ABSTRACT
SUMMARY: The main cause of mortality and disability globally is myocardial infarction (MI). Isoproterenol (ISO), a β-adrenoceptor agonist, has been used to induce rat myocardial necrosis. Whereas interleukin-37 (IL-37) has anti-inflammatory and cytoprotective properties. The study aimed to investigate the potential protective effects of IL-37 administration on cardiac architecture, oxidative stress, and inflammatory markers during ISO-induced MI in rats. Three groups of adult male rats were used in this study, the normal control group (n=8), ISO-induced MI group (n=8) that received isoproterenol hydrochloride (ISO) (100 mg/kg/day, SC, for the first 2 consecutive days), and IL-37-treated group (ISO+IL-37) (n=8) that received recombinant human IL-37 (40 µg/kg /day, intraperitoneally, for 2 weeks during and after ISO injections. Heart rate (HR.) and ECG changes were monitored. Some oxidative stress markers such as superoxide dismutase (SOD), nitric oxide (NOx), malondialdehyde (MDA), and glutathione (GSH) tissue levels in the tissue homogenate were assayed. Interleukin- 6 (IL-6), tumor necrosis factor- α (TNF-α), caspase-8, P53, and C- reactive protein (CRP) were among the inflammatory markers examined. In addition, serum levels of creatinine kinase (CK-MB) and lactate dehydrogenase (LDH) were analyzed to evaluate the myocardial injury. For histological analysis, tissues were sectioned, fixed in paraffin, and stained with hematoxylin and eosin (H&E), Masson Trichrome and, immunohistochemical against NF-kB, TNF-α, and Caspase-9. IL-37 improved ECG changes, cardiac enzyme markers, and some inflammatory markers of oxidative stress in ISO-induced MI. It also improved the histopathological and immunohistochemical changes in MI. In conclusion: IL-37 might be a promising therapeutic modality in myocardial infarction.
La principal causa de mortalidad y discapacidad a nivel mundial es el infarto de miocardio (IM). El isoproterenol (ISO), un agonista de los receptores adrenérgicos β, se ha utilizado para inducir necrosis miocárdica en ratas. Mientras que la interleucina-37 (IL-37) tiene propiedades antiinflamatorias y citoprotectoras. El estudio tuvo como objetivo investigar los posibles efectos protectores de la administración de IL-37 en la arquitectura cardíaca, el estrés oxidativo y los marcadores inflamatorios durante el infarto de miocardio inducido por ISO en ratas. En este estudio se utilizaron tres grupos de ratas macho adultas, el grupo control normal (n=8), el grupo con IM inducido por ISO (n=8) que recibió clorhidrato de isoproterenol (ISO) (100 mg/kg/día, SC, durante los primeros 2 días consecutivos) y el grupo tratado con IL-37 (ISO+IL- 37) (n=8) que recibió IL-37 humana recombinante (40 µg/kg/día, por vía intraperitoneal, durante 2 semanas durante y después de las inyecciones de ISO. Se monitorearon la frecuencia cardíaca (FC) y los cambios en el ECG. Se analizaron algunos marcadores de estrés oxidativo como la superóxido dismutasa (SOD), el óxido nítrico (NOx), el malondialdehído (MDA) y los niveles tisulares de glutatión (GSH) en el homogeneizado de tejido. La interleucina-6 (IL-6), el factor de necrosis tumoral-α (TNF-α), la caspasa-8, la P53 y la proteína C reactiva (CRP) se encontraban entre los marcadores inflamatorios examinados. Se analizaron los niveles de creatinoquinasa (CK-MB) y lactato deshidrogenasa (LDH) para evaluar la lesión miocárdica; para el análisis histológico se seccionaron los tejidos, se fijaron en parafina y se tiñeron con hematoxilina y eosina (H&E), Tricromo de Masson e inmunohistoquímica contra NF-kB, TNF-α y Caspasa-9. IL-37 mejoró los cambios de ECG, los marcadores de enzimas cardíacas y algunos marcadores inflamatorios de estrés oxidativo en el IM inducido por ISO. Además mejoró los cambios histopatológicos e inmunohistoquímicos en MI. En conclusión: la IL-37 podría ser una modalidad terapéutica prometedora en el infarto de miocardio.
Subject(s)
Animals , Male , Rats , Interleukins/administration & dosage , Heart/drug effects , Myocardial Infarction/chemically induced , Myocardial Infarction/prevention & control , Immunohistochemistry , Rats, Wistar , Oxidative Stress/drug effects , Inflammation , Isoproterenol/adverse effectsABSTRACT
SUMMARY: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent a unique class of glucose-declining renal-targeted drugs. The SGLT2i Canagliflozin (CANA) is an anti-hyperglycemic drug that reduces various cardiovascular and renal outcomes in patients with type 2 diabetes mellitus. This study aimed to explore the potential effects of CANA on the isolated healthy adult rat hearts to show if CANA has positive inotropic or cardiac depressant effects via analyzing the amplitude and frequency of cardiac contractions. In isolated normal adult rat hearts, the effects of CANA on cardiac contractility were examined. In a dose-response curve, CANA led to a significant cardiac depressant effect in a dose-dependent manner. This cardiac depressant effect of CANA (10-6 M) was not prevented by atropine. However, this cardiac depressant effect was partially antagonized by both Isoproterenol (10-5 M) and Calcium chloride (10-6 M), suggesting beta-adrenoceptor and calcium channel blocking actions. In addition, the cardiac depressant effect of CANA (10-6 M) was mitigated in part by Nitric oxide synthase inhibitor, L-NAME, suggesting that its action probably depends to some extent on the accumulation of nitric oxide, which decreases the rise of intracellular Calcium. Data from this study demonstrate that CANA has a significant cardiac relaxant effect in isolated hearts of healthy adult rats by different possible mechanisms. This inhibitory effect on cardiac contractility may help improve the diastolic ventricular filling providing a therapeutic potential to help the other cardioprotective mechanisms of CANA in the prevention and treatment of heart failure.
RESUMEN: Los inhibidores del cotransportador de sodio- glucosa 2 (SGLT2i) representan una clase única de fármacos dirigidos a los riñones que disminuyen la glucosa. El SGLT2i Canagliflozin (CANA) es un fármaco antihiperglucémico que reduce varios resultados cardiovasculares y renales en pacientes con diabetes mellitus tipo 2. Este estudio tuvo como objetivo explorar los efectos potenciales de CANA en corazones aislados de ratas adultas sanas para indicar si CANA tiene efectos inotrópicos o depresores cardíacos positivos mediante el análisis de la amplitud y la frecuencia de las contracciones cardíacas. En corazones aislados de ratas adultas normales, se examinaron los efectos de CANA sobre la contractilidad cardíaca. En una curva de dosis-respuesta, CANA condujo a un efecto depresor cardíaco significativo de manera dependiente de la dosis. Este efecto depresor cardíaco de CANA (10-6 M) no fue impedido por la atropina. Sin embargo, este efecto depresor cardíaco fue parcialmente antagonizado tanto por el isoproterenol (10-5 M) como por el cloruro de calcio (10-6 M), lo que sugiere acciones bloqueadoras de los receptores beta adrenérgicos y de los canales de calcio. Además, el efecto depresor cardíaco de CANA (10-6 M) fue mitigado en parte por el inhibidor de la sintasa de óxido nítrico, L-NAME, lo que sugiere que su acción probablemente depende en cierta medida de la acumulación de óxido nítrico, lo que disminuye el aumento de calcio intracelular. Los datos de este estudio demuestran que CANA tiene un efecto relajante cardíaco significativo en corazones aislados de ratas adultas sanas por diferentes mecanismos posibles. Este efecto inhibitorio sobre la contractilidad cardíaca puede ayudar a mejorar el llenado ventricular diastólico proporcionando un potencial terapéutico para ayudar a los otros mecanismos cardioprotectores de CANA en la prevención y tratamiento de la insuficiencia cardíaca.
Subject(s)
Animals , Male , Rats , Canagliflozin/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Heart/drug effects , Myocardial Contraction/drug effects , Rats, Wistar , NG-Nitroarginine Methyl EsterABSTRACT
Doxorubicin (DOX)-induced nephropathy hampered its antineoplastic efficiency. The objective of the current work is to assess the prospective ameliorating effects of meloxicam versus vitamin D3 (Vit D3, cholecalciferol) against progressive DOX-induced nephropathy in rats trying to ascertain the possible mechanism underlying such amelioration. Ninety Male Wistar rats were randomly distributed to five experimental groups for 3 weeks, with saline, meloxicam (daily), DOX (single dose), Vit D3+DOX, or both meloxicam and DOX. We measured levels of urinary protein, serum creatinine, malondialdehyde (MDA) and renal reduced glutathione (GSH). In addition, tumor necrosis factor-alpha (TNF-α) expression and renal histopathology were assessed. Meloxicam alone treated group revealed no significant difference in urinary protein and serum creatinine. It also presented non-significant reduction in the MDA content while an increase in the reduced GSH content in contrast to the control group, which is more evident after the first week. Renal sections of rats received meloxicam only showed no significant histological changes and negative immunoreactivity compared to the control group. DOX induced a significant increase in urinary protein, serum creatinine, decrease reduced GSH, increased renal MDA and disrupted renal morphometric parameters and histology with increased TNF-α expression. Combination groups of Vit D3+DOX and meloxicam+DOX showed improvement of all DOX disturbed parameters. Meloxicam showed better results most likely due to anti-inflammatory and antioxidant activities superimposing the immune-modulatory effect of Vit D3. So, it is recommended to use meloxicam in patients receiving DOX as a renoprotective agent in addition to its analgesic effects required by cancer patients.
ABSTRACT
Doxorubicin (DOX)-induced nephropathy hampered its antineoplastic efficiency. The objective of the current work is to assess the prospective ameliorating effects of meloxicam versus vitamin D3 (Vit D3, cholecalciferol) against progressive DOX-induced nephropathy in rats trying to ascertain the possible mechanism underlying such amelioration. Ninety Male Wistar rats were randomly distributed to five experimental groups for 3 weeks, with saline, meloxicam (daily), DOX (single dose), Vit D3+DOX, or both meloxicam and DOX. We measured levels of urinary protein, serum creatinine, malondialdehyde (MDA) and renal reduced glutathione (GSH). In addition, tumor necrosis factor-alpha (TNF-α) expression and renal histopathology were assessed. Meloxicam alone treated group revealed no significant difference in urinary protein and serum creatinine. It also presented non-significant reduction in the MDA content while an increase in the reduced GSH content in contrast to the control group, which is more evident after the first week. Renal sections of rats received meloxicam only showed no significant histological changes and negative immunoreactivity compared to the control group. DOX induced a significant increase in urinary protein, serum creatinine, decrease reduced GSH, increased renal MDA and disrupted renal morphometric parameters and histology with increased TNF-α expression. Combination groups of Vit D3+DOX and meloxicam+DOX showed improvement of all DOX disturbed parameters. Meloxicam showed better results most likely due to anti-inflammatory and antioxidant activities superimposing the immune-modulatory effect of Vit D3. So, it is recommended to use meloxicam in patients receiving DOX as a renoprotective agent in addition to its analgesic effects required by cancer patients.
ABSTRACT
Desmosomes are intercellular junctions that provide strong adhesion between epidermal keratinocytes. This function is rapidly modulated from calcium independent to calcium dependent upon wounding of an epithelial cell sheet. This modulation was found to be signaled by an isoenzyme named protein kinase C alpha [PKC alpha] which alters the adhesive state of desmosomes at the wound edges. Specimens from intact and wounded mice skin were taken and prepared for immunohistochemical studies and the immune reactions of both desmosomes and PKC alpha were examined, recorded and discussed. It is hypothesized that wounding triggers a stimulus that activates PKC alpha which through a phosphorylation of certain desmosomal proteins modulates desmosomal adhesion. This breaks intercellular contacts enabling keratinocytes to migrate and reepithelialize the wound