Vigeo Promotes Myotube Differentiation and Protects Dexamethasone-Induced Skeletal Muscle Atrophy via Regulating the Protein Degradation, AKT/mTOR, and AMPK/Sirt-1/PGC1α Signaling Pathway In Vitro and In Vivo.

Sarcopenia, a condition caused by an imbalance between muscle growth and loss, can severely affect the quality of life of elderly patients with metabolic, inflammatory, and cancer diseases. Vigeo, a nuruk-fermented extract of three plants (Eleutherococcus senticosus Maxim (ESM), Achyranthes japonica (Miq.) Nakai (AJN), and Atractylodes japonica Koidzumi (AJK)) has been reported to have anti-osteoporotic effects. However, evidence of the effects of Vigeo on muscle atrophy is not available. Here, in the in vivo model of dexamethasone (Dex)-induced muscle atrophy, Vigeo treatment significantly reversed Dex-induced decreases in calf muscle volume, gastrocnemius (GA) muscle weight, and histological cross-section area. In addition, in mRNA and protein analyses isolated from GA muscle, we observed that Vigeo significantly protected against Dex-induced mouse muscle atrophy by inhibiting protein degradation regulated by atrogin and MuRF-1. Moreover, we demonstrated that Vigeo significantly promoted C2C12 cell line differentiation, as evidenced by the increased width and length of myotubes, and the increased number of fused myotubes with three or more nuclei. Vigeo alleviated the formation of myotubes compared to the control group. Vigeo also significantly increased the mRNA and protein expression of myosin heavy chain (MyHC), MyoD, and myogenin compared to that in the control. Vigeo treatment significantly reduced the mRNA and protein expression of muscle degradation markers atrogin-1 and muscle RING Finger 1 (MuRF-1) in the C2C12 cell line in vitro. Vigeo also activated the AMP-activated protein kinase (AMPK)/silent information regulator 1 (Sirt-1)/peroxisome proliferator-activated receptor-γ co-activator-1α (PGC1α) mitochondrial biogenesis pathway and the Akt/mTOR protein synthesis signaling pathway in Dex-induced myotube atrophy. These findings suggest that Vigeo may have protective effects against Dex-induced muscle atrophy. Therefore, we propose Vigeo as a supplement or potential therapeutic agent to prevent or treat sarcopenia accompanied by muscle atrophy and degeneration.

Saururus chinensis (Lour.) Baill. extract promotes skeletal muscle cell differentiation by positively regulating mitochondrial biogenesis and AKT/mTOR signaling in vitro.

Promotion of myoblast differentiation by activating mitochondrial biogenesis and protein synthesis signaling pathways provides a potential alternative strategy to balance energy and overcome muscle loss and muscle disorders. Saururus chinensis (Lour.) Baill. extract (SCE) has been used extensively as a traditional herbal medicine and has several physiological activities, including anti­asthmatic, anti­oxidant, anti­inflammatory, anti­atopic, anticancer and hepatoprotective properties. However, the effects and mechanisms of action of SCE on muscle differentiation have not yet been clarified. In the present study, it was investigated whether SCE affects skeletal muscle cell differentiation through the regulation of mitochondrial biogenesis and protein synthesis in murine C2C12 myoblasts. The XTT colorimetric assay was used to determine cell viability, and myosin heavy chain (MyHC) levels were determined using immunocytochemistry. SCE was applied to C2C12 myotube at different concentrations (1, 5, or 10 ng/ml) and times (1,3, or 5 days). Reverse transcription­quantitative PCR and western blotting were used to analyze the mRNA and protein expression change of factors related to differentiation, mitochondrial biogenesis and protein synthesis. Treatment of C2C12 cells with SCE at 1,5, and 10 ng/ml did not affect cell viability. SCE promoted C2C12 myotube formation and significantly increased MyHC expression in a concentration­ and time­dependent manner. SCE significantly increased the mRNA and protein expression of muscle differentiation­specific markers, such as MyHC, myogenic differentiation 1, myogenin, Myogenic Factor 5, and ß­catenin, mitochondrial biosynthesis­related factors, such as peroxisome proliferator­activated receptor­gamma coactivator­1α, nuclear respirator factor­1, AMP­activated protein kinase phosphorylation, and histone deacetylase 5 and AKT/mTOR signaling factors related to protein synthesis. SCE may prevent skeletal muscle dysfunction by enhancing myoblast differentiation through the promotion of mitochondrial biogenesis and protein synthesis.

Vigeo attenuates cartilage and bone destruction in a collagen­induced arthritis mouse model by reducing production of pro­inflammatory cytokines.

Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease characterized by articular cartilage destruction, bone destruction and synovial hyperplasia. It has been suggested that Vigeo, a mixture of Eleutherococcus senticosus, Achyranthes japonica and Atractylodes japonica fermented with Korean nuruk, has an anti-osteoporotic effect in a mouse model of inflammation-mediated bone loss. The present study evaluated the therapeutic effects of Vigeo in RA using a collagen-induced arthritis (CIA) mouse model. DBA/1J mice were immunized with bovine type II collagen on days 0 and 21 and Vigeo was administered daily for 20 days beginning the day after the second type II collagen injection. The mice were sacrificed on day 42 and the joint tissues were anatomically separated and subjected to micro computed tomography and histological analyses. In addition, the serum levels of TNF-α, IL-6 and IL-1ß were determined by enzyme-linked immunosorbent assays. CIA in DBA/1J mice caused symptoms of RA, such as joint inflammation, cartilage destruction and bone erosion. Treatment of CIA mice with Vigeo markedly decreased the symptoms and cartilage pathology. In addition, radiological and histological analyses showed that Vigeo attenuated bone and cartilage destruction. The serum TNF-α, IL-6 and IL-1ß levels following oral Vigeo administration were also reduced when compared with those in CIA mice. The present study revealed that Vigeo suppressed arthritis symptoms in a CIA-RA mouse model, including bone loss and serum levels of TNF-α, IL-6 and IL-1ß.

Improving quality of life for a patient with fibromyalgia and their caregiver: A protocol for the application of the integrative medical service model.

OBJECTIVES: Patients with incurable diseases experience difficulty carrying out activities of daily living and rely on caregivers. Caregivers of patients with fibromyalgia (FM) are unable to understand the extent of the patients' suffering because the pain sites are invisible. To address this problem, this study will apply an integrative healthcare service model to a single FM case to manage pain and enhance the quality of life and, subsequently, gather feedback from different sources regarding the treatment. This paper presents the study protocol. METHODS: We will conduct an observational study to gather quantitative and qualitative feedback from various perspectives regarding the application of an integrative healthcare service program for FM patients developed in Korea for an FM patient-caregiver pair. The program will comprise eight 100-minute weekly sessions, during which integrative services that combine Western and Oriental medicines (Korean traditional medicine) will be provided to enhance pain management and quality of life. The feedback collected after each session will be reflected in the next session' content. RESULTS: The results will comprise the feedback from the patient and caregiver in accordance with revisions made to the program. CONCLUSIONS: The results will provide basic data for optimizing an integrative healthcare service system in Korea for patients suffering from chronic pain owing to diseases such as FM.

Harpagoside attenuates local bone Erosion and systemic osteoporosis in collagen-induced arthritis in mice.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes local bone erosion and systemic osteoporosis. Harpagoside (HAR), an iridoid glycoside, has various pharmacological effects on pain, arthritis, and inflammation. Our previous study suggests that HAR is more deeply involved in the mechanism of bone loss caused by inflammatory stimuli than hormonal changes. Here, we identified the local and systemic bone loss inhibitory effects of HAR on RA and its intracellular mechanisms using a type 2 collagen-induced arthritis (CIA) mouse model. METHODS: The anti-osteoporosis and anti-arthritic effects of HAR were evaluated on bone marrow macrophage in vitro and CIA in mice in vivo by obtaining clinical scores, measuring hind paw thickness and inflammatory cytokine levels, micro-CT and histopathological assessments, and cell-based assay. RESULTS: HAR markedly reduced the clinical score and incidence rate of CIA in both the prevention and therapy groups. Histological analysis demonstrated that HAR locally ameliorated the destruction of bone and cartilage and the formation of pannus. In this process, HAR decreased the expression of inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-6, and IL-1ß in the serum of CIA mice. Additionally, HAR downregulated the expression of receptor activator of nuclear factor-κB ligand and upregulated that of osteoprotegerin. HAR suppressed systemic bone loss by inhibiting osteoclast differentiation and osteoclast marker gene expression in a CIA mouse model. CONCLUSIONS: Taken together, these findings show the beneficial effect of HAR on local symptoms and systemic bone erosion triggered by inflammatory arthritis.

Anti-Osteoporosis Effects of the Eleutherococcus senticosus, Achyranthes japonica, and Atractylodes japonica Mixed Extract Fermented with Nuruk.

Vigeo is a mixture of fermented extracts of Eleutherococcus senticosus Maxim (ESM), Achyranthes japonica (Miq.) Nakai (AJN), and Atractylodes japonica Koidzumi (AJK) manufactured using the traditional Korean nuruk fermentation method. Although the bioactive effects of ESM, AJN, and AJK have already been reported, the pharmacological effects of Vigeo have not been proven. Therefore, in this study, we investigated whether Vigeo had inhivitory effects on lipopolysaccharide (LPS)-induced inflammatory bone loss in vivo and receptor activator of nuclear factor-B ligand (RANKL)-induced osteoclastogenesis and the related mechanism in vitro. Vigeo administration conferred effective protection against bone loss induced by excessive inflammatory response and activity of osteoclasts in LPS-induced inflammatory osteoporosis mouse model. In addition, Vigeo significantly suppressed the formation of tartrate-resistant acid phosphatase-positive osteoclasts induced by RANKL and inhibited F-actin formation and bone resorbing activity without any cytotoxicity. Moreover, Vigeo significantly inhibited RANKL-induced phosphorylation of p38, ERK, JNK, IκB, and AKT and degradation of IkB. Additionally, Vigeo strongly inhibited the mRNA and protein expression of c-FOS and NFATc1 and subsequently attenuated the expression of osteoclast specific marker genes induced by RANKL. We demonstrated for the first time the anti-osteoporosis effect of Vigeo, suggesting that it could be a potential therapeutic candidate for the treatment of osteoclast-mediated inflammatory bone diseases.

The Impact of Tinnitus on Fibromyalgia.

Objective: Fibromyalgia (FM) is a disorder characterized by chronic diffuse pain and enhanced pain response to stimuli and is caused by central sensitization Tinnitus also is related to central sensitization So we investigated the impact of tinnitus on FM. Methods: We included 22 FM patients with tinnitus and 25 FM patients without tinnitus We assessed a range of symptoms using the Widespread Pain Index; Symptom Severity Score scale; Visual Analogue Scale of pain; and the Korean versions of the Fibromyalgia Impact Questionnaire (FIQ), the Insomnia Severity Index, and the Short-form Health Survey (SF-36) Information about the severity of tinnitus in FM patients was evaluated using the Korean version of the Tinnitus Handicap Questionnaire (THQ-K). Results: There were significant differences between the group that had mild tinnitus (THQ<38) and the group that had moderate-to-severe tinnitus (THQ≥38) for FIQ score (p=0025) and for the physical functioning (p=0003), social functioning (p=0035), and mental health (p=0017) components of the SF-36 Also, after dividing patients into 2 groups according to insomnia severity, significant differences were observed in FIQ score (p=0002) and in body pain (p=0001), general health (p=0008), vitality (p=0003), social functioning (p=0003), role limitation due to emotional condition (p=0001), and mental health (p<0001) components of the SF-36. Conclusion: The FM patients with severe tinnitus had more functional impairments and lower quality of life than those with mild tinnitus Severe insomnia also was accompanied by worse health status and lower quality of life.

Neurovascular Behçet's Disease Presenting with Cavernous Sinus Thrombosis: A Rare Case of Assumed Tolosa-Hunt-Like Syndrome.

Behçet's disease (BD) is a rare, chronic, auto-inflammatory disorder of unknown origin. Mucocutaneous lesions and pan-uveitis constitute the hallmark of BD. Additionally, vessels of all sizes and types are affected. In this article, we report a 53-year-old female patient diagnosed with neurovascular BD with diplopia, ipsilateral headache and ophthalmoplegia associated with cavernous sinus thrombosis, leading to Tolosa-Hunt-like syndrome. To our knowledge, this is the first report of a patient with complicated cavernous sinus thrombosis in BD.