Cinnamaldehyde/lactulose combination therapy alleviates thioacetamide-induced hepatic encephalopathy via targeting P2X7R-mediated NLRP3 inflammasome signaling.

AIMS: Cinnamaldehyde (CA), the main active constituent of cinnamon oil, is reported to have neuroprotective effects. However, the potential benefits of CA for brain protection in hepatic encephalopathy (HE) are still not understood. Thus, the present study investigates the possible ameliorative effect of CA (70 mg/kg/day, I.P.) either alone or in combination with lactulose (Lac) (5.3 g/kg/day, oral) against thioacetamide (TAA)-induced hepatic encephalopathy in rats. MATERIALS AND METHODS: For induction of HE, TAA (200 mg/kg) was intraperitoneally administered for 1 week at alternative days. CA, Lac and Lac+CA were administered for 14 days prior to and for further 7 days together with TAA injection. KEY FINDINGS: CA, Lac and Lac+CA combination effectively attenuated TAA-induced HE; as indicated by the improvement in behavioral tests, mitigation of pathological abnormalities in both liver and brain, the significant reduction in serum hyperammonemia and amelioration in liver function biomarkers; ALT and AST. This was accompanied with a substantial restoration of redox state in liver and brain; MDA and GSH levels. Moreover, CA, Lac and Lac+CA combination reduced neuroinflammation as demonstrated by the notable attenuation of P2X7R, NLRP3, caspase-1, IL-1ß, GFAP and Iba1 brain levels, as well as the amelioration of brain edema as manifested by reduction in AQP4 levels in brain. SIGNIFICANCE: Our study has demonstrated that CA in combination with Lac possesses a superior neuroprotective effect over Lac alone against TAA-induced HE by attenuation of P2X7R/NLRP3 mediated neuroinflammation and relieving brain edema.

Betanin protects against bleomycin-induced pulmonary fibrosis by regulating the NLRP3/IL-1ß/TGF-ß1 pathway-mediated epithelial-to-mesenchymal transition.

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease that leads to dyspnea and progressive loss of lung function. This study aimed to investigate the protective effect of betanin (BET), the major pigment in red beetroot, on pulmonary fibrosis induced by bleomycin (BLM) in rats and to assess the underlying mechanisms. In this view, total and differential cell counts and LDH activity in bronchoalveolar lavage fluid were estimated. Furthermore, MDA and GSH contents in the lungs were colorimetrically measured, while hydroxyproline, NLRP3, ASC, caspase-1, TGF-ß1, and vimentin levels in lung tissue were evaluated using the ELISA technique. Moreover, IL-1ß, E-cadherin, and α-SMA expressions were analyzed by immunostaining of lung specimens. BET treatment protects against pulmonary fibrosis as indicated by the reduction in total and differential cell counts, LDH activity, hydroxyproline, NLRP3, ASC, caspase-1, IL-1ß, and TGF-ß1 levels. MDA content was also decreased following BET administration, while GSH content was elevated. Additionally, BET suppressed the EMT process as evidenced by an increase in E-cadherin expression besides the reduction in vimentin and α-SMA expressions. To conclude, these results revealed the protective effect of BET against pulmonary fibrosis that might be attributed to the attenuation of the NLRP3/IL-1ß/TGF-ß1 signaling pathway and EMT process.

Cytoprotective effects of cinnamaldehyde and adipoRon against cyclophosphamide-induced cardio-renal toxicity in rats: Insights into oxidative stress, inflammation, and apoptosis.

Cyclophosphamide is an alkylating agent used in the treatment of various types of tumors and autoimmune diseases. Unfortunately, cyclophosphamide usage is limited in clinical situations due to its cardio-renal toxicity. The current study investigates the protective effects of cinnamaldehyde and adipoRon against cyclophosphamide-induced cardio-renal toxicity. 24 adult male Sprague-Dawley rats were assorted in a random manner into 4 groups; control, cyclophosphamide, cyclophosphamide+cinnamaldehyde (90 mg/kg) and cyclophosphamide+adipoRon (25 mg/kg), rats treated with cinnamaldehyde and adipoRon for 10 days and on the 7th day of the experiment, rats were given a single I.P. injection of cyclophosphamide (200 mg/kg). Thereafter, specimens of heart and kidney tissues were used for biochemical, immunohistochemical and histopathological analysis. Cinnamaldehyde and adipoRon attenuated the cardio-renal intoxication induced by cyclophosphamide which was manifested by a marked decrease in cardiac-renal injury markers (CK-MB, LDH, cTnI, serum creatinine and blood urea nitrogen) accompanied with normalization of histopathological changes. Moreover, cinnamaldehyde and adipoRon reversed cardio-renal oxidative stress, inflammation, and apoptosis as they have significantly decreased 8-OHdG levels, MDA contents, NF-κB, TNF-α and caspase-3 expression. On the other hand, cinnamaldehyde and adipoRon have upregulated antioxidant biomarkers; GSH concentration, Nrf2 expression as well as the anti-inflammatory cytokine; IL-10 and the antiapoptotic; BCL2. In conclusion, these cytoprotective effects of cinnamaldehyde and adipoRon suggesting the possibility of using them in combination with cyclophosphamide treatment protocols to minimize their unwanted side effects.

Sesamol Upregulates Death Receptors and Acts as a Chemosensitizer in Solid Ehrlich Carcinoma Model in Mice.

AIMS: The aim of the present study was to investigate the anti-tumor effect of sesamol (SML), a nutritional phenolic compound of sesame, in solid Ehrlich carcinoma (SEC) model in mice and its ability to enhance doxorubicin (DOX) anti-tumor activity. Moreover, we analyzed the ability of SML to protect against DOX-induced cardiotoxicity. MAIN METHODS: SML (70 mg/kg), DOX (2 mg/kg) and their combination were given to mice bearing SEC for 21 day. The mRNA level of Fas, FasL, TRAILR2, TRAIL, caspase-3 and Bcl-2 were assessed by qPCR. Tumor and cardiac tissues were examined for histopathological changes by hematoxylin and eosin. Active caspase-3 was scored by immunohistochemical analysis. KEY FINDINGS: SML treatment significantly decreased solid tumor size and weight. In addition, SML enhanced DOX anti-tumor activity. SML treatment either alone or in combination with DOX induced upregulation of Fas/FasL and TRAILR2/TRAIL gene expression. Moreover, SML increased caspase-3 protein and gene expressions and decreased Bcl-2 gene expression. SIGNIFICANCE: SML upregulates death receptors expression and enhances apoptosis induction in tumor cells that may explain its anti-tumor activity. Not only that, but SML also enhances DOX anti-tumor activity and attenuates its cardiotoxicity.