SGCE promotes breast cancer stemness by promoting the transcription of FGF-BP1 by Sp1.

Breast cancer stem cells are mainly responsible for poor prognosis, especially in triple-negative breast cancer (TNBC). In a previous study, we demonstrated that ε-Sarcoglycan (SGCE), a type Ⅰ single-transmembrane protein, is a potential oncogene that promotes TNBC stemness by stabilizing EGFR. Here, we further found that SGCE depletion reduces breast cancer stem cells, partially through inhibiting the transcription of FGF-BP1, a secreted oncoprotein. Mechanistically, we demonstrate that SGCE could interact with the specific protein 1 transcription factor and translocate into the nucleus, which leads to an increase in the transcription of FGF-BP1, and the secreted FBF-BP1 activates FGF-FGFR signaling to promote cancer cell stemness. The novel SGCE-Sp1-FGF-BP1 axis provides novel potential candidate diagnostic markers and therapeutic targets for TNBC.

Targeting Neuronal GPR65 With Delayed BTB09089 Treatment Improves Neurorehabilitation Following Ischemic Stroke.

BACKGROUND: GPR65 (G protein-coupled receptor 65) can sense extracellular acidic environment to regulate pathophysiological processes. Pretreatment with the GPR65 agonist BTB09089 has been proven to produce neuroprotection in acute ischemic stroke. However, whether delayed BTB09089 treatment and neuronal GPR65 activation promote neurorestoration remains unknown. METHODS: Ischemic stroke was induced in wild-type (WT) or GPR65 knockout (GPR65-/-) mice by photothrombotic ischemia. Male mice were injected intraperitoneally with BTB09089 every other day at days 3, 7, or 14 poststroke. AAV-Syn-GPR65 (adenoassociated virus-synapsin-GPR65) was utilized to overexpress GPR65 in the peri-infarct cortical neurons of GPR65-/- and WT mice. Motor function was monitored by grid-walk and cylinder tests. The neurorestorative effects of BTB09089 were observed by immunohistochemistry, Golgi-Cox staining, and Western blotting. RESULTS: BTB09089 significantly promoted motor outcomes in WT but not in GPR65-/- mice, even when BTB09089 was delayed for 3 to 7 days. BTB09089 inhibited the activation of microglia and glial scar progression in WT but not in GPR65-/- mice. Meanwhile, BTB09089 reduced the decrease in neuronal density in WT mice, but this benefit was abolished in GPR65-/- mice and reemerged by overexpressing GPR65 in peri-infarct cortical neurons. Furthermore, BTB09089 increased the GAP43 (growth-associated protein-43) and synaptophysin puncta density, dendritic spine density, dendritic branch length, and dendritic complexity by overexpressing GPR65 in the peri-infarct cortical neurons of GPR65-/- mice, which was accompanied by increased levels of p-CREB (phosphorylated cAMP-responsive element-binding protein). In addition, the therapeutic window of BTB09089 was extended to day 14 by overexpressing GPR65 in the peri-infarct cortical neurons of WT mice. CONCLUSIONS: Our findings indicated that delayed BTB09089 treatment improved neurological functional recovery and brain tissue repair poststroke through activating neuronal GRP65. GPR65 overexpression may be a potential strategy to expand the therapeutic time window of GPR65 agonists for neurorehabilitation after ischemic stroke.

Macrophages regulate healing-associated fibroblasts in diabetic wound.

BACKGROUND: Recovery from a foot ulcer is compromised in a diabetic status, due to the impaired tissue microenvironment that consists of altered inflammation, angiogenesis and fibrosis. Phenotypic alterations in both macrophages and fibroblasts have been detected in the diabetic wound. Recently, a fibroblast subpopulation that expresses high matrix metalloproteinase 1 (MMP1), MMP3, MMP11 and Chitinase-3-Like Protein 1 (CHI3L1) was associated with a successful diabetic wound healing. However, it is not known whether these healing-associated fibroblasts are regulated by macrophages. METHODS AND RESULTS: We used bioinformatic tools to analyze selected public databases on normal and diabetic skin from patients, and identified genes significantly altered in diabetes. In a mouse model for diabetic wound healing, we detected not only a loss of the spatiotemporal changes in interleukin 1ß (IL1ß), IL6, IL10 and vascular endothelial growth factor A (VEGF-A) in wound macrophages, but also a compromised expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in healing-associated wound fibroblasts in a diabetic status. Co-culture with diabetic macrophages significantly reduced the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from non-diabetic wound. Co-culture with non-diabetic macrophages or diabetic macrophages supplied with IL6 significantly increased the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from diabetic wound. Moreover, macrophage-specific expression of IL6 significantly improved wound healing and angiogenesis in diabetic mice. CONCLUSIONS: Macrophages may induce the activation of wound-healing-associated fibroblasts, while the defective macrophages in diabetes may be corrected with IL6 treatment as a promising therapy for diabetic foot disease.

Biomarker-driven targeted therapy in patients with recurrent platinum-resistant epithelial ovarian cancer (BRIGHT): protocol for an open-label, multicenter, umbrella study.

BACKGROUND: Platinum-resistant, recurrent ovarian cancer has an abysmal prognosis with limited treatment options. Poly-(ADP-ribose)-polymerase (PARP), angiogenesis, and immune checkpoint inhibitors might improve the outcomes of platinum-resistant, recurrent ovarian cancer, but accurate patient selections for those therapies remain a significant clinical challenge. PRIMARY OBJECTIVE: To evaluate the efficacy and safety of biomarker-driven combinatorial therapies of pamiparib, tislelizumab, bevacizumab, and nab-paclitaxel in platinum-resistant, recurrent ovarian cancer. STUDY HYPOTHESIS: A precision medicine combination of PARP inhibitors, anti-angiogenic therapy, immunotherapy, and chemotherapy will improve disease outcomes of platinum-resistant, recurrent ovarian cancer by accounting for genomic and immunologic features. TRIAL DESIGN: The BRIGHT Trial is a prospective, open-label, multicenter, phase II, umbrella study planning to enroll 160 patients with serous, endometrioid, or clear cell platinum-resistant, recurrent ovarian cancer from 11 clinical centers in China. Patients are assigned to one of three experimental arms based on biomarkers. Patients with BRCA1/2 mutations will receive pamiparib plus bevacizumab (arm 1, n=40) regardless of CD8+ tumor-infiltrating lymphocytes count. Patients with wild-type BRCA1/2 (BRCAwt) and ≥3 CD8+ tumor-infiltrating lymphocytes count will receive the combination of tislelizumab, bevacizumab, and nab-paclitaxel (arm 2, n=50), while BRCAwt patients with <3 CD8+ tumor-infiltrating lymphocytes count will receive bevacizumab plus dose-dense nab-paclitaxel (arm 3, n=50). After completing patient enrollment in arm 2, another 20 BRCAwt patients with ≥3 CD8+ tumor-infiltrating lymphocytes count will be included as an arm 2 expansion. Treatment will continue until disease progression or intolerable toxicity, and all adverse events will be recorded. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients include those aged ≥18 with serous, endometrioid, or clear cell ovarian cancer, platinum-resistant recurrence, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. PRIMARY ENDPOINT: Objective response rate (ORR) assessed by the investigators by the RECIST 1.1 criteria. SAMPLE SIZE: 160 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Recruitment is estimated to be completed by 2024 and results may be published by 2027. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05044871.

The association of the platelet/high-density lipoprotein cholesterol ratio with self-reported stroke and cardiovascular mortality: a population-based observational study.

BACKGROUND: Previous studies have shown that the relationship between high-density lipoprotein cholesterol (HDL-C) and stroke is controversial, and the association between the platelet/high-density lipoprotein cholesterol ratio (PHR), a novel marker for inflammation and hypercoagulability states, and stroke has not been established. METHODS: This study presents an analysis of cross-sectional data from the 2005-2018 National Health and Nutrition Examination Survey (NHANES). Stroke history, HDL-C levels, and platelet counts were obtained during cross-sectional surveys. The PHR was calculated as the ratio of the number of platelets to HDL-C concentration. Weighted logistic regression was used to assess the associations of HDL-C and the PHR with stroke. Nonlinearity of this relationship was determined through restricted cubic splines (RCSs) and two-piecewise linear regression for identifying inflection points. Furthermore, Cox regression was utilized to prospectively analyze the associations of the PHR and HDL-C concentration with cardiovascular disease (CVD) mortality in stroke survivors. RESULTS: A total of 27,301 eligible participants were included in the study; mean age, 47.28 years and 50.57% were female, among whom 1,040 had a history of stroke. After full adjustment, the odds ratio (OR) of stroke associated with a per standard deviation (SD) increase in the PHR was estimated at 1.13 (95% confidence interval (CI): 1.03 - 1.24, P = 0.01), and the OR of stroke associated with a per SD increase in HDL-C was 0.95 (95% CI: 0.86-1.05, P = 0.30). The RCS indicated a nonlinear relationship for both variables (PPHR = 0.018 and PHDL-C = 0.003), and further piecewise linear regression identified inflection points at PHR = 223.684 and HDL-C = 1.4 mmol/L. Segmental regression indicated that in the PHR ≥ 223.684 segment, the estimated OR of stroke associated with a per-SD increase in the PHR was 1.20 (95% CI: 1.09 - 1.31, P < 0.001), while the association of stroke with HDL-C was not significant before or after the inflection point (P > 0.05). Furthermore, Cox regression and RCS showed that a per-SD increase in the PHR was linearly associated with a greater risk of CVD mortality among stroke survivors (HR: 1.14, 95% CI: 1.06 - 1.22, P < 0.001; nonlinear, P = 0.956), while HDL-C was not significantly associated with CVD mortality. CONCLUSION: The association between the PHR and stroke incidence exhibited a significant threshold effect, with an inflection point at 223.684. A PHR exceeding 223.684 was positively associated with stroke, while the association between HDL-C and stroke was not significant. Additionally, the PHR was positively and linearly associated with CVD mortality among stroke survivors.

Nutrient intake and risk of multimorbidity: a prospective cohort study of 25,389 women.

BACKGROUND: Multimorbidity is becoming an increasingly serious public health challenge in the aging population. The impact of nutrients on multimorbidity remains to be determined and was explored using data from a UK cohort study. METHOD: Our research analysis is mainly based on the data collected by the United Kingdom Women's Cohort Study (UKWCS), which recruited 35,372 women aged 35-69 years at baseline (1995 to 1998), aiming to explore potential associations between diet and chronic diseases. Daily intakes of energy and nutrients were estimated using a validated 217-item food frequency questionnaire at recruitment. Multimorbidity was assessed using the Charlson comorbidity index (CCI) through electronic linkages to Hospital Episode Statistics up to March 2019. Cox's proportional hazards models were used to estimate associations between daily intakes of nutrients and risk of multimorbidity. Those associations were also analyzed in multinomial logistic regression as a sensitivity analysis. In addition, a stratified analysis was conducted with age 60 as the cutoff point. RESULTS: Among the 25,389 participants, 7,799 subjects (30.7%) were confirmed with multimorbidity over a median follow-up of 22 years. Compared with the lowest quintile, the highest quintile of daily intakes of energy and protein were associated with 8% and 12% increased risk of multimorbidity respectively (HR 1.08 (95% CI 1.01, 1.16), p-linearity = 0.022 for energy; 1.12 (1.04, 1.21), p-linearity = 0.003 for protein). Higher quintiles of daily intakes of vitamin C and iron had a slightly lowered risk of multimorbidity, compared to the lowest quintile. A significantly higher risk of multimorbidity was found to be linearly associated with higher intake quintiles of vitamin B12 and vitamin D (p-linearity = 0.001 and 0.002, respectively) in Cox models, which became insignificant in multinomial logistic regression. There was some evidence of effect modification by age in intakes of iron and vitamin B1 associated with the risk of multimorbidity (p-interaction = 0.006 and 0.025, respectively). CONCLUSIONS: Our findings highlight a link between nutrient intake and multimorbidity risk. However, there is uncertainty in our results, and more research is needed before definite conclusions can be reached.

Fully Aromatic Self-Assembled Hole-Selective Layer toward Efficient Inverted Wide-Bandgap Perovskite Solar Cells with Ultraviolet Resistance.

Ultraviolet-induced degradation has emerged as a critical stability concern impeding the widespread adoption of perovskite solar cells (PSCs), particularly in the context of phase-unstable wide-band gap perovskite films. This study introduces a novel approach by employing a fully aromatic carbazole-based self-assembled monolayer, denoted as (4-(3,6-dimethoxy-9H-carbazol-9-yl)phenyl)phosphonic acid (MeO-PhPACz), as a hole-selective layer (HSL) in inverted wide-band gap PSCs. Incorporating a conjugated linker plays a pivotal role in promoting the formation of a dense and highly ordered HSL on substrates, facilitating subsequent perovskite interfacial interactions, and fostering the growth of uniform perovskite films. The high-quality film could effectively suppress interfacial non-radiative recombination, improving hole extraction/transport efficiency. Through these advancements, the optimized wide-band gap PSCs, featuring a band gap of 1.68 eV, attain an impressive power conversion efficiency (PCE) of 21.10 %. Remarkably, MeO-PhPACz demonstrates inherent UV resistance and heightened UV absorption capabilities, substantially improving UV resistance for the targeted PSCs. This characteristic holds significance for the feasibility of large-scale outdoor applications.

circFLNA promotes intestinal injury during abdominal sepsis through Fas-mediated apoptosis pathway by sponging miR-766-3p.

BACKGROUND: Intra-abdominal infections are the second most common cause of sepsis in the intensive care unit. Intestinal epithelial injury due to abdominal sepsis results in a variety of pathological changes, such as intestinal bacteria and toxins entering the blood, leading to persistent systemic inflammation and multiple organ dysfunction. The increased apoptosis of intestinal epithelial cells induced by sepsis further exacerbates the progression of sepsis. Although several studies have revealed that circRNAs are involved in intestinal epithelial injury in sepsis, few studies have identified the roles of circRNAs in intestinal epithelial apoptosis. METHODS: We used laser capture microdissection to obtain purified epithelial cells located in intestinal crypts from four patients with abdominal sepsis induced by intestinal perforation and four samples from age and sex-matched non-septic patients. Microarray analysis of circRNAs was conducted to assess differentially expressed circRNAs between patients with and without sepsis. Lastly, in vitro and in vivo assays were performed to study the mechanism of circFLNA in intestinal epithelial apoptosis during sepsis. RESULTS: circFLNA was upregulated in the intestinal epithelium after abdominal sepsis induced by intestinal perforation. Inhibition of miR-766-3p impaired si-circFLNA-mediated inhibition of apoptosis and inflammation factor levels in lipopolysaccharide (LPS)-treated HIEC-6 cells. circFLNA aggravated apoptosis and inflammation through the Fas-mediated apoptosis pathway in both LPS-treated HIEC-6 cells and a mouse cecal ligation and puncture model. CONCLUSION: Our findings showed that circFLNA promotes intestinal injury in abdominal sepsis through the Fas-mediated apoptosis pathway by sponging miR-766-3p. The circFLNA/miR-766-3p/Fas axis has potential as a novel therapeutic target for treating intestinal injury in sepsis.

Clinical features and treatment outcomes of Castleman disease in children: a retrospective cohort in China.

Castleman disease (CD) is a rare lymphoproliferative disorder of undetermined etiology. Unicentric CD (UCD) and multicentric CD (MCD) are two phenotypes of CD diagnosed by the histopathology of lymph nodes. We attempted to describe a pediatric CD cohort to optimize the management of this disease. We reviewed the medical records of pediatric patients diagnosed with CD between April, 2004, and October, 2022, at the Children's Hospital of Fudan University. Prognosis information was collected in January, 2023, by telephone inquiry. Twenty-two patients with UCD and 2 patients with MCD were identified, all with hyaline vascular (HV) type. The median ages at diagnosis were 10.75 years (IQR 8, 12.81) for UCD and 14.42 years (IQR 13.42, 15.42) for MCD. The most common lesion location of UCD was the neck (9/22, 40.91%) and abdomen (9/22, 40.91%). Systematic symptoms occurred on 10/22 (45.45%) patients with UCD and 1/2 (50%) patients with MCD, and abnormal laboratory indexes were detected in both. Resection and biopsy were performed on all patients. One out of two patients with MCD also received rituximab for upfront therapy. After a median of 4 years (IQR 1.5, 6) of follow-up time, the overall survival was 100% and the complete remission rate in UCD was 63%. There was no relapse or progression. CONCLUSIONS: Our series demonstrated that HV-UCD was the most common type in children. Resection and biopsy were used for both deterministic diagnoses and treatments. Despite the high possibility to develop systematic inflammation, children with CD showed promising outcomes. WHAT IS KNOWN: • Castleman disease is a rare lymphoproliferative disorder with limited cohort studies, especially in pediatrics. • The ubiquity of delayed confirmations and misdiagnoses points to a lack of knowledge about etiology and characteristics, which is a prerequisite for novel therapeutics. WHAT IS NEW: • We retrospectively reviewed and analyzed the clinical and pathological symptoms, laboratory and imaging features, and treatment outcomes of a Chinese pediatric cohort with Castleman disease. • Our work may improve the recognition and optimize the management of this rare disease in children.

Association of the KISS1, LIN28B, VDR and ERα gene polymorphisms with early and fast puberty in Chinese girls.

OBJECTIVES: To explore the association of KISS1, LIN28B, vitamin D receptor (VDR), and estrogen receptor α (ERα) gene polymorphisms and the risk of early with fast puberty (EFP) risk, and with hormone levels in EFP cases, in Chinese girls. METHODS: The analysis was based on the data of 141 girls with EFP and 152 girls without EFP. Clinical features were documented, and all SNP genotyping was conducted using SNaPshot method. Statistical analysis was performed to assess the association of the SNPs with EFP risk, and with hormone levels in EFP cases. RESULTS: There was a significant association between rs7759938-C polymorphism in the LIN28B gene and the risk for EFP in the recessive (TT + CT vs. CC) model (p = 0.040). Remarkably, rs5780218-delA polymorphism in the KISS1 gene and rs2234693-C polymorphism in the ERα gene were significantly associated with peak LH (luteinizing hormone) levels (p = 0.008, 0.045) and peak LH/FSH (follicle-stimulating hormone) ratio (p = 0.007, 0.006). Additionally, on 7 of the 8 variant loci the alleles associated with increased levels of both peak LH levels and peak LH/FSH ratio in EFP cases were also associated with increased CPP risk. CONCLUSIONS: Our findings indicate that rs7759938-C polymorphism in the LIN28B gene might have a protective effect on EFP susceptibility. The most striking findings of this study is that, rs5780218-delA polymorphism in the KISS1 gene and rs2234693-C polymorphism in the ERα gene influenced levels of GnRH-stimulated peak LH and LH/FSH ratio, and in general CPP risk genes might also contributes to the abnormality of hormonal levels in EFP.

ERα/ß/DMP1 axis promotes trans-differentiation of chondrocytes to bone cells through GSK-3ß/ß-catenin pathway.

Estrogen-induced premature closing of the growth plate in the long bones is a major cause of short stature after premature puberty. Recent studies have found that chondrocytes can directly trans-differentiate into osteoblasts in the process of endochondral bone formation, which indicates that cartilage formation and osteogenesis may be a continuous biological process. However, whether estrogen promotes the direct trans-differentiation of chondrocytes into osteoblasts remains largely unknown. Chondrocytes were treated with different concentrations of 17ß-estradiol, and Alizarin Red staining and alkaline phosphatase activity assay were used to detected osteogenesis. Specific short hairpin RNA and tamoxifen were used to block the estrogen receptor (ER) pathway and osteogenic marker genes and downstream gene expression were detected using real-time quantitative polymerase chain reaction, western blot, and immunohistochemistry staining. The findings showed that 17ß-estradiol promoted the chondrocyte osteogenesis in vitro, even at high concentrations. In addition, blocking of the ERα/ß pathway inhibited the trans-differentiation of chondrocytes into osteogenic cells. Furthermore, we found that dentin matrix protein 1 (DMP1), which is a direct downstream molecular of ER, was involved in 17ß-estradiol/ER pathway-regulated osteogenesis. As well, glycogen synthase kinase-3 beta (GSK-3ß)/ß-catenin signal pathway also participates in ERα/ß/DMP1-regulated chondrocyte osteogenesis. The GSK-3ß/ß-catenin signal pathway was involved in ERα/ß/DMP1-regulated chondrocyte osteogenesis. These findings suggest that ER/DMP1/GSK-3ß/ß-catenin plays a vital role in estrogen regulation of chondrocyte osteogenesis and provide a therapeutic target for short stature caused by epiphyseal fusion.

The prognostic value of stromal tumor-infiltrating lymphocytes in intrahepatic cholangiocarcinoma: a population-based study.

OBJECTIVE: We assess the predictive value impacted by tumor-infiltrating lymphocytes (TILs) for overall survival (OS) and progression-free survival (PFS) in patients with intrahepatic cholangiocarcinoma (ICC) undergoing complete resection. METHODS: Sixty-eight patients with resectable ICC were included in this study. We studied stromal TIL density and scored it by staining sections from surgically resected ICC patients with hematoxylin and eosin (HE). The clinical data and prognosis of patients with ICC were obtained by searching clinical and follow-up records. RESULTS: A stromal TIL negative status was a predictor of poor OS (HR = 0.41, 95% CI 0.20-0.83, p = .01) and poor PFS (HR = 0.47, 95% CI 0.23-0.97, p = .04) independently. Low stromal TIL density was associated with high levels of CA125 (p = .03) and CA19-9 (p < .01). The high level of CA19-9 (p = .05), high differentiation (p = .02), a large diameter (p = .05), a positive bile duct/vascular cancer embolus (p = .03) and positive satellite nodules (p = .02) were tendencies to develop tumors for patients with a negative status of stromal TIL. CONCLUSION: Our data prompt for the prediction of the PFS and OS of patients with ICC after complete resection, stromal TILs play an important role.

Oral administration of human FGF21 expressed by mycelium of Cordyceps militaris improves blood glucose and lipid in type II diabetes mellitus.

The purpose of this study was to express human FGF21 (hFGF21) using Cordyceps militaris (C. militaris) as a bioreactor and to observe its hypoglycemic and lipid-lowering effects on type II diabetes. The recombinant plasmid pCB130-hFGF21 was transformed into C. militaris to form recombinant recombinant C. militaris (RhFGF21), the stability of RhFGF21 in vitro and in vivo was analyzed. RhFGF21 significantly promoted glucose uptake in a dose-dependent manner in adipocytes and increased the levels of p-PLCγ, p-FRS2 and p-ERK, which was consistent with the commercial hFGF21. In animal experiments, oral RhFGF21 obviously reduced the levels of glucose, insulin, TG, T-CHO, NEFA, and LDL-C in the blood, the contents of ALT, AST, TNF-α, MCP-1, F4/80, CD68 and CD11b in the fatty liver, and the apoptosis of pancreatic cells. C. militaris is an excellent carrier that can stabilize the expression of hFGF21 and protect the biological activity of hFGF21 during oral administration, which provides a theoretical basis for the development of hFGF21 oral preparations for type II diabetes.

Enhanced Cr(VI) stabilization in soil by chitosan/bentonite composites.

In this study, chitosan/bentonite composites (CSBT) was synthesized and applied to the immobilization of chromium in the soil. The influence of passivating agents on various forms of chromium was investigated by batch experiment. The results showed that CSBT could reduce the content of exchangeable form and oxidizable form, while increase the content of residual form of chromium. The addition of 0.2 g·kg-1 CSBT had the best effect, with the concentration of exchangeable, reducible and oxidizable form decreased by 46.74%, 8.15%, and 14.46%, respectively. During the experiment time, the passivation effect increased rapidly within 14 days, and the content of residual form in the total Cr increased from 0.76% to 14.23%, the equilibrium was reached at the 28th day and was basically maintained in the subsequent period. CSBT had little impact on soil pH, and soil pH maintained constant during the experiment period. The amino, carboxyl and hydroxyl groups of CSBT promoted the conversion of available chromium to residual state in soil, and reduced the bioavailability of chromium in soil.

Pseudo-sapogenin DQ 3-Maleate Derivative Induces Ovarian Carcinoma Cell Apoptosis via Mitochondrial Pathway.

In the present study, four novel ginsenosides fatty acid and aromatic acid derivatives were designed and synthesized, and their cytotoxic effects on human ovarian carcinoma cells (SKOV3) were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The results demonstrated that all derivatives inhibited SKOV3 cell growth, and Compound 3 showed the most outstanding anti-proliferative effect on SKOV3 cells. The IC50 value of Compound 3 was 33.8 ± 2.21 µM, less than half of that of cis-platinum (70.1 ± 7.64 µM). Subsequent analysis revealed that Compound 3 could promote SKOV3 cell apoptosis, and the percentage of apoptotic cell population increased with increasing Compound 3 concentrations. In addition, the expression ratios of Bax/Bcl-2, cleaved-Caspase-3/Caspase-3 and cleaved-Caspase-9/Caspase-9 were gradually elevated in Compound 3-treated SKOV3 cells compared with control cells. Furthermore, translocation of Bax to mitochondria was associated with the release of Cytochrome C. Molecular docking analysis revealed three hydrogen-bonds existed in Compound 3 with poly(ADP-ribose)polymerase (PARP) receptor (PDB code: 5DSY), which may be the target of the anti-ovarian cancer effect of Compound 3. Altogether, our study indicates that Compound 3 induces SKOV3 cell apoptosis via reactive oxygen species (ROS)-dependent mitochondrial pathway, and can serve as an anti-cancer agent for treating ovarian carcinoma.

Traditional Chinese Medicine Rhodiola Sachalinensis Borissova from Baekdu Mountain (RsBBM) for Rheumatoid Arthritis: Therapeutic Effect and Underlying Molecular Mechanisms.

The lack of effective rheumatoid arthritis (RA) therapies is a persistent challenge worldwide, prompting researchers to urgently evaluate traditional Chinese medicines (TCMs) as potential clinical RA treatments. The present investigation was conducted to evaluate the therapeutic effects and potential molecular mechanisms of the active components isolated from TCM Rhodiola sachalinensis Borissova from Baekdu Mountain (RsBBM) using an experimental adjuvant arthritis model induced by injection of rats with Freund's complete adjuvant. After induction of the adjuvant arthritis rat model, the extract-treated and untreated groups of arthritic rats were evaluated for RsBBM therapeutic effects based on comparisons of ankle circumferences and ELISA-determined blood serum inflammatory factor levels (TNF-α, IL-1ß, and PGE2). In addition, the joint health of rats was evaluated via microscopic examination of hematoxylin-eosin-stained synovial tissues. Furthermore, to explore whether NF-κB and RANK/RANKL/OPG signaling pathways participated in observed therapeutic effects from a molecular mechanistic viewpoint, mRNA and protein levels related to the expression of nuclear factor kappa-B (NF-κB), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-Β ligand (RANKL) were analyzed via quantitative RT-PCR and Western blot analysis, respectively. Treatment of arthritic rats with the extract of RsBBM was shown to reduce ankle swelling, reduce blood serum levels of inflammatory factors, and alleviate arthritis-associated synovial inflammation and joint damage. Moreover, an RsBBM 50% ethanol extract treatment inhibited bone destruction by up-regulating OPG-related mRNA and protein expression and down-regulating RANKL-related mRNA and protein expression, while also reducing inflammation by the down-regulating of the NF-κB pathway activity. The results clearly demonstrated that the extract of RsBBM alleviated adjuvant arthritis-associated joint damage by altering activities of inflammation-associated NF-κB and the RANK/RANKL/OPG signaling pathways. Due to its beneficial effects for alleviating adjuvant arthritis, this RsBBM 50% ethanol extract should be further evaluated as a promising new therapeutic TCM treatment for RA.

[Factors affecting phenotypes in the patients with MMACHC gene c.609G>A homozygous variant cblC type methylmalonic acidemia combined with homocysteinuria].

OBJECTIVE: To investigate the factors affecting phenotypes in the patients of methylmalonic acidemia combined with homocysteinemia cblC type with MMACHC c.609G>A homologous variant. METHODS: A retrospective study on the clinical manifestations, complications, treatment, and outcome in 164 patients of cblC type with MMACHC c.609G>A homologous variant was conducted. The patients were diagnosed by biochemical and genetic analysis from January 1998 to December 2020. RESULTS: Among the 164 patients, 2 cases were prenatally diagnosed and began treatment after birth. They are 3 and 12 years old with normal physical and mental development. Twenty-one cases were diagnosed by newborn screening. Among them, 15 cases had with normal development. They were treated from the age of two weeks at the asymptomatic period. Six cases began treatment aged 1 to 3 months after onset. Their development was delayed. One hundred and forty-one cases were clinically diagnosed. Their onset age ranges from a few minutes after birth to 6 years old. 110 cases had early-onset (78.0%). 31 cases had late-onset (22.0%). Five of them died. 24 patients lost to follow-up. Of the 141 clinically diagnosed patients, 130 (92.2%) with psychomotor retardation, 69 (48.9%) with epilepsy, 39 (27.7%) with anemia, 30 (21.3%) had visual impairment, 27 (19.1%) had hydrocephalus, 26 (18.4%) had feeding difficulties, 7 (5.0%) with liver damage, and 5 (3.5%) with metabolic syndrome. The frequency of hydrocephalus and seizures was significantly higher in the early-onset group. The urinary methylmalonic acid increased significantly in the patients with epilepsy. During the long-term follow-up, the level of plasma total homocysteine in the seizure-uncontrolled group was significantly higher than that in the seizure-controlled group, the difference had a statistical significance (P<0.05). CONCLUSION: Most of the patients with MMACHC c.609G>A homozygous variant had early-onset disease, with a high mortality and disability rate. If not treated in time, it will lead to neurological damage, resulting in epilepsy, mental retardation, hydrocephalus, and multiple organ damage. Pre-symptomatic diagnosis and treatment are crucial to prevent irreversible neurological damage. Neonatal screening and prenatal diagnosis are important to improve the outcome of the patients.

CNV profiles of Chinese pediatric patients with developmental disorders.

PURPOSE: To examine the overall genomic copy-number variant (CNV) landscape of Chinese pediatric patients with developmental disorders. METHODS: De-identified chromosomal microarray (CMA) data from 10,026 pediatric patients with developmental disorders were collected for re-evaluating the pathogenic CNV (pCNV) yields of different medical conditions and for comparing the frequency and phenotypic variability of genomic disorders between the Chinese and Western patient populations. RESULTS: The overall yield of pCNVs in the Chinese pediatric patient cohort was 21.37%, with variable yields for different disorders. Yields of pCNVs were positively associated with phenotypic complexity and intellectual disability/developmental delay (ID/DD) comorbidity for most disorders. The genomic burden and pCNV yield in neurodevelopmental disorders supported a female protective effect. However, the stratification analysis revealed that it was seen only in nonsyndromic ID/DD, not in nonsyndromic autism spectrum disorders or seizure. Furthermore, 15 known genomic disorders showed significantly different frequencies in Chinese and Western patient cohorts, and profiles of referred clinical features for 15 known genomic disorders were also significantly different in the two cohorts. CONCLUSION: We defined the pCNV yields and profiles of the Chinese pediatric patients with different medical conditions and uncovered differences in the frequency and phenotypic diversity of genomic disorders between Chinese and Western patients.

Epithelial cell adhesion molecule promotes breast cancer resistance protein-mediated multidrug resistance in breast cancer by inducing partial epithelial-mesenchymal transition.

Overexpression of breast cancer resistance protein (BCRP) plays a crucial role in the acquired multidrug resistance (MDR) in breast cancer. The elucidation of molecular events that confer BCRP-mediated MDR is of major therapeutic importance in breast cancer. Epithelial cell adhesion molecule (EpCAM) has been implicated in tumor progression and drug resistance in various types of cancers, including breast cancer. However, the role of EpCAM in BCRP-mediated MDR in breast cancer remains unknown. In the present study, we revealed that EpCAM expression was upregulated in BCRP-overexpressing breast cancer MCF-7/MX cells, and EpCAM knockdown using siRNA reduced BCRP expression and increased the sensitivity of MCF-7/MX cells to mitoxantrone (MX). The epithelial-mesenchymal transition (EMT) promoted BCRP-mediated MDR in breast cancer cells, and EpCAM knockdown partially suppressed EMT progression in MCF-7/MX cells. In addition, Wnt/ß-catenin signaling was activated in MCF-7/MX cells, and the inhibition of this signaling attenuated EpCAM and BCRP expression and partially reversed EMT. Together, this study illustrates that EpCAM upregulation by Wnt/ß-catenin signaling induces partial EMT to promote BCRP-mediated MDR resistance in breast cancer cells. EpCAM may be a potential therapeutic target for overcoming BCRP-mediated resistance in human breast cancer.

Foods, nutrient intakes and Mediterranean dietary pattern in midlife are not associated with reaction times: a longitudinal analysis of the UK Women's Cohort Study.

Associations between dietary factors and general cognition in the elderly have been documented; however, little is known about reaction time ability in relation to midlife diet. The present study aimed to investigate associations between reaction time and midlife dietary factors, specifically foods, nutrients and Mediterranean diet (MeDi) pattern. The UK Women's Cohort Study collected dietary information from middle-aged women (52 (sd 9·4) years old) using a validated 217-item FFQ in 1995-1998. In 2010-2011, a sub-group of 664 participants completed online reaction time ability tests including simple reaction time (SRT) and choice reaction time; 503 participants were eligible for analysis. Participants were grouped into fast and slow groups by their median reaction time. The intake of particular foods, nutrients, adherence to the MeDi and cooking methods (roasting/baking, frying and barbecuing/grilling) were explored in relation to reaction times. We did not find any significant associations between reaction times and investigated foods, nutrients or adherence to the MeDi in adjusted models. However, consumers of roasted/baked fish and fried vegetables were associated with slower SRT (adjusted OR 1·46, 95 % CI 1·00, 2·13, P = 0·049; and adjusted OR 1·64, 95 % CI 1·12, 2·39, P = 0·010, respectively) compared with non-consumers of that particularly cooked food. Overall, our findings show no significant associations between midlife diet and reaction time ability 10-15 years later.