Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3β and attenuated by lithium

The compound 1-methyl-4-phenylpyridinium (MPP) is a selective inhibitor of mitochondrial complex I, and is widely used in model systems to elicit neurochemical alterations that may be associated with Parkinson’s disease. In the present study treatment of human neuroblastoma SH-SY5Y cells with MPP resulted in a time- and concentration-dependent activation of the apoptosis-associated cysteine protease caspase-3, and caused morphological changes characteristic of apoptosis. To test if the activation state of the cell survival-promoting phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway affects MPP-induced caspase-3 activation, PI3K was inhibited with LY294002, or activated with insulin-like growth factor-1. MPP-induced caspase-3 activation was increased by inhibition of PI3K, and decreased by stimulation of PI3K, indicative of anti-apoptotic signaling by the PI3K/Akt pathway. To test if glycogen synthase kinase-3β (GSK3β), a pro-apoptotic kinase that is inhibited by Akt, is involved in regulating MPP-induced apoptosis, overexpression of GSK3β and lithium, a selective inhibitor of GSK3β, were used to directly alter GSK3β activity. MPP-induced caspase-3 activity was increased by overexpression of GSK3β. Conversely, the GSK3β inhibitor lithium attenuated MPP-induced caspase-3 activation. To test if these regulatory interactions applied to other mitochondrial complex I inhibitors, cells were treated with rotenone. Rotenone-induced activation of caspase-3 was enhanced by inhibition of PI3K or increased GSK3β activity, and was attenuated by inhibiting GSK3β with lithium. Overall, these results indicate that inhibition of GSK3β provides protection against the toxic effects of agents, such as MPP and rotenone, that impair mitochondrial function.     

Pediatric Hematology and Oncology in Pakistan

Pediatric hematology and oncology ha only recently started developing within Pakistan, with centers in Islamabad, Lahore, Karachi, and Multan. Efforts are being made to update blood bank facilities and to standardize the level of care being provided throughout the country. A pediatric oncology group has recently been established. A lot of work still needs to be done, however.     

Novel nonsense IL-12Rβ1 mutation associated with recurrent tuberculosis

Immunologic Research - The interleukin (IL)-12/interferon(IFN)γ axis plays an important role in the control of mycobacterial diseases as demonstrated by the increased susceptibility to...     

Synthetic utility of sydnones: synthesis of pyrazolines derivatized with 1,2,4-triazoles as antihyperglymic, antioxidant agents and their DNA cleavage study

Ring transformation of sydnone (1a–i) to 1,3,4-oxadiazoline-2-one (2a–i) was carried out using bromine in acetic anhydride. The compounds (2a–i) on heating with hydrazine hydrate gave 1,2,4-triazole (3a–i) in good yields. The structure of these unknown compounds was confirmed by IR, ¹H NMR, MS and elemental analysis. Further, these compounds were evaluated for the extent of penetration into biological membranes (clogP) drug likeliness and finally drug score was calculated. The title compounds were also screened for their antihyperglycemic, DNA cleavage and antioxidant activity.     

An efficient one-pot cyclization of quinoline thiosemicarbazones to quinolines derivatized with 1,3,4-thiadiazole as anticancer and anti-tubercular agents

A series of 6,7,8-substituted thiosemicarbazones (2a–j) of 2-chloro-3-formyl-quinoline derivatives were cyclized to the title compounds (3a–j) using acetic anhydride. The structures of the final compounds (3a–j) were confirmed by elemental and spectral (IR, ¹H NMR and MS) analysis. Some of the title compounds have shown promising anticancer and antitubercular activities.     

Synthesis of novel imidazo[2,1-b][1,3,4]thiadiazoles appended to sydnone as anticancer agents

A novel series of 3-aryl-4{6′-(6′′-substituted-coumarin-3′′-yl) imidazo[2,1-b][1,3,4]thiadiazol-2′-yl}-sydnones 5h–5s were synthesized and screened for their anticancer and DNA cleavage activities and analyzed for pharmacological parameters such as toxicity, drug-likeliness, and drug score for oral bioavailability. In vitro toxicity assay was carried out by assessing the survival E. coli AB1157 (wild type) cultures. Some of the compounds have shown significant anticancer activities also.