Neurons Specialize in Presynaptic Autophagy: A Perspective to Ameliorate Neurodegeneration.

The efficient and prolonged neurotransmission is reliant on the coordinated action of numerous synaptic proteins in the presynaptic compartment that remodels synaptic vesicles for neurotransmitter packaging and facilitates their exocytosis. Once a cycle of neurotransmission is completed, membranes and associated proteins are endocytosed into the cytoplasm for recycling or degradation. Both exocytosis and endocytosis are closely regulated in a timely and spatially constrained manner. Recent research demonstrated the impact of dysfunctional synaptic vesicle retrieval in causing retrograde degeneration of midbrain neurons and has highlighted the importance of such endocytic proteins, including auxilin, synaptojanin1 (SJ1), and endophilin A (EndoA) in neurodegenerative diseases. Additionally, the role of other associated proteins, including leucine-rich repeat kinase 2 (LRRK2), adaptor proteins, and retromer proteins, is being investigated for their roles in regulating synaptic vesicle recycling. Research suggests that the degradation of defective vesicles via presynaptic autophagy, followed by their recycling, not only revitalizes them in the active zone but also contributes to strengthening synaptic plasticity. The presynaptic autophagy rejuvenating terminals and maintaining neuroplasticity is unique in autophagosome formation. It involves several synaptic proteins to support autophagosome construction in tiny compartments and their retrograde trafficking toward the cell bodies. Despite having a comprehensive understanding of ATG proteins in autophagy, we still lack a framework to explain how autophagy is triggered and potentiated in compact presynaptic compartments. Here, we reviewed synaptic proteins' involvement in forming presynaptic autophagosomes and in retrograde trafficking of terminal cargos. The review also discusses the status of endocytic proteins and endocytosis-regulating proteins in neurodegenerative diseases and strategies to combat neurodegeneration.

The effect of high intensity ultrasound (HIU) on the kinetics of crystallization of sucrose: Elimination of latent period.

The application of a technique to eliminate the latent period during crystallization of sucrose by high intensity ultrasound (HIU) was investigated in this paper. Employing HIU (20 kHz, 750 W) to crystallization of sucrose, latent period was eliminated and it was found to obey first order kinetics (K ∼10-5s-1) in the temperature range of 30-50 °C. Employing Arrhenius equation, the average energy of activation (Ea) estimated as 5.0 kcal mol-1. Traditional knowledge indicates that crystallization is sufficiently spontaneous; however, the magnitude of "K" and other thermodynamic quantities of the process indicate that crystallization is actually a slow process. Generally, chemical reactions which posses low rate constants, need the high energy of activation. On the contrary, the energy of activation is appreciably less. The energy of activation with a rate constant of the order of 10-5s-1 could be predicted of the order of 20 kcal mol-1 at 27 °C. The low energy of activation for crystallization of sucrose is of interest. A very interesting elucidation can be had from neutron diffraction data and transport property of the sucrose which is discussed in details in this paper.

Association of Polymorphism of Neuronal Nitric Oxide Synthase Gene with Risk to Parkinson's Disease.

Environmental factors are implicated in aging as well as genetic predisposition-induced Parkinson's disease (PD) pathogenesis. Wrongdoers increase oxidative stress and nitrosative burden, which eventually degenerate the nigrostriatal dopaminergic neurons. Inhibition of the expression of nitric oxide synthase (NOS), an enzyme responsible for nitric oxide (NO) biosynthesis, prevents the demise of the nigrostriatal dopaminergic neurons. Polymorphism of NOS is thus expected to alter PD susceptibility. The study therefore aimed to examine an association of neuronal NOS (nNOS) gene polymorphism with nitrite, an indicator of nitrosative load; lipid peroxidation, an index of oxidative stress and PD susceptibility. An age-matched case-control study was performed in the north Indian residents enrolled at the Neurology Department of the King George's Medical University, Lucknow, India. While nNOS exon 29 TT variant genotype [odds ratio (OR) = 2.20, 95 % CI = 1.08-5.34, P = 0.040], combined TT and CT variants [OR = 1.68, 95 % CI = 1.05-2.69, P = 0.031] and T allele [OR = 1.58, 95 % CI = 1.10-2.28, P = 0.014] were found to be significantly associated with PD susceptibility, no association between nNOS exon 18 [OR for TT carriers = 1.97, 95 % CI = 0.89-4.20, P = 0.09 and OR for T allele = 1.35, 95 % CI = 0.94-1.93, P = 0.098] and PD risk was observed. Lipid peroxidation was augmented in all patients irrespective of their genotype. While genotype independent increase in nitrite content was observed in PD patients of exon 29 polymorphic groups, only heterozygous variant genotype of exon 18 was associated with augmentation in nitrite level as compared with respective control. The results obtained thus demonstrate that selected nNOS polymorphisms do not significantly contribute to PD risk in north Indian population.

HCV Inhibitors: Role of Compounds from Botanical Sources.

The developing number of hepatitis C virus infected cases worldwide has threatened people's health. The available therapeutic options have low specificity, side effects and high rate of drug resistance and thus potentiate the need for novel effective anti-HCV drugs. Agents obtained from natural sources offer an enormous scope of structural diversity and broad therapeutic range of coverage. This review summarizes the research and development of anti-HCV agents (plant extracts/isolated components) obtained from various natural sources along with the associated mechanism of HCV inhibition. Some of the reported examples include triterpenes, naringenin, Proanthocyanidin, curcumin, Epigallocatechin-3-gallate, quercetin and abrogates having diverse anti-HCV properties. The compiled knowledge regarding anti-HCV agents from natural sources will provide considerable information for developing novel safe and effective anti-HCV drugs.

Does restraining nitric oxide biosynthesis rescue from toxins-induced parkinsonism and sporadic Parkinson's disease?

Nitric oxide (NO) is an important inorganic molecule of the biological system owing to diverse physiological implications. NO is synthesised from a semi-essential amino acid L-arginine. NO biosynthesis is catalysed by a family of enzymes referred to as nitric oxide synthases (NOSs). NO is accused in many acute and chronic illnesses, which include central nervous system disorders, inflammatory diseases, reproductive impairments, cancer and cardiovascular anomalies. Owing to very unstable nature, NO gets converted into nitrite, peroxynitrite and other reactive nitrogen species that could lead to nitrosative stress in the nigrostriatal system. Nitrosative stress is widely implicated in Parkinson's disease (PD), and its beneficial and harmful effects are demonstrated in in vitro, rodent and primate models of toxins-induced parkinsonism and in the blood, cerebrospinal fluid and nigrostriatal tissues of sporadic PD patients. The current article updates the roles of NO and NOSs in sporadic PD and toxins-induced parkinsonism in rodents along with the scrutiny of how inhibitors of NOSs could open a new line of approach to moderately rescue from PD pathogenesis based on the existing literature. The article also provides a perspective concerning the lack of ample admiration to such an approach and how to minimise the underlying lacunae.

3D-QSAR and docking studies on a series of benzothiadiazine derivatives as genotype 1 HCV polymerase inhibitors.

The Benzothiadiazine derivatives have been regarded as a novel class of HCV genotype 1 polymerase inhibitors. To explore the relationship between the structures of substituted Benzothiadiazine derivatives and their inhibitory activities against HCV, 3D-QSAR and molecular docking studies were performed on a dataset of ninty-eight compounds. The 3D-QSAR models resulted from seventy-eight molecules in the training set gave q(2) value of 0.81 and a test set of twenty compounds, gave predictive r(2) value of 0.94. 3D-QSAR model generated from kNN-MFA along with the docking binding structures provided enough information about the structural requirements for better activity. The results can serve as a useful guideline to design novel HCV genotype 1 inhibitors with better potencies.

Synthesis, in vitro and in silico NS5B polymerase inhibitory activity of benzimidazole derivatives.

Hepatitis C virus (HCV) NS5B polymerase is the key replicating protein of the virus and thus an attractive target for drug development. Here we report on the synthesis and biological evaluation of a new series of benzimidazole derivatives as HCV NS5B inhibitors. This yielded compound 6b and 6d bearing 2-(2-benzyloxy)phenyl and 2-(4-methylbenzyloxy)phenyl moieties, respectively, as promising leads. Binding mode of compound 6d in allosteric pocket (AP)-1 of NS5B will form the basis for future structure-activity relationship optimization.

Cypermethrin alters the expression profile of mRNAs in the adult rat striatum: a putative mechanism of postnatal pre-exposure followed by adulthood re-exposure-enhanced neurodegeneration.

This study was undertaken to investigate the effect of cypermethrin on the expression patterns of mRNAs in the striatum of adulthood alone and postnatal pre-exposed followed by adulthood re-exposed rats using discover chips rat microarrays. The expression patterns of V-akt murine thymoma viral oncogene homolog 1, B-cell lymphoma 2 (BCL-2), BCL-2-associated X protein, caspase 1, caspase 9, death-associated protein 3 and interleukin-1ß were validated by the qRT-PCR. The expressions of inducible nitric oxide synthase (iNOS) and major histocompatibility complex (MHC) II were assessed immunohistochemically; however, tumour protein p53 and cytochrome c (mitochondrial and cytosolic) expressions were checked at protein level by western blotting. Cypermethrin differentially regulated 65 transcripts at one or the other stage of exposure and 21 transcripts exhibited more pronounced alterations in the postnatal pre-exposed and adulthood re-challenged rats. The results of qRT-PCR were in accordance with the microarray observations and the expressions of iNOS, p53 and cytosolic cytochrome c and MHC II positivity were increased while the level of mitochondrial cytochrome c was reduced in adulthood treated animals. The effects were more pronounced in the postnatal pre-exposed followed by adulthood re-exposed rats. The results obtained thus suggest that multiple pathways are involved in the neurodegeneration as well as in enhancing the vulnerability of neurons in cypermethrin pre-exposed postnatal animals upon re-exposure during adulthood.

Role of secondary mediators in caffeine-mediated neuroprotection in maneb- and paraquat-induced Parkinson's disease phenotype in the mouse.

Maneb and paraquat are known to induce Parkinson's disease (PD) phenotype, however, caffeine offers neuroprotection. Nitric oxide (NO) acts an important mediator in PD phenotype and tyrosine kinase (TK), nuclear factor kappa B (NF-kB), p38 mitogen activated protein kinase (p38 MAPK) are known to regulate its production. The present study aimed to elucidate the role of caffeine in the regulation of NO production and microglial activation and their subsequent contribution in dopaminergic neuroprotection. The animals were treated with caffeine and/or maneb and paraquat along with controls. In a few sets of experiments, the animals were also treated with aminoguanidine, an inhibitor of inducible NO synthase, pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kB, genistein, an inhibitor of TK or SB202190, an inhibitor of p38 MAPK. Tyrosine hydroxylase (TH)-immunoreactivity and anti-integrin αM (OX-42) staining were performed to assess the number of dopaminergic neurons and activation of microglia, respectively. NO was measured in terms of nitrite, however, the expressions of p38 MAPK, interleukin (IL)-1ß, NF-kB and TK were checked by western blot analyses. Maneb and paraquat induced the number of degenerating dopaminergic neurons, microglial cells, nitrite content, expressions of IL-1ß, p38 MAPK, NF-kB and TK and caffeine co-treatment reduced the level of such alterations. Reductions were more pronounced in the animals co-treated with aminoguanidine, PDTC, genistein or SB202190. The results obtained thus demonstrate that caffeine down-regulates NO production, neuroinflammation and microglial activation, which possibly contribute to neuroprotection.

A safer technique of closure of peptic ulcer perforation.

There are several variations in the technique of closure of peptic ulcer perforation. The technique of closure of perforation by figure of 8 was found to be very effective in dealing with this common problem.

Molecular docking studies on quinazoline antifolate derivatives as human thymidylate synthase inhibitors.

We have performed molecular docking on quinazoline antifolates complexed with human thymidylate synthase to gain insight into the structural preferences of these inhibitors. The study was conducted on a selected set of one hundred six compounds with variation in structure and activity. The structural analyses indicate that the coordinate bond interactions, the hydrogen bond interactions, the van der Waals interactions as well as the hydrophobic interactions between ligand and receptor are responsible simultaneously for the preference of inhibition and potency. In this study, fast flexible docking simulations were performed on quinazoline antifolates derivatives as human thymidylate synthase inhibitors. The results indicated that the quinazoline ring of the inhibitors forms hydrophobic contacts with Leu192, Leu221 and Tyr258 and stacking interaction is conserved in complex with the inhibitor and cofactor.

Involvement of nitric oxide in maneb- and paraquat-induced Parkinson's disease phenotype in mouse: is there any link with lipid peroxidation?

The study aimed to investigate the involvement of nitric oxide (NO) in maneb (MB)- and paraquat (PQ)-induced Parkinson's disease (PD) phenotype in mouse and its subsequent contribution to lipid peroxidation. Animals were treated intraperitoneally with or without MB and PQ, twice a week for 3, 6 and 9 weeks. In some sets of experiments (9 weeks treated groups), the animals were treated intraperitoneally with or without inducible nitric oxide synthase (iNOS) inhibitor-aminoguanidine, tyrosine kinase inhibitor-genistein, nuclear factor-kappa B (NF-kB) inhibitor-pyrrolidine dithiocarbamate (PDTC) or p38 mitogen activated protein kinase (MAPK) inhibitor-SB202190. Nitrite content and lipid peroxidation were measured in all treated groups along with respective controls. RNA was isolated from the striatum of control and treated mice and reverse transcribed into cDNA. RT-PCR was performed to amplify iNOS mRNA and western blot analysis was done to check its protein level. MB- and PQ-treatment induced nitrite content, expressions of iNOS mRNA and protein and lipid peroxidation as compared with respective controls. Aminoguanidine resulted in a significant attenuation of iNOS mRNA expression, nitrite content and lipid peroxidation demonstrating the involvement of nitric oxide in MB- and PQ-induced lipid peroxidation. Genistein, SB202190 and PDTC reduced the expression of iNOS mRNA, nitrite content and lipid peroxidation in MB- and PQ-treated mouse striatum. The results obtained demonstrate that nitric oxide contributes to an increase of MB- and PQ-induced lipid peroxidation in mouse striatum and tyrosine kinase, p38 MAPK and NF-kB regulate iNOS expression.

Pyrogallol-mediated toxicity and natural antioxidants: triumphs and pitfalls of preclinical findings and their translational limitations.

Pyrogallol, a potent anti-psoriatic drug, produces toxicity due to its ability to generate free radicals, besides its beneficial effects. Oxidative stress is implicated in pyrogallol-mediated toxicity in general and hepatotoxicity in particular. Naturally occurring antioxidants including, resveratrol and silymarin have been proposed as potential supplements to counteract pyrogallol-mediated toxicity, without reducing its efficacy. Due to increase in the popularity of natural antioxidants in combating pyrogallol-mediated toxicity, a literature-based survey was performed to assess their role in experimental studies and possible implications in real life situations. Although preclinical studies revealed the boons of naturally occurring antioxidants in attenuating/abolishing the undesirable effects of pyrogallol exposure, limited studies have been conducted to evaluate their role in clinics. In this review, an update on the recent development in assessing the potential of natural antioxidants in pyrogallol-mediated toxicity in preclinical interventions, triumphs and pitfalls of such investigations, their translational challenges and future possibilities are discussed.

Effect of caffeine on the expression of cytochrome P450 1A2, adenosine A2A receptor and dopamine transporter in control and 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine treated mouse striatum.

Parkinson's disease (PD) is a progressive neurodegenerative disorder, characterized by the selective loss of dopaminergic neurons of the nigrostriatal pathway. Epidemiological studies have shown an inverse relationship between coffee consumption and susceptibility to PD. Cytochrome P450 1A2 (CYP1A2) is involved in caffeine metabolism and its clearance. Caffeine, on the other hand, antagonizes adenosine A(2A) receptor and regulates dopamine signaling through dopamine transporter (DAT). The present study was undertaken to investigate the expression of CYP1A2, adenosine A(2A) receptor and DAT in mouse striatum and to assess their levels in 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropryridine (MPTP) treated mouse striatum with and without caffeine treatment. The animals were treated intraperitoneally daily with caffeine (20 mg/kg) for 8 weeks, followed by MPTP (20 mg/kg)+caffeine (20 mg/kg) for 4 weeks or vice versa, along with respective controls. Tyrosine hydroxylase immunoreactivity, levels of dopamine and 1-methyl 4-phenylpyridinium ion (MPP(+)), expressions of CYP1A2, adenosine A(2A) receptor and DAT and CYP1A2 catalytic activity were measured in control and treated mouse brain. Caffeine partially protected MPTP-induced neurodegenerative changes and modulated MPTP-mediated alterations in the expression and catalytic activity of CYP1A2, expression of adenosine A(2A) receptor and DAT. The results demonstrate that caffeine alters the striatal CYP1A2, adenosine A(2A) receptor and DAT expressions in mice exposed to MPTP.