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Hemorrhagic cystitis often develops in patients treated with cyclophosphamide (CP). Vincamine (vinca alkaloid) is the source of the synthetic derivative vinpocetine (Vinpo). Worldwide, Vinpo is used as a cerebroprotective drug. As it has anti-oxidant, anti-thrombotic and anti-inflammatory effects but the power of Vinpo to prevent CP induced cystitis has not been studied.This research was planned to explore the effect of Vinpo (10-30 mg/kg, orally) administered 1 or 4 h before inducing cystitis by CP injection (300 mg/kg, i.p.) on the urinary bladder of mice.Administration of Vinpo 30 mg/kg, 4 h before CP injection ameliorated inflammatory markers. It reduced inducible nitric oxide synthase (iNOS), tumor necrosis factor- α (TNF-α), and BCL2 Associated X (Bax) expression in the bladder and increased the total antioxidant capacity level. Histological examination of the bladder has further supported these results. The present study suggests a protective effect of Vinpo (30 mg/kg, 4 h before CP injection) against CP-induced bladder inflammation.This proposes that Vinpo 30 mg/kg may become a promising pharmacological drug to prevent urinary adverse effects in patients treated with chemotherapy using CP.

Silver nanoparticles have been shown to increase postnatal toxicity in breastfeeding female rats, with negative consequences for their offspring. We wanted to investigate more about the differences in toxicity between silver nitrates and silver nanoparticles, as well as the impact of zinc chloride treatment on the silver nitrates induced toxicity on female albino rats. For 21 days, breastfeeding female albino rats and their puppies were exposed to silver nitrates at dosages of 0, 50, and 100 mg/kg. The results demonstrated that silver nitrates were more hazardous than nano-silver, as evidenced by higher free radical release, increased MDA levels, and decreased antioxidant enzyme levels (SOD). In addition, the silver ions-treated group had higher levels of liver enzymes and creatinine. Zinc chloride treatment, in particular, had a protective impact and mitigated the negative effects of silver nitrates, as seen by the restoration of baseline levels of liver enzyme, creatinine, and antioxidant enzyme. In addition, zinc chloride therapies reduced the harmful effects of silver nitrates on liver and kidney tissues but not lung tissue.

Salivary glands are greatly responsible for maintaining oral tissue homeostasis by the secretion of saliva. This study was designed to investigate the changes of aquaporin 1 and 4, oxidative stress and autophagy in submandibular and parotid salivary glands of diabetic rats and the possible ameliorative effect of intermittent fasting on these changes. Fifty adult male rats were divided into control and experimental groups. Experimental diabetes was induced by a single intraperitoneal injection of streptozotocin. After diabetic induction, the experimental group was divided into two groups (diabetic without intermittent fasting and diabetic with intermittent fasting). Animals were sacrificed two and four weeks after induction of diabetes. Intermittent fasting significantly decreased malondialdehyde and significantly elevated reduced glutathione (GSH) in the submandibular and parotid glands compared to those in diabetic rats. The salivary secretions were also significantly spared histologically in diabetics with intermittent fasting groups. As well, intermittent fasting up-regulated aquaporin 1 in both glands, while aquaporin 4 was only elevated in submandibular gland. Immunolocalization and gene expression of Lc3-II was higher in diabetic salivary glands than in fasting glands. In conclusion, these findings highlight the pathological role of autophagy in diabetic sub-mandibular and parotid glands and provide potential target for therapeutic role of intermittent fasting to ameliorate submandibular and parotid glands dysfunction in type I diabetes mellitus.

Methotrexate (MTX) is a potent anti-cancer drug, commonly associated with nephrotoxicity via the induction of oxidative stress and apoptosis with alteration of renal water channel proteins, namely aquaporins (AQPs). Omega-3 long-chain polyunsaturated fatty acids (LC-PUFA) have shown cytoprotective effects through their anti-oxidant and antiapoptotic activities. The present study aims for the first time to explore the role of LC-PUFA against MTX-induced nephrotoxicity. Rats were divided into the following groups: saline control, LC-PUFA control, MTX, MTX + LC-PUFA (150 mg/kg), or MTX + LC-PUFA (300 mg/kg). Then, H&E staining and immunohistochemical staining for the anti-apoptosis marker B-cell lymphoma 2 (BCL-2), the apoptosis marker BCL2-Associated X Protein (BAX), the proinflammatory marker Nuclear factor kappa B (NF-kB), AQPs 1 and 2 were performed in kidney sections with an assessment of renal oxidative stress. The MTX caused a renal histopathological alteration, upregulated renal BAX and NF-kB, downregulated Bcl-2 and AQP1, altered the distribution of AQP2, and caused oxidative stress. The LC-PUFA attenuated the pathological changes and decreased renal BAX and NF-kB, increased BCL-2 and AQP1, restored the normal distribution of AQP2, and decreased the oxidative stress. Therefore, LC-PUFA is a good adjuvant to MTX to prevent its adverse effects on kidneys through its antiapoptotic, antioxidant, and anti-inflammatory effect and its role in the restoration of the expression of AQPs 1 and 2.

Cardamonin (CARD) is a chalconoid with anti-inflammatory and antioxidant properties, and it is present in several plants. We sought to explore whether CARD exerts any positive effects against hyperglycemia-induced testicular dysfunction caused by type 2 diabetes and aimed to identify its possible intracellular pathways. Adult male rats were subdivided into six groups: control, CARD, diabetic (DM), DM + glibenclamide (GLIB), DM + CARD and DM + GLIB + CARD. Type 2 DM induced a significant increase in blood glucose and insulin resistance, along with diminished serum insulin, testosterone and gonadotropins levels, which were associated with the impairment of key testicular androgenic enzymes and cellular redox balance. Administration of CARD at a dose of 80 mg/kg for 4 weeks effectively normalized all of these alterations, and the improvement was confirmed by epididymal sperm analysis. After treatment with CARD, the pathological changes in spermatogenic tubules were markedly improved. Significantly, CARD upregulated testicular glucose transporter-8 (GLUT-8) expression and had inhibitory effects on elevated autophagy markers and caspase-3 immunoreactive cells. Furthermore, our results revealed that CARD was able to attenuate damage via activation of Nrf2 through the p62-dependent degradation of testicular anti-Kelch-like ECH-associated protein-1 (Keap-1). In conclusion, this study suggests that CARD provides protection against diabetic stress-mediated testicular damage. The use of CARD with conventional anti-diabetic therapy was associated with improved efficacy compared with conventional therapy alone.

Vigabatrin is the drug of choice in resistant epilepsy and infantile spasms. Ataxia, tremors, and abnormal gait have been frequently reported following its use indicating cerebellar involvement. This study aimed, for the first time, to investigate the involvement of necroptosis and apoptosis in the VG-induced cerebellar cell loss and the possible protective role of combined omega-3 and vitamin B12 supplementation. Fifty Sprague-Dawley adult male rats (160-200 g) were divided into equal five groups: the control group received normal saline, VG200 and VG400 groups received VG (200 mg or 400 mg/kg, respectively), VG200 + OB and VG400 + OB groups received combined VG (200 mg or 400 mg/kg, respectively), vitamin B12 (1 mg/kg), and omega-3 (1 g/kg). All medications were given daily by gavage for four weeks. Histopathological changes were examined in H&E and luxol fast blue (LFB) stained sections. Immunohistochemical staining for caspase-3 and receptor-interacting serine/threonine-protein kinase-1 (RIPK1) as well as quantitative real-time polymerase chain reaction (qRT-PCR) for myelin basic protein (MBP), caspase-3, and receptor-interacting serine/threonine-protein kinase-3 (RIPK3) genes were performed. VG caused a decrease in the granular layer thickness and Purkinje cell number, vacuolations, demyelination, suppression of MBP gene expression, and induction of caspases-3, RIPK1, and RIPK3 in a dose-related manner. Combined supplementation with B12 and omega-3 improved the cerebellar histology, increased MBP, and decreased apoptotic and necroptotic markers. In conclusion, VG-induced neuronal cell loss is dose-dependent and related to both apoptosis and necroptosis. This could either be ameliorated (in low-dose VG) or reduced (in high-dose VG) by combined supplementation with B12 and omega-3.

Vigabatrin is the drug of choice in resistant epilepsy and infantile spasms. Ataxia, tremors, and abnormal gait have been frequently reported following its use indicating cerebellar involvement. This study aimed, for the first time, to investigate the involvement of necroptosis and apoptosis in the VG-induced cerebellar cell loss and the possible protective role of combined omega-3 and vitamin B12 supplementation. Fifty Sprague-Dawley adult male rats (160-200 g) were divided into equal five groups: the control group received normal saline, VG200 and VG400 groups received VG (200 mg or 400 mg/kg, respectively), VG200 + OB and VG400 + OB groups received combined VG (200 mg or 400 mg/kg, respectively), vitamin B12 (1 mg/kg), and omega-3 (1 g/kg). All medications were given daily by gavage for four weeks. Histopathological changes were examined in HE and luxol fast blue (LFB) stained sections. Immunohistochemical staining for caspase-3 and receptor-interacting serine/threonine-protein kinase-1 (RIPK1) as well as quantitative real-time polymerase chain reaction (qRT-PCR) for myelin basic protein (MBP), caspase-3, and receptor-interacting serine/threonine-protein kinase-3 (RIPK3) genes were performed. VG caused a decrease in the granular layer thickness and Purkinje cell number, vacuolations, demyelination, suppression of MBP gene expression, and induction of caspases-3, RIPK1, and RIPK3 in a dose-related manner. Combined supplementation with B12 and omega-3 improved the cerebellar histology, increased MBP, and decreased apoptotic and necroptotic markers. In conclusion, VG-induced neuronal cell loss is dose-dependent and related to both apoptosis and necroptosis. This could either be ameliorated (in low-dose VG) or reduced (in high-dose VG) by combined supplementation with B12 and omega-3.

Cardamonin (CARD) is a chalconoid with anti-inflammatory and antioxidant properties, and it is present in several plants. We sought to explore whether CARD exerts any positive effects against hyperglycemia-induced testicular dysfunction caused by type 2 diabetes and aimed to identify its possible intracellular pathways. Adult male rats were subdivided into six groups: control, CARD, diabetic (DM), DM + glibenclamide (GLIB), DM + CARD and DM + GLIB + CARD. Type 2 DM induced a significant increase in blood glucose and insulin resistance, along with diminished serum insulin, testosterone and gonadotropins levels, which were associated with the impairment of key testicular androgenic enzymes and cellular redox balance. Administration of CARD at a dose of 80 mg/kg for 4 weeks effectively normalized all of these alterations, and the improvement was confirmed by epididymal sperm analysis. After treatment with CARD, the pathological changes in spermatogenic tubules were markedly improved. Significantly, CARD upregulated testicular glucose transporter-8 (GLUT-8) expression and had inhibitory effects on elevated autophagy markers and caspase-3 immunoreactive cells. Furthermore, our results revealed that CARD was able to attenuate damage via activation of Nrf2 through the p62-dependent degradation of testicular anti-Kelch-like ECH-associated protein-1 (Keap-1). In conclusion, this study suggests that CARD provides protection against diabetic stress-mediated testicular damage. The use of CARD with conventional anti-diabetic therapy was associated with improved efficacy compared with conventional therapy alone.

Autophagy is a key metabolic process where cells can recycle its proteins and organelles to regenerate its own cellular building blocks. Chemotherapy is indispensable for cancer treatment but associated with various side-effects, including organ damage. Stem cell-based therapy is a promising approach for reducing chemotherapeutic side effects, however, one of its main culprits is the poor survival of transplanted stem cells in damaged tissues. Here, we aimed to test the effects of activating autophagy in adipose-derived mesenchymal stem/stromal cells (ADSCs) on the survival of ADSCs, and their therapeutic value in cisplatin-induced liver injury model. Autophagy was activated in ADSCs by rapamycin (50 nM/L) for two hours before transplantation and were compared to non-preconditioned ADSCs. Rapamycin preconditioning resulted in activated autophagy and improved survival of ADSCs achieved by increased autophagosomes, upregulated autophagy-specific LC3-II gene, decreased protein degradation/ubiquitination by downregulated p62 gene, downregulated mTOR gene, and finally, upregulated antiapoptotic BCL-2 gene. In addition, autophagic ADSCs transplantation in the cisplatin liver injury model, liver biochemical parameters (AST, ALT and albumin), lipid peroxidation (MDA), antioxidant profile (SOD and GPX) and histopathological picture were improved, approaching near-normal conditions. These promising autophagic ADSCs effects were achieved by modulation of components in TGF-β1/Smad and PI3K-AKT signaling pathways, besides reducing NF-κB gene expression (marker for inflammation), reducing TGF-β1 levels (marker for fibrosis) and increasing SDF-1 levels (liver regeneration marker) in liver. Therefore, current results highlight the importance of autophagy in augmenting the therapeutic potential of stem cell therapy in alleviating cisplatin-associated liver damage and opens the path for improved cell-based therapies, in general, and with chemotherapeutics, in particular.

Stress-induced gastritis is a common problem in the intensive care unit. Zeaxanthin (ZE), a non-provitamin A carotenoid has been known to exert antioxidant and anti-inflammatory effects. In this study, we examined the effect of ZE on water avoidance stress (WAS)-induced gastritis in rats. 24 Sprague' Dawley male rats were divided into four groups; control, ZE, WAS and WAS+ZE. In the stressed rats, treatment with ZE effectively downregulated the gastric levels of total oxidant status (TOS), myeloperoxidase (MPO) and malondialdehyde (MDA), with significant upregulation of the antioxidant enzymes' activities and gastric levels of prostagladin-E2 (PGE2) as compared to the untreated stressed one. As noticed in the present study, ZE significantly decrease the gastric levels of interleukin-1 β (IL-1β) and IL-6 as well as suppression of nuclear transcription factor kappa-B (NF-κB) immunohistochemical expression together with upregulation of trefoil factor-1 (TFF-1) gene expression. Moreover, in the untreated WAS-induced gastritis group, gastrin and corticosterone levels were significantly increased together with upregulation of the gene expression of hypoxia inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), PI3K, Akt and JNK in the gastric tissues, which significantly improved by ZE administration. These all positive effects of ZE reflected on reduction of microscopic gastric mucosal damage and inflammatory cell infiltration with improvement of ulcer score. Our results discover that ZE has a new gastroprotective effect against stress-induced gastritis in rats, primarily through its antioxidative and anti-inflammatory effects, which are expressed in the regulation of the MMP-9 and HIF-1α signaling pathways.