Histomorphological and Immunohistochemical Study of Dacomitinib-Induced Ileal Mucositis in Rats with the Possible Protection by Baicalin.

Introduction: Gastrointestinal (GIT) mucositis is a common problem associated with chemotherapy. Dacomitinib is a chemotherapeutic drug that treats nonsmall cell lung cancer. It irreversibly binds to the receptors at the ileal epithelial cells, leading to mucosal injury. Baicalin (BA) is a flavonoid with anti-inflammatory, antifibrosis, and antibarrier disruption properties. Aim: This work aimed to investigate the possible protective effects of BA on dacomitinib-induced ileal mucositis in rats by histological and immunohistochemical studies. Materials and Methods: 60 Wistar rats (8-12 weeks) were used (180-200 g) and divided into 6 groups (10 rats each). Group 1: Control; Group 2 (dacomitinib): Rats received dacomitinib 7.5 mg/kg/day orally; Group 3 (dacomitinib + carboxyl methylcellulose [CMC]): Rats received dacomitinib 7.5 mg/kg/day and 0.5% CMC orally; Group 4 (dacomitinib + BA low dose): Rats received low-dose BA 30 mg/kg/day and 7.5 mg/kg/day dacomitinib orally; Group 5 (dacomitinib + BA mid dose): Rats received mid-dose BA 60 mg/kg/day and 7.5 mg/kg/day dacomitinib orally; Group 6 (dacomitinib + BA high dose): Rats received high-dose BA 100 mg/kg/day and 7.5 mg/kg/day dacomitinib orally. Results: Dacomitinib group showed short villi, desquamated epithelium, congested blood vessels, inflammatory cellular infiltrations, dilated lacteals, and wide spaces between the crypts. There is a significant increase in collagen fibers and number of tumor necrosis factor-alpha and proliferating cell nuclear antigen-positive cells. Further, there were lost epithelial cadherin (E-cadherin) and epidermal growth factor receptor immunohistochemical reaction. The previous findings were ameliorated by BA in a dose-dependent manner. Conclusion: BA has a protective effect through its anti-inflammatory, antifibrosis, and antibarrier disruption effects. Hence, BA is considered as a promising new drug for the treatment of chemotherapy-associated GIT problems, especially dacomitinib.

Dapagliflozin/Hesperidin Combination Mitigates Lipopolysaccharide-Induced Alzheimer's Disease in Rats.

Alzheimer's disease (AD) is the most common form of neurodegenerative disorders worldwide. Its pathologic features include massive neuroinflammation with abnormal deposition of ß-amyloid peptide in the cerebral tissues leading to degeneration of the brain neurons. Adverse effects associated with the traditional drugs used for the treatment of this pathological condition have directed the research efforts towards searching for alternative effective agents with minimal adverse effects. The aim of this study was to elucidate the potential ameliorative effects of dapagliflozin and/or hesperidin on Alzheimer's disease (AD) induced by lipopolysaccharide (LPS) injection in rats. In a rodent model of AD, the effect of dapagliflozin with or without hesperidin on the biochemical parameters and the behavioral tests as well as the histopathological parameters was determined. Each of dapagliflozin and hesperidin restored the behavioral tests to the reference values, augmented the antioxidant defense mechanisms, ameliorated the neuronal inflammatory responses, combatted the changes in Toll-like receptor-4 (TLR-4)/High-mobility group box 1 (HMGB1) protein signaling and receptors of advanced glycation end products (RAGE) levels, and restored the balance between the apoptotic signals and autophagy in the hippocampal tissues. Additionally, both agents exhibited an outstanding ability to combat LPS-induced perturbations in the histopathological and electron microscopic image of the brain tissues. These favorable effects were significantly encountered in the group treated with dapagliflozin/hesperidin combination when compared versus animals treated with either dapagliflozin or hesperidin. In conclusion, inhibition of the hippocampal HMGB1/TLR4/RAGE signaling, the pro-inflammatory axis, and apoptosis alongside augmentation of the antioxidant defenses and autophagy can be regarded as beneficial effects by which dapagliflozin/hesperidin combination may combat LPS-triggered AD.

Repositioning itraconazole for amelioration of bleomycin-induced pulmonary fibrosis: Targeting HMGB1/TLR4 Axis, NLRP3 inflammasome/NF-κB signaling, and autophagy.

BACKGROUND AND AIMS: Bleomycin (BLM) is one of the antitumor medications that had proven efficacy in the treatment of a wide range of malignant conditions. Pulmonary fibrosis which is frequently encountered during the course of bleomycin therapy may significantly reduce the potential efficacy of bleomycin in cancer therapy. This study tested the hypothesis that itraconazole may have mitigating effects on BLM-induced pulmonary fibrosis and tried to delineate the potential mechanisms of these effects. MATERIALS AND METHODS: In a rat model of pulmonary fibrosis elicited by BLM, the effect of different doses of itraconazole was explored at the biochemical, histopathological, and electron microscopic levels. KEY FINDINGS: Itraconazole, in a dose-dependent manner, exhibited significant effects on the pro-oxidant/antioxidant balance, the inflammatory consequences, high-mobility group box 1/toll-like receptor-4 Axis, autophagy and nuclear factor kappa B/Nod-like receptor protein 3 inflammasome signaling and alleviated the histopathological, immunohistochemical, and electron microscopic perturbations induced by BLM in the pulmonary tissues. SIGNIFICANCE: In view of the afore-mentioned data, itraconazole may be a promising drug that efficiently mitigates the deleterious effects of BLM on the pulmonary tissues.

Perindopril/Ambrosin Combination Mitigates Dextran Sulfate Sodium-Induced Colitis in Mice: Crosstalk between Toll-Like Receptor 4, the Pro-Inflammatory Pathways, and SIRT1/PPAR-γ Signaling.

Colitis is one of the inflammatory states that affect the intestinal wall and may even predispose to malignancy due to chronic irritation. Although the etiology of colitis is not yet fully explored, a combination of genetic and environmental factors is strongly incriminated. Perindopril is an angiotensin-converting enzyme inhibitor that is used for the management of a wide range of cardiovascular diseases. Ambrosin is a sesquiterpene lactone that was proven to have beneficial effects in disorders characterized by inflammatory nature. The objective of this study is to make a comparison between the effects of perindopril or ambrosin on dextran sulfate sodium (DSS)-induced colitis in mice and to explore the effect of their combination. The present findings indicate that each ambrosin or perindopril alone or in combination is able to ameliorate oxidative stress and suppress the proinflammatory pathways in the colonic tissues of DSS-treated mice via mechanisms related to toll-like receptor 4/nuclear factor kappa B signaling and modulation of peroxisome proliferator-activated receptor gamma/sirtuin-1 levels. In addition, each ambrosin or perindopril alone or in combination inhibits apoptosis and augments the mediators of autophagy in DSS-treated mice. These effects are reflected in the amelioration of the histopathological and electron microscopic changes in the colonic tissues. Interestingly, the most remarkable effects are those encountered with the perindopril/ambrosin combination compared to the groups treated with each of these agents alone. In conclusion, the perindopril/ambrosin combination might represent an effective modality for mitigation of the pathogenic events and the clinical sequelae of colitis.

Omarigliptin/galangin combination mitigates lipopolysaccharide-induced neuroinflammation in rats: Involvement of glucagon-like peptide-1, toll-like receptor-4, apoptosis and Akt/GSK-3ß signaling.

AIMS: The objectives of this work were to assess the possibility of administration of omarigliptin and/or galangin to combat lipopolysaccharide (LPS)-induced neuroinflammation in rats and to explore the possible mechanisms that might contribute to their actions. MATERIALS AND METHODS: In a rat model of LPS-induced neuroinflammation, the changes in the behavioral tests, biochemical parameters, and the histopathological picture were assessed. KEY FINDINGS: Administration of either omarigliptin or galangin to LPS-injected rats was able to significantly improve the behavioral changes with restoration of the oxidant/antioxidant balance, decrement of toll-like receptor-4 levels, and amelioration of the neuroinflammation associated with inhibition of apoptosis and restoration of glucagon-like peptide-1 levels in the cerebral tissues. In addition, omarigliptin and/or galangin significantly reduced the levels of phospho-Akt and glycogen synthase kinase 3 beta (GSK-3ß) and significantly increased the expression of beclin-1 in the cerebral tissues compared versus the group treated with LPS alone. As a result, these changes were positively reflected on the histopathological and the electron microscopic picture of the cerebral tissues. These beneficial effects were maximally evidenced in rats treated with omarigliptin/galangin combination relative to the use of either omarigliptin or galangin alone. SIGNIFICANCE: Omarigliptin/galangin combination might be proposed as a promising therapeutic line for mitigation of the pathophysiologic events of LPS-induced neuroinflammation.

Targeting Oxidative Stress, NLRP3 Inflammasome, and Autophagy by Fraxetin to Combat Doxorubicin-Induced Cardiotoxicity.

Doxorubicin belongs to the class of anthracycline antibiotics that is widely used in the treatment protocols of a wide range of malignancies. The major deleterious effect of doxorubicin use is the possible occurrence of cardiotoxicity. This study aimed to delineate the possible effects of targeting oxidative stress, NLRP3 inflammasome, and autophagy by fraxetin on doxorubicin-induced cardiac dysfunction in rats. In a model of doxorubicin-induced cardiotoxicity, the effects of different doses of fraxetin were assessed by determination of biochemical, histopathological, immunohistochemical, and electron microscopic changes. Fraxetin, in a dose-dependent manner, was found to have the ability to mitigate the harmful effects of oxidative stress and inflammation on myocardial muscles with significant decrease in NLRP3 inflammasome, augmentation of autophagy, and amelioration of the apoptotic signaling pathways. In addition, fraxetin, in a dose-dependent manner, had the ability to combat the echocardiographic, histopathological, immunohistochemical, and electron microscopic changes induced by doxorubicin in cardiomyocytes. As a result, fraxetin may be put into consideration as a new adjuvant line of therapy on the way to mitigate doxorubicin-induced cardiotoxicity.

New insight on the role of liraglutide in alleviating dexamethasone-induced pancreatic cytotoxicity via improving redox status, autophagy flux, and PI3K/Akt/Nrf2 signaling.

Chronic glucocorticoids therapy is commonly complicated by steroid diabetes, although the underlying mechanisms are still elusive. Liraglutide, a glucagon-like peptide-1, was initially found to induce glycemic control and recently it was found to have many pleotropic effects; however, its role in pancreas remains unknown. The present study aims to estimate the protective role of liraglutide on dexamethasone-induced pancreatic cytotoxicity and hyperglycemia, highlighting the possible underlying biochemical, molecular, and cellular mechanisms. Twenty-eight male Wistar rats were involved in this study and were randomly divided into four groups. Group III and IV were treated with 1 mg/kg dexamethasone daily for 10 days. Group II and IV were treated with liraglutide in a dose of 0.8 mg/kg per day for 2 weeks. Pancreatic caspase-9, nuclear factor erythroid 2-related factor 2 (Nrf2), phospho-protein kinase-B (pAkt), and sequestrome 1 (p62) levels were assessed by immunoassay. Moreover, phosphoinositide 3-kinase (PI3K) expression by real-time PCR, microtubule-associated protein light chain 3 (LC3B) expression by immunohistochemistry, glycemic status, ß-cell function by homoeostasis model assessment (HOMA) ß index, and pancreatic redox status were assessed. Liraglutide improved blood glucose level, ß-cell function, pancreatic caspase-9 level, redox status, and autophagy. Additionally, it increased pancreatic PI3K, pAkt, and Nrf2 levels. Moreover, preservation of pancreatic histological and the ultrastructural morphological features of ß- and α-cells were observed. In conclusion, liraglutide protected against dexamethasone-induced pancreatic injury and hyperglycemia and decelerated the progression towards steroid diabetes via activating PI3K/Akt/Nrf2 signaling and autophagy flux pathways.

Effect of fish oil and telmisartan on dehydroepiandrosterone-induced polycystic ovarian syndrome in rats: The role of oxidative stress, transforming growth factor beta-1, and nuclear factor kappa B.

Our aim was to explore the effect of telmisartan and/or fish oil on dehydroepiandrosterone (DHEA)-induced PCOS in rats. Sixty female rats were divided into six equal groups as follows: Control; DHEA-induced PCOS; DHEA + Telmisartan; DHEA + Fish oil; DHEA + Carboxymethyl cellulose; and DHEA + Telmisartan +Fish oil group. Plasma sex hormones, anthropometric measurements, and the glycemic indices were measured. Tissue oxidative stress parameters and the proinflammatory cytokines were assessed. The ovaries were subjected to histopathological and electron microscopic examination. Telmisartan and/or fish oil induced significant improvement of insulin resistance with amelioration of oxidative stress and inflammation compared to PCOS group. Also, telmisartan and/or fish oil restored the hormonal levels and the anthropometric measurements to the normal values. This was significant with telmisartan/fish oil combination compared to the use of each of these agents alone. In conclusion, this combination may represent a promising hope for amelioration of PCOS.

Amelioration of Cisplatin-Induced Ototoxicity in Rats by L-arginine: The Role of Nitric Oxide, Transforming Growth Factor Beta 1 and Nrf2/HO-1 Pathway.

BACKGROUND: Cisplatin is an alkylating agent that inhibits DNA replication and interferes with proliferation of cancer cells. However, the major limiting factor for its use is the possible development of adverse effects, including ototoxicity. Up till now, the mechanisms of this ototoxicity remain poorly understood. However, induction of oxidative stress and activation of the inflammatory cascade were suggested as contributing factors. PURPOSE: The aim of this study was to explore the effect of L-arginine on cisplatin-induced ototoxicity in rats. METHODS: Thirty male adult Wistar rats were divided into three equal groups as follows: control group; cisplatin group and cisplatin + L-arginine group. Auditory brainstem response (ABR), tissue oxidative stress parameters, total nitrate/nitrite, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) content, transforming growth factor beta 1 (TGF-ß1), tumor necrosis factor alpha (TNF-α) and interleukin 15 (IL-15) were assessed. Also, the cochlear tissues were subjected to histopathological and electron microscopic examination. RESULTS: Administration of L-arginine to cisplatin-treated rats induced significant decrease in the average ABR threshold shifts at all frequencies, tissue TGF-ß1, TNF-α and IL-15 associated with significant increase in tissue antioxidant enzymes, total nitrate/nitrite and Nrf2/HO-1 content compared to cisplatin group. Also, pretreatment of cisplatin-injected rats with L-arginine induced significant improvement of the histopathological and electron microscopic picture compared to cisplatin group. CONCLUSION: L-arginine may serve as a promising therapeutic modality for amelioration of cisplatin-induced ototoxicity.
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Amelioration of cyclosporine-induced testicular toxicity by carvedilol and/or alpha-lipoic acid: Role of TGF-ß1, the proinflammatory cytokines, Nrf2/HO-1 pathway and apoptosis.

Cyclosporine is an immunosuppressive agent that is used to prevent organ rejection after organ transplantation. Due to the widespread use of this type of surgery, the effect of cyclosporine on reproduction and fertility should have a specific interest. Our aim was to assess the effect of carvedilol and/or alpha-lipoic acid on cyclosporine-induced testicular toxicity in rats. Sixty male Wistar rats were divided into six equal groups: Control; cyclosporine; cyclosporine + carvedilol; cyclosporine + alpha-lipoic acid; cyclosporine + carboxymethyl cellulose; and cyclosporine + carvedilol +alpha-lipoic acid. Food intake, testis weight, testicular functions, serum testosterone, luteinizing hormone and follicle-stimulating hormone were measured. Also, testicular tissue 3 ß-hydroxysteroid dehydrogenase, 17 ß- hydroxysteroid dehydrogenase, paroxonase-1, proinflammatory cytokines, transforming growth factor beta-1, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Heme oxygenase-1 (HO-1) content and sperm characteristics were determined. Parts of the testes were subjected to histopathological and electron microscopic examination. The carvedilol/alpha-lipoic acid combination restored the food intake, testicular weight and functions, sperm characteristics, hormonal profile and the antioxidant defences compared to the use of each of these drugs alone. Also, this combination significantly ameliorated inflammation (P < .05) and induced significant increase in tissue Nrf2/HO-1 content (P < .05) and significant improvement of the histopathological and electron microscopic picture (P < .05) compared to the use of each of these drugs alone. So, carvedilol/alpha-lipoic acid combination might represent a novel therapeutic strategy to ameliorate testicular damage induced by cyclosporine.

Targeting oxidative stress, proinflammatory cytokines, apoptosis and toll like receptor 4 by empagliflozin to ameliorate bleomycin-induced lung fibrosis.

Lung fibrosis is one of the serious complications of bleomycin use in cancer therapy. The aim of this study was to investigate the effect of pre-treatment versus post-treatment with empagliflozin on pulmonary fibrosis induced by bleomycin. One hundred male C57BL/6 mice were divided into 5 equal groups as follows: control group; bleomycin group; bleomycin + carboxymethyl cellulose group; bleomycin group pretreated with empagliflozin and a group treated with empagliflozin after 15 days from starting bleomycin injection. The survival rate, lung weight/body weight ratio, lung tissue hydroxyproline, malondialdehyde, glutathione reductase, superoxide dismutase, nuclear factor (Erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1) and toll-like receptor 4 (TLR4) were assessed. Also, bronchoalveolar lavage fluid (BALF) was analyzed for total and differential leucocytic count, lactate dehydrogenase, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta 1 (TGF-ß1). The pulmonary tissues were subjected to histopathological, immunohistochemical and electron microscopic study. Empagliflozin induced significant decrease in lung weight/body weight ratio, BALF lactate dehydrogenase, total leucocytic count, IL-6, TNF-α, TLR4 and TGF-ß1 associated with significant decrease in lung tissue oxidative stress and hydroxyproline and significant increase in the survival rate and tissue Nrf2/HO-1 content compared to bleomycin group. This was accompanied with significant improvement of the histopathological, immunohistochemical and electron microscopic picture compared to bleomycin group. These effects were significant in mice pretreated with empagliflozin compared to the group that received empagliflozin 15 days after starting bleomycin injection. In conclusion, empagliflozin may be used prophylactically to prevent pulmonary fibrosis induced by bleomycin.

Ameliorative potential of sitagliptin and/or resveratrol on experimentally-induced clear cell renal cell carcinoma.

The aim of this study was to assess the effect of sitagliptin with or without resveratrol on carcinogen-induced clear cell renal cell carcinoma. Sixty male Wistar rats were divided into 6 equal groups as follows: control; clear cell renal cell carcinoma group; clear cell renal cell carcinoma+sitagliptin group; clear cell renal cell carcinoma+resveratrol group; clear cell renal cell carcinoma+carboxymethyl cellulose group and clear cell renal cell carcinoma+sitagliptin+resveratrol group. Blood urea, serum creatinine, creatinine clearance, urinary N-acetyl beta-d-glucosaminidase (NAG), gamma glutamyl transpeptidase (GGT) and urinary albumin excretion rate (UAER) were determined. Renal tissue antioxidant enzymes, lactate dehydrogenase (LDH), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1), transforming growth factor beta-1 (TGF-ß1), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and signal transducers and activators of transcription-3 (STAT3) were determined. Parts of the kidneys were subjected to histopathological and immunohistochemical examination for nuclear factor kappa B (p65). Sitagliptin and/or resveratrol induced significant improvement of the renal functions with significant increase in tissue antioxidant defenses and Nrf2/HO-1 content associated with significant decrease in tissue LDH, TGF-ß1, TNF-α, IL-6 and STAT3 and alleviated the histopathological and immunohistochemical changes compared to the untreated clear cell renal cell carcinoma group. These effects were significant in sitagliptin/resveratrol combination group compared to the use of each of these drugs alone. In conclusion, sitagliptin/resveratrol combination might represent a beneficial therapeutic modality for amelioration of experimentally-induced clear cell renal cell carcinoma.