Muhammad Zafar Khan

Dracorhodin perchlorate inhibits PI3K/Akt and NF-κB activation, up-regulates the expression of p53, and enhances apoptosis.

Dracorhodin perchlorate has been recently shown to induce apoptotic cell death in cancer cells. However, the molecular mechanisms underlying these effects are unknown in human gastric tumor cells. In this study, effects of Dracorhodin perchlorate on cell viability, cell cycle, and apoptosis were investigated in SGC-7901 cells. The results showed that Dracorhodin perchlorate induced cellular and DNA morphological changes and decreased the viability of SGC-7901 cells. Dracorhodin perchlorate-mediated cell cycle arrest was associated with a marked decrease in protein levels of phosphorylated retinoblastoma and E2F1. Dracorhodin perchlorate-induced apoptosis is mediated via upregulation of p53, inhibiting the activation of PI3K/Akt, and NF-κB, thereby decreasing the expression of the anti-apoptotic proteins, Bcl-2 and Bcl-XL. Interestingly, we also found that Dracorhodin perchlorate significantly suppressed the IGF-1-induced phosphorylation of Akt in the stably expressing EGFP-Akt recombinant CHO-hIR cells and inhibited TNF-induced NF-κB transcriptional activity in the NF-κBp65-EGFP recombinant U2OS cells, indicating that inhibition of PI3K/Akt and NF-κB may provide a molecular basis for the ability of Dracorhodin perchlorate to induce apoptosis. Dracorhodin perchlorate induced up-regulation of p53, thereby resulting in the activation of its downstream targets p21 and Bax following the dissipation of mitochondrial membrane potential and activation of caspase-3 and its substrate, PARP. Moreover, Dracorhodin perchlorate dramatically enhanced the wortmannin- and TNF-induced apoptosis in SGC-7901 cells. These results reveal functional interplay among the PI3K/Akt, p53 and NF-κB pathways that are frequently deregulated in cancer and suggest that their simultaneous targeting by Dracorhodin perchlorate could result in efficacious and selective killing of cancer cells.

Isoalantolactone, a sesquiterpene lactone, induces apoptosis in SGC-7901 cells via mitochondrial and phosphatidylinositol 3-kinase/Akt signaling pathways

Isoalantolactone, a sesquiterpene lactone, possesses anti-fungal as well as cytotoxic properties. In this study, the effects of Isoalantolactone on cell viability, cell cycle, and apoptosis were investigated in human gastric adenocarcinoma SGC-7901 cells. The results demonstrated that Isoalantolactone induced morphological changes and decreased cell viability. Subsequently, we found that Isoalantolactone induced G2/M and S phase arrest, which was associated with a decrease in the expression level of cyclin B1. Apoptosis triggered by Isoalantolactone was visualized using propidium iodide (PI) and Annexin V-FITC/PI staining. Isoalantolactone-induced apoptosis of SGC-7901 cells was associated with the dissipation of mitochondrial membrane potential (ΔΨm) that was due to the down-regulation of Bcl-2 and up-regulation of Bax that led to the cleavage of caspase-3. Additionally, it was found that Isoalantolactone was involved in the inhibition of phosphorylation of PI3K/Akt. Isoalantolactone-induced cytotoxicity and apoptosis of SGC-7901 cells involve mitochondria-caspase and PI3K/Akt dependent pathways, which gives the rationale for in vivo studies on the utilization of Isoalantolactone as a potential cancer therapeutic compound.

Evodiamine sensitizes U87 glioblastoma cells to TRAIL via the death receptor pathway.

The tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) has been shown to selectively induce death in cancer cells without affecting healthy cells. Most glioma cells are resistant to TRAIL-induced apoptosis. Resistance to TRAIL limits its potential use as a drug for therapy of glioma. The present study was conducted to identify bioactive compounds that have the potential to sensitize U87 glioblastoma cells to TRAIL. Evodiamine, a major bioactive compound of the Chinese herb Evodiae fructus, has been reported to sensitize U87 glioblastoma cells to TRAIL. TRAIL and evodiamine, in combination or alone, were used to treat U87 glioblastoma cells. We show that evodiamine treatment inhibited cell growth in a dose-dependent manner; however, TRAIL alone failed to exert any cytotoxic effect. Combining TRAIL with evodiamine significantly increased the apoptotic rate of U87 glioblastoma cells, as compared to evodiamine treatment alone. Further investigation of the mechanism underlying these effects revealed that the evodiamine + TRAIL effect is associated with the increased expression of death receptor (DR)4, DR5, caspase-8 and cleaved caspase-3. The present study demonstrated, for the first time to the best of our knowledge, that evodiamine can sensitize U87 glioblastoma cells to TRAIL via the death receptor pathway. Thus, our results suggest that combined treatment with evodiamine and TRAIL may represent a novel chemotherapeutic strategy for the therapy of glioma.

Efficacy and Safety of Mechanical versus Manual Compression in Cardiac Arrest - A Bayesian Network Meta-Analysis.

AIM To compare relative efficacy and safety of mechanical compression devices (AutoPulse and LUCAS) with manual compression in patients with cardiac arrest undergoing cardiopulmonary resuscitation (CPR). METHODS For this Bayesian network meta-analysis, seven randomized controlled trials (RCTs) were selected using PubMed/Medline, EMBASE, and CENTRAL (Inception- 31 October 2017). For all the outcomes, median estimate of odds ratio (OR) from the posterior distribution with corresponding 95% credible interval (Cr I) was calculated. Markov chain Monte Carlo (MCMC) modeling was used to estimate the relative ranking probability of each intervention based on surface under the cumulative ranking curve (SUCRA). RESULTS In analysis of 12, 908 patients with cardiac arrest [AutoPulse (2, 608 patients); LUCAS (3, 308 patients) and manual compression (6, 992 patients)], manual compression improved survival at 30 days or hospital discharge (OR, 1.40, 95% Cr I, 1.09-1.94), and neurological recovery (OR, 1.51, 95% Cr I, 1.06-2.39) compared to AutoPulse. There were no differences between LUCAS and AutoPulse with regards to survival to hospital admission, neurological recovery or return of spontaneous circulation (ROSC). Manual compression reduced the risk of pneumothorax (OR, 0.56, 95% Cr I, 0.33-0.97); while, both manual compression (OR, 0.15, 95% Cr I, 0.01-0.73) and LUCAS (OR, 0.07, 95% Cr I, 0.00-0.43) reduced the risk of hematoma formation compared to AutoPulse. Probability analysis ranked manual compression as the most effective treatment for improving survival at 30 days or hospital discharge (SUCRA, 84%). CONCLUSIONS Manual compression is more effective than AutoPulse and comparable to LUCAS in improving survival at 30 days or hospital discharge and neurological recovery. Manual compression had lesser risk of pneumothorax or hematoma formation compared to AutoPulse.

Population status and migration trends of Marco Polo argali (Ovis ammon polii) in Pakistan

Abstract Marco Polo sheep (Ovis ammon polii) occurring in the rugged mountainous landscapes of Central and South Asia, are difficult to survey and conserve due to their straggling habits in remote and inhospitable habitats. The paper presents population estimates and migration trends of Marco Polo sheep in Khunjerab, Pakistan, over 20 years (1992–2012), determined through direct count method. During this period a total of 1069 sheep visited Pakistan, with mean annual herd size of 76.35 (SD=±40.87). Sex ratio in the population skewed towards females, having male:female ratio of 0.69:1 with 43 lambs to 100 ewes. Annual population density of the immigrant populations oscillated between 0.42 and 2.13 animals/km2 (SD=±0.53). The visitation showed drastic decline over 20 years, possibly due to fencing at the Sino-Pakistan border and dietary competition with wild herbivores. Fewer lambs in summer populations is another point of concern, probably as result of predation of young cohort by avian and mammalian predators. Removing obstructions on migratory routes and reducing dietary competition with sympatric herbivores are suggested for viability of argali populations in Pakistan.

Prevalence of infarct and villous clumps, and the expression of α‑smooth muscle actin in the placental basal plate in severe preeclampsia

The present study was conducted to investigate the prevalence of multifocal infarcts and multifocal villous clumps, as well as the expression of α‑smooth muscle actin (α‑SMA) in the basal plate of the placenta. Multifocal infarcts and/or multifocal villous clumps were more frequently observed in early onset severe preeclampsia (EOSPE; n=20) compared with the early control (n=18), late onset severe preeclampsia (LOSPE; n=20) and late control (n=20) groups. Infarct in transitional and late stages was significantly more frequent compared with that in the early stage in EOSPE. In LOSPE, the infarct in the early stage was significantly increased compared with transitional and late stages. The expression of α‑SMA mRNA and protein was determined by RT‑PCR and western blotting, respectively, and increased progressively in late, transitional and early infarct, and positively correlated with the number of smooth muscle cells of villous vessels and myofibroblasts of villous stroma studied by immunohistochemistry. These results indicated that multifocal infarct and multifocal villous clumps may affect the blood flow through the basal plate, not only by directly blocking vessels, but also by indirectly making the vessels extruded by contraction of cells stained by α‑SMA. In addition, foci in the early stage may be more important in affecting the contractility of the placental basal plate.