Uma Devi

Alpha-linolenic acid stabilizes HIF-1 α and downregulates FASN to promote mitochondrial apoptosis for mammary gland chemoprevention

Alpha linolenic acid is an essential polyunsaturated fatty acid and is reported to have the anti-cancer potential with no defined hypothesis or mechanism/s. Henceforth present study was in-quested to validate the effect of alpha linolenic acid on mitochondrial apoptosis, hypoxic microenvironment and de novo fatty acid synthesis using in-vitro and in-vivo studies. The IC50 value of alpha linolenic acid was recorded to be 17.55μM against ER+MCF-7 cells. Treatment with alpha linolenic acid was evident for the presence of early and late apoptotic signals along with mitochondrial depolarization, when studied through acridine orange/ethidium bromide and JC-1 staining. Alpha linolenic acid arrested the cell cycle in G2/M phase. Subsequently, the in-vivo efficacy was examined against 7, 12-dimethylbenz anthracene induced carcinogenesis. Treatment with alpha linolenic acid demarcated significant effect upon the cellular proliferation as evidenced through decreased in alveolar bud count, restoration of the histopathological architecture and loss of tumor micro vessels. Alpha linolenic acid restored the metabolic changes to normal when scrutinized through 1H NMR studies. The immunoblotting and qRT-PCR studies revealed participation of mitochondrial mediated death apoptosis pathway and curtailment of hypoxic microenvironment after treatment with alpha linolenic acid. With all above, it was concluded that alpha linolenic acid mediates mitochondrial apoptosis, curtails hypoxic microenvironment along with inhibition of de novo fatty acid synthesis to impart anticancer effects.

Dual inhibition of arachidonic acid pathway by mulberry leaf extract

The present work investigates the anti-inflammatory, analgesic and antipyretic activity of methanolic extract of mulberry leaves of variety S-1, S-13 and S-146. The S-146 extract was further evaluated for its efficacy against adjuvant arthritis in albino rats followed by inhibitory potential for COX 1, COX 2 and 5 LOX. The HPLC analysis enumerated the presence of morin, reversterol, scopoletin and 7-hydroxy coumarin as the major constituents. The anti-inflammatory, antipyretic and analgesic activity observed in the present experiment could be accredited to the dual inhibition in the AA pathway. The inhibition of COX and LOX enzymes could be imparted to the presence of resveraterol, morin, scopoletin and 7-hydroxy coumarin.

Rifaximin, a pregnane X receptor (PXR) activator regulates apoptosis in a murine model of breast cancer

The present study was proposed to investigate the effect of rifaximin (RFX) on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. Animals were randomized and divided among four groups of six animals each. Group I (control 0.9% normal saline, 3 ml kg−1, p.o.); Group II (toxic control, MNU 47 mg kg−1, i.v.); Group III (RFX, 25 mg kg−1, p.o.); Group IV (RFX, 50 mg kg−1, p.o.). Toxicity was induced by single i.v. injection of MNU. MNU treatment was evident with increased alveolar bud count, differentiation score, up-regulated inflammatory enzyme markers (COX, LOX, NO and H2S) and oxidative stress markers (TBARs, protein carbonyl, SOD, catalase and Ach). The mammary gland surface architecture was studied using SEM, carmine staining and H&E staining. The treatment with RFX elicited noticeable restoration of the overall histological architecture in the experimental animals similar to the control. In the MNU treated toxic group, the levels of oxidative stress markers significantly increased in comparison to the control, which was subsequently restored after RFX treatment. Furthermore, RFX up regulated the levels of caspase 3 and caspase 8, when compared to the MNU treated animals. MNU associated toxicity was also ascertained, when determined for UCHL-1, COX, NF-κBp65, BAD, and BCL-xl expression, while RFX demonstrated modulation of the same.

Prolyl hydroxylase mediated inhibition of fatty acid synthase to combat tumor growth in mammary gland carcinoma.

Cancer is a group of cells which grow in an uncontrolled manner and invades to the adjacent organs to form malignant tumors. Tumor hypoxia results due to contrast between the cellular oxygen expenditure and oxygen supply to the cells. Hypoxia inducible factor (HIF) is a heterodimeric transcription factor encompass of oxygen sensitive α subunit and constitutively expressed β subunit both of which are basic helix-loop-helix protein. The stability of HIF is primarily regulated by post translational prolyl hydroxylation, catalyzed by prolyl hydroxylase 2 (Phd-2). Phd-2 is a group of enzymes that acts as an oxygen sensor. Cancer cells have altered metabolism as they fulfil their energy needs through glycolysis and lipid biogenesis. HIF-1α is known to upregulate glycolysis by activating the transcription of enzymes on the glycolytic pathway and through lipogenesis. Cancer cells have over expressed fatty acid synthase owing to altered glycolytic pathway. Considering the above, it is hypothesized that chemical activation of Phd-2 can curtail down HIF-1α and subsequently fatty acid synthase expression.

Comparative efficacy of alpha-linolenic acid and gamma-linolenic acid to attenuate valproic acid-induced autism-like features

The present study was undertaken to elucidate the effect of alpha-linolenic acid (ALA, 18:3, ω-3) and gamma-linolenic acid (GLA, 18:3, ω-6) on experimental autism features induced by early prenatal exposure to valproic acid (VPA) in albino wistar pups. The pups were scrutinized on the accounts of behavioral, biochemical, and inflammatory markers, and the results suggested that the GLA can impart significant protection in comparison to ALA against VPA-induced autism features. When scrutinized histopathologically, the cerebellum of the GLA-treated animals was evident for more marked protection toward neuronal degeneration and neuronal loss in comparison to ALA. Concomitant administration of ALA and GLA with VPA demonstrated a marked cutdown in the Pgp 9.5 expression with GLA having more pronounced effect. Henceforth, it can be concluded that ALA and GLA can impart favorable protection against the VPA-induced autism-like features with GLA having pronounced effect.

Preclinical appraisal of terbutaline analogues in precipitation of autism spectrum disorder

Terbutaline is a β2 agonist used in the clinical management of asthma and as a tocolytic agent during pregnancy. In the recent past, the preterm use of terbutaline has been shown to hasten autistic-like symptoms in offsprings. For this reason, the present study was carried out to understand the effects of pharmacological analogues of terbutaline (salbutamol, salmeterol and montelukast) in the progression of ASDs in experimental animals. Pregnant rats were treated with salbutamol (10 mg kg−1, sc), salmeterol (10 μg kg−1, sc) and montelukast (10 mg kg−1, sc) and the offsprings were scrutinized for behavioral, biochemical, neuro-inflammatory and histopathological changes. The offsprings from the rats treated with salbutamol and montelukast were determined to be closely associated with various symptoms of ASDs.

GLA supplementation regulates PHD2 mediated hypoxia and mitochondrial apoptosis in DMBA induced mammary gland carcinoma

The aim of the present study is to evaluate the effect of gamma linolenic acid (GLA) on mitochondrial mediated death apoptosis, hypoxic microenvironment and cholinergic anti-inflammatory pathway against 7, 12-dimethylbenz (a) anthracene (DMBA) induced mammary gland carcinoma. The effects of GLA were evaluated morphologically and biochemically against DMBA induced mammary gland carcinoma. The metabolic study was done for evaluation of biomarkers using 1H NMR. The present study was also verified through immunoblotting and qRT-PCR studies for the evaluation of various pathways. GLA treatment has a delineate implementation upon morphology of the tissues when evaluated through carmine staining, hematoxyline and eosin staining and scanning electron microscopy. GLA also demarked a commendatory proclamation of the fifteen key serum metabolites analogous with amino acid metabolism and fatty acid metabolism when recognized through1H NMR studies. The immunoblotting and qRT-PCR studies accomplished that GLA mediated mitochondrial death apoptosis, curtail hypoxic microenvironment along with hindrance of de novo fatty acid synthesis and also mediate the cholinergic anti-inflammatory pathway to proclaim its anticancer effects.

Palonosetron attenuates 1,2-dimethyl hydrazine induced preneoplastic colon damage through downregulating acetylcholinesterase expression and up-regulating synaptic acetylcholine concentration

The present study was undertaken to evaluate the effect of palonosetron (PAL) against 1,2-dimethylhydrazine (DMH)-induced colon cancer. Wistar albino rats were randomly divided into four groups (n = 8). Group 1 served as normal control (1 mM EDTA + saline, 2 ml per kg per day, s.c.); group 2 toxic control; group 2, 3 and 4 received DMH (20 mg per kg per week, s.c.), for 6 weeks; groups 3 and 4 also received PAL (0.25 and 0.50 mg per kg per day, p.o) for 6 weeks. DMH treated rats showed altered heart rate variability (HRV) factors, increased incidence of aberrant crypt foci (ACF), distorted antioxidant markers (TBARs, SOD, catalase, GSH) and increased levels inflammatory markers (COX). The colonic surface architecture, studied using scanning electron microscopy (SEM), revealed aberrant crypts (500×) and preneoplastic nodules (2000×). PAL treatment helped to minimize the ACF count, and restored oxidative and inflammatory markers favorably. To further validate our results, we directed our study to define the effect of PAL on acetylcholine (Ach) neurotransmission using a simple model organism, C. elegans. Increased cholinergic transmission by PAL (8 μM) was evident in the worms when studied through an aldicarb assay. However, PAL (2 μM, 4 μM and 8 μM) treatment negatively modulated nAchR, when evaluated using the levamisole assay. The increased synaptic Ach levels can be attributed to the decreased levels of acetylcholinesterase (AchE), which could be attributed to the decreased genomic levels of ace-1 and ace-2. The above findings were also supported by the fact, that we observed decreased AchE activity in PAL treated rats. In addition the downregulation in the expression of unc-38 (one of the necessary components of nAchR) sufficiently links with the decreased nAchR activity. Our findings emphasize the potential role of PAL in the suppression of colon carcinogenesis.

Effects of minocycline and doxycycline against terbutaline induced early postnatal autistic changes in albino rats

The current study was initiated to explicate the shielding response of minocycline and doxycycline against early postnatal neurological damage and behavioral alteration convinced by terbutaline. Toxicity was induced by terbutaline at three successive days in the pups. The pups were scrutinized for behavioral, biochemical and inflammatory markers. Subsequent treatment with test drugs commenced a favorable effect on the autistic symptoms with more safeguard by doxycycline. The study also recognized peripheral inflammatory reactions and increased nitric oxide (NO) through terbutaline which was curtailed down by test drugs, with the much more noticeable effect of doxycycline. The GC-FID analysis and histopathological evaluation of the brain tissue elicited more pronounced protection by doxycycline. Doxycycline was also evident with remarkable down-regulation Pgp 9.5 [Ubiquitin carboxy-terminal hydrolase L1 (UCHL-1)] expression in the brain tissue in comparison to minocycline.

Galantamine attenuates N,N-dimethyl hydrazine induced neoplastic colon damage by inhibiting acetylcholinesterase and bimodal regulation of nicotinic cholinergic neurotransmission

Abstract The present study reveals the effect of galantamine (GAL) against 1, 2‐dimethylhydrazine (DMH) induced colon cancer. Wistar albino rats were arbitrarily divided into four groups (n = 8). Group 1 served as normal control (normal saline, 3 ml/kg/day, p.o.); group 2, 3 and 4 received DMH (20 mg/kg/week, s.c.), for 6 weeks; groups 3 and 4 also received GAL (2 and 4 mg/kg/day, p.o) for 6 weeks. DMH treated rats showed decreased heart rate variability (HRV) factors, increased incidence of aberrant crypt foci (ACF), increased thiobarbituric acid reactive substances (TBARs) along with the decrease in the enzymatic activity of superoxide dismutase (SOD) and catalase. Increased levels of inflammatory marker cyclooxygenase (COX) and lipoxygenase (LOX) was also evident in DMH treated animals. The colonic surface architecture was studied using scanning electron microscopy revealed aberrant crypts(X500) and neoplastic nodules (X2000). GAL treatment helped to minimize the ACF count, restored oxidative stress and inflammatory markers favorably. To further validate our results, our study was directed to define the effect of GAL on acetylcholine neurotransmission using a simple model organism, Caenorhabditis elegans (C. elegans). Increased synaptic cholinergic transmission by GAL (32 &mgr;M) was evident in the worms when studied through aldicarb assay. However, GAL (32 &mgr;M) treatment negatively modulated &agr;7 nicotinic acetylcholine receptor (&agr;7nAch receptor), when evaluated using the levamisole assay. GAL (32 &mgr;M) treatment down regulated the genomic expression of ace‐1, ace‐2 along with unc‐29, unc‐38, and unc‐50 (essential components of &agr;7 nAch receptor). GAL by inhibiting AchE and regulating Alpha7nACh activity can improve cholinergic neurotransmission. Graphical abstract Schematic representation of the GAL mediated regression of colon cancer GAL treatment in Albino wistar rats resulted in mitigation of colon cancer as indicated through photomicrographs of scanning electron micrographs; The molecular events underlying neuronal transmission were studied through a different model organism, C. elegans, where in it was revealed that GAL treatment increased synaptic ach resulting from downplaying of genes coding for AchE. Figure. No Caption available.