Icariin ameliorates osteoporosis in ovariectomized rats by targeting Cullin 3/Nrf2/OH pathway for osteoclast inhibition.

Osteoporosis, characterized by low bone mass and bone microarchitecture breakdown, has become a growing public health problem. The increase in oxidative stress could lead to an imbalance between osteoblasts-mediated osteogenesis and osteoclast-mediated bone resorption, which gives rise to osteoporosis. Nrf2 is a master transcription factor that regulates oxidative stress and has recently been reported to take part in the development of osteoporosis. Icariin, a leading active flavonoid in herbal Epimedium pubescens, has significant antioxidant activity in and is widely applied for treating bone diseases. In this study, we aimed to explore the effect of icariin on osteoclastogenesis and its potential mechanism from the perspective of oxidative stress inhibition, using ovariectomized (OVX) rats and RANKL-induced RAW264.7 cells. Our results demonstrated that icariin-treated OVX rats exhibited higher bone density, fewer tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, and lower ROS levels in bone tissues than vehicle-treated OVX rats. Also, icariin suppressed osteoclast differentiation and inhibited the expression of osteoclastogenesis-related genes, such as NFATc1, Ctsk, Trap, and c-Fos, in RANKL-induced RAW264.7 cells. Icariin also reduced intracellular ROS levels by increasing the expression of nuclear Nrf2 and HO-1. Further mechanistic studies showed icariin inhibited Cullin 3 expression and could delay Nrf2 degradation by reducing the ubiquitination of endogenous Nrf2 in RANKL-stimulated RAW264.7 cells, and these effects were markedly reversed by cullin three overexpression. These findings suggest icariin alleviated osteoporosis by suppressing osteoclastogenesis via targeting the Cullin 3/Nrf2/OH signaling pathway. Our study implied that icariin may be a potential candidate to treat osteoporosis.

Application and prospect of metabolomics in the early diagnosis of osteoporosis: a narrative review.

This paper reviews the application of metabolomics in the early diagnosis of osteoporosis in recent years. The authors searched electronic databases for the keywords "metabolomics", "osteoporosis" and "biomarkers", then analyzed the relationship between functional markers and osteoporosis using categorical summarization. Lipid metabolism, amino acid metabolism and energy metabolism are closely related to osteoporosis development and can become early diagnostic markers of the condition. However, the existing studies in metabolomics suffer from varying application methods, difficulty in identifying isomers, small study cohorts and insufficient research on metabolic mechanisms. Consequently, it is important for future research to focus on broadening and standardizing the scope of the application of metabolomics. High-quality studies on a large scale should also be conducted while promoting the early diagnosis of osteoporosis in a more precise, comprehensive and sensitive manner.

Chinese Herbal Medicine Guilu Erxian Glue Inhibits Osteoclast Formation and Activity via Mc3t3-Derived Extracellular Vesicles in vitro.

Background: Osteoporosis is a systemic bone disease characterized by decreased bone density and quality, destruction of bone microstructure, and increased bone fragility. Extracellular vesicles are lipid bilayer nanoparticles that participate in intercellular communication. Extracellular vesicles are becoming popular in the study of osteoporosis and the bone cell microenvironment. Extracellular vesicles can transmit cell signals and regulate bone homeostasis. Our previous studies revealed that the Chinese herbal medicine Guilu Erxian Glue promotes type I collagen synthesis and osteoprotegerin secretion by osteoblasts in rats, reverses the imbalance of bone homeostasis, and alleviates osteoporosis. Objective: We investigated how osteoblast-derived extracellular vesicles treated with Guilu Erxian Glue affected osteoclasts in vitro. Methods: We quantified osteoclast differentiation of RAW 264.7 using TRAP staining, cell apoptosis using flow cytometry, extracellular vesicle uptake by fluorescence tracing, bone absorption functions by bone resorption lacuna , and transcription of key genes by quantitative real-time PCR. Results: Fluorescently labeled mouse preosteoblastic MC3T3-E1 cells secreted nanoscale substances less than 1 µm in diameter. Mouse macrophage RAW 264.7 cells adsorbed these nanoparticles and PKH26-labeled extracellular vesicles derived from MC3T3-E1 cells on the cell membrane surface. Extracellular vesicles from MC3T3-E1 cells treated with Guilu Erxian Glue inhibited the differentiation of osteoclasts induced by receptor activator of nuclear factor-κB ligand and macrophage colony-stimulating factor and reduced the number of lacunae formed by osteoclasts in vitro compared with controls. Extracellular vesicles from MC3T3-E1 cells treated with Guilu Erxian Glue downregulated the relative messenger RNA expression of c-Fos, cathepsin K, nuclear factor of activated T cells 1, and tartrate-resistant acid phosphatase in osteoclasts, which may be part of the mechanism by which they regulate osteoclasts. Conclusions: Our results demonstrate that extracellular vesicles are essential for signal exchange between osteoblasts and osteoclasts. Although we do not know how Guilu Erxian Glue affects the signaling molecules carried by extracellular vesicles, we have shown for the first time, to our knowledge, that Guilu Erxian Glue can inhibit osteoclast differentiation and function via osteoblast-derived extracellular vesicles. Our findings are conducive to providing a new target for the development of osteoporosis drugs.

P110α inhibitor alpelisib exhibits a synergistic effect with pyrotinib and reverses pyrotinib resistant in HER2+ breast cancer.

Human epidermal growth factor receptor 2 (HER2) plays a critical role in breast cancer progression in patients with HER2 overexpression, thereby driving the development of targeted drugs and advancing therapy strategies targeting this gene. Pyrotinib is a novel irreversible pan-ErbB kinase inhibitor, primarily suppresses the downstream MAPK and PI3K/AKT pathways. Alpelisib, a selective PI3K p110α inhibitor, has been approved for clinical application in HR+, HER2-, PIK3CA mutated breast cancers and is also being developed for use in other breast cancer subtypes. In this study, we hypothesised that combining pyrotinib with alpelisib would yield superior results compared to single-drug treatment. Our data demonstrated that the combination of alpelisib and pyrotinib exhibited a synergistic effect in HER2+ breast cancer both in vitro and in vivo. This combination led to decreased cell proliferation and migration, G0-G1 cell cycle arrest, and increased apoptosis rates. Additionally, the deactivation of ErbB receptors and sustained activation of PI3K/AKT pathway by upstream compensatory pathways induced acquired pyrotinib resistant cells resistant to pyrotinib treatment, thus alpelisib combined with pyrotinib showed a tremendous synergistic effect and reverse pyrotinib resistance in acquired pyrotinib resistant cells by suppressing the activated PI3K/AKT pathway. Our results revealed a combination of pyrotinib and alpelisib as an effective therapeutic strategy in treating HER2+ breast cancer, whether sensitive or resistant to pyrotinib treatment.

LINC00891 promotes tumorigenesis and metastasis of thyroid cancer by regulating SMAD2/3 via EZH2.

BACKGROUND: Thyroid cancer (TC), the most common endocrine malignant tumor, is increasingly causing a huge threat to our health nowadays. METHODS: To explore the tumorigenesis mechanism of thyroid cancer, we identified that long intergenic non-coding RNA-00891 (LINC00891) was upregulated in TC using the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and local databases. LINC00891 expression correlated with histological type and lymph node metastasis (LNM). The high expression of LINC00891 could serve as a diagnostic marker for TC and its LNM. In vitro experiments demonstrated that LINC00891 knockdown could inhibit cell proliferation, migration, invasion apoptosis, and of TC cells. We also investigated the related mechanisms of LINC00891 promoting TC progression using RNA sequencing, Gene Set Enrichment Analysis, and Western blotting. RESULTS: Our experiments demonstrated that LINC00891 promoted TC progression via the EZH2-SMAD2/3 signaling axis. In addition, overexpression of EZH2 could reverse the suppressive epithelial-to-mesenchymal transition (EMT) caused by LINC00891 knockdown. CONCLUSION: In conclusion, the LINC00891/EZH2/SMAD2/3 regulatory axis participated in tumorigenesis and metastasis of thyroid cancer, which may provide a novel target for treatment.

The effectiveness of traditional Chinese medicine-based exercise on physical performance, balance and muscle strength among older adults: a systematic review with meta-analysis.

BACKGROUND: Traditional Chinese medicine (TCM) based exercises have been widely used in the prevention and treatment of balance, cardiopulmonary, and other related diseases in older adults. However, there seems to be no consensus on the improvement and comparison of physical performance, balance, and muscle strength in the elderly population. OBJECTIVES: To systematically examine the impact of different TCM-based exercises on physical performance, balance, and muscle strength outcomes in the elderly. METHODS: We searched PubMed, EMBASE, Scopus, and Cochrane Center, CNKI and Wan Fang between their date of inception and March 2021. This meta-analysis was performed using RevMan5.3 software. Only randomized controlled trials (RCT) or controlled clinical trials (CCT) were considered in TCM-based exercises (Tai Chi, Ba Duan Jin, Qigong). The overall mean difference (MD) or standardized mean difference (SMD), and its 95% confidence interval (CI) were calculated. MAIN RESULTS: A total of 27 studies with 2580 older adults met the inclusion criteria. The pooled analysis indicated that Tai Chi could be more effective in Times up and go (TUG) (MD = - 2.62, 95% CI - 4.00 to - 1.24, P = 0.0002), 5 times sit-stand (MD = - 1.89; 95%CI - 3.38 to - 0.40; P = 0.01), and handgrip strength outcomes (SMD = 0.69; 95%CI 0.52-0.86; P < 0.0001) compared to Ba Duan Jin and Qigong. The older adults performing Qigong could have a better benefit in Single-bed balance (SLB) with eyes closed compared to Tai Chi and Ba Duan Jin (MD = 3.42; 95%CI 1.55 to 5.29; P = 0.0003). Tai Chi also had benefits in terms of balance outcomes compared to those in the control group: Berg Balance scale (BBS) (MD = 1.41; 95% CI 0.03-2.85; P = 0.05), Functional reach test (FRT) (MD = 1.57; 95%CI 1.22-1.93; P < 0.0001). The Tai Chi study meta-analysis demonstrated significant effects on lower limb strength: knee extension (SMD = 0.56; 95%CI 0.26-0.86; P = 0.0003), ankle dorsiflexion (SMD = 0.67; 95%CI 0.02-1.31; P = 0.04) compared to the controls. CONCLUSION: This systematic review reveals that TCM-based exercises can effectively improve physical performance outcomes, balance outcomes, and muscle strength in the elderly population. While there is limited evidence on the efficacy of other TCM-based lifestyle interventions, more high-quality clinical trials on this topic are warranted.

When to end the continuing violence against physicians in China.

The trend of violent events against physicians remains ongoing in China. Doctors and medical institutions seem to be a weak side compared with patients and their relatives due to the media's partial attitudes. Harsh laws that punish violent crimes are warranted to be promulgated to protect physicians' safety in China.

Major Vault Protein (MVP) Associated With BRAF V600E Mutation Is an Immune Microenvironment-Related Biomarker Promoting the Progression of Papillary Thyroid Cancer via MAPK/ERK and PI3K/AKT Pathways.

Papillary thyroid cancer (PTC) is the most common malignancy of the endocrine system, with an increase in incidence frequency. Major vault protein (MVP) is the main structural protein of the vault complex that has already been investigated in specific cancers. Yet the underlying biological functions and molecular mechanisms of MVP in PTC still remain considerably uncharacterized. Comprehensive analyses are predicated on several public datasets and local RNA-Seq cohort. Clinically, we found that MVP was upregulated in human PTC than in non-cancerous thyroid tissue and was correlated with vital clinicopathological parameters in PTC patients. MVP expression was associated with BRAF V600E, RAS, TERT, and RET status, and it was correlated with worse progression-free survival in PTC patients. Functionally, enrichment analysis provided new clues for the close relationship between MVP with cancer-related signaling pathways and the immune microenvironment in PTC. In PTC with high MVP expression, we found CD8+ T cells, regulatory T cells, and follicular helper T cells have a higher infiltration level. Intriguingly, MVP expression was positively correlated with multiple distinct phases of the anti-cancer immunity cycle. MVP knockdown significantly suppressed cell viability and colony formation, and promoted apoptosis. In addition, downregulated MVP markedly inhibited the migration and invasion potential of PTC cells. The rescue experiments showed that MVP could reverse the level of cell survival and migration. Mechanistically, MVP exerts its oncogenic function in PTC cells through activating PI3K/AKT/mTOR and MAPK/ERK pathways. These results point out that MVP is a reliable biomarker related to the immune microenvironment and provide a basis for elucidating the oncogenic roles of MVP in PTC progression.

Doctors in China Need More Power of Discourse.

COVID-19 that developed in late 2019 and 2020 is a severe threat to human health. The tragedy of Dr Li Wenliang, the whistleblower, revealed a current status of doctors' insufficient power of disclosure. Therefore, prompt and effective actions warrant to be taken by the government and public to improve Chinese doctors' power of disclosure. A medical system based on the improved doctors' power of disclosure is beneficial to disease prevention in an extended period.

Tai Chi Chuan for Subjective Sleep Quality: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: This review aims to investigate the efficacy of Tai Chi Chuan on subjective sleep quality among adults. METHODS: We systematically searched PubMed, Embase, Cochrane Library, Scopus, CNKI (China National Knowledge Infrastructure), and the Wanfang Database from their inception to August 2019 and identified 25 eligible studies that were published in both English and Chinese. RESULTS: 24 out of 25 studies were identified to be high-quality studies according to the PEDro scale. The pooled results confirmed that Tai Chi Chuan elicited moderate improvements in subjective sleep quality (SMD = -0.512, 95% CI [-0.767, -0.257], P < 0.001). Notably, Tai Chi Chuan yielded more significant effects on sleep quality among the healthy population (SMD = -0.684, 95% CI [-1.056, -0.311], P < 0.001) than the clinical population (SMD = -0.395, 95% CI [-0.742, -0.047], P=0.026) and more benefits among the Asian population (SMD = -0.977, 95% CI [-1.446, -0.508], P < 0.001) than the American population (SMD = -0.259, 95% CI [-0.624, 0.105], P=0.164). After controlling the methodological quality of studies, it has been noted that Asians could achieve the most significant sleep-promoting benefit when Tai Chi Chuan was practiced between 60 and 90 min per session. CONCLUSIONS: Available data implied that subjective sleep quality was improved via Tai Chi training, but more thorough studies must be executed to ascertain our findings and optimize Tai Chi practices accordingly toward various populations.

Effectiveness and safety of Guilu Erxian Glue (a traditional Chinese medicinal product) for the treatment of postmenopausal osteoporosis: A protocol for systematic review and meta-analysis.

BACKGROUND: The prevalence of postmenopausal osteoporosis is rapidly rising, with a high proportion of patients who are vulnerable to fractures and other chronic symptoms. The commonly applied Western medicine lacks cost-efficiency and tends to have various potential side effects. Guilu Erxian Glue (GEG), an orally taken traditional Chinese medicinal product, has been advocated to manage osteoporosis for a long period. However, the evidence of the efficacy of GEG on osteoporosis seems to be less convincing and conclusive. Therefore, the purpose of this study is to assess the effectiveness and safety of GEG on postmenopausal osteoporosis. METHODS: We will implement a systematic review and meta-analysis following the requests of the preferred reporting items for systematic reviews and meta-analyses protocols (PRISMA-P). The PubMed database, Scopus, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, VIP database, Sinomed, and grey literature sources will be retrieved for eligible studies. Randomized controlled trials investigating GEG in women with postmenopausal osteoporosis employing osteoporosis-associated outcomes measures will be eligible for inclusion. Two reviewers will independently complete the study selection procedure, data extraction, and risk of bias assessment. A third reviewer will mediate when irreconcilable discrepancies occur. Should sufficient clinical homogeneity exist, a meta-analysis will be conducted. Additionally, we will utilize the Grading of Recommendations Assessment, Development and Evaluation to assess the strength of quantitative outcomes. RESULTS: The current systematic review and meta-analysis will provide the effectiveness and safety of GEG on postmenopausal osteoporosis. CONCLUSION: The study will offer high-quality and explicit evidence for applying GEG on the treatment of postmenopausal osteoporosis. OSF REGISTRATION: DOI 10.17605/OSF.IO/JCVBH.

Prevalence of osteoporosis in patients with type 2 diabetes mellitus in the Chinese mainland: A protocol of systematic review and meta-analysis.

BACKGROUND: Osteoporosis, as a metabolic disease, has become one of the most rapidly growing complications of diabetes mellitus. Previously, we conducted a systematic review to report the estimated prevalence of osteoporosis among patients with type 2 diabetes mellitus (T2DM) from 2001 to 2016. However, some newer studies have been reported, and more potential risk factors for osteoporosis remain controversial and vague. Therefore, the presented review is tailored to synthesize available evidence regarding the pooled prevalence and related risk factors of osteoporosis among T2DM patients in mainland China. METHODS: Both cross-sectional study and cohort study reporting on the prevalence of osteoporosis among patients with T2DM in mainland China, published in Chinese or English, will be considered for inclusion. Records from 4 English databases and 2 Chinese databases will be retrieved from their inceptions to March 2020. The process of study selection, data extraction, and methodologic quality assessment will be independently executed by 2 reviewers. The pooled prevalence of osteoporosis and the prevalence in the exposed and unexposed groups for each potential risk factor will be calculated by the software Stata version 12.0. RESULTS: The current systematic review and meta-analysis will provide more precise prevalence rates and associated risk factors of osteoporosis among people with T2DM in mainland China. CONCLUSION: The study will offer high-quality and explicit evidence for assisting diabetic patients to prevent osteoporosis in mainland China. OSF REGISTRATION: DOI 10.17605/OSF.IO/5ZKJ6.

Osthole-loaded N-octyl-O-sulfonyl chitosan micelles (NSC-OST) inhibits RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss in rats.

Osthole (OST), a derivative of Fructus Cnidii, has been proved to have potential anti-osteoporosis effects in our recent studies. However, its pharmacological effects are limited in the human body because of poor solubility and bioavailability. Under the guidance of the classical theory of Chinese medicine, Osthole-loaded N-octyl-O-sulfonyl chitosan micelles (NSC-OST), which has not previously been reported in the literature, was synthesized in order to overcome the defects and obtain better efficacy. In this study, we found that NSC-OST inhibited on the formation and resorption activity of osteoclasts through using a bone marrow macrophage (BMM)-derived osteoclast culture system in vitro, rather than affecting the viability of cells. We also found that NSC-OST inhibited osteoclast formation, hydroxyapatite resorption and RANKL-induced osteoclast marker protein expression. In terms of mechanism, NSC-OST suppressed the NFATc1 transcriptional activity and the activation of NF-κB signalling pathway. In vivo, ovariectomized (OVX) rat models were established for further research. We found that NSC-OST can attenuate bone loss in OVX rats through inhibiting osteoclastogenesis. Consistent with our hypothesis, NSC-OST is more effective than OST in parts of the results. Taken together, our findings suggest that NSC-OST can suppress RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss in rats and could be considered a safe and more effective anti-osteoporosis drug than OST.

Tai Chi exercise for sleep problems in older adults: A protocol of systematic review and meta-analysis.

BACKGROUND: Sleep plays a crucial role in the general health of the human body. However, sleep problems become increasingly severe with age, and its incidence is on the rise. Notably, Tai Chi exercise may be an efficacious means to ameliorate sleep problems among older adults. This is especially since Tai Chi has been widely used to manage sleep problems in China for many years, but there is limited evidence regarding its effectiveness. We will conduct this study aiming to investigate the efficacy of Tai Chi as a complementary and alternative therapy for sleep problems in older adults. METHODS: We will systematically search Scopus, Embase, PubMed, Cochrane Library, China National Knowledge Infrastructure, and Wanfang database from their inceptions to August 2019. Only randomized controlled trials of Tai Chi for sleep problems among older adults will be considered for inclusion and the Pittsburgh sleep quality index will be the primary outcome measurement. Moreover, study selection, data extraction, and the evaluation of the methodological quality of trials will each be independently completed by at least 2 researchers. We will employ the software Stata version 12.0 to implement the statistical analysis. RESULTS: The current systematic review and meta-analysis will provide synthesized results of the effectiveness and safety of Tai Chi exercise for sleep problems among older adults. CONCLUSION: This systematic review and meta-analysis will provide high-quality evidence on the effectiveness and safety of Tai Chi exercise for sleep problems in older adults. REGISTRATION: PEROSPERO CRD42019129782.

Prevalence of Osteoporosis in Patients with Type 2 Diabetes Mellitus in the Chinese Mainland: A Systematic Review and Meta-Analysis.

BACKGROUND: Some studies have investigated the prevalence of osteoporosis in patients with type 2 diabetes mellitus (T2DM) in China. However, the results were inconsistent. This review was performed to estimate the prevalence of osteoporosis in T2DM patients in the Chinese mainland and to characterize its epidemiology. METHODS: A literature search was conducted utilizing PubMed, Scopus, Web of Science, Cochrane Library, CNKI, Wanfang database from their inception through June 2017. A total of 54 studies evaluating the prevalence rate of osteoporosis in T2DM patients were collected. Prevalence estimates from the individual study were combined utilizing random-effect models in Stata 12.0. RESULTS: The pooled prevalence rate of osteoporosis in T2DM patients was 37.8%. Notably, osteoporosis was more frequent in females than in males (44.8% vs. 37.0%) and was increased with ageing (over 60: 40.1% vs. below 60: 26.5%). Osteoporosis prevalence was higher in less developed areas than in developed areas (41.0% vs. 32.7%) and almost the same between the southern and northern regions (37.6% vs. 38.2%). The prevalence rate between 2010 and 2017 decreased compared with the period between 2001 and 2009 (42.3% vs. 35.6%). Additionally, the meta-regression suggested that gender and age could significantly influence the estimation of prevalence rates respectively (P = 0.011, P = 0.022). CONCLUSION: Osteoporosis affects more than one-third of T2DM patients in China mainland. Females and older adults more likely require clinical prevention due to a higher prevalence. Further studies are needed to be conducted to incorporate and verify previous results.

Efficacy and safety of Shaoyang Xibi decoction in patients with knee osteoarthritis: a multi-center, single-blind, randomized controlled trial.

PURPOSE: To observe the efficacy and safety of Shaoyang Xibi decoction (SYXBD) in patients with knee osteoarthritis (KOA), and to verify that the theory of ""Shaoyang dominating bone"" in Traditional Chinese Medicine (TCM) can be applied to KOA treatment. METHODS: Participants were randomly allocated to two groups: SYXBD (treatment group, n = 66) and Meloxicam (control group, n = 66). Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and 36-Item Short Form Health Survey (SF-36) were used to assess efficacy before the treatment and 8 weeks after the treatment. RESULTS: Baseline data before the treatment between the two groups were similar. The WOMAC scores significantly decreased and the SF-36 scores significantly increased after 8- week treatment in both groups compared with before the treatment (P < 0.05). SYXBD significantly decreased pain scores (P < 0.001), physical function scores (P < 0.001) and the total scores (P < 0.001) in WOMAC compared to Meloxicam. SYXBD significantly improved physical function (P = 0.021), bodily pain (P = 0.002) and general health (P = 0.014), with no significant difference in role emotional (P = 0.053), role physical (P = 0.517), vitality (P = 0.241), social function (P = 0.712) and mental health (P = 0.800) in SF-36 compared to Meloxicam. No adverse events were reported in the treatment group while 13 adverse events happened in the control group during the study. CONCLUSION: SYXBD, prepared based on the theory of ""Shaoyang dominating bone"", has a better curative efficay and safety in patients with KOA compared with Meloxicam. The TCM theory of ""Shaoyang dominating bone"" may be useful in KOA treatment.