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BackgroundThe Chinese ethnic medicine Jie-Du-Huo-Xue Decoction (JDHXD) is used to alleviate neuroinflammation in cerebral ischemia (CI). Our previous studies have confirmed that JDHXD can inhibit microglial pyroptosis in CI. However, the pharmacological mechanism of JDHXD in alleviating neuroinflammation and pyroptosis needs to be further elucidated. New research points out that there is an interaction between autophagy and inflammasome NLRP3, and autophagy can help clear NLRP3. The NLRP3 is a key initiator of pyroptosis and autophagy. The effect of JDHXD promoting autophagy to clear NLRP3 to inhibit pyroptosis on cerebral ischemia-reperfusion inflammatory injury is currently unknown. We speculate that JDHXD can inhibit pyroptosis in CI by promoting autophagy to clear NLRP3.MethodsChemical characterization of JDHXD was performed using LC-MS. Model of middle cerebral artery occlusion/reperfusion (MCAO/R) was established in SD rats. Neurological deficits, neuron damage, and cerebral infarct volume were evaluated. Western Blot and immunofluorescence were used to detect neuronal pyroptosis and autophagy.Results30 possible substance metabolites in JDHXD medicated serum were analyzed by LC-MS (Composite Score > 0.98). Furthermore, JDHXD protects rat neurological function and cerebral infarct size after CI. JDHXD inhibited the expression of pyroptosis and autophagy after CI. Our western blot and immunofluorescence results showed that JDHXD treatment can reduce the expression of autophagy-related factors ULK1, beclin1, and LC3-Ⅱ. The expression of NLRP3 protein was lower in the JDHXD group than in the I/R group. Compared with the I/R group, the expressions of pyroptosis-related factors caspase-1 P 10, GSDMD-NT, IL-18, and IL-1β decreased in the JDHXD group. Furthermore, we observed an unexpected result: immunofluorescence demonstrated that Gasdermin D (GSDMD) was significantly absent in the infarct core, and highly expressed in the peri-infarct and contralateral cerebral hemispheres. This finding challenges the prevailing view that GSDMD is elevated in the ischemic cerebral hemisphere.ConclusionJDHXD inhibited pyroptosis and autophagy after MCAO/R. JDHXD suppressed pyroptosis and autophagy by inhibiting NLRP3, thereby alleviating CI. In addition, we present a different observation from previous studies that the expression of GSDMD in the infarct core was lower than that in the peri-infarct and contralateral non-ischemic hemispheres on day 3 of CI.

Chronic liver disease, a long-term condition resulting from various causes such as alcohol abuse, metabolic disorders, and viral hepatitis, is becoming a significant global health challenge. Gypenosides (GPs), derived from the traditional Chinese medicine Gynostemma pentaphyllum (Thunb.) Makino, exhibited hepatoprotective properties in recent years, yet the precise therapeutic mechanism remains unclear. In this study, label-free and parallel reaction monitoring (PRM) proteomics were used to elucidate the hepatoprotective mechanism of GPs in liver injury rats. Through label-free proteomics, we identified 2104 differentially expressed proteins (DEPs) associated with liver injury, along with 1974 DEPs related to the effects of GPs. Bioinformatics analysis revealed that GPs primarily restored metabolic processes involving valine, leucine, and isoleucine degradation, as well as propanoate and butanoate metabolism, and steroid hormone biosynthesis during liver injury. Subsequently, overlapping the two groups of DEPs identified 1508 proteins reversed following GPs treatment, with key targets further validated by PRM. Eight target proteins were identified for GPs treatment of liver injury, including Lgals3, Psat1, Phgdh, Cyp3a9, Cyp2c11, Cyp4a2, Glul, and Ces1d. These findings not only elucidated the hepatoprotective mechanism of GPs, but may also serve as potential therapeutic targets of chronic liver disease.

Introduction: Urothelial carcinoma (UC) is a refractory disease for which achieving satisfactory outcomes remains challenging with current surgical interventions. Antibody–drug conjugates (ADCs) are a novel class of targeted therapeutics that have demonstrated encouraging results for UC. Although there is a limited number of high-quality randomized control trials (RCTs) examining the use of ADCs in patients with UC, some prospective non-randomized studies of interventions (NRSIs) provide valuable insights and pertinent information. We aim to assess the efficacy and safety of ADCs in patients with UC, particularly those with locally advanced and metastatic diseases.Methods: A systematic search was conducted across PubMed, Embase, the Cochrane Library, and Web of Science databases to identify pertinent studies. Outcomes, such as the overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse events (AEs), and treatment-related adverse events (TRAEs), were extracted for further analyses.Results: Twelve studies involving 1,311 patients were included in this meta-analysis. In terms of tumor responses, the pooled ORR and DCR were 40% and 74%, respectively. Regarding survival analysis, the pooled median PFS and OS were 5.66 months and 12.63 months, respectively. The pooled 6-month PFS and OS were 47% and 80%, while the pooled 1-year PFS and OS were 22% and 55%, respectively. The most common TRAEs of the ADCs were alopecia (all grades: 45%, grades ≥ III: 0%), decreased appetite (all grades: 34%, grades ≥ III: 3%), dysgeusia (all grades: 40%, grades ≥ III: 0%), fatigue (all grades: 39%, grades ≥ III: 5%), nausea (all grades: 45%, grades ≥ III: 2%), peripheral sensory neuropathy (all grades: 37%, grades ≥ III: 2%), and pruritus (all grades: 32%, grades ≥ III: 1%).Conclusion: The meta-analysis in this study demonstrates that ADCs have promising efficacies and safety for patients with advanced or metastatic UC.Systematic review registration:https://www.crd.york.ac.uk/prospero/, identifier: CRD42023460232

BackgroundEsophageal cancer (EC) is a major cause of cancer-related mortality in Taiwan and globally. Patients with EC are highly prone to malnutrition, which adversely affects their prognosis. While Chinese herbal medicine (CHM) is commonly used alongside conventional anti-cancer treatments, its long-term impact on EC patients with malnutrition remains unclear.MethodsThis study utilized a multi-center cohort from the Chang Gung Research Database, focusing on the long-term outcomes of CHM in EC patients with malnutrition between 1 January 2001, and 31 December 2018. Patients were monitored for up to 5 years or until death. Overall survival (OS) rates were calculated using the Kaplan-Meier method. Overlap weighting and landmark analysis were employed to address confounding and immortal time biases. Additionally, the study analyzed prescription data using a CHM network to identify key CHMs for EC with malnutrition, and potential molecular pathways were investigated using the Reactome database.ResultsEC patients with malnutrition who used CHM had a higher 5-year OS compared with nonusers (22.5% vs. 9% without overlap weighting; 24.3% vs. 13.3% with overlap weighting; log-rank test: p = 0.006 and 0.016, respectively). The median OS of CHM users was significantly longer than that of nonusers (19.8 vs. 12.9 months, respectively). Hazard ratio (HR) analysis showed a 31% reduction in all-cause mortality risk for CHM users compared with nonusers (HR: 0.69, 95% confidence interval: 0.50–0.94, p = 0.019). We also examined 665 prescriptions involving 306 CHM, with Hedyotis diffusa Willd. exhibiting the highest frequency of use. A CHM network was created to determine the primary CHMs and their combinations. The identified CHMs were associated with the regulation of immune and metabolic pathways, particularly in areas related to immune modulation, anti-cancer cachexia, promotion of digestion, and anti-tumor activity.ConclusionThe results of this study suggest a correlation between CHM use and improved clinical outcomes in EC patients with malnutrition. The analysis identified core CHMs and combinations of formulations that play a crucial role in immunomodulation and metabolic regulation. These findings lay the groundwork for more extensive research on the use of CHM for the management of malnutrition in patients with EC.

The therapeutic effect of chemotherapy and targeted therapy are known to be limited by drug resistance. Substantial evidence has shown that ATP-binding cassette (ABC) transporters P-gp and BCRP are significant contributors to multidrug resistance (MDR) in cancer cells. In this study, we demonstrated that a clinical-staged ATR inhibitor ceralasertib is susceptible to P-gp and BCRP-mediated MDR. The drug resistant cancer cells were less sensitive to ceralasertib compared to the parental cells. Moreover, ceralasertib resistance can be reversed by inhibiting the drug efflux activity of P-gp and BCRP. Interestingly, ceralasertib was able to downregulate the level of P-gp but not BCRP, suggesting a potential regulation between ATR signaling and P-gp expression. Furthermore, computational docking analysis predicted high affinities between ceralasertib and the drug-binding sites of P-gp and BCRP. In summary, overexpression of P-gp and BCRP are sufficient to confer cancer cells resistance to ceralasertib, underscoring their role as biomarkers for therapeutic efficacy.

Background: A growing population of individuals diagnosed with idiopathic pulmonary fibrosis (IPF) are receiving treatment with nintedanib and pirfenidone. The aim of our study was to assess the incidence of drug-induced liver injury (DILI) associated with the use of pirfenidone and nintedanib in patients with IPF in Taiwan.Methods: We collected a cohort of adult patients diagnosed with IPF between 2017 and 2020. The research outcomes involved assessing the incidence of DILI in patients treated with nintedanib or pirfenidone. Poisson regression analysis was employed to estimate incidence rates, with and without adjustments for covariates, to calculate and present both unadjusted and adjusted incidence rate ratios (IRRs).Results: The risk of DILI was greater in patients who received nintedanib than in those who received pirfenidone during the 1-year follow-up. Patients treated with nintedanib exhibited a heightened risk of DILI based on inpatient diagnoses using specific codes after adjusting for variables such as gender, age group, comorbidities and concomitant medications, with an adjusted incidence rate ratio (aIRR) of 3.62 (95% confidence interval (CI) 1.11–11.78). Similarly, the risk of DILI was elevated in patients treated with nintedanib according to a per-protocol Poisson regression analysis of outcomes identified from inpatient diagnoses using specific codes. This was observed after adjusting for variables including gender, age group, comorbidities, and concomitant medications, with an aIRR of 3.60 (95% CI 1.11–11.72).Conclusion: Data from postmarketing surveillance in Taiwan indicate that patients who received nintedanib have a greater risk of DILI than do those who received pirfenidone.

Background: Matrine, an alkaloid derived from the dried roots of Sophora flavescens Aiton, has been utilized for the treatment of liver diseases, but its potential hepatotoxicity raises concerns. However, the precise condition and mechanism of action of matrine on the liver remain inconclusive. Therefore, the objective of this systematic review and meta-analysis is to comprehensively evaluate both the hepatoprotective and hepatotoxic effects of matrine and provide therapeutic guidance based on the findings.Methods: The meta-analysis systematically searched relevant preclinical literature up to May 2023 from eight databases, including PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure, WanFang Med Online, China Science and Technology Journal Database, and China Biomedical Literature Service System. The CAMARADES system assessed the quality and bias of the evidence. Statistical analysis was conducted using STATA, which included the use of 3D maps and radar charts to display the effects of matrine dosage and frequency on hepatoprotection and hepatotoxicity.Results: After a thorough screening, 24 studies involving 657 rodents were selected for inclusion. The results demonstrate that matrine has bidirectional effects on ALT and AST levels, and it also regulates SOD, MDA, serum TG, serum TC, IL-6, TNF-α, and CAT levels. Based on our comprehensive three-dimensional analysis, the optimal bidirectional effective dosage of matrine ranges from 10 to 69.1 mg/kg. However, at a dose of 20–30 mg/kg/d for 0.02–0.86 weeks, it demonstrated high liver protection and low toxicity. The molecular docking analysis revealed the interaction between MT and SERCA as well as SREBP-SCAP complexes. Matrine could alter Ca2+ homeostasis in liver injury via multiple pathways, including the SREBP1c/SCAP, Notch/RBP-J/HES1, IκK/NF-κB, and Cul3/Rbx1/Keap1/Nrf2.Conclusion: Matrine has bidirectional effects on the liver at doses ranging from 10 to 69.1 mg/kg by influencing Ca2+ homeostasis in the cytoplasm, endoplasmic reticulum, Golgi apparatus, and mitochondria.Systematic review registration:https://inplasy.com/, identifier INPLASY202340114

Background: Tenofovir and entecavir demonstrated substantial effectiveness in the reversion of fibrosis and reversed cirrhosis in patients with hepatitis B virus (HBV)-related cirrhosis. However, there has not been a definitive conclusion regarding the association between entecavir and tenofovir on the risk of cirrhosis-related complications. Therefore, this study aimed to investigate the comparative effectiveness between tenofovir and entecavir in HBV-related cirrhosis patients.Methods: This was a retrospective study using Taiwan’s Health Insurance Research Database. We enrolled newly diagnosed HBV-related cirrhosis patients who initiated entecavir and tenofovir between 2011 and 2019. Treatment groups were determined by the initial HBV antiviral medication prescribed. The primary composite outcome was the development of hepatocellular carcinoma (HCC), death from any causes, and liver transplantation. The secondary outcomes included all the individual components of the primary outcome. The incidence rate was calculated for each outcome for both treatment groups using the Fine–Gray subdistribution hazard models. Propensity score adjustment was used to balance treatment groups.Results: A total of 7,316 propensity score-matched treatment-naïve patients and 3,524 propensity score-matched treatment-experienced patients were included. Within treatment-naïve patients, those receiving tenofovir showed significantly lower hazards of developing the composite outcome (HR, 0.79; p < 0.0001), hepatocellular carcinoma (HR, 0.86; p = 0.027), mortality (HR, 0.75; p < 0.0001), and liver transplantation (HR, 0.70; p = 0.0189) than those receiving entecavir. As for treatment-experienced patients, tenofovir was associated with a significantly lower risk of the composite outcome (HR, 0.82; p = 0.0033) and hepatocellular carcinoma (HR, 0.60; p < 0.0001), but it did not show a significantly different risk of all-cause mortality (HR, 0.93; p = 0.3374) or liver transplantation (HR, 1.17; p = 0.5112) compared to entecavir.Conclusion: Tenofovir presented a significantly lower incidence of cirrhosis-related complications than entecavir in patients with hepatitis B virus-related cirrhosis. However, no statistically significant difference in death and liver transplantation was seen in treatment-experienced patients.

Background: Surgical patients with aortic dissection often require multiple antihypertensive drugs to control blood pressure. However, the prescription pattern and effectiveness of antihypertensive drugs for these patients are unclear. We aimed to investigate the prescription pattern and effectiveness of different classes of antihypertensive drugs in surgical patients with aortic dissection.Methods: Newly diagnosed aortic dissection patients who underwent surgery, aged >20 years, from 1 January 2012 to 31 December 2017 were identified. Patients with missing data, in-hospital mortality, aortic aneurysms, or congenital connective tissue disorders, such as Marfan syndrome, were excluded. Prescription patterns of antihypertensive drugs were identified from medical records of outpatient visits within 90 days after discharge. Antihypertensive drugs were classified into four classes: 1) β-blockers, 2) calcium channel blockers (CCBs), 3) renin–angiotensin system, and 4) other antihypertensive drugs. Patients were classified according to the number of classes of antihypertensive drugs as follows: 1) class 0, no exposure to antihypertensive drugs; 2) class 1, antihypertensive drugs of the same class; 3) class 2, antihypertensive drugs of two classes; 4) class 3, antihypertensive drugs of three classes; or 5) class 4, antihypertensive drugs of four classes. The primary composite outcomes included rehospitalization associated with aortic dissection, death due to aortic dissection, and all-cause mortality.Results: Most patients were prescribed two (28.87%) or three classes (28.01%) of antihypertensive drugs. In class 1, β-blockers were most commonly used (8.79%), followed by CCBs (5.95%). In class 2, β-blockers+CCB (10.66%) and CCB+RAS (5.18%) were the most common drug combinations. In class 3, β-blockers + CCB+RAS (14.84%) was the most prescribed combination. Class 0 had a significantly higher hazard of the composite outcome (HR, 2.1; CI, 1.46–3.02; p < 0.001) and all-cause mortality (HR, 2.34; CI, 1.56–3.51; p < 0.001) than class 1. There were no significant differences in hazards for rehospitalization associated with aortic dissection among classes.Conclusion: Among operated patients with type A aortic dissection, no specific type of antihypertensive drug was associated with a better outcome, whereas among those with type B aortic dissection, the use of β-blockers and CCBs was related to a significantly lower risk of the composite outcome.

Colorectal cancer (CRC) is the third most common malignant tumor in the world, and it is prone to recurrence and metastasis during treatment. Aerobic glycolysis is one of the main characteristics of tumor cell metabolism in CRC. Tumor cells rely on glycolysis to rapidly consume glucose and to obtain more lactate and intermediate macromolecular products so as to maintain growth and proliferation. The regulation of the CRC glycolysis pathway is closely associated with several signal transduction pathways and transcription factors including phosphatidylinositol 3-kinases/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), hypoxia-inducible factor-1 (HIF-1), myc, and p53. Targeting the glycolytic pathway has become one of the key research aspects in CRC therapy. Many phytochemicals were shown to exert anti-CRC activity by targeting the glycolytic pathway. Here, we review the effects and mechanisms of phytochemicals on CRC glycolytic pathways, providing a new method of drug development.

Background: Data on the neuropsychological outcomes after receiving direct-acting antivirals (DAAs) among chronic hepatitis C (CHC) patients have not been well-documented.Aim: This study aimed to evaluate the difference in incidence of neuropsychological disorders (NPDs) after treatment completion between CHC patients receiving interferon (IFN) therapy and DAA therapy.Methods: A nationwide retrospective cohort study was performed using Taiwan’s National Health Insurance Research Database (NHIRD) between 2010 and 2018. CHC patients without pre-existing mental disorders were included and divided into the treatment (Tx)-naïve DAA group, retreatment (re-Tx) DAA group, and Tx-naïve IFN group based on their HCV therapy. Propensity score matching was used to balance baseline differences between groups. The primary outcome was the incidence of NPDs during 6 months after completion of therapy.Results: After one-to-one matching, there were 6,461 pairs of patients selected from the Tx-naïve DAA group and Tx-naïve IFN group and 3,792 pairs from the re-Tx DAA group and Tx-naïve IFN group. A lower incidence of NPDs was observed in the Tx-naïve DAA group than in the Tx-naïve IFN group (HR = 0.72, 95% CI = 0.55–0.94, and p = 0.017). The risk of NPDs did not differ between the re-Tx DAA group and the Tx-naïve IFN group (HR = 0.74, 95% CI: 0.52–1.05, and p = 0.092).Conclusion: DAA therapy was associated with lower risk of NPDs when compared with IFN therapy among Tx-naïve CHC patients in a 6-month period after treatment completion, especially among the patients less than 65 years, male gender, and cirrhosis.

Introduction: Pulmonary fibrosis (PF) is a severe disease that can lead to respiratory failure and even death. However, currently there is no effective treatment available for patients with PF. Mesenchymal stem cells (MSCs) have been recently shown to have therapeutic potential for PF. We analyzed the literature focused of MSCs and PF to provide a comprehensive understanding of the relationship between MSCs and PF.Methods: We searched the Web of Science Core Collection database for literature from 2002 through 2021 that involved MSCs and PF. The included studies were then analyzed using CiteSpace and VOSviewers software.Results: A total of 1,457 studies were included for analysis. Our findings demonstrated the following: 1) an increasing trend of MSC and PF research; 2) among the 54 countries/regions of author affiliations, the United States was the most frequent, and the University of Michigan (n = 64, 2.8%) was the top institution; 3) Rojas Mauricio published the most articles and PLOS ONE had the most related studies; and 4) keywords, such as idiopathic pulmonary fibrosis, mesenchymal stem cells, and systemic sclerosis, were listed more than 100 times, indicating the research trend. Other common keywords, such as inflammation, myofibroblasts, fibroblasts, aging, telomerase or telomere, and extracellular matrix demonstrate research interests in the corresponding mechanisms.1) The number of publications focused on MSCs and PF research increased during the study period; 2) Among the 54 countries/regions of author affiliations, most articles were published in the United States of America, and the University of Michigan (n = 64, 2.8%) had the largest number of publications; 3) Rojas Mauricio published the most articles and PLOS ONE had the most related studies; 4) Keywords, such as idiopathic pulmonary fibrosis, MSCs, and systemic sclerosis, were listed more than 100 times, representing a research trend. Other common keywords included inflammation, myofibroblasts, fibroblasts, aging, telomerase or telomere, and extracellular matrix.Discussion: During the past 2 decades, MSCs have been proposed to play an important role in PF treatment. An increasing amount of literature focused on MSCs and PF research has been published. Our findings provide insight into the current status and research trends in the field of MSCs and PF research during the past 2 decades, which could help researchers understand necessary research directions. In the future, more preclinical and clinical studies should be conducted in this field to support the application of MSCs in the treatment of PF.

Background: Few studies have investigated traditional Chinese medicine (TCM) utilization patterns for irritable bowel syndrome (IBS), despite the potential benefits of exploring TCM utilization patterns in optimizing TCM management. This study aimed to evaluate TCM utilization patterns and clinical features for IBS patterns in Taiwan.Methods: This was a population-based cross-sectional study using claim data from the National Health Insurance Research Database between 2012 and 2018. Patients newly diagnosed with IBS and aged over 20 years were included. The TCM utilization patterns and characteristics, including Chinese herbal medicine (CHM) treatment types and prescription patterns, were evaluated.Results: A total of 73,306 patients newly diagnosed with IBS used TCM for IBS at least once. Females used TCM for IBS more than males (female-to-male ratio = 1.89: 1). The age distribution showed a peak at 30–39 years (27.29%), followed by 40–49 years (20.74%) and 20–29 years (20.71%). Patients who received Western medications for IBS had a lower tendency to seek TCM. CHM was the most commonly used TCM modality (98.22%), with Jia-wei-xiao-yao-san being the most commonly prescribed Chinese herbal formula and Bai-zhu being the most frequently prescribed single Chinese herb.Conclusion: This study enhances our understanding of TCM usage patterns for IBS, particularly CHM prescriptions. Further research is needed to investigate commonly used TCM formulas and individual herbs.

The phenomenon of T Cell exhaustion (TEX) entails a progressive deterioration in the functionality of T cells within the immune system during prolonged conflicts with chronic infections or tumors. In the context of ovarian cancer immunotherapy, the development, and outcome of treatment are closely linked to T-cell exhaustion. Hence, gaining an in-depth understanding of the features of TEX within the immune microenvironment of ovarian cancer is of paramount importance for the management of OC patients. To this end, we leveraged single-cell RNA data from OC to perform clustering and identify T-cell marker genes utilizing the Unified Modal Approximation and Projection (UMAP) approach. Through GSVA and WGCNA in bulk RNA-seq data, we identified 185 TEX-related genes (TEXRGs). Subsequently, we transformed ten machine learning algorithms into 80 combinations and selected the most optimal one to construct TEX-related prognostic features (TEXRPS) based on the mean C-index of the three OC cohorts. In addition, we explored the disparities in clinicopathological features, mutational status, immune cell infiltration, and immunotherapy efficacy between the high-risk (HR) and low-risk (LR) groups. Upon the integration of clinicopathological features, TEXRPS displayed robust predictive power. Notably, patients in the LR group exhibited a superior prognosis, higher tumor mutational load (TMB), greater immune cell infiltration abundance, and enhanced sensitivity to immunotherapy. Lastly, we verified the differential expression of the model gene CD44 using qRT-PCR. In conclusion, our study offers a valuable tool to guide clinical management and targeted therapy of OC.

Objective: This meta-analysis aimed to determine the efficacy of curcumin in preventing myocardial ischemia/reperfusion (I/R) injury in animal models.Methods: Studies published from inception to January 2023 were systematically searched in databases including PubMed, Web of Science, Embase, China’s National Knowledge Infrastructure (CNKI), Wan-Fang database, and VIP database (VIP). The SYRCLE’s RoB tool was used to determine methodological quality. Sensitivity analysis and subgroup analysis were performed when there was high heterogeneity. Publication bias was assessed using a funnel plot.Results: Thirty-seven studies involving 771 animals were included in this meta-analysis with methodology quality scores ranging from 4 to 7. The results indicated that curcumin treatment significantly improved myocardial infarction size standard mean difference (SMD) = −5.65; 95% confidence interval (CI): 6.94, −4.36; p < 0.01; I2 = 90%). The sensitivity analysis for infarct size showed that the results were stable and reliable. However, the funnel plot was asymmetric. The subgroup analysis included species, animal model, dose, administration, and duration. The results showed that the subgroup dose was statistically significant between subgroups. In addition, curcumin treatment improved cardiac function, myocardial injury enzymes, and oxidative stress levels in animal models of myocardial I/R injury. The funnel plot revealed that there is publication bias for creatine kinase and lactate dehydrogenase. Finally, we performed a meta-analysis of inflammatory cytokines and apoptosis index. The results showed that curcumin treatment downregulated serum inflammatory cytokine levels and myocardial apoptosis index.Conclusion: This meta-analysis suggests that curcumin has excellent potential for the treatment of myocardial I/R injury in animal models. However, this conclusion needs to be further discussed and verified in large animal models and human clinical trials.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier CRD42022383901.

p53 mutations are prevalent in human cancers; approximately half of patients with esophageal cancer present these mutations. Mutant p53 (mutp53) exerts oncogenic functions that promote malignant tumor progression, invasion, metastasis, and drug resistance, resulting in poor prognosis. Some small molecules have been shown to mitigate the oncogenic function of mutp53 by restoring its wild-type activity. Although these molecules have been evaluated in clinical trials, none have been successfully used in the clinic. Here, we investigated the antitumor effects of phenethyl isothiocyanate (PEITC) in p53-mutant esophageal squamous cell carcinoma (ESCC) and elucidated its mechanism to identify new therapeutic strategies. We observed that p53R248Q is a DNA contact mutation and a structural mutation and that PEITC can restore the activity of p53R248Qin vitro and in vivo, further clarifying the antitumor activity of PEITC in cancers with different types of p53 mutations. PEITC can inhibit ESCC growth, induce apoptosis, and arrest cell cycle progression and has a preferential selectivity for ESCC with p53 mutations. Mechanistic studies showed that PEITC induced apoptosis and arrested cells at G2/M transition in cells expressing the p53R248Q mutant by restoring the wild-type conformation and transactivation function of p53; these effects were concentration dependent. Furthermore, PEITC inhibited the growth of subcutaneous xenografts in vivo and restored p53 mutant activity in xenografts. According to these findings, PEITC has antitumor effects, with its ability to restore p53R248Q activity being a key molecular event responsible for these effects.

Background/aim: Hypertensive nephropathy (HN) is a common complication of hypertension. Traditional Chinese medicine has long been used in the clinical treatment of Hypertensive nephropathy. However, botanical drug prescriptions have not been summarized. The purpose of this study is to develop a prescription for improving hypertensive nephropathy, explore the evidence related to clinical application of the prescription, and verify its molecular mechanism of action.Methods: In this study, based on the electronic medical record data on Hypertensive nephropathy, the core botanical drugs and patients’ symptoms were mined using the hierarchical network extraction and fast unfolding algorithm, and the protein interaction network between botanical drugs and Hypertensive nephropathy was established. The K-nearest neighbors (KNN) model was used to analyze the clinical and biological characteristics of botanical drug compounds to determine the effective compounds. Hierarchical clustering was used to screen for effective botanical drugs. The clinical efficacy of botanical drugs was verified by a retrospective cohort. Animal experiments were performed at the target and pathway levels to analyze the mechanism.Results: A total of 14 botanical drugs and five symptom communities were obtained from real-world clinical data. In total, 76 effective compounds were obtained using the K-nearest neighbors model, and seven botanical drugs were identified as Gao Shen Formula by hierarchical clustering. Compared with the classical model, the Area under the curve (AUC) value of the K-nearest neighbors model was the best; retrospective cohort verification showed that Gao Shen Formula reduced serum creatinine levels and Chronic kidney disease (CKD) stage [OR = 2.561, 95% CI (1.025–6.406), p < 0.05]. With respect to target and pathway enrichment, Gao Shen Formula acts on inflammatory factors such as TNF-α, IL-1β, and IL-6 and regulates the NF-κB signaling pathway and downstream glucose and lipid metabolic pathways.Conclusion: In the retrospective cohort, we observed that the clinical application of Gao Shen Formula alleviates the decrease in renal function in patients with hypertensive nephropathy. It is speculated that Gao Shen Formula acts by reducing inflammatory reactions, inhibiting renal damage caused by excessive activation of the renin-angiotensin-aldosterone system, and regulating energy metabolism.

Background: The genetic factors in assessing therapeutic efficacy and predicting antihypertensive drug response are unclear. Therefore, this study aims to identify the associations between variants and antihypertensive drug response.Methods: A longitudinal study including 1837 hypertensive patients was conducted in Northern China and followed up for a median 2.24 years. The associations of 11 candidate variants with blood pressure changes in response to antihypertensive drugs and with the risk of cardiovascular events during the follow-up were examined. The dual-luciferase assay was carried out to assess the effect of genetic variants on gene transcriptional activity.Results: The variant rs11039149A>G in the promoter of nuclear receptor subfamily 1 group H member 3 (NR1H3) was associated with the change in systolic blood pressure (ΔSBP) in response to calcium channel blockers (CCBs) monotherapy. Patients carrying rs11039149AG genotype showed a significant increase of systolic blood pressure (SBP) at follow-up compared with AA carriers, and the difference of ΔSBP between AG and AA carriers was 5.94 mm Hg (95%CI: 2.09–9.78, p = 0.002). In 1,184 patients with CCBs therapy, SBP levels decreased in AA carriers, but increased in AG carriers, the difference of ΔSBP between AG and AA carriers was 8.04 mm Hg (95%CI: 3.28–12.81, p = 0.001). Further analysis in 359 patients with CCBs monotherapy, the difference of ΔSBP between AG and AA carriers was 15.25 mm Hg (95%CI: 6.48–24.02, p = 0.001). However, there was no significant difference in ΔSBP between AG and AA carriers with CCBs multitherapy. The rs11039149A>G was not associated with the cardiovascular events incidence during the follow-up. Additionally, transcriptional factor forkhead box C1 (FOXC1) bound to the NR1H3 promoter containing rs11039149A and significantly increased the transcriptional activity, while rs11039149 A to G change led to a loss-of-function and disabled FOXC1 binding. For the other 10 variants, associations with blood pressure changes or risk of cardiovascular events were not observed.Conclusion: Hypertensive patients with rs11039149AG genotype in the NR1H3 gene have a significant worse SBP control in response to CCBs monotherapy compared with AA carriers. Our findings suggest that the NR1H3 gene might act as a promising genetic factor to affect individual sensitivity to antihypertensive drugs.

Background and aim: For a long time, aspirin has been recommended for the prevention of cardiovascular disease (CVD). However, results of long-term effects of aspirin use on the risk of CVD and all-cause death as well as cause-specific mortality are not consistent. This study aims to investigate the relationship between low- or high-dose preventive aspirin use and the risk of death from all-cause, CVD, and cancer among US adults aged 40 years and older.Methods: A prospective cohort study was conducted by utilizing four cycles of the National Health and Nutrition Examination Survey (NHANES) and linked 2019 mortality files. Cox proportional hazard models accounting for multiple covariates were used to calculate hazard ratio (HR) and 95% confidence interval (CI) for the associations between low- or high-dose aspirin use and risk of death.Results: A total of 10,854 individuals (5,364 men and 5,490 women) were enrolled in the study. During a median follow-up of 4.8 years, 924 death events including 294 CVD death and 223 cancer death were documented. We found no evidence that taking low-dose aspirin decreased the chance of dying from any cause (HR: 0.92, 95% CI: 0.79–1.06), CVD (HR: 1.03, 95% CI: 0.79–1.33), or cancer (HR: 0.80, 95% CI: 0.60–1.08). High-dose aspirin users had a higher risk of CVD death compared to participants who had never used aspirin (HR: 1.63, 95% CI: 1.11–2.41).Conclusion: Using low-dose aspirin has no effect on the risk of death from any causes, whereas taking high doses of aspirin increases the risk of CVD death.

Collagen has been considered a key treatment option in preventing damage to the articular cartilage over time and supporting the healing process, following the onset of osteoarthritis (OA). This study aimed to investigate the effect of collagen fermented from jellyfish (FJC) by Bacillus subtilis natto on anterior cruciate ligament transection with medial meniscectomy (ACLT + MMx)-induced knee OA in high-fat diet (HFD)-induced obesity in rats. The male Sprague–Dawley rats were fed an HFD for 6 weeks before ACLT + MMx surgery, after which they were administered a daily oral gavage of saline (control, OA, and OBOA), either with FJC (20 mg/kg, 40 mg/kg, and 100 mg/kg body weight) or glucosamine sulfate as a positive control (GS; 200 mg/kg body weight) for 6 weeks. Treatment with FJC decreased the fat weight, triglyceride, and total cholesterol levels in obese rats. Additionally, FJC downregulated the expression of some proinflammatory cytokines, including tumor necrosis factor-α, cyclooxygenase-2, and nitric oxide; suppressed leptin and adiponectin expression; and attenuated cartilage degradation. It also decreased the activities of matrix metalloproteinase (MMP)-1 and MMP-3. These results demonstrated that FJC showed a protective effect on articular cartilage and also suppressed the degradation of cartilage in an animal OA model, suggesting its potential efficacy as a promising candidate for OA treatment.

Background: The parabrachial nucleus (PBN) is an important structure regulating the sleep–wake behavior and general anesthesia. Astrocytes in the central nervous system modulate neuronal activity and consequential behavior. However, the specific role of the parabrachial nucleus astrocytes in regulating the sleep-wake behavior and general anesthesia remains unclear.Methods: We used chemogenetic approach to activate or inhibit the activity of PBN astrocytes by injecting AAV-GFAabc1d-hM3Dq-eGFP or AAV-GFAabc1d-hM4Di-eGFP into the PBN. We investigated the effects of intraperitoneal injection of CNO or vehicle on the amount of wakefulness, NREM sleep and REM sleep in sleep–wake behavior, and on the time of loss of righting reflex, time of recovery of righting reflex, sensitivity to isoflurane, electroencephalogram (EEG) power spectrum and burst suppression ratio (BSR) in isoflurane anesthesia.Results: The activation of PBN astrocytes increased wakefulness amount for 4 h, while the inhibition of PBN astrocytes decreased total amount of wakefulness during the 3-hour post-injection period. Chemogenetic activation of PBN astrocytes decreased isoflurane sensitivity and shortened the emergence time from isoflurane-induced general anesthesia. Cortical EEG recordings revealed that PBN astrocyte activation decreased the EEG delta power and BSR during isoflurane anesthesia. Chemogenetic Inhibition of PBN astrocytes increased the EEG delta power and BSR during isoflurane anesthesia.Conclusion: PBN astrocytes are a key neural substrate regulating wakefulness and emergence from isoflurane anesthesia.

Background: Pulmonary arterial hypertension (PAH) is an incurable pulmonary disease that might result in right heart failure and death. Treatment guidelines recommend upfront or sequential combination therapy for patients with PAH. Recently, several PAH-targeted medications have been approved in Taiwan. This study aimed to investigate treatment patterns and medication adherence in real-world settings.Method: This was a new-user design study on patients treated with PAH-specific medication between 1 January 2014, and 31 December 2019. Data were extracted from the National Health Insurance Research Database. Medication adherence was evaluated by the proportion of days covered (PDC). Adherence was defined as PDC ≥ .8. Statistical analyses were performed to compare the study outcomes. Logistic regression analysis was performed to identify the association between baseline characteristics and adherence. P < .05 indicated statistical significance.Results: A total of 1,900 patients with PAH were identified, and 75.3% of them were females. The mean (standard deviation (SD)) age was 57.2 (17.5) years. Only 23 (1.2%) patients began the initial combination therapy. A total of 148 (7.8%) patients switched their initial treatment to another treatment, and 159 (8.4%) patients had sequential combination therapy. The most common combination therapy was endothelin receptor antagonist (ERA) plus phosphodiesterase-5 inhibitor (PDE5i), mostly macitentan plus sildenafil, for initial or sequential combination. The mean (SD) PDC was .71 (.33), and 1,117 (58.8%) patients were adherent. A significant difference in mean PDC was observed between initial ERA users and PDE5i users (p < .0001). No factor was significantly associated with medication adherence.Conclusion: Patients with PAH mostly initiated sildenafil as monotherapy, and macitentan was added as a sequential combination therapy. The initial ERA and combination groups showed higher medication adherence. Further investigations are needed to identify other factors associated with adherence.

A major complication of a joint replacement is prosthesis loosening caused by inflammatory osteolysis, leading to the revision of the operation. This is due to the abnormal activation of osteoclast differentiation and function caused by periprosthetic infection. Therefore, targeting abnormally activated osteoclasts is still effective for treating osteolytic inflammatory diseases. CDZ173 is a selective PI3K inhibitor widely used in autoimmune-related diseases and inflammatory diseases and is currently under clinical development. However, the role and mechanism of CDZ173 in osteoclast-related bone metabolism remain unclear. The possibility for treating aseptic prosthesis loosening brought on by inflammatory osteolysis illness can be assessed using an LPS-induced mouse cranial calcium osteolysis model. In this study, we report for the first time that CDZ173 has a protective effect on LPS-induced osteolysis. The data show that this protective effect is due to CDZ173 inhibiting the activation of osteoclasts in vivo. Meanwhile, our result demonstrated that CDZ173 had a significant inhibitory effect on RANKL-induced osteoclasts. Furthermore, using the hydroxyapatite resorption pit assay and podosol actin belt staining, respectively, the inhibitory impact of CDZ173 on bone resorption and osteoclast fusion of pre-OC was determined. In addition, staining with alkaline phosphatase (ALP) and alizarin red (AR) revealed that CDZ173 had no effect on osteoblast development in vitro. Lastly, CDZ173 inhibited the differentiation and function of osteoclasts by weakening the signal axis of PI3K-AKT/MAPK-NFATc1 in osteoclasts. In conclusion, our results highlight the potential pharmacological role of CDZ173 in preventing osteoclast-mediated inflammatory osteolysis and its potential clinical application.

Hypoxia-inducible factors (HIFs), central regulators for cells to adapt to low cellular oxygen levels, are often overexpressed and activated in breast cancer. HIFs modulate the primary transcriptional response of downstream pathways and target genes in response to hypoxia, including glycolysis, angiogenesis and metastasis. They can promote the development of breast cancer and are associated with poor prognosis of breast cancer patients by regulating cancer processes closely related to tumor invasion, metastasis and drug resistance. Thus, specific targeting of HIFs may improve the efficiency of cancer therapy. In this review, we summarize the advances in HIF-related molecular mechanisms and clinical and preclinical studies of drugs targeting HIFs in breast cancer. Given the rapid progression in this field and nanotechnology, drug delivery systems (DDSs) for HIF targeting are increasingly being developed. Therefore, we highlight the HIF related DDS, including liposomes, polymers, metal-based or carbon-based nanoparticles.

Gastric cancer, a common malignant disease, seriously endangers human health and life. The high mortality rate due to gastric cancer can be attributed to a lack of effective therapeutic drugs. Cancer cells utilize the glycolytic pathway to produce energy even under aerobic conditions, commonly referred to as the Warburg effect, which is a characteristic of gastric cancer. The identification of new targets based on the glycolytic pathway for the treatment of gastric cancer is a viable option, and accumulating evidence has shown that phytochemicals have extensive anti-glycolytic properties. We reviewed the effects and mechanisms of action of phytochemicals on aerobic glycolysis in gastric cancer cells. Phytochemicals can effectively inhibit aerobic glycolysis in gastric cancer cells, suppress cell proliferation and migration, and promote apoptosis, via the PI3K/Akt, c-Myc, p53, and other signaling pathways. These pathways affect the expressions of HIF-1α, HK2, LDH, and other glycolysis-related proteins. This review further assesses the potential of using plant-derived compounds for the treatment of gastric cancer and sheds insight into the development of new drugs.

On 5 April 2022, the World Health Organization was notified of 10 cases of severe acute hepatitis of unknown etiology in children under 10 years of age in the United Kingdom. Although the exact cause of a proportion of pediatric acute hepatitis and acute liver failure cases was unclear, the above event has caused widespread concern worldwide. As of 14 September 2022, approximately 1,296 probable cases of acute hepatitis of unknown etiology have been reported from 37 countries/regions, of which approximately 55 required or received liver transplantation and 29 died. Although the etiology of acute hepatitis of unknown origin in children remains unclear, many hypotheses have been proposed about the disease. Instead of individual factors such as “adenovirus infection,” “SARS-CoV-2 related,” and “Adeno-associated virus 2 with helper virus coinfection,” it is more likely due to a combination of factors. Accordingly, there is an urgent need for more data and research to clarify the disease etiology. This review aims to provide a historical perspective of acute hepatitis of unknown etiology in children in the past decades and summarize the current hypothesis and evidence on this emerging disease.

Esophageal cancer (EC) remains a leading cause of death worldwide and in Taiwan. The prognosis of advanced-stage EC is notably poor, and the treatment options are limited. Chinese herbal medicine (CHM) has been widely used as a complementary treatment for cancer, yet the long-term effect of CHM in stage IV EC remains unclear.The multi-institutional cohort obtained from the Chang Gung research database (CGRD) was used to study the long-term outcome of CHM use among incident stage IV EC patients from 1 January 2002, to 31 December 2018. All patients were followed up to 5 years or the occurrence of death. The overall survival (OS) and disease-specific survival rates were conducted using Kaplan-Meier estimation. Overlap weighing and landmark analysis were used to eliminate confounding and immortal time biases. Furthermore, we demonstrated the core CHMs for stage IV EC by using the Chinese herbal medicine network (CMN) analysis on prescriptions.Nine hundred eighty-five stage IV EC patients were analyzed, including 74 CHM users and 911 non-CHM users. We found the use of CHM was associated with a higher 5-year overall survival rate than CHM nonusers (the cumulative probability: 19.52% versus 6.04%, log-rank test: p < 0.001, and the p < 0.001 with overlap weighting). In addition, the overall median survival time was about 7 months longer among CHM users. Moreover, the lower 1-, 3-, 5-year disease-specific survival rates were higher among CHM users. Additionally, the risk of all-cause mortality was lower among CHM users when considering accessible demographic covariates (adjusted hazard ratio: 0.59, 95%CI: 0.39, 0.89, p = 0.011). Furthermore, the CMN analysis revealed that CHMs improved health while relieving tumor burden. For example, Hedyotis diffusa Willd. was the core CHM with an anti-cancer effect, while Fritillaria thunbergii Miq and Sevilla maindronide Rochebrune were used together to relieve cancer-related gastrointestinal discomfort.The use of CHM seems safe and possibly beneficial among stage IV EC patients with a higher 5-year OS. Further clinical trials on CHM were guaranteed to explore the role of CHM in managing stage IV EC patients.

MAOIs, a well-established class of antidepressant that operate through the inhibition of monoamine oxidase to increase available serotonin, have recently been identified as a surprisingly effective candidate for the circumvention of tumor-induced immune suppression due to their abilities to enhance antitumor T cell activity through autocrine serotonin signaling and depolarize alternatively activated tumor-associated macrophages through a reduction in reactive oxygen species production. However, this impressive class of antidepressants-turned-cancer-drugs can induce aggressive behavioral side effects when administered in immunotherapeutic doses. In this study, we investigated the possibility of avoiding these neurological side effects while simultaneously improving antitumor activity by establishing crosslinked multilamellar liposomal vesicles (cMLVs) containing the MAOI phenelzine (PLZ). Our results showed that cMLV-PLZ treatment increases antitumor efficacy in a B16-OVA mouse melanoma model compared to treatment with free phenelzine. We also found that nanoformulation resulted in the complete elimination of MAOI-related aggression. These findings suggest a promising direction for the future of MAOIs repurposed for cancer immunotherapies.

Introduction: In Taiwan, many people receive Chinese herbal medicine (CHM) as an alternative choice to help control body weight. However, the clinical effectiveness of CHM on weight control has not been well studied, while potential risks and adverse effects are still unknown. The aim of our study is to find out a safe and efficient treatment model of CHM for weight control compared to liraglutide in a real-world setting.Methods: we retrospectively analyzed obese subjects [body mass index (BMI)≧25 kg/m2] from Chang Gung Research Database (2013–2018). We evaluated the effect on body weight and BMI changes in obese groups receiving CHM or western medicine (WM, represented liraglutide) within 180 days. The proportion of subjects who achieved 5 and 10% weight reduction was calculated as well. Furthermore, the potential adverse events were analyzed during the study period. Overlap weighting was used to balance the baseline differences between CHM and WM groups.Results: The full cohort comprised 1,360 participants: 701 in the CHM group and 659 in the WM group. At baseline, the CHM group was younger (42.75 ± 12.12 years old in CHM vs. 52.31 ± 11.7 years old in WM, p-value

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.

Background: Chronic stress-induced diarrhea is a common clinical condition, characterized by an abnormal bowel movement and loose stools, which lacks effective treatment in the clinic. Si-Ni-San (SNS) is a compound traditional Chinese medicine extensively used in China for stress-related diarrhea. However, the mechanism is unclear.Methods: Male Wistar rats (200 ± 20 g) were placed in a restraint cylinder and fixed horizontally for 3 h once daily for 21 consecutive days to establish a chronic restraint stress (CRS) rat model. SNS (0.6944 g/kg or 1.3888 g/kg) was given by gavage 1 h before the restraint once daily for 21 consecutive days. We examined the fecal score, dopamine β hydroxylase (DβH), and c-fos expression in locus coeruleus, norepinephrine (NE) content in ileum and plasma, expression of α1 adrenergic receptors, MLCK, MLC, and p-MLC in the colon and mesenteric arteries, contraction of isolated mesenteric arteries, The expression of subunit δ of ATP synthase (ATP5D) in intestinal tissues, ATP, ADP, and AMP content in the ileum and colon, occludin expression between ileum epithelial cells, the number of enterochromaffin cells (ECs) and mast cells (MCs) in the ileum, and 5-hydroxytryptamine (5-HT) content in the ileum and plasma.Results: After SNS treatment, the fecal score was improved. The increased expression of DβH and c-fos in locus coeruleus was inhibited. SNS suppressed the increased NE content in the ileum and plasma, down-regulated α1 adrenergic receptors in mesenteric arteries and MLCK, MLC, p-MLC in the colon and mesenteric arteries, and inhibited the contraction of mesenteric arteries. SNS also increased the ATP content in the ileum and colon, inhibited low expression of ATP5D in intestinal tissues, inhibited the decrease of ATP/ADP in the ileum and ATP/AMP in the colon, and up-regulated the occludin expression between ileum epithelial cells. In addition, SNS inhibited the increase of ECs and MCs in the ileum and the increase of 5-HT content in the ileum and plasma.Conclusion: This study demonstrated that SNS could improve CRS-induced abnormal feces in rats. This effect was related to the inhibition of CRS-induced increased expression of DβH and c-fos in the locus coeruleus, NE content in the ileum and plasma, and the contraction of isolated mesenteric arteries; inhibition of energy metabolism abnormality and decreased occludin expression; inhibition of increased ECs and MCs in the ileum, and 5-HT content in the ileum and plasma.

Mushrooms and Chinese traditional herbs have bioactive nutraceuticals with multiple therapeutic functions, including antioxidant and antibacterial activities and microbiome modulation properties. Mushroom-derived bioactive compounds are used in medicines for the treatment of neurological disorders with abnormal brain–gut–microbiome axis. This study examined the effects of KI Essence extract, a spleen-tonifying formula, on neurite growth, antioxidant activity, hypomyelination modulation, and the microbiome profile in lipopolysaccharide (LPS)-induced maternal immune activation (MIA) offspring. The KI Essence extract induced PC12 cell neurite growth by increasing extracellular signal–regulated kinase (ERK) phosphorylation, promoting 2,2′-diphenyl-1-picrylhydrazyl radical scavenging activity, reducing the level of tert-butylhydroperoxide–induced lipid peroxidation in brain homogenates, protecting PC12 cells from H2O2-induced cell death (through the inhibition of ERK phosphorylation), alleviating hypomyelination, and downregulating interleukin‐1β through LPS-activated microglia production; moreover, the numbers of Enterobacteriaceae, Actinobacteria, Peptostreptococcaceae, Erysipelotrichaceae, and Bifidobacterium bacteria in MIA offspring increased. In summary, the KI Essence extract promotes neurite outgrowth, alleviates oxidative stress and hypomyelination, and modulates microbiota dysbiosis in MIA offspring.

Exosomes are small extracellular vesicles and play an essential role in the mediation of intercellular communication both in health and disease. Traditional Chinese medicine (TCM) has historically been used to maintain human health and treat various diseases up till today. The interplay between exosomes and TCM has attracted researchers’ growing attention. By integrating the available evidence, TCM formulas and compounds isolated from TCM as exosome modulators have beneficial effects on multiple disorders, such as tumors, kidney diseases, and hepatic disease, which may associate with inhibiting cells proliferation, anti-inflammation, anti-oxidation, and attenuating fibrosis. Exosomes, a natural delivery system, are essential in delivering compounds isolated from TCM to target cells or tissues. Moreover, exosomes may be the potential biomarkers for TCM syndromes, providing strategies for TCM treatment. These findings may provide a novel insight into TCM from exosomes and serve as evidence for better understanding and development of TCM.

Objective: To compare the clinical efficacy and safety of SIX Traditional Chinese Patent Medicines (TCPM) recommended by guidelines in improving lipids for patients with prediabetes by network meta-analysis.Methods: Randomized controlled trials of 6 TCPM in the treatment of prediabetes were searched systematically in various databases. After extracting effective data, the risk of bias was assessed using Review Manager 5.3 and Cochrane Collaboration Systems Evaluator’s Manual. Network meta-analysis was performed using STATA 15.0 based on the frequency statistical model. The effect size and credibility of the evidence for the intervention were summarized based on a minimal contextualized framework.Results: A total of 27 studies involving 2,227 patients were included. Compared with lifestyle modification (LM), Shenqi + LM [SMD −0.49 (95% CI: −0.85, −0.12)] and Jinqi + LM [SMD −0.44 (95% CI: −0.81, −0.06)] showed statistically significant effect in lowering TG, Shenqi + LM [SMD −0.51 (95%CI: −0.86, −0.17)] and Jinqi + LM [SMD −0.44 (95%CI: −0.80, −0.08)] in lowering TC, Jinlida + LM [SMD −0.31 (95%CI: −0.59, −0.04)] in lowering LDL-C, Shenqi + LM [SMD 0.29 (95%CI: 0.06, 0.51)] and Jinqi + LM [SMD 0.16 (95%CI: 0.01, 0.31)] in increasing HDL-C.Conclusion: For patients with prediabetes, Traditional Chinese patent medicine Jinqi and Shenqi combined with lifestyle modification were associated with a significant reduction in TG and TC, while Shenqi + LM was among the most effective. Jinlida + LM was among the least effective.Systematic Review Registration:https://clinicaltrials.gov/, identifier PROSPERO(CRD42021279332).

Background: Fulminant type 1 diabetes mellitus (FT1DM) is a new subtype of type 1 diabetes, first proposed by Japanese scholars in 2000. Herein, the functions of the islets are rapidly destroyed. Its pathogenesis is related to viral infection. Most people have been infected with Epstein–Barr virus (EBV), and many people have also suffered from drug hypersensitivity, however, few cases of FT1DM which were caused by both of the two conditions have been reported. Thus, below, we describe one such valuable case.Case Summary: The plasma glucose levels of a 73‐year‐old man diagnosed with drug-induced dermatitis showed a sudden increase (42 mmol/L) during methylprednisolone therapy. The urine ketone test was positive. The glycated hemoglobin level was 7%, endogenous insulin secretion decreased significantly, and the islet-related autoantibodies were negative. The patient was diagnosed with FT1DM. The lymphocyte EBV-DNA showed high copies numbers. The general condition of the patient improved after symptomatic treatment with insulin. However, the systemic allergic reaction aggravated after the use of iodinated contrast agents, prednisone, and thymic pentapeptide. The re-test for EBV-DNA showed significantly high relative levels, thus indicating the presence of EBV infection. We think that drug hypersensitivity and EBV infection together led to FT1DM in this case. After an indication for multiple daily insulin therapy, the patient’s blood glucose was quickly controlled and he was discharged on the 38th-day post-admission.Conclusion: FT1DM is a rare case, however, drug hypersensitivity and EBV infection are not rare in the population. This is a rare case of FT1DM caused by drug hypersensitivity reaction and EBV infection. Through this case report, we emphasize the importance of the relationship between drug hypersensitivity, EBV infection and FT1DM and vigilance for the occurrence of FT1DM among hypersensitive individuals in clinical practice.

Osmanthus fragrans (scientific name: Osmanthus fragrans (Thunb.) Lour.) is a species of the Osmanthus genus in the family Oleaceae, and it has a long history of cultivation in China. O. fragrans is edible and is well known for conferring a natural fragrance to desserts. This flowering plant has long been cultivated for ornamental purposes. Most contemporary literature related to O. fragrans focuses on its edible value and new species discovery, but the functional use of O. fragrans is often neglected. O, fragrans has many properties that are beneficial to human health, and its roots, stems, leaves, flowers and fruits have medicinal value. These characteristics are recorded in the classics of traditional Chinese medicine. Studies on the metabolites and medicinal value of O. fragrans published in recent years were used in this study to evaluate the medicinal value of O. fragrans. Using keywords such as metabolites and Osmanthus fragrans, a systematic and nonexhaustive search of articles, papers and books related to the medicinal use of Osmanthus fragrans metabolites was conducted. Fifteen metabolites were identified through this literature search and classified into three categories according to their properties and structure: flavonoids, terpenes and phenolic acids. It was found that the pharmacological activities of these secondary metabolites mainly include antioxidant, anticancer, anti-inflammatory and antibacterial activities and that these metabolites can be used to treat many human diseases, such as cancer, skin diseases, cardiovascular diseases, and neurological diseases. Most of the reports that are currently available and concern the secondary metabolites of Osmanthus fragrans have limitations. Some reports introduce only the general classification of compounds in Osmanthus fragrans, and some reports introduce only a single compound. In contrast, the introduction section of this paper includes both the category and the functional value of each compound. While reviewing the data for this study, the authors found that the specific action sites of these compounds and their mechanisms of action in plants are relatively weak, and in the future, additional research should be conducted to investigate this topic further.

Background: Surgical patients with aortic dissection often require multiple antihypertensive drugs to control blood pressure. However, the prescription pattern and effectiveness of antihypertensive drugs for these patients are unclear. We aimed to investigate the prescription pattern and effectiveness of different classes of antihypertensive drugs in surgical patients with aortic dissection. Methods: Newly diagnosed aortic dissection patients who underwent surgery, aged >20 years, from 1 January 2012 to 31 December 2017 were identified. Patients with missing data, in-hospital mortality, aortic aneurysms, or congenital connective tissue disorders, such as Marfan syndrome, were excluded. Prescription patterns of antihypertensive drugs were identified from medical records of outpatient visits within 90 days after discharge. Antihypertensive drugs were classified into four classes: 1) β-blockers, 2) calcium channel blockers (CCBs), 3) renin-angiotensin system, and 4) other antihypertensive drugs. Patients were classified according to the number of classes of antihypertensive drugs as follows: 1) class 0, no exposure to antihypertensive drugs; 2) class 1, antihypertensive drugs of the same class; 3) class 2, antihypertensive drugs of two classes; 4) class 3, antihypertensive drugs of three classes; or 5) class 4, antihypertensive drugs of four classes. The primary composite outcomes included rehospitalization associated with aortic dissection, death due to aortic dissection, and all-cause mortality. Results: Most patients were prescribed two (28.87%) or three classes (28.01%) of antihypertensive drugs. In class 1, β-blockers were most commonly used (8.79%), followed by CCBs (5.95%). In class 2, β-blockers+CCB (10.66%) and CCB+RAS (5.18%) were the most common drug combinations. In class 3, β-blockers + CCB+RAS (14.84%) was the most prescribed combination. Class 0 had a significantly higher hazard of the composite outcome (HR, 2.1; CI, 1.46-3.02; p < 0.001) and all-cause mortality (HR, 2.34; CI, 1.56-3.51; p < 0.001) than class 1. There were no significant differences in hazards for rehospitalization associated with aortic dissection among classes. Conclusion: Among operated patients with type A aortic dissection, no specific type of antihypertensive drug was associated with a better outcome, whereas among those with type B aortic dissection, the use of β-blockers and CCBs was related to a significantly lower risk of the composite outcome. [ABSTRACT FROM AUTHOR]

Adriamycin (ADR) has been utilized to treat cancer for several decades. However, ADR-induced renal injury is one of the most common side effects accompanying ADR therapy. In the present study, we revealed that astragaloside IV (ASIV) was beneficial for renal injury caused by Adriamycin. We demonstrated that ASIV significantly ameliorated kidney injury, improved renal dysfunction, reduced oxidative stress, alleviated iron accumulation, and inhibited the induction of ferroptosis by ADR. ASIV also rescued the intracellular levels of nuclear factor-erythroid-2-related factor 2 (Nrf2) and promoted nuclear translocation of Nrf2. These protective effects of ASIV on renal injury might be attained through the ASIV-induced activation of the Pi3K/Akt signaling pathway. In vitro, the treatment of the HK-2 cells with fer-1 or deferoxamine mesylate obviously improved cell viability during Adriamycin administration. On the other hand, the protective role of ASIV can be abrogated by RSL3 to some extent. Moreover, ASIV lowered the expression of transferrin receptor 1 and divalent metal transporter 1 while enhancing the expression of ferropotin 1 and glutathione peroxidase 4 in ADR administrated cells, the effects of which were akin to those of deferoxamine mesylate. Furthermore, ASIV increased the phosphorylation of Pi3K, Akt, and the expression of Nrf2 and glutathione peroxidase 4 compared to HK-2 cells stimulated by ADR. However, Pi3K inhibitor LY294002 abrogated these activations. In conclusion, ferroptosis may involve in ADR-induced nephrotoxicity, and ASIV might protect nephrocytes against ADR-induced ferroptosis, perhaps via activations of the Pi3K/Akt and Nrf2 signaling pathways.

Bone homeostasis only exists when the physical function of osteoblast and osteoclast stays in the balance between bone formation and resorption. Bone resorption occurs when the two processes are uncoupled, shifting the balance in favour of bone resorption. Excessive activation of osteoclasts leads to a range of osteolytic bone diseases including osteoporosis, aseptic prosthesis loosening, rheumatoid arthritis, and osteoarthritis. Receptor activator of nuclear factor kappa-B ligand (RANKL) and its downstream signaling pathways are recognized as key mediators that drive the formation and activation of osteoclastic function. Hence, osteoclast formation and/or its function remain as dominant targets for research and development of agents reaching the treatment towards osteolytic diseases. Chrysin (CHR) is a flavonoid with a wide range of anti-inflammatory and anti-tumor effects. However, its effect on osteoclasts remains unknown. In this study, we found the effects of CHR on inhibiting osteoclast differentiation which were assessed in terms of the number and size of TRAcP positive multinucleated osteoclasts (OCs). Further, the inhibitory effects of CHR on bone resorption and osteoclast fusion of pre-OC were assessed by hydroxyapatite resorption pit assay and F-actin belts staining; respectively. Western blotting analysis of RANKL-induced signaling pathways and immunofluorescence analysis for p65 nuclear translocation in response to RANKL-induced osteoclasts were used to analyze the mechanism of action of CHR affecting osteoclasts. Lastly, the murine calvarial osteolysis model revealed that CHR could protect against particle-induced bone destruction in vivo. Collectively, our data strongly suggested that CHR with its promising anti-tumor effects would also be a potential therapeutic agent for osteolytic diseases.

Among herbal medicines, magnolia bark extract, particularly its components honokiol (Hono) and magnolol (Mag), has been widely documented to have antineoplastic properties. The present study aimed to evaluate the synergism of Hono and Mag in bladder cancer therapy both in vitro and in vivo. Treatment with Mag alone at concentrations up to 80 μM failed to have an antiproliferative effect. In contrast, the combination of Hono and Mag at 40 μM decreased viability, caused cell cycle arrest and enhanced the proportion of Annexin V/7AAD-positive cells. Moreover, Mag with Hono at 40 μM induced caspase 3-dependent apoptosis and autophagy. Neither Hono nor Mag alone had an anti-migratory effect on bladder cancer cells. In contrast, Hono and Mag at 20 μM inhibited the motility of TSGH8301 and T24 cells in wound-healing and Transwell assays. The above phenomena were further confirmed by decreased phosphorylated focal adhesion kinase (p-FAK), p-paxillin, integrin β1, and integrin β3 protein levels. In a nude mouse xenograft model, Mag/Hono administration preferentially retarded T24 tumor progression, which was consistent with the results of cellular experiments. Current findings suggest Hono and Mag treatment as a potential anticancer therapy for both low- and high-grade urothelial carcinoma.

Laryngeal squamous cell carcinoma (LSCC) is a common malignant tumor that occurs in the head and neck. People living in areas with serious air pollution and those who smoke and drink for a long time belong to high-risk groups. Although great progress has been made in chemotherapy, radiotherapy, and molecular targeted therapy in recent years, the prognosis of patients is still not good. The proliferation, invasion, and apoptosis of LSCC are controlled by many factors, which are the key factors influencing the prognosis of patients. Previous researches have demonstrated that long noncoding RNAs (lncRNAs) can be used as oncogenes or tumor suppressor genes in the occurrence and development of cancer and regulate cancer through various ways including epigenetic regulation and post-transcriptional regulation. The characteristics and roles of lncRNAs in LSCC, however, are not clear. In this review, we will discuss the role and function of lncRNAs in the proliferation, invasion, and apoptosis of LSCC and analyze the relationship between lncRNAs and lncRNA-regulated signaling pathways in LSCC pathological process. The difficulties faced by the related research of LSCC are discussed. It provides reference ideas for the molecular mechanism research of LSCC targeting lncRNA and its signaling pathways, the development of clinical prevention and therapeutic drug and individualized treatment, thereby improving the quality of life of patients.

Alzheimer’s disease (AD) is a progressive age-related neurodegenerative disease characterized by memory loss and cognitive impairment. The major characteristics of AD are amyloid β plaques, apoptosis, autophagy dysfunction, neuroinflammation, oxidative stress, and mitochondrial dysfunction. These are mostly used as the significant indicators for selecting the effects of potential drugs. It is imperative to explain AD pathogenesis and realize productive treatments. Although the currently used chemical drugs for clinical applications of AD are effective in managing the symptoms, they are inadequate to achieve anticipated preventive or therapeutic outcomes. There are new strategies for treating AD. Traditional Chinese Medicine (TCM) has accumulated thousands of years of experience in treating dementia. Nowadays, numerous modern pharmacological studies have verified the efficacy of many bioactive ingredients isolated from TCM for AD treatment. In this review, representative TCM for the treatment of AD are discussed, and among these herbal medicines, the Lamiaceae family accounts for the highest proportion. It is concluded that monomers and extracts from TCM have potential therapeutic effect for AD treatment.

The Ras-Related signaling pathway plays an important role in cell development and differentiation. A growing body of evidence collected in recent years has shown that the aberrant activation of Ras is associated with tumor-related processes. Several studies have indicated that indole and its derivatives can target regulatory factors and interfere with or even block the aberrant Ras-Related pathway to treat or improve malignant tumors. In this review, we summarize the roles of indole and its derivatives in the isoprenylcysteine carboxyl methyltransferase-participant Ras membrane localization signaling pathway and Ras-GTP/Raf/MAPK signaling pathway through their regulatory mechanisms. Moreover, we briefly discuss the current treatment strategies that target these pathways. Our review will help guide the further study of the application of Ras-Related signaling pathway inhibitors.

Background: Surgical patients with aortic dissection often require multiple antihypertensive drugs to control blood pressure. However, the prescription pattern and effectiveness of antihypertensive drugs for these patients are unclear. We aimed to investigate the prescription pattern and effectiveness of different classes of antihypertensive drugs in surgical patients with aortic dissection. Methods: Newly diagnosed aortic dissection patients who underwent surgery, aged >20 years, from 1 January 2012 to 31 December 2017 were identified. Patients with missing data, in-hospital mortality, aortic aneurysms, or congenital connective tissue disorders, such as Marfan syndrome, were excluded. Prescription patterns of antihypertensive drugs were identified from medical records of outpatient visits within 90 days after discharge. Antihypertensive drugs were classified into four classes: 1) ß-blockers, 2) calcium channel blockers (CCBs), 3) renin-angiotensin system, and 4) other antihypertensive drugs. Patients were classified according to the number of classes of antihypertensive drugs as follows: 1) class 0, no exposure to antihypertensive drugs; 2) class 1, antihypertensive drugs of the same class; 3) class 2, antihypertensive drugs of two classes; 4) class 3, antihypertensive drugs of three classes; or 5) class 4, antihypertensive drugs of four classes. The primary composite outcomes included rehospitalization associated with aortic dissection, death due to aortic dissection, and all-cause mortality. Results: Most patients were prescribed two (28.87%) or three classes (28.01%) of antihypertensive drugs. In class 1, ß-blockers were most commonly used (8.79%), followed by CCBs (5.95%). In class 2, ß-blockers+CCB (10.66%) and CCB+RAS (5.18%) were the most common drug combinations. In class 3, ß-blockers + CCB+RAS (14.84%) was the most prescribed combination. Class 0 had a significantly higher hazard of the composite outcome (HR, 2.1; CI, 1.46-3.02; p < 0.001) and all-cause mortality (HR, 2.34; CI, 1.56-3.51; p < 0.001) than class 1. There were no significant differences in hazards for rehospitalization associated with aortic dissection among classes. Conclusion: Among operated patients with type A aortic dissection, no specific type of antihypertensive drug was associated with a better outcome, whereas among those with type B aortic dissection, the use of ß-blockers and CCBs was related to a significantly lower risk of the composite outcome. [ABSTRACT FROM AUTHOR]

Spexin (SPX), also called neuropeptide Q (NPQ), is a novel endogenous neuropeptide. Spexin gene and protein are widely expressed in central nervous system and peripheral tissues in humans, rodents, goldfish, etc. A few of physiological and pathological roles of spexin are gradually emerged recently. This article summarized the roles of spexin in feeding behavior, gastrointestinal motility, obesity, diabetes, energy metabolism, endocrine, mental diseases, and cardiovascular function. Given the broad roles of spexin, this neuropeptide has attracted much interest from investigators and will be as a promising future target for novel therapeutic research and drug design.