Background: Doxorubicin (DOX) is a very powerful chemotherapy drug. However, its severe toxicity and potential for resistance development limit its application. Withania somnifera L. Dunal (WIT) has therapeutic capacities, including anti-inflammatory, antioxidant, and anticancer activities. This study investigates the preventative benefits of a standardized WIT extract against DOX-induced renal damage in vivo. We also investigate the synergistic effects of combining WIT and DOX to improve therapeutic efficacy in breast cancer cells (MCF7-ADR). Methods: This study employed an animal model where rats were administered 300 mg/kg/day of WIT orally for a duration of 14 days. Rats received DOX injections at a dose of 5 mg/kg, for a total of 15 mg, on the 6th, 8th, and 10th days. Results: Present results revealed that WIT reduced DOX-induced increase levels of blood urea and creatinine and the activity of kidney injury molecule-1. WIT also reduced renal tissue damage, oxidative stress, and levels of pro-inflammatory markers. WIT alleviated the effects of DOX on nuclear factor erythroid 2-related factor 2, heme oxygenase-1, and sirtuin 1 in the renal tissues. WIT modulated nuclear factor-κB activity and decreased apoptotic indicators. Furthermore, WIT improves DOX’s capacity to kill drug-resistant MCF7-ADR cells by arresting the cell cycle and promoting apoptosis. Chemical analysis of WIT root extract revealed 34 distinct compounds, including alkaloids, withanolides, flavanones, and fatty acids. Conclusions: These constituents synergistically contribute to WIT’s antioxidant, anti-inflammatory, and anti-apoptotic properties. In addition, they confirm its ability to reduce systemic toxicity while improving treatment efficacy.

The current research employed an animal model of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary gland carcinogenesis. The estrogen receptor-positive human breast adenocarcinoma cell line (MCF-7) was used for in vitro analysis. This was combined with a network pharmacology-based approach to assess the anticancer properties of Spirulina (SP) extract and understand its molecular mechanisms. The results showed that the administration of 1 g/kg of SP increased the antioxidant activity by raising levels of catalase (CAT) and superoxide dismutase (SOD), while decreasing the levels of malonaldehyde (MDA) and protein carbonyl. A histological examination revealed reduced tumor occurrence, decreased estrogen receptor expression, suppressed cell proliferation, and promoted apoptosis in SP protected animals. In addition, SP disrupted the G2/M phase of the MCF-7 cell cycle, inducing apoptosis and reactive oxygen species (ROS) accumulation. It also enhanced intrinsic apoptosis in MCF-7 cells by upregulating cytochrome c, Bax, caspase-8, caspase-9, and caspase-7 proteins, while downregulating Bcl-2 production. The main compounds identified in the LC-MS/MS study of SP were 7-hydroxycoumarin derivatives of cinnamic acid, hinokinin, valeric acid, and α-linolenic acid. These substances specifically targeted three important proteins: ERK1/2 MAPK, PI3K-protein kinase B (AKT), and the epidermal growth factor receptor (EGFR). Network analysis and molecular docking indicated a significant binding affinity between SP and these proteins. This was verified by Western blot analysis that revealed decreased protein levels of p-EGFR, p-ERK1/2, and p-AKT following SP administration. SP was finally reported to suppress MCF-7 cell growth and induce apoptosis by modulating the PI3K/AKT/EGFR and MAPK signaling pathways suggesting EGFR as a potential target of SP in breast cancer (BC) treatment.

Although praziquantel (PZQ) is the main antischistosomal drug currently in use, concerns remain regarding incomplete reversal of schistosomiasis-induced pathology and the emergence of drug resistance. This study evaluates the combined effect of PZQ with safranal, a bioactive saffron constituent, on Schistosoma mansoni-induced pathology in mice. Male CD1 Swiss albino mice were exposed to 60 S. mansoni cercariae and, at week 9 post-infection, were treated with PZQ (500 mg/kg orally for two consecutive days), safranal (50 mg/kg/day), or both, for three weeks. The animals were sacrificed at week 11 post-infection. Worm and egg burdens, liver histopathology, fibrotic markers, oxidative stress, and inflammatory cytokines were assessed. Combined PZQ + safranal therapy significantly reduced adult worm counts and hepatic and intestinal egg loads compared to PZQ alone. All treatments decreased liver index (hepatomegaly), with the combination treatment providing the best intervention. Histological analyses revealed significantly reduced granuloma size and hepatic necrosis post-treatment, particularly in the combination group. The levels of proinflammatory cytokines (TNF-α, IL-1β) and Th2 cytokines (IL-4, IL-5, IL-6, IL-10) were significantly lowered in treated mice, most notably with the combination treatment. Oxidative stress was also markedly attenuated, and infected mice exhibited elevated malondialdehyde and depleted antioxidant enzymes (SOD, CAT, GSH). Interestingly, PZQ and/or safranal restored antioxidant status and reduced lipid peroxidation, with the combination being most effective. Furthermore, collagen deposition and expression of hepatic fibrotic markers α-smooth muscle actin (α-SMA), TGF-β1, and matrix metalloproteinase-9 were most effectively suppressed by combined therapy. To conclude, safranal enhances PZQ’s antischistosomal efficacy and confers additive protection against Schistosoma-induced liver fibrosis.