Accessory navicular in children.

Accessory navicular (AN) is a developmental variation of the secondary ossification center of the navicular tuberosity. Ten percent of patients with AN will have pain symptoms that affect walking and life. As the AN changes the position of the posterior tibial tendon insertion, children with AN often have posterior tibial tendon function insufficiency and flexible flat foot. Surgical treatment is often required after failure of conservative treatment. This article reviewed the etiology, clinical manifestations, complications, and treatment methods of AN.

TP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma.

To identify drivers of sensitivity and resistance to Protein Arginine Methyltransferase 5 (PRMT5) inhibition, we perform a genome-wide CRISPR/Cas9 screen. We identify TP53 and RNA-binding protein MUSASHI2 (MSI2) as the top-ranked sensitizer and driver of resistance to specific PRMT5i, GSK-591, respectively. TP53 deletion and TP53R248W mutation are biomarkers of resistance to GSK-591. PRMT5 expression correlates with MSI2 expression in lymphoma patients. MSI2 depletion and pharmacological inhibition using Ro 08-2750 (Ro) both synergize with GSK-591 to reduce cell growth. Ro reduces MSI2 binding to its global targets and dual treatment of Ro and PRMT5 inhibitors result in synergistic gene expression changes including cell cycle, P53 and MYC signatures. Dual MSI2 and PRMT5 inhibition further blocks c-MYC and BCL-2 translation. BCL-2 depletion or inhibition with venetoclax synergizes with a PRMT5 inhibitor by inducing reduced cell growth and apoptosis. Thus, we propose a therapeutic strategy in lymphoma that combines PRMT5 with MSI2 or BCL-2 inhibition.

Katsuwonus pelamis Peptide and its Complexes Protect Zebrafish and Mice From Hyperuricemia Through Promoting Kidney Excretion of Uric Acid and Inhibiting Liver Xanthine Oxidase Activity.

Katsuwonus pelamis peptide and its complexes have the effect of lowering uric acid (UA)-levels. To identify the effect and possible mechanisms, different concentrations of Katsuwonus pelamis peptide and its complexes were administered to the zebrafish and mice hyperuricemia models, and the UA level was measured. Meanwhile, the hyperuricemic mice were treated orally at 0.83, 1.67, and 5.00 mg/g body weight for 7 days with Katsuwonus pelamis peptide and the complexes groups, separately. The levels of serum UA (SUA), urinary UA (UUA), serum creatinine (SCR), blood urine nitrogen (BUN), and xanthine oxidase (XOD) activities were detected in each group. The results showed that the Katsuwonus pelamis peptide (125 µg/ml) and its complexes (83.3 and 250 µg/ml) effectively reduced UA level in zebrafish with hyperuricemia (p < 0.05). The Katsuwonus pelamis peptide at high concentration (5.00 mg/g) decreased the SUA level, SCR level, BUN level, and hepatic XOD activity, and the complexes (1.67 and 5.00 mg/g) significantly reduced the SUA level and hepatic XOD activity (p < 0.05) in the hyperuricemic mice. In addition, in a hyperuricemic mouse model, the UUA level was increased after treatment with Katsuwonus pelamis peptide and its complexes at high concentrations (p < 0.05). The total therapeutic effects in the Katsuwonus pelamis peptide complex group were better than those in the Katsuwonus pelamis peptide group. Thus, Katsuwonus pelamis peptide and its complexes may possibly be used to prevent hyperuricemia via promoting urate secretion and inhibiting XOD activity production.

Sea Cucumber Intestinal Peptide Induces the Apoptosis of MCF-7 Cells by Inhibiting PI3K/AKT Pathway.

Sea cucumbers are one of many marine echinoderm animals that contain valuable nutrients and medicinal compounds. The bioactive substances in sea cucumbers make them have promising biological and pharmacological properties, including antioxidant, anti-bacterial, and anti-tumor effects. In this study, sea cucumber intestinal peptide (SCIP) is a small molecular oligopeptide (<1,000 Da) extracted from sea cucumber intestines hydrolyzed by alkaline protease. The analysis of amino acid composition showed that hydrophobic amino acids and branched-chain amino acids were rich in SCIP. Nowadays, although increasing studies have revealed the biological functions of the sea cucumber active substances, there are few studies on the function of SCIP. Furthermore, due to the anti-cancer activity being an essential characteristic of sea cucumber active substances, we also investigated the anti-cancer potential and the underlying mechanism of SCIP in vivo and in vitro. The results indicate that SCIP inhibits the growth of MCF-7 tumor cells in zebrafish and increases the apoptosis of human breast cancer MCF-7 cells. Further mechanism studies confirm that SCIP promotes the expression of apoptosis-related proteins and thus promotes the breast cancer cells (MCF-7) apoptosis via inhibition of PI3K/AKT signal transduction pathway.

Curcuma zedoaria petroleum ether extract reverses the resistance of triple-negative breast cancer to docetaxel via pregnane X receptor.

BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by its aggressiveness and poor prognosis. Docetaxel is the common chemotherapeutic drug used in the treatment of TNBC. However, resistance to docetaxel has limited the effectiveness of TNBC treatment. Petroleum ether extracts of Curcuma zedoaria (PECZ) can inhibit the proliferation of MDA-MB-231 cells. However, the effect of PECZ on docetaxel resistance is not clear. METHODS: A docetaxel-resistant MDA-MB-231 (MDA-MB-231/docetaxel) cell line was established, and Cell Counting Kit-8 (CCK-8), quantitative real-time PCR (qRT-PCR), and western blotting assays were used to evaluate the effect of docetaxel resistance in MDA-MB-231 cells. Next, CCK-8 was also performed to detect the effect of docetaxel or the combination treatment of docetaxel and PECZ on the proliferation of MDA-MB-231/docetaxel cells. Thereafter, MDA-MB-231/docetaxel cells were subcutaneously injected into nude mice to induce a TNBC xenograft model, and the mice were divided into a model group, docetaxel group, PECZ group, and combination of docetaxel and PECZ group. Subsequently, hematoxylin and eosin (HE) staining, immunohistochemical, qRT-PCR, and western blotting were used to estimate the effect of pre-treatment with PECZ on docetaxel tolerance reversal. RESULTS: PECZ significantly inhibited the expression of pregnane X receptor (PXR), multidrug resistance 1 (MDR1), breast cancer resistance protein (BCRP), and cytochrome P-450 (CYP3A4) in MDA-MB-231/docetaxel cells. Only higher concentrations of docetaxel could inhibit the viability of MDA-MB-231/docetaxel cells. When pre-treated with PECZ, lower concentrations of docetaxel could significantly inhibit cell viability. Meanwhile, combination treatment also reduced the tumor volume, ameliorated the pathological change of tumor tissues, and down-regulated the expressions of PXR, MDR1, BCRP, and CYP3A4 (according to HE staining, immunohistochemical, qRT-PCR and western blotting results in vivo). CONCLUSIONS: Our research showed that PECZ reversed docetaxel resistance in TNBC by PXR both in vitro and in vivo, which provides the basis for further investigations into the potential therapeutic impact of docetaxel resistance in TNBC.

Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal Domain (BET) Second Bromodomain (BD2) Inhibitors.

The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole 23 (GSK809) and furan 24 (GSK743) that were derived from the pyrrole fragment 6. We transpose the key learnings from a previous pyridone series (GSK620 2 as a representative example) to this novel class of inhibitors, which are characterized by significantly improved solubility relative to our previous research.

GSK137, a potent small-molecule BCL6 inhibitor with in vivo activity, suppresses antibody responses in mice.

B-cell lymphoma 6 (BCL6) is a zinc finger transcriptional repressor possessing a BTB-POZ (BR-C, ttk, and bab for BTB; pox virus and zinc finger for POZ) domain, which is required for homodimerization and association with corepressors. BCL6 has multiple roles in normal immunity, autoimmunity, and some types of lymphoma. Mice bearing disrupted BCL6 loci demonstrate suppressed high-affinity antibody responses to T-dependent antigens. The corepressor binding groove in the BTB-POZ domain is a potential target for small compound-mediated therapy. Several inhibitors targeting this binding groove have been described, but these compounds have limited or absent in vivo activity. Biophysical studies of a novel compound, GSK137, showed an in vitro pIC50 of 8 and a cellular pIC50 of 7.3 for blocking binding of a peptide derived from the corepressor silencing mediator for retinoid or thyroid hormone receptors to the BCL6 BTB-POZ domain. The compound has good solubility (128 µg/ml) and permeability (86 nM/s). GSK137 caused little change in cell viability or proliferation in four BCL6-expressing B-cell lymphoma lines, although there was modest dose-dependent accumulation of G1 phase cells. Pharmacokinetic studies in mice showed a profile compatible with achieving good levels of target engagement. GSK137, administered orally, suppressed immunoglobulin G responses and reduced numbers of germinal centers and germinal center B cells following immunization of mice with the hapten trinitrophenol. Overall, we report a novel small-molecule BCL6 inhibitor with in vivo activity that inhibits the T-dependent antigen immune response.

Screening of miRNAs associated with lymph node metastasis in Her-2-positive breast cancer and their relationship with prognosis.

The aim of this study was to identify some biomarkers for predicting lymph node metastasis and prognosis of human epidermal growth factor receptor 2 (Her-2)-positive breast cancer (BC). We analyzed correlations between microRNAs (miRNAs) and the prognosis of patients with BC based on data collected from The Cancer Genome Atlas (TCGA) database. The expression levels of miR-455, miR-143, and miR-99a were measured in clinical samples of Her-2-positive BC patients with different degrees of lymph node metastasis. We investigated the impacts of overexpressed miR-455 on the proliferation and invasiveness of MDA-MB-453 cells and measured its effects on the expression of long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of miR-455 was significantly and positively correlated to the prognosis and overall survival (OS) of the BC (P=0.028), according to TCGA information. The expression level of miR-455 was positively correlated with OS and relapse-free survival (RFS) of patients with Her-2-positive BC, and was negatively correlated with the number of metastatic lymph nodes (P<0.05). Transwell assay suggested that MDA-MB-453 cells became much less invasive (P<0.01) after being transfected with miR-455 mimics. During the qRT-PCR, the expression level of MALAT1 declined significantly after transfection (P<0.01). Overexpressed miR-455 significantly inhibited the proliferation and migration of MDA-MB-453 cells and the expression of MALAT1. We conclude that miR-455 may be a useful potential biomarker for forecasting lymph node metastasis and the prognosis of Her-2-positive BC patients. miR-455 may play an important role in lymph node metastasis of BC by interacting with MALAT1.

Research Progresses in Cancer Stem Cells of Three Common Fertility-Related Female Malignancies.

With abilities to renew themselves and lead to heterogeneity of tumors, cancer stem cells (CSCs) are similar to stem cells. As three leading causes of death that endanger women's health, breast cancer, ovarian cancer and cervical cancer are characterized by high degree of malignancy, metastasis and recurrence. Associated with women's fertility, these three malignancies are common and representative among females. These years, research findings have suggested that CSCs are closely connected with many cancers (including aforementioned three malignancies) and several processes of tumors such as their genesis and development. CSCs have become great concerns for current cancer treatment and interventions. This paper does not only summarize roles of CSCs in genesis, development, drug resistance, metastasis and recurrence of breast cancer, ovarian cancer and cervical cancer, but also proposes potential methods of treatment and intervention, in hope of inspiring readers and researchers.

Effects of miRNAs on functions of breast cancer stem cells and treatment of breast cancer.

Breast cancer is one of the most common malignancies for women, which accounts for 30% of all female malignancies. The formation of breast cancer stem cells (BCSCs) is attributed to the acquisition of stemness of tumor cells. With self-renewal potential, these stem cells are insensitive to either radiotherapy or chemotherapy but are significant in regulating tumor behaviors and drug resistance. MicroRNA (miRNA) is a kind of noncoding small RNA for negatively regulating gene expressions. Research findings suggest that many miRNAs specifically regulate the expression of target genes and signal pathways of BCSCs. They play an important role in self-renewal, growth, and metastasis of breast cancer cells as potential targets for treating breast cancer. These signal pathways include phosphatase and tensin homolog deleted on chromosome 10-phosphatidylinositol 3-kinase/Akt, Wnt/ß-catenin, Notch, and so on. This paper reviews the progress of research about miRNAs in self-renewal, metastasis, epithelial-mesenchymal transition and metastasis, mediation of resistance to chemotherapies, and treatment of breast cancer.

Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing.

Evasion of the potent tumour suppressor activity of p53 is one of the hurdles that must be overcome for cancer cells to escape normal regulation of cellular proliferation and survival. In addition to frequent loss of function mutations, p53 wild-type activity can also be suppressed post-translationally through several mechanisms, including the activity of PRMT5. Here we describe broad anti-proliferative activity of potent, selective, reversible inhibitors of protein arginine methyltransferase 5 (PRMT5) including GSK3326595 in human cancer cell lines representing both hematologic and solid malignancies. Interestingly, PRMT5 inhibition activates the p53 pathway via the induction of alternative splicing of MDM4. The MDM4 isoform switch and subsequent p53 activation are critical determinants of the response to PRMT5 inhibition suggesting that the integrity of the p53-MDM4 regulatory axis defines a subset of patients that could benefit from treatment with GSK3326595.

MEK inhibitors overcome resistance to BET inhibition across a number of solid and hematologic cancers.

BET inhibitors exhibit broad activity in cancer models, making predictive biomarkers challenging to define. Here we investigate the biomarkers of activity of the clinical BET inhibitor GSK525762 (I-BET; I-BET762) across cancer cell lines and demonstrate that KRAS mutations are novel resistance biomarkers. This finding led us to combine BET with RAS pathway inhibition using MEK inhibitors to overcome resistance, which resulted in synergistic effects on growth and survival in RAS pathway mutant models as well as a subset of cell lines lacking RAS pathway mutations. GSK525762 treatment up-regulated p-ERK1/2 levels in both RAS pathway wild-type and mutant cell lines, suggesting that MEK/ERK pathway activation may also be a mechanism of adaptive BET inhibitor resistance. Importantly, gene expression studies demonstrated that the BET/MEK combination uniquely sustains down-regulation of genes associated with mitosis, leading to prolonged growth arrest that is not observed with either single agent therapy. These studies highlight a potential to enhance the clinical benefit of BET and MEK inhibitors and provide a strong rationale for clinical evaluation of BET/MEK combination therapies in cancer.

Use of liposomal doxorubicin for adjuvant chemotherapy of breast cancer in clinical practice.

Breast cancer is one of the malignant tumors with the highest morbidity and mortality. It is helpful to reduce the rate of tumor recurrence and metastasis by treating breast cancer with adjuvant chemotherapy, so as to increase the cure rate or survival of patients. In recent years, liposomes have been regarded as a kind of new carrier for targeted drugs. Being effective for enhancing drug efficacy and reducing side effects, they have been widely used for developing anticancer drugs. As a kind of anthracycline with high anticancer activity, doxorubicin can treat or alleviate a variety of malignant tumors effectively when it is used on its own or in combination with other anticancer drugs. Although liposomal doxorubicin has been extensively used in the adjuvant chemotherapy of breast cancer, its exact therapeutic efficacy and side effects have not been definitely proven. Various clinical studies have adopted different combined regimes, dosages, and staging, so their findings differ to certain extent. This paper reviews the clinical application of liposomal doxorubicin in the adjuvant chemotherapy of breast cancer and illustrates therapeutic effects and side effects of pegylated liposomal doxorubicin (PLD) and non-PLD (NPLD) in clinical research, in order to discuss the strategies for applying these drugs in such adjuvant chemotherapy, looking forward to providing references for related research and clinical treatment in terms of dosage, staging, combined regimes, and analysis methods and so on.

Effective tracking of bone mesenchymal stem cells in vivo by magnetic resonance imaging using melanin-based gadolinium3+ nanoparticles.

Tracking transplanted stem cells is necessary to clarify cellular properties and improve transplantation success. In this study, we designed and synthesized melanin-based gadolinium3+ (Gd3+ )-chelate nanoparticles (MNP-Gd3+ ) of ∼7 nm for stem cell tracking in vivo. MNP-Gd3+ possesses many beneficial properties, such as its high stability and sensitivity, shorter T1 relaxation time, higher cell labeling efficiency, and lower cytotoxicity compared with commercial imaging agents. We found that the T1 relaxivity (r1 ) of MNP-Gd3+ was significantly higher than that of Gd-DTPA; the nanoparticles were taken up by bone mesenchymal stem cells (BMSCs) via endocytosis and were broadly distributed in the cytoplasm. Based on an in vitro MTT assay, no cytotoxicity of labeled stem cells was observed for MNP-Gd3+ concentrations of less than 800 µg/mL. Furthermore, we tracked MNP-Gd3+ -labeled BMSCs in vivo using 3.0T MRI equipment. After intramuscular injection, MNP-Gd3+ -labeled BMSCs were detected, even after four weeks, by 3T MRI. We concluded that MNP-Gd3+ nanoparticles at appropriate concentrations can be used to effectively monitor and track BMSCs in vivo. MNP-Gd3+ nanoparticles have potential as a new positive MRI contrast agent in clinical applications. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 131-137, 2017.

Inhibitor Response to HER2 G776(YVMA) In-frame Insertion in HER2-positive Breast Cancer.

Human epidermal growth factor receptor 2 (HER2/neu or HER2) has long been recognized as an attractive therapeutic target for breast cancer. The YVMA in-frame insertion at the residue G776 (G776(YVMA)) of HER2 kinase domain is a frequently observed mutation that can largely shift drug sensitivity in targeted therapy of HER2-positive breast cancer. Here, the molecular mechanism and biological significance of tyrosine kinase inhibitor (TKI) response to HER2 G776(YVMA) insertion were investigated in detail. An established protocol that integrated bioinformatics modeling and kinase inhibition assay was employed to examine the structural basis, energetic property, and biological implication underlying the intermolecular interaction between HER2 kinase domain and three representative TKIs, i.e. two FDA-approved drugs lapatinib and gefitinib as well as a pan-kinase inhibitor staurosporine. It was found that the insertion mutation can moderately sensitize lapatinib, but cannot influence the inhibitory capability of staurosporine essentially, suggesting that the two inhibitors exhibit differentiated selectivity between the wild-type HER2 (HER2(WT)) and HER2 G776(YVMA) (HER2(YVMA)) variant. In addition, the gefitinib, which was originally developed as EGFR inhibitor, only possesses modest potency against its noncogate target HER2(WT), and the insertion can further impair the potency, causing a strong resistance for the agent to HER2(YVMA) variant.

Protective effects of Radix Astragali injection on multiple organs of rats with obstructive jaundice.

OBJECTIVE: To investigate the protective effects and mechanisms of Radix Astragali Injection on multiple organs of rats with obstructive jaundice (OJ). METHODS: A total of 180 rats were randomly divided into the sham-operated, model control and treated groups (60 in each group). On 7, 14, 21 and 28 days after operation, the serum contents of alanine aminotransferase (ALT), aspartate aminotransferase (AST), r-glutamyl transpeptidase (r-GT), total bilirubin (TBil), direct bilirubin (DBil), blood urine nitrogen (BUN), and creatinine (CREA) were determined. And the pathological changes of livers, kidneys and lungs, and protein expressions of toll-like receptor-4 (TLR-4) of livers, intercellular adhesion molecule-1 (ICAM-1) of lungs, Bax and nuclear factor-kappa B (NF-κB), as well as apoptotic indexes of multiple organs were observed, respectively. RESULTS: The pathological severity scores of multiple organs (including livers on 7, 14, 21 and 28 days, kidneys on 14 and 28 days, and lungs on 14 days), serum contents of ALT (14 and 21 days), AST (14 days), TBil (7, 14, 21 and 28 days), DBil (14 and 21 days), BUN (28 days), protein expressions of TLR-4 (in livers, 28 days), Bax (in livers and kidneys, 21 days), and apoptotic indexes in livers (7 and 21 days) in the treated group were significantly lower than those in the model control group (P<0.05 or P<0.01). CONCLUSION: Radix Astragali Injection exerts protective effects on multiple organs of OJ rats by improving the pathological changes of lung, liver and kidney, decreasing the serum index of hepatic and renal function as well as inhibiting the protein expression of TLR-4 and Bax in the livers and Bax in the kidneys.

[Treatment of Chemotherapy Related Leukocytopenia by Oral Administration of Multiple Leucogenic Drugs Combined with G-CSF: an Experimental Study].

OBJECTIVE: To evaluate efficacies of three commonly used oral drugs including Berbamine Hydrochloride Tablet (B), Qijiao Shengbai Capsule (Q), and Leucogen Tablet (L) (by single drug, two drugs or three drugs) combined with granulocyte colony-stimulating factor (G-CSF) for treat ment of chemotherapy related leukocytopenia in mice. METHODS: Totally 156 Kunming male mice were divided into the normal control group (A, n=24), the model group (B, n=24), the G-CSF group (C, n =24), the G-CSF+Q group (D, n=12), G-CSF+ B (E, n=12), the G-CSF+L group (F, n=12), the G-CSF + Q + B group (G, n=12), the G-CSF + Q + L group (H, n=12), the G-CSF + L + B group (I, n=12), and the G-CSF + L + Q + B (J, n=12). Mouse models of chemotherapy related leukocytopenia were established by intraperitoneal injection of cyclophosphamide (CTX). A G-CSF group was set up as a positive control. Mice were treated by a single oral drug, a single oral drug combined with G-CSF, and two or three drugs combined with G-CSF respectively, and the death rate calculated. Hemocytes [such as white blood cells (WBC) and its classification, red blood cells (RBC), platelet (PLT), hemoglobin (Hb)] were calculated by hematology analyzer. Mice were anatomized and important organs weighed. Organ indices were calculated. RESULTS: There was no statistical difference in the mortality rate among all groups (P > 0.05). Compared with Group B, WBC was elevated in all other groups (P < 0.01). WBC and PLT were elevated most in Group J, Hb and RBC were also increased at the same time (P < 0.05, P < 0. 01). Compared with Group B, RBC increased in Group E, F, G, I, and J (P < 0.01); Hb obviously increased in Group C, E, F, H, I, and J (P<0.01). Compared with Group B and D, the promotion of erythroid hematopoiesis by G-CSF could be elevated in any group contained drug B and L (P < 0.05, P < 0.01). The spleen index of model mice could be significantly improved in Group C, D, and G (P < 0.01). The thymus index of model mice could be significantly improved in Group H (P < 0.05). CONCLUSIONS: The best scheme to treat mice with chemotherapy related leukopenia or decreased three blood series was to administrate three commonly oral drugs combined with G-CSF. Authors speculated that G-CSF and Q might have a certain effect on CTX induced immune inhibition.

Therapeutic mechanisms of single Chinese medicine herb or their extracts for extrahepatic obstructive jaundice.

Obstructive jaundice (OJ) is classified as extrahepatic OJ or intrahepatic OJ. Extrahepatic OJ is attributed to a variety of intricate etiological factors. Research has begun with Chinese medicine (CM), which can be used as an adjunctive therapy for extrahepatic OJ. Particular attention has been paid to the therapeutic effects and their mechanisms of single CM herb and relevant extracts. The roles of single CM or their extracts during adjunctive therapy for extrahepatic OJ have been described briefly. This review focuses on the effects and their mechanisms of relevant herbal medicines.

The anti-osteoporotic effect of velvet antler polypeptides from Cervus elaphus Linnaeus in ovariectomized rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The deer velvet antler is well known for its traditional medicinal value, and is widely used in the clinic. It is recorded in the Compendium of Materia Medica that the deer velvet antler replenishes vital essence and strengthens the bone. AIM OF THE STUDY: The goal of this study was to investigate the anti-osteoporotic effect of total velvet antler polypeptides from Cervus elaphus Linnaeus (TVAPL) on ovariectomized rats (OVX), and their possible mechanism of the action. MATERIALS AND METHODS: Wistar rats were divided into five groups: sham-operated group, OVX group, and OVX rats treated with 20, 40, or 60 mk/kg TVAPL for 12 weeks. Calcium and phosphorus levels, bone weight coefficient (BWC), bone mineral density (BMD), and bone mineral content (BMC) were evaluated. The MTT assay was used to measure the activities of interleukin-1 (IL-1) and interleukin-6 (IL-6). In addition, cartilage cells and osteoblast-like cells were exposed to TVAPL, natural velvet antler polypeptides (nVAP), and synthetic velvet antler polypeptides (sVAP), to determine their effects on cell proliferation using the tritiated thymidine incorporation assay. Finally, the enzyme-linked immunosorbent assay was used to determine the effects of nVAP and sVAP on cytokines related to bone metabolism. RESULTS: The administration of TVAPL for 12 weeks significantly reversed osteoporosis in OVX rats, thereby improving the BWC, BMD, BMC, and bone microarchitecture. IL-1 and IL-6 were significantly activated in the OVX group, and their activation was inhibited by TVAPL. In addition, nVAP and sVAP promoted the proliferation of cartilage and osteoblast-like cells (p<0.01 or p<0.001), and inhibited the secretion of IL-1α from THP-1 monocytic cells in vitro. CONCLUSION: These results suggest that TVAPL are effective in preventing bone loss in OVX rats. The effect of TVAPL on osteoporosis is due to inhibition of IL-1 and IL-6 by nVAP, and promotion of mitosis. sVAP has similar bioactivity as nVAP. Thus, both TVAPL and sVAP may be potential therapeutic agents for the treatment of postmenopausal osteoporosis.

Effects of dexamethasone and Salvia miltiorrhiza on multiple organs in rats with severe acute pancreatitis.

OBJECTIVE: To investigate the protective effects and mechanisms of action of dexamethasone and Salvia miltiorrhiza on multiple organs in rats with severe acute pancreatitis (SAP). METHODS: The rats were divided into sham-operated, model control, dexamethasone treated, and Salvia miltiorrhiza treated groups. At 3, 6, and 12 h after operation, the mortality rate of different groups, pathological changes, Bcl-2-associated X protein (Bax) and nuclear factor-κB (NF-κB) protein expression levels in multiple organs (the pancreas, liver, kidneys, and lungs), toll-like receptor 4 (TLR-4) protein levels (only in the liver), intercellular adhesion molecule 1 (ICAM-1) protein levels (only in the lung), and terminal deoxynucleotidy transferase mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) staining expression levels, as well as the serum contents of amylase, glutamate-pyruvate transaminase (GPT), glutamic-oxaloacetic transaminase (GOT), blood urea nitrogen (BUN), and creatinine (CREA) were observed. RESULTS: The mortality rate of the dexamethasone treated group was significantly lower than that of the model control group (P<0.05). The pathological changes in multiple organs in the two treated groups were relieved to different degrees (P<0.05 and P<0.01, respectively), the expression levels of Bax and NF-κB proteins, and apoptotic indexes of multiple organs were reduced (P<0.05 and P<0.01, respectively). The contents of amylase, GPT, GOT, BUN, and CREA in the two treated groups were significantly lower than those in model control groups (P<0.05 and P<0.01, respectively). The expression level of ICAM-1 protein in the lungs (at 3 and 12 h) in the dexamethasone treated group was significantly lower than that in the Salvia miltiorrhiza treated group (P<0.05). The serum contents of CREA (at 12 h) and BUN (at 6 h) of the Salvia miltiorrhiza treated group were significantly lower than those in the dexamethasone treated group (P<0.05). CONCLUSIONS: Both dexamethasone and Salvia miltiorrhiza can reduce the inflammatory reaction, regulate apoptosis, and thus protect multiple organs of rats with SAP.