INTRODUCTION:Qingfudaotan Formula (QFDT) is a classical traditional Chinese medicine (TCM) compound used for polycystic ovary syndrome (PCOS), yet its underlying mechanisms remain unclear. This study aimed to elucidate the pharmacological mechanism of QFDT in alleviating PCOS. METHODS:Active ingredients and targets of QFDT, along with PCOS-associated genes, were retrieved from public databases. Protein-protein interaction (PPI) network analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were employed. Core targets and active ingredients were further validated via molecular docking. A PCOS rat model was utilized for experimental verification. RESULTS:QFDT identified 62 potential PCOS targets, with PPI analysis pinpointing 12 core targets (e.g., AKT1, NFKB1). GO/KEGG enrichment implicated insulin resistance and NF-κB pathways. Molecular docking predicted strong binding (≤-5 kcal/mol) for 5 active ingredients to 5 key targets. In PCOS rats, QFDT significantly reduced body weight and cystic follicles and restored estrous cycles. It notably lowered HOMA-IR (QFDT-H, P<0.05), upregulated ovarian P-PI3K/PI3K and P-AKT/AKT ratios (QFDT-H, P<0.05), and downregulated TLR4/MyD88/p-NFκB, alongside inflammatory markers (LPS, IL-6, TNF-α, etc., QFDT-H, P<0.05). DISCUSSION:Chronic low-grade inflammation and insulin resistance play critically important roles in the pathogenesis of PCOS. This study demonstrates that QFDT, as a traditional Chinese herbal formula, alleviates PCOS by ameliorating insulin resistance via the PI3K/AKT pathway and suppressing inflammation through the TLR4/NF-κB pathway. CONCLUSION:This study identified targets for QFDT in PCOS treatment, helping elucidate the mechanisms of action of this ingredient and its potential clinical applications.

Primary ovarian insufficiency (POI) is a major cause of female infertility and endocrine dysfunction, for which effective therapies remain limited. We investigated whether rutin, a bioactive compound from traditional Chinese medicine, protects ovarian function in POI by regulating mitochondrial homeostasis and pyroptosis. In vitro assays using chemically injured oocytes showed that rutin alleviated mitochondrial defects, rescued developmental arrest, enhanced antioxidant signaling, promoted mitophagy, and reduced inflammatory cell death. In a cyclophosphamide-induced murine POI model, rutin restored estrous cyclicity, improved follicle development, normalized hormone levels, and enhanced ovulation, litter outcome, and in vitro-fertilization (IVF)-related developmental competence. Ovarian histological and molecular analyses further showed reduced inflammasome-related pyroptotic signaling, lower oxidative stress levels, and improved mitochondrial integrity. These findings identify rutin as a promising ovarian-protective candidate in POI-associated infertility and support further investigation of its therapeutic potential in female reproductive disorders.

Laser-assisted hatching (LAH) has been reported to improve implantation and pregnancy rates, yet its efficacy and safety profile require rigorous evaluation. To assess the impact of LAH on pregnancy-related outcomes and safety metrics within Assisted Reproductive Technologies (ART) procedures, we conducted a systematic review and meta-analysis. Electronic databases were searched from inception to November 30, 2023. Studies, comparing LAH with other hatching methods or no intervention within ART frameworks, were included. The quality of the included studies was rigorously evaluated using the Risk of Bias In Non-randomized Studies-of Interventions (ROBINS-I) tool with a Weighted Cohen’s kappa coefficient (κ). Summative data, subgroup analyses, and evaluation of heterogeneity were analyzed via Stata 15. 47 eligible studies were included, covering 24,876 couples. When comparing the effectiveness of LAH to other methods or no intervention, the results revealed enhancements in implantation and clinical pregnancy rates. For implantation rates, the pooled effect size showed an OR of 1.22 (95

Background: Recurrent miscarriage (RM), a most common fertility disorder, has plagued us for hundreds of years. The etiology of RM is complex and often remains unexplained. Recent studies suggest mitophagy, as a potential factor in RM. Methods: This study utilized two Gene Expression Omnibus (GEO) datasets (GSE22490 and GSE165004) to identify differential genes associated with RM. By intersecting these genes with autophagy-associated genes, we identified 20 key genes linked to RM. We analyzed their expression and location on chromosomes, their correlation in RM, and their impact on early RM diagnosis through a diagnostic model. Protein-protein interaction (PPI) networks, ceRNA networks, and transcription factor (TF) regulatory networks were constructed, followed by Gene Ontology/Kyoto Encyclopedia of Genes and Genomes (GO/KEGG) functional enrichment analysis and Gene Set Enrichment Analysis (GSEA). The study also assessed the association of these genes with immune cell infiltration in endometrial tissue using single sample GSEA (ssGSEA). The CBA/J × DBA/2 mating method was used to establish an RM model and western blotting was used to detect the expression of BCl-2, BNIP3, VPS37A, PINK1, Parkin proteins in the decidua. Results: The study identified 20 mitophagy-related genes associated with RM. These genes were found to be differentially expressed in RM cases and involved in various biological processes and pathways. The constructed diagnostic model demonstrated significant predictive capability for RM. The PPI, mRNA-miRNA, and mRNA-TF networks revealed intricate molecular interactions. Immune infiltration analysis showed distinct immune cell profiles in RM patients. In comparison to control tissues, the protein level of VPS37A in the RM group was significantly increased, whereas the levels of BCl-2, BNIP3, PINK1, and Parkin were lower than those observed in normal decidua tissues. Conclusion: This study highlights the importance of mitophagy-related genes in the pathogenesis of RM and their potential as diagnostic markers. The findings provide a new perspective on the molecular mechanisms of RM, offering insights for future research and potential therapeutic targets.

Introduction:The journey of assisted reproductive technology (ART) for couples facing recurrent implantation failure (RIF) is fraught with emotional and physical challenges. RIF, often characterized by the failure of high-quality embryos to implant after multiple ART cycles, has directed attention towards interventions like laser-assisted hatching (LAH). However, discrepancies in the literature necessitate a comprehensive review of LAH's efficacy and safety. Materials and methods:Following a thorough search of PubMed, Embase, Cochrane, and Web of Science databases up to November 2023, retrospective studies or RCT were considered for inclusion. Summary effect sizes [odds ratio (OR) or risk ratio (RR) with 95% confidence interval (CI)] were calculated for each outcome. Results and conclusion:Eight studies comprising 2,634 patients were included. LAH significantly improved implantation rates (OR: 1.26, 95% CI: 1.05-1.51). Clinical pregnancy rates increased in patients who had fresh embryos transferred (OR: 1.29, 95% CI: 1.05-1.58). Notably, LAH was associated with higher miscarriage rates in frozen embryo transfers (OR: 1.45, 95% CI: 1.04-2.02). No significant increase in ectopic or multiple pregnancy rates was observed. For patients with RIF, especially older women, LAH presents a potential avenue to improve implantation. Its impact on clinical pregnancy rates is less substantial. However, its impact on final live birth rates and the increased miscarriage risk in frozen transfers necessitate a cautious and individualized approach. The technique's safety, while generally upheld, requires careful application and consideration of the specific challenges RIF patients face. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024497329, PROSPERO (CRD42024497329).

OBJECTIVE:The phase 2, open-label, randomized, 3-arm study (NCT03776812) found that intermittently dosed relacorilant + nab-paclitaxel improved progression-free survival, duration of response, and overall survival compared with nab-paclitaxel monotherapy with minimal additional toxicity. This study analyzed the cost-effectiveness of intermittent relacorilant + nab-paclitaxel (IN), continuous relacorilant + nab-paclitaxel (CN) and nab-paclitaxel monotherapy (N) from the payer's perspective over a 5-year time horizon. METHODS:The health outcome is expressed in quality-adjusted life years (QALYs). IN, CN and N were evaluated using QALYs and incremental cost-effectiveness ratio (ICER). The data for this model come from the NCT03776812 trial and other published literature. The impact of the variables is studied using a one-way deterministic sensitivity analysis and a probabilistic sensitivity analysis based on a second-order Monte Carlo simulation. RESULTS:N was the least costly strategy, at $ 4606.05, followed by IN ($22,597.75) and CN ($44,276.86). Based on a willingness-to-pay threshold of $100,000/QALY, IN was cost-effective compared with N, with an ICER of $21,418.69 per QALY gained for N, whereas CN was ruled out by extended dominance (less effective, more costly), compared with N. The incremental benefits of IN compared to CN and N were 0.72 QALYs and 0.84 QALYs. CONCLUSION:From a US health care system perspective, IN may be cost-effective compared to CN for patients with recurrent platinum-resistant ovarian cancer, and IN is also better than CN and N in terms of efficacy. Therefore, IN is a high-quality regimen for clinicians to treat patients with recurrent platinum-resistant ovarian cancer. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03776812.

Breast cancer is one of the tumors with the highest prevalence rate among women in the world, and its BRCA1/2 gene is a common mutation site. Talazoparib, as a targeted PARP inhibitor, can effectively control the occurrence and development of breast cancer with BRCA1/2 gene mutation, and play a therapeutic role. Based on the findings from the Phase III EMBRACE trial (NCT01945775 clinical trial), our analysis reveals that the talazoparib group demonstrated a significant extension in progression-free survival, along with improved response markers and patient-reported outcomes when compared to conventional therapies. This study aims to assess the cost-effectiveness of talazoparib for treating advanced breast cancer with germline BRCA1/2 mutations and HER2 negativity, considering the perspectives of health services in China and the United States. The results obtained will serve as a valuable reference for promoting rational drug utilization and enhancing medical resource efficiency. To evaluate the cost-effectiveness of Talazoparib more scientifically and provide clinicians with chemotherapy options, this paper developed a Markov model based on the EMBRACA clinical trial (clinical Trails.gov No., NCT01945775) to simulate the survival events of breast cancer patients in the Talazoparib group and the standard treatment group. The state transition probability and clinical data of breast cancer patients during treatment were extracted from the phase III EMBRACA clinical trial. The cost data generated during the treatment process comes from local hospital pricing, other references, and expert consultation. This article uses US dollars to calculate the treatment cost and incremental cost-effectiveness ratio. Health outcomes are expressed in Quality Adjusted Life Years (QALYs). In addition, Outcomes were measured in quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio, which robustness was evaluated by deterministic and probabilistic sensitivity analyses. This article establishes a Markov model for single-item sensitivity analysis. The results show that the economic benefits of using Talazoparib as a new treatment strategy in both China and the United States are higher than other drugs, and it is cost-effective. Compared to the control group, the incremental cost incurred by the Talazoparib treatment group in China was $2484.48/QALY, with an incremental QALY of 1.5. However, Talazoparib in the United States holds a dominant position, saving costs of $10,223.43 and increasing QALYs by 1.5. The clinical treatment effect of Talazoparib group in BRCA1/2 mutant advanced breast cancer patients is better than that of the standard treatment group, and the progression free survival period is significantly prolonged. From the perspective of medical and health services in China and the United States, the Talazoparib group is more economical than the standard treatment group in treating patients with BRCA1/2 mutant advanced breast cancer.

Breast cancer (BC) is a major malignant tumor in females and the incidence rate of BC has increased worldwide in recent years. N6‑methyladenosine (m6A) is a methylation modification that occurs extensively in eukaryotic RNA. The abnormal expression of m6A and related regulatory proteins can activate or inhibit certain signal pathways or oncogenes, thus affecting the proliferation, metastasis and prognosis of BC. Numerous studies have shown that m6A regulator disorder exists in BC, and this disorder can be reversed. Therefore, m6A is predicted as a potential therapeutic target for BC. However, the molecular mechanism of m6A RNA methylation regulating the occurrence and development of BC has not been comprehensively elucidated. In this review article, the functions of various m6A regulators and the specific mechanisms of certain regulators of the progress of BC were summarized. Furthermore, the dual role of RNA methylation in tumor progression was discussed, concluding that RNA methylation can not only lead to tumorigenesis but at times give rise to inhibition of tumor formation. In addition, further comprehensive analysis on mechanisms of m6A regulators in BC is conducive to screening effective potential targets and formulating targeted treatment strategies, which will provide new methods for the prevention and treatment of BC.

Objective and Design: Asthma is becoming an inflammatory disease of the airways involving a variety of inflammatory cells and cell components.In this study,we attempted to investigate the protective effect and underlying mechanism potential of a plant derived natural compound,1,8-cineol.Transforming growth factor-beta TGF-β1-induced epithelial-mesenchymal transition (EMT) in bronchial epithelial cells contributes to airway wall remodeling in asthma. Epithelial-mesenchymal transition (EMT) represents an important source of myofibroblasts, contributing to airway remodelling. This study aims to explore the detailed mechanism in TGF-β1-stimulated BEAS-2B cells by which 1,8-cineol might exert effects on the development of asthma. Here, we investigated the role of 1,8-cineol,an active ingredient in Eucalyptus globulus Labill,in TGF-β1-induced EMT in bronchial epithelial cells and to elucidate the possible mechanisms underlying its biological effects. Material: We used a murine model of airway hyperreactivity, which mimicked some of the characteristic features of asthma. Male BALB/c mice (6–8 weeks) were used for this study. BEAS-2B cells were used to assess the effect of 1,8-cineol on EMT and its interaction with TGF-β1 signalling. To assess the role of 1,8-cineol in vivo and its impact on lung function. Methods: OVA-induced asthma and PSA model were used to evaluate the effect of 1,8-cineol in vivo.Lung tissues were collected for H&E and PAS staining. ELISA was used to determine level of IgE and chemokines (IL-4, IL-13, and IL-17). Nuclear factor-κB (NF-κB) and cyclooxygenase-2 (COX-2) signaling pathway were assessed. Human bronchial epithelial cells (BEAS-2B) were treated with different concentrations (1,10,and 100 mg/L,30 min) of 1,8-cineol to select its suitable concentration. A human bronchial epithelial cell line were incubated with transforming growth factor-beta (TGF-β) to induce EMT, whose phenotype of cells were evaluated by the expressions of EMT markers [alpha-smooth muscle actin (α-SMA), E-cadherin, and N-cadherin] and cell migration capacity. Results:In asthmatic model mice, 1,8-cineol treatment relieved airway wall remodeling and decreased expressions of EMT markers (α-SMA and N-cadherin). In TGF-β-treated bronchial epithelial cells, 1,8-cineol treatment decreased the mRNA and protein levels of EMT markers (α-SMA and N-cadherin) without impairing cell viability.Our results showed that OVA induction resulted in a significant increase in RL, accompanied by a significant decrease in Cdyn.Various inflammatory cells such as eosinophils and lymphocytes were infiltrated and aggregated around the airway of mice in OVA group.1,8-cineol and BAY-11-7083 can improve the pathological changes of airway smooth muscle spasm and lumen stenosis. Compared with Control group, OVA specific antibody IgE content in serum in other groups was up-regulated. The levels of interleukin- IL-4, IL-13,OVA-specific IgE in BALF, and the percentage of IL-17 in the lungs were markedly increased.Furthermore,the expression of NF-κB p-P65,NF-κB P65 and COX-2 in airways were significantly upregulated.Protein expression of N-cadherin,COX-2,NF-κB p-P65/NF-κB P65 was up-regulated in TGF-β1 group compared with Control group. Conclusion:Our study showed that 1,8-cineol inhibited TGF-β1-induced EMT in bronchial epithelial cells and found that the anti-EMT activity of 1,8-cineol might be related to its regulatory effect on NF-κB/COX-2 pathway.

Abstract Objective：To compare the cost-effectiveness of Metronomic Oral Vinorelbine plus Cyclophosphamide and Capecitabine(VEX) and Weekly Intravenous Paclitaxel (P) in patients with Estrogen Receptor–Positive, ERBB2-Negative Metastatic Breast Cancer (MBC). Methods：The Markov model was established to simulate the patients receiving metronomic chemotherapy (VEX regimen) and Weekly Intravenous Paclitaxel. The results of clinical trials and other published literature were comprehensively used to evaluate the cost-effectiveness ratio of the two chemotherapy regimens, and sensitivity analyses were conducted. Results：The QALYs of VEX and P regimen were 1.85 and 1.45, respectively, and the ICERs were $40 333.69/QALY and $4 152.09/QALY, respectively. In China, the total cost of VEX regimen is $74 617.32, while the total cost of P regimen is $6 020.53. The cost of P regimen is much lower than that of the VEX regimen. In addition, the VEX is more effective than the P, with higher TTF and PFS, and higher disease control rates. Sensitivity analysis shows that P regimen has a more cost-effective advantage in China. The analysis of incremental cost-effectiveness shows that with VEX as the reference group, P regimen is the preferred option. Conclusions：Compared with VEX, P regimen is more cost-effective as a first-line treatment for ER+/HER2- metastatic breast cancer from the perspective of Chinese health service system.

ETHNOPHARMACOLOGICAL RELEVANCE:Jianpi Antai Formula (JAF) is an ancient formula from He's gynecology, which has been used clinically for more than 30 years and has significant therapeutic effects on spontaneous abortion (SA). Both macrophage polarization and NLRP3 inflammasome correlate with the occurrence of SA in women with recurrent or threatened miscarriage. Whether JAF prevent SA via mediating activation of decidual macrophage (dMφ) and ubiquitination-associated degradation of NLRP3 remains uncertain. AIM OF THE STUDY:This study aimed to clarify the effects of JAF on pregnancy outcomes and dMφ polarization at the maternal-fetal interface in an SA mouse model, and use in vivo and invitro methods to explore whether JAF can inhibit M1 polarization of dMφ by up-regulating MARCH7-mediated NLRP3 ubiquitination, thereby preventing SA. MATERIALS AND METHODS:The CBA/J × DBA/2 mating method was used to establish an SA model and the dMφs of SA mice were isolated and cultured. Th1-, Th2-, Th17- and Treg-related cytokine levels were evaluated using ELISA. qRT-PCR was used to detect the levels of M1/M2 macrophage-related cytokine mRNA in the decidua, and western blotting was used to detect the expression of NLRP3 inflammasome-related proteins in the decidua and placenta. The expression of M1/M2 markers of dMφ was detected using flow cytometry, ASC speck formation was observed using immunofluorescence, and the ubiquitination level of MARCH7-NLRP3 was detected using co-immunoprecipitation. RESULTS:JAF increased the survival rate of fetuses and the levels of estradiol and progesterone in SA model mice. It also reduced the serum Th1 and Th17-associated cytokine levels and decidual M1 macrophage-associated cytokine levels, while elevating the M2 macrophages in SA mice. NLRP3, caspase-1, ASC, and IL-1β protein expression in the decidua and placenta were also reduced. si-MARCH7 transfection reversed the effect of JAF on inhibiting the formation of the NLRP3 inflammasome and the activation of macrophages in dMφs of SA mice. CONCLUSION:JAF could effectively prevent and treat SA by repressing M1 polarization of dMφs through NLRP3 ubiquitination and pyroptosis inhibition, which were mediated by MARCH7.

Prostate cancer (PCa) affects males of all racial and ethnic groups, and leads to higher rates of mortality in those belonging to a lower socioeconomic status due to the late detection of the disease. PCa affects middle-aged males between the ages of 45 and 60 years, and is the highest cause of cancer-associated mortality in Western countries. As the most abundant and common mRNA modification in higher eukaryotes, N-6-methyladenosine (m(6)A) is widely distributed in mammalian cells and influences various aspects of mRNA metabolism. Recent studies have found that abnormal expression levels of various m(6)A regulators significantly affect the development and progression of various types of cancer, including PCa. The present review discusses the influence of m(6)A regulatory factors on the pathogenesis and progression of PCa through mRNA modification based on the current state of research on m(6)A methylation modification in PCa. It is considered that the treatment of PCa with micro-molecular drugs that target the epigenetics of the m(6)A regulator to correct abnormal m(6)A modifications is a direction for future research into current diagnostic and therapeutic approaches for PCa.

Background: Breast cancer is one of the most common malignant tumors in women. Human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer has poor prognosis and short survival period. EMILIA was a global phase III study to evaluate the efficacy of Trastuzumab emtansine (T-DM1) and Capecitabine plus lapatinib. However, the cost-effectiveness of T-DM1 is still unclear. Therefore, the objective of this study was to evaluate the cost-effectiveness of T-DM1 and Capecitabine plus lapatinib in treating HER2-positive advanced breast cancer within 5 years from the perspective of Chinese payers. Methods: A half cycle adjusted Markov model was established to simulate the process of health status transfer and death of breast cancer patients under the treatment of T and CL schemes, so as to evaluate the cumulative lifetime costs, incremental cost-benefit ratio (ICER), and quality adjusted life year (QALY) of Chinese patients. The parameters of the input model were from the EMILIA Phase III study. In order to determine the stability of the model, we also conducted single factor sensitivity analysis and probability sensitivity analysis. Results: Markov model analysis results showed that compared with Capecitabine plus lapatinib, T-DM1 treatment generates an additional 0.4QALY and an incremental cost of $12282.97. The ICER of T versus CL was $30707.405/QALY and did not exceed Chinese willingness-to-pay (WTP) threshold. Conclusions: Compared with Capecitabine plus lapatinib, T-DM1 treatment can bring better health benefits to patients with breast cancer and is likely to be cost-effective second-line therapies for HER2-positive breast cancer in China.

OBJECTIVES:To investigate the effect of Chinese medicine He's Yangchao recipe on premature ovarian insufficiency (POI) and its relationship with mitochondrial function of ovarian granulose cells in an animal model. METHODS:Thirty-six female C57BL/6J mice were randomly divided into blank control group, model group, low-, medium- and high-dose He's Yangchao recipe treatment group and coenzyme Q10 (Q10) treatment group (positive control). The POI model was induced by a single intraperitoneal injection of cyclophosphamide (90 mg/kg). The animals were sacrificed after 21 days. Primary granulose cells were obtained from POI mice and treated with He's Yangchao recipe, ERβ inhibitor PHTPP, and He's Yangchao recipe+PHTPP in vitro for 24 h, respectively. Ovarian histopathological changes were observed by hematoxylin-eosin (HE) staining, ATP levels were detected by luciferase assay, mtDNA copy numbers were detected by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), mitochondrial structure changes were observed by transmission electron microscopy, protein and mRNA expression levels of estrogen receptor β (ERβ), peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), mitochondrial transcription factor A (TFAM), and superoxide dismutase 2 (SOD2) were detected by Western blotting and qRT-PCR. RESULTS:The ovarian tissue in model group exhibited few secondary and tertiary follicles, whereas the He's Yangchao recipe groups and Q10 group had abundant secondary and tertiary follicles. Compared with the blank control group, ATP and mtDNA levels in model group decreased (P<0.01), mitochondrial crista disappeared or abnormal vacuolated structure increased; the protein and mRNA levels of ERβ, PGC1α, TFAM, and SOD2 decreased (all P<0.01). ATP production increased in granulose cells of high-dose He's Yangchao recipe group and Q10 group; mtDNA copy numbers increased (P<0.05 or P<0.01); abnormal mitochondrial structure was reduced; the protein and mRNA expressions of ERβ, PGC1α, TFAM, and SOD2 increased (P<0.05 or P<0.01). Compared with the PHTPP intervention group, the proportion of normal mitochondrial structure in the granulose cells of He's Yangchao recipe + PHTPP group was higher; ATP content increased (P<0.05 or P<0.01); mtDNA copy numbers increased (P<0.05 or P<0.01); the protein and mRNA expression of ERβ, PGC1α, TFAM and SOD2 increased (P<0.05 or P<0.01). CONCLUSIONS:He's Yangchao recipe can regulate mitochondrial biogenesis through ERβ/PGC1α/TFAM pathway to improve ovarian function in POI mice.

Background Primary ovarian insufficiency (POI) is a common gynecological disease with serious ramifications including low pregnancy rate and low estrogen symptoms. Traditional Chinese medicine is regarded as an effective treatment for POI. However, the therapeutic mechanism of it is unclear. Methods In this study, a mouse model of primary ovarian insufficiency was established by intraperitoneal injection of cyclophosphamide (CTX) and He’s Yang Chao Recipe (HSYC) concentrate was used for intragastric administration. Serum hormone levels (Anti-Müllerian Hormone, Estradiol, Progesterone, Luteinizing Hormone and Follicle Stimulating Hormone) and Oxidative Stress (OS) related products, superoxide dismutase (SOD), GSH-Px, and malondialdehyde (MDA) were measured by enzyme-linked immunosorbent assay. Pathological changes in ovarian tissue were evaluated by hematoxylin and eosin staining, and flow cytometry was used to determine reactive oxygen species content and mitochondrial membrane potential levels in granulosa cells. Mitochondrial distribution and morphology were investigated using immunofluorescence staining. The level of mitophagy was evaluated by LC3 immunofluorescence staining and autophagosome counts using electron microscopy. Western blotting and qPCR were used to detect the expression of proteins and genes related to mitophagy and the NLRP3 inflammasome. Results After HSYC treatment, the ovarian damage was milder than in the CTX group. Compared with the CTX group; SOD, GSH-Px, and the total antioxidant capacity were significantly increased, while MDA and ROS were decreased in the HSYC treatment groups. Furthermore, mitochondrial distribution and membrane potential levels were improved after HSYC treatment compared to the CTX group. After the HSYC treatment, the LC3 fluorescent intensity and autophagosome counts were decreased. Similarly, mitophagy related markers PINK1, Parkin, LC3, and Beclin1 were decreased, while p62 was significantly increased, compared with the CTX groups. The mRNA and protein expression of NLRP3 inflammasome, NLRP3, caspase-1, GSDMD, IL-18, and IL-1β were significantly decreased in the HSYC treatment groups. Conclusion This is the first study in molecular mechanisms underlying HSYC against granulosa cell injury in POI. HSYC protects ovaries from CTX-induced ovarian damage and oxidative stress. HSYC enhanced ovarian function in mice with primary ovarian insufficiency by inhibiting PINK1-Parkin mitophagy and NLRP3 inflammasome activation.

Objectives: The ketogenic diet (KD) is recommended to improve polycystic ovary syndrome (PCOS); however, its mechanisms of action are unclear. We aimed to study the effects and mechanisms of action of the KD on the gut microbiome and metabolites in PCOS rats and determine whether the sex hormone regulatory effects are related to modulations of the gut microbiota and metabolites.Methods: PCOS was induced with a high-fat diet and letrozole in the rats. A KD was fed to rats for 8 wk, serum samples were collected for biochemical analysis, and the rats' fecal samples were subjected to 16S ribosomal RNA sequencing and metabolomic analysis.Results: Feeding with a KD for 8 wk suppressed body weight gain, decreased luteinizing hormone and andro-gen levels, and improved insulin levels. Furthermore, the KD reversed the dysregulation of the gut microbiota in PCOS rats by adjusting the ratio of firmicutes and bacteroidetes. Also, the KD was involved in hormonal metabolic pathways by reducing the levels of some metabolites (such as testosterone and 7a-hydroxytestos-terone) that are closely related to gut microbes.Conclusions: The KD improved the clinical phenotype and insulin resistance in PCOS rats and altered the com-position of the gut microbiome and metabolites, which were associated with androgen metabolism, repre-senting a potential mechanism for mediating the effects of the KD on sex hormone metabolism in PCOS. However, our study found contradictory effects of KD on the gut microbiome in PCOS, which need further research.& COPY; 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Purpose: The aim of this study is to examine, using network pharmacology analysis and experimental validation, the pharmacological processes by which Yulin Formula (YLF) reduces cyclophosphamide-induced diminished ovarian reserve (DOR). Methods: First, information about the active components, associated targets, and related genes of YLF and DOR was gathered from open-access databases. The primary targets and pathways of YLF to reduce DOR were predicted using studies of functional enrichment from the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Protein-Protein Interaction (PPI) networks. Second, we built a cyclophosphamide-induced diminished ovarian reserve (DOR) rat model to verify the primary target proteins implicated in the predicted signaling pathway to explore the mechanism of improve ovarian function of YLF. Results: 98 targets met the targets of the 82 active ingredients in YLF and DOR after searching the intersection of the active ingredient targets and DOR targets. Fourteen targets, including AKT and Caspase-3 among others, were hub targets, according to the PPI network study. The PI3K/AKT pathway was revealed to be enriched by numerous targets by the GO and KEGG enrichment studies, and it was used as a target for in vivo validation. Animal studies showed that YLF administration not only reduced the number of atretic follicles, the proportion of TUNEL-positive ovarian cells, the rate of apoptosis of granulosa cells (GCs) and the proportion of abnormal mitochondria in DOR rats, but also reversed the high expression of Caspase-3, Caspase-9, BAX, cytochrome C, PI3K and P-AKT, improving the ovarian reserve in cyclophosphamide (CTX)-induced DOR rats. Conclusion: Our research results predicted the active ingredients and potential targets of YLF-interfering DOR by an integrated network pharmacology approach, and experimentally validated some key target proteins participated in the predicted signaling pathway. A more comprehensive understanding of the pharmacological mechanism of YLF for DOR treatment was obtained.

Background:Breast cancer (BC) is one of the most common malignant tumors in women. In addition, human epidermal growth factor receptor 2-positive (HER2+) BC is overexpressed in 25% of BC patients, resulting in the predicament of poor prognosis. Although first- and second-line treatments have been established, optimum third-line treatment is still mired in controversies for HER2+ metastatic BC (mBC). Therefore, this study analyzes the cost-effectiveness of neratinib plus capecitabine (N+C) and lapatinib plus capecitabine (L+C) over a 5-year time horizon from a payer perspective.Methods:A half-cycle corrected four-state Markov model was established to simulate the course of BC events and deaths in N+C and L+C armed patients. The data of this model were derived from NCT01808573 trail and other published literatures. One-way deterministic sensitivity analysis (DSA) was conducted to investigate the impact of variables and probabilistic sensitivity analysis (PSA) was performed based on second-order Monte Carlo simulation. In addition, subgroup analysis was performed to verify its cost-effectiveness in China.Result:The base-case results found that N+C was in dominant position in 82.70% of the generation scenarios, providing an improvement of 0.17 quality-adjusted life-years (QALYs) and a reduction of $1,861.28 compared with L+C. The ICER was $-1,3294.86/QALY, which did not exceed the willingness to pay (WTP) threshold, while in subgroup, the ICER decreased to $-2,448.17/QALY.Conclusion:This analysis indicated that the combination of neratinib plus capecitabine is likely to be cost-effective in comparison with lapatinib plus capecitabine in patients with HER2+ mBC who continues to progress during or after second-line HER2-targeted therapy. So neratinib plus capecitabine can become a third-line treatment option.

Abstract Background and objective The third-generation EGFR-TKIs are used in the treatment of non-small cell lung cancer. But its efficacy and safety are still unknown. This meta-analysis was conducted to evaluate the efficacy and safety of the third-generation EGFR-TKIs in randomized controlled trials (RCTs). Methods We searched PubMed, EMBASE, Cochrane Library, and Web of Science for studies in terms of the efficacy and safety of third-generation EGFR-TKIs in patients with non-small cell lung cancer. Meta-analysis was performed using RevMan5.4 and the odds ratio (OR) or the risk ratio (RR) or the weighted mean difference (WMD) with 95% confidence interval (95%CI) of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), treatment-related adverse events (TRAEs), and TRAEs ≥ 3 reported in the literature. Results Six articles and a total of 1968 patients were finally included in this analysis. The PFS, ORR, DCR of the treatment group were significantly higher than that of the control group. The TRAEs ≥ 3 of the treatment group were significantly lower than that of the control group. Nonetheless it is no significant difference in TRAEs among these trials. Conclusion The third-generation EGFR-TKIs is effective and safe in the treatment of patients with NSCLC. Although the number of articles included in this article is limited, according to the search results, a large number of relevant trials are ongoing. Therefore, we look forward to the results of related trials, so that the third-generation EGFR-TKIs can be widely used and cure more patients.

Abstract Background Although antibody-drug conjugate (ADC) fosters hope for the treatment of cancer, the effect of single drug treatment is limited. Therefore, to achieve wider therapeutic effects, the combination of ADC and Immune checkpoint inhibitors (ICI) therapy may hold potential. Methods After literature retrieval, screening and data extraction, quality assessment was done by two investigators. Then, overall response rate (ORR) and adverse effects (AEs) were evaluated to study its efficiency and safety. Publication bias was also calculated through Funnel plot, Begg's Test and Egger's test. Meanwhile, heterogeneity was investigated through subgroup and sensitivity analysis. Results 11 eligible clinical studies with a total sample size of 551 were included. The pooled ORR was 59% (95% CI: 45% − 72%), especially in patients with relapsed classical Hodgkin lymphoma and patient treated with Brentuximab vedotin + Pembrolizumab. The most common AEs was peripheral neuropathy (38.2%) and AEs on skin (13.1% − 18.5%) and digestive system (8.7% − 28.1%) can not be overlooked. Conclusion ADC + ICI therapy may be recommended in cancer treatment, whereas strategies to manage toxicities warranted further exploration (PROSPERO CRD42023375601).