Repositioning of Verrucosidin, a purported inhibitor of chaperone protein GRP78, as an inhibitor of mitochondrial electron transport chain complex I.

Verrucosidin (VCD) belongs to a group of fungal metabolites that were identified in screening programs to detect molecules that preferentially kill cancer cells under glucose-deprived conditions. Its mode of action was proposed to involve inhibition of increased GRP78 (glucose regulated protein 78) expression during hypoglycemia. Because GRP78 plays an important role in tumorigenesis, inhibitors such as VCD might harbor cancer therapeutic potential. We therefore sought to characterize VCD's anticancer activity in vitro. Triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 were treated with VCD under different conditions known to trigger increased expression of GRP78, and a variety of cellular processes were analyzed. We show that VCD was highly cytotoxic only under hypoglycemic conditions, but not in the presence of normal glucose levels, and VCD blocked GRP78 expression only when glycolysis was impaired (due to hypoglycemia or the presence of the glycolysis inhibitor 2-deoxyglucose), but not when GRP78 was induced by other means (hypoxia, thapsigargin, tunicamycin). However, VCD's strictly hypoglycemia-specific toxicity was not due to the inhibition of GRP78. Rather, VCD blocked mitochondrial energy production via inhibition of complex I of the electron transport chain. As a result, cellular ATP levels were quickly depleted under hypoglycemic conditions, and common cellular functions, including general protein synthesis, deteriorated and resulted in cell death. Altogether, our study identifies mitochondria as the primary target of VCD. The possibility that other purported GRP78 inhibitors (arctigenin, biguanides, deoxyverrucosidin, efrapeptin, JBIR, piericidin, prunustatin, pyrvinium, rottlerin, valinomycin, versipelostatin) might act in a similar GRP78-independent fashion will be discussed

Arctigenin reduces neuronal responses in the somatosensory cortex via the inhibition of non-NMDA glutamate receptors

Lignans are biologically active phenolic compounds related to lignin, produced in different plants. Arctigenin, a dibenzylbutyrolactone-type lignan, has been used as a neuroprotective agent for the treatment of encephalitis. Previous studies of cultured rat cerebral cortical neurones raised the possibility that arctigenin inhibits kainate-induced excitotoxicity. The aims of the present study were: 1) to analyse the effect of arctigenin on normal synaptic activity in ex vivo brain slices, 2) to determine its receptor binding properties and test the effect of arctigenin on AMPA/kainate receptor activation and 3) to establish its effects on neuronal activity in vivo. Arctigenin inhibited glutamatergic transmission and reduced the evoked field responses. The inhibitory effect of arctigenin on the evoked field responses proved to be substantially dose dependent. Our results indicate that arctigenin exerts its effects under physiological conditions and not only on hyper-excited neurons. Furthermore, arctigenin can cross the blood-brain barrier and in the brain it interacts with kainate sensitive ionotropic glutamate receptors. These results indicate that arctigenin is a potentially useful new pharmacological tool for the inhibition of glutamate-evoked responses in the central nervous system in vivo

Biosynthesis of lignans. Part I . Biosynthesis of Arctiin (3) and Phillyrin (5)

Lignans constitute a class of naturally occuring phenolic compounds, widely distributed in higher plants. They are formally composed of two phenylpropanoid units, stercospecifically joined at the /f-carbon atoms of their side chains. Their biosynthesis has as yet not been investigated. To sec, if these plant phenolics originate from simple phenylpropancs, various radioactively labelled, putative precursors were fed to Forsythia shoots. Chemically synthezised arylpropane derivatives, such as Ή/1 'C-glucoferulic acid, -glucoferulic aldehyde, and -coniferin were incorporated into the lignans arctiin (3) and phillyrin (5) while 3H-3,4-dimcthoxycinnamic acid was not incorporated. From these results i t may be concluded that the hydroxylated compounds are direct precursors of these dimeric phenylpropanes and are incorporated through a dimerisation step without degradation of the Q - Q skeleton

Arctium lappa contributes to the management of type 2 diabetes mellitus by regulating glucose homeostasis and improving oxidative stress: A critical review of in vitro and in vivo animal-based studies

Diabetes is a metabolic disease highly widespread worldwide, and the most common form is the type 2 diabetes mellitus (T2DM). A large number of synthetic drugs are currently available for the treatment of diabetes; however, they present various side effects and, for this reason, people are increasingly inclined to search natural alternative treatments. Among these, Arctium lappa (A. lappa) has interesting anti-diabetic activities, exerted by improving glucose homeostasis and reducing insulin-resistance. In addition, A. lappa exerts a marked antioxidant activity, an effect known to play a pivotal role in the treatment of T2DM. The purpose of this review is to analyse scientific evidence in order to evaluate the role of A. lappa and its bioactive compounds in management of T2DM. The literature search performed provided only in vitro and animal-based studies. No clinical studies have been conducted in order to investigate the effect of A. lappa on T2DM patients. However, available literature provides evidence for further clinical trials in order to confirm these claimed activities on humans

Pharmacological effect of Actiumlappa: A review study

Actium lappa in the sunflower family, is a biennial plant, rather tall, reaching as much as 3 cultivated in gardens forits root used as a vegetable native This species is native to the temperate regions of the old world. It has large, alternating, cordiform leaves that have a long petiole and are pubescent on the underside. The aim of this study wasto overview its therapeutic effects of this plant. This review article was carried out by searching studies in PubMed, Medline, Web of Science, and IranMedex databases. The initial search strategy identified about 58 references. Inthis study, 27 studies was accepted for further screening and met all our inclusion criteria [in English, full text, therapeutic effects of Actium lappa and dated mainly from the year 1996 to 2016.The search terms were "Actiumlappa", "therapeutic properties", "pharmacological effects". It is commonly used for its antioxidants andantidiabetic, anti-inflammatory effects, anti-cancers, anti-allergic effect, anti-ulcer effect, antitubercular activity, anti-acne, anti-dermal fibroblast, anti-sterility, anti-ulcerogenic, ulcerative colitis, angiostrongyliasis effect, gastroprotective activity, hepatoprotective effects, anti-aging effect, anti-austeric activity, cytotoxicity effect. Different medicinal properties of this plantrequire more studies regarding to other unknown properties of thisvaluable plant

Neuroprotective effect of arctigenin via upregulation of P-CREB in mouse primary neurons and human SH-SY5Y neuroblastoma cells.

Arctigenin (Arc) has been shown to act on scopolamine-induced memory deficit mice and to provide a neuroprotective effect on cultured cortical neurons from glutamate-induced neurodegeneration through mechanisms not completely defined. Here, we investigated the neuroprotective effect of Arc on H89-induced cell damage and its potential mechanisms in mouse cortical neurons and human SH-SY5Y neuroblastoma cells. We found that Arc prevented cell viability loss induced by H89 in human SH-SY5Y cells. Moreover, Arc reduced intracellular beta amyloid (Aβ) production induced by H89 in neurons and human SH-SY5Y cells, and Arc also inhibited the presenilin 1(PS1) protein level in neurons. In addition, neural apoptosis in both types of cells, inhibition of neurite outgrowth in human SH-SY5Y cells and reduction of synaptic marker synaptophysin (SYN) expression in neurons were also observed after H89 exposure. All these effects induced by H89 were markedly reversed by Arc treatment. Arc also significantly attenuated downregulation of the phosphorylation of CREB (p-CREB) induced by H89, which may contribute to the neuroprotective effects of Arc. These results demonstrated that Arc exerted the ability to protect neurons and SH-SY5Y cells against H89-induced cell injury via upregulation of p-CREB

Inhibition of Th1 and Th17 Cells by Medicinal Plants and Their Derivatives: A Systematic Review.

Searching for new natural drugs that are capable of targeting Th1 and Th17 may lead to development of more effective treatments for inflammatory and autoimmune diseases. Most of the natural drugs can be derived from plants that are used in traditional medicine and folk medicine. The aim of this systematic review is to identify and introduce plants or plant derivatives that are effective on inflammatory diseases by inhibiting Th1 and Th17 responses. To achieve this purpose, the search terms herb, herbal medicine, herbal drug, medicinal plant, phytochemical, traditional Chinese medicine, Ayurvedic medicine, natural compound, inflammation, inflammatory diseases, Th1, Th17, T helper 1 or T helper 17 were used separately in Title/Keywords/Abstract in Web of Science and PubMed databases. In articles investigating the effect of the medicinal plants and their derivatives in inhibiting Th1 and Th17 cells, the effects of eight extracts of the medicinal plants, 21 plant-based compounds and some of their derivatives, and eight drugs derived from the medicinal plants' compounds in inhibiting Th1 and Th17 cells were reviewed. The results showed that medicinal plants and their derivates are able to suppress Th17 and Th1 T cell functions as well as cytokine secretion and differentiation. The results can be used to produce herbal drugs that suppress Th, especially Th17, responses. Copyright © 2017 John Wiley & Sons, Ltd

Division of Natural Products Chemistry

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Division of Metabolic Engineering

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