Antidiabetic effects of Centratherum anthelminticum seeds methanolic fraction on pancreatic cells,ß-TC6 and its alleviating role in type 2 diabetic rats

Ethnopharmacological relevance:Seeds of Centratherum anthelminticum (Asteraceae)have been popularly used in Ayurvedic medicine to treat diabetes and skin disorders.Folk medicine from Rayalaseema(Andhra Pradesh,India)reported wide spread usage in diabetes. Aim of the study:To investigate the hypoglycemic properties and mechanism of the me than olic fraction of Centratherum anthelminticum seeds(CAMFs)on mouse ß-TC6 pancreatic cell line and streptozotocin (STZ)induced diabetic rat models. Materials and Methods:We investigated the crude methanolic fraction of Centratherum an thelminticum seeds(CAMFs)on ß-TC6 cellline and confirmed its effects on type 1 and type 2 diabetic rats to understand its mechanism in managing diabetes mellitus.(CAMFs) was initially tested on ß-TC6 cells for cytotoxicity, 2 NBDG glucose uptake,insulin secretion and glucose transporter (GLUT1,2and4)protein expression.Furthermore,streptozotocin(STZ)–induced type 1 diabetic and STZ-nicotinamide–induced type2 diabetic rats were in traperitoneally (i.p)injected or administered orally with CAMFs daily for 28days.The effect of CAMFs on blood glucose and insulin levels was subsequently evaluated

Unraveling the cytotoxicity and metabolic pathways of binary natural deep eutectic solvent systems

In this study, the anticancer potential and cytotoxicity of natural deep eutectic solvents (NADESs) were assessed using HelaS3, PC3, A375, AGS, MCF-7, and WRL-68 hepatic cell lines. NADESs were prepared from choline chloride, fructose, or glucose and compared with an N,N-diethyl ethanolammonium chloride:triethylene glycol DES. The NADESs (98 ≤ EC 50 ≥ 516 mM) were less toxic than the DES (34 ≤ EC 50 ≥ 120 mM). The EC 50 values of the NADESs were significantly higher than those of the aqueous solutions of their individual components but were similar to those of the aqueous solutions of combinations of their chief elements. Due to the uniqueness of these results, the possibility that NADESs could be synthesized intracellularly to counterbalance the cytotoxicity of their excess principal constituents must be entertained. However, further research is needed to explore this avenue. NADESs exerted cytotoxicity by increasing membrane porosity and redox stress. In vivo, they were more destructive than the DES and induced liver failure. The potential of these mixtures was evidenced by their anticancer activity and intracellular processing. This infers that they can serve as tools for increasing our understanding of cell physiology and metabolism. It is likely that we only have begun to comprehend the nature of NADESs

The methanolic fraction of Centratherum anthelminticum seed downregulates pro-inflammatory cytokines, oxidative stress, and hyperglycemia in STZ-nicotinamide-induced type 2 diabetic rats.

This study aimed to ascertain the potential of Centratherum anthelminticum seeds methanolic fraction (CAMFs) for the management of type 2 diabetes and its associated complications. CAMFs was initially tested on β-TC6 cells for H2O2-induced nuclear factor-κB (NF-κB) translocation effects. The result displayed that CAMFs significantly inhibited NF-κB translocation from cytoplasm into the nucleus, dose-dependently. Furthermore, a 12-week sub-chronic CAMFs study was carried out on streptozotocin (STZ)-nicotinamide�induced type 2 diabetic rat model to evaluate glycemia, essential biochemical parameters, lipid levels, oxidative stress markers, and pro-inflammatory cytokines level. Our study result showed that CAMFs reduced hyperglycemia by increasing serum insulin, C-peptide, total protein, and albumin levels, significantly. Whereas, elevated blood glucose, glycated hemoglobin, lipids and enzyme activities were restored to near normal. CAMFs confirmed antioxidant potential by elevating glutathione (GSH) and reducing malondialdehyde (MDA) levels in diabetic rats. Interestingly, CAMFs down-regulated elevated tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 in the tissues and serum of the diabetic rats. We conclude that CAMFs exerted apparent antidiabetic effects and demonstrated as a valuable candidate nutraceutical for insulin-resistant type 2 diabetes and its associated complications such as dyslipidemia, oxidative stress, and inflammation

In vitro antioxidant, PTP-1B inhibitory effects and in vivo hypoglycemic potential of selected medicinal plants

The therapeutic potential of plants varies according to their parts. The present study was aimed to ascertain the antioxidant and antidiabetic potential of crude fractions obtained from different parts of 6 medicinal plants, Centratherum anthelminticum, Cissus quadrangularis, Terminalia bellerica, Terminalia chebula, Terminalia arjuna and Woodfordia fruticosa. Total phenolic (TPC), total flavonoid (TFC) and total tannin content (TTC) were determined. In vitro antioxidant abilities were showed by 1, 1-diphenyl-2-picrylhydrazyl (DPPH), Oxygen Radical Absorbance Capacity (ORAC) and Ferric Reducing/antioxidant Power (FRAP) assays. Furthermore, anti-diabetic potential was determined using in vitro protein tyrosine phosphatase-1B (PTP-1B) inhibition assay and blood glucose lowering effects were evaluated on streptozotocin (STZ)-induced diabetic rats. The result of our study showed that T. chebula fruit exhibited highest amount of TPC (910.43±37.45 mg GAE g-1) and TTC (65.6±6.83 mg Catechin g-1), respectively. Whereas C. anthelminticum seeds contained highest amount of TFC (98.2±27.6 mg Quercetin g-1). The free radical scavenging capacity of T. chebula fruits was the highest among the six plants as determined by DPPH (3.6±0.13 μg mL-1) and FRAP (109.6±2.5 μg mL-1) assays. C. anthelminticum seeds (9.16±0.62 μM mL-1) demonstrated highest oxygen radical absorbance capacity in ORAC test. In addition, C. anthelminticum seeds (38±5.8 μM) showed highest PTP-1B inhibitory effects and maximum blood glucose lowering effects in STZ-induced diabetic rats. Altogether, our findings suggest that T. chebula fruit is potent in ameliorating oxidative damage whereas, C. anthelminticum seeds possess highest antidiabetic and antioxidant properties

A cell-based screening system for anti-influenza A virus agents

Emerging of drug resistant influenza A virus (IAV) has been a big challenge for anti-IAV therapy. In this study, we describe a relatively easy and safe cell-based screening system for anti-IAV replication inhibitors using a non-replicative strain of IAV. A nickel (II) complex of polyhydroxybenzaldehyde N4-thiosemicarbazone (NiPT5) was recently found to exhibit anti-inflammatory activity in vivo and in vitro. NiPT5 impedes the signaling cascades that lead to the activation of NF-κB in response to different stimuli, such as LPS and TNFα. Using our cell-based screening system, we report that pretreating cells with NiPT5 protects cells from influenza A virus (IAV) and vesicular stomatitis virus (VSV) infection. Furthermore, NiPT5 inhibits replication of IAV by inhibiting transcription and translation of vRNAs of IAV. Additionally, NiPT5 reduces IAV-induced type I interferon response and cytokines production. Moreover, NiPT5 prevents activation of NF-κB, and IRF3 in response to IAV infection. These results demonstrate that NiPT5 is a potent antiviral agent that inhibits the early phase of IAV replication

T-cell receptor signaling induces proximal Runx1 transactivation via a calcineurin–NFAT pathway

Runx1 transcription factor is a key player in the development and function of T cells. Runx1 transcripts consist of two closely related isoforms (proximal and distal Runx1) whose expressions are regulated by different promoters. Which Runx1 isoform is expressed appears to be tightly regulated. The regulatory mechanism for differential transcription is, however, not fully understood. In this study, we investigated the regulation of the proximal Runx1 promoter in T cells. We showed that proximal Runx1 was expressed at a low level in naïve T cells from C57BL/6 mice, but its expression was remarkably induced upon T-cell activation. In the promoter of proximal Runx1, a highly conserved region was identified which spans from −412 to the transcription start site and harbors a NFAT binding site. In a luciferase reporter assay, this region was found to be responsive to T-cell activation through Lck and calcineurin pathways. Mutagenesis studies and chromatin immunoprecipitation assay indicated that the NFAT site was essential for NFAT binding and transactivation of the proximal Runx1 promoter. Furthermore, TCR signaling-induced expression of proximal Runx1 was blocked by treatment of cells with cyclosporin A. Together, these results demonstrate that the calcineurin–NFAT pathway regulates proximal Runx1 transcription upon TCR stimulation

Vindogentianine, a hypoglycemic alkaloid from Catharanthus roseus (L.) G. Don (Apocynaceae)

Vindogentianine, a new indole alkaloid together with six known alkaloids, vindoline, vindolidine, vindolicine, vindolinine, perivine and serpentine were isolated from leaf extract (DA) of Catharanthus roseus (L.) G. Don. Their structures were elucidated by spectroscopic methods; NMR, MS, UV and IR. Vindogentianine is a dimer containing a vindoline moiety coupled to a gentianine moiety. After 24 h incubation, vindogentianine exhibited no cytotoxic effect in C2C12 mouse myoblast and β-TC6 mouse pancreatic cells (IC50 > 50 μg/mL). Real-time cell proliferation monitoring also indicated vindogentianine had little or no effect on C2C12 mouse myoblast cell growth at the highest dose tested (200 μg/mL), without inducing cell death. Vindogentianine exhibited potential hypoglycemic activity in β-TC6 and C2C12 cells by inducing higher glucose uptake and significant in vitro PTP-1B inhibition. However, in vitro α-amylase and α-glucosidase inhibition assay showed low inhibition under treatment of vindogentianine. This suggests that hypoglycemic activity of vindogentianine may be due to the enhancement of glucose uptake and PTP-1B inhibition, implying its therapeutic potential against type 2 diabetes

The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges

10.3390/cells8101118Cells81

(6E, 10E) Isopolycerasoidol and (6E, 10E) isopolycerasoidol methyl ester, prenylated benzopyran derivatives from pseuduvaria monticola induce mitochondrial-mediated apoptosis in human breast adenocarcinoma cells

Phytochemicals from Pseuduvaria species have been reported to display a wide range of biological activities. In the present study, a known benzopyran derivative, (6E, 10E) isopolycerasoidol (1), and a new benzopyran derivative, (6E, 10E) isopolycerasoidol methyl ester (2), were isolated from a methanol extract of Pseuduvaria monticola leaves. The structures of the isolated compounds were elucidated by spectroscopic methods including 1D and 2D NMR, IR, UV, and LCMS-QTOF, and by comparison with previously published data. The anti-proliferative and cytotoxic effects of these compounds on human breast cancer cell-lines (MCF-7 and MDA-MB-231) and a human normal breast epithelial cell line (MCF-10A) were investigated. MTT results revealed both (1) and (2) were efficient in reducing cell viability of breast cancer cells. Flow cytometry analysis demonstrated that (1) and (2) induced cell death via apoptosis, as demonstrated by an increase in phosphotidylserine exposure. Both compounds elevated ROS production, leading to reduced mitochondrial membrane potential and increased plasma membrane permeability in breast cancer cells. These effects occurred concomitantly with a dose-dependent activation of caspase 3/7 and 9, a down-regulation of the anti-apoptotic gene BCL2 and the accumulation of p38 MAPK in the nucleus. Taken together, our data demonstrate that (1) and (2) induce intrinsic mitochondrial- mediated apoptosis in human breast cancer cells, which provides the first pharmacological evidence for their future development as anticancer agents

Nickel (II) complexes of polyhydroxybenzaldehyde N4-thiosemicarbazones: synthesis, structural characterization and antimicrobial activities

Nickel(II) complexes with 2,3-dihydroxybenzaldehyde N4-substituted thiosemicarbazone ligands (H3L1�H3L4) have been synthesized and characterized with the aim of evaluating the effect of N4 substitution in the thiosemicarbazone moiety on their coordination behavior and biological activities. Two series of nickel(II) complexes with the general formulae Ni(H3L)(H2L)ClO4 and Ni2(HL)2 were characterized by analytical and spectral techniques. The molecular structure of one of the complexes, namely, Ni(H3L4)(H2L4)ClO4 was established by single crystal X-ray diffraction studies. The crystal structure of this complex revealed that two H3L4 ligands are coordinated to nickel(II) in different modes; one as a neutral tridentate ONS ligand and the other is as a monoanionic tridentate (ONS�) ligand. The antimicrobial activities of the compounds were tested against 25 bacterial strains via the disc diffusion method, and their minimum inhibitory concentration (MIC) and minimum microbicidal concentration were evaluated using microdilution methods. With a few exceptions, most of the compounds exhibited low-to-moderate inhibitory activities against the tested bacterial strains. However, the complexes Ni2(HL3)2 (7) and Ni2(HL4)2 (8) indicated higher inhibitory activity against Salmonella enterica ATCC 9068 (MIC values 15.7 and 50 μg/ml). The toxicities of the compounds were tested on brine shrimp (Artemia salina), where no meaningful toxicity level was noted for both the free ligands and the complexes. The cytotoxicities of the compounds on cell viability were determined on MCF7, PC3, A375, and H413 cancer cells in terms of IC50; complexes Ni(H3L3)(H2L3)ClO4 (3), Ni2(HL3)2 (7) and Ni2(HL4)2 (8) exhibited significant cytotoxicity on the tested cell lines