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One of the strategies in the establishment of in vitro oxidative stress models for neurodegenerative diseases, such as Alzheimer’s disease (AD), is to induce neurotoxicity by amyloid beta (Aβ) peptides in suitable neural cells. Presently, data on the neurotoxicity of Aβ in neural cells differentiated from stem cells are limited. In this study, we attempted to induce oxidative stress in transgenic 46C mouse embryonic stem cell-derived neurons via treatment with Ab peptides (Aβ1-42 and Aβ25-35). 46C neural cells were generated by promoting the formation of multicellular aggregates, embryoid bodies (EBs) in the absence of leukemia inhibitory factor (LIF), followed by the addition of all-trans retinoic acid (ATRA) as the neural inducer. Mature neuronal cells were exposed to different concentrations of Aβ1-42 and Aβ25-35 for 24 h. Morphological changes, cell viability, and intracellular ROS production were assessed. We found that 100 µM Aβ1-42 and 50 µM Aβ25-35 only promoted 40% and 10%, respectively, of cell injury and death in the 46C-derived neuronal cells. Interestingly, treatment with each of the Aβ peptides resulted in a significant increase of intracellular ROS activity, as compared to untreated neurons. These findings indicate the potential of using neurons derived from stem cells and Aβ peptides in generating oxidative stress for the establishment of an in vitro AD model that could be useful for drug screening and natural product studies.

Objectives: The aim of the present study was to isolate and evaluate cytotoxicity and anti-inflammatory activities of new novel compounds isolated from Prismatomeris glabra. Materials and Methods: Dried root of P. glabra was extracted under reflux with methyl alcohol, fractionated through the vacuum liquid chromatography technique, and evaporated and then purified the compounds using column chromatography and preparative thin-layer chromatography. THP-1 cells were treated with amentoflavone, 5,7,4′-hydroxyflavonoid, and stigmasterol with various concentrations (0–30 µg/mL) and then incubated with MTS reagent for 2h. Treatment was done for 24, 48, and 72h. Then, effects of these compounds were also tested on PGE2, TNF-α, and IL-6 expression in human THP-1-derived macrophage cells for 24h. Results: Three new compounds such as amentoflavone, 5,7,4′-hydroxyflavonoid, and stigmasterol were isolated. After 24h of incubation, a significant decrease in cell viability was reported with IC50 values of amentoflavone, 5,7,4′- hydroxyflavonoid, and stigmasterol (21 µg/mL ≡ 38 M), (18 µg/mL ≡ 66 M) and (20 µg/mL ≡ 48.5 M), respectively. Whereas for 48 and 72h treatment showed a less decreased cell viability compared with 24h treatment. These compounds also showed a significant reduction in the production of TNF-α, IL-6, and PGE2 in a dose-dependent manner. Conclusions: The isolated new compounds showed significant cytotoxicity and anti-inflammatory effects.

A series consisting of 30 novel imidazo[4,5-b]pyridine benzohydrazones have been synthesized and evaluated for their antiglycation activity as well as their antioxidative potential. The synthetic part involves a 3-step reaction in which a pyridine diamine was being converted into a imidazo[4,5-b]pyridine, which was then subjected through another reaction to yield benzohydrazide. Subsequently, the attained benzohydrazide of imidazo[4,5-b]pyridine was used to synthesize the target molecules after treating them with the appropriate benzohydrazone derivatives. The derivatives were evaluated for the antiglycation and antioxidant activities. Result obtained showed that di and trihydroxy substituted compounds showed good activity with compound 25 (140.16 ± 0.36 μM) having the most potent antiglycation activity, which is twice lower than Rutin. The results also showed certain correlation between antiglycation activities with DPPH radical scavenging model as well as FRAP which indicated the participation of antioxidative effect in inhibiting glycation activity. Keywords: Imidazo[4,5-b]pyridine, Benzohydrazone, Antiglycation, Antioxidant

Type 2 diabetes mellitus (T2DM) is one of the main non-communicable chronic diseases that has many complications that compromise the quality of life. Hence, the need to find alternatives to replace the current therapy or as an adjuvant. Tubers of Myrmecodia platytytrea (Rubiaceae) has been used traditionally as an alternative therapy for the management of cancer and other inflammatory-related disorders. The aim of this study was to investigate the potency of M. platytytrea methanolic tuber extract (MPMTE) as an antihyperglycemic agent, in vivo. :The streptozotocin (STZ)-induced diabetic rats were treated orally with MPMTE (100, 200 and 400 mg/kg) and metformin (positive control, 100 mg/kg) daily for 14 days. Blood glucose level and other biochemistry analysis were conducted including histological examination on liver, kidney and pancreas. The STZ-induced diabetic rats treated with MPMTE (200 and 400 mg/kg) had significant decreased (p

Background Cancer is a group of diseases involving an abnormal growth of cells which tend to proliferate in an uncontrolled fashion and in some cases metastasize to the surrounding tissues (malignancy). Resistance to chemotherapy is typically intrinsic (heterogeneity); however, acquired resistance has also become prevelant due to multiple factors including expression of energy-dependent transporters causing expulsion of internalized drug contents extracellular, insensitivity of tumor cells to drug-induced apoptosis, and induction of drug-detoxifying mechanisms. Curcumin (CUR) has gained widespread recognition due to remarkable anticancer, anti-mutagenic, and anti-metastasizing potentials via downregulation of proliferation of cancer cells and induction of apoptosis. Nevertheless, pharmaceutical significance and therapeutic feasibility of CUR is restricted due to intrinsic physicochemical characteristics including poor aqueous solubility, inadequate biological stability, low bioavailability, and short half-life. Scope and approach Owing to these pharmaceutical limitations of CUR, nanodelivery systems have attained remarkable fascination in the recent years. Therefore, this review was aimed to overview and critically ponders recent developments in improving anticancer viability of CUR. Key findings and conclusion Critical analysis of the literature revealed that nanodelivery systems showed promising efficiency in achieving tumor specific targetability, maximizing internalization of drugs into cancer cells, mitigating tumor metastasis, as well as improving anticancer efficacy of CUR. Moreover, nanocarrier-mediated improved pharmacokinetics, drug accumulation, induced promising cytotoxicity, and enhanced anticancer efficacy by suppressing Egr-1 induction, Mitogen-activated protein kinase (MAPK) pathway, and protein tyrosine kinase (PTK) cascades while mitigating the progression of tumor, have also been discussed.

Background:Obesity is major contributor to diseases and mortality. Constant weight loss significantly reverses the diseases related to obesityand prolonged human life expectancy. Limited scientific evidence comparing the effectiveness between Aqua Zumba® Fitness program and aqua jog in obese women. Thus, the purpose of this study was to compare the effects between 12 weeks of Aqua Zumba® Fitness and aqua jog on health parameters among middle-age women.Methods:A total of sixty previously sedentary obese women (BMI >30 kg/m2), aged 40-59 years old were randomized to either Aqua Zumba® Fitness (AZ, n=20), aqua jog (AJ, n=20) or control group (C, n=20). Exercise groups were involved in 12-weeks of different aqua exercise programmes, 3 times per week, 60 minutes per session, with the intensity of 50-75% of maximum heart rate. Body mass (BM), lean mass (LM), body fat percentage (BF%), abdominal fat (WC), upper and lower body strength (UBS and LBS), cardiorespiratory fitness (CRF), and flexibility were measured at baseline (week-0) and post-exercise intervention (week-13). Result:Both trained groups demonstrated significant changes (p

Milling is a common machining process with high cutting speed and material removal rate. High cutting speed tends to generate heat at the interface between tool and workpiece. This may reduce the surface quality of the workpiece and reduce the tool life. The application of conventional cutting fluid to reduce friction and heat between tool and workpiece may produce numerous environmental problems. The vegetable-based lubricant as an alternative for measuring the effect on surface quality during milling operation is studied. The relation between machining parameters such as spindle speed, feed rate, depth of cut and lubricants is analyzed by using Analysis of Variance (ANOVA) and Response Surface Methodology (RSM). The optimization of surface quality is analyzed by using Box-Behnken Design of RSM. The research focused on using sunflower oil as lubricant during machining process using mild steel solid block with TiCN coated HSS tools and using synthetic oil as comparison. Surface roughness for using sunflower oil as lubricant is 0.457 μm which lower compared to synthetic oil with 0.679 μm. Feed rate and spindle speed give the most significant effect to the surface roughness during milling operation. The application of vegetable-based oil as lubricant gives better surface quality, prevent tool wear and offer environmental advantages.

Phytochemical studies on the methanolic extract of the leaves of griffithii (Guttiferae) afforded two known xanthones derivatives, 1,3,5,6-Tetrahydroxy-7-(3-methylbut-2-enyl)xanthone (1) and Rubraxanthone (2). The structures of these xanthones derivatives were determined on the basis of extensive spectroscopic data interpretation and comparison with data reported in the literature. In an in vitro test, compound 1 and 2 showed the ability to inhibit platelet aggregation in human whole blood which induced by arachidonic acid (AA), adenosine diphosphate (ADP) and collagen.

Gestational diabetes (GD) is a common complication during pregnancy. Metabolic changes in GD affect fetal development and fetal glucose homeostasis. The present study utilized a rat model of GD to evaluate the effects of nicotinamide on diabetic parameters; antioxidant gene expression viz, superoxide dismutase (SOD) and catalase (CAT); reactive oxygen species (ROS) production by neutrophils and enhancement of lymphocyte mediated immune response. Nicotinamide (50, 100 and 200 mg/kg) was orally supplemented to gestational diabetic rats from days 6 through 20 of gestation. After GD induction, the control group had elevated glucose and reduced insulin while nicotinamide (100 & 200 mg/kg) supplementation reversed these changes. The same doses of nicotinamide upregulated mRNA expressions of SOD and CAT genes in liver but reduced the oxidative burst activity of neutrophils in response to phorbol myristate acetate (PMA), N-formyl-methionyl-leucyl-phenylalanine (FMLP) or E. coli activation. Nicotinamide (100 & 200 mg/kg) supplementation also increased expression of activated T helper (CD4+CD25+) cells and induced proliferation of splenocytes. These findings provide evidence for utilizing nicotinamide as supplement or adjunct to support existing therapeutic agents for gestational diabetes and in pregnant individuals with weakened immune systems.

Injury to podocytes is an early event in diabetic nephropathy leading to proteinuria with possible progression to end-stage renal failure. The podocytes are unique and highly specialized cells that cover the outer layer of kidney ultra-filtration barrier and play an important role in glomerular function. In the past few decades, adult stem cells, such as mesenchymal stem cells (MSCs) with a regenerative and differentiative capacity have been extensively used in cell-based therapies. In addition to their capability for regeneration and differentiation, MSCs contributes to their milieu by paracrine action of a series of growth factors via antiapoptotic, mitogenic and other cytokine actions that actively participate in treatment of podocyte damage through prevention of podocyte effacement, detachment and apoptosis. It is hoped that novel stem cell-based therapies will be developed in the future to prevent podocyte injury, thereby reducing the burden of kidney disease.

Ethnopharmacological relevance Cassia auriculata (CA) is used as an antidiabetic therapy in Ayurvedic and Siddha practice. This study aimed to understand the mode-of-action of CA via combined cheminformatics and in vivo biological analysis. In particular, the effect of 10 polyphenolic constituents of CA in modulating insulin and immunoprotective pathways were studied. Materials and methods In silico target prediction was first employed to predict the probability of the polyphenols interacting with key protein targets related to insulin signalling, based on a model trained on known bioactivity data and chemical similarity considerations. Next, CA was investigated in in vivo studies where induced type 2 diabetic rats were treated with CA for 28 days and the expression levels of genes regulating insulin signalling pathway, glucose transporters of hepatic (GLUT2) and muscular (GLUT4) tissue, insulin receptor substrate (IRS), phosphorylated insulin receptor (AKT), gluconeogenesis (G6PC and PCK-1), along with inflammatory mediators genes (NF-κB, IL-6, IFN-γ and TNF-α) and peroxisome proliferators-activated receptor gamma (PPAR-γ) were determined by qPCR. Results In silico analysis shows that several of the top 20 enriched targets predicted for the constituents of CA are involved in insulin signalling pathways e.g. PTPN1, PCK-α, AKT2, PI3K-γ. Some of the predictions were supported by scientific literature such as the prediction of PI3K for epigallocatechin gallate. Based on the in silico and in vivo findings, we hypothesized that CA may enhance glucose uptake and glucose transporter expressions via the IRS signalling pathway. This is based on AKT2 and PI3K-γ being listed in the top 20 enriched targets. In vivo analysis shows significant increase in the expression of IRS, AKT, GLUT2 and GLUT4. CA may also affect the PPAR-γ signalling pathway. This is based on the CA-treated groups showing significant activation of PPAR-γ in the liver compared to control. PPAR-γ was predicted by the in silico target prediction with high normalisation rate although it was not in the top 20 most enriched targets. CA may also be involved in the gluconeogenesis and glycogenolysis in the liver based on the downregulation of G6PC and PCK-1 genes seen in CA-treated groups. In addition, CA-treated groups also showed decreased cholesterol, triglyceride, glucose, CRP and Hb1Ac levels, and increased insulin and C-peptide levels. These findings demonstrate the insulin secretagogue and sensitizer effect of CA. Conclusion Based on both an in silico and in vivo analysis, we propose here that CA mediates glucose/lipid metabolism via the PI3K signalling pathway, and influence AKT thereby causing insulin secretion and insulin sensitivity in peripheral tissues. CA enhances glucose uptake and expression of glucose transporters in particular via the upregulation of GLUT2 and GLUT4. Thus, based on its ability to modulate immunometabolic pathways, CA appears as an attractive long term therapy for T2DM even at relatively low doses.

This study attempts to develop an experimental gestational diabetes mellitus (GDM) animal model in female Sprague-Dawley rats. Rats were fed with high fat sucrose diet, impregnated, and induced with Streptozotocin and Nicotinamide on gestational day 0 (D0). Sleeping patterns of the rats were also manipulated to induce stress, a lifestyle factor that contributes to GDM. Rats were tested for glycemic parameters (glucose, C-peptide, and insulin), lipid profiles (total cholesterol, triglycerides, HDL, and LDL), genes affecting insulin signaling (IRS-2, AKT-1, and PCK-1), glucose transporters (GLUT-2 and GLUT-4), proinflammatory cytokines (IL-6, TNF-α), and antioxidants (SOD, CAT, and GPX) on D6 and D21. GDM rats showed possible insulin resistance as evidenced by high expression of proinflammatory cytokines, PCK-1 and CRP. Furthermore, low levels of IRS-2 and AKT-1 genes and downregulation of GLUT-4 from the initial to final phases indicate possible defect of insulin signaling. GDM rats also showed an impairment of antioxidant status and a hyperlipidemic state. Additionally, GDM rats exhibited significantly higher body weight and blood glucose and lower plasma insulin level and C-peptide than control. Based on the findings outlined, the current GDM animal model closely replicates the disease state in human and can serve as a reference for future investigations.

Stevioside from Stevia rebaudiana has been reported to exert antihyperglycemic effects in both rat and human subjects. There have been few studies on these effects in vitro. In this paper, radioactive glucose uptake assay was implemented in order to assess improvements in insulin sensitivity in 3T3-L1 cells by elevation of glucose uptake following treatment with stevioside. Oil Red-O staining and MTT assay were utilized to confirm adipocyte differentiation and cell viability, respectively. Findings from this research showed a significant increase in absorbance values in mature adipocytes following Oil Red-O staining, confirming the differentiation process. Stevioside was noncytotoxic to 3T3-L1 cells as cell viability was reduced by a maximum of 17%, making it impossible to determine its IC50. Stevioside increased glucose uptake activities by 2.1 times (p0.001) in normal conditions and up to 4.4 times (p0.001) in insulin-resistant states. At times, this increase was higher than that seen in positive control group treated with rosiglitazone maleate, an antidiabetic agent. Expressions of pY20 and p-IRS1 which were measured via Western blot were improved by stevioside treatment. In conclusion, stevioside has direct effects on 3T3-L1 insulin sensitivity via increase in glucose uptake and enhanced expression of proteins involved in insulin-signalling pathway.

Quassinoids have been reported to possess numerous biological activities such as anticancer, antimalarial and phytotoxicity. They are degraded triterpenoids which give bitterness characteristic of Simaroubaceae and classified according to their basic skeletons; C 18 , C 19 , C 20 , C 22 , C 25 which correspond to their particular genus Quassia , Brucea , Soulamea , Eurycoma , Picrolemnia and others. Quassia borneensis Noot. (Simaroubaceae) (Qb) have not been properly placed in Quassia s.l. thus created confusion. Therefore, a study on Qb for its chemical compounds and biological activity are appropriate for data gathering. There is positive possibility for new quassinoids with potent biological activity to be discovered, in addition to confirmation of placement in Simaroubaceae. The study was accomplished by extracting the secondary metabolites from Qb by soxhlet in methanol. The methanol extract was partitioned to acquire n -hexane, chloroform and aqueous extracts. These extracts underwent isolation and purification through chromatographic techniques before subjected to spectroscopic instruments for structural elucidation. Preliminary findings identified five quassinoids and one canthin-6-one as glaucarubolone ( 1 ), chaparrinone ( 2 ), holacanthone ( 3 ), glaucarubinone ( 4 ), ailanthinone ( 5 ) and canthin-6-one ( 6 ) in reference to past reports. The isolation confirms Qb placement in Simaroubaceae, however, not in Quassia section as indicated by isolated quassinoids. Hence, further study would confirm its proper section in Quassia .

The effect of dietary tocotrienols and α-tocopherol acetate supplementation on paraquat-induced lung toxicity was investigated in rats. The administration of a single dose of paraquat (20 mg/kg, i.p.) to rats increased lung malondialdehyde (MDA) levels and produced lung edema. Tocotrienols (150 mg/kg pellet) or α-tocopherol (34 mg/kg pellet) supplementation of two months significantly reduced lung MDA levels in rats exposed to paraquat but lung edema was unaffected. However lower doses of tocotrienols in the diet did not significantly lower lung MDA levels compared with the unsupplemented controls. Our results showed that dietary supplementation of tocotrienols and α-tocopherol provides protection against paraquat toxicity possibly through their antioxidant property.

Down syndrome (DS) is a common chromosomal abnormality occurring in about 1 in 700 live births. One of the major medical problems in DS individuals is hematologic abnormalities. This study was carried out to compare the hematological status in young individuals with DS aged 5 to 20 years old (divided into three different age groups: 1 to 7 years [n=7], 8 to 12 years [n=49] and 13 to 20 years [n=50]) and in comparison to age-matched controls and also between genders. Blood samples were collected with informed consent from 106 DS participants and another 106 controls. The blood count was evaluated by blood analyzer (Coulter T-540). There were significantly lower levels of red blood cell count in DS females than in males at the ages of 13 to 20 years (p=0.011). Hemoglobin levels in DS females were significantly lower in the age of 13 to 20 years (p=0.016). A significantly lower hematocrit level was observed in DS females at the age of 13 to 20 years (p=0.005). The mean of white blood cells count in DS was significantly lower than in controls at the ages of 1 to 7 years (p=0.014) and 8 to 12 years (p=0.021). The granulocyte levels was significantly lower in DS by about 45% than in controls aged 8 to 12 years (p=0.038) and also in DS females, aged 13 to 20 years as compared to males (p=0.04). These findings indicate that DS individuals experience hematologic abnormalities and further study should be conducted in order to understand the significance of the abnormalities.

Chitosan is a promising biopolymer for drug delivery systems. Because of its beneficial properties, chitosan is widely used in biomedical and pharmaceutical fields. In this review, we summarize the physicochemical and drug delivery properties of chitosan, selected studies on utilization of chitosan and chitosan-based nanoparticle composites in various drug delivery systems, and selected studies on the application of chitosan films in both drug delivery and wound healing. Chitosan is considered the most important polysaccharide for various drug delivery purposes because of its cationic character and primary amino groups, which are responsible for its many properties such as mucoadhesion, controlled drug release, transfection, in situ gelation, and efflux pump inhibitory properties and permeation enhancement. This review can enhance our understanding of drug delivery systems particularly in cases where chitosan drug-loaded nanoparticles are applied.

Polygonum minus(Polygonaceae) is a medicinal herb distributed throughout eastern Asia. The present study investigated antiproliferative effect ofP. minusand its possible mechanisms. Four extracts (petroleum ether, methanol, ethyl acetate, and water) were prepared by cold maceration. Extracts were subjected to phytochemical screening, antioxidant, and antiproliferative assays; the most bioactive was fractionated using vacuum liquid chromatography into seven fractions (F1–F7). Antioxidant activity was measuredviatotal phenolic content (TPC), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and ferric reducing antioxidant power (FRAP) assays. Antiproliferative activity was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Most active fraction was tested for apoptosis induction and cell cycle arrest in HepG2 cells using flow cytometry and confocal microscopy. Apoptotic-related gene expression was studied by RT-PCR. Ethyl acetate extract was bioactive in initial assays. Its fraction, F7, exhibited highest antioxidant capacity (TPC;113.16±6.2 mg GAE/g extract, DPPH;EC50:30.5±3.2 μg/mL, FRAP;1169±20.3 μmol Fe (II)/mg extract) and selective antiproliferative effect (IC50:25.75±1.5 μg/mL). F7 induced apoptosis in concentration- and time-dependent manner and caused cell cycle arrest at S-phase. Upregulation of proapoptotic genes (Bax,p53, andcaspase-3) and downregulation of antiapoptotic gene,Bcl-2, were observed. In conclusion, F7 was antiproliferative to HepG2 cells by inducing apoptosis, cell cycle arrest, andviaantioxidative effects.

International audience; Phenolic Schiff bases are known for their diverse biological activities and ability to scavenge free radicals. To elucidate (1) the structure-antioxidant activity relationship of a series of thirty synthetic derivatives of 2-methoxybezohydrazide phenolic Schiff bases and (2) to determine the major mechanism involved in free radical scavenging, we used density functional theory calculations (B3P86/6-31+(d,p)) within polarizable continuum model. The results showed the importance of the bond dissociation enthalpies (BDEs) related to the first and second (BDEd) hydrogen atom transfer (intrinsic parameters) for rationalizing the antioxidant activity. In addition to the number of OH groups, the presence of a bromine substituent plays an interesting role in modulating the antioxidant activity. Theoretical thermodynamic and kinetic studies demonstrated that the free radical scavenging by these Schiff bases mainly proceeds through proton-coupled electron transfer rather than sequential proton loss electron transfer, the latter mechanism being only feasible at relatively high pH.

Stevioside fromStevia rebaudianahas been reported to exert antihyperglycemic effects in both rat and human subjects. There have been few studies on these effectsin vitro. In this paper, radioactive glucose uptake assay was implemented in order to assess improvements in insulin sensitivity in 3T3-L1 cells by elevation of glucose uptake following treatment with stevioside. Oil Red-O staining and MTT assay were utilized to confirm adipocyte differentiation and cell viability, respectively. Findings from this research showed a significant increase in absorbance values in mature adipocytes following Oil Red-O staining, confirming the differentiation process. Stevioside was noncytotoxic to 3T3-L1 cells as cell viability was reduced by a maximum of 17%, making it impossible to determine its IC50. Stevioside increased glucose uptake activities by 2.1 times (p<0.001) in normal conditions and up to 4.4 times (p<0.001) in insulin-resistant states. At times, this increase was higher than that seen in positive control group treated with rosiglitazone maleate, an antidiabetic agent. Expressions of pY20 and p-IRS1 which were measured via Western blot were improved by stevioside treatment. In conclusion, stevioside has direct effects on 3T3-L1 insulin sensitivity via increase in glucose uptake and enhanced expression of proteins involved in insulin-signalling pathway.

BackgroundWith a higher throughput and lower cost in sequencing, second generation sequencing technology has immense potential for translation into clinical practice and in the realization of pharmacogenomics based patient care. The systematic analysis of whole genome sequences to assess patient to patient variability in pharmacokinetics and pharmacodynamics responses towards drugs would be the next step in future medicine in line with the vision of personalizing medicine.MethodsGenomic DNA obtained from a 55 years old, self-declared healthy, anonymous male of Malay descent was sequenced. The subject's mother died of lung cancer and the father had a history of schizophrenia and deceased at the age of 65 years old. A systematic, intuitive computational workflow/pipeline integrating custom algorithm in tandem with large datasets of variant annotations and gene functions for genetic variations with pharmacogenomics impact was developed. A comprehensive pathway map of drug transport, metabolism and action was used as a template to map non-synonymous variations with potential functional consequences.Principal findingsOver 3 million known variations and 100,898 novel variations in the Malay genome were identified. Further in-depth pharmacogenetics analysis revealed a total of 607 unique variants in 563 proteins, with the eventual identification of 4 drug transport genes, 2 drug metabolizing enzyme genes and 33 target genes harboring deleterious SNVs involved in pharmacological pathways, which could have a potential role in clinical settings.ConclusionsThe current study successfully unravels the potential of personal genome sequencing in understanding the functionally relevant variations with potential influence on drug transport, metabolism and differential therapeutic outcomes. These will be essential for realizing personalized medicine through the use of comprehensive computational pipeline for systematic data mining and analysis.

This study was conducted to determine the potential of both Mitragyna speciosa (MS) and Erythroxylum cuneatum (EC) aqueous leaves extracts as antioxidant, anti-inflammatory and antinociceptive agents. MS has been used traditionally by local folks to treat diarrhea, reducing cough, alleviate pain and to combat fatigue. Meanwhile, EC was used as fish poison and tonic for miscarriage. MS and EC aqueous leaf extracts have the capability to chelate iron and have potent anti-inflammatory and antinociceptive activities but were not effectively inhibiting the production of uric acid. Both extracts (50, 100, 200 and 400 mg/kg, p.o) were given to rodents in carrageenan-induced rat paw edema model and acetic acid-induced writhing in mice models to study their anti-inflammatory and antinociceptive activities, respectively. Animals given (400 mg/kg, p.o) showed significant (p

Gestational diabetes mellitus (GDM) is a common complication during pregnancy. Metabolic changes in GDM affect fetal development and fetal glucose homeostasis. Several complications of diabetes are related to increased intracellular oxidative stress where prooxidants exceed antioxidant capacity. The present study was initiated to evaluate the effects of nicotinamide on CD4+CD25+ regulatory T cells (Tregs), proliferation of splenocytes, production of reactive oxygen species (ROS) by neutrophils and serum glucose levels. Changes in mRNA levels of two antioxidant genes in liver, viz, superoxide dismutase (SOD1) and catalase (CAT) were quantified with real-time PCR (QRT-PCR). Nicotinamide (50, 100 and 200 mg/kg) was supplemented p.o. to pregnant diabetic rats from days 6 through 20 of gestation. The highest dose enhanced expression of Tregs and increased splenocytes proliferation in both resting and lipopolysaccharide (LPS)-stimulated cells. Oxidative burst activity of neutrophils in response to phorbol myristate acetate (PMA), N-formyl-methionyl-leucyl-phenylalanine (FMLP) or E. coli activation was reduced. mRNA expressions of superoxide dismutase (SOD) and catalase (CAT) genes were upregulated by nicotinamide. In summary, nicotinamide boosted the immune system through stimulation of adaptive immune cells with enhancement of antioxidant defences and reduced production of ROS. Serum glucose level was normalised by nicotinamide (200 mg/kg). These findings provide evidence for usage of nicotinamide as a supplement or as adjunct to therapeutic agents in gestational diabetes and in pregnant individuals with weakened immune systems.

The immunomodulatory activity of Cassia auriculata (CA)-derived polyphenols was tested on aged rats. Rats (24-26 months old) were given CA polyphenols supplementation at doses of 25, 50, and 100 mg/kg for 28 days. Flow cytometry analysis of CA polyphenols-treated aged rats showed increased T and B cells percentage along with enhanced proliferation of splenocytes in both resting and LPS-stimulated cells. Increased percentage of pan T cells is further supported by an elevation of CD4+, CD8+, and CD4+CD25+ regulatory cells. In terms of innate immune cell activity, CA polyphenol supplementation reduced the oxidative burst activity of neutrophils in response to PMA and Escherichia coli activation. Our results collectively show that polyphenols derived from CA boost T cell immunity by increasing the number of T cells and its sensitivity towards stimulants and decreasing ROS production by neutrophils that could potentially harm multiple biological systems in aged individuals.

The redox cycling abilities of the pulmonary toxins paraquat and nitrofurantoin have been compared with those of the potent redox cyclers, diquat and menadione in lung and liver microsomes by using the oxidation of NADPH and consumption of oxygen. The relative potencies of these compounds to undergo redox cycling were in the order: diquat approximately menadione much greater than paraquat congruent to nitrofurantoin. This was partly attributed to the much lower affinity (Km) of lung and liver microsomes for paraquat and nitrofurantoin than for diquat and menadione. The potential to redox cycle was assessed in an intact cellular system by determining the oxygen consumption of rat lung slices in the presence (10(-6), 10(-5) and 10(-4) M) or absence of each of the four substrates. At concentrations of paraquat (10(-5) M) known to be accumulated by lung slices, a small but significant stimulation of lung slice oxygen uptake was observed. Nitrofurantoin (10(-4)-10(-6) M) did not affect lung slice oxygen uptake in lung slices, an observation consistent with its being a poor redox cycling compound, which is not actively accumulated into lung cells. This data has important implications in assessing the risk of exposure to paraquat. Low levels of paraquat would not be expected to cause lung damage because insufficient compound is present in the lung to exert its toxicity by redox cycling (due to the high Km observed).

In order to study oxidative stress in the lung, we have developed a rat lung slice model with compromised oxidative defences. Lung slices with markedly inhibited glutathione reductase activity (approximately 80% inhibition) were prepared by incubating slices, with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (100 microM) in an amino acid-rich medium for 45 min at 37 degrees. These lung slices had similar levels of GSH and ATP and polyamine uptake (a marker of alveolar epithelial type I and II cell function) to control rat lung slices. We have utilized these BCNU pretreated slices to study the effects of the herbicide, paraquat, in comparison to those of 2,3-dimethoxy-1,4-naphthoquinone, a potent redox cycler. Paraquat (10-100 microM) caused only minimal changes in the levels of GSH or ATP in control or compromised slices. In contrast, 2,3-dimethoxy-1,4-naphthoquinone caused a decrease in GSH in control slices but a markedly enhanced decrease in both GSH and ATP in compromised slices. Both compounds had only limited effects on putrescine and spermidine uptake in control slices. However, they caused a marked inhibition in compromised slices. Paraquat had little effect on 5-hydroxytryptamine uptake (a marker of endothelial cell function) in either control or compromised slices whereas the quinone inhibited uptake in the compromised slices. Thus, the lack of effect of paraquat on GSH and ATP does not support the involvement of oxidative stress in its toxicity. In contrast, using polyamine uptake, as a functional marker of alveolar epithelial cell damage, suggests a role for redox cycling. As paraquat is known to be accumulated primarily in alveolar type I and II cells (a small fraction of the lung cell population), our data suggest that only a small proportion of pulmonary GSH and ATP is present in alveolar epithelial type I and II cells but that much larger amounts may be present in endothelial cells. These studies highlight the problem of gross tissue measurements in heterogeneous tissues such as the lung.

The common problems that faced during machining process are high cost due to increase tool wear, reduced quality of product due to poor surface finish and widely use of mineral and synthetic oils as metal working fluids that are recognized as harmful to both environment and health of the machine operator. Vegetable oil is renewable oil that possesses good biodegradability and lubricating ability which has potential to replace synthetic oil and mineral oil as environmental friendly cutting fluid if proper researches have been conducted. The aim of this experimental study is to determine and optimize the best additive to be added to the vegetable oil to improve its machinability. Types of additives selected in this experimental study are Propyl Gallate (PG), Boric Acid (BA) and Polydimethylsiloxane (PDMS). The experimental study uses a Taguchi design methodology in designing the experiment. Three different factors at three different levels are selected to conduct the experiment such as feed rate (mm/rev), cutting speed (m/min) and depth of cut (mm). The effect of tool wear and surface roughness during turning of mild steel (AISI 1040) were statistically evaluated using wear area analysis method and analysis of variance (ANOVA) method, respectively. It is observed that sunflower oil added with 3% Boric Acid is the most effective cutting fluid to reduce the tool wear while sunflower oil added with 3% Propyl Gallate is the most effective cutting fluid to reduce the surface roughness.

The hepatic and pulmonary effects of nitrofurantoin (40 mg/kg, intraperitoneally) were determined at 4 and 24 hr following its administration in mice fed for 10 weeks with a vitamin E sufficient, deficient or enriched diet. Liver glutathione (GSH) was reduced by nitrofurantoin at 4 hr but was unchanged 20 hr later. Nitrofurantoin did not affect liver glutathione peroxidase, glutathione reductase or superoxide dismutase activities. Liver catalase activities were decreased by nitrofurantoin at 4 hr. Lung GSH levels were increased whilst glutathione peroxidase activity was decreased at 4 and 24 hr. Lung glutathione reductase activity was reduced in certain groups. Nitrofurantoin did not affect lung superoxide dismutase, but catalase was decreased at 24 hr. Liver malondialdehyde levels were increased by nitrofurantoin in the vitamin E deficient group whilst lung malondialdehyde levels remained unchanged. Both liver and lung malondialdehyde levels were unaffected by vitamin E supplementation when compared to the vitamin E-sufficient group. These results suggest that nitrofurantoin (40 mg/kg) was deleterious to the liver and lung. Nitrofurantoin-induced lipid peroxidation was seen in vitamin E deficiency but an increase in dietary vitamin E content did not provide additional protection compared to the recommended daily allowance. The antioxidant activities of alpha-tocopherol and gamma-enriched tocotrienol were similar.

The Myrmecodia platytyrea extracts (hexane, dichloromethane, ethyl acetate and methanol) were screened using 2, 2-diphenyl1-picrylhydrazyl (DPPH) modified method against ascorbic acid (AA) and Trolox as the positive controls. The ethyl acetate (EtOAc) extract was found potent compared to the other extracts with EC50 value of 32.91 ± 2.23 μg/mL, whereas the EC50 value of AA and trolox were 4.56 ± 0.41 μg/mL and 5.35 ± 0.66 μg/mL, respectively. Then, an automated gradient system of a preparative medium performance liquid chromatography (MPLC) technique was utilized to fractionate the potent EtOAc extract (6 gram). Later, the collected fractions were combined according to the TLC profiles and reduced to 8 fractions (F1 – F8). DPPH scavenging assay was carried out on the fractions and the EC50 value of F5 was found lower with EC50 value of 21.57 ± 1.40 μg/mL. This indicated that F5 was potent in scavenging free radical and this may be due to the rich phenolic constituents which are known as good antioxidants. Next, the ferrous ion chelating (FIC) ability was tested on the crude EtOAc extract and the result was inactive compared to ethylenediaminetetraacetic acid (EDTA, IC50=23.15 ± 2.26 μg/mL), the standard used in this assay. The EtOAc fractions (F1 – F8) also underwent FIC test and surprisingly, the fractions (F1 and F2) were active with IC50 values of 293.30 ± 19.86 μg/mL and 152.74 ± 9.95 μg/mL, respectively. Based on the data, M. platytyrea possessed promising antioxidant activity. Thus, this plant indeed is a medicinal plant, not only claimed by the community web portals but could be proven with the scientific evidences. Successive work would include the identification of the major chemical entities in this extract. This effort would append to more information of the former isolation of stigmasterol and a phenolic from the hexane extract of this plant.