Allosteric inhibition of CXCR1 and CXCR2 abrogates Th2/Th17-associated Allergic Lung Inflammation in Mice.

Background: IL4, IL5, IL13, and IL17-producing CD4 T helper 2 (Th2)-cells and IL17-producing CD4 T helper 17 (Th17)-cells contribute to chronic eosinophilic and neutrophilic airway inflammation in asthma and allergic airway inflammation. Chemokines and their receptors are upregulated in Th2/Th17-mediated inflammation. However, the ability of CXCR1 and CXCR2 modulate Th2 and Th17-cell-mediated allergic lung inflammation has not been reported. Methods: Mice sensitized and challenged with cat dander extract (CDE) mount a vigorous Th2-Th17-mediated allergic lung inflammation. Allosteric inhibitor of CXCR1 and CXCR2, ladarixin was orally administered in this model. The ability of ladarixin to modulate allergen-challenge induced recruitment of CXCR1 and CXCR2-expressing Th2 and Th17-cells and allergic lung inflammation were examined. Results: Allergen challenge in sensitized mice increased mRNA expression levels of Il4, Il5, Il13, Il6, Il1ß, Tgfß1, Il17, Il23, Gata3, and Rorc , and induced allergic lung inflammation characterized by recruitment of CXCR1- and CXCR2-expressing Th2-cells, Th17-cells, neutrophils, and eosinophils. Allosteric inhibition of CXCR1 and CXCR2 vigorously blocked each of these pro-inflammatory effects of allergen challenge. CXCL chemokines induced a CXCR1 and CXCR2-dependent proliferation of IL4, IL5, IL13, and IL17 expressing T-cells. Conclusion: Allosteric inhibition of CXCR1 and CXCR2 abrogates blocks recruitment of CXCR1- and CXCR2-expressing Th2-cells, Th17-cells, neutrophils, and eosinophils in this mouse model of allergic lung inflammation. We suggest that the ability of allosteric inhibition of CXCR1 and CXCR2 to abrogate Th2 and Th17-mediated allergic inflammation should be investigated in humans.

Gallic acid-loaded chitosan nanoparticles enhance the DNA damage and apoptotic features through inhibiting flap endonuclease-1 in triple-negative breast cancer cells.

This study investigated the fabrication of gallic acid-loaded chitosan nanoparticles (Gal-Chi-NPs) that enhanced the DNA damage and apoptotic features by inhibiting FEN-1 expressions in MDA-MB 231 cells. Gal-Chi-NPs were fabricated by the ionic gelation method, and it was characterized by several studies such as dynamic light spectroscopy, Fourier-transforms infrared spectroscopy, x-ray diffraction, scanning electron microscopy, energy-dispersive x-ray, atomic force microscopy, and thermogravimetric analysis. We have obtained that Gal-Chi-NPs displayed 182.2 nm with crystal, smooth surface, and heat stability in nature. Gal-Chi-NPs induce significant toxicity in MDA-MB-231 cells that compared with normal NIH-3T3 cells. A significant reactive oxygen species (ROS) overproduction was observed in Gal-Chi-NPs treated MDA-MB-231. Flap endonuclease-1 (FEN-1) is a crucial protein involved in long patch base excision repair that is involved in repairing the chemotherapeutic mediated DNA-damaged base. Therefore, inhibition of FEN-1 protein expression is a crucial target for enhancing chemotherapeutical efficacy. In this study, we have obtained that Gal-Chi-NPs treatment enhanced the DNA damage by observing increased p-H2AX, PARP1; and suppressed the expression of FEN-1 in MDA-MB-231 cells. Moreover, Gal-Chi-NPs inhibited the expression of tumor proliferating markers p-PI3K, AKT, cyclin-D1, PCNA, and BCL-2; induced proapoptotic proteins (Bax and caspase-3) in MDA-MB 231 cells. Thus, Gal-Chi-NPs induce DNA damage and apoptotic features and inhibit tumor proliferation by suppressing FEN-1 expression in triple-negative breast cancer cells.

An in vivo and in vitro model on the protective effect of corilagin on doxorubicin-induced cardiotoxicity via regulation of apoptosis and PI3-K/AKT signaling pathways.

Globally, doxorubicin (DOX)-induced cardio dysfunction is a serious cause of morbidity and mortality in cancerous patients. An adverse event of cardiotoxicity is the main deem to restrict in the clinical application by oncologists. Corilagin (CN) is well known for its antioxidative, anti-fibrosis, and anticancer effects. Herein, we aimed to evaluate the action of CN on DOX-induced experimental animals and H9c2 cells. The myocardium-specific marker, CK-MB, and the influx of mitochondrial calcium levels were measured by using commercial kits. Biochemical indices reflecting oxidative stress and antioxidant attributes such as malondialdehyde, glutathione peroxidase, reduced glutathione, superoxide dismutase, and catalase were also analyzed in DOX-induced cardiotoxic animals. In addition, mitochondrial ROS were measured by DCFH-DA in H9c2 cells under fluorescence microscopy. DOX induction significantly increased oxidative stress levels and also modulated apoptosis/survival protein expressions in myocardial tissues. Western blots were used to measure the expressional levels of Bax/Bcl-2, caspase-3, PI3-K/AKT, and PPARγ signaling pathways. Histological studies were executed to observe morphological changes in myocardial tissues. All of these DOX-induced effects were attenuated by CN (100 mg/kg bw). These in vitro and in vivo results point towards the fact that CN might be a novel cardioprotective agent against DOX-induced cardiotoxicity through modulating cardio apoptosis and oxidative stress.

P-Coumaric acid ameliorates ethanol-induced kidney injury by inhibiting inflammatory cytokine production and NF- and kappa;B signaling in rats

To examine the effects of p-coumaric acid on ethanol-induced kidney injury in Swiss Wistar rats. Methods: Ethanol (25% v/v) was used to induce nephrotoxicity in rats. p-Coumaric acid was orally administered at 50, 100, or 200 mg/kg body weight. The levels of oxidative parameters were determined; pro-inflammatory biomarkers were analyzed by Western blotting and apoptotic protein was analyzed by immunohistochemistry. Results: Ethanol treated rats showed decreased levels of antioxidants and aberrant production of pro-inflammatory cytokines (IL-6, IL1P, TNF-), NF- and kappa;B activation and imbalance of pro- and anti-apoptotic proteins (Bcl-2, Bax, caspase 3). Meanwhile, jp-coumaric acid restored antioxidant levels and decreased the levels of inflammatory cytokines, NF- and kappa;B, and pro- apoptotic proteins and increased Bcl-2 expression. Conclusions: jp-Coumaric acid ameliorates ethanol-induced kidney injury by restoring antioxidant production and suppressing cellular apoptosis and inhibiting NF- and kappa;B expression. jp-Coumaric acid should be further investigated as a promising candidate for ethanol-induced kidney toxicity.

[6]-Shogaol, a Novel Chemopreventor in 7,12-Dimethylbenz[a]anthracene-induced Hamster Buccal Pouch Carcinogenesis.

Oral cancer is a major cause of morbidity and mortality in developing countries. Despite advances in chemotherapy for the cancer management, the survival rate has not yet been improved. Dietary nutrient has been receiving a lot of attention and interest in the chemotherapeutic development. [6]-Shogaol is a major bioactive compound identified in ginger that possesses many pharmacological properties. The aim of the present study is to investigate the effect of [6]-shogaol on 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch (HBP) carcinogenesis. Oral squamous cell carcinoma induced in HBP by painting with 0.5% 7,12-dimethylbenz(a)anthracene (DMBA), thrice in a week for 16 weeks. We observed 100% tumour incidence, decreased levels of lipid peroxidation, antioxidant, and phase II detoxification enzymes (GST, GR and GSH) in DMBA-induced hamsters. Further, enhanced activity of phase I enzymes (cytochrome p450 and b5) and over-expression of mutant p53, Bcl-2 and decreased expression of wild type p53 and Bax were noticed in DMBA-induced hamsters. Our results indicated that [6]-shogaol (10, 20 and 40 mg/kg body weight) treated with DMBA-painted hamsters, considerably reversed tumour incidence, improved antioxidant status, phase II detoxification enzymes, and also inhibit lipid peroxidation and phase I enzymes. Moreover, [6]-shogaol inhibits mutant p53 and Bcl-2 expression and significantly restored normal p53, Bax levels. Thus, we concluded that [6]-shogaol prevents DMBA-induced HBP carcinogenesis through its antioxidant as well as modulating apoptotic signals.