Aprepitant boasted a protective effect against olanzapine-induced metabolic syndrome and its subsequent hepatic, renal, and ovarian dysfunction; Role of IGF1/p-AKT/FOXO1 and NFκB/IL-1ß/TNF-α signaling pathways in female Wistar albino rats.

Olanzapine-induced metabolic syndrome (MS) is a primary risk factor for insulin resistance, hepatorenal damage, and polycystic ovarian syndrome. The objective of the current study was to assess the protective effects of aprepitant (AP) against MS caused by olanzapine and the associated ovarian, renal, and liver dysfunction via modulation of IGF1/p-AKT/FOXO1 and NFκB/IL-1ß/TNF-α signaling pathways. AP mitigated all biochemical and histopathological abnormalities induced by olanzapine and resulted in a significant reduction of serum HOMA-IR, lipid profile parameters, and a substantial decrease in hepatic, renal, and ovarian MDA, IL-6, IL-1ß, TNF-α, NFκB, and caspase 3. Serum AST, ALT, urea, creatinine, FSH, LH, and testosterone also decreased significantly by AP administration. The FOXO 1 signaling pathway was downregulated in the AP-treated group, while GSH, SOD, and HDL cholesterol levels were elevated.

Proniosomal Gel-Loaded Phosphodiesterase Inhibitors (Sildenafil, Vardenafil, and Tadalafil): Prospects for Topical Penile Therapy of Tadalafil for Treatment of Erectile Dysfunction.

Oral phosphodiesterase inhibitors have emerged as a game changer for the treatment of erectile dysfunction (ED) since attaining FDA approval for its first member, sildenafil, in 1998. Topical penile therapy could be a viable replacement for oral medication that would transform the treatment of ED for many decades to come. This innovative idea could offer a safer topical alternative with less vision and cardiovascular side effects than the oral route. This work aims at developing proniosomal gels for three selected members (sildenafil, vardenafil, and tadalafil) and investigating the proniosomal gels on a rodent model. Niosomes derived from the parent proniosomal gels were characterized for entrapment efficiency (EE%), size, polydispersity index (PDI), zeta potential, and morphology. Proniosomal gels were evaluated for skin permeation, in vivo mating behaviors, and biochemical assays of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) post penile topical administrations. The optimized proniosomes loaded with tadalafil (F1-T) were compared with oral tablets (Cialis®). Proniosomal gels demonstrated significant enhancement of skin penetration by up to 5.5-fold, compared to control topical suspension. Tadalafil-loaded proniosomes showed superior skin permeability over sildenafil- and vardenafil-loaded proniosomes. In addition, significant improvement was noticed regarding intromission number, intromission ratio, NO, and cGMP for the proniosomal gel F1-T, compared to the untreated control. No statistically significant (p > 0.05) differences in sexual performance or biochemical parameters (NO and cGMP levels) were recorded among orally and topically (tadalafil proniosomal gel) administered groups. These findings support tadalafil topical penile therapy as a promising alternative to the oral route.

Role of EGF/ERK1/2/HO-1 axis in mediating methotrexate induced testicular damage in rats and the ameliorative effect of xanthine oxidase inhibitors.

Objectives: Methotrexate (MTX) is commonly used in the management of several malignancies and autoimmune disorders; however, testicular damage is one of the most detrimental effects of MTX administration. The current the protective effect of xanthine oxidase inhibitors either purine analogue; allopurinol (ALL) or non-purine analogue; febuxostat (FEB) in testicular injury induced by MTX in rats.Materials and methods: Thirty-two rats were randomly allocated to four groups; control (received vehicles), MTX (received single dose, 20 mg/kg, i.p.), MTX + ALL (received MTX plus ALL) and MTX + FEB (received MTX plus ALL). ALL and FEB were administered orally at 100- and 10 mg/kg, respectively for 15 days. Total and free testosterone were measured in serum. In addition, total antioxidant capacity (TAC), epidermal growth factor (EGF), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), extracellular signal-regulating kinase1/2 (ERK1/2), and total nitrite/nitrate (NOx) end products were measured in testicular tissues. At the same time, immunoexpression of HO-1in testicular tissue was measured. Histopathological examination was done.Results: ALL and FEB increased total and free serum testosterone. Both drugs showed a significant reduction in testicular MDA, NOx, TNF-α levels with an increase in TAC, EGF, and ERK1/2 levels in testicular tissue. Furthermore, both drugs enhanced HO-1 immunoexpression in testicular tissue. All these findings were parallel to the preservation of normal testicular architecture in rats treated with ALL and FEB.Conclusion: All and FEB were equally protective against testicular damage induced by MTX through anti-inflammatory, anti-apoptotic, and antioxidant actions. Their effects might be through activation of the EGF/ERK1/2/HO-1 pathway.

The IL-6/HO-1/STAT3 signaling pathway is implicated in the amelioration of acetaminophen-induced hepatic toxicity: A neonatal rat model.

The widespread use of acetaminophen (APAP) in children as an over-the-counter treatment can cause acute liver failure through accidental overdose or ingestion. Therefore, the current research sought to investigate the function of hemin in mitigating the acute hepatotoxic effect of APAP in rat offspring. Thirty-two rats were assigned into four groups: control, hemin, APAP, and hemin/APAP groups. Liver enzymes were measured in serum along with oxidative stress indicators, tumor necrosis factor-α (TNF-α), interleukin-1beta (IL-1ß), total nitrites (NOx), and caspase 3 in liver. Immunoblotting of heme oxygenase-1 (HO-1), interleukin-6 (IL-6), Janus kinase 2 (Jak2), and signal transducer and activator of transcription 3 (STAT3) was carried out. The Bax/Bcl2 mRNA expression ratio was determined. A histological study and an immunohistochemical study of phosphorylated STAT3 were also done. Hemin reduced liver enzymes, MDA, TNF-α, NOx, caspase 3, IL-1ß, p-STAT3 expression, p-Jak2 expression, IL-6 expression, and Bax/Bcl2 mRNA expression ratio. In contrast, hemin increased GSH, TAC, and the expression of HO-1, improving the histopathological picture of liver tissue. Thus, hemin could ameliorate APAP-induced hepatic toxicity in rat offspring through anti-oxidant, anti-apoptotic, and anti-inflammatory actions with a possible role for the IL-6/HO-1/Jak2/STAT3 pathway.

Dipeptidyl peptidase-4 inhibitor: Sitagliptin down-regulated toll-like receptor 4 signaling pathway to reduce uterine injury in rats.

Objectives: Uterine ischemia is a common problem with ongoing controversy about its pathogenesis and prevention. The present study aimed to investigate the protective role of sitagliptin against uterine ischemia-reperfusion injury (IRI). Materials and Methods: Rats were allocated into 4 groups: control, sitagliptin (SIT) (5 mg/kg), IR; ischemia was induced followed by reperfusion, and IR+SIT; SIT was administered 1 hr before IRI. Uteri were removed for histopathological and biochemical observations. Malondialdehyde (MDA), total nitrites (NOx), reduced glutathione (GSH), superoxide dismutase (SOD) activity, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and toll-like receptor 4 (TLR4) were all measured. Hematoxylin and eosin (H&E) stain, Periodic acid-Schiff stain (PAS), and caspase-3 immunostaining were applied. Results: In the IR+SIT group; NOx, GSH, and SOD activities increased significantly. Meanwhile, the levels of MDA, TNF-α, IL-6, TLR4, and caspase-3 immunoexpression showed a significant reduction, as compared with the IR group. In the IR+SIT group, an improvement in the histopathological picture was noticed. Conclusion: The results showed that sitagliptin confers protection against uterine IRI through anti-oxidant, anti-inflammatory, and anti-apoptotic effects with a possible role for TLR4.

Leukotriene Receptor Antagonist, Montelukast Ameliorates L-NAME-Induced Pre-eclampsia in Rats through Suppressing the IL-6/Jak2/STAT3 Signaling Pathway.

AIMS: To investigate the potential protective role of montelukast (Mont) in the pre-eclampsia rat model induced by L-NG-Nitro arginine methyl ester (L-NAME). METHODS AND MATERIALS: Thirty-two pregnant female albino Wistar rats were assigned to four groups: the control group: pregnant rats received vehicles; the Mont group: pregnant rats received Mont (10 mg/kg/day, p.o.) from the 6th to the 18th day of gestation; the L-NAME group: pregnant rats received L-NAME (50 mg/kg/day, i.p.) from the 9th to the 18th day of gestation; the Mont/L-NAME group: pregnant rats received Mont (10 mg/kg/day, p.o.) from the 6th to the 18th day of gestation and L-NAME (50 mg/kg/day, i.p.) from the 9th to the 18th day of gestation. Placental, hepatic, and renal malondialdehyde (MDA), total nitrites (NOx), interleukin 6 (IL-6), and tumor necrosis factor (TNF)-α were determined. Serum alanine transaminase (ALT), aspartate transaminase (AST), creatinine, urea, 24-h urinary protein, and the placental growth factor (PGF) were measured. Histopathological examinations of the placental, hepatic, and renal tissues were also performed. In addition, placental, hepatic, and renal Janus kinase 2 (Jak2) and signal transducer and activator of transcription 3 (STAT3) immunoblotting were performed. KEY FINDINGS: Mont improves oxidative stress, IL-6, TNF-α, ALT, AST, creatinine, urea, 24-h urinary protein, PGF, Jak2, and STAT3 which were all affected by L-NAME. Moreover, the histopathological assessment indicated that Mont restored the normal architecture that was markedly disturbed by L-NAME. SIGNIFICANCE: Mont exerted the biochemical and histopathological amelioration of L-NAME-caused pre-eclampsia through its anti-inflammatory, anti-oxidant function and suppression of the IL-6/Jak2/STAT3 signaling pathway.

Role of JNK, ERK, and p38 MAPK signaling pathway in protective effect of sildenafil in cyclophosphamide-induced placental injury in rats.

AIMS: Chemotherapeutic agents; cyclophosphamide (CYC) is used for treatment of cancer and autoimmune diseases. Grievously, CYC is non-selective as it affects both tumor and healthy cells resulting in systemic toxicity including placenta. The present study aimed to evaluate the effect of phosphodiesterase 5 inhibitor, sildenafil (Sild) on CYC-induced placental injury in rats. MATERIALS AND METHODS: Thirty-two female Wister rats were randomly divided into 4 experimental groups. Group 1: control pregnant group; Group 2: Sild-treated pregnant rats; Group 3: pregnant rats received CYC; Group 4: pregnant rats received Sild and CYC. Placental malondialdehyde (MDA), total nitrite/nitrate (NOx), reduced glutathione (GSH), tumor necrosis factor-α (TNF-α), platelet growth factor (PlGF), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38MAPK), extracellular signal-regulated kinase (ERK) and cleaved caspase-3 were measured. Histological changes, Nuclear Factor kappa-light-chain-enhancer of activated B (NF-κB), Connexin 43 (GJA1) and proliferating cell nuclear antigen (PCNA) immuno-expressions were also evaluated. KEY FINDINGS: CYC showed significant decrease in placental GSH, NOx, PlGF, GJA1 and PCNA immuno-expressions but significant increase in placental MDA, TNF-α, JNK, P38MAPK, ERK, caspase-3 and NF-kB immuno-expression. Sild showed significant improvement in all oxidative, inflammatory and apoptotic parameters. SIGNIFICANCE: Sild is a promising protective drug against placental injury induced by CYC through antagonizing MAPK (JNK, ERK, and p38) signaling pathway with anti-oxidant, anti-inflammatory and anti-apoptotic effects.

Ameliorating effect of leukotriene receptor antagonist in multi-organ toxicity induced in rat offspring, a possible role for epidermal growth factor.

Purpose: Nowadays, there is a dramatic increase in the interest of potential impact of consumer-relevant engineered nanoparticles on pregnancy.Materials and methods: This study investigated the possible protective effect of montelukast in neonatal organ toxicity induced by maternal exposure to silver nanoparticles (AgNPs) in rats.Results: It was noticed that montelukast reduced serum urea, creatinine, renal caspase-3 immunoreactivity and IL-1ß and increased total antioxidant capacity, as compared to AgNPs. In kidney and bone tissue, montelukast reduced oxidative stress parameters and TNF-α level that was increased with AgNPs. Surprisingly, montelukast administration increased epidermal growth factor (EGF) in bone and reduced it in kidney. Furthermore, as compared to AgNPs, montelukast improved histopathological picture of kidney and bone.Conclusions: In conclusion, montelukast antagonized the biochemical and histopathological changes occurred in kidneys and bones of rat offspring by maternal exposure to AgNPs, mostly by anti-oxidant, anti-apoptotic and anti-inflammatory actions with a possible role for EGF.

The protective effect of fenofibrate, triptorelin, and their combination against premature ovarian failure in rats.

Cyclophosphamide (CP) is a chemotherapy alkylating agent that causes a lot of side effects including premature ovarian failure (POF). This study aimed to evaluate the possible protective effect of fenofibrate (FEN) in CP-induced POF. Rats were randomly divided into five groups as follows: negative control, CP, triptorelin (TRI)-treated, FEN (FEN)-treated, and FEN + TRI-treated. Histological study, collagen area fraction, and immunoexpression of proliferating cell nuclear antigen (PCNA) were evaluated. Also, estrogen, anti-mullerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and ovarian malondialdehyde (MDA), nitric oxide (NOx), reduced glutathione (GSH), superoxide dismutase (SOD), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor (VEGF) were measured. CP significantly reduced ovarian follicle count, as compared with the control group (1.00 ± 0.76 versus 7.75 ± 1.83, respectively). Meanwhile, FEN, either solely or in combination with TRI, significantly increased ovarian follicle count, as compared with the CP group (3.88 ± 0.83 and 5.75 ± 1.39, respectively). As compared with the control group, CP increased the levels of MDA, NOx, IL-10, TNF-α, FSH, LH, and collagen area fraction; however, levels of GSH, SOD, VEGF, AMH, estrogen, and PCNA immunoexpression were reduced with CP. Administration of FEN either solely or in combination with TRI showed significant improvement in all the parameters previously mentioned. FEN can protect the ovary from CP-induced side effects possibly through antioxidant and anti-inflammatory actions.

Protective effect of dipeptidyl peptidase-4 inhibitors in testicular torsion/detorsion in rats: a possible role of HIF-1α and nitric oxide.

Spermatic cord torsion is a serious and common urologic emergency. It requires early diagnosis for prevention of subfertility and testicular necrosis. Vildagliptin and sitagliptin are anti-diabetic drugs of the dipeptidyl peptidase-4 (DPP-4) inhibitors that have a protective role against cerebral ischemic stroke and cardiac ischemia reperfusion. This study aimed to investigate the role and mechanism of action of vildagliptin and sitagliptin in a model of testicular ischemia/reperfusion injury by testicular torsion/detorsion (T/D). Testicular T/D was done and vildagliptin and sitagliptin were administered either alone or in combination with nitric oxide synthase (NOS) inhibitor. Serum total cholesterol and testosterone were measured, while in testicular tissue testosterone, malondialdehyde (MDA) level, total antioxidant capacity (TAC), nitric oxide level, caspase-3, superoxide dismutase (SOD), hypoxia-inducible factor-1α (HIF-1α), tumor necrosis factor-α (TNF-α) and endothelial NOS (eNOS), and inducible NOS (iNOS) and neuronal NOS (nNOS) were measured. Histopathology of testicular tissue was done. Vildagliptin and sitagliptin increased serum testosterone, expression, and activity of SOD and testicular TAC. It also reduced total serum cholesterol, testicular MDA, caspase-3, HIF-1α, TNF-α, and expression of eNOS, iNOS, and nNOS. Vildagliptin and sitagliptin also improved histopathological picture of testicular tissue. NOS inhibitor produced similar result to DDP-4 inhibitors; however, its co-administration augmented the effect of vildagliptin and sitagliptin on these parameters. DPP-4 inhibitors, vildagliptin, and sitagliptin were protective against testicular T/D-induced injury mostly by anti-oxidative stress, and anti-apoptotic and anti-inflammatory actions that was augmented by NOS inhibition with a possible role for HIF-1α expression.