Reliability of Metformin's protective effects against doxorubicin-induced cardiotoxicity: a meta-analysis of animal studies.

Background: The protective effects of metformin (Met) against doxorubicin (Dox)-induced cardiotoxicity via potential hypotheses of mechanisms of action with unknown reliability and credibility. Objectives: This study aimed to investigate the protective effects of Met against Dox-induced cardiotoxicity and the underlying mechanisms of action, as well as examine their reliability and credibility. Methods: A comprehensive search was conducted within the PubMed, Embase, Web of Science, Science Direct, Scopus, and CNKI databases from inception to 31 December 2023. Animal experiments evaluating the efficacy of Met against Dox-induced cardiotoxicity were included in this study. The primary efficacy outcomes were markers of myocardial injury. Effect size was measured using the standardized mean difference for continuous variables. Data were pooled using a random-effects model in the Stata 18 statistical software package. Results: Twenty-one studies involving 203-208 animals treated with Dox and 271-276 animals treated with Dox and Met were included in this analysis. Quality assessment revealed high-quality scores. Pooled results favored Met treatment based on the serum lactate dehydrogenase (LDH), creatine kinase-myocardial band (CK-MB), cardiac troponin I (cTnI), and aspartate aminotransferase levels. Sensitivity analysis using the leave-one-out method demonstrated stable results. Funnel plots, Egger's test, and Begg's test confirmed potential publication bias. The oxidative stress hypothesis has been investigated extensively based on abundant evidence. Conclusion: Met is effective and safe for protecting against Dox-induced cardiotoxicity, thus making it an appropriate drug for clinical investigation. The oxidative stress hypothesis of mechanism of action is well established with highest reliability and credibility.

Effect of esketamine on hypotension in women with preoperative anxiety undergoing elective cesarean section: a randomized, double-blind, controlled trial.

To investigate the effect of low-doses esketamine on spinal anesthesia-induced hypotension in women with preoperative anxiety undergoing elective cesarean section, the randomized controlled trial enrolled 120 women aged 18-35 years who preoperative State-Trait Anxiety Inventory State scores > 40, conducted from September 2022 to August 2023 in Xuzhou Central Hospital, China. Women in the esketamine group received a single intravenous injection of 0.2 mg/kg esketamine after sensory block level achieved. The incidence of hypotension in the esketamine group was significantly lower than the control group at T2 (10% [6 of 60]; P < 0.001), T3 (5.0% [3 of 60]; P = 0.007) and T4(5.0% [3 of 60]; P = 0.004). Despite being higher in the esketamine group, the overall rates of hypertension (11.7% [7 of 60]; P = 0.186), tachycardia (23.3% [14 of 60]; P = 0.246), and bradycardia (0.0% [0 of 60]; P = 0.079) were no significantly difference between the two groups. STAI-S scores was significantly lower in the esketamine group (mean [SD] 37.52[7.14]) than in the control group (mean [SD] 41.03[9.66], P = 0.39) in postoperative day 1. Spinal anesthesia combined with intravenous low-doses esketamine infusion can significantly reduce the incidence of hypotension in women with preoperative anxiety undergoing elective cesarean section.

Impact of varied anesthesia maintenance strategies on postoperative respiratory complications in pediatric patients undergoing tonsillectomy and adenoidectomy (AmPRAEC study): study protocol for a multicenter randomized, double-blind clinical trial.

BACKGROUND: Postoperative respiratory adverse events are the most common perioperative complications in pediatric anesthesia, particularly prevalent in children undergoing tonsillectomy and adenoidectomy, with an incidence rate as high as 50%. The choice of anesthetic induction regimen directly influences the incidence of respiratory adverse events during the induction period. However, this effect seems to have minimal impact on postoperative outcomes. The occurrence rate of postoperative respiratory adverse events is likely more closely associated with the anesthetic maintenance phase, yet this relationship remains uncertain at present. METHODS: The objective of this study was to assess the impact of different anesthetic maintenance regimens on postoperative respiratory adverse events in pediatric patients undergoing tonsillectomy and adenoidectomy. The AmPRAEC study is a multicenter, randomized, double-blind controlled trial. A total of 717 pediatric patients were recruited from 12 medical centers and randomly assigned to three groups: group A (intravenous maintenance group, receiving propofol infusion); group B (intravenous-inhalational combination group, maintained with 1% sevoflurane combined with propofol); and group C (inhalational maintenance group, maintained with 2-3% sevoflurane inhalation). The primary outcome measure was the incidence rate of postoperative respiratory adverse events. DISCUSSION: This clinical trial aims to elucidate the impact of various anesthetic maintenance regimens on postoperative respiratory adverse events in pediatric patients. The outcomes of this study are anticipated to facilitate anesthesiologists in devising more comprehensive perioperative management strategies, enhancing comfort, and improving the clinical outcomes for this patient population. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( http://www.chictr.org.cn ) ChiCTR2300074803. Registered on August 16, 2023.

Semirecumbent Positioning During Anesthesia Recovery and Postoperative Hypoxemia: A Randomized Clinical Trial.

Importance: The efficacy of a semirecumbent position (SRP) in reducing postoperative hypoxemia during anesthesia emergence is unclear despite its widespread use. Objective: To determine the differences in postoperative hypoxemia between patients in an SRP and a supine position. Design, Setting, and Participants: This randomized clinical trial was performed at a tertiary hospital in China between March 20, 2021, and May 10, 2022. Patients scheduled to undergo laparoscopic upper abdominal surgery under general anesthesia were enrolled. Study recruitment and follow-up are complete. Interventions: Patients were randomized to 1 of the following positions at the end of the operation until leaving the postanesthesia care unit: supine (group S), 15° SRP (group F), or 30° SRP (group T). Main Outcomes and Measures: The primary outcome was the incidence of postoperative hypoxemia in the postanesthesia care unit. Severe hypoxemia was also evaluated. Results: Out of 700 patients (364 men [52.0%]; mean [SD] age, 47.8 [11.3] years), 233 were randomized to group S (126 men [54.1%]; mean [SD] age, 48.2 [10.9] years), 233 to group F (122 men [52.4%]; mean [SD] age, 48.1 [10.9] years), and 234 to group T (118 women [50.4%]; mean [SD] age, 47.2 [12.1] years). Postoperative hypoxemia differed significantly among the 3 groups (group S, 109 of 233 [46.8%]; group F, 105 of 233 [45.1%]; group T, 76 of 234 [32.5%]; P = .002). This difference was statistically significant for groups T vs S (risk ratio [RR], 0.69 [95% CI, 0.55-0.87]; P = .002) and groups T vs F (RR, 0.72 [95% CI, 0.57-0.91]; P = .007), but not for groups F vs S (RR, 0.96 [95% CI, 0.79-1.17]; P = .78). Severe hypoxemia also differed among the 3 groups (group S, 61 of 233 [26.2%]; group F, 53 of 233 [22.7%]; group T, 36 of 234 [15.4%]; P = .01). This difference was statistically significant for groups T vs S (RR, 0.59 [95% CI, 0.41-0.85]; P = .005). Conclusions and Relevance: In this randomized clinical trial of SRP during anesthesia recovery in patients undergoing laparoscopic upper abdominal surgery, postoperative hypoxemia was significantly reduced in group T compared with group F or group S. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2100045087.

A miRNA-7704/IL2RB/AKT feedback loop regulates tumorigenesis and chemoresistance in ovarian cancer.

Ovarian cancer is one of the most common gynecological tumors worldwide. Despite the availability of multiple treatments for ovarian cancer, its resistance to chemotherapy remains a significant challenge. miRNAs play crucial roles in the initiation and progression of cancer by affecting processes such as differentiation, proliferation, and chemoresistance. According to microarray and qPCR analyses, miR-7704 is significantly downregulated in cisplatin-resistant cells compared to parental cells. In this study, we found that miR-7704 inhibited the proliferation and promoted cisplatin sensitivity of ovarian cancer cells in vitro and in vivo. Moreover, ectopic expression of miR-7704 had the same effect as IL2RB knockdown. Further mechanistic studies revealed that miR-7704 played an inhibitory role by regulating IL2RB expression to inactivate the AKT signaling pathway. Furthermore, IL2RB reversed the miR-7704 mediated resistance to cisplatin in ovarian cancer. Based on these findings, miR-7704 and IL2RB show the potential as novel therapeutic targets for ovarian cancer.

Enrichment methods of N-linked glycopeptides from human serum or plasma: A mini-review.

Human diseases often correlate with changes in protein glycosylation, which can be observed in serum or plasma samples. N-glycosylation, the most common form, can provide potential biomarkers for disease prognosis and diagnosis. However, glycoproteins constitute a relatively small proportion of the total proteins in human serum and plasma compared to the non-glycosylated protein albumin, which constitutes the majority. The detection of microheterogeneity and low glycan abundance presents a challenge. Mass spectrometry facilitates glycoproteomics research, yet it faces challenges due to interference from abundant plasma proteins. Therefore, methods have emerged to enrich N-glycans and N-linked glycopeptides using glycan affinity, chemical properties, stationary phase chemical coupling, bioorthogonal techniques, and other alternatives. This review focuses on N-glycans and N-glycopeptides enrichment in human serum or plasma, emphasizing methods and applications. Although not exhaustive, it aims to elucidate principles and showcase the utility and limitations of glycoproteome characterization.

Identification of a Group of Therapeutic Targets and Prognostic Biomarker for Triple Negative Breast Cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease. Mining differentially expressed genes of TNBC is helpful to explore new therapeutic targets. This study aimed to investigate diagnostic biomarker genes in TNBC compared to normal tissue. Additionally, we explored the functions and prognostic value of these key genes as well as potential targeted drugs that could affect these genes. METHODS: Differential gene expression analysis was conducted using the R software with data from the Gene Expression Omnibus (GEO) database. Then, the identified differentially expressed genes (DEGs) were used to construct a protein-protein interaction (PPI) network using the Search Tool for the Retrieval of Interacting Genes (STRING) database and Cytoscape software. The mRNA expression levels of key genes were analyzed using the UALCAN database with data from The Cancer Genome Atlas (TCGA). Enrichment and survival analyses were performed using R software. In addition, potential compounds showing sensitivity to key genes were identified by gene set cancer analysis (GSCA). RESULTS: Compared with normal tissues, a total of 203 DEGs were upregulated in TNBC. These DEGs participated in various biological processes including nuclear division, microtubule binding, cell cycle, and the p53 signaling pathway. Through the PPI network analysis, ten key genes were identified, among which four genes showed significant correlation with poor progression-free interval (PFI) in patients with TNBC. Moreover, the four survival-related genes were found to act as sensitive therapeutic targets. CONCLUSION: The identified four key genes were considered new biomarkers for diagnosis and prognosis and also potential therapeutic targets for TNBC.

Carbon reduction and cost control of container shipping in response to the European Union Emission Trading System.

In response to the EU ETS, we propose a cost model considering carbon emissions for container shipping, calculating fuel consumption, carbon emissions, EUA cost, and total cost of container shipping. We take a container ship operating on a route from the Far East to Northwest Europe as a case study. Environmental and economic impacts of including maritime transport activities in the EU ETS on container shipping are assessed. Results show that carbon emissions from the selected container ship using methanol are the smallest, and total cost of the selected container ship using methanol is the lowest. Among MGO, HFO, LNG, and methanol, methanol is the most environmentally and cost-effective option. Using LNG has greater environmental benefit, while using HFO has greater economic benefit. Compared to MGO, carbon reduction effects of LNG and methanol are 14.2% and 57.1%, and their cost control effects are 7.8% and 26.5%. Compared to HFO, carbon reduction effects of LNG and methanol are 11.7% and 55.8%, and the cost control effect of methanol is 9.3%. Speed reduction is effective in achieving carbon reduction and cost control of container shipping only when the sailing speed of the selected container ship is greater than 8.36 knots. Once the sailing speed is less than this threshold, speed reduction will increase carbon emissions and total cost of container shipping. This model can assess the environmental and economic impacts of including maritime transport activities in the EU ETS on container shipping and explore the measures to achieve carbon reduction and cost control of container shipping in response to the EU ETS.

Bioequivalence and Safety Assessment of 2 Formulations of Low-Dose Metformin Hydrochloride under Fasting Conditions in Healthy Chinese Participants: A Randomized Phase 1 Clinical Trial.

The incidence of type 2 diabetes is high, and the existing metformin hydrochloride (MH) tablets of 250 mg cannot meet the demands of the Chinese drug market. This study aimed to evaluate the bioequivalence and safety of generic formulations of MH tablets (test formulation [T], 250 mg/tablet) and innovative products (reference formulation [R], 250 mg/tablet) under fasting conditions. This was an open-label, single-dose, 2-period, 2-sequence crossover, single-center, randomized phase I clinical trial. T and R were considered bioequivalent if the adjusted geometric mean ratios (GMRs) and 90% confidence intervals of the area under the curve (AUC) and maximum concentration (Cmax ) were within the range of 0.8-1.25. Thirty-five participants completed the trial. The T/R adjusted GMRs (95.7% for Cmax , 98.7% for AUC0→t , 98.8% for AUC0→∞ ) were within the acceptable bioequivalence range of 80%-125%. No serious adverse events or suspected or unexpected serious adverse reactions occurred during this trial. The study findings confirmed that generic MH is a well-tolerated and bioequivalent alternative to innovative products under fasting conditions in healthy Chinese participants. (www.chinadrugtrials.org.cn; registration no. CTR20190356).

Comparing the severity of second preeclampsia with first preeclampsia: a multicenter retrospective longitudinal cohort study.

OBJECTIVE: Compare the clinical severity of second preeclampsia with the first preeclampsia. METHODS: This retrospective longitudinal cohort study was conducted in three teaching hospitals in Guangzhou, where there were a total of 296 405 deliveries between 2010 and 2021. Two consecutive singleton deliveries complicated with preeclampsia were included. Clinical features, laboratory results within 1 week before delivery, and maternal and neonatal outcomes of both deliveries were collected. Univariate analyses were made using paired Wilcoxon tests and McNemar tests. Multivariable logistic regression and generalized linear models were performed to assess the association of adverse maternal and neonatal outcomes with second preeclampsia. RESULTS: A total of 151 women were included in the study. The mean maternal age was 28 and 33 years for the first and second deliveries, respectively. The proportion of preventive acetylsalicylic acid use was 4.6% for the first delivery and 15.2% for the second delivery. No significant differences were observed in terms of blood pressure on admission, gestational weeks of admission and delivery, application of perinatal antihypertensive agents, rates of preterm delivery, and severe features between the two occurrences. However, the rates of heart disease, edema, and admission to the ICU were lower, and hospital stays were shorter in the second preeclampsia compared with the first preeclampsia. Sensitivity analysis conducted among women who did not use preventive acetylsalicylic acid yielded similar results. After adjusting for potential confounding variables, the occurrence of second preeclampsia was associated with significantly decreased risks of heart disease, edema, complications, and admission to the NICU, with odds ratios ranging between 0.157 and 0.336. CONCLUSION: Contrary to expectations, the second preeclampsia did not exhibit worse manifestations or outcomes to the first occurrence. In fact, some clinical features and outcomes appeared to be better in the second preeclampsia.

Development, validation, and clinical utility of a risk prediction model for recurrent preeclampsia.

OBJECTIVES: We aim to establish a predictive model for recurrent preeclampsia. METHODS: A retrospective review of medical records from three hospitals between 2010 and 2021 was conducted. The study included women who had two consecutive singleton deliveries at the same hospital, with the first delivery complicated by preeclampsia. A multivariable logistic regression model was constructed using a training cohort, and subsequently cross-validated and tested using an independent cohort. The model's performance was assessed in terms of discrimination and calibration, and its clinical utility was evaluated using decision curve analysis (DCA). RESULTS: Among 296 405 deliveries, 694 women met the inclusion criteria, with 151 (21.8%) experiencing recurrent preeclampsia. The predictive model incorporated 10 risk factors from previous preeclampsia, including gestational weeks with elevated blood pressure, gestational diabetes mellitus (GDM), pericardial effusion, heart failure, limb edema, serum creatinine, white blood cell count, low platelet counts within one week before delivery, SBP on the first postpartum day, and postpartum antihypertensive use. Additionally, one risk factor from the index pregnancy was included, which was antihypertensive use before 20 weeks. The model demonstrated better discrimination, calibration, and a net benefit across a wide range of recurrent preeclampsia risk thresholds. Furthermore, the model has been translated into a clinical risk calculator, enabling clinicians to calculate individualized risks of recurrent preeclampsia. CONCLUSION: Our study demonstrates that a predictive tool utilizing routine clinical and laboratory factors can accurately estimate the risk of recurrent preeclampsia. This predictive model has the potential to facilitate shared decision-making by providing personalized and risk-stratified care.

Colonic Endoscopic Tubing Is Safe and Effective Approach for Washed Microbiota Transplantation in Autistic Children.

Background: Washed microbiota transplantation (WMT) as the improved methods of fecal microbiota transplantation has been employed as a therapeutic approach for ameliorating symptoms associated with autism spectrum disorder (ASD). In this context, colonic transendoscopic enteral tubing (TET) has been utilized as a novel procedure for administering WMT. Methods: Data of children with ASD who received WMT by TET were retrospectively reviewed, including bowel preparation methods, TET operation time, success rate, tube retention time, the comfort of children, adverse events, and parent satisfaction. Results: A total of 38 participants underwent 124 colonic TET catheterization procedures. The average time of TET operation was 15 minutes, and the success rate was 100% (124/124). There was no significant difference in TET operation time between high-seniority physicians and low-seniority physicians. In 123 procedures (99%), the TET tube allowed the completion of WMT treatment for 6 consecutive days. In 118 procedures (95.2%), the tube was detached spontaneously after the end of the treatment course, and the average TET tube retention time was 8 days. There was no incidence of tube blockage during the treatment course. No severe adverse events occurred during follow-up. Parents of all participants reported a high level of satisfaction with TET. Conclusion: Colonic TET is a safe and feasible method for WMT in children with ASD.

Development and Validation of a Prediction Model for Venous Thrombus Embolism (VTE) in Patients With Colorectal Cancer.

Cancer patients are at high risk of developing venous thromboembolism (VTE). The risk of VTE could be mitigated with the administration of prophylactic anticoagulants. Therefore, risk assessment models would be a useful tool in order to identify those patients who are at higher risk and will be benefited more by prophylactic anticoagulants. This study retrospectively examined 528 newly diagnosed colorectal cancer patients from January 2019 to January 2021. Specified logistic regression models were employed to screen the factors and establish prediction tools based on nomograms according to the final included variables. Discrimination, calibration, and clinical applicability were used to assess the performance of screening tools. In addition, internal verifications were conducted through 10-fold cross-verification, leave-one-out cross-validation, and Bootstrap verification. Four risk factors, closely related to the occurrence of VTE in colorectal cancer patients, were identified after univariate and multivariate logistic regression, including age, body mass index, activated partial thromboplastin time, and D-Dimer value. Besides, the risk assessment model named ABAD was built on the basis, displaying good discriminations and calibrations. The area under the curve was 0.705 (95% confidence interval [CI], 0.644 to 0.766). According to Hosmer-Lemeshow goodness-of-fit test, a good agreement between the predicted and observed VTE events in patients with newly-diagnosed gastrointestinal cancer was observed for χ2 = 6.864, P = .551. Internal validation was applied with a C-index of 0.669 in the 10-fold cross-verification, 0.658 in the leave-one-out cross verification and 0.684 in the bootstrap verification. We developed a prediction model called ABAD for newly diagnosed colorectal cancer patients, which can be used to predict the risk of VTE. After evaluation and internal verification, we believe that ABAD exhibited high predictive performance and availability and could be recommended.

Assessment of ship speed, operational carbon intensity indicator penalty and charterer profit of time charter ships.

The operational carbon intensity indicator (CII) proposed by the International Maritime Organization (IMO) has been officially implemented on January 1, 2023. As an important way of ship operation, applicable time charter ships are subject to the CII regulation. How to properly deal with the CII regulation is a challenge for the shipowner and charterer of time charter ships. Speed reduction is an effective measure to reduce carbon emissions and carbon intensity of ships. This study establishes a speed model including CII penalty for time charter ships. Results show that speed reductions of a time charter ship of 10 %, 20 % and 30 % reduce carbon emissions by 27.1 %, 48.8 % and 65.7 % and carbon intensity by 19 %, 36 % and 51 %, respectively. Speed reduction leads to reductions of carbon emissions, carbon intensity and CII penalty, with greater reductions for larger ships. Under the optimal charterer profit, the speed of a time charter ship increases with the rise of freight rate and reduces with the decrease of freight rate. When the fluctuation range of freight rate is the same, the larger the ship type is, the smaller the speed adjustment range is. For the same ship type, when its freight rate decreases, it is suggested that the charterer reduces speed; otherwise, it is suggested that the charterer increases speed. For different ship types, if the shipping market is booming, the charterer should charter more large ships; otherwise, the charterer can choose more small ships.

Effects of sarcopenia and frailty on postoperative recovery in elderly patients: A prospective cohort study.

BACKGROUND: Sarcopenia and frailty are both age-related declines in functional reserve that are linked to adverse health outcomes. It is critical to know about the outcomes of a combination of these conditions. The study aimed to investigate the effects of sarcopenia and frailty on postoperative recovery in elderly patients and to explore risk factors. METHODS: This prospective cohort study was conducted among 608 patients aged ≥60 years, American Society of Anesthesiologists I-III, who were scheduled to undergo thoracic (non-cardiac) and abdominal surgery from 1 March 2022 to 31 October 2022 at the Affiliated Hospital of Xuzhou Medical University. Frailty was measured by the 28-item frailty index, and sarcopenia was assessed sarcopenia was assessed by skeletal muscle index in computed tomographic scan, handgrip strength and 6-m walk. Participants were classified as follows: Group A: both sarcopenia and frailty; Group B: sarcopenia only; Group C: frailty only; and Group D: neither frailty nor sarcopenia. The primary outcome was 90-day morbidity. Multivariable logistic regression model was used to estimate the association between sarcopenia, frailty and 90-day morbidity. RESULTS: The median (interquartile range) age of participants was 68 (64-72) years, and 62.7% were men. The prevalence rates of sarcopenia and frailty were 32.8% and 47.6%, respectively. The 90-day morbidity in Group A was 58.5%, in Group B was 46.2%, in Group C was 42.0% and in Group D was 28.8%, and the difference was significant (P < 0.001). In the multivariable analysis, both sarcopenia and frailty [odds ratio (OR), 2.21; 95% confidence interval (CI), 1.26-3.89], sarcopenia only (OR, 1.84; 95% CI, 1.01-3.36), frailty only (OR, 1.77; 95% CI, 1.03-3.03), women (OR, 0.67; 95% CI, 0.45-0.99), body mass index (OR, 0.94; 95% CI, 0.88-0.99), pre-operative albumin (OR, 0.96; 95% CI, 0.91-1.00) and operative stress score (OSS) [OSS 3 (OR, 2.09; 95% CI, 1.21-3.67); OSS 4-5 (OR, 3.81; 95% CI, 2.31-6.42)] were independently associated with 90-day morbidity. In the multivariable analysis with inverse probability weighting adjusted cohort, sarcopenia and frailty were also significantly associated with 90-day morbidity. CONCLUSIONS: Sarcopenia and frailty were associated with higher risks of postoperative 90-day morbidity in elderly patients alone and in combination. Sex, body mass index, pre-operative albumin and operative stress were also independent factors for postoperative morbidity within 90 days.

Aflatoxin B1 in poultry liver: Toxic mechanism.

Aflatoxin B1 (AFB1) is the most common carcinogenic toxin in livestock and poultry feed, seriously endangering poultry production and public health. Liver is the most important organ for the metabolism of exogenous and endogenous substances in the body. AFB1 produces toxicity under the biotransformation of cytochrome P450 microparticle oxidase (CYP450). Hepatocytes are the most important cells for synthesizing CYP450 enzymes, so that AFB1 has the most significant effect on the liver. AFB1 can induce liver cell damage in poultry through a variety of molecular mechanisms, and the main of damage mechanisms have been discovered so far include oxidative damage, promoting apoptosis, influencing hepatocyte gene expression, interfering with hepatocyte autophagy, pyroptosis and necroptosis. This article reviewed the molecular mechanism of AFB1 inducing liver injury in poultry, hopefully, to provid a new direction and theoretical basis for the development of a new AFB1 detoxification method.

Effects of food on pharmacokinetics and safety of metformin hydrochloride tablets: A meta-analysis of pharmacokinetic, bioavailability, or bioequivalence studies.

Background: The effects of food on the pharmacokinetics and safety of metformin hydrochloride (MH) are unclear. Objective: To discover the effects of food on the pharmacokinetics and safety of MH, and its influence factors. Methods: English and Chinese databases, and grey (unpublished) literature were searched for eligible studies (registration No. CRD 42022321067 in PROSPERO network). The summary weighted mean difference for continuous variables, and the risk ratio for dichotomous variables was calculated for the main pharmacokinetic parameters. Heterogeneity among the included studies was analyzed using the I2 test. Subgroup analyses, meta-regression, sensitivity analysis, and publication bias test were conducted. Results: Fourteen clinical trials were included, comprising 408 participants. The pooled AUC0→t, AUC0→∞, and Cmax were decreased by about 30.21% (I2 = 16.7%, p = 0.276), 28.00% (I2 = 73.6%, p < 0.001), and 40.38% (I2 = 92.8%, p < 0.001). Tmax was delayed by about 29.42% (I2 = 45.1%, p = 0.034). Subgroup analysis and meta-regression analysis revealed dosage of MH and gender composition as two significant sources of heterogeneity in AUC0→∞ and Cmax. Sensitivity analysis indicated that most of results were stable. The Egger's regression test and the Begg test (p > 0.05) confirmed that there is no publication bias. Conclusions: Pharmacokinetics parameters of MH were affected by food. High-fat, high-calorie diet lowered the extent and rate of absorption while slowing the absorption of metformin. These findings suggest that it is necessary to increase the dosage of MH in order to maintain the same treatment effect when administration of MH after a high fat, high calorie diet.

Promoting proliferation and tumorigenesis of breast cancer: KCND2's significance as a prognostic factor.

In recent years, the potassium voltage-gated channel subfamily D (KCND) channels, particularly KCND2 (also known as Kv4.2), have been suggested to play a role in a variety of cancers, but their role in breast cancer has not yet been revealed. We analyzed RNA sequencing data from The Cancer Genome Atlas database and the Genotype-Tissue Expression database to investigate the differential expression of KCND2 in breast cancer and normal breast tissue. In addition, we leveraged GO and KEGG analysis techniques to gain a better understanding of the potential functional enrichment of 500 genes related to KCND2. Our findings were validated using collected tissue samples and clinical data from hospitals showed that KCND2 is a crucial independent factor in the prognosis of breast cancer patients. The higher the expression of KCND2, the shorter the survival time of breast cancer patients. Colony formation assay confirmed that KCND2 promotes the proliferation of breast cancer cells, whereas transwell assay and wound healing assay verified that KCND2 promoted breast cancer invasion and migration. In addition, 5-Ethynyl-2'-deoxyuridine (EdU) and flow cytometry revealed that KCND2 affected the cycle changes of breast cancer cells and contributed to the G1/S phase transition of breast cancer cells. Overall, our study demonstrates that KCND2 holds a promising potential as a significant target for breast cancer diagnosis and therapy.

Inhibition of Brd4 alleviates osteoarthritis pain via suppression of neuroinflammation and activation of Nrf2-mediated antioxidant signalling.

BACKGROUND AND PURPOSE: Osteoarthritis (OA) pain remains a major clinical problem. It is urgent to identify novel therapeutic approaches for OA pain states. Bromodomain and extra-terminal (BET) protein inhibitors have robust anti-inflammatory effects in several pain models. However, the underlying mechanisms of these inhibitors in OA pain have not been determined. We, therefore, investigated the effects and the underlying mechanism(s) of BET inhibition on pain-related behaviours in a rat model of OA. EXPERIMENTAL APPROACH: The OA model was established by intra-articular injection of monosodium iodoacetate (MIA) in rat knees. Pain behaviours were assessed in rats by hindlimb weight-bearing asymmetry, mechanical allodynia and thermal hyperalgesia. Possible mechanisms underlying BET inhibition were explored in the MIA-induced OA pain model in the spinal cord and dorsal root ganglia (DRG). KEY RESULTS: Inhibiting bromodomain-containing protein 4 (Brd4) with either JQ1 or MS417, or using AAV2/9-shRNA-Brd4-EGFP-mediated knockdown of Brd4 genes, significantly attenuated MIA-induced pain behaviours. Brd4 inhibition suppressed NF-κB and NF-κB-mediated inflammatory cytokines in both the spinal cord and DRG in rats with MIA-induced OA pain. Brd4 inhibition also attenuated the oxidative stress and promoted nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent antioxidant genes in both the spinal cord and DRG in our odel of MIA-induced OA pain. CONCLUSIONS AND IMPLICATIONS: In conclusion, Brd4 inhibition alleviated MIA-induced OA pain in rats, via suppression of neuroinflammation and activation of Nrf2-mediated antioxidant signalling. Although our model does not perfectly represent how OA develops in humans, inhibition of Brd4 may provide novel insights into possible treatments for OA pain.