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Kynurenines And Vitamin B6: Link Between Diabetes And Depression.
Abstract and Figures
The increased association between depression and diabetes mellitus is generally acknowledged. Recent studies suggest that depression leads to diabetes. However, the underlying molecular mechanisms for this association remain unclear. Literature and our data indicate that inflammatory and/or stress factors in depression up-regulate tryptophan (TRP) conversion into kynurenine (KYN), a substrate for nicotinamide adenine dinucleotide (NAD) biosynthesis. Deficiency of vitamin B6, a cofactor of the key enzymes of KYN - NAD pathway, shunts KYN metabolism from formation of NAD towards production of xanthurenic (XA) and kynurenic (KYNA) acids. Human and experimental studies reveal that XA, KYNA and their metabolites interfere with production, release and biological activity of insulin. We propose that inflammation- and/or stress-induced up-regulation of TRP - KYN metabolism in combination with vitamin B6 deficiency is one of the mechanisms mediating increased risk of diabetes in depression. Consequently, monitoring formation of diabetogenic KYN derivatives might help to identify subjects-at-risk for the development of diabetes. Pharmacological down-regulation of the TRP - KYN - NAD pathway and maintenance of adequate vitamin B6 status might help to prevent the development of diabetes in depression and other conditions associated with inflammation/stress- induced excessive production of KYN and vitamin B6 deficiency, e.g., obesity, cardiovascular diseases, aging, menopause, pregnancy, and hepatitis C virus infection.
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... PLP is also an enzymatic cofactor for kynurenine aminotransferase (KAT), which converts kynurenine to KYNA and 3OHKYN to xanthurenic acid (XA). Moreover, flavine adenine dinucleotide (FAD), which is an active form of vitamin B2 (riboflavin), is a cofactor for kynurenine 3-monooxygenase (KMO) which converts kynurenine to 3OHKYN (71,108). Consequently, the ratios in levels of kynurenines such as 3OHKYN:XA and 3OHKYN:3HAA were proposed to be functional markers of vitamin B6 status and KMO activity (109,110). ...
... As discussed above, it has a major role in tryptophan and kynurenines metabolism since flavin adenine dinucleotide (FAD), an active form of riboflavin, is a cofactor for kynurenine 3monooxygenase (KMO) which converts kynurenine to 3OHKYN. This makes riboflavin an important regulator of niacin synthesis and niacin-containing coenzymes such as NAD and NADP (71,108). It is also involved in the conversion of vitamin B6 to its active form pyridoxal 5'-phosphate (PLP). ...
Despite the well-established roles of B-vitamins and their deficiencies in health and disease, there is growing evidence indicating a key role of those nutrients in functions of the central nervous system and in psychopathology. Clinical data indicate the substantial role of B-vitamins in various psychiatric disorders, including major depression, bipolar disorder, schizophrenia, autism, and dementia, including Alzheimer’s and Parkinson’s diseases. As enzymatic cofactors, B-vitamins are involved in many physiological processes such as the metabolism of glucose, fatty acids and amino acids, metabolism of tryptophan in the kynurenine pathway, homocysteine metabolism, synthesis and metabolism of various neurotransmitters and neurohormones including serotonin, dopamine, adrenaline, acetylcholine, GABA, glutamate, D-serine, glycine, histamine and melatonin. Those vitamins are highly involved in brain energetic metabolism and respiration at the cellular level. They have a broad range of anti-inflammatory, immunomodulatory, antioxidant and neuroprotective properties. Furthermore, some of those vitamins are involved in the regulation of permeability of the intestinal and blood-brain barriers. Despite the fact that a substantial amount of the above vitamins is acquired from various dietary sources, deficiencies are not uncommon, and it is estimated that micronutrient deficiencies affect about two billion people worldwide. The majority of gut-resident microbes and the broad range of bacteria available in fermented food, express genetic machinery enabling the synthesis and metabolism of B-vitamins and, consequently, intestinal microbiota and fermented food rich in probiotic bacteria are essential sources of B-vitamins for humans. All in all, there is growing evidence that intestinal bacteria-derived vitamins play a significant role in physiology and that dysregulation of the "microbiota-vitamins frontier" is related to various disorders. In this review, we will discuss the role of vitamins in mental health and explore the perspectives and potential of how gut microbiota-derived vitamins could contribute to mental health and psychiatric treatment.
... Low blood serum B6 is frequently noted in patients with high inflammatory markers [6]. In fact, numerous inflammatory diseases were correlated with vitamin B6 deficiency including atherosclerosis and cardiovascular disease [7][8][9][10][11], rheumatoid arthritis [12,13], inflammatory bowel disease [14][15][16][17][18], type-2 diabetes [19][20][21][22][23][24][25], non-alcoholic fatty liver disease [26,27], and cancer [7,8,21,[28][29][30][31]. Vitamin B6 deficiency can disrupt immune response by decreasing the production of protein and nucleic acids, inhibiting immune cell function, and interfering with the metabolic machinery of cells [3]. ...
Vitamin B6 is shown to have anti-inflammatory properties, which makes it an interesting nutraceutical agent. Vitamin B6 deficiency is well established as a contributor to inflammatory-related conditions, whilst B6 supplementation can reverse these inflammatory effects. There is less information available regarding the effects of high-dose vitamin B6 supplementation as a therapeutic agent. This study set out to examine the effects of high-dose vitamin B6 on an LPS-stimulated monocyte/macrophage cell population via an analysis of protein and gene expression using an RT2 profiler PCR array for Human Innate and Adaptive Immune responses. It was identified that high-dose vitamin B6 has a global anti-inflammatory effect on lipopolysaccharide-induced inflammation in monocyte/macrophage cells by downregulating the key broad-spectrum inflammatory mediators CCL2, CCL5, CXCL2, CXCL8, CXCL10, CCR4, CCR5, CXCR3, IL-1β, IL-5, IL-6, IL-10, IL-18, IL-23-a, TNF-α, CSF2, DDX58, NLRP3, NOD1, NOD2, TLR-1 -2 -4 -5 -7 -8 -9, MYD88, C3, FOXP3, STAT1, STAT3, STAT6, LYZ, CASP-1, CD4, HLA-E, MAPK1, MAPK8 MPO, MX-1, NF-κβ, NF-κβ1A, CD14, CD40, CD40LG, CD86, Ly96, ICAM1, IRF3, ITGAM, and IFCAM2. The outcomes of this study show promise regarding vitamin B6 within the context of a potent broad-spectrum anti-inflammatory mediator and could prove useful as an adjunct treatment for inflammatory-related diseases.
... Chronic inflammation is a common finding linked to DM and has been implicated as an important factor underlying unfavorable course of the disease and its various complications [24,27,28]. Low-grade inflammation may affect the function of the Trp-KYN pathway, and it was suggested to influence the ontogenesis of diabetes [59]. The following sections of this review present the basics of DM pathology and the Trp-KYN pathway alterations observed in experimental animal models, human studies and microbiome research. ...
The tryptophan–kynurenine pathway (Trp–KYN) is the major route for tryptophan conversion in the brain and in the periphery. Kynurenines display a wide range of biological actions (which are often contrasting) such as cytotoxic/cytoprotective, oxidant/antioxidant or pro-/anti-inflammatory. The net effect depends on their local concentration, cellular environment, as well as a complex positive and negative feedback loops. The imbalance between beneficial and harmful kynurenines was implicated in the pathogenesis of various neurodegenerative disorders, psychiatric illnesses and metabolic disorders, including diabetes mellitus (DM). Despite available therapies, DM may lead to serious macro- and microvascular complications including cardio- and cerebrovascular disease, peripheral vascular disease, chronic renal disease, diabetic retinopathy, autonomic neuropathy or cognitive impairment. It is well established that low-grade inflammation, which often coincides with DM, can affect the function of KP and, conversely, that kynurenines may modulate the immune response. This review provides a detailed summary of findings concerning the status of the Trp–KYN pathway in DM based on available animal, human and microbiome studies. We highlight the importance of the molecular interplay between the deranged (functionally and qualitatively) conversion of Trp to kynurenines in the development of DM and insulin resistance. The Trp–KYN pathway emerges as a novel target in the search for preventive and therapeutic interventions in DM.
... Synthesis of B6 and B12 vitamins are also dependent on gut microbiome activity. These compounds are cofactors to kynurenine pathway enzymes (Oxenkrug et al., 2013). ...
The concept of the gut microbiome is emerging as a metabolic interactome influenced by diet, xenobiotics, genetics, and other environmental factors that affect the host’s absorption of nutrients, metabolism, and immune system. Beyond nutrient digestion and production, the gut microbiome also functions as personalized polypharmacy, where bioactive metabolites that our microbes excrete or conjugate may reach systemic circulation and impact all organs, including the brain. Appreciable evidence shows that gut microbiota produce diverse neuroactive metabolites, particularly neurotransmitters (and their precursors), stimulating the local nervous system (i.e., enteric and vagus nerves) and affecting brain function and cognition. Several studies have demonstrated correlations between the gut microbiome and the central nervous system sparking an exciting new research field, neuromicrobiology. Microbiome-targeted interventions are seen as promising adjunctive treatments (pre-, pro-, post-, and synbiotics), but the mechanisms underlying host-microbiome interactions have yet to be established, thus preventing informed evidence-based therapeutic applications. In this paper, we review the current state of knowledge for each of the major classes of microbial neuroactive metabolites, emphasizing their biological effects on the microbiome, gut environment, and brain. Also, we discuss the biosynthesis, absorption, and transport of gut microbiota-derived neuroactive metabolites to the brain and their implication in mental disorders.
... PLP, the active form of Vit-B6, serves as a cofactor of the key enzymes for Kyn catabolic processes 13,45 . We first demonstrated that subjects that were overweight or affected by obesity and HFD-induced mice were characterized by PLP deficiency (Fig. 7a-c). ...
Aberrant amino acid metabolism is a common event in obesity. Particularly, subjects with obesity are characterized by the excessive plasma kynurenine (Kyn). However, the primary source of Kyn and its impact on metabolic syndrome are yet to be fully addressed. Herein, we show that the overexpressed indoleamine 2,3-dioxygenase 1 (IDO1) in adipocytes predominantly contributes to the excessive Kyn, indicating a central role of adipocytes in Kyn metabolism. Depletion of Ido1 in adipocytes abrogates Kyn accumulation, protecting mice against obesity. Mechanistically, Kyn impairs lipid homeostasis in adipocytes via activating the aryl hydrocarbon receptor (AhR)/Signal transducer and activator of transcription 3 /interleukin-6 signaling. Genetic ablation of AhR in adipocytes abolishes the effect of Kyn. Moreover, supplementation of vitamin B6 ameliorated Kyn accumulation, protecting mice from obesity. Collectively, our data support that adipocytes are the primary source of increased circulating Kyn, while elimination of accumulated Kyn could be a viable strategy against obesity. Kynurenine, a tryptophan metabolite, is increased in the circulating plasma of obese individuals, but the source has been unclear. Here, the authors show in mice that mature adipocytes produce kynurenine, with vitamin B6 administration preventing accumulation and protecting against high-fat diet.
... Several scientists have demonstrated that this association may be related to the inflammatory state, angiogenesis, DNA methylation, cell-mediated immune response, and other mechanisms (41). Moreover, if the body is deficient in vitamin B6, KYN metabolism would shift from NAD+ formation to XA and KYNA production (42). Hence, we envisioned the possibility that XA/KYN might affect the survival and prognosis of patients by affecting the concentration of vitamin B6; however, this hypothesis requires further examination. ...
Background
Perturbation of tryptophan (TRP) metabolism contributes to the immune escape of cancer; however, the explored TRP metabolites are limited, and their efficacy in clarifying the susceptibility and progression of esophageal cancer (EC) remains ambiguous. Our study sought to evaluate the effects of the TRP metabolic profile on the clinical outcomes of EC using a Chinese population cohort; and to develop a risk prediction model targeting TRP metabolism.
Method
A total of 456 healthy individuals as control subjects and 393 patients with EC who were followed up for one year as case subjects were enrolled. Quantification of the plasma concentrations of TRP and its metabolites was performed using HPLC-MS/MS. The logistic regression model was applied to evaluate the effects of the clinical characteristics and plasma metabolites of the subjects on susceptibility and tumor metastasis events, whereas Cox regression analysis was performed to assess the overall survival (OS) of the patients.
Results
Levels of creatinine and liver enzymes were substantially correlated with multiple metabolites/metabolite ratios in TRP metabolism, suggesting that hepatic and renal function would exert effects on TRP metabolism. Age- and sex-matched case–control subjects were selected using propensity score matching. Plasma exposure to 5-HT was found to be elevated 3.94-fold in case subjects (N = 166) compared to control subjects (N = 203), achieving an AUC of 0.811 for predicting susceptibility event. Subsequent correlation analysis indicated that a higher plasma exposure to 5-HIAA significantly increased the risk of lymph node metastasis (OR: 2.16, p = 0.0114). Furthermore, it was figured out that OS was significantly shorter for patients with elevated XA/KYN ratio (HR: 1.99, p = 0.0016), in which medium and high levels of XA/KYN versus low level had a significantly lower OS (HR: 0.48, p = 0.0080 and HR: 0.42, p = 0.0031, respectively).
Conclusion
This study provides a pivotal basis for targeting endogenous TRP metabolism as a potential therapeutic intervention.
... Vitamin B6 reduces brain atrophy in Alzheimer's patients, 122 tardive dyskensia in schizophrenics, 123 and diabetes in patients with depression. 124 Low vitamin B6 is believed to play a key role in the oxidative stress associated with Huntington's disease. 125 One of the more interesting studies involves preventing the hippocampal apoptosis associated with bacterial meningitis using vitamin B6. 126 In an experimental version of bacterial meningitis, vitamin B6 supplementation reduced brain inflammation and hippocampal apoptosis by upregulating the neuroprotective factors controlled by the tryptophan-kynurenine pathway. ...
The relationship between nutrition, inflammation, and cancer is complex. Healthy eating can boost the immune system and reduce cancer risk, but both inadequate and excessive nutrition can lead to inflammation and cancer. Vitamin B6 and B12 are crucial for overall health, and their deficiency can disrupt the immune system, leading to hyperhomocysteinemia, oxidative stress, and immune dysfunction. This deficiency can contribute to diseases like cardiovascular disease, kidney disease, neurovascular diseases, osteoporosis, and cancer. Adequate dietary intake of these vitamins can prevent inflammation, immune dysfunction, and cancer progression, with supplements addressing deficiencies. High doses of vitamin B6, exceeding daily recommendations, may protect against cancer by reducing inflammation, oxidative stress, advanced glycation end products (AGEs), hydrogen sulfide (H2S), sphingosine-1-phosphate (S1P), and preventing telomere shortening. Vitamin B6 also shows promise as an immunomodulatory agent in inflammatory conditions. Conversely, excessive vitamin B12 intake may promote tumorigenesis by enhancing one-carbon metabolism, increasing nucleic acid synthesis, and altering DNA methylation, all contributing to cancer. However, further research is needed to understand these mechanisms fully. In this chapter, we describe the intricate connections between, nutrition, inflammation, and cancer. Vitamin B6 and B12 are crucial for maintaining health. Adequate intake can prevent inflammation, immune dysfunction, and cancer, while excess vitamin B12 may have tumorigenic effects. Further research is essential to clarify these vitamins' roles in cancer and immune function.
Im Rahmen der PRIMA-PREG-Studie der Frauenklinik Erlangen wurde die Depressionsentwicklung bei 529 Schwangeren ab der 12. bis zur 40. Schwangerschaftswoche im Abstand von 4 Wochen sowie 2 Wochen und 6 Monate postpartal mittels EPDS-Fragebogen abgefragt und mit verschiedenen Einflussfaktoren auf einen Zusammenhang geprüft. Für eine Depressionsentwicklung zum Zeitpunkt der 38.-40. SSW wurde in einer Partnerschaft zu leben als protektiver Faktor und Multiparität als Risikofaktor identifiziert.
Drosophila melanogaster mutants with deficient kynurenine (KYN) formation from tryptophan (TRP) have longer life span than wild type flies. Administration of alpha-methyl-TRP and 5-methyl-TRY, the inhibitors of TRP-KYN metabo-lism, prolonged life span in wild-type flies. Both inhibitors are not available for human use. Berberine, an isoquinoline alkaloid isolated from Berberis aristata, is known as the herb widely used in traditional Chinese and Indian medicine. Berberin is a strong inhibitor of the enzyme catalyzing TRP conversion into KYN. Considering this particular feature we investigated the effect of berberine on life-and health-span in wild-type Drosophila melanogaster. The results of our study showed that Berberine extended mean, median and maximum life span of female flies. Berberine did not af-fect the number of pupae of filial generation and decreased their lethality. Berberine increased locomotor activity (ver-tical climbing). The results of the study suggest that berberine prolongs life-and improves health-span of Drosophila melanogaster. Berberine might be a candidate drug for prevention and treatment of aging and aging-associated medical and psychiatric disorders.
Up-regulation of kynurenine (KYN) pathway of tryptophan (TRP) was suggested as one of the mechanisms of aging and aging-associated disorders. Genetic and pharmacological impairment of TRP - KYN metabolism resulted in prolongation of life span in Drosophila models. Minocycline, an antibiotic with anti-inflammatory, antioxidant and neuroprotective properties independent of its antibacterial activity, inhibited KYN formation from TRP. Since minocycline is the only FDA approved for human use medication with inhibitory effect on TRP - KYN metabolism, we were interested to study minocycline effect on life- and health-spans in Drosophila model. Minocycline (0.87mM) prolonged mean, median and maximum life span of wild-type Oregon Drosophila melanogaster of both genders. Minocycline (0.87 mM) stimulated vertical climbing in male flies. Minocycline dose-dependently decreased quantity and survivorship of pupae of filial generation. Minocycline might be a promising candidate drug for anti-aging intervention and treatment of aging-associated medical and psychiatric disorders. The role of TRP - KYN metabolism in the mechanisms of minocycline-effect on life- and health-span might be elucidated by the future assessment of minocycline effects in Drosophila mutants naturally or artificially knockout for genes impacting the key enzymes of KYN pathway of TRP metabolism.
Normal brain aging is associated with depression and cognitive decline. One of the mechanisms of aging-associated emotional and cognitive impairment might be the down-regulation of biosynthesis of N-acetylserotonin (NAS), one of the methoxyindole derivatives of tryptophan (TRP). Aging is associated with decreased NAS production, largely resulting from the down-regulation of beta 1 adrenoreceptors that activate serotonin N-acetyltransferase, the enzyme catalyzing formation of NAS from serotonin. NAS exerts antidepressant-like and cognition-enhancing effects. The NAS role in cognition supported by the discovery that scotophobin, decapeptide extracted from brain and associated with cognition improvement, inhibits NAS conversion into melatonin. Furthermore, NAS (and its derivatives) attenuated cognitive impairment induced by cholinergic neurotoxin and protected against beta-amyloid neurotoxicity. Considering that NAS (but not serotonin or melatonin) is a potent agonist to high-affinity BDNF tyrosine kinase (TrkB) receptors, antidepressant and cognition-enhancing effect of NAS might be mediated by activation of TrkB receptors. NAS and TRkB gradually decreased from 1 postnatal week becoming undetectable in the brains of old rats. Additional mechanisms might include non-receptor mediated anti-inflammatory and anti-oxidative effects of NAS. Therapeutic antidepressant and cognition-improving interventions might include administration of NAS and its analogs; inhibition of tryptophan - kynurenine metabolism to increase serotonin availability as a substrate for NAS biosynthesis; up-regulation of NAS formation from serotonin and down-regulation of NAS conversion into melatonin.
Background
Suboptimal glycemic control is a common situation in diabetes, regardless of the wide range of drugs available to reach glycemic targets. Basic research in diabetes is endeavoring to identify new actives working as insulin savers, use of which could delay the introduction of injectable insulin or reduce the insulin dose needed. Commonly available as a nutraceutical, berberine is a potential candidate.
Methods and results
Because its low oral bioavailability can be overcome by P-glycoprotein inhibitors like herbal polyphenols, we have tested the nutraceutical combination of Berberis aristata extract and Silybum marianum extract (Berberol®) in type 2 diabetes in terms of its additive effect when combined with a conventional oral regimen for patients with suboptimal glycemic control. After 90 days of treatment, the nutraceutical association had a positive effect on glycemic and lipid parameters, significantly reducing glycosylated hemoglobin, basal insulin, homeostatic model assessment of insulin resistance, total and low-density lipoprotein cholesterol, and triglycerides. A relevant effect was also observed in terms of liver function by measuring aspartate transaminase and alanine transaminase. The product had a good safety profile, with distinctive gastrointestinal side effects likely due to its acarbose-like action.
Conclusion
Although further studies should be carried out to confirm our data, Berberol could be considered a good candidate as an adjunctive treatment option in diabetes, especially in patients with suboptimal glycemic control.
Predicting the efficacy of antiviral treatment of hepatitis C virus (HCV) is of importance for both patient well-being and health care expense. The expression of interferon-stimulated genes (IFN-SGs) in the liver was suggested as a marker of response to anti-viral therapy. IFN-SGs encode the guanosine triphosphate cyclohydrolase 1 (GTPCH), a rate-limiting enzyme of pteridines biosynthesis. Neopterin, a stable byproduct of GTPCH-catalyzed reaction, is used as a marker of interferon-induced GTPCH activation. We hypothesized that assessment of neopterin concentrations might predict the response to antiviral therapy. Neopterin concentrations were evaluated in 260 HCV patients treated by pegylated interferon combined with ribavirin. Mean and median pretreatment neopterin concentrations were lower in patients with sustained virological response than in nonresponders. The rate of response was twofold higher among patients with pretreatment neopterin levels <16 nmol/L than in patients with neopterin levels ≥16 nmol/L, even after controlling for HCV genotype status. Our study suggests that the pretreatment level of neopterin might be used in routine clinical practice as rapid and cost-effective marker to predict the response to antiviral therapy in HCV patients.
The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper-or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.
Epidemiological and experimental studies have suggested that Hepatitis C virus (HCV) infection is associated with the development of type 2 diabetes. Pancreatic beta cell failure is central to the progression of type 2 diabetes. Using virus infection system, we investigate the influence of HCV infection on the fate of the insulinoma cell line, MIN6. Our experiments demonstrate that the HCV virion itself is indispensable and has a dose- and time-dependent cytopathic effect on the cells. HCV infection inhibits cell proliferation and induces death of MIN6 cells with apoptotic characteristics, including cell surface exposure of phosphatidylserine, decreased mitochondrial membrane potential, activation of caspase 3 and poly (ADP-ribose) polymerase, and DNA fragmentation in the nucleus. However, the fact that HCV-infected cells exhibit a dilated, low-density nucleus with intact plasma and nuclear membrane indicates that a novel apoptosis-like death occurs. HCV infection also causes endoplasmic reticulum (ER) stress. Further, HCV RNA replication was detected in MIN6 cells, although the infection efficiency is very low and no progeny virus particle generates. Taken together, our data suggest that HCV infection induces death of pancreatic beta cells through an ER stress-involved, caspase 3-dependent, special pathway.
Abstract Background Folate, vitamin B-12, and vitamin B-6 are essential nutritional components in one-carbon metabolism and are required for methylation capacity. The availability of these vitamins may therefore modify methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) by PE-N-methyltransferase (PEMT) in the liver. It has been suggested that PC synthesis by PEMT plays an important role in the transport of polyunsaturated fatty acids (PUFAs) like docosahexaenoic acid (DHA) from the liver to plasma and possibly other tissues. We hypothesized that if B-vitamin supplementation enhances PEMT activity, then supplementation could also increase the concentration of plasma levels of PUFAs such as DHA. To test this hypothesis, we determined the effect of varying the combined dietary intake of these three B-vitamins on plasma DHA concentration in rats. Methods In a first experiment, plasma DHA and plasma homocysteine concentrations were measured in rats that had consumed a B-vitamin-poor diet for 4 weeks after which they were either continued on the B-vitamin-poor diet or switched to a B-vitamin-enriched diet for another 4 weeks. In a second experiment, plasma DHA and plasma homocysteine concentrations were measured in rats after feeding them one of four diets with varying levels of B-vitamins for 4 weeks. The diets provided 0% (poor), 100% (normal), 400% (enriched), and 1600% (high) of the laboratory rodent requirements for each of the three B-vitamins. Results Plasma DHA concentration was higher in rats fed the B-vitamin-enriched diet than in rats that were continued on the B-vitamin-poor diet (P = 0.005; experiment A). Varying dietary B-vitamin intake from deficient to supra-physiologic resulted in a non-linear dose-dependent trend for increasing plasma DHA (P = 0.027; experiment B). Plasma DHA was lowest in rats consuming the B-vitamin-poor diet (P > 0.05 vs. normal, P
Kynurenic acid (KYNA), a major tryptophan metabolite, is a glutamate receptor antagonist, which is also reported to inhibit α7 nicotinic acetylcholine receptors (α7nAChRs). Due to variations in experimental approaches, controversy has arisen regarding the ability of KYNA to directly influence α7nAChR function. Here we summarize current concepts of KYNA neurobiology and review evidence pertaining to the proposed role of KYNA as an endogenous modulator of α7nAChRs and synaptic transmission. As dysfunction of α7nAChRs plays a major role in the pathophysiology of central nervous system disorders, elucidation of KYNA's action on this receptor subtype has significant therapeutic implications.
Obesity causes chronic low-grade inflammation that contributes to systemic metabolic dysfunction associated with obesity-linked disorders that fall under the definition of metabolic syndrome. Adipose tissue is a key endocrine organ as it releases multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have proinflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this emerging context, the gut microbiota-metabolism interactions play an increasingly important role in the understanding and hopefully future treatment of complex metabolic unbalances responsible for insulin resistance and cardiovascular high-risk diseases.