Menarche-a journey into womanhood: age at menarche and health-related outcomes in East Asians.

STUDY QUESTION: Are there associations of age at menarche (AAM) with health-related outcomes in East Asians? SUMMARY ANSWER: AAM is associated with osteoporosis, Type 2 diabetes (T2D), glaucoma, and uterine fibroids, as demonstrated through observational studies, polygenic risk scores, genetic correlations, and Mendelian randomization (MR), with additional findings indicating a causal effect of BMI and T2D on earlier AAM. WHAT IS KNOWN ALREADY: Puberty timing is linked to adult disease risk, but research predominantly focuses on European populations, with limited studies in other groups. STUDY DESIGN, SIZE, DURATION: We performed an AAM genome-wide association study (GWAS) with 57 890 Han Taiwanese females and examined the association between AAM and 154 disease outcomes using the Taiwanese database. Additionally, we examined genetic correlations between AAM and 113 diseases and 67 phenotypes using Japanese GWAS summary statistics. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed AAM GWAS and gene-based GWAS studies to obtain summary statistics and identify potential AAM-related genes. We applied phenotype, polygenic risk scores, and genetic correlation analyses of AAM to explore health-related outcomes, using multivariate regression and linkage disequilibrium score regression analyses. We also explored potential bidirectional causal relationships between AAM and related outcomes through univariable and multivariable MR analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Fifteen lead single-nucleotide polymorphisms and 24 distinct genes were associated with AAM in Taiwan. AAM was genetically associated with later menarche and menopause, greater height, increased osteoporosis risk, but lower BMI, and reduced risks of T2D, glaucoma, and uterine fibroids in East Asians. Bidirectional MR analyses indicated that higher BMI/T2D causally leads to earlier AAM. LIMITATIONS, REASONS FOR CAUTION: Our findings were specific to Han Taiwanese individuals, with genetic correlation analyses conducted in East Asians. Further research in other ethnic groups is necessary. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides insights into the genetic architecture of AAM and its health-related outcomes in East Asians, highlighting causal links between BMI/T2D and earlier AAM, which may suggest potential prevention strategies for early puberty. STUDY FUNDING/COMPETING INTEREST(S): The work was supported by China Medical University, Taiwan (CMU110-S-17, CMU110-S-24, CMU110-MF-49, CMU111-SR-158, CMU111-MF-105, CMU111-MF-21, CMU111-S-35, CMU112-SR-30, and CMU112-MF-101), the China Medical University Hospital, Taiwan (DMR-111-062, DMR-111-153, DMR-112-042, DMR-113-038, and DMR-113-103), and the Ministry of Science and Technology, Taiwan (MOST 111-2314-B-039-063-MY3, MOST 111-2314-B-039-064-MY3, MOST 111-2410-H-039-002-MY3, and NSTC 112-2813-C-039-036-B). The funders had no influence on the data collection, analyses, or conclusions of the study. No conflict of interests to declare. TRIAL REGISTRATION NUMBER: N/A.

KCNQ1 variants associate with hypertension in type 2 diabetes and affect smooth muscle contractility in vitro.

KCNQ1 encodes a potassium voltage-gated channel and represents a susceptibility locus for type 2 diabetes mellitus (T2DM). Here, we explored the association between KCNQ1 polymorphisms and hypertension risk in individuals with T2DM, as well as the role of KCNQ1 in vascular smooth muscle cell contraction in vitro. To investigate the relationship between KCNQ1 and the risk of developing hypertension in patients with T2DM, we divided the T2DM cohort into hypertension (n = 452) and non-hypertension (n = 541) groups. The Mann-Whitney U test, chi-square test, and multivariate regression analyses were used to assess the clinical characteristics and genotypic frequencies. In vitro studies utilized the rat aortic smooth muscle A10 cell line. Patients in the hypertension group were significantly older at the time of enrollment and had higher levels of body mass index, waist-to-hip ratio, and triglyceride than those in the non-hypertension group. The KCNQ1 rs3864884 and rs12576239 genetic variants were associated with hypertension in T2DM. KCNQ1 expression was lower in the individuals with the CC versus the CT and TT genotypes. Smooth muscle cell contractility was inhibited by treatment with a KCNQ1 inhibitor. These results suggest that KCNQ1 might be associated with hypertension in individuals with T2DM.

YKL-40-Induced Inhibition of miR-590-3p Promotes Interleukin-18 Expression and Angiogenesis of Endothelial Progenitor Cells.

YKL-40, also known as human cartilage glycoprotein-39 or chitinase-3-like-1, is a pro-inflammatory protein that is highly expressed in rheumatoid arthritis (RA) patients. Angiogenesis is a critical step in the pathogenesis of RA, promoting the infiltration of inflammatory cells into joints and providing oxygen and nutrients to RA pannus. In this study, we examined the effects of YKL-40 in the production of the pro-inflammatory cytokine interleukin-18 (IL-18), and the stimulation of angiogenesis and accumulation of osteoblasts. We observed that YKL-40 induces IL-18 production in osteoblasts and thereby stimulates angiogenesis of endothelial progenitor cells (EPCs). We found that this process occurs through the suppression of miR-590-3p via the focal adhesion kinase (FAK)/PI3K/Akt signaling pathway. YKL-40 inhibition reduced angiogenesis in in vivo models of angiogenesis: the chick embryo chorioallantoic membrane (CAM) and Matrigel plug models. We report that YKL-40 stimulates IL-18 expression in osteoblasts and facilitates EPC angiogenesis.

Berberine attenuates CCN2-induced IL-1ß expression and prevents cartilage degradation in a rat model of osteoarthritis.

Connective tissue growth factor (CTGF; also known as CCN2) is an inflammatory mediator that is abundantly expressed in osteoarthritis (OA). Interleukin-1ß (IL-1ß) plays a pivotal role in OA pathogenesis. Berberine exhibits an anti-inflammatory effect, but the mechanisms by which it modulates CCN2-induced IL-1ß expression in OA synovial fibroblasts (OASFs) remain unknown. We showed that CCN2-induced IL-1ß expression is mediated by the activation of αvß3/αvß5 integrin-dependent reactive oxygen species (ROS) generation, and subsequent activation of apoptosis signal-regulating kinase 1 (ASK1), p38/JNK, and nuclear factor-κB (NF-κB) signaling pathways. This IL-1ß expression in OASFs is attenuated by N-acetylcysteine (NAC), inhibitors of ASK1, p38, or JNK, or treatment with berberine. Furthermore, berberine also reverses cartilage damage in an experimental model of collagenase-induced OA (CIOA). We observed that CCN2 increased IL-1ß expression via αvß3/αvß5 integrins, ROS, and ASK1, p38/JNK, and NF-κB signaling pathways. Berberine was found to inhibit these signaling components in OASFs in vitro and prevent cartilage degradation in vivo. We suggest a novel therapeutic strategy of using berberine for managing OA.

Genetic predisposition to bone mineral density and their health conditions in East Asians.

Osteoporosis, a condition defined by low bone mineral density (BMD) (typically < -2.5 SD), cause a higher fracture risk and lead to significant economic, social, and clinical impacts. Genome-wide studies mainly in Caucasians have found many genetic links to osteoporosis, fractures, and BMD, with limited research in East Asians. We investigated the genetic aspects of BMD in 86,716 individuals from the Taiwan Biobank and their causal links to health conditions within East Asians. A genome-wide association study (GWAS) was conducted, followed by observational studies, polygenic risk score assessments, and genetic correlation analyses to identify associated health conditions linked to BMD. GWAS and gene-based GWAS studies identified 78 significant SNPs and 75 genes related to BMD, highlighting pathways like Hedgehog, WNT-mediated, and TGF-ß. Our cross-trait linkage disequilibrium score regression analyses for BMD and osteoporosis consistently validated their genetic correlations with body mass index (BMI) and type 2 diabetes (T2D) in East Asians. Higher BMD was linked to lower osteoporosis risk but increased BMI and T2D, whereas osteoporosis linked to lower BMI, waist circumference, HbA1c, and reduced T2D risk. Bidirectional Mendelian randomization (MR) analyses revealed that a higher BMI causally increases BMD in East Asians. However, no direct causal relationships were found between BMD and T2D, or between osteoporosis and either BMI or T2D. This study identified key genetic factors for bone health in Taiwan, and revealed significant health conditions in East Asians, particularly highlighting the genetic interplay between bone health and metabolic traits like T2D and BMI.

We investigated how genetics affect bone health and related conditions like diabetes and obesity in 86,716 East Asians. Previously, most studies focused on Caucasian populations, but our work helps to understand these issues in East Asians. Our findings show that stronger bones are linked to a lower chance of osteoporosis but a higher risk of obesity and type 2 diabetes. On the other hand, those with osteoporosis tend to have lower body weight and a decreased risk of diabetes, illustrating a complex relationship between bone health and body metabolism. Future research will focus on deeper genetic interactions and developing targeted interventions for bone health and related metabolic disorders in East Asians.

Si-Wu-tang extract stimulates bone formation through PI3K/Akt/NF-κB signaling pathways in osteoblasts.

BACKGROUND: Si-Wu-Tang (SWT), a Traditional Chinese Medicine (TCM) formula, is widely used for the treatment of gynopathies diseases such as menstrual discomfort, climacteric syndrome, dysmenorrhea, and other estrogen-related diseases. Recent studies have shown that SWT can treat primary dysmenorrhea, have anti-pruritic anti-inflammatory effects, and protect against radiation-induced bone marrow damage in an animal model. It has been reported that anti-inflammatory and anti-oxidant agents have the potential to treat osteoporosis by increasing bone formation and/or suppressing bone resorption. However, the effect of SWT on bone cell function has not yet been reported. METHODS: Alkaline phosphatase (ALP), bone morphogenetic proteins (BMP)-2, and osteopontin (OPN) mRNA expression was analyzed by qPCR. The mechanism of action of SWT extract was investigated using western blotting. The in vivo anti-osteoporotic effect of SWT extract was assessed in ovariectomized mice. RESULTS: Here, we report that SWT increases ALP, BMP-2, and OPN expression as well as bone mineralization. In addition, we show that the PI3K, Akt, and NF-κB signaling pathways may be involved in the SWT-mediated increase in gene expression and bone mineralization. Notably, treatment of mice with SWT extract prevented bone loss induced by ovariectomy in vivo. CONCLUSION: SWT may be used to stimulate bone formation for the treatment of osteoporosis.

Fu's Subcutaneous Needling for Knee Osteoarthritis Pain.

Fu's subcutaneous needling (FSN) is a new acupuncture and dry needling technique based on traditional Chinese medicine. It rapidly produces long-lasting effects in soft tissue injuries, particularly in painful musculoskeletal conditions, by providing stimulation primarily in the subcutaneous area. Osteoarthritis (OA) is the most common joint disease in adults worldwide and is often accompanied by a painful syndrome of structural changes in the peripheral joints of the knee. However, the etiology of OA pain is not fully understood, though myofascial trigger points (MTrPs) are commonly found in the lower limb muscles (so-called "tightened muscles") of patients with knee OA. FSN has been used in many fields for the treatment of acute pain problems and can relieve muscle contraction from MTrPs, thereby improving the local circulation. This study recruited patients with pain from knee OA into an FSN group or a transcutaneous electrical nerve stimulation (TENS) group with three treatment sessions and a follow-up over the course of 2 weeks. The results showed that FSN was effective in treating soft tissue pain around the knee with OA. This study aimed to establish and visualize three key technical indicators during FSN therapy, including the FSN needle insertion point and layer; the frequency and duration of the swaying movement; and the manipulation of the reperfusion approach. These findings have great potential for future applications in myofascial pain treatment, especially for pain management. Following this protocol could enhance FSN skills.

Effect of Chinese herbal medicine therapy on risks of all-cause mortality, infections, parasites, and circulatory-related mortality in HIV/AIDS patients with neurological diseases.

Introduction: Long-term living with human immunodeficiency virus (HIV) and/or antiretroviral therapy (ART) is associated with various adverse effects, including neurocognitive impairment. Heterogeneous neurocognitive impairment remains an important issue, affecting between 15-65% of human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) patients and resulting in work performance, safety, and health-related outcomes that have a heavy economic burden. Methods: We identified 1,209 HIV/AIDS patients with neurological diseases during 2010-2017. The Kaplan-Meier method, log-rank test, and Cox proportional hazards model were used to analyze 308 CHM users and 901 non-CHM users within this population. Major CHM clusters were determined using association rule mining and network analysis. Results and Discussion: Results showed that CHM users had a 70% lower risk of all-cause mortality (adjusted hazard ratio (aHR) = 0.30, 95% confidence interval (CI):0.16-0.58, p < 0.001) (p = 0.0007, log-rank test). Furthermore, CHM users had an 86% lower risk of infections, parasites, and circulatory-related mortality (aHR = 0.14, 95% confidence interval (CI):0.04-0.46, p = 0.001) (p = 0.0010, log-rank test). Association rule mining and network analysis showed that two CHM clusters were important for patients with neurological diseases. In the first CHM cluster, Huang Qin (HQ; root of Scutellaria baicalensis Georgi), Gan Cao (GC; root of Glycyrrhiza uralensis Fisch.), Huang Lian (HL; root of Coptis chinensis Franch.), Jie Geng (JG; root of Platycodon grandiflorus (Jacq.) A.DC.), and Huang Bai (HB; bark of Phellodendron amurense Rupr.) were identified as important CHMs. Among them, the strongest connection strength was identified between the HL and HQ. In the second CHM cluster, Suan-Zao-Ren-Tang (SZRT) and Ye Jiao Teng (YJT; stem of Polygonum multiflorum Thunb.) were identified as important CHMs with the strongest connection strength. CHMs may thus be effective in treating HIV/AIDS patients with neurological diseases, and future clinical trials are essential for the prevention of neurological dysfunction in the population.

Association of combination antiretroviral therapy with risk of neurological diseases in patients with HIV/AIDS in Taiwan: a nested case-control study.

Heterogeneous neurocognitive impairment remains an important issue, even in the era of combination antiretroviral therapy (cART), with an incidence ranging from 15% to 65%. Although ART drugs with higher penetration scores to the central nervous system (CNS) show better HIV replication control in the CNS, the association between CNS penetration effectiveness (CPE) scores and neurocognitive impairment remains inconclusive. To explore whether ART exposure is associated with the risk of neurological diseases among patients with HIV/AIDS, this study in Taiwan involved 2,571 patients with neurological diseases and 10,284 matched, randomly selected patients without neurological diseases between 2010 and 2017. A conditional logistic regression model was used in this study. The parameters for ART exposure included ART usage, timing of exposure, cumulative defined daily dose (DDD), adherence, and cumulative CPE score. Incident cases of neurological diseases, including CNS infections, cognitive disorders, vasculopathy, and peripheral neuropathy, were obtained from the National Health Insurance Research Database in Taiwan. Odds ratios (ORs) for the risk of neurological diseases were conducted using a multivariate conditional logistic regression model. Patients with a history of past exposure (OR: 1.68, 95% confidence interval [CI]:1.22-2.32), low cumulative DDDs (< 2,500) (OR: 1.28, 95% CI: 1.15-1.42), low adherence (0 < adherence (ADH) ≤ 0.8) (OR: 1.46, 95% CI: 1.30-1.64), or high cumulative CPE scores (>14) (OR: 1.34, 95% CI: 1.14-1.57) had a high risk of neurological diseases. When stratified by classes of ART drugs, patients with low cumulative DDDs or low adherence had a high risk of neurological diseases, including NRTIs, PIs, NNRTIs, INSTIs, and multi-drug tablets. Subgroup analyses also suggested that patients with low cumulative DDDs or low adherence had a high risk of neurological diseases when they had high cumulative CPE scores. Patients with high cumulative DDDs or medication adherence were protected against neurological diseases only when they had low cumulative CPE scores (≤ 14). Patients may be at risk for neurological diseases when they have low cumulative DDDs, low adherence, or usage with high cumulative CPE scores. Continuous usage and low cumulative CPE scores of ART drugs may benefit neurocognitive health in patients with HIV/AIDS.

Interleukin-11 increases cell motility and up-regulates intercellular adhesion molecule-1 expression in human chondrosarcoma cells.

Interleukin-11 (IL-11) was originally identified as the cytokine that could induce the proliferation of human cells. Recent studies have shown that IL-11 plays a critical role in tumor growth, angiogenesis, and metastasis. Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. However, the effects of IL-11 on human chondrosarcoma cells are largely unknown. Here, we found that IL-11 increased the migration and expression of intercellular adhesion molecule-1 (ICAM)-1 in human chondrosarcoma cells. We also found that human chondrosarcoma tissues had significant expression of the IL-11 which was higher than that in primary chondrocytes. The phosphatidylinositol 3-kinase (PI3K), Akt, and NF-κB pathways were activated by IL-11 treatment, and the IL-11-induced expression of ICAM-1 and migration activity were inhibited by the specific inhibitors and mutant forms of PI3K, Akt, and NF-κB cascades. Taken together, our results indicate that IL-11 enhanced the migration of the chondrosarcoma cells by increasing ICAM-1 expression through the IL-11Rα receptor, PI3K, Akt, and NF-κB signal transduction pathway.

Efficacy of Fu's Subcutaneous Needling in Treating Soft Tissue Pain of Knee Osteoarthritis: A Randomized Clinical Trial.

Purpose: Fu's subcutaneous needling (FSN) is a new acupuncture technique that produces a long-lasting effect in soft-tissue injuries. In patients with degenerative knee osteoarthritis (OA), myofascial trigger points (MTrPs) are common in the lower-limb muscles. In this randomized clinical trial, we evaluated the immediate, 1-week and 2-week effectiveness of FSN therapy in the treatment of degenerative knee OA. Patients and methods: We randomly divided 32 patients with knee OA into the FSN group (mean age: 65.73 ± 6.79 years) or the transcutaneous electrical nerve stimulation (TENS) group (mean age: 62.81 ± 5.72 years). The pressure pain threshold (PPT) and tissue hardness (TH) of the muscle and tendon attachment sites, knee range of motion, and physical ability (average walking speed) were measured. The subjective pain intensity index, Western Ontario and McMaster Universities OA Index (WOMAC), and Lequesne index were used to determine the efficacy of FSN on MTrP-induced soft-tissue pain compared with that of TENS. Results: A significantly greater improvement in pain qualities in the VAS (p < 0.05) was found in the FSN group. Moreover, in muscle and tendon qualities (including PPT and TH), a significant difference in the PPT of the quadriceps muscle (p < 0.05) was also observed among the immediate treatments in the FSN group. As for the functional index questionnaire assessment, the FSN group exhibited significant improvements among the immediate, 1-week and 2-week efficacies in terms of WOMAC (p < 0.05) and Lequesne index scores (p < 0.05). Conclusion: FSN was effective in treating soft-tissue pain in degenerative knee OA in terms of alleviating pain, strengthening walking ability, and improving overall functional performance. Pain relief was the primary benefit of FSN and a significant correlation between pain relief and knee joint mobility improvement was found. Trial registration: ClinicalTrials.gov Protocol Registration and Results System (registration number: NCT04356651).

Concurrent use of Chinese herbal medicine and anticoagulants may reduce major bleeding events.

BACKGROUND: This retrospective cohort study investigated the risk of major bleeding events during the concurrent use of Chinese herbal medicine (CHM) and anticoagulants in clinical practice. METHODS: A total of 4,470 patients receiving anticoagulant drugs were selected from Taiwan's National Health Insurance Research Database (NHIRD). Half (n = 2,235) were also using CHMs (CHM cohort); the other half were not (non-CHM cohort). Each cohort was matched 1:1 using the propensity score. Chi-square testing and the Student's t-test were used to examine differences between two cohorts. Cox proportional hazard regression analysis assessed the risks for major bleeding events in each cohort, as well as bleeding risks associated with specific CHM formulas and herbs. Cumulative incidence curves for major bleeding events were calculated using Kaplan-Meier analysis. RESULTS: Compared with the non-CHM cohort, the CHM cohort had a lower risk of overall bleeding events (p < 0.001) including hemorrhagic stroke (p = 0.008), gastrointestinal (GI) bleeding (p < 0.001), urogenital bleeding (p ≤ 0.001) and nasal/ear/eye bleeding (p = 0.004). Single herbs, such as Glycyrrhiza uralensis et Rhizoma, Panax notoginseng, Panax ginseng, Platycodon grandiflorum, Eucommia ulmoides Oliver and formulas, such as Shu Jing Huo Xue Tang, Shao Yao Gan Cao Tang and Ji Sheng Shen Qi Wan were associated with a lower risk of major bleeding events. CONCLUSION: Using CHMs with anticoagulants appeared to decrease the risk of major bleeding, especially CHMs products containing Glycyrrhiza uralensis et Rhizoma, Panax notoginseng, Panax ginseng, Platycodon grandiflorum and Eucommia ulmoides Oliver. Further investigations are needed to determine whether CHM can maintain the therapeutic efficacy of anticoagulants while simultaneously reducing potential side effects.

Effect of Chinese Herbal Medicine Therapy on Risks of Overall, Diabetes-Related, and Cardiovascular Diseases-Related Mortalities in Taiwanese Patients With Hereditary Hemolytic Anemias.

Hereditary Hemolytic Anemias (HHAs) are a rare but heterogeneous group of erythrocytic diseases, characterized by intrinsic cellular defects due to inherited genetic mutations. We investigated the efficacy of Chinese herbal medicine (CHM) in reducing the overall, diabetes-related, and cardiovascular diseases (CVDs)-related mortalities among patients with HHAs using a nationwide population database. In total, we identified 33,278 patients with HHAs and included 9,222 non-CHM and 9,222 CHM matched pairs after matching. The Cox proportional hazards model was used to compare the risk of mortality between non-CHM and CHM users. The Kaplan-Meier method and log-rank test were used to compare the cumulative incidence mortality between non-CHM and CHM users. The CHM prescription patterns were presented by the association rules and network analyses, respectively. The CHM prescription patterns were presented by the association rules and network analyses, respectively. CHM users showed significant reduced risks for of overall (adjusted hazard ratio [aHR]: 0.67, 95% confidence interval [CI]: 0.61-0.73, p < 0.001), diabetes-related (aHR: 0.57, 95% CI: 0.40-0.82, p < 0.001), and CVDs-related (aHR: 0.59, 95% CI: 0.49-0.72, p < 0.001) mortalities compared with non-CHM users. Two CHM clusters are frequently used to treat Taiwanese patients with HHAs. Cluster 1 is composed of six CHMs: Bei-Mu (BM; Fritillaria cirrhosa D.Don), Gan-Cao (GC; Glycyrrhiza uralensis Fisch.), Hai-Piao-Xiao (HPX; Endoconcha Sepiae), Jie-Geng (JG; Platycodon grandiflorus (Jacq.) A.DC.), Yu-Xing-Cao (YXC; Houttuynia cordata Thunb.), and Xin-Yi-Qing-Fei-Tang (XYQFT). Cluster 2 is composed of two CHMs, Dang-Gui (DG; Angelica sinensis (Oliv.) Diels) and Huang-Qi (HQi; Astragalus membranaceus (Fisch.) Bunge). Further randomized clinical trials are essential to evaluate the safety and effectiveness of above CHM products and to eliminate potential biases in the current retrospective study.

IGF-I enhances α5ß1 integrin expression and cell motility in human chondrosarcoma cells.

Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. Integrins are the major adhesive molecules in mammalian cells and have been associated with metastasis of cancer cells. Insulin-like growth factor-I (IGF)-I plays an important role in regulating cell growth, proliferation, survival, and metabolism. However, the effects of IGF-I in migration and integrin expression in chondrosarcoma cells are largely unknown. In this study, we found that IGF-I increased the migration and the expression of α5ß1 integrin in human chondrosarcoma cells. Pretreatment of cells with IGF-I receptor antibody reduced IGF-I-induced cell migration and integrin expression. Activations of phosphatidylinositol 3-kinase (PI3K), Akt, and nuclear factor-κB (NF-κB) pathways after IGF-I treatment were demonstrated, and IGF-I-induced expression of integrin and migration activity was inhibited by the specific inhibitor and mutant of PI3K, Akt, and NF-κB cascades. Taken together, our results indicated that IGF-I enhances the migration of chondrosarcoma cells by increasing α5ß1 integrin expression through the IGF-I receptor/PI3K/Akt/NF-κB signal transduction pathway.

Epigallocatechin-3-gallate induces cell apoptosis of human chondrosarcoma cells through apoptosis signal-regulating kinase 1 pathway.

Chondrosarcoma is a malignant primary bone tumor that responds poorly to both chemotherapy and radiation therapy. (-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, has been shown to inhibit tumorigenesis and cancer cell growth in animal models. The aim of this study was to elucidate the mechanism of EGCG-induced apoptosis of human chondrosarcoma cells. EGCG induced cell apoptosis in human chondrosarcoma cell lines but not primary chondrocytes. EGCG induced upregulation of Bax and Bak, downregulation of Bcl-2 and Bcl-XL, and dysfunction of mitochondria in chondrosarcoma. We also found that the accumulation of reactive oxygen species (ROS) is a critical mediator in EGCG-induced cell death. EGCG induced apoptosis signal-regulating kinase 1 (ASK1) dephosphorylation and its dissociation from 14-3-3. Treatment of chondrosarcoma cells with EGCG induced p38 and c-jun-NH2-kinase (JNK) phosphorylation. Transfection with ASK1 siRNA or p38 and JNK mutant antagonized the EGCG-induced cell apoptosis. Therefore, EGCG triggered ROS and activated the ASK1-p38/JNK pathway, resulting chondrosarcoma cell death. Importantly, animal studies revealed a dramatic reduction in tumor volume after 24 days of treatment. Thus, EGCG may be a novel anti-cancer agent for the treatment of chondrosarcoma.

The novel benzimidazole derivative, MPTB, induces cell apoptosis in human chondrosarcoma cells.

Chondrosarcoma is a malignant primary bone tumor that responds poorly to both chemotherapy and radiation therapy. This study is the first to investigate the anti-cancer effects of the new benzimidazole derivative (5-methyl-2(pyridine-3-yl)-1-(3,4,5-trimethoxybenzyl)benzimidazole; MPTB) in human chondrosarcoma cells. MPTB-induced cell apoptosis in two human chondrosarcoma cell lines, JJ012 and SW1353 but not in primary chondrocytes. MPTB-induced upregulation of Bax and Bak and dysfunction of mitochondria in chondrosarcoma. MPTB triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol calcium levels, and increased glucose-regulated protein (GRP) expression. MPTB also increased calpain expression. Transfection of cells with GRP78 or calpain siRNA reduced MPTB-mediated cell apoptosis in JJ012 cells. Importantly, animal studies have revealed a dramatic 44% reduction in tumor volume after 21 d of treatment. This study demonstrates novel anti-cancer activity of MPTB against human chondrosarcoma cells and in murine tumor models.

Electroacupuncture at the Zusanli (ST-36) Acupoint Induces a Hypoglycemic Effect by Stimulating the Cholinergic Nerve in a Rat Model of Streptozotocine-Induced Insulin-Dependent Diabetes Mellitus.

Animal studies have shown that electroacupuncture (EA) at Zusanli (ST-36) and Zhongwan (CV-12) acupoints reduces plasma glucose concentrations in rats with type II diabetes. However, whether EA reduces plasma glucose levels in type I diabetes is still unknown. In this study, we explore the various non-insulin-dependent pathways involved in EA-induced lowering of plasma glucose. Streptozotocin (STZ) (60 mg kg(-1), i.v.) was administered via the femoral vein to induce insulin-dependent diabetes in non-adrenalectomized and in adrenalectomomized rats. EA (15 Hz) was applied for 30 min to bilateral ST-36 acupoints after administration of Atropine (0.1 mg kg(-1) i.p.), Eserine (0.01 mg kg(-1) i.p.), or Hemicholinium-3 (5 µg kg(-1) i.p.) in non-adrenalectomized rats. Rats administered acetylcholine (0.01 mg kg(-1) i.v.) did not undergo EA. Adrenalectomized rats underwent EA at bilateral ST-36 acupoints without further treatment. Blood samples were drawn from all rats before and after EA to measure changes in plasma glucose levels. Expression of insulin signaling proteins (IRS1, AKT2) in atropine-exposed rats before and after EA was measured by western blot. Atropine and hemicholinium-3 completely blocked the plasma glucose lowering effects of EA, whereas eserine led to a significant hypoglycemic response. In addition, plasma glucose levels after administration of acetylcholine were significantly lower than the fasting glucose levels. In STZ-adrenalectomized rats, EA did not induce a hypoglycemic response. EA stimulated the expression of IRS1 and AKT2 and atropine treatment blocked the EA-induced expression of those insulin signaling proteins. Taken together, EA at the ST-36 acupoint reduces plasma glucose concentrations by stimulating the cholinergic nerves.

Evaluating Effectiveness of Fu's Subcutaneous Needling for the Pain Nature and Quality of Life in Patients with Knee Osteoarthritis: A Study Protocol of Randomized Clinical Trial.

BACKGROUND: Knee osteoarthritis (OA) is a common clinical disease. Knee pain is the major symptom of knee OA and the primary reason why patients seek treatment. Fu's subcutaneous needling (FSN) has been used to treat knee OA for more than 20 years. However, the establishment of treatment methods and rigorous evaluation of FSN's efficacy are still lacking. A randomized single-blind clinical trial will be conducted to evaluate whether FSN treatment can immediately alleviate pain due to knee OA surrounding the patella and the curative effective of 1-week and 2-week treatments. In addition, the feasibility and initial effect of FSN treatment for patients with knee OA will be discussed. MATERIALS AND METHODS: Patients with confirmed knee OA, as diagnosed by doctors using X-ray films or from clinical symptoms, who are over 50 years old will be participants recruited. They will be randomly assigned either FSN treatment or transcutaneous electrical nerve stimulation treatment. In addition, their pressure pain threshold, muscle tone of lower leg muscle, and physical ability will be measured. Participants will be asked to complete the questionnaires of Western Ontario and McMaster Universities Osteoarthritis Index and Lequesne' index as the measurements for quality of life. RESULTS: The findings of this study will reveal whether FSN or transcutaneous electrical nerve stimulation is clinically efficacious for treating pain due to knee OA, with respect to muscle stiffness, gait, dynamic balance, the pressure pain threshold, and quality of life before and after treatment. STUDY REGISTRATION: This study is approved by the Research Ethics Committee of China Medical University & Hospital, Taichung, Taiwan (CMUH107-REC3-027) and registered at the ClinicalTrials.gov Protocol Registration and Results System (registration number NCT04356651).

Chinese Herbal Medicine Therapy Reduces the Risks of Overall and Anemia-Related Mortalities in Patients With Aplastic Anemia: A Nationwide Retrospective Study in Taiwan.

Aplastic Anemia (AA) is a rare but fatal hematologic disease that may occur at any age and especially higher in Asia. We investigated whether Chinese herbal medicine (CHM) is beneficial to AA patients as a complementary therapy using a nationwide population-based database in Taiwan between 2000-2016. Patient survival was estimated by Kaplan‒Meier survival analyses and Cox proportional-hazard model. CHM-users presented lower risks of overall and anemia-related mortalities when compared to non-users. The risk of overall mortality for CHM-users in AA patients was 0.70-fold [adjusted hazard ratio (aHR): 0.70, 95% confidence interval (CI): 0.66-0.74, p < 0.001). The risk of anemia-related mortality was lower in CHM-users when compared to non-users (aHR: 0.46, 95% CI: 0.32-0.67, p < 0.001). The association rule analysis revealed that CHM pairs were Ban-Zhi-Lian (BZL; Scutellaria barbata D. Don)→Bai-Hua-She-She-Cao (BHSSC; Oldenlandia diffusa (Willd.) Roxb.), followed by Dang-Gui (DG; Angelica sinensis (Oliv.) Diels)→Huang-Qi (HQi; Astragalus membranaceus (Fisch.) Bunge), and Xian-He-Cao (XHC; Agrimonia pilosa f. borealis (Kitag.) Chu)→Gui-Pi-Tang (GPT). Network analysis showed that BZL, BHSSC, DG, HQi, XHC, GPT, and Dan-Shen (DanS; Salvia miltiorrhiza var. charbonnelii (H.Lév.) C.Y.Wu) were commonly used CHMs for AA patients. Therefore, further studies for these commonly prescribed herbs are needed in functional investigations in hematopoiesis-stimulating effect and large-scale randomized controlled trials (RCT) in bone marrow failure related diseases.

Effects of Chinese herbal medicines on dementia risk in patients with sleep disorders in Taiwan.

ETHNOPHARMACOLOGICAL RELEVANCE: Sleep disorders affect an estimated 150 million people worldwide and result in adverse health, safety, and work performance-related outcomes that have important economic consequences. In Taiwan, Chinese herbal medicine (CHM) is a complementary natural medicine and has been widely used as an adjunctive therapy. AIM OF THE STUDY: This study aimed to investigate the effect of CHM on dementia risk in patients with sleep disorders in Taiwan. MATERIALS AND METHODS: We identified 124,605 patients with sleep disorders between the ages of 20 and 60 years. Of these, 5876 CHM users and 5876 non-CHM users were matched according to age and gender. The chi-squared test, Cox proportional hazard model, Kaplan-Meier method, and log-rank test were used for the comparisons. Association rule mining and network analysis were applied to determine a CHM pattern specialized for sleep disorders. RESULTS: More CHM users did not use sleeping pills than non-CHM users. CHM users had a lower risk of dementia than non-CHM users after adjusting for age, gender, and sleeping pill use (hazard ratio (HR): 0.469, 95% CI = 0.289-0.760; p-value = 0.002). The cumulative incidence of dementia was lower among CHM users (long-rank test, p-value < 0.001). Association rule mining and network analysis showed that Ye-Jiao-Teng (YJT; Caulis Polygoni Multiflori; Polygonum multiflorum Thunb), Suan-Zao-Ren-Tang (SZRT), Jia-Wei-Xiao-Yao-San (JWXYS), He-Huan-Pi (HHP; Cortex Albizziae; Albizia julibrissin Durazz.), and Suan-Zao-Ren (SZR; Semen Zizyphi Spinosae; Ziziphus jujuba Mill.) were important CHMs for patients with sleep disorders in Taiwan. CONCLUSIONS: A comprehensive list of herbal medicines may be useful for the clinical treatment of patients with sleep disorders, and for future scientific investigations into the prevention of dementia in these patients.