The comparative effectiveness of metformin and risperidone in a rat model of valproic acid-induced autism, Potential role for enhanced autophagy.

RATIONALE: Risperidone is the first antipsychotic to be approved by Food and Drug Administration (FDA) for treating autism spectrum disorder (ASD). The potential efficacy of metformin in preventing and/or controlling ASD behavioral deficits was also recently reported. Suppression of hippocampus autophagy was suggested as a potential pathologic mechanism in ASD. OBJECTIVES: Is metformin's ability to improve ASD clinical phenotype driven by its autophagy-enhancing properties? And does hippocampus autophagy enhancement underlie risperidone's efficacy as well? Both questions are yet to be answered. METHODS: The effectiveness of metformin on alleviation of ASD-like behavioral deficits in adolescent rats exposed prenatally to valproic acid (VPA) was compared to that of risperidone. The potential modulatory effects of risperidone on hippocampal autophagic activity were also assessed and compared to those of metformin. RESULTS: Male offspring exposed to VPA during gestation exhibited marked anxiety, social impairment and aggravation of stereotyped grooming; such deficits were efficiently rescued by postnatal risperidone or metformin therapy. This autistic phenotype was associated with suppressed hippocampal autophagy; as evidenced by reduced gene/dendritic protein expression of LC3B (microtubule-associated proteins 1 light chain 3B) and increased somatic P62 (Sequestosome 1) protein aggregates. Interestingly, compared to risperidone, the effectiveness of metformin in controlling ASD symptoms and improving hippocampal neuronal survival was well correlated to its ability to markedly induce pyramidal neuronal LC3B expression while lowering P62 accumulation. CONCLUSIONS: Our work highlights, for the first time, positive modulation of hippocampus autophagy as potential mechanism underlying improvements in autistic behaviors, observed with metformin, as well as risperidone, therapy.

Cardioprotective effect of abscisic acid in a rat model of type 3 cardio-renal syndrome: Role of NOX-4, P-53, and HSP-70.

Cardiorenal syndrome (CRS) is a complex heart and kidney pathophysiologic disorder that leads to a bidirectional interrelationship between them. Abscisic acid (ABA) is a phytohormone that is present in plants, and is known to regulate fundamental physiological functions. This study aimed to explore the efficacy of ABA in surgically induced-CRS type 3 rats. Rats were randomly and equally divided into four groups. Rats in Group 1 received saline (Sham group), Group 2 included control induced-CRS rats, Group 3 rats (CRS+ABA) included CRS rats treated with ABA and Group 4 (CRS + ABA + Verapamil + propofol) were CRS rats treated with Verapamil, propofol and ABA. The rats were treated with the drugs daily for four weeks. At the end of the study, relative heart weight corrected QT interval (QTc), mean blood pressure (MBP), kidney functions, oxidative stress, NADPH oxidase 4 (NOX4), protein 53 (P53), and heat shock proteins-70 (HSP-70) expression was assessed and recorded. ABA led to a significant shortening of the ventricular action potential duration indicated by QTc. Furthermore, it significantly lowered heart weight, MBP, serum creatinine, NOX-4, and P-53 expression and augmented HSP-70 expression. In contrast, adding calcium channel blockers (CCBs) to ABA mitigated this effect. The results suggested that ABA has a potential protective role in CRS-induced cardiac hypertrophy and arrhythmia that could be mediated through inhibition of P-53, NOX-4, and an increase in HSP-70 expression.

The Pattern of Antimicrobial Prescription at a Tertiary Health Center in Egypt: A Point Survey and Implications.

Background: The misuse of antimicrobials has major consequences, particularly antimicrobial resistance (AMR) and antimicrobials' related adverse effects. So, the WHO proposed antimicrobial surveillance to improve antimicrobials use. This point prevalence survey (PPS) was conducted to illustrate the prevalence of antimicrobial use at Mansoura University hospitals (MUH), Egypt. Methods: The survey process used was adapted from the European survey of antimicrobial resistance with modifications. The survey was conducted from 8 AM to 8 PM daily within 2 weeks. Results: A total of 300 patients received antimicrobials and the prevalence rate of antimicrobial prescription was 79.15%. The major indications of antimicrobials were surgical prophylaxis followed by the treatment of community-acquired infection. The most commonly prescribed initial antimicrobial group was Aminopenicillin ± ß-lactamase inhibitors. Although the purpose for antimicrobial administration was recorded in all cases, the stop/review history was recorded only in 19.6% and local guidelines were not available for 77.6% of antimicrobial prescriptions. The use of combined antimicrobials was common (46.6%), particularly in orthopedic and cardiothoracic surgery. Conclusion: The prevalence of antimicrobial prescription at MUH was high which requires serious actions including reviewing the antimicrobial indication, implementing local prescription guidelines, initiating an antimicrobial stewardship program (ASP), and optimizing infection control measures.

Pentosan Polysulfate Sodium augments the therapeutic effect of 5-Aminosalicylic Acid in DSS colitis model; the role of IL-35 expression.

Ulcerative colitis (UC) primarily affects the mucosa of the distal colon. Dysregulated immune response in genetically-prone persons is claimed to be responsible for chronic intestinal inflammation. This study aimed to explore the efficacy and the hematological effects of pentosan polysulfate sodium (PPS) in a dextran sulfate sodium (DSS)-induced colitis model. Forty C57BL/6 female mice were equally divided into five groups: control group, DSS-colitis group, DSS-colitis treated with 5-aminosalicylic acid, DSS-colitis treated with PPS, and DSS-colitis treated with both drugs. Disease activity index (DAI) and colon length were calculated. Colonic IL-6 and IL-35 levels were assayed by ELISA. IL-35 gene expression was evaluated by qRT-PCR. Colon tissue samples were examined by H&E stain and immunohistochemistry (IHC) of Ki67. The colitis group subjected to combined treatment showed the best outcome with significant improvement of DAI and increased colon length. Colonic IL-6 was significantly lower in both PPS- and combination-treated groups accompanied by a significantly higher IL-35 level and its EBI3 subunit mRNA expression. However, the PPS-treated colitis group showed higher gene expression of IL-35 EBI3 subunit by 1.5-fold compared with the combined group. The colon mucosa and crypts were significantly preserved in mice treated with both drugs with the best Ki67 positive cell density. PPS is a safe and promising drug in the treatment of UC as it exerted the best positive effect on the anti-inflammatory IL-35 level and gene expression. However, superior improvement of DAI was seen when PPS was added to ASA with a greater mucosal proliferation and repair.

Calcitonin potentiates the anticonvulsant and antinociceptive effects of valproic acid and pregabalin in pentylenetetrazole-kindled mice.

Antiepileptic drugs are the backbone for epilepsy management. Epilepsy may be accompanied by decreased pain threshold. Thus, anticonvulsant agents with antinociceptive properties are of great importance. This study investigated the possible anticonvulsant and antinociceptive effects of calcitonin in combination with either valproic acid or pregabalin and whether these effects might occur through γ-aminobutyric acid (GABA) modulation. Eighty-four male Balb/C mice were divided into 7 groups: control-naïve, pentylenetetrazole (PTZ)-induced seizures, PTZ-calcitonin, PTZ-valproic acid, PTZ-pregabalin, PTZ-calcitonin-valproic acid (PCV) combination, and PTZ-calcitonin-pregabalin (PCP) combination. PTZ was used in a sub-convulsive dosage, every other day for 11 injections. Drugs were given i.p. 30min before PTZ. After each PTZ injection, mice were put under observation and PTZ-provoked seizures were assessed. After the last dose of PTZ, the hot plate test was used to assess antinociceptive properties. Also, brain GABA neurotransmitter was evaluated by immunoassay. Repeated injection of PTZ induced chemical kindling. Calcitonin was found to have significant antinociceptive property as shown by hot plate latency. The beneficial effects of PCV and PCP combination were statistically significant in epilepsy and pain models as compared to valproic acid and pregabalin. The antiepileptic and antinociceptive activity of calcitonin may not relate to the GABAergic system. Calcitonin enhanced the anticonvulsant and antinociceptive effects of either valproic acid or pregabalin. This new treatment "calcitonin add-on" may provide an improved range of options for patients with refractory epilepsy which is still an important risk factor for sudden death.

Insulin growth factor inhibitor as a potential new anti-schistosoma drug: An in vivo experimental study.

BACKGROUND AND OBJECTIVE: Tyrphostin "AG1024" is an insulin growth factor-1 receptor (IGF-1R) inhibitor that displayed an effect on the viability of larval and mature schistosomes in vitro. We sought to investigate the possible in vivo role of AG1024 as a potential new anti-Schistosoma drug against immature and adult stages of Schistosoma mansoni and its effect on the degree of hepatic fibrosis and insulin pathway. METHODS: The study included a control non-infected group and 5 groups of S. manosoni-infected CD-1 albino mice (20 mice each) assigned to treatment as follows: vehicle-treated, early AG1024, 30µg/100µl DMSO, IP for 10days started 30days post-infection (dpi), early praziquantel (PZQ), 500mg/kg orally for 2days (30dpi), late AG1024 (60dpi), and late PZQ (60dpi). All mice were sacrificed 12 weeks post-infection. Parasitological, chemical and histopathological parameters were studied. Immunohistochemistry of TGF-ß and GLUT4 in liver sections was done to further evaluate the effect of AG1024 on the degree of hepatic fibrosis and insulin signaling pathway, respectively. RESULTS: Early administration of AG1024 (30dpi) resulted in significant reduction of hepatic and intestinal tissue egg count with a reduction of 79.99% and 89.1% respectively. Late administration of AG1024 (60dpi) led to 77.78% reduction of intestinal eggs count; however, hepatic egg count wasn't reduced significantly. No reduction in worm burden was recorded for both administration regimens. Both regimens lead to significant decrease of both ALT and AST, mean hepatic granuloma diameter but an increase in fibrosis percentage (65.2% and 55% respectively). Both early and late treatment with AG1024 showed a significant increment of TGF-ß expression by 71.4% and 39.3%, respectively (p<0.0001) compared to PZQ-treated and infected non-treated groups. Hepatic GLUT4 expression was significantly decreased compared to infected non-treated group (p<0.001) and the corresponding PZQ-treated group. CONCLUSION: Early AG1024 administration induced more significant results compared to early PZQ with a promising activity against egg production and subsequent reduction of tissue egg load rather than direct schistosomicidal effect; however, it induced granuloma fibrosis, TGF-ß expression, and disrupted the insulin signaling pathway.

Association between risk of type 2 diabetes mellitus and angiotensin-converting enzyme insertion/deletion gene polymorphisms in a Saudi Arabian population.

The link between the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and the prevalence of type 2 diabetes mellitus (T2DM) developing in the Saudi Arabian population remains controversial. The aim of the present study was to evaluate the association between the ACE I/D gene polymorphism and the risk of developing T2DM and hypertension (HTN) in Saudi Arabian individuals. A total of 220 individuals consisting of 48 control subjects, 70 T2DM, 48 HTN, and 54 T2DM with HTN patients were recruited. Genotyping was performed by polymerase chain reaction initially and mistyping of the DD genotypes was conducted with an insertion-specific primer. The genotyping frequency for the II, ID and DD polymorphism of the ACE gene was 6.8, 42.6 and 48.6% in T2DM patients, 4.2, 50 and 45.8% in HTN patients, 5.6, 55.5 and 38.9% in T2DM patients with HTN and 58.3, 37.5 and 4.2% in control subjects, respectively. The frequency for the D allele was 70% in T2DM patients, 70.8% in HTN patients and 66.7% in T2DM patients with HTN as compared with 22.9% in the control subjects. The genotype and allele frequency of the ACE gene polymorphism varied significantly (P<0.05) in the patients when compared with the control subjects. The current study demonstrated that the ID/DD genotype and the D allele of the ACE gene I/D polymorphism were strongly associated with the risk of T2DM and HTN developing in a Saudi Arabian population.

Possible antifibrotic effect of GDC-0449 (Vismodegib), a hedgehog-pathway inhibitor, in mice model of Schistosoma-induced liver fibrosis.

Liver fibrosis is a pathological process complicating schistosomiasis. It is an active process of continuous extracellular matrix accumulation. In Egypt, schistosomiasis re-infection is a continuing problem especially in rural areas. In this study we examined the antifibrotic effect of GDC-0449 (Vismodegib), a hedgehog-pathway inhibitor as a new molecular target for Schistosoma-induced liver fibrosis, in addition to exploring its effect as antischistosomal drug. The effect of GDC-0449 alone or combined with Praziquantel was tried experimentally in infected mice with Schistosoma mansoni. Fifty CD-1 Swiss female albino mice were used, forty mice were infected with Schistosoma mansoni cercariae. Animals were grouped into five groups; uninfected control, infected untreated, infected treated with Praziquantel (500mg/kg/day) for two days, infected treated with GDC-0449 (40mg/kg/day) for seven days, and infected treated with combined Praziquantel and GDC-0449. Parasitological and chemical parameters, hydroxyproline level and liver granuloma were assessed. Liver fibrosis was reduced significantly evidenced by reduced hydroxyproline levels [P<0.01 for combined (Praziquantel/GDC-0449) treatment groups, P<0.001 for GDC-0449-treated group]. Also, histopathological examination of liver tissues revealed that the mean diameter of granulomas was statistically reduced (P=0.001) with a reduction rate of 24.4% on treatment with GDC-0449. In GDC-0449/Praziquantel combined treatment group, number and mean diameter of the granulomas were reduced significantly P<0.001, and P=0.001 respectively. No antischistosomal effect was recorded for GDC-0449 in this study.

Comparative study of allogenic and xenogeneic mesenchymal stem cells on cisplatin-induced acute kidney injury in Sprague-Dawley rats.

BACKGROUND: The paracrine and regenerative activities of mesenchymal stem cells (MSCs) may vary with different stem cell sources. The aim of the present study is to compare the effects of MSCs from different sources on acute kidney injury (AKI) induced by cisplatin and their influence on renal regeneration. METHODS: A single intraperitoneal injection of cisplatin (5 mg/kg) was used to induce AKI in 120 Sprague-Dawley rats. Rats were treated with either rat bone marrow stem cells (rBMSCs), human adipose tissue-derived stem cells (hADSCs), or human amniotic fluid-derived stem cells (hAFSCs). 5 × 10(6) MSCs of different sources were administered through rat tail vein in a single dose, 24 hours after cisplatin injection. Within each group, rats were sacrificed at the 4th, 7th, 11th, and 30th day after cisplatin injection. Serum creatinine, BUN, and renal tissue oxidative stress parameters were measured. Renal tissue was scored histopathologically for evidence of injury, regeneration, and chronicity. Immunohistochemistry was also done using Ki67 for renal proliferative activity evaluation. RESULTS: MSCs of the three sources were able to ameliorate cisplatin-induced renal function deterioration and tissue damage. The rat BMSCs-treated group had the lowest serum creatinine by day 30 (0.52 ± 0.06) compared to hADSCs and hAFSCs. All MSC-treated groups had nearly equal antioxidant activity as indicated by the decreased renal tissue malondialdehyde (MDA) and increased reduced glutathione (GSH) level and superoxide dismutase (SOD) activity at different time intervals. Additionally, all MSCs improved injury and regenerative scores. Rat BMSCs had the highest count and earliest proliferative activity in the renal cortex by day 7 as identified by Ki67; while, hAFSCs seem to have the greatest improvement in the regenerative and proliferative activities with a higher count of renal cortex Ki67-positive cells at day 11 and with the least necrotic lesions. CONCLUSIONS: Rat BMSCs, hADSCs, and hAFSCs, in early single IV dose, had a renoprotective effect against cisplatin-induced AKI, and were able to reduce oxidative stress markers. Rat BMSCs had the earliest proliferative activity by day 7; however, hAFSCs seemed to have the greatest improvement in the regenerative activities. Human ADSCs were the least effective in the terms of proliferative and regenerative activities.

Amniotic Fluid-Derived Mesenchymal Stem Cells Cut Short the Acuteness of Cisplatin-Induced Nephrotoxicity in Sprague-Dawley Rats.

BACKGROUND AND OBJECTIVES: Cisplatin is a nephrotoxic chemotherapeutic agent. So, preventive measures worth to be evaluated. Human amniotic fluid stem cells (hAFSCs) in prevention or amelioration of cisplatin-induced acute kidney injury (AKI) in Sprague-Dawley rates have been tested. METHODS: 80 Sprague-Dawley rats (250~300 g) were used and divided into 4 major groups, 20 rats each. Group I: Saline-injected group. Group II: Cisplatin-injected group (5 mg/kg I.P). Group III: Cisplatin-injected and hAFSCs-treated group (5×106 hAFSCs I.V. one day after cisplatin administration). Group IV: Cisplatin-injected and culture media-treated group. Each major group was further divided into 4 equal subgroups according to the timing of sacrifice; 4, 7, 11 and 30 days post-cisplatin injection. Renal function tests were done. Kidney tissue homogenate oxidative stress parameters malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) were determined. Histopathological scoring systems for active injury, regenerative and chronic changes were analyzed separately. RESULTS: hAFSCs characterization and differentiation was proved. Cisplatin injection resulted in a significant increase in serum creatinine and MDA and decrease in SOD, GSH and creatinine clearance. These changes were attenuated early by day 4 with the use of hAFSCs. Cisplatin injection induced tubular necrosis, atrophy, inflammatory cells infiltration and fibrosis. The use of hAFSCs was associated with significantly lowered injury score at day 4, 7, 11 and 30 with marked regenerative changes starting from day 4. CONCLUSION: hAFSCs have both a protective and regenerative activities largely through an antioxidant activity. This activity cut short the acuteness of cisplatin nephrotoxicity.