Gingerol and/or sorafenib attenuates the DAB-induced HCC and hepatic portal vein dilatation via ATG4/CASP3 and COIIV/COX-2/NF-κB expression.

Ginger (Gin) has numerous therapeutic properties. One of Gin's most potent components is 6-gingerol, a naturally occurring phenol. This study aimed to investigate the therapeutic impact of gingerol and/or sorafenib on the ATG4/CASP3 and COIIV/COX-2/NF-B Expression as a potential therapy for DAB-induced HCC. Gin was administered to HCC mice induced by p-Dimethylaminoazobenzene (DAB) alone or combined with sorafenib (Sor). Superoxide dismutase (SOD), catalase (CAT), and oxidative stress malondialdehyde (MDA), as well as biochemical markers including AST, ALT, ALP, Albumin, and Bilirubin, were examined. The expression of oncogenes (COIIV, COX-2, NF-κB, and survivin) and tumor suppressor genes (ATG4 and CASP3) was evaluated using qPCR. According to the results, the levels of MDA have been markedly decreased, while SOD and CAT have been increased. Further, the expression levels of tumor suppressor genes were upregulated, whereas the expression levels of oncogene genes were downregulated. Furthermore, in a dose-dependent manner, gingerol has shown the potential to alleviate hepatic portal vein (PV) dilatation and could offer a reliable therapy for HCC. This suggests combining the two compounds may be more effective than alone and that Gin could be a promising therapeutic option for HCC. The binding of Gin and Sor to the active sites of the target genes prevents them from functioning normally, which in turn stops the pathways from carrying out their oncogenic functions. Additionally, COX-2 inhibition reduces the production of certain pro-inflammatory compounds, which further averts oncogenesis. Conclusively, this study indicated that Gin has cytoprotective properties and anti-cancer activity that may be related to controlling oxidative stress. This effect may be achieved by suppressing the COIIV/COX-2/NF-κB pathway and upregulating the ATG4 /CASP3 pathways.

Hepatocellular Carcinoma cells: activity of Amygdalin and Sorafenib in Targeting AMPK /mTOR and BCL-2 for anti-angiogenesis and apoptosis cell death.

BACKGROUND: Sorafenib (Sor) is the only approved multikinase inhibitor indicated for the treatment of HCC. Previous studies have shown that amygdalin (Amy) possesses anticancer activities against several cancer cell lines; we suggested that these compounds might disrupt AMPK/mTOR and BCL-2. Therefore, the current study used integrated in vitro and in silico approaches to figure out Amy and Sor's possible synergistic activity in targeting AMPK/mTOR and BCL-2 for anti-angiogenesis and apoptosis cell death in HepG2 cells. RESULTS: Notably, Amy demonstrated exceptional cytotoxic selectivity against HepG2 cells in comparison to normal WI-38 cells (IC50 = 5.21 mg/ml; 141.25 mg/ml), respectively. In contrast, WI-38 cells were far more sensitive to the toxicity of Sor. A substantial synergistic interaction between Amy and Sor was observed (CI50 = 0.56), which was connected to cell cycle arrest at the S and G2/M stages and increased apoptosis and potential necroptosis. Amy and Sor cotreatment resulted in the highest glutathione levels and induction of pro-autophagic genes AMPK, HGMB1, ATG5, Beclin 1, and LC3, suppressed the mTOR and BCL2 anti-apoptotic gene. Finally, the docking studies proposed that Amy binds to the active site of the AMPK enzyme, thus inhibiting its activity. This inhibition of AMPK ultimately leads to inhibition of mTOR and thus induces apoptosis in the HepG2 cells. CONCLUSION: Although more in vivo research using animal models is needed to confirm the findings, our findings contribute to the evidence supporting Amy's potential anticancer effectiveness as an alternative therapeutic option for HCC.

Diarylheptanoids/sorafenib as a potential anticancer combination against hepatocellular carcinoma: the p53/MMP9 axis of action.

Hepatocellular carcinoma (HCC) is a serious and potentially fatal form of cancer associated with liver damage. New anticancer drugs are increasingly needed due to the increasing number of cancer cases every year. In this study, diarylheptanoids (DAH) from Alpinia officinarum were examined for their antitumor activity against DAB-induced HCC in mice, as well as their ability to reduce liver damage. Assays for cytotoxicity were conducted using MTT. The DAB-induced HCC Swiss albino male mice were given DAH and sorafenib (SOR) either as single treatments or in combination, and the effects on tumour development and progression were monitored. Malondialdehyde (MDA) and total superoxide dismutase (T-SOD) were evaluated along with biomarkers of liver enzymes (AST, ALT, and GGT). The apoptosis-related gene (CASP8), the apoptosis-related gene (p53), the anti-inflammatory genes (IL-6), the migration-related gene matrix metalloprotease-9 (MMP9), and the angiogenesis-related gene vascular endothelial growth factor (VEGF) were assessed using qRT-PCR in the hepatic tissue. As a final step, DAH and SOR were docked with CASP8 and MMP9 via molecular docking to propose potential mechanisms of action. Our results revealed that the combination of DAH and SOR has a potent inhibitory effect on the growth and viability of the HepG2 cell line. The outcomes demonstrated that DAH and SOR-treated HCC-bearing mice displayed a reduction in the tumour burden and liver damage as demonstrated by (1) parameters of repaired liver function; (2) low levels of hepatic MDA; (3) elevated levels of hepatic T-SOD; (4) p53, IL-6, CASP8, MMP9, and VEGF downregulation; and (5) enhanced hepatic structure. The best results were revealed in mice that were co-treated with DAH (given orally) and SOR (given intraperitoneally). The docking study also proposed that both DAH and SOR could inhibit CASP8 and MMP9's oncogenic activities and had a high affinity for these enzymes. In conclusion, according to study findings, DAH enhances SOR antiproliferative and cytotoxic effects and identifies their molecular targets. Furthermore, the results revealed that DAH was able to boost the anticancer effects of the drug SOR and reduce liver damage caused by HCC in mice. This suggests that DAH could be a potential therapeutic agent against liver cancer.

Modulation of the oxidative damage, inflammation, and apoptosis-related genes by dicinnamoyl-L-tartaric acid in liver cancer.

Cancer cells can become resistant to existing treatments over time, so it is important to develop new treatments that target different pathways to stay ahead of this resistance. Many cancer treatments have severe side effects that can be debilitating and even life-threatening. Developing drugs that can effectively treat cancer while minimizing the risks of these side effects is essential for improving the quality of life of cancer patients. The study was designed to explore whether the combination of dicinnamoyl-L-tartaric (CLT) and sorafenib ((SOR), an anti-cancer drug)) could be used to treat hepatocellular carcinoma (HCC) in the animal model and to assess whether this combination would lead to changes in certain biomarkers associated with the tumour. In this study, 120 male mice were divided into 8 groups of 15 mice each. A number of biochemical parameters were measured, including liver functions, oxidative stress (malondialdehyde, (MDA); nitric oxide (NO)), and antioxidative activity (superoxide dismutase (SOD), and glutathione peroxidase (GPx)). Furthermore, the hepatic expressions of Bax, Beclin1, TNF-α, IL1ß, and BCl-2 genes were evaluated by qRT-PCR. The combination of SOR and CLT was found to reduce the levels of liver enzymes, such as AST, ALT, ALP, and GGT, and reduce the pathological changes caused by DAB and PB. The upregulation of TNF-α, IL1ß, and Bcl-2 genes suggests that the CLT was able to initiate an inflammatory response to combat the tumor, while the downregulation of the Bax and Beclin1 genes indicates that the CLT was able to reduce the risk of apoptosis in the liver. Furthermore, the combination therapy led to increased expression of cytokines, resulting in an enhanced anti-tumor effect.

Evaluation of Bacillus aryabhattai B8W22 peroxidase for phenol removal in waste water effluents.

Environmental contamination by phenol has been reported in both aquatic and atmospheric environments. This study aimed to separate and purify the peroxidase enzyme from bacteria that degrade phenol from wastewater sources. An enrichment culture of MSM was used to screen 25 bacterial isolates from different water samples for peroxidase production, six of the isolates exhibited high levels of peroxidase enzyme activity. Qualitative analysis of peroxidase revealed that isolate No. 4 had the highest halo zones (Poly-R478: 14.79 ± 0.78 mm, Azure B: 8.81 ± 0.61 mm). The promising isolate was identified as Bacillus aryabhattai B8W22 by 16S rRNA gene sequencing with accession number OP458197. As carbon and nitrogen sources, mannitol and sodium nitrate were utilized to achieve maximum peroxidase production. A 30-h incubation period was used with pH 6.0, 30 °C, mannitol, and sodium nitrate, respectively, for maximal production of peroxidase. Purified peroxidase enzyme showed 0.012 U/mg specific activity, and SDS-PAGE analysis indicated a molecular weight of 66 kDa. The purified enzyme exhibits maximum activity and thermal stability at pH values of 4.0 and 8.0, respectively, with maximum activity at 30 °C and complete thermal stability at 40 °C. In the purified enzyme, the Km value was 6.942 mg/ml and the Vmax value was 4.132 mol/ml/hr, respectively. The results demonstrated that Bacillus aryabhattai B8W22 has promising potential for degrading phenols from various phenol-polluted wastewater sources.

Thymoquinone, piperine, and sorafenib combinations attenuate liver and breast cancers progression: epigenetic and molecular docking approaches.

BACKGROUND: Traditional herbal medicine has been used for centuries to cure many pathological disorders, including cancer. Thymoquinone (TQ) and piperine (PIP) are major bioactive constituents of the black seed (Nigella sativa) and black pepper (Piper nigrum), respectively. The current study aimed to explore the potential chemo-modulatory effects, mechanisms of action, molecular targets, and binding interactions after TQ and PIP treatments and their combination with sorafenib (SOR) against human triple-negative breast cancer (MDA-MB-231) and liver cancer (HepG2) cells. METHODS: We determined drug cytotoxicity by MTT assay, cell cycle, and death mechanism by flow cytometry. Besides, the potential effect of TQ, PIP, and SOR treatment on genome methylation and acetylation by determination of DNA methyltransferase (DNMT3B), histone deacetylase (HDAC3) and miRNA-29c expression levels. Finally, a molecular docking study was performed to propose potential mechanisms of action and binding affinity of TQ, PIP, and SOR with DNMT3B and HDAC3. RESULTS: Collectively, our data show that combinations of TQ and/or PIP with SOR have significantly enhanced the SOR anti-proliferative and cytotoxic effects depending on the dose and cell line by enhancing G2/M phase arrest, inducing apoptosis, downregulation of DNMT3B and HDAC3 expression and upregulation of the tumor suppressor, miRNA-29c. Finally, the molecular docking study has identified strong interactions between SOR, PIP, and TQ with DNMT3B and HDAC3, inhibiting their normal oncogenic activities and leading to growth arrest and cell death. CONCLUSION: This study reported TQ and PIP as enhancers of the antiproliferative and cytotoxic effects of SOR and addressed the mechanisms, and identified molecular targets involved in their action.

Amygdalin potentiates the anti-cancer effect of Sorafenib on Ehrlich ascites carcinoma and ameliorates the associated liver damage.

The burden of cancer diseases is increasing every year, therefore, the demands to figure out novel drugs that can retain antitumor properties have been raised. This study aimed to investigate the anti-tumor properties of amygdalin (Amy) against Ehrlich ascites carcinoma (EAC) bearing mice and its protective properties against liver damage. Amy and the standard anticancer drug Sorafenib (Sor) were given alone or in combination to Swiss albino female mice that had been injected with EAC cells. Biochemical parameters of liver function (AST, ALT, GGT, total protein, albumin), tumor volume, oxidative stress [malondialdehyde, (MDA)] and antioxidative [superoxide dismutase (SOD), and reduced glutathione (GSH)] markers were measured. The hepatic expression of the antioxidant-related gene [nuclear factor erythroid-2-related factor 2 (Nrf2)], the migration-related gene [matrix metalloprotease 9 (MMP9)], and the angiogenesis-related gene [vascular endothelial growth factor (VEGF)] were evaluated by qPCR. The results revealed that EAC-bearing mice treated with Amy and/or Sor showed a decrease in the tumor burden and hepatic damage as evidenced by (1) decreased tumor volume, number of viable tumor cells; (2) increased number of dead tumor cells; (3) restored the liver function parameters; (4) reduced hepatic MDA levels; (5) enhanced hepatic GSH and SOD levels; (6) upregulated expression of Nrf2; (7) downregulated expression of MMP9 and VEGF, and (8) improved hepatic structure. Among all treatments, mice co-treated with Amy (orally) and Sor (intraperitoneally) showed the best effect. With these results, we concluded that the Amy improved the antitumor effect of Sor and had a protective role on liver damage induced by EAC in mice.