglycemic drugs.

Nine new azaphilones, including penicilazaphilones I–N (1, 2 and 6–9), epi-geumsanol D (3) and penidioxolanes C (4) and D (5) were isolated from the culture of the marine-derived fungus Penicillium sclerotiorum E23Y-1A. The structures of the isolates were deduced from extensive spectroscopic data (1D and 2D NMR), high-resolution electrospray ionization mass spectrometry (HRESIMS), and electronic circular dichroism (ECD) calculations. All the azaphilones from P. sclerotiorum E23Y-1A were tested for their anti-inflammatory and antitumor activities. Penicilazaphilone N (9) showed moderate anti-inflammatory activity with an IC50 value of 22.63 ± 2.95 μM, whereas penidioxolane C (4) exhibited moderate inhibition against human myeloid leukemia cells (K562), human liver cancer cells (BEL-7402), human gastric cancer cells (SGC-7901), human non-small cell lung cancer cells (A549), and human hela cervical cancer cells, with IC50 values of 23.94 ± 0.11, 60.66 ± 0.13, 46.17 ± 0.17, 60.16 ± 0.26, and 59.30 ± 0.60 μM, respectively.

PurposeThe effect of physical activity on glycemic variability remains controversial. This meta-analysis aimed to assess the overall effect of physical activity treatment on glycemic variability in patients with diabetes.MethodsPubMed/MEDLINE, Embase, and Cochrane databases were searched for clinical trials that conducted in patients with type 1 diabetes mellitus and type 2 diabetes mellitus with reports of the mean amplitude of glycemic excursion (MAGE), time in range (TIR), time above range (TAR), or time below range (TBR). Eligible trials were analyzed by fixed-effect model, random effect model, and meta-regression analysis accordingly.ResultsIn total, thirteen trials were included. Compared with the control group, physical activity intervention was significantly associated with increased TIR (WMDs, 4.17%; 95% CI, 1.11 to 7.23%, P

Abstract Background Vaccination is the principal strategy for prevention and control of diseases, and adjuvant use is an effective strategy to enhance vaccine efficacy. Traditional mineral oil-based adjuvants have been reported with post-immunization reactions. Developing new adjuvant formulations with improved potency and safety will be of great value. Results In the study reported herein, a novel oil-in-water (O/W) Emulsion Adjuvant containing Squalane (termed EAS) was developed, characterized and investigated for swine influenza virus immunization. The data show that EAS is a homogeneous nanoemulsion with small particle size (~ 105 nm), low viscosity (2.04 ± 0.24 cP at 20 °C), excellent stability (at least 24 months at 4 °C) and low toxicity. EAS-adjuvanted H3N2 swine influenza vaccine was administrated in mice subcutaneously to assess the adjuvant potency of EAS. The results demonstrated that in mice EAS-adjuvanted vaccine induced significantly higher titers of hemagglutination inhibition (HI) and IgG antibodies than water-in-oil (W/O) vaccines or antigen alone, respectively, at day 42 post vaccination (dpv) (P