Compounds isolated from Epimedium include the total flavonoids of Epimedium , icariin, and its metabolites (icaritin, icariside I, and icariside II), which have similar molecular structures. Modern pharmacological research and clinical practice have proved that Epimedium and its active components have a wide range of pharmacological effects, especially in improving sexual function, hormone regulation, anti-osteoporosis, immune function regulation, anti-oxidation, and anti-tumor activity. To date, we still need a comprehensive source of knowledge about the pharmacological effects of Epimedium and its bioactive compounds on the male reproductive system. However, their actions in other tissues have been reviewed in recent years. This review critically focuses on the Epimedium , its bioactive compounds, and the biochemical and molecular mechanisms that modulate vital pathways associated with the male reproductive system. Such intrinsic knowledge will significantly further studies on the Epimedium and its bioactive compounds that protect the male reproductive system and provide some guidances for clinical treatment of related male reproductive disorders.
Male ; Epimedium/chemistry* ; Humans ; Genitalia, Male/drug effects* ; Flavonoids/therapeutic use* ; Animals

This study was conducted retrospectively on a cohort of 68 patients with steroid 5 α-reductase 2 (SRD5A2) deficiency and 46,XY disorders of sex development (DSD). Whole-exon sequencing revealed 28 variants of SRD5A2 , and further analysis identified seven novel mutants. The preponderance of variants was observed in exon 1 and exon 4, specifically within the nicotinamide adenine dinucleotide phosphate (NADPH)-binding region. Among the entire cohort, 53 patients underwent initial surgery at Sichuan Provincial People's Hospital (Chengdu, China). The external genitalia scores (EGS) of these participants varied from 2.0 to 11.0, with a mean of 6.8 (standard deviation [s.d.]: 2.5). Thirty patients consented to hormone testing. Their average testosterone-to-dihydrotestosterone (T/DHT) ratio was 49.3 (s.d.: 23.4). Genetic testing identified four patients with EGS scores between 6 and 9 as having this syndrome; and their T/DHT ratios were below the diagnostic threshold. Furthermore, assessments conducted using the crystal structure of human SRD5A2 have provided insights into the potential pathogenic mechanisms of these novel variants. These mechanisms include interference with NADPH binding (c.356G>C, c.365A>G, c.492C>G, and c.662T>G) and destabilization of the protein structure (c.727C>T). The c.446-1G>T and c.380delG variants were verified to result in large alterations in the transcripts. Seven novel variations were identified, and the variant database for the SRD5A2 gene was expanded. These findings contribute to the progress of diagnostic and therapeutic approaches for individuals with SRD5A2 deficiency.
Humans ; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics* ; Disorder of Sex Development, 46,XY/blood* ; Male ; Membrane Proteins/genetics* ; Child, Preschool ; Child ; Retrospective Studies ; Adolescent ; Female ; Mutation ; Testosterone/blood* ; Infant ; Dihydrotestosterone/blood*

Objective:To investigate the effects of thoracolumbar vertebral fracture with incomplete spinal cord injury on male sexual function and postoperative prognosis.Methods:A retrospective review was conducted on data from 144 male patients with thoracolumbar vertebral fractures and incomplete spinal cord injuries treated between May 2009 and May 2021 in the Department of Traumatology and Orthopedics at Peking University Third Hospital. Patients ranged in age from 19 to 55 years (mean: 38.6±10.6 years) and underwent posterior incision and reduction internal fixation. The International Index of Erectile Function-5 (IIEF-5), the Premature Ejaculation Diagnostic Tool (PEDT), and the International Spinal Cord Injury Male Sexual Function Basic Data Set were used for sexual function evaluation. Based on the American Spinal Injury Association (ASIA) Spinal Cord Injury classification, changes in neurological and sexual function were assessed at the pre-injury stage, 3 months post-injury, 2 years postoperatively, and at the final follow-up. Factors influencing sexual dysfunction and recovery were analyzed. Spearman correlation analysis was used to identify factors affecting sexual function injury and recovery.Results:A total of 117 patients were included in the final analysis. Follow-up duration ranged from 26.2 to 161.7 months (mean: 74.6±40.5 months). After injury, ASIA grades were distributed as follows: 43 patients with grade B, 41 with grade C, and 33 with grade D. At the 2-year follow-up, 30 patients were grade E, 63 grade D, 19 grade C, and 5 grade B. Improvement in ASIA classification was observed in 90.6% (106/117) of patients: 79 improved by one grade, 27 by two grades, 8 remained unchanged, 1 worsened by one grade, and 2 worsened by two grades. Mean IIEF-5 scores were 19.5±6.4 pre-injury, 8.7±8.0 at 3 months post-injury, and 17.5±7.1 at 2 years postoperatively, with statistically significant differences ( F=123.247, P<0.001). Differences between 3 months post-injury vs. pre-injury and 2 years postoperatively vs. 3 months post-injury were statistically significant ( P<0.05). Mean PEDT scores were 5.3±3.1 pre-injury, 6.9±5.2 at 3 months post-injury, and 6.4±5.1 at 2 years postoperatively, with statistically significant differences ( F=17.014, P<0.001). The difference between 3 months post-injury and pre-injury was statistically significant ( P<0.05), but not between 2 years postoperatively and 3 months post-injury ( P>0.05). At the 2-year follow-up, 96 patients had their IIEF-5 classification restored to pre-injury levels, 85 restored PEDT classifications, and 83 restored both. Post-injury ASIA classification was positively correlated with a decrease in IIEF-5 score and an increase in PEDT score at 3 months post-injury ( P<0.05). Injury segment was positively correlated with the decrease in IIEF-5 score ( P<0.05). Time from injury to surgery showed a positive correlation with increased PEDT score at 3 months ( P<0.05). Post-injury ASIA grade, injury segment, time to surgery, age, intraoperative decompression, and spinal cord function recovery all showed significant correlations with changes in IIEF-5 and (or) PEDT scores at 2 years postoperatively ( P<0.05). According to the International Spinal Cord Injury Male Sexual Function Basic Data Set, the proportion of patients willing to discuss sexual issues increased from 29.9% at 3 months post-injury to 47.9% at 2 years postoperatively ( P<0.05). The proportion of patients with absent or diminished psychogenic erections remained stable (48.7% vs. 48.9%, P>0.05), while those with normal reflexive erections increased from 34.2% to 65.0% ( P<0.05). Conclusion:Thoracolumbar fractures with incomplete spinal cord injury result in reduced erectile function and increased incidence of premature ejaculation. The degree of spinal cord injury and the level of the injured segment are strongly correlated with the extent of sexual dysfunction. At the 2-year postoperative follow-up, 70.9% of patients had recovered sexual function to pre-injury levels.

Objective:To investigate the feasibility and clinical effects of ultra early enteral nutrition (≤24 h) in critically ill children supported by extracorporeal membrane oxygenation (ECMO).Methods:A retrospective cohort study was conducted. Clinical data of 43 critically ill children who received ECMO support in the pediatric intensive care unit (PICU) of Shanghai Children′s Hospital from January 2016 to December 2023 were collected, including general information, nutritional support modalities, and enteral nutrition tolerance. Based on the timing of enteral nutrition initiation, patients were divided into the within 24 h enteral nutrition group and the after 24 h enteral nutrition group. Nutritive indicators, nutritional intake, duration of ECMO support, duration of mechanical ventilation duration, and mortality rates were compared between the 2 groups using the two independent sample t test, Mann-Whitney U test, χ2 test and Fisher′s exact test. Results:Among the 43 children, 25 were male and 18 were female, with an age of 47 (18, 97) months. There were no statistically significant differences between the within 24 h enteral nutrition group (21 cases) and the after 24 h enteral nutrition group (22 cases) in terms of age, body mass index Z score, total protein, albumin, hemoglobin levels before ECMO support, duration of ECMO support, duration of mechanical ventilation, length of PICU stay, number of enteral nutrition intolerance events, number of enteral nutrition interruption, or mortality rate (all P>0.05). The protein intake adequacy rate during ECMO support was higher in the within 24 h enteral nutrition group than in the after 24 h enteral nutrition group (0 (0, 21%) vs. 0 (0, 0), U=175.00, P<0.05). Conclusions:Ultra early enteral nutrition is safe for children supported by ECMO. Initiating enteral nutrition within 24 h can increase the proportion of days with adequate protein intake in ECMO children without increasing the occurance of enteral nutrition intolerance or interruptions.

Objective:To investigate the mutations of TP53 and KRAS genes in the patients with six common types of digestive system tumors,including colorectal cancer(COAD),cholangiocarcinoma(CHOL),gallbladder cancer(GBC),liver hepatocellular carcinoma(LIHC),stomach adenocarcinoma(STAD),and pancreatic adenocarcinoma(PAAD),and to analyze the relationships between TP53 and KRAS gene mutations and clinical pathological characteristics,tumor mutation burden(TMB),and microsatellite instability(MSI)of the patients.Methods:The pathological paraffin or biopsy samples of 112 patients from January 2022 to December 2023 diagnosed with six types of tumors based on imaging and pathology were collected.Hybrid capture-based gene sequencing technology was used to detect TP53 and KRAS gene mutations in the patients with different types of tumors;mutation landscapes of common digestive system tumor samples were constructed.The patients were divided into high and low TMB groups according to the TMB levels.The mutation statuses of TP53 and KRAS genes in the patients with different types of digestive system tumors were compared,and the TP53 and KRAS gene mutations in the patients with different clinicopathological characteristics were examined.Results:A total of 276 mutations were detected in the 112 samples,with the highest mutation rate in TP53 gene(67％),followed by KARS gene(34％).TP53 gene mutation was most prominent in COAD,followed by LIHC,while KRAS gene mutation was most significant in PAAD.TP53 gene mutation mainly occurred in exons 5-8,while the KRAS gene mutation primarily occurred in exon 2.There was no statistically significant difference in TP53 gene mutation rate among the six types of digestive system tumors(P＞0.05),while the KRAS gene mutation rate showed statistically significant difference(P＜0.05).The mutation rates of TP53 and KRAS gene co-mutation also showed statistically significant difference among the six types of tumors(P＜0.05).There were statistically significant differences in TP53 and KRAS gene mutation rates between the patients with high TMB and low TMB(P＜0.05),while there were no statistically significant differences in TP53 and KRAS mutation rates between the patients with different sex,age,tumor size,differentiation degree,TNM stage,lymph node and/or distant metastasis and MSI(P＞0.05).Conclusion:The mutation rates of TP53 and KRAS genes are higher in common digestive system tumors,which are related to tumor types and TMB.

Mechanical pain is one of the most common causes of clinical pain, but there remains a lack of effective treatment for debilitating mechanical and chronic forms of neuropathic pain. Recently, neurotoxin GsMTx4, a selective mechanosensitive (MS) channel inhibitor, has been found to be effective, while the underlying mechanism remains elusive. Here, with multiple rodent pain models, we demonstrated that a GsMTx4-based 17-residue peptide, which we call P10581, was able to reduce mechanical hyperalgesia and neuropathic pain. The analgesic effects of P10581 can be as strong as morphine but is not toxic in animal models. The anti-hyperalgesic effect of the peptide was resistant to naloxone (an μ-opioid receptor antagonist) and showed no side effects of morphine, including tolerance, motor impairment, and conditioned place preference. Pharmacological inhibition of TRPV4 by P10581 in a heterogeneous expression system, combined with the use of Trpv4 knockout mice indicates that TRPV4 channels may act as the potential target for the analgesic effect of P10581. Our study identified a potential drug for curing mechanical pain and exposed its mechanism.

Early-life stress (ES) leads to cognitive dysfunction in female adolescents, but the underlying neural mechanisms remain elusive. Recent evidence suggests that the cell adhesion molecules NECTIN1 and NECTIN3 play a role in cognition and ES-related cognitive deficits in male rodents. In this study, we aimed to investigate whether and how nectins contribute to ES-induced cognitive dysfunction in female adolescents. Applying the well-established limited bedding and nesting material paradigm, we found that ES impairs recognition memory, suppresses prefrontal NECTIN1 and hippocampal NECTIN3 expression, and upregulates corticotropin-releasing hormone (Crh) and its receptor 1 (Crhr1) mRNA levels in the hippocampus of adolescent female mice. Genetic experiments revealed that the reduction of dorsal CA1 (dCA1) NECTIN3 mediates ES-induced object recognition memory deficits, as knocking down dCA1 NECTIN3 impaired animals' performance in the novel object recognition task, while overexpression of dCA1 NECTIN3 successfully reversed the ES-induced deficits. Notably, prefrontal NECTIN1 knockdown did not result in significant cognitive impairments. Furthermore, acute systemic administration of antalarmin, a CRHR1 antagonist, upregulated hippocampal NECTIN3 levels and rescued object and spatial memory deficits in stressed mice. Our findings underscore the critical role of dCA1 NECTIN3 in mediating ES-induced object recognition memory deficits in adolescent female mice, highlighting it as a potential therapeutic target for stress-related psychiatric disorders in women.
Animals ; Female ; Mice ; CA1 Region, Hippocampal/metabolism* ; Cell Adhesion Molecules/metabolism* ; CRF Receptor, Type 1/metabolism* ; Memory Disorders/etiology* ; Mice, Inbred C57BL ; Nectins/genetics* ; Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors* ; Recognition, Psychology/physiology* ; Stress, Psychological/complications*

Polycystic ovary syndrome (PCOS) is the predominant cause of subfertility in reproductive-aged women; however, its pathophysiology remains unknown. Neurotensin (NTS) is a member of the gut-brain peptide family and is involved in ovulation; its relationship with PCOS is unclear. Here, we found that NTS expression in ovarian granulosa cells and follicular fluids was markedly decreased in patients with PCOS. In the in vitro culture of cumulus-oocyte complexes, the neurotensin receptor 1 (NTSR1) antagonist SR48692 blocked cumulus expansion and oocyte meiotic maturation by inhibiting metabolic cooperation and damaging the mitochondrial structure in oocytes and surrounding cumulus cells. Furthermore, the ERK1/2-early growth response 1 pathway was found to be a key downstream mediator of NTS/NTSR1 in the ovulatory process. Animal studies showed that in vivo injection of SR48692 in mice reduced ovulation efficiency and contributed to irregular estrus cycles and polycystic ovary morphology. By contrast, NTS partially ameliorated the ovarian abnormalities in mice with dehydroepiandrosterone-induced PCOS. Our findings highlighted the critical role of NTS reduction and consequent abnormal NTSR1 signaling in the ovulatory dysfunction of PCOS, suggesting a potential strategy for PCOS treatment.
Polycystic Ovary Syndrome/physiopathology* ; Female ; Animals ; Neurotensin/metabolism* ; Receptors, Neurotensin/antagonists & inhibitors* ; Mice ; Ovulation/drug effects* ; Humans ; Granulosa Cells/metabolism* ; Adult ; Oocytes/metabolism* ; MAP Kinase Signaling System ; Signal Transduction ; Follicular Fluid/metabolism* ; Disease Models, Animal ; Gonadotropin-Releasing Hormone/analogs & derivatives*

This study investigates the mechanism by which Xintong Granules improve myocardial ischemia-reperfusion injury(MIRI) through the regulation of gut microbiota and their metabolites, specifically short-chain fatty acids(SCFAs). Rats were randomly divided based on body weight into the sham operation group, model group, low-dose Xintong Granules group(1.43 g·kg~(-1)·d~(-1)), medium-dose Xintong Granules group(2.86 g·kg~(-1)·d~(-1)), high-dose Xintong Granules group(5.72 g·kg~(-1)·d~(-1)), and metoprolol group(10 mg·kg~(-1)·d~(-1)). After 14 days of pre-administration, the MIRI rat model was established by ligating the left anterior descending coronary artery. The myocardial infarction area was assessed using the 2,3,5-triphenyltetrazolium chloride(TTC) staining method. Apoptosis in tissue cells was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL) assay. Pathological changes in myocardial cells and colonic tissue were observed using hematoxylin-eosin(HE) staining. The levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6), creatine kinase MB isoenzyme(CK-MB), and cardiac troponin T(cTnT) in rat serum were quantitatively measured using enzyme-linked immunosorbent assay(ELISA) kits. The activities of lactate dehydrogenase(LDH), creatine kinase(CK), and superoxide dismutase(SOD) in myocardial tissue, as well as the level of malondialdehyde(MDA), were determined using colorimetric assays. Gut microbiota composition was analyzed by 16S rDNA sequencing, and fecal SCFAs were quantified using gas chromatography-mass spectrometry(GC-MS). The results show that Xintong Granules significantly reduced the myocardial infarction area, suppressed cardiomyocyte apoptosis, and decreased serum levels of pro-inflammatory cytokines(TNF-α, IL-1β, and IL-6), myocardial injury markers(CK-MB, cTnT, LDH, and CK), and oxidative stress marker MDA. Additionally, Xintong Granules significantly improved intestinal inflammation in MIRI rats, regulated gut microbiota composition and diversity, and increased the levels of SCFAs(acetate, propionate, isobutyrate, etc.). In summary, Xintong Granules effectively alleviate MIRI symptoms. This study preliminarily confirms that Xintong Granules exert their inhibitory effects on MIRI by regulating gut microbiota imbalance and increasing SCFA levels.
Animals ; Gastrointestinal Microbiome/drug effects* ; Rats ; Male ; Myocardial Reperfusion Injury/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Rats, Sprague-Dawley ; Apoptosis/drug effects* ; Humans ; Tumor Necrosis Factor-alpha/metabolism* ; Interleukin-6/genetics* ; Malondialdehyde/metabolism*