Myelophil, a 30% ethanol extract that has an equal rate in both Astragali Radix and Salviae Radix , is a remedy for the treatment of fatigue-linked disorders in traditional Oriental medicine. The majority of patients with chronic fatigue have a risk of comorbidity with depression symptoms. To evaluate the anti-depressant activity of Myelophil, mice were subjected to unpredictable chronic mild stress (UCMS, eight different stresses) for 3 weeks with daily administration of distilled water, Myelophil (25, 50, or 100 mg/kg), or n -acetyl- l -cysteine (NAC) (100 mg/kg). After the final stress exposure, three behavioral tests, including the open field test (OFT), forced swimming test (FST), and tail suspension test (TST), and stress-derived alterations of the serotonergic signal and inflammatory response in the hippocampus were measured. UCMS notably induced depressive behaviors, whereas these behavioral alterations were significantly reversed by the administration of Myelophil in regard to the OFT, FST, and TST results. Myelophil also significantly attenuated the over-activation of microglial cells and the inflammatory response in the hippocampal region (TNF-α, tumor necrosis factor-alpha; IL-1β, interleukin-1beta; and caspase-1). Furthermore, Myelophil significantly restored the distortions of serotonergic function in the dorsal raphe nuclei and neurogenesis in the subgranular zone of the hippocampus. These results support the clinical relevance of the anti-depressant activity of Myelophil, specifically by modulating serotonergic function and the neuroinflammatory response.

No abstract

Rhus verniciflua Stoke has been commonly used in traditional medicine to treat gastrointestinal (GI) dysfunction diseases. In order to investigate pharmacological properties of Rhus verniciflua Stoke water extract (RVX) on cisplatin-induced amnesia, RVX (0, 25, 50, or 100 mg/kg) was orally administrated for five consecutive days after a single intraperitoneal injection of cisplatin (6 mg/kg) to SD rat. Cisplatin injection significantly increased the kaolin intake (emesis) but reduced the normal diet intake (anorexia) whereas the RVX treatment significantly improved these abnormal diet behaviors at both the acute and delayed phase. The serotonin concentration and the related gene expressions (5-HT3 receptors and SERT) in small intestine tissue were abnormally altered by cisplatin injection, which were significantly attenuated by the RVX treatment. Histological findings of gastrointestinal tracts, as well as the proteins level of proinflammatory cytokines (TNF-α, IL-6, and IL-1β), revealed the beneficial effect of RVX on cisplatin-induced gastrointestinal inflammation. In addition, RVX significantly improved cisplatin-induced myelosuppression, as evidenced by the observation of leukopenia and by histological examinations in bone marrow. Our findings collectively indicated Rhus verniciflua Stoke improved the resistance of rats to chemotherapy-related adverse effects in the gastrointestinal track and bone marrow.

Although manganese (Mn) has been shown to increase prolactin (PRL) by decreasing dopamine (DA) in the hypothalamus, the mechanism of Mn-induced regulation of the hypothalamic-hypophyseal-pituitary axis is unclear. We assessed the effects of inhaled Mn on hypothalamic DA and pituitary PRL production and evaluated the role of pituitary-specific transacting factor 1 (Pit-1), a transacting factor of PRL gene, in Mn-induced changes in PRL secretion in the rat brain. Male rats exposed to Mn for 4 or 13 weeks (1.5 mg/m3, 6 h/day, 5 days/week) showed a progressive and significant decrease in hypothalamic DA, whereas PRL and Pit-1 mRNA levels increased in response to Mn exposure. These results suggest that exposure to Mn decreases hypothalamic DA and promotes the production of PRL in the pituitary and that Pit-1 might be a regulator of DA and PRL.

The 26S proteasome is the principal protease for regulated intracellular proteolysis. This multi-subunit complex is also pivotal for clearance of harmful proteins that are produced throughout the lifetime of eukaryotes. Recent structural and kinetic studies have revealed a multitude of conformational states of the proteasome in substrate-free and substrate-engaged forms. These conformational transitions demonstrate that proteasome is a highly dynamic machinery during substrate processing that can be also controlled by a number of proteasome-associated factors. Essentially, three distinct family of deubiquitinases–USP14, RPN11, and UCH37–are associated with the 19S regulatory particle of human proteasome. USP14 and UCH37 are capable of editing ubiquitin conjugates during the process of their dynamic engagement into the proteasome prior to the catalytic commitment. In contrast, RPN11-mediated deubiquitination is directly coupled to substrate degradation by sensing the proteasome’s conformational switch into the commitment steps. Therefore, proteasome-bound deubiquitinases are likely to tailor the degradation events in accordance with substrate processing steps and for dynamic proteolysis outcomes. Recent chemical screening efforts have yielded highly selective small-molecule inhibitors for targeting proteasomal deubiquitinases, such as USP14 and RPN11. USP14 inhibitors, IU1 and its progeny, were found to promote the degradation of a subset of substrates probably by overriding USP14-imposed checkpoint on the proteasome. On the other hand, capzimin, a RPN11 inhibitor, stabilized the proteasome substrates and showed the anti-proliferative effects on cancer cells. It is highly conceivable that these specific inhibitors will aid to dissect the role of each deubiquitinase on the proteasome. Moreover, customized targeting of proteasome-associated deubiquitinases may also provide versatile therapeutic strategies for induced or repressed protein degradation depending on proteolytic demand and cellular context.

The global prevalence of nonalcoholic fatty liver disease (NAFLD) is estimated to be 25% and has continued to increase; however, no drugs have yet been approved for NAFLD treatments. The ethyl acetate fraction of Amomum xanthioides (EFAX) was previously reported to have an anti-hepatic fibrosis effect, but its effects on steatosis or steatohepatitis remain unclear. This study investigated the anti-fatty liver of EFAX using a high-fat diet mouse model. High-fat diet intake for 8 weeks induced hepatic steatosis with mild inflammation and oxidative damage and increased the adipose tissue weight along with the development of dyslipidemia. EFAX treatment significantly ameliorated the steatohepatic changes, the increased weight of adipose tissues, and the altered serum lipid profiles. These observed effects were possibly due to the lipolysis-dominant activity of EFAX on multiple hepatic proteins including sterol regulatory element-binding protein (mSREBP)-1c, peroxisome proliferator-activated receptor (PPAR)-α, AMP-activated protein kinase, and diglyceride acyltransferases (DGATs). Taken together, these results show that EFAX might be a potential therapeutic agent for regulating a wide spectrum of NAFLDs from steatosis to fibrosis via multiple actions on lipid metabolism-related proteins. Further studies investigating clear mechanisms and their active compounds are needed.

Amomum xanthioides has been traditionally used to treat diverse digestive system disorders in the Asian countries. We investigated antihepatofibrotic effects of ethyl acetate fraction of Amomum xanthioides (EFAX). Liver fibrosis is induced by dimethylnitrosamine (DMN) injection (intraperitoneally, 10 mg/kg of DMN for 4 weeks to Sprague-Dawley rats). EFAX (25 or 50 mg/kg), silymarin (50 mg/kg), or distilled water was orally administered every day. The DMN injection drastically altered body and organ mass, serum biochemistry, and platelet count, while EFAX treatment significantly attenuated this alteration. Severe liver fibrosis is determined by trichrome staining and measurement of hydroxyproline contents. EFAX treatment significantly attenuated these symptoms as well as the increase in oxidative by-products of lipid and protein metabolism in liver tissues. DMN induced a dramatic activation of hepatic stellate cells and increases in the levels of protein and gene expression of transforming growth factor-beta (TGF-β), platelet derived growth factor-beta (PDGF-β), and connective tissue growth factor (CTGF). Immunohistochemical analyses revealed increases in the levels of protein and gene expression of α-smooth muscle actin. These alterations were significantly normalized by EFAX treatment. Our findings demonstrate the potent antihepatofibrotic properties of EFAX via modulation of fibrogenic cytokines, especially TGF-β in the liver fibrosis rat model.

Didecyldimethylammonium chloride (DDAC) is used in many types of biocidal products including tableware, carpets, humidifiers, and swimming pools, etc. In spite of increased chances of DDAC exposure through inhalation, studies on the inhalation toxicity of DDAC are not common even though the toxicity of DDAC might be significantly higher if it were to be administered through routes other than the respiratory system. DDAC aerosols were exposed to Sprague-Dawley rats in whole body exposure chambers for a duration of 13 weeks. The Mass Median Aerodynamic Diameters of the DDAC aerosol were 0.63 μm, 0.81 μm, and 1.65 μm, and the geometric standard deviations were 1.62, 1.65, and 1.65 in the low (0.11 ± 0.06 mg/m3), the middle (0.36 ± 0.20 mg/m3) and the high (1.41 ± 0.71 mg/m3) exposure groups, respectively. Body weight was confirmed to be clearly influenced by exposure to DDAC and mean body weight was approximately 35% lower in the high (1.41 ± 0.71 mg/m3) male group and 15% lower in the high (1.41 ± 0.71 mg/m3) female group compared to that of the control group. In the bronchoalveolar lavage fluid assay, the levels of albumin and lactate dehydrogenase had no effect on DDAC exposure. The lung weight increased for the middle (0.36 ± 0.20 mg/m3) and the high (1.41 ± 0.71 mg/m3) concentrations of the DDAC exposure group, and inflammatory cell infiltration and interstitial pneumonia were partially observed in the lungs of the middle (0.36 ± 0.20 mg/m3) and the high (1.41 ± 0.71 mg/m3) exposure groups. However, severe histopathological symptoms, including proteinosis and/or fibrosis, were not found. Based on the results of the changes in the body weight and lung weight, it is considered that the NOAEL (no-observed adverse effect) level for the 13-week exposure duration is 0.11 mg/m3.