Yixin Ningshen Tablet Alleviates Comorbidity of Myocardial Infarction and Depression by Enhancing Myocardial Energy Metabolism and Increasing Availability of Monoamine Neurotransmitter / 中国结合医学杂志

OBJECTIVE@#To investigate the therapeutic effect of Yixin Ningshen Tablet (YXNS) on comorbidity of myocardial infarction (MI) and depression in rats and explore the underlying mechanism.@*METHODS@#The Sprague-Dawley rats were randomly divided into 5 groups with 7 rats in each group according to their weights, including control, model, fluoxetine (FLXT, 10 mg/kg), low-dose YXNS (LYXNS, 100 mg/kg), and high-dose YXNS (HYXNS, 300 mg/kg) groups. All rats were pretreated with corresponding drugs for 12 weeks. The rat model of MI and depression was constructed by ligation of left anterior descending coronary artery and chronic mild stress stimulation. The echocardiography, sucrose preference test, open field test, and forced swim test were performed. Myocardial infarction (MI) area and myocardial apoptosis was also detected. Serum levels of interleukin (IL)-6, IL-1β, tumor necrosis factor-α (TNF-α), 5-hydroxytryptamine (5-HT), adrenocorticotrophic hormone (ACTH), corticosterone (CORT), and norepinephrine (NE) were determined by enzyme linked immunosorbent assay. The proteins of adenosine 5'-monophosphate -activated protein kinase (AMPK), p-AMPK, peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and nuclear respiratory factor 1 (NRF1) in heart were detected by Western blot analysis. The expression levels of TNF-α, IL-6, indoleamine 2,3-dioxygenase (IDO1), kynurenine 3-monooxygenase (KMO), and kynureninase (KYNU) in hippocampus were detected by real-time quantitative polymerase chain reaction.@*RESULTS@#Compared with the model group, the cardiac function of rats treated with YXNS improved significantly (P<0.01). Meanwhile, YXNS effectively reduced MI size and cardiomyocytes apoptosis of rats (P<0.01 or P<0.05), promoted AMPK phosphorylation, and increased PGC-1α protein expression (P<0.01 or P<0.05). HYXNS significantly increased locomotor activity of rats, decreased the levels of TNF-α, IL-6 and IL-1β, and increased the serum levels of 5-HT, NE, ACTH, and CORT (all P<0.05). Moreover, HYXNS decreased the mRNA expressions of IDO1, KMO and KYNU (P<0.05).@*CONCLUSIONS@#YXNS can relieve MI by enhancing myocardial energy metabolism. Meanwhile, YXNS can alleviate depression by resisting inflammation and increasing availability of monoamine neurotransmitters. It may be used as a potential drug to treat comorbidity of MI and depression.

Ácido fólico em excesso: efeitos sobre o metabolismo das vitaminas B2 e B6, o catabolismo do triptofano e a resposta imune / Folic acid excess: effects on vitamin B2 and B6 metabolism, tryptophan catabolism and immune response

Introdução: A suplementação com ácido fólico (AF) é recomendada em algumas condições para evitar a deficiência de folato, como para mulheres no período periconcepcional e durante a gestação. Atualmente, existe uma preocupação quanto ao consumo excessivo de AF pela população pelo uso de suplementos com altas doses dessa vitamina. As vitaminas B6 e B2 agem como cofatores no metabolismo de um carbono, e o uso de altas doses de AF pode influenciar o metabolismo de ambas vitaminas e, consequentemente, interferir em metabolismos importantes das quais elas participam, como a via das quinureninas, e no sistema imune. Objetivo: Avaliar os efeitos da intervenção diária com uma alta dose de AF (5 mg) por 90 dias sobre marcadores do estado das vitaminas do complexo B, e as consequências sobre os metabólitos da via das quinureninas e o sistema imune em adultos saudáveis. Material e Métodos: 64 indivíduos saudáveis foram submetidos à intervenção diária com 5 mg de AF por 90 dias. Coletas de sangue foram realizadas antes (baseline) e após 45 e 90 dias de intervenção. As concentrações séricas de folato e vitamina B12 foram avaliadas por métodos microbiológicos. As concentrações séricas das vitaminas B6 (piridoxal 5'-fosfato (PLP), piridoxal (PL) e ácido 4-piridóxico (PA)), B2 (riboflavina e flavina mononucleotídeo (FMN)), B1 (tiamina e tiamina monofosfato (TMP)) e B3 (ácido nicotínico, nicotinamida e N1-metilnicotinamida), bem como de triptofano, quinurenina e metabólitos, foram avaliadas por LC-MS/MS. A proteína C-reativa ultrassensível (PCRus) foi determinada por imunoturbidimetria, e as concentrações séricas de interleucina (IL)-6, IL-8, IL-10, interferon gama (IFN-γ) e fator de necrose tumoral alfa (TNF-α) foram avaliadas por ensaio multiplex. A expressão de RNAm de DHFR (dihidrofolato redutase), MTHFR (metilenotetrahidrofolato redutase), IL8, TNFA e IFNG em leucócitos mononucleares (PBMC) foram avaliadas por PCR em tempo real. O número de células T regulatórias (Treg) (CD3+, CD4+, CD25high, FoxP3+, CD127-) foi avaliado após incubação dos PBMC com PMA e ionomicina ou veículo por 18h, por imunofenotipagem. Resultados: Houve um grande aumento das concentrações de folato sérico após 45 e 90 dias de intervenção com AF. Não houve diferença nas concentrações de vitamina B12 antes e após a intervenção. As concentrações séricas de PLP foram semelhantes antes e após a intervenção, entretanto, um aumento de PL sérico foi observado após 45 e 90 dias, e de PA após 45 dias, quando comparado ao baseline. Riboflavina e FMN foram maiores após 45 e 90 dias em relação ao baseline. A tiamina sérica foi menor após 45 dias, e as concentrações de TMP foram maiores após 90 dias quando comparados aos períodos anteriores. Não houve diferença nas concentrações de vitamina B3 antes e após a intervenção. Dentre os metabólitos da via das quinureninas, apenas o ácido antranílico apresentou aumento após 45 e 90 dias, enquanto o ácido picolínico diminuiu após 90 dias. PCRus, IL-6, IL-8, IL-10, IFN-γ e TNF-α séricos foram semelhantes no baseline e após a intervenção. Um aumento da expressão de RNAm de DHFR e TNFA foi observado após, respectivamente, 90 dias e 45 e 90 dias de intervenção. Após 90 dias de intervenção com AF, foi observada diminuição do número de células Treg após estímulo com PMA e ionomicina. Conclusão: O uso diário de 5 mg de AF foi associado a alterações nas concentrações séricas de marcadores do estado de vitaminas do complexo B e da via das quinureninas, bem como a diminuição do número de células Treg

Introduction: Folic acid (FA) supplementation is recommended in some conditions to avoid folate deficiency, as women during periconceptional period and pregnancy. Currently, there is a concern about the excessive consumption of FA by population by using supplements with high doses of this vitamin. Vitamins B6 and B2 are cofactors of enzymes of one carbon metabolism and, consequently, may disturb key metabolism in which they participate, as kynurenine pathway, and the immune system. Aim: To assess the effects of a daily intervention with high dose of FA (5 mg) for 90 days on biomarkers of complex B vitamins status and its outcomes in kynurenine pathway metabolites and immune system in healthy adults. Material and Methods: 64 healthy individuals were submitted to a daily intervention with 5 mg of FA for 90 days. Blood samples were collected before (baseline) and after 45 and 90 days of intervention. Serum folate and vitamin B12 were assessed by microbiological assays. Serum vitamin B6 (pyridoxal 5'-phosphate (PLP), pyridoxal (PL) and 4-pyridoxic acid (PA)), vitamin B2 (riboflavin and flavin mononucleotide (FMN)), vitamin B1 (thiamin and thiamin monophosphate)) and vitamin B3 (nicotinic acid, nicotinamide and N1-methylnicotinamide), as well as tryptophan, kynurenine and metabolites, were assessed by LC-MS/MS. C-reactive protein (hs-CPR) was assessed by immunoturbidimetry, and serum interleukin (IL)-6, IL-8, IL-10, interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) were assessed by multiplex assay. Mononuclear leukocytes mRNA expression of DHFR (dihydrofolate reductase), MTHFR (methylenetetrahydrofolate reductase), IL8, TNFA and IFNG were assessed by real time PCR. Regulatory T Cell (Treg) number (CD3+, CD4+, CD25high, FoxP3+, CD127-) was determined after mononuclear leukocytes incubation with PMA and ionomycin or vehicle for 18h, by immunophenotyping. Results: A great increase on serum folate was observed after 45 and 90 days of FA intervention. No differences in serum vitamin B12 were observed before and after intervention. Serum PLP was similar before and after intervention, however, an increase in serum PL was observed after 45 and 90 days, and in PA after 45 days, when compared to baseline. Riboflavin and FMN were increased after 45 and 90 days than in baseline. Serum thiamine was decreased after 45 days than in baseline. Serum TMP was increased after 90 days when compared with previous timepoints. No differences in vitamin B3 were observed after and before FA intervention. Among kynurenine pathway metabolites, anthranilic acid was increased after 45 and 90 days, while picolinic acid was decreased after 90 days. hs-CPR, serum IL-6, IL-8, IL-10, IFN-γ and TNF-α were similar at baseline and after intervention. An increase on mRNA expression of DHFR and TNFA was observed after, respectively, 90 days and 45 and 90 days of intervention. After 90 days of FA intervention, it was observed a decrease on Treg cell number after PMA and ionomycin stimulation. Conclusion: Daily use of 5 mg of FA was associated with changes in serum markers of B-complex vitamins status and kynurenine pathway, as well as decreased number of Treg cells

Advanced research of kynurenine pathway mechanism in suicide of major depressive disorder / 上海交通大学学报（医学版）

Major depressive disorder (MDD) is one of the world’s major chronic and disabling mental diseases. By 2030, MDD is expected to be the top of all the disease burden in the world, with high prevalence, high recurrence rate, high disability rate, and high suicide rate. Suicide is the most serious consequence of MDD. Current studies showed that inflammatory levels in the central nervous system and peripheral blood of patients with MDD were higher, and increased more significantly in depressive patients with suicidal ideation or behavior. Related researches showed that increased levels of inflammatory cytokines were associated with dysregulation of kynurenine metabolic pathway, leading to imbalances in neurometabolites, such as an excess of the neurotoxic product quinolinic acid and a decrease in the protective neuropeptide picolinic acid. This paper reviews kynurenine metabolic pathway, expecting to identify the biomarkers of MDD patients with suicide.

High-Fat Diet and Voluntary Chronic Aerobic Exercise Recover Altered Levels of Aging-Related Tryptophan Metabolites along the Kynurenine Pathway

Tryptophan metabolites regulate a variety of physiological processes, and their downstream metabolites enter the kynurenine pathway. Age-related changes of metabolites and activities of associated enzymes in this pathway are suggestable and would be potential intervention targets. Blood levels of serum tryptophan metabolites in C57BL/6 mice of different ages, ranging from 6 weeks to 10 months, were assessed using high-performance liquid chromatography, and the enzyme activities for each metabolic step were estimated using the ratio of appropriate metabolite levels. Mice were subjected to voluntary chronic aerobic exercise or high-fat diet to assess their ability to rescue age-related alterations in the kynurenine pathway. The ratio of serum kynurenic acid (KYNA) to 3-hydroxylkynurenine (3-HK) decreased with advancing age. Voluntary chronic aerobic exercise and high-fat diet rescued the decreased KYNA/3-HK ratio in the 6-month-old and 8-month-old mice groups. Tryptophan metabolites and their associated enzyme activities were significantly altered during aging, and the KYNA/3-HK ratio was a meaningful indicator of aging. Exercise and high-fat diet could potentially recover the reduction of the KYNA/3-HK ratio in the elderly.