Imidazole-pyridine hybrids as potent anti-cancer agents.

In the current investigation, fifteen novel imidazole-pyridine-based molecules were synthesized and tested against cell lines of the lung (H1299) and colon (HCT116) adenocarcinomas by proliferation assay. The results demonstrated that compounds 5a, 5d, 5e, and 5f were the most active (IC50<30 µM). Based on recent literature and the current results, the glycogen synthase kinase-3ß (GSK-3ß) protein was investigated in-silico as a possible target. The molecular docking and QSAR revealed an excellent binding affinity of the selected imidazole-pyridine compounds to GSK-3ß. Notably, GSK-3ß protein levels were significantly upregulated in hepatocellular liver carcinoma (LIHCs) tissues and negatively affected patient prognosis. Consequently, the compounds were evaluated on liver cancer cell lines (HepG2, HUH-7, and PLC/PRF/5) by the MTT assay, and 5d showed the highest antitumor activity. This study offers new compounds with interesting biological activity on GSK-3ß as a target, exhibiting a potential therapeutic impact for hepatocellular carcinoma patients.

Persistent Herpes Simplex Virus Type 1 Infection of Enteric Neurons Triggers CD8+ T Cell Response and Gastrointestinal Neuromuscular Dysfunction.

Behind the central nervous system, neurotropic viruses can reach and persist even in the enteric nervous system (ENS), the neuronal network embedded in the gut wall. We recently reported that immediately following orogastric (OG) administration, Herpes simplex virus (HSV)-1 infects murine enteric neurons and recruits mononuclear cells in the myenteric plexus. In the current work, we took those findings a step forward by investigating the persistence of HSV-1 in the ENS and the local adaptive immune responses against HSV-1 that might contribute to neuronal damage in an animal model. Our study demonstrated specific viral RNA transcripts and proteins in the longitudinal muscle layer containing the myenteric plexus (LMMP) up to 10 weeks post HSV-1 infection. CD3+CD8+INFγ+ lymphocytes skewed towards HSV-1 antigens infiltrated the myenteric ganglia starting from the 6th week of infection and persist up to 10 weeks post-OG HSV-1 inoculation. CD3+CD8+ cells isolated from the LMMP of the infected mice recognized HSV-1 antigens expressed by infected enteric neurons. In vivo, infiltrating activated lymphocytes were involved in controlling viral replication and intestinal neuromuscular dysfunction. Indeed, by depleting the CD8+ cells by administering specific monoclonal antibody we observed a partial amelioration of intestinal dysmotility in HSV-1 infected mice but increased expression of viral genes. Our findings demonstrate that HSV-1 persistently infects enteric neurons that in turn express viral antigens, leading them to recruit activated CD3+CD8+ lymphocytes. The T-cell responses toward HSV-1 antigens persistently expressed in enteric neurons can alter the integrity of the ENS predisposing to neuromuscular dysfunction.

Secondary metabolic profiles and anticancer actions from fruit extracts of immature pomegranates.

Immature fruits from Punica granatum L. thinning are a neglected side product of pomegranate production with cumbersome disposal costs for farmers. To explore value potential of immature fruits from pomegranate 'Wonderful' cultivars, the compositional landscapes and antitumorigenic activities of pomegranate extracts from two different stages of maturation were assessed. Cancer cell proliferation and cytotoxicity was quantified in human lung H1299 and colon HCT116 adenocarcinomas by crystal violet staining, MTS assay and caspase-3 activity. High performance liquid chromatography-diode array detector (HPLC/DAD) and high performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC/ESI-MS) analyses indicate that immature fruits are rich sources of gallotannins and ellagitannins, with the highest amounts contained in immature fruit peels. Biological investigations reveal a robust anticancer activity by those immature P. granatum fruit extracts, which reflected induction of tumor cytotoxicity and cell death mechanisms. Together, present observations suggest P. granatum byproducts from the thinning process may provide unexplored values for virtuous circular economy.

Multifunctional, CD44v6-Targeted ORMOSIL Nanoparticles Enhance Drugs Toxicity in Cancer Cells.

Drug-loaded, PEGylated, organic-modified silica (ORMOSIL) nanoparticles prepared by microemulsion condensation of vinyltriethoxysilane (VTES) were investigated as potential nanovectors for cancer therapy. To target cancer stem cells, anti-CD44v6 antibody and hyaluronic acid (HA) were conjugated to amine-functionalized PEGylated ORMOSIL nanoparticles through thiol-maleimide and amide coupling chemistries, respectively. Specific binding and uptake of conjugated nanoparticles were studied on cells overexpressing the CD44v6 receptor. Cytotoxicity was subsequently evaluated in the same cells after the uptake of the nanoparticles. Internalization of nanocarriers loaded with the anticancer drug 3N-cyclopropylmethyl-7-phenyl-pyrrolo- quinolinone (MG2477) into cells resulted in a substantial increase of the cytotoxicity with respect to the free formulation. Targeting with anti-CD44v6 antibodies or HA yielded nanoparticles with similar effectiveness, in their optimized formulation.