The association between inflammation and kynurenine pathway metabolites in electroconvulsive therapy for schizophrenia: Implications for clinical efficacy.

The kynurenine pathway (KP) of tryptophan has been implicated in the pathogenesis of schizophrenia and its interaction with the immune system has been suggested to play a role. In this study, 28 schizophrenia patients and 25 healthy controls were recruited and divided into different inflammatory subgroups using a two-step recursive clustering analysis. Cytokine gene expression and plasma KP metabolites were measured before, during and after treatment. Our findings indicated that schizophrenia patients had lower levels of Tryptophan (TRP), N-formylkynurenine (NFK), xanthinic acid (XA), quinolinic acid (QA), kynurenic acid (KYNA), KYNA/KYN and QA/KYNA, but higher levels of IL-18 mRNA, KYN/TRP compared to healthy controls (all p < 0.05). After electroconvulsive therapy (ECT), patients with low inflammation achieved better clinical improvement (PANSS scores) compared to those with high inflammation (F = 5.672, P = 0.025), especially in negative symptoms (F = 6.382, P = 0.018, η2 = 0.197). While IL-18 mRNA (F = 32.910, P < 0.0001) was significantly decreased following ECT, the KYN/TRP (F = 3.455, p = 0.047) and KYNA/TRP (F = 4.264, P = 0.026) only significantly decreased in patients with low inflammation. Correlation analyses revealed that baseline IL-18 gene expression significantly correlated with pre- (r = 0.537, p = 0.008) and post-KYNA/TRP (r = 0.443, p = 0.034), post-KYN/TRP (r = 0.510, p = 0.013), and post-negative symptoms (r = 0.525, p = 0.010). Moreover, baseline TRP (r = -0.438, p = 0.037) and XA (r = -0.516, p = 0.012) were negatively correlated with baseline PANSS, while post-KYN (r = -0.475, p = 0.022), 2-AA (r = -0.447, p = 0.032) and KYN/TRP (r = -0.566, p = 0.005) were negatively correlated with Montreal Cognitive Assessment (MoCA) following ECT. Overall, these findings suggested that the association between inflammation and kynurenine pathway plays an essential role in mechanism of ECT for schizophrenia and that the regulation of ECT on KP is influenced by inflammatory characteristics, which may relate to clinical efficacy in schizophrenia.

Mood Disorder in Systemic Lupus Erythematosus Induced by Antiribosomal P Protein Antibodies Associated with Decreased Serum and Brain Tryptophan.

Antiribosomal P protein (anti-P) autoantibodies commonly develop in patients with systemic lupus erythematosus. We have previously established hybridoma clones producing anti-P mAbs. In this study, we explored the pathogenesis of behavioral disorders induced by anti-P Abs using these mAbs. New Zealand Black × New Zealand White F1, New Zealand White, C57BL/6, and BALB/c mice were treated with 1 mg of anti-P Abs once every 2 wk. The behavioral disorder was evaluated by the tail suspension test, forced swim test, and open field test. Following administration of anti-P Abs, New Zealand Black × New Zealand White F1 and C57BL/6 mice developed depressive behavior and showed increased anxiety with elevated serum TNF-α and IL-6 levels. Anti-P Abs were not deposited in the affected brain tissue; instead, this mood disorder was associated with lower serum and brain tryptophan concentrations. Tryptophan supplementation recovered serum tryptophan levels and prevented the behavioral disorder. TNF-α and IL-6 were essential for the decreased serum tryptophan and disease development, which were ameliorated by treatment with anti-TNF-α neutralizing Abs or dexamethasone. Peritoneal macrophages from C57BL/6 mice produced TNF-α, IL-6, and IDO-1 via interaction with anti-P Abs through activating FcγRs, which were required for disease development. IVIg, which has an immunosuppressive effect partly through the regulation of FcγR expression, also prevented the decrease in serum tryptophan and disease development. Furthermore, serum tryptophan concentrations were decreased in the sera of systemic lupus erythematosus patients with anti-P Abs, and lower tryptophan levels correlated with disease activity. Our study revealed some of the molecular mechanisms of mood disorder induced by anti-P Abs.

Biological Effects of Indole-3-Propionic Acid, a Gut Microbiota-Derived Metabolite, and Its Precursor Tryptophan in Mammals' Health and Disease.

Actions of symbiotic gut microbiota are in dynamic balance with the host's organism to maintain homeostasis. Many different factors have an impact on this relationship, including bacterial metabolites. Several substrates for their synthesis have been established, including tryptophan, an exogenous amino acid. Many biological processes are influenced by the action of tryptophan and its endogenous metabolites, serotonin, and melatonin. Recent research findings also provide evidence that gut bacteria-derived metabolites of tryptophan share the biological effects of their precursor. Thus, this review aims to investigate the biological actions of indole-3-propionic acid (IPA), a gut microbiota-derived metabolite of tryptophan. We searched PUBMED and Google Scholar databases to identify pre-clinical and clinical studies evaluating the impact of IPA on the health and pathophysiology of the immune, nervous, gastrointestinal and cardiovascular system in mammals. IPA exhibits a similar impact on the energetic balance and cardiovascular system to its precursor, tryptophan. Additionally, IPA has a positive impact on a cellular level, by preventing oxidative stress injury, lipoperoxidation and inhibiting synthesis of proinflammatory cytokines. Its synthesis can be diminished in the presence of different risk factors of atherosclerosis. On the other hand, protective factors, such as the introduction of a Mediterranean diet, tend to increase its plasma concentration. IPA seems to be a promising new target, linking gut health with the cardiovascular system.

5-methoxytryptophan: an arsenal against vascular injury and inflammation.

5-methoxytryptophan (5-MTP) is an endothelial factor with anti-inflammatory properties. It is synthesized from L-tryptophan via two enzymatic steps: tryptophan hydroxylase-1 (TPH-1) and hydroxyindole O-methyltransferase. Lipopolysaccharide (LPS) and pro-inflammatory cytokines suppress endothelial 5-MTP production by inhibiting TPH-1 expression. 5-MTP protects endothelial barrier function and promotes endothelial repair, while it blocks vascular smooth muscle cell migration and proliferation by inhibiting p38 MAPK activation. 5-MTP controls macrophage transmigration and activation by inhibiting p38 MAPK and NF-κB activation. 5-MTP administration attenuates arterial intimal hyperplasia, defends against systemic inflammation and prevents renal fibrosis in relevant murine models. Serum 5-MTP level is depressed in human sepsis as well as in mice with sepsis-like disorder. It is reduced in chronic kidney disease and acute myocardial infarction in humans. The reported data suggest that serum 5-MTP may be a theranostic biomarker. In summary, 5-MTP represents a new class of tryptophan metabolite which defends against inflammation and inflammation-mediated tissue damage and fibrosis. It may be a valuable lead compound for developing new drugs to treat complex human inflammatory disorders.

Selective dietary supplementation in early postpartum is associated with high resilience against depressed mood.

Medical research is moving toward prevention strategies during prodromal states. Postpartum blues (PPB) is often a prodromal state for postpartum depression (PPD), with severe PPB strongly associated with an elevated risk for PPD. The most common complication of childbearing, PPD has a prevalence of 13%, but there are no widespread prevention strategies, and no nutraceutical interventions have been developed. To counter the effects of the 40% increase in monoamine oxidase A (MAO-A) levels that occurs during PPB, a dietary supplement kit consisting of monoamine precursor amino acids and dietary antioxidants was created. Key ingredients (tryptophan and tyrosine) were shown not to affect their total concentration in breast milk. The aim of this open-label study was to assess whether this dietary supplement reduces vulnerability to depressed mood at postpartum day 5, the typical peak of PPB. Forty-one healthy women completed all study procedures. One group (n = 21) received the dietary supplement, composed of 2 g of tryptophan, 10 g of tyrosine, and blueberry juice with blueberry extract. The control group (n = 20) did not receive any supplement. PPB severity was quantitated by the elevation in depressed mood on a visual analog scale following the sad mood induction procedure (MIP). Following the MIP, there was a robust induction of depressed mood in the control group, but no effect in the supplement group [43.85 ± 18.98 mm vs. 0.05 ± 9.57 mm shift; effect size: 2.9; F(1,39) = 88.33, P < 0.001]. This dietary supplement designed to counter functions of elevated MAO-A activity eliminates vulnerability to depressed mood during the peak of PPB.

Developmental Programming and Reprogramming of Hypertension and Kidney Disease: Impact of Tryptophan Metabolism.

The concept that hypertension and chronic kidney disease (CKD) originate in early life has emerged recently. During pregnancy, tryptophan is crucial for maternal protein synthesis and fetal development. On one hand, impaired tryptophan metabolic pathway in pregnancy impacts fetal programming, resulting in the developmental programming of hypertension and kidney disease in adult offspring. On the other hand, tryptophan-related interventions might serve as reprogramming strategies to prevent a disease from occurring. In the present review, we aim to summarize (1) the three major tryptophan metabolic pathways, (2) the impact of tryptophan metabolism in pregnancy, (3) the interplay occurring between tryptophan metabolites and gut microbiota on the production of uremic toxins, (4) the role of tryptophan-derived metabolites-induced hypertension and CKD of developmental origin, (5) the therapeutic options in pregnancy that could aid in reprogramming adverse effects to protect offspring against hypertension and CKD, and (6) possible mechanisms linking tryptophan metabolism to developmental programming of hypertension and kidney disease.

α-[11C] methyl-L tryptophan-PET as a surrogate for interictal cerebral serotonin synthesis in migraine without aura.

BACKGROUND: Alteration in central serotonin biology has been implicated in migraine, and serotonin (5-HT) agonists have been available for more than a decade in the treatment of that condition. OBJECTIVES: To test this hypothesis, we studied in vivo using positron-emission tomography (PET) and α-[(11)C] methyl-L-tryptophan (α-[(11)C]MTrp) as a surrogate marker of cerebral 5-HT synthetic rate before and after administration of eletriptan in migraine and control subjects. METHODS: Six nonmenopausal female migraine subjects with migraine without aura (MoA) and six nonmenopausal age-matched female control subjects were scanned at baseline and after oral administration of 40 mg of eletriptan. Migraine subjects at the time of PET had to have been headache free for a minimum of three days. Images of (α-[(11)C]MTrp) brain trapping were colocalized with individual MRI images in three dimensions and analyzed. RESULTS: There was no difference in baseline cerebral global 5-HT synthesis between migraine and control subjects. After administration of eletriptan, there was a striking global reduction in cerebral 5-HT synthesis (K*) in the migraine group and in 22 regions of interest (ROIs). In control subjects, no significant changes were found in global cerebral 5-HT synthesis (K*) or in any of the ROIs. CONCLUSIONS: These findings suggest in migraine an interictal alteration in the regulation mechanisms of cerebral 5-HT synthesis.

[Properties of milk in sleep induction]. / Propiedades de la leche en la inducción del sueño.

Introduction: Sleep induction and its quality are issues of growing concern because its deterioration affects a large number of people and poses a risk to their well-being and quality of life and long-term health. There are several factors involved in the problem, but nutrition is one of them and in particular milk consumption has often been linked to sleep habits, sometimes as a promoter and sometimes as an inhibitor. The purpose of this review is to examine the matter further. On reaching the brain, tryptophan is the basis for the synthesis of serotonin and melatonin, which improve the induction and quality of sleep. But there is competition between tryptophan and other long-chain neutral amino acids (LNAA) (valine, leucine, isoleucine, tyrosine and phenylalanine) to cross the blood-brain barrier and reach the brain. In this sense, milk proteins with a high tryptophan content and the highest ratio between tryptophan and LNAA are very useful in promoting sleep. Moreover, milk also provides various micronutrients that help in the transformation of tryptophan into serotonin and melatonin, as well as antioxidant components, anti-inflammatory and bioactive peptides, and recent studies indicate that it favorably modulates the composition of the intestinal microbiota. Studies show that increasing milk consumption, up to the recommended intake and within a correct diet, favors the achievement and maintenance of quality sleep.

Introducción: La inducción del sueño y su calidad son temas de preocupación creciente porque su deterioro afecta a un número elevado de personas y supone un riesgo en su bienestar y calidad de vida y en la salud a largo plazo. Hay diversos factores implicados en el problema, pero la nutrición es uno de ellos y, en concreto, el consumo de leche se ha relacionado frecuentemente con los hábitos de sueño, a veces como factor promotor y otras como inhibidor. Profundizar en el tema es el objeto de la presente revisión. El triptófano, al llegar al cerebro, es la base para la síntesis de serotonina y melatonina, que mejoran la inducción y la calidad del sueño. Pero hay una competencia entre el triptófano y otros aminoácidos neutros de cadena larga (ANCL) (valina, leucina, isoleucina, tirosina y fenilalanina) para cruzar la barrera hematoencefálica y llegar al cerebro. En este sentido, las proteínas de la leche, con elevado contenido en triptófano y la relación más elevada entre triptófano y ANCL, son muy útiles en la promoción del sueño. Por otra parte, la leche también aporta diversos micronutrientes que ayudan en la transformación del triptófano en serotonina y melatonina, así como componentes antioxidantes, antiinflamatorios y péptidos bioactivos, y estudios recientes indican que modula favorablemente la composición de la microbiota intestinal. Los estudios realizados ponen de relieve que aumentar el consumo de leche, hasta el aporte aconsejado y dentro de una alimentación correcta, favorece el conseguir y mantener un sueño de calidad.

Suppression of Kynurenine 3-Monooxygenase as a Treatment for Triple-negative Breast Carcinoma.

Kynurenine 3-monooxygenase (KMO), a key enzyme within the kynurenine (KYN) pathway of tryptophan (TRY) metabolism, enables the excess production of toxic metabolites (such as 3-hydroxykynurenine, xanthurenic acid, 3-hydroxyanthranilic acid and quinolinic acid), and modulates the balance between these toxic molecules and the protective metabolite, kynurenic acid (KYNA). Despite its importance, KMO suppression as a treatment for cancer has not been fully explored. Instead, researchers have focused on prevention of KYN pathway activity by inhibition of enzymes indoleamine 2,3-dioxygenase (IDO1 and IDO2) or tryptophan 2,3-dioxygenase (TDO, also known as TDO2). However, studies using IDO/TDO inhibitors against cancer have not yet shown that this type of treatment can be successful. We argue that KMO suppression can be an effective strategy for treatment of cancer by 1) decreasing toxic metabolites within the KYN pathway and 2) increasing levels of KYNA, which has important protective and anticancer properties. This strategy may be beneficial in the treatment of aggressive breast cancer, particularly in patients with triple-negative breast cancer. A major challenge to this strategy, when searching for an effective treatment for tumors, especially tumors like breast carcinoma that often metastasize to the brain, is finding KMO inhibitors that adequately cross the blood-brain barrier.

A nexus of progression of chronic kidney disease: tryptophan, profibrotic cytokines, and charcoal.

Fibrosis plays a major role in the pathogenesis of progressive chronic kidney disease (CKD). The inhibition of the renin-angiotensin system, which promotes fibrosis, has become the standard of care in the treatment of patients with CKD. The use of alternative agents capable of blocking the actions of profibrotic cytokines such as transforming growth factor-beta (TGF-ß) is also an important strategy that is in its early stages of development. An example of such a drug is AST-120, a charcoal compound that ultimately inhibits the synthesis of TGF-ß in the kidney. The inhibition is mediated by blocking the intestinal absorption of tryptophan-derived indole by AST-120. This reduces the hepatic conversion of indole to indoxyl sulfate (IS). IS stimulates the production of TGF-ß in the renal parenchyma, and lowering the level of IS with AST-120 appears to slow progression of CKD. The status of recent trials examining the safety and efficacy of AST-120 has been described, including a multicenter, randomized, placebo-controlled, phase III trial of approximately 2,000 subjects being conducted to gain approval of this drug by the U.S. Food and Drug Administration.

Reconsideration of the Benefits of Pharmacological Interventions for the Attenuation of the Cognitive Adverse Effects of Electroconvulsive Therapy.

The cognitive adverse effects (AEs) of electroconvulsive therapy (ECT) limit the wider use of the treatment. These AEs can be attenuated by changing the way ECT is administered; however, such changes may reduce the response rate, the speed of response, or both. A recent systematic review and meta-analysis identified more than a dozen pharmacologic interventions in 26 randomized controlled trials (RCTs) that sought to reduce ECT-induced cognitive AEs. Because of large differences across RCTs, only a few outcomes for a few interventions could be pooled in meta-analysis, and most pooled analyses included only 2-3 RCTs. Important findings were that acetylcholinesterase inhibitors, ketamine, memantine, and liothyronine were associated with improved global cognitive functioning at 1-14 days post-ECT. Anti-inflammatory treatments and opioid receptor antagonists were not associated with improvement in general cognitive outcome at 1-14 days post-ECT. Meta-analysis was not possible for the remaining interventions, including piracetam, melatonin, pemoline, nortriptyline, herbal agents, drugs acting on the cortisol pathway, opioid receptor antagonists, l-tryptophan, vasopressin analogs, calcium channel blockers, and others; in individual RCTs, some of these interventions attenuated some cognitive measures as some time points after ECT. Regrettably, none of the RCTs examined clinically meaningful outcomes such as subjective cognitive impairment, impairments in daily life, and persistent autobiographical memory deficits. Future research should study such clinically meaningful outcomes (rather than laboratory tests), using pharmacologic interventions, perhaps in combination, for ECT procedures that are associated with higher cognitive AE burden. A risk is that whatever attenuates ECT-induced cognitive AEs may also attenuate ECT-related therapeutic benefits.

[Unable to Work Due to Migraine for Which Tryptan is Taken 14 Times a Month or Less: Medication-Overuse Headache (MOH)].

Management of refractory headache, particularly medication-overuse headache (MOH), is often difficult. In the management of MOH, it is important to determine the underlying primary headaches. Therefore, history taking and medical examinations are crucial for the diagnosis of headache type. Patient education and appropriate preventive therapy are beneficial in ameliorating MOH. As migraine is an underlying primary headache, the use of calcitonin gene-related peptide antibodies should be considered.

[Unable to Work Due to Migraine for Which Tryptan is Taken 14 Times a Month or Less: How to Choose Preventive Medication].

Migraineurs often experience severe headache attacks and their quality of life is inhibited. Most migraineurs treat their headaches with acute treatment, but preventive treatment is often not chosen appropriately. Because migraine attack frequency and medication overuse are risk factors for headache progression (chronification) and medication-overuse headache, it is possible that preventive medication may also reduce risk progression. Therefore, it is necessary to select preventive medication if required.

Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite.

BACKGROUND: Despite the great success, the therapeutic benefits of immune checkpoint inhibitors (ICIs) in cancer immunotherapy are limited by either various resistance mechanisms or ICI-associated toxic effects including gastrointestinal toxicity. Thus, novel therapeutic strategies that provide manageable side effects to existing ICIs would enhance and expand their therapeutic efficacy and application. Due to its proven role in cancer development and immune regulation, gut microbiome has gained increasing expectation as a potential armamentarium to optimize immunotherapy with ICI. However, much has to be learned to fully harness gut microbiome for clinical applicability. Here we have assessed whether microbial metabolites working at the interface between microbes and the host immune system may optimize ICI therapy. METHODS: To this purpose, we have tested indole-3-carboxaldehyde (3-IAld), a microbial tryptophan catabolite known to contribute to epithelial barrier function and immune homeostasis in the gut via the aryl hydrocarbon receptor (AhR), in different murine models of ICI-induced colitis. Epithelial barrier integrity, inflammation and changes in gut microbiome composition and function were analyzed. AhR, indoleamine 2,3-dioxygenase 1, interleukin (IL)-10 and IL-22 knockout mice were used to investigate the mechanism of 3-IAld activity. The function of the microbiome changes induced by 3-IAld was evaluated on fecal microbiome transplantation (FMT). Finally, murine tumor models were used to assess the effect of 3-IAld treatment on the antitumor activity of ICI. RESULTS: On administration to mice with ICI-induced colitis, 3-IAld protected mice from intestinal damage via a dual action on both the host and the microbes. Indeed, paralleling the activation of the host AhR/IL-22-dependent pathway, 3-IAld also affected the composition and function of the microbiota such that FMT from 3-IAld-treated mice protected against ICI-induced colitis with the contribution of butyrate-producing bacteria. Importantly, while preventing intestinal damage, 3-IAld did not impair the antitumor activity of ICI. CONCLUSIONS: This study provides a proof-of-concept demonstration that moving past bacterial phylogeny and focusing on bacterial metabolome may lead to a new class of discrete molecules, and that working at the interface between microbes and the host immune system may optimize ICI therapy.

Vagus nerve stimulation in refractory epilepsy: effects on pro- and anti-inflammatory cytokines in peripheral blood.

OBJECTIVE: The vagus nerve has important immunological functions that may be relevant for its anticonvulsive action. We postulate that this anticonvulsive action is activated by a shift in the immune system resulting in a reduction of neurotoxic and an increase of neuroprotective tryptophan metabolites. METHODS: Eleven patients with refractory epilepsy and 11 controls matched for age and gender were included in this study. The primary outcome measure was a 50% seizure reduction. Other variables were pro-inflammatory cytokines IL-6 and TNF-α, anti-inflammatory cytokine IL-10, cortisol, and the tryptophan metabolites 3-hydroxykynurenine (3-OH-KYN), kynurenic acid (KYNA), kynurenine, serotonin (5-HT) and 5-hydroxyindol acetic acid (5-HIAA). Blood samples were scheduled during baseline, and in week 28 of add-on treatment. RESULTS: IL-6 levels were higher in the responders than in the control group, and decreased after vagus nerve stimulation (VNS), whereas IL-10 was low and increased after VNS. In nonresponders, VNS resulted in an increase of IL-6 plasma levels and in a decrease of IL-10. Cortisol concentrations are higher in the epilepsy group than in the control group. After VNS, these concentrations decreased. The concentrations of the tryptophan metabolites were lower in the epilepsy group than in the control group. The KYNA ratios are defined as the ratio of neuroprotective KYNA versus neurotoxic 3-OH-KYN and KYNA versus neurotoxic kynurenine: these ratios were lower in epilepsy patients than in controls, and they both moderately increased after VNS. CONCLUSION: The outcome of this preliminary study indicates that VNS causes a rebalancing of the immune system. This results in: (1) a reduction of neurotoxic and an increase of neuroprotective kynurenine metabolites and (2) in the normalization of cortisol levels.

[Effect of acupuncture-moxibustion on negative emotions and plasma tryptophan metabolism in patients with Crohn's disease at active stage].

OBJECTIVE: To observe the effect of acupuncture-moxibustion on negative emotions and plasma tryptophan (Trip)-kynurenine (Kyn) metabolism in the patients with Crohn's disease (CD) at the mild and moderate active stage. METHODS: A total of 66 CD patients were randomized into an observation group (33 cases, 1 case dropped off) and a control group (33 cases, 2 cases dropped off). In the observation group, acupuncture was applied in combination with moxibustion. In the control group, the sham-acupuncture was used in combination with sham-moxibustion. In both of the observation group and the control group, acupuncture was applied to Zhongwan (CV 12), Shangjuxu (ST 37), Sanyinjiao (SP 6), Gongsun (SP 4), Hegu (LI 4), Quchi (LI 11), Taixi (KI 3) and Taichong (LR 3), and moxibustion was applied to Tianshu (ST 25) and Zusanli (ST 36). The treatment was given once every two days, 3 times a week, totally for 12 weeks. Separately, before and after treatment, the score of the hospital anxiety-depression scale (HADS) and the score of intestinal core symptoms (degree of abdominal pain and frequency of diarrhea) were observed in the patients of the two groups. The concentration of plasma indoleamine 2,3-dioxygenase 1 (IDO1) and the ratios of Kyn/Trp, QuinA/Kyn, KynA/Kyn and KynA/QuinA were compared between the two groups. RESULTS: Compared with before treatment, the scores of HADS-A and HADS-D in the observation group and the score of HADS-A in the control group were all reduced after treatment (P<0.01, P<0.05). The scores of abdominal pain degree in the two groups and score of diarrhea frequency in the observation group were all reduced after treatment (P<0.001). After treatment, the reducing ranges of the score of HADS-A and the scores of abdominal pain degree and diarrhea frequency in the observation group were all larger than the control group (P<0.01, P<0.05). Compared with before treatment, the plasma IDO1 concentration in the two groups and the ratios of plasma Kyn/Trp and QuinA/Kyn in the observation group were all reduced after treatment (P<0.001, P<0.05, P<0.01), the ratios of plasma KynA/Kyn and KynA/QuinA were increased after treatment in the observation group (P<0.05, P<0.01). After treatment, the changes in IDO1 concentration and the ratios of plasma QuinA/Kyn and KynA/QuinA in the observation were larger than the control group (P≤0.01, P<0.05). In the observation group, the difference in the ratio of plasma KynA/Kyn before and after treatment was negatively related to the improvement value of HADS-D (r =-0.67, P<0.05). After treatment, plasma IDO1 concentration was positively related to HADS-A in the observation group (r =0.65, P<0.05). CONCLUSION: Acupuncture and moxibustion relieve the negative emotions of anxiety and depression in CD patients at mild and moderate active stage, which is probably related to the regulation of plasma Trp-Kyn metabolic pathway.

[L-tryptophan as dietetic supplement and treatment for hot flashes, astenia, and insomnia in cancer patients]. / Triptófano como suplemento dietético y tratamiento de los sofocos, la astenia y el insomnio en el cáncer.

INTRODUCTION: Introduction: in women with breast cancer and gynecologic cancer, as well as in men with prostate carcinoma, hot flashes, asthenia, and insomnia are common and bothersome symptoms that impair quality of life. Objective: to evaluate the effectiveness of tryptophan intake as a treatment for hot flushes, asthenia, and insomnia in patients with prostate, breast, and uterine cervical cancer. Materials and methods: intervention study without a control group at the HUCA Radiation Oncology Service, from July 2018 to July 2019. A total of 60 patients with prostate, breast, or uterine cervical cancer who had received treatment with radiotherapy and hormone therapy, and who presented with hot flushes, asthenia, and insomnia were included. L-tryptophan was administered at a dose of 3 g per day. Results: a significant increase in serum tryptophan levels at the end of the study (p < 0.001) and a significant decrease in the scores of the study symptoms were reported. Although statistical significance was not found, a significant improvement in each symptom was observed, as well as an improvement in quality of life (p < 0.001). Conclusions: the study suggests that, in patients with breast, prostate, or uterine cervical cancer, and symptoms such as hot flushes, asthenia, and insomnia, the administration of tryptophan as a nutritional supplement is well tolerated, improves quality of life, and is associated with improvement in the scale scores of the symptoms of interest, although no statistically significant relationship with increased blood tryptophan levels was found.

INTRODUCCIÓN: Introducción: tanto en las mujeres con cáncer de mama y cáncer ginecológico como en los hombres con carcinoma prostático, los sofocos, la astenia y el insomnio son síntomas frecuentes y molestos que alteran la calidad de vida. Objetivo: evaluar la eficacia del aporte de triptófano como tratamiento de los sofocos, la astenia y el insomnio en pacientes con cáncer de próstata, de mama y cervicouterino. Materiales y métodos: estudio de intervención sin grupo de control en el Servicio de Oncología Radioterápica del HUCA, en el período de julio de 2018 a julio de 2019. Se incluyeron en total 60 pacientes con cáncer de próstata, de mama y cervicouterino que habían recibido tratamiento con radioterapia y hormonoterapia, y que presentaban sofocos, astenia e insomnio. Se administraron 3 g de L-triptófano al día. Resultados: se reportan un aumento significativo del valor del triptófano sérico al final del estudio (p < 0,001) y una disminución significativa de las puntuaciones de los síntomas estudiados; aunque no hemos hallado ninguna significación estadística entre ellos, sí se aprecia una mejoría significativa de cada uno de los síntomas, así como una mejoría de la calidad de vida (p < 0,001). Conclusiones: el estudio actual sugiere que, en los pacientes con cáncer de mama, de próstata o cervicouterino y síntomas de sofocos, astenia e insomnio, el aporte de triptófano como suplemento nutricional se tolera bien, mejora la calidad de vida y puede asociarse a una mejoría de los valores obtenidos en las escalas de los síntomas referidos, aunque no se demuestra ninguna relación estadísticamente significativa con la elevación del triptófano en sangre.

Multiple roles of haem in cystathionine ß-synthase activity: implications for hemin and other therapies of acute hepatic porphyria.

The role of haem in the activity of cystathionine ß-synthase (CBS) is reviewed and a hypothesis postulating multiple effects of haem on enzyme activity under conditions of haem excess or deficiency is proposed, with implications for some therapies of acute hepatic porphyrias. CBS utilises both haem and pyridoxal 5'-phosphate (PLP) as cofactors. Although haem does not participate directly in the catalytic process, it is vital for PLP binding to the enzyme and potentially also for CBS stability. Haem deficiency can therefore undermine CBS activity by impairing PLP binding and facilitating CBS degradation. Excess haem can also impair CBS activity by inhibiting it via CO resulting from haem induction of haem oxygenase 1 (HO 1), and by induction of a functional vitamin B6 deficiency following activation of hepatic tryptophan 2,3-dioxygenase (TDO) and subsequent utilisation of PLP by enhanced kynurenine aminotransferase (KAT) and kynureninase (Kynase) activities. CBS inhibition results in accumulation of the cardiovascular risk factor homocysteine (Hcy) and evidence is emerging for plasma Hcy elevation in patients with acute hepatic porphyrias. Decreased CBS activity may also induce a proinflammatory state, inhibit expression of haem oxygenase and activate the extrahepatic kynurenine pathway (KP) thereby further contributing to the Hcy elevation. The hypothesis predicts likely changes in CBS activity and plasma Hcy levels in untreated hepatic porphyria patients and in those receiving hemin or certain gene-based therapies. In the present review, these aspects are discussed, means of testing the hypothesis in preclinical experimental settings and porphyric patients are suggested and potential nutritional and other therapies are proposed.

Quarrelsomeness in daily life.

It is common in studies of interpersonal characteristics to examine personality variables as static predictors. Yet in recent years it has also become possible to examine personality and related interpersonal processes as they unfold over time in association with event specific cues. The present article reviews research that (1) identifies behaviors that reflect the occurrence of hostile-irritable-quarrelsome traits in daily life, (2) demonstrates both the stability and within-person variability of these behaviors over time, (3) documents event-level interpersonal cues that are systematically associated with within-person variation in quarrelsome behavior, and (4) describes how dispositional level agreeableness and irritability moderate the associations of event-level cues with quarrelsome behavior. The influence of the neurotransmitter serotonin on quarrelsome behavior is also considered. The studies indicate that quarrelsome individuals have reduced affective reactivity to engaging in quarrelsome behavior, increased behavioral reactivity to perceptions of quarrelsomeness in others, and greater responsiveness to change in serotonin levels.

Role of Indoleamine-2,3-Dioxygenase Inhibitors in Salvage Therapy for Non-Muscle Invasive Bladder Cancer.

Due to significant risks of cancer recurrence and progression, and limited options after intravesical Bacillus Calmette Guerin (BCG) therapy, there is a critical unmet need to identify novel treatments for those patients with BCG-unresponsive bladder cancer. There is active investigation of immunotherapies which provide both biologic and clinical rationales for indoleamine-2,3- dioxygenase inhibitors in salvage therapy for non-muscle invasive bladder cancer.