Ziziphus spina-christi L. extract attenuates bleomycin-induced lung fibrosis in mice via regulating TGF-ß1/SMAD pathway: LC-MS/MS Metabolic profiling, chemical composition, and histology studies.

Ancient Egyptians (including Bedouins and Nubians) have long utilized Ziziphus spina-christi (L.), a traditional Arabian medicinal herb, to alleviate swellings and inflammatory disorders. It is also mentioned in Christian and Muslim traditions. Ziziphus spina-christi L. (Family: Rhamnaceae) is a plentiful source of polyphenols, revealing free radical scavenging, antioxidant, metal chelating, cytotoxic, and anti-inflammatory activities. Herein, different classes of the existing bioactive metabolites in Z. spina-christi L. were detected using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the first time. The study also aimed to assess the anti-inflammatory and antifibrotic properties of Z. spina-christi L. extract against bleomycin-induced lung fibrosis in an experimental mouse model. 32 male Swiss Albino mice were assigned into 4 groups; the first and second were the normal control group and the bleomycin positive control (single 2.5 U/kg bleomycin intratracheal dose). The third and fourth groups received 100 and 200 mg/kg/day Z. spina-christi L. extract orally for 3 weeks, 2 weeks before bleomycin, and 1 week after. The bioactive metabolites in Z. spina-christi L. extract were identified as phenolic acids, catechins, flavonoids, chalcones, stilbenes, triterpenoid acids, saponins, and sterols. The contents of total phenolic compounds and flavonoids were found to be 196.62 mg GAE/gm and 33.29 mg QE/gm, respectively. In the experimental study, histopathological examination revealed that lung fibrosis was attenuated in both Z. spina-christi L.- treated groups. Z. spina-christi L. extract downregulated the expression of nuclear factor kappa B (NF-κB) p65 and decreased levels of the inflammatory markers tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and c-Jun N-terminal kinase (JNK) in lung tissue. Z. spina-christi L. also downregulated the expression of the fibrotic parameters collagen-1, alpha-smooth muscle actin (α-SMA), transforming growth factor-beta 1 (TGF-ß1), matrix metalloproteinase-9 (MMP-9) and SMAD3, with upregulation of the antifibrotic SMAD7 in lung tissue. Overall, the present study suggests a potential protective effect of Z. spina-christi L. extract against bleomycin-induced lung fibrosis through regulation of the TGF-ß1/SMAD pathway.

Empagliflozin protects against isoprenaline-induced fibrosis in rat heart through modulation of TGF-ß/SMAD pathway.

AIM: Cardiac fibrosis is characterized by excessive accumulation of fibrous tissue, particularly collagens, in the myocardium. Accumulated fibrous tissue renders myocardium stiffer and reduces its contractility. Empagliflozin is an oral hypoglycemic agent with extra-diabetic functional profile toward maintaining cardiac functions. The present study aimed to examine protective effect of empagliflozin against an in-vivo model of cardiac fibrosis induced by isoprenaline and targeting TGF-ß/SMAD signaling as a possible pathway responsible for such effect. MAIN METHODS: Sixty animals were divided into six groups; the first was normal, and the second was treated with isoprenaline only (5 mg/kg/day I.P.) as a control. The third received pirfenidone (500 mg/kg/day P.O.), and the remaining groups received graded doses (5, 10, 20 mg/kg respectively) of empagliflozin for 14 days before fibrosis induction by isoprenaline (5 mg/kg/day) for 30 days. KEY FINDINGS: Isoprenaline increased cardiac enzymes, and cardiac tissues revealed elevated concentrations of transforming growth factor ß (TGF-ß1), monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor α (TNF-α), and c-jun N-terminal kinase (JNK) proteins. Expression of nuclear factor kappa B (NF-κB), alpha smooth muscle actin (α-SMA), collagens, suppressor of mothers against decapentaplegic (SMADs), connective tissue growth factor (CTGF), and fibronectin was upregulated. Empagliflozin improved the histological picture of heart tissue in comparison to fibrosis developed in controls, and protected against fibrosis through significant modulation of all mentioned parameters' concentrations and expressions. SIGNIFICANCE: Empagliflozin demonstrated a promising protective approach against biological model of cardiac fibrosis through an anti-fibrotic effect through targeting TGF-ß signaling pathways.

Antitumor effect of trimetazidine in a model of solid Ehrlich carcinoma is mediated by inhibition of glycolytic pathway and AKT signaling.

Disturbance in glucose metabolism was proposed to be a pathogenetic mechanism of breast cancer. Trimetazidine (TMZ) inhibits ß-oxidation of fatty acids through blocking the activity of 3-ketoacylCoA thiolase enzyme, leading to enhancement of glucose oxidation and metabolic respiration. The present study aimed to examine the cytotoxic effect of TMZ in both in vivo and in vitro models of breast cancer, focusing on its impact on the expression of some glycolytic enzymes and AKT signaling. The cytotoxic effect of TMZ was screened against breast (MCF-7) cancer cell line at different concentrations [0.01-100 µM]. In vivo, graded doses (10, 20, 30 mg/kg) of TMZ were tested against solid Ehrlich carcinoma (SEC) in mice. Tumor tissues were isolated for assessment of the expression of glucose transporter-1 (GLUT-1) and glycolytic enzymes by quantitative PCR. The protein expression of AKT and cellular myelocytomatosis (c-Myc) was determined by western blotting, while p53 expression was evaluated by immunohistochemistry. Molecular docking study of TMZ effect on AKT and c-Myc was performed using Auto-Dock Vina docking program. TMZ showed a cytotoxic action against MCF-7 cells, having IC50 value of 2.95 µM. In vivo, TMZ reduced tumor weight, downregulated the expression of glycolytic enzymes, suppressed AKT signaling, but increased p53 expression. Molecular docking and in silico studies proposed that TMZ is an AKT and c-Myc selective inhibitor. In conclusion, TMZ demonstrated a viable approach to suppress tumor proliferation in biological models of breast cancer.

Simvastatin attenuates aluminium chloride-induced neurobehavioral impairments through activation of TGF-ß1/ SMAD2 and GSK3ß/ß-catenin signalling pathways.

Alzheimer's disease (AD) is a neurodegenerative disease characterised by the presence of ß-amyloid plaques and acetylcholine depletion leading to neurobehavioral defects. AD was contributed also with downregulation of TGF-ß1/SMAD2 and GSK3ß/ß-catenin pathways. Simvastatin (SMV) improved memory function experimentally and clinically. Hence, this study aimed to investigate the mechanistic role of SMV against aluminium chloride (AlCl3) induced neurobehavioral impairments. AD was induced by AlCl3 (50 mg/kg) for 6 weeks. Mice received Simvastatin (10 or 20 mg/kg) or Donepezil (3 mg/kg) for 6 weeks after that the histopathological, immunohistochemical and biochemical test were examined. Treatment with SMV improved the memory deterioration induced by AlCl3 with significant recovery of the histopathological changes. This was concomitant with the decrease of AChE and Aß (1-42). SMV provides its neuroprotective effect through upregulating the protein expression of ß-catenin, TGF-ß1 and downregulating the expression of GSK3ß, TLR4 and p-SMAD2.

Dapagliflozin Ameliorates Cognitive Impairment in Aluminum-Chloride-Induced Alzheimer's Disease via Modulation of AMPK/mTOR, Oxidative Stress and Glucose Metabolism.

Alzheimer's disease (AD) is a progressive neurological illness characterized by memory loss and cognitive deterioration. Dapagliflozin was suggested to attenuate the memory impairment associated with AD; however, its mechanisms were not fully elucidated. This study aims to examine the possible mechanisms of the neuroprotective effects of dapagliflozin against aluminum chloride (AlCl3)-induced AD. Rats were distributed into four groups: group 1 received saline, group 2 received AlCl3 (70 mg/kg) daily for 9 weeks, and groups 3 and 4 were administered AlCl3 (70 mg/kg) daily for 5 weeks. Dapagliflozin (1 mg/kg) and dapagliflozin (5 mg/kg) were then given daily with AlCl3 for another 4 weeks. Two behavioral experiments were performed: the Morris Water Maze (MWM) and the Y-maze spontaneous alternation (Y-maze) task. Histopathological alterations in the brain, as well as changes in acetylcholinesterase (AChE) and amyloid ß (Aß) peptide activities and oxidative stress (OS) markers, were all evaluated. A western blot analysis was used for the detection of phosphorylated 5' AMP-activated protein kinase (p-AMPK), phosphorylated mammalian target of Rapamycin (p-mTOR) and heme oxygenase-1 (HO-1). Tissue samples were collected for the isolation of glucose transporters (GLUTs) and glycolytic enzymes using PCR analysis, and brain glucose levels were also measured. The current data demonstrate that dapagliflozin represents a possible approach to combat AlCl3-induced AD in rats through inhibiting oxidative stress, enhancing glucose metabolism and activating AMPK signaling.

Arctigenin improves neuropathy via ameliorating apoptosis and modulating autophagy in streptozotocin-induced diabetic mice.

BACKGROUND: Oxidative stress mediates the pathophysiology of diabetic neuropathy (DN) with activation of apoptotic pathway and reduction of autophagy. Arctigenin (ARC) is a natural lignan isolated from some plants of the Asteraceae family that shows antioxidant property. The present study aimed to explore the mechanistic neuroprotective effect of ARC on animal model for DN. METHODS: DN was induced using streptozotocin (STZ) at a dose of 45 mg/kg, i.p, for five consecutive days and ARC was administered orally (25 or 50 mg) for 3 weeks. The mechanical sensitivity and thermal latency were determined using von Frey and hotplate, respectively. Beclin, p62, and LC3 were detected as markers for autophagy by western blot. Levels of reduced glutathione, lipid peroxides, and activities of catalase and superoxide dismutase were detected as readout for oxidative stress. Apoptotic parameters and histopathological changes were revealed in all experimental groups. RESULTS: The present study showed deterioration of the function and structure of neurons as a result of hyperglycemia. Oxidative stress and impaired autophagy were observed in diabetic neurons as well as the activation of apoptotic pathway. ARC improved the behavioral and histopathological changes of diabetic mice. ARC combated oxidative stress through diminishing lipid peroxidation and improving the activity of antioxidant enzymes. This was concomitant by reducing the biomarkers of apoptosis. ARC augmented the expression of Beclin and LC3 while it lessened the expression of p62 indicating the activation of autophagy. These findings suggest that ARC can ameliorate DN by combating apoptosis and oxidative stress and improving autophagy.

Canagliflozin alleviates valproic acid-induced autism in rat pups: Role of PTEN/PDK/PPAR-γ signaling pathways.

Autism is complex and multifactorial, and is one of the fastest growing neurodevelopmental disorders. Canagliflozin (Cana) is an antidiabetic drug that exhibits neuroprotective properties in various neurodegenerative syndromes. This study investigated the possible protective effect of Cana against the valproic acid (VPA)-induced model of autism. VPA was injected subcutaneously (SC) into rat pups at a dose of 300 mg/kg, twice daily on postnatal day-2 (PD-2) and PD-3, and once on PD-4 to induce an autism-like syndrome. Graded doses of Cana were administered (5 mg/kg, 7.5 mg/kg, and 10 mg/kg, P.O.) starting from the first day of VPA injections and continued for 21 days. At the end of the experiment, behavioral tests and histopathological alterations were assessed. In addition, the gene expression of peroxisome proliferator-activated receptor γ (PPAR γ), lactate dehydrogenase A (LDHA), pyruvate dehydrogenase kinase (PDK), cellular myeloctomatosis (c-Myc) with protein expression of glucose transporter-1 (GLUT-1), phosphatase and tensin homolog (PTEN), and level of acetylcholine (ACh) were determined. Treatment with Cana significantly counteracted histopathological changes in the cerebellum tissues of the brain induced by VPA. Cana (5 mg/kg, 7.5 mg/kg, and 10 mg/kg) improved sociability and social preference, enhanced stereotypic behaviors, and decreased hyperlocomotion activity, in addition to its significant effect on the canonical Wnt/ß-catenin pathway via the downregulation of gene expression of LDHA (22%, 64%, and 73% in cerebellum tissues with 51%, 60%, and 75% in cerebrum tissues), PDK (27%, 50%, and 67% in cerebellum tissues with 34%, 66%, and 77% in cerebrum tissues), c-Myc (35%, 44%, and 72% in cerebellum tissues with 19%, 58%, and 79% in cerebrum tissues), protein expression of GLUT-1 (32%, 48%, and 49% in cerebellum tissues with 30%, 50%, and 54% in cerebrum tissues), and elevating gene expression of PPAR-γ (2, 3, and 4 folds in cerebellum tissues with 1.5, 3, and 9 folds in cerebrum tissues), protein expression of PTEN (2, 5, and 6 folds in cerebellum tissues with 6, 6, and 10 folds in cerebrum tissues), and increasing the ACh levels (4, 5, and 7 folds) in brain tissues. The current study confirmed the ameliorating effect of Cana against neurochemical and behavioral alterations in the VPA-induced model of autism in rats.

Rosiglitazone Mitigates Dexamethasone-Induced Depression in Mice via Modulating Brain Glucose Metabolism and AMPK/mTOR Signaling Pathway.

Major depressive disorder (MDD) is a common, complex disease with poorly understood pathogenesis. Disruption of glucose metabolism is implicated in the pathogenesis of depression. AMP-activated protein kinase (AMPK) has been shown to regulate the activity of several kinases, including pAKT, p38MAPK, and mTOR, which are important signaling pathways in the treatment of depression. This study tested the hypothesis that rosiglitazone (RGZ) has an antidepressant impact on dexamethasone (DEXA)-induced depression by analyzing the function of the pAKT/p38MAPK/mTOR pathway and NGF through regulation of AMPK. MDD-like pathology was induced by subcutaneous administration of DEXA (20 mg/kg) for 21 days in all groups except in the normal control group, which received saline. To investigate the possible mechanism of RGZ, the protein expression of pAMPK, pAKT, p38MAPK, and 4EBP1 as well as the levels of hexokinase, pyruvate kinase, and NGF were assessed in prefrontal cortex and hippocampal samples. The activities of pAMPK and NGF increased after treatment with RGZ. The administration of RGZ also decreased the activity of mTOR as well as downregulating the downstream signaling pathways pAKT, p38MAPK, and 4EBP1. Here, we show that RGZ exerts a potent inhibitory effect on the pAKT/p38MAPK/mTOR/4EBP1 pathway and causes activation of NGF in brain cells. This study has provided sufficient evidence of the potential for RGZ to ameliorate DEXA-induced depression. A new insight has been introduced into the critical role of NGF activation in brain cells in depression. These results suggest that RGZ is a promising antidepressant for the treatment of MDD.

Lycopene protects against Bisphenol A induced toxicity on the submandibular salivary glands via the upregulation of PPAR-γ and modulation of Wnt/ß-catenin signaling.

BACKGROUND AND AIM: The submandibular salivary glands (SMG) represent a suitable model for studying epithelial cell growth and differentiation. Bisphenol A (BPA) is a xenoestrogen, synthesized to produce polymers such as polycarbonates and epoxy resins. There are concerns about the occurrence of BPA in food, water as well as its appearance in human tissues and body fluids. Lycopene (LYC) is a carotenoid compound that exerts antioxidant and anti-inflammatory properties. This work was performed to study possible protective effect of LYC against BPA toxicity in SMG. MATERIAL AND METHODS: 40 albino rats were divided into 4 groups; Group I: served as controls. Group II: rats received LYC (4 mg/kg, p.o), Group III: rats received BPA (10 mg/kg, p.o) and Group IV: rats received LYC (4 mg/kg, p.o) and BPA (10 mg/kg, p.o). All drugs were administered for 45 days then under anesthesia, rats were sacrificed. The SMG specimens were taken for histological and biochemical studies. RESULTS: BPA resulted in a significant rise of malondialdehyde, tumor necrosis factor-α and interleukine-1ß. In contrast, the tissue levels of glutathione and PPAR-γ were significantly decreased. BPA activated Wnt/ß-catenin pathway evidenced by upregulating WNT3a, ß-catenin and c-myc expression. Moreover, SMG of BPA showed degenerative changes that affected the parenchymal and stromal elements of the glands. The immunohistochemical localization of cytokeratin 5,6 and 18 of BPA rats revealed weak immunostaining of the serous secretory cells, myoepithelial cells and ductal cells. Upon treatment with LYC, glutathione and PPAR-γ were restored. CONCLUSION: LYC acted as a protective agent against BPA-induced pathological changes in SMG.

Pioglitazone Ameliorates Hippocampal Neurodegeneration, Disturbances in Glucose Metabolism and AKT/mTOR Signaling Pathways in Pentyelenetetrazole-Kindled Mice.

Disturbance of glucose metabolism, nerve growth factor (NGF) and m-TOR signaling have been associated with the pathophysiology of epilepsy. Pioglitazone (PGZ) is an anti-diabetic drug that shows a protective effect in neurodegenerative diseases including epilepsy; however, its exact mechanism is not fully elucidated. The present study aimed to investigate the potential neuroprotective effect of PGZ in pentylenetetrazole (PTZ) kindled seizure in mice. Swiss male albino mice were randomly distributed into four groups, each having six mice. Group 1 was considered the control. Epilepsy was induced by PTZ (35 mg/kg i.p.) thrice a week for a total of 15 injections in all other groups. Group 2 was considered the untreated PTZ group while Group 3 and Group 4 were treated by PGZ prior to PTZ injection at two dose levels (5 and 10 mg/kg p.o., respectively). Seizure activity was evaluated after each PTZ injection according to the Fischer and Kittner scoring system. At the end of the experiment, animals were sacrificed under deep anesthesia and the hippocampus was isolated for analysis of glucose transporters by RT-PCR, nerve growth factor (NGF) by ELISA and mTOR by western blotting, in addition to histopathological investigation. The PTZ-treated group showed a significant rise in seizure score, NGF and m-TOR hyperactivation, along with histological abnormalities compared to the control group. Treatment with PGZ demonstrated a significant decrease in NGF, seizure score, m-TOR, GLUT-1 and GLUT-3 in comparison to the PTZ group. In addition, improvement of histological features was observed in both PGZ treated groups. These findings suggest that PGZ provides its neuroprotective effect through modulating m-TOR signaling, glucose metabolism and NGF levels.

Pyrvinium pamoate ameliorates cyclosporin A- induced hepatotoxicity via the modulation of Wnt/ß-catenin signaling and upregulation of PPAR-γ.

BACKGROUND: Cyclosporin A (CsA) is an immunosuppressive agent that can be used to treat autoimmune diseases. Despite its hepatotoxicity, CsA is a backbone in organ transplantation. Pyrvinium pamoate (PP) is an inhibitor of Wnt signaling approved by the U.S. Food and Drug Administration for its anthelmintic properties. AIM: The goal of this investigation was to determine whether PP could protect against CsA-induced hepatotoxicity. METHOD: Five groups of 50 albino male mice were selected and divided into five groups; group 1 was the control, groups 2 to 4 were subjected to daily CsA (25 mg/kg, i.p), in which groups 3 and 4 were treated with graded dose of PP (0.25, 0.5 mg/kg), and group 5 was treated with PP (0.5 mg/ kg) for 21 days. The mice were sacrificed under anesthesia, and their livers were removed for histological and biochemical assessment. RESULTS: CsA was found to cause a striking increase in liver enzymes, total bilirubin, and malondialdehyde levels while significantly decreasing the levels of albumin, glutathione, and antioxidant enzymes in the treated groups. The tissue levels of tumor necrosis factor-α, interleukin-1ß, and NFКB were also significantly higher with CsA treatment. Moreover, CsA triggered a notable increase in the levels of apoptotic marker P53. CsA activated the Wnt/ß-catenin pathway by increasing WNT3a expression, frizzled receptor-7, ß-catenin, and c-myc. On the other hand, the levels of PPAR-γ decreased significantly with CsA. CsA-induced alterations in the previously stated parameters were greatly reduced by PP, indicating its antioxidant, anti-inflammatory, and antiapoptotic properties. CONCLUSIONS: PP may be considered as a promising agent to prevent CsA hepatotoxicity.

Dapagliflozin attenuates diabetic cardiomyopathy through erythropoietin up-regulation of AKT/JAK/MAPK pathways in streptozotocin-induced diabetic rats.

PURPOSE: This study was designed to investigate the mechanism of Dapagliflozin (Dapa) cardioprotection against diabetic cardiomyopathy (DCM). Structural and functional changes in the heart as well as decrease of erythropoietin (EPO) levels were reported in DCM. EPO simultaneously activates three pathways: the Janus-activated kinase-signal transducer and activator of transcription (JAK2/STAT5), phosphatidylinositol-3-kinase-Akt (PI3K/Akt), and extracellular signal-related kinase (ERK/MAPK) cascades, that result in proliferation and differentiation of cardiac cells. METHODS AND RESULTS: DCM was induced by a high fat diet for 10 weeks followed by administration of streptozotocin. After confirmation of diabetes, rats were divided randomly to 5 groups: Group 1; normal control group, Group 2; untreated diabetic group and Groups (3-5); diabetic groups received Dapa daily (0.75 mg, 1.5 or 3 mg/Kg, p.o) respectively for a month. At the end of the experiment, full anaesthesia was induced in all rats using ether inhalation and ECG was recorded. Blood samples were collected then rats were sacrificed and their heart were dissected out and processed for biochemical and histopathological studies. Untreated diabetic rats showed abnormal ECG pattern, elevation of serum cardiac enzymes, decrease EPO levels, downregulation of P-Akt, P-JAK2 and pMAPK pathways, abnormal histological structure of the heart and increase immunostaining intensity of P53 and TNF α in the cardiomyocytes. Dapa in a dose dependent manner attenuated the alterations in the previously mentioned parameters. CONCLUSION: The cardioprotective effect of Dapa could be mediated by increasing EPO levels and activation of P-Akt, P-JAK2 and pMAPK signalling cascades which in turn decrease apoptosis.

Raspberry Ketones Attenuate Cyclophosphamide-Induced Pulmonary Toxicity in Mice through Inhibition of Oxidative Stress and NF-ΚB Pathway.

Cyclophosphamide (CP) was found to have a potential toxic effect on lung tissues. Raspberry ketones (RKs) are natural antioxidant chemicals isolated from red raspberries (Rubus ideaus). They are commonly used for weight loss and obesity. The current study aimed to evaluate the possible protective effects of RKs against lung toxicity induced by CP. Mice were allocated into six groups: (1) control group; (2) CP group: received a single intraperitoneal dose of CP (150 mg/kg, i.p.); and (3-6) mice were pre-treated orally with different doses of RKs (25, 50, 100, and 200 mg/kg) for 14 consecutive days, respectively, before the administration of an intraperitoneal dose of CP (150 mg/kg, i.p.). Mice were then sacrificed under anesthesia, then lungs were removed for histopathological and biochemical investigations. A single dose of CP markedly altered the levels of some oxidative stress biomarkers and resulted in the fragmentation of DNA in lung homogenates. Histological examination of CP-treated mice demonstrated diffuse alveolar damage that involved apparent hyalinization of membranes, thickening of inter alveolar septa, and proliferation of type II pneumocytes. The immunohistochemical results of CP-treated mice revealed strongly positive Bax and weakly positive proliferating cell nuclear antigen (PCNA) staining reactivity of the nuclei of the lining epithelium of the bronchioles and alveoli. CP activated the cyclooxygenase-2/nuclear factor-kappa B pathway. However, pre-treatment with RKs significantly attenuated CP-evoked alterations in the previously mentioned parameters, highlighting their antioxidant, anti-inflammatory, and anti-apoptotic potential. RKs may be suggested to be a potential candidate to ameliorate CP-induced pulmonary toxicity.

Jaceidin Flavonoid Isolated from Chiliadenus montanus Attenuates Tumor Progression in Mice via VEGF Inhibition: In Vivo and In Silico Studies.

Phytochemical study of Chiliadenus montanus aerial parts afforded six compounds; Intermedeol (1), 5α-hydroperoxy-ß-eudesmol (2), 5,7-dihydroxy-3,3',4'-trimethoxyflavone (3), 5,7,4'-trihydroxy-3,6,3'-trimethoxyflavone (jaceidin) (4), eudesm-11,13-ene-1ß,4ß,7α-triol (5) and 1ß,4ß,7ß,11-tetrahydroxyeudesmane (6). These compounds were identified based on their NMR spectral data. The isolated compounds were tested for their cytotoxicity against liver cancer cell line (HepG2) and breast cancer cell line (MCF-7). Jaceidin flavonoid (4) exhibited the highest cytotoxic effect in vitro. Therefore, both of jaceidin and C. montanus extract were evaluated for their in vivo anti-tumor activity against Ehrlich's ascites carcinoma (EAC). Compared to control group, jaceidin and C. montanus extract decreased the tumor weight, improved the histological picture of tumor cells, lowered the levels of VEGF and ameliorate the oxidative stress. Molecular docking and in silico studies suggested that jaceidin was a selective inhibitor of VEGF-mediated angiogenesis with excellent membrane permeability and oral bioavailability.

Nano selenium ameliorates oxidative stress and inflammatory response associated with cypermethrin-induced neurotoxicity in rats.

Cypermethrin (CYP), a class II synthetic pyrethroid, is used to control household insects. CYP can cross the blood-brain barrier to exert neurotoxicity through changes in sodium ion channels. Selenium is an essential component of glutathione peroxidise enzyme; in addition, it shows a potential anti-inflammatory property. The present study aimed to investigate the neuroprotective role of Nano-Se on CYP-induced neurotoxicity. Twenty-four adult male Wister rats were randomly divided into three groups: a) control, b) CYP (1mg/kg) administered orally for 21 days, c) CYP (1mg/kg) administered orally for 21 days and Nano-Se (2.5 mg/kg) given once a day three times a week for three weeks). Locomotor activity was assessed using open field test then rats were sacrificed under anaesthesia, and their brains were dissected out and processed for biochemical and histopathological studies. Histological examination of CYP-treated rats demonstrated some degenerative changes; besides, CYP affected rat locomotor activity. CYP-treated rats showed increased levels of malondialdehyde (MDA), TNF-α and IL-1ß in addition to the reduction of glutathione (GSH) levels and gamma-Aminobutyric acid (GABA). Nano-Se restored normal behavioural function and significantly attenuated CYP-evoked degenerative changes. Nano-Se increased levels of GABA and glutathione; on the other hand, it significantly prevented the rise in the levels of MDA, TNF-α and IL-1ß. Therefore, Nano-Se demonstrated both anti-oxidant and anti-inflammatory potential. Nano-Se may be suggested to be a prospective candidate to ameliorate CYP-induced neurotoxicity.

Toward a treatment of diabesity: Rational design, synthesis and biological evaluation of benzene-sulfonamide derivatives as a new class of PTP-1B inhibitors.

Targeting of protein tyrosine phosphatase-1B (PTP1B) has emerged as a promising strategy for therapeutic intervention of diabetes and obesity. Investigation of new inhibitors with good bioavailability and high selectivity is the major challenge of drug discovery program targeting PTP1B. Therefore, herein, new neutral benzene-sulfonamide containing compounds were designed, synthesized and biologically evaluated as potent PTP1B inhibitors. New series of thiazolidine, oxazolidine, thiazinan, oxazinan, oxazole, thiazole, tetrazole, cyanopyridine, chromenone, and iminochromene of benzene-sulfonamide derivatives (MSE-1 to MSE-15) were synthesized in a good yield under mild condition using sulfadiazine as a starting material. Among the synthesized compounds, MSE-13 and MSE-14 showed the most in vitro potent PTP-1B inhibitory activity (IC50 of 0.88 µM and 3.33 µM, respectively). Animal treatment by the target compounds significantly improved the insulin resistance, diminished plasma glucose level, decreased initial body weight, and normalized the serum lipid profile compared to pioglitazone, a standard PTP1B inhibitor. The molecular modeling study showed a high affinity and selectivity of our synthesized compounds to the active site and B-site of PTP1B holding hydrogen bonding, hydrophobic, and electrostatic interactions. Furthermore, Electrostatic Surface Potential (ESP) and HOMO/LUMO analysis indicated the importance of sulfamoyl moiety for PTP1B binding. In silico ADME predictions of such compounds also showed the promising pharmacokinetic and physicochemical properties. The proposed compounds could be considered a lead inhibitory scaffold to PTP1B.

Donepezil improves neuropathy through activation of AMPK signalling pathway in streptozotocin-induced diabetic mice.

Diabetic neuropathy (DN) is a common complication of diabetes mellitus and is associated with structural changes in the nerves. However, the molecular basis for DN is poorly understood. Adenosine monophosphate activated protein kinase (AMPK) has been shown to regulate the activity of some kinases including protein kinase B (AKT), mitogen-activated protein kinases (MAPK) and mammalian target of rapamycin complex 1 (mTORC1) that represent important signalling pathways modulating the function of peripheral nociceptive neuron. Donepezil can activate AMPK and exerts neuroprotective effects. In this study, streptozotocin (45 mg/kg for 5 Day, i.p.) was used to induce experimental DN. After confirmation of development of neuropathy, mice were randomly distributed into five groups: Group 1; negative control group received saline (0.9%NaCl), Group 2; diabetic mice received saline, Group (3-5); diabetic mice received daily donepezil (1, 2 or 4 mg/kg, p.o.) respectively for 20 days. Mice were then sacrificed under anesthesia then their sciatic nerve and spinal cord were dissected out and processed for biochemical and histopathological studies. Diabetic mice revealed severe histological abnormalities including degenerated neurons in the spinal cord and swollen myelin sheath with inflammatory edema observed in sciatic nerves. In addition, diabetic mice showed reduced expression of p-AMPK in sciatic nerves with consequent activation of AKT/MAPK/4EBP1. A significant upregulation of the N-Methyl-d-aspartate (NMDA) receptors in both cervical and lumbar regions of spinal cord of diabetic mice was also demonstrated. Donepezil, an AMPK activator, blocked the phosphorylation of AKT/MAPK/4EBP1, down regulate the expression of NMDA receptors and reversed hyperalgesia developed in diabetic mice. Therefore, Donepezil could be a potential pharmacological agent for management of DN.

Isolated compounds from Cuscuta pedicellata ameliorate oxidative stress and upregulate expression of some energy regulatory genes in high fat diet induced obesity in rats.

BACKGROUND: Cuscuta pedicellata and some of its isolated compounds were suggested previously to have an anti-obesity effect in rats. This study aimed to investigate the effect of ten isolated compounds from C. pedicellata on insulin resistance, some oxidative stress markers and expression of the mitochondrial uncoupling protein-1 (UCP-1) and Carnitine palmitoyltransferase-I (CPT-1) genes in brown adipose tissue of high fat diet (HFD) rats. METHODS: One hundred and four male albino rats were divided into 13 groups. Group (1) was considered as normal untreated rats. Obesity was induced in all other groups by HFD. Group (2) served as obese control group and groups (3-11) were treated for four weeks with C. pedicellata extract or one of its isolated compounds (naringenin, kaempferol, aromadenderin, quercetin, 3,5,7,30,50-pentahydroxy flavanone, naringenin-7-O-b-d-glucoside, aromadenderin-7-O-b-d-glucoside, taxifolin 7-O-b-d-glucoside, kaempferol-3-O-b-d-glucoside [astragalin], and quercitin-3-O-b-d-glucoside [isoquercitrin]). At the end of the experiment, rats were then sacrificed under anesthesia and their brown adipose tissues were dissected out for determination of UCP-1 and CPT-1 genes using quantitative PCR. Blood samples were collected for determination of blood glucose, insulin, thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD) and catalase. RESULTS: A significant reduction in homeostasis model assessment-insulin resistance (HOMA-IR) and TBARS levels was observed in rats treated with C. pedicellata crude extract and some of its isolated compounds, with a significant increase in SOD and catalase levels and upregulation of UCP-1 and CPT-1 genes expression compared to the obese control group. CONCLUSIONS: This study suggests a beneficiary role of C. pedicellata in reducing insulin resistance, oxidative stress and enhancing energy expenditure.

Glutamine up-regulates pancreatic sodium-dependent neutral aminoacid transporter-2 and mitigates islets apoptosis in diabetic rats.

BACKGROUND: Glutamine aminoacid regulates insulin exocytosis from pancreatic ß-cells. Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has fascinated function in inhibiting ß-cell apoptosis and preserving pancreatic ß-cell mass. The present study investigated the benefit of adding glutamine to a regimen of liraglutide in diabetic rats focusing on their role in increasing insulin production and upregulation of the expression of sodium-dependent neutral aminoacid transporter-2 (SNAT2). METHODS: In the present study, diabetes mellitus was induced in rats using streptozotocin (STZ, 50mg/kg, ip). Male rats were allocated into 5 groups, (i) vehicle group, (ii) STZ-diabetic rats, (iii) STZ-diabetic rats treated with liraglutide (150µg/kg, sc), (iv) STZ-diabetic rats treated with glutamine (po) and (v) STZ-diabetic rats treated with a combination of liraglutide and glutamine for four weeks. After finishing the therapeutic courses, the fasting blood glucose value was determined and rats were sacrificed. Pancreases were used for quantification of mRNA expression for SNAT2. Paraffin fixed samples were used for histologic staining and immunohistochemistry for insulin and apoptosis markers (activated caspase-3, BCL2 and BAX). RESULTS: Treatment with liraglutide and/or glutamine enhanced insulin production and hence glycemic control in diabetic male rats with favorable effects on apoptosis markers. Treatment with glutamine and its combination with liraglutide significantly increased pancreatic expression of SNAT2 by approximately 30-35 folds. CONCLUSION: Addition of glutamine to liraglutide regimen enhances the glycemic control and may have utility in clinical settings.

Cytotoxic effect of chlorpyrifos is associated with activation of Nrf-2/HO-1 system and inflammatory response in tongue of male Wistar rats.

Repeated administration of chlorpyrifos (CPF), an organophosphate pesticide, can increase the risk of oral cytotoxicity. The current study was designed to assess the mechanism by which CPF mediates its cytotoxic effect on lingual mucosa of rats. Twenty-four male Wistar rats were used in the present study and divided into three groups: group I: healthy rats (negative control), group II: rats treated with CPF 1/40 LD50 (3.375 mg/kg, orally/daily) for 28 days, group III: rats treated with CPF 1/10 LD50 (13.5 mg/kg, orally/daily) for 28 days. At the end of the experiment, all rats were sacrificed by cervical dislocation under ketamine anesthesia. Tongue samples were dissected out at their base for detection of heme oxygenase-1 (HO-1) and nuclear erythroid 2-related factor 2 (Nrf-2) by western blotting and histopathological and electron microscopic studies. Immunostaining was used to determine cleaved caspase 3 and the nuclear factor kappa B (NF-κB) localization. Structural and ultrastructural examination of treated lingual mucosa with CPF demonstrated degenerative changes that involved both the dorsal and ventral surfaces of the tongue as well as the lingual glands. CPF-treated rats demonstrated a significant increase in the levels of pro-inflammatory cytokines such as interleukin-1ß (IL-1ß) and tumor necrosis factor (TNF-α) in addition to a significant dose-dependent activation of NF-κB and cleaved caspase 3. Furthermore, CPF activated HO-1 and Nrf-2 pathway in a dose-dependent manner. In conclusion, this data suggests that the CPF-induced cytotoxicity may be explained by NF-κB activated inflammatory cascade. In addition, CPF triggers an adaptive activation of Nrf-2/HO-1 pathway.