Evaluation of coronary function in female rats with severe type 1 diabetes: Effects of combined treatment with insulin and pyridoxamine.

BACKGROUND: This study aimed to evaluate the coronary function, myocardium, and epicardial adipose tissue (EAT) in female rats with severe type 1 diabetes and the effects of combined treatment with insulin and pyridoxamine (AGEs inhibitor). METHODS: Female Wistar rats were divided into groups: control (CTR, n = 13), type 1 diabetes (DM1, n = 12), type 1 diabetes treated with insulin (DM1 + INS, n = 11), and type 1 diabetes treated with insulin and pyridoxamine (DM1 + INS + PDX, n = 14). The vascular responsiveness was performed in the septal coronary artery and the protein expressions of AGE, RAGE, GPER, NF-kB was evaluated in the left ventricle (LV), as well as the reactive oxygen species (ROS) was measured in LV and in EAT. We analyzed plasma levels of glucose, estradiol, Nε-carboxymethylisine (CML), thiobarbituric acid reactive substances (TBARS), catalase (CAT), and superoxide dismutase (SOD). RESULTS: The maximal responses to ACh were reduced in the DM1 compared with the CTR group, accompanied by an increase in circulating glucose, CML, and TBARS. Additionally, the expression of NF-kB in LV and generation of ROS in the presence of MnTMPyP (SOD mimetic) were increased in the DM1 group compared with CTR. Only the combined treatment was effective for fully re-establish ACh relaxation response, NF-kB protein expression, ROS generation, and increased SOD activity in the DM1 + INS + PDX group. CONCLUSION: The reduction of the endothelium-dependent relaxation response in the septal coronary artery of female rats with severe type 1 diabetes was normalized with the combined treatment with insulin and pyridoxamine, associated with reduced inflammation and oxidative stress in the myocardium and increased circulating antioxidant activity.

Pyridoxamine improves metabolic and microcirculatory complications associated with nonalcoholic fatty liver disease.

OBJECTIVE: We investigated the protective effects of pyridoxamine against metabolic and microcirculatory complications in nonalcoholic fatty liver disease. METHODS: Nonalcoholic fatty liver disease was established by a high-fat diet administration over 28 weeks. Pyridoxamine was administered between weeks 20 and 28. The recruitment of leukocytes and the number of vitamin A-positive hepatic stellate cells were examined by in vivo microscopy. Laser speckle contrast imaging was used to evaluate microcirculatory hepatic perfusion. Thiobarbituric acid reactive substances measurement and RT-PCR were used for oxidative stress and inflammatory parameters. advanced glycation end products were evaluated by fluorescence spectroscopy. RESULTS: The increase in body, liver, and fat weights, together with steatosis and impairment in glucose metabolism observed in the nonalcoholic fatty liver disease group were attenuated by pyridoxamine treatment. Regarding the hepatic microcirculatory parameters, rats with high-fat diet-induced nonalcoholic fatty liver disease showed increased rolling and adhesion of leukocytes, increased hepatic stellate cells activation, and decreased tissue perfusion, which were reverted by pyridoxamine. Pyridoxamine protected against the increased hepatic lipid peroxidation observed in the nonalcoholic fatty liver disease group. Pyridoxamine treatment was associated with increased levels of tumor necrosis factor alpha (TNF-α) mRNA transcripts in the liver. CONCLUSION: Pyridoxamine modulates oxidative stress, advanced glycation end products, TNF-α transcripts levels, and metabolic disturbances, being a potential treatment for nonalcoholic fatty liver disease-associated microcirculatory and metabolic complications.

Papel de produtos finais de glicação avançada nas alterações hepáticas e metabólicas em modelo experimental de síndrome metabólica / Role of advanced glycation end products in liver and metabolic changes in an experimental model of metabolic syndrome

A doença hepática gordurosa não alcoólica (DHGNA) afeta um terço da população adulta e é definida como o acúmulo de gordura no fígado de indivíduos que não consomem excessiva quantidade de álcool. No entanto, os mecanismos moleculares responsáveis pela progressão da doença ainda não foram completamente elucidados. Estudos anteriores do nosso grupo e outros autores demonstraram que o aumento nos níveis de produtos finais de glicação avançada (AGEs) e distúrbios da microcirculação estão presentes na DHGNA, mas nenhuma evidência direta da ligação entre os níveis de AGEs, estresse oxidativo, inflamação e alterações microcirculatórias hepáticas foi demonstrada. No presente trabalho, nós investigamos os efeitos protetores da piridoxamina (PirPM), um inibidor da formação de AGEs, nas complicações metabólicas e microcirculatórias na DHGNA. A DHGNA foi induzida por uma dieta hiperlipídica (HFD) em ratos Wistar durante 28 semanas. O tratamento com Pir (60 mg/Kg/dia, i.p.) foi administrado entre as semanas 20 e 28. Na microcirculação do fígado, o recrutamento de leucócitos e o número de células estreladas hepáticas (HSC´s) ativadas foram examinados por microscopia intravital.

A perfusão tecidual foi acessada por fluxometria utilizando o laser speckle. O estresse oxidativo e o marcador de inflamação foram avaliados pela dosagem de substâncias reativas ao ácido tiobarbitúrico (TBARs) e RT-PCR, respectivamente. Os AGEs no fígado foram avaliados por espectroscopia de fluorescência. Foi observado que a alteração no metabolismo da glicose e aumento do peso corporal, hepático e de tecido adiposo e esteatose no grupo DHGNA foi revertido pelo tratamento com Pir. Em relação aos parâmetros microcirculatórios hepáticos, ratos com DHGNA apresentaram aumento do rolamento e adesão de leucócitos, da ativação de HSCs e diminuição da perfusão tecidual. A Pir mostrou um efeito vasoprotetor nas alterações da microcirculação hepática induzidas pela DHGNA. O fígado de grupo DHGNA apresentou níveis elevados de peroxidação lipídica, que foram parcialmente revertidos pelo tratamento com Pir. Em conclusão, a Pir apresenta importante efeito vasoprotetor e antioxidante, além de modular os distúrbios metabólicos, sendo, portanto, um potencial tratamento para complicações microcirculatórias e metabólicas associadas à DHGNA. (AU)

Established and Emerging Strategies in the Treatment of Chronic Kidney Disease.

Chronic kidney disease (CKD) is a common condition that has become a significant public health concern. The mainstay therapeutic approach to CKD is based on renin-angiotensin system blockade as well as blood pressure and glycemic control. Despite these interventions, the management of CKD remains suboptimal, with a large proportion of the CKD population progressing to end-stage renal disease. Newer strategies for the treatment of CKD have emerged over the past years focusing on decreasing inflammation and delaying the development of fibrosis. Despite promising results in experimental models and small randomized studies, adequately powered randomized trials are required to evaluate the benefits and risks of these therapies in the CKD population. In this review, we discuss the evidence behind, and gaps in our knowledge of, established therapies as well as newer potential strategies for managing CKD, concentrating on interventions that currently are being evaluated in randomized studies.

Photophysics and photochemical studies of the vitamin B6 group and related derivatives.

The photophysics and photochemical properties of vitamin B6 constituents and analogs were studied as function of pH and solvent. The pK of the phenolic oxygen and the pyridine ring nitrogen depends on the electron donor-acceptor ability of the 4-substituent, and agrees with the calculated proton affinity. For all studied compounds, the fluorescence properties showed that the phenolic oxygen is 8 units more acidic in the lowest singlet excited state than in the ground state. The pyridine N-atom is slightly more basic in the excited state. At pH of biological significance, pH 6-8, pyridoxamine and 4-pyridoxic acid are the more efficient chromophores with higher fluorescence yield and longer lifetime. Spectroscopic studies showed that the tautomeric equilibrium depends on the nature of the 4-substituent. The quenching of the singlet excited state of pyridoxamine and 4-pyridoxic acid by amino acids, free or in a peptide, and DNA bases at pH 7 was studied by time-resolved fluorescence techniques. The quenching rate constants are well correlated with the redox properties of the pyridoxinic compound and amino acids, and are related to the free energy change in the electron transfer process. Guanosine and pyrimidine bases also are efficient quenchers, involving an electron transfer reaction.

[Advanced glycosylation end products and chronic complications of diabetes mellitus]. / Productos finales de glicación avanzada y complicaciones crónicas de la diabetes mellitus.

OBJECTIVE: To review the literature on the advanced glycation end products (AGEs) in diabetes, with especial interest on their role in the pathophysiology of the chronic complications of diabetes mellitus. MATERIALS: Representative papers were selected through a computer MEDLINE search from 1985 to 2000. RESULTS: Hyperglycemia causes irreversible microvascular and macrovascular complications, including retinopathy, neuropathy, nephropathy, atherosclerosis and cerebrovascular disease. There is evidence that glycation leads to chemical modification of proteins, and other macromolecules and it contributes to the pathogenesis of diabetic complications. Several AGEs and their receptors have been identified. The inhibition of AGE formation is under intensive investigation to prevent diabetic complications. From several inhibitors studied, Amadorins offer great therapeutic potential. CONCLUSIONS: It is known that a heterogeneous group of AGEs is formed by glycation. The mechanism of AGE formation is partially understood, making it difficult to identify the precise chemical products responsible for in vivo damage and also to develop specific inhibitors.