Association of microsomal epoxide hydrolase exon 3 Tyr113His and exon 4 His139Arg polymorphisms with gastric cancer in India

Background

Microsomal epoxide hydrolase, an important phase II xenobiotic enzyme, exhibits polymorphisms at exon 3 (Tyr113His [T/C]) and exon 4 (His139Arg [A/G]), which modulate enzyme activity; this may affect susceptibility to cancers. We studied association between these polymorphisms and gastric cancer (GC).

Methods

In a prospective study, 77 patients with GC, 50 with peptic ulcer, and 160 healthy controls (HC) were genotyped for exon 3 (PCR-RFLP followed by sequencing) and exon 4 (PCR-RFLP). Helicobacter pylori was considered to be present if two of three tests (histology, rapid urease test, and IgG antibody) were positive.

Results

Tyr113His and His139Arg genotypes and haplotypes were comparable among groups. 113His carriers were commoner among H. pylori-negative patients with GC than HC (p-value?=?0.019, odds ratio (OR)?=?2.5, 95 % confidence interval (CI)?=?1.2–5.4). Haplotype combination of exons 3 and 4 113Tyr-139Arg (TA) were associated with higher and reduced risk in patients with GC than HC in presence and absence of H. pylori (25 % vs. 11 %; p-value?=?0.033, OR?=?2.61, 95 % CI?=?1.08–6.3 and 11.6 % vs. 28.7 %; p-value?=?0.004, OR?=?0.33, 95 % CI?=?0.15–0.7, respectively).

Conclusions

Though 113Tyr-139Arg was associated with GC in presence of H. pylori, in its absence, it appeared to be protective. Exon 3, 113His, however, was associated with GC even in absence of H. pylori infection.     

Combinatorial antimicrobial effect of curcumin with selected phytochemicals on Staphylococcus epidermidis

Staphylococcus epidermidis is reported to be the main causative agent of nosocomial infections. It has become increasingly difficult to treat this micro-organism because of the emergence of new antibiotic-resistant strains and its ability to form biofilm on medical associated devices. Phytochemicals acting in synergy are effective in killing the micro-organisms by lowering the doses, and synergistic compounds evade the development of resistance due to different mechanism of action. This study aims to determine the synergistic antimicrobial potential of curcumin with cinnamaldehyde, eugenol, and ellagic acid against S. epidermidis. Curcumin with ellagic acid as well as eugenol were found to have additive antimicrobial effect, whereas, in combination, curcumin and cinnamaldehyde were found to have synergistic effect against S. epidermidis (fractional inhibitory concentration index (FICI) = 0.5). Synergy between curcumin and cinnamaldehyde was established by time–kill kinetics and was further evaluated for antibiofilm activity. The dose required to inhibit biofilm formation was reduced to half than that needed to inhibit its planktonic culture (minimal inhibitory concentration (MIC) of curcumin = 3.12 μg/ml; MIC of cinnamaldehyde = 15.62 μg/ml; FICI = 0.248). Both curcumin and cinnamaldehyde disrupted the bacterial membrane for killing the bacteria as determined by permeability studies on Escherichia coli ML-35p.     

Molecular cloning and characterization of Plasmodium falciparum transketolase

The pentose phosphate pathway (PPP) is an important metabolic pathway for yielding reducing power in the form of NADPH and production of pentose sugar needed for nucleic acid synthesis. Transketolase, the key enzyme of non-oxidative arm of PPP, plays a vital role in the survival/replication of the malarial parasite. This enzyme in Plasmodium falciparum is a novel drug target as it has least homology with the human host. In the present study, the P. falciparum transketolase (PfTk) was expressed, localized and biochemically characterized. The recombinant PfTk harboring transketolase activity catalyzed the oxidation of donor substrates, fructose-6-phosphate (F6P) and hydroxypyruvate (HP), with K(m)(app) values of 2.25 and 4.78 mM, respectively. p-Hydroxyphenylpyruvate (HPP) was a potent inhibitor of PfTk, when hydroxypyruvate was used as a substrate, exhibiting a K(i) value of 305 microM. At the same time, noncompetitive inhibition was observed with F6P. The native PfTk is a hexamer with subunit molecular weight of 70kDa, which on treatment with low concentrations of guanidine hydrochloride (GdmCl) dissociated into functionally active dimers. This protein was localized in the cytosol and nucleus of the parasite as studied by confocal microscopy. A model structure of PfTk was constructed based on the crystal structure of the transketolases of Saccharomyces cerevisae, Leishmania mexicana and Escherichia coli to assess the structural homology. Consistent with the homology modeling predictions, CD analysis indicated that PfTk is composed of 39% alpha-helices and 26% beta-sheets. The availability of a structural model of PfTk and the observed differences in its kinetic properties compared to the host enzyme may facilitate designing of novel inhibitors of PfTk with potential anti-malarial activity.     

Electrochromic Response of Nanostructured Poly(3,4‐ethylenedioxythiophene) Films Grown in an Aqueous Micellar Solution

Poly(3,4‐ethylenedioxythiophene) (PEDOT) films have been electropolymerized from an aqueous micellar solution encompassing the monomer (EDOT) and the moieties sodium dodecyl sulfate (SDS) and lithium triflate. The presence of these anionic dopants in the polymer matrix and a doping level of 0.26 have been confirmed by X‐ray photoemission and electron paramagnetic resonance (EPR) spectroscopy. The hydrophobic micellar core encompassing the monomer orchestrates the growth of a uniform homogeneous polymer deposit as electron microscopy and atomic force microscopy studies reveal the film to be composed of a continuous interlinked network of quasi‐spherical grains (50–150 nm in dimensions) and pores alongwith a low surface roughness. The film exhibits a large coloration efficiency of 153 cm² · C^?1 and a transmission modulation of 62% (λ = 632.8 nm), which are manifestations of the open ion‐permeable morphology. The Q_{(inserted/extracted)} ratio ranges between 1.2 and 1.4 when cycled back and forth between the clear and blue states 2 500 times, thereby affirming the suitability of these films for practical electrochromic smart windows.

     

Can Surface Neuromuscular Electrical Stimulation of the Wrist and Hand Combined With Routine Therapy Facilitate Recovery of Arm Function in Patients With Stroke?

Rosewilliam S, Malhotra S, Roffe C, Jones P, Pandyan AD. Can surface neuromuscular electrical stimulation of the wrist and hand combined with routine therapy facilitate recovery of arm function in patients with stroke?ObjectiveTo investigate whether treatment with surface neuromuscular electrical stimulation to the wrist extensors improves recovery of arm function in severely disabled patients with stroke.DesignSingle blinded randomized controlled trial.SettingAcute stroke unit and stroke rehabilitation wards of a university hospital.ParticipantsPatients with no upper limb function (Action Research Arm Test [ARAT] score 0) (N=90; mean age ± SD, 74±11y; 49% men) were recruited to the study within 6 weeks of stroke. Only 67 participants were alive at the end of the study and data from 66 of these people were analyzed.InterventionsParticipants were randomized to surface neuromuscular electrical stimulation using surface electrical stimulators for 30 minutes, twice in a working day for 6 weeks in addition to standardized upper limb therapy or just standardized upper limb therapy.Main Outcome MeasureThe primary outcome measure was the ARAT score. Assessments were made at baseline and at 6, 12, 24, and 36 weeks after recruitment.ResultsThere were statistically significant improvements in measures of wrist extensor (mean difference 0.5; 95% confidence interval [CI], 0.0–1.0) and grip strength (mean difference 0.9; 95% CI, 0.1–1.7) over the treatment period. Arm function (ARAT score) was not significantly different between the groups over the treatment period at 6 weeks (mean difference 1.9; 95% CI, ?2.9 to 6.8) or over the study period at 36 weeks (mean difference 6.4; 95% CI, ?1.8 to 14.7), and the rate of recovery was not significantly different (mean difference 0.7; 95% CI, ?0.2 to 1.6).ConclusionsIn patients with severe stroke, with no functional arm movement, electrical stimulation of wrist extensors improves muscle strength for wrist extension and grip, and larger studies are required to study its influence on arm function.     

Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease

Alzheimer's disease is associated with a disruption of amyloid β (Aβ) homeostasis, resulting in the accumulation and subsequent deposition of Aβ peptides within the brain. The peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated nuclear receptor that acts in a coupled metabolic cycle with Liver X Receptors (LXRs) to increase brain apolipoprotein E (apoE) levels. apoE functions to promote the proteolytic clearance of soluble forms of Aβ, and we found that the synthetic PPARγ agonist, pioglitazone, stimulated Aβ degradation by both microglia and astrocytes in an LXR and apoE-dependent manner. Remarkably, a brief 9 d oral treatment of APPswe/PS1Δe9 mice with pioglitazone resulted in dramatic reductions in brain levels of soluble and insoluble Aβ levels which correlated with the loss of both diffuse and dense-core plaques within the cortex. The removal of preexisting amyloid deposits was associated with the appearance of abundant Aβ-laden microglia and astrocytes. Pioglitazone treatment resulted in the phenotypic polarization of microglial cells from a proinflammatory M1 state, into an anti-inflammatory M2 state that was associated with enhanced phagocytosis of deposited forms of amyloid. The reduction in amyloid levels was associated with a reversal of contextual memory deficits in the drug-treated mice. These data provide a mechanistic explanation for how PPARγ activation facilitates amyloid clearance and supports the therapeutic utility of PPARγ agonists for the treatment of Alzheimer's disease.