Recently, male reproductive health has attracted extensive attention, with the adverse effects of circadian disruption on male fertility gradually gaining recognition. However, the mechanism by which circadian disruption leads to damage to male reproductive system remains unclear. In this review, we first summarized the dual regulatory roles of circadian clock genes on the male reproductive system: (1) circadian regulation of testosterone synthesis via the hypothalamic-pituitary-testicular (HPT) and hypothalamic-pituitary-adrenal (HPA) axes; (2) non-circadian regulation of spermatogenesis. Next, we further listed the possible mechanisms by which circadian disruption impairs male fertility, including interference with the oscillatory function of the reproductive system, i.e., synchronization of the HPT axis, crosstalk between the HPT axis and the HPA axis, as well as direct damage to germ cells by disturbing the non-oscillatory function of the reproductive system. Future research using spatiotemporal omics, epigenomic assays, and neural circuit mapping in studying the male reproductive system may provide new clues to systematically unravel the mechanisms by which circadian disruption affects male reproductive system through circadian clock genes.
Male ; Humans ; Animals ; Circadian Clocks/physiology* ; Hypothalamo-Hypophyseal System/physiology* ; Circadian Rhythm/genetics* ; Spermatogenesis/physiology* ; Pituitary-Adrenal System/physiology* ; Testis/physiology* ; Testosterone/biosynthesis* ; CLOCK Proteins ; Infertility, Male/physiopathology*

OBJECTIVES: To evaluate and integrate evidence on the management of sleep disorders in children with attention deficit hyperactivity disorder (ADHD). METHODS: Literature was retrieved based on the 6S model, and evidence related to sleep disorder management in children with ADHD was extracted from the included references. RESULTS: A total of 17 studies were included, from which 16 pieces of evidence were extracted. Of these, 6 were classified as Level 1 evidence and 10 as Level 5. The evidence covered screening, assessment, non-pharmacological interventions, pharmacological interventions, follow-up, and multidisciplinary collaboration. CONCLUSIONS This study integrated evidence on the management of sleep disorders in children with ADHD using an evidence-based approach, providing an evidence-based foundation for managing sleep disorders in this population.
Humans ; Attention Deficit Disorder with Hyperactivity/complications* ; Sleep Wake Disorders/etiology* ; Child ; Evidence-Based Medicine

OBJECTIVE: The aim of this study is to explore the clinical efficacy and safety of endocrinotherapy combined with Shenqi Pills on hormone-sensitive prostate cancer (HSPC). METHODS: Eighty patients who were diagnosed with HSPC and renal-yang deficiency at the First Affiliated Hospital of Hunan University of Traditional Chinese Medicine and the Hospital of Traditional Chinese Medicine of Mayang Miao Autonomous County from 1st April 2021 to 30th April 2024 were randomly divided into 2 groups. The patients in the control group were treated with androgen deprivation therapy (ADT). And the patients in treatment group were treated with Shenqi Pills orally on the basis of the control group. The baseline data of the two groups were analyzed. After 36 months of treatment, the differences between the two groups were compared in terms of overall survival (OS), prostate-specific antigen (PSA) level, PSA response rate, Functional Assessment Scale for Prostate Cancer Therapy (FACT-P), Chinese medicine evidence scores, testosterone level and safety. RESULTS: A total of 80 study subjects were included in this study, including 42 cases in the treatment group and 38 cases in the control group. There was no statistical difference in the baseline data between the two groups before treatment (P>0.05). At the end of the observation period, a statistically significant difference in OS was found in the treatment group compared to the control group in the subgroup of patients with a disease duration ranged of 0-6 months (P<0.05). There was no statistically significant difference in PSA levels in the treatment group at 3 months (P>0.05). And the differences in the proportion of PSA50 (98.1% vs 91.4%), PSA90 (92.9% vs 84.6%) and the proportion of decrease in PSA (56.7% vs 33.8%) in the treatment group were found compared to those in the control group after 6 months of tre atment. After 12 months of treatment, the scores of FACT-4 and renal-yang deficiency in the treatment group were (95.28±7.93) and (15.73±5.70) respectively, compared to the scores in the control group (［85.46±10.12］ and ［18.20±4.27］ (P<0.05). However, there was no significant difference in serum testosterone (［0.60±0.24］ nmol/L vs ［1.09±2.10］ nmol/L) between the two groups (P>0.05). After 24 months of treatment, there were significant differences in in the FACT-4 total score (［97.95±7.54］ vs ［80.33±8.58］), renal-yang deficiency syndrome score (［14.64±5.15］ vs ［24.94±8.75］) between the treatment group and the control group (P<0.05). However, there was no significant difference in serum testosterone ( ［0.73±1.01］ nmol/L vs ［0.59±0.25］ nmol/L) between the two groups (P> 0.05). Better therapeutic results were showed in the treatment group in terms of total FACT-P score, physical situation score, social and family situation score, emotional state score, functional state score, additional score and renal-yang deficiency symptom score (P<0.05). After treatment, there was no serious adverse reaction in the course of treatment, and no obvious abnormality was found in the liver and kidney function of the patients from two groups. CONCLUSION Endocrinotherapy combined with Shenqi Pills is safe and effective in HSPC and can reduce the risk of death in HSPC patients, and the earlier the intervention, the longer the overall survival of the patients. In addition, this treatment regimen can increase the PSA response rate, improve patients' quality of life, and reduce the renal-yang deficiency syndrome score without the risk of elevating serum testosterone levels.
Humans ; Male ; Drugs, Chinese Herbal/therapeutic use* ; Prostatic Neoplasms/drug therapy* ; Androgen Antagonists/therapeutic use* ; Prostate-Specific Antigen/blood* ; Aged ; Middle Aged ; Treatment Outcome ; Testosterone

With the continuous development of experimental biology, the limitations of commonly utilized model organisms are becoming increasingly apparent. Discrepancies between research conducted on laboratory animals and humans significantly impede the translational application of findings derived from animal experiments. This review introduces ascidian Ciona intestinalis as a novel model organism, an invertebrate that is evolutionarily closest to vertebrates and is a sister group to vertebrates. The review summarizes recent research progress on Ciona intestinalis in various fields to illustrate the significant advantages and promising application prospects of it as a model organism. The research progress outlined in the review mainly encompasses: (1) The whole-genome sequencing of Ciona intestinalis has been determined and numerous related databases have been established. Various embryonic gene editing technologies have been successfully applied, making it an animal model easy to manipulate genetically and study the functions and interactions of target genes visually. (2) In the field of neurobiology, Ciona intestinalis boasts a central nervous system structure similar to that of vertebrates and possesses numerous homologous neuropeptides and hormone molecules. These features grant it an edge in exploring the mechanisms and functional evolution of endocrine and neuroendocrine-related molecules. Additionally, the sensitivity and habituation of its larvae to light stimulation provide an avenue for exploring mechanisms related to behavioral plasticity. (3) In the field of immunology, Ciona intestinalis possesses a mature innate immune system and has evolved precursor genes to the adaptive immune system, with a relatively simple coding of immune-related genes. These features make it an exemplary model organism for immunological studies. (4) In the field of developmental biology, many studies have focused on the notochord development process in Ciona intestinalis and the regulatory mechanisms of gene expression within it, indicating common evolutionary developmental strategies among chordates. Additionally, insights into its heart development also significantly enhance our comprehension on the genetic network of human heart development. (5) In medical research, the ability of Ciona intestinalis to regenerate its neural complex and siphon, as well as the resilience of its heart to recover contractile function from substantial damage, renders it a valuable animal model for the study of regeneration and heart injury. It also has unique advantages as a research model for Alzheimer's disease and new drug development. Furthermore, its brief five-month lifespan facilitates the observation and recording of the entire aging process and the exploration of the effects of various factors on aging. In summary, this review aims to demonstrate that Ciona intestinalis stands out as a model organism with unique attributes and is expected to play a significant role in a wider range of scientific research areas.

ObjectiveTo analyze the epidemiological characteristics of hand, foot, and mouth disease (HFMD) in Zhangjiakou City, Hebei Province from 2013 to 2022, so as to provide a basis for HFMD prevention, control, and evaluation of intervention effectiveness. MethodsHFMD data of Zhangjiakou City from 2013 to 2022 were collected. Descriptive statistics and the Joinpoint regression model were used to analyze the trend of the epidemic. ResultsThe incidence of HFMD in Zhangjiakou was predicted to decrease with APC=-14.86% in 2013‒2022. The top five regions with the highest incidence showed varying trends: Qiaodong District (APC=-26.21%), Qiaoxi District (APC=-18.29%), Xuanhua District (APC=-14.28%), Chicheng District (APC=-18.68%), and Zhuolu County (APC=51.43% in 2013‒2016, APC=-14.27% in 2016‒2022), indicating a downward trend. Three age groups showed an upward trend in incidence: the 0-year-old group (APC=-42.82% in 2013‒2016, APC=16.54% in 2016‒2022), the 7-year-old group (AAPC=9.60%), and the 9-year-old group (AAPC=12.76%). HFMD cases occurred throughout the year, peaking from June to August, with July being the most significant month. The male-to-female ratio was1.40∶1, with no statistical difference (χ²=5.932, P>0.05). A high incidence was in children under 5 years old, with those aged 1‒4 years being the main affected group. In terms of occupation, scattered children (6 245 cases, 57.65%) and preschool children (3 653 cases, 33.72%) were the most affected. A total of 504 laboratory-confirmed cases were reported, with a detection rate of 4.65% (504/10 832). The composition of confirmed cases included CoxA 16 (193 cases, 38.29%), EV71 (75 cases, 14.88%), and other enteroviruses (236 cases, 46.83%). ConclusionFrom 2013 to 2022, HFMD in Zhangjiakou City showed a downward trend with clear seasonal, regional, and occupational distributions. It is suggested that epidemic monitoring should be strengthened, etiological detection should be enhanced, and education efforts in key areas should be improved. High-incidence counties should analyze data and conduct risk assessments effectively.

Objective To evaluate the pharmacokinetics characteristics of single-dose of Etripamil nasal spray 70 mg in healthy adult Chinese subjects.Methods This was a single-center,randomized,double-blind,placebo-controlled study.Twelve healthy adult Chinese subjects were randomized to receive single-dose of Etripamil nasal spray 70 mg(n=10)or placebo nasal spray(n=2).Blood and urine samples were collected prior and post dose.Etripamil in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry.The pharmacokinetic parameters were calculated by WinNonlin non-compartmental model.Results Following the single-dose of Etripamil nasal spray 70 mg in healthy adult Chinese subjects,the peak concentration of Etripamil in plasma was quickly attained,with a Cmax of(66.76±56.61)ng·mL-1 and a median(range)tmax of 4.00(3.00-5.00)min.The plasma concentrations of Etripamil had fallen approximately 65％from peak value at 25 min after dosing,and close to 80％within 50 min.The AUC0-last and AUC0-∞ were(3 104.16±2 654.46)and(4 048.77±2 682.38)ng·min·mL-1,respectively.The urine excretion percentage of Etripamil during 24 h was(0.01±0.01)％.Among the 12 subjects who were treated with Etripamil or placebo,10 subjects reported a total of 29 treatment-emergent adverse events(TEAEs).All of the TEAEs were mild in severity.The most common TEAEs were rhinorrhoea and lacrimation increased.Conclusion Etripamil was quickly absorbed after intranasal administration,followed by rapid distribution and elimination(not primarily excreted by renal);Etripamil 70 mg was safe and well tolerated by the healthy Chinese adult subjects.

Humans ; Comorbidity ; Diabetes Mellitus/genetics* ; East Asian People ; Hypertension/genetics* ; Hypertriglyceridemia/genetics* ; Obesity/genetics* ; Receptors, Calcitriol/genetics*

The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease, including the devastating COVID-19. Novel effective antivirals with broad-spectrum coverage are urgently needed. Herein, we reported a novel broad-spectrum antiviral compound PAC5. Oral administration of PAC5 eliminated HBV cccDNA and reduced the large antigen load in distinct mouse models of HBV infection. Strikingly, oral administration of PAC5 in a hamster model of SARS-CoV-2 omicron (BA.1) infection significantly decreases viral loads and attenuates lung inflammation. Mechanistically, PAC5 binds to a pocket near Asp49 in the RNA recognition motif of hnRNPA2B1. PAC5-bound hnRNPA2B1 is extensively activated and translocated to the cytoplasm where it initiates the TBK1-IRF3 pathway, leading to the production of type I IFNs with antiviral activity. Our results indicate that PAC5 is a novel small-molecule agonist of hnRNPA2B1, which may have a role in dealing with emerging infectious diseases now and in the future.
Animals ; Mice ; Antiviral Agents/pharmacology* ; COVID-19 ; Hepatitis B virus ; Interferon Type I/metabolism* ; SARS-CoV-2/drug effects* ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/antagonists & inhibitors*

Cinnabaris is a traditional Chinese medicine(TCM) commonly used for sedation and tranquilization in clinics, and its safety has always been a concern. This study intends to investigate the species and tissue distribution of mercury in rats after continuous administration of Cinnabaris. In the experiment, 30 rats were randomly divided into the control group(equivalent to 0.5% carboxy-methyl cellulose sodium), low-dose Cinnabaris group(0.2 g·kg~(-1)), high-dose Cinnabaris group(2 g·kg~(-1)), pseudogerm-free control group(equivalent to 0.5% sodium carboxymethyl cellulose), and pseudogerm-free Cinnabaris group(2 g·kg~(-1)). They were orally administered for 30 consecutive days. Ultrasound-assisted acid extraction method combined with high performance liquid chromatography and inductively coupled plasma-mass spectrometry(HPLC-ICP-MS) was adopted to determine inorganic mercury [Hg(Ⅱ)], methylmercury(MeHg), and ethylmercury(EtHg) in different tissue, plasma, urine, and feces of rats. The optimal detection conditions and extraction methods were optimized, and the linearity(R~2>0.999 3), precision(RSD<7.0%), and accuracy(spike recoveries ranged from 73.05% to 109.5%) of all the mercury species were satisfied, meeting the requirements of analysis. The results of mercury species detection showed that Hg(Ⅱ) was detected in all the tissue of the five experimental groups, and the main accumulating organs were the intestinal tract, stomach, and kidney. MeHg existed at a low concentration in most tissue, and EtHg was not detected in all groups. In addition, pathological examination results showed that hepatocyte vacuolar degeneration, loose cytoplasm, light staining, and mononuclear cell infiltration were observed in the high-dose Cinnabaris group, low-dose Cinnabaris group, and pseudogerm-free Cinnabaris group, with slightly milder lesions in the low-dose Cinnabaris group. Hydrous degeneration of renal tubular epithelium could be seen in the high-dose Cinnabaris group and pseudogerm-free Cinnabaris group, but there was no significant difference between the other groups and the control group. No abnormal changes were found in the brain tissue of rats in each group. This paper studied the different mercury species and tissue distribution in normal and pseudogerm-free rats after continuous administration of Cinnabaris for 30 days and clarified its effects on the tissue structure of the liver, kidney, and brain, which provided supporting evidence for the safety evaluation of Cinnabaris.
Rats ; Animals ; Mercury/analysis* ; Tissue Distribution ; Methylmercury Compounds/analysis* ; Chromatography, High Pressure Liquid/methods* ; Sodium

BACKGROUND: All-trans retinoic acid (ATRA) promotes the osteogenic differentiation induced by bone morphogenetic protein 9 (BMP9), but the intrinsic relationship between BMP9 and ATRA keeps unknown. Herein, we investigated the effect of Cyp26b1, a critical enzyme of ATRA degradation, on the BMP9-induced osteogenic differentiation in mesenchymal stem cells (MSCs), and unveiled possible mechanism through which BMP9 regulates the expression of Cyp26b1. METHODS: ATRA content was detected with ELISA and HPLC–MS/MS. PCR, Western blot, and histochemical staining were used to assay the osteogenic markers. Fetal limbs culture, cranial defect repair model, and micro–computed tomographic were used to evaluate the quality of bone formation. IP and ChIP assay were used to explore possible mechanism. RESULTS: We found that the protein level of Cyp26b1 was increased with age, whereas the ATRA content decreased. The osteogenic markers induced by BMP9 were increased by inhibiting or silencing Cyp26b1 but reduced by exogenous Cyp26b1. The BMP9-induced bone formation was enhanced by inhibiting Cyp26b1. The cranial defect repair was promoted by BMP9, which was strengthened by silencing Cyp26b1 and reduced by exogenous Cyp26b1. Mechanically, Cyp26b1 was reduced by BMP9, which was enhanced by activating Wnt/b-catenin, and reduced by inhibiting this pathway. b-catenin interacts with Smad1/5/9, and both were recruited at the promoter of Cyp26b1. CONCLUSIONS Our findings suggested the BMP9-induced osteoblastic differentiation was mediated by activating retinoic acid signalling, viadown-regulating Cyp26b1. Meanwhile, Cyp26b1 may be a novel potential therapeutic target for the treatment of bone-related diseases or accelerating bone-tissue engineering.