In vivo antioxidative and neuroprotective effect of 4-Allyl-2-methoxyphenol against chlorpyrifos-induced neurotoxicity in rat brain

Chlorpyrifos exposure leads to various neurological disorders adverting disturbance in molecular pathways and normal brain functions. Major complications arise when these potent nerve agents access neuronal mechanisms causing adverse effect on acetylcholinesterase and brain lipids with generation of reactive oxygen species. Chlorpyrifos elicits chronic intoxication leading to redox disturbance with irreversible brain damage and oxidative stress. In the present study, neuroprotective and anti-apoptotic effects of eugenol (EO), a phenolic antioxidant, against chlorpyrifos-induced neurotoxicity was explored on rat brain cortex. Rats treated orally with chlorpyrifos [89.4 mg/kg body weight (BW)] for 15 consecutive days showed changes in brain lipid profile, increased levels of lipid peroxidation, inhibition of acetylcholinesterase activity, and changes in antioxidant enzymes. EO (250 mg/kg BW), administered 1 h after chlorpyrifos treatment, restored lipid, acetylcholinesterase, and antioxidant enzyme levels of brain cortex by suppressing chlorpyrifos-induced oxidative stress and neurotoxicity. Histological findings further demonstrated damage to brain morphology with increased protein levels of caspase-3 in CPF-treated animals. Alterations caused by neurotoxic effects of chlorpyrifos were attenuated by EO administration with decreased protein expressions of caspase-3. Thus, through its antioxidant and anti-apoptotic activities, EO showed protective effect against chlorpyrifos-induced neuronal damage.     

Self-Assembling Raloxifene Loaded Mixed Micelles: Formulation Optimization, <Emphasis Type="Italic">In Vitro</Emphasis> Cytotoxicity and <Emphasis Type="Italic">In Vivo</Emphasis> Pharmacokinetics

Raloxifene (RLX) has been strongly recommended for postmenopausal women at high risk of invasive breast cancer and for prevention of osteoporosis. However, low aqueous solubility and reduced bioavailability hinder its clinical application. The objective of this study was to explore the potential of RLX loaded mixed micelles (RLX-MM) using Pluronic F68 and Gelucire 44/14 for enhanced bioavailability and improved anticancer activity on human breast cancer cell line (MCF-7). RLX-MM were prepared by solvent evaporation method and optimized using 3² factorial design. The average size, entrapment efficiency and zeta potential of the optimized formulation were found to be 190?±?3.3 nm, 79?±?1.3%, 13?±?0.8 mV, respectively. In vitro study demonstrated 74.68% drug release from RLX-MM in comparison to 42.49% drug release from RLX dispersion. According to the in vitro cytotoxicity assay, GI₅₀ values on MCF-7 breast cancer cell line for RLX-MM and free RLX were found to be 22.5 and 94.71 μg/mL, respectively. Significant improvement (P?<?0.05) in the anticancer activity on MCF-7 cell line was observed in RLX-MM over RLX pure drug. Additionally, oral bioavailability of RLX-MM was improved by 1.5-fold over free RLX when administered in female Wistar rats. Incorporation of RLX in the hydrophobic core and improved solubility of the drug due to hydrophilic shell attributed to the enhanced cytotoxicity and bioavailability of RLX-MM. This research establishes the potential of RLX loaded mixed micelles of Pluronic F68 and Gelucire 44/14 for improved bioavailability and anticancer activity on MCF-7 cell line.     

RETRACTED ARTICLE: Homo and heterologous expression of the HpPKS2 gene in Hypericum perforatum and Bacopa monnieri

Plant Cell, Tissue and Organ Culture (PCTOC) -     

Ultra Rapidly Dissolving Repaglinide Nanosized Crystals Prepared via Bottom-Up and Top-Down Approach: Influence of Food on Pharmacokinetics Behavior

The present work was undertaken with the objectives of improving the dissolution velocity, related oral bioavailability, and minimizing the fasted/fed state variability of repaglinide, a poorly water-soluble anti-diabetic active by exploring the principles of nanotechnology. Nanocrystal formulations were prepared by both top-down and bottom-up approaches. These approaches were compared in light of their ability to provide the formulation stability in terms of particle size. Soluplus® was used as a stabilizer and Kolliphor™ E-TPGS was used as an oral absorption enhancer. In vitro dissolution profiles were investigated in distilled water, fasted and fed state simulated gastric fluid, and compared with the pure repaglinide. In vivo pharmacokinetics was performed in both the fasted and fed state using Wistar rats. Oral hypoglycemic activity was also assessed in streptozotocin-induced diabetic rats. Nanocrystals TD-A and TD-B showed 19.86 and 25.67-fold increase in saturation solubility, respectively, when compared with pure repaglinide. Almost 10 (TD-A) and 15 (TD-B)-fold enhancement in the oral bioavailability of nanocrystals was observed regardless of the fasted/fed state compared to pure repaglinide. Nanocrystal formulations also demonstrated significant (p < 0.001) hypoglycemic activity with faster onset (less than 30 min) and prolonged duration (up to 8 h) compared to pure repaglinide (after 60 min; up to 4 h, respectively).KEY WORDS: diabetes mellitus, fasted and fed state variability, nanocrystal, oral hypoglycemic activity, repaglinide     

Surge ammonium uptake in macroalgae from a coral atoll

Surge (non-linear) uptake of ammonium, measured by incorporation of ¹⁵N, was investigated in three species of macroalgae (Ulva lactuca Linnaeus (Chlorophyta), Soliera robusta (Greville) Kylin (Rhodophyta) and Dictyota dichotoma (Hudson) Lamouroux (Phaeophyta)) from Kavaratti atoll (Lakshadweep, India). Addition of ammonium (up to 20 μmol L^− 1) led to pronounced uptake within 4-6 min, with the amount of ammonium taken up during surge phase (< 4 min) accounting for from about half to 10 times that taken up during the remaining period of incubation (5-30 min). Amount of ammonium taken up during surge related linearly to the concentration of ammonium given. Surge uptake in the dark was also substantial, averaging 80% of that in light. Capability for rapid uptake of pulses of ammonium released by heterotrophs during the day or night could thus be an important mechanism of survival and proliferation of macroalgae in the N-impoverished atoll waters.     

Preoperative diagnosis of renal angiomyolipoma with fine needle aspiration cytology: a report of 3 cases

BACKGROUND: Angiomyolipoma is a rare benign neoplasm, commonly involving the kidney. Preoperative diagnosis on fine needle aspiration cytology can confirm the diagnosis, reducing the chances of unnecessary surgery. CASES: We studied cases of renal angiomyolipoma (AML) presenting within 1 year with palpable renal masses confirmed on ultrasound to be of renal origin. Fine needle aspiration cytology (FNAC) smears showed a few cohesive syncytial fragments with adipocytes, spindle cells and isolated single cells with foamy cytoplasm; a diagnosis of AML was made. The diagnosis was confirmed on histopathology, which showed mature adipose tissue, tortuous and thick-walled blood vessels lacking elastic tissue lamina and bundles of smooth muscles that seemed to emanate from the blood vessels. CONCLUSION: A preoperative diagnosis of renal AML is of great importance for correct management. In fact, when the lesion is small and asymptomatic, a conservative approach may be considered. Partial nephrectomy is possible with masses < 5 cm. Preoperative FNAC along with computed tomographic findings and immunocytochemical analysis of FNAC smears with HNB-45 can confirm the diagnosis of AML, thus preventing unindicated nephrectomy.     

The transferable tail: fusion of the N-terminal acidic extension of heparin cofactor II to alpha1-proteinase inhibitor M358R specifically increases the rate of thrombin inhibition

The conversion of the reactive center bond of the serpin alpha1-proteinase inhibitor (alpha1-PI, also known as alpha1-antitrypsin) from Met-Ser to Arg-Ser decreases the rate at which it inhibits neutrophil elastase and endows it with the ability to inhibit thrombin and activated protein C (APC). Another serpin, heparin cofactor II (HCII), contains a unique N-terminal extension that binds thrombin exosite 1. We fused residues 1-75 of HCII to the N-terminus of alpha1-PI M358R, forming an HCII-alpha1-PI chimera (HAPI M358R). It inhibited alpha-thrombin 21-fold faster than alpha1-PI M358R, with second-order rate constants of 2.3 x 10(8) M(-1) min(-1) versus 1.1 x 10(7) M(-1) min(-1), respectively. When gammaT-thrombin, which lacks an intact exosite 1, was substituted for alpha-thrombin, the kinetic advantage of HAPI M358R over alpha1-PI M358R was reduced to 9-fold, whereas APC and trypsin, proteases lacking exosite 1-like regions, were inhibited only 1.3- and 2-fold more rapidly by HAPI M358R than by alpha1-PI M358R, respectively. Maximal enhancement of alpha1-PI M358R activity required the acidic residues found between HCII residues 55 and 75, because no enhancement was observed either by fusion of residues 1-54 alone or by fusion of a mutated HCII acidic extension in which all Glu and Asp residues between positions 55 and 75 were neutralized by mutation. Fusing residues 55-75 to alpha1-PI M358R yielded a relative rate enhancement of only 6-fold, suggesting a need for the full tail region to achieve maximal enhancement. Our results suggest that transfer of the N-terminal acidic extension of HCII to alpha1-PI M358R enhanced its inhibition of thrombin by conferring the ability to bind exosite 1 on HAPI M358R. This enhancement may aid in efforts to tailor this inhibitor for therapeutic use.