Pinoresinol diglucoside exhibits protective effect on dexamethasone-induced osteoporosis in rats

Purpose: To investigate the effect of pinoresinol diglucoside (PDG) on dexamethasone-induced osteoporosis in rats.Methods: Sixty Wistar rats were randomly and equally divided into normal, control, alendronate and PDG (10, 20 or 40 mg/kg) groups. Bone tissue parameters, including length, transverse diameter, weight, bone mineral content (BMC) and bone mineral density (BMD), were determined using vernier caliper, electronic balance and single photon bone mineral density meter. Serum biochemical indices, including Ca2+, inorganic phosphorus (IP), IL-6, TNF-α and alkaline phosphatase (ALP), were determined using colorimetry and enzyme-linked immunosorbent assay (ELISA). Osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) proteins were detected by Western blot.Results: PDG (10, 20 or 40 mg/kg) increased significantly (p < 0.05 or 0.01) transverse diameter (3.64 – 3.79 vs. 3.31 mm), weight (0.73 – 0.78 vs. 0.67 g), BMC (0.16 – 0.23 vs. 0.12 g/cm), BMD (0.27 – 0.35 vs. 0.22 g/cm2) of right femur, serum Ca2+ level (2.16 – 2.39 vs. 1.94 mmol/L), and OPG level of left femur, compared with those in the control group. PDG (10, 20 or 40 mg/kg) reduced significantly (p < 0.05 or 0.01) serum IP (1.34 – 1.14 vs. 1.76 mmol/L), IL-6 (103.25 – 95.38 vs. 108.74 ng/L), TNF-α (87.46 – 82.05 vs. 92.38 ng/L), ALP (334.79 – 276.32 vs. 486.45 U/L) levels or activities, and RANKL level of left femur, compared with those in the control group.Conclusion: PDG exhibits a protective effect on dexamethasone-induced osteoporosis by increasing bone mass and regulating bone metabolism. Thus, PDG may be a candidate drug for treating osteoporosis.Keywords: Pinoresinol diglucoside, Osteoporosis, Bone mass, Bone metabolism, Dexamethasone, Osteoprotegeri

Cough Test during Tension-Free Vaginal Tape Procedure in Preventing Postoperative Urinary Retention

Objective. To discuss the practical value of the cough test during the tension-free vaginal tape (TVT) procedure. Methods. In the first group, 41 patients of female stress incontinence received TVT operations which were performed according to the Ulmsten’s method strictly, only that the stress of tape was adjusted in light of the cough test. In the second group, 44 patients of female stress incontinence received TVT operations in which the tape was put under the urethral tract without stress, not adjusted by cough test. Results. The cure rate was 38/41 (92.6%) in the cough test group and 41/44 (93.1%) in the noncough test group; detrusor pressure-uroflow study indicated that there were 11 cases in the obstruction zone in the cough test group while only 3 cases were in the obstruction zone in the noncough test group; 4 cases of urinary retention and 5 cases of voiding dysfunction were found in the cough test group, while difficulties of urination were not found in the non-cough test group. Conclusion. Adjusting the tape stress in accordance with the cough test during the TVT can increase the opportunity of urinary retention or difficulty of urination after operation. So there is no benefit of the cough test during tension-free vaginal tape procedure in preventing post-operative urinary retention

DEVELOPMENT AND APPLICATION OF A SIMULATED ALTITUDE CABIN

The purpose of this study was to examine the techniques of simulated altitude cabin developed by the Shandong Sports Science Center, China. Blood lactate of two male and two female long distance taking the contrast test of the same exercise load of Monark 829 bicycle and treadmill both in and out of the cabin was measured. Hemoglobin of four elite walk runners who lived in the cabin with the altitude of 3,000m for 14 hours every day and took the training out of the cabin in the rest of the time was also measured. Results showed that the value of blood lactate for same athlete after exercise load in the cabin is obviously higher than those outside of cabin, and that the mean value of hemoglobin of the four elite athletes increased 1.3g/dl before and after the test. It is concluded that the manufacture of the simulated altitude cabin is successful in simulating actual altitude training

Major adverse cardiovascular events associated with testosterone treatment: a pharmacovigilance study of the FAERS database

Background and purpose: Testosterone is an essential sex hormone in maintaining masculine characteristics, which is prescribed for male hypogonadism as testosterone replacement treatment (TRT). Herein, we investigated long-standing controversies about the association between TRT and major adverse cardiovascular events (MACEs), based on real world adverse event (AE) reports, registered in the Food and Drug Administration Adverse Event Reporting System (FAERS).Methods: Publicly available FAERS data from 1 January 2004 to 31 December 2022 were retrieved from the Food and Drug Administration (FDA) website. The data mining protocol including the reporting odds ratio (ROR) and the Bayesian confidence propagation neural network (BCPNN) was applied to analyze overreporting caused by risk factors and MACEs, including TRT, morbidities, and ages. The ROR and the BCPNN were also applied to investigate the annually developing trend of pharmacovigilance (PV) signals in the real world, retrospectively.Results: A total of 3,057 cases referring to MACEs, with a median age of 57 years old (yo), were identified from 28,921 cases of testosterone users. MACEs related to PV signals have emerged since 2014, including cardiac death, non-fatal myocardial infarction, and non-fatal stroke. Myocardial infarction (MI) (ROR: 9.46; IC025: 3.08), acute myocardial infarction (AMI) (ROR: 16.20; IC025: 3.72), ischemic cardiomyopathy (ROR: 11.63; IC025: 2.20), and cardiomyopathy (ROR: 5.98; IC025: 1.96) were the most significant signals generated, and weaker signals included cardiac failure acute (ROR: 4.01; IC025: 0.71), cardiac arrest (ROR: 1.88; IC025: 0.56), and ventricular fibrillation (VF) (ROR: 2.38; IC025: 0.38). The time-to-onset (TTO) of MACEs was calculated with a median of 246 days for AMI.Conclusion: For myocardial infarction and cardiomyopathy, TRT statistically tended to increase the risk of MACEs, while for cardiac arrhythmia, cardiac failure, and stroke, TRT demonstrated beneficial effects among the population with morbidities, such as testosterone deficiency (TD), diabetes mellitus (DM), and hypertension. MACEs were rare but led to serious outcomes including significant increase in death and disability. Since 2018, and before 2014, reports referring to TRT associated with MACEs were relatively scarce, which indicated that there might be a considerable number of cases that went unrecorded, due to neglection. Health workers and testosterone users might pay more attention to testosterone-induced MACEs

DISCOVERY OF POTENT, ORALLY ACTIVE COMPOUNDS OF TYROSINE KINASE AND SERINE/THREONINE-PROTEIN KINASE INHIBITOR WITH ANTI-TUMOR ACTIVITY IN PRECLINICAL ASSAYS

Traditional medicines have become the most productive source of leads for drugs development, particularly as anti-cancer agents. Various screening approaches are being applied. Sorafenib, a multikinase inhibitor, is used to treat primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer. A small library of compounds analogous to sorafenib were designed and screened for the treatment of liver cancer. Multiple members of the family in an assay panel of tyrosine kinase family and serine/threonine-protein kinase family, including VEGFR, Abl, Aurora A, p 38, Lck, Src, PDGFR, Flt3, c-RAF, c-KIT, MEK(MAPKK) were selected to test these compounds. Analysis of the selectivity patterns for these compounds shows specificity for many kinase families. IC50 were measured for the selected compounds. Multiple compounds have very similar kinase inhibition profiles of VEGFR, Flt3, FGFR to that of sorafenib. The IC50 of c-RAF of BB1 is lower than sorafenib. The IC50 of c-RAF of BB3-12 is higher than that of sorafenib. For Flt3, IC50 of BB1-4 is less than sorafenib. The IC50 value of KDR of BB1-10 is less than sorafenib. especially against c-RAF, PDGFR, c-KIT, KDR compared to sorafenib. These compounds are potent Raf1 and Flt4 kinase inhibitors

miR-191 Inhibition Induces Apoptosis Through Reactivating Secreted Frizzled-Related Protein-1 in Cholangiocarcinoma

Background/Aims: Cholangiocarcinoma (CCA) is one of the most common malignant tumors of the biliary tract originating from biliary epithelial cells. Although many therapeutic strategies have been developed to treat CCA, the survival rate for CCA patients is still quite low. Thus it is urgent to elucidate the pathogenesis of CCA and to explore novel therapeutic targets. miR-191 has been shown to be associated with many human solid cancers, but the function of miR-191 in CCA is still poorly understood. Methods: We first investigated the expression level of miR-191 in human CCA tissues and cell lines with quantitative real-time PCR (qRT-PCR). The effects of miR-191 on CCA cells were determined by Cell Counting Kit-8 assay, colony formation assay and acridine orange/ethidium bromide staining. Finally, we utilized qRT-PCR, western blot and luciferase reporter assays to verify the miR-191 target gene. Results: We showed that miR-191 was up-regulated in CCA cell lines and patients. Knockdown of miR-191 by transfection of its inhibitor sequence blocked RBE cells viability and induced apoptosis of RBE cells. Both qRT-PCR and western blot analysis showed that the secreted frizzled-related protein-1 (sFRP1) level was negatively correlated with that of miR-191. Luciferase assay validated that sFRP1 was a direct target of miR-191. Moreover, knockdown of miR-191 led to suppression of Wnt/β-catenin signaling activation. Co-transfection of sFRP1 small interfering RNA (siRNA) and miR-191 inhibitor re-activated the Wnt/β-catenin signaling pathway as detected by an increased level of β-catenin and phosphorylation of GSK-3β, and restored the expression of survivin and c-myc in RBE cells. Co-transfection of sFRP1 siRNA with miR-191 inhibitor restored the colony formation ability and viability of RBE cells. Conclusion: Taken together, our results demonstrate a novel insight into miR-191 biological function in CCA. Our findings suggest that miR-191 is a potential therapeutic target of CCA treatment