Quercetin: an effective polyphenol in alleviating diabetes and diabetic complications.

Various studies, especially in recent years, have shown that quercetin has beneficial therapeutic effects in various human diseases, including diabetes. Quercetin has significant anti-diabetic effects and may be helpful in lowering blood sugar and increasing insulin sensitivity. Quercetin appears to affect many factors and signaling pathways involved in insulin resistance and the pathogenesis of type 2 of diabetes. TNFα, NFKB, AMPK, AKT, and NRF2 are among the factors that are affected by quercetin. In addition, quercetin can be effective in preventing and ameliorating the diabetic complications, including diabetic nephropathy, cardiovascular complications, neuropathy, delayed wound healing, and retinopathy, and affects the key mechanisms involved in the pathogenesis of these complications. These positive effects of quercetin may be related to its anti-inflammatory and anti-oxidant properties. In this article, after a brief review of the pathogenesis of insulin resistance and type 2 diabetes, we will review the latest findings on the anti-diabetic effects of quercetin with a molecular perspective. Then we will review the effects of quercetin on the key mechanisms of pathogenesis of diabetes complications including nephropathy, cardiovascular complications, neuropathy, delayed wound healing, and retinopathy. Finally, clinical trials investigating the effect of quercetin on diabetes and diabetes complications will be reviewed.

Vitamin D in respiratory viral infections: a key immune modulator?

Respiratory viral infections are common respiratory diseases. Influenza viruses, RSV and SARS-COV2 have the potential to cause severe respiratory infections. Numerous studies have shown that unregulated immune response to these viruses can cause excessive inflammation and tissue damage. Therefore, regulating the antiviral immune response in the respiratory tract is of importance. In this regard, recent years studies have emphasized the importance of vitamin D in respiratory viral infections. Although, the most well-known role of vitamin D is to regulate the metabolism of phosphorus and calcium, it has been shown that this vitamin has other important functions. One of these functions is immune regulation. Vitamin D can regulate the antiviral immune response in the respiratory tract in order to provide an effective defense against respiratory viral infections and prevention from excessive inflammatory response and tissue damage. In addition, this vitamin has preventive effects against respiratory viral infections. Some studies during the COVID-19 pandemic have shown that vitamin D deficiency may be associated with a higher risk of mortality and sever disease in patients with COVID-19. Since, more attention has recently been focused on vitamin D. In this article, after a brief overview of the antiviral immune response in the respiratory system, we will review the role of vitamin D in regulating the antiviral immune response comprehensively. Then we will discuss the importance of this vitamin in influenza, RSV, and COVID-19.

Oxidized LDL-regulated microRNAs for evaluating vascular endothelial function: molecular mechanisms and potential biomarker roles in atherosclerosis.

As a simple monolayer, vascular endothelial cells can respond to physicochemical stimuli. In addition to promoting the formation of foam cells, oxidized low-density lipoprotein (ox-LDL) contributes to the atherosclerotic process through different mechanisms, including endothelial cell dysfunction. As conserved noncoding RNAs, microRNAs (miRNAs) naturally lie in different genomic positions and post-transcriptionally regulate the expression of many genes. They participate in integrated networks formed under stress to maintain cellular homeostasis, vascular inflammation, and metabolism. These small RNAs constitute therapeutic targets in different diseases, including atherosclerosis, and their role as biomarkers is crucial given their detectability even years before the emergence of diseases. This review was performed to investigate the role of ox-LDL-regulated miRNAs in atherosclerosis, their molecular mechanisms, and their application as biomarkers of vascular endothelial cell dysfunction.

From inflammatory bowel disease to colorectal cancer: what's the role of miRNAs?

Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease with relapse and remission periods. Ulcerative colitis and Crohn's disease are two major forms of the disease. IBD imposes a lot of sufferings on the patient and has many consequences; however, the most important is the increased risk of colorectal cancer, especially in patients with Ulcerative colitis. This risk is increased with increasing the duration of disease, thus preventing the progression of IBD to cancer is very important. Therefore, it is necessary to know the details of events contributed to the progression of IBD to cancer. In recent years, the importance of miRNAs as small molecules with 20-22 nucleotides has been recognized in pathophysiology of many diseases, in which IBD and colorectal cancer have not been excluded. As a result, the effectiveness of these small molecules as therapeutic target is hopefully confirmed. This paper has reviewed the related studies and findings about the role of miRNAs in the course of events that promote the progression of IBD to colorectal carcinoma, as well as a review about the effectiveness of some of these miRNAs as therapeutic targets.

Polyphenols and inflammatory bowel disease: Natural products with therapeutic effects?

Inflammatory bowel disease (IBD) is a long-life disease with periods of recurrence and relief. Oxidative stress plays an important role in the pathogenesis of this disease. Recent years' studies in the field of IBD treatment mostly have focused on targeting cytokines and immune cell trafficking using antibodies and inhibitors, altering the composition of intestinal bacteria in the line of attenuation of inflammation using probiotics and prebiotics, and attenuating oxidative stress through antioxidant supplementation. Studies in animal models of IBD have shown that some polyphenolic compounds including curcumin, quercetin, resveratrol, naringenin, and epigallocatechin-3-gallate can affect almost all of the above aspects and are useful compounds in the treatment of IBD. Clinical studies performed on IBD patients have also confirmed the findings of animal model studies and have shown that supplementation with some of the above-mentioned polyphenolic compounds has positive effects in reducing disease clinical and endoscopic activity, inducing and maintaining remission, and improving quality of life. In this review article, in addition to a detailed reviewing the effects of the above-mentioned polyphenolic compounds on the events involved in the pathogenesis of IBD, the results of these clinical studies will also be reviewed.

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.

CRISPR/Cas9 gene editing: a new approach for overcoming drug resistance in cancer.

The CRISPR/Cas9 system is an RNA-based adaptive immune system in bacteria and archaea. Various studies have shown that it is possible to target a wide range of human genes and treat some human diseases, including cancers, by the CRISPR/Cas9 system. In fact, CRISPR/Cas9 gene editing is one of the most efficient genome manipulation techniques. Studies have shown that CRISPR/Cas9 technology, in addition to having the potential to be used as a new therapeutic approach in the treatment of cancers, can also be used to enhance the effectiveness of existing treatments. Undoubtedly, the issue of drug resistance is one of the main obstacles in the treatment of cancers. Cancer cells resist anticancer drugs by a variety of mechanisms, such as enhancing anticancer drugs efflux, enhancing DNA repair, enhancing stemness, and attenuating apoptosis. Mutations in some proteins of different cellular signaling pathways are associated with these events and drug resistance. Recent studies have shown that the CRISPR/Cas9 technique can be used to target important genes involved in these mechanisms, thereby increasing the effectiveness of anticancer drugs. In this review article, studies related to the applications of this technique in overcoming drug resistance in cancer cells will be reviewed. In addition, we will give a brief overview of the limitations of the CRISP/Cas9 gene-editing technique.

Assessment of mucin and alpha-amylase levels in gingival crevicular fluid of chronic periodontitis patients.

BACKGROUND: Chronic periodontitis is the most common form of periodontitis. Several immune and inflammatory factors responsible for periodontal destruction have been found in gingival crevicular fluid (GCF). The current study was conducted to determine the correlation between mucin and alpha-amylase protein values in GCF with chronic periodontitis. METHOD: Forty-five patients with moderate-to-severe chronic periodontitis were selected. Samples of GCF were taken from a specific part of a single root tooth and placed in a closed test tube containing phosphate-buffered saline (PBS) (pH = 7). Sampling was done again after one month. Pre- and post-treatment samples were analyzed for measuring the levels of mucin and alpha-amylase proteins. RESULTS: Paired t test results for these two variables showed that the difference between mucin and alpha-amylase levels before and after treatment is significant. CONCLUSION: The level of both mucin and alpha-amylase in GCF in patients with chronic periodontitis was higher than that of patients who have recovered successfully; and evaluating the values of these two markers could be used to determine the activity of the periodontal disease.

Signaling, metabolism, and cancer: An important relationship for therapeutic intervention.

In cancerous cells, significant changes occur in the activity of signaling pathways affecting a wide range of cellular activities ranging from growth and proliferation to apoptosis, invasiveness, and metastasis. Extensive changes also happen with respect to the metabolism of a cancerous cell encompassing a wide range of functions that include: nutrient acquisition, biosynthesis of macromolecules, and energy generation. These changes are important and some therapeutic approaches for treating cancers have focused on targeting the metabolism of cancerous cells. Oncogenes and tumor suppressor genes have a significant effect on the metabolism of cells. There appears to be a close interaction between metabolism and the signaling pathways in a cancerous cell, in which the interaction provides the metabolic needs of a cancerous cell for uncontrolled proliferation, resistance to apoptosis, and metastasis. In this review, we have reviewed the latest findings in this regard and briefly review the most recent research findings regarding targeting the metabolism of cancer cells as a therapeutic approach for treatment of cancer.

The regulatory functions of circular RNAs in osteosarcoma.

Osteosarcoma (OS) is known as a malignant bone tumor affecting mainly children and younger adults. Despite all the improvements in the treatment of OS, the overall survival among patients remained mostly unsatisfied. It involves different mechanisms and signaling pathways. Some recent studies confirmed that circular RNAs (circRNAs) have a revelatory role in controlling OS cell proliferation, invasion, and metastasis. CircRNAs consist of a covalently closed-loop structure with neither 5' nor 3' poly adenylated tail, lacking protein-encoding ability formed by back-splicing mechanisms. They mainly act as microRNA (miRNA) sponges and modulate the downstream biological processes. Up/down regulation of some circRNAs demonstrated to serve as the oncogenic factor in some tumor tissues such as OS. In this article, we review the regulatory functions of circRNAs resulting in OS cell progression or restraint and the potential for being used in vitro or in vivo as diagnostic or therapeutic biomarkers.

CRISPR/Cas9 gene editing: A new therapeutic approach in the treatment of infection and autoimmunity.

CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein9) may be viewed as an adaptive bacterial immune system. When a virus infects a bacterium, a fragment of the virus genome is inserted into the CRISPR sequence of the bacterial genome as a memory. When the bacterium becomes infected again with the same virus, an RNA molecule that is a transcript of the memory sequence, directs Cas9, an endonuclease, to the complementary region of the virus genome, and Cas9 disables the virus by a double-strand break. In recent years, studies have shown that by designing synthetic RNA molecules and delivering them along with Cas9 into eukaryotic cells, different regions of the cell's genome can be targeted and manipulated. These findings have drawn much attention to this new technology and it has been shown that CRISPR/Cas9 gene editing can be used to treat some human diseases. These include infectious diseases and autoimmune diseases. In this review article, in addition to a brief overview of the biology of the CRISPR/Cas9 system, we collected the most recent findings on the applications of CRISPR/Cas9 technology for better investigation of the pathogenesis and treatment of viral infections (human immunodeficiency virus infection, hepatitis virus infections, and onco-virus infections), non-viral infections (parasitic, fungal, and bacterial infections), and autoimmune diseases.

The anticancer effects of curcumin via targeting the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway.

The mammalian target of rapamycin (mTOR) is a protein kinase that has been considered as a key regulator of a large number of cellular processes, including cell growth, proliferation, differentiation, survival, and motility. Overactivation of mTOR (especially mTORC1) signaling is related to oncogenic cellular processes. Therefore targeting mTORC1 signaling is a new promising strategy in cancer therapy. In this regard, various studies have shown that curcumin, a polyphenol produced from the turmeric rhizome, has anti-inflammatory, antioxidant and anticancer properties. Curcumin may exert its anticancer function, at least in part, by suppressing mTOR-mediated signaling pathway in tumor cells. However, the exact underlying mechanisms by which curcumin blocks the mTORC1 signaling remain unclear. According to literature, curcumin inhibits insulin-like growth factor 1 (IGF-1)/phosphoinositide 3-kinase (PI3K)/Akt/mTORC1 pathway which leads to apoptosis and cell cycle arrest via suppression of erythroblastosis virus transcription factor 2 and murine double minute 2 oncoprotein. In addition, activation of unc-51-like kinase 1 by curcumin, as a downstream target of IGF-1/PI3K/Akt/mTORC1 axis, enhances autophagy. Curcumin induces AMP-activated protein kinase, a negative regulator of mTORC1, via inhibition of F0F1-ATPase. Interestingly, curcumin suppresses IκB kinase ß, the upstream kinase in mTORC1 pathway. Moreover, evidence revealed that curcumin downregulates the E3-ubiquitin ligases NEDD4, neural precursor cell-expressed developmentally downregulated 4. NEDD4 is frequently overexpressed in a wide range of cancers and degrades the phosphatase and tensin homolog, which is a negative regulator of mTORC1. Finally another suggested mechanism is suppression of MAOA/mTORC1/hypoxia-inducible factor 1α signaling pathway by curcumin.

Association of serum 25-OH vitamin D3 with serum IgE and the Pediatric Asthma Severity Score in patients with pediatric asthma.

Background: Pediatric asthma is a prevalent disease and has a significant immunologic and inflammatory nature. In recent years, the role of vitamin D3 in immunologic processes has been studied, and many aspects of this role have been clarified in some human diseases. Objective: The aim of this study was to evaluate the relationship among the vitamin D3 status, Pediatric Asthma Severity Score (PASS), and inflammatory indicators of pediatric asthma. Methods: Among all of the pediatric patients with asthma and with asthma exacerbation, 100 patients were randomly enrolled in the study and subdivided into three groups according to serum levels of 25-OH vitamin D3. The control group consisted of 100 sex- and age-matched healthy subjects. Asthma exacerbation severity was evaluated based on the PASS before starting the medical care. The count of the white blood cells, eosinophil count, and serum levels of total immunoglobulin E (IgE) plus 25-OH vitamin D3 were measured in all the subjects. The obtained data were then compared via proper statistical tests. A p value of <0.05 was considered as statistically significant. Results: The median level of serum IgE was increased in patients with vitamin D3 deficiency compared with other groups. There was a significant inverse correlation between serum levels of 25-OH vitamin D3 and IgE in pediatric patients with asthma (r = -0.483, p = 0.001). Furthermore, the serum levels of 25-OH vitamin D3 also significantly inversely correlated with the PASS (r = -0.285, p = 0.004). Conclusion: Vitamin D3 deficiency is associated with exacerbation severity and serum IgE levels in patients with pediatric asthma; hence, it can have an important role in pediatric asthma pathogenesis, possibly through IgE.

MiRNAs and inflammatory bowel disease: An interesting new story.

Inflammatory bowel disease (IBD), as a chronic and recurrent inflammatory disorder, is caused by a dysregulated and aberrant immune response to exposed environmental factors in genetically susceptible individuals. Despite huge efforts in determining the molecular pathogenesis of IBD, an increasing worldwide incidence of IBD has been reported. MicroRNAs (miRNAs) are a set of noncoding RNA molecules that are about 22 nucleotides long, and these molecules are involved in the regulation of the gene expression. By clarifying the important role of miRNAs in a number of diseases, their role was also considered in IBD; numerous studies have been performed on this topic. In this review, we attempt to summarize a number of studies and discuss some of the recent developments in the roles of miRNAs in the pathophysiology, diagnosis, and treatment of IBD.

The interplay of Klotho with signaling pathway and microRNAs in cancers.

Klotho (KL) gene has been accepted as an "aging suppressor" gene that encodes a single transmembrane protein in human known as Klotho which is commonly expressed in renal tubes. The interruption in the secretion of Klotho protein expedites aging whereas its high expression extends lifespan. The family of Klotho proteins has been reported to act as distinct receptors for endocrine fibroblast growth factors (FGFs), which manage multifarious metabolic processes. Further, the secreted Klotho is a hormonal factor that takes part in the ion channel organization. Numerous studies determined that this protein affects the function of a number of important signaling pathways, which may present an impact in tumorigenesis via the coordination of receptors located on them. This review article focuses on the effects of microRNAs on the performance of Klotho and how the interplay between Klotho and certain pathways like insulin-like growth factor, FGF, Wnt, and transforming growth factor ß contribute to the biogenesis of cancer. The present study is also pointed at defining the molecular mechanisms of these interactions.

The crosstalk between trace elements with DNA damage response, repair, and oxidative stress in cancer.

DNA damage response (DDR) is a regulatory system responsible for maintaining genome integrity and stability, which can sense and transduce DNA damage signals. The severity of damage appears to determine DDRs, which can include damage repair, cell-cycle arrest, and apoptosis. Furthermore, defective components in DNA damage and repair machinery are an underlying cause for the development and progression of various types of cancers. Increasing evidence indicates that there is an association between trace elements and DDR/repair mechanisms. In fact, trace elements seem to affect mediators of DDR. Besides, it has been revealed that oxidative stress (OS) and trace elements are associated with cancer development. In this review, we discuss the role of some critical trace elements in the risk of cancer. In addition, we provide a brief introduction on DDR and OS in cancer. Finally, we will further review the interactions between some important trace elements including selenium, zinc, chromium, cadmium, and arsenic, and DDR, and OS in cancer.

The role of microRNAs in the healing of diabetic ulcers.

MicroRNAs (miRNAs) are small protected molecules with a length of 18 to 25 nucleotides. Many studies have recently been conducted on miRNAs, illustrating their role in regulating many biological, physiological, and pathological activities, such as maintaining cellular signalling and regulating cellular pathways. The main role of miRNAs is to regulate the expression of genes after translation, which can lead to the destruction or suppression of translation by binding to mRNAs. As any change in the regulation of miRNAs is associated with several physiological abnormalities, such as type 2 diabetes and its complications, these molecules can be used for therapeutic purposes or as biomarkers for the diagnosis of diseases such as diabetes and its complications. In this review article, we will discuss important findings about the miRNAs and the role of these molecules in different phases of the wound-healing process of chronic wounds, especially diabetic ulcer.

Some of the effective factors in the pathogenesis of gastro-oesophageal reflux disease.

Oesophageal adenocarcinoma is one of the most fatal tumours to affect the digestive tract and is the eighth most common malignancy worldwide. Gastro-oesophageal reflux has an important role in the incidence of adenocarcinoma of the oesophagus. Gastro-oesophageal reflux disease (GERD) is a multifactorial, acid-peptic disorder that results from the reflux of noxious material from the stomach into the oesophagus. The refluxed material causes the occurrence of oesophageal inflammation which creates a condition that is called reflux oesophagitis. The prevalence of this disease has increased dramatically in recent decades, mostly in the western world, where it affects about 10% to 30% of the population. The aetiology of oesophageal mucosal damage is complicated. Many inflammatory mediators are produced within the gastrointestinal (GI) tract, but their contributions in pathophysiology and disease pathogenesis have not been well investigated. Despite the protective barrier provided by the oesophageal mucosa, refluxed materials can cause oxidative injury and in?ammatory responses that involve the epithelium and immune cells. The analysing cellular events in gastro- oesophageal reflux disease and physiological responses to such conditions are important and necessary for a better grasp of the pathogenesis of GERD and the expansion of new treatments. Therefore, we want to discuss some of the important and key factors of GERD disease in this article.

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.

Paraoxonase-2 variants potentially influence insulin resistance, beta-cell function, and their interrelationships with alanine aminotransferase in type 2 diabetes.

BACKGROUND: The aim of this study was to determine whether insulin resistance, beta-cell function, and their associations with alanine aminotransferase (ALT) are affected by the functional variants of paraoxonase-2 (PON2) as an intracellular antioxidant in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: Quantitative insulin sensitivity check index (QUICKI) and homeostasis model assessment for beta-cell function (HOMA-BCF) were assessed in T2D patients. Insulin levels were determined using ELISA. The variants PON2-A148G and PON2-S311C were genotyped using polymerase chain reaction-based restriction fragment length polymorphism. RESULTS: According to the PON2-G148A variant, ALT was found to be significantly correlated with QUICKI (r = -0.616, P = 0.005) and HOMA-BCF (r = 0.573, P = 0.01) in the GA + GG group; however, the correlations were not statistically significant in the AA genotypes. Based on the genotypes of PON2-S311C, there was a significant correlation between ALT with QUICKI (r = -0.540, P = 0.031) and HOMA-BCF (r = 0.567, P = 0.022) in the SC + CC group. In the multiple adjusted logistic regression analyses, considering the variants PON2-G148A and PON2-C311S as independent variables and QUICKI and HOMA-BCF as the dependent variables, both variants were significantly associated with the QUICKI (P = 0.019 for PON2-G148A and P = 0.041 for PON2-C311S). Furthermore, PON2-C311S remained significantly associated with HOMA-BCF (P = 0.03). CONCLUSION: These data implicate a role for the functional variants of PON2 in insulin resistance and beta-cell function as well as underscore the effective role of these variants in the associations between them and ALT. Our data contribute to our understanding of the important physiologic functions of PON2 in glucose metabolism and its related metabolic diseases.