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1.
Arch Dermatol Res ; 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31587106

RESUMO

Anti-desmoglein (anti-Dsg) antibodies are key players in the pathogenesis of pemphigus vulgaris (PV) disease. We aimed to evaluate the pathogenicity of anti-Dsg antibodies of PV patients using human organ culture assay and to assess the correlation between the pathogenicity and the disease score. In this cross-sectional study, sera from 37 PV patients were included. The organ culture acantholysis index (OCAI) was calculated as (width of blister/total width of the specimen) × 100. The sera were analyzed using Dsg ELISAs and ethylenediaminetetraacetic acid (EDTA) treated ELISAs. OCAI ranged from 0 to 100%, median = 50%. There was a moderate significant correlation between OCAI and the disease severity, r = 0.503, p = 0.002. There was a moderate significant correlation between OCAI and non-Ca2+-dependent anti-Dsg3 and anti-Dsg1 antibodies, p values were 0.01 and 0.021, respectively. The OCAI was assessed along the disease time course of four patients. The OCAI fluctuated parallel to the disease severity along the time course of the four patients. Human organ culture assay is an objective tool that detects the pathogenicity of anti-desmoglein antibodies. It can be used before stopping systemic steroids especially in patients in remission with high titer or if the Dsg ELISA is not available.

2.
J Cardiovasc Pharmacol Ther ; : 1074248419876632, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533469

RESUMO

BACKGROUND: Diabetic cardiomyopathy (DCM) is accompanied by microvascular complications that lead to myocardial dysfunction and heart failure. Most conventional therapies cannot ameliorate the microvascular insufficiency in DCM. In this study, we tested the hypothesis that undercarboxylated osteocalcin (ucOC) may be a new adjuvant therapy against the progression of DCM and its underlying microvascular pathology. MATERIALS AND METHODS: Diabetes was induced in Wistar rats with a high-fat diet combined with streptozotocin injections, and ucOC was upregulated after warfarin administration in the treated group. After 8 weeks, cardiac functions were assessed using a Langendorff apparatus. Cardiac tissue samples were also extracted to assess the ucOC receptor and vascular endothelial growth factor (VEGF) for histopathological studies. RESULTS: Both the systolic and the diastolic dysfunction observed in the DCM group were significantly improved after the increase in ucOC blood levels. Significant improvement in VEGF and CD31 expression after warfarin injection was associated with increased capillary density, neovascularization, and decreased myocardial fibrosis together with the reestablishment of myocardial structural and ultrastructural patterns. CONCLUSION: Undercarboxylated osteocalcin may have a promising effect in improving microvascular insufficiency and myocardial dysfunction in DCM.

3.
Cells ; 8(8)2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31382595

RESUMO

Rheumatoid arthritis (RA) is a disease of the joints that causes decreased quality of life. Mesenchymal stromal cells (MSCs) have immunosuppressive properties, with possible use in the treatment of RA. Similarly, interleukin (IL)-4 has been shown as a potential RA treatment. However, their combination has not been explored before. Therefore, this study aimed to investigate the effect of a combination therapy of MSCs and IL-4 in the treatment of RA, using a murine collagen-induced arthritis (CIA) model. Arthritis was induced in Balb/c mice by two intradermal injections of type II collagen (CII), at days 0 and 21. CIA mice were randomly assigned to four groups; group I received an intravenous injection of mouse bone marrow-derived MSCs, while group II received an intraperitoneal injection of IL-4. Group III received a combined treatment of MSC and IL-4, while group IV served as a CIA diseased control group receiving phosphate buffer saline (PBS). A fifth group of healthy mice served as the normal healthy control. To assess changes induced by different treatments, levels of RA-associated inflammatory cytokines and biomarkers were measured in the serum, knee joints, and synovial tissue, using ELISA and Real Time-qPCR. Histopathological features of knee joints were analyzed for all groups. Results showed that combined MSC and IL-4 treatment alleviated signs of synovitis in CIA mice, reverting to the values of healthy controls. This was evident by the decrease in the levels of rheumatic factor (RF), C-reactive protein (CRP) and anti-nuclear antibodies (ANA) by 64, 80, and 71%, respectively, compared to the diseased group. Moreover, tumor necrosis factor-alpha (TNF- α) and monocyte chemoattractant protein-1 (MCP-1) levels decreased by 63 and 68%, respectively. Similarly, our gene expression data showed improvement in mice receiving combined therapy compared to other groups receiving single treatment, where cartilage oligomeric matrix protein (Comp), tissue inhibitor metalloproteinase-1 (Timp1), matrix metalloproteinase1 (Mmp-1), and IL-1 receptor (Il-1r) gene expression levels decreased by 75, 70, and 78%, respectively. Collectively, treatment with a combined therapy of MSC and IL-4 might have an efficient therapeutic effect on arthritis. Thus, further studies are needed to assess the potential of different MSC populations in conjugation with IL-4 in the treatment of experimental arthritis.

4.
Eur. j. anat ; 23(3): 201-213, mayo 2019. ilus, graf, tab
Artigo em Inglês | LILACS-Express | ID: ibc-ET2-2048

RESUMO

Cisplatin is a potent chemotherapeutic agent used to treat a variety of cancers such as ovarian, uterine, and bladder. The major limiting side effect of cisplatin is its hepatotoxicity. The possible mechanism of cisplatin hepatotoxicity was due to the affection of oxidant-antioxidant system. Platelet-rich plasma (PRP) has a powerful therapeutic option for its ability to deliver a great variety of biologically active GFs to the site of injury. PRP has grown as an attractive biologic instrument in regenerative medicine for its powerful healing properties. It is considered as a source of growth factors that may induce tissue repairing and improve fibrosis. This product has proven its efficacy in multiple studies, but its effect on cisplatin-induced hepatotoxicity has not yet been elucidated. The present study was designed to analyze the therapeutic role of PRP in cisplatin-induced hepatotoxicity. 30 adult male adult male albino rats were used in the present study divided into 3 groups (control group, cisplatin-treated group and PRP-treated group). By the end of the experimental period, blood samples were collected for measurement of serum AST, ALT and ALP enzymes; then the rats were sacrificed by cervical dislocation. Fresh liver parts were used to measure the oxidative markers in liver homogenates, while other parts were processed and subjected for histopathological and histomorphometric and immunohistochemical analyses for VEGF, Caspase 3 expression of the different experimental groups. The statistical study was done for the resultant data. Group II (Cisplatin-treated group) showed marked pathological hepatic changes; loss of architecture, congested dilated sinusoids lined by darkly stained pyknotic Kupffer cells; and hepatocytes nuclei were pyknotic and karyolitic. Dilated congested portal vein, interstitial acidophilic exudate, marked polymorphic cellular infiltration. There were increased collagen fibers deposition, a weak positive PAS reaction, strong positive caspase 3 reactions and strong positive VEGF reaction. Also, there were a marked increase in hepatic enzymes, MDA levels and a marked decrease in GSH level. Treatment with PRP in Group III revealed improvement of the hepatic parenchymal architecture with strong PAS reaction and minimal collagen fibers deposition. Weak positive caspase immunoreaction and strong positive VEGF reaction were noticed. Also, there was a marked improvement in the parameter of hepatic enzymes, MDA and GSH level comparable with the control group. It is concluded that PRP could ameliorate the liver against cisplatin-induced hepatotoxicity


No disponible

5.
Tumour Biol ; 41(4): 1010428319846803, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31018830

RESUMO

Mesenchymal stem cells have therapeutic properties that are related to their potentials for trans-differentiation, immunomodulation, anti-inflammatory, inhibitory effect on tumor proliferation, and induction of apoptosis. This study was performed to analyze the role of mesenchymal stem cells as an alternative for cellular signaling growth factors involved in the pathogenesis of leukemogenesis in rats. Treatment of rats with 7,12-dimethyl benz [a] anthracene induced leukemogenesis appeared as a significant decrease in hematological parameters with concomitant significant increase in bone marrow oxidative and inflammatory indices (transforming growth factor beta and interleukin-6) in comparison with normal groups. On the contrary, Western immunoblotting showed a significant increase in the signaling growth factors: PI3K, AKT, mTOR proteins and a significant decrease in PTEN in 7,12-dimethyl benz [a] anthracene-treated group. In addition, a significant increase in the transcript levels of B cell lymphoma-2 protein gene in the 7,12-dimethyl benz [a] anthracene group, while that of C-X-C motif chemokine receptor-4 and B cell lymphoma-2 protein associated x-protein were significantly downregulated compared to controls. Meanwhile, therapeutic mesenchymal stem cells treatment predict a significant improvement versus 7,12-dimethyl benz [a] anthracene group through the modulation of growth factors that confront bone marrow dysplasia. In the same direction treatment of 7,12-dimethyl benz [a] anthracene group with mesenchymal stem cells, it induced apoptosis and increased the homing efficacy to bone marrow. In conclusion, mesenchymal stem cells improve hematopoiesis and alleviate inflammation, and modulated PI3K/AKT signaling pathway contributed to experimental leukemogenesis.


Assuntos
Leucemia/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Proteína Oncogênica v-akt/genética , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Apoptose/genética , Células da Medula Óssea/patologia , Diferenciação Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Humanos , Leucemia/induzido quimicamente , Leucemia/genética , Leucemia/patologia , PTEN Fosfo-Hidrolase , Fosfatidilinositol 3-Quinases/genética , Ratos , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Fator de Crescimento Transformador beta/genética
6.
Biomed Pharmacother ; 112: 108584, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784910

RESUMO

Stem cell therapy represents a promising therapeutic avenue for cardiac disorders, including heart failure. Although stem cell transplantation showed encouraging preliminary results, the outcomes of clinical studies are still unsatisfactory. This study aimed to compare the outcomes of two therapeutic approaches, in vivo co-delivery of sodium hydrogen sulfide (NaHS) concomitant with bone marrow-derived mesenchymal stem cell (BMSC) transplantation and in vitro preconditioning of BMSCs with NaHS, both of which are intended to promote the success of stem cell therapy in rats with isoprenaline-induced heart failure. Heart failure developed 4 weeks after the subcutaneous injection of isoprenaline (170 mg/kg) for 4 consecutive days. The in vivo approach involved the co-delivery of intraperitoneally administered NaHS concomitant with BMSC transplantation for a period of 14 days. The in vitro approach involved preconditioning BMSCs with NaHS for 30 min before transplantation. Compared to treatment with BMSCs alone, in vitro preconditioning of BMSCs with NaHS improved left ventricular function as measured by echocardiography and electrocardiography and enhanced stem cell homing, proliferation and differentiation as manifested by higher cardiac expression of GATA-4 and myocyte enhancer factor 2. Moreover, the measurement of cardiac transforming growth factor beta 1 levels and histopathological investigation revealed mitigated fibrosis and myocardial injury scores. Compared with BMSC therapy alone, the in vivo approach enhanced stem cell homing and differentiation, alleviated fibrosis and augmented vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) expression. In conclusion, NaHS can potentiate the efficiency of BMSC therapy for heart failure by in vitro preconditioning or in vivo co-delivery. The in vitro approach is superior with regard to improving cardiac function in addition to enhancing stem cell proliferation, while the in vivo approach is superior with regard to increasing cardiac VEGF and eNOS expression.


Assuntos
Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/terapia , Sulfeto de Hidrogênio/administração & dosagem , Precondicionamento Isquêmico Miocárdico/métodos , Animais , Terapia Combinada , Insuficiência Cardíaca/fisiopatologia , Masculino , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/fisiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Resultado do Tratamento
7.
Arch Physiol Biochem ; : 1-10, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30612469

RESUMO

Obesity and atherosclerosis are inflammatory states involving variable metabolic signals. The adipokine resistin is implicated in adipose tissue dysfunction and is modulated by PPARγ. In this study, resistin and PPARγ role is investigated in the development of CVS disease. Forty-eight Adult male albino rats were divided into control, obesity and atherosclerotic groups; each group is divided into two subgroups; with and without PPARγ agonist administration for 8 weeks. To assess pathological changes; lipid profile, inflammatory mediator, serum resistin level and resistin expression in adipose tissue were measured. Aorta is histopathologically evaluated. It was found that resistin expression is significantly correlated with lipid profile and inflammatory status in obesity and atherosclerotic groups, and PPARγ agonist administration significantly improves inflammatory status and dyslipidemic profile across studied groups (p < .05). Aortic wall shows histopathological evidence of atherosclerosis in obesity group which is more evident in atherosclerotic group, and milder changes upon receiving PPARγ agonist.

8.
Int J Impot Res ; 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30287894

RESUMO

This cross-sectional comparative study aimed to compare serum L-carnitine and 25(OH)D levels between men with ED non-responding for oral sildenafil citrate and healthy volunteers. Overall, 192 men, recruited from two University Hospitals, were allocated into two equal groups of matched age; healthy potent men and men with ED non-responders for oral sildenafil citrate. Oral sildenafil citrate non-responders self-reported inadequate erectile responses after four attempts using 100 mg with the manufacturer's guidelines relative to meals, associated medications, and sexual stimulation/arousal. Exclusion criteria were: diabetes, cardiovascular disorders, beta blockers treatment, morbid obesity, thyroid disorders, post-radical prostatectomy, and hepatic/renal failure. All participants were subjected to; history taking, clinical examination, validated IIEF-5 questionnaire, estimation of serum L-carnitine by calorimetric method and serum 25(OH)D by ELISA method. Compared with potent controls, ED men non-responders for oral sildenafil citrate showed significant decreases in the mean serum L-carnitine level (16.8 ± 3.6 uM/L versus 66.3 ± 11.9 uM/L, P = 0.001), the mean serum 25(OH)D level (21.2 ± 7.1 ng/ml versus 54.6 ± 7.9 ng/mL, P = 0.001) and IIEF-5 score (7.8 ± 2.6 versus 23.9 ± 1.3). Serum L-carnitine showed significant positive correlation with IIEF-5 scores (r = 0.873, P = 001), serum 25(OH)D (r = 0.796, P = 0.001) and significant negative correlation with the age (r = -0.515, P = 0.001). Serum 25(OH)D showed significant positive correlation with IIEF-5 scores (r = 0.855, P = 0.001) and significant negative correlation with the age (r = -0.223, P = 0.005). It is concluded that normal homeostasis of serum L-carnitine and 25(OH)D play a role in male sexual health being significantly decreased in ED non-responding for oral sildenafil citrate.

9.
Lipids ; 53(5): 505-515, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-30015391

RESUMO

The present study investigated the molecular effects of rice bran oil (RBO) on lipid-regulatory genes (sterol regulatory element binding protein-1 [Srebf1] and peroxisome proliferator-activated receptors-α [Ppara]) and the expression of catalase (CAT) and superoxide dismutase (SOD1) genes in insulin-resistant rats. Rats were divided into five groups: animals that received standard diet (control); rats fed standard diet containing RBO as the sole source of fat (RBO); a high-fructose diet (HFD) group, which was further divided into two subgroups: rats fed HFD either for only 1 month (HFD1) or for 2 months (HFD2) and rats fed HFD containing RBO for 1 month; while rats in the last group fed HFD for 30 days then treated with RBO for another 30 days. The HFD induced a state of insulin resistance (IR) as indicated by the hyperinsulinemia and elevated homeostasis model assessment insulin resistance index. Hepatic lipid levels and radical scavenging enzymes were altered by the HFD. Lipid-regulatory genes, Srebf1 and Ppara, were upregulated while Sod1 and Cat were downregulated in insulin-resistant rats. Addition of RBO to the two diet regimens alleviated the disorders of IR to some extent. RBO reduced the hepatic levels of triacylglycerol, malondialdehyde, SREBP, and PPAR-α mRNA. Hepatic SOD and CAT were elevated at gene and protein levels. The HFD induces de novo lipogenesis by upregulating the lipid-regulatory genes resulting in increased serum and hepatic triacylglycerol. Moreover, IR induced by the HFD caused a state of oxidative stress. Supplementation of RBO to fructose-fed rats not only improves insulin resistance but also downregulates lipogenic genes and improves the unbalanced oxidative status.

10.
Diabetes Res Clin Pract ; 143: 56-61, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29959950

RESUMO

Autophagy is a major cellular clearance mechanism that maintains cellular survival and homeostasis. Autophagy has a crucial role in the progression of diabetes and kidney diseases. AIMS: To investigate serum concentrations of Beclin-1, a key regulator of autophagy, in patients with diabetic kidney disease (DKD). METHODS: The study included 70 patients with type 2 diabetes and DKD (group 1; 35 patients with estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m2 and group 2; 35 patients with eGFR < 30 ml/min/1.73 m2) and 20 age- and sex-matched healthy subjects (group 3). Laboratory work up included; glycated hemoglobin (HbA1c), serum creatinine, eGFR using modification of diet in renal disease (MDRD) formula, urine albumin to creatinine ratio (ACR), and serum Beclin-1 measurement. RESULTS: Patients with DKD had significantly lower Beclin-1 levels (2.38 ±â€¯1.46 ng/mL) compared to control group (6.03 ±â€¯1.94 ng/mL; P < 0.001). Moreover, serum Beclin-1 significantly decreased in group 2 (1.43 ±â€¯0.83 ng/mL) compared to group 1 (3.36 ±â€¯1.30 ng/mL; P < 0.001). In univariate analysis, the concentration of Beclin-1 correlated well with eGFR (r = 0.64, P < 0.001), ACR (r = -0.63, P < 0.001), and duration of diabetes (r = -0.43, P < 0.001) but didn't correlate with HbA1c (r = -0.17, P = 0.15). However, ACR was the only significant predictor of Beclin-1 level on performing multiple regression analysis (ß = -0.40, P = 0.01). CONCLUSION: Serum level of Beclin-1 is reduced in patients with DKD. Furthermore, its level is related to the stage of DKD and correlates with the degree of albuminuria.


Assuntos
Proteína Beclina-1/sangue , Biomarcadores/sangue , Nefropatias Diabéticas/diagnóstico , Autofagia , Estudos Transversais , Nefropatias Diabéticas/sangue , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
J Enzyme Inhib Med Chem ; 33(1): 1095-1107, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29944015

RESUMO

Herein, we report the synthesis of different novel sets of coumarin-6-sulfonamide derivatives bearing different functionalities (4a, b, 8a-d, 11a-d, 13a, b, and 15a-c), and in vitro evaluation of their growth inhibitory activity towards the proliferation of three cancer cell lines; HepG2 (hepatocellular carcinoma), MCF-7 (breast cancer), and Caco-2 (colon cancer). HepG2 cells were the most sensitive cells to the influence of the target coumarins. Compounds 13a and 15a emerged as the most active members against HepG2 cells (IC50 = 3.48 ± 0.28 and 5.03 ± 0.39 µM, respectively). Compounds 13a and 15a were able to induce apoptosis in HepG2 cells, as assured by the upregulation of the Bax and downregulation of the Bcl-2, besides boosting caspase-3 levels. Besides, compound 13a induced a significant increase in the percentage of cells at Pre-G1 by 6.4-folds, with concurrent significant arrest in the G2-M phase by 5.4-folds compared to control. Also, 13a displayed significant increase in the percentage of annexin V-FITC positive apoptotic cells from 1.75-13.76%. Moreover, QSAR models were established to explore the structural requirements controlling the anti-proliferative activities.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cumarínicos/química , Relação Quantitativa Estrutura-Atividade , Sulfonamidas/química , Antineoplásicos/síntese química , Células CACO-2 , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cumarínicos/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Células MCF-7 , Estrutura Molecular , Sulfonamidas/farmacologia
12.
Toxicol Mech Methods ; 28(7): 529-538, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29716418

RESUMO

The present study aimed to investigate the role of bone marrow mesenchymal stem cells (MSCs) and/or melatonin (MT) for improvement of ß-cell functions in STZ diabetic rats. Male albino rats (130-150 g) were divided into six groups. CONTROL GROUP: received phosphate-buffered saline (PBS); melatonin group received melatonin (10 mg/kg b.wt./day for 2 months by oral gavage); diabetic untreated group; diabetic group treated with melatonin; diabetic group treated with MSCs (a single intravenous injection of 3 × 106 cell in PBS); and diabetic group co-treated with stem cells and melatonin. The results showed significant improvement in glucose, insulin, total antioxidant, and malondialdehyde level in diabetic rats treated with either MSCs alone or in combination with melatonin. The imumuno-histochemical analysis showed that MSCs and/or melatonin treatment reduced the rate of inflammation and apoptosis of the islet cells as well as increased the rate of pancreatic cell division. Such results were indicated by a significant improvement in the level of TNF-α, IL-10, PCNA, and caspase-3 to levels very close to the control. Co-treatment of MSCs and MT resulted in an improvement in the tissue of the pancreas and reduced number of damaged ß-cells. It can be concluded that co-treatment of stem cells and melatonin has a significant role in restoring the structural and functional efficiency of ß-cells in the pancreas more than stem cells alone. Such results may be due to the role of melatonin as an antioxidant in increasing the efficiency and vitality of stem cells.


Assuntos
Antioxidantes/uso terapêutico , Diabetes Mellitus Experimental/terapia , Suplementos Nutricionais , Melatonina/uso terapêutico , Transplante de Células-Tronco Mesenquimais , Estresse Oxidativo , Pâncreas/patologia , Animais , Apoptose , Biomarcadores/sangue , Biomarcadores/metabolismo , Células da Medula Óssea/citologia , Proliferação de Células , Células Cultivadas , Terapia Combinada , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Hiperglicemia/prevenção & controle , Insulina/sangue , Interleucina-10/sangue , Masculino , Tamanho do Órgão , Pâncreas/imunologia , Pâncreas/metabolismo , Ratos
13.
Korean J Anesthesiol ; 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29843508

RESUMO

Background: Autism is a challenging neurodevelopmental disorder. Previous clinical observations suggest altered sedation requirements for autistic children. Our study aimed to test this observation experimentally with an animal model and, to explore its possible mechanisms. Methods: Eight adult pregnant female Sprague Dawley rats were randomly selected into two groups. Four were injected with intraperitoneal sodium valproate on the gestational day 12 and four were injected with normal saline. On post-natal day 28 the newborn male rats were subjected to an open field test to confirm autistic features. Each rat was injected intraperitoneally with a single dose of propofol (50 mg/kg) or dexmedetomidine (0.2 mg/kg). Times to Loss of Righting Reflex (LORR) and to Return of Righting Reflex (RORR) were recorded. On the next day, all rats were re-sedated and their EEGs were recorded. The rats were sacrificed and hippocampal GABAA and glutamate NMDA receptor gene expression were assessed. Results: Autistic rats showed significantly longer time to LORR and a shorter time to RORR compared to controls (Median time to LORR: 12.0 versus 5.0 for dexmedetomidine and 22.0 and 8.0 for propofol; p < 0.05). EEG showed a low frequency, high amplitude wave pattern two minutes after LORR in control rats. Autistic rats showed a high frequency, low amplitude awake pattern. Hippocampal GABAA receptor gene expression was significantly less in autistic rats and NMDA gene expression was greater. Conclusions: This study in rat supports the clinical observations of increased anesthetic sedative requirements in autistic children and proposes a mechanism for it.

14.
Artigo em Inglês | MEDLINE | ID: mdl-29697857

RESUMO

Ischaemia-reperfusion (I-R) injury is a serious pathology that is often encountered with thrombotic events, during surgery when blood vessels are cross-clamped, and in organs for transplantation. Increased oxidative stress is the main pathology in I-R injury, as assessed in studies on the heart, kidney, and brain with little data available on gastric I-R (GI-R). Liraglutide is a GLP-1 receptor agonist that has insulinotropic and weight reducing actions, and melatonin that has been much studied as a chronotropic hormone; have also studied as being anti-oxidative stress agents. Herein, we aimed to explore the effects of liraglutide and melatonin on GI-R injury with high-fat/sucrose diet. Rats were divided into six groups; two diet-control, two melatonin- and two liraglutide-pretreated groups. All rats were subjected to 30 minutes of gastric ischaemia followed by 1 hour of reperfusion. Gastric tissues were assessed for the percentage of DNA fragmentation, myeloperoxidase activity, total oxidant status, total antioxidant capacity, oxidative stress index, BMI and histopathological examination. We showed that high-fat feeding for four weeks prior to GI-R significantly increased BMI, oxidative stress indices and decreased total antioxidant capacity, with a neutral effect on apoptosis compared to controls. Pretreatment with either melatonin (10 mg/kg per day orally) or liraglutide (25 µg/kg per day ip) reverses these effects. Furthermore, both drugs reduced weight only in HFS-fed rats. Both liraglutide and melatonin have nearly similar protective effects on gastric I-R injury through decreasing the oxidative stress and apoptosis.

15.
Inflammation ; 41(2): 541-554, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29204871

RESUMO

Sepsis is a systemic inflammatory disorder which often occurs during extremely stressful conditions such as trauma, burn, shock, and infection. This study investigated the curative effects of bone marrow-derived mesenchymal stem cells (BM-MSCs) against hepatic, renal, and pulmonary responses caused by a single administration of lipopolysaccharide (LPS) (10 mg/kg, i.p) in rats. Treatment with BM-MSCs (5 × 105 in 0.1 ml PBS, i.p.) 3 h after LPS antagonized the LPS-induced increment of the liver enzymes (ALT, AST) and kidney functions (BUN, sCr). BM-MSCs decreased tissue levels of P38-MAPK, NF-κB, STAT-3, TNF-α, IL-1ß, iNOS, Bax together with elevation of the anti-inflammatory cytokine IL-10 and the anti-apoptotic biomarker Bcl-2. Meanwhile, rats exhibited marked reduction of the broncho-alveolar lavage fluid levels of TNF-α, IL-1ß, and IFN-γ. Interestingly, BM-MSCs normalized both broncho-alveolar lavage fluid (BALF) neutrophils count and lung wet/dry ratios. Briefly, these findings may provide a preclinical platform for the management of LPS-induced sepsis using BM-MSCs via their ameliorative anti-inflammatory, anti-oxidant, and anti-apoptotic potentials.


Assuntos
Sistema de Sinalização das MAP Quinases , Células-Tronco Mesenquimais/fisiologia , Sepse/terapia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/metabolismo , Rim/fisiopatologia , Lipopolissacarídeos/farmacologia , Fígado/enzimologia , Pulmão/metabolismo , Transplante de Células-Tronco Mesenquimais , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Exp Clin Endocrinol Diabetes ; 126(1): 27-38, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28449155

RESUMO

Therapy targeting mitochondria may provide novel ways to treat diabetes and its complications. Bone marrow-derived mesenchymal stem cells (MSCs), the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists and exendin-4; an analog of glucagon-like peptide-1 have shown cardioprotective properties in many cardiac injury models. So, we evaluated their effects in diabetic cardiomyopathy (DCM) in relation to mitochondrial dysfunction. This work included seven groups of adult male albino rats: the control group, the non-treated diabetic group, and the treated diabetic groups: one group was treated with MSCs only, the second with pioglitazone only, the third with MSCs and pioglitazone, the forth with exendin-4 only and the fifth with MSCs and exendin-4. All treatments were started after 6 weeks from induction of diabetes and continued for the next 4 weeks. Blood samples were collected for assessment of glucose, insulin, and cardiac enzymes. Hearts were removed and used for isolated heart studies, and gene expression of: myocyte enhancer factor-2 (Mef2), peroxisome proliferator-activated receptor gamma coactivator1-alpha (PGC1α), nuclear factor kappa B (NFKB) and autophagic markers: light chain 3 (LC3) and beclin by real-time reverse transcription-polymerase chain reaction. The cardiac mitochondrial protein levels of cardiolipin and uncoupler protein 2 (UCP2) were assessed by ELISA and western blot technique, respectively. Treated groups showed significant improvement in left ventricular function associated with improvement in the cardiac injury and myopathic markers compared to the non treated diabetic group. NFKB was down-regulated while cardiolipin, PGC1α, LC.3 and beclin were up-regulated in all treated groups. These data suggest that the cardioprotective effects of MSCs, exendin-4 or pioglitazone based on their ability to improve mitochondrial functions through targeting inflammatory and autophagy signaling. The co- administration of pioglitazone or exendin-4 with MSCs showed significant superior improvement compared with MSCs alone, indicating the ability to use them in supporting cardioprotective effects of MSCs.


Assuntos
Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/terapia , Hipoglicemiantes/farmacologia , Transplante de Células-Tronco Mesenquimais , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/terapia , PPAR gama/agonistas , Peptídeos/farmacologia , Tiazolidinedionas/farmacologia , Peçonhas/farmacologia , Animais , Cardiolipinas/metabolismo , Cardiomiopatias Diabéticas/sangue , Cardiomiopatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Exenatida , Hipoglicemiantes/administração & dosagem , Fatores de Transcrição MEF2/metabolismo , Masculino , Peptídeos/administração & dosagem , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Pioglitazona , Proteínas Serina-Treonina Quinases/metabolismo , Tiazolidinedionas/administração & dosagem , Proteína Desacopladora 2/metabolismo , Peçonhas/administração & dosagem
17.
Inflammation ; 41(1): 20-32, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28871508

RESUMO

Sepsis caused by lipopolysaccharide (LPS) is a life-threatening disease accompanied by multiple organ failure. This study investigated the curative effects of imatinib (IMA) against hepatic, renal, and pulmonary responses caused by a single administration of LPS (10 mg/kg, i.p.) in rats. Treatment with IMA (15 mg/kg, i.p.) 30 min after LPS antagonized the LPS-induced boost of liver enzymes (ALT, AST), kidney functions (BUN, sCr) as well as the elevated pulmonary vascular permeability and edema. IMA declined tissue contents of NF-κB, STAT-3, P38-MAPK, TNF-α, IL-1ß, and iNOS. It also amplified the anti-inflammatory cytokine IL-10 as well as the Bcl-2/Bax ratio, a cardinal indicator of the anti-apoptotic effect. Meanwhile, the rats exhibited marked reduction of the broncho-alveolar lavage fluid (BALF) contents of TNF-α, IL-1ß, IFN-γ, and neutrophil count; however, they revealed prominent augmentation of the BALF content IL-10. In conclusion, these findings suggest that IMA is endowed with anti-inflammatory, anti-oxidant, and anti-apoptotic properties and hence may provide a novel agent for the management of sepsis.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Endotoxemia/tratamento farmacológico , Mesilato de Imatinib/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Modelos Animais de Doenças , Endotoxemia/metabolismo , Endotoxemia/patologia , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/patologia , Ratos Wistar
18.
J Cell Physiol ; 233(8): 5768-5779, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29205344

RESUMO

Diabetes Mellitus is a chronic generalized disorder due to insulin insufficiency or resistance. Skeletal muscles represent one of the most important target organs that is affected by insulin signaling. The aim of the current work was to investigate the effect of metformin versus vitamin D (and also simultaneous administration) therapy in type 2 diabetic (T2D) rats on the state of the muscle and insulin sensitivity. Thirty six male rats constituted the animal model and have been divided into five groups: control, Diabetic, Diabetic + Metformin, Diabetic + Vitamin D, Diabetic + Metformin + Vitamin D. Blood samples were taken for biochemical measurements of serum calcium, interleukin-6 (IL-6), Triglycerides (TG), glucose, insulin, and calculation of HOMA-IR, and then rats were sacrificed, dissected for removal of gastrocnemius muscle that is used for both biochemical, histopathological and electron microscopy examination. Oral administration of vitamin D alone or in combination with metformin improved insulin sensitivity in skeletal muscles, and sustained the metabolic complications along with muscle atrophy and inflammation in T2D rats. We demonstrated super-beneficial action on insulin resistance of additional vitamin D therapy in T2DM rats that were insufficiently controlled by metformin alone.

19.
Future Sci OA ; 3(1): FSO162, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28344826

RESUMO

AIM: This study evaluated the potential of bone marrow derived mesenchymal stem cells (MSCs) to regulate cytokines and remodel the lung induced by lipopolysaccharide (LPS; O-antigen). MATERIALS & METHODS: A group of mice (n = 21) was inoculated intraperitoneally with one dose 0.1 ml containing 0.025 mg LPS/mouse, and another treated intravenously with one dose of labeling bone marrow derived MSCs at 7.5 × 105 cell/mouse 4 h after LPS injection. All animals were sacrificed on the 1st, 7th and 14th days post-injection. RESULTS: MSCs increased the level of IL-10 with suppression of TNF-α, decrease of collagen fibers and renewal of alveolar type I cells, together with lung tissue remodeling. CONCLUSION: MSCs were shown to modulate inflammatory cytokines (TNF-α and IL-10) and to differentiate into alveolar type I cells, which prevented fibrosis in lung tissue from LPS-treated mice.

20.
Biomed Pharmacother ; 88: 293-301, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28113081

RESUMO

OBJECTIVES: Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a central role in metabolic homeostasis and regulation of inflammatory responses through attenuation of nuclear factor kappa-B (NF-κB), Thus AMPK may be a promising pharmacologic target for the treatment of various chronic inflammatory diseases. We examined the effect of 6-gingerol, an active ingredient of ginger on AMPK-NF-κB pathway in high fat diet (HFD) rats in comparison to fish oil. METHODS: Protein levels of AMPK-α1 and phosphorylated AMPK-α1 were measured by western blot while Sirtuin 6 (Sirt-6), resistin and P65 were estimated by RT-PCR, TNF-α was determined by ELISA, FFAs were estimated chemically as well as the enzymatic determination of the metabolic parameters. RESULTS: 6-Gingerol substantially enhanced phosphorylated AMPK-α1 more than fish oil and reduced the P65 via upregulation of Sirt-6 and downregulation of resistin, and resulted in attenuation of the inflammatory molecules P65, FFAs and TNF-α more than fish oil treated groups but in an insignificant statistical manner, those effects were accompanied by a substantial hypoglycemic effect. CONCLUSION: Gingerol treatment effectively modulated the state of inflammatory privilege in HFD group and the metabolic disorders via targeting the AMPK-NF-κB pathway, through an increment in the SIRT-6 and substantial decrement in resistin levels.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Catecóis/farmacologia , Dieta Hiperlipídica/efeitos adversos , Álcoois Graxos/farmacologia , NF-kappa B/metabolismo , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Peso Corporal/efeitos dos fármacos , Óleos de Peixe , Gengibre/química , Masculino , NF-kappa B/efeitos dos fármacos , Fosforilação , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sirtuínas/efeitos dos fármacos , Sirtuínas/metabolismo , Fator de Transcrição RelA/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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