The role of inflammasome complex in ischemia-reperfusion injury.

Ischemia-reperfusion injury refers to a temporary interruption of blood flow in a tissue. Restoration of blood flow initiates the inflammation in tissue causing ischemic damage through the activation of a multiprotein complex termed inflammasome. The complex contains a receptor, mainly a member of nucleotide oligomerization domain-like receptors, that receives danger signals. The receptor is oligomerized as a response to danger signals and then the apoptosis-associated speck-like protein containing a caspase recruitment domain and procaspase protein are added to the oligomerized receptors to form the inflammasome complex. In the next step, the isolated procaspase is converted into an active caspase molecule that initiates the inflammation through the release of interleukin-1ß and interleukin-18. The inflammasome has an important role in the pathogenesis of ischemia-reperfusion injury in different tissues. Here, we summarized the role of inflammasome in the pathogenesis of ischemia-reperfusion of brain, liver, kidney, and heart. Moreover, we highlighted the expression of inflammasome components, the mechanisms involved in activation of the complex, and its inhibition as an optimistic therapeutic technique in ischemia-reperfusion injuries.

Curcumin: A therapeutic strategy for targeting the Helicobacter pylori-related diseases.

Helicobacter pylori is a significant human pathogen of the stomach's epithelial lining. This type of carcinogen is associated with gastric cancer, indigestion, peptic ulcers, and upper digestive diseases. Therefore, successful treatment and eradication of this bacterium are required to reduce the prevalence of these diseases, especially in high-risk individuals. Moreover, some concerns exist regarding the extensive use of elimination therapy, such as anti-microbial resistance and rising H. pylori-associated diseases. Since there is still no effective vaccine, finding alternative therapies would appear to be a worthwhile pursuit. In this regard, curcumin exhibits anti-inflammatory, anti-carcinogenic, anti-oxidant properties and is widely used as a natural product-derived medicine or nutraceutical. Furthermore, curcumin has been reported to have anti-bacterial activity. Therefore, curcumin might be an effective herbal-based medicine for preventing, managing, or treating H. pylori infection. This review discusses the anti-inflammatory, anti-cancer, and anti-bacterial properties of curcumin as it pertains to gastric cancer and H. pylori-associated diseases.

Diffusion-weighted magnetic resonance imaging at 1.5 T for peripheral zone prostate cancer: the influence of the b-value combination on the diagnostic performance of apparent diffusion coefficient.

Purpose: Diffusion-weighted imaging as a noninvasive functional modality plays a valuable role in the evaluation of prostate cancer. However, there is still no agreement on the number and range of b-values to be used. Therefore, the purpose of this study is to investigate the influence of b-value choice on the diagnostic performance of apparent diffusion coefficient (ADC) values for prostate cancer detection. Material and methods: Fifty-nine consecutive patients with abnormal digital rectal examination findings and raised serum prostate-specific antigen were chosen for magnetic resonance imaging of the prostate before systematic 12-core trans-rectal ultrasound-guided prostate biopsies. ADC values for each ROI were calculated from different b-value combinations (0-1600 s/mm2) by a monoexponential model. Mann-Whitney and the paired-sample t-test were used to compare the mean ADC values for malignant lesions and noncancerous tissues. ROC curve analysis was used to evaluate the diagnostic performance of ADC values in distinguishing prostate cancer from normal-tissue ROIs. Results: The differences between mean ADC values of malignant lesions and contralateral healthy tissues were significant for all the pairs of b-value combinations. The pair of b-values 50 and 1200 provided the highest AUC (0.94), with a sensitivity of 90.2%, a specificity of 92.6%, and an accuracy of 91.2% at an ADC cut-off of 1.23 × 10-3 mm2/s. Conclusions: Our study showed that using a 1.5-Tesla MRI scanner the diagnostic performance of ADC values estimated from the b-value pair 50 and 1200 s/mm2 was highest. However, some other b-value pairs provided statically comparable diagnostic performance.

Evaluation of the Effect of Crocin on Doxorubicin-Induced Cardiotoxicity.

Despite newer advances in cancer treatment, chemotherapy is still one of the most widely used treatment strategies in this field. However, this treatment strategy faces major challenges. Doxorubicin (Dox) is an effective chemotherapeutic agent used to treat various cancers. However, several studies have shown that the use of Dox in therapeutic concentrations is associated with serious side effects, such as cardiac toxicity. The use of natural products in combination with chemotherapeutic agents to reduce side effects is a novel approach, and several studies have shown promising results. In this regard, we examined the effect of Crocin on doxorubicin-induced cardiotoxicity in rat and H9c2 cell line. The in vitro model on H9C2 cells and the in vivo models on rats were treated with doxorubicin. Cell viability, DNA damage, and apoptosis were measured in H9C2 cell line in the presence and absence of Crocin. Oxidative stress and various inflammatory parameters, as well as cardiac function tests, also were assessed in doxorubicin-induced cardiotoxicity animal model in the presence and absence of Crocin. Our results showed that Crocin can significantly decrease apoptosis in H9C2 cell line through a reduction in ROS production and DNA damages. Moreover, evaluation of the effect of Crocin on doxorubicin-induced cardiotoxicity animal model showed that Crocin also can significantly reduce oxidative stress and inflammatory parameters in the serum of the animals. Assessment of cardiac function revealed that Crocin has a significant protective effect against doxorubicin-induced cardiotoxicity in the animal model. Our data indicate that Crocin significantly attenuated doxorubicin-induced cardiotoxicity. Hence, Crocin could be potentially used as an adjuvant treatment in combination with Dox to reduce cardiotoxicity.

An update on enterovirus 71 infection and interferon type I response.

Enteroviruses are members of Pichornaviridae family consisting of human enterovirus group A, B, C, and D as well as nonhuman enteroviruses. Hand, foot, and mouth disease (HFMD) is a serious disease which is usually seen in the Asia-Pacific region in children. Enterovirus 71 and coxsackievirus A16 are two important viruses responsible for HFMD which are members of group A enterovirus. IFN α and ß are two cytokines, which have a major activity in the innate immune system against viral infections. Most of the viruses have some weapons against these cytokines. EV71 has two main proteases called 2A and 3C, which are important for polyprotein processing and virus maturation. Several studies have indicated that they have a significant effect on different cellular pathways such as interferon production and signaling pathway. The aim of this study was to investigate the latest findings about the interaction of 2A and 3C protease of EV71 and IFN production/signaling pathway and their inhibitory effects on this pathway.

Harnessing CRISPR/Cas 9 System for manipulation of DNA virus genome.

The recent development of the Clustered Regularly Interspaced Palindromic Repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) system, a genome editing system, has many potential applications in virology. The possibility of introducing site specific breaks has provided new possibilities to precisely manipulate viral genomics. Here, we provide diagrams to summarize the steps involved in the process. We also systematically review recent applications of the CRISPR/Cas9 system for manipulation of DNA virus genomics and discuss the therapeutic potential of the system to treat viral diseases.

Curcumin Delivery Mediated by Bio-Based Nanoparticles: A Review.

Todays, nano-pharmaceutics is emerging as an important field of science to develop and improve efficacy of different drugs. Although nutraceuticals are currently being utilized in the prevention and treatment of various chronic diseases such as cancers, a number of them have displayed issues associated with their solubility, bioavailability, and bio-degradability. In the present review, we focus on curcumin, an important and widely used polyphenol, with diverse pharmacological activities such as anti-inflammatory, anti-carcinogenic, anti-viral, etc. Notwithstanding, it also exhibits poor solubility and bioavailability that may compromise its clinical application to a great extent. Therefore, the manipulation and encapsulation of curcumin into a nanocarrier formulation can overcome these major drawbacks and potentially may lead to a far superior therapeutic efficacy. Among different types of nanocarriers, biological and biopolymer carriers have attracted a significant attention due to their pleiotropic features. Thus, in the present review, the potential protective and therapeutic applications of curcumin, as well as different types of bio-nanocarriers, which can be used to deliver curcumin effectively to the different target sites will be discussed.

Fractionated radiotherapy might induce epithelial-mesenchymal transition and radioresistance in a cellular context manner.

Despite the fact that radiotherapy is a main therapeutic modality in cancer treatment, recent evidence suggests that fractionated radiotherapy (FR) might confer radioresistance through epithelial-mesenchymal transition (EMT). Nevertheless, the effects of FR on EMT phenotype and the potential link between EMT induction and radioresistance development yet to be clarified. The aim of this study was to assess whether FR could promote EMT, and to elucidate if induction of EMT contributes to the acquisition of radioresistance. To this end, two human cancer cell lines (A549 and HT-29) were irradiated (2 Gy/day) and analyzed using wound healing, transwell migration and invasion assays, real-time polymerase chain reaction (for E-cadherin, N-cadherin, Vimentin, CD44, CD133, Snail, and Twist), clonogenic assay, Annexin V/PI, and 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. Irradiation of A549 (for 5 or 10 consecutive days) resulted in morphological changes including elongation of cytoplasm and nuclei and pleomorphic nuclei. Also, irradiation-enhanced migratory and invasive potential of A549. These phenotypic changes were in agreement with decreased expression of the epithelial marker (E-cadherin), enhanced expression of mesenchymal markers (N-cadherin, Vimentin, Snail, and Twist) and increased stemness factors (CD44 and CD133). Moreover, induction of EMT phenotype was accompanied with enhanced radioresistance and proliferation of irradiated A549. However, FR (for 5 consecutive days) did not increase HT-29 motility. Furthermore, molecular alterations did not resemble EMT phenotype (downregulation of E-cadherin, Vimentin, ALDH, CD44, CD133, and Snail). Eventually, FR led to enhanced radiosensitivity and decreased proliferation of HT-29. Altogether, our findings suggest that FR might induce EMT and confer radioresistance in a cell context-dependent manner.

The interplay between microRNAs and Twist1 transcription factor: a systematic review.

Twist1 (also known as Twist) is a transcription factor that belongs to the family of basic helix-loop-helix (bHLH) proteins. It functions as a negative regulator of epithelial gene expression and a positive regulator of mesenchymal gene expression, thereby leading to induction of the epithelial mesenchymal transition (EMT), a process in which epithelial cells acquire the motile and migratory characteristics of mesenchymal cells. In addition to regulating the expression of protein-coding genes, Twist1 regulates the expression of microRNAs (miRNAs), adding a regulatory layer to EMT induction. Interestingly, the mRNA of Twist1 represents a downstream target of miRNAs, indicating an intricate network between miRNAs and Twist1. This network was shown to play multiple roles in cancer cell migration, invasion, and metastasis. The network can induce angiogenesis, protect cells from oncogene-induced apoptosis and senescence, enhance cancer cell resistance to conventional therapies, and increase cancer stem cell (CSC) populations. Recently, miRNAs have attracted considerable attention as potential promising tools in cancer therapies. Thus, this systematic review was conducted to clarify the reciprocal link between Twist1 and miRNAs in order to provide potential candidate miRNAs for diagnostic and therapeutic approaches in cancer treatment.

CRISPR-Cas System: A Promising Diagnostic Tool for Covid-19.

More than a year has passed since the beginning of the 2019 novel coronavirus diseases (COVID-19) pandemic which has created massive problems globally affecting all aspects of people's life. Due to the emergence of new strains of the SARS-CoV-2, pandemic risk still remains, despite the start of vaccination. Therefore, rapid diagnostic tests are essential to control infection, improve clinical care and stop the spread of the disease. Recently CRISPR-based diagnostic tools have facilitated rapid diagnostic. Here, we review the diagnostic applications of CRISPR-Cas system in COVID-19.

Non-coding RNAs and epithelial mesenchymal transition in cancer: molecular mechanisms and clinical implications.

Epithelial-mesenchymal transition (EMT) is a fundamental process for embryonic development during which epithelial cells acquire mesenchymal characteristics, and the underlying mechanisms confer malignant features to carcinoma cells such as dissemination throughout the organism and resistance to anticancer treatments. During the past decades, an entire class of molecules, called non-coding RNA (ncRNA), has been characterized as a key regulator of almost every cellular process, including EMT. Like protein-coding genes, ncRNAs can be deregulated in cancer, acting as oncogenes or tumor suppressors. The various forms of ncRNAs, including microRNAs, PIWI-interacting RNAs, small nucleolar RNAs, transfer RNA-derived RNA fragments, long non-coding RNAs, and circular RNAs can orchestrate the complex regulatory networks of EMT at multiple levels. Understanding the molecular mechanism underlying ncRNAs in EMT can provide fundamental insights into cancer metastasis and may lead to novel therapeutic approaches. In this review, we describe recent advances in the understanding of ncRNAs in EMT and provide an overview of recent ncRNA applications in the clinic.

Effect of Ionizing Radiation on the Transcript Variants Expression of p21 Gene.

PURPOSE: CDK1A is one of the most important genes that have different key roles in cell lines. This gene has several transcript variants. Investigating of expression of each one actually can be so important because any one of them may have a separate unknown role in cancer cells so can be used to increase therapeutic efficacy. METHODS: A549, MDA-MB-231 and Hek-AD cell lines were used in this study. Firstly, three primers for variants of p21 gene were designed by Snapgene and BLAST software. Secondly, the variants expression was checked for each cell lines by RT-qPCR technique, separately. Then the variants that expressed in the cells were selected for more investigation. Finally 2 Gy irradiation was used to evaluate the effect of that on variants expression. RESULTS: The results show that for all cell lines, primer num1 and 3 expressed before any stimuli. After irradiation, for MDA-MB-231 and A549, the expression of primer num3 was decreased, while for Hek-AD no change was observed. The primer num1 expression after the irradiation was different for the cells, V1 expression was decreased in A549 by fold of 0.03 while expression of this for MDA-MB-231 cells was not changed after 2Gy irradiation. CONCLUSION: It is very necessary to pay attention to the function of each splice variant as well as the response to external stimuli. Understanding the role of each variant in a gene is critical and researchers can use that to improve radiotherapy as well.

Curcumin: A Dietary Phytochemical for Targeting the Phenotype and Function of Dendritic Cells.

Dendritic cells (DCs) are the most powerful antigen-presenting cells which link the innate and adaptive immune responses. Depending on the context, DCs initiate the immune responses or contribute to immune tolerance. Any disturbance in their phenotypes and functions may initiate inflammatory or autoimmune diseases. Hence, dysregulated DCs are the most attractive pharmacological target for the development of new therapies aiming at reducing their immunogenicity and at enhancing their tolerogenicity. Curcumin is the polyphenolic phytochemical component of the spice turmeric with a wide range of pharmacological activities. It acts in several ways as a modulator of DCs and converts them into tolerogenic DCs. Tolerogenic DCs possess anti-inflammatory and immunomodulatory activities that regulate the immune responses in health and disease. Curcumin by blocking maturation markers, cytokines and chemokines expression, and disrupting the antigen-presenting machinery of DCs render them non- or hypo-responsive to immunostimulants. It also reduces the expression of co-stimulatory and adhesion molecules on DCs and prevents them from both migration and antigen presentation but enhances their endocytosis capacity. Hence, curcumin causes DCs-inducing regulatory T cells and dampens CD4+ T helper 1 (Th1), Th2, and Th17 polarization. Inhibition of transcription factors such as NF-κB, AP-1, MAPKs (p38, JNK, ERK) and other intracellular signaling molecules such as JAK/STAT/SOCS provide a plausible explanation for most of these observations. In this review, we summarize the potential effects of curcumin on the phenotypes and functions of DCs as the key players in orchestration, stimulation, and modulation of the immune responses.

Targeted Delivery of CRISPR/Cas13 as a Promising Therapeutic Approach to Treat SARS-CoV-2.

On a worldwide scale, the outbreak of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to extensive damage to the health system as well as the global economy. Hitherto, there has been no approved drug or vaccine for this disease. Therefore, the use of general antiviral drugs is at the first line of treatment, though complicated with limited effectiveness and systemic side effects. Given the pathophysiology of the disease, researchers have proposed various strategies not only to find a more specific therapeutic way but also to reduce the side effects. One strategy to accomplish these goals is to use CRISPR/Cas13 system. Recently, a group of scientists has used the CRISPR/Cas13 system, which is highly effective in eliminating the genome of RNA viruses. Due to the RNA nature of the coronavirus genome, it seems that this system can be effective against the disease. The main challenge regarding the application of this system is to deliver it to the target cells efficiently. To solve this challenge, it seems that using virosomes with protein S on their membrane surface can be helpful. Studies have shown that protein S interacts with its specific receptor in target cells named Angiotensin-Converting Enzyme 2 (ACE2). Here, we propose if CRISPR/Cas13 gene constructs reach the infected cells efficiently using a virosomal delivery system, the virus genome will be cleaved and inactivated. Considering the pathophysiology of the disease, an important step to implement this hypothesis is to embed protein S on the membrane surface of virosomes to facilitate the delivery of gene constructs to the target cells.

New epigenetic players in stroke pathogenesis: From non-coding RNAs to exosomal non-coding RNAs.

Non-coding RNAs (ncRNAs) have critical role in the pathophysiology as well as recovery after ischemic stroke. ncRNAs, particularly microRNAs, and the long non-coding RNAs (lncRNAs) are critical for angiogenesis and neuroprotection, and they have been suggested to be therapeutic, diagnostic and prognostic tools in cerebrovascular diseases, including stroke. Moreover, exosomes have been considered as nanocarriers capable of transferring various cargos, such as lncRNAs and miRNAs to recipient cells, with prominent inter-cellular roles in the mediation of neuro-restorative events following strokes and neural injuries. In this review, we summarize the pathogenic role of ncRNAs and exosomal ncRNAs in the stroke.

Autophagy and gastrointestinal cancers: the behind the scenes role of long non-coding RNAs in initiation, progression, and treatment resistance.

Gastrointestinal (GI) cancers comprise a heterogeneous group of complex disorders that affect different organs, including esophagus, stomach, gallbladder, liver, biliary tract, pancreas, small intestine, colon, rectum, and anus. Recently, an explosion in nucleic acid-based technologies has led to the discovery of long non-coding RNAs (lncRNAs) that have been found to possess unique regulatory functions. This class of RNAs is >200 nucleotides in length, and is characterized by their lack of protein coding. LncRNAs exert regulatory effects in GI cancer development by affecting different functions such as the proliferation and metastasis of cancer cells, apoptosis, glycolysis and angiogenesis. Over the past few decades, considerable evidence has revealed the important role of autophagy in both GI cancer progression and suppression. In addition, recent studies have confirmed a significant correlation between lncRNAs and the regulation of autophagy. In this review, we summarize how lncRNAs play a behind the scenes role in the pathogenesis of GI cancers through regulation of autophagy.

Therapeutic Potential of the miRNA-ATM Axis in the Management of Tumor Radioresistance.

The ataxia-telangiectasia mutated (ATM) protein kinase is widely known for its function as a chief mobilizer of the DNA damage response (DDR) upon DNA double-strand breaks. ATM orchestrates the DDR by modulating the expression of various miRNAs through several mechanisms. On the other hand, a set of miRNAs contribute to tight regulation of ATM by directly targeting the 3'-untranslated region of ATM mRNA. This review addresses the therapeutic application and molecular mechanisms that underlie the intricate interactions between miRNAs and ATM. It also describes therapeutic delivery of miRNAs in different environments such as hypoxic tumor microenvironments.

Bismuth-Based Nanomaterials: Recent Advances in Tumor Targeting and Synergistic Cancer Therapy Techniques.

Despite all of the efforts in the field of cancer therapy, the heterogeneous properties of tumor cells induce an insufficient therapeutic outcome when treated with conventional monotherapies, necessitating a shift in cancer treatment from monotherapy to combination therapy for complete cancer treatment. Multifunctional bismuth (Bi)-based nanomaterials (NMs) with therapeutic functions hold great promise for the fields of cancer diagnosis and therapy based on their low toxicity, X-ray sensitive capabilities, high atomic number, near-infrared driven semiconductor properties, and low cost. Herein, a comprehensive review of recent advances in various medicinal aspects of Bi-based NMs is presented including: evaluation of in-tumor site accumulation, tumor targeting, and therapeutic performance, as well as the characteristics, benefits, and shortcomings of Bi-based NM-mediated major monotherapies. In addition, the cooperative enhancement mechanisms between two or more of these monotherapies are described in detail to address common challenges in cancer therapy, such as multidrug resistance, hypoxia, and metastasis. Finally, this review opens new insights into the design of multimodal synergistic therapies for potential future clinical applications of Bi-based NMs.

Vitamin D receptor ApaI (rs7975232), BsmI (rs1544410), Fok1 (rs2228570), and TaqI (rs731236) gene polymorphisms and susceptibility to pulmonary tuberculosis in an Iranian population: A systematic review and meta-analysis.

Polymorphisms of vitamin D receptors (VDRs), ApaI, BsmI, FokI, and TaqI might affect susceptibility to tuberculosis (TB). In this systematic review and meta-analysis, all published articles which investigated the effects of these polymorphisms on the risk of TB in the Iranian population were retrieved. PubMed and Scopus were searched with no date or language restrictions. In this meta-analysis, the Comprehensive Meta-Analysis (CMA) version 2.0 and random effects model were applied. The association of polymorphisms with TB risk was assessed by measuring the odds ratio (ORs) at 95% CI. Heterogeneity was investigated based on Cochran Q-test and I2-index statistics. The significance level was set at 0.05. Also, Egger's regression intercept was determined to measure publication bias. A total of six articles on Iranian populations were included. TaqI (5/6 included studies) showed a significant association with the increased risk of TB based on ORs (allele comparison: 1.57 (1.0, 2.3), p-value: 0.02; additive model of tt/TT: 1.57 (0.9, 2.5), p-value: 0.05; recessive model (tt/Tt + TT): 1.99 (1.2, 3.2), p-value: 0.00; dominant model (tt + Tt/TT): 1.98 (1.1, 3.5), p-value: 0.01). BsmI showed a significant positive effect on TB risk only in its dominant genotype (bb + bB/BB) (1.44 (1.0, 1.9); p-value: 0.02). FokI and ApaI did not show any significant effects on TB development in Iranian populations. Findings showed the significant effect of TaqI polymorphism in all genetic models and the dominant model of BsmI on the increased risk of TB. However, the effects of TaqI and BsmI should be further investigated in a larger sample size.

Vitamin D receptor genetic polymorphisms and the risk of multiple sclerosis: A systematic review and meta-analysis.

There are conflicting results regarding the exact effect of the vitamin D receptor (VDR) gene polymorphisms on the susceptibility to multiple sclerosis (MS). Therefore, we aimed to investigate the impact of four major studied VDR gene polymorphisms consisting of ApaI, BsmI, FokI, and TaqI on the risk of MS in the Iranian population. A literature search was performed in various databases to find case-control studies evaluating the association between VDR gene polymorphisms and MS risk in Iran. Data were extracted and odds ratios (OR) with 95% confidence intervals (CI) were calculated. Subgroup analyze was performed to detect potential sources of heterogeneity. A total of 1206 cases and 1402 controls in nine case-control studies were included. ApaI was the only variant which showed statistically significant relation in allelic (OR = 0.54 (95% CI: 0.37-0.79); P = 0.00), homozygote (OR = 3.48 (95% CI: 1.7-6.9); P = 0.00), dominant (OR = 0.56 (95% CI: 0.3-0.79); P = 0.01), and recessive (OR = 0.35 (95% CI: 0.18-0.66); P = 0.00) models. The TaqI polymorphism showed a significant negative association with MS only in the homozygote model (OR = 0.28 (95% CI: 0.08-0.9); P = 0.04). The BsmI polymorphism also showed significant relation in allelic (OR = 0.69 (95% CI: 0.51-0.94); P = 0.01), homozygote (OR = 0.46 (95% CI: 0.25-0.86); P = 0.01), and recessive OR = 0.56 (95% CI: 0.39-0.8); P = 0.00) models after performing sensitivity analysis. FokI polymorphism showed no significant association with MS risk. ApaI and TaqI TT genotype were found contributing to MS susceptibility and BsmI and FokI showed no relation with MS susceptibility in the Iranian population.