OBJECTIVES: To assess the efficacy and safety of Tiaozhou Ziyin (TZZY) recipe for treatment of premature ovarian insufficiency (POI) and explore the possible mechanisms. METHODS: We used bioinformatics analyses and network pharmacology to identify the main active ingredients in TZZY recipe and their core targets, which were verified by Western blotting. We tested the efficacy and safety of the recipe in 60 POI patients, who were randomized into control group (n=30) with Femoston treatment and TZZY group (n=30) with additional TZZY recipe treatment for 3 menstrual cycles. RESULTS: The core active ingredients of TZZY recipe included kaempferol, β-sitosterol, luteolin, and quercetin. The core targets included SRC, TP53, STAT3, PIK3CA, and MAPK3, which were involved in positive regulation of cell movement and protein phosphorylation, the cancer pathways and the PI3K-Akt signaling pathway. Molecular docking showed that the core active ingredients had good binding ability with the core targets. In female rat models of POI, TZZY recipe treatment significantly up-regulated ovarian expressions of p-PI3K and p-Akt proteins. In the clinical trial, treatment with Femoston and Femoston plus TZZY recipe both significantly increased E₂ levels and reduced FSH and LH levels and Kupperman scores of the patients, and the combined treatment produced significantly stronger effects. Both treatments increased the number of antral follicles of the patients, but the combined treatment also significantly increased the levels of AMH. CONCLUSIONS The therapeutic mechanism of TZZY recipe for POI involves multiple active ingredients, multiple therapeutic targets and multiple pathways, and activating the PI3K /Akt pathway is one of its main mechanisms of action, to improve ovarian reserve function, alleviate clinical symptoms, and enhance clinical efficacy in POI patients.
Female ; Primary Ovarian Insufficiency/drug therapy* ; Humans ; Drugs, Chinese Herbal/therapeutic use* ; Animals ; Rats ; Molecular Docking Simulation ; Signal Transduction ; Sitosterols/therapeutic use* ; Kaempferols/therapeutic use*

The NOD-like receptor protein 3 (NLRP3) inflammasome is essential in innate immune-mediated inflammation, with its overactivation implicated in various autoinflammatory, metabolic, and neurodegenerative diseases. Pharmacological inhibition of NLRP3 offers a promising treatment strategy for inflammatory conditions, although no medications targeting the NLRP3 inflammasome are currently available. This study demonstrates that clioquinol (CQ), a clinical drug with chelating properties, effectively inhibits NLRP3 activation, resulting in reduced cytokine secretion and cell pyroptosis in both human and mouse macrophages, with a half maximal inhibitory concentration (IC₅₀) of 0.478 μM. Additionally, CQ mitigates experimental acute peritonitis, gouty arthritis, sepsis, and colitis by lowering serum levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α). Mechanistically, CQ covalently binds to Arginine 335 (R335) in the NACHT domain, inhibiting NLRP3 inflammasome assembly and blocking the interaction between NLRP3 and its component protein. Collectively, this study identifies CQ as an effective natural NLRP3 inhibitor and a potential therapeutic agent for NLRP3-driven diseases.

ObjectiveTo investigate the epidemiological characteristics of hand, foot, and mouth disease (HFMD) in Baoshan District of Shanghai from 2008 to 2023, and to provide scientific evidence for surveillance and standardized management of HFMD. MethodsCase data for HFMD reported in the China Disease Control and Prevention Information System from 2008 to 2023 were collected. Descriptive epidemiological methods were used to analyze the population characteristics, and the Joinpoint regression models were applied to assess the temporal trends of HFMD in Baoshan District. ResultsA total of 43 853 HFMD cases were reported from 2008 to 2023 in Baoshan District, with a male-to-female ratio of 1.50∶1. The majority of cases were children, among which scattered children and preschool children accounted for 54.67% and 36.58%, respectively, with 88.00% occurring in children under 5 years old. The average annual incidence rate was147.22/100 000 individuals. The pathogen detection rate in 2018 was 58.60% (109/186). Prior to 2020, CoxA16 was the predominant strain, while EV71 was not detected after 2019. ConclusionThe incidence of HFMD in Baoshan District of Shanghai was influenced by multiple factors including the inclusion in the notifiable infectious disease surveillance system, the introduction of EV71 vaccination, and the COVID-19 pandemic timeline. Populations characterized by highly mobility and frequent external contacts were at high risk for HFMD in Baoshan District. The predominant circulating strains had shifted sequentially from EV71 and CoxA16 to CoxA6.

The NOD-like receptor protein 3(NLRP3)inflammasome is essential in innate immune-mediated inflammation,with its overactivation implicated in various autoinflammatory,metabolic,and neurode-generative diseases.Pharmacological inhibition of NLRP3 offers a promising treatment strategy for in-flammatory conditions,although no medications targeting the NLRP3 inflammasome are currently available.This study demonstrates that clioquinol(CQ),a clinical drug with chelating properties,effec-tively inhibits NLRP3 activation,resulting in reduced cytokine secretion and cell pyroptosis in both human and mouse macrophages,with a half maximal inhibitory concentration(IC50)of 0.478 μM.Additionally,CQ mitigates experimental acute peritonitis,gouty arthritis,sepsis,and colitis by lowering serum levels of interleukin-1β(IL-1β),IL-6,and tumor necrosis factor-α(TNF-α).Mechanistically,CQ covalently binds to Arginine 335(R335)in the NACHT domain,inhibiting NLRP3 inflammasome assembly and blocking the interaction between NLRP3 and its component protein.Collectively,this study identifies CQ as an effective natural NLRP3 inhibitor and a potential therapeutic agent for NLRP3-driven diseases.

Objective To assess the efficacy and safety of Tiaozhou Ziyin(TZZY)recipe for treatment of premature ovarian insufficiency(POI)and explore the possible mechanisms.Methods We used bioinformatics analyses and network pharmacology to identify the main active ingredients in TZZY recipe and their core targets,which were verified by Western blotting.We tested the efficacy and safety of the recipe in 60 POI patients,who were randomized into control group(n=30)with Femoston treatment and TZZY group(n=30)with additional TZZY recipe treatment for 3 menstrual cycles.Results The core active ingredients of TZZY recipe included kaempferol,β-sitosterol,luteolin,and quercetin.The core targets included SRC,TP53,STAT3,PIK3CA,and MAPK3,which were involved in positive regulation of cell movement and protein phosphorylation,the cancer pathways and the PI3K-Akt signaling pathway.Molecular docking showed that the core active ingredients had good binding ability with the core targets.In female rat models of POI,TZZY recipe treatment significantly up-regulated ovarian expressions of p-PI3K and p-Akt proteins.In the clinical trial,treatment with Femoston and Femoston plus TZZY recipe both significantly increased E2 levels and reduced FSH and LH levels and Kupperman scores of the patients,and the combined treatment produced significantly stronger effects.Both treatments increased the number of antral follicles of the patients,but the combined treatment also significantly increased the levels of AMH.Conclusion The therapeutic mechanism of TZZY recipe for POI involves multiple active ingredients,multiple therapeutic targets and multiple pathways,and activating the PI3K/Akt pathway is one of its main mechanisms of action,to improve ovarian reserve function,alleviate clinical symptoms,and enhance clinical efficacy in POI patients.

Neuropathic pain(NPP)is a recurrent and intractable pain syndrome,and microglial polarization is closely related to it.Recent studies have shown that after cell polarization,M1 pro-inflammatory and M2 anti-inflammatory types could be formed,and M1 and M2 microglial cells are involved in NPP through the modulation of inflammatory responses.The two types of microglial cells have different roles in NPP,just like a double-edged sword.M1 pro-inflammatory type plays an injurious role in NPP through the release of pro-inflammatory factors and noxious substances,whereas M2 anti-inflammatory type plays a protective role by secreting anti-inflammatory factors.In this article,the role of microglia polarization on NPP are reviewed.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

ObjectiveTo explore the clinical efficacy of Dingkundan in the treatment of ovulation disorder infertility based on the real world and provide reliable evidence-based medical support for clinical practice. MethodClinical diagnosis and treatment data of patients with ovulation disorder infertility in the real world were collected through the Medroad Cloud system. Patients were grouped according to their real-world treatments， and the total effective rate， ovulation rate per cycle， number of days of follicle development， gonadotropin （Gn） dosage， levels of mature follicle-related hormones， endometrial thickness and classification， pregnancy rate per cycle， clinical pregnancy rate， ectopic pregnancy rate， and early pregnancy loss rate were observed. ResultA total of 207 patients were included， and the most common traditional Chinese medicine （TCM） syndrome in the entire population was liver depression and kidney deficiency. The patients were divided into a Chinese medicine group （Dingkundan， 60 cases）， a western medicine group （ovulation induction， 51 cases）， and a combination group （Dingkundan + ovulation induction， 96 cases）. The combination group（98.96%，95/96） had the highest total effective rate， which was statistically significant when compared with the Chinese medicine group（88.33%，53/60） （χ²=8.328， P<0.05）. The mature follicle estradiol （E₂） and luteinizing hormone （LH） levels were the highest in the combination group， and there were statistically significant differences when compared with the western medicine group （P<0.01）. The endometrial thickness was higher in the Chinese medicine group and the combination group than in the western medicine group （P<0.01）. The proportion of type A endometrium was highest in the combination group（85.90%，201/234）， and there was a statistically significant difference when compared with the western medicine group（73.81%，93/126） （χ²=7.993， P<0.01）. The clinical pregnancy rate was 60.42%（58/96） in the combination group， which was higher than 36.67%（22/60） in the Chinese medicine group （χ²=8.336， P<0.01） and 39.22%（20/51） in the western medicine group （χ²=6.011， P<0.05）. Compared with the western medicine group， the combination group showed a favorable trend in total effective rate， ovulation rate per cycle， number of days of follicle development， Gn dosage， pregnancy rate per cycle， ectopic pregnancy rate， and early pregnancy loss rate， but the differences were not statistically significant. ConclusionIn real-world clinical practice， the combination of Dingkundan with ovulation induction can increase endometrial thickness， improve the proportion of type A endometrium， enhance egg quality， and increase the clinical pregnancy rate in patients with ovulation disorder infertility. This approach deserves further clinical research and application.

Objective:To explore the application value of guide tube fenestration and drainage technology in intracranial artery stenting surgery.Methods:A total of 120 patients with symptomatic intracranial atherosclerotic stenosis admitted to the Xingtai Third Hospital from January 2021 to December 2022 were selected and randomly divided into an observation group ( n=60) and a control group ( n=60). Both groups were treated with intracranial artery stenting, with the observation group receiving guidance catheterization and window opening technique during the surgery. Two groups of surgeries were observed and compared: the degree of vascular stenosis before and after surgery, the Montreal Cognitive Assessment Scale (MoCA) scores before and one month after surgery, intraoperative complications, and prognosis. Results:The surgical time and catheter placement time in the observation group were (110.20±23.32)minutes and (11.32±2.01)minutes, respectively, which were significantly shorter than those in the control group (all P<0.05). The stent placement rate and operation success rate in the observation group were 95.00% and 96.67%, respectively, significantly higher than those in the control group (all P<0.05). The degree of postoperative vascular stenosis in the observation group was (32.29±7.11)%, significantly milder than that in the control group [(44.43±8.15)%, P<0.05]. One month after surgery, the MoCA scores of both groups improved significantly compared to before surgery (all P<0.05), and there was no statistically significant difference between the groups ( P>0.05). There was no statistically significant difference in the incidence of collateral circulation occlusion and vascular rupture between the two groups (all P>0.05). During the follow-up period, there was no statistically significant difference in the incidence of restenosis, intracranial hemorrhage, and recurrent ischemic stroke between the observation group and the control group (all P>0.05); The good prognosis rate of the observation group was 73.33%, significantly higher than that of the control group (53.33%, P<0.05). Conclusions:The application of guided catheter fenestration technique in intracranial artery stenting has good value, which is beneficial for improving the stent placement rate and operation success rate, and improving the degree of vascular stenosis.

Microemulsions are promising drug delivery systems for the oral administration of poorly water-soluble drugs. However, the evolution of microemulsions in the gastrointestinal tract is still poorly characterized, especially the structural change of microemulsions under the effect of lipase and mucus. To better understand the fate of microemulsions in the gastrointestinal tract, we applied small-angle X-ray scattering (SAXS) and fluorescence resonance energy transfer (FRET) to monitor the structural change of microemulsions under the effect of lipolysis and mucus. First, the effect of lipolysis on microemulsions was studied by SAXS, which found the generation of liquid crystalline phases. Meanwhile, FRET spectra indicated micelles with smaller particle sizes were generated during lipolysis, which could be affected by CaCl, bile salts and lecithin. Then, the effect of mucus on the structural change of lipolysed microemulsions was studied. The results of SAXS and FRET indicated that the liquid crystalline phases disappeared, and more micelles were generated. In summary, we studied the structural change of microemulsions in simulated gastrointestinal conditions by SAXS and FRET, and successfully monitored the appearance and disappearance of the liquid crystalline phases and micelles.