The molecular crosstalk between innate immunity and DNA damage repair/response: Interactions and effects in cancers.

DNA damage can lead to erroneous alterations and mutations which in turn can result into wide range of disease condition including aging, severe inflammation, and, most importantly, cancer. Due to the constant exposure to high-risk factors such as exogenous and endogenous DNA-damaging agents, cells may experience DNA damage impairing stability and integrity of the genome. These perturbations in DNA structure can arise from several mutations in the genome. Therefore, DNA Damage Repair/Response (DDR) detects and then corrects these potentially tumorigenic problems by inducing processes such as DNA repair, cell cycle arrest, apoptosis, etc. Additionally, DDR can activate signaling pathways related to immune system as a protective mechanism against genome damage. These protective machineries are ignited and spread through a network of molecules including DNA damage sensors, transducers, kinases and downstream effectors. In this review, we are going to discuss the molecular crosstalk between innate immune system and DDR, as well as their potential effects on cancer pathophysiology.

Communication between Mast Cells and Group 2 Innate Lymphoid Cells in the Skin.

The skin is a dynamic organ with a complex immune network critical for maintaining balance and defending against various pathogens. Different types of cells in the skin, such as mast cells (MCs) and group 2 innate lymphoid cells (ILC2s), contribute to immune regulation and play essential roles in the early immune response to various triggers, including allergens. It is beneficial to dissect cell-to-cell interactions in the skin to elucidate the mechanisms underlying skin immunity. The current manuscript concentrates explicitly on the communication pathways between MCs and ILC2s in the skin, highlighting their ability to regulate immune responses, inflammation, and tissue repair. Furthermore, it discusses how the interactions between MCs and ILC2s play a crucial role in various skin conditions, such as autoimmune diseases, dermatological disorders, and allergic reactions. Understanding the complex interactions between MCs and ILC2s in different skin conditions is crucial to developing targeted treatments for related disorders. The discovery of shared pathways could pave the way for novel therapeutic interventions to restore immunological balance in diseased skin tissues.

Modulation of Immune-Related Gene Expressions in Zebrafish (Danio rerio) by Dietary Purslane (Portulaca oleracea) Extract.

To promote fish's immunity against pathogens in the aquaculture industry, fish dietary fortification with additives or compounds has increasingly attracted attention. In the present study, zebrafish (Danio rerio) was used as an animal model to investigate the effects of purslane, Portulaca oleracea, extract (PE) on the relative expression level of some immune-related genes. A total of 300 zebrafish were randomly divided into four treatment groups and fed for 8 weeks with the basal diets supplemented with 0.5, 1, 1.5, and 2% of PE. The control group was fed with a basal diet without PE. At the end of 8 weeks, the mRNA expression levels of interleukin 1-beta (IL-1ß), interleukin 10 (IL-10), transforming growth factor-beta (TGF-ß), tumor necrosis factor-alpha (TNF-α), superoxide dismutase (SOD), and lysozyme (LYZ) in the fish were evaluated. The results showed that the mRNA expression level of IL-1ß was significantly upregulated in the fish fed with 1 and 2% PE compared to the control group (p < 0.05). Moreover, the evaluation of the mRNA expression level of TGF-ß was significantly increased in a dose-dependent manner in the 1.5 and 2% fed groups compared to the control group (p < 0.05). However, the IL-10 was significantly downregulated in all treated groups compared to the control group (p < 0.05). The expression of the TNF-α gene was not affected amongst all groups by the inclusion of PE in the zebrafish diet (p > 0.05). Based on the results, the diet supplemented with 1.5 and 2% PE significantly upregulated the mRNA expression levels of LYZ and SOD, respectively, compared to the control group (p < 0.05). In conclusion, dietary inclusion of PE may result in beneficial effects on some immune responses via upregulation of some immune genes in zebrafish.

Prognostic utility of shock index and modified shock index on long-term mortality in acute decompensated heart failure; Persian Registry of cardioVascular diseasE/Heart Failure (PROVE/HF) study.

BACKGROUND: Shock index (SI) and modified SI (MSI) are used for prognosis in patients with cardiovascular diseases (CVDs), especially myocardial infarction. However, the utility of these indices in heart failure(HF) is less frequently investigated. We aimed to evaluate the long-term prognostic capability of SI and MSI among Iranian HF patients. METHODS: This retrospective cohort study was implemented in the context of the Persian Registry Of cardioVascular diseasE/HF (PROVE/HF). A total of 3896 acute decompensated HF (ADHF) patients were enrolled from March 2016 to March 2020. SI and MSI were assessed at admission. Receiver operating characteristic (ROC) and Kaplan-Meier curves were used to define optimum SI and MSI cut-off points and depict mortality during follow-up, respectively. The association of CVD death according to different SI and MSI cut-off points and quartiles was assessed through univariate and multivariate regression hazard models. RESULTS: Mean age of participants was 70.22 ± 12.65 years (males: 62.1%). We found 0.66 (sensitivity:62%, specificity: 51%) and 0.87 (sensitivity: 61%, specificity: 51%) as optimised cut-off points for SI and MSI, respectively. Mean follow-up was 10.26 ± 7.5 months and 1110 (28.5%) deaths occurred during this time. Multivariate adjusted models revealed patients had SI ≥ 0.66 or within the third and fourth quartiles had higher likelihood of mortality compared to reference group (hazard ratio(HR): 1.58, 95%CI: 1.39-1.80, p < 0.001, HR: 1.38,95%CI:1.14-1.66, p = 0.001 and HR:2.00,95%CI:1.68-2.38, p < 0.001, respectively). MSI outcomes were similar (MSI ≥ 0.87: HR: 1.52,95%CI: 1.34-1.72, p < 0.001, third quartile (0.89 ≤ MSI < 1.00):HR:1.23,95%CI:1.009-1.50, p = 0.041, fourth quartile (MSI ≥ 1.00): HR: 1.80,95%CI: 1.53-2.13, p < 0.001). Kaplan-Meier curves showed patients with higher SI and MSI cut-off values and quartiles had lower survival rates. CONCLUSION: Higher SI and MSI values were associated with increased mortality risk, and these two bedside indices could be appropriately considered for long-term prognosis in ADHF patients.

Targeted therapy in Coronavirus disease 2019 (COVID-19): Implication from cell and gene therapy to immunotherapy and vaccine.

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) is a highly pathogenic and transmissible virus. Infection caused by SARS-CoV-2 known as Coronavirus disease 2019 (COVID-19) can be severe, especially among high risk populations affected of underlying medical conditions. COVID-19 is characterized by the severe acute respiratory syndrome, a hyper inflammatory syndrome, vascular injury, microangiopathy and thrombosis. Antiviral drugs and immune modulating methods has been evaluated. So far, a particular therapeutic option has not been approved for COVID-19 and a variety of treatments have been studied for COVID-19 including, current treatment such as oxygen therapy, corticosteroids, antiviral agents until targeted therapy and vaccines which are diverse in each patient and have various outcomes. According to the findings of different in vitro and in vivo studies, some novel approach such as gene editing, cell based therapy, and immunotherapy may have significant potential in the treatment of COVID-19. Based on these findings, this paper aims to review the different strategies of treatment against COVID-19 and provide a summary from traditional and newer methods in curing COVID-19.

Pterostilbene increases Fas expression in T-lymphoblastic leukemia cell lines.

Treatment of acute lymphoblastic leukemia (ALL) has been promising in last decades, but side effects still persist and searching for the least toxic agents continue. Pterostilbene (PTE) is a natural compound with several anti-cancer and anti-oxidant properties. Fas, as a member of death inducing family of tumor necrosis factor (TNF) receptors with an intracellular death domain, can initiate the extrinsic apoptosis signaling pathway. Here after the half maximal inhibitory concentration (IC50) determination in cell lines, we searched for PTE effects on Fas, both in mRNA and surface levels in two ALL cell lines, Jurkat and Molt-4. After harvesting cells in optimum situations, MTS assay was used to determine IC50 concentrations. Real-time polymerase chain reaction (RT-PCR) and flow cytometry were performed for Fas mRNA and surface expression variations after exposure to PTE. The findings showed that PTE decreases cell viability with different extent in two ALL cell lines. In addition to inducing apoptosis, it can increase Fas in both gene and cell surface expression in the same concentrations. Pterostilbene as a natural anti-cancer agent can increase Fas expression both in mRNA and surface levels that results in apoptosis signal transduction improvement which sensitizes cells to apoptosis by immune effector cells. As a result, abnormal cells removal would be more efficiently with the minimum side effects on normal cells.

The Inhibitory Effect of Epigallocatechin Gallate on the Viability of T Lymphoblastic Leukemia Cells is Associated with Increase of Caspase-3 Level and Fas Expression.

Acute lymphoblastic leukemia is the most prevalent cancer in children. Novel components to help struggle aggressive malignancies and overcome some side effects of conventional treatments could be a promising strategy. Epigallocatechingallate (EGCG), have attracted the attention of scientists for prevention or treatment of some cancers. Jurkat cells were incubated with the different concentrations of EGCG (30-100 µm) for 24, 48, and 72 h and cell viability was investigated using MTS test. Apoptosis and the level of caspase 3 alterations were evaluated using flowcytometry and expression of Fas by Real Time PCR. EGCG decreased viability of cells with an inhibition concentration (IC50) of 82.8 ± 3.1, 68.8 ± 4 and 59.7 ± 4.8 µM in 24,48 and 72 h. 50, 70 and 100 µM concentrations of EGCG induced apoptosis in about 31, 40 and 71% of the cells, respectively. The mean value of caspase 3 positive cells in the presence of 50, 70 and 100 µm concentrations of EGCG was 19.3 ± 2.9, 29.5 ± 3.1 and 61.2 ± 3.4 respectively compared to 7.8 ± 1.1 in control with a significant difference at 100 µm concentration. Treatment with EGCG for 48 h enhanced the expression of Fas reaching to a significant level at 100 µM concentration. EGCG is effective in decrease cell viability, apoptosis induction and enhancement of caspase 3 and Fas expression level in jurkat cells. A comprehensive understanding of molecular events and pharmacokinetics of the component and experiments in animal models are required for dose determination and its interaction with other components of combination chemotherapy.

Interaction between Gallic acid and Asparaginase to potentiate anti-proliferative effect on lymphoblastic leukemia cell line.

BACKGROUND: Treatment of acute lymphoblastic leukemia (ALL) fails in some cases and the side effects cause mortality in certain patients. Gallic acid (GA), a polyhydroxyphenolic compound has biological functions including anti-proliferative properties. The aim of the present study was to investigate the growth inhibition effects of GA in combination with asparaginase (ASP), as a component of combination chemotherapy, in a lymphoblastic leukemia cell line. METHODS: Jurkat cells were incubated with different concentrations of GA with or without ASP. Proliferation inhibition was investigated using MTS test. The level of apoptosis alterations were evaluated using flow cytometry. The expression of Fas gene level and surface expression were investigated by quantitative real time PCR and flow cytometry respectively. RESULTS: GA at 50µM concentration and ASP at 0.5 IU/ml inhibited 50% cell proliferation in 48 hours. GA also increased the inhibitory effect of ASP and some combinations had synergistic results. The increase of cell apoptosis and Fas expression were observed in GA-treated cells compared to control. GA increased the effect of ASP on proliferation inhibition, induction of apoptosis and Fas expression. CONCLUSION: GA is an effective component in proliferation inhibition, apoptosis induction and enhancement of Fas expression level in Jurkat cell line. GA in some combination with ASP increases the effect of the latter on the cells. The study of the mechanism of these effects could be a further step towards target therapy. This study is a preliminary phase to the use of GA and should be carried out by more comprehensive study and animal models.

Antiproliferative and Apoptosis-Inducing Activities of Thymoquinone in Lymphoblastic Leukemia Cell Line.

Acute lymphoblastic leukemia is one of the malignant proliferations of lymphoid cells in the early stages of differentiation and accounts for about 80% of all cases of childhood leukemia. Side effects of available treatment are still main concern. Thymoquinone (TQ), a natural compound isolated from Nigella sativa, induces growth inhibition and apoptosis in several cancer cell lines. The aim of the present study was to investigate the effect of TQ alone and in combination with doxorubicine on the proliferation inhibition and apoptosis induction of TQ in a lymphoblastic leukemia cell line. Jurkat cell line was cultured in standard condition and with concentrations of TQ (0-30 µm) and doxorubicine for 24, 48 and 72 h. Cell viability was measured by MTS assay. Apoptosis induction by TQ was assessed by annexin V-FITC/PI and flow cytometry analysis. TQ and DOX decreased cell viability with a time and dose dependent manner. The IC50 values were 19.461 ± 1.141, 17.342 ± 1.949 and 14.123 ± 1.874 µM in 24, 48 and 72 h, respectively for TQ. IC50 values for DOX were. 075 ± .0124, .028 ± .007 and.007 ± .001 µM in 24, 48 and 72 h, respectively. The level of cell apoptosis in all used concentrations of TQ (4, 8, 12, 16 and 20 µm) was higher than control group (10.2, 14.1, 36.6, 87.5 and 93.3% respectively after 24 h; 10.7, 13.9, 64.6, 92.2 and 93.1 respectively after 48 h; 2.83, 5.83, 41.4, 71.6 and 86.6% respectively after 72 h) and reached to a significant level at 12, 16 and 20 µm concentration for 24 and 48 h and 16 and 20 µm for 72 h incubation. Combination of doxorubicine and TQ lead to a synergistic cytotoxicity as compared to any of them alone. The study indicated that TQ is effective on proliferation inhibition and is a strong apoptotic inducer in Jurkat lymphoblastic cell line and has synergistic effect in combination with DOX. This combination strategy can be an alternative way for more powerful anticancer effects. Therefore, the study of the mechanism of apoptosis induction of TQ can be a step forward to in target therapy which might be considered in the future studies.

Gallic Acid Inhibits Proliferation and Induces Apoptosis in Lymphoblastic Leukemia Cell Line (C121).

Leukemia is known as the world's fifth most prevalent cancer. New cytotoxic drugs have created considerable progress in the treatment, but side effects are still the important cause of mortality. Plant derivatives have been recently considered as important sources for the treatment of various diseases, including cancer. Gallic acid (GA) is a polyhydroxyphenolic compound with a wide range of biological functions. The aim of the present study was to evaluate the effect of GA on proliferation inhibition and apoptosis induction of a lymphoblastic leukemia cell line. Jurkat cell (C121) line was cultured in RPMI 1640 supplemented with 10% heat-inactivated fetal bovine serum (FBS) with different concentrations of GA (10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 µM) for 24, 48 and 72 hours. The effect of GA on cell viability was measured using MTS assay. Induction of apoptosis was evaluated with Annexin V-FITC/PI kit and flow cytometry. Data were analyzed by SPSS version 20 using Kruskal-Wallis and Dunn's multiple comparison tests. Decline of cell viability to less than 50% was observed at 60.3±1.6, 50.9±1.5, and 30.9±2.8 µM concentration after 24, 48, and 72 hours incubation, respectively. All concentrations of GA (10, 30, 50 and 80 µM) enhanced apoptosis compared to the control (P<0.05). The results demonstrate that the polyphenolic compound, GA, is effective in inhibition of proliferation and induction of apoptosis in Jurkat cell line. It is recommended to study the mechanism of apoptosis induction in future investigations.