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BackgroundThe relation between mental disorders (MDs) and infertility can be reciprocal. But exactly which MD affects infertility remains controversial. Our aim was to use Mendelian randomization (MR) to explore bidirectional causality between 15 MDs and male infertility and female infertility.MethodsThe data of MDs, male infertility, and female infertility were derived from published genome-wide association studies (GWAS). The inverse variance weighted method was considered to be the main analytical approach. Sensitivity analysis was performed using MR-Egger, Cochran’s Q, radial MR, and MR-PRESSO tests.ResultsOur results found that mood disorders (OR, 1.4497; 95% CI, 1.0093 – 2.0823; P = 0.0444) and attention deficit hyperactivity disorder (OR, 1.3921; 95% CI, 1.0943 – 1.7709; P = 0.0071) were positively correlated with male infertility, but obsessive-compulsive disorder (OR, 0.8208; 95% CI, 0.7146 – 0.9429; P = 0.0052) was negatively associated with male infertility. For females, anorexia nervosa (OR, 1.0898; 95% CI, 1.0070 – 1.1794; P = 0.0329), attention deficit hyperactivity disorder (OR, 1.1013; 95% CI, 1.0041 – 1.2079; P = 0.0406), and major depressive disorder (OR, 1.1423; 95% CI, 1.0213 – 1.2778; P = 0.0199) increased risk of infertility. In reverse relationship, female infertility increased the incidence of bipolar disorder (OR, 1.0009; 95% CI, 1.0001 – 1.0017; P = 0.0281).ConclusionWe demonstrated the association between five MDs and male or female infertility. Female infertility was also found to be associated with an increased risk of one MD. We look forward to better designed epidemiological studies to support our results.

AimsTo evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cetagliptin (CAS number:2243737-33-7) in Chinese patients with type 2 diabetes mellitus (T2DM). A population PK/PD model was developed to quantify the PK and PD characteristics of cetagliptin in patients.Materials and methods32 Chinese adults with T2DM were enrolled in this study. The subjects were randomly assigned to receive either cetagliptin (50 mg or 100 mg), placebo, or sitagliptin (100 mg) once daily for 14 days. Blood samples were collected for PK and PD analysis. Effects on glucose, insulin, C-peptide, and glucagon were evaluated following an oral glucose tolerance test (OGTT) (day15). Effects on HbA1c and glycated albumin (GA), and safety assessments were also conducted. Meanwhile, a population PK/PD model was developed by a sequential two-step analysis approach using Phoenix.ResultsFollowing multiple oral doses, cetagliptin was rapidly absorbed and the mean half-life were 34.9-41.9 h. Steady-state conditions were achieved after 1 week of daily dosing and the accumulation was modest. The intensity and duration of DPP-4 inhibition induced by 50 mg cetagliptin were comparable with those induced by sitagliptin, and 100 mg cetagliptin showed a much longer sustained DPP-4 inhibition (≥80%) than sitagliptin. Compared with placebo group, plasma active GLP-1 AUEC0-24h increased by 2.20- and 3.36-fold in the 50 mg and 100 mg cetagliptin groups. A decrease of plasma glucose and increase of insulin and C-peptide were observed following OGTT in cetagliptin groups. Meanwhile, a tendency of reduced GA was observed, whereas no decreasing trend was observed in HbA1c. All adverse events related to cetagliptin and sitagliptin were assessed as mild. A population PK/PD model was successfully established. The two-compartment model and Sigmoid-Emax model could fit the observed data well. Total bilirubin (TBIL) was a covariate of volume of peripheral compartment distribution (V2), and V2 increased with the increase of TBIL.ConclusionsCetagliptin was well tolerated, inhibited plasma DPP-4 activity, increased plasma active GLP-1 levels, and exhibited a certain trend of glucose-lowering effect in patients with T2DM. The established population PK/PD model adequately described the PK and PD characteristics of cetagliptin.

BackgroundAlthough immune checkpoint inhibitors (ICIs) show a significant overall survival advantage over standard advanced renal cell carcinoma (aRCC) therapies, tumor response to these agents remains poor. Some studies have shown that combination therapy including an ICI appears to be the best treatment; however, the overall benefit in terms of efficacy and toxicity still needs to be assessed. Thus, we performed a network meta-analysis to evaluate the differences in the efficacy of several combinations that include an ICI to provide a basis for clinical treatment selection.MethodsWe conducted a thorough search of PubMed, EMBASE, and the Cochrane Library for articles from January 2010 to June 2023. R 4.4.2 and STATA 16.0 were used to analyze data; hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CI) were used to assess the results.ResultsAn indirect comparison showed that nivolumab plus cabozantinib and pembrolizumab plus lenvatinib were the most effective treatments for progression-free survival (PFS), with no significant differences between the two interventions (HR, 1.31; 95% CI, 0.96–1.78; P=0.08); rank probability showed that pembrolizumab plus lenvatinib had a 57.1% chance of being the preferred treatment. In the absence of indirect comparisons between pembrolizumab plus axitinib, nivolumab plus ipilimumab, avelumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib, pembrolizumab plus axitinib (40.2%) was the best treatment option for overall survival (OS). Compared to pembrolizumab plus lenvatinib, nivolumab plus ipilimumab (OR, 0.07; 95% CI, 0.01–0.65; P=0.02) and pembrolizumab plus axitinib (OR, 0.05; 95% CI, 0.00–0.78; P

ObjectiveThis network meta-analysis (NMA) was conducted to compare and rank the effects of training interventions including aerobic exercise (AE), resistance training (RT), combined aerobic and resistance training (CT), and high-intensity interval training (HIIT) on vital metabolic indicators in adults with overweight and obesity.MethodsPubMed, Cochrane, Embase, and Web of Science were searched from 1990 to February 2023. Articles were included if they described randomized controlled trials (RCTs) examining the effects of exercise training on anthropometry parameters, lipid profiles, glucose metabolism, blood pressure, and cardiorespiratory fitness in adults with overweight and obesity. Weighted mean difference with 95% CI was calculated.ResultsA total of 28 studies with 1,620 patients were included. Results revealed that AE exerts best effects on weight loss (−2.35 [−4.05, −0.64]) and body mass index (−0.9 [−1.38, −0.42]), while HIIT is the most effective in reducing waist circumference (−5.93 [10.71, −1.15]), percentage body fat (−3.93 [−5.73, −2.12]), serum triglycerides (−20.55 [−37.20, −3.91]), and fasting blood glucose (−14.31 [−22.47, −6.16]) and improving VO2 max (7.41 [4.37, 10.45]). However, no significant benefit was observed in terms of total cholesterol and blood pressure.ConclusionsAE is the optimal exercise type for reducing body weight and BMI, while HIIT exerts the most beneficial effects on improving body composition, cardiorespiratory fitness, and metabolic abnormalities in adults with overweight and obesity.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023444322, identifier CRD42023444322.

BackgroundStudies using novel antiandrogens (NAA) in patients with metastatic castration-resistant prostate cancer (mCRPC) have shown overall survival benefit. As patients develop resistance to NAA therapy, the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib in combination with NAA may become a promising therapy. However the overall benefit of olaparib monotherapy or combination therapy still needs to be evaluated. Therefore, we performed a network meta-analysis to assess the efficacy and toxicity between olaparib, olaparib combined with abiraterone and NAA.MethodsWe searched PubMed, EMBASE, the Cochrane Library and American Society of Clinical Oncology (ASCO) University Meeting abstracts for randomized controlled trials reporting olaparib and NAA from 2010 up to March, 2023. Network meta-analysis using Stata 16.0 and R 4.4.2, hazard ratios (HR) with 95% confidence intervals (CI) were used to assess the results.ResultsFour trials reported olaparib, olaparib plus abiraterone and apalutamide plus abiraterone. radiographic progression-free survival (rPFS) was significantly lower in patients on apalutamide plus abiraterone compared to olaparib (HR, 1.43; 95% CI, 1.06-1.93). rPFS was similar for olaparib plus abiraterone and olaparib (HR, 1.35; 95% CI, 0.99-1.84); likewise, olaparib plus abiraterone and apalutamide plus abiraterone were similar (HR, 1.06; 95% CI, 0.83-1.35). In addition, there was no significant difference between the three interventions for OS. But olaparib has the highest probability of being a preferred treatment for improving rPFS and OS.ConclusionrPFS was in favor of olaparib compared with apalutamide plus abiraterone. But there were no difference between olaparib plus abiraterone and either olaparib or apalutamide plus abiraterone. Apalutamide plus abiraterone might be the most preferred intervention in cases where AEs are involved.Systematic review registrationhttps://inplasy.com, identifier INPLASY2023100072.

IntroductionBrown adipose tissue (BAT) is mainly responsible for mammalian non-shivering thermogenesis and promotes energy expenditure. Meanwhile, similar to white adipose tissue (WAT), BAT also secretes a variety of adipokines to regulate metabolism through paracrine, autocrine, or endocrine ways. The chemokine C-X-C motif chemokine ligand-13 (CXCL13), a canonical B cell chemokine, functions in inflammation and tumor-related diseases. However, the role of CXCL13 in the adipose tissues is unclear.MethodsThe expression of CXCL13 in BAT and subcutaneous white adipose tissue (SWAT) of mice under cold stimulation were detected. Local injection of CXCL13 into BAT of normal-diet and high-fat-diet induced obese mice was used to detect thermogenesis and determine cold tolerance. The brown adipocytes were treated with CXCL13 alone or in the presence of macrophages to determine the effects of CXCL13 on thermogenic and inflammation related genes expression in vitro.ResultsIn this study, we discovered that the expression of CXCL13 in the stromal cells of brown adipose tissue significantly elevated under cold stimulation. Overexpression of CXCL13 in the BAT via local injection could increase energy expenditure and promote thermogenesis in obese mice. Mechanically, CXCL13 could promote thermogenesis via recruiting M2 macrophages in the BAT and, in the meantime, inhibiting pro-inflammatory factor TNFα level. DiscussionThis study revealed the novel role of adipose chemokine CXCL13 in the regulation of BAT activity and thermogenesis.

At present, the aging population is one of China's basic national concerns, and physical exercise offers endless potential to cope with it. However, the life expectancy of men in China is generally lower than that of women, and the health status of older men is more worrying. Could it be that differences in physical exercise cause the difference in life expectancy between older men and women? This study analyzes the exercise regimen of older men and women and its influence on their quality of life. Approximately 200 respondents aged over 60 were investigated using the SF-36 and exercise questionnaires. Our findings revealed the following: (1) The scores of seven dimensions of life quality of older men were significantly lower than those of older women (p < 0.001), but there was no significant difference only in physiological function (p > 0.05); (2) The exercise frequency and persistence of older men were significantly lower than those of older women (p < 0.001), but there was no significant difference in exercise time (p > 0.05); and (3) All eight indices of quality of life of older men were positively correlated with the four indices of exercise (0.250 < R < 0.597). Our study offered the following conclusions: (1) The health of older men who lack physical exercise is poor. From the perspective of healthy aging, older men are a vulnerable group that deserves more attention. (2) Within an appropriate range, the more older men participate in physical activity programs, the more conducive they are to improved health. (3) This study focuses on promoting physical exercise for older adults and suggests organizing them to participate in sports activities as an important measure to promote healthy aging in China.

Background: SHR8554 is a novel μ-opioid receptor-biased agonist. It has analgesic effects by selectively activating the G protein-coupled pathway. Additionally, it can weakly activate the ß-arrestin-2 pathway, resulting in a limited number of side effects, such as gastrointestinal inhibition. Previous studies have shown that SHR8554 has good analgesic effects, safety and tolerability, but the pharmacokinetic characteristics of SHR8554 in humans have not been reported. This study was designed to investigate the pharmacokinetics and safety of SHR8554 in healthy Chinese male subjects.Methods: A single 1 mg/41.3 μCi intravenous dose of [14C]SHR8554 was administered to six healthy male subjects. Blood, urine and faecal samples were collected at continuous time points to analyse SHR8554 parent drug levels and their metabolites. The total radioactivity in blood, plasma, urine and faeces was detected by using a liquid scintillation counter. The dynamic changes of SHR8554 and its metabolite concentration were by liquid chromatography-tandem mass spectrometry (LC/MS), and then pharmacokinetic analysis. The safety of the drug on the subjects was also observed after a single intravenous injection.Results: The total recovery of radioactivity in urine and faeces was 99.68% ± 0.79% in 216 h, including 76.22% ± 1.12% in urine and 23.46% ± 1.36% in faeces. Seventeen major metabolites in blood, urine and faeces were analysed and identified. The main metabolic pathways of SHR8554 in the human body involve 1) N-dealkylation; 2) O-deethylation; 3) mono-oxidation; 4) glucuronidation, etc. The primary mechanism of SHR8554 clearance in the human body is through urinary excretion, primarily in its parent drug and metabolite forms. The drug has good safety, and no serious adverse effects were observed.Conclusion: SHR8554 showed favourable pharmacokinetic characteristics and safety profiles in this study. SHR8554 is extensively metabolized in human body. The main metabolic pathways include N-dealkylation and O-deethylation, as well as mono-oxidation and glucuronidation. The main excretion route of SHR8554 and its metabolites is through urine.Clinical Trial Registration:http://www.chinadrugtrials.org.cn/, identifier CTR20220450

BackgroundReceiving a breast cancer diagnosis and treatment is both a physical and emotional journey. Previous studies using single-source data have revealed common and culture-specific emotional experiences of patients living with breast cancer. However, few studies have combined such data from multiple sources. Thus, using a variety of data sources, the current study sought to explore the emotional experiences of women in China newly diagnosed, post-operative, or undergoing chemotherapy. We posited that even though women living with breast cancer in China have multiple channels through which they can express these emotional experiences, little variance would be found in their emotional expressivity and the themes they want to express due to cultural inhibitions.MethodsText data from female patients newly diagnosed, post-operative, or undergoing chemotherapy were collected between June 2021 and January 2022 via a Python web crawler, semi-structured interviews, and an expressive writing intervention. Data were transcribed and subjected to thematic analysis. Reporting followed the consolidated criteria for reporting qualitative studies (COREQ) guidelines.ResultsAnalyses were based on 5,675 Weibo posts and comments published by 448 posters and 1,842 commenters, transcription texts from 17 semi-structured interviews, and 150 expressive writing texts. From this total collection of 461,348 Chinese characters, three major themes emerged: (i) conflicting emotions after diagnosis; (ii) long-term suffering and treatment concerns; and (iii) benefit finding and cognitive reappraisal.ConclusionsDespite gathering information from various sources, we found that distress from body-image disturbances, gender role loss and conflict, and changes in sexuality and fertility, were consistent among this sample of female Chinese patients with breast cancer. However, when women engaged actively in benefit finding and cognitive reappraisal with strong social support, patients were able to find ways to adapt and reported post-traumatic growth. Strong social support was an important facilitator in this growth. These study findings emphasize that healthcare professionals ought to increase cultural sensitivity, provide multiple channels to encourage patients to express their emotions, and incorporate screening for patients' emotional distress at all diagnostic and treatment phases as part of routine nursing care.

Background: Previous studies have suggested that proton pump inhibitors could impair the antiplatelet effect of clopidogrel. It is uncertain whether ilaprazole affects the antiplatelet effect of clopidogrel. This study aimed to determine the drug-drug interaction between ilaprazole and clopidogrel.Methods: A randomized crossover trial of 40 healthy subjects was performed. Clopidogrel was administered alone or in combination with ilaprazole for 7 days. The maximal platelet aggregation (MPA) to 5 μmol/L adenosine diphosphate was measured by light transmission aggregometry and the platelet reactivity index (PRI) was determined by vasodilator-stimulated phosphoprotein P2Y12 assay. High on-treatment platelet reactivity (HOPR) was defined as a MPA of >40%. The inhibition of platelet aggregation (IPA) and PRI in the two phases were compared between two regimens after the last dosing.Results: IPA was comparable between the two regimens at 0, 10 and 24 h (p > 0.05), but higher at 4 h in the clopidogrel alone regimen compared with that in the combined treatment regimen (75.66 ± 18.44% vs. 70.18 ± 17.67%, p = 0.031). The inhibition of PRI was comparable between the two regimens at 0 and 24 h. There were no significant differences in the area under the time-IPA% curve (AUC) or the incidence of HOPR at all time-points between the two regimens.Conclusion: In healthy subjects, ilaprazole has limited effect on the pharmacodynamics of clopidogrel and it may not be clinically relevant.Clinical Trial Registration: [www.chictr.org.cn], identifier [ChiCTR2000031482].

The rapid increase of obesity and associated diseases has become a major global health problem. Adipose tissues are critical for whole-body homeostasis. The gut microbiota has been recognized as a significant environmental factor in the maintenance of energy homeostasis and host immunity. A growing body of evidence suggests that the gut microbiota regulates host metabolism through a close cross-talk with adipose tissues. It modulates energy expenditure and alleviates obesity by promoting energy expenditure, but it also produces specific metabolites and structural components that may act as the central factors in the pathogenesis of inflammation, insulin resistance, and obesity. Understanding the relationship between gut microbiota and adipose tissues may provide potential intervention strategies to treat obesity and associated diseases. In this review, we focus on recent advances in the gut microbiota and its actions on adipose tissues and highlight the joint actions of the gut microbiota and adipose tissue with each other in the regulation of energy metabolism.

Type 2 diabetes mellitus (T2DM) is a major global health concern. Psidium guajava L. (guava) is widely used for food as well as a folk medicine. Previous studies have shown its anti-diabetic and anti-inflammatory properties. However, the underlying mechanisms remains to be elusive. In this study, we assessed the potential therapeutic effects of aqueous extract of guava leaves (GvAEx) on T2DM and explored their potential mechanisms in vivo and in vitro. GvAEx was gavage administered for 12 weeks in diabetic db/db mice. Our results have demonstrated that GvAEx significantly lowered fasting plasma glucose levels (p < 0.01) and improved glucose tolerance and insulin sensitivity (p < 0.01, p < 0.05, respectively). Additionally, GvAEx increased hepatic glycogen accumulation, glucose uptake and decreased the mRNA expression levels of gluconeogenic genes. Furthermore, GvAEx-treatment caused higher glucose transporter 2 (GLUT2) expression in the membrane in hepatocytes. Notably, for the first time, we have elaborated the possible mechanism of the hypoglycemic effect of GvAEx from the perspective of intestinal microbiota. GvAEx has significantly changed the composition of microbiota and increased short chain fatty acid (SCFA) -producing Lachnospiraceae family and Akkermansia genus in the gut. Taken together, GvAEx could alleviate hyperglycemia and insulin resistance of T2DM by regulating glucose metabolism in the liver and restoring the gut microbiota. Thus, GvAEx has the potential for drug development against T2DM.

Aggregation-induced emission (AIE) has attracted much attention in the past 2 decades. To develop novel AIE-active materials, ACQ-to-AIE transformation via regioisomerization is one of the most straightforward method. However, most of the reported ACQ-to-AIE transformations are achieved by migrating bulky units. In this work, a facile conversion was realized by migrating a small pyrrolidinyl group from para- to ortho-position on the rofecoxib scaffold. As a result, a pair of new isomers named MOX2 and MOX4 exhibited AIE behavior and ACQ activity, respectively. Moreover, MOX2 also showed solvatochromic, mechanochromic, and acidochromic properties with reversible multi-stimulus behavior. Single crystal X-ray analysis of MOX2 revealed that the molecular conformation and its packing mode were responsible for the AIE emission behavior. Further investigation indicated that MOX2 showed high lipid droplets staining selectivity. Taken together, the current work not only provides a new design philosophy for achieving ACQ-to-AIE conversion by migrating a small pyrrolidinyl group but also presents a promising candidate MOX2 for potential applications such as in security ink, optical recording and biological applications.

Background: SHR8554 is a novel μ-opioid receptor-biased agonist. It has analgesic effects by selectively activating the G protein-coupled pathway. Additionally, it can weakly activate the ß-arrestin-2 pathway, resulting in a limited number of side effects, such as gastrointestinal inhibition. Previous studies have shown that SHR8554 has good analgesic effects, safety and tolerability, but the pharmacokinetic characteristics of SHR8554 in humans have not been reported. This study was designed to investigate the pharmacokinetics and safety of SHR8554 in healthy Chinese male subjects. Methods: A single 1 mg/41.3 μCi intravenous dose of [14C]SHR8554 was administered to six healthy male subjects. Blood, urine and faecal samples were collected at continuous time points to analyse SHR8554 parent drug levels and their metabolites. The total radioactivity in blood, plasma, urine and faeces was detected by using a liquid scintillation counter. The dynamic changes of SHR8554 and its metabolite concentration were by liquid chromatographytandem mass spectrometry (LC/MS), and then pharmacokinetic analysis. The safety of the drug on the subjects was also observed after a single intravenous injection. Results: The total recovery of radioactivity in urine and faeces was 99.68% ± 0.79% in 216 h, including 76.22% ± 1.12% in urine and 23.46% ± 1.36% in faeces. Seventeen major metabolites in blood, urine and faeces were analysed and identified. The main metabolic pathways of SHR8554 in the human body involve 1) N-dealkylation; 2) O-deethylation; 3) mono-oxidation; 4) glucuronidation, etc. The primary mechanism of SHR8554 clearance in the human body is through urinary excretion, primarily in its parent drug and metabolite forms. The drug has good safety, and no serious adverse effects were observed. Conclusion: SHR8554 showed favourable pharmacokinetic characteristics and safety profiles in this study. SHR8554 is extensively metabolized in human body. The main metabolic pathways include N-dealkylation and O-deethylation, as well as mono-oxidation and glucuronidation. The main excretion route of SHR8554 and its metabolites is through urine. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/, identifier CTR20220450 [ABSTRACT FROM AUTHOR]