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L-Tryptophan (Trp) was shown to improve the gut barrier and growth of weaning piglets. However, whether excessive dietary Trp regulates amino acids (AAs) metabolism and gut serotonin (5-HT) homeostasis in piglets with gut inflammation is not clear yet. We hypothesize that excessive dietary Trp alleviates acetate-induced colonic inflammation and gut barrier damage in weaning piglets partially through the regulation of colonic AAs metabolism and 5-HT signaling. Fifty-four 21-day-old weaned piglets were divided into six groups: control, acetate, 0.2%Trp, 0.2%Trp + acetate, 0.4% Trp, and 0.4%Trp + acetate. Piglets were fed a basal diet supplemented with 0%, 0.2%, or 0.4% of Trp throughout the 12-day experiment. During days 0-7, all piglets had free access to diet and drinking water. On day 8, piglets were intrarectal administered with 10 mL of 10% acetate saline solution or 0.9% saline. During days 8-12, all piglets were pair-fed the same amount of feed per kg bodyweight. Results showed that excessive dietary Trp alleviated acetate-induced reductions in daily weight gain and increase in feed/gain ratio. Trp restored (P < 0.05) acetate-induced increase in concentrations of free aspartate, glutamate/glutamine, glycine, 5-HT, and 3-methylindole in the colon, downregulation of zonula occludens-1 and 5-HT reuptake transporter (SERT) expression and upregulation of IL-1ß, IL-8, TLR4, and 5-HT receptor 2A (HTR2A) expression, and the increase in ratios of p-STAT3/ STAT3 and p-p65/p65 in the colon. The above findings suggested that excessive dietary Trp in the proper amount regulated colonic AAs metabolism, 5-HT homeostasis, and signaling that may contribute as important regulators of gut inflammation during the weaning transition.
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Serotonina , Triptófano , Animales , Porcinos , Triptófano/farmacología , Serotonina/metabolismo , Destete , Dieta , Suplementos Dietéticos , Inflamación/inducido químicamente , Colon/metabolismo , Alimentación Animal/análisisRESUMEN
The trillions of commensal microorganisms comprising the gut microbiota have received growing attention owing to their impact on host physiology. Recent advances in our understandings of the host-microbiota crosstalk support a pivotal role of microbiota-derived metabolites in various physiological processes, as they serve as messengers in the complex dialogue between commensals and host immune and endocrine cells. In this review, we highlight the importance of tryptophan-derived metabolites in host physiology, and summarize the recent findings on the role of tryptophan catabolites in preserving intestinal homeostasis and fine-tuning immune and metabolic responses. Furthermore, we discuss the latest evidence on the effects of microbial tryptophan catabolites, describe their mechanisms of action, and discuss how perturbations of microbial tryptophan metabolism may affect the course of intestinal and extraintestinal disorders, including inflammatory bowel diseases, metabolic disorders, chronic kidney diseases, and cardiovascular diseases.
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Research has demonstrated that tryptophan (Trp) regulated the composition and metabolism of the gut microbiota. However, the detailed mode of action of Trp on the metabolism of intestinal commensal lactobacilli has not been well characterized. This study aimed to compare the effects of Trp concentration (0.2, 0.4, 0.6 mmol/L) in the media on the metabolism of Lactobacillus amylovorus and Limosilactobacillus mucosae isolated from the small intestine of piglets in vitro by high-performance liquid chromatography and metabolomics study. Results showed that increased Trp concentration increased (P < 0.05) net utilization of lysine, methionine, tryptophan, asparagine/aspartate, glutamine/glutamate, however, increased net production of glycine and taurine in Lac. amylovorus. In contrast, increased Trp concentration decreased (P < 0.05) net utilization of leucine, phenylalanine, and serine and increased (P < 0.05) net utilization of arginine and net production of ornithine and glycine in Lim. mucosae. Targeted metabolomics analysis showed that increased Trp concentration promoted (P < 0.05) the production of indole-3-lactic acid and 3-indoleacetic acid in the two lactobacilli strains. Increased concentration of Trp increased (P < 0.01) glycochenodeoxycholic acid metabolism in Lim. mucosae and glycocholic acid and taurocholic acid metabolism in Lac. amylovorus. Untargeted metabolomics analysis showed that metabolic pathways related to phenylalanine and tryptophan metabolism, and nicotinate and nicotinamide metabolism were regulated by Trp in Lim. mucosae. These findings will help develop new biomarkers and dietary strategies to maintain the functionality of the gut microbiota aiming at improving the nutrition and health of both humans and animals.
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Aminoácidos , Triptófano , Humanos , Porcinos , Animales , Triptófano/metabolismo , Aminoácidos/metabolismo , Bilis/metabolismo , Metabolómica , Fenilalanina , Glicina , Nitrógeno/metabolismoRESUMEN
Importin α has been described as a nuclear protein transport receptor that enables proteins synthesized in the cytoplasm to translocate into the nucleus. Besides its function in nuclear transport, an increasing number of studies have examined its non-nuclear transport functions. In both nuclear transport and non-nuclear transport, a functional domain called the IBB domain (importin ß binding domain) plays a key role in regulating importin α behavior, and is a common interacting domain for multiple binding partners. However, it is not yet fully understood how the IBB domain interacts with multiple binding partners, which leads to the switching of importin α function. In this study, we have distinguished the location and propensities of amino acids important for each function of the importin α IBB domain by mapping the biochemical/physicochemical propensities of evolutionarily conserved amino acids of the IBB domain onto the structure associated with each function. We found important residues that are universally conserved for IBB functions across species and family members, in addition to those previously known, as well as residues that are presumed to be responsible for the differences in complex-forming ability among family members and for functional switching.
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alfa Carioferinas , beta Carioferinas , Transporte Activo de Núcleo Celular , Núcleo Celular/metabolismo , Señales de Localización Nuclear/metabolismo , Unión Proteica , Receptores Citoplasmáticos y Nucleares/metabolismo , alfa Carioferinas/genética , alfa Carioferinas/metabolismo , beta Carioferinas/química , beta Carioferinas/metabolismoRESUMEN
The effects of long-term nitrate therapy are compromised due to protein S-Nitrosylation, which is mediated by nitric oxide (NO). This study is to determine the role of Akt S-Nitrosylation in the recovery of heart functions after ischaemia. In recombinant Akt protein and in HEK293 cells, NO donor decreased Akt activity and induced Akt S-Nitrosylation, but was abolished if Akt protein was mutated by replacing cysteine 296/344 with alanine (Akt-C296/344A). In endothelial cells, NO induced Akt S-Nitrosylation, reduced Akt activity and damaged multiple cellular functions including proliferation, migration and tube formation. These alterations were ablated if cells expressed Akt-C296/344A mutant. In Apoe-/- mice, nitroglycerine infusion increased both Akt S-Nitrosylation and infarct size, reduced Akt activity and capillary density, and delayed the recovery of cardiac function in ischaemic hearts, compared with mice infused with vehicle. Importantly, these in vivo effects of nitroglycerine in Apoe-/- mice were remarkably prevented by adenovirus-mediated enforced expression of Akt-C296/344A mutant. In conclusion, long-term usage of organic nitrate may inactivate Akt to delay ischaemia-induced revascularization and the recovery of cardiac function through NO-mediated S-Nitrosylation.
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Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Revascularización Miocárdica , Nitratos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Adenoviridae/metabolismo , Secuencia de Aminoácidos , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cisteína/metabolismo , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Ratones , Mutación/genética , Neovascularización Fisiológica/efectos de los fármacos , Óxido Nítrico/metabolismo , Nitroglicerina/farmacología , Nitroprusiato/farmacología , NitrosaciónRESUMEN
BACKGROUND: L-tryptophan (Trp) has been reported to regulate gut immune responses during inflammation. However, the underlying mechanisms are largely unknown. OBJECTIVE: We investigated the role of Trp supplementation on the serotonin receptor (HTR)-mediated immune response in the colon of mice with dextran sodium sulfate (DSS)-induced colitis. METHODS: In Experiment 1, male C57BL/6 mice were randomly assigned to 1 of 4 groups: Control (Con) or L-Trp supplementation [0.1 mg/(g body weight·d) in drinking water] (Trp) with (+DSS) or without 2% DSS in drinking water from days 8 to 14 of the 17-d study. In Experiments 2 and 3, Trp + DSS (Expt. 2) or DSS (Expt. 3) mice were treated as described above and subcutaneously administered with HTR1A or HTR4 antagonists (or their combination) or an HTR2 agonist from days 8 to 14 of the 15-d study. Changes in immune cell phenotypes, inflammatory mediators, and related cell signaling molecules were assessed by flow cytometry, real-time PCR, or Western blot. The mRNA abundances of Trp hydroxylase (Tph1), serotonin reuptake transporter (Slc6a4), and Htr in the colon were also assessed. RESULTS: Trp supplementation before DSS treatment upregulated the expression of colonic Slc6a4 (0.49 compared with 0.30), Htr1a (1.14 compared with 0.65), and Htr4 (1.08 compared with 0.70), downregulated the expression of Htr2a (1.54 compared with 1.89), and decreased the colonic serotonin concentration (11.5 compared with 14.8 nmol/g tissue) (P < 0.01). Trp regulated the DSS-induced immune response partly through attenuating the activation of toll-like receptor 4 (TLR4)-STAT3 signaling and nucleus p-65. Either an HTR2 agonist or HTR1A and HTR4 antagonists reversed the effects of Trp. CONCLUSIONS: In mice treated with DSS, Trp supplementation before DSS administration improved colonic immune responses partly by reducing colonic serotonin and subsequent interactions with HTR1A and HTR4, which are known to be present on neutrophils and macrophages.
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Colitis/metabolismo , Colon/metabolismo , Sulfato de Dextran/toxicidad , Suplementos Dietéticos , Homeostasis/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Serotonina/metabolismo , Triptófano/farmacología , Animales , Colitis/inducido químicamente , Dieta , Masculino , Ratones , Ratones Endogámicos C57BL , Piperazinas/farmacología , Distribución Aleatoria , Antagonistas de la Serotonina/administración & dosificación , Triptófano/administración & dosificaciónRESUMEN
Tryptophan is a nutritionally essential amino acid for both humans and animals. Besides acting as a building block for protein synthesis, tryptophan (Trp) and its metabolites are crucial for maintaining neurological function, immunity, and homeostasis in the body. To uncover the regulatory role of Trp and its metabolites in cell nutrition, metabolism and physiology, various analytical methods, including high-performance liquid chromatography (HPLC), have been developed to determine key Trp metabolites. Here we describe a rapid and sensitive method for the simultaneous analysis of Trp and its metabolites along with other amino acids by HPLC involving in-line pre-column derivatization with o-phthaldialdehyde (OPA) and dual-channel fluorescence detection. OPA reacts very rapidly (within 1 min) with Trp, 5-hydroxytryptophan, 5-hydroxytryptamine, and tryptamine at room temperature (e.g., 20-25 °C) in an autosampler. Their derivatives are immediately injected into the HPLC column without the need for extraction. Trp metabolites that cannot react with OPA but are fluorescent can be detected by setting the excitation and emission wavelengths of the fluorescence detector in another detection channel. The autosampler is programmed to mix Trp and its metabolites with OPA for 1 min to generate highly fluorescent derivatives for HPLC separation and detection (Channel A, excitation = 270 nm and emission = 350 nm; Channel B, excitation = 340 nm and emission = 450 nm). The detection limit for Trp and its metabolites is 30 pmol/mL or 150 fmol/injection. The total time for chromatographic separation (including column regeneration) is 55 min for each sample. Our HPLC method can be used for the analysis of amino acids (including Trp) in alkaline protein hydrolysates and of Trp and its metabolites in biological samples.
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Triptófano/análisis , Animales , Líquidos Corporales/química , Línea Celular , Cromatografía Líquida de Alta Presión/instrumentación , Cromatografía Líquida de Alta Presión/métodos , Fluorescencia , Humanos , Indicadores y Reactivos/química , Mucosa Intestinal/química , Triptófano/química , Triptófano/metabolismo , o-Ftalaldehído/químicaRESUMEN
Exhausted exercise has been reported to cause the damage of myocardial structure and function in terms of cardiomyocyte apoptosis, oxidative stress, and energy metabolism disturbance. Trimetazidine (TMZ), as an anti-ischemic agent, has been approved to be effective in promoting myocardial energy metabolism, anti-inflammatory, and anti-oxidation. However, few studies examined the effects of TMZ on myocardial injury induced by exhausted exercise. To investigate whether TMZ could ameliorate the exhaustive exercise-induced myocardial injury and explore the underlying mechanisms, here the rat model of exhaustive exercise was induced by prolonged swimming exercise and TMZ was administrated to rats before exhaustive exercise. According to the results, we demonstrated that exhaustive exercise led to cardiomyocyte damage in rats as evidenced by elevations in cTnI and NT-proBNP levels, and decrease in CX43 expression, which was attenuated by TMZ treatment. Moreover, the administration of TMZ was found to restrain exhaustive exercise-induced oxidative stress damage by increasing GSH level, SOD and GSH-Px activities, and decreasing MDA level. Additionally, TMZ ameliorated myocardial injury by inhibiting apoptosis via reducing Bax/Bcl-2 ratio and down-regulating cleaved caspase-3, cleaved PARP, and cytochrome c levels in the myocardium of rats. Furthermore, we found that TMZ suppressed oxidative stress and cardiomyocyte apoptosis via activation of Nrf2/HO-1 and inactivation of NF-κB signaling pathways. Therefore, our study suggested that TMZ provided cardioprotection in rats after exhaustive exercise, indicating TMZ might served as a potential therapeutic drug for exhaustive exercise-induced myocardial injury.
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AIMS: The impaired angiogenesis is the major cause of diabetic delayed wound healing. The molecular insight remains unknown. Previous study has shown that high glucose (HG) activates Na+/H+ exchanger 1 (NHE1) and induces intracellular alkalinization, resulting in endothelial dysfunction. The aim of this study is to investigate whether activation of NHE1 in endothelial cells by HG damages the angiogenesis in vitro and in vivo. METHODS AND RESULTS: We used western blot to detect the phosphorylations of both Akt and Girdin, and pH-sensitive BCECF fluorescence to assay NHE1 activity and pHi value, respectively. The angiogenesis was evaluated by measuring the number of tube formation in vitro, and blood perfusion by laser doppler and neovascularization by staining CD31 in vivo. Our results indicated that induction of intracellular acidosis (IA) increased p-Akt and p-Girdin in human umbilical vein endothelial cells (HUVEC). HG activated NHE1 and increased pHi value in a time-dependent manner, associated with the decreased phosphorylations of both Akt and Gridin, while inhibition of NHE1 by amiloride abolished the HG-induced reductions of p-Akt and p-Girdin. However, silence of Akt by siRNA transfection or pharmacological inhibitors (wortmannin and LY294002) bypassed IA-induced Girdin phosphorylation. Overexpression of constitutively active Akt abolished HG-reduced Girdin phosphorylation. In addition, upregulation of Akt or inhibition of NHE1 remarkably attenuated HG-impaired tube formation in HUVEC. In vivo study revealed that amiloride dramatically rescued hyperglycemia-delayed blood perfusion and neovascularization by augmenting ischemia-induced angiogenesis. CONCLUSION: IA promotes ischemia-induced angiogenesis via Akt-dependent Girdin phosphorylation in diabetic mice.
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Acidosis/metabolismo , Hiperglucemia/metabolismo , Isquemia/metabolismo , Proteínas de Microfilamentos/metabolismo , Neovascularización Patológica/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Acidosis/patología , Animales , Miembro Posterior/irrigación sanguínea , Miembro Posterior/metabolismo , Miembro Posterior/patología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Hiperglucemia/patología , Líquido Intracelular/metabolismo , Isquemia/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Neovascularización Patológica/patología , Transducción de Señal/fisiologíaRESUMEN
AIMS: Diabetes mellitus (DM) has overtaken infection and immunological factors as the most common cause of end-stage renal disease. The 2007 Kidney Disease Outcomes Quality Initiative (KDOQI) guideline is a widely accepted guideline for the clinical diagnosis of diabetic nephropathy (DN) and non-diabetic renal disease (NDRD). Our study sought to verify its diagnostic ability in the Chinese population. METHODS: We included 773 patients with DM who underwent a renal biopsy at the Chinese PLA General Hospital from 2007 to 2016. All patients were divided into three groups according to their pathological findings: isolated DN, isolated NDRD, and DN combined with NDRD. RESULTS: Good sensitivity and poor specificity were found for the prediction of NDRD in the Chinese population. Rapidly decreasing estimated glomerular filtration rate, systemic disease, refractory hypertension, and the existence of "grey area" patients may have contributed to the poor diagnostic ability. CONCLUSIONS: The diagnostic ability of the 2007 KDOQI guideline for DN and NDRD was unsatisfactory. The high sensitivity and low specificity of the guideline made it more suitable as screening criteria rather than as diagnostic criteria.
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Nefropatías Diabéticas , Insuficiencia Renal Crónica , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , China , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/patología , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/patología , Resultado del Tratamiento , Estudios de Validación como AsuntoRESUMEN
Diabetic nephropathy (DN) and nondiabetic renal disease (NDRD) are two major categories of renal diseases in diabetes mellitus patients. The clinical differentiation among them is usually not so clear and effective. In this study, sera from DN and NDRD patients were collected, and glycan profiles of serum proteins from DN and NDRD patients were investigated and compared by using lectin microarray and lectin blot. Then, altered glycoproteins were enriched by lectin coupled magnetic particle conjugate and characterized by LC-MS/MS. We found significant change in glycan patterns between DN and NDRD patients. In particular, the relative abundance of the glycopattern of Galß1-3GalNAc which was identified by BPL (Bauhinia purpurea lectin) was significantly decreased in DN patients compared to four types of NDRD patients (p < 0.05). Moreover, BPL blotting indicated that the proteins with a molecular weight of about 53 kDa exhibited low staining signal in DN compared to all NDRD groups, which was consistent with results of lectin microarrays. After enriching by BPL and identification by LC-MS/MS, a total of 235 and 258 proteins were characterized from NDRD and DN respectively. Among these, the relative abundance of 12 isolated serum proteins exhibited significantly alteration between DN and NDRD (p < 0.05). Our findings indicated not only the relative abundance of Galß1-3GalNAc on serum proteins but also certain glycoproteins modified with this glycopattern showed a difference between DN and NDRD patients. This suggested that the analysis of this alteration by using urine specimens may constitute an additional valuable diagnostic tool for differentiating DN and NDRD with a non-invasive method.
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Diabetic nephropathy is a major cause of chronic kidney disease and end-stage kidney disease. However, so little is known about alterations of the glycopatterns in urine with the development of diabetic nephropathy. Presently, we interrogated glycopatterns in urine specimens using a lectin microarray. The results showed that expression levels of Siaα2-6Gal/GalNAc recognized by SNA exhibited significantly increased tendency with the development of diabetic nephropathy; moreover, SNA blotting indicated glycoproteins (90 kDa, 70 kDa, and 40 kDa) in urine may contribute to this alteration. Furthermore, the glycopatterns of (GlcNAc)2-4 recognized by STL exhibited difference between diabetic and nondiabetic nephropathy. The results of urinary protein microarray fabricated by another 48 urine specimens also indicated (GlcNAc)2-4 is a potential indictor to differentiate the patients with diabetic nephropathy from nondiabetic nephropathy. Furtherly, STL blotting showed that the 50 kDa glycoproteins were correlated with this alteration. In conclusion, our data provide pivotal information to monitor the development of diabetic nephropathy and distinguish between diabetic nephropathy and nondiabetic renal disease based on precise alterations of glycopatterns in urinary proteins, but further studies are needed in this regard.
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Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/orina , Glicoproteínas/química , Urinálisis/métodos , Adulto , Anciano , Biomarcadores/orina , Biopsia , Diabetes Mellitus Tipo 2/orina , Femenino , Glicoproteínas/análisis , Humanos , Fallo Renal Crónico/orina , Lectinas/química , Masculino , Persona de Mediana Edad , Análisis por Matrices de Proteínas , Insuficiencia Renal Crónica/orina , Análisis de Matrices Tisulares , Adulto JovenRESUMEN
Despite the success of CD20 antibody rituximab in immunotherapy, acquired resistance is one of the prime obstacles for the successful treatment of B-cell malignancies. There is an urgent need to intensify efforts against resistance in cancer treatment. Growing evidence indicated that lysosomes may form an "Achilles heel" for cancer cells by sensitizing them to death pathways. Here, we uncover an important role of CD20 in initiation of ceramide/lysosomal membrane permeabilization (LMP)-mediated cell death, showing that colocalization of CD20-TNFR1 after type II CD20 antibody ligation can stimulate de novo ceramide synthesis by ceramide synthase and consequently induce remarkable lysosomal permeabilization (LMP) and lysosome-mediated cell death. Further studies show that the potent lysosome-mediated cell death induced by CD20 antibodies exhibits a profound killing effect against both rituximab-sensitive and -resistant (RR) lymphoma. Furthermore, engineering of rituximab by introducing a point mutation endows it with the ability to induce potent ceramide/LMP-mediated cell death in both RR lymphoma and primary B-cell malignancies from patients with rituximab-refractory, suggesting the potential clinical application to combat rituximab resistance.
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AIMS/INTRODUCTION: There are sparse and limited studies on erythrocyte morphology in renal biopsy identifying nephropathic patients among type 2 diabetics. The present study sought to clarify the predictive value of dysmorphic erythrocytes in type 2 diabetics with non-diabetic renal disease and influences on hematuria. MATERIALS AND METHODS: We examined 198 patients with type 2 diabetes who underwent kidney biopsies between 2012 and 2013. Hematuria was defined as >3 or >10 red blood cells per high-power field (RBCs/hpf) in urine sediment. If >80% of the erythrocytes were dysmorphic, glomerular hematuria was diagnosed. Clinical findings and predictive value of dysmorphic erythrocytes were compared between patients with hematuria (n = 19) and those without (n = 61). The potential risk factors for hematuria among diabetic nephropathy patients were also screened. RESULTS: There was a statistically significant difference between the diabetic nephropathy group and the non-diabetic renal disease group (6.6 vs 16.8%; P = 0.04) when the demarcation point of hematuria was 10 RBCs/hpf. When the definition of hematuria was based on an examination of urinary erythrocyte morphology, a marked difference was seen (3.3 vs 24.8%; P < 0.001). Glomerular hematuria showed high specificity and a positive predictive value (0.97 and 0.94, respectively) in non-diabetic renal disease. A multivariate analysis showed that nephrotic syndrome was significantly associated with hematuria (odds ratio 3.636; P = 0.034). CONCLUSIONS: Dysmorphic erythrocytes were superior to hematuria for indicating non-diabetic renal disease in type 2 diabetics. Nephrotic syndrome was an independent risk factor for hematuria.
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Forma de la Célula/fisiología , Diabetes Mellitus Tipo 2/sangre , Nefropatías Diabéticas/sangre , Eritrocitos/metabolismo , Eritrocitos/patología , Hematuria/sangre , Adulto , China/epidemiología , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/epidemiología , Femenino , Hematuria/diagnóstico , Hematuria/epidemiología , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/diagnóstico , Enfermedades Renales/epidemiología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Persistent proteinuria is an important factor contributing to the progression of diabetic nephropathy. The present randomized double-blind placebo-controlled multicenter clinical study evaluated the efficacy and safety of telmisartan combined with the antioxidant probucol in reducing urinary protein levels in patients with type 2 diabetes (T2D). METHODS: Patients with T2D and 24-h proteinuria 0.5-3 g were enrolled in the study and randomly assigned to one of two groups: a telmisartan or a probucol + telmisartan group. Both groups were given telmisartan 80 mg q.d. for 48 weeks. The probucol + telmisartan group was given probucol 500 mg b.i.d. for the first 24 weeks, with the dosage then reduced to 250 mg b.i.d. for the remaining 24 weeks. The telmisartan group was given probucol placebo. RESULTS: In all, 160 patients were enrolled in the present study. The 24-h proteinuria levels were significantly reduced in the probucol + telmisartan compared with telmisartan group. For patients with baseline 24-h proteinuria levels <1.0 g, both treatments resulted in significant reductions in 24-h proteinuria levels after 48 weeks treatment. However, in patients with baseline 24-h proteinuria levels ≥1.0 g, 24-h proteinuria levels after 48 weeks treatment were only reduced in the probucol + telmisartan group. There was no significant difference between the two groups for either adverse cardiovascular or other events. CONCLUSIONS: In patients with diabetic nephropathy, probucol combined with telmisartan more effectively reduces urinary protein levels than telmisartan alone.
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Bencimidazoles/uso terapéutico , Benzoatos/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Probucol/uso terapéutico , Proteinuria/prevención & control , Anciano , Análisis de Varianza , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/uso terapéutico , Bencimidazoles/efectos adversos , Benzoatos/efectos adversos , Glucemia/metabolismo , Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/prevención & control , Método Doble Ciego , Quimioterapia Combinada , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hiperpotasemia/inducido químicamente , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Masculino , Persona de Mediana Edad , Probucol/efectos adversos , Proteinuria/complicaciones , Telmisartán , Resultado del TratamientoRESUMEN
Although trastuzumab has succeeded in breast cancer treatment, acquired resistance is one of the prime obstacles for breast cancer therapies. There is an urgent need to develop novel HER2 antibodies against trastuzumab resistance. Here, we first rational designed avidity-imporved trastuzumab and pertuzumab variants, and explored the correlation between the binding avidity improvement and their antitumor activities. After characterization of a pertuzumab variant L56TY with potent antitumor activities, a bispecific immunoglobulin G-like CrossMab (Tras-Permut CrossMab) was generated from trastuzumab and binding avidity-improved pertuzumab variant L56TY. Although, the antitumor efficacy of trastuzumab was not enhanced by improving its binding avidity, binding avidity improvement could significantly increase the anti-proliferative and antibody-dependent cellular cytotoxicity (ADCC) activities of pertuzumab. Further studies showed that Tras-Permut CrossMab exhibited exceptional high efficiency to inhibit the progression of trastuzumab-resistant breast cancer. Notably, we found that calreticulin (CRT) exposure induced by Tras-Permut CrossMab was essential for induction of tumor-specific T cell immunity against tumor recurrence. These data indicated that simultaneous blockade of HER2 protein by Tras-Permut CrossMab could trigger CRT exposure and subsequently induce potent tumor-specific T cell immunity, suggesting it could be a promising therapeutic strategy against trastuzumab resistance.
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BACKGROUND: The aims of the present study were to validate the differential diagnostic model of diabetic nephropathy (DN) and non-diabetic renal diseases (NDRD) established in 2003 and to establish a new diagnostic model suitable for the current clinical characteristics of DN. METHODS: We examined 200 patients with Type 2 diabetes who underwent kidney biopsy from 2004 to 2012. The 2003 differential diagnostic model based on the data collected from 1993 to 2003 was evaluated by the diagnostic test and changes in the clinical differentiation parameters of DN and NDRD were analyzed. Logistic regression, receiver operating characteristics (ROC) curve, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analysis were applied. RESULTS: The 2003 diagnostic model showed an accuracy of 77.5%. A significantly elevated incidence of hematuria, longer history of diabetes, and reduced level of glycated hemoglobin (HbA1c) were observed in the DN group from 2004 to 2012 compared with DN group from 1993 to 2003. Histories of diabetes mellitus (Dm), systolic blood pressure (Bp), HbA1c (Gh), hematuria (Hu), diabetic retinopathy (Dr), and hemoglobin (Hb) are independently related to DN. Thus, a new diagnostic model was constructed as follows: PDN = exp (0.846 + 0.022 Dm + 0.033Bp + 2.050 Gh-2.664 Hu-0.078 Hb + 2.942Dr)/[1 + exp (0.846 + 0.022 Dm + 0.033 Bp + 2.050 Gh-2.664 Hu-0.078 Hb + 2.942 Dr)].Validation tests determined that the accuracy of the new model were 90.9%. CONCLUSIONS: Changes in people with DN, clinical characteristics have reduced the diagnostic efficacy of the 2003 diagnostic model. The newly established model can provide a better, more current differentiation between DN and NDRD.
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Nefropatías Diabéticas/diagnóstico , Enfermedades Renales/diagnóstico , Riñón/patología , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos TeóricosRESUMEN
BACKGROUND AND OBJECTIVES: The outcome of idiopathic membranous nephropathy (IMN) in adults with nephrotic-range proteinuria and decreased renal function has seldom been described and the predictive value of pathological features is debated. This study aimed to describe the clinical course of this patient subgroup and to identify independently predictive pathological features. MATERIALS AND METHODS: We evaluated 129 adults with biopsy-proven IMN diagnosed from 2002 to 2011. All patients had chronic kidney disease (CKD) stages 2-4 and nephrotic-range proteinuria (≥3.5 g/day). Primary outcomes were a 20 or 50 % decline in renal function, progression to end-stage renal disease (ESRD), or all-cause mortality. RESULTS: Of 129 patients, 38 (30 %) presented with proteinuria ≥8.0 g/day and 37 (29 %) with CKD stages 3-4. Thirteen (10 %) presented with segmental sclerosis, 97 (75 %) with arteriosclerosis, 42 (33 %) with moderate-to-severe tubulointerstitial injury, and 86 (67 %) with C3 deposition. Over a median follow-up of 34 months (range 12-135), 51 patients (40 %) had a 20 % decline in renal function, 27 (21 %) a 50 % decline, 14 (11 %) developed ESRD, and 19 (15 %) died. Segmental sclerosis and tubulointerstitial injury but not arteriosclerosis or C3 deposition were independent risk factors for 20 and 50 % renal function decline and progression to ESRD. CONCLUSIONS: Segmental sclerosis and tubulointerstitial injury predict renal outcomes independent of clinical data in nephrotic IMN patients with decreased renal function.
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Tasa de Filtración Glomerular , Glomerulonefritis Membranosa/complicaciones , Riñón/patología , Riñón/fisiopatología , Síndrome Nefrótico/etiología , Insuficiencia Renal Crónica/etiología , Anciano , Biopsia , Progresión de la Enfermedad , Femenino , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/mortalidad , Glomerulonefritis Membranosa/fisiopatología , Humanos , Fallo Renal Crónico/etiología , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/mortalidad , Síndrome Nefrótico/fisiopatología , Valor Predictivo de las Pruebas , Proteinuria/etiología , Proteinuria/fisiopatología , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/mortalidad , Insuficiencia Renal Crónica/fisiopatología , Estudios Retrospectivos , Factores de Riesgo , Esclerosis , Factores de TiempoRESUMEN
BACKGROUND: Laparoscopic cholecystectomy is the gold standard treatment for cholecystectomy. Recently, single-incision laparoscopic cholecystectomy (SILC) has been suggested as an alternative technique. METHODS: Six databases were searched and reference lists of retrieved articles were checked to identify eligible studies. Data from randomized clinical trials related to the safety and effectiveness of SILC versus conventional laparoscopic cholecystectomy (CLC) were extracted by 2 independent reviewers. Odds ratio and mean differences were calculated with 95% confidence intervals based on intention-to-treat analyses whenever possible. RESULTS: Fifteen studies with 1113 patients met the eligibility criteria. Methodologic quality was unclear in most trails. Operating time was significantly longer in the single-incision laparoscopic surgery group compared with the CLC group (P<0.00001). Cosmesis was improved in single-incision laparoscopic patients at 1 month (P<0.00001). The pooled mean difference in pain scores at 24 hours was -0.75 in favor of the SILC technique (P=0.04). There was no significant difference in the conversion rates, adverse events, analgesia requirements, or the length of hospital stay between the 2 groups. CONCLUSIONS: The current evidence shows that patients with uncomplicated cholelithiasis or polypoid lesions of the gallbladder who prefer a better cosmetic outcome, SILC offers a safe alternative to CLC. Further high-powered randomized trials are need to determine whether SILC truly offer any advantages, especially be focused on failure of technique, adverse events, cosmesis, and quality of life.
Asunto(s)
Colecistectomía Laparoscópica/métodos , Colelitiasis/cirugía , Enfermedades de la Vesícula Biliar/cirugía , Adulto , Analgésicos/uso terapéutico , Conversión a Cirugía Abierta/estadística & datos numéricos , Femenino , Humanos , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Tempo Operativo , Satisfacción del Paciente , Complicaciones Posoperatorias/etiología , Sesgo de Publicación , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
BACKGROUND: Cisplatin (DDP) is one of most effective and most commonly used therapeutic agent in treating tumors, it can accumulate in the kidney and lead to acute renal failure. MicroRNA-181a can induce cell apoptosis by suppressing the expression of Bcl-2 family. In the present study, we investigated the role of microRNA-181a in the apoptosis of tubular epithelial cell induced by DDP. METHODS: HK-2 cells were cultured, transfected with microRNA-181a inhibitor for 48 hours, and stimulated with 50 µmol/L cisplatin for 24 hours. MicroRNA-181a expression was analyzed by real time PCR, and cell apoptosis was detected by flow cytometry. Moreover, Bcl-2 and Bcl-2-associated X protein (Bax) expression were measured by Western blotting. RESULTS: MicroRNA-181a expression significantly down-regulated in cells transfected with microRNA-181a inhibitor, compared with that in untransfectd cells (21.19 ± 2.01 vs. 38.87 ± 1.97, P < 0.05). Cell apoptosis induced by DDP significantly decreased in cells transfected with MicroRNA-181a inhibitor. Compared with DDP treated cells alone, Bcl-2 expression strikingly was up-regulated and Bax expression was down-regulated in cells transfected with microRNA-181a inhibitor. CONCLUSION: One pathway of DDP induces apoptosis of tubular epithelial cell by suppressing Bcl-2 expression is achieved by regulating the target gene of MicroRNA-181a.