The Powdered Root of Eurycoma longifolia Jack Improves Beta-Cell Number and Pancreatic Islet Performance through PDX1 Induction and Shows Antihyperglycemic Activity in db/db Mice.

Non-insulin-dependent diabetes mellitus (NIDDM) is a common metabolic disorder worldwide. In addition to the chief feature of long-standing hyperglycemia, dyslipidemia, hyperinsulinemia, and a number of complications develop in parallel. It is believed that an adequate control of blood glucose levels can cause these complications to go into remission. This study was performed to evaluate the antidiabetic activity of Eurycoma longifolia Jack (EL) in vivo. The blood-glucose-lowering activity of EL was studied in db/db mice administered crude powdered EL root (25, 50, and 100 mg/kg) orally for eight weeks. At the end of the study, HbA1c, insulin, plasma lipid levels, and histopathology were performed. Powdered EL root showed significant antihyperglycemic activity along with the control of body weight. After eight weeks of treatment, both the blood cholesterol level and the glycogen deposit in hepatocytes were remarkably lower, whereas the secreting insulin level was elevated. An improvement in islet performance was manifested as an increase in beta-cell number and pancreatic and duodenal homeobox 1 (PDX1) expression. Neogenesis or formation of new islets from pancreatic duct epithelial cells seen in the EL-treated group was encouraging. This study confirms the antihyperglycemic activity of EL through PDX1-associated beta-cell expansion resulting in an enhancement of islet performance.

Glycemia Lowering Effect of an Aqueous Extract of Hedychium coronarium Leaves in Diabetic Rodent Models.

Hedychium coronarium has a long history of use worldwide as a food and in folk medicine. In this study, we aimed to investigate the effect of an aqueous extract of H. coronarium leaves (HC) on type 2 diabetes mellitus (T2DM). Two types of animal models were used in this study: Streptozotocin (STZ)-induced T2DM (Wistar rats; N = 8) and C57BKSdb/db mice (N = 5). After treatment with HC for 28 days, glucose tolerance improved in both of the diabetic animal models. As significant effects were shown after 14 days of treatment in the STZ-induced T2DM model, we carried out the experiments with it. After 28 days of treatment with HC, the levels of cholesterol, triglyceride, high-density lipoprotein, and low-density lipoprotein were significantly improved in the STZ-induced T2DM model. The lesions degree of islet ß-cells was decreased after the HC treatment. Although the insulin level increased moderately, the aldosterone level was significantly decreased in the HC-treated groups, suggesting that aldosterone might play an important role in this effect. In summary, HC is a natural product and it is worth exploring its effect on T2DM.

Evaluation of Acute 13-Week Subchronic Toxicity and Genotoxicity of the Powdered Root of Tongkat Ali (Eurycoma longifolia Jack).

Tongkat Ali (Eurycoma longifolia) is an indigenous traditional herb in Southern Asia. Its powdered root has been processed to produce health supplements, but no detailed toxicology report is available. In this study, neither mutagenicity nor clastogenicity was noted, and acute oral LD50 was more than 6 g/kg b.w. After 4-week subacute and 13-week subchronic exposure paradigms (0, 0.6, 1.2, and 2 g/kg b.w./day), adverse effects attributable to test compound were not observed with respect to body weight, hematology, serum biochemistry, urinalysis, macropathology, or histopathology. However, the treatment significantly reduced prothrombin time, partial thromboplastin time, blood urea nitrogen, creatinine, aspartate aminotransferase, creatine phosphate kinase, lactate dehydrogenase, and cholesterol levels, especially in males (P < 0.05). These changes were judged as pharmacological effects, and they are beneficial to health. The calculated acceptable daily intake (ADI) was up to 1.2 g/adult/day. This information will be useful for product development and safety management.

Zinc oxide nanoparticles-induced intercellular adhesion molecule 1 expression requires Rac1/Cdc42, mixed lineage kinase 3, and c-Jun N-terminal kinase activation in endothelial cells.

The explosive development of nanotechnology has caused an increase in unintended biohazards in humans and in the ecosystem. Similar to particulate matter, nanoparticles (NPs) are strongly correlated with the increase in incidences of cardiovascular diseases, yet the mechanisms behind this correlation remain unclear. Within the testing concentrations of 0.1-10 µg/ml, which did not cause a marked drop in cell viability, zinc oxide NPs (ZnO-NPs) induced intercellular adhesion molecule-1 (ICAM-1) messenger RNA, and protein expression in both concentration- and time-dependent manner in treated human umbilical vein endothelial cells (HUVECs). ZnO-NPs treatment cause the activation of Ras-related C3 botulinum toxin substrate 1 (Rac1)/cell division control protein 42 homolog (Cdc42) and protein accumulation of mixed lineage kinase 3 (MLK3), followed by c-Jun N-terminal kinase (JNK) and transcription factor c-Jun activation. Induction of ICAM-1 and phosphorylation of JNK and c-Jun could be inhibited by either JNK inhibitor SP600125 or Rac guanosine triphosphatase inhibitor NSC23766 pretreatment. In addition, pretreatment with NSC23766 significantly reduced MLK3 accumulation, suggesting the involvement of Rac1/Cdc42-MLK3-JNK-c-Jun signaling in the regulation of ZnO-NPs-induced ICAM-1 expression, whereas these signaling factors were not activated in zinc oxide microparticles (ZnO-MPs)-treated HUVECs. The increase of ICAM-1 expression on ZnO-NPs-treated HUVECs enables leukocytes to adhere and has been identified as an indicator of vascular inflammation. Our data are essential for safety evaluation of the clinical usage of ZnO-NPs in daily supplements, cosmetics, and biomedicines.

Chloramphenicol-induced mitochondrial stress increases p21 expression and prevents cell apoptosis through a p21-dependent pathway.

Pretreatment of HepG2 and H1299 cells with chloramphenicol rendered the cells resistant to mitomycin-induced apoptosis. Both mitomycin-induced caspase 3 activity and PARP activation were also inhibited. The mitochondrial DNA-encoded Cox I protein, but not nuclear-encoded proteins, was down-regulated in chloramphenicol-treated cells. Cellular levels of the p21(waf1/cip1) protein and p21(waf1/cip1) mRNA were increased through a p53-independent pathway, possibly because of the stabilization of p21(waf1/cip1) mRNA in chloramphenicol-treated cells. The p21(waf1/cip1) was redistributed from the perinuclear region to the cytoplasm and co-localized with mitochondrial marker protein. Several morphological changes and activation of the senescence-associated biomarker, SA beta-galactosidase, were observed in these cells. Both p21(waf1/cip1) antisense and small interfering RNA could restore apoptotic-associated caspase 3 activity, PARP activation, and sensitivity to mitomycin-induced apoptosis. Similar effects were seen with other antibiotics that inhibit mitochondrial translation, including minocycline, doxycycline, and clindamycin. These findings suggested that mitochondrial stress causes resistance to apoptosis through a p21-dependent pathway.

Induction of vasorelaxation through activation of nitric oxide synthase in endothelial cells by brazilin.

The vasorelaxant activity of Caesalpinia sappan L., a traditional Chinese medicine, and its major component brazilin were investigated in isolated rat aorta and human umbilical vein endothelial cells. In isolated rat aorta, C. sappan L. extract and brazilin relaxed phenylephrine-induced vasocontraction and increased cyclic guanosine 3',5'-monophosphate (cGMP) content. Induction of vasorelaxation of brazilin was endothelium-dependent and could be markedly blocked by pretreatment with nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME); N(G)-monomethyl-L-arginine acetate (L-NMMA) and guanylyl cyclase inhibitor, methylene blue; 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and nitric oxide (NO) scavenger, hemoglobin. The increasing cGMP content induced by brazilin was also blocked by pretreatment with L-NAME, methylene blue, and the removal of extracellular Ca(2+). In human umbilical vein endothelial cells, brazilin dose-dependently induced an increase in NO formation and NOS activity, which were greatly attenuated by either the removal of extracellular Ca(2+) or the chelating of intracellular Ca(2+) chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM). Moreover, brazilin dose-dependently induced the influx of extracellular Ca(2+) in human umbilical vein endothelial cells. Collectively, these results suggest that brazilin induces vasorelaxation by the increasing intracellular Ca(2+) concentration in endothelial cells of blood vessels and hence activating Ca(2+)/calmodulin-dependent NO synthesis. The NO is released and then transferred into smooth muscle cells to activate guanylyl cyclase and increase cGMP content, resulting in vasorelaxation.