The Natural Occurring Compounds Targeting Endoplasmic Reticulum Stress

ER stress has been implicated in pathophysiological development of many diseases. Persistent overwhelming stimuli trigger ER stress to initiate apoptosis, autophagy, and cell death. IRE1-JNK and eIF2α-CHOP signaling pathways are the two important players of ER stress, which is also modulated by ROS production, calcium disturbance, and inflammatory factors. ER stress has been developed as a novel strategy for diseases management. Recently, a vast of research focuses on the natural occurring compounds targeting ER stress, which results in medical benefits to human diseases. These small reported molecules mainly include polyphenols, alkaloids, and saponins. Many of them have been developed for use in clinical applications. To better understand the pharmacological mechanism of these molecules in ER stress in diseases, efforts have been made to discover and deliver medical merits. In this paper, we will summarize the natural occurring compounds targeting ER stress

Chondroprotective Activity of Murraya exotica

Osteoarthritis (OA) is a degenerative joint disease that affects millions of people. Currently, there is no effective drug treatment for it. The purpose of this study is to investigate the chondroprotective effects of Murraya exotica (L.) on OA. The rat OA models were duplicated to prepare for separating OA chondrocytes, synovial fluid (SF), and serum containing M. exotica (50 mg/kg, 100 mg/kg, and 200 mg/kg), M. exotica showed the activity of decreasing the contents of TNF-α and IL-1β in SF and the chondrocyte apoptosis in a dose-dependent manner. To investigate the probable mechanism, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to determine gene expression and protein profiles, respectively. The results reveal that M. exotica can downregulate mRNA and protein expressions of β-catenin and COX-2 and reporter activity significantly. Conclusively, M. exotica exhibits antiapoptotic chondroprotective activity probably through inhibiting β-catenin signaling

The Multifunctional Effects of Nobiletin and Its Metabolites In Vivo

Nobiletin (NOB) chemically known as 5,6,7,8,3′,4′-hexamethoxyflavone is a dietary polymethoxylated flavonoid found in Citrus fruits. Recent evidences show that NOB is a multifunctional pharmaceutical agent. The various pharmacological activities of NOB include neuroprotection, cardiovascular protection, antimetabolic disorder, anticancer, anti-inflammation, and antioxidation. These events may be underpinned by modulation of signaling cascades, including PKA/ERK/MEK/CREB, NF-κB, MAPK, Ca2+/CaMKII, PI3K/Akt1/2, HIF-1α, and TGFβ signaling pathways. The metabolites may exhibit stronger beneficial effects than NOB on diseases pathogenesis. The biological activities of NOB have been clarified on many systems. This review aims to discuss the pharmacological effects of NOB with specific mechanisms of actions. NOB may become a promising candidate for potential drug development. However, further investigations of NOB on specific intracellular targets and clinical trials are still needed, especially for in vivo medical applications

Geniposide Alleviates Glucocorticoid-Induced Inhibition of Osteogenic Differentiation in MC3T3-E1 Cells by ERK Pathway

Glucocorticoid (GC) therapy is the leading cause of secondary osteoporosis and the therapeutic and preventative drugs for GC-induced osteoporosis are limited. In this study, we investigated the protective effects of geniposide on dexamethasone (DEX)-induced osteogenic inhibition in MC3T3-E1 cells. The results showed that there was no obvious toxicity on MC3T3-E1 cells when geniposide was used at the doses ranging from 1 to 75 μM. In DEX-treated MC3T3-E1 cells, geniposide promoted the alkaline phosphatase (ALP) activity and the mineralization. In addition, geniposide also significantly increased the mRNA and protein expression of osteopontin (OPN), Runt-related transcription factor 2 (Runx2), and Osterix (Osx) in DEX-treated MC3T3-E1 cells. Furthermore, geniposide activated ERK pathway in DEX-treated MC3T3-E1 cells. The ERK activation inhibitor U0126 and glucagon-like peptide-1 (GLP-1) receptor antagonist exendin 9-39 abolished the geniposide-induced activation of ERK and inhibited the protective effect of geniposide. Taken together, our study revealed that geniposide alleviated GC-induced osteogenic suppression in MC3T3-E1 cells. The effect of geniposide was at least partially associated with activating ERK signaling pathway via GLP-1 receptor. Geniposide might be a potential therapeutic agent for GC-induced osteoporosis

miR-365 Ameliorates Dexamethasone-Induced Suppression of Osteogenesis in MC3T3-E1 Cells by Targeting HDAC4

Glucocorticoid administration is the leading cause of secondary osteoporosis. In this study, we tested the hypotheses that histone deacetylase 4 (HDAC4) is associated with glucocorticoid-induced bone loss and that HDAC4 dependent bone loss can be ameliorated by miRNA-365. Our previous studies showed that miR-365 mediates mechanical stimulation of chondrocyte proliferation and differentiation by targeting HDAC4. However, it is not clear whether miR-365 has an effect on glucocorticoid-induced osteoporosis. We have shown that, in MC3T3-E1 osteoblasts, dexamethasone (DEX) treatment decreased the expression of miR-365, which is accompanied by the decrease of cell viability in a dose-dependent manner. Transfection of miR-365 ameliorated DEX-induced inhibition of MC3T3-E1 cell viability and alkaline phosphatase activity, and attenuated the suppressive effect of DEX on runt-related transcription factor 2 (Runx2), osteopontin (OPN), and collagen 1a1 (Col1a1) osteogenic gene expression. In addition, miR-365 decreased the expression of HDAC4 mRNA and protein by direct targeting the 3′-untranslated regions (3′-UTR) of HDAC4 mRNA in osteoblasts. MiR-365 increased Runx2 expression and such stimulatory effect could be reversed by HDAC4 over-expression in osteoblasts. Collectively, our findings indicate that miR-365 ameliorates DEX-induced suppression of cell viability and osteogenesis by regulating the expression of HDAC4 in osteoblasts, suggesting miR-365 might be a novel therapeutic agent for treatment of glucocorticoid-induced osteoporosis

Asiatic Acid (AA) Sensitizes Multidrug-Resistant Human Lung Adenocarcinoma A549/DDP Cells to Cisplatin (DDP) via Downregulation of P-Glycoprotein (MDR1) and Its Targets

Background/Aims: P-glycoprotein (P-gp, i.e., MDR1) is associated with the phenotype of multidrug resistance (MDR) and causes chemotherapy failure in the management of cancers. Searching for effective MDR modulators and combining them with anticancer drugs is a promising strategy against MDR. Asiatic acid (AA), a natural triterpene isolated from the plant Centella asiatica, may have an antitumor activity. The present study assessed the reversing effect of AA on MDR and possible molecular mechanisms of AA action in MDR1-overexpressing cisplatin (DDP)-resistant lung cancer cells, A549/DDP. Methods: Human lung adenocarcinoma A549/DDP cells were either exposed to different concentrations of AA or treated with DDP, and their viability was measured by the MTT assay. A Rhodamine 123 efflux assay, immunofluorescent staining, ATPase assay, reverse-transcription PCR (RT-PCR), and western blot analysis were conducted to elucidate the mechanisms of action of AA on MDR. Results: Our results showed that AA significantly enhanced the cytotoxicity of DDP toward A549/DDP cells but not its parental A549 cells. Furthermore, AA strongly inhibited P-gp expression by blocking MDR1 gene transcription and increased the intracellular accumulation of the P-gp substrate Rhodamine 123 in A549/DDP cells. Nuclear factor (NF)-kB (p65) activity, IkB degradation, and NF-kB/p65 nuclear translocation were markedly inhibited by pretreatment with AA. Additionally, AA inhibited the MAPK–ERK pathway, as indicated by decreased phosphorylation of ERK1 and -2, AKT, p38, and JNK, thus resulting in reduced activity of the Y-box binding protein 1 (YB1) via blockage of its nuclear translocation. Conclusions: AA reversed P-gp-mediated MDR by inhibition of P-gp expression. This effect was likely related to downregulation of YB1, and this effect was mediated by the NF-kB and MAPK–ERK pathways. AA may be useful as an MDR reversal agent for combination therapy in clinical trials