ObjectiveTo explore the potential mechanism of Zuoguiwan in ameliorating polycystic ovary syndrome （PCOS） by network pharmacology and liquid chromatography-mass spectrometry （LC-MS）-based metabolomics. MethodThe active ingredients and potential targets of Zuoguiwan for treating PCOS were predicted by bioinformatics. SD rats were assigned into a control group and a modeling group. The rat model of PCOS was established by gavage with letrozole （1 mg·kg^-1） combined with feeding with a high-fat diet. At the end of modeling， the modeled rats were assigned into model （normal saline）， metformin （300 mg·kg^-1）， and Zuoguiwan （concentrate 1.62 g·kg^-1） groups. The body weight and oestrous cycle of each rat were recorded， and the ovary was stained with hematoxylin and eosin for observation of ovarian morphology. Enzyme-linked immunosorbent assay was employed to determine the serum levels of follicle-stimulating hormone （FSH）， luteinizing hormone （LH）， anti-mullerian hormone （AMH）， testosterone （T）， and estradiol （E₂）， and the LH/FSH ratio was calculated. Serum metabolomics of rats was conducted by orthogonal partial least squares-discriminant analysis （OPLS-DA） to screen the metabolite-enriched pathways. Furthermore， network pharmacology and association analysis were employed construct the compound-response-enzyme-gene network. ResultA total of 503 potential targets of Zuoguiwan and 5 843 targets of PCOS were screened out， with 271 common targets. The Gene Ontology enrichment analysis revealed that the common targets were involved in the response to lipopolysaccharide， etc.， and the Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment yielded 119 pathways. Animal experiments showed that compared with the control group， the model group presented increased body weight （P<0.01）， elevated LH and AMH levels （P<0.01）， increased LH/FSH ratio （P<0.01）， lowered E₂ level （P<0.01）， and increased cystic follicles. Compared with the model group， Zuoguiwan and metformin decreased the body weight （P<0.01）， reduced atretic follicles and cystic follicles， increased mature follicles and corpus luteum， and thickened the granulosa layer. Moreover， Zuoguiwan lowered the T， FSH， LH， and AMH， and LH/FSH levels （P<0.01） and elevated the E₂ level （P<0.01）. The principal component analysis and OPLS-DA in metabolomics showed that the differential metabolites between Zuoguiwan and model groups included 26 up-regulated metabolites in the Zuoguiwan group. There were 8 common pathways predicted by the KEGG enrichment analysis in network pharmacology and the metabolite enrichment in metabolomics. The results of topological analysis revealed the pathways of steroid hormone biosynthesis and glycerol-phospholipid metabolism， and the constructed compound-response-enzyme-gene network revealed that the key targets were protein kinase B1 （Akt1）， epithelial growth factor receptor （EGFR）， prostaglandin-endoperoxide synthase 2 （PTGS2）， and mitogen-activated protein kinase 1 （MAPK1）. ConclusionZuoguiwan regulated the steroid hormone biosynthesis pathway to recover hormone levels， promote follicle production and development， and improve ovarian function， which may be the potential mechanism of this medicine in treating PCOS.

As a kind of traditional Chinese medicine,which has a medicinal site of rhizomes,contains rich active ingredients,mainly including steroidal saponins,flavonoids,phenols,stilbenes,organic acids and other compounds,which together give a wide range of pharmacological effects,including anti-inflammatory,antibacterial,anti-tumor,hypolipidemic,hypoglycemic,and so on.In recent years,with the continuous development of modern science and technology,the research on Smilacis chinae rhizoma has been deepening,and the pharmacological mechanism of its active ingredients has been gradually revealed.This paper reviews the research progress on the active ingredients and pharmacological effects of Smilacis chinae rhizoma over the last few years at home and abroad,in order to provide a scientific basis for further development and utilization of Smilacis chinae rhizoma,and inject new vitality into the modernization and international development of traditional Chinese medicine.

【Objective】 To compare the clinical efficacy of robot-assisted and open surgery in the treatment of renal carcinoma with inferior vena cava cancer thrombus, and to analyze the safety and feasibility of robot-assisted radical nephrectomy. 【Methods】 Clinical data of 55 patients surgically treated for renal carcinoma with Mayo Ⅰ-Ⅲ inferior vena cava tumor thrombus during Dec.2015 and Dec.2021 were retrospectively analyzed. Based on the operation methods, the patients were divided into the robotic surgery group (n=36) and open surgery group (n=19). The perioperative data, oncological results and survival of the two groups were compared. 【Results】 All operations were successful. The median operation time was 176 (IQR:137-234) min, and grade Ⅲ and above complications occurred in 9(16.4%) cases. The robotic surgery group had lower intraoperative blood loss [300 (IQR:200-625) mL vs.1 000 (IQR:600-1 184) mL] and blood transfusion ratio [(20/36) vs. (18/19)] than the open surgery group, but higher postoperative hemoglobin level[109(98-120) g/L vs. 90(84-100) g/L]. During a median follow-up of 26 (IQR:19-39) months, 19(34.5%) patients developed new metastases and 12(21.8%) patients died. The postoperative tumor-specific survival (HR=0.39, 95%CI:0.13-1.16, P=0.090) and overall survival (HR=0.71, 95%CI:0.22-2.23,P=0.554) were not significantly different between the two groups. 【Conclusion】 There are no significant differences in the incidence of postoperative complications, tumor-specific survival and overall survival between robot-assisted and open surgery for Mayo Ⅰ-Ⅲ inferior vena cava tumor thrombus, but the intraoperative blood loss in robotic group is lower than that in the open surgery group.

OBJECTIVE: The study aimed to estimate the benchmark dose (BMD) of coke oven emissions (COEs) exposure based on mitochondrial damage with the mitochondrial DNA copy number (mtDNAcn) as a biomarker. METHODS: A total of 782 subjects were recruited, including 238 controls and 544 exposed workers. The mtDNAcn of peripheral leukocytes was detected through the real-time fluorescence-based quantitative polymerase chain reaction. Three BMD approaches were used to calculate the BMD of COEs exposure based on the mitochondrial damage and its 95% confidence lower limit (BMDL). RESULTS: The mtDNAcn of the exposure group was lower than that of the control group (0.60 ± 0.29 vs. 1.03 ± 0.31; P < 0.001). A dose-response relationship was shown between the mtDNAcn damage and COEs. Using the Benchmark Dose Software, the occupational exposure limits (OELs) for COEs exposure in males was 0.00190 mg/m ³. The OELs for COEs exposure using the BBMD were 0.00170 mg/m ³ for the total population, 0.00158 mg/m ³ for males, and 0.00174 mg/m ³ for females. In possible risk obtained from animal studies (PROAST), the OELs of the total population, males, and females were 0.00184, 0.00178, and 0.00192 mg/m ³, respectively. CONCLUSION Based on our conservative estimate, the BMDL of mitochondrial damage caused by COEs is 0.002 mg/m ³. This value will provide a benchmark for determining possible OELs.
Male ; Female ; Animals ; Coke ; Polycyclic Aromatic Hydrocarbons ; DNA Copy Number Variations ; Benchmarking ; Occupational Exposure/analysis* ; DNA, Mitochondrial/genetics* ; DNA Damage

Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenozoospermia categorized by immotile spermatozoa with abnormal flagella in ejaculate. Whole-exome sequencing (WES) is used to detect pathogenic variants in patients with MMAF. In this study, a novel homozygous frameshift variant (c.6158_6159insT) in dynein axonemal heavy chain 8 (DNAH8) from two infertile brothers with MMAF in a consanguineous Pakistani family was identified by WES. Reverse transcription-polymerase chain reaction (RT-PCR) confirmed DNAH8 mRNA decay in these patients with the DNAH8 mutation. Hematoxylin-eosin staining and transmission electron microscopy revealed highly divergent morphology and ultrastructure of sperm flagella in these patients. Furthermore, an immunofluorescence assay showed the absence of DNAH8 and a reduction in its associated protein DNAH17 in the patients' spermatozoa. Collectively, our study expands the phenotypic spectrum of patients with DNAH8-related MMAF worldwide.
Humans ; Male ; Consanguinity ; Pakistan ; Infertility, Male/metabolism* ; Semen/metabolism* ; Sperm Tail/metabolism* ; Spermatozoa/metabolism* ; Flagella/pathology* ; Mutation

SARS-CoV-2 is an emerging viral pathogen and a major global public health challenge since December of 2019, with limited effective treatments throughout the pandemic. As part of the innate immune response to viral infection, type I interferons (IFN-I) trigger a signaling cascade that culminates in the activation of hundreds of genes, known as interferon stimulated genes (ISGs), that collectively foster an antiviral state. We report here the identification of a group of type I interferon suppressed genes, including fatty acid synthase (FASN), which are involved in lipid metabolism. Overexpression of FASN or the addition of its downstream product, palmitate, increased viral infection while knockout or knockdown of FASN reduced infection. More importantly, pharmacological inhibitors of FASN effectively blocked infections with a broad range of viruses, including SARS-CoV-2 and its variants of concern. Thus, our studies not only suggest that downregulation of metabolic genes may present an antiviral strategy by type I interferon, but they also introduce the potential for FASN inhibitors to have a therapeutic application in combating emerging infectious diseases such as COVID-19.

OBJECTIVE To prepare quercetin-human serum albumin-nanoparticles （Que-HSA-NPs），and to evaluate the in vivo and in vitro inhibitory effects of Que-HSA-NPs on hepatic fibrosis of non-alcoholic steatohepatitis （NASH）. METHODS Que-HSA-NPs were prepared by desolvation-chemical cross-linking method ，their appearance characteristics were observed ，and their particle size ，polydispersity index （PDI），Zeta potential and drug loading were detected. Quercetin （Que）and Que-HSA-NPs were applied to murine HSC-T 6 cells. The effects of them on survival rate of HSC-T 6，mRNA expression of transforming growth factor β（TGF-β），Type Ⅰ collagen α1（COL1A1）and α-smooth muscle actin （α-SMA）were compared. Que and Que-HSA-NPs were applied to mice fed with low methionine and choline deficient high-fat diet. The serum levels of liver injury indexes ，liver pathological characteristics ，mRNA expressions of TGF-β，COL1A1 and α-SMA，protein expression of α-SMA in liver tissue were determined to evaluate the improvement effects of them on hepatic fibrosis of NASH in mice. RESULTS The prepared Que-HSA-NPs was spherical ，the particle size was （172.9±2.2）nm，the PDI was 0.233，the Zeta potential was －29.2 mV，and the drug loading was 2.99％. Que and Que-HSA-NPs were nontoxic to HSC-T 6 at concentrations of 0-250 μg/mL. Both of them could significantly decrease mRNA expressions of TGF-β，COL1A1 and α-SMA，especially Que-HSA-NPs （P＜0.05）. They also could significantly decrease the serum levels of liver inju ry index ，relieve liver injury and down-regulate mRNA expressions of TGF-β，COL1A1 and α-SMA and protein expression of α-SMA， especially Que-HSA-NPs （P＜0.05）. CONCLUSIONS Que- HSA-NPs is successfully prepared ，and confirm that its anti- NASH hepatic fibrosis effect is better than that of Que .

Exploring the genetic basis of human infertility is currently under intensive investigation.However,only a handful of genes have been validated in animal models as disease-causing genes in infertile men.Thus,to better understand the genetic basis of human spermatogenesis and bridge the knowledge gap between humans and other animal species,we construct the FertilityOnline,a data-base integrating the literature-curated functional genes during spermatogenesis into an existing sper-matogenic database,SpermatogenesisOnline 1.0.Additional features,including the functional annotation and genetic variants of human genes,are also incorporated into FertilityOnline.By searching this database,users can browse the functional genes involved in spermatogenesis and instantly narrow down the number of candidates of genetic mutations underlying male infertility in a user-friendly web interface.Clinical application of this database was exampled by the identifi-cation of novel causative mutations in synaptonemal complex central element protein 1(SYCE1)and stromal antigen 3(STAG3)in azoospermic men.In conclusion,FertilityOnline is not only an integrated resource for spermatogenic genes but also a useful tool facilitating the exploration of the genetic basis of male infertility.

Background::The study aimed to describe the aortic valve morphology in Chinese patients underwent transcatheter aortic valve replacement (TAVR) for symptomatic severe aortic stenosis (AS), and the impact of sizing strategies and related procedural outcomes.Methods::Patients with severe AS who underwent TAVR were consecutively enrolled from 2012 to 2019. The anatomy and morphology of the aortic root were assessed. "Downsize" strategy was preformed when patients had complex morphology. The clinical outcomes of patients who performed downsize strategy were compared with those received annular sizing strategy. The primary outcome was device success rate, and secondary outcomes included Valve Academic Research Consortium-3 clinical outcomes variables based on 1-year follow-up.Results::A total of 293 patients were enrolled. Among them, 95 patients (32.4%) had bicuspid aortic valve. The calcium volume (Hounsfield Unit-850) of aortic root was 449.90 (243.15-782.15) mm 3. Calcium is distributed mostly on the leaflet level. Downsize strategy was performed in 204 patients (69.6%). Compared with the patients who performed annular sizing strategy, those received downsize strategy achieved a similar device success rate (82.0% [73] vs. 83.3% [170], P= 0.79). Aortic valve gradients (downsize strategy group vs. annular sizing group, 11.28 mmHg vs. 11.88 mmHg, P = 0.64) and percentages of patients with moderate or severe paravalvular regurgitation 2.0% (4/204) vs. 4.5% (4/89), P = 0.21) were similar in the two groups at 30 days after TAVR. These echocardiographic results were sustainable for one year. Conclusions::Chinese TAVR patients have more prevalent bicuspid morphology and large calcium volume of aortic root. Calcium is distributed mostly on the leaflet level. Compare with annular sizing strategy, downsize strategy provided a non-inferior device success rate and transcatheter heart valve hemodynamic performance in self-expanding TAVR procedure.

Objective:To evaluate the recovery of daytime and nighttime urinary continence in patients with robotic-assisted radical cystectomy and ileal orthotopic neobladder from 1 to 60 months after surgery, and systematically analyze the influencing factors of daytime and nighttime urinary continence recovery.Methods:The convenient sampling method was used to select clinical data of 60 patients who underwent robotic-assisted radical cystectomy and ileal orthotopic neobladder by a single operator from December 2014 to January 2020 and they were followed up for daytime and nighttime use of urine pads and prognosis. A total of 44 patients were eligible for follow-up data. Satisfactory recovery of daytime and nighttime urinary continence was defined as the use of less than or equal to 1 pad, and complete recovery of daytime and nighttime urinary continence was defined as no urine leakage. The daytime and nighttime urinary continence recovery in patients with robotic-assisted radical cystectomy and ileal orthotopic neobladder was assessed at 1, 3, 6, 12, 24, 36, and 60 months. Cox regression was used to analyze the influencing factors of postoperative urinary continence recovery.Results:Cox regression multivariate analysis showed that preservation of neurovascular bundles was associated with satisfactory recovery of daytime urinary continence, satisfactory recovery of nighttime urinary continence and complete recovery of daytime urinary continence ( P<0.05) . Clevien grading of complications within 90 d could affect the satisfaction of daytime urinary control recovery. Preoperative hydronephrosis was an independent factor affecting the satisfaction of nighttime urinary continence recovery. Conclusions:Preserving neurovascular bundles is an influencing factor in promoting postoperative urinary continence recovery in patients with robotic-assisted radical cystectomy and ileal orthotopic neobladder. In addition, postoperative complications and preoperative hydronephrosis are independent factors affecting the satisfaction of daytime and nighttime urinary continence recovery, respectively, but it need to be further confirmed by multicenter prospective studies.