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Colorectal cancer is one of the most incident and lethal cancers in the world. The search for new compounds to treat this disease is being motivated by the occurrence of side effects and the rising in the resistance to chemotherapy. We synthesized a new class of conjugates bearing quinazolinone and melatonin which were prepared in good yields (63–93%) through one-pot three-component approach. quinazolinone/melatonin conjugates were proved against SW480 human colorectal adenocarcinoma cells and non-malignant colonic cells (NCM460). The cytotoxic and antiproliferative activities were determined through the sulforhodamine B assay. Compounds 1f, 1g and 1i–l displayed the best activity, being hybrids 1i–l the most selective against malignant cells, causing either a cytostatic and/or cytotoxic effect with evident morphological changes. Moreover, a theoretical drug-like/pharmacokinetics/toxicological study suggested that the hit-promising compounds 1i and 1j would have a great chance to advance to further preclinical studies as anti-cancer therapeutic candidate for oral oncological management. Our study evidently identified the potency of these quinazolinone/melatonin hybrids to be a prototype drug for further investigations toward novel therapeutics treatments of colorectal cancer. [ABSTRACT FROM AUTHOR]

Immature dentate granule cells (DGCs) generated in the hippocampus during adulthood are believed to play a unique role in dentate gyrus (DG) function. Although immature DGCs have hyperexcitable membrane properties in vitro, the consequences of this hyperexcitability in vivo remain unclear. In particular, the relationship between experiences that activate the DG, such as exploration of a novel environment (NE), and downstream molecular processes that modify DG circuitry in response to cellular activation is unknown in this cell population. We first performed quantification of immediate early gene (IEG) proteins in immature (5‐week‐old) and mature (13‐week‐old) DGCs from mice exposed to a NE. Paradoxically, we observed lower IEG protein expression in hyperexcitable immature DGCs. We then isolated nuclei from active and inactive immature DGCs and performed single‐nuclei RNA‐Sequencing. Compared to mature nuclei collected from the same animal, immature DGC nuclei showed less activity‐induced transcriptional change, even though they were classified as active based on expression of ARC protein. These results demonstrate that the coupling of spatial exploration, cellular activation, and transcriptional change differs between immature and mature DGCs, with blunted activity‐induced changes in immature cells. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma is the third leading cause of cancer death. Single or multiple mutations in genes related to growth control, apoptosis, invasion and metastasis have been determined; so a better understanding of the molecular genetic basis of malignant transformation, tumor progression and host interaction has led to significant progress in the development of new therapeutic agents. The ability of adenovirus vectors to deliver and express genes at high yields in HCC treatment has been demonstrated and well documented over the last few years. Objective: To overview and provide an update of what has been accomplished in the field of adenoviral gene therapy and its application in hepatocellular carcinoma treatment. Methods : Original articles were searched using Pubmed and other medical databases to get the most representative and actual information to establish the current state of the investigation of Ad vectors in HCC. Results : Good results have been accomplished in preclinical models using new Ad vectors and especially AAV vectors, it is important to motivate further clinical trials to corroborate all the experience obtained. Conclusions : Ad and AAV must be considered as an opportunity to improve the quality of life and survival of HCC patients. [ABSTRACT FROM AUTHOR]

The aim of this work was to establish a potential correlation between specific polymorphisms and presence of hepatic fibrosis in Mexican patients with established liver fibrosis (ELF). Second, necroinflammatory index improvement was correlated with Pirfenidone (PFD) treatment response and the same polymorphisms.We analyzed TGF-β polymorphisms in codon 25, a single basepair guanine insertion-deletion polymorphism (4G/5G) for PAI-1 and angiotensin AT-6 single nucleotide polymorphism located in -6 promoter region. Twenty patients infected with either hepatitis C virus (HCV) (n = 13) or affected by alcohol consumption (n= 7) were included. Thirty subjects with no hepatic damage were included in control group. Blood samples for genomic DNA were obtained and plasminogen activator inhibitor-1 polymorphisms were done by polymerase chain reaction-artificial introduction of a restriction site, TGF-β by polymerase chain reaction-amplification refractory mutation system and AT by polymerase chain reaction-restriction fragment length polymorphisms. Liver biopsies were obtained at baseline and after 12 months of PFD treatment.Established liver fibrosis patients had the homozygote G/G TGF-β genotype, which has been associated with increased development of fibrosis. None of our patients had the G/C genotype. All pure HCV and pure alcohol abuse subjects carried G/G TGF-β genotype (100% vs 37% control) (P = 0.0006). The odds of having TGF-β G/G genotype was 19.5 for HCV patients and 10.83 for alcohol consumption patients as compared with healthy subjects (P < 0.001). Established liver fibrosis patients had an improvement in necroinflammatory index after PFD treatment when correlated with plasminogen activator inhibitor-1 and angiotensinogen-6 genotypes.Our data suggested that a combination of inherited polymorphisms increased the risk of advanced fibrosis in ELF patients. Pure HCV and pure alcohol consumption patients which were homozygous G/G carriers had 19.5- and 10.8-fold higher risk to develop advanced fibrosis respectively.Abbreviations: TGF-β, transforming growth factor β; RAS, renin angiotensin system [ABSTRACT FROM AUTHOR]