Hesperetin and Capecitabine Abate 1,2 Dimethylhydrazine-Induced Colon Carcinogenesis in Wistar Rats via Suppressing Oxidative Stress and Enhancing Antioxidant, Anti-Inflammatory and Apoptotic Actions.

Colon cancer is a major cause of cancer-related death, with significantly increasing rates of incidence worldwide. The current study was designed to evaluate the anti-carcinogenic effects of hesperetin (HES) alone and in combination with capecitabine (CAP) on 1,2 dimethylhydrazine (DMH)-induced colon carcinogenesis in Wistar rats. The rats were given DMH at 20 mg/kg body weight (b.w.)/week for 12 weeks and were orally treated with HES (25 mg/kg b.w.) and/or CAP (200 mg/kg b.w.) every other day for 8 weeks. The DMH-administered rats exhibited colon-mucosal hyperplastic polyps, the formation of new glandular units and cancerous epithelial cells. These histological changes were associated with the significant upregulation of colon Ki67 expression and the elevation of the tumor marker, carcinoembryonic antigen (CEA), in the sera. The treatment of the DMH-administered rats with HES and/or CAP prevented these histological cancerous changes concomitantly with the decrease in colon-Ki67 expression and serum-CEA levels. The results also indicated that the treatments with HES and/or CAP showed a significant reduction in the serum levels of lipid peroxides, an elevation in the serum levels of reduced glutathione, and the enhancement of the activities of colon-tissue superoxide dismutase, glutathione reductase and glutathione-S-transferase. Additionally, the results showed an increase in the mRNA expressions of the anti-inflammatory cytokine, IL-4, as well as the proapoptotic protein, p53, in the colon tissues of the DMH-administered rats treated with HES and/or CAP. The TGF-ß1 decreased significantly in the DMH-administered rats and this effect was counteracted by the treatments with HES and/or CAP. Based on these findings, it can be suggested that both HES and CAP, singly or in combination, have the potential to exert chemopreventive effects against DMH-induced colon carcinogenesis via the suppression of oxidative stress, the stimulation of the antioxidant defense system, the attenuation of inflammatory effects, the reduction in cell proliferation and the enhancement of apoptosis.

WRH-2412 alleviates the progression of hepatocellular carcinoma through regulation of TGF-ß/ß-catenin/α-SMA pathway.

Hepatocellular carcinoma is considered one of the most lethal cancers, which is characterised by increasing prevalence associated with high level of invasion and metastasis. The novel synthetic pyrazolo[3,4-b]pyridine compound, WRH-2412, was reported to exhibit in vitro antitumor activity. This study was conducted to evaluate the antitumor activity of WRH-2412 in HCC induced in rats through affecting the TGF-ß/ß-catenin/α-SMA pathway. Antitumor activity of WRH-2412 was evaluated by calculating the rat's survival rate and by assessment of serum α-fetoprotein. Protein expression of TGF-ß, ß-catenin, E-cadherin, fascin and gene expression of SMAD4 and α-SMA were determined in hepatic tissue of rats. WRH-2412 produced antitumor activity by significantly increasing the rats' survival rate and decreasing serum α-fetoprotein. WRH-2412 significantly reduced an HCC-induced increase in hepatic TGF-ß, ß-catenin, SMAD4, fascin and α-SMA expression. In addition, WRH-2412 significantly increased hepatic E-cadherin expression.

Silybum marianum total extract, silymarin and silibinin abate hepatocarcinogenesis and hepatocellular carcinoma growth via modulation of the HGF/c-Met, Wnt/ß-catenin, and PI3K/Akt/mTOR signaling pathways.

Hepatocellular carcinoma (HCC) has been identified as one of the most deadly malignancies with limited therapeutic efficacy worldwide. However, understanding the molecular mechanisms of crosstalk between signaling pathways in HCC and predicting cancer cell responses to targeted therapeutic interventions remain to be challenge. Thus, in this study, we aimed to evaluate the anticancerous efficacy of Silybum marianum total extract (STE), silymarin (Sm), and silibinin (Sb) against experimentally-induced HCC in rats. In vitro investigations were also performed and the anticancer effects against HCC cell lines (HepG2 and Huh7) were confirmed. Wistar rats were given diethylnitrosamine (DEN)/2-acetylaminofluorene (AAF)/carbon tetrachloride (CCl4) and were orally treated with STE (200 mg/kg body weight (bw)), Sm (150 mg/kg bw), and Sb (5 mg/kg bw) every other day from the 1st or 16th week to the 25th week of DEN/AAF/CCl4 injection. Treatment with STE, Sm, and Sb inhibited the growth of cancerous lesions in DEN/AAF/CCl4-treated rats. This inhibition was associated with inhibition of Ki-67 expression and repression of HGF/cMet, Wnt/ß-catenin, and PI3K/Akt/mTOR signaling pathways. STE, Sm, and Sb improved liver function biomarkers and tumor markers (AFP, CEA, and CA19.9) and increased total protein and albumin levels in serum. STE, Sm, and Sb treatment was also noted to reduce the hepatic production of lipid peroxides, increase hepatic glutathione content, and induce the activities of hepatic antioxidant enzymes in DEN/AAF/CCl4-treated rats. These results indicate that STE, Sm, and Sb exert anti-HCC effects through multiple pathways, including suppression of Ki-67 expression and HGF/cMet, Wnt/ß-catenin, and PI3K/Akt/mTOR pathways and enhancement of antioxidant defense mechanisms.

Intratracheally Inhalable Nifedipine-Loaded Chitosan-PLGA Nanocomposites as a Promising Nanoplatform for Lung Targeting: Snowballed Protection via Regulation of TGF-ß/ß-Catenin Pathway in Bleomycin-Induced Pulmonary Fibrosis.

Pulmonary fibrosis is a serious ailment that may progress to lung remodeling and demolition, where the key participants in its incidence are fibroblasts responding to growth factors and cellular calcium swinging. Calcium channel blockers, like nifedipine (NFD), may represent auspicious agents in pulmonary fibrosis treatment. Unfortunately, NFD bears complicated pharmacodynamics and a diminished systemic bioavailability. Thus, the current study aimed to develop a novel, non-invasive nanoplatform for NFD for direct/effective pulmonary targeting via intratracheal instillation. A modified solvent emulsification-evaporation method was adopted for the fabrication of NFD-nanocomposites, integrating poly(D,L-lactide-co-glycolide) (PLGA), chitosan (CTS), and polyvinyl alcohol, and optimized for different physiochemical properties according to the 32 full factorial design. Additionally, the aerodynamic behavior of the nanocomposites was scrutinized through cascade impaction. Moreover, the pharmacokinetic investigations were conducted in rats. Furthermore, the optimum formulation was tested in bleomycin-induced pulmonary fibrosis in rats, wherein fibrotic and oxidative stress parameters were measured. The optimum nanocomposites disclosed a nanosized spherical morphology (226.46 nm), a high entrapment efficiency (61.81%) and a sustained release profile over 24 h (50.4%). As well, it displayed a boosted in vitro lung deposition performance with a mass median aerodynamic diameter of 1.12 µm. Pharmacokinetic studies manifested snowballed bioavailability of the optimal nanocomposites by 3.68- and 2.36-fold compared to both the oral and intratracheal suspensions, respectively. The intratracheal nanocomposites revealed a significant reduction in lung fibrotic and oxidative stress markers notably analogous to normal control besides repairing abnormality in TGF-ß/ß-catenin pathway. Our results conferred a compelling proof-of-principle that NFD-CTS-PLGA nanocomposites can function as a promising nanoparadigm for pulmonary fibrosis management.

Tackling of Renal Carcinogenesis in Wistar Rats by Silybum marianum Total Extract, Silymarin, and Silibinin via Modulation of Oxidative Stress, Apoptosis, Nrf2, PPARγ, NF-κB, and PI3K/Akt Signaling Pathways.

The present work was designed to assess the efficacy of Silybum marianum total extract (STE), silymarin (Sm), and silibinin (Sb) against experimentally induced renal carcinogenesis in male Wistar rats and their roles in regulating oxidative stress, inflammation, apoptosis, and carcinogenesis. The diethylnitrosamine (DEN)/2-acetylaminofluorene (AAF)/carbon tetrachloride (CCl4)-administered rats were orally treated with STE (200 mg/kg b.w.), Sm (150 mg/kg b.w.), and Sb (5 mg/kg b.w.) every other day either from the 1st week or from the 16th week of carcinogen administration to the end of 25th week. The treatments with STE, Sm, and Sb attenuated markers of toxicity in serum, decreased kidney lipid peroxidation (LPO), and significantly reinforced the renal antioxidant armory. The biochemical results were further confirmed by the histopathological alterations. The treatments also led to suppression of proinflammatory mediators such as NF-κß, p65, Iκßα, and IL-6 in association with inhibition of the PI3K/Akt pathway. Furthermore, they activated the expressions of PPARs, Nrf2, and IL-4 in addition to downregulation of apoptotic proteins p53 and caspase-3 and upregulation of antiapoptotic mediator Bcl-2. The obtained data supply potent proof for the efficacy of STE, Sm, and Sb to counteract renal carcinogenesis via alteration of varied molecular pathways.

Pyrazolo[3,4-d]pyrimidine-based dual EGFR T790M/HER2 inhibitors: Design, synthesis, structure-activity relationship and biological activity as potential antitumor and anticonvulsant agents.

A new series of pyrazolo[3,4-d]pyrimidine/triazine hybrids 6a-r was designed as antitumor and anticonvulsant agents. All the prepared compounds were evaluated against colon (HCT-116), breast (MCF-7) and normal human fibroblast (WI38) cell lines. The most potent derivatives against HCT-116 and MCF-7 cells were 6o and 6q, with IC50 = 4.80 and 6.50 nM, respectively, when compared to lapatinib, the reference drug (IC50 = 12.00 and 21.00 nM, on HCT-116 and MCF-7, sequentially). All other derivatives exhibited good to moderate cytotoxic activity. Four compounds 6f, 6j, 6o and 6q were evaluated for their EGFR T790M/HER2 inhibitory activity. They revealed 81.81-65.70% and 86.66-54.49% inhibitory activity against EGFR T790M and HER2 in a sequent. The most potent derivatives 6o and 6q were further estimated for cell cycle analysis showing pre G1 apoptotic activity and cell growth arrest at G2/M phase. Apoptotic marker proteins expression levels (caspase-3/7/9, Bax and Bcl-2) were measured for 6o and 6q. They showed pro-apoptotic effect by increasing caspase-3/7/9 protein levels and Bax/Bcl-2 ratio. Moreover, anticonvulsant activity for the prepared compounds 6a-r were evaluated in vivo using lithium-pilocarpine mice model of Status Epilepticus. EEG changes where recorded and MDA, GSH, GABA and glutamate were measured in brain tissue of different groups. All tested compounds revealed variable anti-epileptic effects, the most potent compounds were 6b and 6m. Also 6d, 6e, 6h, 6i, 6k, 6l and 6n compounds exhibited good anti-seizure activity, while compound 6j showed the lower activity. The rest of compounds displayed a neutral activity.