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1.
Pflugers Arch ; 476(5): 755-767, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38305876

RESUMEN

It has been suggested that the novel selective phosphodiesterase 9 (PDE9) inhibitor may improve cardiac and renal function by blocking 3',5'-cyclic guanosine monophosphate (cGMP) degradation. 5/6 nephrectomized (5/6Nx) rats were used to investigate the effects of the PDE9 inhibitor (BAY 73-6691) on the heart and kidney. Two doses of BAY 73-6691 (1 mg/kg/day and 5 mg/kg/day) were given for 95 days. The 5/6Nx rats developed albuminuria, a decrease in serum creatinine clearance (Ccr), and elevated serum troponin T levels. Echocardiographic data showed that 5/6 nephrectomy resulted in increased fractional shortening (FS), stroke volume (SV), and left ventricular ejection fraction (EF). However, 95 days of PDE9 inhibitor treatment did not improve any cardiac and renal functional parameter. Histopathologically, 5/6 nephrectomy resulted in severe kidney and heart damage, such as renal interstitial fibrosis, glomerulosclerosis, and enlarged cardiomyocytes. Telmisartan attenuated renal interstitial fibrosis and glomerulosclerosis as well as improved cardiomyocyte size. However, except for cardiomyocyte size and renal perivascular fibrosis, BAY 73-6691 had no effect on other cardiac and renal histologic parameters. Pathway enrichment analysis using RNA sequencing data of kidney and heart tissue identified chronic kidney disease pathways, such as phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway, complement and coagulation cascades, and nuclear factor kappa B (NF-κB) signaling pathway. PDE9i did not affect any of these disease-related pathways. Two dosages of the PDE9 inhibitor BAY 73-6691 known to be effective in other rat models have only limited cardio-renal protective effects in 5/6 nephrectomized rats.


Asunto(s)
Corazón , Riñón , Nefrectomía , Animales , Masculino , Ratas , Corazón/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Miocardio/metabolismo , Miocardio/patología , Nefrectomía/métodos
2.
Trop Anim Health Prod ; 56(2): 48, 2024 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-38236357

RESUMEN

Fascioliasis, a prevalent disease in livestock globally, is primarily caused by the trematode parasites Fasciola hepatica and Fasciola gigantica. This parasitic infection leads to significant economic repercussions. In this study, our objective was to gain insight into the pathophysiological consequences of Fascioliasis in cattle through the evaluation of metabolic, oxidative stress, and histological parameters. A thorough investigation was carried out on the liver of 197 bovines after their slaughter, which unveiled the occurrence of Fascioliasis, with a prevalence rate of 13.2% observed. The bovine that were infected exhibited notable increase in serum transaminases (ALT, AST, and ALP) and malondialdehyde (MDA) and catalase (CAT) while the decrease in glutathione (GSH) and superoxide dismutase (SOD) levels. The lipid profile analysis of infected cattle revealed alterations in the cholesterol and triglyceride levels. Moreover, the histopathological examination revealed a range of hepatic lesions associated with Fascioliasis, including necrosis, inflammation, fibrosis, and proliferative alterations. The bile ducts also displayed distinct pathological changes, including hyperplasia, thickening, and edema, and harbored various developmental stages of Fasciola spp. highlighting the parasitic infestation's effects on the biliary system. These results highlight the serious effects of Fascioliasis on lipid metabolism and the oxidative damage that is induced in the livers of cattle. Thus, Fasciola infestation in bovine causes alteration in biochemical and antioxidant activities, which are considered as important factors in the diagnosis of Fascioliasis.


Asunto(s)
Enfermedades de los Bovinos , Fasciola hepatica , Fasciola , Fascioliasis , Bovinos , Animales , Fascioliasis/veterinaria , Estrés Oxidativo
3.
Am J Physiol Cell Physiol ; 324(4): C951-C962, 2023 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-36779666

RESUMEN

The mechanisms of nephroprotection in nondiabetic chronic kidney disease (CKD) models by sodium-glucose cotransporter 2 (SGLT2) inhibitors are not well defined. Five groups were established: sham-operated rats, placebo-treated rats with 5/6 nephrectomy (5/6Nx), 5/6Nx + telmisartan (5 mg/kg/day), 5/6Nx + empagliflozin (3 mg/kg/day), and 5/6Nx + empagliflozin (15 mg/kg/day). Treatment duration was 95 days. Empagliflozin showed a dose-dependent beneficial effect on the change from baseline of creatinine clearance (Ccr). The urinary albumin-to-creatinine ratio likewise improved in a dose-dependent manner. Both dosages of empagliflozin improved morphological kidney damage parameters such as renal interstitial fibrosis and glomerulosclerosis. 5/6 nephrectomy led to a substantial reduction of urinary adenosine excretion, a surrogate parameter of the tubuloglomerular feedback (TGF) mechanism. Empagliflozin caused a dose-dependent increase in urinary adenosine excretion. The urinary adenosine excretion was negatively correlated with renal interstitial fibrosis and positively correlated with Ccr. Immunofluorescence analysis revealed that empagliflozin had no effect on CD8+ and CD4+ T cells as well as on CD68+ cells (macrophages). To further explore potential mechanisms, a nonhypothesis-driven approach was used. RNA sequencing followed by quantitative real-time polymerase chain reaction revealed that complement component 1Q subcomponent A chain (C1QA) as well as complement component 1Q subcomponent C chain (C1QC) gene expression were upregulated in the placebo-treated 5/6Nx rats and this upregulation was blunted by treatment with empagliflozin. In conclusion, empagliflozin-mediated nephroprotection in nondiabetic CKD is due to a dose-dependent activation of the TGF as well as empagliflozin-mediated effects on the complement system.


Asunto(s)
Diabetes Mellitus Tipo 2 , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Ratas , Animales , Complemento C1q , Creatinina , Retroalimentación , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Fibrosis
4.
FASEB J ; 36(4): e22259, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35294083

RESUMEN

Effects of feeding male rats during spermatogenesis a high-fat, high-sucrose and high-salt diet (HFSSD) over two generations (F0 and F1) on renal outcomes are unknown. Male F0 and F1 rats were fed either control diet (F0CD+F1CD) or HFSSD (F0HD+F1HD). The outcomes were glomerular filtration rate and urinary albumin excretion in F1 and F2 offspring. If both outcomes were altered a morphological and molecular assessment was done. F2 offspring of both sexes had a decreased GFR. However, increased urinary albumin excretion was only observed in female F2 F0HD+F1HD offspring compared with controls. F0HD+F1HD female F2 offspring developed glomerulosclerosis (+31%; p < .01) and increased renal interstitial fibrosis (+52%; p < .05). RNA sequencing followed by qRT-PCR validation showed that four genes (Enpp6, Tmem144, Cd300lf, and Actr3b) were differentially regulated in the kidneys of female F2 offspring. lncRNA XR-146683.1 expression decreased in female F0HD+F1HD F2 offspring and its expression was (r = 0.44, p = .027) correlated with the expression of Tmem144. Methylation of CpG islands in the promoter region of the Cd300lf gene was increased (p = .001) in female F2 F0HD+F1HD offspring compared to controls. Promoter CpG island methylation rate of Cd300lf was inversely correlated with Cd300lf mRNA expression in F2 female offspring (r = -0.483, p = .012). Cd300lf mRNA expression was inversely correlated with the urinary albumin-to-creatinine ratio in female F2 offspring (r = -0.588, p = .005). Paternal pre-conceptional unhealthy diet given for two generations predispose female F2 offspring to chronic kidney disease due to epigenetic alterations of renal gene expression. Particularly, Cd300lf gene promotor methylation was inversely associated with Cd300lf mRNA expression and Cd300lf mRNA expression itself was inversely associated with urinary albumin excretion in F2 female offspring whose fathers and grandfathers got a pre-conceptional unhealthy diet.


Asunto(s)
Efectos Tardíos de la Exposición Prenatal , Insuficiencia Renal Crónica , Albúminas , Animales , Dieta , Dieta Alta en Grasa/efectos adversos , Femenino , Humanos , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , ARN Mensajero , Ratas , Cloruro de Sodio , Cloruro de Sodio Dietético , Espermatogénesis , Sacarosa/efectos adversos
5.
Microb Pathog ; 166: 105541, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35469999

RESUMEN

Lumpy skin disease (LSD) is a devastating, emerging viral disease of cattle. It causes significant economic losses due to trade restrictions that are placed on infected animals and the biological effects of the disease: infertility, dramatic loss in milk production, induction of abortion and mortality. It is caused by lumpy skin disease virus (LSDV), which belongs to the Poxviridae family. Vaccination has been determined to be the most effective way to control LSD infection among livestock. However, some adverse effects have been reported in animals vaccinated with live vaccines. To the best of our knowledge, this is the first study to report the systemic lesions that are associated with LSD vaccination in xenogeneic animals. The aim of our study was to compare the immunogenicity and pathogenicity of a live attenuated vaccine of Romanian strain of sheeppox virus (SPPV) through study of two different routes of administration in xenogeneic animals (mice). Swiss male mice were inoculated with two doses of SPPV vaccine by two different routes intranasal (IN, through nebulisation), and intraperitoneal (IP) injection) and the levels of immunoglobulins and histopathological findings were reported. Our results showed marked increases in levels of immunoglobulins (Ig) dependent on the administration route: IgG in IP-inoculated mice and IgA in IN-vaccinated mice. IgM levels became markedly high after vaccination via both routes. Histologically, nebulisation of mice with SPPV vaccine caused more pulmonary lesions than did IP injection and promoted the proliferation of megakaryocytes in splenic tissues. In contrast, IP injection had less effect on pulmonary tissues and induced activation of extramedullary haematopoiesis (EH) in the hepatic tissues. LSD vaccination in xenogeneic animals caused serious systemic complications and the severity of the lesions caused to tissue depended on the route of administration.


Asunto(s)
Capripoxvirus , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Dermatosis Nodular Contagiosa , Virus de la Dermatosis Nodular Contagiosa , Vacunas Virales , Animales , Bovinos , Masculino , Ratones , Capripoxvirus/fisiología , Dermatosis Nodular Contagiosa/prevención & control , Vacunación/veterinaria , Vacunas Atenuadas
6.
Kidney Blood Press Res ; 47(9): 565-575, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35878596

RESUMEN

INTRODUCTION: The angiotensin-converting enzyme 2 (ACE2) as well as the transmembrane protease serine type 2 (TMPRSS2) have been found to play roles in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19). SARS-CoV-2 infection risk and severity of COVID-19 might be indicated by the expression of ACE2 and TMPRSS2 in the lung. METHODS: A high-salt diet rat model and renin-angiotensin-aldosterone system (RAAS) blockade were used to test whether these factors affect ACE2 and TMPRSS2 expression in the lung. A normal (0.3% NaCl), a medium (2% NaCl), or a high (8% NaCl) salt diet was fed to rats for 12 weeks, along with enalapril or telmisartan, before examining the lung for histopathological alteration. Using immunofluorescence and qRT-PCR, the localization as well as mRNA expression of ACE2 and TMPRSS2 were investigated. RESULTS: The findings provide evidence that both TMPRSS2 and ACE2 are highly expressed in bronchial epithelial cells as well as ACE2 was also expressed in alveolar type 2 cells. High-salt diet exposure in rats leads to elevated ACE2 expression on protein level. Treatment with RAAS blockers had no effect on lung tissue expression of ACE2 and TMPRSS2. CONCLUSIONS: These findings offer biological support regarding the safety of these drugs that are often prescribed to COVID-19 patients with cardiovascular comorbidity. High salt intake, on the other hand, might adversely affect COVID-19 outcome. Our preclinical data should stimulate clinical studies addressing this point of concern.


Asunto(s)
COVID-19 , Sistema Renina-Angiotensina , SARS-CoV-2 , Enzima Convertidora de Angiotensina 2 , Animales , Enalapril/farmacología , Pulmón , ARN Mensajero/metabolismo , Ratas , Sistema Renina-Angiotensina/efectos de los fármacos , Serina Endopeptidasas , Cloruro de Sodio Dietético/efectos adversos , Telmisartán/farmacología
7.
Am J Nephrol ; 51(5): 373-380, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32320989

RESUMEN

BACKGROUND: Endostatin is a 20-kDa C-terminal fragment of collagen XVIII, known for its ability to inhibit the proliferation of capillary endothelial cells. Previous studies suggested that circulating endostatin independently predicts incident chronic kidney disease. However, the impact of endostatin on graft loss level in kidney transplant recipients (KTRs) remains unknown. METHODS: We conducted a prospective observational cohort study in 574 maintenance KTRs. Patients were followed for kidney graft loss and all-cause mortality during a median follow-up of 48 months. Serum-, and urine-samples and clinical data were collected at baseline. Serum Endostatin concentration was analyzed by an ELISA. RESULTS: Among 574 patients, 37 patients had graft loss and 62 patients died. For graft loss, the optimal cut-off value based on receiver operating characteristics analysis (area under the curve 0.79, 95% CI 0.71-0.86, p < 0.001) of endostatin was 147.3 pmol/L. Kaplan-Meier curves revealed that higher serum endostatin concentrations positively correlated with graft loss (p < 0.001). Multivariable Cox regression analyses showed that baseline endostatin concentrations were significantly associated with graft loss after adjusting for graft loss risk factors (adjusted hazard ratio [HR] 8.34; 95% CI 2.19-31.72; p = 0.002). The adjusted HRs for classical graft loss risk factors such as baseline estimated glomerular filtration rate and urinary protein excretion were lower (1.91 and 5.44, respectively). In contrast to graft loss, baseline endostatin concentrations were not associated with all-cause mortality. CONCLUSION: Increased serum endostatin at baseline is independently associated with the risk of graft loss in KTRs.


Asunto(s)
Endostatinas/sangre , Rechazo de Injerto/epidemiología , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Adulto , Anciano , Biomarcadores/sangre , Estudios Transversales , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/etiología , Humanos , Estimación de Kaplan-Meier , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Valores de Referencia , Medición de Riesgo/métodos , Factores de Riesgo
8.
Clin Exp Nephrol ; 24(12): 1177-1183, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32816133

RESUMEN

BACKGROUND: Sclerostin is a hormone contributing to the bone-vascular wall cross talk and has been implicated in cardiovascular events and mortality in patients with chronic kidney disease (CKD). We analyzed the relationship between sclerostin and mortality in renal transplant recipients. METHODS: 600 stable renal transplant recipients (367men, 233 women) were followed for all-cause mortality for 3 years. Blood and urine samples for analysis and clinical data were collected at study entry. We performed Kaplan-Meier survival analysis and Cox regression models considering confounding factors such as age, eGFR, cold ischemia time, HbA1c, phosphate, calcium, and albumin. Optimal cut-off values for the Cox regression model were calculated based on ROC analysis. RESULTS: Sixty-five patients died during the observation period. Nonsurvivors (n = 65; sclerostin 57.31 ± 30.28 pmol/L) had higher plasma sclerostin levels than survivors (n = 535; sclerostin 47.52 ± 24.87 pmol/L) (p = 0.0036). Kaplan-Meier curve showed that baseline plasma sclerostin concentrations were associated with all-cause mortality in stable kidney transplant recipients (p = 0.0085, log-rank test). After multiple Cox regression analysis, plasma levels of sclerostin remained an independent predictor of all-cause mortality (hazard ratio, 1.011; 95% CI 1.002-1.020; p = 0.0137). CONCLUSIONS: Baseline plasma sclerostin is an independent risk factor for all-cause mortality in patients after kidney transplantation.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/sangre , Trasplante de Riñón/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Femenino , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia Arriba , Adulto Joven
9.
Kidney Int ; 95(6): 1373-1388, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30979564

RESUMEN

Dipeptidyl peptidase type 4 (DPP-4) inhibitors were reported to have beneficial effects in experimental models of chronic kidney disease. The underlying mechanisms are not completely understood. However, these effects could be mediated via the glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP1R) pathway. Here we investigated the renal effects of the DPP-4 inhibitor linagliptin in Glp1r-/- knock out and wild-type mice with 5/6 nephrectomy (5/6Nx). Mice were allocated to groups: sham+wild type+placebo; 5/6Nx+ wild type+placebo; 5/6Nx+wild type+linagliptin; sham+knock out+placebo; 5/6Nx+knock out+ placebo; 5/6Nx+knock out+linagliptin. 5/6Nx caused the development of renal interstitial fibrosis, significantly increased plasma cystatin C and creatinine levels and suppressed renal gelatinase/collagenase, matrix metalloproteinase-1 and -13 activities; effects counteracted by linagliptin treatment in wildtype and Glp1r-/- mice. Two hundred ninety-eight proteomics signals were differentially regulated in kidneys among the groups, with 150 signals specific to linagliptin treatment as shown by mass spectrometry. Treatment significantly upregulated three peptides derived from collagen alpha-1(I), thymosin ß4 and heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) and significantly downregulated one peptide derived from Y box binding protein-1 (YB-1). The proteomics results were further confirmed using western blot and immunofluorescence microscopy. Also, 5/6Nx led to significant up-regulation of renal transforming growth factor-ß1 and pSMAD3 expression in wild type mice and linagliptin significantly counteracted this up-regulation in wild type and Glp1r-/- mice. Thus, the renoprotective effects of linagliptin cannot solely be attributed to the GLP-1/GLP1R pathway, highlighting the importance of other signaling pathways (collagen I homeostasis, HNRNPA1, YB-1, thymosin ß4 and TGF-ß1) influenced by DPP-4 inhibition.


Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Riñón/efectos de los fármacos , Linagliptina/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Colágeno Tipo I/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/genética , Ribonucleoproteína Nuclear Heterogénea A1/metabolismo , Humanos , Riñón/patología , Riñón/cirugía , Linagliptina/uso terapéutico , Masculino , Ratones , Ratones Noqueados , Nefrectomía/efectos adversos , RNA-Seq , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/patología , Timosina/metabolismo , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Regulación hacia Arriba/efectos de los fármacos
10.
Diabetologia ; 61(8): 1862-1876, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29777263

RESUMEN

AIMS/HYPOTHESIS: Paternal high-fat diet prior to mating programmes impaired glucose tolerance in female offspring. We examined whether the metabolic consequences in offspring could be abolished by folate treatment of either the male rats before mating or the corresponding female rats during pregnancy. METHODS: Male F0 rats were fed either control diet or high-fat, high-sucrose and high-salt diet (HFSSD), with or without folate, before mating. Male rats were mated with control-diet-fed dams. After mating, the F0 dams were fed control diet with or without folate during pregnancy. RESULTS: Male, but not female offspring of HFSSD-fed founders were heavier than those of control-diet-fed counterparts (p < 0.05 and p = 0.066 in males and females, respectively). Both male and female offspring of HFSSD-fed founders were longer compared with control (p < 0.01 for both sexes). Folate treatment of the pregnant dams abolished the effect of the paternal diet on the offspring's body length (p Ë‚ 0.05). Female offspring of HFSSD-fed founders developed impaired glucose tolerance, which was restored by folate treatment of the dams during pregnancy. The beta cell density per pancreatic islet was decreased in offspring of HFSSD-fed rats (-20% in male and -15% in female F1 offspring, p Ë‚ 0.001 vs controls). Folate treatment significantly increased the beta cell density (4.3% and 3.3% after folate supplementation given to dams and founders, respectively, p Ë‚ 0.05 vs the offspring of HFSSD-fed male rats). Changes in liver connective tissue of female offspring of HFSSD-fed founders were ameliorated by treatment of dams with folate (p Ë‚ 0.01). Hepatic Ppara gene expression was upregulated in female offspring only (1.51-fold, p Ë‚ 0.05) and was restored in the female offspring by folate treatment (p Ë‚ 0.05). We observed an increase in hepatic Lcn2 and Tmcc2 expression in female offspring born to male rats exposed to an unhealthy diet during spermatogenesis before mating (p Ë‚ 0.05 vs controls). Folate treatment of the corresponding dams during pregnancy abolished this effect (p Ë‚ 0.05). Analysis of DNA methylation levels of CpG islands in the Ppara, Lcn2 and Tmcc2 promoter regions revealed that the paternal unhealthy diet induced alterations in the methylation pattern. These patterns were also affected by folate treatment. Total liver DNA methylation was increased by 1.52-fold in female offspring born to male rats on an unhealthy diet prior to mating (p Ë‚ 0.05). This effect was abolished by folate treatment during pregnancy (p Ë‚ 0.05 vs the offspring of HFSSD-fed male rats). CONCLUSIONS/INTERPRETATION: Folate treatment of pregnant dams restores effects on female offspring's glucose metabolism induced by pre-conception male founder HFSSD.


Asunto(s)
Fenómenos Fisiológicos Nutricionales de los Animales , Dieta Alta en Grasa/efectos adversos , Ácido Fólico/uso terapéutico , Preñez , Alimentación Animal , Animales , Metilación de ADN , Femenino , Perfilación de la Expresión Génica , Prueba de Tolerancia a la Glucosa , Hígado/embriología , Hígado/metabolismo , Masculino , Páncreas/metabolismo , Embarazo , ARN/análisis , Ratas , Ratas Sprague-Dawley , Cloruro de Sodio/química , Espermatogénesis , Sacarosa/química , Triglicéridos/metabolismo , Regulación hacia Arriba
11.
Kidney Int ; 94(3): 491-501, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29861059

RESUMEN

Fibroblast growth factor 23 (FGF23) is a proteohormone regulating renal phosphate transport and vitamin D metabolism as well as inducing left heart hypertrophy. FGF23-deficient mice suffer from severe tissue calcification, accelerated aging and a myriad of aging-associated diseases. Bone cells produce FGF23 upon store-operated calcium ion entry (SOCE) through the calcium selective ion channel Orai1. AMP-activated kinase (AMPK) is a powerful energy sensor helping cells survive states of energy deficiency, and AMPK down-regulates Orai1. Here we investigated the role of AMPK in FGF23 production. Fgf23 gene transcription was analyzed by qRT-PCR and SOCE by fluorescence optics in UMR106 osteoblast-like cells while the serum FGF23 concentration and phosphate metabolism were assessed in AMPKα1-knockout and wild-type mice. The AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) down-regulated, whereas the AMPK inhibitor, dorsomorphin dihydrochloride (compound C) and AMPK gene silencing induced Fgf23 transcription. AICAR decreased membrane abundance of Orai1 and SOCE. SOCE inhibitors lowered Fgf23 gene expression induced by AMPK inhibition. AMPKα1-knockout mice had a higher serum FGF23 concentration compared to wild-type mice. Thus, AMPK participates in the regulation of FGF23 production in vitro and in vivo. The inhibitory effect of AMPK on FGF23 production is at least in part mediated by Orai1-involving SOCE.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Riñón/metabolismo , Proteína ORAI1/metabolismo , Fosfatos/metabolismo , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/genética , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Animales , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Riñón/efectos de los fármacos , Ratones , Ratones Noqueados , Pirazoles/farmacología , Pirimidinas/farmacología , Ratas , Eliminación Renal/efectos de los fármacos , Ribonucleótidos/farmacología , Regulación hacia Arriba/efectos de los fármacos
12.
Naunyn Schmiedebergs Arch Pharmacol ; 397(3): 1875-1888, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-37773524

RESUMEN

The objective of this study was to investigate whether the neurotoxic effects caused by methotrexate (MTX), a frequently used chemotherapy drug, could be improved by administering Spirulina platensis (SP) and/or thymoquinone (TQ). Seven groups of seven rats were assigned randomly for duration of 21 days. The groups consisted of a control group that was given saline only. The second group was given 500 mg/kg of SP orally; the third group was given 10 mg/kg of TQ orally. The fourth group was given a single IP dose of 20 mg/kg of MTX on the 15th day of the experiment. The fifth group was given both SP and MTX, the sixth group was given both TQ and MTX, and the seventh group was given SP, TQ, and MTX. After MTX exposure, the study found that AChE inhibition, depletion of glutathione, and increased levels of MDA occurred. MTX also decreased the activity of SOD and CAT, as well as the levels of inflammatory mediators such as IL-1, IL-6, and tumor necrosis factor-α. MTX induced apoptosis in brain tissue. However, when MTX was combined with either SP or TQ, the harmful effects on the body were significantly reduced. This combination treatment resulted in a faster return to normal levels of biochemical, oxidative markers, inflammatory responses, and cell death. In conclusion, supplementation with SP or TQ could potentially alleviate MTX-induced neuronal injury, likely due to their antioxidant, anti-inflammatory, and anti-apoptotic effects.


Asunto(s)
Antioxidantes , Benzoquinonas , Spirulina , Ratas , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antioxidantes/metabolismo , Metotrexato/toxicidad , Spirulina/metabolismo , Ratas Wistar , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Estrés Oxidativo
13.
Anat Histol Embryol ; 53(3): e13046, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38712731

RESUMEN

The present study aims to evaluate the morphometric and histopathological properties of Modified Elnady's plastinated tissue after a period compared to non-plastinated tissue. The plastination technique is utilized in research and teaching due to the potential health risks associated with prolonged exposure to formalin. The tissues and organs are permanently dried during plastination and can be used for further anatomical, histopathological and surgical educational purposes. This method involves drying tissue and allowing synthetic materials like glycerin to permeate it. The study compared non-plastinated and plastinated tissue post-plastination to determine if structural alterations differed from those linked to plastination. The study examined the histopathological examination of dogs' skin, muscles, liver, lung, and intestine using formalin-fixed organs for paraffin embedding and previously plastinated organs for a plastinated group. The study examined non-plastinated and plastinated tissues, their histological composition and biometric parameters revealing typical structures in the non-plastinated group. Plasmodiumted tissues exhibited a compacted appearance, volume changes, nuclear clarity, and cytoplasmic hypereosinophilia, with statistical differences between the two groups. The study reveals that plastinated tissues, after 5 years of plastination, maintain their histological architecture well, with some exceptions. Plastinated tissues can be utilized in future microscopic and immunological studies and will be beneficial for teaching and research.


Asunto(s)
Hígado , Pulmón , Plastinación , Animales , Perros , Plastinación/métodos , Pulmón/patología , Hígado/patología , Piel/patología , Piel/anatomía & histología , Intestinos/anatomía & histología , Intestinos/patología , Adhesión en Parafina/veterinaria , Formaldehído , Anatomía Veterinaria/educación
14.
Vet Res Commun ; 2024 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-39316350

RESUMEN

BACKGROUND: Newcastle disease (ND) is widely regarded as one of the most virulent and destructive viral infections that create chaos in the poultry industry and cause widespread epidemics and consequentially debilitating economic losses on a global scale in terms of chicken products. The current experiment evaluates the protective effect of Glycyrrhiza glabra ( G. glabra) against the Newcastle disease virus (NDV) in chickens. Ninety (90) 1-day-old SPF chicks were treated according to ethical approval (BUFVTM 05-02-22) as follows (1) non-treated non-challenged control group; (2) NDV group: Challenged with genotype VII ND virus; and (3) LE/NDV group: Challenged with the virus and intermittently treated with powdered extract of G. glabra roots (LE) in drinking water (0.5 g/L) before and after viral challenge. RESULT: The water medication of NDV-challenged chicks has resulted in a significant decrease in the severity of clinical symptoms, morbidity, and mortality rates, as well as the quantity of virus shed, compared with the NDV group. Treatment with LE has led to a significant reduction in serum ALT and AST activities, blood glucose level, urea, and creatinine, and significant restoration of serum proteins. In addition, the treatment has resulted in a decrease in MDA and NO levels, as well as an increase in T-SOD and catalase activities compared with untreated challenged chicks. LE decreased IFN-γ and TLR-3 gene expression in comparison with the NDV group. The treated challenged birds had fewer macroscopically detectable lesions in their respiratory, digestive, and lymphoid organs than the untreated challenged birds. Microscopically, the LE/NDV group exhibited mild to moderate pathological changes in the respiratory and digestive systems as well as lymphoid tissues, in contrast to the NDV group, which exhibited severe pathological changes. Furthermore, molecular docking assessment proved the efficacy of G. glabra against viral proliferation and invasion. CONCLUSION: We concluded that Glycyrrhiza glabra powdered extract at a dose of 0.5 g/L drinking water can effectively mitigate the debilitating effects of Newcastle disease in chickens.

15.
Life Sci ; 341: 122499, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38342375

RESUMEN

Angiogenesis is one of the defining characteristics of cancer. Vascular endothelial growth factor (VEGF) is crucial for the development of angiogenesis. A growing interest in cancer therapy is being caused by the widespread use of antiangiogenic drugs in treating several types of human cancer. However, this therapeutic approach can worsen resistance, invasion, and overall survival. As we proceed, refining combination strategies and addressing the constraint of targeted treatments are paramount. Therefore, major challenges in using novel combinations of antiangiogenic agents with cytotoxic treatments are currently focused on illustrating the potential of synergistic therapeutic strategies, alongside advancements in nanomedicine and gene therapy, present opportunities for more precise interference with angiogenesis pathways and tumor environments. Nanoparticles have the potential to regulate several crucial activities and improve several drug limitations such as lack of selectivity, non-targeted cytotoxicity, insufficient drug delivery at tumor sites, and multi-drug resistance based on their unique features. The goal of this updated review is to illustrate the enormous potential of novel synergistic therapeutic strategies and the targeted nanoparticles as an alternate strategy for t treating a variety of tumors employing antiangiogenic therapy.


Asunto(s)
Antineoplásicos , Nanopartículas , Neoplasias , Humanos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Neovascularización Patológica/metabolismo , Neoplasias/patología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico
16.
Front Pharmacol ; 15: 1433793, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39314751

RESUMEN

Hesperidin (Hes) protects different organs from damage by acting as a potent antioxidant and anti-inflammatory. This study aims to evaluate the gastroprotective effects of free hesperidin and its chitosan nanoparticles (HNPs) against ethanol-induced gastric ulcers in rats, hypothesizing that HNPs will enhance bioavailability and therapeutic efficacy due to improved solubility and targeted delivery. HNPs were synthesized via ion gelation and characterized using TEM, SEM, and zeta potential analyses. Key assessments included gastric acidity, histological analysis, and markers of inflammation, oxidative stress, and apoptosis. HNPs significantly decreased gastric acidity, reduced inflammatory and apoptotic markers, and enhanced antioxidant enzyme activities compared to free hesperidin and esomeprazole. Furthermore, Sirt-1, PGC-1α, HO-1, and FOXO1 gene expression were also evaluated. HNPs raised Sirt-1, PGC-1α, HO-1, and downregulated FOXO1, and they suppressed the activities of NF-κB p65, COX-2, IL-1ß, CD86, FOXO1 P53, and caspase-3 and increased Sirt-1 activity. HNPs treatment notably restored antioxidant enzyme activity, reduced oxidative stress and inflammatory markers, and improved histological outcomes more effectively than free hesperidin and esomeprazole. These results indicate that chitosan nanoparticles significantly enhance the gastroprotective effects of hesperidin against ethanol-induced gastric ulcers, potentially offering a more effective therapeutic strategy. Further research should explore the clinical applications of HNPs in human subjects.

17.
Pharmaceuticals (Basel) ; 17(9)2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-39338308

RESUMEN

Hesperidin (Hes) functions as a strong antioxidant and anti-inflammatory to guard against damage to the heart, liver, and kidneys. Nevertheless, due to its restricted solubility and bioavailability, a delivery method is required for it to reach a specific organ. In this study, ion gelation was used to synthesize a chitosan/hesperidin nanoformulation. Numerous characterization techniques, such as zeta potential, particle size, XRD, TEM, SEM, and FTIR analyses, were used to corroborate the synthesis of hesperidin nanoparticles (Hes-NPs). Male albino mice were given a pretreatment dose of 100 mg/kg, PO, of Hes or Hes-NPs, which was administered daily for 14 days before the induction of doxorubicin nephrotoxicity on the 12th day. Kidney function (urea and creatinine levels) was measured. Lipid peroxidation (MDA) and antioxidant enzyme (CAT and SOD) activities were estimated. TNF-α, IL-1ß, and VEGF content; histopathological examination of kidney tissue; and immunohistochemical staining of NF-κB, Caspase-3, BAX, Bcl-2, and TGF-ß1 were evaluated. The gene expressions of Sirt-1, Bcl-2, VEGF, HIF1-α, and Kim-1 were also considered. The results showed that pretreatment with Hes or Hes-NPs reduced doxorubicin's nephrotoxic effects, with Hes-NPs showing the greatest reduction. Kidney enzyme and MDA content were lowered in response to the Hes or Hes-NP pretreatment, whereas antioxidant enzyme activities were increased. Hes or Hes-NP pretreatment suppressed the levels of TNF-α, IL-1ß, VEGF, NF-κB, Caspase-3, BAX, and TGF-ß1; however, pretreatment increased Bcl-2 protein levels. Furthermore, the gene expressions of Sirt-1, Bcl-2, VEGF, HIF1-α, and Kim-1 were considerably higher with Hes-NP than with Hes treatment. These results suggest that Hes-NP treatment might reduce DOX-induced nephrotoxicity in mice via modulating Sirt-1/HIF1-α/VEGF/NF-κB signaling to provide antioxidant, anti-inflammatory, and anti-apoptotic effects.

18.
Vet Sci ; 10(2)2023 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-36851378

RESUMEN

(1) Background: Cystic echinococcosis is a zoonotic helminth disease that causes severe economic losses. The study aimed to assess the prevalence and viability of cystic echinococcosis in examined camels. In addition, assessing the histological, morphological, oxidative, and antioxidant state related to the cystic echinococcosis infection; (2) Methods: The study was performed on 152 slaughtered dromedary camels between March and September 2022 at El-Basatin abattoir in Cairo Governorate, Egypt; (3) Results: The results revealed that the prevalence of hydatidosis was 21.7% in slaughtered camel and the highest infection rate observed in lungs was 87.87%, while it was 9% in livers. Camels' liver infections were rare, whereas their lung infections were more common. By comparing to non-infected camels, the level of MAD was significantly increased with hydatid cysts infection, while the level of GSH, SOD and CAT was significantly decreased. Histopathological section of camel cyst revealed layered membranes surrounded by a zone of cellular infiltration and an outermost fibrous tissue reaction. In addition, there was evidence of atelectasis, emphysema, hemorrhage, congestion, and fibrosis in the surrounding tissues. Nonetheless, the degeneration and necrosis of hepatocytes and other pathological alterations in liver cyst sections were remarkably comparable to those seen in the lungs. Furthermore, calcification was detected.

19.
J Pathol Transl Med ; 56(2): 81-91, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35220710

RESUMEN

BACKGROUND: Acute respiratory distress syndrome (ARDS) is one of the most common complications in coronavirus disease 2019 patients suffering from acute lung injury (ALI). In ARDS, marked distortion of pulmonary architecture has been reported. The pulmonary lesions in ARDS include hemodynamic derangements (such as alveolar edema and hemorrhage), vascular and bronchiolar damage, interstitial inflammatory cellular aggregations, and eventually fibrosis. Bleomycin induces ARDS-representative pulmonary damage in mice and rats; therefore, we used bleomycin model mice in our study. Recently, Toll-like receptor 9 (TLR9) was implicated in the development of ARDS and ALI. METHODS: In this study, we evaluated the efficiency of a TLR9 blocker (ODN2088) on bleomycin-induced pulmonary damage. We measured the apoptosis rate, inflammatory reaction, and fibroplasia in bleomycin- and bleomycin + ODN2088-treated mice. RESULTS: Our results showed a significant amelioration in bleomycin-induced damage to pulmonary architecture following ODN2088 treatment. A marked decrease in pulmonary epithelial and endothelial apoptosis rate as measured by cleaved caspase-3 expression, inflammatory reaction as indicated by tumor necrosis factor α expression, and pulmonary fibrosis as demonstrated by Van Gieson staining and α-smooth muscle actin immunohistochemistry were observed following ODN2088 treatment. CONCLUSIONS: All these findings indicate that blocking downstream TLR9 signaling could be beneficial in prevention or mitigation of ARDS through hemodynamic derangements, inflammation, apoptosis, and fibrosis.

20.
Biomed Pharmacother ; 153: 113357, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35792391

RESUMEN

The CREDENCE trial testing canagliflozin and the EMPA-REG OUTCOME trial testing empagliflozin suggest different effects on acute kidney injury (AKI). AKI diagnosis was mainly made based on changes of serum creatinine (sCr) although this also reflect mode of action of SGLT-2 inhibitors. We analyzed both compounds in a rat AKI model. The renal ischemia-reperfusion injury (I/R) model was used. Four groups were analyzed: sham, I/R+placebo, I/R+canagliflozin (30 mg/kg/day), I/R+ empagliflozin (10 mg/kg/day). Glucose excretion was comparable in both treatment groups indicating comparable SGLT-2 inhibition. Comparing GFR surrogate markers after I/R (sCr and blood urea nitrogen (BUN)), sCr peaked 24 h after I/R, BUN after 48 h, respectively, in the placebo treated I/R group. At all investigated time points after I/R sCr and BUN was higher in the I/R + canagliflozin group as compared to placebo treated rats, whereas the empagliflozin group did not differ from the placebo group. I/R led to tubular dilatation and necrosis. Empagliflozin was able to reduce that finding whereas canagliflozin had no effect. Treatment with empagliflozin also resulted in a significant reduction in an improved inflammatory score (p = 0.006). Renal expression of kidney injury molecule-1 (KIM-1) increased after I/R and empagliflozin but not canagliflozin significantly alleviated KIM-1 expression. I/R reduced urinary miR-26a excretion. Empagliflozin but not canagliflozin was able to restore normal levels of urinary miR-26a. This study in an AKI model confirmed safety data in the EMPA-REG OUTCOME trial suggesting that empagliflozin might reduce AKI risk. The empagliflozin effects on KIM-1 and miR-26a might indicate beneficial regulation of inflammation. These data should stimulate clinical studies with AKI risk as primary endpoint.


Asunto(s)
Lesión Renal Aguda , Enfermedades Cardiovasculares , MicroARNs , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Ratas , Lesión Renal Aguda/tratamiento farmacológico , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , Canagliflozina/farmacología , Canagliflozina/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Isquemia/tratamiento farmacológico , MicroARNs/uso terapéutico , Reperfusión , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico
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