scholarly journals Potential drug targets in the kynurenine pathway to treat acute schizophrenia

BJPsych Open ◽  
2021 ◽  
Vol 7 (S1) ◽  
pp. S167-S167
Author(s):  
Ayush Malhotra ◽  
Paul Manowitz
Keyword(s):  
Drug Targets ◽  
Kynurenic Acid ◽  
Meta Analysis ◽  
Kynurenine Pathway ◽  
Supporting Evidence ◽  
Biochemical Pathway ◽  
Acute Schizophrenia ◽  
Plasma Tryptophan ◽  
Wide Range ◽  
Dopamine Hypothesis

AimsSchizophrenia is a serious developmental psychiatric disorder with a neurodegenerative component that causes marked deterioration in social relationships and ability to work. Present treatments are not satisfactory. Meta-analysis of placebo-controlled studies in acute schizophrenia shows that only a minority of patients have a good response to current antipsychotic medications. Therefore, there is a need for more effective psychopharmacologic treatments for this disorder.MethodThe purpose of this paper is to provide new interpretations of existing data to provide a scaffolding for the development of novel drug targets for the treatment of schizophrenia. The causes of schizophrenia are most likely heterogeneous and involve both genetic and environmental factors. The authors examined a wide range of purported causes of schizophrenia to identify a common biochemical pathway that would contribute to this disorder. This review specifically did not consider pathways that supported the dopamine hypothesis of schizophrenia since historically drugs focused on dopaminergic mechanism, as noted in the aims, have not been successful for many patients with schizophrenia.ResultTwo prominent schizophrenia-associated factors that have been widely studied with significant supporting evidence are stress and inflammation. Stress and inflammation share a common biochemical pathway that converges on the kynurenine pathway of the metabolism of tryptophan, an essential amino acid. At one end of the pathway, recently hospitalized patients with schizophrenia have been found to have low plasma tryptophan levels, whereas chronic schizophrenics have not, suggesting stress- and/or inflammation-induced increased metabolism of tryptophan. At the other end of the pathway, there is increased level of cerebrospinal fluid kynurenic acid in patients with schizophrenia as compared with healthy controls. Salivary kynurenic acid is associated with stress intolerance in schizophrenia. Importantly, natural occurring compounds in this pathway have significant CNS effects that include neurotoxicity and altered neural transmitter behavior.ConclusionStress and inflammation, both associated as causes of schizophrenia, are linked by a common biochemical pathway involving kynurenine. Examination of specific elements of the kynurenine pathway may aid in the identification of drug targets for schizophrenia.

scholarly journals The tryptophan catabolite or kynurenine pathway in schizophrenia: meta-analysis reveals dissociations between central, serum and plasma compartments.

2021 ◽  
Author(s):  
Abbas F. Almulla ◽  
Asara Vasupanrajit ◽  
Chavit Tunvirachaisakul ◽  
Hussein K. Al-Hakeim ◽  
Marco Solmi ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Kynurenic Acid ◽  
Meta Analysis ◽  
Kynurenine Pathway ◽  
Blood Levels ◽  
Indoleamine Dioxygenase ◽  
The Central Nervous System ◽  
Stress Mediators ◽  
Rate Limiting ◽  
And Oxidative Stress

The tryptophan catabolite (TRYCAT) pathway is implicated in the pathophysiology of schizophrenia (SCZ) since the rate-limiting enzyme indoleamine-dioxygenase (IDO) may be induced by inflammatory and oxidative stress mediators. This systematic review searched PubMed, Web of Science, and Google Scholar for papers published from inception until August 2021 and meta-analyzed the association between SCZ and TRYCATs in the central nervous system (CNS) and peripheral blood. We included 61 studies comprising 2813 patients and 2948 healthy controls. In the CNS we found a significant (p<0.001) increase in the kynurenine/tryptophan (KYN/TRP) (standardized mean difference, SMD=0.769, 95% confidence interval, CI: 0.456; 1.082) and kynurenic acid (KA)/KYN+TRP (SMD=0.697, CI:0.478-0.917) ratios, KA (SMD=0.646, CI: 0.422; 0.909) and KYN (SMD=1.238; CI: 0.590; 1.886), while the 3OH-kynurenine (3HK) + KYN-3-monooxygenase (KMO)/KYN ratio was significantly reduced (SMD=-1.089, CI: -1.682; -0.496). There were significant differences between KYN/TRP, (KYN+KA)/TRP, (3HK+KMO)/KYN, KA, and KYN levels among the CNS and peripheral blood, and among serum and plasma KYN. The only useful peripheral marker of CNS TRYCATs findings was the increased KYN/TRP ratio in serum (SMD=0.211, CI: 0.056; 0.366, p=0.007), but not in plasma. There was no significant increase in a neurotoxic composite score based on KYN, 3HK, and picolinic, xanthurenic, and quinolinic acid. SCZ is accompanied by increased IDO activity in the CNS and serum, and reduced KMO activity and a shift towards KA production in the CNS. This CNS TRYCATs profile indicates neuroprotective, negative immunoregulatory and anti-inflammatory effects. Peripheral blood levels of TRYCATs are dissociated from CNS findings except for a modest increase in serum IDO activity.

scholarly journals The Tryptophan Catabolite or Kynurenine Pathway in Schizophrenia: Meta-Analysis Reveals Dissociations Between Central, Serum and Plasma Compartments

2021 ◽  
Author(s):  
Abbas F. Almulla ◽  
Asara Vasupanrajit ◽  
Chavit Tunvirachaisakul ◽  
Hussein K. Al-Hakeim ◽  
Marco Solmi ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Kynurenic Acid ◽  
Meta Analysis ◽  
Kynurenine Pathway ◽  
Blood Levels ◽  
Indoleamine Dioxygenase ◽  
The Central Nervous System ◽  
Stress Mediators ◽  
Rate Limiting ◽  
And Oxidative Stress

The tryptophan catabolite (TRYCAT) pathway is implicated in the pathophysiology of schizophrenia (SCZ) since the rate-limiting enzyme indoleamine-dioxygenase (IDO) may be induced by inflammatory and oxidative stress mediators. This systematic review searched PubMed, Web of Science, and Google Scholar for papers published from inception until August 2021 and meta-analyzed the association between SCZ and TRYCATs in the central nervous system (CNS) and peripheral blood. We included 61 studies comprising 2813 patients and 2948 healthy controls. In the CNS we found a significant (p&lt;0.001) increase in the kynurenine/tryptophan (KYN/TRP) (standardized mean difference, SMD=0.769, 95% confidence interval, CI: 0.456; 1.082) and kynurenic acid (KA)/KYN+TRP (SMD=0.697, CI:0.478-0.917) ratios, KA (SMD=0.646, CI: 0.422; 0.909) and KYN (SMD=1.238; CI: 0.590; 1.886), while the 3OH-kynurenine (3HK) + KYN-3-monooxygenase (KMO)/KYN ratio was significantly reduced (SMD=-1.089, CI: -1.682; -0.496). There were significant differences between KYN/TRP, (KYN+KA)/TRP, (3HK+KMO)/KYN, KA, and KYN levels among the CNS and peripheral blood, and among serum and plasma KYN. The only useful peripheral marker of CNS TRYCATs findings was the increased KYN/TRP ratio in serum (SMD=0.211, CI: 0.056; 0.366, p=0.007), but not in plasma. There was no significant increase in a neurotoxic composite score based on KYN, 3HK, and picolinic, xanthurenic, and quinolinic acid. SCZ is accompanied by increased IDO activity in the CNS and serum, and reduced KMO activity and a shift towards KA production in the CNS. This CNS TRYCATs profile indicates neuroprotective, negative immunoregulatory and anti-inflammatory effects. Peripheral blood levels of TRYCATs are dissociated from CNS findings except for a modest increase in serum IDO activity.

scholarly journals Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets

2021 ◽  
Vol 22 (24) ◽  
pp. 13497
Author(s):  
Artur Wnorowski ◽  
Sylwia Wnorowska ◽  
Jacek Kurzepa ◽  
Jolanta Parada-Turska
Keyword(s):  
Inflammatory Bowel Disease ◽  
Successful Treatment ◽  
Bowel Disease ◽  
Drug Targets ◽  
De Novo ◽  
Meta Analysis ◽  
Kynurenine Pathway ◽  
Infliximab Treatment ◽  
Nad Synthesis ◽  
Inflammatory Bowel

A meta-analysis of publicly available transcriptomic datasets was performed to identify metabolic pathways profoundly implicated in the progression and treatment of inflammatory bowel disease (IBD). The analysis revealed that genes involved in tryptophan (Trp) metabolism are upregulated in Crohn’s disease (CD) and ulcerative colitis (UC) and return to baseline after successful treatment with infliximab. Microarray and mRNAseq profiles from multiple experiments confirmed that enzymes responsible for Trp degradation via the kynurenine pathway (IDO1, KYNU, IL4I1, KMO, and TDO2), receptor of Trp metabolites (HCAR3), and enzymes catalyzing NAD+ turnover (NAMPT, NNMT, PARP9, CD38) were synchronously coregulated in IBD, but not in intestinal malignancies. The modeling of Trp metabolite fluxes in IBD indicated that changes in gene expression shifted intestinal Trp metabolism from the synthesis of 5-hydroxytryptamine (5HT, serotonin) towards the kynurenine pathway. Based on pathway modeling, this manifested in a decline in mucosal Trp and elevated kynurenine (Kyn) levels, and fueled the production of downstream metabolites, including quinolinate, a substrate for de novo NAD+ synthesis. Interestingly, IBD-dependent alterations in Trp metabolites were normalized in infliximab responders, but not in non-responders. Transcriptomic reconstruction of the NAD+ pathway revealed an increased salvage biosynthesis and utilization of NAD+ in IBD, which normalized in patients successfully treated with infliximab. Treatment-related changes in NAD+ levels correlated with shifts in nicotinamide N-methyltransferase (NNMT) expression. This enzyme helps to maintain a high level of NAD+-dependent proinflammatory signaling by removing excess inhibitory nicotinamide (Nam) from the system. Our analysis highlights the prevalent deregulation of kynurenine and NAD+ biosynthetic pathways in IBD and gives new impetus for conducting an in-depth examination of uncovered phenomena in clinical studies.

Understanding Schizophrenia: Genetic Causes and Treatment

2019 ◽  
Vol 1 (1) ◽  
pp. 6-12
Author(s):  
Fatima Javeria ◽  
Shazma Altaf ◽  
Alishah Zair ◽  
Rana Khalid Iqbal
Keyword(s):  
Copy Number ◽  
Drug Targets ◽  
Disease Risk ◽  
Mental Disease ◽  
Copy Number Variants ◽  
Aminobutyric Acid ◽  
Epigenetic Mechanisms ◽  
Gamma Aminobutyric Acid ◽  
Wide Range ◽  
Severe Mental Disease

Schizophrenia is a severe mental disease. The word schizophrenia literally means split mind. There are three major categories of symptoms which include positive, negative and cognitive symptoms. The disease is characterized by symptoms of hallucination, delusions, disorganized thinking and speech. Schizophrenia is related to many other mental and psychological problems like suicide, depression, hallucinations. Including these, it is also a problem for the patient’s family and the caregiver. There is no clear reason for the disease, but with the advances in molecular genetics; certain epigenetic mechanisms are involved in the pathophysiology of the disease. Epigenetic mechanisms that are mainly involved are the DNA methylation, copy number variants. With the advent of GWAS, a wide range of SNPs is found linked with the etiology of schizophrenia. These SNPs serve as ‘hubs’; because these all are integrating with each other in causing of schizophrenia risk. Until recently, there is no treatment available to cure the disease; but anti-psychotics can reduce the disease risk by minimizing its symptoms. Dopamine, serotonin, gamma-aminobutyric acid, are the neurotransmitters which serve as drug targets in the treatment of schizophrenia. Due to the involvement of genetic and epigenetic mechanisms, drugs available are already targeting certain genes involved in the etiology of the disease.

Current Status and Future Perspective for Research on Medicinal Plants with Anticancerous Activity and Minimum Cytotoxic Value

2019 ◽  
Vol 20 (12) ◽  
pp. 1227-1243
Author(s):  
Hina Qamar ◽  
Sumbul Rehman ◽  
D.K. Chauhan
Keyword(s):  
Side Effects ◽  
Medicinal Plants ◽  
Anticancer Agents ◽  
Drug Targets ◽  
Psidium Guajava ◽  
Current Status ◽  
Future Perspective ◽  
Wide Range

Cancer is the second leading cause of morbidity and mortality worldwide. Although chemotherapy and radiotherapy enhance the survival rate of cancerous patients but they have several acute toxic effects. Therefore, there is a need to search for new anticancer agents having better efficacy and lesser side effects. In this regard, herbal treatment is found to be a safe method for treating and preventing cancer. Here, an attempt has been made to screen some less explored medicinal plants like Ammania baccifera, Asclepias curassavica, Azadarichta indica, Butea monosperma, Croton tiglium, Hedera nepalensis, Jatropha curcas, Momordica charantia, Moringa oleifera, Psidium guajava, etc. having potent anticancer activity with minimum cytotoxic value (IC50 >3μM) and lesser or negligible toxicity. They are rich in active phytochemicals with a wide range of drug targets. In this study, these medicinal plants were evaluated for dose-dependent cytotoxicological studies via in vitro MTT assay and in vivo tumor models along with some more plants which are reported to have IC50 value in the range of 0.019-0.528 mg/ml. The findings indicate that these plants inhibit tumor growth by their antiproliferative, pro-apoptotic, anti-metastatic and anti-angiogenic molecular targets. They are widely used because of their easy availability, affordable price and having no or sometimes minimal side effects. This review provides a baseline for the discovery of anticancer drugs from medicinal plants having minimum cytotoxic value with minimal side effects and establishment of their analogues for the welfare of mankind.

Structure, Function and Interactions of Tau: Particular Focus on Potential Drug Targets for the Treatment of Tauopathies

2018 ◽  
Vol 17 (5) ◽  
pp. 325-337 ◽  
Author(s):  
Hojjat Borna ◽  
Kasim Assadoulahei ◽  
Gholamhossein Riazi ◽  
Asghar Beigi Harchegani ◽  
Alireza Shahriary
Keyword(s):  
Tau Protein ◽  
Drug Targets ◽  
Brain Injuries ◽  
Potential Drug ◽  
Microtubule Network ◽  
Wide Range ◽  
Potential Risk Factors ◽  
Range Of Functions ◽  
Potential Drug Targets

Background & Objective: Neurodegenrative diseases are among the most widespread lifethreatening disorders around the world in elderly ages. The common feature of a group of neurodegenerative disorders, called tauopathies, is an accumulation of microtubule associated protein tau inside the neurons. The exact mechanism underlying tauopathies is not well-understood but several factors such as traumatic brain injuries and genetics are considered as potential risk factors. Although tau protein is well-known for its key role in stabilizing and organization of axonal microtubule network, it bears a broad range of functions including DNA protection and participation in signaling pathways. Moreover, the flexible unfolded structure of tau facilitates modification of tau by a wide range of intracellular enzymes which in turn broadens tau function and interaction spectrum. The distinctive properties of tau protein concomitant with the crucial role of tau interaction partners in the progression of neurodegeneration suggest tau and its binding partners as potential drug targets for the treatment of neurodegenerative diseases. Conclusion: This review aims to give a detailed description of structure, functions and interactions of tau protein in order to provide insight into potential therapeutic targets for treatment of tauopathies.

scholarly journals Natural Molecules and Neuroprotection: Kynurenic Acid, Pantethine and α-Lipoic Acid

2021 ◽  
Vol 22 (1) ◽  
pp. 403
Author(s):  
Fanni Tóth ◽  
Edina Katalin Cseh ◽  
László Vécsei
Keyword(s):  
Neurodegenerative Diseases ◽  
Lipoic Acid ◽  
Kynurenic Acid ◽  
Biological Activities ◽  
Neuroprotective Effect ◽  
Structural Diversity ◽  
Kynurenine Pathway ◽  
Glutamate Excitotoxicity ◽  
Neuroprotective Agents ◽  
Starting Point

The incidence of neurodegenerative diseases has increased greatly worldwide due to the rise in life expectancy. In spite of notable development in the understanding of these disorders, there has been limited success in the development of neuroprotective agents that can slow the progression of the disease and prevent neuronal death. Some natural products and molecules are very promising neuroprotective agents because of their structural diversity and wide variety of biological activities. In addition to their neuroprotective effect, they are known for their antioxidant, anti-inflammatory and antiapoptotic effects and often serve as a starting point for drug discovery. In this review, the following natural molecules are discussed: firstly, kynurenic acid, the main neuroprotective agent formed via the kynurenine pathway of tryptophan metabolism, as it is known mainly for its role in glutamate excitotoxicity, secondly, the dietary supplement pantethine, that is many sided, well tolerated and safe, and the third molecule, α-lipoic acid is a universal antioxidant. As a conclusion, because of their beneficial properties, these molecules are potential candidates for neuroprotective therapies suitable in managing neurodegenerative diseases.

scholarly journals Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Vincent Millischer ◽  
Matthias Heinzl ◽  
Anthi Faka ◽  
Michael Resl ◽  
Ada Trepci ◽  
...  
Keyword(s):  
Human Subjects ◽  
Picolinic Acid ◽  
Plasma Concentrations ◽  
Experimental Studies ◽  
Placebo Treatment ◽  
Kynurenine Pathway ◽  
Healthy Male ◽  
Systemic Injection ◽  
Plasma Tryptophan ◽  
Endotoxemia Model

Abstract Background Administration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects. Methods The present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP). The study included 10 healthy, non-smoking men (18–40 years) free from medication. Statistical differences in tryptophan and kynurenine metabolites as well as associations with IL-6 and CRP in LPS and placebo treated subjects were assessed with linear mixed-effects models. Results Systemic injection of LPS was associated with significantly lower concentrations of plasma tryptophan and kynurenine after 4 h, as well as higher concentrations of quinolinic acid (QUIN) after 48 h compared to the placebo injection. No differences were found in kynurenic acid (KYNA) or picolinic acid plasma concentrations between LPS or placebo treatment. The KYNA/kynurenine ratio peaked at 6 h post LPS injection while QUIN/kynurenine maintained significantly higher from 3 h post LPS injection until 24 h. The kynurenine/tryptophan ratio was higher at 24 h and 48 h post LPS treatment. Finally, we report an association between the kynurenine/tryptophan ratio and CRP. Conclusions Our findings strongly support the concept that an inflammatory challenge with LPS induces the kynurenine pathway in humans, activating both the neurotoxic (QUIN) and neuroprotective (KYNA) branch of the kynurenine pathway. Trial registration This study is based on a study registered at ClinicalTrials.gov, NCT03392701. Registered 21 December 2017.

scholarly journals COVID-19 in People Living with HIV: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 18 (7) ◽  
pp. 3554
Author(s):  
Kai Wei Lee ◽  
Sook Fan Yap ◽  
Yun Fong Ngeow ◽  
Munn Sann Lye
Keyword(s):  
Systematic Review ◽  
Laboratory Testing ◽  
Meta Analysis ◽  
Clinical Signs ◽  
Adverse Outcomes ◽  
People Living With Hiv ◽  
Common Symptom ◽  
Chest Imaging ◽  
Wide Range ◽  
Epidemiological Characteristics

COVID-19 is a global health emergency. People living with human immunodeficiency virus (PLHIV) have concerns about whether they have a higher risk of getting the infection and suffer worse COVID-19 outcomes. Findings from studies on these questions have largely been inconsistent. We aimed to determine the epidemiological characteristics, clinical signs and symptoms, blood parameters, and clinical outcomes among PLHIV who contracted COVID-19. Relevant studies were identified through Medline, Cinahl, and PubMed databases. A random-effects model was used in meta-analyses with a 95% confidence interval. Eighty-two studies were included in the systematic review and sixty-seven studies for the meta-analysis. The pooled incidence proportion of COVID-19 among PLHIV was 0.9% (95% CI 0.6%, 1.1%) based on the data from seven cohort studies. Overall, 28.4% were hospitalised, of whom, 2.5% was severe-critical cases and 3.5% needed intensive care. The overall mortality rate was 5.3%. Hypertension was the most commonly reported comorbidity (24.0%). Fever (71.1%) was the most common symptom. Chest imaging demonstrated a wide range of abnormal findings encompassing common changes such as ground glass opacities and consolidation as well as a spectrum of less common abnormalities. Laboratory testing of inflammation markers showed that C-reactive protein, ferritin, and interleukin-6 were frequently elevated, albeit to different extents. Clinical features as well as the results of chest imaging and laboratory testing were similar in highly active antiretroviral therapy (HAART)-treated and non-treated patients. PLHIV were not found to be at higher risk for adverse outcomes of COVID-19. Hence, in COVID-19 management, it appears that they can be treated the same way as HIV negative individuals. Nevertheless, as the pandemic situation is rapidly evolving, more evidence may be needed to arrive at definitive recommendations.

scholarly journals Definitions and Prevalence of Multimorbidity in Large Database Studies: A Scoping Review

2021 ◽  
Vol 18 (4) ◽  
pp. 1673
Author(s):  
Ying Pin Chua ◽  
Ying Xie ◽  
Poay Sian Sabrina Lee ◽  
Eng Sing Lee
Keyword(s):  
Scoping Review ◽  
Chronic Conditions ◽  
Meta Analysis ◽  
Epidemiological Studies ◽  
Cross Sectional ◽  
Coding Systems ◽  
Wide Range ◽  
Scoping Reviews ◽  
Retrospective Cohort Studies ◽  
Definition Of

Background: Multimorbidity presents a key challenge to healthcare systems globally. However, heterogeneity in the definition of multimorbidity and design of epidemiological studies results in difficulty in comparing multimorbidity studies. This scoping review aimed to describe multimorbidity prevalence in studies using large datasets and report the differences in multimorbidity definition and study design. Methods: We conducted a systematic search of MEDLINE, EMBASE, and CINAHL databases to identify large epidemiological studies on multimorbidity. We used the Preferred Reporting Items for Systematic Reviews and Meta-analysis Extension for Scoping Reviews (PRISMA-ScR) protocol for reporting the results. Results: Twenty articles were identified. We found two key definitions of multimorbidity: at least two (MM2+) or at least three (MM3+) chronic conditions. The prevalence of multimorbidity MM2+ ranged from 15.3% to 93.1%, and 11.8% to 89.7% in MM3+. The number of chronic conditions used by the articles ranged from 15 to 147, which were organized into 21 body system categories. There were seventeen cross-sectional studies and three retrospective cohort studies, and four diagnosis coding systems were used. Conclusions: We found a wide range in reported prevalence, definition, and conduct of multimorbidity studies. Obtaining consensus in these areas will facilitate better understanding of the magnitude and epidemiology of multimorbidity.

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