Galantamine mitigates testicular injury and disturbed spermatogenesis in adjuvant arthritic rats via modulating apoptosis, inflammatory signals, and IL-6/JAK/STAT3/SOCS3 signaling.

Rheumatoid arthritis (RA) affects the joints and the endocrine system via persistent immune system activation. RA patients have a higher frequency of testicular dysfunction, impotence, and decreased libido. This investigation aimed to evaluate the efficacy of galantamine (GAL) on testicular injury secondary to RA. Rats were allocated into four groups: control, GAL (2 mg/kg/day, p.o), CFA (0.3 mg/kg, s.c), and CFA + GAL. Testicular injury indicators, such as testosterone level, sperm count, and gonadosomatic index, were evaluated. Inflammatory indicators, such as interleukin-6 (IL-6), p-Nuclear factor kappa B (NF-κB p65), and anti-inflammatory cytokine interleukin-10 (IL-10), were assessed. Cleaved caspase-3 expression was immunohistochemically investigated. Protein expressions of Janus kinase (JAK), signal transducers and activators of transcription (STAT3), and Suppressors of Cytokine Signaling 3 (SOCS3) were examined by Western blot analysis. Results show that serum testosterone, sperm count, and gonadosomatic index were increased significantly by GAL. Additionally, GAL significantly diminished testicular IL-6 while improved IL-10 expression relative to CFA group. Furthermore, GAL attenuated testicular histopathological abnormalities by CFA and downregulated cleaved caspase-3 and NF-κB p65 expressions. It also downregulated JAK/STAT3 cascade with SOCS3 upregulation. In conclusion, GAL has potential protective effects on testicular damage secondary to RA via counteracting testicular inflammation, apoptosis, and inhibiting IL-6/JAK/STAT3/SOCS3 signaling.

The enteroprotective effect of nifuroxazide against methotrexate-induced intestinal injury involves co-activation of PPAR-γ, SIRT1, Nrf2, and suppression of NF-κB and JAK1/STAT3 signals.

Methotrexate (MTX) has long manifested therapeutic efficacy in several neoplastic and autoimmune disorders. However, MTX-associated intestinal toxicity restricts the continuation of treatment. Nifuroxazide (NIF) is an oral antibiotic approved for gastrointestinal infections as an effective antidiarrheal agent with a high safety profile. The current study was designed to explore the potential efficacy of NIF in alleviating intestinal toxicity associated with MTX chemotherapy with the elucidation of the proposed molecular mechanisms. Rats were administered NIF (50 mg/kg; p.o.) for ten days. On day five, a single i.p. injection of MTX (20 mg/kg) was given to induce intestinal intoxication. At the end of the experiment, duodenal tissue samples were isolated for biochemical, Western blotting, immunohistochemical (IHC), and histopathological analysis via H&E, PSA, and Alcian blue stains. NIF showed antioxidant enteroprotective effects against MTX intestinal intoxication through enhanced expression of the redox-sensitive signals of PPAR-γ, SIRT1, and Nrf2 estimated by IHC. Moreover, NIF down-regulated the pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6), NF-κB protein expression, and the phosphorylation of JAK1/STAT3 proteins, leading to mitigation of intestinal inflammation. In accordance, the histological investigation revealed that NIF ameliorated the intestinal pathological changes, preserved the goblet cells, and reduced the inflammatory cells infiltration. Therefore, NIF could be a promising candidate for adjunctive therapy with MTX to mitigate the associated intestinal injury and increase its tolerability.

Zafirlukast protects against hepatic ischemia-reperfusion injury in rats via modulating Bcl-2/Bax and NF-κB/SMAD-4 pathways.

Hepatic ischemia/reperfusion injury (IRI) is a clinical problem commonly during liver transplantation and other liver surgery. This study aimed to evaluate the protective effect of zafirlukast (ZFK) on IR-induced hepatic injury and investigate its relevant protective mechanism. Thirty-two male Wistar albino rats were randomly allocated to four groups: sham, IRI, ZFK, and ZFK + IR groups. ZFK was administered orally in a dose of 80 mg/kg/day for 10 consecutive days. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBL) levels, and gamma glutamyl transferase (GGT) activity were estimated. Liver tissues were used to assess oxidative stress biomarkers including malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NOx), and reduced glutathione (GSH) contents. Inflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-33 (IL-33), in addition to apoptosis biomarkers, BCL2 associated X protein (Bax), B-cell lymphoma 2 (Bcl2) and galactine-9 (GAL9) proteins were also assessed. Western blot analysis was performed for vascular endothelial growth factor (VEGF) and fibrinogen expressions. Immunohistochemical analysis for hepatic nuclear factor-kappa B (NF-κB) and SMAD-4 was done in addition to histopathological examination. Our study revealed that ZFK pre-treatment resulted in liver function restoration and oxidative stress correction. Moreover, inflammatory cytokines were significantly reduced and a remarkable reduction of apoptosis, angiogenesis, and clotting formation has been indicated. Additionally, a significant reduction in SMAD-4 and NF-kB protein expressions was observed. These results were supported by hepatic architecture improvement. Our findings revealed that ZFK possesses a potential protective effect against liver IR possibly through its antioxidant, anti-inflammatory and anti-apoptotic properties.

LCZ696 (sacubitril/valsartan) mitigates cyclophosphamide-induced premature ovarian failure in rats; the role of TLR4/NF-κB/NLRP3/Caspase-1 signaling pathway.

AIM: Cyclophosphamide (CP) is used to treat a variety of cancers and autoimmune illnesses. CP has been found to frequently cause premature ovarian failure (POF). The study's objective was to assess LCZ696's potential for protection against CP-induced POF in a rat model. MAIN METHODS: Rats were randomly assigned into seven groups as follows: control, valsartan (VAL), LCZ696, CP, CP + VAL, CP + LCZ696, and CP + triptorelin (TRI). Ovarian malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), interleukin-18 (IL-18), IL-1ß, and tumor necrosis factor-alpha (TNF-α) were assessed using ELISA. Serum anti-mullerian hormone (AMH), estrogen, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were also measured using ELISA. The expression of NLRP3/Caspase-1/GSDMD C-NT and TLR4/MYD88/NF-B P65 proteins was estimated using western blot assay. The histopathology of the ovaries was also investigated. The estrous cycle, body, and ovarian weights were also monitored. KEY FINDINGS: CP treatment significantly elevated levels of MDA, IL-18, IL-1ß, TNF-α, FSH, LH, and up-regulated TLR4/NF-κB/NLRP3/Caspase-1 proteins, as compared to the control group, however, ovarian follicles count, and levels of GSH, SOD, AMH, and estrogen were reduced with CP administration. All the aforementioned biochemical and histological abnormalities were considerably alleviated by the LCZ696 therapy compared to valsartan alone. SIGNIFICANCE: LCZ696 effectively mitigated CP-induced POF, offering promising protection that could be related to its suppression power on NLRP3-induced pyroptosis and TLR4/NF-B P65 pathway.

Protective effects of rivaroxaban against cisplatin-induced testicular damage in rats: Impact on oxidative stress, coagulation, and p-NF-κB/VCAM-1 signaling.

Coagulation is a main pathway in various diseases pathogenesis including testicular damage. This study evaluated rivaroxaban (RVX) protective effects in testicular impairment by cisplatin (CP). Rats were randomly allocated into five groups: Control, RVX (7 mg/kg/day), CP (10 mg/kg), RVX 5 mg + CP and RVX 7 mg + CP. Serum testosterone and testicular ALT, AST, and ALP were assessed. Testicular oxidative stress and antioxidant parameters and inflammatory indicators including interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) were assessed. qRT-PCR was used to determine mRNA expression of 3ß-hydroxysteroid dehydrogenase (3ß-HSD), 17ß-hydroxysteroid dehydrogenase (17ß-HSD), and steroidogenic acute regulatory protein (stAR). Protein expressions of p-Nuclear factor kappa B (p- NF-κB) and vascular cell adhesion protein-1 (VCAM-1) were analyzed by Western blot analysis. Tissue factor (TF) expression was immunohistochemically analyzed. Results revealed that RVX significantly increased serum testosterone and sperm count while significantly reduced IL-1ß and TNF-α. It significantly decreased tissue MDA and NO contents while increased SOD and GPx. In addition, RVX attenuated CP-induced histopathological aberrations and normalized TF. It also decreased the VCAM-1 and p-NF-κB expression and showed strong expression of 3ß-HSD, 17ß-HSD, and stAR, indicating improvement of steroidogenesis. In conclusion, RVX counteracted testicular damage by CP via suppressing oxidative stress, inflammation, and coagulation and downregulating p-NF-κB/VCAM-1 signaling.

Novel therapeutic modalities target cell signaling of Renin-Angiotensin system/NF-κB-induced cell cycle arrest and apoptosis in urethane-induced lung cancer in mice: An in vivo study.

BACKGROUND: Lung cancer has risen to the top of the list of cancer-related deaths worldwide. Aliskiren is a direct renin inhibitor. AIM: This study aims to investigate the impact of cell signaling of Renin-Angiotensin system (RAS)/NF-κB on lung cancer by investigating the potential therapeutic effects of aliskiren for lung cancer treatment in urethane-induced lung cancer in mice. METHODS: Male BALB/c mice were randomly assigned to one of five treatment groups for 150 days, including (1) normal control; (2) aliskiren (25 mg/kg/i.p) daily, (3) urethane at a dose of 1.5 g/kg (i.p) at Day 1 and 60 (nonsmall cell lung cancer[NSCLC] group) (4) NSCLC mice received carboplatin (15 mg/kg/i.p) every other day for the last 4 successive weeks and (5) NSCLC mice treated with aliskiren daily. Tumor size was determined based on blood sampling, and lungs were isolated for biochemical analysis, western blot analysis assay, and histopathological examination. RESULTS: Urethane demonstrated significant changes in all biochemical and molecular parameters and histological patterns. Aliskiren-treated mice had significantly lower levels of NF-κB p65, Bcl-2, cyclin D1, ICAM-1, MMP-2, and Nrf2, with an increase in the catalytic activity of caspase-3 due to its RAS inhibitory mechanism. The combined urethane administration with aliskiren demonstrated a significant improvement in the histopathological examination. CONCLUSION: RAS/NF-B cell signaling is a potential therapeutic target for preventing and treating lung adenocarcinoma, evidenced by the fundamental cytotoxic mechanism and attenuation of metastasis and angiogenesis induced by the treatment of NSCLC mice with aliskiren.

Ameliorate impacts of scopoletin against vancomycin-induced intoxication in rat model through modulation of Keap1-Nrf2/HO-1 and IκBα-P65 NF-κB/P38 MAPK signaling pathways: Molecular study, molecular docking evidence and network pharmacology analysis.

Nephrotoxicity is an indication for the damage of kidney-specific detoxification and excretion mechanisms by exogenous or endogenous toxicants. Exposure to vancomycin predominantly results in renal damage and losing the control of body homeostasis. Vancomycin-treated rats (200 mg/kg/once daily, for seven consecutive days, i.p.) revealed significant increase in serum pivotal kidney function, oxidative stress, and inflammatory biomarkers. Histologically, vancomycin showed diffuse acute tubular necrosis, denudation of epithelium and infiltration of inflammatory cells in the lining tubular epithelium in cortical portion. In the existing study, the conservative consequences of scopoletin against vancomycin nephrotoxicity was investigated centering on its capacity to alleviate oxidative strain and inflammation through streamlining nuclear factor (erythroid-derived-2) like 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling and prohibiting the nuclear factor kappa B (NF-κB)/mitogen-activated protein kinase (p38 MAPK) pathway. With respect to vancomycin group, scopoletin pretreatment (50 mg/kg/once daily, i.p.) efficiently reduced kidney function, oxidative stress biomarkers and inflammatory mediators. Moreover, histological and immunohistochemical examination of scopoletin-treated group showed remarkable improvement in histological structure and reduced vancomycin-induced renal expression of iNOS, NF-κB and p38 MAPK. In addition, scopoletin downregulated (Kelch Like ECH Associated Protein1) Keap1, P38MAPK and NF-κB expression levels while upregulated renal expression levels of regulatory protein (IκBα), Nrf2 and HO-1. Furthermore, molecular docking and network approach were constructed to study the prospect interaction between scopoletin and the targeted proteins that streamline oxidative stress and inflammatory pathways. The present investigations elucidated that scopoletin co-treatment with vancomycin may be a rational curative protocol for mitigation of vancomycin-induced renal intoxication.

Empagliflozin and neohesperidin protect against methotrexate-induced renal toxicity via suppression of oxidative stress and inflammation in male rats.

Kidney injury from chemotherapy is one of the worsening problems associated with methotrexate (MTX) use. This work aims to examine the nephroprotective effects of empagliflozin (EMPA) and neohesperidin dihydrochalcone (NHD) provoked by MTX. A rat model was implemented by a single administration of MTX (20 mg/kg, i.p.). EMPA and NHD were administered in two doses (10 and 30 mg/kg, p.o.) and (40 and 80 mg/kg, p.o.), respectively for 14 consecutive days, using N-acetylcysteine (150 mg/kg, p.o.) as a reference standard. Pretreatment with EMPA and NHD showed significant attenuation in the renal function biomarkers, histopathological abrasions, and renal oxidative parameters. Also, EMPA and NHD pretreatment produced marked reductions in the expression of IL-6 and TNF-α level as proinflammatory biomarkers. Furthermore, EMPA and NHD pretreatment revealed marked decreases in the expression level of NF-ĸB, Keap1, HSP70, and caspase-3 and notable increases in Nrf2, PPARγ and HO-1 expression levels. EMPA and NHD can constrain oxidative stress liberation, inflammatory mediators proliferation, and apoptotic reactions in the renal tissue, which may be promising for further clinical applications to protect against MTX-induced renal injury or at least to reduce its adverse effects.

RETRACTED: Empagliflozin and neohesperidin mitigate methotrexate hepatotoxicity via Nrf2/PPARγ/HO-1 signalling initiation and suppression of NF-κB/Keap1/HSP70/caspase-3 axis in rats.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. A reader reported several mistakes in the paper including duplicated images in Figures 9 and 10, incorrect names of primer sequences and reference gene, as well as unclear description of the statistical analysis. The authors requested that a corrigendum be published, however, due to the large number of corrections applied, it cannot be concluded that these changes would not alter the conclusions of the paper. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.

Resveratrol mitigates pancreatic TF activation and autophagy-mediated beta cell death via inhibition of CXCL16/ox-LDL pathway: A novel protective mechanism against type 1 diabetes mellitus in mice.

The role of CXC chemokine ligand 16 (CXCL16), oxidized LDL (ox-LDL), tissue factor (TF) and autophagy-induced beta cell death in type 1 diabetes mellitus (T1DM) pathogenesis is still unclear. We examined the therapeutic potential and mechanism of resveratrol (RES) against T1DM. Diabetes was induced in Balb/c mice by i. p. injection of 55 mg/kg streptozotocin (STZ) for five consecutive days. The control group received vehicles. RES or (RES + STZ) groups received RES (50 mg/kg, i. p.) daily for 12 days starting from the fourth day of buffer or STZ injections, respectively. Blood glucose, serum insulin, beta cell mass, serum lipid profiles, histological changes, oxidative stress biomarkers were determined. Moreover, CXCL16, TF, ox-LDL, P62 and LC3 tissue expression were also analyzed. Diabetic mice showed a marked deterioration in biochemical, physical and oxidative stress parameters. Interestingly, immunofluorescence analysis showed a remarkable elevation in CXCL16 (12 folds), ox-LDL (9 folds), TF (8.3 folds) in pancreatic B-cells. Moreover, western blotting revealed a profound increase in ox-LDL (2.6 folds), TF (3.2 folds), while a significant decline in P62 (0.34) and LC3 (0.25) when compared to control. RES mitigated biochemical, physical, oxidative imbalance and distorted pancreatic architecture in T1DM mice. Intriguingly, CXCL16, ox-LDL, TF and autophagic markers were also restored after RES treatment. Our data give the first direct evidence that beta cell-specific CXCL16/ox-LDL pathway activation is a potential trigger of TF activation and autophagic beta cell death in T1DM. Moreover, RES may have potential therapeutic applications for prevention of T1DM mainly via ameliorating this pathway.

Resveratrol inhibits macrophage infiltration of pancreatic islets in streptozotocin-induced type 1 diabetic mice via attenuation of the CXCL16/NF-κΒ p65 signaling pathway.

AIM: Despite CXC chemokine ligand 16 (CXCL16) contributes to the pathogenesis of many inflammatory disorders, the mechanism by which CXCL16 is involved in T1DM remains unclear. In this study, we examined the role of the CXCL16/NF-κΒ p65 signaling pathway in the progression of this disease and the possible protective effect of resveratrol (RES) on streptozotocin (STZ)-induced T1DM. MAIN METHODS: Mice were classified into four groups of 10 animals each. The control group received citrate buffer. The RES group received 50 mg/kg i.p. RES for 12 days beginning on day 4 of citrate buffer. The STZ group received 55 mg/kg i.p. STZ once a day for 5 consecutive days. The fourth group injected with RES (50 mg/kg) for 12 days starting on day 4 of STZ injection. Biochemical, physical and oxidative stress parameters were measured in all groups. Moreover, expression of CXCL16 and CD45 was measured in pancreatic islets and spleen. Additionally, NF-κΒ p65 was investigated in isolated islets. KEY FINDINGS: Our results showed a significant elevation of CXCL16, NF-κΒ p65 and CD45 in islets of diabetic (DM) mice. Intriguingly, RES significantly restored distorted biochemical, physical and oxidative stress parameters after STZ treatment as well as inhibited the expression of CXCL16/NF-κΒ p65 in pancreatic islets. Moreover, RES normalized CXCL16 and CD45 expression in islets and spleen. SIGNIFICANCE: This study demonstrates first evidence that CXCL16/NF-κΒ p65 signaling pathway is associated with macrophage infiltration to pancreatic islet in T1DM and that RES successfully improved T1DM may be at least via inhibiting this pathway.

Amlodipine alleviates cisplatin-induced nephrotoxicity in rats through gamma-glutamyl transpeptidase (GGT) enzyme inhibition, associated with regulation of Nrf2/HO-1, MAPK/NF-κB, and Bax/Bcl-2 signaling.

BACKGROUND: The therapeutic utility of the effective chemotherapeutic agent cisplatin is hampered by its nephrotoxic effect. We aimed from the current study to examine the possible protective effects of amlodipine through gamma-glutamyl transpeptidase (GGT) enzyme inhibition against cisplatin nephrotoxicity. METHODS: Amlodipine (5 mg/kg, po) was administered to rats for 14 successive days. On the 10th day, nephrotoxicity was induced by a single dose of cisplatin (6.5 mg/kg, ip). On the last day, blood samples were collected for estimation of kidney function, while kidney samples were used for determination of GGT activity, oxidative stress, inflammatory, and apoptotic markers, along with histopathological evaluation. RESULTS: Amlodipine alleviated renal injury that was manifested by significantly diminished serum creatinine and blood urea nitrogen levels, compared to cisplatin group. Amlodipine inhibited GGT enzyme, which participates in the metabolism of extracellular glutathione (GSH) and platinum-GSH-conjugates to a reactive toxic thiol. Besides, amlodipine diminished mRNA expression of NADPH oxidase in the kidney, while enhanced the anti-oxidant defense by activating Nrf2/HO-1 signaling. Additionally, it showed marked anti-inflammatory response by reducing expressions of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB), with subsequent down-regulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1). Moreover, amlodipine reduced Bax/Bcl-2 ratio and elevated hepatocyte growth factor (HGF), thus favoring renal cell survival. CONCLUSIONS: Effective GGT inhibition by amlodipine associated with enhancement of anti-oxidant defense and suppression of inflammatory signaling and apoptosis support our suggestion that amlodipine could replace toxic GGT inhibitors in protection against cisplatin nephrotoxicity.

Febuxostat attenuates testosterone-induced benign prostatic hyperplasia in rats via inhibiting JAK/STAT axis.

AIM: To investigate the possible modulatory effect of febuxostat in testosterone-induced benign prostatic hyperplasia (BPH) in rats with emphasis on xanthine oxidase (XO)/Janus Kinases (JAK)/signal transducer and activator of transcription (STAT) axis. MAIN METHODS: Male Wistar rats were treated with testosterone with/out febuxostat. Effect of febuxostat on BPH was assessed at the structural level by histopathology and determination of prostate weight/index. Cyclin D1 protein expression was assessed immunohistochemically and the ratio of Bax/Bcl-2 mRNA expression was determined by real time polymerase chain reaction analysis (RT-PCR). Besides, uric acid serum level was determined colorimetrically. Prostatic XO activity, as well as oxidative stress and inflammatory markers were evaluated. Additionally, western blot analysis was performed for determination of JAK-1 and phosphorylated form of STAT-3 expression in tissues. KEY FINDINGS: Results revealed that febuxostat inhibited the increase in prostatic weight and index compared to testosterone-treated group. Additionally, febuxostat ameliorated testosterone-induced histopathological changes, prevented the rise in cyclin D1 expression and enhanced Bax/Bcl2 ratio. Febuxostat suppressed testosterone induced- increase in XO activity in prostates and serum level of uric acid. Moreover, it regulated oxidative stress markers including; malondialdehyde (MDA), superoxide dismutase (SOD) activity and glutathione (GSH) content. Also, it inhibited the increase in prostate contents of interleukin-6 (IL-6), interleukin-1ß (IL-1 ß), tumor necrosis factor (TNF-α) and nuclear factor (NF-κB). Interestingly, febuxostat markedly reduced JAK-1 and subsequent phosphorylation of STAT-3 protein expression. SIGNIFICANCE: Febuxostat ameliorates testosterone-induced BPH via suppressing XO/JAK/STAT axis. This may help to re-purpose the use of XO inhibitors.

The modulatory effects of cinnamaldehyde on uric acid level and IL-6/JAK1/STAT3 signaling as a promising therapeutic strategy against benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a widespread disorder in elderly men. Cinnamaldehyde, which is a major constituent in the essential oil of cinnamon, has been previously reported to reduce xanthine oxidase activity, in addition to its anti-inflammatory, anti-oxidant, and anti-proliferative activities. Our study was designed to investigate the potential modulatory effects of cinnamaldehyde on testosterone model of BPH in rats through reduction of uric acid level, and suppression of IL-6/JAK1/STAT3 signaling pathway. Cinnamaldehyde (40 and 75 mg/kg) was orally administered to male Wistar rats for 3 weeks, and concurrently with testosterone (3 mg/kg, s.c.) from the second week. Cinnamaldehyde ameliorated the elevation in prostatic weight and index compared to rats treated with testosterone only, that was also confirmed by alleviation of histopathological changes in prostate architecture. The protective mechanisms of cinnamaldehyde were elucidated through inhibition of xanthine oxidase activity and reduced uric acid level. That was accompanied by reduction of the pro-inflammatory cytokines; interleukin-6 (IL-6), IL-1ß, tumor necrosis factor-alpha (TNF-α), and the nuclear translocation of the transcription factor NF-κB p65, that could be attributed also to the enhanced anti-oxidant defense by cinnamaldehyde. The protein expression of JAK1, which is IL-6 receptor linked protein, was reduced with subsequently reduced activation of STAT3 protein. That eventually suppressed the formation of the proliferation protein cyclin D1, while elevated Bax/Bcl2 ratio. It can be concluded that reducing uric acid level through xanthine oxidase inhibition and suppression of the inflammatory signaling cascade; IL-6/JAK1/STAT3; by cinnamaldehyde could be a novel and promising therapeutic approach against BPH.

Perindopril ameliorates experimental Alzheimer's disease progression: role of amyloid ß degradation, central estrogen receptor and hyperlipidemic-lipid raft signaling.

Accumulating evidence indicates that over-stimulation of angiotensin-converting enzyme 1 (ACE1) activity is associated with ß-amyloid (Aß) and phosphorylated tau (p-tau)-induced apoptosis, oxido-nitrosative neuroinflammatory stress and neurodegeneration in Alzheimer's disease (AD). Alternatively, activation of the ACE2, the metalloprotease neprilysin (Neutral Endopeptidase; NEP) and the insulin-degrading enzyme (IDE) could oppose the effects of ACE1 activation. We aim to investigate the relationship between ACE1/ACE2/NEP/IDE and amyloidogenic/hyperlipidemic-lipid raft signaling in hyperlipidemic AD model. Induction of AD was performed in ovariectomized female rats with high-fat high fructose diet (HFFD) feeding after 4 weeks following D-galactose injection (150 mg/kg). The brain-penetrating ACE1 inhibitor perindopril (0.5 mg/kg/day, p.o.) was administered on a daily basis for 30 days. Perindopril significantly decreased hippocampal expression of ACE1 and increased expression of ACE2, NEP and IDE. Perindopril markedly decreased Aß1-42, improved lipid profile and ameliorated the lipid raft protein markers caveolin1 (CAV1) and flotillin 1 (FLOT1). This was accompanied by decreased expression of p-tau and enhancement of cholinergic neurotransmission, coupled with decreased oxido-nitrosative neuroinflammatory stress, enhancement of blood-brain barrier (BBB) functioning and lower expression of the apoptotic markers glial fibrillary acidic protein (GFAP), Bax and ß-tubulin. In addition, perindopril ameliorated histopathological damage and improved learning, cognitive and recognition impairment as well as depressive behavior in Morris water maze, Y maze, novel object recognition and forced swimming tests, respectively. Conclusively, perindopril could improve cognitive defects in AD rats, at least through activation of ACE2/NEP/IDE and inhibition of ACE1 and subsequent modulation of amyloidogenic/hyperlipidemic-lipid raft signaling and oxido-nitrosative stress.

The anti-Alzheimer effect of telmisartan in a hyperglycemic ovariectomized rat model; role of central angiotensin and estrogen receptors.

The central renin angiotensin system (RAS) is implicated in Alzheimer's disease (AD). Here, induction of experimental AD simulation was performed by D-galactose (D-Gal) injection to ovariectomized (OVX) rats fed on high fat high fructose diet (HFFD). Telmisartan administration to OVX/HFFD/D-Gal rats lowered the expression of hippocampal angiotensin 1 and 2 receptors and glucose transporter 2 in addition to lowering of the peripheral and central glucose levels. Furthermore, it improved cognitive impairment and suppressed hippocampal amyloidogenic markers including amyloid-beta level, phosphorylated tau protein and beta site amyloid precursor protein cleaving enzyme 1 expression, while elevated levels of insulin degrading enzyme and recovered permeability of blood brain barrier (BBB). In addition, it inhibited hippocampal oxido-nitrosative stress as well as neuroinflammatory and apoptotic biomarkers. Telmisartan improved memory and cognitive impairment as shown in the behavioral Morris water maze, Y-maze, novel object recognition and open field tests in addition to amelioration of depressive like behavior as shown in forced swimming test. Histopathological examination of brain and immune expression of glial fibrillary acidic protein were also improved together with astrogliosis improvement. In conclusion, telmisartan improved memory and cognitive impairment, recovered amyloidogenesis-hyperglycemic axis, astrogliosis, integrity of BBB, memory deficit and oxidonitrosative stress induced in OVX/HFFD/D-Gal rats.

The potential chemotherapeutic effect of ß-ionone and/or sorafenib against hepatocellular carcinoma via its antioxidant effect, PPAR-γ, FOXO-1, Ki-67, Bax, and Bcl-2 signaling pathways.

Proliferation and apoptosis are two primary driving forces behind the pathogenesis of hepatocellular carcinoma (HCC). HCC is associated with Ki-67 and Bcl-2 overexpression, reduced Bax expression inducing disturbance of equilibrium between cellular proliferation and apoptosis, and exacerbated by reduced expression of PPAR-γ and FOXO-1. Our objective was to examine the mechanism by which the cyclic isoprenoid, ß-ionone (ßI), attenuated hepatocarcinogenesis and compare its possible anticancer activity with sorafenib (SF) as standard HCC treatment. HCC induction was achieved by supplying Wistar rats with 0.01% diethylnitrosamine (DENA) for 8 consecutive weeks by free access of drinking water. The effects of ßI (160 mg/kg/day) administered orally were evaluated by biochemical, oxidative stress, macroscopical, and histopathological analysis. In addition, immunohistochemical assay for localization and expression of Bax and Bcl-2 and RT-PCR for expression levels of PPAR-γ, FOXO-1, and Ki-67 mRNA were performed. ßI treatment significantly reduced the incidence, total number, and multiplicity of visible hepatocyte nodules, attenuated LPO, near-normal restoration of all cancer biomarkers, and antioxidant activities, indicating the chemotherapeutic impact of ßI. Histopathological analysis of the liver confirmed that further. ßI also induced pro-apoptotic protein Bax expression and reduced anti-apoptotic expression of Bcl-2 protein. Moreover, ßI induced mRNA expression of tumor suppressor genes (PPAR-γ and FOXO-1) and decreased proliferative marker Ki-67 mRNA expression. For the first time, the present study provides evidence that ßI exerts a major anticancer effect on DENA-induced HCC, at least in part, through inhibition of cell proliferation, oxidative stress, and apoptogenic signal induction mediated by downregulation of Bcl-2 and upregulation of Bax, PPAR-γ, and FOXO-1 expressions.

Apixaban exhibits anti-arthritic effects by inhibiting activated factor X-mediated JAK2/STAT3 and MAPK phosphorylation pathways.

Activated factor X (FXa) is strongly linked to various inflammatory events. This study aimed to investigate the effect of FXa on janus kinase2/signal transducers and activators of transcription3 (JAK2/STAT3) and mitogen-activated protein kinase (MAPK) phosphorylation in relation to rheumatoid arthritis (RA). It also extends its scope to explore the possible anti-arthritic effects of apixaban, a selective FXa inhibitor. Rats were allocated into normal control; complete Freund's adjuvant (CFA, 0.4 ml/4 days/12 days); FXa (120 µg/kg/day/3 days) and CFA + FXa groups as well as three treated groups including CFA + apixaban; FXa + apixaban and CFA + FXa + apixaban. Apixaban was administered at a dose of 10 mg/kg/12 h for15 days. By the end of the experimental period, tissue samples were collected for the assessment of phosphorylated (p)-JAK2, STAT3, MAPK, matrixmetalloprotein-1 (MMP-1) and protease-activated receptor 2. Furthermore, Serum interleukin-6 (IL-6), platelet-derived growth factor (PDGF), anti-citrullinated protein antibody (ACPA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), plasma level of FXa and prothrombin time were evaluated. In support, histopathological and macroscopical examinations were performed. FXa activated JAK2, STAT3 and MAPK phosphorylation through activation of PAR 2, PDGF and IL-6 and concomitantly led to a significant elevation in ACPA, MMP-1 and 8-OHdG. Apixaban markedly amended FXa-induced changes. Conclusively, the current study revealed that FXa may have a drastic role in RA progression and pathogenesis at least through stimulation of JAK2/STAT3 and MAPK phosphorylation. Furthermore, apixaban exerted robust arthro-protective effects. These beneficial outcomes could be attributed to its ability to impede JAK2/STAT3 and MAPK activation, as well as to its antioxidant property.

The potential hepatoprotective effects of lovastatin combined with oral hypoglycemic agents in streptozotocin-induced diabetes in rats.

Aims: Epidemiologic studies have shown that individuals with diabetes have a higher risk of hepatic diseases which represent a true clinical problem. The purpose of the present study was to assess the possible modulatory effect of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin on therapeutic efficiency of traditional antidiabetics, as metformin and gliclazide, regarding hepatic complications in streptozotocin (STZ)-induced diabetes in rats.Methods: Animals were divided into seven groups; normal control group, STZ control group (50 mg/kg, i.p., single dose), lovastatin group, metformin group, gliclazide group, lovastatin plus metformin group and lovastatin plus gliclazide group. Serum HMG-CoA reductase, in addition to serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) as hepatocyte integrity loss markers, hepatic tissue thiobarbituric acid reactive substances (TBARS), glutathione reduced (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD) and catalase as oxidative stress markers, as well as serum tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) and hepatic nitric oxide end products (NOx) as inflammatory markers were assessed, coupled with a confirmatory histopathological study.Results: The combined effect of lovastatin with metformin or gliclazide was significantly better than either drug alone regarding serum AST, ALP and TNF-α, and hepatic TBARS, GSH, GST, SOD and NOx levels.Conclusions: Hepatic complications associated with diabetes could be improved by combination of metformin or gliclazide with lovastatin.