The chemopreventive effect of thymol against dimethylhydrazine and/or high fat diet-induced colon cancer in rats: Relevance to NF-κB.

AIM: Evaluating the possible protective effect of thymol as an approach against 1,2 N,N-dimethylhydrazine and/or high-fat diet (HFD)-induced colon cancer. MAIN METHODS: Adult male Wistar rats were divided into 7 groups, namely a normal control group, colon cancer groups received DMH (40 mg/kg i.p., twice weekly), 20% HFD and DMH/HFD, thymol (20 mg/kg/day, p.o.), thymol/DMH and thymol/DMH/HFD (treatment of all groups continued for 16 weeks). KEY FINDINGS: Thymol significantly reduced the elevated serum levels of colon related tumor markers carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) as well as the apoptotic marker, caspase-3 compared with the colon cancer group. In addition, it mitigated colonic tissue oxidative stress markers and inflammatory mediators. Moreover, the histopathological study revealed reduction of mucous secretion with elongated nuclei, frequent mitotic figures, focal nuclear stratification, mild interstitial edema, and markedly dilated congested blood vessels, aberrant crypt foci (ACF); adenoma with moderate to severe dysplasia of colon corrected by thymol treatment. SIGNIFICANCE: The administration of thymol had a promising preclinical protective efficacy and could be considered as a new strategy for the prophylaxis from colon cancer in clinical practices.

Pioglitazone ameliorates high fat diet-induced hypertension and induces catechol o-methyl transferase expression in rats.

Our study aimed to investigate the effect of pioglitazone (PIO) on the obesity-associated metabolic effects and whether this effect is associated with modulation of catechol O-methyl transferase (COMT) expression in the high fat diet (HFD) induced obese rats. Male Wistar rats fed HFD were used to evaluate the effect of PIO on obesity-associated hypertension and the expression of COMT. The HFD-induced obesity was confirmed by the change in body weights, the fasting serum insulin (FSI) which assessed by ELISA, homeostasis model assessment - insulin resistance (HOMA-IR), fasting blood glucose (FBG), oral glucose tolerance test (OGTT) and lipid profile which were determined by colorimetric methods. Plasma epinephrine (EP) and norepinephrine (NE) were determined by ELISA and the systolic blood pressure (SBP) was recorded using the tail-cuff method. COMT expression was assessed by quantitative real time-polymerase chain reaction (qRT-PCR), and western blotting. The HFD-induced obesity was associated with glucose intolerance, derangement of the lipid profile, increased SBP, reduced COMT expression with a concomitant increase in plasma catecholamines. Most importantly, treatment with PIO ameliorated the HFD-induced metabolic changes, improved the lipid profile, reduced SBP, increased COMT expression, and reduced plasma catecholamines. Treatment with PIO reversed HFD-induced glucose intolerance and the associated metabolic derangement. In addition, these effects of PIO were associated with up-regulating COMT expression with a subsequent reduction in plasma catecholamines levels.

Androgen/androgen receptor affects gentamicin-induced nephrotoxicity through regulation of megalin expression.

AIM: Investigation whether androgen/androgen receptor (AR) might regulate megalin expression and/or functionality and thus affecting Gentamicin-induced nephrotoxicity (GIN). MAIN METHODS: Male Wistar rats were treated with gentamicin with/out AR ligands (testosterone as agonist and flutamide as antagonist). Megalin expression in the kidney tissues was determined by real-time RT-PCR and western blot. Besides, megalin functionality was assessed using immunofluorescence imaging of fluorescein isothiocyanate (FITC) conjugated bovine serum albumin (BSA) (FITC-BSA). The effects of different treatments on the kidney were assessed at the structural level by histopathological evaluation and the biochemical level by colorimetric assay of blood urea nitrogen (BUN), serum creatinine (SCr) and urinary albumin/creatinine (A/C) ratio, besides, kidney expression of neutrophil gelatinase-associated lipocalin (NGAL) by immunoblotting. KEY FINDINGS: Our results revealed that treatment with testosterone either alone or combined with gentamicin increased megalin expression at mRNA and protein levels as well as at the functional level. These effects were paralleled by increased GIN as manifested by increased SCr, BUN, A/C ratio, renal expression of NGAL or histopathological changes. On the other hand, treatment with flutamide ameliorated GIN and megalin expression and functionality. Computational analysis of megalin promotor revealed the presence of multiple response elements that mediate androgen response. SIGNIFICANCE: Androgen/AR regulates megalin expression at the transcriptional level and consequently GIN. This may explain the sexual dimorphism in GIN and might represent a druggable target for treatment or prevention of GIN.

The effect of aryl hydrocarbon receptor ligands on gentamicin-induced nephrotoxicity in rats.

Polycyclic aromatic hydrocarbons (PAHs)/aryl hydrocarbon receptor (AhR) regulate the expression of target genes, including drug transporter genes which harbor xenobiotic response element (XRE) in their promoter regions. Thus, PAHs/AhR could alter the toxicokinetic profile of many nephrotoxic drugs, including aminoglycosides. In the current study, we investigated the expression and localization of AhR and megalin in rat kidney. Furthermore, we investigated whether AhR and its ligands could modulate the expression of megalin and consequently the gentamicin-induced nephrotoxicity (GN) in rats. Both megalin and AhR receptors are expressed in the proximal tubules of the rat kidney. Treatment with AhR agonist benzo(a)pyrene aggravated GN as indicated by a significant increase in serum creatinine, BUN, KIM1, NAGL, CD-86, and urinary albumin/creatinine ratio. On the other hand, treatment with AhR antagonist resveratrol ameliorated GN as manifested by a pronounced decrease in the aforementioned parameters. The effects of AhR ligands on GN were associated with altered expression of megalin receptor.

GATA3 as a master regulator for interactions of tumor-associated macrophages with high-grade serous ovarian carcinoma.

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic cancer. Emerging evidence suggests that tumor-associated macrophages (TAMs) play an immunosuppressive role in the tumor microenvironment and promote tumor growth, angiogenesis, and metastasis in ovarian cancer. Therefore, targeting TAMs in patients with ovarian cancer is an appealing strategy; however, all trials to date have failed. To improve the efficacy of this approach, we sought to elucidate the underlying mechanisms of the role of TAMs in ovarian cancer. We found that the developmental transcription factor GATA3 was highly expressed in HGSOC cell lines but not in the fallopian tube, which is the main origin of HGSOC. GATA3 expression was associated with poor prognosis in HGSOC patients (P < .05) and was found to promote proliferation and migration in HGSOC cell lines. GATA3 was released abundantly from TAM cells via exosomes and contributed to tumor growth in the tumor microenvironment. Moreover, GATA3 acted as a regulator for macrophage polarization and interactions between TAMs and HGSOC to support proliferation, motility, and cisplatin chemoresistance in mutant TP53 HGSOC cell lines. Furthermore, GATA3 played a critical role in the interactions between TAMs and mutant TP53 HGSOC to promote angiogenesis and epithelial-mesenchymal transition with epigenetic regulation. Targeting GATA3 using GATA3siRNA in TAMs impeded GATA3-driven proliferation, migration, cisplatin chemoresistance, and angiogenesis in mutant TP53 HGSOC cell lines. Our findings indicate that GATA3 plays a novel role in immunoediting of HGSOC and demonstrate that GATA3 may serve as a prognostic marker for HGSOC and a promising target in the treatment of HGSOC.