Potential exacerbation of polycystic ovary syndrome by saccharin sodium Via taste receptors in a letrozole rat model.

The most common cause of anovulatory infertility is polycystic ovarian syndrome (PCOS), which is closely associated with obesity and metabolic syndrome. Artificial sweetener, notably saccharin sodium (SS), has been utilized in management of obesity in PCOS. However, accumulating evidence points towards SS deleterious effects on ovarian physiology, potentially through activation of ovarian sweet and bitter taste receptors, culminating in a phenotype reminiscent of PCOS. This research embarked on exploration of SS influence on ovarian functions within a PCOS paradigm. Rats were categorized into six groups: Control, Letrozole-model, two SS groups at 2 dose levels, and two groups receiving 2 doses of SS with Letrozole. The study underscored SS capability to potentiate PCOS-related anomalies. Elevated cystic profile with outer thin granulosa cells, were discernible. This owed to increased apoptotic markers as cleaved CASP-3, mirrored by high BAX and low BCL-2, with enhanced p38-MAPK/ERK1/2 pathway. This manifestation was accompanied by activation of taste receptors and disruption of steroidogenic factors; StAR, CYP11A1, and 17ß-HSD. Thus, SS showed an escalation in testosterone, progesterone, estrogen, and LH/FSH ratio, insinuating a perturbation in endocrine regulation. It is found that there is an impact of taste receptor downstream signaling on ovarian steroidogenesis and apoptosis instigating pathophysiological milieu of PCOS.

Potential for cardiac toxicity with methylimidazolium ionic liquids.

Methylimidazolium ionic liquids (MILs) are solvent chemicals used in industry. Recent work suggests that MILs are beginning to contaminate the environment and lead to exposure in the general population. In this study, the potential for MILs to cause cardiac toxicity has been examined. The effects of 5 chloride MIL salts possessing increasing alkyl chain lengths (2 C, EMI; 4 C, BMI; 6 C; HMI, 8 C, M8OI; 10 C, DMI) on rat neonatal cardiomyocyte beat rate, beat amplitude and cell survival were initially examined. Increasing alkyl chain length resulted in increasing adverse effects, with effects seen at 10-5 M at all endpoints with M8OI and DMI, the lowest concentration tested. A limited sub-acute toxicity study in rats identified potential cardiotoxic effects with longer chain MILs (HMI, M8OI and DMI) based on clinical chemistry. A 5 month oral/drinking water study with these MILs confirmed cardiotoxicity based on histopathology and clinical chemistry endpoints. Since previous studies in mice did not identify the heart as a target organ, the likely cause of the species difference was investigated. qRT-PCR and Western blotting identified a marked higher expression of p-glycoprotein-3 (also known as ABCB4 or MDR2) and the breast cancer related protein transporter BCRP (also known as ABCG2) in mouse, compared to rat heart. Addition of the BCRP inhibitor Ko143 - but not the p-glycoproteins inhibitor cyclosporin A - increased mouse cardiomyocyte HL-1 cell sensitivity to longer chain MILs to a limited extent. MILs therefore have a potential for cardiotoxicity in rats. Mice may be less sensitive to cardiotoxicity from MILs due in part, to increased excretion via higher levels of cardiac BCRP expression and/or function. MILs alone, therefore may represent a hazard in man in the future, particularly if use levels increase. The impact that MILs exposure has on sensitivity to cardiotoxic drugs, heart disease and other chronic diseases is unknown.

Targeting α7-nAChR by galantamine mitigates reserpine-induced fibromyalgia-like symptoms in rats: Involvement of cAMP/PKA, PI3K/AKT, and M1/M2 microglia polarization.

Fibromyalgia (FM) is a pain disorder marked by generalized musculoskeletal pain accompanied by depression, fatigue, and sleep disturbances. Galantamine (Gal) is a positive allosteric modulator of neuronal nicotinic acetylcholine receptors (nAChRs) and a reversible inhibitor of cholinesterase. The current study aimed to explore the therapeutic potential of Gal against reserpine (Res)-induced FM-like condition along with investigating the α7-nAChR's role in Gal-mediated effects. Rats were injected with Res (1 mg/kg/day; sc) for 3 successive days then Gal (5 mg/kg/day; ip) was given alone and with the α7-nAChR blocker methyllycaconitine (3 mg/kg/day; ip), for the subsequent 5 days. Galantamine alleviated Res-induced histopathological changes and monoamines depletion in rats' spinal cord. It also exerted analgesic effect along with ameliorating Res-induced depression and motor-incoordination as confirmed by behavioral tests. Moreover, Gal produced anti-inflammatory effect through modulating AKT1/AKT2 and shifting M1/M2 macrophage polarization. The neuroprotective effects of Gal were mediated through activating cAMP/PKA and PI3K/AKT pathways in α7-nAChR-dependent manner. Thus, Gal can ameliorate Res-induced FM-like symptoms and mitigate the associated monoamines depletion, neuroinflammation, oxidative stress, apoptosis, and neurodegeneration through α7-nAChR stimulation, with the involvement of cAMP/PKA, PI3K/AKT, and M1/M2 macrophage polarization.

Microglia polarization in nociplastic pain: mechanisms and perspectives.

Nociplastic pain is the third classification of pain as described by the International Association for the Study of Pain (IASP), in addition to the neuropathic and nociceptive pain classes. The main pathophysiological mechanism for developing nociplastic pain is central sensitization (CS) in which pain amplification and hypersensitivity occur. Fibromyalgia is the prototypical nociplastic pain disorder, characterized by allodynia and hyperalgesia. Much scientific data suggest that classical activation of microglia in the spinal cord mediates neuroinflammation which plays an essential role in developing CS. In this review article, we discuss the impact of microglia activation and M1/M2 polarization on developing neuroinflammation and nociplastic pain, besides the molecular mechanisms engaged in this process. In addition, we mention the impact of microglial modulators on M1/M2 microglial polarization that offers a novel therapeutic alternative for the management of nociplastic pain disorders. Illustrating the mechanisms underlying microglia activation in central sensitization and nociplastic pain. LPS lipopolysaccharide, TNF-α tumor necrosis factor-α, INF-γ Interferon gamma, ATP adenosine triphosphate, 49 P2Y12/13R purinergic P2Y 12/13 receptor, P2X4/7R purinergic P2X 4/7 receptor, SP Substance P, NK-1R Neurokinin 1 receptor, CCL2 CC motif ligand 2, CCR2 CC motif ligand 2 receptor, CSF-1 colony-stimulating factor 1, CSF-1R colony-stimulating factor 1 receptor, CX3CL1 CX3C motif ligand 1, CX3XR1 CX3C motif ligand 1 receptor, TLR toll-like receptor, MAPK mitogen-activated protein kinases, JNK jun N-terminal kinase, ERK extracellular signal-regulated kinase, iNOS Inducible nitric oxide synthase, IL-1ß interleukin-1ß, IL-6 interleukin-6, BDNF brain-derived neurotrophic factor, GABA γ-Aminobutyric acid, GABAR γ-Aminobutyric acid receptor, NMDAR N-methyl-D-aspartate receptor, AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropi-onic acid receptor, IL-4 interleukin-4, IL-13 interleukin-13, IL-10 interleukin-10, Arg-1 Arginase 1, FGF fibroblast growth factor, GDNF glial cell-derived neurotrophic factor, IGF-1 insulin-like growth factor-1, NGF nerve growth factor, CD Cluster of differentiation.

Boosting amygdaloid GABAergic and neurotrophic machinery via dapagliflozin-enhanced LKB1/AMPK signaling in anxious demented rats.

Anxiety is a neuropsychiatric disturbance that is commonly manifested in various dementia forms involving Alzheimer's disease (AD). The mechanisms underlying AD-associated anxiety haven't clearly recognized the role of energy metabolism in anxiety represented by the amygdala's autophagic sensors; liver kinase B1 (LKB1)/adenosine monophosphate kinase (AMPK). Dapagliflozin (DAPA), a SGLT2 inhibitor, acts as an autophagic activator through LKB1 activation in several diseases including AD. Herein, the propitious yet undetected anxiolytic potential of DAPA as an autophagic enhancer was investigated in AD animal model with emphasis on amygdala's GABAergic neurotransmission and brain-derived neurotrophic factor (BDNF). Alzheimer's disease was induced by ovariectomy (OVX) along with seventy-days-D-galactose (D-Gal) administration (150 mg/kg/day, i.p). On the 43rd day of D-Gal injection, OVX/D-Gal-subjected rats received DAPA (1 mg/kg/day, p.o) alone or with dorsomorphin the AMPK inhibitor (DORSO, 25 µg/rat, i.v.). In the amygdala, LKB1/AMPK were activated by DAPA inducing GABAB2 receptor stimulation; an effect that was abrogated by DORSO. Dapagliflozin also replenished the amygdala GABA, NE, and 5-HT levels along with glutamate suppression. Moreover, DAPA triggered BDNF production with consequent activation of its receptor, TrkB through activating GABAB2-related downstream phospholipase C/diacylglycerol/protein kinase C (PLC/DAG/PKC) signaling. This may promote GABAA expression, verifying the crosstalk between GABAA and GABAB2. The DAPA's anxiolytic effect was visualized by improved behavioral traits in elevated plus maze together with amendment of amygdala' histopathological abnormalities. Thus, the present study highlighted DAPA's anxiolytic effect which was attributed to GABAB2 activation and its function to induce BDNF/TrkB and GABAA expression through PLC/DAG/PKC pathway in AMPK-dependent manner.

Neuroprotective Effect of Gold Nanoparticles and Alpha-Lipoic Acid Mixture against Radiation-Induced Brain Damage in Rats.

The current study aims to evaluate the possible neuroprotective impact of gold nanoparticles (AuNPs) and an alpha-lipoic acid (ALA) mixture against brain damage in irradiated rats. AuNPs were synthesized and characterized using different techniques. Then, a preliminary investigation was carried out to determine the neuroprotective dose of AuNPs, where three single doses (500, 1000, and 1500 µg/kg) were orally administrated to male Wistar rats, one hour before being exposed to a single dose of 7Gy gamma radiation. One day following irradiation, the estimation of oxidative stress biomarkers (malondialdehyde, MDA; glutathione peroxidase, GPX), DNA fragmentation, and histopathological alterations were performed in brain cortical and hippocampal tissues in both normal and irradiated rats. The chosen neuroprotective dose of AuNPs (1000 µg/kg) was processed with ALA (100 mg/kg) to prepare the AuNPs-ALA mixture. The acute neuroprotective effect of AuNPs-ALA in irradiated rats was determined against valproic acid as a neuroprotective centrally acting reference drug. All drugs were orally administered one hour before the 7Gy-gamma irradiation. One day following irradiation, animals were sacrificed and exposed to examinations such as those of the preliminary experiment. Administration of AuNPs, ALA, and AuNPs-ALA mixture before irradiation significantly attenuated the radiation-induced oxidative stress through amelioration of MDA content and GPX activity along with alleviating DNA fragmentation and histopathological changes in both cortical and hippocampal tissues. Notably, the AuNPs-ALA mixture showed superior effect compared to that of AuNPs or ALA alone, as it mitigated oxidative stress, DNA damage, and histopathological injury collectively. Administration of AuNPs-ALA resulted in normalized MDA content, increased GPX activity, restored DNA content in the cortex and hippocampus besides only mild histopathological changes. The present data suggest that the AuNPs-ALA mixture may be considered a potential candidate for alleviating radiation-associated brain toxicity.

Inosine mitigated diabetic peripheral neuropathy via modulating GLO1/AGEs/RAGE/NF-κB/Nrf2 and TGF-ß/PKC/TRPV1 signaling pathways.

Inosine is a dietary supplement that is widely used for managing numerous central neurological disorders. Interestingly, recent experimental investigation of inosine revealed its potential to promote peripheral neuroprotection after sciatic nerve injury. Such investigation has guided the focus of the current study to expose the potential of inosine in mitigating diabetic peripheral neuropathy (DPN) in rats and to study the possible underlying signaling pathways. Adult male Wistar rats were arbitrarily distributed into four groups. In the first group, animals received saline daily for 15 days whereas rats of the remaining groups received a single injection of both nicotinamide (50 mg/Kg/i.p.) and streptozotocin (52.5 mg/Kg/i.p.) for DPN induction. Afterward, inosine (10 mg/Kg/p.o.) was administered to two groups, either alone or in combination with caffeine (3.75 mg/Kg/p.o.), an adenosine receptor antagonist. As a result, inosine showed a hypoglycemic effect, restored the sciatic nerve histological structure, enhanced myelination, modulated conduction velocities and maintained behavioral responses. Furthermore, inosine increased GLO1, reduced AGE/RAGE axis and oxidative stress which in turn, downregulated NF-κB p65 and its phosphorylated form in the sciatic nerves. Inosine enhanced Nrf2 expression and its downstream molecule HO-1, resulting in increased CAT and SOD along with lowered MDA. Moreover, pain was relieved due to suppression of PKC and TRPV1 expression, which ultimately lead to reduced SP and TGF-ß. The potential effects of inosine were nearly blocked by caffeine administration; this emphasizes the role of adenosine receptors in inosine-mediated neuroprotective effects. In conclusion, inosine alleviated hyperglycemia-induced DPN via modulating GLO1/AGE/RAGE/NF-κB p65/Nrf2 and TGF-ß/PKC/TRPV1/SP pathways.

Nano-ivabradine averts behavioral anomalies in Huntington's disease rat model via modulating Rhes/m-tor pathway.

Huntington's disease (HD) is characterized by abnormal involuntary movements together with cognitive impairment and disrupted mood changes. 3-nitropropionic acid (3-NP) is one of the chemo-toxic models used to address the striatal neurotoxicity pattern encountered in HD. This study aims to explain the neuroprotective effect of nano-formulated ivabradine (nano IVA) in enhancing behavioral changes related to 3-NP model and to identify the involvement of ras homolog enriched striatum (Rhes)/mammalian target of rapamycin (m-Tor) mediated autophagy pathway. Rats were divided into 6 groups, the first 3 groups received saline (control), ivabradine (IVA), nano IVA respectively, the fourth received a daily dose of 3-NP (20 mg/kg, s.c) for 2 weeks, the fifth received 3-NP + IVA (1 mg/kg, into the tail vein, every other day for 1 week) and the last group received 3-NP + nano IVA (1 mg/kg, i.v, every other day for 1 week). Interestingly, nano IVA reversed motor disabilities, improved memory function and overcame the psychiatric changes. It boosted expression of autophagy markers combined with down regulation of Rhes, m-Tor and b-cell lymphoma 2 protein levels. Also, it restored the normal level of neurotransmitters and myocardial function related-proteins. Histopathological examination revealed a preserved striatal structure with decreased number of darkly-degenerated neurons. In conclusion, the outcomes of this study provide a well-recognized clue for the promising neuroprotective effect of IVA and the implication of autophagy and Rhes/m-Tor pathways in the 3-NP induced HD and highlight the fact that nano formulations of IVA would be an auspicious approach in HD therapy.

The role of KATP channel blockade and activation in the protection against neurodegeneration in the rotenone model of Parkinson's disease.

AIMS: Several studies suggested that ATP-sensitive potassium channels (KATP) are potential therapeutic targets for protection against various neurodegenerative disorders, yet, there is an ongoing controversy regarding their role in Parkinson's disease (PD). Thus, the aim of the current study is to investigate the protective effect of KATP blockade and activation in the mice rotenone model of PD. MAIN METHODS: PD has been induced by 9 subcutaneous injections of rotenone (1.5 mg/kg; 3 times/week) in adult male Swiss albino mice. For 3 consecutive weeks, parkinsonian mice were either untreated or treated with L-dopa (25 mg/kg), the KATP channel blocker glibenclamide (3 mg/kg) or the KATP channel opener nicorandil (6 mg/kg). KEY FINDINGS: Glibenclamide significantly improved motor performance in the wire hanging and stair tests and halted the decline in striatal dopamine content as well as dopaminergic neurons' density. In addition, it reduced the rotenone-induced apoptosis as portrayed in the immunohistopathological examination via increasing Bcl-2 and decreasing caspases-3, -8, -9 contents. Furthermore, through its anti-inflammatory potential, glibenclamide reduced tumor necrosis factor-alpha level. On the other hand, nicorandil failed to mitigate the rotenone-induced neurodegenerative consequences. SIGNIFICANCE: KATP channel blockade by glibenclamide has neuroprotective effect against rotenone-induced neurotoxicity, that was mediated by its anti-inflammatory effect along with hindering apoptosis through extrinsic and intrinsic pathways.

Cognitive enhancing effect of diapocynin in D-galactose-ovariectomy-induced Alzheimer's-like disease in rats: Role of ERK, GSK-3ß, and JNK signaling.

NADPH oxidase (NOX) has been identified as a crucial contender of oxidative damage in Alzheimer's disease (AD). However, the capability of diapocynin, a NOX inhibitor, to offer neuroprotection in AD models is still a matter of debate. Hence, the current work is dedicated to investigate the influence of diapocynin on cognitive impairment prompted by ovariectomy combined with D-galactose injection in rats (an AD animal model), and to elucidate the signaling mechanisms regulating diapocynin-induced effects. Female rats were exposed to ovariectomy or sham operation. Ovariectomized rats were injected intraperitoneally with D-galactose (150 mg/kg/day) for 70 days and, on day 43, they were orally treated with diapocynin (10 mg/kg/day) for 28 days. Diapocynin amended cognitive functions as confirmed using novel object recognition and Morris water maze tests along with histopathological improvement. It caused a prominent decrement in ß-secretase, p-tau, and amyloid ß, contrary to α-secretase elevation in hippocampus and hampered neuroinflammation and oxidative stress, manifested by declined levels of NOX1, tumor necrosis factor-α, and nuclear factor-kappa B p65. In addition, diapocynin augmented synaptophysin, brain-derived neurotrophic factor, and phospho-cAMP response element binding protein and enhanced protein expression of phosphorylated forms of phosphoinositide 3-kinase (PI3K), glycogen synthase kinase-3ß (GSK-3ß), protein kinase B (Akt), extracellular signal-regulated kinase (ERK) 1/2, ERK kinase kinase (Raf-1), and ERK kinase (MEK) 1/2, while inhibiting those of c-Jun and c-Jun N-terminal kinase (JNK). In conclusion, diapocynin attenuated memory impairment and AD-like anomalies via activating Raf-1/MEK/ERK and PI3K/Akt/GSK-3ß, while inhibiting JNK/c-Jun signaling cascades.

Ellagic acid attenuates liver toxicity induced by valproic acid in rats.

Valproic acid is a commonly used drug for many psychiatric disorders, particularly for epilepsy. However, it has been reported that its use is associated with possible side effects including hepatotoxicity. The present study investigated the hepatoprotective effect of ellagic acid against valproic acid-induced hepatotoxicity in rats. Ellagic acid (60 mg/kg/day; p.o) was treated for one week, followed by concomitant injection of valproic acid (250 mg/kg/day; i.p.) for another 14 consecutive days to induce hepatocellular damage in adult Sprague-Dawley rats. Valproic acid showed a marked increase in serum enzyme activities, AST, ALT, ALP and GGT. In addition, it significantly increased MDA and NO along with a marked decline in reduced GSH content. At the same time, valproic acid administration resulted in marked elevation in hydroxyproline, TNF-α production and NF-kB expression. These results were confirmed by histopathological examination. Treatment with ellagic acid markedly attenuated valproic acid-induced hepatic injury in rats.

New combination therapy of gliclazide and quercetin for protection against STZ-induced diabetic rats.

AIMS: The use of natural agents with anti-diabetic effect in combination therapy adds further positive clinical implications in the management of diabetes mellitus. Interestingly, quercetin is one of the most potent naturally occurring antioxidant which possesses various pharmacological actions including anti-diabetic effect. Thus, this research was conducted to assess the efficiency of a new combination from gliclazide and quercetin on glycemic control as well as pancreatic islets and beta cells in STZ-experimental model of diabetes. MAIN METHODS: Diabetes has been induced by a single intraperitoneal injection of streptozotocin (STZ; 45 mg/kg) in adult male Wistar rats. For 3 consecutive weeks, diabetic rats were given orally either gliclazide (10 mg/kg), quercetin (50 mg/kg), or their combination. At the end of the experiment, histological, immunohistochemical and morphometrical examination of pancreatic tissues was performed. Furthermore, the changes in glucose metabolism, lipid profile, oxidative and inflammatory status were evaluated. KEY FINDINGS: Treatment with gliclazide alone decreased serum glucose, total cholesterol, triglycerides, malondialdehyde, tumor necrosis factor-alpha and nuclear factor kappa-Beta while increased serum C-peptide, superoxide dismutase, reduced glutathione and adiponectin levels. Combined administration of quercetin with gliclazide markedly augmented serum superoxide dismutase and reduced glutathione more than gliclazide alone and normalized all the above-mentioned parameters. Besides, this combination therapy restored immunostaining intensity, number of pancreatic islets and beta cells along with its area and perimeter. SIGNIFICANCE: Based on the aforementioned results, this combination could be considered a promising one in diabetes mellitus management.

Telmisartan/17ß-estradiol mitigated cognitive deficit in an ovariectomized rat model of Alzheimer's disease: Modulation of ACE1/ACE2 and AT1/AT2 ratio.

AIMS: The higher incidence rate of Alzheimer's disease (AD) among women has led to explorations on the association between estrogen deficiency and AD. Also, usage of antihypertensive drugs has been suggested to reduce the incidence of AD in elderly hypertensive patients. Thus, this study aimed to investigate the effects of telmisartan and/or 17ß-estradiol on a cognitively impaired ovariectomized rat model of AD. MAIN METHODS: 75 female Wistar rats were randomly allocated into five groups. One group was sham operated and the other four groups were subjected to ovariectomy, received D-galactose and either untreated or treated with telmisartan and/or 17ß-estradiol for 6 weeks. KEY FINDINGS: Ovariectomized rats showed cognitive impairment in Morris water maze and novel object recognition tests, increasing inflammatory biomarkers (tumor necrosis factor-α, and interleukin-1ß), increasing AD biomarkers (amyloid beta1-42, and acetylcholine esterase), and over activation of classical arm of renin angiotensin system (RAS) (ACE1/Ang2/AT1) in hippocampi. Also, hippocampi histopathological examination revealed amyloid beta deposition. Whereas, administration of telmisartan and/or 17ß-estradiol improved animals' behavior, alleviated histopathological alterations and reduced the level of inflammatory and AD biomarkers, modulated RAS activity favoring the novel neuroprotective arm (ACE2/Ang(1-7)/MasR). SIGNIFICANCE: Our findings suggest that combined administration of both drugs has synergetic neuroprotective effects; supporting their potential application in AD treatment.

Escitalopram Ameliorates Cognitive Impairment in D-Galactose-Injected Ovariectomized Rats: Modulation of JNK, GSK-3ß, and ERK Signalling Pathways.

Though selective serotonin reuptake inhibitors (SSRIs) have been found to increase cognitive performance in some studies on patients and animal models of Alzheimer's disease (AD), other studies have reported contradictory results, and the mechanism of action has not been fully described. This study aimed to examine the effect of escitalopram, an SSRI, in an experimental model of AD and to determine the involved intracellular signalling pathways. Ovariectomized rats were administered D-galactose (150 mg/kg/day, i.p) over ten weeks to induce AD. Treatment with escitalopram (10 mg/kg/day, p.o) for four weeks, starting from the 7th week of D-galactose injection, enhanced memory performance and attenuated associated histopathological changes. Escitalopram reduced hippocampal amyloid ß 42, ß-secretase, and p-tau, while increasing α-secretase levels. Furthermore, it decreased tumor necrosis factor-α, nuclear factor-kappa B p65, and NADPH oxidase, while enhancing brain-derived neurotrophic factor, phospho-cAMP response element binding protein, and synaptophysin levels. Moreover, escitalopram diminished the protein expression of the phosphorylated forms of c-Jun N-terminal kinase (JNK)/c-Jun, while increasing those of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase-3ß (GSK-3ß), extracellular signal-regulated kinase (ERK) and its upstream kinases MEK and Raf-1. In conclusion, escitalopram ameliorated D-galactose/ovariectomy-induced AD-like features through modulation of PI3K/Akt/GSK-3ß, Raf-1/MEK/ERK, and JNK/c-Jun pathways.

Modulating impacts of quercetin/sitagliptin combination on streptozotocin-induced diabetes mellitus in rats.

BACKGROUND: Since many diabetic patients require combination therapy, the use of herbal remedies with anti-diabetic activity represents a vital option in diabetes mellitus (DM) management. It has been reported that quercetin has hypoglycemic alongside anti-inflammatory and antioxidant activities. AIM: The present study aimed to investigate the effectiveness of combining quercetin with sitagliptin; a selective dipeptidyl peptidase-IV (DPP-IV) inhibitor, in the management of streptozotocin (STZ)-induced diabetic rats. METHODS: DM was induced by a single injection of STZ (45 mg/kg, i.p.) in male adult albino Wistar rats. Diabetic rats were orally treated with sitagliptin (70 mg/kg), quercetin (50 mg/kg) or their combination daily for three consecutive weeks. Serum levels of glucose, C-peptide, total cholesterol, triglycerides, malondialdehyde (MDA), superoxide dismutase, (SOD), reduced glutathione (GSH), tumor necrosis factor alpha, (TNF-α), nuclear factor kappa-B, (NF-κB) and adiponectin were estimated. In addition, histopathological, morphometrical and immunohistochemical examinations of pancreatic tissues were conducted. RESULTS: The combined administration of quercetin and sitagliptin normalized serum C-peptide, MDA, and significantly increased SOD, GSH and decreased NF-κB more than sitagliptin alone. Moreover, this combination normalized Islet number, ß-cells' number, area and perimeter alongside restoring the immunostaining intensity of ß-cells. CONCLUSION: Our results suggest the use of quercetin/sitagliptin combination for treating DM based on the observed improvements in glycemic control, metabolic profile, oxidative and inflammatory status, islet structure as well as ß-cells function compared with either treatment alone.

Extracellular Matrix Remodeling and Modulation of Inflammation and Oxidative Stress by Sulforaphane in Experimental Diabetic Peripheral Neuropathy.

The peripheral nervous system is one of many organ systems that can be profoundly impacted in diabetes mellitus. Diabetic peripheral neuropathy has a significant negative effect on patients' quality of life as it begins with loss of limbs' sensation and may result in lower limb amputation. This investigation aimed at exploring the effect of sulforaphane on peripheral neuropathy in diabetic rats. Experimental diabetes was induced through single intraperitoneal injections of nicotinamide (50 mg/kg) and streptozotocin (52.5 mg/kg). Rats were divided into five groups. Two groups were treated with saline or sulforaphane (1 mg/kg, p.o.). Three diabetic groups were either untreated or given sulforaphane (1 mg/kg, p.o.) or pregabalin (10 mg/kg, i.p.). Two weeks after drugs' administration, biochemical, behavioral, histopathological, and immunohistochemical investigations were carried out. Treatment with sulforaphane restored animals' body weight, reduced blood glucose, glycated hemoglobin, and increased insulin levels. In parallel, it normalized motor coordination and the latency withdrawal time of tail flick test, increased the latency withdrawal time of cold allodynia test, and ameliorated histopathological changes. Treatment of sulforaphane, likewise, decreased sciatic nerve malondialdehyde, nitric oxide, interleukin-6, and matrix metalloproteinase-2 and -9 contents. Similarly, it reduced sciatic nerve DNA fragmentation and expression of cyclooxygenase-2 and nuclear factor kappa-B p65. Meanwhile, it increased sciatic nerve superoxide dismutase and interleukin-10 contents. These results reveal the neuroprotective effect of sulforaphane against peripheral neuropathy in diabetic rats possibly through modulating oxidative stress, inflammation, and extracellular matrix remodeling. Graphical Abstract Diagram that illustrates the effects of sulforaphane in treating experimental diabetic peripheral neuropathy. In NA-STZ model of diabetes mellitus, sulforaphane, restored animals' body weight, reduced blood glucose, glycated hemoglobin and increased insulin levels. In parallel, it normalized motor coordination and the latency withdrawal time of tail flick test, increased the latency withdrawal time of cold allodynia test and ameliorated histopathological changes. Treatment of sulforaphane, likewise, decreased sciatic nerve malondialdehyde, nitric oxide, interleukin-6, matrix metalloproteinase-2 and -9 contents. Similarly, it reduced sciatic nerve DNA fragmentation and expression of cyclooxygenase-2 and nuclear factor kappa-B p65. Meanwhile, it increased sciatic nerve superoxide dismutase and interleukin-10 contents.

A Novel Role of Irbesartan in Gastroprotection against Indomethacin-Induced Gastric Injury in Rats: Targeting DDAH/ADMA and EGFR/ERK Signaling.

The advent of angiotensin II type 1 receptor blockers (ARBs) as intriguing gastroprotective candidates and the superior pharmacokinetics and pharmacodynamics displayed by irbesartan compared to many other ARBs raised the interest to investigate its gastroprotective potential in a rat model of gastric injury. Irbesartan (50 mg/Kg) was orally administered to male Wistar rats once daily for 14 days; thereafter gastric injury was induced by indomethacin (60 mg/Kg, p.o). Irbesartan reduced gastric ulcer index, gastric acidity, and ameliorated indomethacin-induced gastric mucosal apoptotic and inflammatory aberrations, as demonstrated by hampering caspase-3, prostaglandin E2 and tumor necrosis factor-alpha levels and cyclooxygenase-2 mRNA expression. This ARB increased mucosal dimethylarginine dimethylaminohydrolase-1 (DDAH-1) gene expression and decreased elevated levels of matrix metalloproteinase-9, asymmetric dimethylarginine (ADMA), epidermal growth factor receptor (EGFR) mRNA and phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2). Histopathological evaluation corroborated biochemical findings. Overall efficacy of irbesartan was comparable to ranitidine, the widely used H2 receptor blocker. In conclusion, irbesartan exerts significant gastroprotection against indomethacin-induced mucosal damage via acid-inhibitory, anti-inflammatory, anti-apoptotic and extracellular matrix remodeling mechanisms that are probably mediated, at least partly, by down-regulating DDAH/ADMA and EGFR/ERK1/2 signaling.

Liraglutide ameliorated peripheral neuropathy in diabetic rats: Involvement of oxidative stress, inflammation and extracellular matrix remodeling.

Diabetic peripheral neuropathy is one of the most common microvascular complications that occurs with both type 1 and type 2 diabetes mellitus. It has a significant negative impact on patients' quality of life; as it starts with loss of limbs' sensation and may lead to lower limb amputation. This study aimed at investigating the effect of liraglutide on peripheral neuropathy in diabetic rats. Experimental diabetes was induced by single intraperitoneal injections of nicotinamide (50 mg/kg) and streptozotocin (52.5 mg/kg). Rats were allocated into five groups. Two groups were given saline or liraglutide (0.8 mg/kg, s.c.). Three diabetic groups were either untreated or treated with liraglutide (0.8 mg/kg, s.c.) or pregabalin (10 mg/kg, i.p.). After 2 weeks of treatment, behavioral, biochemical, histopathological, and immunohistochemical investigations were performed. Treatment with liraglutide-restored animals' body weight, normalized blood glucose, decreased glycated hemoglobin, and increased insulin levels. In parallel, it normalized motor coordination and the latency withdrawal time of both tail flick and hind paw cold allodynia tests and reversed histopathological alterations. Treatment with liraglutide also normalized malondialdehyde, matrix metalloproteinase-2 and -9 contents in sciatic nerve. Likewise, it decreased sciatic nerve nitric oxide and interleukin-6 contents, DNA fragmentation and expression of cyclooxygenase-2. Meanwhile, it increased superoxide dismutase and interleukin-10 contents in sciatic nerve. These findings indicate the neuroprotective effect of liraglutide against diabetic peripheral neuropathy probably via modulating oxidative stress, inflammation, and extracellular matrix remodeling.

Stimulation of ACE2/ANG(1-7)/Mas Axis by Diminazene Ameliorates Alzheimer's Disease in the D-Galactose-Ovariectomized Rat Model: Role of PI3K/Akt Pathway.

Overactivation of angiotensin-converting enzyme/angiotensin 2/angiotensin receptor-1 (ACE/Ang2/AT1) axis provokes amyloid-ß-induced apoptosis and neurodegeneration in Alzheimer's disease (AD). Moreover, activation of AT1 impairs the survival pathway phosphoinositide 3-kinase/protein kinase B (PI3K/Akt). Interestingly, the coupling between ACE2/Ang(1-7)/Mas receptor (MasR) axis and PI3K/Akt activation opposes AT1-induced apoptosis. However, the effect of in vivo stimulation of MasR against AD and its correlation to PI3K/Akt is not yet elucidated. Thus, the present study aimed to investigate the relationship between PI3K/Akt pathway and the activation of ACE2/MasR in the AD model of D-galactose-ovariectomized rats. AD features were induced following 8-week injection of D-galactose (150 mg/kg, i.p.) in ovariectomized female rats. The ACE2 activator dimenazine (15 mg/kg, i.p.) was daily administered for 2 months. DIZE administration boosted the hippocampal expression of ACE2 and Mas receptors while suppressing AT1 receptor. Notably, dimenazine enhanced the expression of phosphorylated survival factors (PI3K, Akt, signal transducer, and activator of transcription-3) and neuroplasticity proteins such as cyclic adenosine monophosphate-responsive element-binding protein and brain-derived neurotrophic factor along with nicotinic and glutamatergic receptors. Such effects were accompanied by suppressing phosphorylated tau and glycogen synthase kinase3ß along with caspase-3, cytochrome-c, nuclear factor kappa B, tumor necrosis factor alpha, and glial fibrillary acidic protein contents. Dimenazine ameliorated the histopathological damage observed in D-galactose-ovariectomized rats and improved their learning and recognition memory in Morris water maze and novel object recognition tests. In conclusion, dimenazine-induced stimulation of ACE2/Ang(1-7)/Mas axis subdues cognitive deficits in AD most probably through activation of PI3K/Akt pathway.

Punica granatum suppresses colon cancer through downregulation of Wnt/β-Catenin in rat model

Abstract This study aims to elucidate the beneficial effect of Punica granatum L., Lythraceae (pomegranate) peel extract in the management of colon cancer induced intrarectally with N-methylnitrosourea. Adult male Sprague-Dawley rats were administered N-methylnitrosourea (2 mg in 0.5 ml water/rat) intrarectally three times/week for five weeks to induce colorectal cancer, followed by treatment with either 5-fluorouracil (12.5 mg/kg, i.p.) or Punica peel extract (2.25 or 4.5 g/kg, p.o.). Developed tumor elevated plasma TGF-β, and Bcl2, serum epidermal growth factor, carcinoembryonic antigen, colon cancer specific antigens, and matrix metalloproteinase-7. Besides, immune-histochemical studies revealed an increase in COX-2, cyclin D1 and survivin content, as well as upregulation of the expression of colonic β-Catenin, K-ras and C-myc genes. These results were further supported by the histological findings. Punica peel extract-treated rats, particularly those treated with a high dose, exhibited a marked reduction in the aforementioned parameters and improved the histological organization of the colon tissue. These alterations were consistent with those mediated through 5-fluorouracil. The present study encourages the use of P. granatum L. against colon cancer. Because Punica peel extract promotes apoptosis, mitigates inflammation and suppresses tumor cell proliferation in vivo, the potential mechanism underlying these activities might depend on the inhibition of the Wnt/β-Catenin signaling pathway.