Association of the matrix metalloproteinases (MMPs) family gene polymorphisms and the risk of coronavirus disease 2019 (COVID-19); implications of contribution for development of neurological symptoms in the COVID-19 patients.

BACKGROUND: Seemingly, the Matrix metalloproteinases (MMPs) play a role in the etiopathogenesis of coronavirus disease 2019 (COVID-19). Here in this study, we determined the association of MMP9 rs3918242, MMP3 rs3025058, and MMP2 rs243865 polymorphisms with the risk of COVID-19, especially in those with neurological syndrome (NS). METHODS: We enrolled 500 patients with COVID-19 and 500 healthy individuals. To genotype the target SNPs, the Real-time allelic discrimination technique was used. To determine serum levels of MMPs, Enzyme-linked immunosorbent assay (ELISA) was exerted. RESULTS: The MMP9 gene rs3918242 and MMP3 gene rs3025058 SNP were significantly associated with increased COVID-19 risk and susceptibility to COVID-19 with NS. The serum level of MMP-9 and MMP-3 was significantly higher in COVID-19 cases compared with the healthy controls. Serum MMP-9 and MMP-3 levels were also higher in COVID-19 subjects with NS in comparison to the healthy controls. The polymorphisms in MMP genes were not associated with serum level of MMPs. CONCLUSION: MMP9 and MMP3 gene polymorphisms increases the susceptibility to COVID-19 as well as COVID-19 with neurologic syndrome, but they probably have no role in the regulation of serum MMP-9 and MMP-3 levels.

Up-regulation of KISS1 as a novel target of Let-7i in melanoma serves as a potential suppressor of migration and proliferation in vitro.

Melanoma is a kind of skin cancer that is begun by the alteration of melanocytes. miRNAs are small non-coding RNA molecules that regulate a variety of biological processes. KISS1, the metastasis-suppressor gene, encodes kisspeptins which inhibits migration and proliferation of cancers. This study was aimed to determine the role of Let-7i and KISS1 in melanoma cell migration and proliferation. At first, the expression of Let-7i and KISS1 was determined in patients with melanoma. In the in vitro part of the study, Let-7i mimics were transfected and the impact of its restoration on target gene expression, proliferation, migration and apoptosis of SK-MEL-3 melanoma cell line was assessed by real-time PCR and Western blotting, MTT assay, wound-healing assay and flow cytometry, respectively. Besides, KISS1 inhibitor siRNA alone and along with Let-7i was transfected to determine their probable correlation. The results revealed that either Let-7i or KISS1 were down-regulated in patients with melanoma. The results obtained from the in vitro part of the study revealed that restoration of Let-7i reduced the expression of metastasis- and proliferation-related target genes. Moreover, it was revealed that up-regulation of Let-7i attenuated migration and proliferation capability of SK-MEL-3 cells. Besides, it was demonstrated that Let-7i restoration induced apoptosis in melanoma cells. More importantly, the KISS1 inhibitor caused a prominent cell migration and proliferation, attenuated by Let-7i re-expression. To sum up, the present study revealed the impressive role of Let-7i restoration along with its correlation with KISS1 on melanoma carcinogenicity which may be applicable in future in vivo studies.

Natural killer cell epigenetic reprogramming in tumors and potential for cancer immunotherapy.

Natural killer (NK) cells are critical members of the innate lymphoid cell population and have a pivotal role in cancer eradication. NK cell maturation, development and function are tightly regulated by epigenetic modifications, which can also be recruited for cancer propagation and immune escape. NK cells have the potential to be activated against tumors through several epigenetic regulators. Given that epigenetic changes are inducible and reversible, focusing on aberrant epigenetic regulations recruited by tumor cells provides a tremendous opportunity for cancer treatment. This review presents a comprehensive picture of NK cell normal epigenetic regulation and cancer-driven epigenetic modifications. From our perspective, a better understanding of epigenetic regulators that can edit and revise NK cells' activity is a promising avenue for NK cell-based therapy in cancer management.

Natural killer (NK) cells are one of the critical cell types in our immune system, fighting against cancers, especially in the first stages of cancer formation. NK cells are produced in the bone marrow and develop to mature cells in the blood. NK cell development is tightly regulated in our body by different mechanisms, including genetic and epigenetic factors. Unlike genetic determinants, epigenetic factors are inducible and changeable via multiple triggers; for example, NK cell activity is enhanced after exercise. Cancers have an 'intelligent' function: they try to counteract the immune system and make it functionally impaired. So cancer cells produce different substances and use diverse mechanisms to suppress NK cell activity. In other words, they use epigenetic modifications to create inactive NK cells. Fortunately, as the epigenetic changes are reversible, it is possible to reverse epigenetic alterations and activate NK cells against cancers. There are some studies indicating the successful use of epigenetic modifiers in activating NK cells in labs. Furthermore, some studies have focused on the use of epigenetic modifiers of NK cell behavior in different human cancers. The more we know about the epigenetic modifications in normal NK cells, the higher possibility we have to create an anticancer treatment based on them.

Chimeric antigen receptor-natural killer cells: a promising sword against insidious tumor cells.

Natural killer (NK) cells are a critical component of innate immunity, particularly in initial cancer recognition and inhibition of additional tumor growth or metastasis propagation. NK cells recognize transformed cells without prior sensitization via stimulatory receptors and rapidly eradicate them. However, the protective tumor microenvironment facilitates tumor escaping via induction of an exhaustion state in immune cells, including NK cells. Hence, genetic manipulation of NK cells for specific identification of tumor-associated antigens or a more robust response against tumor cells is a promising strategy for NK cells' tumoricidal augmentation. Regarding the remarkable achievement of engineered CAR-T cells in treating hematologic malignancies, there is evolving interest in CAR-NK cell recruitment in cancer immunotherapy. Innate functionality of NK cells, higher safety, superior in vivo maintenance, and the off-the-shelf potential move CAR-NK-based therapy superior to CAR-T cells treatment. In this review, we have comprehensively discussed the recent genetic manipulations of CAR-NK cell manufacturing regarding different domains of CAR constructs and their following delivery systems into diverse sources of NK cells. Then highlight the preclinical and clinical investigations of CAR-NK cells and examine the current challenges and prospects as an optimistic remedy in cancer immunotherapy.

Aberrant DNA Methylation Status and mRNA Expression Level of SMG1 Gene in Chronic Myeloid Leukemia: A Case-Control Study.

OObjective: Chronic myeloid leukemia (CML) is a myeloproliferative malignancy with different stages. Aberrant epigenetic modifications, such as DNA methylation, have been introduced as a signature for diverse cancers which also plays a crucial role in CML pathogenesis and development. Suppressor with morphogenetic effect on genitalia (SMG1) gene recently has been brought to the spotlight as a potent tumor suppressor gene that can be suppressed by tumors for further progress. The present study aims to investigate SMG1 status in CML patients. MATERIALS AND METHODS: In this case-control study, peripheral blood from 30 patients with different phases of CML [new case (N)=10, complete molecular remission (CMR)=10, blastic phase (BP)=10] and 10 healthy subjects were collected. Methylation status and expression level of SMG1 gene promoter was assessed by methylation-specific polymerase chain reaction (MSP) and quantitative reverse-transcription PCR, respectively. RESULTS: MSP results of SMG1 gene promotor in the new case group were methylated (60% methylated, 30% hemimethylated and 10% unmethylated). All CMR and control group patients were unmethylated in the SMG1 gene promoter. In the BP group, methylated SMG1 promoter was seen (50% of patients had a methylated status and 50% had hemimethylated status). In comparison with the healthy subjects, expression level of SMG1 in the new case group was decreased (P<0.01); in the CMR group and BP-CML groups, it was increased (P<0.05). No significant correlation between patients' hematological features and SMG1 methylation was seen. CONCLUSION: Our results demonstrated that aberrant methylation of SMG1 occurred in CML patients and it had a significant association with SMG1 expression. SMG1 gene promoter showed diverse methylated status and subsequent expression levels in different phases of CML. These findings suggested possible participation of SMG1 suppression in the CML pathogenesis.

NK cells - Dr. Jekyll and Mr. Hyde in autoimmune rheumatic diseases.

Natural killer (NK) cells belong to innate immune system that are large granular lymphocytes differentiating from the common lymphoid progenitors. These cells were first identified by their functional response against tumor cells and virus-infected cells. That notwithstanding, NK cells are able to affect both adaptive and innate immune arms and modulate a wide range of immune cells. As a consequence, NK cells are capable of bridging between the innate and adaptive immune responses. The effector cytokines as well as direct cell-cell cytotoxicity by NK cells have been shown to be involved in the regulation of the immune responses and might participate in the etiopathogenesis of several disorders, particularly autoimmune rheumatic diseases (AIRDs), such as Ankylosing spondylitis (AS), Rheumatoid arthritis (RA), Systemic lupus erythematosus (SLE), Behcet's disease (BD), Systemic sclerosis (SSc), and psoriasis. Nonetheless, NK cells demonstrate both harmful and protective functions during autoimmune diseases pathogenesis based on the subset of NK cell as well as disease microenvironment and disease phase or genetic/environmental stimuli. Here in this review, we intend to go through the recent findings in the etiology and pathogenesis of AIRDs and discuss about their clinical potential to be utilized as targets for the sake of therapy in the context of such disorders.

Promoter Methylation Status and Expression Levels of RASSF1A Gene in Different Phases of Acute Lymphoblastic Leukemia (ALL).

Background: Although the precise pathogenesis of acute lymphoblastic leukemia (ALL) remains unclear, studying gene-regulating mechanisms during ALL pathogeneses may shed light on the underlying mechanisms driving malignant behavior. There is some evidence showing the promoter hypermethylation and silencing of RASSF1A tumor suppressor gene in ALL cells; however, there is a lack of evidence for whether the gene indeed alters during different phases of ALL or in response to therapy. Thus, the current study aimed to clarify this issue using groups of adult ALL patients who have been scarcely investigated regarding expression levels and promoter methylation status. Materials and Methods: In this case/control study, the expression levels and methylation status of the gene promoter was evaluated using quantitative real-time PCR and methylation-specific PCR (MSP), respectively in adults with ALL. The study included peripheral blood of patients with newly diagnosed ALL (n=10), complete remission (CR) (n=10), or relapse (n=10), and 10 control samples from healthy individuals. Results: MSP results revealed an unmethylated status for almost all patients and control samples, except a case with relapsing ALL, which showed a hemimethylated pattern. RASSF1A also showed no difference in terms of gene expression in the patients compared with the control group (p>0.05). Conclusion: The results revealed an up-regulation of RASSF1A tumor suppressor in adult ALL patients experiencing CR, suggesting this to be a marker of therapy response. However, further investigations using more sensitive methylation detecting tools with larger sample sizes may better clarify the involvement of the promoter methylation of RASSF1A in these patients.