Neuroprotective effect of curcumin against experimental autoimmune encephalomyelitis-induced cognitive and physical impairments in mice: an insight into the role of the AMPK/SIRT1 pathway.

Multiple sclerosis (MS) is an incurable chronic neurodegenerative disease where autoimmunity, oxidative stress, and neuroinflammation collaboration predispose myelin sheath destruction. Interestingly, curcumin, a natural polyphenol, showed a neuroprotective effect in numerous neurodegenerative diseases, including MS. Nevertheless, the influence of curcumin against MS-induced cognitive impairment is still vague. Hence, we induced experimental autoimmune encephalomyelitis (EAE) in mice using spinal cord homogenate (SCH) and complete Freund's adjuvant, which eventually mimic MS. This study aimed not only to evaluate curcumin efficacy against EAE-induced cognitive and motor dysfunction, but also to explore a novel mechanism of action, by which curcumin exerts its beneficial effects in MS. Curcumin (200 mg/kg/day) efficacy was evaluated by behavioral tests, histopathological examination, and biochemical tests. Concisely, curcumin amended EAE-induced cognitive and motor impairments, as demonstrated by the behavioral tests and histopathological examination of the hippocampus. Interestingly, curcumin activated the adenosine monophosphate (AMP)-activated protein kinase/silent mating type information regulation 2 homolog 1 (AMPK/SIRT1) axis, which triggered cyclic AMP response element-binding protein/brain-derived neurotrophic factor/myelin basic protein (CREB/BDNF/MBP) pathway, hindering demyelination of the corpus callosum. Furthermore, AMPK/SIRT1 activation augmented nuclear factor erythroid 2-related factor 2 (Nrf2), a powerful antioxidant, amending EAE-induced oxidative stress. Additionally, curcumin abolished EAE-induced neuroinflammation by inhibiting Janus kinase 2 /signal transducers and activators of transcription 3 (JAK2/STAT3) axis, by various pathways, including AMPK/SIRT1 activation. JAK2/STAT3 inhibition halts inflammatory cytokines synthesis. In conclusion, curcumin's neuroprotective effect in EAE is controlled, at least in part, by AMPK/SIRT1 activation, which ultimately minimizes EAE-induced neuronal demyelination, oxidative stress, and neuroinflammation.

Semaglutide, a novel glucagon-like peptide-1 agonist, amends experimental autoimmune encephalomyelitis-induced multiple sclerosis in mice: Involvement of the PI3K/Akt/GSK-3ß pathway.

Multiple sclerosis (MS) is a disabling neurodegenerative disease that causes demyelination and axonal degeneration of the central nervous system. Current treatments are partially effective in managing MS relapses and have a negligible impact on treating MS cognitive deficits and cannot enhance neuronal remyelination, imposing a need for a new MS remedy. Semaglutide, a novel glucagon-like peptide-1 agonist, has recently displayed a neuroprotective effect on several neurodegenerative diseases, suggesting that it may have a protective effect in MS. Therefore, this study was conducted to investigate the influence of semaglutide on experimental autoimmune encephalomyelitis (EAE)-induced MS in mice. Here, EAE was induced in mice using spinal cord homogenate, which eventually altered the mice's cognitive and motor functions, similar to what is observed in MS. Interestingly, intraperitoneally administered semaglutide (25 nmol/kg/day) amended EAE-induced cognitive and motor deficits observed in novel object recognition, open field, rotarod, and grip strength tests. Moreover, histological examination revealed that semaglutide treatment attenuated hippocampal damage and corpus callosum demyelination caused by EAE. Additionally, biochemical testing revealed that semaglutide activates the PI3K/Akt axis, which eventually hampers GSK-3ß activity. GSK-3ß activity inhibition attenuates demyelination and triggers remyelination through CREB/BDNF; furthermore, it boosts Nrf2 and SOD levels, protecting the mice from EAE-induced oxidative stress. Additionally, GSK-3ß inhibition minimizes neuroinflammation, as reflected by decreased NF-kß and TNF-α levels. In conclusion, semaglutide has a neuroprotective effect in EAE-induced MS in mice, which is mediated by activating the ramified PI3K/Akt/GSK-3ß pathway.

PAR1, a therapeutic target for remote lung injury associated with hind limb ischemia/reperfusion: ERK5/KLF2-dependent lung capillary barrier preservation.

Protease-activated receptor 1 (PAR1) is expressed in pneumocytes and endothelial cells of the alveolar barrier. Its activation by thrombin disrupts the barrier integrity dynamics and induces lung injury in in vitro and in vivo paradigms. Nonetheless, the role of PAR1, as a therapeutic target, in hind limb ischemia/reperfusion (I/R)-mediated remote lung injury has been unclear. Therefore, this study aimed to determine the potential benefit of PAR1 blockade using the selective antagonist SCH79797 in distant lung dysfunction following hind limb I/R injury with special emphasis on the extracellular signal-regulated kinase 5 (ERK5)/Krüppel-like factor 2 (KLF2) axis. Rats were subdivided into control, bilateral hind limb I/R, SCH79797, and SCH79797+BIX02189 (ERK5 inhibitor) groups. PAR1 blockade, ERK5-dependently, alleviated alveolar barrier disruption as evidenced by reductions in both pulmonary systemic leakage of surfactant protein-D and lung fluid accumulation with increase in pulmonary claudin 5, vascular endothelial cadherin, and connexin 37 levels. Such improvements are downstream targets of the ERK5/KLF2-mediated sphingosine-1-phosphate receptor 1 (S1PR1) upregulated expression and pS536-nuclear factor-κB (NF-κB) p65 inhibition. SCH79797 effectively impedes the evoked inflammatory response and oxidative burst by suppressing vascular endothelial growth factor, tumor necrosis factor-α, lipid peroxidation, and neutrophil infiltration while boosting the glutathione antioxidant defense. Accordingly, PAR1 could be a therapeutic target, where its blockade mitigated pulmonary-endothelial barrier disruption via mutual S1PR1 enhancement and NF-κB p65 inhibition following ERK5/KLF2 activation.

Protective effects of olmesartan and l-carnitine on doxorubicin-induced cardiotoxicity in rats.

Doxorubicin (DOX), an anthracycline antibiotic, is an important antineoplastic agent due to its high antitumor efficacy in hematological as well as in solid malignancies. The clinical use of DOX is limited due to its cardiotoxic effects. The present study aimed to investigate the possible protective effect of olmesartan (Olm), l-carnitine (L-CA), and their combination in cardiotoxicity induced by DOX in rats. Male albino rats were randomly divided into seven experimental groups (n = 8): group I: normal control, group II: L-CA, group III: Olm, group IV: DOX. The other three groups were treated with Olm (10 mg/kg), L-CA (300 mg/kg), and their combination for 2 weeks after induction of cardiotoxicity by a single dose of DOX (20 mg/kg). In the results, DOX showed a significant elevation in serum troponin I, creatine kinase-MB (CK-MB), and lactate dehydrogenase (LDH) together with increased inflammation manifested by the rise of tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecules-1 (ICAM-1), interleukin IL-1ß (IL-1ß), myeloperoxidase (MPO), nuclear factor-kappa B (NF-κB), and transforming growth factor beta (TGF-ß) in cardiac tissues as well as DOX-induced oxidative stress by increasing in malondialdehyde (MDA) and decreasing in superoxide dismutase (SOD) and glutathione (GSH) in heart tissues. In addition, caspase-3 activity was boosted as indication of increased apoptosis. On the other hand, administration of L-CA and Olm attenuated the DOX-evoked disturbances in the abovementioned parameters. In addition, DOX exhibited echocardiographic changes and severe histopathological changes, which were significantly reversed by L-CA and Olm treatment. In conclusion, the present study data confirm the protective role of L-CA and Olm in DOX-induced cardiotoxicity, which may be related to its antioxidant, antiinflammatory, and antiapoptotic agents.

Telluric acid ameliorates hepatic ischemia reperfusion-induced injury in rats: Involvement of TLR4, Nrf2, and PI3K/Akt signaling pathways.

In past tellurium-based compounds had limited use, however, their therapeutic potential have been target of interest recently due to antioxidant and anti-inflammatory capabilities in experimental endotoxemia. Nevertheless, their potential hepatoprotective effect against ischemia reperfusion (IR) injury is still obscure. This study examined the possible hepatoprotective effect of telluric acid (TELL), one of tellurium-based compound, against the deteriorating effect hepatic IR injury in rats through directing toll like receptor-4 (TLR4) cascade, phosphoinositide 3-kinase(PI3K)/Akt axis, and nuclear erythroid-related factor-2 (Nrf-2) pathway as possible mechanisms contributed to TELL's effect. Indeed, male Wistar rats were randomized into 3 groups: sham-operated, control IR and TELL (50 µg/kg). TELL was administrated once daily for seven consecutive days prior to the IR induction. Pretreatment with TELL attenuated hepatic IR injury as manifested by hampered plasma aminotransaminases and lactate dehydrogenase activities. Also, TELL opposed IR induced elevation in tissue expression/activity of high-mobility group box protein-1 (HMGB1), TLR4, myeloid differentiation primary-response protein 88 (MyD88), phospho-nuclear factor-kappa B p65 (p-NF-κB p65), phospho-mitogen activated protein kinasep38 (p-MAPKp38) and tumor necrosis factor-alpha (TNF-α). Moreover, TELL reduced the elevated thiobarbituric acid reactive substances along with increased both Nrf-2 and endothelial nitric oxide synthase (eNOS) protein expression, beside replenishment of hepatic reduced glutathione. In addition, TELL induced obvious upregulation of p-PI3K and p-Akt protein expressions together with restoration of histopathological changes in IR injury. In conclusion, TELL purveyed conceivable novel hepatoprotective mechanisms and attenuated events associated with acute hepatic injury via inhibition of TLR4 downstream axis and activation of Nrf-2 and PI3K/Akt signaling cascades. Thus, TELL may provide a novel therapeutic potential for complications of hepatic IR injury.

Urinary tract injuries during cesarean section in patients with morbid placental adherence: retrospective cohort study.

BACKGROUND/OBJECTIVE: The purpose of this study is to evaluate the cases of lower urinary tract injuries during cesarean section with or without hysterectomy in cases with morbid placental adherence. METHODS: This record based retrospective study was conducted at Ain Shams University Maternity Hospital in Cairo, Egypt during the period between January 2014 and December 2016. It included all patients who had urinary tract injuries during cesarean section with or without hysterectomy in the cases with morbid placental adherence and they were collected from files of pregnant women who were admitted at hospital planned for termination of pregnancy. Patients were enrolled in four groups, Group 1: cases without urinary tract injuries. Group 2: cases with injuries to the bladder. Group 3: cases with injuries of the ureter. Group 4: cases with injuries to the bladder and ureter. RESULTS: This study gave us new information about the incidence of urinary tract injuries during cesarean section with morbid adherence placenta was 21.7% (Bladder 11.7%, Ureter 4.7%, and bladder with ureter 5.3%). There were various types of repair of urinary tract injury, as the following, bladder repair 10.8%, ureteric catheterization 0.9%, ureterovesical repair or reimplantation 1.5%, bladder repair and ureterovesical 1.2%, bladder repair and ureteric catheterization 2.3%, ureteric catheterization and ureterovesical 1.5 and 6.4% of cases needed urologic consultations. There is a real relation between urinary tract injury and obesity (55.3%). Bladder invasion was found in only 26.9% of all cases according to sonography findings. Most of the cases were delivered by cesarean section in 67.5%, and the remainders were delivered by cesarean hysterectomy 32.5%. About 96.5% of cases needed a blood transfusion. CONCLUSIONS: The morbid adherent placenta is still a challenge, which faces us as obstetricians, due to high morbidity and mortality. A multidisciplinary team is mandatory to avoid complications.

Telluric Acid Ameliorates Endotoxemic Kidney Injury in Mice: Involvement of TLR4, Nrf2, and PI3K/Akt Signaling Pathways.

Being one of the most abundant trace elements in the human body, the therapeutic potential of tellurium-based compounds has been a target of interest. Recent reports denoted their redox-modulating and anti-inflammatory activities in experimental endotoxemia. However, their potential nephroprotective effect against endotoxemic kidney injury is yet to be elucidated. This study investigated the possible renoprotective effect of telluric acid (TEL) against lipopolysaccharide (LPS)-induced acute kidney injury (AKI) in mice, targeting toll-like receptor 4 (TLR4), phosphoinositide 3-kinase (PI3K)/Akt, and nuclear factor-erythroid 2-related factor-2 (Nrf2) pathways as possible mechanistic contributors to TEL's effect. AKI was induced by LPS (2 mg/kg). TEL (60 µg/kg; i.p.) was administered once daily for seven consecutive days before LPS injection. Pretreatment with TEL alleviated LPS-induced AKI as evidenced by the hampered serum levels of creatinine and cystatin C. TEL also opposed LPS-induced elevation in renal kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, nuclear factor-kappa B p65, interleukin-1ß, and thiobarbituric acid-reactive substance contents. This was accompanied by a replenishment of renal glutathione, transcriptional upregulation of Nrf2, enhancement of heme oxygenase-1 activity, and a marked upregulation of phospho-PI3K and phospho-Akt protein expressions. Histopathological findings corroborated with the amendment of biochemical parameters. In view of these findings, we may conclude that TEL pretreatment purveyed novel nephroprotective effects against endotoxemic kidney injury, which might be partly attributed to the modulation of TLR4, PI3K/Akt, and Nrf2 signaling pathways and may hence provide a valuable asset for the management of endotoxemic renal complications.

Potential effects of yohimbine and sildenafil on erectile dysfunction in rats.

In this study the effects of yohimbine and sildenafil on cold stress-induced erectile dysfunction in rats were investigated. Yohimbine hydrochloride (0.2 mg/kg, i.p.) and sildenafil citrate (20 mg/kg, i.p) were administered to rats 1h before the stress session daily for 14 consecutive days and their effect was assessed. Results of this section revealed that, immersion of rats in cold water significantly decreased sexual arousal and motivation as indicated by increased latencies and intervals. Furthermore decreased copulatory performance and potency as indicated by decreased ejaculation frequency was observed. Decreased copulatory activity was confirmed by decreased testosterone, luteinizing hormone (LH) and follicle-stimulating-hormone (FSH) levels as well as decreased cholesterol content in rat testes. Treatment with yohimbine or sildenafil significantly increased the sexual arousal and potency and corrected the effects induced by stress on the mating behavior of male rats. On the contrary they did not significantly alter testosterone, FSH and LH levels which is reflected by failure of both drugs to alter cholesterol content in rat testes. Regarding the effect of yohimbine and sildenafil on isolated rat corpus cavernosum, their cumulative dose response curves (3×10(-7), 3×10(-6) and 3×10(-5) M) were determined in corpus cavernosum strips isolated from normal rats and pre-contracted with phenylephrine (3×10(-6) M) were also assessed. Results of this part showed that both yohimbine and sildenafil have a relaxant effect on rat corpus cavernosum strips in a dose dependant manner, which is confirmed by the increase in nitric oxide content in rats' penis shown by sildenafil.

Adnexal mass vascularity assessed by 3-dimensional power Doppler: does it add to the risk of malignancy index in prediction of ovarian malignancy?: four hundred-case study.

The Risk of Malignancy Index (RMI) is used for the prediction of ovarian malignancy. It includes menopausal status, carbohydrate antigen 125 serum levels, and ultrasound criteria. Three-dimensional power Doppler (3-DPD) is a reproducible investigation for assessment of tumor vascularity, classifying vascularity to avascular, parallel, and chaotic patterns. In this study; 3-DPD was added to RMI for prediction of malignancy in 400 cases of ovarian masses. Sensitivity of RMI for prediction of malignancy was 88%, with a cutoff value of 202.5 at 95% confidence interval. Sensitivity of 3-DPD for prediction of malignancy was 75%, adding 3-DPD to RMI increased its sensitivity to 99%. Considering the pilot nature of the study, further studies are needed to corroborate such findings.

Vaginal reconstruction with sigmoid colon in vaginal agenesis.

This study was conducted to evaluate the anatomical and functional results of sigmoid colon vaginoplasty. From June 2000 to June 2005, 26 patients with congenital vaginal agenesis were evaluated and treated with sigmoid colon reconstruction at Ain Shams University Maternity Hospital as a primary procedure in 17 patients and a secondary procedure in 9 patients after previous failed Abbe-McIndoe vaginoplasty elsewhere. The anatomical results were good in 22 patients, while 3 patients suffered from introital stenosis. Two of them were treated successfully by dilatation while one required Z-plasty. Eight patients were lost to follow-up and only ten patients are currently sexually active as the rest were divorced or remained unmarried. Of the sexually active patients, 8 (80%) had satisfactory intercourse whereas 2 (20%) complained of dyspareunia. Sigmoid colon vaginoplasty has satisfactory long-term anatomical and functional results and should be considered as primary option for the treatment of vaginal agenesis.