Project description:Cathepsin K is a key enzyme involved in the degradation of organic bone matrix by osteoclasts. Inhibition of bone resorption observed in human and animal models deficient for cathepsin K has identified this enzyme as a suitable target for intervention by small molecules with the potential to be used as therapeutic agents in the treatment of osteoporosis. Odanacatib (ODN) is a nonbasic selective cathepsin K inhibitor with good pharmacokinetic parameters such as minimal in vitro metabolism, long half-life, and oral bioavailability. In preclinical studies, ovariectomized monkeys and rabbits treated with ODN showed substantial inhibition of bone resorption markers along with increases in bone mineral density (BMD). Significant differences were observed in the effects of ODN treatment compared with those of other antiresorptive agents such as bisphosphonates and denosumab. ODN displayed compartment-specific effects on trabecular versus cortical bone formation, with treatment resulting in marked increases in periosteal bone formation and cortical thickness in ovariectomized monkeys whereas trabecular bone formation was reduced. Furthermore, osteoclasts remained viable. Phase I and II studies conducted in postmenopausal women showed ODN to be safe and well tolerated. After 5 years, women who received ODN 50 mg weekly continuously from year 1 (n = 13), showed BMD increases from baseline of 11.9% at the lumbar spine, 9.8% at the femoral neck, 10.9% at the hip trochanter, and 8.5% at the total hip. Additionally, these subjects maintained a low level of the urine bone resorption marker N-terminal telopeptide/creatinine (-67.4% from baseline) through 5 years of treatment, while levels of serum bone-specific alkaline phosphatase remained only slightly reduced relative to baseline (-15.3%). In women who were switched from ODN to placebo after 2 years, bone turnover markers were transiently increased and BMD gains reversed after 12 months off medication. Adverse experiences in the ODN-treated group were not significantly different from the placebo group. In conclusion, available data suggests that cathepsin K inhibition could be a promising intervention with which to treat osteoporosis. Ongoing studies are expected to provide information on the long-term efficacy in fracture reduction and safety of prolonged treatment with ODN.

Project description:Background and objectiveCardiovascular diseases (CVDs) have been one of the most common threats to human health in recent decades. At present, despite many diagnostic, prognostic and therapeutic methods being applied in the clinic, the prevalence of CVDs continues to rise. Therefore, new discovery is needed and exosomes have received extensive attention. Exosomes are extracellular vesicles that enable communication between cells. They are widely distributed in biofluids, suggesting that they may be useful in CVD diagnosis and prognosis. Furthermore, exosomes are ideal drug transporters with relatively high transport efficiency and the capability to target different kinds of tissues. However, the present research concentrates, for the most part, on mechanistic studies with less attention to clinical applications.MethodsMore than 150 relevant scientific articles from databases like PubMed, Web of Science were screened and analysed for this narrative review. Data of clinical trials are collected from clinicaltrials.gov.Key content and findingsIn this review, we concentrate on different exosomes and CVDs, and we summarize the physiological and pathological roles of CVD-related exosomes. We focused on the role exosomes may have as biomarkers of CVDs, therapeutic opportunities, and possible hurdles to the clinical application of exosomes, aiming to provide a useful reference for its translational use in the CVD field.ConclusionsSpecific changes in exosome cargos (mainly miRNAs and proteins) are in accordance with the occurrence and development of CVDs including acute myocardial infarction (AMI), arrhythmia, coronary artery disease (CAD), heart failure (HF) and cardiomyopathy, therefore meaningful for diagnosis and prognosis of CVDs. For exosome related therapeutic methods, potential ways consist of direct administration of exosomes, targeting on exosome synthesis, processing and release, and working as adjuvants. All in all, exosomes are expected to serve as meaningful tools in the diagnosis, treatment and prognosis of CVDs.

Project description:Many clinical trials and meta-analyses related to acupuncture for osteoporosis (OP) have been published. However, identifying the evidence from these studies still remains a challenge for acupuncturists. We conducted a systematic search of the Chinese Biomedical Medicine (CBM), VIP Database, Wanfang Data, China National Knowledge Infrastructure (CNKI), PubMed, Springer, Cochrane Library, and Embase to identify relevant trials, systematic reviews, and/or meta-analyses up to October 31, 2018. Data were extracted to assess the methodological quality using Veritas plots and to explore potential acupuncture prescriptions using the Traditional Chinese Medicine inheritance support system (TCMISS). In addition, potential mechanisms of core acupoints identified by data mining were summarized based on published studies. A total of 218 clinical trials and ten meta-analyses were included, involving 212 acupuncture prescriptions, 102 acupoints, 13 meridians, three extra meridians, and one Ashi point. The mean Veritas score of publication year, type of study, Assessment of Multiple Systematic Reviews 2, Preferred Reporting Items for Systematic Reviews and Meta-Analyses, heterogeneity, and publication bias were 5.5, 7.2, 6, 5.6, 5.8, and 7.5, respectively. The study of Pan et al. received the highest Veritas score of 8.67 points. The most frequently used meridian was BL. Acupoint combinations BL23 and BL20, BL23 and GV4, and BL23 and ST36 were used frequently. The core acupoints association networks were acupoints BL23, BL20, ST36, GV4, SP6, CV4, and KI3. The potential mechanisms of core acupoints involved upregulated expression of members in OPG/RANKL, Wnt/β-catenin, and MAPK pathways, such as LRP5, β-catenin, Runx2, and OPG. In conclusion, our Veritas plots enable acupuncturists to evaluate key attributes of meta-analysis quality related to acupuncture for primary OP and to improve the quality of evidence-based medicine relating to acupuncture. Data mining analysis revealed an association network of meridians, acupoint combinations, core acupoints, and the underlying mechanisms of acupuncture for primary OP.

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The Potential of Exosomes for Osteoporosis Treatment: A Review

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