Nootropic activity of tuber extract of Pueraria tuberosa (Roxb)

Nootropic effect of alcoholic (ALE; 50, 75, 100 mg/kg) and aqueous (AQE; 100, 200, 400 mg/kg) extracts of P. tuberosa was evaluated by using Elevated Plus Maze (EPM), scopolamine-induced amnesia (SIA), diazepam-induced amnesia (DIA), clonidine-induced (NA-mediated) hypothermia (CIH), lithium-induced (5-HT mediated) head twitches (LIH) and haloperidol-induced (DA- mediated) catalepsy (HIC) models. Piracetam was used as the standard drug. A significant increase in inflexion ratio (IR) was recorded in EPM, SIA and DIA models. A significant reversal effect was observed on rectal temperature in CIH model, reduction of head twitches in LIH models. However no significant reduction in catalepsy scores in HIC models were observed with test extracts and standard piracetam. The results indicate that nootropic activity observed with ALE and AQE of tuber extracts of P. tuberosa could be through improved learning and memory either by augmenting the noradrenaline (NA) transmission or by interfering with 5-hydroxytryptamine (5-HT) release. Further, the extracts neither facilitated nor blocked release of the dopamine (DA). Thus ALE and AQE elicited significant nootropic effect in mice and rats by interacting with cholinergic, GABAnergic, adrenergic and serotonergic systems. Phytoconstituents like flavonoids have been reported for their nootropic effect and these are present in both ALE and AQE extracts of tubers of P. tuberosa (Roxb) and these active principles may be responsible for nootropic activity.     

Antitumor activity of Noscapine in combination with Doxorubicin in triple negative breast cancer

Background

The aim of this study was to investigate the anticancer activity and mechanism of action of Noscapine alone and in combination with Doxorubicin against triple negative breast cancer (TNBC).

Methods

TNBC cells were pretreated with Noscapine or Doxorubicin or combination and combination index values were calculated using isobolographic method. Apoptosis was assessed by TUNEL staining. Female athymic Nu/nu mice were xenografted with MDA-MB-231 cells and the efficacy of Noscapine, Doxorubicin and combination was determined. Protein expression, immunohistochemical staining were evaluated in harvested tumor tissues.

Results

Noscapine inhibited growth of MDA-MB-231 and MDA-MB-468 cells with the IC₅₀ values of 36.16±3.76 and 42.7±4.3 µM respectively. The CI values (<0.59) were suggestive of strong synergistic interaction between Noscapine and Doxorubicin and combination treatment showed significant increase in apoptotic cells. Noscapine showed dose dependent reduction in the tumor volumes at a dose of 150–550 mg/kg/day compared to controls. Noscapine (300 mg/kg), Doxorubicin (1.5 mg/kg) and combination treatment reduced tumor volume by 39.4±5.8, 34.2±5.7 and 82.9±4.5 percent respectively and showed decreased expression of NF-KB pathway proteins, VEGF, cell survival, and increased expression of apoptotic and growth inhibitory proteins compared to single-agent treatment and control groups.

Conclusions

Noscapine potentiated the anticancer activity of Doxorubicin in a synergistic manner against TNBC tumors via inactivation of NF-KB and anti-angiogenic pathways while stimulating apoptosis. These findings suggest potential benefit for use of oral Noscapine and Doxorubicin combination therapy for treatment of more aggressive TNBC.     

Entry of bovine viral diarrhea virus into ovine cells occurs through clathrin-dependent endocytosis and low pH-dependent fusion

Although mechanisms of bovine viral diarrhea virus (BVDV) entry into bovine cells have been elucidated, little is known concerning pestivirus entry and receptor usage in ovine cells. In this study, we determined the entry mechanisms of BVDV-1 and BVDV-2 in sheep fetal thymus cells. Both BVDV-1 and BVDV-2 infections were inhibited completely by chlorpromazine, β-methyl cyclodextrin, sucrose, bafilomycin A1, chloroquine, and ammonium chloride. Simultaneous presence of reducing agent and low pH resulted in marked loss of BVDV infectivity. Moreover, BVDV was unable to fuse with ovine cell membrane by the presence of reducing agent or low pH alone, while combination of both led to fusion at low efficiency. Furthermore, sheep fetal thymus cells acutely infected with BVDV-1 or BVDV-2 were found protected from heterologous BVDV infection. Taken together, our results showed for the first time that entry of both BVDV-1 and BVDV-2 into ovine cells occurred through clathrin-dependent endocytosis, endosomal acidification, and low pH-dependent fusion following an activation step, besides suggesting the involvement of a common ovine cellular receptor during attachment and entry.     

Distinct evolutionary histories of the DNA-A and DNA-B components of bipartite begomoviruses

Background  

Viruses of the genus Begomovirus (family Geminiviridae) have genomes consisting of either one or two genomic components. The component of bipartite begomoviruses known as DNA-A is homologous to the genomes of all geminiviruses and encodes proteins required for replication, control of gene expression, overcoming host defenses, encapsidation and insect transmission. The second component, referred to as DNA-B, encodes two proteins with functions in intra- and intercellular movement in host plants. The origin of the DNA-B component remains unclear. The study described here was initiated to investigate the relationship between the DNA-A and DNA-B components of bipartite begomoviruses with a view to unraveling their evolutionary histories and providing information on the possible origin of the DNA-B component.     

Triglyceride-Increasing Alleles Associated with Protection against Type-2 Diabetes

Elevated plasma triglyceride (TG) levels are an established risk factor for type-2 diabetes (T2D). However, recent studies have hinted at the possibility that genetic risk for TG may paradoxically protect against T2D. In this study, we examined the association of genetic risk for TG with incident T2D, and the interaction of baseline TG with TG genetic risk on incident T2D in 13,247 European-Americans (EA) and 3,238 African-Americans (AA) from three prospective cohort studies. A TG genetic risk score (GRS) was calculated based on 31 validated single nucleotide polymorphisms (SNPs). We considered several baseline covariates, including body- mass index (BMI) and lipid traits. Among EA and AA, we find, as expected, that baseline levels of TG are strongly positively associated with incident T2D (p<2 x 10^-10). However, the TG GRS is negatively associated with T2D (p=0.013), upon adjusting for only race, in the full dataset. Upon additionally adjusting for age, sex, BMI, high-density lipoprotein cholesterol and TG, the TG GRS is significantly and negatively associated with T2D incidence (p=7.0 x 10^-8), with similar trends among both EA and AA. No single SNP appears to be driving this association. We also find a significant statistical interaction of the TG GRS with TG (p_interaction=3.3 x 10^-4), whereby the association of TG with incident T2D is strongest among those with low genetic risk for TG. Further research is needed to understand the likely pleiotropic mechanisms underlying these findings, and to clarify the causal relationship between T2D and TG.     

IGF1 stimulates differentiation of primary follicles and their growth in ovarian explants of zebrafish (<Emphasis Type="Italic">Danio rerio)</Emphasis> cultured <Emphasis Type="Italic">in vitro</Emphasis>

The present study is an attempt to elucidate the involvement of insulin-like growth factor (IGF1) in the differentiation and growth of primary follicles in ovarian explant cultures of zebrafish. Ovaries from adult females were cultured in triplicate sets/treatment group for 15 days at 22°C in the laboratory. Culture medium was supplemented with either insulin (1 ng/mL) or IGF1 (1 ng/mL) or insulin + IGF1 (Experiment 1) or 0.1 or 1.0 or 10 ng/mL of IGF1 (Experiment 2). Ovaries cultured in medium alone served as controls and those fixed at the beginning of the culture as initial controls. Experiments were repeated. On the 16th day ovarian explants were fixed in Bouin’s fluid and processed for paraffin embedding, sections (3 µm) were cut and stained with hematoxylin-eosin. Follicles were classified into 6 stages and atretic follicles (AF). Previtellogenic, vitellogenic and total follicle number was calculated. At the start of the culture, ovaries contained all stages of growing and degenerating follicles. In in vitro cultured control ovaries, vitellogenic follicles underwent atresia, while, primary follicles remained unaffected. Insulin or insulin + IGF1 treated ovaries did not differ significantly while IGF1 exposed ovarian explants had greater (P < 0.05) number of primary follicles compared to controls. IGF1 also caused an increase in the number and growth of primary follicles in a dose dependent manner although; cultures were not supplemented with gonadotrophic hormones. Results suggest that locally derived intra-ovarian IGF1 may have a role in the differentiation and growth of primary follicles in zebrafish ovary.     

Anti-tubercular activity and molecular docking studies of indolizine derivatives targeting mycobacterial InhA enzyme

A series of 1,2,3-trisubstituted indolizines (2a–2f, 3a–3d, and 4a–4c) were screened for in vitro whole-cell anti-tubercular activity against the susceptible H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 2b–2d, 3a–3d, and 4a–4c were active against the H37Rv-MTB strain with minimum inhibitory concentration (MIC) ranging from 4 to 32 µg/mL, whereas the indolizines 4a–4c, with ethyl ester group at the 4-position of the benzoyl ring also exhibited anti-MDR-MTB activity (MIC = 16–64 µg/mL). In silico docking study revealed the enoyl-acyl carrier protein reductase (InhA) and anthranilate phosphoribosyltransferase as potential molecular targets for the indolizines. The X-ray diffraction analysis of the compound 4b was also carried out. Further, a safety study (in silico and in vitro) demonstrated no toxicity for these compounds. Thus, the indolizines warrant further development and may represent a novel promising class of InhA inhibitors and multi-targeting agents to combat drug-sensitive and drug-resistant MTB strains.