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OBJECTIVE: Breast cancer, a global concern predominantly impacting women, poses a significant threat when not identified early. While survival rates for breast cancer patients are typically favorable, the emergence of regional metastases markedly diminishes survival prospects. Detecting metastases and comprehending their molecular underpinnings are crucial for tailoring effective treatments and improving patient survival outcomes. METHODS: Various artificial intelligence methods and techniques were employed in this study to achieve accurate outcomes. Initially, the data was organized and underwent hold-out cross-validation, data cleaning, and normalization. Subsequently, feature selection was conducted using ANOVA and binary Particle Swarm Optimization (PSO). During the analysis phase, the discriminative power of the selected features was evaluated using machine learning classification algorithms. Finally, the selected features were considered, and the SHAP algorithm was utilized to identify the most significant features for enhancing the decoding of dominant molecular mechanisms in lymph node metastases. RESULTS: In this study, five main steps were followed for the analysis of mRNA expression data: reading, preprocessing, feature selection, classification, and SHAP algorithm. The RF classifier utilized the candidate mRNAs to differentiate between negative and positive categories with an accuracy of 61% and an AUC of 0.6. During the SHAP process, intriguing relationships between the selected mRNAs and positive/negative lymph node status were discovered. The results indicate that GDF5, BAHCC1, LCN2, FGF14-AS2, and IDH2 are among the top five most impactful mRNAs based on their SHAP values. CONCLUSION: The prominent identified mRNAs including GDF5, BAHCC1, LCN2, FGF14-AS2, and IDH2, are implicated in lymph node metastasis. This study holds promise in elucidating a thorough insight into key candidate genes that could significantly impact the early detection and tailored therapeutic strategies for lymph node metastasis in patients with breast cancer.

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The long-term survival of solid organ allografts remains a challenge for organ transplantation systems worldwide. T-cell exhaustion has been supposed to be associated with immunologic tolerance in transplantation and might reflect the immunologic status in recipients. The aim of the present study was to compare the TCD4+ cells of kidney transplant recipients with high and low serum creatinine levels for their expressions of PD-1 and TIGIT as two well-known exhaustion markers. Blood samples were taken from 20 kidney allograft recipients with serum creatinine levels above 2 mg/dL and 20 recipients with creatinine levels below 2 mg/dL. The percentages of PD-1+ CD4+ and TIGIT+ CD4+ cells were analyzed along with the evaluation of TNF-α, IFN-γ, and IL-10 release from peripheral blood mononuclear cells (PBMCs). The patients with serum creatinine levels below 2 mg/dL demonstrated a higher frequency of PD-1+ CD4+ T-cells (p = 0.003) along with lower TNF-α secretion from PBMCs (p = 0.028). The frequency of PD-1 + CD4+ T-cells was reversely correlated with the serum creatinine levels in recipients of kidney allografts (r = 0.59, p < 0.001). Besides, the MFI of TIGIT on TCD4+ cells demonstrated a trend for higher expression in patients with serum creatinine levels below 2 mg/dL (p = 0.070). The expression of PD-1+ on CD4+ T-cells demonstrated a potential for estimation of the immunologic status of the host in interaction with alloantigens. The exhaustion markers could be regarded as potential diagnostic indicators for the evaluation of immunologic tolerance in renal transplantation.

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Coronary artery disease (CAD) is one of the principal causes of death worldwide. Among several predisposing factors, inflammation and inflammatory genes play a significant role in disease pathogenesis. Inflammatory microRNAs, small noncoding RNAs involved in regulating inflammation, are promising candidates for understanding pathogenesis of CAD and developing diagnostic biomarkers. The aim of the study was to evaluate the alteration of miR-200c, miR-125b, miR-27b, miR-203 and, miR-155 in patients suffering from coronary artery stenosis and insignificant coronary artery stenosis compared to healthy subjects. In this study we compared expressions of five inflammatory miRNAs in peripheral blood mononuclear cells (PBMCs) of 72 patients suffering significant coronary artery stenosis (CAD), 74 individuals without coronary artery disease and 30 individuals with insignificant coronary artery stenosis (ICAD). After blood collection, PBMCs were isolated and RNA was extracted. Gene expression levels were assessed by SYBR green based real-time PCR. Statistical analysis was performed using R program. Expression levels of miR-200c, miR-203, and miR-155 were lower in subjects with ICAD than that in CAD patients and subjects of the control group. MiR-125b was downregulated in CAD and ICAD groups compared to the control group. PBMC miR-27b was upregulated in the CAD group as compared to the ICAD and control groups. Receiver operating characteristic curve analysis verified potential of three miRNAs in separating subjects with ICAD from CAD patients and healthy individuals. In conclusion, this original investigation suggested that altered expression of these five miRNAs may serve as a novel diagnostic biomarker discriminating clinical presentations of coronary artery diseases.

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BACKGROUND: Diabetic nephropathy (DN) is a common complication of type 2 diabetes (T2D). Chronic inflammation and a combination of environmental and genetic factors are involved in the pathogenesis and development of DN. OBJECTIVE: This case-control study aimed to determine the relationship between rs7529229 and rs2228145 polymorphisms of the IL-6R gene with the incidence of nephropathy among T2D patients. METHODS: Fifty-six diabetic patients with nephropathy and 57 T2D patients without nephropathy were included based on inclusion criteria, along with 150 healthy individuals. METHODS: Fifty-six diabetic patients with nephropathy and 57 T2D patients without nephropathy were included based on inclusion criteria, along with 150 healthy individuals. RESULTS: The frequencies of AC and CC genotype distributions of the rs2228145 polymorphism in DN patients were significantly higher than in healthy individuals (24.1 and 9.3% versus 10.7 and 6.7%, respectively, P= 0.02). Moreover, the frequency of allele C was higher in DN patients compared to healthy controls (21.30% versus 12%, P=0.025). However, genotype distribution and allele frequencies of the rs7529229 IL-6R polymorphism in DN patients were not statistically significant in comparison with diabetic patients and healthy individuals (P> 0.05). CONCLUSION: The results showed that the allele and genotype distribution frequencies of rs2228145 IL-6R gene polymorphism in patients with DN were significantly higher than in healthy individuals. Therefore, the presence of this polymorphism may be involved in the development of diabetic nephropathy in this population.

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Background: The covid-19 disease has caused many deaths worldwide since December 2019. Many thromboembolic events, such as VTE and TTP, have been reported since the beginning of this pandemic. Considering the prominent role of complement in developing TTP and TTP-like syndrome in recent studies, this study aimed to assess the prevalence of TTP-like syndrome and its relationship with complement activity in critically ill patients with COVID-19. Method: This study was conducted on 77 COVID-19 patients admitted to the ICU wards of Tabriz Imam Reza hospital from March to June 2021. TTP-like syndrome was diagnosed using a blood specimen for evidence of thrombocytopenia, microangiopathic hemolysis (low hemoglobin, increased LDH level, schistocytes in a peripheral blood smear, and negative direct agglutination test), and end-organ injury, including acute kidney injury or neurological deficit. ADAMTS 13 activity levels could not be achieved owing to logistic issues; therefore, we could not accurately diagnose TTP and TTP-like syndrome based on ADAMTS 13 levels, so to increase the accuracy of diagnosis, we have included people with classical pentad evidence in the TTP-like syndrome group. Complement parameters, including C3, C4, and CH50, were measured. Result: Seven cases of TTP-like syndrome were diagnosed using the previously mentioned criteria, which stands for 9.1% of the study population. Compared with patients without TTP-like syndrome, C3 was significantly lower in patients with TTP-like syndrome (p-value = 0.014), and C4 and CH50 demonstrated insignificant differences between the two groups (p-value = 0.46, p-value = 0.75). Conclusion: Our study showed that the TTP-like syndrome was present in a significant percentage of critically ill patients with COVID-19. Lower C3 levels in TTP-like syndrome-diagnosed patients can indicate complement activation as one of the influential factors in initiating TTP-like syndrome in COVID-19 patients. More studies are recommended to clarify the exact mechanism to achieve adequate therapeutic methods and better manage the disease and its complications.

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Acute kidney injury (AKI) is a common subsequent problem after many medical conditions. AKI is associated with distant organ dysfunction where systemic inflammation and oxidative stress play major roles. In this study, the effect of Prazosin, an α1-Adrenergic receptor antagonist, was investigated on the liver injury induced by kidney ischemia-reperfusion (I/R) in rats. Male adult Wistar rats (n=21) were divided into three groups: sham, kidney I/R, and kidney I/R pre-treated with Prazosin (1 mg/kg). Kidney I/R was induced by vascular clamping of the left kidney for 45 min to reduce the blood flow. Oxidative and antioxidant factors along with apoptotic (Bax, Bcl-2, caspase3), and inflammatory (NF-κß, IL-1ß, and IL-6) factors were measured in the liver at protein levels. Prazosin could reserve liver function (p<0.01) and increase glutathione level (p<0.05) after kidney I/R significantly. Malonil dialdehyde (MDA), a lipid peroxidation marker, was diminished more significantly in Prazosin-treated rats compared to the kidney I/R group (p<0.001). Inflammatory and apoptotic factors were diminished by Prazosin pre-treatment in the liver tissue (p<0.05). Pre-administration of Prazosin could preserve liver function and decrease its inflammatory and apoptotic factors under kidney I/R conditions.

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BACKGROUND: Curcumin has been isolated from the rhizomes of Curcuma longa. Over the years, it has shown outstanding therapeutic potential in various human disorders, including cancers. OBJECTIVE: The aim is to study curcumin's effects on the apoptosis signaling pathway in the head and neck squamous cell carcinoma (HNSCC) cell line HN5. METHODS: The cytotoxicity of curcumin on HN5 cells were assessed. In addition, HN5 cells were also treated with curcumin to evaluate its effect on the caspase-8, -9, Bcl-2, Bax, and Stat3 gene expressions. RESULTS: The results exhibited that cell viability reduced following curcumin treatment in a concentration- dependent manner. Curcumin treatment caused decreased expression of Bcl2, with simultaneous upregulation of the Bax/Bcl2 ratio. Curcumin increased caspase-9 expression, did not affect caspase-8, and decreased Stat3 expression. The induction of the mitochondria-dependent apoptosis pathway of curcumin happened by modulating the expression of Bcl2 and Bax genes, resulting in the caspase-9 activation. Furthermore, curcumin decreased the expression of the Stat3 in HN-5 cells. CONCLUSIONS: In conclusion, curcumin showed marked anticancer effects in the HN-5 cell line by modulating Stat-3; Bax/Bcl-2 expression in vitro.

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Renal Cell Carcinoma (RCC) encompasses three histological subtypes, including clear cell RCC (KIRC), papillary RCC (KIRP), and chromophobe RCC (KICH) each of which has different clinical courses, genetic/epigenetic drivers, and therapeutic responses. This study aimed to identify the significant mRNAs and microRNA panels involved in the pathogenesis of RCC subtypes. The mRNA and microRNA transcripts profile were obtained from The Cancer Genome Atlas (TCGA), which were included 611 ccRCC patients, 321 pRCC patients, and 89 chRCC patients for mRNA data and 616 patients in the ccRCC subtype, 326 patients in the pRCC subtype, and 91 patients in the chRCC for miRNA data, respectively. To identify mRNAs and miRNAs, feature selection based on filter and graph algorithms was applied. Then, a deep model was used to classify the subtypes of the RCC. Finally, an association rule mining algorithm was used to disclose features with significant roles to trigger molecular mechanisms to cause RCC subtypes. Panels of 77 mRNAs and 73 miRNAs could discriminate the KIRC, KIRP, and KICH subtypes from each other with 92% (F1-score ≥ 0.9, AUC ≥ 0.89) and 95% accuracy (F1-score ≥ 0.93, AUC ≥ 0.95), respectively. The Association Rule Mining analysis could identify miR-28 (repeat count = 2642) and CSN7A (repeat count = 5794) along with the miR-125a (repeat count = 2591) and NMD3 (repeat count = 2306) with the highest repeat counts, in the KIRC and KIRP rules, respectively. This study found new panels of mRNAs and miRNAs to distinguish among RCC subtypes, which were able to provide new insights into the underlying responsible mechanisms for the initiation and progression of KIRC and KIRP. The proposed mRNA and miRNA panels have a high potential to be as biomarkers of RCC subtypes and should be examined in future clinical studies.

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The conventional treatment options (including alkylating agents, steroids, calcinurine inhibitors) have been largely replaced by anti-CD20 antibodies to achieve remission of nephrotic proteinuria in primary membranous nephropathy (PMN) patients. Two-third of rituximab-receiving PMN patients develop remission of proteinuria, and the results of MENTOR trial turned this drug into the first-line therapeutic agent in non-severe cases. However, in 20-40% of patients, remission is not achieved. Therefore, rituximab-resistant membranous nephropathy cases are increasingly reported. Different molecular mechanisms have been implicated in this context resulting in the introduction of new biologic agents. Second-generation anti-CD20 antibodies and other options such as plasma cell depleting agents and proteasome inhibition might lead to a novel treatment paradigm for patients with PMN.

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Collagen is an important macromolecule of Extracellular Matrix (ECM) in bones, teeth, and temporomandibular joints. Mesenchymal Stem Cells (MSCs) interact with the components of the ECM such as collagen, proteoglycans, Glycosaminoglycans (GAGs), and several proteins on behalf of variable matrix elasticity and bioactive cues. Synthetic collagen-based biomaterials could be effective scaffolds for regenerative dentistry applications due to mimicking of host tissues' ECM. These biomaterials are biocompatible, biodegradable, readily available, and non-toxic to cells whose capability promotes cellular response and wound healing in the craniofacial region. Collagen could incorporate other biomolecules to induce mineralization in calcified tissues like bone and tooth. Moreover, the addition of these molecules or other polymers to collagen-based biomaterials could enhance mechanical properties, which is important in load-bearing areas such as the mandible. A literature review was performed via a reliable internet database (mainly PubMed) based on MeSH keywords. This review first describes the properties of collagen as a key protein in the structure of hard tissues. Then, it introduces different types of collagens, the correlation between collagen and MSCs, and the methods used to modify collagen in regenerative dentistry, including recent progression on the regeneration of periodontium, dentin-pulp complex, and temporomandibular joint by applying collagen. The prospects and challenges of collagen-based biomaterials in the craniofacial region are pointd out.

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Attaining a fair long-term allograft survival remains a challenge for allogeneic transplantation worldwide. Although the emergence of immunosuppressants has caused noticeable progress in the management of immunologic rejection, proper application of these therapeutics and dose adjustments require delicate and real-time monitoring of recipients. Nevertheless, the majority of conventional allograft monitoring approaches are based on organ damage or functional tests that render them unable to predict the rejection events in early time points before the establishment of a functional alloimmune response. On the other hand, biopsy-based methods include invasive practices and are accompanied by serious complications. In recent years, there have been a myriad of attempts on the discovery of reliable and non-invasive approaches for the monitoring of allografts that regarding a close relationship between allografts and hosts' immune system, most of the attempts have been devoted to the studies on the immune response-associated biomarkers. The discovery of gene and protein expression patterns in immune cells along with their phenotypic characterization and secretome analysis as well as tracking the immune responses in allograft tissues and clinical specimens are among the notable attempts taken to discover the non-invasive predictive markers with a proper coincidence to the pathologic condition. Collectively, these studies suggest a list of candidate biomarkers with ideal potentials for early and non-invasive prediction of allograft rejection and shed light on the way towards developing more standardized and reproducible approaches for monitoring the allograft rejection.

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Appropriate mitochondrial physiology is an essential for health and survival. Cells have developed unique mechanisms to adapt to stress circumstances and changes in metabolic demands, by meditating mitochondrial function and number. In this context, sufficient mitochondrial biogenesis is necessary for efficient cell function and haemostasis, which is dependent on the regulation of ATP generation and maintenance of mitochondrial DNA (mtDNA). These procedures play a primary role in the processes of inflammation, aging, cancer, metabolic diseases, and neurodegeneration. Polyphenols have been considered as the main components of plants, fruits, and natural extracts with proven therapeutic effects during the time. These components regulate the intracellular pathways of mitochondrial biogenesis. Therefore, the current review is aimed at representing an updated review which determines the effects of different natural polyphenol compounds from various plant kingdoms on modulating signaling pathways of mitochondrial biogenesis that could be a promising alternative for the treatment of several disorders.

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MicroRNAs (miRNAs) have emerged as a critical component of regulatory networks that modulate and fine-tune gene expression in a post-transcriptional manner. The microRNA-196 family is encoded by three loci in the human genome, namely hsa-mir-196a-1, hsa-mir-196a-2, and hsa-mir-196b. Increasing evidence supports the roles of different components of this miRNA family in regulating key cellular processes during differentiation and development, ranging from inflammation and differentiation of stem cells to limb development and remodeling and structure of adipose tissue. This review first discusses about the genomic context and regulation of this miRNA family and then take a bird's eye view on the updated list of its target genes and their biological processes to obtain insights about various functions played by members of the microRNA-196 family. We then describe evidence supporting the involvement of the human microRNA-196 family in regulating critical cellular processes both in physiological and non-malignant inflammatory conditions, highlighting recent seminal findings that carry implications for developing novel therapeutic or diagnostic strategies.

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The aims of the present study were the determination of antimicrobial and antibiofilm effects of meropenem-loaded mesoporous silica nanoparticles (MSNs) on carbapenem resistant Pseudomonas aeruginosa (P. aeruginosa) and cytotoxicity properties in vitro. The meropenem-loaded MSNs had shown antibacterial and biofilm inhibitory activities on all isolates at different levels lower than MICs and BICs of meropenem. The viability of HC-04 cells treated with serial concentrations as MICs and BICs of meropenem-loaded MSNs was 92-100%. According to the obtained results, meropenem-loaded MSNs display the significant antibacterial and antibiofilm effects against carbapenem resistant and biofilm forming P. aeruginosa and low cell toxicity in vitro. Then, the prepared system can be an appropriate option for the delivery of carbapenem for further evaluation in vivo assays.

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The exposure of Bacteroides fragilis to highly oxygenated tissues induces an oxidative stress due to a shift from the reduced condition of the gastrointestinal tract to an aerobic environment of host tissues. The potent and effective responses to reactive oxygen species (ROS) make the B. fragilis tolerant to atmospheric oxygen for several days. The response to oxidative stress in B. fragilis is a complicated event that is induced and regulated by different agents. In this review, we will focus on the B. fragilis response to oxidative stress and present an overview of the regulators of responses to oxidative stress in this bacterium.

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BACKGROUND: Acute kidney injury (AKI) is the main clinical concern resulted from ischemia-reperfusion injury (IRI). Ample clinical data indicates that AKI is associated with distant organ dysfunctions and poor patients' outcomes. Oxidative stress and inflammation have a critical role in the pathogenesis of organ injuries following IRI. The objectives of this study were to determine the impact of Gamma Oryzanol (GO), extracted from rice bran oil, on distant organs in rats after IRI. METHODS: Twelve out of 24 Wistar rats were treated by one dosage of GO (100mg/kg) 1 h before I/R induction through both oral gavage and intraperitoneal injection. Then, the AKI model rats were induced by IRI. Oxidative stress and antioxidant protein levels were assessed in the brain, heart, and liver tissues in the experimental groups. Furthermore, the effects of GO on IRI-induced liver dysfunction, apoptosis, and inflammation were measured by Western blot. RESULTS: GO pretreatment could significantly restore the levels and activity of antioxidant proteins in the brain, heart, and liver tissues (P < 0.05). Moreover, GO pretreatment could decrease the inflammatory cytokine (IL-1, IL-6, and TNF-α) in the liver (P < 0.01). By reducing Bax/Bcl-2 ratio and down-regulating caspase-3, GO could significantly diminish apoptosis in the liver tissue after the kidney I/R (P < 0.01). Additionally, GO could significantly diminish the deterioration of liver function in the kidney I/R model. CONCLUSION: GO protects distant organs against renal IRI-induced oxidative stress. Furthermore, it ameliorates liver function and remarkably exerts anti-oxidative, anti-inflammatory, and anti-apoptotic roles in the liver as an important detoxifying organ.

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Bacteroides fragilis is a most frequent anaerobic pathogen isolated from human infections, particularly found in the abdominal cavity. Different factors contribute to the pathogenesis and persistence of B. fragilis at infection sites. The knowledge of the virulence factors can provide applicable information for finding alternative options for the antibiotic therapy and treatment of B. fragilis caused infections. Herein, a comprehensive review of the important B. fragilis virulence factors was prepared. In addition to B. fragilis toxin (BFT) and its potential role in the diarrhea and cancer development, some other important virulence factors and characteristics of B. fragilis are described including capsular polysaccharides, iron acquisition, resistance to antimicrobial agents, and survival during the prolonged oxidative stress, quorum sensing, and secretion systems.

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Diabetic nephropathy as a deleterious complication of diabetes mellitus and an important cause of end-stage renal failure is characterized by changes in the molecular and cellular levels. Cell-cell communication via the gap and tight junctions are involved in the pathogenesis of diseases such as diabetes and kidney failure. Studying cell junctions including gap junctions, tight junctions, and anchoring junctions within the nephron can be used as an early sign of diabetic nephropathy. Furthermore, cell junctions may be an upcoming target by pharmacological methods to improve treatments of diabetic nephropathy and pave the way to introduce promising therapeutic strategies based on cell-cell communications effects and its translation into clinical studies for the treatment of diabetic nephropathy.

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Detection and identification of special cells via aptamer-based nano-conjugates sensors have been revolutionized over the past few years. These sensing platforms rely on selecting aptamers using systematic evolution of ligands by exponential enrichment (SELEX) in vitro, which allows for sensitive detection of cells. Integration of the aptamer-based sensors (aptasensors) with nanomaterials offers enhanced specificity and sensitivity, which in turn, offers great promise for numerous applications, spanning from bioanalysis to biomedical applications. Accordingly, the demand for using aptamer-conjugated nanomaterials for various applications has progressively increased over the past years. In light of this, this Review seeks to highlight the recent advances in the development of aptamer-conjugated nanomaterials and their utilization for the detection of various pathogens involved in infectious diseases and food contamination.

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BACKGROUND: Proinflammatory genes are highly expressed in several metabolic disorders associated with obesity. But it is not clarified whether gene expression levels and downstream inflammatory markers are related to the metabolic state or the presence of obesity. Hence, the present study aimed to compare Toll-Like Receptor 2 (TLR2), Myeloid Differentiation Factor 88 (MyD88), and NFĸB mRNA expression levels between metabolically healthy abdominally obese (MHAO) and metabolically unhealthy abdominally obese (MUAO) individuals. RESULTS: We compared mRNA expression levels of the genes as well as serum FFAs and IL-1ß in MUAO (n = 36) and MHAO (n = 34) groups. Serum FBS, TG, and HDL-C in addition to systolic and diastolic blood pressure were significantly higher in MUAO than MHAO groups (p < 0.05). The odds of MUAO was significantly decreased with high HDL-C (OR = 0.22, 95%CI: 0.08-0.63) and increased with high FBS (OR = 7.04, 95%CI: 1.42-34.69) and TG (OR = 30.55, 95%CI: 7.48-60.67). There were no significant differences in proinflammatory genes as well as serum FFAs and IL-1ß between the two groups. No associations were found between the genes expression and serum markers. However, NFĸB expression was significantly correlated with TLR2 and MyD88 (r = 0.747; p < 0.001). Significant correlations were also noticed between TLR2 and MyD88 expression as well as between serum FFAs and IL-1ß in each group (p < 0.001). CONCLUSION: Serum concentration of IL-1ß, FFAs, and mRNA expression levels of TLR2, MyD88, and NFĸB may be resulted from abdominal obesity and not be related to the presence or absence of metabolic health.

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