Xuemin Qiu

Bu-Shen-Ning-Xin decoction suppresses osteoclastogenesis via increasing dehydroepiandrosterone to prevent postmenopausal osteoporosis

Bu-Shen-Ning-Xin decoction (BSNXD), a traditional Chinese medicine, has been used to prevent and treat age-related diseases such as postmenopausal osteoporosis (PMO) for decades. This study sought to investigate the underlying mechanisms of BSNXD in terms of receptor activation of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis in vitro because of the critical roles of bone resorption in the development and progression of osteoporosis. In mice, serum levels of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and 17-β-estradiol (E2) were evaluated with an enzyme immunoassay kit after ovariectomy. Levels of DHEA and DHEAS increased significantly following administration of BSNXD while the level of E2 did not. In addition, tartrate-resistance acid phosphatase staining showed that DHEA profoundly inhibited RANKL-induced osteoclastogenesis in vitro in a dose-dependent manner via estrogen receptor α (ERα) but not via estrogen receptor β or androgen receptors. Cytotoxicity was not detected in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. These data suggest that BSNXD prevents PMO by increasing DHEA via the ERαpathway to suppress osteoclastogenesis.

DHEA promotes osteoblast differentiation by regulating the expression of osteoblast-related genes and Foxp3 + regulatory T cells

Several studies have reported that dehydroepiandrosterone (DHEA) promotes osteoblast proliferation and inhibits osteoblast apoptosis and that DHEA inhibits osteoclast maturation. However, whether DHEA regulates osteoblast differentiation remains unclear. The present study first examined the effect of DHEA on bone morphology in vivo. DHEA was found to increase bone volume (BV), bone mineral density (BMD), and the number of trabeculae in bone (Th.N) and it was found to decrease trabecular spacing in bone (Th.sp) in ovariectomized (OVX) mice. Next, the effect of DHEA on osteoblast differentiation was examined in vitro and osteoblastogenesis-related marker genes, such as Runx2, Osterix, Collagen1, and Osteocalcin, were also detected. DHEA increased osteoblast production in mesenchymal stem cells (MSCs) cultured in osteoblastogenic medium, and DHEA increased the expression of Runx2 and osterix, thereby increasing the expression of osteocalcin and collagen1. Immune cells and bone interact, so changes in immune cells were detected in vivo. DHEA increased the number of Foxp3(+) regulatory T cells (Tregs) in the spleen but it did not affect CTLA-4 or IL-10. When MSCs were treated with DHEA in the presence of Tregs, alkaline phosphatase (ALP) activity increased. Osteoblasts and adipocytes are both generated by MSCs. If osteoblast differentiation increases, adipocyte differentiation will decrease, and the reverse also holds true. DHEA was found to increase the number of adipocytes in osteoblastogenic medium but it had no effect on the number of adipocytes and expression of PPARγ mRNA in adipogenic medium. This finding suggests that osteoblasts may be involved in adipocyte production. In conclusion, the current results suggest that DHEA can improve postmenopausal osteoporosis (PMO) by up-regulating osteoblast differentiation via the up-regulation of the expression of osteoblastogenesis-related genes and via an increase in Foxp3(+) Tregs.

DHEA prevents bone loss by suppressing the expansion of CD4+ T cells and TNFa production in the OVX-mouse model for postmenopausal osteoporosis

Recent studies have suggested that dehydroepiandrosterone (DHEA) might serve as a form of immunomodulatory therapy for postmenopausal osteoporosis (PMO). The current study investigated the effects of DHEA administration on ovariectomy (OVX)-induced bone loss and its corresponding immunological changes. Adult OVX mice were treated with DHEA or 17-β-estradiol (E2) for 12 weeks, with or without the aromatase inhibitor letrozole. DHEA improved bone mass after OVX and displayed action like that of E2 with regard to decreasing osteoclast-related parameters. DHEA also suppressed an OVX-induced increase in CD4(+) T cell subsets and TNF-α production. However, DHEA elevated serum E2 levels to a lesser extent than E2. Although letrozole decreased serum E2 levels in OVX mice treated with DHEA, it did not alter DHEAs effects on corresponding immunological changes due to OVX. In conclusion, DHEA may prevent bone loss by suppressing the OVX-induced expansion of CD4(+) T cells and TNF-α production in mice, independent of E2.

Bu-Shen-Ning-Xin Decoction ameliorated the osteoporotic phenotype of ovariectomized mice without affecting the serum estrogen concentration or uterus

Introduction Bu-Shen-Ning-Xin Decoction (BSNXD), a traditional Chinese medicinal composition, has been used as a remedy for postmenopausal osteoporosis, but its effects on bone metabolism and the uterus have not been reported. Purpose We aimed to determine the respective effects of BSNXD on the bones and the uterus of ovariectomized (OVX) mice to evaluate the efficacy and safety of this herbal formula. Materials and methods Postmenopausal osteoporosis animal models that were generated by ovariectomy were treated with BSNXD. Dual-energy X-ray absorptiometry was performed to analyze the bone mineral density, and histomorphometric analysis was performed to measure the parameters related to bone metabolism. Calcein labeling was performed to detect bone formation. The uteruses from the mice were weighed, and the histomorphometry was analyzed. Drug-derived serum was prepared to assess the 17-β-estradiol concentration via enzyme immunoassay. Results BSNXD administration ameliorated the osteoporotic phenotype of OVX mice, as evidenced by an increase in the bone mineral density and bone volume; these effects could not be abolished by the administration of the aromatase inhibitor letrozole. Moreover, BSNXD had no effect on the serum estrogen concentration or uterus. Conclusion These results suggest that BSNXD has ameliorating effects on bone loss due to estrogen deprivation without affecting the peripheral blood estrogen concentration or the uterus in OVX mice.

APOBEC-mediated genomic alterations link immunity and viral infection during human papillomavirus-driven cervical carcinogenesis

Cervical cancer is one of the most frequently diagnosed cancers and is a major cause of death from gynecologic cancers worldwide; the cancer burden from cervical cancer is especially heavy in less developed countries. Most cases of cervical cancer are caused by persistent infection with carcinogenic human papillomavirus (HPV) genotypes 16 and 18. Non-resolving inflammation caused by HPV infection provides a microenvironment that facilitates cancer development. Molecular alterations during the process of HPV-induced carcinogenesis are characterized by DNA methylation within the HPV genome, promoter hypermethylation of tumor suppressor genes in the host genome, as well as genomic instability caused by viral DNA integrating into the host genome. Catalytic polypeptide-like apolipoprotein B mRNA editing enzymes (APOBECs) normally function as part of the innate immune system. APOBEC expression is stimulated upon viral infection and plays an important role in HPV-induced cervical cancer. APOBECs catalyze the deamination of cytosine bases in nucleic acids, which leads to a conversion of target cytosine (C) to uracil (U) and consequently a change in the single-stranded DNA/RNA sequence. APOBEC proteins mediate the complex interactions between HPV and the host genome and link immunity and viral infection during HPV-driven carcinogenesis. Understanding the effects of APOBECs in HPV-induced cervical carcinogenesis will enable the development of better tools for HPV infection control and personalized prevention and treatment strategies.

Bu-Shen-Ning-Xin decoction: inhibition of osteoclastogenesis by abrogation of the RANKL-induced NFATc1 and NF-κB signaling pathways via selective estrogen receptor α.

Introduction Bu-Shen-Ning-Xin decoction (BSNXD) is a traditional Chinese medicinal composition that has been used as a remedy for postmenopausal osteoporosis, but the mechanisms affecting bone metabolism are not fully understood. Purpose We investigated the molecular mechanism and signaling pathway underlying the effect of BSNXD on osteoclastogenesis. Materials and methods A postmenopausal osteoporosis animal model generated by ovariectomy was administered BSNXD and drug-derived serum was prepared. An enzyme immunoassay was conducted to measure the 17-β-estradiol (E2) concentration in the drug-derived serum. Bone marrow-derived monocyte/macrophage precursor cells were treated with drug-derived serum, and tartrate-resistance acid phosphatase staining was conducted to observe osteoclastogenesis. A bone resorption assay was performed to analyze the effect on osteoclastic resorptive function. Real-time PCR, flow cytometry, Western blotting, transfection, and luciferase assays were conducted to explore the related mechanism. Results E2 was not elevated in BSNXD-derived serum. BSNXD-derived serum suppressed receptor activation of nuclear factor κB ligand (RANKL)-activated osteoclastogenesis in a dose-dependent manner; this effect could be reversed by estrogen receptor α antagonist methyl-piperidino-pyrazole. The serum suppressed RANKL-induced NF-κB transcription and inhibited the accumulation of nuclear factor of activated T-cells, cytoplasmic 1 in osteoclast precursor cells; the inhibitory effect was abolished by methyl-piperidino-pyrazole but not the estrogen receptor β antagonist or androgen receptor antagonist. Conclusion These results collectively suggest that administration of BSNXD presents inhibitory effects on osteoclast differentiation by abrogating the RANKL-induced nuclear factor of activated T-cells, cytoplasmic 1 and NF-κB signaling pathways downstream of estrogen receptor α, thereby contributing to the inhibitory effect on bone resorption.

A general description for Chinese medicine in treating premature ovarian failure

Premature ovarian failure (POF) is a kind of gynecological disease that causes amenorrhea, infertility, menopause and urogenital symptoms. Currently hormone replacement therapy (HRT) is the most popular choice for women with POF to get rid of menopausal syndrome. However, as the popularization of Chinese herbs made Chinese medicine (CM) shine new lights, physicians are able to treat POF with both meno-herbs and integrated therapy. HRT has its own indications and contraindications. For example, unexplained vaginal bleeding, acute liver damage, liver dysfunction, vascular embolization, and breast cancer are all contraindications of HRT, and CM is taken by more physicians as an adjuvant therapy. This review, including a range of common Chinese herbs and formulations according to the existing literature, provides a general description of CM treating POF from the aspects of mechanisms and clinical application. It also highlights acupuncture as a unique physiotherapy for POF. Although the validity of CM has been supported by the evidence of many preclinical trials, clinical trials and meta-analysis, the adverse events with CM therapy still exist and no guarantee has been made for its safety. This review concludes the updated information for CM treating POF contributing to further studies.

Chinese single herbs and active ingredients for postmenopausal osteoporosis: From preclinical evidence to action mechanism

Postmenopausal osteoporosis is a systemic metabolic skeletal disease generally ascribable to a dearth of estrogen. Whether traditional Chinese medicine is effective in management of postmenopausal osteoporosis remains unclear. This article reviews the experimental evidence of both in vitro and in vivo preclinical studies with the theme of the application of Chinese single herbs and active ingredients in postmenopausal osteoporosis. It includes three single herbs (Herba Epimedium, Rhizoma Drynariae, and Salvia miltiorrhiza) and eight active ingredients (saikosaponins, linarin, echinacoside, sweroside, psoralen, poncirin, vanillic acid, and osthole). The experimental studies indicated their potential use as treatment for postmenopausal osteoporosis and investigated the underlying mechanisms including osteoprotegerin/receptor activator of nuclear factor κB ligand (OPG/RANKL), extracellular-signal-regulated kinase/c-Jun N terminal kinase/mitogen-activated protein kinase (ERK/JNK/MAPK), estrogen receptor (ER), bone morphogenetic protein (BMP), transforming growth factor (TGF)-β, Wnt/β-catenin, and Notch signaling pathways. This review contributes to a better understanding of traditional Chinese medicine and provides useful information for the development of more effective anti-osteoporosis drugs.

The effect of DHEA on apoptosis and cohesin levels in oocytes in aged mice

Female fertility declines with age as the number of ovarian follicles decreases and aneuploidy increases. Degradation of the cohesin complex might be responsible for age-related aneuploidy. Dehydroepiandrosterone (DHEA) can improve the ovarian reserve and reduce the rate of aneuploidy, but the relationship between DHEA and cohesin levels in oocytes is still unknown. The aim of the current study was to evaluate the effect of the supplement DHEA on ovarian function, including the number of follicles and cohesin levels in oocytes. C57BL/6J mice at 3 weeks, 6 weeks, 12 weeks, 6 months, and 10 months of age were used to obtain a systematic view into follicle apoptosis and cohesin levels in oocytes. Nine-month-old C57BL/6J mice were administered saline (n = 5), 17β-estradiol (100 µg/kg per day, n = 5), or DHEA (5mg/Kg per day, n = 5). After 4 weeks, aged mice were weighed and sacrificed, and ovarian tissue samples were prepared. Anti-VASA staining and HE staining were used to count the number of follicles. Anti-γH2AX staining and TUNEL were used to measure follicle apoptosis and immunofluorescent staining was used to detect the levels of three oocyte cohesin subunits: REC8, SMC1β, and SMC3. Administration of the supplements 17β-estradiol and DHEA to aged mice increased the number of primordial and primary follicles and decreased the age-related apoptosis of follicles. Levels of the cohesin subunits REC8 and SMC1β declined with age, but DHEA and 17β-estradiol tended to delay that decline. The supplement DHEA increased the number of primordial and primary follicles in aged mice by inhibiting follicle apoptosis and tended to delay the decrease in cohesin levels in oocytes.

The interconnected role of chemokines and estrogen in bone metabolism.

Over the past few decades, researchers have paid considerable attention to the relationship between estrogen and bone metabolism. Nevertheless, few studies have examined the potential role of chemokines in estrogen regulation of bone metabolism. Chemokines are members of a superfamily of low-molecular-weight chemoattractant cytokines. Various chemokines and their corresponding transmembrane G protein-coupled receptors play distinct roles in the functional regulation and homeostasis of the immune and skeletal systems. This review summarizes the evidence that chemokines and estrogen display cooperative behavior in the skeletal system, with a focus on the mechanisms by which estrogen regulates the chemotactic factors that affect bone metabolism. Chemokines appear to represent a novel area for further examination in order to develop new therapeutics to treat disorders of bone metabolism.