Shikonin mitigates cyclophosphamide-induced cardiotoxicity in mice: the role of sirtuin-1, NLRP3 inflammasome, autophagy, and apoptosis.

OBJECTIVES: The aim of this study was to elucidate the protective potential of shikonin (SHK) on cyclophosphamide (CP)-induced cardiotoxicity in Swiss albino mice. METHODS: Mice received SHK in three different doses by oral gavage daily for 14 days and CP at 100 mg/kg, intraperitoneally once on the seventh day. On the 15th day, mice were euthanized, blood collected, and hearts were removed to estimate various biochemical and histopathological parameters. KEY FINDINGS: CP significantly increased serum lactate dehydrogenase, creatine kinase-MB, troponin I and NT pro-BNP, and cardiac malondialdehyde and decreased cardiac total antioxidant capacity and Nrf2, whereas increased inflammatory markers in the cardiac tissues. CP also caused hypertrophy and fibrosis in the cardiac tissues via activation of IL6/JAK2/STAT3 while depressed SIRT1 and PI3K/p-Akt pathway with consequent increased apoptosis and dysregulation of autophagy. SHK treatment reversed these changes in a dose-dependent manner and showed a significant protective effect against CP-induced cardiotoxicity via suppressing oxidative stress, inflammation, and apoptosis with modulation of autophagy via induction of SIRT1/PI3K/p-Akt signaling. CONCLUSIONS: Shikonin may be used as an adjuvant to cyclophosphamide in cancer treatment, but further research is needed to investigate its effects on cardiotoxicity in distinct animal cancer models.

Omarigliptin/rosinidin combination ameliorates cyclophosphamide-induced lung toxicity in rats: The interaction between glucagon-like peptide-1, TXNIP/NLRP3 inflammasome signaling, and PI3K/Akt/FoxO1 axis.

Cyclophosphamide is an anti-neoplastic drug that has shown competence in the management of a broad range of malignant tumors. In addition, it represents a keystone agent for management of immunological conditions. Despite these unique properties, induction of lung toxicity may limit its clinical use. Omarigliptin is one of the dipeptidyl peptidase-4 inhibitors that has proven efficacy in management of diabetes mellitus. Rosinidin is an anthocyanidin flavonoid that exhibited promising results in management of diseases characterized by oxidative stress, inflammation, and apoptosis. The present work investigated the possible effects of omarigliptin with or without rosinidin on cyclophosphamide-induced lung toxicity with an exploration of the molecular mechanisms that contribute to these effects. In a rodent model of cyclophosphamide elicited lung toxicity, the potential efficacy of omarigliptin with or without rosinidin was investigated at both the biochemical and the histopathological levels. Both omarigliptin and rosinidin exhibited a synergistic ability to augment the tissue antioxidant defenses, mitigate the inflammatory pathways, restore glucagon-like peptide-1 levels, modulate high mobility group box 1 (HMGB1)/receptors of advanced glycation end products (RAGE)/nuclear factor kappa B (NF-κB) axis, downregulate the fibrogenic mediators, and create a balance between the pathways involved in apoptosis and the autophagy signals in the pulmonary tissues. In conclusion, omarigliptin/rosinidin combination may be introduced as a novel therapeutic modality that attenuates the different forms of lung toxicities induced by cyclophosphamide.

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.

The immunomodulatory effects of ethosuximide and sodium butyrate on experimentally induced fibromyalgia: The interaction between IL-4, synaptophysin, and TGF-ß1/NF-κB signaling.

BACKGROUND AND AIMS: Fibromyalgia is a widespread chronic pain syndrome associated with several comorbid conditions that affect the quality of patients' life. Its pathogenesis is complex, and the treatment strategies are limited by partial efficacy and potential adverse effects. So, our aim was to investigate the possible ameliorative effects of ethosuximide and sodium butyrate on fibromyalgia and compare their effects to pregabalin. MATERIALS AND METHODS: In a mouse model of reserpine induced fibromyalgia, the effect of ethosuximide, sodium butyrate, and pregabalin was investigated. Evaluation of mechanical allodynia, cold hypersensitivity, anxiety, cognitive impairment, and depression was performed. Also, the brain and spinal cord tissue serotonin, dopamine and glutamate in addition to the serum levels of interleukin (IL)-4 and transforming growth factor beta 1 (TGF-ß1) were assayed. Moreover, the expression of nuclear factor kappa B (NF-κB) synaptophysin was immunoassayed in the hippocampal tissues. KEY FINDINGS: Ethosuximide and sodium butyrate restored the behavioral tests to the normal values except for the antidepressant effect which was evident only with ethosuximide. Both drugs elevated the levels of the anti-inflammatory cytokines IL-4 and TGF-ß1, reduced the hippocampal NF-κB, and increased synaptophysin expression with superiority of sodium butyrate. Ethosuximide reduced only spinal cord and brain glutamate while improved brain dopamine while sodium butyrate elevated spinal cord dopamine and serotonin with no effect on glutamate. Also, sodium butyrate elevated brain serotonin and reduced glutamate with no effect on brain dopamine. SIGNIFICANCE: Each of sodium butyrate and ethosuximide would serve as a promising therapeutic modality for management of fibromyalgia and its comorbid conditions.

Targeting p-AKT/mTOR/MAP kinase signaling, NLRP3 inflammasome and apoptosis by fluvastatin with or without taxifolin mitigates gonadal dysfunction induced by bisphenol-A in male rats.

Bisphenol-A (BPA) is a chemical substance that is widely used in industry for manufacturing of plastic bottles and resins. Recent reports found that BPA may mimic the effects of estrogen to a great manner that might disrupt the normal hormonal balance in the human body. Fluvastatin is an agent used for treatment of hypercholesterolemia that was proven to possess promising antioxidant ant anti-inflammatory properties. Taxifolin is a polyphenolic compound with potential antioxidant and antiestrogenic effects. The present study investigated the prospect of fluvastatin with or without taxifolin to mitigate testicular dysfunction elicited by BPA in rats. In a model of BPA-induced testicular toxicity, the hormonal profile was assessed and the testicular tissues were examined by biochemical analysis, histopathology, and immunohistochemistry. Fluvastatin with or without taxifolin improved the body weight gain, hormonal profile, testicular weight and functions, sperm characteristics, the antioxidant status, and the anti-inflammatory mechanisms together with enhancement of autophagy and suppression of the proapoptotic events induced by BPA in the testicular tissues. In addition, fluvastatin with or without taxifolin significantly mitigated the histopathological and the immunohistochemical changes induced by BPA in the testicular tissues. These desirable effects were more pronounced with fluvastatin/taxifolin combination relative to the use of each of these agents alone. In tandem, fluvastatin/taxifolin combination might counteract the pathogenic events induced by BPA in the testicular tissues which may be considered as a novel strategy for amelioration of these disorders.

Effect of dapagliflozin and/or L-arginine on solid tumor model in mice: The interaction between nitric oxide, transforming growth factor-beta 1, autophagy, and apoptosis.

BACKGROUND: Nitric oxide was reported to play an essential role in various physiological and pathological processes in the body. Recent reports suggested that nitric oxide may affect the pathogenesis of cancer. Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor which is commonly used for type-2 diabetes mellitus management. PURPOSE: The current work aimed to detect the potential impact of dapagliflozin and/or L-arginine on solid Ehrlich carcinoma (SEC) in mice. METHODS: Six equal groups of male BALB/c mice were divided as follows: Control; SEC; SEC + Dapagliflozin; SEC + L-arginine; SEC + carboxymethyl cellulose; and SEC + Dapagliflozin + L-arginine group. Tumor volume, survival rate, tissue total nitrate/nitrite, paraoxonase-1, interleukin 1 alpha (IL-1α), and transforming growth factor-beta 1 (TGF-ß1) were determined. Also, caspase 3, beclin-1, and c-Jun NH2-terminal kinase (JNK) activities were estimated in the tumor tissues. Sections of the tumor tissues were examined by histopathology and immunohistochemistry. RESULTS: Dapagliflozin and/or L-arginine induced a significant increment of the survival rate, tissue total nitrate/nitrite, paraoxonase-1, caspase 3, beclin-1, and JNK activities, significant lowering of the tumor volume, tissue TGF-ß1, and IL-1α expression alongside an improvement of the histopathologic findings, versus the SEC group. Notably, the combination of dapagliflozin/L-arginine exerted more pronounced effects versus each agent alone. CONCLUSION: Dapagliflozin/L-arginine combination may confer a novel therapeutic line for cancer therapy.

Pre-treatment with Empagliflozin ameliorates Cisplatin induced acute kidney injury by suppressing apoptosis.

Dose-limiting nephrotoxicity restricts Cisplatin use in high therapeutic doses. Empagliflozin showed a reno-protective effect in diabetic nephropathy. We investigated if Empagliflozin can ameliorate Cisplatin nephrotoxicity whether used prophylactically or therapeutically. Forty male Wistar rats were divided into 5 groups: (1) control; (2) Cisplatin-induced nephrotoxicity by single intraperitoneal dose; (3) Empagliflozin was given for 10 days before a single dose of Cisplatin; (4) a single dose of Cisplatin followed by Empagliflozin for 10 days; (5) received Empagliflozin only. Regular assessment of weight was done, biochemical evaluation for serum urea, creatinine, uric acid, albumin, and glucose was performed, kidney tissue nerve growth factor-ß (NGF-ß) and oxidative stress parameters were measured, kidneys were evaluated histopathologically and immunostained for caspase 3. Cisplatin significantly reduced body weight, NGF-ß, and reduced glutathione, elevated urea, creatinine, and malondialdehyde with no effect on other serum biochemical parameters. Histopathologically, there was high acute tubular necrosis (ATN) score with strong immunostaining of caspase 3. The use of Empagliflozin significantly reduced urea and creatinine in both prophylactic and therapeutic, reduced ATN score in the prophylactic group associated with minimal staining of caspase 3 and elevated reduced glutathione. In conclusion, prophylactic Empagliflozin protected against Cisplatin-induced acute kidney injury mainly via anti-apoptotic effect.

The promising effect of linagliptin and/or indole-3-carbinol on experimentally-induced polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is one of the most common medical conditions that lead to female infertility worldwide. The aim of this study was to assess the effect of linagliptin and/or indole-3-carbinol (I3C) on PCOS in female rats. Fifty female Wistar rats were randomly allocated into five equal groups: Control group; Letrozole-induced PCOS group; Letrozole + Linagliptin group; Letrozole + I3C group and Letrozole + Linagliptin + I3C group. Body weight, body mass index, Lee index and ovarian indices were determined. Plasma levels of luteinizing hormone (LH), free testosterone, estradiol, progesterone, prolactin, fasting blood glucose (FBG) and fasting plasma insulin were measured. Quantitative Insulin Sensitivity Check Index (QUICKI) was calculated. Tissue antioxidant status, transforming growth factor beta 1 (TGF-ß1), tumor necrosis factor alpha (TNF-α), interleukin 10 (IL-10) and Nrf2/HO-1 content were assessed. Histopathological and immunohistochemical examination of the ovaries were done. Linagliptin and/or I3C induced significant decrease in tissue TGF-ß1, TNF-α, IL-10, plasma free testosterone, luteinizing hormone, progesterone, estradiol, FBG and insulin levels associated with significant improvement of insulin resistance whereas tissue Nrf2/HO-1 content and antioxidant enzymes were significantly increased compared to PCOS group. In addition, final body weight, final body mass and Lee indices were significantly decreased compared to PCOS group. Also, there was significant improvement of the ovarian morphology compared to PCOS group. This improvement was significant with linagliptin/I3C combination compared to the use of each of these drugs alone. In conclusion, linagliptin/I3C combination might represent a beneficial therapeutic modality for amelioration of PCOS.

RETRACTED: Ameliorative potential of linagliptin and/or calcipotriol on bleomycin-induced lung fibrosis: In vivo and in vitro study.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted due to the authors' plagiarism of text and images from the work of Eman Said Abd-Elkhalek, Hatem Abdel-Rahman Salem, Ghada Mohamed SuddeK, Marwa Ahmed Zaghloul and Ramy Ahmed Abdel-Salam, Faculties of Pharmacy and Medicine, Mansoura University, Mansoura, Egypt.

Ameliorative potential of omega 3 fatty acids and HMG-CoA reductase inhibitors on experimentally-induced non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) has a relation to obesity. It may lead to hepatocellular carcinoma. To date, the therapeutic options are limited due to complex pathogenesis. This study aimed to investigate the effect of atorvastatin and omega 3 fatty acids on experimentally-induced NASH. Sixty male albino rats were divided into 6 equal groups; control group, high fat emulsion/sucrose (HFE/S) diet, HFE/S+carboxymethyl cellulose, HFE/S +Atorvastatin, HFE/S+Fish oil and HFE/S+Atorvastatin+Fish oil. Serum alanine aminotransferase, total cholesterol (TC), triglycerides (TG), high density lipoproteins, insulin, glucose, C-reactive protein and quantitative insulin sensitivity check index were measured. Also, hepatic TC, TG, malondialdehyde, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and transforming growth factor beta 1 (TGF-ß1) were determined. Liver sections were examined histopathologically. Atorvastatin improved lipid profile, inflammation and oxidative stress but did not improve insulin resistance, hepatic TGF-ß1 or body weight while fish oil improved lipid profile, decreased inflammation and oxidative stress, improved insulin resistance, hepatic TGF-ß1 and body weight compared to HFE/S group. Atorvastatin/fish oil combination produced significant improvement in the lipid profile, inflammation, oxidative stress, insulin resistance, hepatic TGF-ß1 and body weight compared to the use of each of these drugs alone. This might be attributed to the effect of fish oil on the lipid profile, inflammatory cytokines, insulin resistance and TGF-ß1 which potentiates the effect of atorvastatin on NASH.