A well-known natural ingredient found in several medicinal plants, berberine (Ber), has been shown to have anticancer properties against a range of malignancies. The limited solubility and bioavailability of berberine can be addressed using Ber-loaded nanoparticles. In this study, we compared the in vitro cytotoxic effects of both Ber-loaded silver nanoparticles (Ber-AgNPs) and Ber-loaded selenium nanoparticles (Ber-SeNPs) in the human liver cancer cell line (HepG2) and mouse normal liver cells (BNL). The IC₅₀ values in HepG2 for berberine, Ber-AgNPs, Ber-SeNPs, and cisplatin were 26.69, 1.16, 0.04, and 0.33 µg/mL, respectively. Our results show that Ber and its Ag and Se nanoparticles exerted a good antitumor effect against HepG2 cells by inducing apoptosis via upregulating p53, Bax, cytosolic cytochrome C levels, and caspase-3 activity, and the down-regulation of Bcl-2 levels. Similarly, incubation with Ber and both Ber-NPs (Ag and Se) led to a significant dose-dependent elevation in inflammatory markers’ (TNF-α, NF-κB, and COX-2) levels compared to the control group. In addition, it led to the arrest of the G1 cell cycle by depleting the expression of cyclin D1 and CDK-2 mRNA. Furthermore, Ber and both Ber-NPs (Ag and Se) caused a significant dose-dependent increase in LDH activity in HepG2 cells. Furthermore, our findings offer evidence that Ber and its nanoparticles intensified oxidative stress in HepG2 cells. Furthermore, the migration rate of cells subjected to berberine and its nanoforms was notably decreased compared to that of control cells. It can be inferred that Ber nanoparticles exhibited superior anticancer efficacy against HepG2 compared to unprocessed Ber, perhaps due to their improved solubility and bioavailability. Furthermore, Ber-SeNPs exhibited greater efficacy than Ber-AgNPs, possibly as a result of the inherent anticancer characteristics of selenium.

Sildenafil is a potent phosphodiesterase-5 (PDE5) inhibitor that effectively inhibits cGMP and increases the strength of nitric oxide. PDE5 was overexpressed in several carcinomas, including breast cancer, which inhibited tumor growth and cell division. The current research aims to investigate the in vivo sildenafil's immunomodulatory and antineoplastic potentials against Ehrlich Ascites Carcinoma. This study looked at the effects of sildenafil mono-treatment and co-treatment with cisplatin; tumor cell count, viability and the inhibition rate were determined. Apoptosis, cell cycle distribution, alterations in tumor cells and splenocytes proliferation, changes in splenocytes immunophenotyping using flowcytometry, plasma levels of malondialdehyde (MDA), reduced glutathione (GSH), interferone (IFN)-γ, granzyme B, alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine and hematological alterations were detected. Additionally, docking study was conducted to get further insights on how Sildenafil exerts its activity. Sildenafil mono-treatment and co-treatment with cisplatin markedly reduced tumor cell count, viability, growth rate and proliferative capability accompanied by apoptosis enhancement and G₀/G₁ and sub G₁ cells cycle arrest. Fortunately, sildenafil evoked efficient cellular immune response by increasing plasma levels of granzyme B and IFN-γ, proportion of splenic T cytotoxic (CD3⁺CD8⁺) and T helper (CD3⁺CD4⁺), accompanied by decrease in the proportion of splenic regulatory T cells. . Moreover, in silico data suggest LcK and MAPKs as the potential targets of sildenafil. Furthermore, sildenafil rebalanced the oxidant-antioxidant status by decreasing MDA and increasing GSH plasma levels. Sildenafil successfully retrieved various hematological values besides renal and hepatic functions in EAC-bearing animals. In conclusion, our results suggest that sildenafil could be potential safe anti-tumor agent with immuno-modulatory properties against Ehrlich ascites carcinoma.

Objective: The existing study sought to highlight the modulatory effect of co-treatment based on grape seed extract (GSE) and L. ascorbic acid (AA) on tumor microenvironment and immune response in murine solid Ehrlich carcinoma (SEC). Methods: GSE (200 mg / kg; orally) and AA (50 mg/ kg; orally) were given either separately or in a combination for 14 days. GSE active metabolites were identified using GC-MS and LC-MS/MS. Tumor size, Ki-67, Caspase-3, intratumoral infiltrated CD4+, CD8+ and FOXP3+ cells were detected immunohistochemically. Oxidative stress of tumor cells was determined. Serum levels of IL-12, IFN-γ, IL-4 and IL-10 were detected using ELISA. Results and discussion: The results revealed treatment with GSE and/or AA markedly diminished tumor size, intensified intratumoral oxidative stress, downregulated tumor cell proliferation along with upregulated tumor cells’ apoptosis. GSE and AA enhanced tumor immune microenvironment through increasing CD8+ and CD4+ T cells accompanied by decreasing FOXP3+ Treg cells infiltrated in tumors. GSE and/ or AA moved Th1/Th2 balance in favor of Th1 as evidenced by increased serum levels of IFN-γ and IL-12 accompanied with decreased serum levels of IL-4 and IL-10. These findings may be attributed to the presence of different chemical scaffolds of phenolic acids, Flavan-3-ols and its glycosides, glycerolipids and its glycosides, glycosylated seco-iridoids, dihydrochalcone, stilbenoid, flavone, dihydroxyflavone, and methylated flavone, sugars, and fatty acids. In conclusion, results suggested that dual treatment based on GSE & AA are promising anticancer therapeutics, through their potency to control proliferation, induce apoptosis, intratumoral oxidative stress, modulate tumor immune microenvironment and shifting Th1/Th2 response toward Th1