A Drug Repurposing Screen Identifies Fludarabine Phosphate as a Potential Therapeutic Agent for N-MYC Overexpressing Neuroendocrine Prostate Cancers.

Neuroendocrine prostate cancer (NEPC) represents a highly aggressive form of prostate tumors. NEPC results from trans-differentiated castration-resistant prostate cancer (CRPC) with increasing evidence indicating that the incidence of NEPC often results from the adaptive response to androgen deprivation therapy. Recent studies have shown that a subset of NEPC exhibits overexpression of the MYCN oncogene along with the loss of tumor suppressing TP53 and RB1 activities. N-MYC is structurally disordered with no binding pockets available on its surface and so far, no clinically approved drug is available. We adopted a drug-repurposing strategy, screened ~1800 drug molecules, and identified fludarabine phosphate to preferentially inhibit the proliferation of N-MYC overexpressing NEPC cells by inducing reactive oxygen species (ROS). We also show that fludarabine phosphate affects N-MYC protein levels and N-MYC transcriptional targets in NEPC cells. Moreover, enhanced ROS production destabilizes N-MYC protein by inhibiting AKT signaling and is responsible for the reduced survival of NEPC cells and tumors. Our results indicate that increasing ROS production by the administration of fludarabine phosphate may represent an effective treatment option for patients with N-MYC overexpressing NEPC tumors.

Identification of suitable internal control genes for transcriptional studies in Eleusine coracana under different abiotic stress conditions.

Finger millet [Eleusine coracana (L.) Gaertn] is an excellent food and forage crop of arid and semiarid areas in Africa and Asia. It is well adapted to drought, heat, high salinity, poor soil fertility and low pH with an efficient C4 carbon fixation mechanism for high yield potential. To normalize the target gene expression data, the identification of suitable reference genes is essential. Ten candidate reference genes were selected and their expression stability was analyzed in various samples treated with different abiotic stress conditions. Five different statistical algorithms: geNorm, NormFinder, BestKeeper, ΔCt, and RefFinder were used to determine the stability of these genes. Our results revealed GAPDH, EEF1a, ACT and CYC as highly stable reference genes and PP2A and eIF4A as least stable reference genes across all the samples and suggesting that these genes could be used for accurate transcript normalization under abiotic stress. To the best of our knowledge, this is the first report on identification of suitable reference genes for accurate transcript normalization using qRT-PCR in finger millet under abiotic stress.

Conjugated linoleic acid enriched skim milk prepared with Lactobacillus fermentum DDHI27 endorsed antiobesity in mice.

AIM: This study evaluated the antiobesity effect of skim milk prepared with conjugated linoleic acid producing probiotic Lactobacillus fermentum DDHI27 (PCLA). MATERIALS & METHODS: C57BL/6 J mice were divided into five groups, and different obesity-associated parameters were studied. RESULTS: PCLA supplementation alleviated body weight, epididymal and mesenteric fats and improves lipid profiles. Significant ameliorations in leptin, blood glucose, hepatic steatosis and reduction in adipocytes size were also observed. Additionally, feeding also led to positive alterations in the adipogenesis transcription factors and key lipogenesis genes. Improvement in the gut microbiota dysbiosis was also revealed. CONCLUSION: Results inferred that PCLA exerted an antiobesity effect in diet-induced obese mice and may be further developed in the functional foods for the management of obesity.

Gut Microbiota Modulation and Its Relationship with Obesity Using Prebiotic Fibers and Probiotics: A Review.

In the present world scenario, obesity has almost attained the level of a pandemic and is progressing at a rapid rate. This disease is the mother of all other metabolic disorders, which apart from placing an added financial burden on the concerned patient also has a negative impact on his/her well-being and health in the society. Among the various plausible factors for the development of obesity, the role of gut microbiota is very crucial. In general, the gut of an individual is inhabited by trillions of microbes that play a significant role in host energy homeostasis by their symbiotic interactions. Dysbiosis in gut microbiota causes disequilibrium in energy homeostasis that ultimately leads to obesity. Numerous mechanisms have been reported by which gut microbiota induces obesity in experimental models. However, which microbial community is directly linked to obesity is still unknown due to the complex nature of gut microbiota. Prebiotics and probiotics are the safer and effective dietary substances available, which can therapeutically alter the gut microbiota of the host. In this review, an effort was made to discuss the current mechanisms through which gut microbiota interacts with host energy metabolism in the context of obesity. Further, the therapeutic approaches (prebiotics/probiotics) that helped in positively altering the gut microbiota were discussed by taking experimental evidence from animal and human studies. In the closing statement, the challenges and future tasks within the field were discussed.