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.

Effect of sub-acute exposure of metal-organic framework-199 on cognitive function and oxidative stress level of brain tissue in rat.

Metal-Organic Framework-199 (MOF-199) is a subgroup of MOFs that is utilized in different medical fields such as drug delivery. In the current study, the effect of sub-acute exposure to MOF-199 on spatial memory, working memory, inflammatory mediators' expression, and oxidative stress level of brain tissue has been investigated. Thirty-two male Wistar rats were randomly divided into four groups as vehicle, MOF-199 at doses 0.3, 3, or 6 mg/kg. After four injections of relevant interventions via tail vein during 14 days, behavioral parameters were investigated using Y-maze and Morris Water Maze (MWM) tests. Oxidative stress was measured by ferric reducing antioxidant power (FRAP) and thiobarbituric acid-reacting substance (TBARS) tests. The expression levels of TNF-α and IL-1ß were assessed by quantitative real-time reverse-transcription PCR (qRT-PCR). No significant differences were observed in working memory, spatial learning and memory of MOF-199 receiving rats. Additionally, the level of oxidative stress and inflammatory genes expression were not remarkably changed in the brain tissues of MOF-199 treated rats. Despite the lack of remarkable toxic effects of sub-acute exposure to MOF-199, more studies with a longer duration of administration are necessary to use this substance for drug delivery systems in diseases related to the nervous system.

Potential therapeutic and diagnostic approaches of exosomes in multiple sclerosis pathophysiology.

Exosomes are bilayer lipid vesicles that are released by cells and contain proteins, nucleic acids, and lipids. They can be internalized by other cells, inducing inflammatory responses and instigating toxicities in the recipient cells. Exosomes can also serve as therapeutic vehicles by transporting protective cargo to maintain homeostasis. Multiple studies have shown that exosomes can initiate and participate in the regulation of neuroinflammation, improve neurogenesis, and are closely related to the pathogenesis of central nervous system (CNS) diseases, including multiple sclerosis (MS). Exosomes can be secreted by both neurons and glial cells in the CNS, and their contents change with disease occurrence. Due to their ability to penetrate the blood-brain barrier and their stability in peripheral fluids, exosomes are attractive biomarkers of CNS diseases. In recent years, exosomes have emerged as potential therapeutic agents for CNS diseases, including MS. However, the molecular pathways in the pathogenesis of MS are still unknown, and further research is needed to fully understand the role of exosomes in the occurrence or improvement of MS disease. Thereby, in this review, we intend to provide a more complete understanding of the pathways in which exosomes are involved and affect the occurrence or improvement of MS disease.

Sub-acute administration of metal-organic Framework-5 induces behavioral impairments and augments the levels of oxidative stress and inflammation in the brain of rats.

Metal-organic frameworks (MOFs) are known as potential pharmaceutical carriers because of their structure. Here, we evaluated the sub-acute administrations of MOF-5 on behavioral parameters, oxidative stress, and inflammation levels in rats. Thirty-two male Wistar rats received four injections of saline or MOF-5 at different doses which were 1, 10, and 50 mg/kg via caudal vein. Y-Maze and Morris-Water Maze (MWM) tests were used to explore working memory and spatial learning and memory, respectively. The antioxidant capacity and oxidative stress level of brain samples were assessed by ferric reducing antioxidant power (FRAP) and thiobarbituric acid-reacting substance (TBARS) assay, respectively. The expression levels of GFAP, IL-1ß, and TNF-α were also measured by quantitative real-time reverse-transcription PCR (qRT-PCR). Sub-acute administration of MOF-5 reduced the spatial learning and memory as well as working memory, dose-dependently. The levels of FRAP were significantly reduced in rats treated with MOF-5 at higher doses. The Malondialdehyde (MDA) levels increased at the dose of 50 mg/kg. Additionally, the expression levels of IL-1ß and TNF-α were significantly elevated in the rats' brains that were treated with MOF-5. Our findings indicate that sub-acute administration of MOF-5 induces cognitive impairment dose-dependently which might be partly mediated by increasing oxidative stress and inflammation.

Characteristics, outcome, duration of hospitalization, and cycle threshold of patients with COVID-19 referred to four hospitals in Babol City: a multicenter retrospective observational study on the fourth, fifth, and sixth waves.

BACKGROUND: The aim of the present study was to compare the epidemiological patterns of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infections, hospitalizations, deaths, and duration of hospitalization during the fourth, fifth and sixth epidemic waves of coronavirus disease 2019 (COVID-19) in Iran. METHODS: A multicenter retrospective observational study was conducted on hospitalized patients in four hospitals in the Babol district of northern Iran. The study periods were during the fourth, fifth, and sixth waves of the epidemic in Iran, (March 2021 to March 2022). A total of 13,312 patients with suspected COVID-19 were included. Patient demographics, medical history, length of hospital stay, and clinical outcomes were obtained from the hospital information system. Data on the cycle threshold (Ct) and SARS-CoV2 variant were collected for SARS-CoV2-positive cases. RESULTS: The highest number of hospitalized patients was reported during the fifth (Delta) wave (5231; 39.3%), while the lowest number of hospitalized patients was reported during the sixth (Omicron) wave (2143; 16.1%). In total, 6459 (48.5%) out of 13,312 hospitalized patients with suspected COVID-19 had a positive rRT-PCR result. The fifth (Delta) wave had the highest number of SARS-CoV2 rRT-PCR-positive hospitalized patients (3573, 55.3%), while the sixth (Omicron) wave had the lowest number (835, 12.9%). Moreover, 238 (3.7%) patients with laboratory-confirmed COVID-19 died. The hospital mortality rate was 6.8% in the fourth (Alpha) wave, which reduced to 2.7 and 3.5% in the fifth (Delta) and sixth (Omicron) waves, respectively (p < 0.001). CONCLUSIONS: This is the most comprehensive study evaluating the epidemiologic characteristics of laboratory-confirmed SARS-CoV2 cases in Iran during the Alpha, Delta, and Omicron waves. The highest number of SARS-CoV2-positive hospitalized patients was in the fifth wave of COVID-19 (dominance of the Delta variant), while the sixth wave (dominance of the Omicron variant) had the lowest number. Comorbidities were similar, and cardiovascular disease, diabetes, kidney disease, and hypertension were the main risk factors in all waves.

Critical involvement of circular RNAs in virus-associated cancers.

Virus-related cancer is cancer where viral infection leads to the malignant transformation of the host's infected cells. Seven viruses (e.g., human papillomavirus (HPV), Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human T-lymphotropic virus (HTLV), and Merkel cell polyomavirus (MCV)) that infect humans have been identified as an oncogene and have been associated with several human malignancies. Recently, growing attention has been attracted to exploring the pathogenesis of virus-related cancers. One of the most mysterious molecules involved in carcinogenesis and progression of virus-related cancers is circular RNAs (circRNA). These emerging non-coding RNAs (ncRNAs), due to the absence of 5' and 3' ends, have high stability than linear RNAs and are found in some species across the eukaryotic organisms. Compelling evidence has revealed that viruses also encode a repertoire of circRNAs, as well as dysregulation of these viral circRNAs play a critical role in the pathogenesis and progression of different types of virus-related cancers. Therefore, understanding the exact role and function of the virally encoded circRNAs with virus-associated cancers will open a new road for increasing our knowledge about the RNA world. Hence, in this review, we will focus on emerging roles of virus-encoded circRNAs in multiple cancers, including cervical cancer, gastric cancer, Merkel cell carcinoma, nasopharyngeal carcinoma, Kaposi cancer, and liver cancer.

The critical role of circular RNAs in drug resistance in gastrointestinal cancers.

Nowadays, drug resistance (DR) in gastrointestinal (GI) cancers, as the main reason for cancer-related mortality worldwide, has become a serious problem in the management of patients. Several mechanisms have been proposed for resistance to anticancer drugs, including altered transport and metabolism of drugs, mutation of drug targets, altered DNA repair system, inhibited apoptosis and autophagy, cancer stem cells, tumor heterogeneity, and epithelial-mesenchymal transition. Compelling evidence has revealed that genetic and epigenetic factors are strongly linked to DR. Non-coding RNA (ncRNA) interferences are the most crucial epigenetic alterations explored so far, and among these ncRNAs, circular RNAs (circRNAs) are the most emerging members known to have unique properties. Due to the absence of 5' and 3' ends in these novel RNAs, the two ends are covalently bonded together and are generated from pre-mRNA in a process known as back-splicing, which makes them more stable than other RNAs. As far as the unique structure and function of circRNAs is concerned, they are implicated in proliferation, migration, invasion, angiogenesis, metastasis, and DR. A clear understanding of the molecular mechanisms responsible for circRNAs-mediated DR in the GI cancers will open a new window to the management of GI cancers. Hence, in the present review, we will describe briefly the biogenesis, multiple features, and different biological functions of circRNAs. Then, we will summarize current mechanisms of DR, and finally, discuss molecular mechanisms through which circRNAs regulate DR development in esophageal cancer, pancreatic cancer, gastric cancer, colorectal cancer, and hepatocellular carcinoma.

Serum soluble Fas ligand is a severity and mortality prognostic marker for COVID-19 patients.

Finding cytokine storm initiator factors associated with uncontrolled inflammatory immune response is necessary in COVID-19 patients. The aim was the identification of Fas/Fas Ligand (FasL) role in lung involvement and mortality of COVID-19 patients. In this case-control study, mild (outpatient), moderate (hospitalized), and severe (ICU) COVID-19 patients and healthy subjects were investigated. RNA isolated from PBMCs for cDNA synthesis and expression of mFas/mFasL mRNA was evaluated by RT-PCR. Serum sFas/sFasL protein by ELISA and severity of lung involvement by CT-scan were evaluated. Also, we docked Fas and FasL via Bioinformatics software (in silico) to predict the best-fit Fas/FasL complex and performed molecular dynamics simulation (MDS) in hyponatremia and fever (COVID-19 patients), and healthy conditions. mFasL expression was increased in moderate and severe COVID-19 patients compared to the control group. Moreover, mFas expression showed an inverse correlation with myalgia symptom in COVID-19 patients. Elevation of sFasL protein in serum was associated with reduced lung injury and mortality. Bioinformatics analysis confirmed that blood profile alterations of COVID-19 patients, such as fever and hyponatremia could affect Fas/FasL complex interactions. Our translational findings showed that decreased sFasL is associated with lung involvement; severity and mortality in COVID-19 patients. We think that sFasL is a mediator of neutrophilia and lymphopenia in COVID-19. However, additional investigation is suggested. This is the first report describing that the serum sFasL protein is a severity and mortality prognostic marker for the clinical management of COVID-19 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.

Biochemical Aspects of Scaffolds for Cartilage Tissue Engineering; from Basic Science to Regenerative Medicine.

Chondral defects are frequent and important causes of pain and disability. Cartilage has limited self-repair and regeneration capacity. The ideal approach for articular cartilage defects is the regeneration of hyaline cartilage with sustainable symptom-free constructs. Tissue engineering provides new strategies for the regeneration of functional cartilage tissue through optimized scaffolds with architectural, mechanical, and biochemical properties similar to the native cartilage tissue. In this review, the basic science of cartilage structure, interactions between proteins, stem cells, as well as biomaterials, scaffold characteristics and fabrication methods, as well as current and potential therapies in regenerative medicine will be discussed mostly from a biochemical point of view. Furthermore, the recent trends in scaffold-based therapies and supplementary factors in cartilage tissue engineering will be considered.

Melatonin: A smart molecule in the DNA repair system.

DNA repair is an important pathway for the protection of DNA molecules from destruction. DNA damage can be produced by oxidative reactive nitrogen or oxygen species, irritation, alkylating agents, depurination and depyrimidination; in this regard, DNA repair pathways can neutralize the negative effects of these factors. Melatonin is a hormone secreted from the pineal gland with an antioxidant effect by binding to oxidative factors. In addition, the effect of melatonin on DNA repair pathways has been proven by the literature. DNA repair is carried out by several mechanisms, of which homologous recombination repair (HRR) and non-homologous end-joining (NHEJ) are of great importance. Because of the importance of DNA repair in DNA integrity and the anticancer effect of this pathway, we presented the effect of melatonin on DNA repair factors regarding previous studies conducted in this area.

Modulation of telomerase expression and function by miRNAs: Anti-cancer potential.

Telomerase is a nucleoprotein reverse transcriptase that maintains the telomere, a protective structure at the ends of the chromosome, and is active in cancer cells, stem cells, and fetal cells. Telomerase immortalizes cancer cells and induces unlimited cell division by preventing telomere shortening. Immortalized cancer cells have unlimited proliferative potential due to telomerase activity that causes tumorigenesis and malignancy. Therefore, telomerase can be a lucrative anti-cancer target. The regulation of catalytic subunit of telomerase (TERT) determines the extent of telomerase activity. miRNAs, as an endogenous regulator of gene expression, can control telomerase activity by targeting TERT mRNA. miRNAs that have a decreasing effect on TERT translation mediate modulation of telomerase activity in cancer cells by binding to TERT mRNA and regulating TERT translation. In this review, we provide an update on miRNAs that influence telomerase activity by regulation of TERT translation.

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.

Biological Effects of Hesperetin on Interleukin-6/Phosphorylated Signal Transducer and Activator of Transcription 3 Pathway Signaling in Prostate Cancer PC3 Cells.

BACKGROUND: Interleukin-6 (IL-6) is a multifunctional glycoprotein that regulates the growth of some tumors, including prostate carcinomas due to signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinases 1/2 (ERK1/2), and AKT signaling pathways. Hesperetin, as a flavanone, has several biological properties such as antitumor and anti-inflammatory. OBJECTIVE: This study was carried out to evaluate the biological effects of hesperetin on the IL-6 gene expression and phosphorylated STAT3, AKT, and ERK1/2 signaling pathways in PC3 prostate cancer (PC) cells. MATERIALS AND METHODS: In this study, we used real-time quantitative polymerase chain reaction (RT-qPCR) and ELISA to evaluate IL-6 gene expression and IL-6 protein secretion, respectively, in the treated PC3 cells with 0, 400, 450, and 500 µM of hesperetin. Cell survival studies were done by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay after 48 h treatment with hesperetin, and cell apoptosis was determined by flow cytometry. The protein levels of activated signaling molecules (pSTAT3, pAKT, and pERK1/2) analyzed by immunoprecipitation technique. RESULTS: Hesperetin-treated PC3 cells resulted in reduction of cell viability. Hesperetin led to the elevation of phosphorylated STAT3, ERK1/2, and AKT signaling proteins after 48 h in a dose-dependent manner as compared to the control cells. IL-6 gene expression, as well as protein level, significantly increased (P < 0.05) in a dose-dependent pattern in treated PC3 with hesperetin compared to the control cells. Further, hesperetin exposure resulted in the induction of cell cycle arrest at G0/G1 phase. CONCLUSION: Hesperetin in PC3 cells led to elevation IL-6 gene expression, IL-6 protein secretion, pSTAT3, pERK1/2 and pAKT intracellular signaling proteins. Our results indicate that hesperetin treatment leads to the inhibition of cell proliferation and the induction of cell cycle arrest at the G1 phase. Hesperetin can be considered a potent agent which synchronizes and stops cell cycle at G0/G1 phase to apply suitable chemotherapeutic agents and radiotherapy in PC cells. SUMMARY: This study evaluates biological effects of hesperetin on the cell cycle, interleukin-6 gene expression and some phosphorylated signaling pathways in PC3 prostate cancer cells. Hesperetin resulted in the inhibition of cell proliferation via inducing G0/G1 phase arrest in spite of the elevation of interleukin-6 gene expression and phosphorylated AKT, STAT3, and ERK1/2 intracellular signaling proteins. Therefore, hesperetin can be considered a potent agent which synchronizes and stop cell cycle at G0/G1 phase so that suitable chemotherapeutic agents can be applied in PC3 prostate cancer cells. Abbreviations Used: PC: Prostate cancer, IL-6: Interleukin-6, STAT3: Signal transducer activator of transcription 3, ERK1/2: Extracellular signal-regulated kinases 1/2, IC50: Inhibitory concentration of 50%.

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.