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This study aimed to evaluate the cardioprotective effects of ghrelin in septic mice, focusing on its anti-inflammatory and antioxidant properties. Thirty-five male Swiss mice (8-12 weeks old, 23-33g) were randomly assigned to five groups (n = 7 each): (1) Normal, fed usual diets, (2) Sham, subjected to anesthesia and laparotomy, (3) Sepsis, subjected to cecal ligation and puncture, (4) Vehicle, given an equivalent volume of intraperitoneal saline injections immediately after cecal ligation and puncture, and (5) Ghrelin-treated, administered 80 µg/kg ghrelin intraperitoneal injections immediately following cecal ligation and puncture. Serum levels of tumor necrosis factor-alpha (TNF-α), macrophage migration inhibitory factor (MIF), toll-like receptor 4 (TLR4), and 8-epi-prostaglandin F2 alpha (8-epi-PGF2α) were measured. The extent of cardiac damage was also evaluated histologically. The mean serum levels of TNF-α, MIF, TLR4, and 8-epi-PGF2α levels were significantly higher in the sepsis and vehicle groups than in the normal and sham groups. The levels were significantly lower in the ghrelin-treated group than in the vehicle and sepsis groups. Histological analysis revealed normal myocardial architecture in the normal and sham groups, whereas the sepsis and vehicle groups had severe myocardial injury. The ghrelin-treated group displayed histological features similar to the sham group, indicating reduced myocardial damage. Ghrelin ameliorated sepsis-induced cardiotoxicity in mice by exhibiting strong anti-inflammatory and antioxidant effects. These findings suggest that ghrelin may be a promising therapeutic candidate for the prevention of sepsis-induced cardiotoxicity.
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Cardiotónicos , Endotoxemia , Ghrelina , Factor de Necrosis Tumoral alfa , Animales , Ratones , Masculino , Ghrelina/sangre , Endotoxemia/sangre , Endotoxemia/tratamiento farmacológico , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Factor de Necrosis Tumoral alfa/sangre , Receptor Toll-Like 4/metabolismo , Modelos Animales de Enfermedad , Dinoprost/análogos & derivados , Dinoprost/sangre , Factores Inhibidores de la Migración de Macrófagos/sangre , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Antioxidantes/farmacologíaRESUMEN
OBJECTIVE: Aim: The study aims to investigate the effect of solute carriers organic anions transporters 1B1 (SLCO1B1) gene polymorphisms rs4149056, rs2306283, rs55901008, and rs729559745 in a sample of patients with dyslipidemia, and relate it to atorvastatin response and associated myopathy. PATIENTS AND METHODS: Materials and Methods: A cross sectional enrolled 200 patients both males and females of Arabic race, Iraqi nationality aged between 30-65 years. The patients were divided into two groups: Group 1 (Atorvastatin responders and tolerant), Group 2 (Atorvastatin non responder and intolerant). Blood samples collected from the patients for biochemical studies and analyzed statistically by Student T-test and Chi-square, and DNA extracted for polymerase chains reactions (PCR). RESULTS: Results: The results showed insignificant association P≥0.05 between the demographic characteristics of the study population with different genotypes, and significant difference P<0.05 in the biochemical parameters regarding (T-cholesterol, triglycerides, low density lipoproteins, and Creatine kinase-MM) when comparing the two groups. Odds ratio (OR) with confidence intervals CI (95%) used to evaluate the risk association to develop myopathy and poor response to atorvastatin therapy show relevant association for CC and CT genotype of rs4149056, while rs2306283 GG genotype show low association, also rs55901008 show low association for CC genotype, and moderate association for rs72559745 genotypes GG, AG. CONCLUSION: Conclusions: The mutant allele's genotypes of rs4149056, rs55901008, and rs72559745, and the wild allele genotype of rs2306283 show significant association with the development of poor response to atorvastatin and elevated the level of CK-MM plasma concentration.
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Dislipidemias , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Enfermedades Musculares , Transportadores de Anión Orgánico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atorvastatina/efectos adversos , Estudios Transversales , Dislipidemias/tratamiento farmacológico , Dislipidemias/genética , Genotipo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Irak , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/genética , Enfermedades Musculares/epidemiología , Transportadores de Anión Orgánico/genética , Polimorfismo GenéticoRESUMEN
This study examined the reno-protective potential of Compound 21 during renal ischemia-reperfusion injury by regulating the PI3K expression. 20 adult male Swiss-albino mice, aged 8-12 weeks and weighing 20-30g, were randomly assigned to four equal groups: sham, control, vehicle, and Compound 21. Serum urea, creatinine, inflammatory mediators, tissue 8-isoprostane, and myeloperoxidase were quantified using ELISA. Compared to the sham group, blood levels of urea, creatinine, TNF-α, IL-6, and IL-10 were significantly higher in the ischemia-reperfusion group than in the sham group (p<0.05). However, these indicators were significantly lower in the Compound 21 group (p<0.05). Histological analysis revealed significant renal tissue damage in the ischemia-reperfusion group (p<0.05), which was significantly reduced in the Compound 21 group (p<0.05). PCR results showed that PI3K expression was significantly lower (p<0.05) in the control group compared to the sham group but significantly higher in the Compound 21 group (p<0.05). Furthermore, P-AKT expression levels in the control group were considerably lower than in the sham group (p<0.05). On the other hand, the level of P-AKT expression in the Compound 21 group was significantly upregulated compared to the control group (p<0.05). The findings revealed that Compound 21 could mitigate renal dysfunction induced by ischemia-reperfusion injury in male mice through modulation of the PI3K/AKT signaling pathway, resulting in decreased levels of pro-inflammatory cytokines and renal oxidative stress markers.
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Receptor de Angiotensina Tipo 2 , Daño por Reperfusión , Animales , Masculino , Ratones , Creatinina , Isquemia , Riñón , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor de Angiotensina Tipo 2/agonistas , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Daño por Reperfusión/patología , Urea/sangreRESUMEN
This study aimed to investigate the potential of nebivolol in preventing doxorubicin-induced cardiotoxicity by targeting the inflammatory, oxidative, and apoptotic pathways. Twenty-eight male rats were randomly divided into four groups, each consisting of seven rats. The control group received standard diets and unrestricted access to water. The rats in the normal saline (N/S) group were administered a 0.9% normal saline solution for two weeks. The doxorubicin group (the "induced group") received doxorubicin at a dosage of 2.5 mg/kg three times per week for two weeks. The nebivolol group received an oral dose of 4 mg/kg of nebivolol for the same duration. The cardiac tissues of rats treated with doxorubicin exhibited increased levels of tumor necrosis factor, interleukin-1, malondialdehyde, and caspase-3 compared to the normal saline control group (p<0.05), along with decreased levels of total antioxidant capacity and Bcl-2. These results show that doxorubicin is harmful to the heart. The administration of nebivolol significantly reduced the cardiotoxic effects induced by doxorubicin, as indicated by a statistically significant decrease in the levels of inflammatory markers, specifically tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) (p<0.05). The nebivolol group exhibited a significant decrease in malondialdehyde levels, which serves as a signal of oxidation, in cardiac tissue compared to the doxorubicin-only group (p<0.05). Additionally, the nebivolol group showed a significant increase in overall antioxidant capacity. Nebivolol dramatically attenuated doxorubicin-induced cardiotoxicity in rats, likely by interfering with oxidative stress, the inflammatory response, and the apoptotic pathway.
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Antioxidantes , Cardiotoxicidad , Masculino , Ratas , Animales , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/etiología , Cardiotoxicidad/prevención & control , Antioxidantes/metabolismo , Nebivolol/farmacología , Nebivolol/uso terapéutico , Solución Salina/farmacología , Solución Salina/uso terapéutico , Doxorrubicina/toxicidad , Estrés Oxidativo , Factor de Necrosis Tumoral alfa/metabolismo , Malondialdehído/metabolismo , ApoptosisRESUMEN
Renal ischemia-reperfusion injury is caused by a temporary reduction in oxygen-carrying blood flow to the kidney, followed by reperfusion. During ischemia, kidney tissue damage induces overproduction of reactive oxygen species, which produces oxidative stress. The blood flow restoration during the reperfusion period causes further production of reactive oxygen species that ends with apoptosis and cell death. This study aimed to investigate the potential renoprotective effects of Raloxifene on bilateral renal ischemia-reperfusion injury in rats by looking into kidney function biomarkers, urea and creatinine, inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß). Additionally, antioxidant markers such as total antioxidant capacity (TAC) and the pro-apoptotic marker caspase-3 were assessed. Histopathological scores were also employed for evaluation. Our experimental design involved 20 rats divided into four groups: the sham group underwent median laparotomy without ischemia induction, the control group experienced bilateral renal ischemia for 30 minutes followed by 2 hours of reperfusion, the vehicle group received pretreatment with a mixture of corn oil and dimethyl sulfoxide (DMSO) before ischemia induction, and the Raloxifene-treated group was administered Raloxifene at a dose of 10 mg/kg before ischemia induction, followed by ischemia-reperfusion. Urea and creatinine, TNF-α, IL-1ß, and caspase-3 in the Raloxifene group were significantly lower compared to the control and vehicle groups. On the other hand, TAC levels in the Raloxifene group were significantly higher than in the control and vehicle groups. This study concluded that Raloxifene had a renoprotective impact via multiple actions as an anti-inflammatory, anti-apoptotic, and antioxidant agent.
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Enfermedades Renales , Daño por Reperfusión , Ratas , Masculino , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antioxidantes/metabolismo , Caspasa 3/metabolismo , Caspasa 3/farmacología , Caspasa 3/uso terapéutico , Clorhidrato de Raloxifeno/farmacología , Clorhidrato de Raloxifeno/uso terapéutico , Clorhidrato de Raloxifeno/metabolismo , Especies Reactivas de Oxígeno , Factor de Necrosis Tumoral alfa , Creatinina , Riñón , Estrés Oxidativo , Enfermedades Renales/patología , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Daño por Reperfusión/metabolismo , Urea/metabolismo , Urea/farmacología , Urea/uso terapéutico , IsquemiaRESUMEN
Trastuzumab is a successful treatment option for HER2-positive breast cancer, but a decline in left ventricular ejection fraction (LVEF) and an increase in inflammatory and cardiac enzyme biomarkers can lead to cessation and termination of therapy. This study aimed to investigate the ability of Coenzyme Q10 (Coq10) to avoid these adverse effects. The study included 100 female patients with HER2+ (HER2+3 or amplified gene) breast cancer. All patients underwent standard adjuvant chemotherapy regimens, which involved a four-cycle treatment of Adriamycin, Cyclophosphamide, Docetaxel, and an initial 8 mg/kg loading dose of trastuzumab, followed by a year of 6 mg/kg maintenance doses every three weeks. One group of 50 patients received trastuzumab and a placebo, while the other 50 were given trastuzumab and CoQ10 for a full year. The CoQ10-treated group exhibited a statistically significant decrease in levels of monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL6), soluble toll-like receptor 4 (sTLR4), and cardiac troponin I (cTnI) compared to the control group (p<0.05). However, there was no significant difference in the mean F2-isoprostane levels between the treated and the control groups at any data collection point. Furthermore, the CoQ10-treated group experienced a significant reduction in the decline of EF levels compared to the control group at all stages except for baseline. According to our findings, Coenzyme Q10 protected patients with HER2+3 breast cancer from the cardiotoxicity of trastuzumab by increasing ejection fraction and decreasing inflammatory biomarkers and cardiac enzyme levels.
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Neoplasias de la Mama , Humanos , Femenino , Trastuzumab/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Cardiotoxicidad/etiología , Cardiotoxicidad/prevención & control , Cardiotoxicidad/tratamiento farmacológico , Volumen Sistólico , Receptor ErbB-2 , Anticuerpos Monoclonales Humanizados/efectos adversos , Función Ventricular Izquierda , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Atherosclerosis, a long-term inflammatory and immune condition affecting medium- and large-sized arteries, results in the thickening of artery walls and the accumulation of inflammatory cells and fatty streaks that establish fibrous capsules with macrophages at the site of injury. Atherosclerosis has a major impact on the pathogenesis of cardiovascular diseases. Oridonin has been shown to exclusively inhibit the NLRP3 inflammasome without affecting the activation of AIM-2 or NLRC-4 inflammasomes. The current study aimed to evaluate how adding Oridonin to a diet impacts the onset of atherosclerosis. Twenty-one male rabbits weighing 1.5 to 2.0 kg were included in the study. The rabbits were kept in controlled environmental conditions and divided into three groups: a normal control group fed a conventional chow diet, an atherogenic control group fed a high-cholesterol diet (2% cholesterol-rich), and an Oridonin-treated group (Ori) fed an atherogenic diet supplemented with Oridonin (20 mg/kg) administered orally once daily. Compared to animals on a normal diet, an atherogenic diet was associated with a statistically significant (p=0.001) increase in the mean expression of the NLRP3 inflammasome mRNA. The Oridonin-treated group showed a statistically significant (p=0.001) decline in the mean expression of NLRP3 inflammasome mRNA compared to the atherogenic group. Furthermore, the initial atherosclerotic lesion in the group treated with Oridonin was statistically (p=0.001) less severe compared to the atherogenic group. Finally, Ori treated group had significantly (p≤0.001) lower IL-1B immunostaining intensity than the atherogenic group (mean rank 14.5,25 respectively). The study concluded that Oridonin supplementation resulted in less severe initial atherosclerotic lesions, likely due to the suppression of NLRP3 inflammasome and the anti-inflammatory effect through the downregulation of IL1B expression.
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Aterosclerosis , Inflamasomas , Animales , Masculino , Conejos , Inflamasomas/genética , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Aterosclerosis/tratamiento farmacológico , Colesterol/metabolismo , Colesterol/farmacología , ARN Mensajero/metabolismoRESUMEN
Sepsis, a life-threatening condition arising from infection, often results in multi-organ failure, including cardiac dysfunction. This study investigated Xanthohumol, a natural compound, and its potential mechanism of action to enhance heart function following sepsis. A total of twenty-four adult male Swiss albino mice were allocated randomly to one of four equal groups (n=6): sham, CLP, vehicle Xanthohumol the same amount of DMSO injected IP 10 minutes before the CLP, and Xanthohumol group (0.4 mg/kg of Xanthohumol administered IP before the CLP process). Toll-like receptor 4, pro-inflammatory mediators, anti-inflammatory markers, oxidative stress indicators, apoptosis markers, and serum cardiac damage biomarkers were measured in the cardiac tissue using ELISA. Data with normal distribution were analyzed using t-test and ANOVA tests (p<0.05). In comparison to the sham group, the sepsis group had significantly higher levels of TLR-4, IL-6, TNF-α, MIF, F2-isoprostane, caspase-3, cTn-I, and CK-MB, while the pre-treated group with Xanthohumol had significantly lower levels (p<0.05) of these markers than the sepsis group. Bcl-2 showed no significant difference in Xanthohumol pre-treated group relative to the sepsis group, while IL-10 was significantly elevated. Xanthohumol dramatically reduced cardiac tissue injury (p<0.05) relative to the CLP group. By blocking the downstream signal transduction pathways of TLR-4 and NF-kB, Xanthohumol was shown to lessen cardiac damage in male mice during CLP-induced polymicrobial sepsis.
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Sepsis , Receptor Toll-Like 4 , Ratones , Masculino , Animales , Receptor Toll-Like 4/metabolismo , Transducción de Señal , FN-kappa B/metabolismo , Sepsis/complicaciones , Sepsis/tratamiento farmacológicoRESUMEN
As sepsis is associated with a 50% increase in mortality, sepsis-induced cardiomyopathy has become a critical topic. A multidisciplinary approach is required for the diagnosis and treatment of septic cardiomyopathy. This study looked at Sulforaphane, a natural product that aims to evaluate cardiac function after sepsis, and its likely mechanism of action. Twenty-four adult male Swiss albino mice were randomly divided into 4 equal groups (n=6): sham, CLP, vehicle Sulforaphane (the same amount of DMSO injected IP one hour before the CLP), and Sulforaphane group (one hour before the CLP, a 5mg/kg dose of Sulforaphane was injected). Cardiac tissue levels of toll-like receptor 4 (TLR-4), pro-inflammatory mediators, anti-inflammatory markers, oxidative stress markers, apoptosis markers, and serum cardiac damage biomarkers were assessed using ELISA. Statistical analyses, including t-tests and ANOVA tests, were performed with a significance level of 0.05 for normally distributed data. Compared to the sham group, the sepsis group had significantly elevated levels of TLR-4, IL-6, TNF-α, MIF, F2-isoprostane, caspase-3, cTn-I, and CK-MB (p<0.05). In contrast, the Sulforaphane pre-treated group demonstrated significantly lower levels of these markers (p<0.05). Additionally, Bcl-2 levels were significantly reduced (p<0.05) in the Sulforaphane group. Sulforaphane administration also significantly attenuated cardiac tissue injury (p<0.05). The findings suggest that Sulforaphane can decrease heart damage in male mice during CLP-induced polymicrobial sepsis by suppressing TLR-4/NF-kB downstream signal transduction pathways.
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Cardiomiopatías , Lesiones Cardíacas , Sepsis , Ratones , Masculino , Animales , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/uso terapéutico , Cardiomiopatías/etiología , Cardiomiopatías/complicaciones , Lesiones Cardíacas/complicaciones , Sepsis/complicaciones , Sepsis/tratamiento farmacológicoRESUMEN
Renal ischemia-reperfusion injury is a critical clinical condition with a potentially fatal prognosis if not adequately managed. NHWD-870, a known Brd4 inhibitor with anti-cancer properties, exhibits additional attributes such as antioxidant, anti-inflammatory, and anti-apoptotic effects, suggesting its potential to preserve renal tissue and mitigate damage during ischemic insults. We aimed to assess the potential nephroprotective effect of NHWD-870 by investigating its anti-apoptotic, anti-inflammatory, and antioxidant properties in a rat model of renal ischemia-reperfusion injury. Male Wistar Albino rats (n=24) were randomly assigned to four groups: sham, control, vehicle, and NHWD-870. The control group experienced bilateral renal ischemia for 30 minutes, followed by 2 hours of reperfusion, while the sham group underwent a laparotomy without ischemia-reperfusion induction. The vehicle group received a DMSO injection, and the NHWD-870 group was administered 3mg/kg NHWD-870 orally 24 hours before repeating the control group protocol. Blood samples were collected after reperfusion for blood urea nitrogen (BUN) and serum creatinine (SCr) analysis. ELISA method was used to assess IL-1B, BCL-2, PGF-2, and PI3K/AKT signaling pathways in renal tissue. Tubular injury severity was evaluated through histopathological analysis. NHWD-870 treatment improved renal function and histological preservation compared to the control and vehicle groups. BUN, sCR, IL-1B, BCL-2, and PGF-2 levels in renal tissue were significantly improved in the NHWD-870 group (p<0.05). Furthermore, the PI3K/AKT signaling pathway was significantly upregulated (p<0.01), and tubular injury severity was reduced in the NHWD-870 group. NHWD-870 demonstrated substantial nephroprotective effects in reducing renal damage induced by ischemia-reperfusion injury in rats. These effects may be attributed to the anti-apoptotic properties, as indicated by increased levels of the anti-apoptotic protein Bcl-2, and the reduction in oxidative stress marker PGF-2 through upregulation of the PI3K/AKT signaling pathway, along with the decrease in the inflammatory marker IL-1B.
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Fosfatidilinositol 3-Quinasas , Daño por Reperfusión , Masculino , Animales , Ratas , Ratas Wistar , Proteínas Proto-Oncogénicas c-akt , Antioxidantes , Proteínas Nucleares , Factores de Transcripción , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Riñón/fisiología , Transducción de SeñalRESUMEN
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. This study aimed to investigate the potential protective effect of the lungs in sepsis by modulating inflammatory and oxidative stress markers. Twenty-four adult male Swiss-albino mice, aged 8-12 weeks and weighing 20-30 g, were divided into four equal groups (n=6): sham (laparotomy only), CLP (laparotomy plus cecal ligation and puncture), vehicle (DMSO administered one hour before CLP), and Ticagrelor (50 mg/kg IP administered one hour before CLP). Tissue levels of pro-inflammatory and oxidative stress markers in the lung were assessed using ELISA. F2 isoprostane levels were significantly higher in the sepsis group (p<0.05) compared to the sham group, while Ticagrelor significantly decreased the inflammatory and oxidative stress markers compared to the sepsis group. All mice in the sepsis group had considerable (p=0.05) lung tissue damage, but Ticagrelor considerably decreased lung tissue injury (p=0.05). Furthermore, Ticagrelor was found to reduce tissue cytokine levels of the lung (IL-1, TNF a, IL-6, F2 isoprostane, GPR 17, MIF) in male mice during CLP-induced polymicrobial sepsis by modulation of pro-inflammatory and oxidative stress cascade signaling pathways.
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Endotoxemia , Sepsis , Masculino , Animales , Ratones , Endotoxemia/tratamiento farmacológico , F2-Isoprostanos , Ticagrelor/farmacología , Ticagrelor/uso terapéutico , PulmónRESUMEN
Ischemia-reperfusion injury (IRI) is a major contributor to acute and chronic kidney failure, heart failure, and ischemic stroke. This study aimed to investigate the therapeutic potential of Iberin, known for its anti-inflammatory, antioxidant, and antiapoptotic properties, in a rat model of renal IRI. Twenty-four adult male rats were randomly divided into four groups: Group I (Sham group) underwent laparotomy without IRI induction; Group II (Control group) underwent laparotomy followed by renal artery clamping for 30 minutes to induce ischemia, followed by 2 hours of reperfusion; Group III (Iberin treatment group) received a pre-injection of Iberin (15 mg/kg) and underwent 30 minutes of ischemia followed by 2 hours of reperfusion; and Group IV (Vehicle-treated group) received the vehicle (ethanol) 1 hour prior to ischemia and reperfusion induction. Iberin was diluted with ethanol. Biomarkers associated with inflammation, oxidative stress, and apoptosis were measured using enzyme-linked immunosorbent assay. Iberin treatment significantly reduced levels of inflammatory cytokines interleukin-1ß (IL-1ß) and IL-6, Bcl-2-associated X protein (BAX), tumor necrosis factor α (TNF-α), nuclear factor kappa p56, high mobility group B1, and neutrophil gelatinase-associated lipocalin. Moreover, Iberin increased levels of heat shock protein and Bcl2 compared to the control and vehicle groups. Iberin treatment prolonged the ischemic tolerance of renal tissue, potentially preventing or delaying irreversible injuries. These findings highlight the potential of Iberin as a promising candidate for mitigating renal injury caused by ischemia-reperfusion, due to its ability to modulate inflammatory markers.
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Fallo Renal Crónico , Daño por Reperfusión , Masculino , Animales , Ratas , Daño por Reperfusión/tratamiento farmacológico , Riñón , IsotiocianatosRESUMEN
OBJECTIVE: The aim: To evaluate the potential protective effect of Eprosartan (ARB) in bilateral renal IRI in male rats. PATIENTS AND METHODS: Materials and methods: 20 Sprague-Dawley rats divided into four groups. Sham group had surgery without IRI. Control group was subjected to 30 min ischemia and 2 hours of reperfusion. Vehicle group received 14 ml/kg (IP) injection of solvent mixture containing (10% DMSO, 40% PEG300, 5% Tween-80, and 45% normal saline) 30 minutes before clamping. Eprosartan-treated group with 30 mg/kg Eprosartan intraperitoneally 30 min before occlusion of renal pedicles followed by 30 minutes of ischemia and 2 hours of reperfusion. Serum BUN and Creatinine used to assess renal function. Renal tissue was used to measure the levels of TNF-α, IL-1ß, IL-6, F2-isoprostane, and Caspase3 were measured by assessment of renal tissue. Histopathological examinations were conducted to detect parenchymal damage. RESULTS: Results: Mean serum levels of BUN and Creatinine as well as mean renal tissue levels of TNF-α, IL-1ß, IL-6, F2-isoprostane, and Caspase3 were significantly increased in control and vehicle groups together with increase in histological damage score compared to sham group, whereas treatment of rats with Eprosartan resulted in significant reduction in mean serum levels of BUN and Creatinine and mean renal tissue levels of TNF-α, IL-1ß, IL-6, F2-isoprostane, and Caspase3 and obvious reduction in tissue injury. CONCLUSION: Conclusions: This study demonstrates that Eprosartan pretreatment enhances kidney function by decreasing serum BUN and Creatinine, oxidative stress, cytokines, and apoptotic markers.
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Antagonistas de Receptores de Angiotensina , Daño por Reperfusión , Masculino , Ratas , Animales , Ratas Sprague-Dawley , Creatinina , F2-Isoprostanos , Interleucina-6 , Factor de Necrosis Tumoral alfa , Inhibidores de la Enzima Convertidora de Angiotensina , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Inflamación , Estrés OxidativoRESUMEN
OBJECTIVE: The aim: To evaluate the effect of Necrostatin-1s (Nec-1s), an inhibitor of necroptosis, on acute Dox-induced cardiotoxicity in a mice model. PATIENTS AND METHODS: Materials and methods: Fifteen male mice were used. The animals were allocated into three groups. On the third day of the experiment, a single intraper¬itoneal dose of 20 mg/kg Dox was used to induce cardiotoxicity. Mice in the control group were given vehicle (DMSO) intraperitoneally, whereas mice in the third group were given 5 mg/kg Nec-1s two days before Dox treatment and continued for a total of five days. Animals were euthanized at the conclusion of the research. ELISA was used to assess the following parameters: cTnI, TNF-α, IL-1ß, GPX-4, and Hmox-1. The expression of TNF-R1 and phosphorylated NF-κß p65 was measured using immunohistochemistry. In addition, a histopathologic evaluation of the cardiac lesions was conducted. RESULTS: Results: Our results showed that Dox treatment substantially elevated serum cTnI levels, increased tissue inflammatory biomarkers (TNF-α, IL-1ß, phospho NF-κß p65 and TNF-R1), and reduced tissue antioxidant enzymes (GPX-4, Hmox-1). A histopathological analysis showed pronounced necrosis and vacuolization. These results were drastically changed by pretreatment with Nec-1s, with serum cTnI levels in this group being much lower than in the Dox group. In addition to a significant decrease in inflammatory markers, antioxidant enzymes were partially recovered. Moreover, there was preservation of the cardiac morphology to a level that was roughly normal. CONCLUSION: Conclusions: Our findings demonstrate that pretreatment with Nec-1s protected against acute Dox-induced cardiotoxicity. This cardioprotective effect was mainly due to amelioration of inflammation that reflected by inhibition of NF-κß/TNF-α/TNF-R1 pathway, with partial restoration of antioxidant enzymes, GPX-4 and Hmox1.
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Antioxidantes , Cardiotoxicidad , Masculino , Animales , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/etiología , Cardiotoxicidad/prevención & control , Receptores Tipo I de Factores de Necrosis Tumoral , Factor de Necrosis Tumoral alfa , Modelos Animales de Enfermedad , Doxorrubicina/efectos adversosRESUMEN
This study aimed to investigate the effects of JQ1 in a renal ischemia-reperfusion (IR) rat model. Twenty-four adult male Wistar Albino rats were randomly divided into four equal groups. The sham group underwent laparotomy without ischemia-reperfusion induction. The control group experienced bilateral renal ischemia for 30 minutes, followed by a 2-hour reperfusion period. The vehicle group (IR group + DMSO) and JQ1 group (same as in control IR + 25 mg/kg JQ1). Kidney and blood samples were collected 2 hours after reperfusion. Blood samples were used to analyze serum creatinine and blood urea nitrogen levels. Renal tissue was assessed for TNF-alpha, caspase-3, FOXO4, PI3K/AKT signaling pathway, and histological analysis. The control group exhibited significantly higher serum creatinine, blood urea nitrogen, caspase-3, TNF-alpha, and FOXO4 levels in renal tissue compared to the sham group. Additionally, the PI3K/AKT signaling pathway was significantly decreased in the control group. Histopathological examination revealed severe kidney damage in the control group compared to the sham group. In rats treated with JQ1, serum creatinine, BUN, caspase-3, TNF-alpha, and FOXO4 levels in renal tissue significantly improved. The PI3K/AKT signaling pathway was substantially increased (p-value 0.01) compared to the Vehicle and Control groups. The tubular severity score was also significantly reduced in the JQ1-treated groups compared to the Control and Vehicle groups. In conclusion, JQ1 significantly ameliorated renal ischemia-reperfusion injury in rats by suppressing apoptosis and inflammatory pathways.
Asunto(s)
Proteínas Proto-Oncogénicas c-akt , Daño por Reperfusión , Ratas , Masculino , Animales , Ratas Sprague-Dawley , Caspasa 3/metabolismo , Caspasa 3/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Creatinina , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/farmacología , Ratas Wistar , Riñón , Estrés Oxidativo , Isquemia , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Factores de Transcripción Forkhead/metabolismoRESUMEN
Evolocumab, a PCSK-9 inhibitor, is known for its ability to reduce low-density lipoprotein cholesterol (LDL-C). This study aimed to investigate the effects of evolocumab, alone or in combination with atorvastatin, on the progression of atherosclerosis. Fifty male domestic rabbits were randomly assigned to five groups: control, high cholesterol diet, evolocumab vehicle (dimethyl sulfoxide, DMSO), evolocumab alone, and evolocumab plus atorvastatin. Serum levels of interleukin 10 (IL-10), IL-17, IL-1ß, intracellular adhesion molecule (ICAM), and vascular adhesion molecule (VCAM) were measured. Toll-like receptor (TLR) expression on monocytes was evaluated using flow cytometry. Histopathological examination and measurement of intimal thickness (IT) were also conducted. The results revealed that the evolocumab produced a statistically significant (p<0.05) reduction in lipid profile at 5 weeks, with the peak effect occurring at 10 weeks. Furthermore, the inhibitor reduced TLRs at 10 weeks to 10.83±1.8 and intimal thickness to 160.66±9.45. IL-17, IL-1ß, ICAM, and VCAM were significantly reduced by evolocumab treatment, with the improvement of the histopathological changes in the aortic wall. The combination of evolocumab and atorvastatin caused a more statistically significant reduction in TLRs at 10 weeks to 5.08±1.2 and intimal thickness to 121.79±5.3. IL-17, IL-1ß, ICAM, and VCAM were significantly (p<0.05) reduced by the combination, and the histopathological changes in the aortic wall were significantly improved. In conclusion, evolocumab delays the progression of atherosclerosis by modulating inflammatory pathways.
Asunto(s)
Aterosclerosis , Interleucina-17 , Animales , Masculino , Conejos , Atorvastatina/farmacología , Atorvastatina/uso terapéutico , Aterosclerosis/tratamiento farmacológico , LDL-Colesterol , Resultado del TratamientoRESUMEN
Ischemia/reperfusion injury (IRI) is a common cause of kidney damage, characterized by oxidative stress and inflammation. In this study, we investigated the potential protective effects of IAXO-102, a chemical compound, on experimentally induced IRI in male rats. The bilateral renal IRI model was used, with 24 adult male rats randomly divided into four groups (N=6): sham group (laparotomy without IRI induction), control group (laparotomy plus bilateral IRI for 30 minutes followed by 2 hours of reperfusion), vehicle group (same as control but pre-injected with the vehicle), and treatment group (similar to control but pre-injected with IAXO-102). We measured several biomarkers involved in IRI pathophysiology using enzyme-linked immunosorbent assay (ELISA), including High mobility group box1 (HMGB1), nuclear factor kappa b-p65 (NF-κB p65), interleukin beta-1 (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), 8-isoprostane, Bcl-2 associated X protein (BAX), heat shock protein 27 (HSP27), and Bcl-2. Statistical analysis was performed using one-way ANOVA and Tukey post hoc tests. Our results showed that IAXO-102 significantly improved kidney function, reduced histological alterations, and decreased the inflammatory response (IL-1, IL-6, and TNF) caused by IRI. IAXO-102 also decreased apoptosis by reducing pro-apoptotic Bax and increasing anti-apoptotic Bcl-2 without impacting HSP27. In conclusion, our findings suggest that IAXO-102 had a significant protective effect against IRI damage in the kidneys.
Asunto(s)
Proteínas de Choque Térmico HSP27 , Daño por Reperfusión , Masculino , Animales , Ratas , Proteína X Asociada a bcl-2 , Interleucina-6 , Riñón , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & controlRESUMEN
Atherosclerosis is a common and serious vascular disease that underlies many cardiovascular and cerebrovascular illnesses, including heart attack and stroke. Atherosclerosis-related illnesses have increased in prevalence and now pose a substantial burden on individuals and society. Autophagy (AP) is a process in which cytoplasmic components are engulfed by a double-membrane structure, such as defective organelles and aged, damaged, and flawed proteins. Autophagy is essential for maintaining a proper cellular equilibrium and plays a vital homeostatic role in physiological settings by liberating nutrients from macromolecules and removing undesirable cellular components. This study aimed to investigate the effect of Sitagliptin on the progression of atherosclerosis. Twenty-one male New Zealand White rabbits weighing 2-2.5 kg each were split into three groups: normal control, atherogenic control, and Sitagliptin-treated. The following parameters: serum triglycerides (TG), total cholesterol (TC), LDL, and a tissue autophagy marker (p62) using ELISA, aortic mRNA expression of mTORC1 marker using Real-Time Quantitative PCR(RT-qPCR), and histological inspection of the aorta were assessed. The mRNA expression of mTORC1 and the lipid profile of aortic tissue are considerably elevated in atherogenic diet-fed animals. Histopathological analysis confirmed the presence of a substantial atherosclerotic lesion in the animals fed an atherogenic diet. However, compared to an atherogenic control group, Sitagliptin dramatically reduced lipid profile, P62 aortic level, and mRNA expression of mTORC1. Sitagliptin medication slowed the development of atherosclerosis via increasing autophagy through suppression of the mTORC1 signaling pathway.
Asunto(s)
Aterosclerosis , Fosfato de Sitagliptina , Conejos , Masculino , Animales , Fosfato de Sitagliptina/farmacología , Fosfato de Sitagliptina/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Lípidos , Serina-Treonina Quinasas TOR , ARN Mensajero , Diana Mecanicista del Complejo 1 de la RapamicinaRESUMEN
Hypertension and diabetes represent a significant public health burden worldwide and are significant risk factors for heart disease and stroke. Nevertheless, Iraqi people, in particular, experience higher levels of stress due to political instability and economic issues. The study aimed to investigate the prevalence of common morbidities among Iraqi patients and the possible relationship with exposure to stress. The data was collected from patients (n=500) who attended the health center in Najaf, Iraq, between 25 August 2021 and 30 September 2021. The prevalence of hypertension, diabetes, and asthma among Iraqi people was determined along with patients' awareness and control of these conditions. In addition, patients were asked about their experiences with stress, including the type of stress they encountered. Our findings revealed that nearly 47% of patients involved in this study had hypertension, with the highest percentage in patients over 40. Moreover, the incidence of diabetes was 12%, with the highest incidence in the age group of 40-59. The incidence of asthma was lower in all groups. Data analysis concerning exposure to stress demonstrated that about 60% of patients suffer from a stressful life. We found that the incidence of hypertension and diabetes was high while the incidence of asthma was low. This study also reveals that a considerable number of people were unaware of their hypertension and diabetes. Exposure to daily life stress among Iraqi people may play a role in the observed incidence of these morbidities.
Asunto(s)
Asma , Diabetes Mellitus , Hipertensión , Humanos , Adulto , Persona de Mediana Edad , Irak/epidemiología , Incidencia , Diabetes Mellitus/epidemiología , Diabetes Mellitus/etiología , Hipertensión/epidemiología , Hipertensión/etiología , Asma/epidemiología , Asma/etiologíaRESUMEN
Ischemia and reperfusion injury (I/R) is a serious condition leading to organ failure, characterized by poor blood supply followed by rapid resuscitation of blood flow and reoxygenation. Renal failure caused by renal ischemia has high mortality and morbidity. This study aimed to explore the potential role of Semaglutide as a novel and effective therapeutic strategy for acute renal failure. Additionally, we aimed to assess the possible protective effect of Semaglutide on kidney I/R injury in mice through modulation of the inflammatory and oxidative pathways via phosphatidylinositol 3-kinase/adenosine triphosphate (PI3K/AKT) activation. We employed twenty-eight albino mice to induce the I/R injury model by clamping the renal artery for 30 min followed by a period of reperfusion for 2 hours. The control group was exposed to I/R injury, while the Semaglutide-treated group was pretreated with the drug 12 hours before induction of ischemia at a dose of 100 nmol/L/kg via the intraperitoneal route (i.p). In addition, the DMSO-treated group was subjected to similar conditions to the Semaglutide-treated group. At the end of the experiments, kidneys and blood samples were collected for investigation. Semaglutide could act as a protective agent against acute kidney injury by reducing inflammatory molecules such as tumor necrosis factor-alpha (TNF-α) and its cognate receptor, TNF-α R, interleukine-6 (IL-6). Furthermore, Semaglutide reduced F8 isoprostane levels, increased PI3K and AKT levels in renal tissues, and mitigated renal damage. Semaglutide had renoprotective effects via modulation of the inflammatory response and oxidative pathway by targeting the PI3K/AKT signaling pathway.