Chronic kidney disease (CKD) is linked to an elevated fecal abundance of Enterobacteriaceae , but the ecological drivers of this shift and its impact on disease progression remain unclear. The uremic toxin indoxyl sulfate is produced from microbiota-derived indole in the liver. Here, we found that in mice with adenine-induced CKD, impaired clearance of indoxyl sulfate elevated mucosal expression of the gene encoding inducible nitric oxide synthase (iNOS). The resulting rise in luminal nitrate levels promoted Escherichia coli growth by means of nitrate respiration. Fecal microbiota from CKD patients generated more indole than feces of healthy controls during anaerobic culture, but only in the presence of nitrate. Nitrate enhanced indole production by E. coli , thereby worsening renal pathology in CKD mice, which was mitigated by iNOS inhibition.

Humans are frequently exposed to various carcinogens capable of inducing cancer in multiple organs. Phyllanthus emblica (P. emblica) is known for its strong antioxidant properties and potential in cancer prevention. However, its effectiveness against combined carcinogens remains relatively unexplored. This study aimed to assess the chemopreventive potential of the ethanolic extract of P. emblica fruits against preneoplastic lesions in the liver and colon using a rat model. Rats were administered with diethylnitrosamine (DEN) and 1,2-dimethylhydrazine (DMH) to induce hepato- and colon carcinogenesis, respectively. The ethanolic extract of P. emblica fruit at 100 and 500 mg/kg bw significantly reduced the number of preneoplastic lesions in the liver by 74.7% and 55.6%, respectively, and in the colon by 39.2% and 40.8%, respectively. Similarly, the extract decreased the size of preneoplastic lesions in the liver by 75.2% (100 mg/kg bw) and 70.6% (500 mg/kg bw). Furthermore, the extract significantly reduced the cell proliferation marker in the liver by 70.3% (100 mg/kg bw) and 61.54% (500 mg/kg bw), and in the colon by 62.7% (100 mg/kg bw) and 60.5% (500 mg/kg bw). The ethanolic extract also enhanced liver antioxidant enzyme activities and demonstrated free radical scavenging in DPPH, ABTS, and FRAP assays. Additionally, the dichloromethane fraction of P. emblica showed significant cancer prevention potential by reducing intracellular ROS and NO production by 61.7% and 35.4%, respectively, in RAW 264.7 macrophages. It also exhibited antimutagenic effects with a reduction of 54.0% against aflatoxin B1 and 52.3% against 2-amino-3,4-dimethylimidazo[4,5-f]quinoline-induced mutagenesis in Salmonella typhimurium. Finally, this study highlights the chemopreventive activity of P. emblica fruit extract against the initiation of early-stage carcinogenic lesions in the liver and colon in rats treated with dual carcinogens.

The incidence of multiple-organ cancers has recently increased due to simultaneous exposure to various environmental carcinogens. Houttuynia cordata Thunb. (H. cordata) is recognized for its many health benefits, including its anti-cancer properties. The fermentation of its leaves has been shown to significantly enhance the bioflavonoid content and its bioactivities. This study aimed to evaluate the effectiveness of fermented H.cordata leaf (FHCL) extracts against combined carcinogens and investigate the underlying mechanisms. The crude ethanolic extract of FHCL was partitioned to obtain hexane- (HEX), dichloromethane- (DCM), ethyl acetate- (ETAC), butanol- (nBA), and residue fractions. The crude ethanolic extract (200–250 μg/mL) and the DCM fraction (50 μg/mL) significantly reduced NO production in RAW264.7 macrophages. In addition, the crude extract and the DCM and ETAC fractions showed anti-genotoxicity against aflatoxin B₁ and 2-amino-3,4-dimethylimidazo [4,5-f]quinoline (MeIQ) in Salmonella typhimurium assays (S9+). Despite demonstrating genotoxicity in the Salmonella mutation assay (with and without S9 activation), oral administration of the crude extract at 500 mg/kg of body weight (bw) for 40 days in rats did not induce micronucleated hepatocytes, indicating that the extract is non-genotoxic in vivo. Moreover, the crude extract significantly decreased Phase I but increased Phase II xenobiotic-metabolizing enzyme activities in the rats. Next, the anti-cancer effects of FHCL were evaluated in a dual-organ carcinogenesis model of the colon and liver in rats induced by 1,2-dimethylhydrazine (DMH) and diethylnitrosamine (DEN), respectively. The crude extract significantly reduced not only the number and size of glutathione S-transferase placental form positive foci in the liver (at doses of 100 and 500 mg/kg bw) but also the number of aberrant crypt foci in rat colons (at 500 mg/kg bw). Furthermore, FHCL significantly reduced the expression of proliferating cell nuclear antigen (PCNA) in the colon (at 100 and 500 mg/kg bw) and liver (at 500 mg/kg bw) of the treated rats. In conclusion, FHCL exhibits significant preventive properties against colon and liver cancers in this dual-organ carcinogenesis model. Its mechanisms of action may involve anti-inflammatory effects, the prevention of genotoxicity, the modulation of xenobiotic-metabolizing enzymes, and the inhibition of cancer cell proliferation. These findings support the use of FHCL as a natural supplement for preventing cancer.

Background: Rice bran proteins and their hydrolysates exhibit anticancer activity. Our previous study demonstrated that Riceberry glutelin and its hydrolysates possessed potent in vitro antioxidant and antimutagenic properties. However, their cancer chemopreventive effects in animals remain unclear. Methods: This study investigated chemopreventive mechanisms in diethylnitrosamine (DEN)- and 1,2-dimethylhydrazine (DMH)-induced preneoplastic lesions, including glutathione S-transferase placental form (GST-P)-positive foci in the liver and aberrant crypt foci (ACF) in the colon of rats. Rats received GTL, GTLH, and total protein hydrolysate (TPH) at 500 mg/kg body weight, five days per week for ten weeks. Results: GTLH significantly reduced GST-P-positive foci in the liver and ACF in the colon, while GTL decreased GST-P-positive foci only in the liver. However, TPH did not affect preneoplastic lesions in both the liver and the colon. GTLH suppressed cell proliferation by reducing proliferating cell nuclear antigen (PCNA)-positive cells and promoted apoptosis, as indicated by an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells in both organs. GTL also decreased PCNA-positive cells in the liver and colon. Moreover, GTLH significantly upregulated BAX and CASP3 in the liver, while only BAX in the colon was observed. Conclusions: This study highlighted the cancer chemopreventive potential of Riceberry GTLH with its underlying mechanism to reduce the number of preneoplastic lesions in the liver and colon through cell proliferation inhibition and apoptosis induction. These findings suggested that this protein hydrolysate might be used as a functional food ingredient or dietary supplement for cancer prevention.