Genetic association of insulin receptor substrate-1 (IRS-1, rs1801278) gene with insulin resistant of type 2 diabetes mellitus in a Pakistani population

Molecular Biology Reports - Insulin resistance (IR), a pathological condition of type 2 diabetes mellitus (T2DM) is characterized by an inability of body’s tissue to respond the secreted or...     

Ameliorative effect of carnosine and N-acetylcysteine against sodium nitrite induced nephrotoxicity in rats

The widespread use of sodium nitrite (NaNO₂) for various industrial purposes has increased human exposure to alarmingly high levels of nitrate/nitrite. Because NaNO ₂ is a strong oxidizing agent, induction of oxidative stress is one of the mechanisms by which it can exert toxicity in humans and animals. We have investigated the possible protection offered by carnosine (CAR) and N-acetylcysteine (NAC) against NaNO ₂-induced nephrotoxicity in rats. Animals orally received CAR at 100 mg/kg body weight/d for seven days or NAC at 100 mg/kg body weight/d for five days followed by a single oral dose of NaNO ₂ at 60 mg/kg body weight. The rats were killed after 24 hours, and the kidneys were removed and processed for various analyses. NaNO ₂ induced oxidative stress in kidneys, as shown by the decreased activities of antioxidant defense, brush border membrane, and metabolic enzymes. DNA-protein crosslinking and DNA fragmentation were also observed. CAR/NAC pretreatment significantly protected the kidney against these biochemical alterations. Histological studies supported these findings, showing kidney damage in NaNO ₂-treated animals and reduced tissue impairment in the combination groups. The protection offered by CAR and NAC against NaNO ₂-induced damage, and their nontoxic nature, makes them potential therapeutic agents against nitrite-induced nephrotoxicity.     

Effect of tannic acid on brush border disaccharidases in mammalian intestine

Tannic acid is a glucoside (penta-m-digallolyl-glucose), which exhibits a wide variety of physiological functions. Around neutral pH, 0.4 mM tannic acid produced 84% inhibition of rat brush border sucrase activity, but 35-40% enzyme inhibition was observed in the rabbit intestine at 0.08 mM concentration. In the mice, 74-77% enzyme inhibition was observed at 0.05 mM concentration of tannic acid. The observed inhibition was reversible in rat intestine. Tannic acid (0.2 mM) also inhibited lactase (18% in adult and 71% in suckling animals), maltase (76%) and trehalase (88%) activities in rat intestine. pH versus activity curves showed that 0.2 mM tannic acid inhibited enzyme activity in rat by 91% at pH 5.5 which was reduced to 14% at pH 8.5 compared to the respective controls. In the rabbit 18-60% enzyme inhibition was noticed below pH 7.0, however at pH 8.5, it was of the order of 38%. Kinetic analysis revealed that tannic acid is a competitive inhibitor of rat brush border sucrase at pH 6.8. Effect of tannic acid together with various -SH group reacting reagents revealed that the enzyme inhibition is additive in nature, suggesting the distinct nature of binding sites on the enzyme for these compounds. The results suggest that tannic acid is a potent inhibitor of intestinal brush border disaccharidases, and could modulate the intestinal functions.     

Cost-effectiveness of Antivenoms for Snakebite Envenoming in Nigeria

Background

Snakebite envenoming is a major public health problem throughout the rural tropics. Antivenom is effective in reducing mortality and remains the mainstay of therapy. This study aimed to determine the cost-effectiveness of using effective antivenoms for Snakebite envenoming in Nigeria.

Methodology

Economic analysis was conducted from a public healthcare system perspective. Estimates of model inputs were obtained from the literature. Incremental Cost Effectiveness Ratios (ICERs) were quantified as deaths and Disability-Adjusted-Life-Years (DALY) averted from antivenom therapy. A decision analytic model was developed and analyzed with the following model base-case parameter estimates: type of snakes causing bites, antivenom effectiveness to prevent death, untreated mortality, risk of Early Adverse Reactions (EAR), mortality risk from EAR, mean age at bite and remaining life expectancy, and disability risk (amputation). End-user costs applied included: costs of diagnosing and monitoring envenoming, antivenom drug cost, supportive care, shipping/freezing antivenom, transportation to-and-from hospital and feeding costs while on admission, management of antivenom EAR and free alternative snakebite care for ineffective antivenom.

Principal Findings

We calculated a cost/death averted of ($2330.16) and cost/DALY averted of $99.61 discounted and $56.88 undiscounted. Varying antivenom effectiveness through the 95% confidence interval from 55% to 86% yield a cost/DALY averted of $137.02 to $86.61 respectively. Similarly, varying the prevalence of envenoming caused by carpet viper from 0% to 96% yield a cost/DALY averted of $254.18 to $78.25 respectively. More effective antivenoms and carpet viper envenoming rather than non-carpet viper envenoming were associated with lower cost/DALY averted.

Conclusions/Significance

Treatment of snakebite envenoming in Nigeria is cost-effective with a cost/death averted of $2330.16 and cost/DALY averted of $99.61 discounted, lower than the country''s gross domestic product per capita of $1555 (2013). Expanding access to effective antivenoms to larger segments of the Nigerian population should be a considered a priority.     

Chemopreventive Activity of Ferulago angulate against Breast Tumor in Rats and the Apoptotic Effect of Polycerasoidin in MCF7 Cells: A Bioassay-Guided Approach

Ferulago angulata leaf hexane extract (FALHE) was found to be a potent inducer of MCF7 cell apoptosis. The aims of the present study were to investigate the in vivo chemopreventive effect of FALHE in rats, to identify the contributing anticancer compound in FALHE and to determine its potential mechanism of action against MCF7 cells. Thirty rats harboring LA7-induced breast tumors were divided into five groups: tumor control, low-dose FALHE, high-dose FALHE, treatment control (tamoxifen) and normal control. Breast tissues were then subjected to histopathological and immunohistochemical analyses. A bioassay-guided investigation on FALHE was performed to identify the cytotoxic compound and its mechanism of action through flow cytometry, real-time qPCR and western blotting analyses. An in vivo study showed that FALHE suppressed the expression of the tumor markers PCNA and Ki67. The tumor size was reduced from 2031 ± 281 mm³ to 432 ± 201 mm³ after FALHE treatment. FALHE administration induced apoptosis in breast tumor cells, and this was confirmed by high expression levels of Bax, p53 and caspase 3. Cell cycle arrest was suggested by the expression of p21 and p27. The in vitro experimental results resulted in the isolation of polycerasoidin as a bioactive ingredient of FALHE with an IC₅₀ value of 3.16 ± 0.31 μg/ml against MCF7 cells. Polycerasoidin induced mitochondrial-dependent apoptosis in breast cancer cells via caspase activation and changes in the mRNA and protein expression of Bax and Bcl-2. In addition, flow cytometric analysis demonstrated that the treated MCF7 cells were arrested at the G₁ phase, and this was associated with the up-regulation of p21 and p27 at both the mRNA and protein levels. The results of the present study reinforce further investigations scrutinizing the promising potential of the F. angulata chemical constituents as breast cancer chemopreventive agents.     

Control of Blood Pressure and Risk Attenuation: Post Trial Follow-Up of Randomized Groups

Background

Evidence on long term effectiveness of public health strategies for lowering blood pressure (BP) is scarce. In the Control of Blood Pressure and Risk Attenuation (COBRA) Trial, a 2 x 2 factorial, cluster randomized controlled trial, the combined home health education (HHE) and trained general practitioner (GP) intervention delivered over 2 years was more effective than no intervention (usual care) in lowering systolic BP among adults with hypertension in urban Pakistan. However, it was not clear whether the effect would be sustained after the cessation of intervention. We conducted 7 years follow-up inclusive of 5 years of post intervention period of COBRA trial participants to assess the effectiveness of the interventions on BP during extended follow-up.

Methods

A total of 1341 individuals 40 years or older with hypertension (systolic BP 140 mm Hg or greater, diastolic BP 90 mm Hg or greater, or already receiving treatment) were followed by trained research staff masked to randomization status. BP was measured thrice with a calibrated automated device (Omron HEM-737 IntelliSense) in the sitting position after 5 minutes of rest. BP measurements were repeated after two weeks. Generalized estimating equations (GEE) were used to analyze the primary outcome of change in systolic BP from baseline to 7- year follow-up. The multivariable model was adjusted for clustering, age at baseline, sex, baseline systolic and diastolic BP, and presence of diabetes.

Findings

After 7 years of follow-up, systolic BP levels among those randomised to combined HHE plus trained GP intervention were significantly lower (2.1 [4.1–0.1] mm Hg) compared to those randomised to usual care, (P = 0.04). Participants receiving the combined intervention compared to usual care had a greater reduction in LDL-cholesterol (2.7 [4.8 to 0.6] mg/dl.

Conclusions

The benefit in systolic BP reduction observed in the original cohort assigned to the combined intervention was attenuated but still evident at 7- year follow-up. These findings highlight the potential for scaling-up simple strategies for cardiovascular risk reduction in low- and middle- income countries.

Trial Registration

ClinicalTrials.gov NCT00327574     

Differential Gene Expression Reflects Morphological Characteristics and Physiological Processes in Rice Immunity against Blast Pathogen Magnaporthe oryzae

The rice blast fungus Magnaporthe oryzae is a serious pathogen that jeopardises the world’s most important food-security crop. Ten common Malaysian rice varieties were examined for their morphological, physiological and genomic responses to this rice blast pathogen. qPCR quantification was used to assess the growth of the pathogen population in resistant and susceptible rice varieties. The chlorophyll content and photosynthesis were also measured to further understand the disruptive effects that M. oryzae has on infected plants of these varieties. Real-time PCR was used to explore the differential expression of eight blast resistance genes among the ten local varieties. Blast disease has destructive effects on the growth of rice, and the findings of our study provide evidence that the Pikh, Pi9, Pi21, and Osw45 genes are involved in defence responses in the leaves of Malaysian rice at 31 h after inoculation with M. oryzae pathotype P7.2. Both the chlorophyll content and photosynthesis were reduced, but the levels of Pikh gene expression remained constant in susceptible varieties, with a developed pathogen population and mild or severe symptoms. The Pi9, Pi21, and Osw45 genes, however, were simultaneously upregulated in infected rice plants. Therefore, the presence of the Pikh, Pi9, Pi21, and Osw45 genes in the germplasm is useful for improving the resistance of rice varieties.     

OsPIN5b modulates rice (Oryza sativa) plant architecture and yield by changing auxin homeostasis,transport and distribution

Plant architecture attributes such as tillering, plant height and panicle size are important agronomic traits that determine rice (Oryza sativa) productivity. Here, we report that altered auxin content, transport and distribution affect these traits, and hence rice yield. Overexpression of the auxin efflux carrier‐like gene OsPIN5b causes pleiotropic effects, mainly reducing plant height, leaf and tiller number, shoot and root biomass, seed‐setting rate, panicle length and yield parameters. Conversely, reduced expression of OsPIN5b results in higher tiller number, more vigorous root system, longer panicles and increased yield. We show that OsPIN5b is an endoplasmic reticulum (ER) ‐localized protein that participates in auxin homeostasis, transport and distribution in vivo. This work describes an example of an auxin‐related gene where modulating its expression can simultaneously improve plant architecture and yield potential in rice, and reveals an important effect of hormonal signaling on these traits.