Type-2 diabetes mellitus-associated cancer risk: In pursuit of understanding the possible link.

BACKGROUND AND AIM: The insulin resistance-mediated abnormal gluconeogenesis when exceeds a given threshold culminates in type 2 diabetes mellitus (T2DM). This induces severe cellular oxidative stress that may eventually facilitate typical neoplastic transformations. This narrative review aims to portray some of the plausible key mechanistic links bridging T2DM and specific cancers. METHODS: A thorough literature search was conducted in the PubMedCentral database to retrieve information from various reputed biomedical reports/articles published from the year 2000. The information regarding the key biochemical signaling pathways mediating the carcinogenic transformation, especially in T2DM patients, was extensively excavated to systematically compile and present a narrative review. RESULTS: T2DM-associated insulin resistance is known to negatively influence certain crucial genetic and metabolic components (such as insulin/IGFs, PI-3K/Akt, AMPK, and AGEs/RAGE) that may eventually lead to neoplastic transformation. In particular, the risk of developing cancers like pancreatic, colorectal, breast, liver, endometrial, and bladder seems to be more significant in T2DM patients. CONCLUSION: Despite the fact that several studies have suggested a possible correlation between T2DM and cancer mortality, a more detailed research at both pre-clinical and clinical levels is still required so as to fully understand the intricate relationship and make a precise conclusion.

Correction to: Antiobesity potential of Piperonal: promising modulation of body composition, lipid profiles and obesogenic marker expression in HFD-induced obese rats.

[This corrects the article DOI: 10.1186/s12986-017-0228-9.].

Antiobesity potential of Piperonal: promising modulation of body composition, lipid profiles and obesogenic marker expression in HFD-induced obese rats.

Background: Black pepper or Piper nigrum is a well-known spice, rich in a variety of bioactive compounds, and widely used in many cuisines across the world. In the Indian traditional systems of medicine, it is used to treat gastric and respiratory ailments. The purpose of this investigation is to study the antihyperlipidemic and antiobesity effects of piperonal in high-fat diet (HFD)-induced obese rats. Methods: Piperonal, an active constituent of Piper nigrum seeds, was isolated and confirmed by HPLC, 1H and 13C NMR spectroscopy. Male SD rats were fed on HFD for 22 weeks; Piperonal was supplemented from the 16th week as mentioned in the experimental design. Changes in body weight and body composition were measured by TOBEC, bone mineral composition and density were measured by DXA, and adipose tissue distribution was measured by 7 T-MRI. Plasma levels of glucose, insulin, insulin resistance and lipid profiles of plasma, liver and kidney, adipocyte hormones and liver antioxidants were evaluated using standard kit methods. Expression levels of adipogenic and lipogenic genes, such as PPAR-γ, FAS, Fab-4, UCP-2, SREBP-1c, ACC, HMG-COA and TNF-α were measured by RT-PCR. Histopathological examination of adipose and liver tissues was also carried out in experimental rats. Results: HFD substantially induced body weight, fat%, adipocyte size, circulatory and tissue lipid profiles. It elevated the plasma levels of insulin, insulin resistance and leptin but decreased the levels of adiponectin, BMC and BMD. Increased expression of PPAR-γ, FAS, Fab-4, UCP-2, SREBP-1c, ACC, and TNF-α was noticed in HFD-fed rats. However, supplementation of piperonal (20, 30 and 40 mg/kg b.wt) for 42 days considerably and dose-dependently attenuated the HFD-induced alterations, with the maximum therapeutic activity being noticed at 40 mg/kg b.wt. Conclusions: Piperonal significantly attenuated HFD-induced body weight and biochemical changes through modulation of key lipid metabolizing and obesogenic genes. Our findings demonstrate the efficacy of piperonal as a potent antiobesity agent, provide scientific evidence for its traditional use and suggest the possible mechanism of action.

Development of α-glucosidase inhibitors by room temperature C-C cross couplings of quinazolinones.

Novel quinazolinone based α-glucosidase inhibitors have been developed. For this purpose a virtual screening model has been generated and validated utilizing acarbose as a α-glucosidase inhibitor. Homology modeling, docking, and virtual screening were successfully employed to discover a set of structurally diverse compounds active against α-glucosidase. A search of a 3D database containing 22,500 small molecules using the structure based virtual model yielded ten possible candidates. All ten candidates were N-3-pyridyl-2-cyclopropyl quinazolinone-4-one derivatives, varying at the 6 position. This position was modified by Suzuki-Miyaura cross coupling with aryl, heteroaryl, and alkyl boronic acids. A catalyst screen was performed, and using the best optimal conditions, a series of twenty five compounds was synthesized. Notably, the C-C cross coupling reactions of the 6-bromo-2-cyclopropyl-3-(pyridyl-3-ylmethyl)quinazolin-4(3H)-one precursor have been accomplished at room temperature. A comparison of the relative reactivities of 6-bromo and 6-chloro-2,3-disubstituted quinazolinones with phenyl boronic acid was conducted. An investigation of pre-catalyst loading for the reaction of the 6-bromo-2-cyclopropyl-3-(pyridyl-3-ylmethyl)quinazolin-4(3H)-one substrate was also carried out. Finally, we submitted our compounds to biological assays against α-glucosidase inhibitors. Of these, three hits (compounds 4a, 4t and 4r) were potentially active as α-glucosidase inhibitors and showed activity with IC50 values <20 µM. Based on structural novelty and desirable drug-like properties, 4a was selected for structure-activity relationship study, and thirteen analogs were synthesized. Nine out of thirteen analogs acted as α-glucosidase inhibitors with IC50 values <10 µM. These lead compounds have desirable physicochemical properties and are excellent candidates for further optimization.