A Review of Immunological and Neuropsychobehavioral Effects of Latent Toxoplasmosis on Humans.

Toxoplasmosis as a zoonotic disease has a worldwide distribution and can infect a wide range of animal hosts, as well as at least one third of the world's human population. The disease is usually mild or asymptomatic in immunocompetent individuals, but dormant tissue cysts survive especially in the brain for the host lifespan, known as latent toxoplasmosis (LT). Recent studies suggest that LT can have certain neurological, immunological psychological and behavioural effects on human including schizophrenia, bipolar disorder, Alzheimer's disease, depression, suicide anxiety and sleeping disorders. LT effects are controversial, and their exact mechanisms of action is not yet fully understood. This review aims to provide an overview of the potential effects, their basic mechanisms including alteration of neurotransmitter levels, immune activation in the central nervous system and induction of oxidative stress. Additionally, beneficial effects of LT, and an explanation of the effects within the framework of manipulation hypothesis, and finally, the challenges and limitations of the current research are discussed.

Involvement of T-bet and GATA3 transcription factors in Mesenchymal stem cells and royal jelly combination treatment in brain stroke.

INTRODUCTION: Mesenchymal stem cells (MSC) therapy is a promising therapeutic strategy to overcome the brain stroke side effects. However, it may be associated with long-term complications, including induction of inflammation. This project was designed to examine the effects of MSC administration and its combination with royal jelly (RJ) on the differentiation of T helper subsets. MATERIAL AND METHODS: In this project, the mice were divided to the six groups, including control (healthy without stroke), stroke (mice model of middle cerebral artery occlusion (MCAO)), treated with mouse MSC (mMSC), royal jelly (RJ), combination of mMSC and RJ (mMSC + RJ) and MSC conditioned medium (SUP). Thereafter, sticky test, brain mRNA levels of T-bet (transcription factor for Th1 subset), GATA3 (transcription factor for Th2 subset), and ROR-γ (transcription factor for Th17 subset) and percentage of myeloperoxidase (MPO) activities were explored in the groups. RESULTS: Administration of mMSC and mMSC + RJ improved the sticky test times and decreased the MPO activities. Using mMSCs and RJ was associated with increased expression of T-bet and GATA3 transcription factors. Transplantation of mMSCs in combination with RJ reduced expression of T-bet in the infarcted tissue. CONCLUSION: Using mMSC may be associated with Th1-related inflammation in the long term. RJ co-administration significantly reduced the risks, hence, to decrease the plausible side effects of MSCs, it can be proposed to use RJ in combination with MSC to reduce stroke complications.

Application of the Leishmania infantum 21-kDa recombinant protein for the development of an immunochromatographic test.

BACKGROUND: Visceral leishmaniasis (VL), caused by Leishmania infantum, is a systemic parasitic disease and presents a global health problem which can be fatal if not diagnosed and treated. Dogs are the main hosts and provide reservoirs for the transmission of the disease to humans. METHODS: In this study, the gene encoding a 21-kDa protein was cloned and expressed as a fusion protein in Escherichia coli strain BL21 (DE3) for developing a rapid immunochromatographic test (ICT) to identify infected dogs. The expression of the recombinant 21-kDa protein (r21) was investigated using SDS-PAGE and Western blot methods. The purified r21-kDa protein was spotted onto ICT strips and tested by sera from experimentally infected, naturally infected and uninfected dogs. RESULTS: The SDS-PAGE and Western blot methods showed the successful expression of r21-kDa protein. The ICT strip test revealed that the r21-kDa protein was detected by the sera of experimentally and naturally infected dogs. The specificity tests also confirmed no cross-reactivity with animals infected with Trypanosoma cruzi, Toxoplasma gondii and Ehrlichia canis. CONCLUSIONS: Based on these findings, the new r21-kDa protein may be a suitable target for developing a new simple, specific and rapid serological method to detect VL in infected dogs.

Role of maternal interleukin-8 (IL-8) in normal-term birth in the human.

Cytokines are the main factors involved in the normal functions of the placenta and delivery process. The aim of this project was to compare serum levels of interleukin-8 (IL-8), IL-6, tumour necrosis factor α (TNF-α) and transforming growth factor ß (TGF-ß) in term and prolonged-pregnancy mothers and their neonates. This study was performed on 240 participants including 60 term and prolonged-pregnancy neonates and their corresponding mothers. Serum levels of IL-8, IL-6, TNF-α and TGF-ß were evaluated by the enzyme-linked immunosorbent assay technique. The results revealed that IL-8 serum levels were significantly lower in the prolonged-pregnancy mothers and their neonates when compared with term mothers and their neonates. Data analysis also revealed a negative correlation between TGF-ß and age of prolonged-pregnancy mothers. A poor positive correlation between IL-6 and head circumference of term neonates was also observed. IL-8 may play crucial roles in the process of on-time delivery and age may significantly affect TGF-ß production in prolonged-pregnancy mothers. Pro-inflammatory cytokines, such as IL-6, can also be considered as main factors involved in fetal growth.

Comparison of serum levels of IL-6, IL-8, TGF-ß and TNF-α in coronary artery diseases, stable angina and participants with normal coronary artery.

Cytokines, which typically regulate the immune responses, play a role in cardiovascular diseases such as coronary artery diseases (CAD) and ischemic heart diseases (IHD). The aims of this study were to evaluate serum levels of IL-6, IL-8, TGF-ß and TNF-α in patients with or without CAD, as well as stable angina, and to assess the effects of drug administration on the serum levels of these cytokines. Serum levels of the cytokines were analyzed in the three groups: patients with acute coronary syndrome, stable angina and participants with normal coronary arteries as controls. Cohort study of the patients showed that Nitrocontin was the only drug used in a significantly different pattern between the groups where it was used less frequently in patients with stable angina compared to the acute coronary syndrome or control groups. Serum levels of the evaluated cytokines were not different neither between the studied groups nor between the groups with variable Gensini scores. However, IL-8 in controls that were not engaged in regular exercise was higher than the controls performing regular exercise. In the stable angina group, TNF-α in non-smokers was higher than the smokers. It was revealed that serum levels of pro-inflammatory cytokines are not associated with atherosclerosis and stable angina in patients from the South-East of Iran. However, suppressed expression of TGF-ß, may increase the risk of CAD. Exercise can reduce the risk of CAD through downregulation of pro-inflammatory cytokines.

Vitamin B12 in Association with Antipsychotic Drugs Can Modulate the Expression of Pro-/Anti-Inflammatory Cytokines in Alzheimer Disease Patients.

INTRODUCTION: Patients with Alzheimer disease (AD) suffer from psychotic symptoms including pain. The current antipsychotic drugs confer limited effectiveness, and hence new strategies are being designed to decrease pain in order to increase antipsychological effectiveness. Vitamin B12 is a safe supplementary drug to decrease pain. Additionally, cytokines participate in the pathogenesis of immune-related diseases such as AD. Thus, the main aim of this clinical trial study was to determine the effects of treatment with risperidone and quetiapine, as antipsychotic drugs, with and without vitamin B12 on the psychotic symptoms of AD patients and the expression of IL-6, IL-8, tumor growth factor (TGF)-ß, tumor necrosis factor (TNF)-α, and endothelin (ET)-1). MATERIAL AND METHODS: Serum levels of IL-6, IL-8, TGF-ß, TNF-α, and ET-1 were evaluated in the following groups: healthy controls, nonpsychotic AD patients, psychotic AD patients, psychotic AD patients under treatment with risperidone, psychotic AD patients under treatment with risperidone plus vitamin B12, psychotic AD patients under treatment with quetiapine, and psychotic AD patients under treatment with quetiapine plus vitamin B12. RESULTS: Treatment with antipsychotic drugs plus vitamin B12 led to a decreased expression of IL-8 and TNF-α and an increased expression of TGF-ß. Vitamin B12 in association with quetiapine reduced the pain in psychotic AD patients. DISCUSSION: Proinflammatory cytokines play important roles in the pathogenesis of psychosis in AD patients. Antipsychotic drugs plus vitamin B12 can reduce and induce the expression of proinflammatory and anti-inflammatory cytokines to improve psychotic symptoms in AD patients.

The Possible Role of Toll-Like Receptor 4 in the Pathology of Stroke.

Stroke is a prevalent and dangerous health problem, which triggers an intense inflammatory response to Toll-like receptor (TLR) activation. TLRs are the essential components of the response of the innate immunity system, and, therefore, they are one of the key factors involved in recognizing pathogens and internal ligands. Among TLRs, TLR4 significantly participates in the induction of inflammation and brain functions; hence, it has been hypothesized that this molecule is associated with several immune-related brain diseases such as stroke. It has also been proved that animals with TLR4 deficiency have higher protection against ischemia and that the absence of TLR4 reduces neuroinflammation and injuries associated with brain trauma. TLR4 deficiency may play a neuroprotective role in the occurrence of stroke. This article reviews recent information regarding the impact of TLR4 on the pathogenicity of stroke.

Interferon-ß 1a Modulates Expression of RAGE but Not S100A12 and Nuclear Factor-κB in Multiple Sclerosis Patients.

OBJECTIVES: Interferon-ß 1a (IFN-ß 1a) is a common strategy therapy for multiple sclerosis (MS) with unknown mechanisms. S100A12 (S100 calcium-binding protein A12) is a damage-associated molecular pattern molecule which binds to its receptor, RAGE (receptor for advanced glycation end products), and activates nuclear factor-κB (NF-κB). NF-κB is transcribed from proinflammatory molecules, which may participate in the pathogenesis of MS. Therefore, the aims of this study were to compare mRNA levels of S100A12, RAGE, and NF-κB in newly diagnosed MS patients with healthy controls and determine whether IFN-ß 1a therapy affects the expression of the molecules. METHODS: S100A12, RAGE, and NF-κB mRNA levels in 30 new cases of untreated MS patients and 35 healthy controls were evaluated using the real-time PCR technique. The mRNA levels were also evaluated in the MS patients after 6 months of IFN-ß 1a therapy. RESULTS: S100A12, RAGE, and NF-κB mRNA levels were significantly decreased in the new cases of untreated MS patients in comparison to healthy controls. IFN-ß 1a therapy results in upregulation of RAGE in MS patients, but not S100A12 and NF-κB. CONCLUSIONS: It appears that S100A12 participates in the pathogenesis of MS, and it seems that IFN-ß 1a modulates immune responses in an S100A12-independent manner. Based on the reported anti-inflammatory effects of RAGE, it seems that RAGE may be considered as a mechanism by IFN-ß 1a to modulate immune responses. NF-κB is produced permanently in the human cells and is inactive in the cytoplasm; therefore, the effects of IFN-ß 1a may be related to its functions rather than expressions.

Anxiety leads to up-regulation of CD36 on the monocytes of chronic hepatitis B-infected patients.

Introduction It has been hypothesized that mental disorders including depression and anxiety can affect immune responses. The study was done to evaluate the relation between depression and anxiety and expression levels of CD36, CD68, and CD9 on peripheral blood monocytes of chronic hepatitis B (CHB) patients. Methods Sixty CHB patients were selected with various ranges of depression and anxiety. Depression and anxiety were evaluated using a standard questionnaire by an expert psychiatrist according to BECK's Depression Inventory II and Hamilton Anxiety Rating Scale, respectively. The levels of CD36, CD68, and CD9 on the peripheral blood monocytes have been performed using flow cytometry technique. Results The results demonstrated that levels of CD36 were significantly increased on the peripheral blood monocytes of CHB patients when compared with CHB patients with no anxiety. Expression levels of CD68 and CD9 were not significantly altered on the CHB patients with various ranges of anxiety. Expression levels of CD36, CD68, and CD9 were also not significantly altered on the CHB patients with various ranges of depression. Discussion It seems that anxiety induces inflammation in the CHB patients by induction of alteration in several molecules including up-regulation of CD36. CD36 plays important roles in the induction of tissue damage; hence, it may be hypothesized that anxiety may participate in the induction of some hepatitis B complications.

ASC provides a potential link between depression and inflammatory disorders: A clinical study of depressed Iranian medical students.

Background and aims AIM2 is a component of inflammasomes which can activate caspase-1 via an adaptor protein (ASC) after pathogen-associated molecular pattern (PAMP) or danger-associated molecular pattern (DAMP) recognition. Activation of caspase-1 is a trigger for the induction of IL-1 and IL-18 which are important pro-inflammatory cytokines. Furthermore, IL-1ß, which can regulate inflammatory responses, has also been associated with depression. Previous studies revealed that patients suffering from depression may also have altered immune responses, but the mechanisms underlying this correlation are unclear. Thus, the aim of this study was to determine the mRNA levels of AIM2 and ASC in the peripheral blood mononuclear cells (PBMCs) isolated from Iranian medical students suffering from depression. Materials and methods The participants used for the study included 38 Iranian medical students diagnosed with depression and 43 non-depressed students as a control group. The mRNA levels of AIM2 and ASC were evaluated by quantitative real-time polymerase chain reaction (PCR) using ß-actin as a housekeeping gene for the normalization of expression. Results The results showed that mRNA levels of AIM2 were similar in both groups. However, ASC levels were significantly increased in PBMCs isolated from individuals with elevated depressive symptoms when compared to non-depressed participants. Conclusions Based on the current results, it appears that ASC transcript expression may be a surrogate marker for depression and may represent a link between depression and the altered immune responses observed in these categories of individuals with elevated depressive symptoms.

The effect of depression and anxiety on expression levels of toll like receptor signaling molecules in chronic HBV infected patients.

BACKGROUND: Toll- like receptors (TLRs) play an important role in the recognition of DAMPs and PAMPs and induction of inflammation. Previous studies demonstrated that depression and anxiety can influence the expression levels of immune related molecules. Our previous study revealed that mRNA levels of IRAKIRAK4, TRAF3 and IRF7 were significantly decreased in chronic HBV infected (CHB) patients when compared to healthy controls. Therefore, the aim of this study was to evaluate the effects of depression and anxiety on the expression levels of these molecules in CHB patients. METHODS: Sixty CHB patients participated in this study and filled out the standard questionnaires; and the expression of IRAK4, TRAF3 and IRF7 were examined using Real-Time PCR techniques. RESULTS: The results of this study demonstrated that expression of IRAK4, TRAF3 and IRF7 did not differ between patients with various stages of depression and anxiety (all p>0.05). CONCLUSION: According to the results, it seems that declined expression of IRAK4, TRAF3 and IRF7 in CHB patients were not related to depression and anxiety, and other factors including genetic and immunoregulatory effects of HBV may be responsible for the declined expression of these molecules.

The biological functions, structure and sources of CXCL10 and its outstanding part in the pathophysiology of multiple sclerosis.

The etiology of several autoimmune diseases, including multiple sclerosis (MS), has still not been completely clarified. MS is defined as an autoimmune disease with clinical features of a chronic, inflammatory and demyelinating autoimmune disorder which affects the central nervous system. The course of the disease includes phases of remission and relapses which can be exacerbated in both severity and duration. Chemokines, which are a subfamily of the cytokines, act as chemoattractants for a wide variety of cells, including immune cells. CXCL10 is a small protein that is defined as an 'inflammatory' chemokine and binds to CXCR3 to mediate immune responses through the activation and recruitment of leukocytes such as T cells, eosinophils, monocytes and NK cells. The aim of this review is to address recent findings regarding the relationship between CXCL10 and MS.

Morphine Reduces Expression of TRPV1 Receptors in the Amygdala but not in the Hippocampus of Male Rats.

BACKGROUND: Chronic use of opioids usually results in physical dependence. The underlying mechanisms for this dependence are still being evaluated. Transient receptor potential vanilloid type 1 (TRPV1) are important receptors of pain perception. Their role during opioid dependence has not been studied well. The aim of this study was to evaluate the effect of morphine-dependence on the expression of TRPV1 receptors in the amygdala and CA1 region of the hippocampus. METHODS: This study used four groups of rats. Two groups of rats (morphine and morphine+naloxone) received morphine based on the following protocol: 10 mg/kg (twice daily, 3 days) followed by 20, 30, 40 and 50 mg/kg (twice daily), respectively, for 4 consecutive days. Another group received vehicle (1 ml/kg) instead of morphine given using the same schedule. The morphine+naloxone group of rats additionally received naloxone (5 mg/kg) at the end of the protocol. The control group rats received no injections or intervention. The amygdala and CA1 regions of the morphine, saline-treated and intact animals were isolated and prepared for real-time PCR analysis. RESULTS: Administration of naloxone induced withdrawal signs in morphine-treated animals. The results showed a significant decrease in TRPV1 gene expression in the amygdala (P<0.05) but not the CA1 region of morphine dependent rats. CONCLUSION: TRPV1 receptors may be involved in morphine-induced dependence.

TLR2, as a Pathogen Recognition Receptor, Plays Critical Roles in Hepatitis B Outcome.

The immune system of active and inactive chronic hepatitis B, as prolonged forms of hepatitis B, is unable to eradicate hepatitis B virus (HBV) from the infected hepatocytes completely. Toll-like receptors (TLRs) play key roles in the viral recognition and promotion of appropriate immune responses. The molecules also participate in the alteration of the target cell functions and transformation. TLR2 is the unique molecule that makes either homodimer or heterodimer with TLR1 and 6 and shows variable roles against viral infections. Therefore, it has been hypothesized that TLR2 may participate in both immune response against HBV and induction of the virus-related hepatic complications. The studies confirm the hypothesis and revealed that TLR2 is not only one of the main molecules altering the course of HBV infection, but also plays key roles in induction of hepatocellular carcinoma (HCC) and liver cirrhosis. However, recent studies demonstrated that the molecule can fight against HCC and liver cirrhosis. Collectively, it appears that nutrition habits, TLR2 gene polymorphisms, gut microbiome, HBV antigens, and activation of other receptors may play key roles in the determination of TLR2 functions.

TLR9 in the Human Papilloma Virus Infections: Friend or Foe?

Immune system plays dual roles during human papilloma virus (HPV) infections, from defense against the virus to induction or stimulation of the HPV-related cancers. It appears that various differences within the immune-related genes and the functions of the immunological parameters of the patients are the main factors responsible for the roles played by immune system during HPV infections. Toll-like receptors (TLRs) play key roles in the recognition of viruses and activation of immune responses. The molecules also can alter the target cell intracellular signaling and may participate in the transformation of the infected cells. TLR9 is the unique intracellular member of TLRs that recognize foreign DNA, including viral DNA. Thus, TLR9 may play significant roles in the defense against HPV and its related cancers. This review article discusses TLR9 antiviral and pathological roles during HPV infection.

Enhancing the efficacy of Hypericum perforatum in the treatment of an experimental model of multiple sclerosis using gold nanoparticles: an in vivo study.

Objective: Hypericum perforatum is a herbal medicine used in traditional medicine for the treatment of depression due to its antidepressant and anti-inflammatory activities. Therefore, we evaluated the therapeutic efficacy of H. perforatum extract (HPE) in combination with gold nanoparticles (HPE-GNP) against experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Materials and Methods: EAE was induced in C57BL/6 mice with subcutaneous injection of MOG35-55 emulsified in complete Freund's adjuvant, and intraperitoneal pertussis toxin. Mice were treated with drugs in free (HPE) and nano-form (HPE-GNP) preparations. Splenocytes were isolated from all mice and the level of inflammatory and anti-inflammatory cytokines were evaluated by ELISA. The expression of T cells' transcription factors was also assessed using Real-Time PCR. Results: Clinical score was reduced after HPE-GNP treatment. This change was associated with a decrease in the incidence and infiltration of inflammatory cells into the central nervous system. Additionally, treatment with HPE-GNP decreased the level of pro-inflammatory cytokines (IFN-γ, IL-17A and IL-6) and increased anti-inflammatory cytokines (TGF-ß, IL-10 and IL-4). The real-time analysis revealed a decrease in the level of T-bet and ROR-γt but an increase in FoxP3 and GATA3 expression. Conclusion: The current study demonstrated that HPE-GNP could potentially reduce clinical and pathological complications of EAE, but laboratory data showed that HPE-GNP was significantly more effective than HPE in the treatment of EAE.

Breastfeeding Increases the Expression of TLR4, TNF-α, CCL2, and CCL3 in the Prepuce Tissue of Neonates.

INTRODUCTION: Innate immunity plays a significant role in the tissue repair process. It is well documented that breastfeeding may alter immune responses. Thus, this study was designed to evaluate the effects of breastfeeding on the levels of TLR1-4, TNF-α, TGF-ß, CCL2, and CCL3 in the prepuce tissue of neonates. MATERIAL AND METHODS: This study was conducted on 90 samples of prepuce tissue obtained from neonates (45 neonates who were breastfed with human milk [HM] and 45 neonates who were not breastfed and received non-human milk [NHM]). The tissues were homogenized and mRNA levels of TLR1-4 and protein levels of TNF-α, TGF-ß, CCL2, and CCL3 were analyzed using Real-Time PCR and ELISA techniques, respectively. RESULTS: Protein levels of TNF-α, CCL2 and CCL3, and mRNA levels of TLR4 were significantly lower in the NHM neonates than in the HM neonates. There was a significant negative correlation between duration of pregnancy and mRNA levels of TLR1 in the NHM neonates. CONCLUSION: These results indicate that breastfeeding may be associated with the regulated expression of TLR4 and its related cytokines/chemokines and that it may improve wound healing and aid in the fight against pathogens.

Gender affects IL-23 serum levels in the hospitalized COVID-19 infected patients.

Cytokine storm is a main complication in the hospitalized patients, who are infected with the novel coronavirus (COVID-19). The pro-inflammatory cytokines are the main causes of the cytokine storm, however, the roles played by IL-17A, IL-23 and CCL3 are yet to be clarified completely. This prospective study was aimed to explore serum levels of these cytokines in the hospitalized patients infected by COVID-19. Serum levels of IL-17A, IL-23 and CCL3 were measured in 30 COVID-19 infected patients in parallel with 30 healthy controls using ELISA technique. Although serum levels of IL-17A, IL-23 and CCL3 did not alter in the patients in comparison to healthy controls, male patients had higher serum levels of IL-23 than women. Hypertension, type 2 diabetes, lung involvement and age did not affect serum levels of IL-17A, IL-23 and CCL3 in the patients. It appears that IL-17A, IL-23 and CCL3 do not participate in the pro-inflammatory responses in Iranian hospitalized COVID-19 infected patients. However, the gender can be considered as a risk factor for production of more IL-23, which needs to be explored further.

Interleukin 17A: A Potential Target for Its Plausible Roles in the Pathogenesis of Idiopathic Epistaxis.

INTRODUCTION: It has been reported that inflammation may be a potential risk factor for the progression of epistaxis. Due to the major roles played by Th17 in the induction of inflammation, the present study aimed to assess the serum levels of Interleukin 17A (IL-17A) and IL-23, as the most important cytokines in the Th17 pathway, as well as IFN-, IL-4, and IL-10 serum levels, as regulatory cytokines for Th17 cells in patients with idiopathic epistaxis. MATERIALS AND METHODS: The serum levels of IL-4, IL-10, IL-17A, IL-23, and IFN- were evaluated in 90 patients with idiopathic epistaxis and 90 healthy controls using enzyme-linked immunosorbent assay (ELISA) technique. RESULTS: The obtained results pointed out that the serum levels of IL-17A and IL-10, but not IL-4 and IL-23, were significantly up-regulated, and IFN- serum levels were significantly down-regulated in patients with idiopathic epistaxis. Furthermore, female patients with epistaxis had higher IL-10 serum levels. CONCLUSIONS: As evidenced by the results of the present study, IL-17A is the main cytokine which participates in the pathogenesis of idiopathic epistaxis; moreover, in association with IL-10, it can be regarded as the suppressor of IFN- in patients.

Ionizing radiation and toll like receptors: A systematic review article.

Ionizing radiation, including X and gamma rays, are used for various purposes such as; medicine, nuclear power, research, manufacturing, food preservation and construction. Furthermore, people are also exposed to ionizing radiation from their workplace or the environment. Apart from DNA fragmentation resulting in apoptosis, several additional mechanisms have been proposed to describe how radiation can alter human cell functions. Ionizing radiation may alter immune responses, which are the main cause of human disorders. Toll like receptors (TLRs) are important human innate immunity receptors which participate in several immune and non-immune cell functions including, induction of appropriate immune responses and immune related disorders. Based on the role played by ionizing radiation on human cell systems, it has been hypothesized that radiation may affect immune responses. Therefore, the main aim of this review article is to discuss recent information regarding the effects of ionizing radiation on TLRs and their related disorders.