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Fulltext Effects of stress associated with academic examination on the kynurenine pathway profile in healthy students

Myint K, Jacobs K, Myint AM, Lam SK, Henden L, Hoe SZ, et al.

PLoS One, 2021;16(6):e0252668.
PMID: 34081742 DOI: 10.1371/journal.pone.0252668

The effects of stress on the neuroendocrine, central nervous and immune systems are extremely complex. The kynurenine pathway (KP) of the tryptophan metabolism is recognised as a cross-link between the neuroendocrine- and immune systems. However, the effects of acute stress from everyday life on KP activation have not yet been studied. This study aims to investigate changes in the levels of the KP neuroactive metabolites and cytokines in response to stress triggered by academic examinations. Ninety-two healthy first year medical students benevolently participated in the study. Parameters were measured pre- examination, which is considered to be a high-stress period, and post-examination, as a low-stress period. Stress induced by academic examinations significantly increases the perceived stress scores (p<0.001), serum cortisol levels (p<0.001) and brain-derived neurotrophic factor (BDNF) levels (p<0.01). It decreased IL-10 levels (p<0.05) but had no effect on IL-6 and TNF-alpha levels. Only the KP neuroactive metabolite, 3-hydroxykynurenine (3-HK) significantly increased (p<0.01) in the post-examination period. In addition, the stress scores positively correlated with the levels of cortisol (r2 = 0.297, p<0.01) at post examination. Acute stress triggered by academic examinations increases cortisol and BDNF production and suppresses the anti-inflammatory cytokine, IL-10, but did not increase significantly the levels of other pro-inflammatory cytokines, tryptophan, kynurenine and downstream KP metabolites. The concomitant increased levels of BDNF under the duress of acute examination stress appear to limit the levels pro-inflammatory markers, which may attenuate the action of cortisol and the neuroinflammatory branch of the KP.
Oncolytic viruses as a promising therapeutic strategy against the detrimental health impacts of air pollution: The case of glioblastoma multiforme

Kazemi Shariat Panahi H, Dehhaghi M, Lam SS, Peng W, Aghbashlo M, Tabatabaei M, et al.

Semin Cancer Biol, 2022 Nov;86(Pt 3):1122-1142.
PMID: 34004331 DOI: 10.1016/j.semcancer.2021.05.013

Human livelihood highly depends on applying different sources of energy whose utilization is associated with air pollution. On the other hand, air pollution may be associated with glioblastoma multiforme (GBM) development. Unlike other environmental causes of cancer (e.g., irradiation), air pollution cannot efficiently be controlled by geographical borders, regulations, and policies. The unavoidable exposure to air pollution can modify cancer incidence and mortality. GBM treatment with chemotherapy or even its surgical removal has proven insufficient (100% recurrence rate; patient's survival mean of 15 months; 90% fatality within five years) due to glioma infiltrative and migratory capacities. Given the barrage of attention and research investments currently plowed into next-generation cancer therapy, oncolytic viruses are perhaps the most vigorously pursued. Provision of an insight into the current state of the research and future direction is essential for stimulating new ideas with the potentials of filling research gaps. This review manuscript aims to overview types of brain cancer, their burden, and different causative agents. It also describes why air pollution is becoming a concerning factor. The different opinions on the association of air pollution with brain cancer are reviewed. It tries to address the significant controversy in this field by hypothesizing the air-pollution-brain-cancer association via inflammation and atopic conditions. The last section of this review deals with the oncolytic viruses, which have been used in, or are still under clinical trials for GBM treatment. Engineered adenoviruses (i.e., DNX-2401, DNX-2440, CRAd8-S-pk7 loaded Neural stem cells), herpes simplex virus type 1 (i.e., HSV-1 C134, HSV-1 rQNestin34.5v.2, HSV-1 G207, HSV-1 M032), measles virus (i.e., MV-CEA), parvovirus (i.e., ParvOryx), poliovirus (i.e., Poliovirus PVSRIPO), reovirus (i.e., pelareorep), moloney murine leukemia virus (i.e., Toca 511 vector), and vaccinia virus (i.e., vaccinia virus TG6002) as possible life-changing alleviations for GBM have been discussed. To the best of our knowledge, this review is the first review that comprehensively discusses both (i) the negative/positive association of air pollution with GBM; and (ii) the application of oncolytic viruses for GBM, including the most recent advances and clinical trials. It is also the first review that addresses the controversies over air pollution and brain cancer association. We believe that the article will significantly appeal to a broad readership of virologists, oncologists, neurologists, environmentalists, and those who work in the field of (bio)energy. Policymakers may also use it to establish better health policies and regulations about air pollution and (bio)fuels exploration, production, and consumption.
Engineered bacteria for valorizing lignocellulosic biomass into bioethanol

Kazemi Shariat Panahi H, Dehhaghi M, Dehhaghi S, Guillemin GJ, Lam SS, Aghbashlo M, et al.

Bioresour Technol, 2022 Jan;344(Pt A):126212.
PMID: 34715341 DOI: 10.1016/j.biortech.2021.126212

Appropriate bioprocessing of lignocellulosic materials into ethanol could address the world's insatiable appetite for energy while mitigating greenhouse gases. Bioethanol is an ideal gasoline extender and is widely used in many countries in blended form with gasoline at specific ratios to improve fuel characteristics and engine performance. Although the bioethanol production industry has long been operational, finding a suitable microbial agent for the efficient conversion of lignocelluloses is still an active field of study. Among available microbial candidates, engineered bacteria may be promising ethanol producers while may show other desired traits such as thermophilic nature and high ethanol tolerance. This review provides the current knowledge on the introduction, overexpression, and deletion of the genes that have been performed in bacterial hosts to achieve higher ethanol yield, production rate and titer, and tolerance. The constraints and possible solutions and economic feasibility of the processes utilizing such engineered strains are also discussed.
The Cytokines CXCL10 and CCL2 and the Kynurenine Metabolite Anthranilic Acid Accurately Predict Patients at Risk of Developing Dengue With Warning Signs

Jusof FF, Lim CK, Aziz FN, Soe HJ, Raju CS, Sekaran SD, et al.

J Infect Dis, 2022 Nov 28;226(11):1964-1973.
PMID: 35767283 DOI: 10.1093/infdis/jiac273

BACKGROUND: The resolution or aggravation of dengue infection depends on the patient's immune response during the critical phase. Cytokines released by immune cells increase with the worsening severity of dengue infections. Cytokines activate the kynurenine pathway (KP) and the extent of KP activation then influences disease severity.
METHODS: KP metabolites and cytokines in plasma samples of patients with dengue infection (dengue without warning signs [DWS-], dengue with warning signs [DWS+], or severe dengue) were analyzed. Cytokines (interferon gamma [IFN-ɣ], tumor necrosis factor, interleukin 6, CXCL10/interferon-inducile protein 10 [IP-10], interleukin 18 [IL-18], CCL2/monocyte chemoattractant protein-1 [MCP-1], and CCL4/macrophage inflammatory protein-1beta [MIP-1β] were assessed by a Human Luminex Screening Assay, while KP metabolites (tryptophan, kynurenine, anthranilic acid [AA], picolinic acid, and quinolinic acid) were assessed by ultra-high-performance liquid chromatography and Gas Chromatography Mass Spectrophotometry [GCMS] assays.
RESULTS: Patients with DWS+ had increased activation of the KP where kynurenine-tryptophan ratio, anthranilic acid, and picolinic acid were elevated. These patients also had higher levels of the cytokines IFN-ɣ, CXCL10, CCL4, and IL-18 than those with DWS-. Further receiver operating characteristic analysis identified 3 prognostic biomarker candidates, CXCL10, CCL2, and AA, which predicted patients with higher risks of developing DWS+ with an accuracy of 97%.
CONCLUSIONS: The data suggest a unique biochemical signature in patients with DWS+. CXCL10 and CCL2 together with AA are potential prognostic biomarkers that discern patients with higher risk of developing DWS+ at earlier stages of infection.
Targeting microRNAs as a promising anti-cancer therapeutic strategy against traffic-related air pollution-mediated lung cancer

Kazemi Shariat Panahi H, Dehhaghi M, Guillemin GJ, Peng W, Aghbashlo M, Tabatabaei M

Cancer Metastasis Rev, 2023 Nov 01.
PMID: 37910296 DOI: 10.1007/s10555-023-10142-x

Air pollutants are increasingly emitted into the atmosphere because of the high dependency of humans on fossil-derived fuels. Wind speed and direction assisted high dispersibility and uncontrolled nature of air pollution across geo-/demographical borders, making it one of the major global concerns. Besides climate change, air pollution has been found to be associated with various diseases, such as cancer. Lung cancer, which is the world's most common type of cancer, has been found to be associated with traffic-related air pollution. Research and political efforts have been taken to explore green/renewable energy sources. However, these efforts at the current intensity cannot cope with the increasing need for fossil fuels. More specifically, political tensions such as the Russian-Ukraine war, economic tension (e.g., China-USA economic tensions), and other issues (e.g., pandemic, higher inflation rate, and poverty) significantly hindered phasing out fossil fuels. In this context, an increasing global population will be exposed to traffic-related air pollution, which justifies the current uptrend in the number of lung cancer patients. To combat this health burden, novel treatments with higher efficiency and specificity must be designed. One of the potential "life changer" options is microRNA (miRNA)-based therapy to target the expression of oncogenic genes. That said, this review discusses the association of traffic-related air pollution with lung cancer, the changes in indigenous miRNAs in the body during lung cancer, and the current status of miRNA therapeutics for lung cancer treatment. We believe that the article will significantly appeal to a broad readership of oncologists, environmentalists, and those who work in the field of (bio)energy. It may also gain the policymakers' attention to establish better health policies and regulations about air pollution, for example, by promoting (bio)fuel exploration, production, and consumption.
Fulltext Psychological Stresses in Children Trigger Cytokine- and Kynurenine Metabolite-Mediated Abdominal Pain and Proinflammatory Changes

Myint K, Jacobs K, Myint AM, Lam SK, Lim YA, Boey CC, et al.

Front Immunol, 2021;12:702301.
PMID: 34539633 DOI: 10.3389/fimmu.2021.702301

Recurrent abdominal pain (RAP) is a common medically unexplained symptom among children worldwide. However, the biological mechanisms behind the development of functional and behavioral symptoms and changes in blood markers have not been well explored. This study aimed to assess changes in the concentrations of inflammatory markers, including cytokines and tryptophan catabolites, in the serum of children with RAP compared to those with subclinical infections. Children with RAP but without organic diseases were included, and those with asymptomatic intestinal parasitic infections were used as a subclinical infection cohort. Blood samples were collected and used to measure the cytokine profile using Multiplex Immunoassay and tryptophan catabolites using high performance liquid chromatography. Children with RAP showed significantly higher concentrations of serum tumor necrotic factor-α, p<0.05, but lower concentrations of IL-10, p<0.001, IL-6, p<0.001 and brain-derived neurotrophic factors (BDNF) p<0.01. In addition, a significant increase in the metabolite of the kynurenine pathway, 3-hydroxyanthranilic acid (3-HAA) p<0.01, a significant decrease in the concentrations of anthranilic acid (AA) p<0.001, together with an increased ratio of serum 3-HAA to AA (3-HAA/AA) p<0.001, was found in this cohort. These findings indicate the significant activation of the immune system and presence of inflammation in children with RAP than those with subclinical parasitic infections. Moreover, children with RAP tested with the Strengths and Difficulties Questionnaire (SDQ), displayed high psychological problems though these SDQ scores were not statistically associated with measured cytokines and kynurenine metabolites. We however could hypothesize that the pro-inflammatory state together with concomitant low concentrations of BDNF in those children with RAP could play a role in psychological stress and experiencing medically unexplained symptoms.
Fulltext Activation of the kynurenine pathway and increased production of the excitotoxin quinolinic acid following traumatic brain injury in humans

Yan EB, Frugier T, Lim CK, Heng B, Sundaram G, Tan M, et al.

J Neuroinflammation, 2015 May 30;12:110.
PMID: 26025142 DOI: 10.1186/s12974-015-0328-2

During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims. Acute QUIN levels were further correlated with outcome scores to explore its prognostic value in TBI recovery.
METHODS: Twenty-eight patients with severe TBI (GCS ≤ 8, three patients had initial GCS = 9-10, but rapidly deteriorated to ≤8) were recruited. CSF was collected from admission to day 5 post-injury. TRP, kynurenine (KYN), kynurenic acid (KYNA), QUIN, anthranilic acid (AA) and 3-hydroxyanthranilic acid (3HAA) were measured in CSF. The Glasgow Outcome Scale Extended (GOSE) score was assessed at 6 months post-TBI. Post-mortem brains were obtained from the Australian Neurotrauma Tissue and Fluid Bank and used in qPCR for quantitating expression of KP enzymes (indoleamine 2,3-dioxygenase-1 (IDO1), kynurenase (KYNase), kynurenine amino transferase-II (KAT-II), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3HAO) and quinolinic acid phosphoribosyl transferase (QPRTase) and IDO1 immunohistochemistry.
RESULTS: In CSF, KYN, KYNA and QUIN were elevated whereas TRP, AA and 3HAA remained unchanged. The ratios of QUIN:KYN, QUIN:KYNA, KYNA:KYN and 3HAA:AA revealed that QUIN levels were significantly higher than KYN and KYNA, supporting increased neurotoxicity. Amplified IDO1 and KYNase mRNA expression was demonstrated on post-mortem brains, and enhanced IDO1 protein coincided with overt tissue damage. QUIN levels in CSF were significantly higher in patients with unfavourable outcome and inversely correlated with GOSE scores.
CONCLUSION: TBI induced a striking activation of the KP pathway with sustained increase of QUIN. The exceeding production of QUIN together with increased IDO1 activation and mRNA expression in brain-injured areas suggests that TBI selectively induces a robust stimulation of the neurotoxic branch of the KP pathway. QUIN's detrimental roles are supported by its association to adverse outcome potentially becoming an early prognostic factor post-TBI.
Current and emerging applications of saccharide-modified chitosan: a critical review

Kazemi Shariat Panahi H, Dehhaghi M, Amiri H, Guillemin GJ, Gupta VK, Rajaei A, et al.

Biotechnol Adv, 2023 Sep;66:108172.
PMID: 37169103 DOI: 10.1016/j.biotechadv.2023.108172

Chitin, as the main component of the exoskeleton of Arthropoda, is a highly available natural polymer that can be processed into various value-added products. Its most important derivative, i.e., chitosan, comprising β-1,4-linked 2-amino-2-deoxy-β-d-glucose (deacetylated d-glucosamine) and N-acetyl-d-glucosamine units, can be prepared via alkaline deacetylation process. Chitosan has been used as a biodegradable, biocompatible, non-antigenic, and nontoxic polymer in some in-vitro applications, but the recently found potentials of chitosan for in-vivo applications based on its biological activities, especially antimicrobial, antioxidant, and anticancer activities, have upgraded the chitosan roles in biomaterials. Chitosan approval, generally recognized as a safe compound by the United States Food and Drug Administration, has attracted much attention toward its possible applications in diverse fields, especially biomedicine and agriculture. Despite some favorable characteristics, the chitosan's structure should be customized for advanced applications, especially due to its drawbacks, such as low drug-load capacity, low solubility, high viscosity, lack of elastic properties, and pH sensitivity. In this context, derivatization with relatively inexpensive and highly available mono- and di-saccharides to soluble branched chitosan has been considered a "game changer". This review critically scrutinizes the emerging technologies based on the synthesis and application of lactose- and galactose-modified chitosan as two important chitosan derivatives. Some characteristics of chitosan derivatives and biological activities have been detailed first to understand the value of these natural polymers. Second, the saccharide modification of chitosan has been discussed briefly. Finally, the applications of lactose- and galactose-modified chitosan have been scrutinized and compared to native chitosan to provide an insight into the current state-of-the research for stimulating new ideas with the potential of filling research gaps.
The degree of astrocyte activation in multiple system atrophy is inversely proportional to the distance to α-synuclein inclusions

Radford R, Rcom-H'cheo-Gauthier A, Wong MB, Eaton ED, Quilty M, Blizzard C, et al.

Mol. Cell. Neurosci., 2015 Mar;65:68-81.
PMID: 25731829 DOI: 10.1016/j.mcn.2015.02.015

Multiple system atrophy (MSA) exhibits widespread astrogliosis together with α-synuclein (α-syn) glial cytoplasmic inclusions (GCIs) in mature oligodendrocytes. We quantified astrocyte activation by morphometric analysis of MSA cases, and investigated the correlation to GCI proximity. Using Imaris software, we obtained "skinned" three-dimensional models of GFAP-positive astrocytes in MSA and control tissue (n=75) from confocal z-stacks and measured the astrocyte process length and thickness and radial distance to the GCI. Astrocytes proximal to GCI-containing oligodendrocytes (r<25μm) had significantly (p, 0.05) longer and thicker processes characteristic of activation than distal astrocytes (r>25μm), with a reciprocal linear correlation (m, 90μm(2)) between mean process length and radial distance to the nearest GCI (R(2), 0.7). In primary cell culture studies, α-syn addition caused ERK-dependent activation of rat astrocytes and perinuclear α-syn inclusions in mature (MOSP-positive) rat oligodendrocytes. Activated astrocytes were also observed in close proximity to α-syn deposits in a unilateral rotenone-lesion mouse model. Moreover, unilateral injection of MSA tissue-derived α-syn into the mouse medial forebrain bundle resulted in widespread neuroinflammation in the α-syn-injected, but not sham-injected hemisphere. Taken together, our data suggests that the action of localized concentrations of α-syn may underlie both astrocyte and oligodendrocyte MSA pathological features.