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.

MicroRNAs, DNA damage response and ageing.

Ageing is a multifactorial and integrated gradual deterioration affecting the most of biological process of cells. MiRNAs are differentially expressed in the cellular senescence and play important role in regulating of genes expression involved in features of ageing. The perception of miRNAs functions in ageing regulation can be useful in clarifying the mechanisms underlying ageing and designing of therapeutic strategies. The preservation of genomic integrity through DNA damage response (DDR) is related to the process of cellular senescence. The recent studies have shown that miRNAs has directly regulated the expression of numerous proteins in DDR pathways. In this review study, DDR pathways, miRNA biogenesis and functions, current finding on DDR regulations, molecular biology of ageing and the role of miRNAs in these processes have been studied. Finally, a brief explanation about the therapeutic function of miRNAs in ageing regarding its regulation of DDR has been provided.

An investigation of the effects of curcumin on iron overload, hepcidin level, and liver function in ß-thalassemia major patients: A double-blind randomized controlled clinical trial.

This study investigated the effects of curcumin, the active polyphenol in turmeric, on iron overload, hepcidin level, and liver function in ß-thalassemia major patients. This double-blind randomized controlled clinical trial was conducted on 68 ß-thalassemia major patients. The subjects were randomly divided into 2 groups to receive either 500 mg curcumin capsules (total: 1,000 mg) twice daily or placebo for 12 weeks. Dietary intakes and biochemical variables including hemoglobin, transferrin saturation, total iron binding capacity, nontransferrin bound iron (NTBI), ferritin, hepcidin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were assessed at the beginning and end of the trial. Curcumin significantly reduced serum levels of NTBI (2.83 ± 1.08 compared with 2.22 ± 0.97 µmol/L, p = .001), ALT (42.86 ± 11.15 compared with 40.60 ± 9.89 U/L, p = .018), and AST (49.45 ± 12.39 compared with 46.30 ± 10.85 U/L, p = .002) at the end of the study. Based on analysis of covariance, a significant decrease was also observed in levels of NTBI (2.22 ± 0.97 vs. 2.55 ± 0.94 µmol/L, p = .026), ALT (40.60 ± 9.89 vs. 45.01 ± 10.42 U/L, p = .004), and AST (46.30 ± 10.85 vs. 50.99 ± 9.36 U/L, p = .009) in curcumin group in comparison with placebo group. There were no significant changes in hepcidin and other variables in any of the 2 groups. Curcumin administration alleviated iron burden and liver dysfunction by reducing NTBI, ALT, and AST levels in patients with ß-thalassemia major.

The effects of high doses of selenium supplementation on mRNA and protein levels of cMLCK levels and total antioxidant capacity in rat heart tissue.

BACKGROUND: High doses of selenium are associated with heart disease prevalence in high-risk areas. Cardiac myosin light chain kinase (cMLCK) is an essential enzyme for normal function of heart tissue. Therefore, we studied the effect of high doses of selenium on the expression of cMLCK gene and its protein in normal heart tissue in rats. MATERIALS AND METHODS: Twenty male rats were randomly divided into four groups: control, Se 0.3mg/kg, Se 1.5mg/kg, and Se 3mg/kg. Sodium-selenite was administered orally into drinking water for 20 weeks. Se levels of heart tissue were measured by atomic absorption. Serum creatine phosphokinase (CPK) and total serum antioxidant capacity were measured. Moreover, the concentration of MLCK protein and the gene expression level of cMLCK in normal heart tissue were analyzed. RESULTS: Excess Se in dietary can significantly increase CPK. Se concentration of heart tissue in the Se 3mg/kg group was significantly higher than the control. cMLCK mRNA levels were decreased by 0.3mg/kg and 3mg/kg sodium selenite intake. There was no significant difference between the three groups for total antioxidant capacity and MLCK protein. CONCLUSION: High concentrations of selenium can probably effect on normal function of the heart tissue by changing the expression levels of cMLCK.

Importance of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs) in cancer cells.

Background: In most regions, cancer ranks the second most frequent cause of death following cardiovascular disorders. Aim: In this article, we review the various aspects of glycolysis with a focus on types of MCTs and the importance of lactate in cancer cells. Results and Discussion: Metabolic changes are one of the first and most important alterations in cancer cells. Cancer cells use different pathways to survive, energy generation, growth, and proliferation compared to normal cells. The increase in glycolysis, which produces substances such as lactate and pyruvate, has an important role in metastases and invasion of cancer cells. Two important cellular proteins that play a role in the production and transport of lactate include lactate dehydrogenase and monocarboxylate transporters (MCTs). These molecules by their various isoforms and different tissue distribution help to escape the immune system and expansion of cancer cells under different conditions.

The Potential Preventive and Therapeutic Roles of NSAIDs in Prostate Cancer.

Prostate cancer (PC) is the second most common type of cancer and the leading cause of death among men worldwide. Preventing the progression of cancer after treatments such as radical prostatectomy, radiation therapy, and hormone therapy is a major concern faced by prostate cancer patients. Inflammation, which can be caused by various factors such as infections, the microbiome, obesity and a high-fat diet, is considered to be the main cause of PC. Inflammatory cells are believed to play a crucial role in tumor progression. Therefore, nonsteroidal anti-inflammatory drugs along with their effects on the treatment of inflammation-related diseases, can prevent cancer and its progression by suppressing various inflammatory pathways. Recent evidence shows that nonsteroidal anti-inflammatory drugs are effective in the prevention and treatment of prostate cancer. In this review, we discuss the different pathways through which these drugs exert their potential preventive and therapeutic effects on prostate cancer.

DNA repair pathways as a novel therapeutic strategy in esophageal cancer: A review study.

Esophageal cancer (EC) is a common malignancy with a poor prognosis worldwide. There are two core pathways that repair double-strand breaks, homologous recombination (HR) and non-homologous end joining (NHEJ) and numerous proteins are recognized that affect the occurrence of HR and NHEJ. Altered DNA damage response (DDR) pathways are associated with cancer susceptibility and affect therapeutic response and resistance in cancers. DDR pathway alterations in EC are still poorly understood. Therefore, the identification of alterations in specific genes in DDR pathways may potentially result in novel treatments for resistant cancers, especially EC. In this review, we aimed to focus on different aspects of DNA damage and repair processes in EC. Also, we reviewed new therapeutic strategies via targeting DNA repair machinery components.

MicroRNAs in esophageal squamous cell carcinoma: Application in prognosis, diagnosis, and drug delivery.

MicroRNAs (miRNAs) play a vital role in various cell biology processes, including cancer formation. These small non-coding RNAs could function as diagnostic and prognostic markers. They may involve esophageal squamous cell carcinoma (ESCC) and distinctive miRNA expression profiles; they are also known as therapeutic targets in human diseases. Therefore, in this study, the function of miRNAs was reviewed regarding the prognosis and diagnosis of ESCC. The changes in miRNAs before and after cancer therapy and the effects of miRNAs on chemo-susceptibility patterns were also investigated. MiRNA delivery systems in ESCC were also highlighted, providing a perspective on how these systems can improve miRNA efficiency.

Evaluation of biochemical characteristics of 183 COVID-19 patients: A retrospective study.

INTRODUCTION AND AIM: Coronavirus disease 2019 (COVID-19), with a high mortality rate, has caught the eyes of researchers worldwide and placed a heavy burden on the health care system. Accordingly, this study aimed to evaluate the values of biochemical parameters on the outcomes of COVID-19 patients in Golestan, Iran. MATERIALS AND METHODS: This retrospective study was conducted on 183 COVID-19 patients (i.e., 94 males and 89 females) between March and September 2020. The biochemical parameters and demographic data of the patients (including age, sex, urea, creatinine [Cr], lactate dehydrogenase [LDH], and creatine kinase [CK]) were obtained from electrical medical records. According to the outcome of COVID-19, the patients were categorized into two groups (i.e., death [n = 63] and survival [n = 120] groups), and the biochemical parameters and outcomes of COVID-19 were analyzed. RESULTS: Of the 183 patients, 120 (65.5%) had a non-severe type and recovered from COVID-19, and 63 (34.4%) developed into a critically severe type and died. The mean age of all patients was 56.5 years old. The highest mortality was observed in patients with LDH ≥280. The data obtained by the one-sample t-test showed that there were significantly higher mean values of urea, Cr, CK, and LDH in COVID-19 patients when compared to their reference intervals (P˂0.0001 for all). CONCLUSIONS: Some biochemical parameters are effective in the evaluation of dynamic variations in COVID-19 patients. It can be concluded from the results that biochemical parameters and reinforce LDH may be useful for the evaluation of the COVID-19 outcome.

Chitosan-based biomaterials for the treatment of bone disorders.

Bone is an alive and dynamic organ that is well-differentiated and originated from mesenchymal tissues. Bone undergoes continuous remodeling during the lifetime of an individual. Although knowledge regarding bones and their disorders has been constantly growing, much attention has been devoted to effective treatments that can be used, both from materials and medical performance points of view. Polymers derived from natural sources, for example polysaccharides, are generally biocompatible and are therefore considered excellent candidates for various biomedical applications. This review outlines the development of chitosan-based biomaterials for the treatment of bone disorders including bone fracture, osteoporosis, osteoarthritis, arthritis rheumatoid, and osteosarcoma. Different examples of chitosan-based formulations in the form of gels, micro/nanoparticles, and films are discussed herein. The work also reviews recent patents and important developments related to the use of chitosan in the treatment of bone disorders. Although most of the cited research was accomplished before reaching the clinical application level, this manuscript summarizes the latest achievements within chitosan-based biomaterials used for the treatment of bone disorders and provides perspectives for future scientific activities.

Oncostatic activities of melatonin: Roles in cell cycle, apoptosis, and autophagy.

Melatonin, the major secretory product of the pineal gland, not only regulates circadian rhythms, mood, and sleep but also has actions in neoplastic processes which are being intensively investigated. Melatonin is a promising molecule which considered a differentiating agent in some cancer cells at both physiological and pharmacological concentrations. It can also reduce invasive and metastatic status through receptors MT1 and MT2 cytosolic binding sites, including calmodulin and quinone reductase II enzyme, and nuclear receptors related to orphan members of the superfamily RZR/ROR. Melatonin exerts oncostatic functions in numerous human malignancies. An increasing number of studies report that melatonin reduces the invasiveness of several human cancers such as prostate cancer, breast cancer, liver cancer, oral cancer, lung cancer, ovarian cancer, etc. Moreover, melatonin's oncostatic activities are exerted through different biological processes including antiproliferative actions, stimulation of anti-cancer immunity, modulation of the cell cycle, apoptosis, autophagy, the modulation of oncogene expression, and via antiangiogenic effects. This review focuses on the oncostatic activities of melatonin that targeted cell cycle control, with special attention to its modulatory effects on the key regulators of the cell cycle, apoptosis, and telomerase activity.

Oncostatic activities of melatonin: Roles in cell cycle, apoptosis, and autophagy.

Melatonin, the major secretory product of the pineal gland, not only regulates circadian rhythms, mood, and sleep but also has actions in neoplastic processes which are being intensively investigated. Melatonin is a promising molecule which considered a differentiating agent in some cancer cells at both physiological and pharmacological concentrations. It can also reduce invasive and metastatic status through receptors MT1 and MT2 cytosolic binding sites, including calmodulin and quinone reductase II enzyme, and nuclear receptors related to orphan members of the superfamily RZR/ROR. Melatonin exerts oncostatic functions in numerous human malignancies. An increasing number of studies report that melatonin reduces the invasiveness of several human cancers such as prostate cancer, breast cancer, liver cancer, oral cancer, lung cancer, ovarian cancer, etc. Moreover, melatonin's oncostatic activities are exerted through different biological processes including antiproliferative actions, stimulation of anti-cancer immunity, modulation of the cell cycle, apoptosis, autophagy, the modulation of oncogene expression, and via antiangiogenic effects. This review focuses on the oncostatic activities of melatonin that targeted cell cycle control, with special attention to its modulatory effects on the key regulators of the cell cycle, apoptosis, and telomerase activity.

Melatonin and doxorubicin co-delivered via a functionalized graphene-dendrimeric system enhances apoptosis of osteosarcoma cells.

A functionalized graphene-dendrimeric system was designed via Fe3O4 nanoparticle (NP) as a magnetic nanocarrier for co-delivery of doxorubicin (DOX) and melatonin (MLT). Accordingly, ß-Cyclodextrin (ß-CD) was modified by creating amine functional groups. The modified ß-CD was grafted with Graphene oxide (GO), and the resulting platform gain many functional groups, including the hydroxyl (-OH), carboxylic acid (-COOH), and amine functional groups (-NH2). Finally, magnetic NPs were synthesized on the prepared platform to efficiently controlling and targeting drugs to tumor sites. The human osteosarcoma cell lines including Saos-2 and MG-63, as well as Human Bone Marrow Mesenchymal Stem Cells (hBM-MSC) line, were used to determine the in vitro biological effects of the functionalized graphene-dendrimeric system. The magnetic nanocarrier has encapsulation efficiency (EE) values of 99.92% for DOX and 21.5% for MLT. The biocompatibility tests of the nanocarrier revealed that the magnetic nanocarrier was appropriate as a drug carrier. Co-delivery of DOX and MLT with an efficiently anticancer performance was also was confirmed by cellular uptake, 4',6-diamidino-2-phenylindole (DAPI) staining, and apoptosis analysis in comparison with free DOX and MLT. Moreover, there was a synergy in the antitumor effect when MLT was combined with DOX, especially in the nano-formulation form, which may be due to the down-regulation of X-linked Inhibitor of Apoptosis (XIAP), survivin, and human telomerase catalytic subunit (hTERT) (p < 0.0001). Overall, the result of our study suggests that the designed carrier is a promising nanocarrier for targeted co-delivery of DOX and MLT with improved anticancer efficacy in cancer cells and thus reduced toxicity in normal cells.

Shelterin Complex at Telomeres: Implications in Ageing.

Different factors influence the development and control of ageing. It is well known that progressive telomere shorting is one of the molecular mechanisms underlying ageing. The shelterin complex consists of six telomere-specific proteins which are involved in the protection of chromosome ends. More particularly, this vital complex protects the telomeres from degradation, prevents from activation of unwanted repair systems, regulates the activity of telomerase, and has a crucial role in cellular senescent and ageing-related pathologies. This review explores the organization and function of telomeric DNA along with the mechanism of telomeres during ageing, followed by a discussion of the critical role of shelterin components and their changes during ageing.

miRNA-29a reverses P-glycoprotein-mediated drug resistance and inhibits proliferation via up-regulation of PTEN in colon cancer cells.

Colon cancer is a serious malignant type of cancer in the world. Acquisition of multi-drug resistance (MDR) during chemotherapy is still a controversial challenge during cancer treatment. Accordingly, detection of safe and impressive MDR-reversing targets such as microRNAs (miRNAs/miRs) can play critical role in cancer treatment. Here, the functional effects of miR-29a in chemo-resistant colon cancer cells is scrutinized. The effect of doxorubicin (DOX) on cell proliferation after miR-29a transfection has been evaluated using MTT assay in HT29 and HT29/DOX cells. Rhodamine123 (Rh123) assay is used to identify the activity of common drug efflux through membrane transporters P-glycoprotein (P-gp). P-gp and PTEN mRNA/protein expression levels were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analyses. Flow cytometry was employed to the investigation of apoptosis. ANOVA followed by Bonferroni's and Sidak's tests were used to compare the data from different groups. Thus, it was shown that miRNA-29a overexpression considerably inhibited the HT29/DOX viability. miR-29a significantly down-regulated P-gp expression and activity in HT29/DOX cells and declined drug resistance through elevation of intracellular DOX. Furthermore, upon miRNA-29a transfection, PTEN expression could be restored in resistant cells. These results have indicated that miR-29a target PTEN ultimately P-gp, which is downstream of PTEN, inhibit drug resistance, proliferation, and apoptosis through PI3K/Akt pathway. As a result, miR-29a overexpression is led to enhance the sensitivity of HT29/DOX cells to DOX-treatment by targeting P-gp. MiR-29a might proffer a novel promising candidate for colon cancer therapeutics during chemotherapy.

Effect of Rubus anatolicus Leaf Extract on Glucose Metabolism in HepG2, CRI-D2 and C2C12 Cell Lines.

INTRODUCTION: The aim of this study was to assess the effects of Rubus anatolicus on glucose metabolism in HepG2, CRI-D2 and C2C12 cell lines. MATERIALS AND METHODS: R. anatolicus was collected in Golestan province, Iran. Three different cell lines HepG2 (human liver cell), CRI-D2 (mice pancreatic cell) and C2C12 (rat myoblast) were used for cell culture experiments. Cell viability was measured using MTT assay. Cells were treated with various concentrations of the extract (6.25-400 µg/mL) and then the extracellular glucose level and intracellular glycogen content were measured using colorimetric methods. The insulin level of the culture medium was measured using the ELISA method. RESULTS: Our findings showed that R. anatolicus extract enhances glucose uptake and consumption by all three cell lines. The R. anatolicus extract exposure also elevated cellular glycogen content in HepG2 and C2C12 cells (for 200 and 100 µg/mL) significantly. We found a significant increase in glucose uptake and consequently higher stimulation of insulin secretion in CRI-D2 cell pancreatic cells treated with R. anatolicus extract. CONCLUSION: The R. anatolicus appears to activate glucose uptake and cellular glycogen synthesis probably by activating the glycogenesis or inhibition of glycogenolysis pathways. The extract enhances insulin secretion in the pancreatic cells by increased glucose uptake.

Nanocrystalline cellulose: Preparation, physicochemical properties, and applications in drug delivery systems.

Cancer is the leading cause of death all over the world and chemotherapy is an important approach to fight cancer, however, there are many obstacles against successful cancer chemotherapy such as development of multidrug resistance, poor solubility of chemotherapeutic agents and adverse side effects to healthy tissues. An important strategy to overcome these obstacles, is the use of nanotechnology. In recent years, natural polymers such as cellulose and its nanoform structure, nanocrystalline cellulose (NCC), have attracted the interest of researchers in the field of nanotechnology and specially drug delivery systems, due to biocompatibility and biodegradability of NCC. Cellulose is the most abundant natural biopolymer and changes to NCC by several chemical and mechanical methods. In this review, we mainly focus on the methods for production of NCC, physicochemical properties and medical applications of NCC (e.g. regenerative medicine, replacement of vascular grafts, tissue engineering, anti-bacterial/anti-viral applications, diagnosis and biosensing) with a special emphasize on drug delivery systems.

Suppression of p53R2 gene expression with specific siRNA sensitizes HepG2 cells to doxorubicin.

INTRODUCTION: p53R2 is a p53-inducible protein that contributes to DNA repair by providing dNTPs in response to DNA damage. The roles of p53R2 in cancer cells and malignancies still remain controversial. Herein, we examined the effects of p53R2 silencing on HepG2 human hepatocellular carcinoma (HHC) cell line (wild-type p53) viability, apoptosis and cell cycle arrest in the presence and absence of doxorubicin. METHODS: Cell transfection was performed using a liposomal approach. Gene silencing was determined by quantitative real-time PCR and western blot analysis. To evaluate the cell growth rate after transfection, trypan blue dye exclusion assay was employed. The cytotoxicity of the doxorubicin and p53R2 siRNA as single agents or in combination against HepG2 cell was analyzed by MTT assay and the drug combination effects was evaluated by calculating the combination index. The effects of treatments on different stages of cell cycle were analyzed by flow cytometry using propidium iodide (PI) and induction of apoptosis was assessed using DNA-histone ELISA. RESULTS: We found that silencing of p53R2 alone had a strong effect on growth inhibition and spontaneous apoptosis in HepG2 cells. p53R2 siRNA synergistically enhanced the cytotoxic effect of doxorubicin. Furthermore, when used in combination with doxorubicin (0.4µM), a significant increase in the rate of apoptosis was observed (P<0.05). Moreover, cell cycle at S and G2/M phases progressed at a lower rate after p53R2 combination treatment compared with doxorubicin mono-therapy. CONCLUSION: These findings suggest that siRNA-mediated silencing of p53R2 has great potential as a therapeutic tool and adjuvant in chemotherapy.