RESUMEN
Vincristine (VCR), an alkaloid isolated from vinca, is a commonly used chemotherapeutic drug. However, VCR therapy can lead to dose-dependent peripheral neurotoxicity, mainly manifesting as neuropathic pain, which is one of the dominant reasons for limiting its utility. Experimentally, we discovered that VCR-induced neuropathic pain (VINP) was accompanied by astrocyte activation; the upregulation of phospho-CaMKII (p-CaMKII), CaV3.2, and Connexin-43 (Cx43) expression; and the production and release of inflammatory cytokines and chemokines in the spinal cord. Similar situations were also observed in astrocyte cultures. Interestingly, these alterations were all reversed by intrathecal injection of KN-93 (a CaMKII inhibitor) or L-Ascorbic acid (a CaV3.2 inhibitor). In addition, KN-93 and L-Ascorbic acid inhibited the increase in [Ca2+]i associated with astrocyte activation. We also verified that knocking down or inhibiting Cx43 level via intrathecal injection of Cx43 siRNA or Gap27 (a Cx43 mimetic peptide) relieved pain hypersensitivity and reduced the release of inflammatory factors; however, they did not affect astrocyte activation or p-CaMKII and CaV3.2 expression. Besides, the overexpression of Cx43 through the transfection of the Cx43 plasmid did not affect p-CaMKII and CaV3.2 expressions in vitro. Therefore, CaMKII and CaV3.2 may activate astrocytes by increasing [Ca2+]i, thereby mediating Cx43-dependent inflammation in VINP. Moreover, we demonstrated that the CaMKII signalling pathway was involved in VCR-induced inflammation, apoptosis, and mitochondrial damage. Collectively, our findings show a novel mechanism by which CaMKII and CaV3.2 mediate Cx43-dependent inflammation by activating astrocytes in neuropathic pain induced by VCR.
Asunto(s)
Canales de Calcio Tipo T , Neuralgia , Humanos , Conexina 43/genética , Conexina 43/metabolismo , Vincristina/farmacología , Vincristina/metabolismo , Vincristina/uso terapéutico , Canales de Calcio Tipo T/metabolismo , Canales de Calcio Tipo T/uso terapéutico , Astrocitos/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/uso terapéutico , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismoRESUMEN
Vincristine-induced peripheral neuropathy (VIPN) is a common adverse effect of vincristine (VCR) for which there is no preventative or curative treatment. Here, we report a case of a patient suffering from severe VCR-related neurotoxicity. To explore the possible causes of severe VIPN in this patient, a set of genes involved in VCR metabolism, transport or are related to the cytoskeleton, microtubules, and inherited neurological diseases gene polymorphisms were examined via pharmacogenetic analyses. The genotyping results revealed the presence of a complex pattern of polymorphisms in CYP3A5, ABCC2, SYNE2, BAHD1, NPSR1, MTNR1B, CEP72, miR-4481 and miR-3117. A comprehensive understanding of all the pharmacogenetic risk factors for VIPN may explain the occurrence of severe neurotoxicity in our patient. This case brings to light the potential importance of pharmacogenetic testing in clinical practice. It also exemplifies the importance of developing early-detection strategies to optimize treatment regimens through prior risk stratification while reducing adverse drug reactions and personalizing therapy.
RESUMEN
Vincristine (VCR) is the first-line chemotherapeutic medication often co-administered with other drugs to treat childhood acute lymphoblastic leukemia. Dose-dependent neurotoxicity is the main factor restricting VCR's clinical application. VCR-induced peripheral neuropathy (VIPN) sometimes results in dose reduction or omission, leading to clinical complications or affecting the patient's quality of life. With regard to the genetic basis of drug responses, preemptive pharmacogenomic testing and simultaneous blood level monitoring could be helpful for the transformation of various findings into individualized therapies. In this review, we discussed the potential associations between genetic variants in genes contributing to the pharmacokinetics/pharmacodynamics of VCR and VIPN incidence and severity in patients with acute lymphoblastic leukemia. Of note, genetic variants in the CEP72 gene have great potential to be translated into clinical practice. Such a genetic biomarker may help clinicians diagnose VIPN earlier. Besides, genetic variants in other genes, such as CYP3A5, ABCB1, ABCC1, ABCC2, TTPA, ACTG1, CAPG, SYNE2, SLC5A7, COCH, and MRPL47, have been reported to be associated with the VIPN, but more evidence is needed to validate the findings in the future. In fact, a variety of complex factors jointly determine the VIPN. In implementing precision medicine, the combination of genetic, environmental, and personal variables, along with therapeutic drug monitoring, will allow for a better understanding of the mechanisms of VIPN, improving the effectiveness of VCR treatment, reducing adverse reactions, and improving patients' quality of life.
RESUMEN
The aim of the present study was to investigate the effect of testosterone on glucolipid metabolism and vascular injury in male rats, and examine the underlying molecular mechanisms. A total of 40 male Sprague-Dawley rats were divided into a control group (n=10), high-fat-diet + castration group (n=10), highfatdiet + castration + low dose testosterone group (n=10), and high-fat-diet + castration + high dose testosterone group (n=10). Hematoxylin and eosin staining was performed to evaluate the morphology of the thoracic aortic tissues. Immunohistochemical staining was used to detect biomarkers of the phosphoinositide 3kinase (PI3K) signaling pathway. The mRNA and protein expression levels of PI3K, AKT, insulin receptor substrate1 (IRS1), glucose transporter type 4 (GLUT4), nuclear factor (NF)κB and tumor necrosis factor (TNF)α in the aortas were determined using quantitative polymerase chain reaction and Western blot analyses, respectively. Apoptosis in the aortic tissues was detected using a TUNEL assay. Castration induced apoptosis in the animals fed a highfatdiet, whereas low dose testosterone replacement ameliorated the apoptosis in the aorta. However, the levels of apoptosis was more severe following highdose testosterone treatment. Lowdose testosterone induced upregulation in the levels of IRS1, AKT, GLUT4 protein, NFκB, TNFα and PI3K, compared with those in the animals fed a highfat diet following castration. A high dose of testosterone resulted in a significant decrease in the levels of IRS1, AKT, GLUT4, NFκB, TNFα and PI3K. Compared with the rats in the highfat diet + castration group, a low dose of testosterone induced upregulation in the mRNA levels of IRS1, AKT and GLUT4, and downregulation of the mRNA levels of NFκB, TNFα and PI3K. A high dose of testosterone resulted in a significant decrease in the levels of IRS1, AKT and GLUT4, and marked increases in the mRNA levels of NFκB, TNFα and PI3K, compared with the low dose group. Castration induced marked disorders of glucolipid metabolism and vascular injuries in the pubescent male rats. Lowdose testosterone treatment was found to ameliorate the vascular damage caused by castration via the PI3K/AKT signaling pathway.
Asunto(s)
Orquiectomía/efectos adversos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Maduración Sexual/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Testosterona/farmacología , Enfermedades Vasculares/etiología , Enfermedades Vasculares/metabolismo , Animales , Aorta Torácica/metabolismo , Aorta Torácica/patología , Biomarcadores , Modelos Animales de Enfermedad , Masculino , FN-kappa B/metabolismo , Ratas , Enfermedades Vasculares/tratamiento farmacológicoRESUMEN
OBJECTIVE: To investigate the association between fasting plasma glucose (FPG), 2-hour post challenge plasma glucose (2hPG), fasting plasma insulin (FINS), 2-hour post challenge plasma insulin (2hINS), and cardiovascular risk factors in obese and overweight children. METHODS: This is a cross-sectional study of 452 obese and overweight children (male: 312, female: 140, aged 6-16 years). This study was conducted in the Department of Pediatrics, General Hospital of Tianjin Medical University, Tianjin, China between June 2008 and November 2012. Anthropometries and blood analysis were carried out. Pearson correlation analysis and multiple stepwise linear regression analysis were used to investigate the association among FPG, 2hPG, FINS, 2hINS and cardiovascular risk factors. RESULTS: Body mass index, waist circumference, waist to hip ratio, systolic blood pressure, diastolic blood pressure, and triglyceride were highly correlated with FINS. Fasting plasma insulin influenced greater variance in most cardiovascular risk factors than 2hPG and 2hINS. CONCLUSION: Fasting plasma insulin was closely associated with most cardiovascular risk factors compared with FPG, 2hPG and 2hINS.