Investigation into antibacterial and wound healing properties of platelets lysate against Acinetobacter baumannii and Klebsiella pneumoniae burn wound infections.

BACKGROUND AND AIM: Treatment of burn wound infections has become a global challenge due to the spread of multidrug-resistant bacteria; therefore, the development of new treatment options for the mentioned infections is essential. Platelets have drawn much attention for this purpose because they are a safe and cost-effective source of different antimicrobial peptides and growth factors. The present study evaluated antibacterial effects and wound healing properties of Platelet-derived Biomaterial (PdB) against Acinetobacter baumannii and Klebsiella pneumoniae burn wound infections. METHODS: PdB was prepared through the freezing and thawing process and then, in vitro antibacterial effect was determined by disk diffusion and broth microdilution methods. Afterward, burn wound was inflicted on 56 rats, infected with both bacteria, and topical administration was performed to evaluate antibacterial effects and wound healing properties of PdB. RESULTS: In vitro results showed that PdB inhibited the growth of A. baumannii in the highest dose (0.5), while we did not detect any inhibitory effects against K. pneumoniae. By contrast, PdB significantly inhibited the growth of bacteria in treated animal wounds compared to the control groups (P value < 0.05). Macroscopic assessments pointed to the significant enhancement of wound closure in the treated animals. In addition, histopathological examination demonstrated that treatment of rats with PdB led to a considerable increase in re-epithelialization and attenuated the formation of granulation tissue (P value < 0.05). CONCLUSION: The use of topical PdB is an attractive strategy for treating A. baumannii and K. pneumoniae burn wound infections because it inhibits bacterial growth and promotes wound healing properties.

STAT3 inhibition reduced PD-L1 expression and enhanced antitumor immune responses.

Colon cancer is one the most common diagnosed cancers in America and Europe. Signal transducer and activator of transcription 3 (STAT3) in colon cancer is associated with proliferation of the tumor cells and suppression of immune responses. STAT3 activation upregulates the transcription of many suppressor genes, including programmed death-ligand 1 (PD-L1). This study was aimed to investigate the effect of STAT3 inhibition in a colon cancer cell line, HCT-15, and particularly in presence of samples obtained from the patients suffering from colon cancer. In this project, the expression of PD-L1 and apoptosis-related proteins were assessed following STAT3 inhibition, using FLLL32, in HCT-15 cells. To evaluate the effects of STAT3 inhibition on immune response, lymphocytes from 20 men with Stage III colon cancer and 20 healthy donors were cocultured with HCT-15 cells in presence or absence of STAT3 inhibitor. Then, T regulatory (T-reg) cell evaluation and intracellular cytokine staining (ICS) were performed using flowcytometry to assess the T-reg and T helper (Th) subset cytokines following STAT3 inhibition. STAT3 inhibition suppressed PD-L1 expression and induced apoptosis in HCT-15 cells. The population of T-reg cells in patients with colon cancer significantly decreased after treatment with STAT3 inhibitor. ICS revealed that STAT3 inhibition promotes Th1 protective immune responses. These findings suggest that STAT3 inhibition through either induction of apoptosis in the colon cancer cells and/or activation of efficient immune responses can lead to overcome cancer-induced immune tolerance.

HIV-1 drug resistance mutations detection and HIV-1 subtype G report by using next-generation sequencing platform.

BACKGROUND: Based on world health organization (WHO) recommend, drug resistance assay should be performed in initial of treatment and after treatment for administering and monitoring of anti-retroviral regime in HIV-1 infected patients. MATERIAL AND METHOD: NGS analyses were performed on forty-one plasma samples from HIV-1 affected patients using the Sentosa SQ HIV genotyping assay (Vela-Diagnostics, Germany). This system comprises a semi-automated Ion torrent based platform and the sequencing results were analyzed based on ANRS, REGA and Stanford drug resistance algorithms. Phylogenetic analysis was analyzed based on https://comet.lih.lu database as well as MEGA5 Software. RESULTS: Drug resistances were identified in thirty-three samples (80%) out of forty-one samples. The Phylogenetic analysis results showed that CRF-35AD (94%) and subtypes B (2.4%) and G (2.4%) were dominant subtypes in this study. NRTI and NNRTI associated dominant mutations were M184I/V and K103 N.High-level resistance to lamivudine (3 TC) and Emtricitabine (FTC) were detected in 34.3% of patients while 53.1% were resistant to Efavirenz (EFV) and Nevirapine (NVP). The Protease inhibitor (PI) minor and major mutations were not reported but more than 95% of samples had polymorphisms mutation in K20R, M36I, H69K, L89 M positions. These mutations are subtype dependent and completely are absent in subtype B virus. The secondary mutations were reported in positions of E157Q, S230 N, and T97A of integrase gene and four samples represent low-level resistance to integrase strand transfer inhibitor (INSTI). CONCLUSIONS: This is the first preliminary evaluation of HIV-1 drug resistance mutation (DRM) by using the Sentosa SQ HIV Genotyping Assay in Iran. The NGS represent a promising tool for the accurate detection of DRMs of CRF-35AD that is dominant subtype in Iranian HIV-1 infected population and for the first time revealed HIV-1 subtype G in Iranian population. In the present study polymorphic mutation in the position of K20R, M36I, H69K, L89 M were properly reported in CRF35AD that is dominant in Iranian HIV patients.

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.

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.

Current information concerning association of IL-12 and hepatitis B infection.

BACKGROUND: Hepatitis B is one of the most prevalent infectious diseases and is induced by hepatitis B virus (HBV). The chronic, asymptomatic, and occult forms of hepatitis B are long-term infections that can lead to various hepatic cancers and cirrhosis in the carrier. IL-12 is one of the main cytokines involved in inducing appropriate immune responses against viral infections, especially HBV. Therefore, the aim of the present review was to address the most recent information within the database regarding the status and association between IL-12 and hepatitis B infection and its complications including cirrhosis and hepatocellular carcinoma. METHODS: The data presented was collected by searching the following keywords in the Pubmed and Scopous databases: Hepatitis B, occult HBV infection, chronic HBV infection, asymptomathic HBV infection, acute HBV infection, fulminant HBV infection, IL-12, and all the papers regarding the relation between IL-12 and hepatitis B were used. These data were presented in the current review article. RESULTS: Results showed that IL-12 plays important roles in Hepatitis B infection and patients infected with the long-term form of hepatitis B are unable to produce sufficient amount of this cytokine. CONCLUSIONS: Our research provided mechanistic insights into the immunoprotective roles of IL-12 and proposed that it can be considered as an important molecule for immunotherapy of HBV infected infection.

Differential pattern of cytokine production by depressed medical students; evidence for involvement of cytokine network in pathology of depression.

BACKGROUND: Previous studies revealed that the immune responses of depressed patients can be affected by alteration of immune system factors; however, the immune genes mainly influenced are yet to be fully understood. Therefore, the main aim of present study was to identify serum levels of drastic inflammatory cytokines including IL-17A, IL-12, and IL-6 as well as anti-inflammatory cytokines, IL-10 and TGF-beta, amongst Iranian depressed medical students. METHODS: Peripheral blood specimens were collected from 38 Iranian medical student patients with moderate and severe depression along with 43 healthy students as control subjects. The serum levels of IL-17A, IL-12, IL-6, IL-10, and TGF-beta were assessed using the ELISA technique. RESULTS: Our results showed that the serum IL-10 level was significantly (p = 0.011) decreased in depressed patients (2.8 +/- 0.41 pg/mL) compared to healthy controls (4.3 +/- 0.4 pg/mL). The results also revealed that serum levels of TGF-beta were significantly increased in severely (12.75 +/- 5.22) compared to moderately (5.3 +/- 0.7) depressed patients (p = 0.045). CONCLUSIONS: According to the results of the present study, the decreased IL-10 level in the depressed patients may be responsible for the induction of inflammation in Iranian depressed patients. Additionally, increased serum levels of TGF-beta in severely compared to moderately depressed patients may be related to normal immune responses against inflammation in severely depressed patients.

Evaluation of Tcell exhaustion based on the expression of EOMES, Tbet and co-inhibitory receptors in severe and non-severe covid-19 patients.

During viral infections, especially Covid-19, Tcell exhaustion plays a crucial role in reducing the activity of lymphocytes and the immune system's antiviral activities. This research aimed to investigate the co-inhibitory receptors and transcription factors involved in the Tcell exhaustion process in ICU-admitted (ICUA) compared to non-ICU admitted (non-ICUA) Covid-19 patients. A total of 60 Covid-19 patients (30 patients in the severe group who were admitted in the ICU (ICUA) and 30 patients in the mild group who were admitted in departments other than the ICU (non-ICUA)) and 10 healthy individuals were included in this study. Laboratory tests and the level of gene expressions related to 4 inhibitory co-receptors, including LAG-3, TIM-3, TIGIT, PD-1, and T-bet and Eomes transcription factors involved in the process of Tcell exhaustion in severe and mild patients of Covid-19 were investigated. The results showed lymphopenia and an increase in other hematologic laboratory factors such as NLR, PLR, CRP, ALT, and AST in people with a severe form of the disease (ICUA) compared to mild groups (non-ICUA) (P < 0.001). Furthermore, a significant increase in 3 co-inhibitory receptors, TIM-3, LAG-3, and PD-1, was observed in severe patients compared to mild and healthy people (P < 0.001). An increase in TIGIT gene expression was lesser than the other three mentioned receptors (P < 0.05). Concerning the transcription factors, we observed a significant increase in Eomes in ICUA patients compared to the non-ICUA group (P < 0.001), and this increment in T-bet gene expression was minor compared to Eomes (P < 0.05). In conclusion, Patients with a severe form of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represented a higher level of gene expressions in terms of co-inhibitory receptors and transcription factors involved in the T cell exhaustion process.

Mesenchymal stem cells and allergic airway inflammation; a therapeutic approach to induce immunoregulatory responses.

Allergic airway inflammations are among the essential disorders worldwide that are already considered a significant concern. Mesenchymal stem cells (MSCs) are stromal cells with regenerative potential and immunomodulatory characteristics and are widely administered for tissue repair as an immunoregulatory agent in different inflammatory diseases. The current review summarized primary studies conducted to evaluate the therapeutic potential of MSCs for allergic airway disorders. In this case, modulation of airway pathologic inflammation and infiltration of inflammatory cells were examined, and modulation of the Th1/Th2 cellular balance and humoral responses. Also, the effects of MSCs on the Th17/Treg ratio and inducing Treg immunoregulatory responses along with macrophage and dendritic cell function were evaluated.

Mesenchymal Stem Cell-derived Exosome; An Interesting Nanocarrier to Improve Allergen-specific Intranasal Immunotherapy.

Increasing the efficacy of allergen-specific intranasal immunotherapy (INIT) has recently been the main goal of several studies to establish this route as a safe delivery method through mucosal pathways. In this case, the present study evaluated the potential of INIT using ovalbumin (OVA)-loaded mesenchymal stromal/stem cell (MSC)-derived exosomes (Exo-OVA) in an allergic asthma mouse model. Together with control groups, sensitized Balb/c mice underwent intranasal immunotherapy with Exo-OVA (10 µg OVA per dose) for three consecutive weeks. Serum-specific immunoglobulin E (IgE) levels, transforming growth factor-beta (TGF-ß), interleukin (IL)-4, and interferon-gamma (IFN-γ) production by cultured spleen cells, lung histopathologic analysis, and nasopharyngeal lavage fluid cellular examinations were then conducted. The results showed that INIT using Exo-OVA significantly increased IFN-γ and TGF-ß secretion, while allergen-specific IgE and IL-4 production were dramatically decreased compared to the control group receiving phosphate-buffered saline. In addition, the eosinophil and total cell counts in the nasopharyngeal lavage fluid were reduced, and inflammatory conditions and cell accumulation in lung tissue were ameliorated. In conclusion, the Exo-OVA improved the INIT efficacy compared to free OVA. Therefore, this formulation could be introduced as an effective approach for immunomodulatory purposes with a shorter treatment duration and reduced side effects.

ß-D-mannuronic Acid (M2000) and Inflammatory Cytokines in COVID-19; An In vitro Study.

coronavirus disease of 2019 (COVID-19) can be complicated by acute respiratory distress syndrome (ARDS) and may be associated with cytokine storm and multiorgan failure. Anti-inflammatory agents, such as systemic corticosteroids, monoclonal antibodies, and nonsteroidal anti-inflammatory drugs (NSAIDs) can be used for this purpose. In this study, we evaluated the immunomodulatory effect of mannuronic acid (M2000), which is a novel NSAID, on COVID-19-related cytokine storms. This study was conducted in vitro on blood samples of 30 COVID-19 patients who presented with ARDS to a referral center. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples and incubated with phorbol myristate acetate for 24 hours. M2000 was administered with the dosages of 25 µg/well and 50 µg/well after 4 hours of incubation at 37°C. The quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to assess mRNA gene expression. Enzyme-linked immunosorbent assay (ELISA) was performed to evaluate the supernatant PBMC levels of interleukin (IL)-6, IL-17, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. Both mRNA expression and the supernatant PBMC levels of IL-17, TNF-α, IL­6, and IFN­Î³ were decreased in PBMCs of COVID-19 patients treated with M2000 compared with the control  group. For the first time, it was observed that M2000 could be effective in alleviating the inflammatory cascade of COVID-19 patients based on an in vitro model. After further studies in vitro and in animal models, M2000 could be considered a novel NSAID drug in COVID-19 patients.

Smaller Copper Oxide Nanoparticles have More Biological Effects Versus Breast Cancer and Nosocomial Infections Bacteria.

BACKGROUND AND OBJECTIVES: Despite promising successes in developing new drugs and pharmaceutical biotechnology, infectious diseases and cancer are still the principal causes of mortality and morbidity globally. Therefore, finding effective ways to deal with these pathogens and cancers is critical. Metal nanoparticles are one of the new strategies to combat bacteria and cancers. METHODS: We examined the antimicrobial activity of 30 and 60 nm copper oxide nanoparticles (CuO-NPs) against Acinetobacter baumannii and Staphylococcus epidermidis bacteria responsible for nosocomial infections in standard and clinical strains and anti-cancer activity against 4T1 cell line as malignancy breast cancer cells. Synthesis of CuO-NPs was performed by a one-step reduction method and confirmed by DLS and TEM microscopy at 30 and 60 nm sizes. The antibacterial and anti-cancer activities of the nanoparticles were then investigated against the aforementioned bacteria and breast cancer. RESULTS: Using disk, well, MIC, MBC methods, and viability/bacterial growth assay, 30 nm CuO NPs were found to have more antibacterial activity on standard and clinical strains than 60 nm CuO NPs. On the other hand, using MTT, apoptosis, and gene expression method, 30 nm nanoparticles were found to have more anti-cancer potential than 60 nm CuO NPs. CONCLUSIONS: Our findings implicate CuO-NPs to possess antimicrobial and anti-cancer effects and more significant potential in smaller sizes, suggesting their pharmaceutical and biomedical capacity.
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Combined effects of Allium sativum and Cuminum cyminum essential oils on planktonic and biofilm forms of Salmonella typhimurium isolates.

Sa lmonella typhimurium (S. typhimurium) represents an important global public health problem and has the ability to survive under desiccation conditions in foods and food processing facilities for years. The aim of this study was to investigate the effects of Allium sativum (A. sativum) and Cuminum cyminum (C. cyminum) essential oils (EOs) against planktonic growth, biofilm formation and quorum sensing (QS) of S. Typhimurium isolates, the strong biofilm producers. The major components of EOs were determined by gas chromatography-mass spectrometry (GC-MS). Biofilm formation of S. Typhimurium isolates was measured by crystal violet staining. Then, the effects of the EOs on the planktonic cell growth (using determination of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC)), measurement of the synergistic effects of EOs (using checkerboard method), biofilm formation (using microtiter-plate test and scanning electron microscope (SEM)), and expression of QS and cellulose synthesis genes (using quantitative real-time PCR) were assessed. Finally, tetrazolium-based colorimetric (MTT) assay was used to examine EOs cytotoxicity on the Vero cell line. GC-MS analysis showed that terpineol, carene and pinene in C. cyminum EO and sulfur compounds in A. sativum EO were the major components of the plant extract. The Geometric mean of MIC values of the A. sativum and C. cyminum were 0.66 and 2.62 µL mL-1, respectively. The geometric means of the fractional inhibitory concentration index (FICi) for both EOs were calculated as 1.05. The qPCR results showed that MIC/2 concentrations of both EOs significantly down-regulated of QS (sdiA and luxS) and cellulose synthesis (csgD and adrA) genes. Scanning electron microscopy showed the EOs reduced the amount of S. Typhimurium mature biofilm. In general, we showed that C. cyminum and A. sativum EOs can be considered as the potential agents against planktonic and biofilm form of S. Typhimurium without any concern of cytotoxic effect at 4 MIC concentrations on the eukaryotic Vero cells.

CD40 DNA hypermethylation in primary gastric tumors; as a novel diagnostic biomarker.

AIMS: Gastric cancer (GC) remains one of the deadliest malignancies worldwide due to its poor prognosis. DNA methylation changes, as an early event during tumor progression, constitute attractive markers for cancer diagnostics. In the current study, CD40 DNA methylation was investigated in GC as a novel epigenetic biomarker. MAIN METHODS: We first analyzed DNA methylation microarrays from the Gene Expression Omnibus database on GC samples to evaluate the potential diagnostic value of CD40 methylation. Moreover, using q-MSP, in a set of internal samples including GC primary tumors and adjacent normal specimens, CD40 DNA methylation levels were determined. The Cancer Genome Atlas (TCGA) data on GC was also analyzed for further validation. KEY FINDINGS: Our results illustrated significant CD40 hypermethylation in GC samples compared to normal specimens which was significantly correlated with the clinical stage of malignancy. Besides, the high accuracy of CD40 methylation as a diagnostic biomarker in GC was confirmed using the ROC curve analysis with an AUC value of 0.9089. Also, gene set enrichment analysis showed that CD40 is mainly involved in biological processes regulating immune response activation in GC. Further analysis of other prevalent cancer entities in TCGA showed that CD40 hypermethylation is a common event during tumor progression and could be considered as a potential biomarker for the detection of breast, colorectal, and prostate cancers as well. SIGNIFICANCE: The finding of this study suggests that CD40 methylation as a potential pan biomarker could be a valuable target for liquid biopsy application of human cancers.

Serum levels of subfatin in patients with type 2 diabetes mellitus and its association with vascular adhesion molecules.

Subfatin is a newly discovered adipokine with insulin-sensitizing properties. Studies reported conflicting data with regard to the circulating levels and expression of Subfatin in the context of type 2 diabetes mellitus (T2DM) and obesity. The present study was conducted on 52 patients with T2DM, 36 prediabetes subjects, and 50 controls. The serum levels of Subfatin, adhesion molecules were measured by the ELISA technique. The serum Subfatin was lower in the T2DM and prediabetes groups. The serum levels of adhesion molecules were higher in the T2DM group. In addition, Subfatin demonstrated lower levels in obese patients with T2DM in comparison to lean T2DM patients. Furthermore, Subfatin showed a negative association with vascular adhesion molecules in prediabetes subjects and the T2DM group. A decrease in the serum Subfatin in T2DM patients and prediabetes subjects, and its association with vascular adhesion molecules suggested the possible role of Subfatin in diabetes and endothelial dysfunction.

Inflammasomes and their roles in the pathogenesis of viral hepatitis and their related complications: An updated systematic review.

Inflammasomes are a set of innate receptors which are the responsible molecules for activation of pro-interleukin (IL)-1ß and IL-18 and induction of inflammation. Due to the key roles of the inflammasomes in the induction of inflammation, it has been hypothesized that the molecules may be the main parts of immune responses against viral infections and the tissue damage. Because some cases of viral hepatitis infections, including hepatitis B and C, are diagnosed as chronic and may be associated with various complications such as liver cirrhosis and hepatocellular carcinoma (HCC), several studies focused on the roles played by the inflammation on the pathogenesis of viral hepatitis. Based on the roles played by inflammasomes in induction of inflammation, it has been hypothesized that inflammasomes may be the main parts of the puzzle of the viral hepatitis complications. This article reviews the roles of the inflammasomes in the pathogenesis of hepatitis B and C viral infections and their complications, liver cirrhosis, and HCC.

Antitumor Effects of HPV DNA Vaccine Adjuvanted with Beclin-1 as an Autophagy Inducer in a Mice Model

Background: There is a growing interest in development of an effective adjuvant system for improving DNA vaccines. Recent findings have confirmed an important role for autophagy in both innate and adaptive immunity. The current study was undertaken to determine the efficacy of autophagy induction with Beclin-1, as a novel adjuvant system, in mice immunized with human papilloma virus (HPV) DNA vaccine. Methods: To determine whether autophagy induction with Beclin-1 enhances the efficacy of HPV DNA vaccine, female C57BL/6 mice were challenged with TC-1 tumor cells and were immunized three times at one-week intervals. Two weeks after the final immunization, the mice were sacrificed, and the antitumor effects were assessed by measurement of lymphocyte proliferation, cytotoxicity, cytokine production, and tumor regression. Results: Beclin-1 in combination with HPV-16 DNA vaccine encoding the E7 antigen induced a higher level of lymphocyte proliferation and cytotoxicity than the DNA vaccine alone. The novel combination increased the production of IFN-γ and highly inhibited tumor progression in comparison with DNA vaccine alone. Conclusion: Administration of Beclin-1, as an autophagy inducer, with HPV DNA vaccine produces antitumor effects, providing an effective adjuvant for the induction of a strong antitumor immune response.

PTPN22 1858 C/T polymorphism is associated with alteration of cytokine profiles as a potential pathogenic mechanism in rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is one of the most common prevalent autoimmune diseases. The 1858 C/T (rs2476601) single nucleotide polymorphism (SNP) within the PTPN22 gene has been associated with susceptibility to inflammatory based diseases in several populations. It is implicated that altered cytokine production has a potential pathogenic role in the development of RA. The aim of this work was to analyze the association of 1858 C/T PTPN22 polymorphism in RA patients with cytokine profiles. MATERIALS AND METHODS: This study was performed on 120 RA patients who were referred to the Rheumatology Research Centre, Shariati Hospital (Tehran, Iran), and 120 healthy controls. Genomic DNA was extracted and genotyped for 1858 C/T PTPN22 gene SNP using the PCR-RFLP technique. Serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ as well as Anti-CCP and RF was measured by ELISA method. RESULTS: Results showed that 1858 C/T PTPN22 SNP significantly (P =  0.007, OR = 2.321, 95% CI = 1.063-5.067) associated with RA. The 1858 T allele frequency was also significantly increased in RA patients in comparison to the controls (P =  0.008, OR = 3.583, 95% CI = 1.3-9.878). Our data demonstrated a significant reduction of IL-4 and IL-10 in PTPN22 1858C/T compared to 1858C/C RA patients. In addition, upregulation of IL-6, IFN-γ, and TNF-α was observed in PTPN22 1858C/T vs. 1858C/C RA patients. DISCUSSION: Our findings implicate altered cytokine profiles as a possible pathogenic mechanism by which the 1858 T allele may contribute to the progress of RA.

Suppression of STAT3 by S31-201 to reduce the production of immunoinhibitory cytokines in a HIF1-α-dependent manner: a study on the MCF-7 cell line.

Signal transducer and activator of transcription 3 (STAT3) interacts with many gene promoters and transcription factors such as hypoxia-induced factor 1α (HIF-1α). Recent evidences proposed that STAT3 and HIF-1α together are responsible for angiogenesis and immune response suppression. The main aim of this study was to inhibit STAT3 and HIF-1α and assess their effects on the expression of immunosuppressive cytokines. S31-201 and PX-478 were used to inhibit STAT3 and HIF-1α, respectively. In both hypoxic and normoxic conditions, intracellular levels of HIF-1α were evaluated by western blotting and flow cytometry. Supernatant levels were also measured for VEGF, IL-10, and TGF-ß concentration. S31-201 suppressed proliferation of MCF-7 cells and led to reduced HIF-1α expression in both hypoxic and normoxic conditions. It also decreased production of the immunosuppressive cytokines. STAT3 inhibition suppressed tumor cell growth and cytokine production in a HIF-1α-dependent manner, and can be used as a promising target in cancer therapies.

Lower serum levels of Meteorin-like/Subfatin in patients with coronary artery disease and type 2 diabetes mellitus are negatively associated with insulin resistance and inflammatory cytokines.

Meteorin-like (Metrnl) is a newly discovered adipokine with favorable effect on insulin sensitivity. Previous studies have reported lower levels of Metrnl in obese patients. However, there is conflicting data regarding its circulating levels in type 2 diabetes mellitus (T2DM) and there is no data in patients with coronary artery disease (CAD). The aim of the present study was to evaluate the Metrnl serum level in patients with T2DM and CAD, and also to evaluate the serum levels of Metrnl with serum levels of adiponectin, IL-6 and TNF-α in patients. This study was conducted on 66 patients with CAD, 63 T2DM patients and 41 controls. The serum levels of Metrnl, adiponectin, IL-6 and TNF-α were measured using ELISA techniques. The serum levels of Metrnl were found to be lower in CAD (75.18 ± 28.48 pg/mL) and T2DM patients (73.89 ± 33.60 pg/mL) compared to the control group (95.33 ± 32.56 pg/mL) (p < 0.005 and p<0.003, respectively). Additionally, adiponectin decreased in CAD and T2DM patients as compared to the control group, while IL-6 and TNF-α were higher in CAD and T2DM patients. Metrnl showed independent association with the risk of CAD and T2DM presence. Furthermore, Metrnl illustrated a negative correlation with IL-6 and TNF-α in both CAD patients and also with BMI, insulin resistance, IL-6 and TNF-α in T2DM patients. Metrnl showed an association with CAD and T2DM presence and with components of their pathogenesis such as inflammation and insulin resistance. These results suggested a possible interaction between Metrnl and the pathogenesis of CAD and T2DM, however more studies are needed to prove this concept.