Circular RNAs in tuberculosis: From mechanism of action to potential diagnostic biomarker.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tuberculosis), continues to be a major global health concern. Understanding the molecular intricacies of TB pathogenesis is crucial for developing effective diagnostic and therapeutic approaches. Circular RNAs (circRNAs), a class of single-stranded RNA molecules characterized by covalently closed loops, have recently emerged as potential diagnostic biomarkers in various diseases. CircRNAs have been demonstrated to modulate the host's immunological responses against TB, specifically by reducing monocyte apoptosis, augmenting autophagy, and facilitating macrophage polarization. This review comprehensively explores the roles and mechanisms of circRNAs in TB pathogenesis. We also discuss the growing body of evidence supporting their utility as promising diagnostic biomarkers for TB. By bridging the gap between fundamental circRNA biology and TB diagnostics, this review offers insights into the exciting potential of circRNAs in combatting this infectious disease.

Lansoprazole as a potent HDAC2 inhibitor for treatment of colorectal cancer: An in-silico analysis and experimental validation.

BACKGROUND: Histone deacetylase 2 (HDAC2), belonging to the class I HDAC family, holds significant therapeutic potential as a crucial target for diverse cancer types. As key players in the realm of epigenetic regulatory enzymes, histone deacetylases (HDACs) are intricately involved in the onset and progression of cancer. Consequently, pursuing isoform-specific inhibitors targeting histone deacetylases (HDACs) has garnered substantial interest in both biological and medical circles. The objective of the present investigation was to employ a drug repurposing approach to discover novel and potent HDAC2 inhibitors. MATERIALS AND METHODS: In this study, our protocol is presented on virtual screening to identify novel potential HDAC2 inhibitors through 3D-QSAR, molecular docking, pharmacophore modeling, and molecular dynamics (MD) simulation. Afterward, In-vitro assays were employed to evaluate the cytotoxicity, apoptosis, and migration of HCT-116 cell lines under treatment of hit compound and valproic acid as a control inhibitor. The expression levels of HDAC2, TP53, BCL2, and BAX were evaluated by QRT-PCR. RESULTS: RMSD, RMSF, H-bond, and DSSP analysis results confirmed that among bioinformatically selected compounds, lansoprazole exhibited the highest HDAC2 inhibitory potential. Experimental validation revealed that lansoprazole displayed significant antiproliferative activity. The determined IC50 value was 400 ± 2.36 µM. Furthermore, the apoptotic cells ratio concentration-dependently increased under Lansoprazole treatment. Results of the Scratch assay indicated that lansoprazole led to decreasing the migration of CRC cells. Finally, under Lansoprazole treatment the expression level of BCL2 and HDAC2 decreased and BAX and TP53 increased. CONCLUSION: Taking together the results of the current study indicated that Lansoprazole as a novel HDAC2 inhibitor, could be used as a potential therapeutic agent for the treatment of CRC. Although, further experimental studies should be performed before using this compound in the clinic.

Surfaceome Profiling Suggests Potential of Anti-MUC1×EGFR Bispecific Antibody for Breast Cancer Targeted Therapy.

Breast cancer (BC) treatment has traditionally been challenging due to tumor heterogeneity. Bispecific antibodies (bsAbs) offer a promising approach for overcoming these challenges by targeting multiple specific epitopes. In the current study, we designed a new bsAb against the most common BC cell surface proteins (SPs). To achieve this, we analyzed RNA-sequencing data to identify differentially expressed genes, which were further evaluated using Gene Ontology enrichment, Hidden Markov Models, clinical trial data, and survival analysis to identify druggable gene-encoding cell SPs. Based on these analyses, we constructed and expressed a bsAb targeting the mucin 1 (MUC1) and epidermal growth factor receptor (EGFR) proteins, which are the dominant druggable gene-encoding cell SPs in BC. The recombinant anti-MUC1×EGFR bsAb demonstrated efficient production and high specificity for MUC1 and EGFR + cell lines and BC tissue. Furthermore, the bsAb significantly reduced the proliferation and migration of BC cells. Our results suggested that simultaneous targeting with bsAbs could be a promising targeted therapy for improving the overall efficacy of BC treatment.

Genotyping of Environmental Isolates of Acanthamoeba in Hamadan, West of Iran.

Background: Different genotypes of Acanthamoeba have been abundantly isolated in environmental samples such as water, soil, and dust, as well as in different hospital departments and eyewash stations. This protozoan is a potential hazard for immunocompromised patients and contact lens wearers. The aim of the present study was isolation and genotyping of environmental and corneal isolates of Acanthamoeba in Hamadan, west of Iran. Methods: During 2018-2020, a total of 104 environmental samples including, water, soil, and dust and 16 corneal scraping samples were collected and investigated for the presence of Acanthamoeba using morphological and molecular identification tools. Genotypes were determined using sequence analysis of the diagnostic fragment 3 (DF3) from Acanthamoeba-specific amplimer S1 (ASA.S1) gene. Phylogenetic tree was constructed with the MEGA7 software using Neighbor-Joining method. Results: The presence of Acanthamoeba spp. was determined in 87.5% of water, 53.1% of soil, and 25% of dust samples. From 30 dust samples collected from eight wards of three hospitals, 7 (23.3%) were contaminated with Acanthamoeba. Sequencing analysis of environmental samples revealed that the T4 genotype was the most prevalent (92.6%) one. Genotypes T2 (1.9%), T2/T6 (1.9%), and mixed T4 and T2/T6 (3.7%) were also identified in environmental samples. Acanthamoeba was seen in none of the examined corneal scraping samples from patients with suspected keratitis. Conclusion: The widespread occurrence of this potentially pathogenic amoeba in most hospital wards and environmental resources and areas of the region highlights a strong need to increase awareness regarding this ubiquitous amoeba among susceptible individuals, such as immunocompromised patients and contact lens wearers.

Prognostic biomarkers and molecular pathways mediating Helicobacter pylori-induced gastric cancer: a network-biology approach.

Cancer of the stomach is the second most frequent cancer-related death worldwide. The survival rate of patients with gastric cancer (GC) remains fragile. There is a requirement to discover biomarkers for prognosis approaches. Helicobacter pylori in the stomach is closely associated with the progression of GC. We identified the genes associated with poor/favorable prognosis in H. pylori-induced GC. Multivariate statistical analysis was applied on the Gene Expression Omnibus (GEO) dataset GSE54397 to identify differentially expressed miRNAs (DEMs) in gastric tissues with H. pylori-induced cancer compared with the H. pylori-positive with non-cancerous tissue. A protein interaction map (PIM) was built and subjected to DEMs targets. The enriched pathways and biological processes within the PIM were identified based on substantial clusters. Thereafter, the most critical genes in the PIM were illustrated, and their prognostic impact in GC was investigated. Considering p-value less than 0.01 and |Log2 fold change| as >1, five microRNAs demonstrated significant changes among the two groups. Gene functional analysis revealed that the ubiquitination system, neddylation pathway, and ciliary process are primarily involved in H. pylori-induced GC. Survival analysis illustrated that the overexpression of DOCK4, GNAS, CTGF, TGF-b1, ESR1, SELE, TIMP3, SMARCE1, and TXNIP was associated with poor prognosis, while increased MRPS5 expression was related to a favorable prognosis in GC patients. DOCK4, GNAS, CTGF, TGF-b1, ESR1, SELE, TIMP3, SMARCE1, TXNIP, and MRPS5 may be considered prognostic biomarkers for H. pylori-induced GC. However, experimental validation is necessary in the future.

Polymorphisms in vitamin D receptor genes and its relation with susceptibility to brucellosis: a case-control study.

OBJECTIVE: One of the systemic infections is Brucellosis which is caused by facultative intracellular bacteria of the genus Brucella. Vitamin D is a fat-soluble prohormone, that metabolizes enzymes and its intracellular receptor creates the active hormone and also mediate in responses of immune system. METHODS: Current research consists of 102 patients with brucellosis who were selected based on culture, PCR results serology, and clinical symptoms. The control group composed of 102 healthy people. The polymorphism of genes (Bsm I, Fok I, Taq I, Apa I) encoding Vitamin D receptor (VDR) were assessed by the PCR-RFLP method. RESULTS: The results showed that ff, tt, aa, and bb genotypes in Fok I, ApaI, TaqI, and BsmI were significant in case/control groups (P-value ≤ 0.0001). The genotype frequency AA in the control group is higher than that of the study group, while genotype frequency aa in the study group is more than the control. The odds ratio for brucellosis in individuals with ff genotype is 37 times higher than that of Ff genotype. Also, the odds ratio of brucellosis in individuals with genotype tt, aa, and bb was 12, 53, and 6 times higher than those of the Aa, Bb, and Tt genotypes. CONCLUSION: The genotypes aa and ff in the positions of the ApaI and FokI are of higher importance. The brucellosis risk in individuals accompanied aa genotype at Apa I is 53 times higher than that of the genotype AA, in other words, AA and BB, TT and FF genotypes are protective against the disease.

A Novel Hyperthermostable Recombinant Protein Nanocage

Background: Background: Ferritin has an important role in iron storage in the cells, and due to its nanocage structure and self-assembly properties, it has wide application prospects in nanobiotechnology. Methods: Methods: The maize (Zea mays) ferritin gene ZmFer1 was cloned and expressed in Escherichia coli BL21 (DE3) for the first time. Change in macromolecular structure of ZmFer1 ferritin due to heat treatment was investigated using native PAGE electrophoresis, dynamic light scattering (DLS), and transmission electron microscopy (TEM). Change in the secondary structures of the protein was evaluated using circular dichroism spectroscopy. Moreover, alteration in the conformation of the protein was evaluated using UV-absorption spectra and intrinsic fluorescence spectra. The melting temperature (Tm) of ZmFer1 was obtained using differential scanning calorimetry (DSC). Finally, the effect of heat on the function of ZmFer1 was assessed by iron loading ability. Results: Results: The purified ZmFer1 protein showed a homopolymer nanocage structure. The results of native PAGE electrophoresis, DLS, and TEM techniques showed that ZmFer1 protein nanocage is stable to heat treatment up to 90 °C, and some of the protein nanocages retain their macromolecular structures even at 100 °C in liquid aqueous solution. Based on the DSC results, ZmFer1 protein nanocage had a Tm of 81.9 °C. After treatment at 100 °C, stable ZmFer1 protein nanocages were able to store iron atoms. Conclusion: Conclusion: Recombinant ZmFer1 ferritin with a Tm > 80°C is a hyperthermostable protein nanocage. The results of this study are beneficial for the development of protein nanocages that are stable under extreme temperature conditions, as well as application of ZmFer1 in nanobiotechnology, biomaterials, and biomedical fields.

Role of EFNA1 SNP (rs12904) in Tumorigenesis and Metastasis of Colorectal Cancer: A Bioinformatic Analysis and HRM SNP Genotyping Verification.

OBJECTIVE: Colorectal cancer is a prevalent disease with a poor prognosis and is known as a heterogeneous disease with many differences in clinical Symptoms and molecular profiles. The present study aimed to systematically evaluate the association of SNPs in miRNA binding sites of target genes that are involved in CRC angiogenesis, epithelial to mesenchymal transition, and cytoskeleton organization with tumorigenesis and metastasis of CRC. METHODS: A case-control study was performed on 146 samples of CRC patients and 132 healthy samples. After that, the DNA of all samples was isolated by the salting-out method. Finally, the genotypes for EFNA1 SNP (rs12904) were identified by HRM (High-resolution melting analysis) method. In order to evaluate the results of genotyping, two samples from each genotype were sequenced using the sanger sequencing method. RESULT: The frequency of AA genotype and the frequency of GG for rs12904 in satge4 and other stages are different from each other (P-value <0.0001) (P-value = 0.008). Also, the frequency of AA genotype in patients with different grades is different from each other (P-value = 0.035), while the frequency of AG   genotype and the frequency of GG   genotype is not significantly different in patients with different grades (P-value = 0.377) (P-value = 0.284). CONCLUSION: Results of this study indicated that patients carrying the GA and GG genotypes reduced the risk of disease progression compared to the AA genotype. As a result, this polymorphism plays a key role in CRC pathogenesis and metastasis and could be used as a biomarker in molecular diagnosis and metastatic state prediction in the near future after further study of its signaling pathways and molecular mechanism.

AS1411 aptamer-functionalized exosomes in the targeted delivery of doxorubicin in fighting colorectal cancer.

Severe side effects of chemotherapy agents on vital organs are the major causes of cancer-related mortality, not merely cancer disease. Encapsulating chemotherapeutic molecules in nanocarriers is a justifiable solution in decreasing the risk of their side effects and boosting the efficiency of treatment. The present study has developed the doxorubicin (DOX)-loaded AS1411 (anti-nucleolin) aptamer surface-functionalized exosome (DOX-Apt-Exo) to treat colorectal cancer in both in-vitro and in-vivo experimental models. HEK293-derived exosomes were loaded with DOX through the incubation method with a nearly 13% encapsulation efficiency. Afterwards, the 5-terminal carboxyl group of AS1411-aptamer was converted into amine-reactive NHS esters with EDC/NHS amide coupling chemistry before being conjugated to the amine groups on the exosome surface. DLS and TEM estimated the designed formulation (DOX-Apt-Exo) size of about 200 nm. Aptamer-binding affinity and cellular uptake of DOX-Apt-Exo by nucleolin-overexpressing cancer cells were depicted through fluorescence microscopy. Comparing the in-vitro cytotoxicity impact of DOX-loaded exosomes, either targeted or non-targeted by MTT assay, clearly verified a high effectiveness of ligand-receptor mediated target therapy. Subsequently, in-vivo experiments which were conducted on four groups of ectopic mouse models of colon cancer (5 in each group) demonstrated the tumor growth suppression through professional long-term accumulation and retention of DOX-Apt-Exo at the tumor site by ligand-receptor interaction. The results suggested that AS1411 aptamer-functionalized exosomes can be recommended as a safe and effective system to site-specific drug delivery in possible clinical applications of colon cancer.

miR-1290 contributes to oncogenesis and angiogenesis via targeting of THBS1, DKK3 and, SCAI.

Introduction: Colorectal cancer (CRC) is the third most common cancer in the world with high mortality, hence, understanding the molecular mechanisms involved in the tumor progression are important for CRC diagnosis and treatment. MicroRNAs (miRNAs) are key gene expression regulators that can function as tumor suppressors or oncogenes in tumor cells, and modulate angiogenesis as a critical process in tumor metastasis. MiR-1290 has been demonstrated as an onco-miRNA in various types of cancer, however, the role of miR-1290 in CRC is not fully understood. This study aimed to investigate the oncogenic and angiogenic potential of miR-1290 in CRC. Methods: Lenti-miR-1290 was transduced into HCT116, SW480, and human umbilical vein endothelial cells (HUVECs). By bioinformatics analysis, we identified thrombospondin 1 (THBS1) as a novel predicted target for miR-1290. Quantitative real-time PCR, western blotting, and luciferase reporter assay were used to demonstrate suppression of miR-1290 target genes including THBS1, Dickkopf Wnt signaling pathway inhibitor 3 (DKK3), and suppressor of cancer cell invasion (SCAI) in HCT116 and HUVECs. Cell cycle analysis, proliferation, migration and, tube formation were determined by flow cytometry, MTT, wound healing, and tube formation assays, respectively. Results: MiR-1290 significantly decreased the expression of THBS1, DKK3, and SCAI. We demonstrated that miR-1290 enhanced proliferation, migration, and angiogenesis partially through suppression of THBS1, DKK3, and SCAI in CRC. Conclusion: These results suggest a novel function of miR-1290 which may contribute to tumorigenesis and angiogenesis in CRC.

Anti-CD44 and EGFR Dual-Targeted Solid Lipid Nanoparticles for Delivery of Doxorubicin to Triple-Negative Breast Cancer Cell Line: Preparation, Statistical Optimization, and In Vitro Characterization.

Background: Despite being more aggressive than other types of breast cancer, there is no suitable treatment for triple-negative breast cancer (TNBC). Here, we designed doxorubicin-containing solid lipid nanoparticles (SLNs) decorated with anti-EGFR/CD44 dual-RNA aptamers, which are overexpressed in TNBC. For more efficiency in the nuclear delivery of doxorubicin, dexamethasone (Dexa) was chemically attached to the surface of nanoparticles. Methods: To prepare the cationic SLNs, 6-lauroxyhexyl BOC-ornithine (LHON) was synthesized and was chemically attached to dexamethasone to form Dexa-LHON complexes. The doxorubicin-containing SLNs were prepared via double emulsification (w/o/w) and the solvent evaporation technique. The preparation of SLNs was statistically optimized using the central composite response surface methodology. Independent factors were the GMS/lecithin concentration ratio and the amount of Tween 80, while responses considered were particle size, polydispersity index, and entrapment efficiency of the nanoparticles. The optimized nanoparticles were studied morphologically using transmission electron microscopy, and in vitro release of doxorubicin from nanoparticles was studied in phosphate-buffered saline. Then, the designated aptamers were attached to the surface of nanoparticles using electrostatic interactions, and their cytotoxicity was assessed in vitro. Results: The size, PDI, zeta potential, EE%, and LE% of the prepared nanoparticles were 101 ± 12.6 nm, 0.341 ± 0.005, +13.6 ± 1.83 mV, 69.98 ± 7.54%, and 10.2 ± 1.06%, respectively. TEM images revealed spherical nanoparticles with no sign of aggregation. In vitro release study exhibited that 96.1 ± 1.97% of doxorubicin was released within 48 h of incubation. The electrostatic attachment of the designated aptamers to the nanoparticles' surface was confirmed by reducing the zeta potential to -15.6 ± 2.07 mV. The in vitro experiments revealed that the SLNs/DOX/Dexa/CD44 or EGFR aptamers were substantially more successful than SLNs/DOX/Dexa at inhibiting cell proliferation. Using the MDA-MB-468 cell line, we discovered that SLN/DOX/Dexa/CD44/EGFR aptamers were more effective than other constructs in inhibiting cell proliferation (p < 0.001). The reduction of cell viability using this construct suggests that targeting numerous proliferation pathways is effective. Conclusion: Overall, the finding of this investigation suggested that SLNs/DOX/Dexa/CD44/EGFR could be a promising new enhanced anticancer delivery system and deserved further preclinical consideration.

Neuroprotective effects of coenzyme Q10-loaded exosomes obtained from adipose-derived stem cells in a rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a degenerative disease that causes memory and learning impairments as well as dementia. Coenzyme Q10 (CoQ10) is an anti-inflammatory and anti-oxidative stress supplement that can improve inflammation and oxidative stress associated with AD. This study investigated the effects of drug delivery of COQ10 by exosomes derived from adipose-derived stem cells (ADSCs-Exo) on cognition, memory, and neuronal proliferation in a rat model of Streptozotocin (STZ)-induced AD. Since the establishment of the AD model, the rats have received intraperitoneal injections of CoQ10, Exo, or CoQ10-loaded ADSCs-Exo (Exo+ CoQ10). The passive avoidance test and the Morris water maze (MWM) were used to assess memory and cognition changes. Cell density was determined using histological methods. The expression of BDNF was measured using an ELISA kit. SOX2 expression was determined using immunohistochemistry. According to the results of the MWM and passive avoidance task, Exo+CoQ10 significantly improved STZ-induced memory impairment compared to CoQ10 and Exo groups alone. Furthermore, BDNF expression increased in the STZ-induced rats after Exo+ CoQ10, when compared to the CoQ10 and Exo groups. In addition, Exo+CoQ10 had the highest cell density and SOX2 gene expression, when compared to the CoQ10 and Exo groups. According to the findings of this study, Exo+ COQ10 enhanced cognition and memory deficiency in Alzheimer's disease by boosting BDNF and SOX2 levels in the hippocampus. Hence, the use of exosomes derived from adipose-derived stem cells as the carrier of CoQ10 may increase the therapeutic effect of CoQ10, which can possibly be due to the regenerative properties of the exosomes.

Molecular Detection of blaOXA -type Carbapenemase Genes and Antimicrobial Resistance Patterns among Clinical Isolates of Acinetobacter baumannii.

Acinetobacter baumannii is a bacterium found in most places, especially in clinics and hospitals, and an important agent of nosocomial infections. The presence of class D enzymes such as OXA-type carbapenemases in A. baumannii is proven to have a key function in resistance to carbapenem. The aim of the current study is to determine the blaOXA -type carbapenemase genes and antimicrobial resistance among clinically isolated samples of A. baumannii. We assessed 100 clinically isolated specimens of A. baumannii from patients in intensive care units of educational hospitals of Hamadan, West of Iran. The A. baumannii isolates' susceptibility to antibiotics was performed employing disk diffusion method. Multiplex polymerase chain reaction was used to identify the bla OXA-24-like , bla OXA-23-like , bla OXA-58-like , and bla OXA-51-like genes. The bla OXA-23-like , bla OXA-24-like , and bla OXA-58-like genes' prevalence were found to be 84, 58, and 3%, respectively. The highest coexistence of the genes was for bla OXA-51/23 (84%) followed by bla OXA-51/24-like (58%). The bla OXA-51/23- like pattern of genes is a sort of dominant gene in resistance in A. baumannii from Hamadan hospitals. The highest resistance to piperacillin (83%) and ciprofloxacin (81%) has been observed in positive isolates of bla OXA-23-like . The A. baumannii isolates with bla OXA-58-like genes did not show much resistance to antibiotics. Based on the results of the phylogenetic tree analysis, all isolates have shown a high degree of similarity. This study showed the high frequency of OXA -type carbapenemase genes among A. baumannii isolates from Hamadan hospitals, Iran. Thus, applying an appropriate strategy to limit the spreading of these strains and also performing new treatment regimens are necessary.

A novel epigenetic biomarker, plasma miR-138-5p gene promoter-methylated DNA, for colorectal cancer diagnosis.

Aim: The miR-138-5p promoter-methylated DNA level, miR-138-5p and PDL1 expression were investigated in colorectal cancer (CRC) patients. Materials & methods: miR-138-5p promoter methylation status and miR-138-5p expression were investigated using the MethyLight and qPCR method, respectively. For measuring PDL-1, we applied the Bioassay Technology Elisa kit. Results: The percentage of methylated reference values of plasma and tissue samples from patients was higher than control groups. The area under curve presented a sensitivity of 55% and a specificity of 82.5% for plasma samples. Compared with the control groups, lower expression of miR-138-5p and higher concentration of PDL1 protein were observed in the patients group. Conclusion: CRC may be detected early by identifying miR-138-5p methylated DNA in plasma as a diagnostic biomarker.

Unfortunately, most patients with colorectal cancer (CRC) are diagnosed late in advanced stages. Genetic alterations due to a person's behavior or environment, such as miRNA dysregulation and methylation, occur in the initial phases of tumorigenesis. This study investigated the disease causing role of methylation of the miR-138-5p gene and its target protein, PDL1, in CRC as well as their potential ability to be used in the early diagnosis of this cancer. Using molecular techniques, higher methylated miR-138-5p as well as a higher PDL1 concentration were found in patients. This suggested a link between PDL1 protein and hyper methylation of the miR-138-5p gene. On the other hand, the hypermethylation of miR-138-5p happened before the increase of PDL1 protein, which resulted in decreased miR-138-5p and as a result decreased PDL1 protein. Compared with other biomarkers, miR-138-5p methylation and PDL1 had high diagnostic accuracy (acceptable sensitivity and specificity). Thus, the methylated miR-138-5p and PDL1 are proposed as diagnostic biomarkers for CRC.

Assessment of Association between miR-146a Polymorphisms and Expression of miR-146a, TRAF-6, and IRAK-1 Genes in Patients with Brucellosis.

BACKGROUND: Brucellosis is a major zoonosis all over the world. MicroRNAs are significant gene expression regulators and could be involved during the infections and also genetic alterations in the miRNAs sequence can affect primary miRNAs and precursor miRNAs processing and thus alter miRNAs expression. Current research studied the impact of the miR-146a polymorphism on miR-146a, TRAF-6, and IRAK-1 genes expression in patients with brucellosis illness. METHODS AND RESULTS: In this research, 25 patients with brucellosis and 25 healthy participants with determined genotypes for miR-SNP rs2910164 and miR-SNP rs57095329 were recruited. IRAK-1, TRAF-6, and miR-146a expressions in peripheral blood mononuclear cells (PBMCs) were specified by quantitative real- time PCR (qRT-PCR). Moreover, interleukin-1ß (IL-1ß) and tumor necrosis factor- alpha (TNF-α) serum levels were assessed by a sandwich enzyme-linked immunosorbent assay (ELISA) technique. There was no significant difference in the expression level of miR-146a, IRAK-1, and TRAF-6, among the patients with brucellosis and control group. TRAF-6 PBMCs expression levels in the distinctive genotypes of rs2910164 were significantly observed in patients (P = 0.048). No significant distinctions were found in miR-146a, IRAK-1, and TRAF-6 expression levels and among the rs57095329 different genotypes in brucellosis patients and controls. Meanwhile, no significant relationship was found between the rs2910164 and rs57095329 genotypes and the serum level of cytokines mentioned between the two groups. We did not find any association between expression of TRAF-6, miR-146a, and IRAK-1 in PBMCs, and cytokines serum levels with two single nucleotide polymorphisms (SNPs) in miR-146a. CONCLUSIONS: To the best of writers' knowledge, this research is the first one evaluating the probable link between the miR-146a rs2910164 and rs57095329 variant with miRNAs, relevant cytokine levels, and target genes in brucellosis.

Beneficial effects of genistein in suppression of proliferation, inhibition of metastasis, and induction of apoptosis in PC3 prostate cancer cells.

OBJECTIVES: Beneficial effects of genistein have been studied in various cancer types but the underlying molecular mechanisms of its actions have not been well established. This study investigated the effects of genistein on caspase-3 and p38 mitogen-activated protein kinase (p38MAPK) as main cellular signalling targets in PC3 prostate cancer cells. METHODS: Caspase-3 and p38MAPK gene expression and intracellular protein levels were determined. Matrix metalloproteinase-2 (MMP2) gelatinase activity and caspase-3 enzyme activity were measured and PC3 cell migration and proliferation potencies were assessed. RESULTS: Genistein induced apoptosis by enhancing the gene expression, intracellular protein level, and enzyme activity of caspase-3. Genistein also inhibited cell proliferation by reducing p38MAPK gene expression and protein level and strongly suppressed metastatic potency of PC3 cells by reducing MMP2 activity. CONCLUSION: Genistein exhibits its beneficial anticancer properties on PC3 cells by reducing metastatic potency and regulating caspase-3 and p38MAPK pathways at different transcriptional and protein levels.

Downregulation of serum miR-106b: a potential biomarker for Alzheimer disease.

Analysis of miRNAs has a strong potential for the identification of novel prognostic or predictive biomarkers in the serum of AD patients. In this study, we investigated the serum levels of miR-106b as a diagnostic biomarker for AD and evaluate its predictive value for therapeutic response to the drug rivastigmine. Patients were divided into either responding (n = 33) or non-responding (n = 23) groups according to rivastigmine treatment and to Mini-Mental State Exam score. The serum concentrations of miR-106b were measured with real-time PCR. Here, we found that miR-106b was significantly down-regulated in the serum samples of AD patients compared with those of controls (p < .001). ROC results showed a specificity of 62% and a sensitivity of 94%. The serum values of miR-106b tended to be positively associated with the therapeutic response but were not significant (p = .15). Taken together, detection of serum miR-106b might be a promising serum biomarker for early diagnosis of AD.

Impact of PIN1 Inhibition on Tumor Progression and Chemotherapy Sensitivity in Colorectal Cancer.

BACKGROUND: Deregulated PIN1 is associated with cancer development and progression. Herein, for the first time, we evaluate the roles that PIN1 in tumorigenic characteristics of colorectal cancer (CRC) cells. METHODS: In this study, PIN1 expression was knocked down in SW-48 cells by synthetic small interfering RNA (siRNA). After confirming the knockdown of PIN1, cell viability, colony formation, apoptosis, autophagy, cancer stem cell (CSC)-related genes, CSC-related signaling pathways, cell migration, and 5-FU chemosensitivity were evaluated in vitro. RESULTS: Transfection of PIN1 siRNA into SW-48 cells inhibited cancer cell proliferation, migration, and increased apoptosis and autophagy. Transfected SW-48 cells had lower properties of CSCs through the inhibition of ß-catenin and Notch1 gene expression. Moreover, inhibition of PIN1 enhanced the inhibitory effect of 5-FU on SW-48 cell proliferation. CONCLUSION: Our results indicated that targeting of PIN1 serves as a promising therapeutic solution for the suppression of tumor progression processes in CRC.

Near-infrared 940-nm diode laser photobiomodulation of inflamed periodontal ligament stem cells.

Photobiomodulation (PBM) is an acceptable method of stimulating stem cells through its non-invasive absorption by the cell photoreceptors and the induction of cellular response. The current research was aimed at evaluating the effect of near-infrared PBM on proliferation and osteogenic differentiation in inflamed periodontal ligament stem cells (I-PDLSCs). I-PDLSCs were isolated and characterized. Third passage cells were irradiated with 940-nm laser at an output power of 100 mW in a continuous wave. A fluence of 4 J/cm2 in three sessions at 48-h intervals was applied and compared with non-irradiated controls. Cell viability and proliferation were evaluated by MTT assay. Alkaline phosphatase activity, quantitative Alizarin red staining test, and q-RT-PCR were used to evaluate the osteogenic properties of the I-PDLSCs in four groups of (a) osteogenic differentiation medium + laser (ODM + L), (b) osteogenic differentiation medium without laser (ODM), (c) non-osteogenic differentiation medium + laser (L), and (d) non-osteogenic differentiation medium (control). There was a non-significant increase in the viability of cells at 48- and 72-h post last laser irradiation. Alizarin red staining revealed no significant stimulatory effect of PBM at 14 and 21 days. However, alkaline phosphatase activity was significantly higher in the L + ODM group. Expression of osteogenic-related genes had a statistically significant increase at 21-day post irradiation. The irradiation used in the present study showed no significant increase in the proliferation of I-PDLSCs by PBM. However, expression levels of osteogenic-related genes and alkaline phosphatase activity were significantly increased in irradiated groups.

Identification of Key Gene Targets for Sensitizing Colorectal Cancer to Chemoradiation: an Integrative Network Analysis on Multiple Transcriptomics Data.

PURPOSE: Colorectal cancer (CRC) is a main cause of morbidity and mortality in the world. Chemoradioresistance is a major problem in CRC treatment. Identification of novel therapeutic targets in order to overcome treatment resistance in CRC is necessary. METHODS: In this study, gene expression omnibus (GEO) database was searched to find microarray datasets. Data normalization/analyzing was performed using ExAtlas. The gene ontology (GO) and pathway enrichment analysis was performed using g:Profiler. Protein-protein interaction network (PPIN) was constructed by Search Tool for the Retrieval of Interacting Genes (STRING) and analyzed using Cytoscape. Survival analysis was done using Kaplan-Meier curve method. RESULTS: Forty-one eligible datasets were included in study. A total of 12,244 differentially expressed genes (DEGs) and 7337 unique DEGs were identified. Among them, 1187 DEGs were overlapped in ≥ 3 datasets. Fifty-five overlapped genes were considered as hub genes. Common hub genes in chemo/radiation/chemoradiation datasets were chosen as the essential candidate genes (n = 13). Forty-one hub gene and 7 essential candidate genes were contributed in the significant modules. The modules were mainly enriched in the signaling pathways of senescence, autophagy, NF-κB, HIF-1, stem cell pluripotency, notch, neovascularization, cell cycle, p53, chemokine, and PI3K-Akt. NGFR, FGF2, and PROM1 genes were significantly predictors of CRC patient's survival. CONCLUSION: Our study revealed three-gene signatures as potential therapeutic targets and also candidate molecular markers in CRC chemoradioresistance.