Sitagliptin (STG) is a highly selective dipeptidyl peptidase-4 inhibitor recently used in the treatment of type 2 diabetes. The current study aimed to investigate the anti-neoplastic effect of STG alone and in combination with Doxorubicin (Dox), a known chemotherapeutic agent but with ominous side effects. After intramuscular inoculation of 2 × 10⁶ Ehrlich tumor cells, Female Swiss mice were divided into tumor-bearing control, STG-treated, Dox-treated, and a combination of STG and Dox-treated groups. The results showed a significant reduction in the tumor growth of the treated animals in comparison with those of the positive control group with a more prominent effect in the co-treated group. Where, the anti-proliferative and apoptotic effect of STG, and its chemo-sensitizing ability, when used in combination with Dox, was mediated by modulation of oxidative stress (MDA and GSH), attenuation of tumor inflammation (IL-6 and IL-1β), and angiogenesis (VEGF), suppressing proliferation (β-catenin and cyclin-D1) and enhancement of apoptosis (survivin, p53, caspase 3). Thus, in conclusion, STG as adjunctive therapy for Dox could be a strategy for the treatment of breast cancer patients, by their ability in hindering cell proliferation and minimizing the associated oxidative and inflammatory adverse reactions.

Natural bioactive compounds with anti-neoplastic effects, such as celastrol (CLS), have attracted considerable interest in recent years. The present study aimed to investigate the effect of CLS on wnt/β-catenin signaling, and its potential combination with doxorubicin (Dox) to enhance chemotherapeutic effects. After intramuscular inoculation of Ehrlich tumor cells, tumor-bearing mice received CLS (2 mg/kg, i.p), Dox (5 mg/kg, once/week, i.p), and their combination for 21 days. Treatment with CLS showed showing antioxidant and anti-inflammatory, as evidenced by a significant increase in glutathione content and a significant decrease in the malondialdehyde, interleukin 6, and interleukin 1β concentrations. CLS also inhibited VEGF-mediated angiogenesis. The current study revealed that CLS downregulated β‐catenin gene expression with subsequent downstream target genes, such as cyclin-D1, and survivin, which dampens tumor cell proliferation and triggers cell cycle arrest as well as induces apoptosis as indicated by the increased expression of p53, caspase‐3. The current study concludes that CLS exerted its anti-neoplastic activity by suppressing the wnt/β-catenin signaling pathway, and opens a new perspective for combining CLS with Dox to enhance its chemotherapeutic effects and reduce the oxidative imbalance and inflammatory responses associated with Dox treatment.

Fibromyalgia (FM) is a chronic syndrome characterized by widespread pain, fatigue, cognitive dysfunction and neuropsychiatric disturbances, associated with dysregulated oxidative stress and neuroinflammation. Emerging evidence suggests that microRNAs guiding these pathways, including miR-145-5p and miR-451a, may play a central role in FM pathogenesis. However, currently available pharmacological therapies provide limited efficacy and are frequently associated with adverse effects. Therefore, the present study investigated whether the methanolic extract of Hibiscus sabdariffa (MeOH-Exs), a polyphenol rich extract with known antioxidant and anti-inflammatory properties, alleviates reserpine (Res)-induced FM in rats through modulation of the neuroinflammation-oxidative stress-microRNA axis. FM was induced by Res (1 mg/kg, s.c., for three days), followed by 28-day treatment with MeOH-Exs (25 or 50 mg/kg, p.o.) compared with the standard drug Neurontin (Neu). Behavioral assessments, serum hydrogen peroxide, brain serotonin, peripheral expression of miR-145-5p and miR-451a, and spinal cord inflammatory and histopathological alterations were evaluated. MeOH-Exs significantly improved hyperalgesia, depressive- and anxiety-like behaviors, locomotion, and cognition relative to the Res group. The 50 mg/kg dose exerted the most pronounced effects, restoring expression of miR-145-5p and miR-451a, reducing oxidative stress, and elevating brain serotonin levels. Histological and immunohistochemical analyses confirmed attenuation of spinal cord inflammation and neuronal degeneration, caspase 3 expression and TNF-α immunoreactivity with effects comparable to or greater than Neu. Collectively, these findings indicate that Hibiscus sabdariffa may ameliorate FM - like menifistations by targeting an integrated biochemical pathway linking oxidative stress, neuroinflammation, apoptosis, microRNA dysregulation and spinal cord histopathological alterations. While the precise molecular mechanisms require further investigation, MeOH-Exs demonstrates a promising multi-target neuroprotective profile and may represent a potential complementary preclinical therapeutic candidate for FM.