Luteolin and quercetin are effective antileishmanial agents. Quercetin has nonspecific effects on normal human T cells, but luteolin appears nontoxic. So, luteolin can be a strong candidate for antileishmanial drug design.

We have investigated the role of mitochondria on the development of indomethacin (a non-steroidal anti-inflammatory drug)-induced gastric mucosal apoptosis and associated gastropathy in rat. Transmission electron microscopic studies indicate that indomethacin damages mitochondrial ultrastructure and causes mitochondrial dysfunction as evident from decreased stage-3 respiration, dehydrogenase activity, and transmembrane potential (⌬ m ). Mitochondrial pathology is associated with increased generation of intra-mitochondrial-reactive oxygen species, such as O 2 . , H 2 O 2 and ⅐OH, leading to oxidative stress. O 2 . is the most effective to damage mitochondrial aconitase, leading to the release of iron from its iron-sulfur cluster. The released iron, by interacting with intra-mitochondrial H 2 O 2 , forms ⅐OH. Immunoprecipitation of mitochondrial aconitase and subsequent Western immunoblotting indicate carbonylation of aconitase along with the loss of activity in vivo after indomethacin treatment. The release of iron has been documented by fluorescence imaging of mucosal cells by using Phen Green SK, a specific probe for chelatable iron. Interestingly, intra-mitochondrial ⅐OH generation is crucial for the development of mitochondrial pathology and activation of mitochondrial death pathway by indomethacin. Scavenging of ⅐OH by dimethyl sulfoxide or ␣-phenyl-n-tert-butylnitrone, a spin-trap, prevents indomethacin-induced mitochondrial ultrastructural changes, oxidative stress, collapse of ⌬ m , and mitochondrial dysfunction. The scavengers also restore indomethacin-induced activation of caspase-9 and caspase-3 to block mitochondrial pathway of apoptosis and gastric mucosal damage. This study, thus, reveals the critical role of O 2 . -mediated mitochondrial aconitase inactivation to release intra-mitochondrial iron, which by generating ⅐OH promotes gastric mucosal cell apoptosis and gastropathy during indomethacin treatment.Non-steroidal anti-inflammatory drugs (NSAIDs) 2 are one of the most commonly prescribed drugs in the world to treat pain and inflammation (1). Everyday about 30 million people consume NSAIDs (1). These drugs are gaining enormous interest for cancer therapy as well (2, 3), as they are potent inducers of apoptosis and inhibitors of cell proliferation (4). However, long term use of NSAIDs is associated with severe gastropathy (1, 5) that may arise from induction of gastric mucosal cell apoptosis (6 -9). NSAIDs induce apoptosis in vitro in varieties of cancer cells such as esophageal (10) and gastric adenocarcinoma cells (11), lung carcinoma cells (12), myeloid leukemia cells (13), and prostate carcinoma cells (3). NSAIDs also induce apoptosis in normal gastric mucosal cells (7, 9), hepatocytes (14), and chondrocytes (15). Up-regulation of proapoptotic Bax, Bak, and down-regulation of antiapoptotic Bcl-2, BclxL, are found to occur in NSAID-induced gastric mucosal apoptosis (7). Up-regulation of Bax as well as down-regulation of Bcl-2 are also observed in indomethacin-induced chronic myeloid leukemic c...

Augmentation of gastric mucosal cell apoptosis due to development of oxidative stress is one of the main pathogenic events in the development of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. Identification of a nontoxic, anti-apoptotic molecule is warranted for therapy against NSAID-induced gastropathy. The objective of the present study was to define the mechanism of the anti-apoptotic effect of melatonin, a nontoxic molecule which scavenges reactive oxygen species. Using an array of experimental approaches, we have shown that melatonin prevents the development of mitochondrial oxidative stress and activation of mitochondrial pathway of apoptosis induced by indomethacin (a NSAID) in the gastric mucosa. Melatonin inhibits the important steps of indomethacin-induced activation of mitochondrial pathway of apoptosis such as upregulation of the expression of Bax and Bak, and the downregulation of Bcl-2 and BclxL. Melatonin also prevents indomethacin-induced mitochondrial translocation of Bax and prevents the collapse of mitochondrial membrane potential. Moreover, melatonin reduces indomethacin-mediated activation of caspase-9 and caspase-3 by blocking the release of cytochrome c and finally rescues gastric mucosal cells from indomethacin-induced apoptosis as measured by the TUNEL assay. Histologic studies of gastric mucosa further document that melatonin almost completely protects against gastric damage induced by indomethacin. Thus, melatonin has significant anti-apoptotic effects to protect gastric mucosa from NSAID-induced apoptosis and gastropathy, which makes its use as potential therapy against gastric damage during NSAID treatment.

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We have investigated the DNA-binding nature as well as the function of a putative Alba (Acetylation lowers binding affinity) family protein (PfAlba3) from Plasmodium falciparum. PfAlba3 possesses DNA-binding property like Alba family proteins. PfAlba3 binds to DNA sequence non-specifically at the minor groove and acetylation lowers its DNA-binding affinity. The protein is ubiquitously expressed in all the erythrocytic stages of P. falciparum and it exists predominantly in the acetylated form. PfAlba3 inhibits transcription in vitro by binding to DNA. Plasmodium falciparum Sir2 (PfSir2A), a nuclear localized deacetylase interacts with PfAlba3 and deacetylates the lysine residue of N-terminal peptide of PfAlba3 specific for DNA binding. PfAlba3 is localized with PfSir2A in the periphery of the nucleus. Fluorescence in situ hybridization studies revealed the presence of PfAlba3 in the telomeric and subtelomeric regions. ChIP and ChIP ReChIP analyses further confirmed that PfAlba3 binds to the telomeric and subtelomeric regions as well as to var gene promoter.