With the spread of chloroquine (CQ)-resistant malaria in India, sulfadoxine-pyrimethamine (SP) alone or in combination with artesunate is used as an alternative antimalarial drug. Due to continuous drug pressure, the Plasmodium falciparum parasite is exhibiting resistance to antifolates because of mutations in candidate genes dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps). Our earlier study on flanking microsatellite markers of dhfr mutant alleles from India had shown a single origin of the pyrimethamine resistance and some minor haplotypes which shared haplotypes with Southeast Asian (Thailand) strains. In the present study, we have analyzed 193 of these Indian P. falciparum isolates for 15 microsatellite loci around dhps to investigate the genetic lineages of the mutant dhps alleles in different parts of the country. Eighty-one of these samples had mutant dhps alleles, of which 62 were from Andaman and Nicobar Islands and the remaining 19 were from mainland India. Of 112 isolates with a wild-type dhps allele, 109 were from mainland India and only 3 were from Andaman and Nicobar Islands. Consistent with the model of selection, the mean expected heterozygosity (H e ) around mutant dhps alleles (H e ؍ 0.55; n ؍ 81) associated with sulfadoxine resistance was lower (P < 0.05) than the mean H e around the wild-type dhps allele (H e ؍ 0.80; n ؍ 112). There was more genetic diversity in flanking microsatellites of dhps than dhfr among these isolates, which confirms the assertion that dhps mutations are at a very early stage of fixation in the parasite population. Microsatellite haplotypes around various mutant dhps alleles suggest that the resistant dhps alleles have multiple independent origins in India, especially in Andaman and Nicobar Islands. Determining the genetic lineages of the resistant dhps alleles on Andaman and Nicobar Islands and mainland India is significant, given the role of Asia in the intercontinental spread of chloroquine-and pyrimethamine-resistant parasites in the past.
Parkinson's disease (PD) is associated with neurodegeneration of the nigrostriatal tract and is accompanied with loss of tyrosine hydroxylase (TH) and dopamine (DA). Development of neuroprotective strategies targeting PD is often undermined by lack of proper understanding of processes contributing to the pathology. In this mini review we have tried to briefly outline the involvement of TH and α-synuclein in PD. Aberrant expression of α-synuclein is toxic to dopaminergic neurons. It interacts with ubiquitin-proteasomal processing system, implicated in oxidative injury and mitochondrial dysfunction which ultimately induce neurodegenration and cell death. The contributions of DJ-1 in TH regulation have also been discussed. Brain specific TH expression with the combined use of the pegylated immunoliposome (PILs) gene transfer technology and brain specific promoters as a new approach to treat PD has also been included.
Background:
Protein kinases are the enzymes involved in phosphorylation of different proteins which
leads to functional changes in those proteins. They belong to serine-threonine kinases family and are classified
into the AGC (Protein kinase A/ Protein kinase G/ Protein kinase C) families of protein and Rho-associated
kinase protein (ROCK). The AGC family of kinases are involved in G-protein stimuli, muscle contraction, platelet
biology and lipid signaling. On the other hand, ROCK regulates actin cytoskeleton which is involved in the
development of stress fibres. Inflammation is the main signal in all ROCK-mediated disease. It triggers the cascade
of a reaction involving various proinflammatory cytokine molecules.
Methods:
Two ROCK isoforms are found in mammals and invertebrates. The first isoforms are present mainly in
the kidney, lung, spleen, liver, and testis. The second one is mainly distributed in the brain and heart.
Results:
ROCK proteins are ubiquitously present in all tissues and are involved in many ailments that include
hypertension, stroke, atherosclerosis, pulmonary hypertension, vasospasm, ischemia-reperfusion injury and heart
failure. Several ROCK inhibitors have shown positive results in the treatment of various disease including cardiovascular
diseases.
Conclusion:
ROCK inhibitors, fasudil and Y27632, have been reported for significant efficiency in dropping
vascular smooth muscle cell hyper-contraction, vascular inflammatory cell recruitment, cardiac remodelling and
endothelial dysfunction which highlight ROCK role in cardiovascular diseases.
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