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Aging as an inevitable phenomenon is associated with pervasive changes in physiological functions. There is a relationship between aging and the increase of several chronic diseases. Most age-related disorders are accompanied by an underlying chronic inflammatory state, as demonstrated by local infiltration of inflammatory cells and greater levels of proinflammatory cytokines in the bloodstream. Within inflammaging, many epigenetic events, especially DNA methylation, change. During the aging process, due to aberrations of DNA methylation, biological processes are disrupted, leading to the emergence or progression of a variety of human diseases, including cancer, neurodegenerative disorders, cardiovascular disease and diabetes. The focus of this review is on DNA methylation, which is involved in inflammaging-related activities, and how its dysregulation leads to human disorders.Aging as a natural process is associated with variation in physiological functions. One of the hallmarks of aging is epigenetic changes, which are directly involved in the aging process and aging-related diseases. DNA methylation is one of the epigenetic changes during aging. Consequently, changes in DNA methylation affect various cellular processes and cause age-related diseases. This review discusses the role of DNA methylation in aging processes and age-related diseases.

Efflux pumps play an important role in the emergence of antibiotic-resistant Pseudomonas aeruginosa strains. The present study aimed to assess the expression of the MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM efflux pumps in carbapenem-resistant and multidrug-resistant (MDR) P. aeruginosa strains isolated from clinical specimens between June 2019 and January 2022 in Ardabil city. The presence of efflux pump-encoding genes, i.e. mexA, mexC, mexE, and mexY, was assessed using the polymerase chain reaction (PCR) technique in 48 carbapenem-resistant and MDR P. aeruginosa strains. Real-time reverse transcription PCR was employed to evaluate the expression levels of mexA, mexC, mexE, and mexY genes. All 48 carbapenem-resistant and MDR P. aeruginosa strains harbored efflux pump-encoding genes including mexA, mexC, mexE, and mexY according to the PCR results. Overexpression of the MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM efflux pumps was detected in 75% (n = 36), 83.3% (n = 40), 10.4% (n = 5) and 41.6% (n = 20) of the clinical isolates of P. aeruginosa, respectively. This study revealed that the presence and overexpression of efflux pumps are associated with the emergence of carbapenem-resistant and MDR P. aeruginosa strains. Therefore, research on efflux pump inhibitors of P. aeruginosa will be a worthwhile endeavor to increase the clinical efficiency of available antibiotics and prevent ensuing treatment failure.

A global pandemic has erupted as a result of the new brand coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This pandemic has been consociated with widespread mortality worldwide. The antiviral immune response is an imperative factor in confronting the recent coronavirus disease 2019 (COVID-19) infections. Meantime, cytokines recognize as crucial components in guiding the appropriate immune pathways in the restraining and eradication of the virus. Moreover, SARS-CoV-2 can induce uncontrolled inflammatory responses characterized by hyper-inflammatory cytokine production, which causes cytokine storm and acute respiratory distress syndrome (ARDS). As excessive inflammatory responses are contributed to the severe stage of the COVID-19 disease, therefore, the pro-inflammatory cytokines are regarded as the Achilles heel during COVID-19 infection. Among these cytokines, interleukin (IL-) 1 family cytokines (IL-1, IL-18, IL-33, IL-36, IL-37, and IL-38) appear to have a strong inflammatory role in severe COVID-19. Hence, understanding the underlying inflammatory mechanism of these cytokines during infection is critical for reducing the symptoms and severity of the disease. Here, the possible mechanisms and pathways involved in inflammatory immune responses are discussed.

COVID-19 is a systematic disease that frequently implies neurological and non-neurological manifestations, predominantly by inducing hypoxia. Brain-derived neurotrophic factor (BDNF) is a key factor in regulating functions of nervous and respiratory systems and has been strongly related to hypoxia. Therefore, this study planned to investigate BDNF association with the COVID-19 manifestations especially neurological impairments and the infection-induced hypoxia. We enrolled sixty-four COVID-19 patients and twenty-four healthy individuals in this study. Patients were divided into two groups, with and without neurological manifestations, and their serum BDNF levels were measured by enzyme-linked immunosorbent assay (ELISA). COVID-19 patients had significantly lower BDNF levels than healthy individuals (p = 0.023). BDNF levels were significantly lower in patients with neurological manifestations compared to healthy individuals (p = 0.010). However, we did not observe a statistically significant difference in BDNF levels between patients with and without neurological manifestations (p = 0.175). BDNF's levels were significantly lower in patients with CNS manifestations (p = 0.039) and higher in patients with fever (p = 0.03) and dyspnea (p = 0.006). Secondly, BDNF levels have a significant negative association with oxygen therapy requirement (p = 0.015). These results strongly suggest the critical association between dysregulated BDNF and hypoxia in promoting COVID-19 manifestations, particularly neurological impairments.

Background Helicobacter pylori (H.pylori) is one of the leading causes of peptic ulcers, and its treatment is a worldwide challenge. Matrix metalloproteinases and their inhibitors influence the development and healing of peptic ulcers. This study aimed to evaluate the ratios of matrix metalloproteinase-2 (MMP-2) to tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients with a peptic ulcer that are sensitive or resistant to H. pylori treatment and compare them with healthy individuals. Methods In this study, 95 patients were included and divided into two groups sensitive (41 patients) and resistant to treatment (54 patients). The results were compared with a control group of twenty participants with normal endoscopy. After obtaining written informed consent, five ml of venous blood was taken to determine their serum MMP-2 and TIMP-1 levels using an enzyme-linked immunosorbent assay. Results In patients with H. pylori-induced peptic ulcers, the MMP-2/TIMP-1 ratio was significantly higher than those of the healthy controls (P

Background Severe coronavirus disease-2019 (COVID-19) is associated with dysregulated immune response and extreme inflammatory injury. Considering the role of insulin growth factor-1 (IGF-1) in immune-mediated and inflammatory reactions, this study was conducted to investigate the IGF-1 contribution to the pathogenesis of severe form of COVID-19. Material and methods Sixty-two patients with severe COVID-19 and 52 healthy subjects were enrolled in this study. The serum levels of IGF-1 were measured using a solid-phase enzyme-linked chemiluminescent immunoassay on an Immulite 2000 system (Siemens Healthcare Diagnostics. Result The serum levels of IGF-1 had no significant difference in COVID-19 patients compared to the healthy subjects (p = 0.359). There was a positive correlation between IGF-1 and age in the severe COVID-19 patients, while a negative correlation was observed for the serum levels of IGF-1 and age in the control group (r = 0.364, p = 0.036, r = − 0.536, p = 0.001, respectively). Moreover, IGF-1 was remarkably associated with hypertension, neurogenic disease, shock, and nausea in patients with the severe form of COVID-19 (p = 0.031, p = 0.044, p = 0.01, p = 0.03, respectively). Conclusion Our results pointed to the complex role of IGF-1 in the severe form of COVID-19, and its association with clinical parameters, and some risk factors in the severe form of COVID-19.

Autoantibodies (AABs) play a critical role in the pathogenesis of autoimmune diseases (AIDs) and serve as a diagnostic and prognostic tool in assessing these complex disorders. Viral infections have long been recognized as a principal environmental factor affecting the production of AABs and the development of autoimmunity. COVID-19 has primarily been considered a hyperinflammatory syndrome triggered by a cytokine storm. In the following, the role of maladaptive B cell response and AABs became more apparent in COVID-19 pathogenesis. The current review will primarily focus on the role of extrafollicular B cell response, Toll-like receptor-7 (TLR-7) activation, and neutrophil extracellular traps (NETs) formation in the development of AABs following SARS-CoV-2 infection. In the following, this review will clarify how these AABs dysregulate immune response to SARS-CoV-2 by disrupting cytokine function and triggering neutrophil hyper-reactivity. Finally, the pathologic effects of these AABs will be further described in COVID-19 associate clinical manifestations, including venous and arterial thrombosis, a multisystem inflammatory syndrome in children (MIS-C), acute respiratory distress syndrome (ARDS), and recently described post-acute sequelae of COVID-19 (PASC) or long-COVID.

There is limited information regarding the protective factors of SARS-CoV-2 infection. This research is focused on analyzing the role of vitamin D and albumin in the severity, progression, or possible prevention of COVID-19 infection. In this case–control study, 191 patients and 203 healthy individuals were enrolled. Blood samples were taken to test the albumin and vitamin D levels of both groups. Our results show a direct association of vitamin D deficiency with the infection of COVID-19 and severity. According to our findings, 84.4% of patients with COVID-19 in this study had vitamin D deficiency. Moreover, the average level of albumin was significantly decreased in those infected patients who had respiratory symptoms. In the present study, a considerable negative correlation was established between the levels of vitamin D and the severity of COVID-19 infection. This reflects on the immunomodulatory and inhibitory nature of vitamin D to the viral replication. Supplementary Information The online version contains supplementary material available at 10.1007/s00203-021-02482-5.

A significant body of literature emphasizes the role of insecticide, particularly organophosphates (OPs), as the major environmental factor in the etiology of neurodegenerative diseases. This review aims to study the relationship between OP insecticide exposure, cognitive impairment, and neurodegenerative disease development. Human populations, especially in developing countries, are frequently exposed to OPs due to their extensive applications. The involvement of various signaling pathways in OP neurotoxicity are reported, but the OP-induced cognitive impairment and link between OP exposure and the pathophysiology of neurodegenerative diseases are not clearly understood. In the present review, we have therefore aimed to come to new conclusions which may help to find protective and preventive strategies against OP neurotoxicity and may establish a possible link between organophosphate exposure, cognitive impairment, and OP-induced neurotoxicity. Moreover, we discuss the findings obtained from animal and human research providing some support for OP-induced cognitive impairment and neurodegenerative disorders.

Resistance to conventional chemotherapy remains a major cause of cancer relapse and cancer-related deaths. Therefore, there is an urgent need to overcome resistance barriers. To improve cancer treatment approaches, it is critical to elucidate the basic mechanisms underlying drug resistance. Increasingly, the mechanisms involving micro-RNAs (miRNAs) are studied because miRNAs are also considered practical therapeutic options due to high degrees of specificity, efficacy, and accuracy, as well as their ability to target multiple genes at the same time. Years of research have firmly established miR-34 as a key tumor suppressor miRNA whose target genes are involved in drug resistance mechanisms. Indeed, numerous articles show that low levels of circulating miR-34 or tumor-specific miR-34 expression are associated with poor response to chemotherapy. In addition, elevation of inherently low miR-34 levels in resistant cancer cells effectively restores sensitivity to chemotherapeutic agents. Here, we review this literature, also highlighting some contradictory observations. In addition, we discuss the potential utility of miR-34 expression as a predictive biomarker for chemotherapeutic drug response. Although caution needs to be exercised, miR-34 is emerging as a biomarker that could improve cancer precision medicine.

Background: The diagnosis of venous thromboembolism (VTE) during pregnancy is a challenging task. Due to its naturally high level during pregnancy, D-Dimer concentration is not reliable diagnostic. P-selectin is another diagnostic biomarker that can aid the diagnosis of VTE. In the present study, an attempt was made to determine the relationship between P-selectin and acute VTE in pregnant women and compare it’s predictive value with Wells criteria.Materials and methods: In this case-control study, 29 pregnant women with pulmonary thromboembolism (PTE), 33 pregnant women with deep vein thrombosis (DVT), and 32 matched healthy pregnant women were investigated. After obtaining informed written consent, 3 cc of venous blood sample was taken from each of the participants. The samples were then assessed for P-selectin and D-Dimer concentrations via the use of ELISA tests. Finally, statistical analyses were performed. Findings: Significant differences were observed between all of the groups under investigation in terms of both mean P-selectin and mean D-Dimer concentrations (PConclusion: The increase in P-selectin concentration during pregnancy is associated with high incidence of VTE. Compared with D-Dimer, P-selectin is a predictor of thrombosis, especially in patients with high clinical probability based on Wells score.

Introduction: Since December 2019, coronavirus disease 2019 (COVID-19) has rapidly expanded to cause a worldwide pandemic. Objectives: We aimed to report the clinical characteristics of infected patients at the first wave in northwest of Iran. Patients and Methods: In this study, the epidemiological, demographic, clinical, and laboratory data of 1152 confirmed patients with COVID-19 who were admitted to two main hospitals at the first outbreak in northwest of Iran were collected and analyzed. Results: The most common clinical manifestations at onset were cough (65.8%), dyspnea (40.2%), myalgia (37.8%), and fever (63.4%), loss of appetite (47%), chest pain (38.6%), and headache (49.4%). While the less common were agitation (17.3%), vomiting (22.2%), diarrhea (16.7%), and nausea (24.3%). Laboratory data indicated significant correlation between lymphocyte counts with the severity of the disease based on O2 saturation. Conclusion: Overall, assessment the clinical data of COVID-19 patients play a crucial role in understanding the outbreak of novel viral pneumonia, which helps to identify high risk individuals with COVID-19.

Many studies have been performed about regenerative and immunomodulatory properties of mesenchymal stem cells (MSCs) and their application in different treatment approaches. The present study aimed to investigate the immunomodulatory effect of umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) on the gene expression profile of cytokines in stimulated T-lymphocytes. For this purpose, MSCs were isolated from umbilical cord blood samples and cultured in Dulbecco's Modified Eagle Medium supplemented with 10% fetal bovine serum. The nature of MSCs was identified by flow cytometry analysis and differentiation to the adipocyte and osteocyte lineage. Moreover, to investigate the immunomodulatory effects of MSCs on T cells, a co-culture system was designed and expression levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IL-13, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β) genes were measured; using the real-time polymerase chain reaction (RT-PCR) technique. Our results demonstrated the ability of MSCs to differentiate into adipocyte and osteocyte lineages. Further investigation also displayed that although UCB-MSCs could significantly reduce the expression of pro-inflammatory cytokines like IL-2, IL-6, IFN-γ, and TNF-α in activated T-lymphocytes, they noticeably potentiated the expression levels of IL-4, IL-10, IL-13, and TGF-β in the co-culture setting. In conclusion, UCB-MSCs have immunomodulatory effects on activated T-lymphocytes in favor of anti-inflammatory responses.

MicroRNAs play crucial roles in controlling cellular biological processes. miR-143 expression is usually downregulated in different cancers. In this study, we focused on exploring the role of miR143 in NSCLC development.Bioinformatics analyses were used to detect the expression level of miR-143 in lung tumors. The cells were transfected by pCMV-miR-143 vectors. The efficacy of transfection was verified by Flow cytometry. The influence of miR-143 replacement on NSCLC cells migration, proliferation, and apoptosis was detected using wound-healing assay, MTT assay, and DAPI staining, respectively.MTT assay revealed that overexpression of miR143 inhibited cell growth and proliferation. Scratch assay results demonstrated that restoration of miR143 suppressed cell migration. The qRT-PCR assay was further used to detect the assumed relationship between miR143 and apoptotic and metastatic-related genes.The findings showed that miR-143 could reduce cell proliferation, invasion, and migration by reducing CXCR4, Vimentin, MMP-1, Snail-1, C-myc expression level, and increasing E-cadherin expression levels in lung cancer cells and might be a potential target in NSCLC's targeted therapy.

Background: EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit), as one of the polycyclic group proteins (PcGs), is an epigenetic regulator that plays a crucial role in the pathophysiology of hematologic malignancies through regulating cell differentiation. Also, it is well known that aberrant expression of specific transcription factors can be involved in the pathogenesis of various cancers. Objective: Herein, we aimed to suppress EZH2 expression in MOLT-4 cells, T-ALL (T cell acute lymphoblastic leukemia) cell line, and evaluate the role of EZH2 on the expression of transcription factors that regulate T cell maturation, differentiation, and apoptosis. Methods: EZH2-siRNA was transfected into MOLT-4 cells, and the expression levels of EZH2, NOTCH1, TCF1, IKZF1, and NFATC1 were measured using real-time PCR. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay was performed to study the effect of EZH2 knockdown on MOLT-4 cell viability. The apoptosis rate of EZH2-siRNA transfected cells was assessed by flow cytometry. The interaction of mentioned genes was investigated using STRING and GO (gene ontology). Results: Our results have shown that EZH2-siRNA transfection can substantially decrease EZH2 expression in MOLT-4 cells. Besides, EZH2 suppression can upregulate NOTCH1, TCF1, IKZF1, and NFATC1 expression levels. EZH2 knockdown does not affect the viability and apoptosis of MOLT-4 cells. The most remarkable protein-protein interaction of EZH2 has been with NOTCH1. Besides, GO analysis has demonstrated that EZH2, NOTCH1, TCF1, IKZF1, and NFATC1 were located within nucleoplasm and can regulate RNA polymerase II-mediated transcription. Conclusion: Our results have shown that MOLT-4 cells harbor increased expression of EZH2 in comparison with normal human T cells. EZH2 knockdown can upregulate the expression of the transcription factors involved in T cell differentiation. Thus, EZH2 can halt the differentiation of immature lymphoblastic T cells.

Objective: The present study concerns the cytotoxic activity of A. nemorosa different extracts on breast cancer cells (MCF-7) and normal cell lines (HFFF). Methods: Different extracts of aerial parts of A. nemorosa were prepared using Soxhlet apparatus. The cytotoxicity of samples was assessed by MTT assay on breast cancer cells (MCF-7) and noncancerous cells (HFFF) with different concentrations of extracts in 24 and 48 hours. The most potent extract was fractioned and cytotoxic activity of fractions was considered, As well. A flow cytometry (annexin V/PI) assay has been used for detecting the mechanism of cell death in sample treated cell lines. Moreover, for clarifying volatile components of n-Hexane extract and its 80% and 100% VLC fractions were subjected to GC-MS apparatus. Results: Results indicated that n-Hexane extract and its 80% and 100% VLC fractions exhibited a significant (p

Background Ankylosing spondylitis (AS) is a prototype of chronic inflammatory arthritis termed seronegative spondyloarthropathies that typically affects the joints. Among the non-Human leukocyte antigen (HLA) loci, the strongest association has been observed with Endoplasmic reticulum aminopeptidase 1 (ERAP1) gene single nucleotide polymorphisms (SNPs). Moreover, the effect of ERAP1 gene SNPs on the pro-inflammatory and anti-inflammatory cytokines in AS disease has still been poorly elucidated. In this study, we aimed to determine the association of ERAP1 gene SNPs (rs30187 and rs2287987) with AS risk as well as their effect on the mRNA expression of pro-inflammatory and anti-inflammatory cytokines, with emphasis on the immunoregulation of the IL-17/IL-23 pathway, in an Iranian population. Methods We performed Single specific primer (SSP)-PCR for genotyping of 160 AS patients and 160 healthy controls. After isolation of peripheral blood mononuclear cells (PBMCs), total RNA of PBMCs was isolated, complementary DNA (cDNA) was synthesized, and quantitative analyses of mRNA expression of cytokines were performed by Real-time PCR for 40 HLA-B27 positive AS patients and 40 healthy individuals as controls. Results It was seen that T allele of rs30187 (OR = 1.54, 95% CI = 1.07–2.22, P = 0.017) and C allele of rs2287987 (OR 1.50, 95% CI 1.05–2.14, P = 0.024) were associated with the risk of AS. Both of these alleles were associated more strongly in the HLA-B27 positive AS patients. There was a significant overexpression of mRNAs of pro-inflammatory (IL-17A, IL-17F, IL-23, TNF-α and IFN-γ), while downregulation of anti-inflammatory cytokines (IL-10 and TGF-β) in PBMCs from 40 HLA-B27 positive AS patients in comparison to controls. AS patients with rs30187 SNP TT genotype expressed mRNA of IL-17A, IL-17F, and IL-23 significantly higher than patents with CT and CC genotypes for this SNP. Conclusions This study represented the association of ERAP1 gene rs30187 and rs2287987 polymorphism with the risk of AS. Additionally, it appears that rs30187 polymorphism may be involved in the immunomodulation of the IL-17/IL-23 pathway in the AS disease.

Cancer stem cells (CSCs) are a subgroup of tumor cells that are characterized by their tumor initiating capacity, low proliferation rate, self-renewal capacity, pluripotency and chemoresistance. The immune system, including innate and adaptive immune cells, plays pro-tumorigenic and anti-tumorigenic roles in cancer biology. Immunosurveillance often initially successfully eradicates tumor cells. However, following a phenomenon referred to as immunoediting, cancer cells may ultimately evade immune destruction, thus enabling tumor progression. Here, we review how CSCs both escape immune destruction and foster establishment of an immunosuppressive tumor microenvironment through intricate interactions with and recruitment of a broad range of immune cells, including natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), tumor-associated macrophages (TAMs), cytotoxic T-lymphocytes (CTLs) and T helper (Th) cells. Further elucidation of CSC-immune cell interactions and the underlying signaling mechanisms will open up novel opportunities to improve cancer immunotherapy.

Systemic lupus erythematosus (SLE) is a recognized chronic condition associated with immune system disorders that affect women nine times more commonly than men. SLE is characterized by over-secretion and release of autoantibodies in response to different cellular compartments and self-tolerance breaks to its own antigens. The detailed immunological dysregulation as an associated event that elicits the onset of clinical manifestations of SLE has not been clarified yet. Though, research using several animal models in the last two decades has indicated the role of the immune system in the pathogenesis of this disease. Myeloid-derived suppressor cells (MDSCs) as heterogeneous myeloid cells, are responsible for severe pathological conditions, including infection, autoimmunity, and cancer, by exerting considerable immunosuppressive effects on T-cells responses. It has been reported that these cells are involved in the regulation process of the immune response in several autoimmune diseases, particularly SLE. The function of MDSC is deleterious in infection and cancer diseases, though their role is more complicated in autoimmune diseases. In this review, we summarized the role and function of MDSCs in the pathogenesis and progression of SLE and its possible therapeutic approach.

Natural killer (NK) cells seem to be the most common innate lymphocyte subtypes, and they're known for their ability to guide anti-tumor and anti-viral responses, making them potentially therapeutic. Since NK cells lack polymorphic clonotypic receptors, they must rely on inhibitory receptors to develop, mature, and distinguish between "self" and "non-self." In the clinic, genetically engineered immune cells expressing a chimeric antigen receptor (CAR) that consists of an extracellular antigen recognizing domain connected to an intracellular signaling domain have gained interest. The U.S. food and drug administration (FDA) approved two CAR-T cells, anti-CD19 CARs, for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL). Nevertheless, CAR-T cell therapy is linked to a series of negative side effects, including fatal cytokine release syndrome (CRS) and tumor lysis syndrome (TLS), as well as a lack of regulatory control. CAR-transduced NK cells (CAR-NK) are thought to have many benefits, including clinical safety, the mechanisms by which they identify cancerous cells, and their abundance in clinical specimens, according to a growing number of studies. In pre-clinical and clinical trials, human primary NK cells and the NK-92 cell line were effectively transduced to express CARs against hematological cancers and solid tumors. Here, it is tried to summarize the development of CAR-NK cells, challenges and coping strategies, as well as managing the challenges and obstacles related to its protection, which promises to eliminate the shortcomings of conventional CARs.

Cancer cells escape immune destruction. From this perspective, myeloid-derived suppressor cells (MDSCs), which are immunosuppressive in various cancers including breast cancer (BC), are significant. However, the precise mechanisms are unknown. We isolated HLA-DR-CD33+ MDSCs and CD3+ T cells from BC patients’ peripheral blood and healthy donors through MACS and immunophenotyped by flow cytometry. Transfection of short-interfering RNAs and treatment with a TLR7/8 agonist altered pathway activities in vitro. Gene expression was analyzed using qRT-PCR, western blotting, and immunohistochemistry. Our findings showed an association between the progression of BC and increased levels of circulating HLA-DR-CD33+ MDSCs. These cells strongly suppress both autologous and analogous CD3+ T cell proliferation and enter the tumor microenvironment. We also identified increased STAT3 signaling and increased IDO and IL-10 expression in BC-derived MDSCs as immunosuppression mechanisms. Further, STAT3 inhibition and TLR7/8 pathway stimulation reduce the immunosuppressive activity of patient-derived MDSCs on T cells by inducing MDSC repolarization and differentiation into mature myeloid cells. This also alters the expression of critical cytokines and transcription factors in CD3+ T cells and, importantly, reduces breast cancer cells’ proliferation. Finally, while chemotherapy is able to significantly reduce circulating MDSCs’ level in patients with breast cancer, these MDSCs remained highly T cell-suppressive. We identified a novel molecular mechanism of MDSC-mediated immunosuppression. STAT3 inhibition and TLR7/8 pathway stimulation in MDSCs repolarize and suppress MDSCs from breast cancer patients. This offers new opportunities for BC immunotherapy. Cancer cells escape immune destruction. From this perspective, myeloid-derived suppressor cells (MDSCs), which are immunosuppressive in various cancers including breast cancer (BC), are significant. However, the precise mechanisms are unknown. We isolated HLA-DR-CD33+ MDSCs and CD3+ T cells from BC patients’ peripheral blood and healthy donors through MACS and immunophenotyped by flow cytometry. Transfection of short-interfering RNAs and treatment with a TLR7/8 agonist altered pathway activities in vitro. Gene expression was analyzed using qRT-PCR, western blotting, and immunohistochemistry. Our findings showed an association between the progression of BC and increased levels of circulating HLA-DR-CD33+ MDSCs. These cells strongly suppress both autologous and analogous CD3+ T cell proliferation and enter the tumor microenvironment. We also identified increased STAT3 signaling and increased IDO and IL-10 expression in BC-derived MDSCs as immunosuppression mechanisms. Further, STAT3 inhibition and TLR7/8 pathway stimulation reduce the immunosuppressive activity of patient-derived MDSCs on T cells by inducing MDSC repolarization and differentiation into mature myeloid cells. This also alters the expression of critical cytokines and transcription factors in CD3+ T cells and, importantly, reduces breast cancer cells’ proliferation. Finally, while chemotherapy is able to significantly reduce circulating MDSCs’ level in patients with breast cancer, these MDSCs remained highly T cell-suppressive. We identified a novel molecular mechanism of MDSC-mediated immunosuppression. STAT3 inhibition and TLR7/8 pathway stimulation in MDSCs repolarize and suppress MDSCs from breast cancer patients. This offers new opportunities for BC immunotherapy.

CD44, as a superficial cellular glycoprotein, is an essential factor in cell–cell and cell–matrix interaction. The CD44 expression level has been substantially up-regulated in breast cancer, and this upregulation facilitates tumor proliferation and angiogenesis. This study aims to evaluate the combination therapy of Jet Pei/CD44-specific-siRNA/doxorubicin in breast cancer MDA-MB468 cell line. The MTT assay, wound healing test, colony formation assay, DAPI staining, and flow cytometry were performed to investigate the tumoral cell viability, migration, clonogenesis, and apoptosis progression. The quantitative real-time PCR (qRT-PCR) was performed to demonstrate the CD44 expression level. Finally, the effect of CD44 silencing on the expression of VEGF, CXCR4, MMP9, and MiR-142-3p was measured. The combination of CD44-specific-siRNA with doxorubicin decreased tumoral metastasis, proliferation, invasion, and migration, and increased apoptosis in MDA-MB468 cells. In conclusions, CD44 can serve as a therapeutic target in breast cancer. Moreover, the combination therapy of CD44-specific-siRNA with doxorubicin can be a promising treatment for patients with breast cancer.

Cell death resistance is a key feature of tumor cells. One of the main anti-cancer therapies is increasing the susceptibility of cells to death. Cancer cells have developed a capability of tumor immune escape. Hence, restoring the immunogenicity of cancer cells can be suggested as an effective approach against cancer. Accumulating evidence proposes that several anticancer agents provoke the release of danger-associated molecular patterns (DAMPs) that are determinants of immunogenicity and stimulate immunogenic cell death (ICD). It has been suggested that ICD inducers are two different types according to their various activities. Here, we review the well-characterized DAMPs and focus on the different types of ICD inducers and recent combination therapies that can augment the immunogenicity of cancer cells.

Evading immune destruction is a hallmark of cancer. Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid immune cells, are thought to foster the establishment of an immunosuppressive tumor microenvironment, but it remains unclear how. This study aims to determine the levels of circulating MDSCs and their subpopulations and test their immunosuppressive functions in patients with breast cancer (BC). We analyzed the fractions of MDSCs in freshly isolated peripheral blood mononuclear cells of patients with BC and healthy donors using flow cytometry. Circulating MDSCs were further phenotyped using fluorescently labeled antihuman monoclonal antibodies. Coculture experiments revealed the effects of MDSCs on CD3 + T cell response. Moreover, we correlated circulating MDSC levels with clinicopathological features of patients with BC. We show that the fraction of HLA-DR – CD33 + MDSCs in peripheral blood is about 10-fold higher in patients with BC than in healthy control individuals. The levels of all MDSC subpopulations, including monocytic and granulocytic MDSCs, are significantly elevated. Coculture experiments of purified HLA-DR – CD33 + MDSCs and CD3 + T cells demonstrate that T cell proliferation is more effectively inhibited by BC patient-derived MDSCs than by healthy control MDSCs. Moreover, increased circulating MDSC levels robustly associate with advanced BC stage and positive lymph node status. By being more abundant and more effective T cell suppressors, BC patient-derived circulating MDSCs exert a dual immunosuppressive effect. Our findings pave the way to develop novel diagnostic and immunotherapeutic strategies, aimed at detecting and inhibiting MDSCs in patients with BC. Refereed/Peer-reviewed

Infection with COVID-19 has resulted in considerable mortality all around the world. This study aimed to investigate the effect of convalescent plasma on the treatment of hospitalized patients with COVID-19 in Imam Khomeini Hospital at Ardabil, Iran.In this quasi-experimental clinical trial, patients over 18 years of age with polymerase chain reaction-positive COVID-19 were admitted based on the clinical criteria of respiratory distress with hypoxia (OAnalyses revealed that length of stay in hospital was significantly lower in the CPT group as compared to the control group (It seems that CPT can be used as an alternative treatment at the early stages of COVID-19 to prevent the progress of the disease, reduce the need for intubation and consequently the length of stay in hospital, and finally, decrease mortality.

Myeloid-derived suppressor cells (MDSCs) are traditionally considered among the major components of the immunosuppressive tumor microenvironment (TME). However, there is currently increasing evidence indicating that MDSCs in addition to suppression of immune surveillance is also involved in an array of non-immunological functions like augmenting metastatic potential of tumor cells. Indeed, MDSCs can promote metastasis in animal models and cancer patients through promoting premetastatic niche formation, tumor angiogenesis and invasion. Moreover, MDSC frequency and function have been associated with progressive disease and correlated with clinical outcome. This review will summarize and discusses the data demonstrating the role for MDSCs in tumor metastasis.

Pancreatic cancer is related to a very weak diagnosis; the close parallel between disease incidence and mortality rates from pancreatic cancer reflects the fatal nature of this disease. Although early detection procedures are growing, they are not applicable yet for pancreatic cancer. The majority of cancer patients suffer from advanced disease, in which surgery has no potential effect. Based on the growing evidence, it is predicated that cancer immunotherapy alone or in combination will probably be an essential section of different cancer treatment methods. There are different kinds of immune processes, including various antitumour and tumour-promoting leukocytes. Moreover, tumour cells utilise numerous approaches to overwhelm the immune response. Use of antibody in the therapeutic protocols is proving significant success and is probably a key element of cancer treatment. This method is directed against numerous negative immunologic regulators and immune checkpoints. In the present review, the clinical outlines of immune checkpoint inhibition are discussed in pancreatic cancer.

MicroRNAs (miRNAs) have the ability to regulate gene expression programs in cells. Hence, altered expression of miRNAs significantly contributes to breast cancer development and progression. Here, we demonstrate that the miRNA miR-142-3p directly targets the 3′ untranslated region of HMGA2, which encodes an onco-embryonic protein that is overexpressed in most cancers, including breast cancer. Down regulation of miR-142-3p predicting poor patient survival in grade 3 breast cancer (P-value = 0.045). MiR-142-3p downregulates HMGA2 mRNA and protein levels. Higher miR-142-3p and lower HMGA2 expressed are found in breast cancer versus normal breast tissue (P-value

Introduction: Coronavirus disease 2019 (COVID-19) is responsible for severe acute respiratory syndrome. The present study planned to evaluate the accuracy of laboratory parameters and clinical findings in predication of the infected cases through RT-PCR. Methods: All related laboratory tests of 180 cases (62.8% male and 37.2% female) with an average of 62 years old (45.3-69) were performed by several laboratory techniques. The obtained results as well as other clinical and biography findings of the patients during the treatment and recovery were compared and analyzed to find out the possible relationship among the considered parameters. Results: The considered hematological and biochemistry factors were completely different in all cases regardless to their health and lifestyle condition, including being at ICU, being addict or not, whether having previous diseases or not and others. Conclusion: COVID-19 has brought a huge burden to the health system and infected patients, especially those who have a background of chronic diseases or addicted to some drugs.

Multiple sclerosis (MS) is a heterogeneous neurological disorder with multifactorial etiologies characterized by demyelination, axonal degeneration, and oligodendroglial death. It is believed that both genetics and environmental risk factors such as infection are involved in disease etiology. Accumulating evidence indicates that alteration in purinergic system signaling is involved in immunity and inflammation. Adenosine, a key purine nucleoside, has been shown to be produced during metabolic stress, including ischemia, inflammatory condition, and tissue injury. Extracellular adenosine directly affects various physiological and pathological processes of MS by stimulating G protein-coupled adenosine receptors A1, A2A, A2B, and A3 on the surface of immune cells. It has been suggested that promotion of adenosinergic system may be an important factor in MS pathophysiology and considered as promising therapeutic target for this disease. In this review, we will discuss about the immunopathologic effects of adenosine on MS and its animal model, experimental autoimmune encephalomyelitis.

Cancer is the second cause of mortality in the world after cardiovascular disease. Various studies attribute the emergence of therapeutic resistance in tumors to the presence of cancer stem cells or cancer-initiating cells (CSC/CIC). These relatively rare cells because of their typical stemness features, are responsible for tumor cell progression and recurrence. Moreover, CSCs have immunomodulatory capabilities and through orchestrating, some immunological profiles can stay safe from host anticancer immunity, and provide immunotherapy resistance in cancer patients. Many studies have shown that CSCs by producing immune system inhibitory factors and interacting with immune checkpoint molecules like CD47, PDL-1, CTLA4, Tim3, and LAG3, are able to communicate with tumor microenvironment (TME) components and protect cancer cells from immune clearance. In this review, we summarize the CSCs immunological mechanisms and comprehensively discuss interactions between these cells and factors that are present in the TME to repress immune system responses and enhance tumor survival. Therefore, it seems that further studies on this topic will open new doors to improve the therapeutic approaches of malignant cancers.

Background: In many cases of breast cancer, the aberrant methylation of TP53 gene leads to uncontrolled cell proliferation and apoptosis inhibition. Moreover, expression of oncogenes which are under the control of P53 protein could be altered. Survivin as a conspicuous example of this category plays important roles in tumorigenesis, drug resistance and apoptosis inhibition. The present study was done to reveal the effects of Scrophularia atropatana extract on epigenetic situation of TP53 gene promoter and the expression levels of anti-apoptotic gene, survivin and its potential for production of cancer epi-drugs. Methods: Cytotoxic effect of dichloromethane extracts of Scrophularia plant on MCF-7 cell line was assessed in our previous study. Cell death ELISA (enzyme-linked immunosorbent assay) and TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) tests were used to investigate the occurrence of apoptosis in the treated cells. Methylation Specific PCR (MSP) was employed to assess the changes in methylation status of the TP53 gene promoter. Furthermore, quantitative real time PCR was utilized to evaluate the resulting changes in TP53 and survivin genes expression. Results: Cell death ELISA and TUNEL assays confirmed the occurrence of apoptosis. MSP test revealed a significant change in the methylation status of TP53 promoter. QRT-PCR showed an increased TP53 gene expression in the treated cells while a significant decrease in survivin mRNA was evident. Conclusions: According to the outcomes, dichloromethane extract of S. atropatana returned the TP53 gene promoter hypermethylation to normal state. This plant could be a promising source for production of epi-drugs due to its apoptotic effects and reversal of TP53 epigenetic alterations.

Cancer stem cells (CSCs) are a small subpopulation of tumor cells that have been identified in most types of cancer. Features that distinguish them from the bulk of tumor cells include their pluripotency, self-renewal capacity, low proliferation rate, and tumor-initiating ability. CSCs are highly malignant, as they confer drug resistance and facilitate tumor progression, relapse, and metastasis. The molecular mechanisms underlying CSC biology are now beginning to be understood. In this context, microRNAs (miRNAs) occupy a prominent place. These endogenous, small noncoding RNA molecules control gene expression at the posttranscriptional level. This study reviews our current understanding of how the misexpression of tumor suppressor and oncogenic miRNAs in CSCs sustain their abundance and malignant properties. We discuss how they partly do so by acting on major CSC signaling pathways, including the Wnt, Notch, Hedgehog, and BMI-1 pathways. Our current knowledge of miRNA functions in CSCs may now be used for cancer diagnostic and prognostic purposes. In addition, when combined with recent technical advances in the in vivo delivery of miRNAs, we are now in an excellent position to develop strategies that harness miRNA interference and replacement technologies for the therapeutic targeting of CSCs.

Ankylosing spondylitis (AS) is a type of arthritis that is referred to a group of chronic immune-mediated inflammatory diseases termed as seronegative spondyloarthropathies or spondyloarthritides. It typically affects the joints of the spinal and axial skeleton and exhibits common clinical features and genetic factors such as human leukocyte antigen class I allele HLA-B27, the Endoplasmic Reticulum Aminopeptidase 1 (ERAP1), and environmental factors such as microbial triggers. Although the precise etiopathogenic mechanisms that implicate the pathogenesis of AS have still remained to be clarified, the IL-23/IL-17 immune axis has been detected as an important factor in the immunopathogenesis of AS. Moreover, therapeutic options targeting this signaling pathway have been demonstrated to be effective in various other inflammatory diseases that share similar genetic etiology and pathogenetic pathways. In mammalian intestinal, there are trillions of commensal microbes that create the intricate symbiotic relationship with host well-known as the microbiota and play the major role in human health and disease. Several publications have appeared in recent years documenting the pivotal role of the gut microbiota and the IL-23/IL-17 pathway in the pathogenesis of spondyloarthritides. In this review, several points are discussed and summarized including recent advances on the role of the IL-17/IL-23 immune pathway in the pathogenesis of AS, HLA-B27, and ERAP 1 and 2 mediated pathogenesis, AS-related microbiota compositions, and new potential therapies for AS.

Immune system acts as a host defensive mechanism protecting against attacking pathogens and transformed cells, including cancer cells. Th17 cells are a specific subset of T helper lymphocytes determined by high secretion of IL-17 and other inflammatory cytokines. Th17 cells increase tumor progression by activating angiogenesis and immunosuppressive activities. They can also mediate antitumor immune responses through recruiting immune cells into tumors, stimulating effector CD8+ T cells, or surprisingly by altering toward Th1 phenotype and producing IFN-γ, so Th17 cells are supposed as a double-edged sword in cancer. A comprehensive approach to indicating the activity of Th17 cells in tumor progression could help in the planning of new therapeutic approaches specially targeting Th17 cells in cancer.

New water soluble thiosemicarbazone ligands, namely 3-(3-{[(aminocarbonothioyl) hydrazono]methyl}-4-hydroxybenzyl)-1-methyl-1H-imidazol-3-ium chloride (H2L1Cl), 3-[4-hydroxy-3-({[(methylamino)carbonothioyl]hydrazono}methyl)benzyl]-1-methyl-1H-imidazol-3-ium chloride (H2L2Cl) and 3-(3-{[(anilinocarbonothioyl)hydrazono]methyl}-4-hydroxybenzyl)-1-methyl-1H-imidazol-3-ium chloride (H2L3Cl) were synthesized through 1:1 condensation reaction of thiosemicarbazide derivatives with 3-(3-formyl-4-hydroxybenzyl)-1-methyl-1H-imidazole-3-ium chloride (SalimiCl) and characterized by elemental analysis and spectroscopic methods (UV–Vis, 1H NMR, FTIR). Single crystals of H2L1Cl and H2L2Cl were prepared for crystallographic analysis, which showed similar X-ray structures for both ligands with chiral P212121 space group. The ligands were used for synthesis of the following copper(II) complexes: [Cu(HL1)Cl]Cl, [Cu(HL2)Cl]Cl·H2O, and [Cu(HL3)Cl]Cl. All complexes were characterized by physico-chemical and spectroscopic methods. The X-ray structure of [Cu(HL1)Cl]Cl was orthorhombic with Pcba space group while [Cu(HL2)Cl]Cl·H2O was triclinic with Pī space group. Both complexes were mononuclear, with tridentate ligands in a thione form. All of the studied compounds showed good solubility and stability in water. The measurement of the molar conductance showed the release of Cl− into solution and substitution of water instead of the coordinated chloride. Among the studied complexes, only [Cu(HL3)Cl]Cl shows a quasi-reversible redox behavior with its reduction and oxidation peak potentials separated by a value of about 0.120 V (Epc = −0.310 V and Epa = −0.190 V) indicating one-step and one-electron transfer for CuII/CuI redox couple. The cytotoxic effect of the compounds was measured using the MTT assay on MCF-7 and K562 cell lines and the results showed that [Cu(HL3)Cl]Cl and H2L3Cl had lower IC50 values compared to the other compounds. Flow cytometry analysis on the MCF-7 cells showed the apoptosis cell death after treating with the H2L3Cl and [Cu(HL3)Cl]Cl. Also studies of cell cycles confirmed the cell cycle arrest in G2 phase for H2L3Cl and [Cu(HL3)Cl]Cl.

Insulin-like growth factor I receptor (IGF-IR) is expressed on breast cancer cells and involves in metastasis, survival, and proliferation. Currently, application of IGF-IR-targeting monoclonal antibodies (mAbs), alone or in combination with other drugs, is a promising strategy for breast cancer therapy. Single-chain fragment variable (scFv) antibodies have been introduced as appropriate tools for tumor-targeting purposes because of their advantages over whole antibodies. In the present study, we employed a naive phage library and isolated scFvs against a specific epitope from extracellular domain of IGF-IR by panning process. The selected scFvs were further characterized using polyclonal and monoclonal phage ELISA, soluble monoclonal ELISA, and colony PCR and sequencing. Antiproliferative and apoptotic effects of selected scFv antibodies on breast cancer cell lines were also evaluated by MTT and Annexin V/PI assays. The results of ELISA indicated specific reactions of the isolated scFvs against the IGF-IR peptide, and analyses of PCR product and sequencing confirmed the presence of full length VH and Vκ inserts. Treatment of MCF7 and SKBR3 cells with anti-IGF-IR scFv led to a significant growth inhibition. The results also showed that scFv treatment significantly augmented trastuzumab growth inhibitory effects on SKBR3 cells. The percentage of the apoptotic MCF7 and SKBR3 cells after 24-h treatment with scFv was 39 and 30.70 %, respectively. Twenty-four-hour treatment with scFv in combination with trastuzumab resulted in 44.75 % apoptosis of SKBR3 cells. Taken together, our results demonstrate that the targeting of IGF-IR by scFv can be an effective strategy in the treatment of breast cancer and provide further evidence for effectiveness of dual targeting of HER2 and IGF-IR in breast cancer therapy.