Central Administration of 1-Deoxynojirimycin Attenuates Hypothalamic Endoplasmic Reticulum Stress and Regulates Food Intake and Body Weight in Mice with High-Fat Diet-Induced Obesity.

The α-glucosidase inhibitor, 1-deoxynojirimycin (DNJ), is widely used for its antiobesity and antidiabetic effects. Researchers have demonstrated that DNJ regulates body weight by increasing adiponectin levels, which affects energy intake and prevents diet-induced obesity. However, the mechanism by which centrally administered DNJ exerts anorexigenic effects has not been studied until now. We investigated the effect of DNJ in the hypothalamus of mice with high-fat diet-induced obesity. Results showed that intracerebroventricular (ICV) administration of DNJ reduced hypothalamic ER stress, which activated the leptin-induced Janus-activated kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) signaling pathway to cause appetite suppression. We conclude that DNJ may reduce obesity by moderating feeding behavior and ER stress in the hypothalamic portion of the central nervous system (CNS).

Orostachys japonicus inhibits the expression of MMP-2 and MMP-9 mRNA and modulates the expression of iNOS and COX-2 genes in human PMA-differentiated THP-1 cells via inhibition of NF-κB and MAPK activation.

Orostachys japonicus has been used in traditional medicine as an anticancer agent. The present study aimed to investigate the mechanism by which O. japonicus extract affects the expression of matrix metalloproteinase (MMP)-2 and MMP-9, its association with the expression of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) genes in phorbol myristate acetate-differentiated THP-1 human monocytic leukemia cells and how it mediates the nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) pathways. Cell proliferation was analyzed by MTT assay, mRNA expression was detected by quantitative polymerase chain reaction and protein expression was measured by western blot analysis. It was demonstrated that O. japonicus suppressed the mRNA expression of MMP-2 and MMP-9. In addition, O. japonicus was found to downregulate iNOS and COX-2 transcription and translocation. Furthermore, O. japonicus inhibited NF-κB p65 activity as well as the phosphorylation of p38 MAPK, MAPK kinase (MEK) and extracellular signal regulated kinase (ERK). The present results suggested that O. japonicus inhibited not only MMP-2 and MMP-9 mRNA expression, but also iNOS and COX-2 gene expression, suppressed NF-κB activation and reduced phosphorylation of p38 MAPK, MEK and ERK. The present results therefore indicated that O. japonicus was able to inhibit the expression of MMP-2 and MMP-9 and suppress the transcription and translocation of iNOS and COX-2 by directly inhibiting the activation of NF-κB and the phosphorylation of the MAPK pathway in THP-1 cells.

Chelidonium majus L. extract induces apoptosis through caspase activity via MAPK-independent NF-κB signaling in human epidermoid carcinoma A431 cells.

Chelidonium majus L. (C. majus L.) is known to possess certain biological properties such as anti-inflammatory, antimicrobial, antiviral and antitumor activities. We investigated the effects of C. majus L. extract on human epidermoid carcinoma A431 cells through multiple mechanisms, including induction of cell cycle arrest, activation of the caspase-dependent pathway, blocking of nuclear factor-κB (NF-κB) activation and involvement in the mitogen-activated protein kinase (MAPK) pathway. C. majus L. inhibited the proliferation of A431 cells in a dose- and time-dependent manner, increased the percentage of apoptotic cells, significantly decreased the mRNA levels of cyclin D1, Bcl-2, Mcl-1 and survivin and increased p21 and Bax expression. Exposure of A431 cells to C. majus L. extract enhanced the activities of caspase-3 and caspase-9, while co-treatment with C. majus L., the pan-caspase inhibitor Z-VAD-FMK and the caspase-3 inhibitor Z-DEVE-FMK increased the proliferation of A431 cells. C. majus L. extract not only inhibited NF-κB activation, but it also activated p38 MAPK and MEK/ERK signaling. Taken together, these results demonstrate that C. majus L. extract inhibits the proliferation of human epidermoid carcinoma A431 cells by inducing apoptosis through caspase activation and NF-κB inhibition via MAPK-independent pathway.

Effect of Orostachys japonicus on cell growth and apoptosis in human hepatic stellate cell line LX2.

Orostachys japonicus (O. japonicus), used to treat diseases such as various cancers, gastric ulcers, fever, hepatitis, arthritis, eczema, for hemostasis, and intoxication in folk medicine, has been an important constituent in many herbal formulae. We demonstrated that the water extract of O. japonicus led to growth inhibition of LX2 cells by inducing apoptosis through the caspase activation, related to the MAPK pathway. O. japonicus inhibited proliferation of LX2 cells in a dose- and time-dependent manner, increased the apoptosis fraction at cell cycle progression with an accompanying DNA fragmentation, and resulted in a significant decrease in Bcl-2 and an increase in Bax mRNA levels. Exposure of LX2 cells to O. japonicus induced caspase-3 activation, however when the LX2 cells were also treated with the pan-caspase inhibitor Z-VAD-FMK and the caspase-3 inhibitor Z-DEVE-FMK, apoptosis was blocked. O. japonicus inhibited anti-apoptotic Mcl-1 protein and MEK/ERK phosphorylation in LX2 cells. The results indicate that O. japonicus inhibits the cell growth of LX2 cells by inducing apoptosis through caspase activity. O. japonicus down-regulated Mcl-1 protein levels and inhibited the phosphorylation of MEK/ERK, suggesting that it mediates cell death in LX2 cells through the down-regulation of Mcl-1 protein via a MEK/ERK-independent pathway.

Anti-HIV-1 efficacy of extracts from medicinal plants.

The anti-HIV-1 activities of butanol, hexane, chloroform and water extracts from four widely used folk medicinal plants (Sophora flavescens, Tulipa edulis, Herba ephedra, and Pachyma hoelen Rumph) were evaluated in this study. The hexane extract of Pachyma hoelen Rumph, PH-4, showed effective inhibition against HIV-1. The 50% effective concentration (EC(50)) of PH-4 was 37.3 microg/ml in the p24 antigen assay and 36.8% in the HIV-1 recombinant RT activity test (at 200 microg/ml). In addition, the PH-4 showed the protective effect on the infected MT-4 cells, with a 58.2% rate of protection. The 50% cytotoxic concentration (CC(50)) of PH-4 was 100.6 microg/ml. These results suggest that PH-4 from Pachyma hoelen Rumph might be the candidate for the chemotherapy agent against HIV-1 infection with further study.

Neuroprotective effect of ginseng total saponins in experimental traumatic brain injury.

In the present study, we investigated whether ginseng total saponins (GTSs) protect hippocampal neurons after experimental traumatic brain injury (TBI) in rats. A moderate-grade TBI was made with the aid of a controlled cortical impact (CCI) device set at a velocity of 3.0 m/sec, a deformation of 3.0 mm, and a compression time of 0.2 sec at the right parietal area for adult male Sprague-Dawley rats. Shamoperated rats that underwent craniectomy without impact served as controls. GTSs (100 and 200 mg/kg) or saline was injected intraperitoneally into the rats immediately post-injury. Twenty-four hours after the injury, the rats underwent neurological evaluation. Contusion volume and the number of hippocampal neurons were calculated with apoptosis evaluated by TUNEL staining. 24 hr post-injury, saline-injected rats showed a significant loss of neuronal cells in the CA2 region of the right hippocampus (53.4%, p<0.05) and CA3 (34.6%, p<0.05) compared with contralateral hippocampal region, a significant increase in contusion volume (34+/-8 microL), and significant increase in neurologic deficits compared with the GTSs groups. Treating rats with GTSs seemed to protect the CCI-induced neuronal loss in the hippocampus, decrease cortical contusion volume, and improve neurological deficits.

All trans-retinoic acid (ATRA) elevated eukaryotic translation initiation factor 4A1 (eIF4A1) mRNA in ATRA-responsive vitiliginous epidermis.

Chronic skin disorders that require long-term treatment with corticosteroids, such as vitiligo, may use a combination of topical corticosteroids and topical all-trans-retinoic acid (ATRA) to prevent corticosteroid-induced skin atrophy. Besides protecting against the side effects of corticosteroids, ATRA produces a better clinical outcome in some patients. This study examined whether ATRA influences the expression of mRNAs responsible for the clinical correlation. Differential display was performed using kits incorporating an annealing control primer. Epidermis from suction blisters taken from six patients diagnosed with a generalized type of vitiligo, who were included in a placebo-controlled paired-comparison left-right study using ATRA and vehicle for 3-6 months, were used. Ten differentially expressed mRNAs were identified in those six patients. Expression levels were restored to normal particularly in four types of mRNAs, which were matched with sequences encoding eukaryotic translation initiation factor 4A1 (eIF4A1), ribosomal protein L13, mediator of RNA polymerase to transcription (MRT) and ribosomal phosphoprotein PO. Of those mRNAs, the level of eIF4A1 mRNA showed a clinical correlation; The expression of eIF4A1 mRNA, examined by real-time PCR, was elevated in four patients who showed a favorable clinical response to ATRA, whereas no change or a decrease occurred in three patients whose clinical responses did not differ between ATRA and vehicle treatment. The eIF4A1 protein expression from the other two patients, one of them with a favorable response to ATRA, also showed a clinical correlation. Therefore, eIF4A1 mRNA may be an important gene related to ATRA effects, although further studies are required.