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Indigo naturalis (IN), derived from the leaves of the indigo plant, is a traditional Chinese medicine that has historically been used for its anti-inflammatory properties in the treatment of various diseases, including ulcerative colitis (UC). However, long-term use of IN in UC patients is incontrovertibly associated with the onset of pulmonary arterial hypertension (PAH). To investigate the mechanisms by which IN induces PAH, we focused on the raw material of IN, indigo leaves (IL). Only the condition of long-term chronic (6 months) and high-dose (containing 5% IL in the control diet) administration of IL induced medial thickening in the pulmonary arteries without right ventricular hypertrophy in our rat model. IL administration for a month did not induce pulmonary arterial remodeling but increased endothelin-1 (ET-1) expression levels within endothelial cell (EC) layers in the lungs. Gene Expression Omnibus analysis showed that ET-1 is a key regulator of PAH and that the IL component indican and its metabolite IS induced ET-1 mRNA expression via reactive oxygen species-dependent mechanism. We identified the roles of indican and IS in ET-1 expression in ECs, which were linked to pulmonary arterial remodeling in an animal model.
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Endotelina-1 , Hipertrofia Ventricular Derecha , Hojas de la Planta , Arteria Pulmonar , Ratas Sprague-Dawley , Remodelación Vascular , Animales , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Masculino , Endotelina-1/metabolismo , Remodelación Vascular/efectos de los fármacos , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/fisiopatología , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Ratas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismoRESUMEN
2-Deoxy-d-glucose (2DG) induces anticancer effects through glycolytic inhibition but it may raise the risk of arrhythmia. The rare monosaccharide d-allose also has anticancer properties, but its cardiac effects are unknown. We examined the effects of d-allose on adenosine triphosphate (ATP) production in neonatal rat cardiomyocytes. We showed that 25 mM d-allose selectively reduced glycolytic ATP, but had minimal impact on mitochondrial ATP, while 1 mM 2DG strongly inhibited both. Furthermore, d-allose had less impact on cell viability and was less cytotoxic than 2DG; neither compound caused apoptosis. Thus, d-allose selectively diminished glycolytic ATP production with no apparent effects on cardiomyocytes.
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Adenosina Trifosfato , Miocitos Cardíacos , Ratas , Animales , Animales Recién Nacidos , Supervivencia Celular , Glucosa/farmacologíaRESUMEN
The Japan Accreditation Council for Medical Education has strengthened the promotion of horizontal and vertical integration of medical education, assuring the quality of medical education in Japan from an international perspective. Pharmacology plays an important role as a central hub that connects basic medical education with clinical medical education. As part of promoting horizontal integration of medical education, Tokushima University has started a joint practice with three basic medical subjects such as Biochemistry, Physiology, and Pharmacology for 2nd grade medical students in 2019. Each subject is in charge of two or four items of practice, and a total 8 of items are performed for 10 days in integrated practice every year. This joint practice has become an official subject in 2022. We introduce our experiences of unique practices based on their advantages and limitations.
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Educación Médica , Humanos , Universidades , JapónRESUMEN
A strong hypoxic environment has been observed in pancreatic ductal adenocarcinoma (PDAC) cells, which contributes to drug resistance, tumor progression, and metastasis. Therefore, we performed bioinformatics analyses to investigate potential targets for the treatment of PDAC. To identify potential genes as effective PDAC treatment targets, we selected all genes whose expression level was related to worse overall survival (OS) in The Cancer Genome Atlas (TCGA) database and selected only the genes that matched with the genes upregulated due to hypoxia in pancreatic cancer cells in the dataset obtained from the Gene Expression Omnibus (GEO) database. Although the extracted 107 hypoxia-responsive genes included the genes that were slightly enriched in angiogenic factors, TCGA data analysis revealed that the expression level of endothelial cell (EC) markers did not affect OS. Finally, we selected CA9 and PRELID2 as potential targets for PDAC treatment and elucidated that a CA9 inhibitor, U-104, suppressed pancreatic cancer cell growth more effectively than 5-fluorouracil (5-FU) and PRELID2 siRNA treatment suppressed the cell growth stronger than CA9 siRNA treatment. Thus, we elucidated that specific inhibition of PRELID2 as well as CA9, extracted via exhaustive bioinformatic analyses of clinical datasets, could be a more effective strategy for PDAC treatment.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Anhidrasa Carbónica IX/genética , Anhidrasa Carbónica IX/metabolismo , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Antígenos de Neoplasias/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Hipoxia/metabolismo , ARN Interferente Pequeño , Biología Computacional , Neoplasias PancreáticasRESUMEN
BACKGROUND AND PURPOSE: TJ-17 (Goreisan), a traditional Japanese Kampo medicine, has been generally used to treat edema, such as heart failure, due to its diuretic effect. In the present study, we investigate the effects of TJ-17 on chronic kidney disease (CKD). METHODS: We the preventive action of TJ-17 against acute kidney injury (AKI) transition to CKD in vivo using a folic acid (FA)-induced mouse model. Mice were treated with food containing TJ-17 at 48 h after FA intraperitoneal injection (AKI phase). RESULTS: Histological analysis, as well as renal function and renal injury markers, deteriorated in mice with FA-induced CKD and were ameliorated by TJ-17 treatment. Increased levels of inflammatory cytokines and macrophage infiltration were also alleviated in mice treated with TJ-17. Renal fibrosis, a crucial factor in CKD, was induced by FA administration and inhibited by TJ-17 treatment. Pretreatment with TJ-17 did not exert an inhibitory effect on FA-induced AKI. The increase in urinary volume in FA-induced CKD mice was ameliorated by TJ-17 treatment, with a concurrent correction of reduced aquaporins expression in the kidney. CONCLUSION: TJ-17 may have a novel preventive effect against inflammation, oxidative stress, and fibrosis, contributing to innovation in the treatment of CKD.
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Heart failure results from various physiological and pathological stimuli that lead to cardiac hypertrophy. This pathological process is common in several cardiovascular diseases and ultimately leads to heart failure. The development of cardiac hypertrophy and heart failure involves reprogramming of gene expression, a process that is highly dependent on epigenetic regulation. Histone acetylation is dynamically regulated by cardiac stress. Histone acetyltransferases play an important role in epigenetic remodeling in cardiac hypertrophy and heart failure. The regulation of histone acetyltransferases serves as a bridge between signal transduction and downstream gene reprogramming. Investigating the changes in histone acetyltransferases and histone modification sites in cardiac hypertrophy and heart failure will provide new therapeutic strategies to treat these diseases. This review summarizes the association of histone acetylation sites and histone acetylases with cardiac hypertrophy and heart failure, with emphasis on histone acetylation sites.
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AIMS: Peroxisome proliferator-activated receptor-alpha (PPARα) levels are markedly lower in the kidneys of chronic kidney disease (CKD) patients. Fibrates (PPARα agonists) are therapeutic agents against hypertriglyceridemia and potentially against CKD. However, conventional fibrates are eliminated by renal excretion, limiting their use in patients with impaired renal function. Here, we aimed to evaluate the renal risks associated with conventional fibrates via clinical database analysis and investigate the renoprotective effects of pemafibrate, a novel selective PPARα modulator mainly excreted into the bile. MAIN METHODS: The risks associated with conventional fibrates (fenofibrate, bezafibrate) to the kidneys were evaluated using the Food and Drug Administration Adverse Event Reporting System. Pemafibrate (1 or 0.3 mg/kg/day) was administered daily using an oral sonde. Its renoprotective effects were examined in unilateral ureteral obstruction (UUO)-induced renal fibrosis model mice (UUO mice) and adenine-induced CKD model mice (CKD mice). KEY FINDINGS: The ratios of glomerular filtration rate decreased and blood creatinine increased were markedly higher after conventional fibrate use. Pemafibrate administration suppressed increased gene expressions of collagen-I, fibronectin, and interleukin 1 beta (IL-1ß) in the kidneys of UUO mice. In CKD mice, it suppressed increased plasma creatinine and blood urea nitrogen levels and decreased red blood cell count, hemoglobin, and hematocrit levels, along with renal fibrosis. Moreover, it inhibited the upregulation of monocyte chemoattractant protein-1, IL-1ß, tumor necrosis factor-alpha, and IL-6 in the kidneys of CKD mice. SIGNIFICANCE: These results demonstrated the renoprotective effects of pemafibrate in CKD mice, confirming its potential as a therapeutic agent for renal disorders.
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Fenofibrato , Insuficiencia Renal Crónica , Obstrucción Ureteral , Ratones , Animales , PPAR alfa/metabolismo , Creatinina/metabolismo , Riñón/metabolismo , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/complicaciones , Fenofibrato/farmacología , Fibrosis , Obstrucción Ureteral/patologíaRESUMEN
AIMS: Thrombin exerts various pathophysiological functions by activating protease-activated receptors (PARs), and thrombin-induced activation of PARs promotes the development of non-alcoholic fatty liver disease (NAFLD). Since heparin cofactor II (HCII) specifically inactivates thrombin action, we hypothesized that plasma HCII activity correlates with the severity of NAFLD. METHODS: A cross-sectional study was conducted. Plasma HCII activity and noninvasive clinical markers of hepatic fibrosis including fibrosis-4 (FIB-4) index, NAFLD fibrosis score (NFS) and aspartate aminotransferase-to-platelet ratio index (APRI) were determined in 305 Japanese patients with type 2 diabetes mellitus (T2DM). The relationships between plasma HCII activity and the clinical markers were statistically evaluated. RESULTS: Multiple regression analysis including confounding factors showed that plasma HCII activity independently contributed to decreases in FIB-4 index (pï¼0.001), NFS (pï¼0.001) and APRI (p=0.004). In addition, logistic regression analysis for the prevalence of advanced hepatic fibrosis defined by the cutoff points of the clinical scores showed that plasma HCII activity was the sole and common negative factor for prevalence of advanced hepatic fibrosis (FIB-4 index: p=0.002, NFS: p=0.026 and APRI: p=0.012). CONCLUSIONS: Plasma HCII activity was inversely associated with clinical hepatic fibrosis indices including FIB-4 index, NFS and APRI and with the prevalence of advanced hepatic fibrosis in patients with T2DM. The results suggest that HCII can serve as a novel biomarker for assessment of hepatic fibrosis of NAFLD in patients with T2DM.
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Diabetes Mellitus Tipo 2 , Enfermedad del Hígado Graso no Alcohólico , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Cofactor II de Heparina , Estudios Transversales , Trombina , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/complicaciones , Biomarcadores , Índice de Severidad de la EnfermedadRESUMEN
Aims: Hypertension is a strong risk factor for heart failure with preserved ejection fraction. Curcumin has p300-specific histone acetyltransferase inhibitory activity, suppresses cardiomyocyte hypertrophy and fibrosis, and significantly reduces myocardial brain natriuretic peptide (BNP) expression without altering blood pressure in a rat model of hypertensive heart disease. This double-blind, placebo-controlled, randomized study, for the first time, aimed to examine the efficacy of a high-absorption curcumin for the prevention of hypertensive heart disease in humans. Methods and results: Patients exhibiting initial signs of hypertensive heart disease with left ventricular ejection fraction ≥60% and stable blood pressure <140/90â mmHg orally took a double-blinded capsule (either a 90â mg curcumin capsule or placebo) twice daily for 24 weeks. The primary endpoint was per cent changes in left ventricular diastolic function (E/E') from baseline to 6 months after administration. The secondary endpoint was the per cent change in plasma BNP levels. The E/E' ratio per cent change from baseline to 6 months after administration was similar between the placebo (n = 69) and the curcumin (n = 73) groups. The per cent change in plasma BNP levels was significantly lower in the curcumin group than in the placebo group. In patients <65 years, BNP per cent changes were significantly lower in the curcumin group than in the placebo group, but similar between groups in ≥65 years (<65 vs. ≥65 years: P for interaction = 0.011). Conclusions: A high-absorption curcumin agent did not affect the E/E' ratio, rather it significantly inhibited the increase in plasma BNP levels in patients with initial signs of hypertensive heart disease.
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BACKGROUND AND PURPOSE: Chinese herbal medicine has been developed as the traditional Japanese Kampo medicine, and it has been widely used to cure various symptoms in clinical practice. However, only a few studies are currently available on the effect of the Kampo medicine on renal disease. Nephrotoxicity is one of major side effect of cisplatin, the first metal-based anticancer drug. In the present study, we examined the effect of the Kampo medicine against cisplatin-induced nephrotoxicity (CIN). METHODS: First, we screened the ethical Kampo extract formulation having positive effect against CIN using HK-2 cells. Next, we examined the preventive action of the selected ethical Kampo extract formulation against CIN in vivo using a mouse model. RESULTS: Cisplatin-induced cell death was significantly suppressed by TJ-43 (Rikkunshito) and TJ-90 (Seihaito); however, cisplatin-induced cleaved caspase-3 expression was inhibited only by TJ-90. In an in vivo mouse model of cisplatin-induced kidney injury with dysfunction and increased inflammatory cytokine expression, TJ-90 showed amelioration of these damaging effects. Cisplatin-induced apoptosis and superoxide production were inhibited by treatment with TJ-90. The expression of cleaved caspase-3, 4-hydroxynonenal, and MAPK phosphorylation increased after cisplatin administration, but decreased after the administration of TJ-90. Among 16 crude drug extracts present in Seihaito, Bamboo Culm (Chikujo in Japanese) inhibited cisplatin-induced cell death and cleaved caspase-3 expression in HK-2 cells. Moreover, the anti-tumor effect of cisplatin was not affected by TJ-90 co-treatment in cancer cell lines. CONCLUSION: TJ-90 might have a novel preventive action against CIN through the suppression of inflammation, apoptosis, and oxidative stress without interfering with the anti-tumor effect of cisplatin. Collectively, these findings might contribute to innovations in supportive care for cancer treatment-related side effects.
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Cisplatino , Medicamentos Herbarios Chinos , Apoptosis , Caspasa 3/metabolismo , Cisplatino/efectos adversos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Japón , Medicina KampoRESUMEN
Iron is an essential trace metal for all life, but excess iron causes oxidative stress through catalyzing the toxic hydroxy-radical production via the Fenton reaction. The number of patients with obesity and diabetes has been increasing worldwide, and their onset and development are affected by diet. In both clinical and experimental studies, a high body iron content was associated with obesity and diabetes, and the reduction of body iron content to an appropriate level can ameliorate the status and development of obesity and diabetes. Macrophages play an essential role in the pathophysiology of obesity and diabetes, and in the metabolism and homeostasis of iron in the body. Recent studies demonstrated that macrophage polarization is related to adipocyte hypertrophy and insulin resistance through their capabilities of iron handling. Control of iron in macrophages is a potential therapeutic strategy for obesity and diabetes. J. Med. Invest. 69 : 1-7, February, 2022.
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Diabetes Mellitus , Resistencia a la Insulina , Tejido Adiposo/metabolismo , Humanos , Resistencia a la Insulina/fisiología , Hierro , Macrófagos/metabolismo , Obesidad/etiologíaRESUMEN
Hanudel et al. investigated the effects of hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) on iron metabolism in a chronic kidney disease (CKD) mouse model and showed that vadadustat, an HIF-PHI, exerted beneficial effects on anemia and iron disorders independently of erythroferrone. Vadadustat also inhibited the progression of CKD and the CKD-associated increase of plasma fibroblast growth factor 23 in CKD mice. This study provides new insights into the action of HIF-PIHs in CKD.
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Anemia , Insuficiencia Renal Crónica , Animales , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos , Glicina/análogos & derivados , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Hierro , Riñón , Ratones , Ácidos Picolínicos , Insuficiencia Renal Crónica/tratamiento farmacológicoRESUMEN
BACKGROUND: Cisplatin is widely used as an antitumor drug for the treatment of solid tumors. However, its use has been limited owing to nephrotoxicity, a major side effect. The mechanism of cisplatin-induced nephrotoxicity (CIN) has long been investigated in order to develop preventive/therapeutic drugs. Ferroptosis is a newly identified form of non-apoptotic regulated cell death induced by iron-mediated lipid peroxidation and is involved in the pathophysiology of various diseases. In this study, we examined the role of ferroptosis in CIN. METHODS: We evaluated the role of ferroptosis in CIN by in vivo experiments in a mouse model. RESULTS: Cisplatin increased the protein expressions of transferrin receptor-1 and ferritin, and iron content in the kidney of mice. In addition, treatment with cisplatin augmented renal ferrous iron and hydroxyl radical levels with co-localization. Mice administered cisplatin demonstrated kidney injury, with renal dysfunction and increased inflammatory cytokine expression; these changes were ameliorated by Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis. The expression of the ferroptosis markers, COX2 and 4-hydroxynonenal (4-HNE), increased with cisplatin administration, and decreased with the administration of Fer-1. By contrast, cisplatin-induced apoptosis and necroptosis were inhibited by treatment with Fer-1. Moreover, deferoxamine, an iron chelator, also inhibited CIN, with a decrease in the expression of COX-2 and 4-HNE. CONCLUSION: Ferroptosis is involved in the pathogenesis of CIN and might be used as a new preventive target for CIN.
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Cisplatino/toxicidad , Ferroptosis , Animales , Ferritinas , Hierro/metabolismo , Peroxidación de Lípido , RatonesRESUMEN
AIMS/INTRODUCTION: Thrombin exerts various pathophysiological functions by activating protease-activated receptors (PARs). Recent data have shown that PARs influence the development of glomerular diseases including diabetic kidney disease (DKD) by regulating inflammation. Heparin cofactor II (HCII) specifically inactivates thrombin; thus, we hypothesized that low plasma HCII activity correlates with DKD development, as represented by albuminuria. MATERIALS AND METHODS: Plasma HCII activity and spot urine biomarkers, including albumin and liver-type fatty acid-binding protein (L-FABP), were determined as the urine albumin-to-creatinine ratio (uACR) and the urine L-FABP-to-creatinine ratio (uL-FABPCR) in 310 Japanese patients with diabetes mellitus (176 males and 134 females). The relationships between plasma HCII activities and those DKD urine biomarkers were statistically evaluated. In addition, the relationship between plasma HCII activities and annual uACR changes was statistically evaluated for 201/310 patients (115 males and 86 females). RESULTS: The mean plasma HCII activity of all participants was 93.8 ± 17.7%. Multivariate-regression analysis including confounding factors showed that plasma HCII activity independently contributed to the suppression of the uACR and log-transformed uACR values (P = 0.036 and P = 0.006, respectively) but not uL-FABPCR (P = 0.541). In addition, plasma HCII activity significantly and inversely correlated with annual uACR and log-transformed uACR increments after adjusting for confounding factors (P = 0.001 and P = 0.014, respectively). CONCLUSIONS: The plasma HCII activity was inversely and specifically associated with glomerular injury in patients with diabetes. The results suggest that HCII can serve as a novel predictive factor for early-stage DKD development, as represented by albuminuria.
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Albuminuria/sangre , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/orina , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/orina , Cofactor II de Heparina/análisis , Adulto , Anciano , Albúminas/metabolismo , Albuminuria/orina , Biomarcadores/sangre , Biomarcadores/orina , Creatinina/orina , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/etiología , Proteínas de Unión a Ácidos Grasos/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores Proteinasa-Activados/sangre , Análisis de Regresión , Trombina/metabolismoRESUMEN
Despite the availability of more than 20 clinical antiepileptic drugs, approximately 30% of patients with epilepsy do not respond to antiepileptic drug treatment. Therefore, it is important to develop antiepileptic products that function via novel mechanisms. In the present study, we evaluated data from one of the largest global databases to identify drugs with antiepileptic effects, and subsequently attempted to understand the effect of the combination of antiepileptic drugs and valacyclovir in epileptic seizures using a kindling model. To induce kindling in mice, pentylenetetrazol at a dose of 40 mg/kg was administered once every 48 h. Valacyclovir was orally administered 30 min before antiepileptic drug injection in kindled mice, and behavioral seizures were monitored for 20 min following pentylenetetrazol administration. Additionally, c-Fos expression in the hippocampal dentate gyrus was measured in kindled mice. Valacyclovir showed inhibitory effects on pentylenetetrazol-induced kindled seizures. In addition, simultaneous use of levetiracetam and valacyclovir caused more potent inhibition of seizure activity, and neither valproic acid nor diazepam augmented the anti-seizure effect in kindled mice. Furthermore, kindled mice showed increased c-Fos levels in the dentate gyrus. The increase in c-Fos expression was significantly inhibited by the simultaneous use of levetiracetam and valacyclovir. The findings of the present study indicate that a combination of levetiracetam and valacyclovir had possible anticonvulsive effects on pentylenetetrazol-induced kindled epileptic seizures. These results suggest that valacyclovir may have an antiseizure effect in patients with epilepsy.
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Anticonvulsivantes/farmacología , Excitación Neurológica/efectos de los fármacos , Convulsiones/tratamiento farmacológico , Valaciclovir/farmacología , Animales , Anticonvulsivantes/uso terapéutico , Cefepima/efectos adversos , Bases de Datos Factuales , Modelos Animales de Enfermedad , Reposicionamiento de Medicamentos , Quimioterapia Combinada , Hipocampo/efectos de los fármacos , Humanos , Levetiracetam/farmacología , Levetiracetam/uso terapéutico , Masculino , Ratones , Pentilenotetrazol/toxicidad , Proteínas Proto-Oncogénicas c-fos/metabolismo , Convulsiones/inducido químicamente , Valaciclovir/uso terapéuticoRESUMEN
The relationship between cellular senescence and fibrosis in the kidney is being elucidated and we have identified it as therapeutic target in recent studies. Chronic kidney disease has also become a lifestyle disease, often developing on the background of hypertension and dyslipidemia. In this study, we clarify the effect of interaction between these two conditions on kidney fibrosis and senescence. Wild type mice (WT), apolipoprotein E-/- mice (ApoEKO), and endothelial nitric oxide synthase (eNOS)-/- ApoE-/- mice (DKO) were obtained by breeding. Unilateral ureteral obstruction (UUO) was performed on 8-10 week old male mice and the degree of renal tubular injury, fibrosis and kidney senescence were evaluated. DKO manifested elevated blood pressure, higher total cholesterol and lower HDL than WT. DKO showed sustained kidney injury molecule-1 protein expression. Kidney fibrosis was significantly higher in ApoEKO and DKO. mRNA expression of genes related to kidney fibrosis was the highest in DKO. The mRNA expression of Zinc-α2-Glycoprotein and heme oxygenase-1 were significantly decreased in DKO. Furthermore, mRNA expression of p53, p21 and p16 were increased both in ApoEKO and DKO, with DKO being the highest. Senescence associated ß-gal positive tubule area was significantly increased in DKO. Increased DNA damage and target of rapamycin-autophagy spatial coupling compartments (TASCCs) formation was found in DKO. Mice with endothelial dysfunction and dyslipidemia developed kidney fibrosis and accelerated senescence even in young mice after injury. These data highlight the fact managing lifestyle-related diseases from a young age is important for CKD prevention.
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Apolipoproteínas E/deficiencia , Senescencia Celular/genética , Fibrosis/genética , Eliminación de Gen , Riñón/patología , Óxido Nítrico Sintasa de Tipo III/deficiencia , Insuficiencia Renal Crónica/genética , Animales , Apolipoproteínas E/genética , Autofagia , Presión Sanguínea , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Daño del ADN/genética , Genes p16 , Genes p53 , Humanos , Riñón/lesiones , Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo III/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Patients who undergo multiple-day chemotherapy sessions experience hard-to-treat nausea and vomiting. Currently, there is no effective standard treatment for this condition. This study compared the preventive effect of first-generation 5-hydroxytryptamine 3 receptor antagonists (5-HT3 RAs) and second-generation 5-HT3 RAs palonosetron in multiple-day chemotherapy-induced nausea and vomiting. The design of this study was a retrospective case-control study of patients who received a five-day cisplatin-based chemotherapy and were treated with aprepitant, dexamethasone, granisetron, and ramosetron or palonosetron. The patients were divided into two groups: patients given granisetron and ramosetron (the first-generation group), and those given palonosetron (palonosetron group). The percentage of patients with a complete response or total control was assessed. They were divided into three phases: 0-216 h (overall phase), 0-120 h (remedial phase), and 120-216 h (after phase). The remedial phase was further divided into 0-24 h (early phase) and 24-120 h (later phase). Moreover, the nutritional status of each patient was assessed by noting the patients' total calorie-intake per day and total parenteral nutrition. First-generation 5-HT3 RAs and palonosetron were used for treatment in 18 and 28 patients, respectively. The complete response rate and caloric oral intake of the later phase were higher in the palonosetron group than in the first-generation group. We conclude that palonosetron treatment was more effective than first-generation 5-HT3 RAs in controlling multiple-day chemotherapy-induced nausea and vomiting.
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Antieméticos/administración & dosificación , Bencimidazoles/administración & dosificación , Granisetrón/administración & dosificación , Náusea/tratamiento farmacológico , Palonosetrón/administración & dosificación , Antagonistas del Receptor de Serotonina 5-HT3/administración & dosificación , Vómitos/tratamiento farmacológico , Adulto , Antineoplásicos/efectos adversos , Bleomicina/efectos adversos , Quimioterapia Combinada , Etopósido/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Compuestos de Platino/efectos adversos , Estudios Retrospectivos , Neoplasias Testiculares/tratamiento farmacológico , Vómitos/inducido químicamenteRESUMEN
Cisplatin is widely used as an anti-tumor drug for the treatment of solid tumors. Unfortunately, it causes kidney toxicity as a critical side effect, limiting its use, given that no preventive drug against cisplatin-induced kidney toxicity is currently available. Here, based on a repositioning analysis of the Food and Drug Administration Adverse Events Reporting System, we found that a previously developed drug, diphenhydramine, may provide a novel treatment for cisplatin-induced kidney toxicity. To confirm this, the actual efficacy of diphenhydramine was evaluated in in vitro and in vivo experiments. Diphenhydramine inhibited cisplatin-induced cell death in kidney proximal tubular cells. Mice administered cisplatin developed kidney injury with significant dysfunction (mean plasma creatinine: 0.43 vs 0.15 mg/dl) and showed augmented oxidative stress, increased apoptosis, elevated inflammatory cytokines, and MAPKs activation. However, most of these symptoms were suppressed by treatment with diphenhydramine. Furthermore, the concentration of cisplatin in the kidney was significantly attenuated in diphenhydramine-treated mice (mean platinum content: 70.0 vs 53.4 µg/g dry kidney weight). Importantly, diphenhydramine did not influence or interfere with the anti-tumor effect of cisplatin in any of the in vitro or in vivo experiments. In a selected cohort of 98 1:1 matched patients from a retrospective database of 1467 patients showed that patients with malignant cancer who had used diphenhydramine before cisplatin treatment exhibited significantly less acute kidney injury compared to ones who did not (6.1 % vs 22.4 %, respectively). Thus, diphenhydramine demonstrated efficacy as a novel preventive medicine against cisplatin-induced kidney toxicity.
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Lesión Renal Aguda , Antineoplásicos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control , Animales , Antineoplásicos/toxicidad , Apoptosis , Cisplatino/toxicidad , Difenhidramina/metabolismo , Difenhidramina/farmacología , Difenhidramina/uso terapéutico , Humanos , Riñón/metabolismo , Ratones , Estrés Oxidativo , Estudios RetrospectivosRESUMEN
BACKGROUND: In patients treated with bevacizumab, hypertension may be a biomarker of therapeutic efficacy. However, it is not clear whether drugs that control blood pressure influence bevacizumab's efficacy. In this study, we investigated drugs that may affect hypertension in bevacizumab-treated patients and examined the impact on the therapeutic effect. PATIENTS AND METHODS: We analyzed 3,724,555 reports from the third quarter of 2010 to the second quarter of 2015. All data were obtained from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) analysis. In this retrospective cohort study, we investigated a total of 58 patients diagnosed with colorectal cancer and treated for the first time with bevacizumab containing XELOX or mFOLFOX6 at The University of Tokushima Hospital between January 2010 and December 2015. The effect of the treatment was evaluated according to Response Evaluation Criteria in Solid Tumors version 1.0. Thereafter, the effect was confirmed using Gene Expression Omnibus (GEO) and cultured cells. RESULTS: There are few reports in FAERS of hypertension in patients treated with omeprazole on bevacizumab. Based on the chart review, patients who used proton pump inhibitors (PPI) had a lower response to treatment than those who did not (response rate: 25% vs 50%). Furthermore, experiments on GEO and cell lines suggested that induction of vascular endothelial growth factor (VEGF) gene expression by PPIs is the cause of the reduced therapeutic effect. CONCLUSION: PPIs prevent hypertension in bevacizumab-treated patients but may reduce bevacizumab's anti-tumoral effects by inducing VEGF expression.