RESUMEN
OBJECTIVES: Performing an updated meta-analysis to compare the safety and efficacy of insulin glargine and insulin detemir in adults with type 1 and type 2 diabetes. METHODS: Electronic databases were searched up to 18 August 2021. A random-effects model was applied to pool data from included studies to calculate the standardized mean differences (SMDs) for the continuous variables and relative risks (RRs) for the dichotomous variable. RESULTS: Nine studies compared insulin detemir and insulin glargine in type 2 diabetes and three studies in patients with type 1 diabetes. The pooled SMD of weight gain was -0.59 (95% CI -1.05 to -0.14; P=0.01; I2=98%) in patients with type 2 diabetes. The pooled RR of severe hypoglycemia was 0.28 (95% CI 0.12 to 0.63; P=0.002; I2=0%) in patients with type 1 diabetes. The effects of detemir and glargine on HbA1c, fasting plasma glucose, nocturnal hypoglycemia, and overall hypoglycemia were not statistically different (P>0.05). CONCLUSIONS: It was found that there is no clinically considerable difference between the impacts of insulin detemir and insulin glargine in diabetic patients. The only statistically significant differences were less weight gain in type 2 diabetes and fewer episodes of severe hypoglycemia in type 1 diabetes with insulin detemir.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Hipoglucemia , Adulto , Glucemia , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemiantes/efectos adversos , Insulina , Insulina Detemir/efectos adversos , Insulina Glargina/efectos adversos , Insulina de Acción Prolongada/efectos adversos , Aumento de PesoRESUMEN
Cyclin-dependent kinase 3 (CDK3) is a major player driving retinoblastoma (Rb) phosphorylation during the G0/G1 transition and in the early G1 phase of the cell cycle, preceding the effects of CDK4/cyclin D, CDK6/cyclin D, and CDK2/cyclin E. CDK3 can also directly regulate the activity of E2 factor (E2F) by skipping the role of Rb in late G1, potentially via the phosphorylation of the E2F1 partner DP1. Beyond the cell cycle, CDK3 interacts with various transcription factors involved in cell proliferation, differentiation, and transformation driven by the epidermal growth factor receptor (EGFR)/rat sarcoma virus (Ras) signaling pathway. The expression of CDK3 is extremely low in normal human tissue but upregulated in many cancers, implying a profound role in oncogenesis. Further evaluation of this role has been hampered by the lack of selective pharmacological inhibitors. Herein, we provide a comprehensive overview about the therapeutic potential of targeting CDK3 in cancer.
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Neoplasias , Animales , Ciclo Celular , Ciclina D/metabolismo , Quinasa 3 Dependiente de Ciclina/metabolismo , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , FosforilaciónRESUMEN
PURPOSE: Sepsis originates from the host inflammatory response, especially to bacterial infections, and is considered one of the main causes of death in intensive care units. Various agents have been developed to inhibit mediators of the inflammatory response; one prospective agent is ß-sitosterol (ßS), a phytosterol with a structure similar to cholesterol. This study is aimed at evaluating the effects of ßS on the biomarkers of inflammation and liver function in cecal ligation and puncture- (CLP-) induced septic rats. METHODS: Thirty male Wistar rats were divided equally into six groups as follows: sham, CLP, CLP+dexamethasone (DX, 0.2 mg/kg), CLP+ßS (1 mg/kg), CLP+imipenem (IMI, 20 mg/kg), and CLP+IMI (20 mg/kg)+ßS (1 mg/kg). Serum levels of IL-1ß, IL-6, IL-10, AST, ALT, and liver glutathione (GSH) were assessed by ELISA. Liver expression levels of TNF-α and NF-κBi mRNAs were evaluated by RT-qPCR. RESULTS: Serum concentrations of IL-1ß, IL-6, IL-10, ALT, and AST and mRNA levels of TNF-α and NF-κBi were all significantly higher in septic rats than in normal rats (p < 0.05). Liver GSH content was markedly lower in the CLP group than that in the sham group. ßS-treated rats had remarkably lower levels of IL-1ß, IL-6, IL-10, TNF-α, NF-κBi, AST, and ALT (51.79%, 62.63%, 41.46%, 54.35%, 94.37%, 95.30%, 34.87%, and 46.53% lower, respectively) and greater liver GSH content (35.71% greater) compared to the CLP group (p < 0.05). CONCLUSION: ßS may play a protective role in the septic process by mitigating inflammation. This effect is at least partly mediated by inhibition of the NF-κB signaling pathway. Thus, ßS can be considered as a supplementary treatment in septic patients.
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Inflamación/metabolismo , Hígado , FN-kappa B/metabolismo , Sepsis , Sitoesteroles/farmacología , Animales , Antiinflamatorios/farmacología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Hígado/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratas , Ratas Wistar , Sepsis/metabolismo , Sepsis/mortalidad , Transducción de Señal/efectos de los fármacosRESUMEN
OBJECTIVE: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. Metformin is reported to have pleiotropic neuroprotective effects through anti-inflammatory, antioxidative, and anti-ischemic activity, and improvements in vascular hemodynamics and endothelial function. The aim of this study is to examine the efficacy and safety of metformin therapy in severe TBI patients. METHODS: This single-blind, parallel-group, randomized controlled trial enrolled adult TBI patients. Of 158 trauma patients assessed, 30 met the eligibility criteria and were randomly allocated in a one-to-one ratio to receive 1 g metformin every 12 h for five consecutive days (intervention group) or to usual management only (control group). For efficacy analysis, temporal profiles of serum levels of S100b, neutrophil to lymphocyte ratio (NLR), and glial fibrillary acidic protein (GFAP) were assessed. For pharmacokinetic analysis, serum concentrations of metformin were evaluated in the intervention group. RESULTS: The two study groups were similar in terms of demographics, baseline clinical characteristics, and on-admission biomarkers' serum levels. Longitudinal analysis of S100b and NLR levels showed statistically significant declines in values toward normal levels in the intervention group (p values of < 0.001 and 0.030, respectively), different from the profiles of the control group (p values of 0.074 and 0.645, respectively). Pharmacokinetic analysis demonstrated that metformin absorption is delayed in TBI patients. No events of hypoglycemia and lactic acidosis occurred. CONCLUSIONS: Metformin could potentially be an effective and safe therapeutic intervention in patients with severe TBI. Large-scale, multicentre studies are needed to confirm our encouraging results.
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Lesiones Traumáticas del Encéfalo/sangre , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Metformina/sangre , Metformina/uso terapéutico , Índice de Severidad de la Enfermedad , Adulto , Biomarcadores/sangre , Lesiones Traumáticas del Encéfalo/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/sangre , Hipoglucemiantes/uso terapéutico , Estudios Longitudinales , Masculino , Metformina/efectos adversos , Persona de Mediana Edad , Subunidad beta de la Proteína de Unión al Calcio S100/sangre , Método Simple Ciego , Resultado del Tratamiento , Adulto JovenRESUMEN
AIMS: Sepsis is a potentially fatal illness that can lead to impairment of multiple organs such as liver. The condition is deeply associated with oxidative stress and inflammation. Monomethyl fumarate (MMF) has manifested antioxidant and immunomodulatory properties. The aim of current study was to evaluate protective effects of MMF in sepsis-induced hepatic dysfunction. MAIN METHODS: Sepsis was induced by cecal ligation and puncture (CLP). Wistar rats were assigned to one of sham, CLP, CLPâ¯+â¯dexamethasone (as positive control of inflammation) and CLPâ¯+â¯MMF groups. Levels of serum IL-1ß, IL-6, IL-10, AST, ALT and γGT were quantified. Furthermore, Hepatic levels of GSH and MDA and mRNA expression of TNF and NFKBIA along with hepatic protein level of TLR-4 were assessed. Also, histopathological study of liver was carried out to evaluate hepatic injuries. KEY FINDINGS: Septic rats demonstrated risen levels of IL-1ß, IL-6, IL-10, AST, ALT and γGT, while treatment with dexamethasone or MMF attenuated these levels. Moreover, enhancements in protein level of TLR-4 and mRNA levels of TNF and NFKBIA were observed in CLP rats. These elevations were mitigated in CLP-induced rats that were treated with either dexamethasone or MMF. Treatment with dexamethasone or MMF also shifted sepsis-induced disturbance in the levels of GSH and MDA towards sham levels. Hepato-protective effects of dexamethasone and MMF were further confirmed by histopathological observations. SIGNIFICANCE: Our findings imply that MMF alleviates sepsis-induced hepatic dysfunction by mitigating the inflammatory and oxidative state and this effect is at least partly mediated by the inhibition of TLR-4/NF-κB signalling pathway.
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Antioxidantes/farmacología , Fumaratos/farmacología , Inflamación/tratamiento farmacológico , Hepatopatías/prevención & control , Maleatos/farmacología , Sepsis/tratamiento farmacológico , Animales , Dexametasona/farmacología , Modelos Animales de Enfermedad , Inflamación/patología , Hepatopatías/etiología , Masculino , Inhibidor NF-kappaB alfa/genética , Inhibidor NF-kappaB alfa/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Sepsis/complicaciones , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismoRESUMEN
1. Alterations in the activity of hepatic cytochrome P-450 isoenzymes result in changes in the pharmacokinetic behavior of drugs. This study was designed to explore the impact of type II diabetes, metformin and cinnamon on the activity of CYP2D isoenzyme. 2. Streptozotocin-nicotinamide-induced diabetic and normal rats were gavaged by cinnamon and/or metformin for 14 days. Using isolated perfusion of rat livers, the metabolic activity of CYP2D in the study groups was evaluated based on the oxidative biotransformation of tramadol hydrochloride. 3. The metabolic ratios of O-desmethyltramadol, the product of CYP2D-mediated metabolism of tramadol, in normal and diabetic control rats were found to be 0.33 ± 0.12 and 0.29 ± 0.07, respectively. Cinnamon significantly reduced the mentioned ratio in both normal and diabetic rats (0.13 ± 0.05 and 0.15 ± 0.04) and metformin increased the reduced activity in diabetic rats (0.37 ± 0.09 versus 0.29 ± 0.07). 4. In conclusion, it is evident that this study has shown the significant inhibitory effect of cinnamon on CYP2D. This finding suggests that it should be taken into consideration the possible metabolism-related pharmacokinetic drug-cinnamon interactions. 5. Additionally, type 2 diabetes condition reduced the enzyme activity and metformin consumption reversed this reduction; however, the significance of the latest is not clear.
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Cinnamomum zeylanicum/química , Familia 2 del Citocromo P450/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/enzimología , Metformina/uso terapéutico , Extractos Vegetales/uso terapéutico , Alanina Transaminasa/metabolismo , Animales , Aspartato Aminotransferasas/metabolismo , Masculino , Metformina/administración & dosificación , Metformina/farmacología , Extractos Vegetales/administración & dosificación , Ratas Wistar , Tramadol/metabolismoRESUMEN
Industrial and agricultural developments in recent years have resulted in the excessive discharge of arsenic into the environment, making arsenic toxicity a major worldwide concern. Oxidative stress is considered the primary mechanism for arsenic toxicity. The main objective of this study was to evaluate acetyl-l-carnitine's (ALC) protective ability against the arsenic-induced hepatotoxicity. For this purpose, male Wistar rats were distributed randomly into 5 groups of 8 rats each: control, arsenic (5â¯mg/kg) and arsenic plus ALC (5â¯mg/kg; 100, 200, 300â¯mg/kg). The animals were gavaged for 21 consecutive days. Liver tissue samples were extracted 24â¯h after the last treatment and were later analyzed for biochemical and histological alterations. The arsenic-induced oxidative damage was confirmed by elevation of malondialdehyde (MDA), a lipid peroxidation byproduct, as well as depletion in physiological antioxidant content such as superoxide dismutase (SOD) and catalase (CAT). Furthermore, alterations in mitochondrial functions including a significant decrease of mitochondrial outer membrane potential and reactive oxygen species (ROS) generation increase, mitochondrial swelling, release of cytochrome c and consequent activation of caspase-3 and caspase-9 and initiation of apoptosis, was observed following arsenic administration. Moreover, the inflammation was confirmed by the overexpression of inflammatory mediators such as NF-ĸB and IL-1 and IL-6. The present study demonstrated that ALC ameliorates arsenic-induced oxidative damage, mitochondrial dysfunction, apoptosis, inflammation and histological damage. ALC's protective features against arsenic hepatotoxicity may be due to this agent's antioxidant and anti-inflammatory properties as well as its stabilizing effects on mitochondrial function.