Objective To analyze the pharmacological mechanism of Shenling Baizhu powder in the treatment of cancer cachexia based on the network pharmacological method and provide a reference for the clinical application of classical traditional Chinese medicine(TCM) prescriptions. Methods Through TCMSP and BATMAN-TCM databases, the main chemical components and their targets of the TCM prescription of Shenling Baizhu powder were obtained, and the active components of the TCM were screened according to ADME. The main targets of cancer cachexia were obtained through OMIM, Genecards, Disgenet and DRUGBANK databases, and protein interaction analysis was conducted using String platform to build a PPI network. The “drug-active ingredient-target” network of Shenling Baizhu powder was constructed by Cytoscape 3.7.2 software, and then the biological processes and pathways involved were analyzed by using Metascape platform. Finally, molecular docking verification was conducted by Discovery Studio. Results The core active ingredients of Shenling Baizhu powder in the treatment of cancer cachexia were quercetin, kaempferol, pyrolignous acid, stigmasterol, luteolin, β-sitosterol, etc. The core targets were AKT1, TP53, TNF, IL-6, MAPK3, CASP3, JUN, CTNNB1, HIF1A, EGFR, etc. The molecular docking test also showed that the top 10 active ingredients, such as pyrolignous acid, stigmasterol and β-sitosterol, had good binding activities with most of the target sites. The biological pathway of Shenling Baizhu powder in treating cancer cachexia wss mainly to regulate tumor related pathway, metabolism related pathway, inflammatory factors and appetite related pathway. Conclusion This study preliminarily revealed the mechanism of action of Shenling Baizhu powder in treating cancer cachexia with multi components, multi targets and multi pathways, which provided a basis for the clinical development and utilization of Shenling Baizhu powder.

Objective　This study aims to explore the impact of demographic characteristics, sexual behavioral , and epidemiological history on mpox infection among the MSM in Chengdu, providing a theoretical basis for prevention and control of mpox. Methods　A case-control study was conducted, including mpox patients in Chengdu from June 2023 March 2024 as the study group and MSM without mpox as controls, we carried out a retrospective investigation. Basic information, sexual history and behavior, and travel history were obtained for both mpox patients and controls. Univariate and multivariate logistic regression analysis were used to explore the risk factors for mpox infection. Results　In this study, 128 MPXV cases (including 53 HIV individuals) and 151 controls (including 50 HIV individuals) were investigated. The average age of the cases was (32.48±6.67) years, all of whom were male, 101 were single, 100 had a college degree or higher, 60 were business services and self-owned occupations, 89 were homosexual, and 116 reported history of having homosexual behavior; 109 had an average of four or fewer homosexual behavior per month; 48 used condoms usually. The proportion of unmarried and those with a college degree or higher was lower in the monkeypox case group than the control group, while proportion of those with sexually transmitted diseases other than HIV was higher than the control group (P<0.05). Bisexuals or heterosexuality had a higher risk of MPXV compared to homosexuals (OR=4.65), the ones who never use condoms during homosexual activities were at higher risk for monkeypox (OR=3.25). There were no significant differences in epidemiological history between the two groups. Multivariate logistic regression showed that being unaware of other STD infections was negatively associated with MPXV infection, while having other STDs other than HIV, being bisexual or heterosexual sexual behavior were positively associated with MPXV infection. Conclusion　The MSM in Chengdu with concurrent infection with other sexually transmitted diseases other than HIV, bisexual or heterosexual sexual orientation were risk factors for mpox. It is necessary to strengthen health education for the ones at high-risk .Chengdu

The aim of this study was to investigate the improvement effect of Wenpi Pills(WPP) on non-alcoholic fatty liver disease(NAFLD). The experiment was divided into two parts, using C57BL/6 mouse models induced by a high-fat diet(HFD) and a methionine and choline deficiency diet(MCD). The HFD-induced experiment lasted for 16 weeks, while the MCD-induced experiment lasted for 6 weeks. Mice in both parts were divided into four groups: control group, model group, low-dose WPP group(3.875 g·kg~(-1), WPP＿L), and high-dose WPP group(15.5 g·kg~(-1), WPP＿H). After sample collection from the HFD-induced mice, lipid content in the serum and liver, liver function indexes in the serum, and hepatic pathology were examined. Real-time fluorescent quantitative reverse transcription PCR(qRT-PCR) was used to detect the expression of lipid-related genes. After sample collection from the MCD-induced mice, serum liver function indexes and inflammatory factors were measured, and hepatic pathology and lipid changes were analyzed by hematoxylin-eosin(HE) staining and widely targeted lipidomic profiling, respectively. The results from the HFD-induced experiment showed that, compared with the HFD group, WPP administration significantly reduced the levels of aspartate aminotransferase(AST), alanine aminotransferase(ALT), triglyceride(TG), and total cholesterol(TC) in the serum, with the WPP＿H group showing the most significant improvement. HE staining results indicated that, compared with the HFD group, WPP treatment improved the morphology of white adipocytes, reducing their size, and alleviated hepatic steatosis and lipid droplet accumulation. The qRT-PCR results suggested that WPP might increase the mRNA expression of liver cholesterol-converting genes, such as liver X receptor α(LXRα) and cytochrome P450 family 27 subfamily A member 1(CYP27A1), as well as lipid consumption genes like peroxisome proliferator-activated receptor α(PPARα) and adenosine mono-phosphate-activated protein kinase(AMPK). Meanwhile, WPP decreased the mRNA expression of lipid synthesis genes, including fatty acid synthetase(FAS), stearoyl-CoA desaturase 1(SCD1), and sterol regulatory element-binding protein 1c(SREBP-1c), thereby reducing liver lipid accumulation. The results from the MCD-induced experiment showed that, compared with the MCD group, WPP administration reduced the levels of ALT, AST, and inflammatory factors in the serum, thereby alleviating liver injury and the inflammatory response. HE staining of liver tissue indicated that WPP effectively improved hepatic steatosis. Non-targeted lipidomics analysis showed that WPP improved lipid metabolism disorders in the liver, mainly by affecting the metabolism of TG and cholesterol esters. In conclusion, WPP can improve hepatic lipid accumulation in NAFLD mice induced by both HFD and MCD. This beneficial effect is primarily achieved by alleviating liver injury and inflammation, as well as regulating lipid metabolism.
Animals ; Non-alcoholic Fatty Liver Disease/genetics* ; Lipid Metabolism/drug effects* ; Mice ; Mice, Inbred C57BL ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Diet, High-Fat/adverse effects* ; Liver/drug effects* ; Humans ; Disease Models, Animal ; Methionine

OBJECTIVE: To explore the co-morbid influencing factors of postmenopausal osteoporosis(PMOP) and dyslipidemia, and to provide evidence-based basis for clinical co-morbidity management. METHODS: Based on the 2017 to 2018 Beijing community cross-sectional survey data, PMOP patients were included and divided into the dyslipidemia group and the uncomplicated dyslipidemia group according to whether they were comorbid with dyslipidemia. Demographic characteristics, living habits and disease history were collected through questionnaires, and bone mineral density and bone metabolism biomarkers (osteocalcin, blood calcium, serum typeⅠprocollagen N-terminal prepeptide, etc.) were detected on site. Co-morbidity risk factors were analyzed using binary logistic regression. RESULTS: Three hundred and twenty patients with PMOP were included, including the comorbid group (75 patients) and the uncomplicated group (245 patients). The results showed that history of cardiovascular disease [OR=1.801, 95%CI(1.003, 3.236), P=0.049], history of cerebrovascular disease [OR=2.923, 95%CI(1.460, 5.854), P=0.002], frying and cooking methods[OR=5.388, 95%CI(1.632, 17.793), P=0.006], OST results[OR=0.910, 95%CI(0.843, 0.983), P=0.016], and blood Ca results [OR=60.249, 95%CI(1.862, 1 949.926), P=0.021] were the influencing factors of PMOP complicated with dyslipidemia. CONCLUSION Focus should be placed on the influencing factors of PMOP and dyslipidemia co-morbidities, with emphasis on multidimensional assessment, combining lifestyle interventions with bone metabolism marker monitoring to optimize co-morbidity management.
Humans ; Dyslipidemias/epidemiology* ; Female ; Middle Aged ; Osteoporosis, Postmenopausal/metabolism* ; Aged ; Cross-Sectional Studies ; Risk Factors ; Bone Density

Spermatogenesis is a fundamental process that requires a tightly controlled epigenetic event in spermatogonial stem cells (SSCs). The mechanisms underlying the transition from SSCs to sperm are largely unknown. Most studies utilize gene knockout mice to explain the mechanisms. However, the production of genetically engineered mice is costly and time-consuming. In this study, we presented a convenient research strategy using an RNA interference (RNAi) and testicular transplantation approach. Histone H3 lysine 9 (H3K9) methylation was dynamically regulated during spermatogenesis. As Jumonji domain-containing protein 1A (JMJD1A) and Jumonji domain-containing protein 2C (JMJD2C) demethylases catalyze histone H3 lysine 9 dimethylation (H3K9me2), we firstly analyzed the expression profile of the two demethylases and then investigated their function. Using the convenient research strategy, we showed that normal spermatogenesis is disrupted due to the downregulated expression of both demethylases. These results suggest that this strategy might be a simple and alternative approach for analyzing spermatogenesis relative to the gene knockout mice strategy.
Spermatogenesis/physiology* ; Animals ; Male ; Mice ; Epigenesis, Genetic ; Jumonji Domain-Containing Histone Demethylases/metabolism* ; Histones/metabolism* ; RNA Interference ; Testis/metabolism* ; Methylation ; Mice, Knockout ; Histone Demethylases

OBJECTIVE: To investigate the effects of oridonin on platelet function and related mechanisms. METHODS: Washed platelets from healthy adults and mice were incubated with different concentrations of oridonin (2.5, 5 and 10 μmol/L) in vitro . The surface expression level of P-selectin and the activation of integrin αIIbβ3 in platelets were detected by flow cytometry, and the aggregation ability of platelets under the stimulation by various agonists was detected by light transmission aggregometry. The expression of P-AKT (Ser473) was detected by protein immunoblotting. Arterial thrombosis model was established in mice with mesenteric injury induced by ferric chloride, and tail hemorrhage model was established by cutting off the tail of mice. The effect of intraperitoneal injection of oridonin (10 mg/kg) on thrombosis and haemostasis was tested. RESULTS: Oridonin inhibited platelet P-selectin expression and integrin αIIbβ3 activation. In the presence of different stimulants, oridonin inhibited platelet aggregation in a concentration-dependent manner. The phosphorylation level of AKT Ser473 was reduced in the groups treated with different concentrations of oridonin. Oridonin significantly prolonged the time of mesenteric artery thrombosis in mice, but did not affect the tail bleeding time. CONCLUSION Oridonin inhibits platelet activation, aggregation, and thrombosis by inhibiting AKT phosphorylation, and may be used as a potential antiplatelet drug.
Diterpenes, Kaurane/pharmacology* ; Animals ; Mice ; Blood Platelets/drug effects* ; Platelet Aggregation/drug effects* ; P-Selectin/metabolism* ; Thrombosis ; Platelet Glycoprotein GPIIb-IIIa Complex/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Humans ; Phosphorylation ; Platelet Activation/drug effects*

OBJECTIVE: The aim of this study is to analyze the clinical features and genetic etiology of a patient with multiple morphological abnormalities of the sperm flagella (MMAF) retrospectively. METHODS: A severely oligospermic patient from the Reproductive Center of the First Affiliated Hospital of Ningbo University was selected as the study subject. Clinical data and examination results were collected. High-throughput sequencing and bioinformatics were used to analyze the genetic etiology. And Sanger sequencing was employed to validate findings in the family. Transmission electron microscopy (TEM) was used to observe the sperm ultrastructure, and immunofluorescence analysis was performed to examine the localization of FSIP2 protein in the sperm. RESULTS: The patient presented with severe oligospermia, and sperm morphology displayed MMAF. TEM revealed fibrous sheath and 9+2 microtubule structural disruptions in the sperm. Sequencing identified compound heterozygous variants in the FSIP2 gene (c.17798C > T, c.5927T > G), inherited from the father and mother, respectively. According to the guidelines of the American College of Medical Genetics and Genomics, the variants were classified as pathogenic. The patient's spouse underwent intracytoplasmic single sperm injection, resulting in one embryo, but no clinical pregnancy occurred after embryo transfer. CONCLUSION This study reported the mutation of FSIP2 gene c.17798C > T, c.5927T > G in a patient with MMAF. These findings expand the mutational spectrum of the FSIP2 gene and provide insights for genetic and assisted reproductive counseling for patients with MMAF.
Humans ; Male ; Sperm Tail/pathology* ; Heterozygote ; Oligospermia/genetics* ; Spermatozoa ; Mutation ; Infertility, Male/genetics* ; Adult ; Pedigree ; Retrospective Studies ; Sperm Injections, Intracytoplasmic

OBJECTIVE: To investigate the protective effects of stir-fried Semen Armeniacae Amarum (SAA) against aristolochic acid I (AAI)-induced nephrotoxicity and DNA adducts and elucidate the underlying mechanism involved for ensuring the safe use of Asari Radix et Rhizoma. METHODS: In vitro, HEK293T cells overexpressing Flag-tagged multidrug resistance-associated protein 3 (MRP3) were constructed by Lentiviral transduction, and inhibitory effect of top 10 common pairs of medicinal herbs with Asari Radix et Rhizoma in clinic on MRP3 activity was verified using a self-constructed fluorescence screening system. The mRNA, protein expressions, and enzyme activity levels of NAD(P)H quinone dehydrogenase 1 (NQO1) and cytochrome P450 1A2 (CYP1A2) were measured in differentiated HepaRG cells. Hepatocyte toxicity after inhibition of AAI metabolite transport was detected using cell counting kit-8 assay. In vivo, C57BL/6 mice were randomly divided into 5 groups according to a random number table, including: control (1% sodium bicarbonate), AAI (10 mg/kg), stir-fried SAA (1.75 g/kg) and AAI + stir-fried SAA (1.75 and 8.75 g/kg) groups, 6 mice in each group. After 7 days of continuous gavage administration, liver and kidney damages were assessed, and the protein expressions and enzyme activity of liver metabolic enzymes NQO1 and CYP1A2 were determined simultaneously. RESULTS: In vivo, combination of 1.75 g/kg SAA and 10 mg/kg AAI suppressed AAI-induced nephrotoxicity and reduced dA-ALI formation by 26.7%, and these detoxification effects in a dose-dependent manner (P<0.01). Mechanistically, SAA inhibited MRP3 transport in vitro, downregulated NQO1 expression in vivo, increased CYP1A2 expression and enzymatic activity in vitro and in vivo, respectively (P<0.05 or P<0.01). Notably, SAA also reduced AAI-induced hepatotoxicity throughout the detoxification process, as indicated by a 41.3% reduction in the number of liver adducts (P<0.01). CONCLUSIONS Stir-fried SAA is a novel drug candidate for the suppression of AAI-induced liver and kidney damages. The protective mechanism may be closely related to the regulation of transporters and metabolic enzymes.
Aristolochic Acids/toxicity* ; Animals ; Humans ; NAD(P)H Dehydrogenase (Quinone)/genetics* ; HEK293 Cells ; Kidney/pathology* ; Cytochrome P-450 CYP1A2/genetics* ; Mice, Inbred C57BL ; DNA Adducts/drug effects* ; Male ; Kidney Diseases/drug therapy* ; Drugs, Chinese Herbal/therapeutic use* ; Mice ; Prunus armeniaca ; Plant Extracts

The development of anticancer drugs to treat triple-negative breast cancer (TNBC) is an ongoing challenge. Immunogenic cell death (ICD) has garnered considerable interest worldwide as a promising synergistic modality for cancer chemoimmunotherapy. However, only few drugs or treatment modalities can trigger an ICD response and none of them exert a considerable clinical effect against TNBC. Therefore, new agents with potentially effective chemoimmunotherapeutic response are required. In this study, five new cyclometalated Ir(III) complexes containing isoquinoline alkaloid CˆN ligands were designed and synthesized. Among them, Ir-1 exhibited the highest in vitro cytotoxicity. Mechanistically, Ir-1 could trigger autophagy-dependent ferroptosis and a subsequent ferroptosis-dependent ICD response as well as indoleamine 2,3-dioxygenase (IDO) inhibition via reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress in MDA-MB-231 cells. When immunocompetent BALB/c mice were vaccinated with Ir-1-treated dying TNBC cells, antitumor CD8⁺ T-cell response and Foxp3⁺ T-cell depletion were induced, resulting in long-lasting antitumor immunity in TNBC cells. Moreover, combination therapy with Ir-1 and anti-PD1 could substantially augment in vivo therapeutic effects. Based on these results, Ir-1 is a promising candidate for chemoimmunotherapy against TNBC and its effects are mediated synergistically via ICD induction and IDO blockage.

This paper explains the mechanism of the mutual switching between physiological sleep and wakefulness from the aspects of the sleep circadian system and the sleep homeostasis system. In the circadian rhythm system, with the suprachiasmatic nucleus as the core, the anatomical connections between the suprachiasmatic nucleusand various systems that affect sleep are summarized, starting from the suprachiasmatic nucleus, passing through the four pathways of the melatonin system, namely, subventricular area of the hypothalamus, the ventrolateral nucleus of the preoptic area, orexin neurons, and melatonin, then the related mechanisms of their regulation of sleep and wakefulness are expounded. In the sleep homeostasis system, with adenosine and prostaglandin D2 as targets, the role of hypnogen in sleep arousal mechanisms in regulation is also expounded.