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BackgroundDiabetic kidney disease (DKD) is a common pathway to End-stage renal disease (ESRD). Podocytes are crucial due to their dual barrier functions in kidney diseases. Their role in renal fibrosis and DKD regulatory mechanisms is increasingly studied. However, bibliometric research in this field has not been explored.Methods1,250 publications from Jan. 1, 2000, to Feb. 16, 2024, were retrieved from the WoSCC database and analyzed by the Web of Science results analysis tool, VOSviewer, and CiteSpace.ResultsOur scrutiny reveals that authors Liu Youhua, Fogo Agnes B, and Zhao Yingyong have made substantial contributions to this domain. Notably, “Kidney International” has the highest volume of publications in this area. Furthermore, our analysis identifies ten co-citation clusters: DKD, IncRNA, reactive oxygen species, glomerulosclerosis, Poria cocos, glomerular diseases, fibroblasts, connective tissue growth factor, coagulation, and Wnt. Recent research accentuates keywords such as autophagy, TRPC6, ERS, epigenetics, and NLRP3 inflammasome as frequently occurring terms in this field. The prevailing research hotspot keywords include autophagy, biomarker, and exosomes.ConclusionThrough the utilization of bibliometric tools and knowledge graph analysis, we have undertaken a comprehensive review of the intricate nexus between podocytes in DKD and renal fibrosis. This study imparts valuable insights to scholars regarding the dynamic evolution of this association and delineates prospective research avenues in this pivotal realm.

All-trans retinoic acid (ATRA) plays a role in tissue development, neural function, reproduction, vision, cell growth and differentiation, tumor immunity, and apoptosis. ATRA can act by inducing autophagic signaling, angiogenesis, cell differentiation, apoptosis, and immune function. In the blood system ATRA was first used with great success in acute promyelocytic leukemia (APL), where ATRA differentiated leukemia cells into mature granulocytes. ATRA can play a role not only in APL, but may also play a role in other hematologic diseases such as immune thrombocytopenia (ITP), myelodysplastic syndromes (MDS), non-APL acute myeloid leukemia (AML), aplastic anemia (AA), multiple myeloma (MM), etc., especially by regulating mesenchymal stem cells and regulatory T cells for the treatment of ITP. ATRA can also increase the expression of CD38 expressed by tumor cells, thus improving the efficacy of daratumumab and CD38-CART. In this review, we focus on the mechanism of action of ATRA, its role in various hematologic diseases, drug combinations, and ongoing clinical trials.

Herb compatibility is the soul of traditional Chinese Medicine prescriptions. Coptidis rhizoma (CR) (Coptis chinensis Franch., Coptis deltoidea C.Y.Cheng et Hsiao, or Coptis teeta Wall.; family Ranunculaceae), is a well-known herb. The bitter and cold nature of CR can irritate the spleen and stomach, and certain ingredients in CR may trigger allergic reactions. Herb combinations can help alleviate the side effects caused by CR. Through data analysis and literature research, there are many herbs combined with CR have a high frequency, but only a few are currently used as formulae in clinical practice. The results showed that these six herb pairs are usually widely studied or used as prescriptions in the clinic. This paper describes the six herb pairs from the key traditional uses, changes in bioactive constituents, and compatibility effects, especially with Euodiae fructus (family Rutaceae), Scutellariae radix (family Lamiaceae), Magnoliae Officinalis cortex (family Magnoliaceae), Glycyrrhizae radix et rhizoma (family Fabaceae), Ginseng radix et rhizoma (family Araliaceae), and Aucklandiae radix (family Asteraceae), and found that herbs are more effective when used in combination. Therefore, it is feasible to establish some methods to study herb pairs comprehensively from different perspectives. This paper aims to provide the latest and most comprehensive information on the six herb pairs and summarize the pattern of CR compatibility effects. It aims to attract more attention, and further experimental studies will be conducted to investigate and evaluate the effects of herb pairs containing CR. These data can also provide valuable references for researchers and also provide more possibilities for future applications in clinical practice and new drug development.

Background: Percutaneous left atrial appendage occlusion (LAAO) has emerged as a stroke prevention strategy in patients with nonvalvular atrial fibrillation (NVAF), and these patients were required to receive antithrombotic therapy post-procedure. However, the optimal antithrombotic strategy after LAAO remains controversial. This study explored the safety and efficacy of different antithrombotic strategies after LAAO through a network comparison method.Methods: We systematically searched the MEDLINE, Embase, and Cochrane Library databases for studies that reported the interested efficacy and safety outcomes (stroke, device-related thrombus (DRT), and major bleeding) of different antithrombotic strategies [DAPT (dual antiplatelet therapy), DOACs (direct oral anticoagulants), and VKA (vitamin k antagonist)] in patients who had experienced LAAO. Pairwise comparisons and network meta-analysis were performed for the interested outcomes. Risk ratios (RRs) with their confidence intervals (CIs) were calculated using a random-effects model. The rank of the different strategies was calculated using the surface under the cumulative ranking curve (SUCRA).Results: Finally, 10 observational studies involving 1,674 patients were included. There was no significant difference in stroke, DRT, and major bleeding among the different antithrombotic strategies (DAPT, DOACs, and VKA). Furthermore, DAPT ranked the worst in terms of stroke (SUCRA: 19.8%), DRT (SUCRA: 3.6%), and major bleeding (SUCRA: 6.6%). VKA appeared to be superior to DOACs in terms of stroke (SUCRA: 74.9% vs. 55.3%) and DRT (SUCRA: 82.3% vs. 64.1%) while being slightly inferior to DOACs in terms of major bleeding (SUCRA: 71.0% vs. 72.4%).Conclusion: No significant difference was found among patients receiving DAPT, DOACs, and VKA in terms of stroke, DRT, and major bleeding events after LAAO. The SUCRA indicated that DAPT was ranked the worst among all antithrombotic strategies due to the higher risk of stroke, DRT, and major bleeding events, while VKAs were ranked the preferred antithrombotic strategy. However, DOACs are worthy of consideration due to their advantage of convenience.

Objective: Crohn’s disease (CD) is an incurable chronic disease that requires long-term treatment. As an anti-tumor necrosis factor (TNF) agent, Infliximab (IFX) is widely used in the treatment of Crohn’s disease, while the adherence is not high. The purpose of this study was to investigate the adherence to IFX among CD patients in China and evaluate the association between medication belief and IFX adherence.Methods: Demographic data, clinical information and patients’ medication beliefs were collected using an online questionnaire and reviewing electronic medical records (EMRs). The Beliefs about Medicines Questionnaire (BMQ)-specific was used to assess medication beliefs which contains the BMQ-specific concern score and the BMQ-specific necessity score. An evaluation of adherence factors was conducted using univariate and multidimensional logistic regression analyses.Results: In all, 166 CD patients responded the online questionnaire among which 77 (46.39%) patients had high adherence. The BMQ-specific concern score in patients in low adherence was 30.00 and in high adherence patients was 27.50, and patients with lower BMQ-specific concern score had higher adherence (p = 0.013). The multiple regression analysis showed that the BMQ-specific concern score (OR = 0.940, 95% CI: 0.888–0.996) significantly affected the IFX adherence in CD patients. Otherwise, gender, marital status, time spent on the way (including the waiting time in infusion center) and accommodation to the center were also the influencing factors of adherence.Conclusion: The IFX adherence to CD in China was not high. Medicine concerns may be predictive factor of adherence. Education, the duration of IFX therapy and experience of adverse effects were not significantly associated with IFX adherence. By enhancing knowledge and relieving medicine concerns, we may increase patients’ adherence to IFX.

Breast cancer is the most prevalent malignancy among women. Doxorubicin (Dox) resistance was one of the major obstacles to improving the clinical outcome of breast cancer patients. The purpose of this study was to investigate the relationship between the FABP signaling pathway and Dox resistance in breast cancer. The resistance property of MCF-7/ADR cells was evaluated employing CCK-8, Western blot (WB), and confocal microscopy techniques. The glycolipid metabolic properties of MCF-7 and MCF-7/ADR cells were identified using transmission electron microscopy, PAS, and Oil Red O staining. FABP5 and CaMKII expression levels were assessed through GEO and WB approaches. The intracellular calcium level was determined by flow cytometry. Clinical breast cancer patient’s tumor tissues were evaluated by immunohistochemistry to determine FABP5 and p-CaMKII protein expression. In the presence or absence of FABP5 siRNA or the FABP5-specific inhibitor SBFI-26, Dox resistance was investigated utilizing CCK-8, WB, and colony formation methods, and intracellular calcium level was examined. The binding ability of Dox was explored by molecular docking analysis. The results indicated that the MCF-7/ADR cells we employed were Dox-resistant MCF-7 cells. FABP5 expression was considerably elevated in MCF-7/ADR cells compared to parent MCF-7 cells. FABP5 and p-CaMKII expression were increased in resistant patients than in sensitive individuals. Inhibition of the protein expression of FABP5 by siRNA or inhibitor increased Dox sensitivity in MCF-7/ADR cells and lowered intracellular calcium, PPARγ, and autophagy. Molecular docking results showed that FABP5 binds more powerfully to Dox than the known drug resistance-associated protein P-GP. In summary, the PPARγ and CaMKII axis mediated by FABP5 plays a crucial role in breast cancer chemoresistance. FABP5 is a potentially targetable protein and therapeutic biomarker for the treatment of Dox resistance in breast cancer.

Background: This study aimed to analyze the clinical characteristics and treatment response of patients with chronic obstructive pulmonary disease (COPD) with low body mass index (BMI).Methods: In this cross-sectional study, we enrolled patients with stable COPD from the database setup by the Second Xiangya Hospital of Central South University. We classified the patients into three groups based on BMI: low-BMI (

Lenvatinib (LVN) has been appoved to treat advanced renal cell carcinoma, differentiated thyroid carcinoma, hepatocellular carcinoma. Further other cancer types also have been tried in pre-clinic and clinic without approvation by FDA. The extensive use of lenvastinib in clinical practice is sufficient to illustrate its important therapeutic role. Although the drug resistance has not arised largely in clinical, the studies focusing on the resistance of LVN increasingly. In order to keep up with the latest progress of resistance caused by LVN, we summerized the latest studies from identify published reports. In this review, we found the latest report about resistance caused by lenvatinib, which were contained the hotspot mechanism such as the epithelial-mesenchymal transition, ferroptosis, RNA modification and so on. The potential ways to conquer the resistance of LVN were embraced by nanotechnology, CRISPR technology and traditional combined strategy. The latest literature review of LVN caused resistance would bring some ways for further study of LVN. We call for more attention to the pharmacological parameters of LVN in clinic, which was rarely and would supply key elements for drug itself in human beings and help to find the resistance target or idea for further study.

Aim: This study sought to compare treatment persistence, adherence, and risk of exacerbation among patients with COPD treated with single-inhaler triple therapy (SITT) and multiple-inhaler triple therapy (MITT) in the Chinese population.Methods: This was a multicenter, prospective observational study. Patients with COPD from ten hospitals in Hunan and Guangxi provinces in China were recruited from 1 January 2020 to 31 November 2021 for the study and were followed up for one year. Treatment persistence, adherence, and exacerbation rates during the 12-month follow-up were analyzed in COPD patients treated with SITT and MITT.Results: A total of 1,328 patients were enrolled for final analysis, including 535 (40.3%) patients treated with SITT and 793 (59.7%) treated with MITT. Of these patients, the mean age was 64.9 years and most patients were men. The mean CAT score was 15.2 ± 7.1, and the median (IQR) FEV1% was 54.4 (31.2). The SITT group had a higher mean CAT score, more patients with mMRC >1, and lower mean FEV1% and FEV1/FVC than the MITT patients. Moreover, the proportion of patients with ≥1 exacerbation in the previous year was higher in the SITT cohort. SITT patients had, compared to MITT patients, a higher proportion of adherence (proportion of days covered, PDC) ≥0.8 (86.5% vs. 79.8%; p = 0.006), higher treatment persistence [HR: 1.676 (1.356–2.071), p < 0.001], lower risk of moderate-to-severe exacerbation [HR: 0.729 (0.593–0.898), p = 0.003], and severe exacerbation [HR: 0.675 (0.515–0.875), p = 0.003], as well as reduced all-cause mortality risk [HR: 0.475 (0.237-0.952), p = 0.036] during the 12-month follow-up. Persistence was related to fewer future exacerbations and mortality than non-persistence in the SITT and MITT groups.Conclusion: Patients with COPD treated with SITT showed improved treatment persistence and adherence, as well as a reduction in the risk of moderate-to-severe exacerbation, severe exacerbation, and mortality compared to patients treated with MITT in the Chinese population.Clinical Trial Registration: https://www.chictr.org.cn/, identifier ChiCTR-POC-17010431.

Apoptosis and extracellular matrix degradation of the nucleus pulposus are the main initiators of intervertebral disc degeneration (IVDD) and can be explained by endoplasmic reticulum (ER) stress. Thus, pharmacological therapy aimed at suppressing this pathway may be a promising approach for the management of intervertebral disc degeneration. In this study, we aimed to explore the protective effects of Sal003 against intervertebral disc degeneration and its underlying mechanisms. Thapsigargin (Tg)-stimulated rat nucleus pulposus cells and a needle puncture-induced intervertebral disc degeneration rat model were used to explore the protective effects of Sal003. Our results showed that Sal003 inhibited apoptosis and extracellular matrix degradation by suppressing the endoplasmic reticulum stress pathway. The therapeutic effects of Sal003 were also observed in the intervertebral disc degeneration rat model, as evidenced by improved degeneration along with decreased apoptosis and extracellular matrix degradation in intervertebral discs. Our results demonstrated Sal003 as a potential treatment for intervertebral disc degeneration.

Background: Insulin secretory agents are commonly used to treat type 2 diabetes. However, traditional insulin secretory agents such as sulfonylureas and glinides have side effects of hypoglycemia. In recent years, researchers have discovered that berberine can inhibit the voltage-gated k+ channels of pancreatic β cell membrane and promote insulin secretion without causing hypoglycemia, because the glucose-lowering effects of berberine are only under hyperglycemic conditions or in a high-glucose-dependent manner. In order to shed light on the glucose-lowing effects of berberine in type 2 diabetes with different baseline fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c), we conducted a meta-analysis of randomized controlled trials.Methods: We searched eight databases, which included PubMed, EMBASE, Web of Science, the Cochrane Library, and the Chinese databases such as Sino-Med, China National Knowledge Infrastructure (CNKI), Wanfang Database, and VIP Database for Chinese Technical Periodicals, for randomized controlled trials, with berberine as the intervention and patients with type 2 diabetes mellitus as subjects, published up until November 2021. We analyzed the glucose-lowing effects of berberine, including its effects on FPG, HbA1c and 2-h plasma blood glucose (2hPBG), by calculating weighted mean differences (WMD) and 95% confidence interval (CI). To assess the safety of berberine, we analyzed the incidence of total adverse events and hypoglycemia by calculating relative risk (RR) and 95% CI.Results: Thirty-seven studies involving 3,048 patients were included in the meta-analysis. The results showed that berberine could reduce FPG (WMD = -0.82 mmol/L, 95% CI (-0.95, -0.70)), HbA1c (WMD = -0.63%, 95% CI (-0.72, -0.53)), and 2hPBG (WMD = -1.16 mmol/L, 95% CI (-1.36, -0.96)), with all results being statistically significant. Subgroup analyses revealed that the glucose-lowering effect of berberine was associated with baseline mean FPG and HbA1c in type 2 diabetes. In addition, berberine alone or in combination with oral hypoglycemic agents (OHAs) in the treatment of T2DM did not significantly increase the incidence of total adverse events (RR = 0.73, 95% CI (0.55, 0.97), p = 0.03) and the risk of hypoglycemia (RR = 0.48, 95% CI (0.21, 1.08), p = 0.08).Conclusion: Berberine has a glucose-lowering effect, which is related to the baseline FPG and HbA1c levels of patients. Treatment with berberine may be safe since it does not increase the incidence of total adverse events and the risk of hypoglycemia.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=292975, identifier CRD42021292975.

Phyllanthi Fructus (PF), the edible fruits of Phyllanthus emblica L., serves as an important resource for some health products, foods and drugs due to its high safety and sufficient nutritional value. In recent years, in vivo and in vitro experiments have been conducted to reveal the active components of PF. More than 180 compounds have been isolated and identified from the PF so far, primarily including tannins, phenolic acids, flavonoids, terpenoids, polysaccharides, fatty acids and amino acids. In traditional Chinese medicine (TCM), PF is used to cure several diseases such as bronchitis, asthma, diabetes, peptic ulcer, hepatopathy, leprosy, and jaundice. Consistent with ethnopharmacology, numerous modern studies have demonstrated that the extracts or monomeric compounds derived from PF exhibit various pharmacological effects including anti-oxidation, anti-bacteria, anti-inflammation, anti-tumour, anti-virus, immunity improvement, hypoglycemic and hypolipidemic effects, and multiple organ protective protection. Toxicological studies on PF indicated the absence of any adverse effects even at a high dose after oral administration. Due to strict quality control, these pharmacological activities and the safety of PF greatly improve the development and utilization of products. Our comprehensive review aims to summarize the phytochemistry, pharmacological effects, toxicology, and product development of PF to provide theoretical guidance and new insights for further research on PF in the future.

Objectives: This study aims to characterize the population pharmacokinetics of polymyxin B in lung transplant recipients and optimize its dosage regimens.Patients and methods: This prospective study involved carbapenem-resistant organisms-infected patients treated with polymyxin B. The population pharmacokinetic model was developed using the NONMEM program. The clinical outcomes including clinical treatment efficacy, microbiological efficacy, nephrotoxicity, and hyperpigmentation were assessed. Monte Carlo simulation was performed to calculate the probability of target attainment in patients with normal or decreased renal function.Results: A total of 34 hospitalized adult patients were included. 29 (85.29%) patients were considered of clinical cure or improvement; 14 (41.18%) patients had successful bacteria elimination at the end of the treatment. Meanwhile, 5 (14.71%) patients developed polymyxin B-induced nephrotoxicity; 19 (55.88%) patients developed skin hyperpigmentation. A total of 164 concentrations with a range of 0.56–11.66 mg/L were obtained for pharmacokinetic modeling. The pharmacokinetic characteristic of polymyxin B was well described by a 1-compartment model with linear elimination, and only creatinine clearance was identified as a covariate on the clearance of polymyxin B. Monte Carlo simulations indicated an adjusted dosage regimen might be needed in patients with renal insufficiency and the currently recommended dose regimens by the label sheet of polymyxin B may likely generate a subtherapeutic exposure for MIC = 2 mg/L.Conclusion: Renal function has a significant effect on the clearance of polymyxin B in lung transplant recipients, and an adjustment of dosage was needed in patients with renal impairments.

Liver cancer is the third most common cause of cancer-related deaths in the world and has become an urgent problem for global public health. Bioactive substances are widely used for the treatment of liver cancer due to their widespread availability and reduced side effects. This review summarizes the main pathogenic factors involved in the development of liver cancer, including metabolic fatty liver disease, viral infection, and alcoholic cirrhosis, and focuses on the mechanism of action of bioactive components such as polysaccharides, alkaloids, phenols, peptides, and active bacteria/fungi. In addition, we also summarize transformation methods, combined therapy and modification of bioactive substances to improve the treatment efficiency against liver cancer, highlighting new ideas in this field.

GRAPHICAL ABSTRACT

Background: Hepatocellular carcinoma (HCC) is a lethal disease with high relapse and dismal survival rates. Alternative splicing (AS) plays a crucial role in tumor progression. Herein, we aim to integratedly analyze the relapse-associated AS events and construct a signature predicting tumor relapse in stage I–III HCC.Methods: AS events of stage I–III HCC with tumor relapse or long-term relapse-free survival were profiled to identify the relapse-associated AS events. A splicing network was set up to analyze the correlation between the relapse-associated AS events and splicing factors. Cox regression analysis and receiver operating characteristic curve were performed to develop and validate the relapse-predictive AS signature. Single-sample gene set enrichment analysis (ssGSEA) and the ESTIMATE algorithm were used to assess the immune infiltration status of the HCC microenvironment between different risk subgroups. Unsupervised cluster analysis was conducted to assess the relationship between molecular subtypes and local immune status and clinicopathological features.Results: In total, 2441 ASs derived from 1634 mRNA were identified as relapse-associated AS events. By analyzing the proteins involved in the relapse-associated AS events, 1573 proteins with 11590 interactions were included in the protein–protein interaction (PPI) network. In total, 16 splicing factors and 61 relapse-associated AS events with 85 interactions were involved in the splicing network. The relevant genes involved in the PPI network and splicing network were also analyzed by Gene Ontology enrichment analysis. Finally, we established a robust 16-gene AS signature for predicting tumor relapse in stage I–III HCC with considerable AUC values in all of the training cohort, testing cohort, and entire cohort. The ssGSEA and ESTIMATE analyses showed that the AS signature was significantly associated with the immune status of the HCC microenvironment. Moreover, four molecular subgroups with distinguishing tumor relapse modes and local immune status were also revealed.Conclusion: Our study built a novel 16-gene AS signature that robustly predicts tumor relapse and indicates immune activity in stage I–III HCC, which may facilitate the deep mining of the mechanisms associated with tumor relapse and tumor immunity and the development of novel individualized treatment targets for HCC.

Neuropathic pain (NP) affects 7%–10% of the general population and is still hard to cure. Here, we validated the therapeutic effect and demonstrated the mechanism of paeoniflorin and liquiritin combination (PL) on NP from the perspective of integrated lipidomics and transcriptomics for the first time. SwissTargetPrediction indicated that PL mainly targets lipid metabolism. Notably, lipidomics revealed that imbalanced lipid levels in the NP model could be reprogrammed to normal levels by PL treatment. RNA-sequencing showed that PL treatment could also rebalance the lipid metabolism in an indirect manner. Pathway analysis highly enriched the calcium signaling pathway among the most significant categories. Altogether, these findings suggested that PL can not only balance the lipid metabolism in direct and indirect manners but also reverse the dysfunctional activation of the calcium signaling pathway, thereby alleviating NP. This helps to better understand the mechanisms of NP and provides a new important potential therapeutic option for NP.

Cardiac hypertrophy initially serves as an adaptive response to physiological and pathological stimuli. Sustained hypertrophy progress to pathological cardiac hypertrophy, cardiac fibrosis and ultimately lead to heart failure, one of the leading medical causes of mortality worldwide. Intervention of pathological cardiac hypertrophy can effectively reduce the occurrence of heart failure. Abundant factors, such as adrenergic, angiotensin, and endothelin (ET-1) receptors, have been shown to participate in the regulation of pathological cardiac hypertrophy. Recently, an increasing number of studies have indicated that circRNA and circRNA-miRNA–mRNA network regulation is indispensable for the posttranscriptional regulation of mRNA in cardiac hypertrophy. In our study, the morphological, cardiac function and pathological changes during cardiac hypertrophy were investigated. RNA sequencing identified 93 circRNAs that were differentially expressed in the TAC_2w group, and 55 circRNAs in the TAC_4w group compared with the sham group. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses identified several significant pathways, including hypertrophic cardiomyopathy, extracellular matrix (ECM)-receptor interaction and focal adhesion. Coexpression analyses were performed for differentially expressed circRNAs and differentially expressed mRNAs. Based on gene set enrichment analysis (GSEA), 8 circRNAs (mmu-Nfkb1_0001, mmu-Smad4_0007, mmu-Hecw2_0009, mmu-Itgbl1_0002, mmu-Lrrc2_0005, mmu-Cpeb3_0007, mmu-Ryr2_0040, and mmu-Rtn4_0001) involved in cardiac hypertrophy and cardiac fibrosis were identified. We validated some key circRNAs by qPCR. The crucial coexpression of circRNA–mRNA and its interaction with miRNA showed the possible mechanism of circRNAs in the process of cardiac dysfunction. Our results may provide promising targets for the treatment of pathological cardiac hypertrophy and fibrosis.

Background: Stable angina is a common condition with high morbidity and mortality rates. It has been reported that combining oral Chinese patent medicines (OCPMs) and Western medicine (WM) could potentially achieve a better effect than WM alone. However, the optimal OCPMs for stable angina remain controversial and merit further empirical research.Methods: PubMed, Embase, Web of Science, Cochrane Library, Ovid-Medline, Clinical Trials.gov, China National Knowledge Infrastructure, Wanfang Database, Weipu Journal Database, and Chinese Biomedical Literature Database were all searched from inception to 13 March 2022. We employed Version 2 of the Cochrane risk-of-bias tool (ROB2) to assess the overall quality of the selected studies. We also used R 4.1.2 and STATA 14.0 software applications to perform network meta-analysis, followed by sensitivity and subgroup analysis.Results: A total of 179 randomized controlled trials with 16,789 patients were included. The selected trials were all assessed as some concerns. OCPMs combined with WM had a better treatment effect than WM alone. In terms of the effective clinical rate, a significant increase was detected for Qishen Yiqi dripping pill (QSYQ)+WM as compared with Shensong Yangxin capsule (SSYX)+WM, Shexiang Baoxin pill (SXBX)+WM, Tongxinluo capsule (TXL)+WM, Xuefu Zhuyu capsule (XFZY)+WM, Qiliqiangxin capsule (QLQX)+WM, Naoxintong capsule (NXT)+WM, Fufang Danshen dripping pill (FFDS)+WM, and Danlou tablet (DL)+WM. QSYQ + WM had the highest-ranking probability (98.12%). Regarding the effective rate in ECG, QSYQ + WM was superior to SXBX + WM, TXL + WM, DL + WM, FFDS + WM, and NXT + WM. QSYQ + WM ranked first (94.21%). In terms of weekly frequency of angina, QLQX + WM obtained a better effect than FFDS + WM, Kuanxiong aerosol (KXQW)+WM, NXT + WM, QLQX + WM, SSYX + WM, SXBX + WM, and TXL + WM. QLQX + WM ranked first (100.00%). Regarding the duration of an angina attack, KXQW + WM was superior to SSYX + WM; KXQW + WM ranked first (95.71%). Adverting to weekly nitroglycerin usage, TXL + WM had the highest-ranking probability (82.12%). Referring to cardiovascular event rate, DL + WM had the highest effect (73.94%). Additionally, SSYX + WM had the lowest rate of adverse drug reactions (1.14%).Conclusion: OCPMs combined with WM had a higher efficacy. QSYQ + WM, QLQX + WM, KXQW + WM, TXL + WM, DL + WM, SSYX + WM, and SXBX + WM merit further investigation. SXBX + WM is presumably the optimal treatment prescription for both clinically effective and cardiovascular event rates. Further high-quality empirical research is needed to confirm the current results.Systematic Review Registration: URL = https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=316534, CRD 42022316534

Background: Acute tonsillitis has high morbidity. Chinese herbal injections (CHIs) were reported to be useful in treating acute tonsillitis and might reduce the probability of antibiotic resistance. Nevertheless, the optimal strategy for combining CHIs with western medicine (WM) to treat acute tonsillitis remains unclear.Methods: We retrieved data from the following databases with retrieval time from inception to 11 January 2022: PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, Weipu Journal Database, and Chinese Biomedical Literature Database. Version 2 of the Cochrane risk-of-bias tool (ROB2) was used for evaluating the quality of the included studies. R 4.1.2, STATA 14.0, and Python 3.10.4 were employed for network meta-analysis, with 5-dimensional K-means cluster analysis, meta-regression analyses, sensitivity analyses, and subgroup analyses.Results: A total of 110 randomized controlled trials including 12,152 patients were included. All the studies were rated as “high risk” and “some concerns”. In terms of improving clinical effectiveness rate, Qingkailing injection + WM ranked ahead of other interventions (89.51%). Regarding reducing antipyretic time, Reduning injection + WM had the highest-ranking probability (68.48%). As for shortening sore throat relief time, Shuanghuanglian injection + WM ranked first (76.82%). Concerning shortening red and swollen tonsils relief time, Yanhuning injection + WM possessed the highest-ranking probability (89.17%). In terms of reducing tonsillar exudate relief time, Xuebijing injection + WM ranked ahead of the other interventions (94.82%). Additionally, the results of the cluster analysis suggested that Xuebijing injection + WM, Reduning injection + WM, and Yanhuning injection + WM were probably the best interventions. Furthermore, adverse drug reactions rate of Xuebijing injection + WM, Reduning injection + WM, Yanhuning injection + WM, Qingkailing injection + WM, and Shuanghuanglian injection + WM were individually 0.00%, 3.11%, 3.08%, 4.29%, and 4.62%.Conclusions: CHIs + WM have a better impact on patients with acute tonsillitis than WM alone. Xuebijing injection, Reduning injection, and Yanhuning injection might have potential advantages in treating the disease. Concerning adverse drug reactions, Xuebijing injection is presumably the optimal CHI. More high-quality studies are needed to further confirm our findings.Systematic Review Registration: CRD42022303243; URL= https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=303243

Cancer drug resistance has always been a major factor affecting the treatment of non-small cell lung cancer, which reduces the quality of life of patients. The clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) technology, as an efficient and convenient new gene-editing technology, has provided a lot of help to the clinic and accelerated the research of cancer and drug resistance. In this review, we introduce the mechanisms of drug resistance in non-small cell lung cancer (NSCLC), discuss how the CRISPR/Cas9 system can reverse multidrug resistance in NSCLC, and focus on drug resistance gene mutations. To improve the prognosis of NSCLC patients and further improve patients’ quality of life, it is necessary to utilize the CRISPR/Cas9 system in systematic research on cancer drug resistance.

The herb-pair ginseng-Fuzi (the root of Aconitum carmichaelii) is the material basis of Shenfu prescriptions and is popular in traditional Chinese medicine for the treatment of heart failure, and even shock with severe-stage of COVID-19. A narrow therapeutic window of Fuzi may cause significant regional loss of property and life in clinics. Therefore, systemic elucidation of active components is crucial to improve the safety dose window of Shenfu oral prescriptions. A high performance liquid chromatography-mass spectrometry method was developed for quantification of 10 aconitines in SD rat plasma within 9 min. The limit of detection and the limit of quantification were below 0.032 ng/ml and 0.095 ng/ml, respectively. Furthermore, a systemic comparison with their pharmacokinetic characteristics after oral administration of a safe dosage of 2 g/kg of Fuzi and ginseng-Fuzi decoction for 24 h was conducted. Eight representative diester, monoester, and non-ester aconitines and two new active components (i.e., songorine and indaconitine) were all adopted to elucidating the differences of the pharmacokinetic parameters in vivo. The compatibility of Fuzi and ginseng could significantly increase the in vivo exposure of active components. The terminal elimination half-life and the area under the concentration-time curve of mesaconitine, benzoylaconitine, benzoylmesaconitine, benzoylhypaconitine, and songorine were all increased significantly. The hypaconitine, benzoylmesaconitine, and songorine were regarded as the main active components in vivo, which gave an effective clue for the development of new Shenfu oral prescriptions.

Background: Septic shock is associated with high morbidity and mortality. Studies have reported that Chinese herbal injections (CHIs) in combination with Western medicine (WM) were more favorable. However, the debate on optimal CHIs is ongoing. The objective of this study is to explore the comparative effectiveness of CHIs for septic shock.Methods: We retrieved data from the English and Chinese databases with retrieval time from database inception to 30 September 2021. Network meta-analysis was performed, with evaluation of methodological quality among the included studies and assessment of strength of evidence among the outcomes.Results: A total of 77 RCTs with 5,647 patients were included. All the studies were rated as some concerns. In terms of 28-days-mortality, Yiqifumai injection (YQFM)+WM, Shuxuetong injection (SXT)+WM, Xuebijing injection (XBJ)+WM, and Shenfu injection (SF)+WM were better than WM; YQFM + WM and SXT + WM were superior for Shenmai injection (SM)+WM; YQFM + WM was superior for SF + WM; YQFM + WM ranked first. Regarding ICU length of stay, SF + WM and XBJ + WM were better than WM; XBJ + WM was superior for SF + WM; XBJ + WM ranked first. Concerning hospital length of stay, Shenqifuzheng injection (SQFZ)+WM, Shengmai injection (SGM)+WM, and XBJ + WM had greater potential than WM and SF + WM; SQFZ + WM ranked first. As for SOFA score at 7-days, XBJ + WM and SF + WM were superior for WM; XBJ + WM was superior for SF + WM; XBJ + WM ranked first. Regarding procalcitonin level at 7-days, SF + WM, SM + WM, and Xiyanping injection (XYP)+WM were better than WM; XYP + WM was superior for SF + WM, SGM + WM, SM + WM, Danshen injection (DS)+WM, and XBJ + WM; XYP + WM ranked first. Concerning serum lactate level at 7-days, SF + WM and SM + WM were more effective than XBJ + WM and WM; SM + WM ranked first. The comparisons were rated as moderate (15.05%), low (40.86%), and very low quality (44.09%); the strength of evidence of ranking probability for hospital length of stay was low whereas the remaining outcomes were rated as very low.Conclusions: CHIs combined with WM might have higher efficacies for septic shock than WM alone. YQFM, XBJ, SQFZ, XYP, SM, SGM, and SF may be the potential optimal CHIs for septic shock. More and better evidence is needed to validate the conclusions.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?, identifier CRD42021282958.

It is generally accepted that geriatric patients are more sensitive to propofol than adults; thus, a dose-adjusted propofol is recommended for these patients during the induction of anesthesia. However, for patients aged 75 years and over, established guidelines for propofol induction doses do not provide dose references. To this end, we observed 80 surgical patients (female 39, male 41, American Society of Anesthesiologists physical status score I ∼ II) to access the appropriate dose of propofol for inducing loss of consciousness (LOC). Accordingly, patients were subdivided into group A (20 patients, 45–64 years), group B (20 patients, 65–74 years), group C (20 patients, 75–84 years), and group D (20 patients, ≥ 85 years). All patients received propofol (at a rate of 0.3 mg/kg/min) alone for inducing LOC, which was defined by loss of both eyelash reflex and verbal response. Compared with group A, the propofol requirement for LOC in Group B, C and D decreased by 14.8, 25.2 and 38.5%, respectively. Bivariate linear correlation analysis showed that propofol requirement was negatively correlated with age. After adjusting for potential confounders, age was still an independent factor affecting propofol requirement. In conclusion, the propofol requirement for inducing LOC decreased significantly in elderly patients. We demonstrated that age was an independent factor impacting propofol requirement for LOC during the induction of general anesthesia, implying that the propofol dose for anesthesia induction should be further reduced in elderly surgical patients, especially those aged 75 years and over.

It is a viable strategy to inhibit osteoclast differentiation for the treatment of osteolytic diseases such as osteoporosis, rheumatoid arthritis and tumor bone metastases. Here we assessed the effects of insulicolide A, a natural nitrobenzoyl sesquiterpenoid derived from marine fungus, on receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclastogenesis in vitro and its protective effects on LPS-induced osteolysis mice model in vivo. The results demonstrated that insulicolide A inhibited osteoclastogenesis from 1 μM in vitro. Insulicolide A could prevent c-Fos and nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) nuclear translocation and attenuate the expression levels of osteoclast-related genes and DC-STAMP during RANKL-stimulated osteoclastogenesis but have no effects on NF-κB and MAPKs. Insulicolide A can also protect the mice from LPS-induced osteolysis. Our research provides the first evidence that insulicolide A may inhibit osteoclastogenesis both in vitro and in vivo, and indicates that it may have potential for the treatment of osteoclast-related diseases.

Background: Although medical guidelines discourage the use of methylxanthines in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD), they are still widely used in clinical practice. This study investigated the real-world use of methylxanthines in the management of AECOPD.Methods: Patient data from the Acute exacerbation of Chronic obstructive pulmonary disease Using REgistry data (ACURE, NCT02657525) study database were screened. Enrolled patients were divided into treatment and control groups. Propensity score (PS) matching and Cox regression analyses were used to minimize confounding factors and determine the association between methylxanthine treatment and the length of stay (LOS).Results: Among the 2088 eligible patients, 1,563 (74.9%) were in the methylxanthine treatment group. Patients treated with methylxanthines had more severe respiratory symptoms and worse lung function than those in the control group. Doxophylline was the most commonly used methylxanthine in both secondary and tertiary hospitals. After PS matching, 966 patients were equally divided into two groups. The LOS of patients in the two groups was similar [median: 8 days, interquartile range (IQR): 7–11 days, p = 0.730]. Patients in the treatment group (median: 8, IQR: 4–12) had a more significant decrease in the COPD Assessment Test score from admission to discharge than those in the control group (median: 6, IQR: 2–10, p < 0.001). Among all matched patients, the LOS was not significantly associated with methylxanthine treatment [adjusted hazard ratio (HR): 1.02, 95% confidence intervals (CIs): 0.89–1.16]. However, in the subgroup analysis, methylxanthines were significantly associated with a short LOS in patients with blood eosinophil count >4% (adjusted HR: 1.56, 95% CIs: 1.12–2.17).Conclusion: This study revealed that methylxanthines, especially doxophylline, are widely used in China. Methylxanthines were effective in improving symptoms in AECOPD patients. Higher blood eosinophil count may be associated with a better efficacy of methylxanthine treatment.

Antimalarial drugs Dihydroartemisinin (DHA) and chloroquine phosphate (CQ) exhibit evident anti-cancer activity, particularly as combination therapy. DHA and CQ combination therapy has been proved to exhibit higher cytotoxic effect in tumor cells and lower toxicity to normal cells than combination of artemisinin derivatives (ARTs) and anticancer chemotherapy drugs. However, different physiochemical properties of DHA and CQ, leading to distinctive in vivo outcomes, considerably limited their synergistic effect in cancer treatment. Herein, we developed a lipid nanoparticle (LNP) for co-delivery of DHA and CQ to inhibit proliferation and metastasis of colorectal cancer. Considering the beneficial effects of acid/reactive oxide species (ROS)-sensitive phospholipids and targeting ligands for colorectal cancer cells, an RGD peptide-modified pH/ROS dual-sensitive LNP loaded with DHA and CQ (RLNP/DC) was prepared. It exhibited optimal cytotoxicity and suppression of invasion and metastasis in HCT116 cells in vitro, attributable to irreversible upregulation of intracellular ROS levels, downregulation of VEGF expression, and upregulation of paxillin expression. A mouse model of orthotopic metastasis of colorectal cancer was established to evaluate anti-proliferation and anti-metastasis effects of RLNP/DC in vivo. Thus, an optimized nanoplatform for DHA and CQ combination therapy was developed in this study that offered potential antitumor efficacy against colorectal cancer.

Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir (TFV) that has been approved for the treatment of chronic hepatitis B virus (HBV) infection. It has greater plasma stability and more favorable renal safety than tenofovir disoproxil fumarate (TDF), the first approved oral prodrug of TFV. However, the distribution of TFV in the breast milk of mothers treated with TAF is still unclear. In this study, sixteen participants with chronic HBV infection were enrolled and received antiretroviral therapy with 25 mg of TAF or 300 mg of TDF daily from 24 to 28 weeks of gestation until the 4th week postpartum. For the first time, the distribution of TFV in the breast milk of mothers with chronic HBV infection treated with TAF and its difference from TDF were evaluated by using a sensitive UPLC–MS/MS method. Chromatographic separation was achieved on a Waters ACQUITY UPLC BEH C18 column (1.7 µm 2.1 × 100 mm). Mass spectrometry analysis was performed in positive electrospray ionization mode and multiple reaction monitoring (MRM) conditions of transitions m/z 288.1→176.2 for TFV. This method was linear from 0.5 to 500 ng/ml. Surprisingly, on the third postpartum day, the median Cmax of TFV in the breast milk was much higher in the mothers treated with TAF (101.2 ng/ml) than TDF (21.6 ng/ml) at a similar Tmax of 4 h. Accordingly, the median AUC0-8 value was 755.6 ng h/mL in the mothers taking TAF, which was at a 5-fold higher level than TDF. The concentration of TFV in the breast milk of mothers in both groups decreased with increasing lactation time. These data indicated that there was a relatively higher exposure of TFV in the breast milk of mothers taking TAF, despite the lower dosage compared to TDF. This study provides support for further evaluating the safety of breastfeeding after the administration of TAF and TDF.

Background: Despite the development of such multiple therapeutic approaches, approximately 20% patients experience recurrence. Identification of molecular markers for stratifying the different risks of tumour recurrence and progression is considered imperative.Methods: We used a RayBio Human Cytokine Antibody Array that simultaneously detected the levels of 297 proteins and profiled the conditioned medium of HONE1 cells and the radioresistant NPC cells HONE1-IR. We found Angiogenin(ANG) expression to be significantly increased in HONE1-IR and HONE1-IR cells exposed to 4-Gy X-ray radiation.Results: We investigated the expression of ANG in NPC tissues and explored its prognostic significance in patients with NPC. We found that ANG expression was increased in recurrent NPC tissues. Elevated expression of ANG induced radio-resistance in NPC cells, in addition to being significantly associated with shorter PFS, OS, and LRFS in patients with NPC. Multivariate analysis results revealed that ANG was an independent prognostic factor that predicted PFS, OS, and LRFS. Furthermore, a nomogram model was generated to predict OS in terms of ANG expression.Conclusion: Our results found the radioresistant function of ANG and proved the clinical prognostic significance of ANG, and the results could help predict radio-sensitivity and stratify high-risk patients or tumour recurrence.

Chronic constipation is a common gastrointestinal disorder, with a worldwide incidence of 14–30%. It negatively affects quality of life and is associated with a considerable economic burden. As a disease with multiple etiologies and risk factors, it is important to understand the pathophysiology of chronic constipation. The purpose of this review is to discuss latest findings on the roles of gut motility, fluid, and electrolyte transport that contribute to chronic constipation, and the main drugs available for treating patients. We conducted searches on PubMed and Google Scholar up to 9 February 2021. MeSH keywords “constipation”, “gastrointestinal motility”, “peristalsis”, “electrolytes”, “fluid”, “aquaporins”, and “medicine” were included. The reference lists of searched articles were reviewed to identify further eligible articles. Studies focusing on opioid-induced constipation, evaluation, and clinic management of constipation were excluded. The occurrence of constipation is inherently connected to disorders of gut motility as well as fluid and electrolyte transport, which involve the nervous system, endocrine signaling, the gastrointestinal microbiota, ion channels, and aquaporins. The mechanisms of action and application of the main drugs are summarized; a better understanding of ion channels and aquaporins may be helpful for new drug development. This review aims to provide a scientific basis that can guide future research on the etiology and treatment of constipation.

Objectives: A controlled open clinical study was conducted to evaluate the role of Ricnoat, a high-content complex dietary fiber powder produced by Zhuhai Aimed Biotechnology Co. Ltd., in medical nutrition therapy (MNT) to treat gestational diabetes mellitus (GDM). The study aimed to investigate glycemic control, lipid control, weight control, and pregnancy outcomes (neonatal weight) in patients with GDM, as well as evaluate the clinical safety of Ricnoat.Methods: A total of 120 patients with GDM who were admitted to three hospitals in Shanghai between January 2019 and January 2020 were enrolled. Ricnoat was used for intervention for patients in the experimental group. Using a χ2 test and t-test, respectively, comparisons were conducted between the measurement data and countable data of the demographics and baseline disease characteristics of the experimental group and control group.Results: Fasting blood glucose, 2-h postprandial blood glucose, glycated hemoglobin, total cholesterol, triglycerides, low-density lipoprotein, maternal gestational weight gain, neonatal weight, serum creatinine, glutamate transaminase, and aspartate aminotransferase were lower in the experimental group than in the control group, whereas high-density lipoprotein was higher in the experimental group than in the control group. Ricnoat intervention resulted in satiety higher than the expected 80% and more common occurrence of type 4 (smooth and soft, like salami or a snake) and type 5 (a soft mass with clear edges) stools.Conclusion: Ricnoat intervention had a significant effect on glycemic control, lipid control, weight control, and pregnancy outcomes (neonatal weight) in patients with GDM by enhancing maternal satiety and improving the stool features of pregnant women. It was also found to be safe for application during pregnancy.

The combination of chemotherapy with natural products is a common strategy to enhance anticancer effects while alleviating the dose-dependent adverse effects of cancer treatment. Oxymatrine (OMT) has been extensively reported as having anticancer activity. Doxorubicin (DOX) is a chemotherapeutic DNA-damaging agent used for the treatment of carcinoma. In this study, we investigated whether synergistic effects exist with the combination treatment with OMT and DOX using human colorectal cancer cell (CRC) lines and the potential mechanisms involved in in vitro and in vivo activities. The MTT and colony formation assay results showed that compared to either OMT or DOX monotherapy, the combination of OMT + DOX markedly inhibited the growth of HT-29 and SW620 cells. Wound healing assays showed significant inhibition of cell migration with co-treatment, supported by the change in E-cadherin and N-cadherin expressions in Western blotting. Furthermore, flow cytometry analysis revealed that OMT + DOX co-treatment enhanced cell apoptosis as a result of ROS generation, whereas NAC attenuated OMT + DOX–induced apoptosis. Similarly, the apoptosis-related proteins (cleaved caspase-3, cleaved caspase-9, and the ratio of Bax/Bcl-2) were determined by Western blotting, which showed that the expressions of these markers were notably increased in the co-treatment group. Furthermore, co-administration of a low dose of DOX and OMT inhibited xenograft tumor growth in a dose-dependent manner. TUNEL assay and Ki67 staining images indicated more apoptosis and less proliferation occurred in OMT plus DOX-treated xenograft tumors. Meanwhile, the combination strategy decreased cardiotoxicity, which is the most serious side effect of DOX. RNA sequencing was performed to explore the precise molecular alterations involved in the combination group. Among the numerous differentially expressed genes, downregulated FHL-2 and upregulated cleaved SPTAN1 were validated in both mRNA and protein levels of HT-29 and SW620 cells. These two proteins might play a pivotal role involving in OMT + DOX synergistic activity. Overall, OMT in combination with DOX presented an outstanding synergistic antitumor effect, indicating that this beneficial combination may offer a potential therapy for CRC patients.

Background: The evidence for real-world antibiotic use in treating acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is insufficient. This study aimed to investigate real-world antibiotic use in the management of AECOPD in China.Methods: All hospitalized AECOPD patients from the acute exacerbation of chronic obstructive pulmonary disease inpatient registry (ACURE) study conducted at 163 sites between January 2018 and December 2019 were screened according to the eligible criteria. The eligible study population was divided into secondary and tertiary hospital groups. Patients’ baseline characteristics, antibiotic use, and bacterial pathogen characteristics were retrieved and analyzed using SPSS 23.0.Results: A total of 1663 patients were included in the study, including 194 patients from secondary hospitals and 1469 patients from tertiary hospitals. Among the 1663 AECOPD patients enrolled, 1434 (86.2%) received antibiotic treatment, comprising approximately 85.6% and 86.3% of patients in the secondary and tertiary hospital groups, respectively. The median antibiotic therapy duration was 9.0 (interquartile range [IQR]: 7.0 - 11.0)°days. Regarding the routes of antibiotic use, 1400 (97.6%) patients received intravenous antibiotics, 18 (1.3%) patients received oral antibiotics, 15 (1.0%) patients received both intravenous and oral antibiotics, and one (0.1%) patient received both oral and nebulized antibiotic treatment. In addition, cephalosporin, penicillin, and quinolone were the most commonly prescribed antibiotics (43.6%, 37.0%, and 34.2%, respectively). In total, 990 (56.5%) patients underwent pathogen examinations; the proportion of patients receiving pathogen examinations in the second hospital group was significantly lower than that in the tertiary hospital group (46.4% vs 61.3%, p < 0.001).Conclusion: This study demonstrates that an antibiotic overuse may exist in the treatment of AECOPD in China. Measures should be taken to prevent the overuse of antibiotics and potential antimicrobial resistance (AMR) in Chinese AECOPD patients.

Mitochondria are the key organelles that supply cellular energy. As the most active organ in the body, the energy required to maintain the mechanical function of the heart requires a high quantity of high-quality mitochondria in cardiomyocytes. MicroRNAs (miRNAs) are single-stranded noncoding RNAs, approximately 22 nt in length, which play key roles in mediating post-transcriptional gene silencing. Numerous studies have confirmed that miRNAs can participate in the occurrence and development of cardiac diseases by regulating mitochondrial function-related genes and signaling pathways. Therefore, elucidating the crosstalk that occurs between miRNAs and mitochondria is important for the prevention and treatment of cardiac diseases. In this review, we discuss the biogenesis of miRNAs, the miRNA-mediated regulation of major genes involved in the maintenance of mitochondrial function, and the effects of miRNAs on mitochondrial function in cardiac diseases in order to provide a theoretical basis for the clinical prevention and treatment of cardiac disease and the development of new drugs.

NLRP3 inflammasome has been implicated in impaired post-injury muscle healing and in muscle atrophy. Histamine receptors play an important role in inflammation, but the role of histamine H3 receptor (H3R) in myocyte regeneration and in the regulation of NLRP3 inflammasome is not known. We studied the effects of H3R signaling on C2C12 myocyte viability, apoptosis, and tumor necrosis factor alpha (TNFα)-induced NLRP3 inflammasome activation during striated myogenic differentiation at three time points (days 0, 3, and 6). Expression of Nlrp3, interleukin-1β (IL-1β), and myogenesis markers were determined. TNFα reduced overall viability of C2C12 cells, and exposure to TNFα induced apoptosis of cells at D6. Activation of H3R had no effect on viability or apoptosis, whereas inhibition of H3R increased TNFα-induced apoptosis. Stimulation of C2C12 cells with TNFα increased Nlrp3 mRNA expression at D3 and D6. Moreover, TNFα reduced the expression of myogenesis markers MyoD1, Myogenin, and Myosin-2 at D3 and D6. H3R attenuated TNFα-induced expression of Nlrp3 and further inhibited the myogenesis marker expression; while H3R -blockage enhanced the proinflammatory effects of TNFα and increased the myogenesis marker expression. TNFα-induced secretion of mature IL-1β was dependent on the activation of the NLRP3 inflammasome, as shown by the reduced secretion of mature IL-1β upon treatment of the cells with the small molecule inhibitor of the NLRP3 inflammasome (MCC950). The activation of H3R reduced TNFα-induced IL-1β secretion, while the H3R blockage had an opposite effect. In conclusion, the modulation of H3R activity regulates the effects of TNFα on C2C12 myocyte differentiation and TNFα-induced activation of NLRP3 inflammasome. Thus, H3R signaling may represent a novel target for limiting postinjury muscle inflammation and muscle atrophy.

Crocetin and crocin are two important carotenoids isolated from saffron (Crocus sativus L.), which have been used as natural biomedicines with beneficial effects for improving the suboptimal health status associated with abnormal angiogenesis. However, the anti-angiogenic effects and underlying mechanisms of the effects of crocetin and crocin have not been investigated and compared. The anti-angiogenic effects of crocetin and crocin were tested on human umbilical vein endothelial cells (HUVECs) in vitro, and in zebrafish in vivo. In vivo, crocetin (20 μM) and crocin (50 and 100 μM) significantly inhibited subintestinal vein vessels formation, and a conversion process between them existed in zebrafish, resulting in a difference in their effective concentrations. In the HUVEC model, crocetin (10, 20 and 40 μM) and crocin (100, 200 and 400 μM) inhibited cell migration and tube formation, and inhibited the phosphorylation of VEGFR2 and its downstream pathway molecules. In silico analysis further showed that crocetin had a higher ability to bind with VEGFR2 than crocin. These results suggested that crocetin was more effective than crocin in inhibiting angiogenesis through regulation of the VEGF/VEGFR2 signaling pathway. These compounds, especially crocetin, are potential candidate natural biomedicines for the management of diseases associated with abnormal blood vessel growth, such as age-related macular degeneration.

Background: Nosocomial pneumonia is a major health and economic burden globally. Multidrug-resistant (MDR) or extensively drug-resistant (XDR) Gram-negative bacteria are the most common causative pathogens in critically-ill patients. Polymyxin B is a salvage therapy for MDR Gram-negative pathogens; however, the current literature on its effectiveness and nephrotoxicity is limited, including in Chinese patients.Methods: We retrospectively analyzed 107 patients with nosocomial pneumonia caused by MDR or XDR Gram-negative bacteria treated with intravenous polymyxin B (2–3 mg/kg/day). Renal function was evaluated on the day before commencement of polymyxin B therapy and on the third and 7 days of treatment. Univariate and multivariate analyses were conducted to determine risk factors for the effectiveness and nephrotoxicity of polymyxin B. Sixty-seven (62.6%) and sixty-five (60.7%) patients had favorable clinical and microbiological responses, respectively. Acute physiology and chronic health evaluation II (APACHE II) scores, cardio-pulmonary resuscitation (CPR) history, numbers of pathogens per patient and a favorable microbiological response were independently associated with favorable clinical outcomes of polymyxin B treatment in Chinese patients with MDR or XDR nosocomial pneumonia. Initial renal dysfunction was not associated with late nephrotoxicity (on day 7), although early nephrotoxicity (on day 3) was independently associated with late nephrotoxicity (OR = 39.43, 95% CI 7.64–203.62, p = 0.00).Conclusion: Our findings support polymyxin B treatment for MDR and XDR pneumonia, with the severity of disease and polymicrobial infection being risk factors for a poor clinical outcome. Nephrotoxicity following 3 days of polymyxin B treatment was found to be a reliable risk factor for later nephrotoxicity.

Background: The pandemic of coronavirus disease 2019 (COVID-19) resulted in grave morbidity and mortality worldwide. There is currently no effective drug to cure COVID-19. Based on analyses of available data, we deduced that excessive prostaglandin E2 (PGE2) produced by cyclooxygenase-2 was a key pathological event of COVID-19.Methods: A prospective clinical study was conducted in one hospital for COVID-19 treatment with Celebrex to suppress the excessive PGE2 production. A total of 44 COVID-19 cases were enrolled, 37 cases in the experimental group received Celebrex as adjuvant (full dose: 0.2 g, bid; half dose: 0.2 g, qd) for 7–14 days, and the dosage and duration was adjusted for individuals, while seven cases in the control group received the standard therapy. The clinical outcomes were evaluated by measuring the urine PGE2 levels, lab tests, CT scans, vital signs, and other clinical data. The urine PGE2 levels were measured by mass spectrometry. The study was registered and can be accessed at http://www.chictr.org.cn/showproj.aspx?proj=50474.Results: The concentrations of PGE2 in urine samples of COVID-19 patients were significantly higher than those of PGE2 in urine samples of healthy individuals (mean value: 170 ng/ml vs 18.8 ng/ml, p < 0.01) and positively correlated with the progression of COVID-19. Among those 37 experimental cases, there were 10 cases with age over 60 years (27%, 10/37) and 13 cases (35%, 13/37) with preexisting conditions including cancer, atherosclerosis, and diabetes. Twenty-five cases had full dose, 11 cases with half dose of Celebrex, and one case with ibuprofen. The remission rates in midterm were 100%, 82%, and 57% of the full dose, half dose, and control group, respectively, and the discharged rate was 100% at the endpoint with Celebrex treatment. Celebrex significantly reduced the PGE2 levels and promoted recovery of ordinary and severe COVID-19. Furthermore, more complications, severity, and death rate were widely observed and reported in the COVID-19 group of elders and with comorbidities; however, this phenomenon did not appear in this particular Celebrex adjunctive treatment study.Conclusion: This clinical study indicates that Celebrex adjuvant treatment promotes the recovery of all types of COVID-19 and further reduces the mortality rate of elderly and those with comorbidities.

Imatinib mesylate (IM) is the standard treatment for advanced, metastatic gastrointestinal stromal tumors (GISTs) and chronic myeloid leukemia (CML) with a fixed daily standard dosage via the oral route. Interindividual and intraindividual variability in plasma concentrations have been closely linked to the efficacy of IM therapy. Therefore, this review identifies and describes the key factors influencing the plasma concentration of IM in patients with GISTs and CML. We used the following keywords to search the PubMed, EMBASE, Ovid, Wangfang, and CNKI databases to identify published reports: IM, plasma concentration, GISTs, CML, drug combination/interaction, pathology, and genotype/genetic polymorphism, either alone or in combination. This literature review revealed that only 10 countries have reported the mean concentrations of IM in GISTs or CML patients and the clinical outcomes in different ethnic groups and populations. There were totally 24 different gene polymorphisms, which were examined for any potential influence on the steady-state plasma concentration of IM. As a result, some genotype locus made discrepant conclusion. Herein, the more sample capacity, multicenter, long-term study was worthy to carry out. Eleven reports were enumerated on clinical drug interactions with IM, while there is not sufficient information on the pharmacokinetic parameters altered by drug combinations with IM that could help in investigating the actual drug interactions. The drug interaction with IM should be paid more attention in the future research.

Cadmium is an important environmental pollutant that poses a serious threat to the health of humans and animals. A large number of studies have shown that the liver is one of the important target organs of cadmium. Stimulation of cells can lead to rapid changes in gap junction intercellular communication (GJIC) and autophagy. Previous studies have shown that cadmium can inhibit GJIC and induce autophagy. In order to understand the dynamic changes of GJIC and autophagy in the process of cadmium-induced hepatotoxic injury and the effects of GJIC on autophagy, a time-gradient model of cadmium cytotoxicity was established. The results showed that within 24 h of cadmium exposure, 5 μmol/L cadmium inhibited GJIC by down regulating the expression levels of connexin 43 (Cx43) and disturbing the localization of Cx43 in Buffalo rat liver 3A (BRL 3A) cells. In addition, cadmium induced autophagy and then inhibited autophagic flux in the later stage. During this process, inhibiting of GJIC could exacerbate the cytotoxic damage of cadmium and induce autophagy, but further blocked autophagic flux, promoting GJIC in order to obtain the opposite results.

The incidence rate of cardio-cerebrovascular diseases (CCVDs) is increasing worldwide, causing an increasingly serious public health burden. The pursuit of new promising treatment options is thus becoming a pressing issue. Hydroxysafflor yellow A (HSYA) is one of the main active quinochalcone C-glycosides in the florets of Carthamus tinctorius L., a medical and edible dual-purpose plant. HSYA has attracted much interest for its pharmacological actions in treating and/or managing CCVDs, such as myocardial and cerebral ischemia, hypertension, atherosclerosis, vascular dementia, and traumatic brain injury, in massive preclinical studies. In this review, we briefly summarized the mode and mechanism of action of HSYA on CCVDs based on these preclinical studies. The therapeutic effects of HSYA against CCVDs were presumed to reside mostly in its antioxidant, anti-inflammatory, and neuroprotective roles by acting on complex signaling pathways.

Effective chemotherapy drugs for colorectal cancer remain a challenge. In this research, Ziyuglycoside II (Ziyu II), exhibits considerable antitumor activity against CRC cells both in vitro and in vivo. The results showed that Ziyu II induced apoptosis through the accumulation of reactive oxygen species (ROS), which was necessary for Ziyu II to inhibit colorectal cancer cells. Intriguingly, The treatment of Ziyu II triggered complete autophagic flux in CRC cells. Inhibition of autophagy partially reversed Ziyu II-induced growth inhibition, demonstrating a cytotoxic role of autophagy in response to Ziyu II-treated. Mechanism indicated that Ziyu II-induced autophagy by inhibiting Akt/mTOR pathway. Akt reactivation partially reduced Ziyu II-induced LC3-II turnover and LC3 puncta accumulation. Especially, Ziyu II improves the sensitivity of 5-fluorouracil which is the first-line chemotherapy drug in colorectal cancer cells. This research provides novel insight into the molecular mechanism of Ziyu II’s anti-proliferation, including apoptosis and autophagy, and lays a foundation for the potential application of Ziyu II in clinical CRC treatment.

BackgroundCoronavirus disease 2019 (COVID-19) has developed into a worldwide pandemic. This study aimed to retrospectively describe the use of corticosteroids in treating COVID-19.MethodsFor this multicenter retrospective study, medical records from 488 symptomatic COVID-19 patients were reviewed. Patients were divided into severe and nonsevere groups. Baseline characteristics, signs and symptoms, laboratory findings, treatments, and disease outcomes were compared. Specific data for corticosteroid treatment were further analyzed.ResultsFour hundred fifty COVID-19 patients were included in this study, including 82 severe patients and 368 nonsevere cases. Out of the 450 patients, 126 (28.0%) received corticosteroid treatment. In the 126 patients treated with corticosteroids, the median daily dose of corticosteroid therapy was 56.6 [interquartile range (IQR): 40.0–78.4] mg and median corticosteroid therapy duration was 5.0 (IQR: 3.0–7.0) days. Among nonsevere cases, patients treated with corticosteroids were significantly older in comparison with patients who did not receive corticosteroid treatment (p0.05).ConclusionOur study indicates that corticosteroids are regarded as one of treatments in the general clinical practice of COVID-19. However, corticosteroid use may be accompanied by increased use of antibiotics, longer hospitalization, and prolonged viral shedding.

In December 2019, a severe outbreak of a novel coronavirus (COVID-19) occurred in the whole world, posing a great threat to people’s health. With the outbreak and development of the epidemic, how to improve the cure rate, find effective drugs against this virus, has been the most urgent problem. Chloroquine (CQ) was verified effective against COVID-19 in vitro. As CQ’s analogue, hydroxychloroquine (HCQ) was also reminded as a potential candidate for treating COVID-19. This review summarizes the latest clinical trials of CQ and HCQ against COVID-19 and its therapeutic regimen in China aiming to share their current usage to the whole world and provide insight into its appropriate future use in the treatment of COVID-19. Through searching the CNKI and Wangfang databases in Chinese language and PubMed, EMBASE, and Ovid databases in English language to identify published reports with the keywords including “coronavirus/COVID, chloroquine, hyroxychloroquine” in alone or combined, we found out the potential preclinical or clinical evidence for using CQ and HCQ against COVID-19. Consequently, we also searched the website of Chinese Clinical Trial Registry (http://www.chictr.org.cn/) till the day on 27th, June, 2020. This review found that there are 23 programs aimed to treat the different phases under COVID-19 pipeline in clinic with CQ and HCQ, totally. The inclusion criteria, exclusion criteria and therapeutic regimen were all shared to consult. Among them, seven have been canceled due to lack of patients or other objective factors. There are two trials have completed, which the potential relationship between usage and adverse reactions was discussed emphatically. Through literature research, we suggested that paid close attention to retinal toxicity and ophthalmologic adverse symptom of CQ and HCQ. And the outcome of HCQ in clinic shows better than CQ especially in protective effect with low dosage.

The selection of optimum statin intensity is inconclusive, and the association of plasma exposure of statins and metabolites with major adverse cardiovascular events (MACEs) is unclear. This study sought to compare the effect of low (quartile 1), intermediate (quartiles 2 and 3), and high (quartile 4) plasma exposure of statins and metabolites on MACE, re-ischemia events and death in patients with coronary artery disease (CAD) at 5 years. A total of 1,644 patients in atorvastatin (AT) cohort and 804 patients in rosuvastatin (RST) cohort were included, and their plasma concentration of statins and metabolites was categorized as low-, mid-, or high-group. The association between the plasma levels of statins and metabolites and the incidence of primary endpoint in patients was assessed by Cox proportional hazard models. Intensive AT exposure (Q4 > 5.32 ng/ml) was significantly associated with increased risk of death compared with low (hazard ratio [HR]: 1.522; 95% confidence interval [CI]: 1.035–1.061; P = 0.0022) or moderate exposure (HR: 2.054; 95% CI: 1.348–3.130; P = 0.0008). This association was also found in AT’s five metabolites (all P < 0.01). In patients with RST treatment, moderate RST concentration (0.53–4.29 ng/ml) versus low concentration had a significantly lower risk of MACE and re-ischemia events. (HR: 0.532, 95% CI: 0.347–0.815, P = 0.0061 and HR: 0.505, 95% CI: 0.310–0.823, P = 0.0061, respectively). A higher plasma exposure of AT and metabolites has a significantly higher risk of death, and moderate RST exposure has a significantly lower risk of MACE and re-ischemia events in Chinese patients with CAD. The harms of high plasma exposure should be considered when prescribing statins to patients because it may be a risk factor for having poor prognosis in patients with CAD.

There is increasing evidence that members of the gut microbiota, especially Fusobacterium nucleatum (F. nucleatum), are associated with Crohn’s disease (CD), but the specific mechanism by which F. nucleatum promotes CD development is unclear. Here, we first examined the abundance of F. nucleatum and its effects on CD disease activity and explored whether F. nucleatum aggravated intestinal inflammation and promoted intestinal mucosal barrier damage in vitro and in vivo. Our data showed that F. nucleatum was enriched in 41.21% of CD tissues from patients and was correlated with the clinical course, clinical activity, and refractory behavior of CD (P < 0.05). In addition, we found that F. nucleatum infection is involved in activating the endoplasmic reticulum stress (ERS) pathway during CD development to promote intestinal mucosal barrier destruction. Mechanistically, F. nucleatum targeted caspase activation and recruitment domain 3 (CARD3) to activate the ERS pathway and promote F. nucleatum-mediated mucosal barrier damage in vivo and in vitro. Thus, F. nucleatum coordinates a molecular network involving CARD3 and ERS to control the CD process. Measuring and targeting F. nucleatum and its associated pathways will provide valuable insight into the prevention and treatment of CD.

Catalpol, an iridoid glycoside extracted from Rehmannia glutinosa, has been found to ameliorate diabetic nephropathy (DN), but the mechanism has not been clarified. Podocyte injury play a key role in the pathogenesis of DN. This study mainly investigated the protective effect and potential mechanism of catalpol on podocyte injury of DN in vivo and in vitro. The results indicated that the pathological features of DN in mice were markedly ameliorated after treatment with catalpol. Moreover, podocyte foot process effacement, and down-regulation of nephrin and synaptopodin expression in DN mice were also significantly improved after treatment with catalpol. In vitro, catalpol rescued disrupted cytoskeleton and increased migration ratio in podocytes induced by high glucose, the effect might be attributable to the inhibition of RhoA and Cdc42 activities but not Rac1. Furthermore, the impaired podocyte autophagy in DN mice was significantly enhanced after catalpol treatment. And catalpol also enhanced autophagy and lysosome biogenesis in cultured podocytes under high glucose condition. In addition, we found that catalpol could inhibit mTOR activity and promote TFEB nuclear translocation in vivo and in vitro experiments. Our study demonstrated that catalpol could ameliorate podocyte injury in DN, and the protective effect of catalpol might be attributed to the stabilization of podocyte cytoskeleton and the improvement of impaired podocyte autophagy.

Salidroside, a phenylpropanoid glycoside, is the main bioactive component of Rhodiola rosea L. Salidroside has prominent anti-stroke effects in cerebral ischemia/reperfusion models. However, the underlying mechanisms of its actions are poorly understood. This study examined the anti-stroke effects of salidroside in middle cerebral artery occlusion (MCAO)-induced rat model of stroke and its potential mechanisms involving the dopaminergic system. Salidroside administration increased the levels of dopamine (DA), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) in the ipsilateral striatum after induction of transient ischemia, which were assessed using microdialysis with high-performance liquid chromatography coupled with electrochemical detection (HPLC-ECD). Furthermore, treatment with salidroside ameliorated neurobehavioral impairment, assessed with the modified neurological severity scores (mNSS), the balance beam test, and the foot fault test. Moreover, enzyme-linked immunosorbent assay (ELISA) suggested that MCAO-induced reduction in monoamine oxidase (MAO) was inhibited by salidroside. Immunohistochemical and immunofluorescence analyses revealed high level of tyrosine hydroxylase (TH) in the ipsilateral striatal caudate putamen (CPu) after cerebral ischemia/reperfusion, which could be further elevated by salidroside. In addition, salidroside could reverse the decreased immunoreactivity of TH in the substantia nigra pars compacta (SNpc). These results suggest that the anti-stroke effects of salidroside in MCAO-induced cerebral ischemia/reperfusion may involve the modulation of monoamine metabolism in the striatum and SNpc, which may be related to the function of the dopaminergic system in the rat brain.