Chemopreventive effect of a milk whey by-product derived from Buffalo (Bubalus bubalis) in protecting from colorectal carcinogenesis.

BACKGROUND: Several studies show that natural foods are a source of compounds with anticancer properties that affect the gut microbiota and its metabolites. In the present study, we investigate the effect of a delactosed buffalo milk whey by-product (DMW) on colorectal carcinogenesis. METHODS: The effect of DMW on colorectal carcinoma (CRC) was investigated in the established mouse model of azoxymethane (AOM)-induced colon carcinoma, which closely resembles the human clinical condition of CRC. The effect of DMW on CRC immortalized cell lines was also evaluated to further identify the antineoplastic mechanism of action. RESULTS: Pretreatment of AOM-treated mice with DMW significantly (P < 0.05) reduced the percentage of mice bearing both aberrant crypt foci with more than four crypts (which are early precancerous lesions that progress to CRC) and tumors. In addition, DMW completely counteracted the effect of AOM on protein expression of caspase-9, cleaved caspase-3 and poly ADP-ribose polymerase in colonic tissue. Administration of DMW alone (i.e. without AOM) resulted in changes in the composition of the gut microbiota, leading to enrichment or depletion of genera associated with health and disease, respectively. DMW was also able to restore AOM-induced changes in specific genera of the gut microbiota. Specifically, DMW reduced the genera Atopobiaceae, Ruminococcus 1 and Lachnospiraceae XPB1014 and increased the genera Parabacteroides and Candidatus Saccharimonas, which were increased and reduced, respectively, by AOM. Blood levels of butyric acid and cancer diagnostic markers (5-methylcytidine and glycerophosphocholine), which were increased by AOM treatment, were reduced by DMW. Furthermore, DMW exerted cytotoxic effects on two human CRC cell lines (HCT116 and HT29) and these effects were associated with the induction of apoptotic signaling. CONCLUSIONS: Our results suggest that DMW exerts chemopreventive effects and restores the gut microbiota in AOM-induced CRC, and induces cytotoxic effect on CRC cells. DMW could be an important dietary supplement to support a healthy gut microbiota and reduce the prevalence of CRC in humans. Video Abstract.

Efficacy of combined therapy with fish oil and phytocannabinoids in murine intestinal inflammation.

Fish oil (FO) and phytocannabinoids have received considerable attention for their intestinal anti-inflammatory effects. We investigated whether the combination of FO with cannabigerol (CBG) and cannabidiol (CBD) or a combination of all three treatments results in a more pronounced intestinal antiinflammatory action compared to the effects achieved separately. Colitis was induced in mice by 2,4-dinitrobenzenesulfonic acid (DNBS). CBD and CBG levels were detected and quantified by liquid chromatography coupled with time of flight mass spectrometry and ion trap mass spectrometry (LC-MS-IT-TOF). Endocannabinoids and related mediators were assessed by LC-MS. DNBS increased colon weight/colon length ratio, myeloperoxidase activity, interleukin-1ß, and intestinal permeability. CBG, but not CBD, given by oral gavage, ameliorated DNBS-induced colonic inflammation. FO pretreatment (at the inactive dose) increased the antiinflammatory action of CBG and rendered oral CBD effective while reducing endocannabinoid levels. Furthermore, the combination of FO, CBD, and a per se inactive dose of CBG resulted in intestinal anti-inflammatory effects. Finally, FO did not alter phytocannabinoid levels in the serum and in the colon. By highlighting the apparent additivity between phytocannabinoids and FO, our preclinical data support a novel strategy of combining these substances for the potential development of a treatment of inflammatory bowel disease.

Pharmacological insights and prediction of lead bioactive isolates of Dita bark through experimental and computer-aided mechanism.

Dita bark (Alstonia scholaris (L.) R. Br.) is an ethnomedicine used for the management of various ailments. This study aimed to investigate the biological properties of methanol extract of A. scholaris bark (MEAS), through in vivo, in vitro and in silico approaches alongside its phytochemical profiling. Identification and nature of the bioactive secondary metabolites were studied by the established qualitative tests and GC-MS analysis. The antidepressant activity was determined by forced swimming test (FST) and tail suspension test (TST) in mice. The anti-inflammatory and thrombolytic effect was evaluated using inhibition of protein denaturation technique and clot lysis technique, respectively. Besides, computational studies of the isolated compounds and ADME/T analysis were performed by Schrödinger-Maestro (v11.1) software, and PASS prediction was conducted through PASS online tools. The GC-MS analysis revealed the presence of several secondary metabolites in MEAS. Treatment with MEAS revealed a significant reduction of immobility time in a dose-dependent manner in FST and TST. Besides, MEAS showed substantial anti-inflammatory effects at the higher dose (400 µg/mL) as well as revealed notable clot lysis effect as compared to control. In the case of computer-aided investigation, all compounds meet the condition of Lipinski's rule of five. PASS study also predicted for all compounds, and among these safe compound furazan-3-amine showed the most spontaneous binding energy for both antidepressant and thrombolytic activities, as well as 5-dimethylamino-6 azauracil, found promising for anti-inflammatory activity. Taken together, the investigation concludes that MEAS can be a potent source of antidepressant, anti-inflammatory, and thrombolytic agents.