The preferential effect of Clemastine on F3/Contactin-1/Notch-1 compared to Jagged-1/Notch-1 justifies its remyelinating effect in an experimental model of multiple sclerosis in rats.

Clemastine (CLM) is repurposed to enhance remyelination in multiple sclerosis (MS) patients. CLM blocks histamine and muscarinic receptors as negative regulators to oligodendrocyte differentiation. These receptors are linked to the canonical and non-canonical Notch-1 signaling via specific ligands; Jagged-1 and F3/Contactin-1, respectively. Yet, there are no previous studies showing the influence of CLM on Notch entities. Herein, the study aimed to investigate to which extent CLM aligns to one of the two Notch-1 arms in experimental autoimmune encephalomyelitis (EAE) rat model. Three groups were utilized where first group received vehicles. The second group was injected by spinal cord homogenate mixed with complete Freund's adjuvant on days 0 and 7. In the third group, CLM (5 mg/kg/day; p.o) was administered for 15 days starting from the day of the first immunization. CLM ameliorated EAE-associated motor and gripping impairment in rotarod, open-field, and grip strength arena beside sensory anomalies in hot plate, cold allodynia, and mechanical Randall-Selitto tests. Additionally, CLM alleviated depressive mood observed in tail suspension test. These findings harmonized with histopathological examinations of Luxol-fast blue stain together with enhanced immunostaining of myelin basic protein and oligodendrocyte lineage gene 2 in corpus callosum and spinal cord. Additionally, CLM enhanced oligodendrocyte myelination and maturation by increasing 2',3'-cyclic nucleotide 3'-phosphodiesterase, proteolipid protein, aspartoacylase as well. CLM restored the level of F3/Contactin-1 in the diseased rats over Jagged-1 level; the ligand of the canonical pathway. This was accompanied by elevated gene expression of Deltex-1 and reduced hairy and enhancer-of-split homologs 1 and 5. Additionally, CLM suppressed microglial and astrocyte activation via reducing the expression of ionized calcium-binding adaptor molecule-1 as well as glial fibrillary acidic protein, respectively. These results outlined the remyelinating beneficence of CLM which could be due to augmenting the non-canonical Notch-1 signaling over the canonical one.

Agmatine-mediated inhibition of NMDA receptor expression and amelioration of dyskinesia via activation of Nrf2 and suppression of HMGB1/RAGE/TLR4/MYD88/NF-κB signaling cascade in rotenone lesioned rats.

Dyskinesia is characterized by abnormal involuntary movements (AIMs). Such movements are considered restrictive problem associated with the chronic use of L-dopa in Parkinson's disease (PD) treatment; the thing that renders the definite pathological mechanism unclear. However, there is a correlation between excitotoxicity of glutamatergic NMDA receptors, neuroinflammation, and oxidative stress in the lesioned nigrostriatal pathway; which mediates the firing of basal ganglia neurons involved in dyskinesia. AIMS: The current study investigated the novel neuroprotective effect of agmatine in ameliorating both PD and dyskinesia with a focus on its antioxidant, anti-inflammatory, and anti-apoptotic potentiality through Nrf2 activation and suppression of HMGB1/RAGE/TLR4/MYD88/NF-κB signaling pathway. MAIN METHODS: PD was induced in animals by ten consecutive doses of rotenone (3 mg/kg/day; s.c.). Agmatine (100 mg/kg/day; i.p.) was injected for 16 days after modeling PD either alone or in combination with L-dopa/carbidopa (50/25 mg/kg/day; i.p.). KEY FINDINGS: A statically significant deteriorating effect was showed on the behavioral, neurochemical, histopathological, and immunochemical analysis of PD rats. Moreover, dyskinesia observed in PD rats that received L-dopa. Agmatine improved animals' behavior and abolished dyskinetic AIMs. It inhibited NMDA receptors expression in nigral tissues leading to inhibition of inflammatory and oxidative stress cascades. It increased both nigral TH immunoreactive cells and striatal dopamine contents. Besides, it increased the antioxidant defense mechanism of Nrf2/TAC contents along with a significant decrease of HMGB1/RAGE/TLR4/MYD88/NF-κB protein expression. SIGNIFICANCE: The current investigated data signifies the novel role of agmatine in ameliorating both PD and dyskinesia through mediating NMDA receptors, Nrf2, and HMGB1/RAGE/TLR4/NF-κB signaling pathways.

Empagliflozin mitigates type 2 diabetes-associated peripheral neuropathy: a glucose-independent effect through AMPK signaling.

Diabetic peripheral neuropathy (DPN) represents a severe microvascular condition that dramatically affects diabetic patients despite adequate glycemic control, resulting in high morbidity. Thus, recently, anti-diabetic drugs that possess glucose-independent mechanisms attracted attention. This work aims to explore the potentiality of the selective sodium-glucose cotransporter-2 inhibitor, empagliflozin (EMPA), to ameliorate streptozotocin-induced DPN in rats with insight into its precise signaling mechanism. Rats were allocated into four groups, where control animals received vehicle daily for 2 weeks. In the remaining groups, DPN was elicited by single intraperitoneal injections of freshly prepared streptozotocin and nicotinamide (52.5 and 50 mg/kg, respectively). Then EMPA (3 mg/kg/p.o.) was given to two groups either alone or accompanied with the AMPK inhibitor dorsomorphin (0.2 mg/kg/i.p.). Despite the non-significant anti-hyperglycemic effect, EMPA improved sciatic nerve histopathological alterations, scoring, myelination, nerve fibers' count, and nerve conduction velocity. Moreover, EMPA alleviated responses to different nociceptive stimuli along with improved motor coordination. EMPA modulated ATP/AMP ratio, upregulated p-AMPK while reducing p-p38 MAPK expression, p-ERK1/2 and consequently p-NF-κB p65 as well as its downstream mediators (TNF-α and IL-1ß), besides enhancing SOD activity and lowering MDA content. Moreover, EMPA downregulated mTOR and stimulated ULK1 as well as beclin-1. Likewise, EMPA reduced miR-21 that enhanced RECK, reducing MMP-2 and -9 contents. EMPA's beneficial effects were almost abolished by dorsomorphin administration. In conclusion, EMPA displayed a protective effect against DPN independently from its anti-hyperglycemic effect, probably via modulating the AMPK pathway to modulate oxidative and inflammatory burden, extracellular matrix remodeling, and autophagy.

Naringenin affords protection against lipopolysaccharide/D-galactosamine-induced acute liver failure: Role of autophagy.

Acute liver failure (ALF) is considered a fatal clinical disorder and novel therapeutic interventions are mandatory. Naringenin is a flavonoid with anti-inflammatory, antioxidant and antiapoptotic effects that have displayed beneficial effects in different animal models of ALF. The current study aimed at investigating the hepatoprotective effect and the possible underlying molecular mechanisms of naringenin in lipopolysaccharide (LPS)/D-galactosamine (D-Gal) mouse model of ALF. Interestingly, naringenin pretreatment substantially alleviated LPS/D-Gal-induced liver injury, enhanced survival, improved liver function and ameliorated histopathological liver changes. Importantly, naringenin potently activated autophagy as evidenced by the increased Beclin-1 expression and LC3 II/LC3 I ratio. Furthermore, results demonstrated that naringenin alleviated oxidative stress by inducing nuclear factor-erythroid 2-related factor 2 (Nrf2) and increasing hepatic SOD activity and GSH level as well as ameliorated endoplasmic reticulum (ER) stress. Likewise, naringenin mitigated LPS/D-Gal-triggered inflammation by suppressing NF-κB and NLRP3 pathways. Accordingly, apoptotic cell death provoked by LPS/D-Gal challenge was markedly attenuated as depicted by the decrease in caspase-3 and p53 in naringenin-treated mice. To investigate the contribution of autophagy to naringenin-conferred hepatoprotection, autophagy was inhibited using 3-methyladenine (3 MA). Strikingly, 3 MA co-treatment abolished the hepatoprotective effect of naringenin, a finding that strongly suggests that naringenin-afforded protection is, at least in part, attributed to autophagy. Taken together, the present study revealed that naringenin exerted a prominent hepatoprotective effect by promoting autophagy with consequent attenuation of inflammatory responses, oxidative stress, ER stress and apoptosis. Our results provide evidence that naringenin use holds a promise as a potential therapeutic agent for ALF management.

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.

Lutein exerts its cardioprotective effect against the experimental model of isoprenaline-induced myocardial infarction via MIAT/miR-200a/Nrf2/TXINP pathway.

Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. Lutein (LU) possesses numerous pharmacological activities, including anti-inflammatory, antioxidant, and antiapoptotic effects. This study aimed to investigate the cardioprotective potential of LU in isoprenaline (ISO)-induced MI and to explore its molecular mechanisms of action. AMI was induced by two consecutive subcutaneous doses of ISO (65 mg/kg; s.c.). The LU group was pretreated with LU (20 mg/kg; p.o.) for 30 days followed by ISO injections on Days 29 and 30. ISO group showed elevated serum creatine kinas-MB (CK-MB) and considerable electrocardiographic changes along with reduced ejection fraction compared to the normal group. LU pretreatment could decrease serum CK-MB activity, normalize QRS and QTc intervals and restore ejection fraction compared to the untreated group. The ISO group demonstrated infarcted-like lesions, which were ameliorated in the LU-pretreated group. Immunohistochemical investigation revealed upregulated cardiac troponin T (cTn T) and desmin expressions in the LU-pretreated group. LU pretreatment also enhanced cardiac thioredoxin (Trx) and glutathione (GSH) contents as well as reduced lipid peroxidation, compared to the untreated group. Importantly, LU pretreatment could downregulate long noncoding MI associated transcript (lncRNA MIAT) and thioredoxin-interacting protein (TXNIP) and augment micro RNA (miR)-200a and nuclear factor erythroid 2-related factor 2 (Nrf2) expressions compared to the ISO group. Moreover, a significant inverse correlation between MIAT and miR-200a was observed. In conclusion, this study revealed that LU could ameliorate ISO-induced MI in rats by modulating MIAT/miR-200a/Nrf2 pathway.

Dimethyl fumarate abridged tauo-/amyloidopathy in a D-Galactose/ovariectomy-induced Alzheimer's-like disease: Modulation of AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3ß, adiponectin/Adipo1R, and NF-κB/IL-1ß/ROS trajectories.

Since the role of estrogen in postmenauposal-associated dementia is still debatable, this issue urges the search for other medications. Dimethyl fumarate (DMF) is a drug used for the treatment of multiple sclerosis and has shown a neuroprotective effect against other neurodegenerative diseases. Accordingly, the present study aimed to evaluate the effect of DMF on an experimental model of Alzheimer disease (AD) using D-galactose (D-Gal) administered to ovariectomized (OVX) rats, resembling a postmenopausal dementia paradigm. Adult 18-month old female Wistar rats were allocated into sham-operated and OVX/D-Gal groups that were either left untreated or treated with DMF for 56 days starting three weeks after sham-operation or ovariectomy. DMF succeeded to ameliorate cognitive (learning/short- and long-term memory) deficits and to enhance the dampened overall activity (NOR, Barnes-/Y-maze tests). These behavioral upturns were associated with increased intact neurons (Nissl stain) and a reduction in OVX/D-Gal-mediated hippocampal CA1 neurodegeneration and astrocyte activation assessed as GFAP immunoreactivity. Mechanistically, DMF suppressed the hippocampal contents of AD-surrogate markers; viz., apolipoprotein (APO)-E1, BACE1, Aß42, and hyperphosphorylated Tau. Additionally, DMF has augmented the neuroprotective parameters p-AKT, its downstream target CREB and BDNF. Besides, it activated AMPK, and enhanced SIRT-1, as well as antioxidant defenses (SOD, GSH). On the other hand, DMF inhibited the transcription factor NF-κB, IL-1ß, adiponectin/adiponectin receptor type (AdipoR)1, GSK-3ß, and MDA. Accordingly, in this postmenopausal AD model, DMF treatment by pursuing the adiponectin/AdipoR1, AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3ß, and APO-E1 quartet hampered the associated tauo-/amyloidopathy and NF-κB-mediated oxidative/inflammatory responses to advance insights into its anti-amnesic effect.

Antiulcerogenic effect of melittin via mitigating TLR4/TRAF6 mediated NF-κB and p38MAPK pathways in acetic acid-induced ulcerative colitis in mice.

Ulcerative colitis (UC) is a chronic disease driven primarily by uncontrolled pervasive inflammatory responses affecting the colon and rectum. Currently available medications carry multiple detrimental adverse effects, which have emphasized the mandatory need for safer and more efficient novel therapeutic alternatives. Melittin is the main constituent of bee venom and exhibits potent anti-inflammatory properties. The antiulcerogenic effect of oral melittin (40 µg/kg) was explored in the current study using the acetic acid-induced colitis model. Increase in body weight and decrease in colon mass index were observed in the melittin group. Microscopically, melittin ameliorated acetic acid-induced histological damage. Melittin administration has efficiently amended the elevated levels of the cytokines, tumor necrosis factor (TNF-α) and interleukin 6 (IL-6) seen in the colitis group. This was accompanied by inhibition of the upstream signaling molecules, Toll-like receptor 4 (TLR4), tumor necrosis factor receptor (TNF-R)-associated factor (TRAF6), mitogen-activated protein kinase 38 (p38 MAPK), and nuclear factor kappaB (NF-κB) in the melittin group. Moreover, treatment with melittin resulted in marked decrease in colonic level of prostaglandin E2 (PGE2) together with the enzymes involved in its synthesis, secretory phospholipase A2 (sPLA2) and cyclooxygenase 2 (COX-2). Additionally, melittin has attenuated acetic acid-induced oxidative stress as manifested by the significant diminishment in malondialdehyde (MDA) as well as the increase in superoxide dismutase (SOD) and reduced glutathione (GSH) levels. Therefore, melittin mitigated UC pathogenesis and could be considered as a potent and promising therapeutic alternative for UC treatment.

Immunomodulatory effect of diallyl sulfide on experimentally-induced benign prostate hyperplasia via the suppression of CD4+T/IL-17 and TGF-ß1/ERK pathways.

Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate common in older men. Diallyl sulfide (DAS), a major component of garlic, has been reported to possess antioxidant, anti-inflammatory, and antiproliferative effects. However, the underlying protective immunomodulatory mechanism of DAS on BPH remains vague. Herein, experimental BPH was induced in rats by daily subcutaneous injection of testosterone propionate (TP) (3 mg/kg, s.c.) for 4 weeks. In parallel, finasteride (Fin) (5 mg/kg, p.o) or DAS (50 mg/kg, p.o.) was administered orally during BPH induction. TP-induced histological alterations and the immune-inflammatory cascade. On the other hand, DAS or Fin administration alleviated all abnormalities induced testosterone. Fin and DAS administration markedly reduced prostate weight by 53% with Fin, and by 60% with DAS. Moreover, serum testosterone and DHT were reduced by 55% and 52%, respectively, with Fin and by 68% and 75%, respectively, with DAS, in concordance with decreased protein expression of androgen receptor (AR), and prostate-specific antigen (PSA). Furthermore, both regime lessen immune-inflammatory milieu, as evidenced by decrease CD4+ T-cells protein expression and associated inflammatory cytokines. Concomitantly, Fin and DAS exhibited marked mitigation in insulin-like growth factor-1 (IGF-1), transforming growth factor-beta1 (TGF-ß1), and phosphorylated extracellular signal-regulated kinase (ERK1/2) signaling. Besides alleviating oxidative stress by 53% and 68% in prostatic MDA and by 27% and 7% in prostatic iNOS with Fin and DAS, respectively. In conclusion, this work highlighted a potential therapeutic approach of DAS as a dietary preventive agent against BPH via its anti-inflammatory and immunomodulatory effect along with suppression of the ERK pathway.

Activation of α7 Nicotinic Acetylcholine Receptor Ameliorates Zymosan-Induced Acute Kidney Injury in BALB/c Mice.

Zymosan, a natural compound, provokes acute peritonitis and multiple organ dysfunction that affects the kidney, beside other organs via exaggerated inflammatory response. The aim of the present study is to test the role of cholinergic anti-inflammatory pathway (CAP) in alleviating acute kidney injury (AKI) induced by zymosan in BALB/c mice, using galantamine, a cholinesterase inhibitor, known to act via α7 nicotinic acetylcholine receptor (α7 nAChR) to stimulate CAP. Galantamine verified its anti-inflammatory effect by elevating acetylcholine (ACh) level, while abating the interleukin-6/ janus kinase 2 (Y1007/1008)/ signal transducer and activator of transcription 3 (Y705) (IL-6/ pY(1007/1008)-JAK2/ pY705-STAT3) inflammatory axis, with a consequent inhibition in suppressor of cytokine signaling 3 (SOCS3). This effect entails also the nuclear factor-kappa B (p65)/ high mobility group box protein-1/ (NF-κB (p65)/ HMGB-1) signaling pathway. Furthermore, the reno-curattive effect of galantamine was associated by a reduction in plasma creatinine (Cr), cystatin (Cys)-C, IL-18, and renal neutrophil gelatinase-associated lipocalin (NGAL), as well as an improved histopathological structure. Blocking the α7 nAChR by methyllycaconitine abolished the beneficial effect of galantamine to document the involvement of this receptor and the CAP in the amelioration of AKI induced by zymosan.

Geraniol, alone and in combination with pioglitazone, ameliorates fructose-induced metabolic syndrome in rats via the modulation of both inflammatory and oxidative stress status.

Geraniol (GO) potent antitumor and chemopreventive effects are attributed to its antioxidant and anti-inflammatory properties. In the current study, the potential efficacy of GO (250 mg/kg) in ameliorating metabolic syndrome (MetS) induced by fructose in drinking water was elucidated. Moreover, the effect of pioglitazone (5 and 10 mg/kg; PIO) and the possible interaction of the co-treatment of GO with PIO5 were studied in the MetS model. After 4 weeks of treatment, GO and/or PIO reduced the fasting blood glucose and the glycemic excursion in the intraperitoneal glucose tolerance test. GO and PIO5/10 restrained visceral adiposity and partly the body weight gain. The decreased level of peroxisome proliferator activated receptor (PPAR)-γ transcriptional activity in the visceral adipose tissue of MetS rats was increased by single treatment regimens. Though GO did not affect MetS-induced hyperinsulinemia, PIO5/10 lowered it. Additionally, GO and PIO5/10 suppressed glycated hemoglobin and the receptor for advanced glycated end products (RAGE). These single regimens also ameliorated hyperuricemia, the disrupted lipid profile, and the elevated systolic blood pressure evoked by MetS. The rise in serum transaminases, interleukin-1ß, and tumor necrosis factor-α, as well as hepatic lipid peroxides and nitric oxide (NO) was lowered by the single treatments to different extents. Moreover, hepatic non-protein thiols, as well as serum NO and adiponectin were enhanced by single regimens. Similar effects were reached by the combination of GO with PIO5; however, a potentiative interaction was noted on fasting serum insulin level, while synergistic effects were reflected as improved insulin sensitivity, as well as reduced RAGE and triglycerides. Therefore, GO via the transcriptional activation of PPAR-γ reduces inflammation and free radical injury produced by MetS. Thereby, these effects provide novel mechanistic insights on GO management of MetS associated critical risk factors. Moreover, the co-administration of GO to PIO5 exalted the antidiabetic drug anti-MetS efficacy.