Matrilin-2 prevents the TNFα-induced apoptosis of WB-F344 cells via suppressing JNK pathway.

Oval cells, a kind of hepatic progenitor cell quiescent at normal condition, activates to proliferate and differentiate into hepatocytes under severe and long-term liver injury, which usually raises severe inflammation. However, how oval cell survives in the inflammatory milieu interne is still unclear. Tumor necrosis factor α (TNFα), mimicking inflammatory hepatic milieu interne, was used to treat oval cell line, WB-F344, to test the protective function of matrilin-2. In this study, our data suggested that matrilin-2 prevented TNFα-induced apoptosis in WB-F344 cells via inhibiting ASK1/MKK7/JNK pathway. In conclusion, we determined that matrilin-2 plays the key role in maintaining the survival of oval cell and guarantees its proliferation under various injury factors.

Exploring the mechanisms of action of Cordyceps sinensis for the treatment of depression using network pharmacology and molecular docking.

Background: Depression is the most common type of psychological disorder, with continuous, prolonged, and persistent bad moods as the main clinical feature. Cordyceps sinensis is a complex consisting of the ascospores and bodies of insect larvae from the Hepialidae family that have been parasitized by Cordyceps sinensis militaris. Previous studies have reported that this herb has antidepressant activity. The present study used network pharmacology and molecular docking techniques to investigate the potential antidepressant mechanisms of Cordyceps sinensis. Methods: The active ingredients of Cordyceps sinensis were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the potential targets were predicted using the PharmMapper platform. The GeneCards database was then used to obtain sub-targets for depression. Common targets were screened and enrichment analyses were performed using the Metascape platform. Finally, the relationship between the active ingredients and the core targets were verified by molecular docking. Results: Through network pharmacological analysis, 7 active ingredients in Cordyceps sinensis and 41 common targets of drugs and diseases were identified. The active ingredients of Cordyceps sinensis may exert antidepressant effects by acting on important targets such as catalase (CAT), CREB binding protein (CREBBP), epidermal growth factor (EGF), and E1A binding protein P300 (EP300), and by modulating the signaling pathways in which these targets are involved. Subsequently, the core targets were docked to the active ingredients and good binding was observed. Conclusions: The active ingredients of Cordyceps sinensis may exert antidepressant effects by regulating the CREB binding protein and anti-oxidative stress effects. The foxo signaling pathway (hsa04068), hypoxia-inducible factor 1 (HIF-1) signaling pathway (hsa04066), and Huntington's disease (hsa05016) may be involved in the underlying mechanisms of Cordyceps sinensis. The joint application of network pharmacology and molecular docking provides a new approach to study the mechanisms of action of traditional Chinese medicine. Cordyceps sinensis may play an important role in the future treatment of patients with depression.

Comprehensive analysis of lncRNA and mRNA based on expression microarray profiling reveals different characteristics of osteoarthritis between Tibetan and Han patients.

BACKGROUND: Osteoarthritis (OA) is thought to be the most prevalent chronic joint disease, especially in Tibet of China. Here, we aimed to explore the integrative lncRNA and mRNA landscape between the OA patients of Tibet and Han. METHODS: The lncRNA and mRNA expression microarray profiling was performed by SurePrint G3 Human Gene Expression 8x60K v2 Microarray in articular cartilage samples from OA patients of Han nationality and Tibetans, followed by GO, KEGG, and trans-regulation and cis-regulation analysis of lncRNA and mRNA. RESULTS: We found a total of 117 lncRNAs and 297 mRNAs differently expressed in the cartilage tissues of Tibetans (n = 5) comparing with those of Chinese Han (n = 3), in which 49 lncRNAs and 158 mRNAs were upregulated, and 68 lncRNAs and 139 mRNAs were downregulated. GO and KEGG analysis showed that several unreported biological processes and signaling pathways were particularly identified. LncRNA-mRNA co-expression analysis revealed a remarkable lncRNA-mRNA relationship, in which OTOA may play a critical role in the different mechanisms of the OA progression between Tibetans and Chinese Han. CONCLUSION: This study identified different lncRNA/mRNA expression profiling between OA patients of Tibetans and Han, which were involved in many characteristic biological processes and signaling pathways.

Conjugated linoleic acid prompts bone formation in ovariectomized osteoporotic rats and weakens osteoclast formation after treatment with ultraviolet B.

BACKGROUND: Ultraviolet B (UVB) has been reported to prevent bone loss by promoting the synthesis of vitamin D. However, UVB can also enhance osteoclastic differentiation, inhibit osteogenic differentiation, and cause oxidative damage. The present study aimed to analyze the osteoprotective effects of UVB and conjugated linoleic acid (CLA) in rats with ovariectomy-induced osteoporosis, and to determine the interactions between UVB and CLA and their effects on bone mesenchymal stem cells (BMSCs) and bone marrow mononuclear cells (BMMCs). METHODS: In vitro, the distance of UVB irradiation and the dose of CLA were selected by immunofluorescence assays and Cytotoxicity assay. BMSCs and BMMCs were detected by immunohistochemical and immunofluorescence assays. In vivo, three-month-old female Sprague-Dawley rats that had undergone ovariectomy were treated with UVB and CLA. After 8 weeks of therapy, the femurs of the rats were examined by micro-computed tomography (CT) and immunohistochemical detection to assess the therapeutic efficacy. RESULTS: The least inhibitive UVB distance and dosage of CLA were selected for the in vivo experiments. CLA effectively weakened the osteogenic inhibitory effect of UVB (72 cm), significantly improved the activity of alkaline phosphatase (ALP), promoted the formation of mineralized nodules, and alleviated the oxidative damage induced by UVB. CLA also effectively weakened the osteoclast-promoting effect of UVB (72 cm), inhibited osteoclast formation, and inhibited the inflammatory damage to BMMCs caused by UVB (72 cm) irradiation. Micro-CT results showed that UVB irradiation could promote bone formation in ovariectomized Sprague-Dawley rats, while CLA could significantly promote bone regeneration. Immunofluorescence assays results showed that CLA alleviated UVB-induced oxidative damage to osteoblasts. The ROS detection results demonstrated that CLA effectively alleviated UVB-induced oxidative damage to BMSCs. Furthermore, Immunohistochemical assays showed that UVB and CLA treatment increased bone density, inhibited osteolytic osteolysis, and enhanced osteogenic activity. CONCLUSIONS: CLA can effectively weaken osteoclast promotion, osteogenic inhibition, and oxidative damage caused by UVB. Combination treatment of UVB and CLA exerts an osteoprotective effect on ovariectomized osteoporotic rats and stimulates osteogenesis. The molecular mechanism of this interaction requires further investigation.

Photocytotoxicity of white light-emitting diode irradiation on human lens epithelium and retinal pigment epithelium via the JNK and p38 MAPK signaling pathways.

WLEDs have lately been the preferred lighting device based on properties such as energy saving, high efficiency, longevity, and environmental protection. However, studies on the safety of white light-emitting diode (WLED) are limited. In our previous study, we found that WLED light (4000 K ± 500 K color temperature, 250 lx, and 20 min exposure) is photocytotoxic to three mammalian cell lines by causing cell lipid peroxidation. To further investigate the potential photocytotoxicity of WLEDs on the human body, we used two human eye cell lines SRA01/04 and D407 as target cells for evaluating its potential phototoxicity on the human eye in the present study based on cell viability, apoptosis, and intracellular oxidative stress assays, as well as the activation levels of reactive oxygen species (ROS)-related apoptosis pathways, including extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK) and p38 kinase (p38), using mitogen-activated protein kinase (MAPK) signaling pathway assays. The results showed that WLED light has photocytotoxicities on SRA01/04 and D407 cells, which were both in a time-, irradiance-, and color temperature-dependent manner and strongest at the conditions of 2 h irradiation time, 60 W/m2 irradiance, and 4000 K color temperature. Moreover, the photocytotoxicity of red light-emitting diode (LED) light was the strongest in the three tested monochromatic light compositions of WLED. Mechanism studies show that the potential phototoxicity of WLED on human lens epithelium and retinal pigment epithelium may be caused by its induced oxidative stress damage via the JNK and p38 MAPKs pathways.

Tobacco Mosaic Viral Nanoparticle Inhibited Osteoclastogenesis Through Inhibiting mTOR/AKT Signaling.

INTRODUCTION: Tobacco mosaic virus-based nanoparticles (TMV VNPs) were previously shown to promote osteogenic differentiation in vitro. This study aims to investigate whether and how TMV VNPs impact on osteoclastogenesis in vitro and bone injury healing in vivo. METHODS: Raw264.7 cells were cultured in osteoclastogenic medium in culture plates coated with or without TMV and TMV-RGD1 VNPs, followed by TRAP staining, RT-qPCR and WB assessing expression of osteoclastogenic marker genes, and immunofluorescence assessing NF-κB activation. TMV and TMV-RGD1-modified hyaluronic acid hydrogel were used to treat mouse tibial bone injury. Bone injury healing was checked by micro-CT and Masson staining. RESULTS: TMV and TMV-RGD1 VNPs significantly inhibited osteoclast differentiation and downregulated the expression of osteoclastogenic marker genes Ctr, Ctsk, Mmp-9, Rank, and Trap. Moreover, TMV and TMV-RGD1 VNPs inhibited NF-κB p65 phosphorylation and nuclear translocation, as well as activation of mTOR/AKT signaling pathway. TMV and TMV-RGD1-modified HA hydrogel strongly promoted mouse tibial bone injury with increased bone mass compared to plain HA hydrogel. The amount of osteoclasts was significantly reduced in TMV and TMV-RGD1 treated mice. TMV-RGD1 was more effective than TMV in inhibiting osteoclast differentiation and promoting bone injury repair. DISCUSSION: These data demonstrated the great potential of TMV VNPs to be developed into biomaterial for bone injury repair or replacement.

Ma-Nuo-Xi decoction has an immunostimulating effect in cyclophosphamide-immunosuppressed mice.

BACKGROUND: Ma-Nuo-Xi decoction (MNXD), as well as its hundreds of derivative preparations, has been used in Tibetan medicine since the 14th century. MNXD is in accordance with the theory of treatment determination based on syndrome differentiation. This study aimed to compare the effect of the auxiliary MNXD prescription (MNXD-AD) with that of the basic MNXD prescription (MNXD-BD) on the immunostimulating activity of MNXD. METHODS: The immunopotentiation of MNXD, MNXD-BD, and MNXD-AD was evaluated using a cyclophosphamide (CTX)-immunosuppressed mouse model. Their influences on non-specific and specific immunity were evaluated using immune organ indexes, peripheral white blood cell (WBC) count, red blood cell (RBC) count, platelet count, phagocytosis, macrophage-secreted nitric oxide (NO) and cytokines, natural killer (NK) cytotoxic activity, lymphocyte proliferation, serum cytokines, splenic T-lymphocyte subpopulations, and quantitative hemolysis of sheep red blood cell (QHS SRBC) assays. RESULTS: MNXD, MNXD-BD, and MNXD-AD increased the spleen and thymus indexes, as well as the peripheral WBC, RBC, and platelet counts. They also promoted phagocytosis, NO and cytokine secretion from macrophages, NK cytotoxic activity, and lymphocyte proliferation, and also raised the CD4+ /CD8+ T-cell ratio, serum cytokine concentrations, and haemolysin formation in CTX-treated immunosuppressed mice. Compared with MNXD-BD and MNXD-AD, MNXD was superior in restoring the phagocytic index, concanavalin A (ConA)-induced T-lymphocyte proliferation, NO secretion from macrophages, and haemolysin formation, as well as the levels of interleukin 1 beta (IL-1ß), and serum interleukin-2 (IL-2) and interferon gamma (INF-γ). CONCLUSIONS: MNXD, MNXD-BD, and MNXD-AD have excellent immunostimulating and myelosuppression-restoring activities on CTX-immunosuppressed mice. Among them, MNXD-AD might be an immunomodulator, which may happen to be in line with the clinical experience of Tibetan medicine physicians of using it to promote the efficacy of MNXD-BD.

Immunostimulating effect of polysaccharides isolated from Ma-Nuo-Xi decoction in cyclophosphamide-immunosuppressed mice.

Ma-Nuo-Xi Decoction (MNXD) is well-known in Tibetan medicine to be in line with the theory of treatment determination based on syndrome differentiation. However, the components responsible for its immunomodulating effect are unknown. In this study, three polysaccharide components-MNXD-P, MNXD-BD-P, and MNXD-AD-P-were isolated from MNXD and its basic and auxiliary prescription decoctions, of which MNXD-BD-P is composed of ß-(1,4)-d-glucan and RG-I pectin, MNXD-AD-P contains mainly α-(1,4)-d-glucan and some amount of arabinogalactan and/or arabinorhamnogalactan, and MNXD-P contains components of both MNXD-BD-P and MNXD-AD-P. And treatment with these polysaccharides could significantly improve the host's specific and non-specific immunity, including cellular and humoral immunities, as well as promote recovery from myelosuppression in cyclophosphamide (CTX)-immunosuppressed mice. To our knowledge, this is the first report on chemical and immunoactivity study on polysaccharides from traditional Tibetan medicine compounds, which may provide a new idea for development of carbohydrate drugs from them.

Promotion of fracture healing by conjugated linoleic acid in rats.

BACKGROUND: The ability of fracture healing in Tibetans is significantly superior to Chinese Hans, which may attribute to factors from diet, altitude to physical conditions. Conjugated linoleic acid (CLA) is an important ingredient in Tibetan diet, playing a role in antioxidation, antiatherosclerosis, and decrease in body fat accumulation.  Methods: This study further quantified CLA effect in fracture healing in rats using combined structural evaluation (X-ray and micro-computed tomography), biomechanical test, and histological examination. RESULTS: CLA could promote fracture healing with quicker development of trabecular connection, network and thickening and were more active at the stage of bony union and remodeling. The load to failure could reach 78.12 ± 10.03 N, 41.4% stronger than the control by week 6 ( p = 0.0209). CONCLUSIONS: CLA improved the quality and mechanical strength of fracture healing in rats callus. The information may offer insight in development of new therapeutic strategies of fracture healing for general populations beyond Tibetans.