Astragalin Promotes Osteoblastic Differentiation in MC3T3-E1 Cells and Bone Formation in vivo

Astragalin (AG) is a biologically active flavonoid compound that can be extracted from a number of medicinal plants. However, the effects of AG on osteoblastic differentiation in mouse MC3T3-E1 cells and on bone formation in vivo have not been studied fully. In this study, we found that the activities of alkaline phosphatase (ALP) and mineralized nodules in MC3T3-E1 cells were both significantly increased after treatment with AG (5, 10, and 20 μM). Meanwhile, the mRNA and protein levels of osteoblastic marker genes in MC3T3-E1 cells after AG treatment were markedly increased compared with a control group. In addition, the levels of BMP-2, p-Smad1/5/9, and Runx2 were significantly elevated in AG-treated MC3T3-E1 cells. Moreover, we found that the protein levels of Erk1/2, p-Erk1/2, p38, p-p38, and p-JNK were also significantly increased in AG-treated MC3T3-E1 cells compared to those in the control group. Finally, in vivo experiments demonstrated that AG significantly promoted bone formation in an ovariectomized (OVX)-induced osteoporotic mouse model. This was evidenced by significant increases in the values of osteoblast-related parameters (BFR/BS, MAR, Ob.S/BS, and Ob.N/B.Pm) and bone histomorphometric parameters (BMD, BV/TV, Tb.Th, and Tb.N.) in OVX mice after AG treatment (5, 10, and 20 mg/kg). Collectively, these results demonstrated that AG may promote osteoblastic differentiation in MC3T3-E1 cells via the activation of the BMP and MAPK pathways and promote bone formation in vivo. These novel findings indicated that AG may be a useful bone anabolic agent for the prevention and treatment of osteoporosis

Bifunctional enzyme ATIC promotes propagation of hepatocellular carcinoma by regulating AMPK-mTOR-S6 K1 signaling

Abstract Background Hepatocellular carcinoma (HCC) is one of the cancer types with poor prognosis. To effectively treat HCC, new molecular targets and therapeutic approaches must be identified. 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate (IMP) cyclohydrolase (ATIC), a bifunctional protein enzyme, catalyzes the last two steps of the de novo purine biosynthetic pathway. Whether ATIC contributes to cancer development remains unclear. Methods ATIC mRNA levels in different types of human HCC samples or normal tissues were determined from Gene Expression across Normal and Tumor tissue (GENT) database. The expression level of ATIC in human HCC samples or cell lines were examined by RT-PCR and western blot. Overall survival and disease-free survival of HCC patients in the ATIC low and ATIC high groups were determined by Kaplan-Meier analysis. Effects of ATIC knockdown by lentivirus infection were evaluated on cell-proliferation, cell-apoptosis, colony formation and migration. The mechanisms involved in HCC cells growth, apoptosis and migration were analyzed by western blot and Compound C (C-C) rescue assays. Results Here, we first demonstrated that expression of ATIC is aberrantly up-regulated in HCC tissues and high level of ATIC is correlated with poor survival in HCC patients. Knockdown of ATIC expression resulted in a dramatic decrease in proliferation, colony formation and migration of HCC cells. We also identified ATIC as a novel regulator of adenosine monophosphate-activated protein kinase (AMPK) and its downstream signaling mammalian target of rapamycin (mTOR). ATIC suppresses AMPK activation, thus activates mTOR-S6 K1-S6 signaling and supports growth and motility activity of HCC cells. Conclusion Taken together, our results indicate that ATIC acts as an oncogenic gene that promotes survival, proliferation and migration by targeting AMPK-mTOR-S6 K1 signaling

VAOS, a novel vanadyl complexes of alginate saccharides, inducing apoptosis via activation of AKT-dependent ROS production in NSCLC

Previous studies have confirmed that protein tyrosine phosphatase 1B (PTP1B) can promote tumour progression in non-small cell lung cancer (NSCLC). Vanadyl alginate oligosaccharides (VAOS) is a new coordination compounds that possesses a good PTP1B inhibitory activity. However, the potent anticancer efficacy of VAOS in human NSCLC requires further study. In this study, VAOS exhibited effective inhibitory effects in NSCLC both in cultured cells and in a xenograft mouse model. VAOS was further identified to induce NSCLC cell apoptosis through activating protein kinase B (AKT) to elevate intracellular reactive oxygen species (ROS) levels by increasing in oxygen consumption and impairing the ROS-scavenging system. Neither silencing of PTP1B by siRNA nor transient overexpression of PTP1B had an effect on the AKT phosphorylation triggered by VAOS, indicating that PTP1B inhibition was not involved in VAOS-induced apoptosis. Through phosphorus colorimetric assay, we demonstrated that VAOS notably inhibited phosphatase and tensin homologue deleted on chromosome 10 (PTEN) dephosphorylation activity, another member of the protein tyrosine phosphatases (PTPases)-upstream factor of AKT. Interestingly, PTEN knockdown sensitized cells to VAOS, whereas ectopic expression of PTEN markedly rescued VAOS-mediated lethality. In vivo, VAOS treatment markedly reduced PTEN activity and tumour cell burden with low systemic toxicity. Thus, our data not only provided a new therapeutic drug candidate for NSCLC, but presented new understanding into the pharmacological research of VAOS

Additional file 1: of Bifunctional enzyme ATIC promotes propagation of hepatocellular carcinoma by regulating AMPK-mTOR-S6Â K1 signaling

Supplementary Materials. (DOCX 818 kb

Significant Increase of Erectile Dysfunction in Men With Post-stroke: A Comprehensive Review

Men with erectile dysfunction (ED) are considered to be at risk from stroke events. Conversely, post-stroke patients are also at high risk of ED, whereas a quantitative result from all the relevant studies has not been previously addressed. Therefore, we have performed a comprehensive review and meta-analysis on this issue. This study was registered on PROSPERO (ID No. CRD42021226618). Twenty studies with a total of 3,382 stroke events were included, of which six studies were included for quantitative analysis, and the remaining 14 studies were calculated for the ratio of ED. Synthetic results from four eligible studies providing the ED cases showed that stroke patients were associated with a significantly higher risk of ED than the general population [pooled relative risk (RR) = 3.32, 95% confidence interval (CI): 1.25-8.82

Is There an Association Between Hypothyroidism and Sexual Dysfunction: A Systematic Review and Cumulative Analysis

Introduction: Many investigators have found a detrimental effect on sexual functioning developed by hypothyroidism in both sexes, but a cumulative analysis has not been conducted. Aim: This study aims to summarize and quantify the association between overt or subclinical hypothyroidism and the risk of sexual dysfunction (SD) through a meta-analysis. Methods: 4 electronic databases were systematically searched. The quality of evidence was rated by the GRADE approach. This meta-analysis was registered on the PROSPERO (ID: CRD42020186967). Main Outcome Measure: The strength of the relationship between overt/subclinical hypothyroidism and SD was quantified by presenting the relative risk (RR) with its 95% confidence interval (CI). Results: 7 studies involving 460 patients with hypothyroidism and 2,143 healthy controls were included in this meta-analysis. Among the 7 included studies, 2 studies were provided the data of both overt and subclinical hypothyroidism. Pooled results from 4 included studies investigating overt hypothyroidism indicated that overt hypothyroidism led to significant SD in both sexes (RR = 2.26, 95% CI: 1.42 to 3.62, P = 0.001), while synthetic RR of 5 eligible studies reporting subclinical hypothyroidism failed to find a positive association between subclinical hypothyroidism and SD (RR = 1.3, 95% CI: 0.85 to 1.99, P = 0.229), irrespective of gender (all P > 0.05). Subgroup analyses revealed that women with overt hypothyroidism rather than men with overt hypothyroidism were correlated with a significant higher risk of SD. The quality of evidence in the study of overt hypothyroidism and subclinical hypothyroidism was considered low and moderate, respectively. Conclusion: SD is a devastating problem in female patients with clinical hypothyroidism but insusceptible in either women or men with subclinical hypothyroidism. Clinicians should be aware of these phenomena and manage the sufferers accordingly in clinical practice. More rigorous studies are still needed to validate this evidence.Shen M, Li X, Wu W, et al. Is There an Association Between Hypothyroidism and Sexual Dysfunction: A Systematic Review and Cumulative Analysis. Sex Med 2021;9:100345