Hormonal influence: unraveling the impact of sex hormones on vascular smooth muscle cells.

Sex hormones play a pivotal role as endocrine hormones that exert profound effects on the biological characteristics and vascular function of vascular smooth muscle cells (VSMCs). By modulating intracellular signaling pathways, activating nuclear receptors, and regulating gene expression, sex hormones intricately influence the morphology, function, and physiological state of VSMCs, thereby impacting the biological properties of vascular contraction, relaxation, and growth. Increasing evidence suggests that abnormal phenotypic changes in VSMCs contribute to the initiation of vascular diseases, including atherosclerosis. Therefore, understanding the factors governing phenotypic alterations in VSMCs and elucidating the underlying mechanisms can provide crucial insights for refining interventions targeted at vascular diseases. Additionally, the varying levels of different types of sex hormones in the human body, influenced by sex and age, may also affect the phenotypic conversion of VSMCs. This review aims to explore the influence of sex hormones on the phenotypic switching of VSMCs and the development of associated vascular diseases in the human body.

Ferredoxin 1 regulates granulosa cell apoptosis and autophagy in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), a common reproductive endocrine disorder in women of reproductive age, causes anovulatory infertility. Increased apoptosis of granulosa cells has been identified as one of the key factors contributing to abnormal follicular development. Ferredoxin 1 (FDX1) encodes a small ferredoxin that is involved in the reduction in mitochondrial cytochromes and the synthesis of various steroid hormones and has the potential to influence the function of granulosa cells. In the present study, we aimed to determine the relationship between FDX1 and follicular granulosa cell function. To this end, we investigated the difference between FDX1 expression in the granulosa cells of 50 patients with PCOS and that of the controls. Furthermore, we sought to elucidate the role and mechanism of FDX1 in PCOS granulosa cells by establishing a mouse PCOS model with dehydroepiandrosterone and KGN (a steroidogenic human granulosa cell-like tumor cell line). The results indicated significant up-regulation of FDX1 in the granulosa cells after androgen stimulation. Knockdown of FDX1 promoted the proliferation of KGN and inhibited apoptosis. Moreover, FDX1 could regulate autophagy by influencing the autophagy proteins ATG3 and ATG7. Our results demonstrated that FDX1 plays a critical role in female folliculogenesis by mediating apoptosis, autophagy, and proliferation. Therefore, FDX1 may be a potential prognostic factor for female infertility.

The utilization of nanotechnology in the female reproductive system and related disorders.

The health of the reproductive system is intricately linked to female fertility and quality of life. There has been a growing prevalence of reproductive system disorders among women, particularly in younger age groups, resulting in significant adverse effects on their reproductive health. Consequently, there is an urgent need for effective treatment modalities. Nanotechnology, as an advanced discipline, provides innovative avenues for managing and treating diseases of the female reproductive system by enabling precise manipulation and regulation of biological molecules and cells. By utilizing nanodelivery systems, drugs can be administered with pinpoint accuracy, leading to reduced side effects and improved therapeutic efficacy. Moreover, nanomaterial imaging techniques enhance diagnostic precision and sensitivity, aiding in the assessment of disease severity and progression. Furthermore, the implementation of nanobiosensors facilitates early detection and prevention of ailments. This comprehensive review aims to summarize recent applications of nanotechnology in the treatment of female reproductive system diseases. The latest advancements in drug delivery, diagnosis, and treatment approaches will be discussed, with an emphasis on the potential of nanotechnology to improve treatment outcomes and overall quality of life.

Micelle encapsulation zinc-doped copper oxide nanocomposites reverse Olaparib resistance in ovarian cancer by disrupting homologous recombination repair.

Micelle Encapsulation Zinc-doped copper oxide nanocomposites (MEnZn-CuO NPs) is a novel doped metal nanomaterial prepared by our group based on Zinc doped copper oxide nanocomposites (Zn-CuO NPs) using non-micellar beam. Compared with Zn-CuO NPs, MEnZn-CuO NPs have uniform nanoproperties and high stability. In this study, we explored the anticancer effects of MEnZn-CuO NPs on human ovarian cancer cells. In addition to affecting cell proliferation, migration, apoptosis and autophagy, MEnZn-CuO NPs have a greater potential for clinical application by inducing HR repair defects in ovarian cancer cells in combination with poly (ADP-ribose) polymerase inhibitors for lethal effects.

Integrating network pharmacology and experimental verification to explore the pharmacological mechanisms of asparagus against polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder in women of reproductive age that still lacks effective treatment. Inflammation is one of the important features of PCOS. Asparagus (ASP) has anti-inflammatory, antioxidant, and anti-aging pharmacological effects, and its anti-tumor effects have been demonstrated in a variety of tumors. However, the role and mechanism of ASP in PCOS remain unclear. METHODS: The active components of ASP and the key therapeutic targets for PCOS were obtained by network pharmacology. Molecular docking was used to simulate the binding of PRKCA to the active components of ASP. The effects of ASP on inflammatory and oxidative stress pathways in PCOS, and the regulation of PRKCA were examined by KGN, a human derived granulosa cell line. PCOS mouse model validated the results of in vivo experiments. RESULTS: Network pharmacology identified 9 major active ingredients of ASP with 73 therapeutic targets for PCOS. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment yielded 101 PCOS-related signaling pathways. The hub gene PRKCA was obtained after taking the gene intersection of the top 4 pathways. Molecular docking showed the binding of PRKCA to the 7 active components in ASP. In vitro and in vivo experiments showed that ASP alleviated the course of PCOS through antioxidant, anti-inflammatory effects. ASP can partially restore the low expression of PRKCA in the PCOS models. CONCLUSION: The therapeutic effect of ASP on PCOS is mainly achieved by targeting PRKCA through the 7 active components of ASP. Mechanistically, ASP alleviated the course of PCOS through antioxidant, anti-inflammatory effects, and PRKCA was its potential target.

Integrated bioinformatics analysis and screening of hub genes in polycystic ovary syndrome.

PURPOSE: Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders, posing a serious threat to the health of women. Herein, we aimed to explore new biomarkers and potential therapeutic targets for PCOS by employing integrated bioinformatics tools. METHODS: Three gene expression profile datasets (GSE138518, GSE155489, GSE106724) were obtained from the Gene Expression Omnibus database and the differentially expressed genes in PCOS and normal groups with an adjusted p-value < 0.05 and a |log fold change (FC) | > 1.2 were first identified using the DESeq package. The weighted correlation network analysis (WGCNA) R package was used to identify clusters of highly correlated genes or modules associated with PCOS. Protein-protein interaction (PPI) network analysis and visualization of genes in the key module were performed using the STRINGdb database and the NetworkX package (edge > 5), respectively. The genes overlapping among the key module genes and PCOS-associated genes were further analyzed. Ligand molecules with strong binding energy < -10 kJ/mol to GNB3 were screened in the drug library using MTiOpenScreen. AutoDock, ChimeraX, and BIOVIA Discovery Studio Visualizer were further used to elucidate the mechanism of ligand interaction with GNB3. Finally, the relationship between GNB3 and PCOS was verified using experimental models in vivo and in vitro. RESULTS: Of the 11 modules identified by WGCNA, the black module had the highest correlation with PCOS (correlation = 0.96, P = 0.00016). The PPI network of 351 related genes revealed that VCL, GNB3, MYH11, LMNA, MLLT4, EZH2, PAK3, and CHRM1 have important roles in PCOS. The hub gene GNB3 was identified by taking the intersection of PCOS-related gene sets. MTiOpenScreen revealed that five compounds interacted with GNB3. Of these five, compound 1 had the strongest binding ability and can bind amino acids in the WD40 motif of GNB3, which in turn affects the function of the G protein-coupled receptor ß subunit. GNB3 was also significantly downregulated in PCOS models. CONCLUSION: We identified the hub gene GNB3 as the most important regulatory gene in PCOS. We suggest that compound 1 can target the WD40 motif of GNB3 to affect related functions and must be considered as a lead compound for drug development. This study will provide new insights into the development of PCOS-related drugs.

The c.323 G>C mutation in LORICRIN causes new-found late-onset autosomal dominant loricrin keratoderma in a Chinese Han Pedigree.

BACKGROUND: Loricrin keratoderma is a rare early-onset autosomal dominant skin disorder. At present, no clinical reports have been published on characteristics of progressive aggravation and late-onset. OBJECTIVES: To identified a new-found pedigree with c.323 G>C mutation leading to progressive aggravation and late-onset loricrin keratoderma. METHODS: Targeted next-generation sequencing of 267 genes associated with all skin abnormalities, sanger sequencing, and bioinformatics tools were used to identify the mutation in this new-found pedigree. Palm skin biopsy was used to observe the clinicopathological features of patient. Further, we constructed pcDNA3.1/V5-His-wild-LORICRIN, pcDNA3.1/V5-His-c.323G>C-LORICRIN, and pcDNA3.1/V5-His-730insG-LORICRIN vectors, nucleofected into HaCaT strain to observe the subcellular localization of loricrin by using the laser scanning confocal microscopy. RESULTS: The proband and his affected father carried a heterozygous c.323 G>C missense mutation (p.Gly108Ala) on LORICRIN. Bioinformatics analysis hinted that it had potential pathogenicity; the types of ligands, enzyme commission active sites, and the spatial structure of protein changed enormously. Laser scanning confocal microscopy showed that the signals from cells transfected with the pcDNA3.1/V5-His-730insG-LORICRIN vector were distributed mainly in the nucleus, whereas those from cells transfected with the pcDNA3.1/V5-His-c.323G>C-LORICRIN vector were mainly located in the cytoplasm. Wild type loricrin was distributed in the nucleus and cytoplasm homogeneously CONCLUSION: The heterozygous c.323G>C missense mutation on LORICRIN caused late-onset and progressive loricrin keratoderma in this large Chinese family. Our study revealed that a large number of loricrin gathered in the cytoplasm may disturb the normal proliferation and terminal differentiation of keratinocytes and lead to the late-onset loricrin keratoderma disease.

Comprehensive analysis of LASS6 expression and prognostic value in ovarian cancer.

BACKGROUND: Ceramide plays an important role in the occurrence and development of tumor. The synthesis of ceramide needs the participation of LASS. Current studies have shown that different LASS family members play different functions in tumors, especially LASS6, has been proved to play a key role in breast cancer, gastric cancer, melanoma and so on, but the research on ovarian cancer is very limited. METHODS: Bioinformatics web resources, including Oncomine, UALCAN, Kaplan-Meier Plotter and TIMER were used to analyze the expression profile, prognostic value and immune infiltration of LASS6. The related genes of LASS6 in ovarian cancer were mined by Regulome Explorer and LinkedOmics database, and cluster analysis was done by DAVID. The PPI network involving LASS6 was constructed by STRING database. Finally, the correlation between 10 genes and LASS6 was analyzed by GEPIA database, and their prognostic value in ovarian cancer was analyzed by Kaplan-Meier plotter. RESULTS: The expression of LASS6 was up-regulated in ovarian cancer, which was related to the progression and poor prognosis of ovarian cancer. Through GO/KEGG cluster analysis, we also found that LASS6 may affect calcium ion channel and its transport pathways. The analysis of regulatory network involved in LASS6 showed that the high mRNAs of 7 key genes were associated with poor prognosis of OS in patients with ovarian cancer, among which DEGS1 was the most significant. CONCLUSIONS: LASS6 may play an important role in the regulation of calcium pathway and become a new therapeutic target and potential prognostic marker in ovarian cancer.

Research update on the anticancer effects of buparlisib.

Buparlisib is a highly efficient and selective PI3K inhibitor and a member of the 2,6-dimorpholinopyrimidine-derived family of compounds. It selectively inhibits four isomers of PI3K, PI3Kα, PI3Kß, PI3Kγ and PI3Kδ, by competitively binding the lipid kinase domain on adenosine 5'-triphosphate (ATP), and serves an important role in inhibiting proliferation, promoting apoptosis and blocking angiogenesis, predominantly by antagonizing the PI3K/AKT pathway. Buparlisib has been confirmed to have a clinical effect in patients with solid tumors and hematological malignancies. A global, phase II clinical trial with buparlisib and paclitaxel in head and neck squamous cell carcinoma has now been completed, with a manageable safety profile. Buparlisib currently has fast-track status with the United States Food and Drug Administration. The present review examined the biochemical structure, pharmacokinetic characteristics, preclinical data and ongoing clinical studies of buparlisib. The various mechanisms of influence of buparlisib in tumors, particularly in preclinical research, were summarized, providing a theoretical basis and direction for basic research on and clinical treatment with buparlisib.

BTF3 confers oncogenic activity in prostate cancer through transcriptional upregulation of Replication Factor C.

High levels of Basic Transcription Factor 3 (BTF3) have been associated with prostate cancer. However, the mechanisms underlying the role of BTF3 as an oncogenic transcription factor in prostate tumorigenesis have not been explored. Herein, we report that BTF3 confers oncogenic activity in prostate cancer cells. Mechanistically, while both BTF3 splicing isoforms (BTF3a and BTF3b) promote cell growth, BTF3b, but not BTF3a, regulates the transcriptional expression of the genes encoding the subunits of Replication Factor C (RFC) family that is involved in DNA replication and damage repair processes. BTF3 knockdown results in decreased expression of RFC genes, and consequently attenuated DNA replication, deficient DNA damage repair, and increased G2/M arrest. Furthermore, knockdown of the RFC3 subunit diminishes the growth advantage and DNA damage repair capability conferred by ectopic overexpression of BTF3b. Importantly, we show that enforced BTF3 overexpression in prostate cancer cells induces substantial accumulation of cisplatin-DNA adducts and render the cells more sensitive to cisplatin treatment both in vitro and in vivo. These findings provide novel insights into the role of BTF3 as an oncogenic transcription factor in prostate cancer and suggest that BTF3 expression levels may serve as a potential biomarker to predict cisplatin treatment response.

Targeting the EphB4 receptor tyrosine kinase sensitizes HER2-positive breast cancer cells to Lapatinib.

Clinical data analysis reveals that the expression of the EphB4 receptor tyrosine kinase is significantly elevated in HER2-positive breast cancer and high levels of EphB4 strongly correlate with poor disease prognosis. However, the impact of EphB4 activation on HER2-positive breast cancer cells and the potential of EphB4 as a therapeutic target remain to be explored. Here, we show that EphB4 overexpression confers gain-of-function activities to HER2-positive breast cancer cells, rendering resistance to a HER2/EGFR inhibitor Lapatinib. Furthermore, using integrated transcriptomic and tyrosine phosphoproteomic analyses, followed by biochemical confirmation, we establish that EphB4 activation engages the SHP2/GAB1-MEK signaling cascade and downstream c-MYC activation, and thereby limits the overall drug responses to Lapatinib. Finally, we demonstrate that, in HER2-positive breast tumors, inhibition of EphB4 combined with Lapatinib is more effective than either alone. These findings provide new insights into the signaling networks dictating therapeutic response to Lapatinib as well as a rationale for co-targeting EphB4 in HER2-positive breast cancer.

Inhibition of SGK1 confers vulnerability to redox dysregulation in cervical cancer.

Cervical cancer has poor prognosis and patients are often diagnosed at advanced stages of the disease with limited treatment options. There is thus an urgent need for the discovery of new therapeutic strategies in cervical cancer. The activation of SGK1 has been linked to the development of various cancer types but little is known about the role of SGK1 in cervical cancer and its potential as a therapeutic target. Here we report that SGK1 is an antioxidative factor that promotes survival of cervical cancer cells. Gene set enrichment analysis of RNA-Seq data reveals a strong inverse association between SGK1 and oxidative phosphorylation. Consistently, inhibition of SGK1 via siRNA or pharmacological inhibitor GSK650394 induces ROS and cytotoxicity upon H2O2 stress. Further analysis of clinical data associates SGK1 with gene expression signatures regulated by the antioxidant transcription factor NRF2 in cervical cancer. Mechanistically, SGK1 activation exerts antioxidant effect through induction of c-JUN-dependent NRF2 expression and activity. Importantly, we find that inhibition of SGK1 confers vulnerability to melatonin as a pro-oxidant, resulting in ROS over-accumulation and consequently enhanced cell cytotoxicity. We further demonstrate that combined use of GSK650394 and melatonin yields substantial regression of cervical tumors in vivo. This work opens new perspectives on the potential of SGK1 inhibitors as sensitizing agents to enable the design of therapeutically redox-modulating strategies against cervical cancer.

MYC status as a determinant of synergistic response to Olaparib and Palbociclib in ovarian cancer.

BACKGROUND: While PARP inhibitors and CDK4/6 inhibitors, the two classes of FDA-approved agents, have shown promising clinical benefits, there is an urgent need to develop new therapeutic strategies to improve clinical response. Meanwhile, extending the utility of these inhibitors beyond their respective molecularly defined cancer types is challenging and will likely require biomarkers predictive of treatment response especially when used in a combination drug development setting. METHODS: The effects of PARP inhibitor Olaparib and CDK4/6 inhibitor Palbociclib on ovarian cancer cells lines including those of high-grade serous histology were examined in vitro and in vivo. We investigated the molecular mechanism underlying the synergistic effects of drug combination. FINDINGS: We show for the first time that combining PARP and CDK4/6 inhibition has synergistic effects against MYC overexpressing ovarian cancer cells both in vitro and in vivo. Mechanistically, we find that Palbociclib induces homologous recombination (HR) deficiency through downregulation of MYC-regulated HR pathway genes, causing synthetic lethality with Olaparib. We further demonstrate that MYC expression determines sensitivity to combinatorial treatment with Olaparib and Palbociclib. INTERPRETATION: Our data provide a rationale for clinical evaluation of therapeutic synergy of these two classes of inhibitors in ovarian cancer patients whose tumors show high MYC expression and who do not respond to PARP inhibitors or CDK4/6 inhibitors monotherapies. FUND: This work was supported by the National Natural Science Foundation of China [81672575, 81874111, 81472447 to HC; 81572586 and 81372853 to PL], and the Liaoning Provincial Key Basic Research Program for Universities [LZ2017002 to HC].

Targeting P16INK4A in uterine serous carcinoma through inhibition of histone demethylation.

Uterine serous carcinoma (USC) is a subtype of endometrial cancer. Compared with endometrial endometroid carcinoma, the majority of USC cases are more aggressive. Cyclin-dependent kinase inhibitor 2A (P16INK4A) is a canonical tumor suppressor that blocks cell cycle progression; however, P16INK4A is overexpressed in USC. The aim of the present study was to determine the role of P16INK4A in P16INK4A­positive endometrial cancer, with the hope of elucidating a novel therapeutic approach for this type of malignancy. A total of 2 endometrial cancer cell lines, ETN­1 and EFE­184, were selected for further investigation, due to them being known to express high levels of P16INK4A. Using short hairpin RNA targeting P16INK4A, P16INK4A was downregulated in these cancer cell lines. Cell viability and migration were examined via 2D/3D clonogenic and wound healing assays. Subsequently, GSK­J4, a histone demethylase inhibitor, was employed to deplete P16INK4A in these cancer cell lines and an ex vivo culture system of a patient­derived xenograft (PDX) endometrial tumor sample. Following P16INK4A knockdown, the proliferation and migration of ETN­1 and EFE­184 cells markedly declined. When exposed to GSK­J4, the levels of KDM6B and P16INK4A were almost completely abrogated, and the cell viability was significantly reduced in these cell lines and the ex vivo­cultured PDX tumor explants. The association between the levels of P16INK4A, lysine demethylase 6B (KDM6B) and the methylation status of histone 3 lysine 27 (H3K27) in these cell lines and the human USC tumor sample was also demonstrated. P16INK4A appears to be oncogenic in a number of endometrial cancer cell lines. The level of P16INK4A is associated with the methylation status of H3K27. Increased methylation of H3K27 coexists with downregulation of KDM6B and, subsequently, P16INK4A, which reduces cell proliferation and invasiveness in endometrial cancer. The observations of the present study may enable the development of a novel therapeutic strategy for P16INK4A­positive endometrial cancer, particularly USC.

Inhibition of BTF3 sensitizes luminal breast cancer cells to PI3Kα inhibition through the transcriptional regulation of ERα.

Selective phosphatidylinositol 3 kinase (PI3K) inhibitors are being actively tested in clinical trials for ERα-positive (ER+) breast cancer due to the presence of activating PIK3CA mutations. However, recent studies have revealed that increased ERα transcriptional activity limits the efficacy of PI3K inhibitor monotherapy for ER + breast cancers. Herein, we report the identification of BTF3 as an oncogenic transcription factor that regulates ERα expression in luminal breast cancers. Our TCGA analysis reveals high expression levels of BTF3 in luminal/ER + breast cancer and cell line models harboring ERα overexpression. Concordantly, BTF3 expression is highly and strongly associated with ESR1 expression in multiple breast cancer cohorts. We further show that BTF3 promotes the proliferation, survival and migration of ER + breast cancer cells by modulating ESR1 expression and ERα-dependent transcription. Moreover, BTF3 knockdown sensitizes ER + breast cancer cells to the PI3Kα inhibitor BYL-719 in both in vitro and in vivo models. Together, our findings highlight a novel role of BTF3 in modulation of ERα-dependent transcriptional activity and its potential as a predictive marker for the response to PI3K-targeted therapy in ER + breast cancer.