Do chemokine/chemokine receptor axes play paramount parts in trafficking and oriented locomotion of monocytes/macrophages toward the lungs of COVID-19 infected patients? A systematic review.

The COVID-19 (coronavirus disease 2019) is a well-defined viral infection, resulting from SARS-CoV-2 (severe acute respiratory syndrome- coronavirus-2). The innate immune system serves as the first line of defense to limit viral spreading and subsequently stimulate adaptive immune responses by the prominent aids of its cellular and molecular arms. Monocytes are defined as the most prominent innate immune cells (IICs) that are reactive against invading pathogens. These cells support host protection against the virus that is mediated by several non-specific mechanisms such as phagocytosis, producing antiviral enzymes, and recruitment of immune cells toward and into the infected tissues. They have the ability to egress from blood and migrate to the SARS-CoV-2 infected regions by the aid of some defense-related functions like chemotaxis, which is mediated by chemical compounds, e.g., chemokines. Chemokines, in addition to their related ligands are categorized within the most important and deserved agents involved in oriented trafficking of monocytes/macrophages towards and within the lung parenchyma in both steady state and pathological circumstances, including COVID-19-raised infection. However, the overexpression of chemokines could have deleterious effects on various organs through the induction of cytokine storm and may be the most important leading mechanisms in the pathogenesis of COVID-19. Authors have aimed the current review article to describe present knowledge about the interplay between monocytes/macrophages and SARS-CoV-2 with a focus on the ability of IICs to migrate and home into the lung of COVID-19 patients through various chemokine-chemokine receptor axes to promote our understanding regarding this disease.

A better understanding of the role of the CTLA-CD80/86 axis in the treatment of autoimmune diseases.

Autoimmune diseases are diseases in which the regulatory mechanisms of the immune response are disturbed. As a result, the body loses self-tolerance. Since one of the main regulatory mechanisms of the immune response is the CTLA4-CD80/86 axis, this hypothesis suggests that autoimmune diseases potentially share a similar molecular basis of pathogenesis. Hence, investigating the CTLA4-CD80/86 axis may be helpful in finding an appropriate treatment strategy. Therefore, this study aims to investigate the molecular basis of the CTLA4-CD80/86 axis in the regulation of the immune response, and then its role in developing some autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. As well, the main therapeutic strategies affecting the CTLA4-CD80/86 axis have been summarized to highlight the importance of this axis in management of autoimmune diseases.

Royal Jelly Nanoparticle Alleviates Experimental Model of Breast Cancer Through Suppressing Regulatory T Cells and Upregulating TH1 Cells.

BACKGROUND: Royal jelly, a natural product from bees' hypopharyngeal glands, is commonly used in biomedicine due to its antioxidant and anti-tumor activities. The aim of this study was to compare royal jelly in free form and loaded in layered double hydroxide (LDH) nanoparticle for the treatment of breast cancer with a focus on Th1 and T regulatory parameters in an animal model. METHODS: Nanoparticles were produced using the coprecipitation method and characterized using DLS, FTIR, and SEM techniques. Forty female BALB/c mice were inoculated with 7.5 x 105 4T1 cells and treated with royal jelly in free and nanoparticle form. Clinical signs and tumor volume were assessed weekly. The effect of royal jelly products on the serum level of IFN-γ and TGF-ß was measured by ELISA. In addition, the mRNA expression of these cytokines and Th1 and regulatory T cells' transcription factors (T-bet and FoxP3) was assessed by real-time PCR in the splenocytes of tumor-bearing mice. RESULTS: The physicochemical analysis of nanoparticles confirmed the synthesis of LDH nanoparticles and loading of royal jelly into the LDH structures (RJ-LDH). Animal studies showed that royal jelly and RJ-LDH significantly reduced the size of tumor in BALB/c mice. Additionally, treatment with RJ-LDH significantly inhibited TGF-ß and increased IFN-γ production. The data also revealed that RJ-LDH inhibited the differentiation of regulatory T cells, while promoting Th1 cell differentiation via regulating their master transcription factors. CONCLUSIONS: These results indicated that royal jelly and RJ-LDH could inhibit breast cancer progression by in-hibiting regulatory T cells and expansion of Th1 cell. Furthermore, the current study demonstrated the therapeutic efficacy of royal jelly is enhanced by LDH nanoparticles; hence, RJ-LDH is significantly more efficient than Free-RJ in the treatment of breast cancer.

Involvement of various chemokine/chemokine receptor axes in trafficking and oriented locomotion of mesenchymal stem cells in multiple sclerosis patients.

Multiple sclerosis (MS) is a specific type of chronic immune-mediated disease in which the immune responses are almost run against the central nervous system (CNS). Despite intensive research, a known treatment for MS disease yet to be introduced. Thus, the development of novel and safe medications needs to be considered for the disease management. Application of mesenchymal stem cells (MSCs) as an emerging approach was recruited forthe treatment of MS. MSCs have several sources and they can be derived from the umbilical cord, adipose tissue, and bone marrow. Chemokines are low molecular weight proteins that their functional activities are achieved by binding to the cell surface G protein-coupled receptors (GPCRs). Chemokine and chemokine receptors are of the most important and effective molecules in MSC trafficking within the different tissues in hemostatic and non-hemostatic circumstances. Chemokine/chemokine receptor axes play a pivotal role in the recruitment and oriented trafficking of immune cells both towards and within the CNS and it appears that chemokine/chemokine receptor signaling may be the most important leading mechanisms in the pathogenesis of MS. In this article, we hypothesized that the chemokine/chemokine receptor axes network have crucial and efficacious impacts on behavior of the MSCs, nonetheless, the exact responsibility of these axes on the targeted tropism of MSCs to the CNS of MS patients yet remained to be fully elucidated. Therefore, we reviewed the ability of MSCs to migrate and home into the CNS of MS patients via expression of various chemokine receptors in response to chemokines expressed by cells of CNS tissue, to provide a great source of knowledge.

A Review of Immunomodulatory Effects of Fluoroquinolones.

Past researches indicate that some types of antibiotics, apart from their antimicrobial effects, have some other important effects which indirectly are exerted by modulating and regulating the immune system's mediators. Among the compounds with antimicrobial effects, fluoroquinolones (FQs) are known as synthetic antibiotics, which exhibit the property of decomposing of DNA and prevent bacterial growth by inactivating the enzymes involved in DNA twisting, including topoisomerase II (DNA gyrase) and IV. Interestingly, immune responses are indirectly modulated by FQs through suppressing pro-inflammatory cytokines, such as interleukin 1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-α), and super-inducing IL-2, which tend to increase both the growth and activity of T and B lymphocytes. In addition, they affect the development of immune responses by influencing of expression of other cytokines and mediators. This study aims to review past research on the immunomodulatory effects of FQs on the expression of cytokines, especially IL-2 and to discuss controversial investigations.

Protective effect against brain tissues oxidative damage as a possible mechanism for beneficial effects of L-arginine on lipopolysaccharide induced memory impairment in rats.

L-Arginine (LA) and nitric oxide (NO) have been suggested to have some effects on learning, memory, brain tissues oxidative damage, and neuroinflammation. In this study, protective effect against brain tissues oxidative damage as a possible mechanism for beneficial effects of LA on lipopolysaccharide (LPS) induced memory impairment was investigated. The rats were grouped into and treated by (1) control (saline), (2) LPS (1 mg/kg, IP), (3) LA (200 mg/kg) - LPS (4) LA. In passive avoidance (PA) test, LPS administration shortened the latency to enter the dark compartment in LPS group compared to control (p < .001) which was accompanied with a high level of malondialdehyde (MDA) and NO metabolite concentrations in the hippocampal tissues (p < .001and p < .05, respectively). Pretreatment with LA prolonged the latency in LA-LPS group compared with LPS group (p < .01-.001) and re-stored MDA and NO metabolites in the hippocampal tissues (p < .05). LPS also reduced superoxide dismutase (SOD) and catalase (CAT) activities and thiol content in the hippocampal tissues in LPS group compared to control (p < .05 and p < .001, respectively) which improved by LA when it was administered before LPS in LA-LPS group (p < .05 and p < .001). Finally, the serum TNFα level of LPS group was higher than the control (p < .01) while, in LA-LPS group it was lower than LPS group (p < .01). It seems that the beneficial effects of LA on memory impairment of LPS-treated rats may be due to its protective effects against brain tissues oxidative damage.

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.

Hyperforin-loaded gold nanoparticle alleviates experimental autoimmune encephalomyelitis by suppressing Th1 and Th17 cells and upregulating regulatory T cells.

Hyperforin an herbal compound, is commonly used in traditional medicine due to its anti-inflammatory activities. The aim of this study was to use a hyperforin loaded gold nanoparticle (Hyp-GNP) in the treatment of experimental autoimmune encephalomyelitis (EAE) an animal model of multiple sclerosis (MS). Hyp-GNP and hyperforin significantly reduced clinical severity of EAE, which was accompanied by a decrease in the number of inflammatory cell infiltration in the spinal cord. Additionally, treatment with Hyp-GNP significantly inhibited disease-associated cytokines as well as an increase in the anti-inflammatory cytokines in comparison to all groups including the free-hyp group. Furthermore, hyperforin and Hyp-GNP inhibited the differentiation of Th1 and Th17 cells while promoting Treg and Th2 cell differentiation via regulating their master transcription factors. The current study demonstrated the although, free-hyp improved clinical and laboratory data Hyp-GNP is significantly more efficient than free hyperforin in the treatment of EAE.

Important roles played by TGF-ß in hepatitis B infection.

Hepatitis B virus (HBV) which includes, fulminant, acute, chronic, asymptomatic, and occult HBV infection is the most prevalent virus that leads to human liver diseases. Chronic, asymptomatic, and occult infection can induce further sever diseases such as hepatocellular carcinoma (HCC) and cirrhosis of the liver. The underlying mechanisms that allow progression of the prolonged forms of the infection and subsequent HCC or cirrhosis of the liver are yet to be clarified. However, many researchers have suggested that immunological and genetic parameters may play important roles in the etiology of hepatitis B. Transforming growth factor beta (TGF-ß) is an important cytokine with dual regulatory functions in the immune system and in the responses against viral infections. However, the pathways and mechanisms controlling these are not fully understood. The crucial roles of TGF-ß in the development of Th17 and T regulatory lymphocytes, the main cell types involved in autoimmunity and destructive immune related diseases, have been documented and this provides insights into TGF-ß function during hepatitis infection and subsequent HCC and cirrhosis of the liver. Recent findings also confirm that TGF-ß directly alters hepatocyte function during hepatitis B, hence, the aim of this review is to address the current data regarding the association and status of TGF-ß with hepatitis B infection and its related disorders including HCC and cirrhosis of the liver.

In Vitro Effects of Curcumin in Free and Phytosomal Forms on the Expression of T Helper1 and Regulatory T Cells' Transcription Factors in Collagen-Induced Arthritis.

Background: Curcumin as a polyphenolic compound has a potential capacity to reduce autoimmune reactions by skewing the balance of Thelper1 (Th1)/regulatory T cells (Treg) toward Treg cells. However, the low absorption and bioavailability of this agent have prompted researchers to use various drug delivery systems such as phytosomes to reduce these drawbacks. To date, few studies have evaluated the effects of phytosomal curcumin (nano-curcumin) on immune responses. Hence, we compared the modulatory effects of curcumin in free and phytosomal form on the expression of Th1 and Treg transcription factors, T-bet (T-box-containing protein) and Foxp3 (forkhead box p3), respectively, in a collagen-induced arthritis model (CIA). Materials and Methods: Following the induction of CIA, splenocytes were isolated and re-stimulated with collagen in the absence or presence of two different doses of curcumin in free and phytosomal form. Then, expression of T-bet and Foxp3 was assessed by real-time PCR. Results: The expression of T-bet was reduced in curcumin and phytosomal curcumin groups rather than in the untreated group. The level of T-bet was not significantly different between free and phytosomal groups. Moreover, mRNA expression of Foxp3 enhanced after treatment with curcumin, while phytosomal curcumin groups showed no difference in comparison with the untreated group. Conclusions: curcumin in nano/free form showed a modulatory effect on the expression of T-bet. However, only free-form enhanced Foxp3 expression, which could be owing to the low amount of curcumin in the phytosomal complex rather than free-form at the same dose or due to leakage of curcumin from the complex.

Teucrium polium Extract Alleviates Pathological Features of Asthma via lL-12 and IFN-γ Modulation in Murine OVA-induced Allergic Asthma.

Asthma is a chronic disorder characterized by airway overreaction and remodeling, eosinophilia, and neutrophilic inflammation, accompanied by thickening of the airways and breathlessness. Teucrium polium (TP) is a plant with anti-inflammatory properties and is considered for the treatment of allergic disorders. In this study, we examined the effects of TP extract on ovalbumin (OVA)-induced asthma. Thirty female mice (5-6 weeks old) were divided into 5 groups of 6 each, including a control group and 4 groups treated with OVA, OVA + TP extract (50 mg/kg), OVA + TP extract (150 mg/kg), OVA + TP extract (300 mg/kg). Twenty-four hours after the last treatment, lung, serum, and spleen samples were collected and used for the evaluation of leukocyte infiltration, serum cytokine Interferon-gamma (IFN-γ) levels, and the expression of the Interleukin-12A (IL12A) gene, respectively. Hematoxylin-eosin staining was used to evaluate pathological changes in the lung tissue sections. Treatment with TP extract reduced inflammatory cells such as eosinophils and neutrophils in the airways. Furthermore, it increased serum levels of IFN-γ and IL-12A at a dose of 50, 150, and 300 mg/kg compared to the OVA group. This study showed that the administration of TP extract could improve pathological features, such as airway inflammation, and reduce systemic inflammation.

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.

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.

Severe Acute Respiratory Syndrome Coronavirus 2: The Role of the Main Components of the Innate Immune System.

At the end of December 2019, the COVID-19 pandemic began in Wuhan of China. COVID-19 affects different people with a wide spectrum of clinical manifestations, ranging from asymptomatic with recovery without hospitalization up to a severe acute respiratory syndrome (SARS). The innate and adaptive immunity appears responsible for the defense against the virus and recovery from the disease. The innate immune system, as the first line of defense, is essential for the detection of virus and subsequent activation of acquired immunity. The innate immune response is carried out by sentinel cells such as monocytes/macrophages and dendritic cells and by receptors known as pattern recognition receptors (PRR). These receptors can recognize various components of the virus, which lead to intracellular signaling and subsequently the synthesis of various cytokines. These cytokines then recruit other immune cells, activate adaptive immune responses, and inhibit viral spreading. The most common receptors include Toll-like receptors, C-type lectin receptors, and RIG-I like receptors. This review describes the current knowledge about the interplay between innate immune responses and SARS-CoV-2 with a focus on the innate immune cells and the role of their receptors in viral RNA recognition, as well as their mechanisms for recognizing SARS-CoV-2.

Acylated and deacylated quillaja saponin-21 adjuvants have opposite roles when utilized for immunization of C57BL/6 mice model with MOG35-55 peptide.

BACKGROUND: The majority of patients with multiple sclerosis (MS) suffer from central neuropathic pain (CNP). Using experimental autoimmune encephalomyelitis (EAE) model, only a few experiments were performed to assess pain behaviors in MS. To address this issue, complete Freund's adjuvant (CFA) was replaced with an acylated triterpene glycoside saponin adjuvant named quillaja saponin-21 (QS-21) to develop CNP in the EAE mouse model. The deacylated form of QS-21, named QT-0101, has been suggested to have an immunomodulatory effect. Thus, QT-0101 was used as a vaccine adjuvant to modulate the immune system against myelin oligodendrocyte glycoprotein (MOG35-55) antigen. METHODS: In this study, C57BL/6 mice, except for mice in the negative control (PBS) and MOG groups, were divided into three groups and immunized by MOG35-55 emulsified with CFA, QS-21, or QT-0101 adjuvants, respectively. Thermal hyperalgesia, as a CNP clinical manifestation, through the Hot Plate test and the clinical signs, was assessed for 60 days after immunization. On days 21 and 60, mice were sacrificed and the frequency of TCD4+, TCD8+, IL-17+, IL-4+, and CD25+/FoxP3+ cells population in the total splenocytes population was assessed by flow cytometry. Infiltration of Leukocytes into the brain and demyelination of white matter were also evaluated by histopathologic studies. RESULTS: Our results revealed that unlike the MOG+QT-0101 group, the MOG+QS-21 and MOG+CFA groups represented clinical symptoms that mimic the mild relapsing-remitting and monophasic models, respectively. Thermal hyperalgesia, as a CNP clinical manifestation, developed in the bilateral hind paws in the MOG+CFA and MOG+QS-21 mice groups during the onset of neurologic deficits, but it is maintained until completion of the study only in MOG+QS-21 mice group. The frequency of TCD4+, TCD8+ and IL-17+ cells population in the MOG+QS-21 and MOG+CFA mice groups, as well as IL-4+ and CD25+/Foxp3+ cells population in the MOG+QT-0101 mice group, significantly increased in comparison with the PBS mice group. Infiltration of inflammatory cells increased significantly in the MOG+QS-21 and MOG+CFA mice groups compared with the PBS mice group. Demyelination of white matter was identified significantly only in the MOG+CFA mice group compared with the PBS mice group. CONCLUSION: These results showed that QS-21 is a suitable adjuvant for the establishment of a mild relapsing-remitting EAE model for CNP development and open a new avenue to future pre-clinical and clinical research studies related to CNP treatment. Nevertheless, QT-0101 seems to have the potential to act as a vaccine adjuvant with immunomodulatory property against auto-antigens.

Exposure of metals and PAH through local foods and risk of cancer in a historically contaminated glassworks area.

BACKGROUND: Production of crystal glass and colored art glassware have been going on in the south-eastern part of Sweden since the 1700s, at over 100 glassworks and smaller glass blowing facilities, resulting in environmental contamination with mainly arsenic (As), cadmium (Cd), lead (Pb) and polycyclic hydrocarbons (PAH). High levels of metals have been found in soil, and moderately elevated levels in vegetables, mushrooms and berries collected around the glassworks sites compared with reference areas. Food in general, is the major exposure source to metals, such as Cd and Pb, and PAHs. Exposure to these toxic metals and PAH has been associated with a variety of adverse health effects in humans including cancer. OBJECTIVE: The aim of the present study was to evaluate the occurrence of cancer in a cohort from the contaminated glasswork area in relation to long-term dietary intake of locally produced foods, while taking into account residential, occupational and life styles factors. METHODS: The study population was extracted from a population cohort of 34,266 individuals who, at some time between the years 1979-2004, lived within a 2 km radius of a glassworks or glass landfill. Register information on cancer incidence and questionnaire information on consumption of local foods (reflecting 30 years general eating habits), life-time residence in the area, life style factors and occupational exposure was collected. Furthermore, blood (n = 660) and urine (n = 400) samples were collected in a subsample of the population to explore associations between local food consumption frequencies, biomarker concentrations in blood (Cd, Pb, As) and urine (PAH metabolite 1-OHPy) as well as environmental and lifestyle factors. The concurrent exposure to persistent organic pollutants (POPs) from food was also considered. A case-control study was performed for evaluation of associations between intakes of local food and risk of cancer. RESULTS: Despite high environmental levels of Cd, Pb and As at glasswork sites and landfills, current metal exposure in the population living in the surrounding areas was similar or only moderately higher in our study population compared to the general population. Reported high consumption of certain local foods was associated with higher Cd and Pb, but not As, concentrations in blood, and 1-OHPy in urine. An increased risk of cancer was associated with smoking, family history of cancer, obesity, and residence in glasswork area before age 5 years. Also, a long-term high consumption of local foods (reflecting 30 years general eating habits), i.e. fish and meat (game, chicken, lamb), was associated with increased risk of various cancer forms. CONCLUSIONS: The associations between consumption of local food and different types of cancer may reflect a higher contaminant exposure in the past, and thus, if consumption of local food contributes to the risk of acquiring cancer, that contribution is probably lower today than before. Furthermore, it cannot be ruled out that other contaminants in the food contribute to the increased cancer risks observed.

Vitamin D and toll like receptors.

It has been demonstrated that vitamin D (VD) significantly modulates immune responses. Toll like receptors (TLRs) are the main innate immunity receptors which are expressed on the cell membrane and intracellular vesicles and recognize several pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) to induce immune responses. Based on the important roles played by TLRs in physiologic and pathologic functions of immune responses and due to the immunomodulatory functions of VD, it has been hypothesized that VD may present its immunomodulatory functions via modulation of TLRs. This review article collates recent studies regarding the interactions between VD and TLRs and discussed the controversial investigations.

Association of S100 calcium-binding protein A12, receptor for advanced glycation endproducts, and nuclear factor-κB expression with inflammation in pulp tissues from tooth caries.

AIM: S100 calcium-binding protein A1 (S100A12) is a pro-inflammatory molecule which is secreted during inflammation and induces chemotaxis and the production of pro-inflammatory cytokines via interaction with receptor for advanced glycation endproducts (RAGE) and subsequent, activation of nuclear factor-κB (NF-κB). The present study was designed to determine the expression levels of S100A12, RAGE, and NF-κB in the inflamed pulp of carried teeth. METHODS: In the present study, mRNA from 50 inflamed pulp and 50 healthy pulp were used for expression studies using real-time polymerase chain reaction. The expression levels of S100A12, RAGE, and NF-κB were compared between inflamed and healthy tissues. RESULTS: The results revealed that the expression of S100A12, but not of RAGE or NF-κB, was significantly decreased in inflamed pulp when compared to healthy pulp. mRNA levels of RAGE were also increased in the inflamed pulp taken from men when compared with women. CONCLUSION: The results suggest that S100A12 does not participate in the induction of inflammation in dental pulp. However, RAGE can participate in the inflammation in the pulp of males.

Analysis of Th22, Th17 and CD4+cells co-producing IL-17/IL-22 at different stages of human colon cancer.

T-helper (Th) 22 cells are involved in the immunopathogenesis of inflammatory diseases, but their specific role in the immunopathogenesis of cancer is unknown. In this study, we examined the profile of circulating and intratumoral Th17, Th22 and CD4+ cells co-producing IL-17/IL-22 in colon cancer (CC) patients in relation to tumor staging. Thirty newly diagnosed colon cancer (CC) patients participated in this study. The percentage of Th1 (CD4+IFN-γ+IL-17-IL-22-), Th17 (CD4+IFN-γ-IL-17+IL-22-), Th22 (CD4+IFN-γ-IL-17-IL-22+) and CD4+ cells co-producing IL-17/IL-22 (CD4+IFN-γ-IL-17+IL-22+) in the peripheral blood, tumor and paratumor tissues was assessed by multicolor flow cytometry. The percentage of circulating Th17 and Th22 cells was significantly increased in CC patients compared to that in healthy controls (HCs). In addition, the percentage of infiltrating Th1, Th17, Th22 and CD4+ cells co-producing IL-17/IL-22 was significantly increased in the tumor tissues compared to that in the parartumor tissues. Furthermore, we also found that the percentage of circulating and intratumoral Th17, Th22 and CD4+ cells co-producing IL-17/IL-22 was higher in advanced stages than in early stages. Our findings revealed that Th17, Th22 and CD4+ cells co-producing IL-17/IL-22 were accumulated in colon cancer tissues and may be involved in the tumor development and progression. A better comprehension of the immunopathogenesis of Th17, Th22 and CD4+ cells co-producing IL-17/IL-22 in colon cancer patients would help in the development of novel therapies.

The Effect of Zataria multiflora on Th1/Th2 and Th17/T Regulatory in a Mouse Model of Allergic Asthma.

Asthma is a chronic inflammatory disease with no definite treatment and more research is needed to overcome this condition. The aim of this study was to investigate the effect of the extract of Zataria multiflora (Z. multiflora) as a medicinal plant on cytokine genes expression in an experimental mouse model of asthma. Adult mice were randomly divided into the following groups: control (C), untreated asthma (A), asthmatic groups treated with dexamethasone (D) and Z. multiflora extract (200, 400, and 800 µg/mL; Z1, Z2, and Z3, respectively), (for groups C, A, and D n = 5 and for groups Z1, Z2, and Z3 n = 6). For induction of the mouse model of asthma, animals were sensitized with intraperitoneal injection and inhalation of ovalbumin (OVA). The number of T helper (Th) subtype cells (using flow cytometry) and the levels of IFN-γ, FOXP3, IL-4, TGF-ß, IL-17 gene expression (by real time PCR) were assessed in mice splenocytes. The observed changes in spleen cells of group A compared to group C were increased number of Th2 and Th17 cells, enhancement of gene expression of IL-4, IL-17, and TGF-ß (p < 0.001 for all cases), reduction of Th1 cells and Th1/Th2 ratio (p < 0.001 for both cases) and decrease in gene expression of IFN-γ, FOXP3 and IFN-γ/IL-4 ratio (p < 0.01 for IFN-γ and p < 0.001 for other cases). The observed changes in spleen cells of treated compared to untreated A group were enhancement of Treg cells and Th1/Th2 ratio (p < 0.001 for both cases), increase in IFN-γ (p < 0.05) and FOXP3 (p < 0.001) gene expression and IFN-γ/IL-4 ratio (p < 0.01) as well as reduction of Th2 and Th17 cells (p < 0.01 to p < 0.001), decrease gene expression of IL-4, IL-17, and TGF-ß (p < 0.05 to p < 0.001). The findings showed that the extract of Z. multiflora decreased pro-inflammatory cytokines in asthma (IL-4 and IL-17 and TGF-ß) but increased anti-inflammatory cytokines (IFN-γ) gene expression and the number of Treg (FOXP3) in splenocytes of asthmatic mice which may indicate the specific therapeutic effect of the plant extract in allergy, autoimmunity, and infectious diseases via potentiating Th1 and suppressing Th2 and Th17 cells.