Dose selection for intracerebroventricular cerliponase alfa in children with CLN2 disease, translation from animal to human in a rare genetic disease.

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is an ultra-rare pediatric neurodegenerative disorder characterized by deficiency of the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). In the absence of adequate TPP1, lysosomal storage material accumulation occurs in the central nervous system (CNS) accompanied by neurodegeneration and neurological decline that culminates in childhood death. Cerliponase alfa is a recombinant human TPP1 enzyme replacement therapy administered via intracerebroventricular infusion and approved for the treatment of CLN2 disease. Here, we describe two allometric methods, calculated by scaling brain mass across species, that informed the human dose selection and exposure prediction of cerliponase alfa from preclinical studies in monkeys and a dog model of CLN2 disease: (1) scaling of dose using a human-equivalent dose factor; and (2) scaling of compartmental pharmacokinetic (PK) model parameters. Source PK data were obtained from cerebrospinal fluid (CSF) samples from dogs and monkeys, and the human exposure predictions were confirmed with CSF data from the first-in-human clinical study. Nonclinical and clinical data were analyzed using noncompartmental analysis and nonlinear mixed-effect modeling approaches. Both allometric methods produced CSF exposure predictions within twofold of the observed exposure parameters maximum plasma concentration (Cmax ) and area under the curve (AUC). Furthermore, cross-species qualification produced consistent and reasonable PK profile predictions, which supported the allometric scaling of model parameters. The challenges faced in orphan drug development place an increased importance on, and opportunity for, data translation from research and nonclinical development. Our approach to dose translation and human exposure prediction for cerliponase alfa may be applicable to other CNS administered therapies being developed.

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.

Role of Chikungunya nsP3 in Regulating G3BP1 Activity, Stress Granule Formation and Drug Efficacy.

BACKGROUND: Ras-GTPase activating protein SH3-domain-binding proteins (G3BP) are a small family of RNA-binding proteins implicated in regulating gene expression. Changes in expression of G3BPs are correlated to several cancers including thyroid, colon, pancreatic and breast cancer. G3BPs are important regulators of stress granule (SG) formation and function. SG are ribonucleoprotein (RNP) particles that respond to cellular stresses to triage mRNA resulting in transcripts being selectively degraded, stored or translated resulting in a change of gene expression which confers a survival response to the cell. These changes in gene expression contribute to the development of drug resistance. Many RNA viruses, including Chikungunya (and potentially Coronavirus), dismantle SG so that the cell cannot respond to the viral infection. Non-structural protein 3 (nsP3), from the Chikungunya virus, has been shown to translocate G3BP away from SG. Interestingly in cancer cells, the formation of SG is correlated to drug-resistance and blocking SG formation has been shown to reestablish the efficacy of the anticancer drug bortezomib. METHODS: Chikungunya nsP3 was transfected into breast cancer cell lines T47D and MCF7 to disrupt SG formation. Changes in the cytotoxicity of bortezomib were measured. RESULTS: Bortezomib cytotoxicity in breast cancer cell lines changed with a 22 fold decrease in its IC50 for T47D and a 7 fold decrease for MCF7 cells. CONCLUSIONS: Chikungunya nsP3 disrupts SG formation. As a result, it increases the cytotoxicity of the FDA approved drug, bortezomib. In addition, the increased cytotoxicity appears to correlate to improved bortezomib selectivity when compared to control cell lines.

G3BP1 and G3BP2 regulate translation of interferon-stimulated genes: IFITM1, IFITM2 and IFITM3 in the cancer cell line MCF7.

G3BPs are members of an RNA-binding protein family and their aberrant expression is common in various cancers and there is growing evidence that G3BPs possess antiviral activities and are targeted by various viruses. G3BPs have also been implicated in both stabilization and degradation of specific mRNAs as well as translational control of mRNA targets. G3BPs have been shown to control translation of interferon-stimulated genes (ISGs), implying that G3BPs are involved in the regulation of the interferon system in response to viral infections and/or cellular stress. The interferon induced transmembrane (IFITM1, IFITM2 and IFITM3) proteins are antiviral proteins, and are also involved in cancer progression and metastasis. Therefore, these genes were selected in the studies reported here as potential transcript targets of G3BPs. Furthermore, G3BPs are involved in the regulation of the MEK pathway which also impacts on the translation of ISGs. Therefore, the role of this pathway was also analysed in regulation of IFITM1-3 proteins. Overall, this research study suggests that G3BPs are essential for the accumulation of IFITM1-3 proteins and intersect twice in the regulation of IFITM1-3 expression, first through MEK pathway and then through an interaction with the 3'-UTRs of its target transcripts. However, it is still to be determined whether the two apparent functions are part of a single control mechanism or the two functions are mutually exclusive.

Psammaplysin F increases the efficacy of bortezomib and sorafenib through regulation of stress granule formation.

The past few decades have delivered significant improvements in diagnosis and treatment of cancer, however, despite these improvements cancer continues to be a major global health issue requiring the urgent development of new strategies for treatment. Stress granules are cytoplasmic structures that triage gene expression in response to environmental stresses, including chemotherapies, and have been implicated in the development of drug resistance. One novel approach to developing a new anti-cancer strategy involves inhibiting stress granules with compounds derived from natural products. In a previous rapid screen, a subset of 132 compounds from the Davis Open Access Natural Product Library was screened using a stress granule inhibition assay and provisionally one hit was identified which was the known marine sponge-derived metabolite, psammaplysin F. Using cell based assays psammaplysin F was assessed to determine whether it could inhibit the formation of stress granules after exposure to sodium arsenite in Vero, HEK293 MCF7, T47D, HeLa and MCF7MDR cells by analysing the number of stress granules using high content imaging. A significant reduction in the number of stress granules was observed and subsequent analysis by western blot revealed that treatment with psammaplysin F decreased levels of phosphorylated eIF2α. Combinational studies in MCF7, HeLa and MCF7MDR cells revealed that psammaplysin F increased the efficacy of bortezomib and sorafenib and a synergistic effect was observed in vitro. Stress granules appear to be one tool in a battery of responses that cancer cells can exploit to elicit drug resistance. Disrupting stress granule formation by use of orally available drugs presents a potential mechanism to restore drug efficacy. The work presented here provides evidence that small molecules derived from nature, such as psammaplysin F, can prevent the formation of stress granules and therefore may represent a useful strategy to improving drug efficacy.

Rasputin a decade on and more promiscuous than ever? A review of G3BPs.

Ras-GTPase-activating protein (SH3 domain)-binding proteins (G3BPs, also known as Rasputin) are a family of RNA binding proteins that regulate gene expression in response to environmental stresses by controlling mRNA stability and translation. G3BPs appear to facilitate this activity through their role in stress granules for which they are considered a core component, however, it should be noted that not all stress granules contain G3BPs and this appears to be contextual depending on the environmental stress and the cell type. Although the role of G3BPs in stress granules appears to be one of its major roles, data also strongly suggests that they interact with mRNAs outside of stress granules to regulate gene expression. G3BPs have been implicated in several diseases including cancer progression, invasion, and metastasis as well as virus survival. There is now a body of evidence that suggests targeting of G3BPs could be explored as a form of cancer therapeutic. This review discusses the important discoveries and advancements made in the field of G3BPs biology over the last two decades including their roles in RNA stability, translational control of cellular transcripts, stress granule formation, cancer progression and its interactions with viruses during infection. An emerging theme for G3BPs is their ability to regulate gene expression in response to environmental stimuli, disease progression and virus infection making it an intriguing target for disease therapies.

Interleukin-6 and Tumor Growth Factor-ß are Risk Factors for Idiopathic Epistaxis.

OBJECTIVE: To evaluate the serum levels of interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, tumor growth factor (TGF)-ß, endothelin, and immunoglobulin (Ig)E in patients with idiopathic epistaxis, compared with healthy control individuals. METHODS: Serum levels of IL-6, IL-8, TNF-α, TGF-ß, endothelin, and IgE were evaluated in 110 patients with idiopathic epistaxis and 100 healthy controls using the enzyme-linked immunosorbent assay (ELISA) technique. RESULTS: Serum levels of IL-6 (P <.001) and TGF-ß (P = .001) were significantly increased in patients with idiopathic epistaxis, compared with controls. TNF-α serum levels were significantly increased in male patients, compared with female patients (P = .053). We observed decreased antihistamine levels and increased expression of TGF-ß (P = .02) and TNF-α (P = .02), respectively. CONCLUSIONS: IL-6 and TGF-ß appear to participate in the pathogenesis of idiopathic epistaxis. TNF-α may be considered a risk factor for male patients in developing epistaxis. Antihistamines may inhibit angiogenesis by decreasing expression of TGF-ß and increasing expression of TNF-α.

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.

Immunomodulatory effects of a rationally designed peptide mimetic of human IFNß in EAE model of multiple sclerosis.

The efficiency of interferon beta (IFNß)-based drugs is considerably limited due to their undesirable properties, especially high immunogenicity. In this study, for the first time we investigated the impact of a computationally designed peptide mimetic of IFNß, called MSPEP27, in the animal model of MS. A peptide library was constructed using the Rosetta program based on the predominant IFNAR1-binding site of IFNß. Molecular docking studies were carried out using ClusPro and HADDOCK tools. The GROMACS package was subsequently used for molecular dynamics (MD) simulations. Validation of peptide-receptor interaction was carried out using intrinsic fluorescence measurements. To explore in silico findings further, experimental autoimmune encephalomyelitis (EAE) was induced by subcutaneous immunization of myelin oligodendrocyte glycoprotein (MOG35-55). Mice were then separated into distinct groups and intravenously received 10 or 20mgkg-1 of MSPEP27 or IFNß. The inflammatory mediators were monitored by immunohistochemistry (IL17, CD11b, CD45), quantitative real-time PCR (MMP2, MMP9, TIMP-1) and enzyme-linked immunosorbent assay (IL1ß, TNFα) methods. Among the library of tolerated peptides, MSPEP27, a peptide with favorable physicochemical properties, was chosen for further experiments. This peptide was shown to significantly interact with IFNAR1 in a dose-dependent manner. Like IFNß, MSPEP27 could efficiently bind to IFNAR1 and form a stable peptide-receptor complex during 30ns MD simulations. In vivo analyses revealed that MSPEP27 could lessen inflammation by modulating the levels of inflammatory mediators. According to our results, MSPEP27 peptide could efficiently bind to IFNAR1 and suppress neuroinflammation in vivo. We conclude that MSPEP27 has protective effects against MOG-induced EAE via reduction of immune dysfunction and inflammation.

Sox2 modulates motility and enhances progression of colorectal cancer via the Rho-ROCK signaling pathway.

Sox2 (Sry-box2) is essential for a variety of stem cells and is also expressed in colorectal cancer (CRC). However, the underlying mechanism by which Sox2 enhances CRC progression remains unclear. In the present study, we show that elevated Sox2 expression is significantly correlated with poor clinical prognosis. CRC is phenotypically heterogeneous, and harbors several subtypes of cancer cells. Elevated Sox2 expression was always detected in rounded-shape cells, which co-located to poorly differentiated regions, the invasive frontier and metastatic lesions. Knockdown of Sox2 in CRC cells not only decreased the number of round-shaped cells, but also suppressed cell migration, invasion as well as attenuated colony forming capacity and tumorigenicity. By contrast, overexpression of Sox2 in CRC cells was associated with up-regulation of multidrug resistance genes and accelerated CRC progression. Moreover, Sox2 conferred activation of Rho-ROCK signaling, whereas inhibition of ROCK signaling decreased cell migration, invasion, colony formation and self-renewal of CRC. Our results reveal that CRC is phenotypically and functionally heterogeneous. Elevated Sox2 expression activates the Rho-ROCK pathway, which in turn changes cell morphology and promotes cell migration and progression.

Chronoinflammaging in Alzheimer; A systematic review on the roles of toll like receptor 2.

Aging is associated with a range of chronic low-grade inflammation (Chronoinflammaging) which may play a significant role in some chronic inflammatory based diseases, such as Alzheimer disease (AD). However, the events which lead to the induction of chronoinflammaging in AD are yet to be clarified. It has been proposed that the recognition of endogenous ligands by pathogen recognition receptors (PRRs) may be involved in the induction of chronoinflammaging. Toll like receptors (TLRs) are a family of PRRs which recognize endogenous damage associated molecular patterns (DAMPs) and subsequently induce inflammation. Therefore, TLRs are worthy of investigation to elucidate their roles in chronoinflammaging associated AD. This review article explores the main roles played by TLR2 in the pathogenesis of chronoinflammaging in patients suffering from AD.

Multidrug-resistant cancer cells and cancer stem cells hijack cellular systems to circumvent systemic therapies, can natural products reverse this?

Chemotherapy is one of the most effective and broadly used approaches for cancer management and many modern regimes can eliminate the bulk of the cancer cells. However, recurrence and metastasis still remain a major obstacle leading to the failure of systemic cancer treatments. Therefore, to improve the long-term eradication of cancer, the cellular and molecular pathways that provide targets which play crucial roles in drug resistance should be identified and characterised. Multidrug resistance (MDR) and the existence of tumor-initiating cells, also referred to as cancer stem cells (CSCs), are two major contributors to the failure of chemotherapy. MDR describes cancer cells that become resistant to structurally and functionally unrelated anti-cancer agents. CSCs are a small population of cells within cancer cells with the capacity of self-renewal, tumor metastasis, and cell differentiation. CSCs are also believed to be associated with chemoresistance. Thus, MDR and CSCs are the greatest challenges for cancer chemotherapy. A significant effort has been made to identify agents that specifically target MDR cells and CSCs. Consequently, some agents derived from nature have been developed with a view that they may overcome MDR and/or target CSCs. In this review, natural products-targeting MDR cancer cells and CSCs are summarized and clustered by their targets in different signaling pathways.

Reveglucosidase alfa (BMN 701), an IGF2-Tagged rhAcid α-Glucosidase, Improves Respiratory Functional Parameters in a Murine Model of Pompe Disease.

Pompe disease is a rare neuromuscular disorder caused by an acid α-glucosidase (GAA) deficiency resulting in glycogen accumulation in muscle, leading to myopathy and respiratory weakness. Reveglucosidase alfa (BMN 701) is an insulin-like growth factor 2-tagged recombinant human acid GAA (rhGAA) that enhances rhGAA cellular uptake via a glycosylation-independent insulin-like growth factor 2 binding region of the cation-independent mannose-6-phosphate receptor (CI-MPR). The studies presented here evaluated the effects of Reveglucosidase alfa treatment on glycogen clearance in muscle relative to rhGAA, as well as changes in respiratory function and glycogen clearance in respiratory-related tissue in a Pompe mouse model (GAAtm1Rabn/J). In a comparison of glycogen clearance in muscle with Reveglucosidase alfa and rhGAA, Reveglucosidase alfa was more effective than rhGAA with 2.8-4.7 lower EC50 values, probably owing to increased cellular uptake. The effect of weekly intravenous administration of Reveglucosidase alfa on respiratory function was monitored in Pompe and wild-type mice using whole body plethysmography. Over 12 weeks of 20-mg/kg Reveglucosidase alfa treatment in Pompe mice, peak inspiratory flow (PIF) and peak expiratory flow (PEF) stabilized with no compensation in respiratory rate and inspiratory time during hypercapnic and recovery conditions compared with vehicle-treated Pompe mice. Dose-related decreases in glycogen levels in both ambulatory and respiratory muscles generally correlated to changes in respiratory function. Improvement of murine PIF and PEF were similar in magnitude to increases in maximal inspiratory and expiratory pressure observed clinically in late onset Pompe patients treated with Reveglucosidase alfa (Byrne et al., manuscript in preparation).

Evaluation of NLRC4, NLRP1, and NLRP3, as Components of Inflammasomes, in Chronic Hepatitis B Virus-Infected Patients.

Nucleotide-binding domain leucine repeats (NLRs) are required for the recognition of various molecules that are expressed within microbes and are able to actuate appropriate immune responses via activation of cytokines. The current study evaluates the expression levels of NLRP1 and NLRC4, which are components of inflammasomes, in chronic hepatitis B (CHB) virus-infected patients. This study recruited two series of CHB patients (each contained 60 patients) and 60 healthy controls. Real-time polymerase chain reaction (PCR) was employed to evaluate mRNA expression levels of NLRP1, NLRP3, and NLRC4 as well as hepatitis B virus (HBV)-DNA copy number. Serum levels of liver markers were also used to evaluate the patients. Hepatitis B envelope antigen (HBeAg) and hepatitis B surface antigen (HBsAg) were also examined in all patients to evaluate infection. The data showed that expression levels of NLRC4 and NLRP1 were not significantly different in circulating monocytes of CHB patients when compared with those of healthy controls. Furthermore, the data indicate that mRNA levels of NLRP1, NLRP3, and NLRC4 were also not altered in CHB patients regardless of HBV-DNA copy numbers/mL and HBeAg status. The data revealed that mRNA expression levels of NLRP1 and NLRC4 were not altered in CHB patients, suggesting that these genes are not responsible for the impaired immune responses against HBV observed in these patients.

Increased Serum Levels of IL-17A and IL-23 Are Associated with Decreased Vitamin D3 and Increased Pain in Osteoarthritis.

INTRODUCTION: Osteoarthritis (OA) is the most common type of arthritis and proinflammatory cytokines have been considered as the main etiologic factor in the pathogenesis of the disease. Serum levels of cytokines, that are associated with innate immunity and TH1 cells, have been analyzed in OA patients, however, there is limited research that profiles cytokines associated with Th17 cells and their relation to vitamin D3 and pain. MATERIAL AND METHODS: The sera from 131 patients with OA and 262 healthy controls were evaluated for serum levels of IL-17A, IL-21, IL-23 and vitamin D3 using ELISA. RESULTS: Serum levels of IL-17A, and IL-23 were statistically higher in OA patients than in healthy controls, while IL-21 and vitamin D3 were significantly lower in OA patients when compared to controls. A significant positive correlation was found between the serum levels of IL-17A and IL-23 using WOMAC pain scores and vitamin D3 serum levels. DISCUSSION: The results suggest that IL-17A plays a significant role in OA pathogenesis and the induction of pain. Decreased serum levels of vitamin D3 may reflect a positive role played by the factor in the regulation of immune responses in OA patients.

Cytotoxic ethnic Yao medicine Baizuan, leaves of Schisandra viridis A. C. Smith.

ETHNOPHARMACOLOGICAL RELEVANCE: The ethnic Chinese Yao medicine Baizuan, which are the leaves of Schisandra viridis A. C. Smith, is traditionally used, in combination with other herbs, to soften hard lumps and dispel nodes in the treatment of cancer, however, this property has not been well studied with a clear indication of the active principles. AIM OF THE STUDY: The experiments were carried out to investigate the cytotoxic activity of the extracts and to identify the active principles from the extract, which could support the traditional application of treating cancer. MATERIALS AND METHODS: Dried and ground plant material was extracted with water and ethanol and further purified by HPLC. The cytotoxicity of the extracts, fractions and pure compounds were evaluated for their abilities to inhibit the proliferation of breast cancer cells MCF7 and tongue cancer cells CAL27. The cytotoxicity of the pure compounds were also tested against Human Embryonic Kidney cell line HEK293. RESULTS: Both aqueous and ethanol extracts showed activities against MCF7 and CAL27 cancer cells. Bioassay-guided fractionation and purification of the extracts resulted in six active principles, including five dibenzocyclooctene lignans namely gomisin H (1), schisandrin (2), angeloylgomisin H (3), (+)-gomisin M2 (4) and (-)-rubschisandrin (5), and one triterpenoid, schisanol (6). Compounds 1-3 showed moderate cytotoxic activities with IC50 values ranging from 100 to 200µg/mL against MCF7 and CAL27 cell lines. Dioxane containing lignans 4-5 and triterpenoid 6 were 10 times more active with IC50 values of 14.5, 13.4, 10.6µg/mL against MCF7, and 21.2, 17.9, 11.7µg/mL against CAL27, respectively. Compounds 1-6 also showed cytotoxicity against HEK293 with IC50 values ranging from 10 to 150µg/mL, respectively. CONCLUSIONS: The traditional extraction protocol using boiled water afforded three moderately active lignans 1-3. Ethanol extraction, which is widely used in the preparation of herbal remedies in China, yielded three additional active compounds 4-5 with more potent activities. These results provided a rationale for the traditional application of the ethnic Yao medicine Baizuan in the treatment of cancer.

The role of CXCR3 and its ligands in renal transplant outcome.

Chemokines and their corresponding receptors serve as pro-inflammatory and migratory signals for immune cells. CXCR3 and its corresponding ligands, CXCL9, CXCL10 and CXCL11, participate in the induction of immune responses against several foreign antigens. Numerous cells, including macrophages, NK cells and T lymphocytes, express CXCR3 and thus, expression of the receptor and its ligands can induce activity of these important immune cells against foreign antigens, including allogeneic grafts. Several parameters of the immune system participate in the induction and stimulation of powerful immune responses against allogeneic grafts. A thorough understanding of the parameters that regulate these responses can provide insights into new methods for immunotherapy during organ transplantation. The aim of this review is to address the most recent information regarding the roles played by CXCR3 and its corresponding ligands in the outcome of renal transplantation.

The link between TLR7 signaling and hepatitis B virus infection.

Toll-Like Receptors (TLRs) play crucial roles in recognition and induction of appropriate immune responses against viral infections, including hepatitis B. TLR7 detects intracellular viral single strand RNA which leads to the activation of several pro-inflammatory transcription factors via the MYD88 dependent pathway. Patients with prolonged infectious forms of hepatitis B, including active and inactive chronic forms, are unable to clear HBV from hepatocytes completely. It is believed that the differences in genetic and immunological parameters of the patients and clearance subjects, who successfully clear HBV infections, are the main factors responsible for allowing the long term infections to persist. It appears that defective expression of TLR7 may result in impaired immune responses against HBV. The aim of this review is to address the recent information regarding the crucial roles played by TLR7 in hepatitis B infection and also the main mechanisms used by HBV to escape from recognition by TLR7 in prolonged HBV infected patients. Considering that chronic hepatitis B infection is not yet curable, it could be possible to activate TLR7-related immunological pathways as a therapy directed towards persistent HBV infection. Hence, another aim of this study is to present recent developments of TLR7 agonists as a therapeutic strategy for chronic hepatitis B.

TGF-ß in Toxoplasmosis: Friend or foe?

Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan causing several forms of toxoplasmosis in humans. The main mechanisms that allow the development of the prolonged forms of the disease and its subsequent pathology are yet to be clarified. However, many researchers have hypothesized that immunological and genetic parameters may play crucial roles in the etiology of the disease. Transforming growth factor beta (TGF-ß) is a cytokine with a dual role in the regulation of immune responses including those against parasites. However, the relationship between TGF-ß and immune responses against T .gondii are not fully understood. The important roles played by TGF-ß in the development of Th17 and T regulatory lymphocytes, mucosal immunity and regulation of immune responses have been documented and this provides insights into TGF-ß function during parasitic infections such as toxoplasmosis. Therefore, the aim of this review is to collate the current information regarding the status and association of TGF-ß with T. gondii infection.

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.