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Samaneh Tokhanbigli,1,* Ali Asadirad,2,* Kaveh Baghaei,1 Andrea Piccin,3,4 Fatemeh Yarian,5 Gilda Parsamanesh,1 Seyed Mahmoud Hashemi,6 Hamid Asadzadeh Aghdaei,1 Mohammad Reza Zali7 1Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 2Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 3Haematology Department, Our Lady’s Children’s Hospital, Dublin, Ireland; 4Department of Internal Medicine V, University of Innsbruck, Innsbruck, Austria; 5Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 6Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 7Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran*These authors contributed equally to this workCorrespondence: Kaveh BaghaeiResearch Institute of Gastroenterology and Liver Disease (RIGLD), Aerabi St, Yemen St, Chamran Highway, Tehran, IranTel +98 9123592868Email kavehbaghai@gmail.comAndrea PiccinHaematology Department, Our Lady’s Children’s Hospital, Dublin, IrelandTel +353 89 6082831Email apiccin@gmail.comIntroduction: Albeit early stage gastrointestinal (GI) carcinomas have a good prognosis if treated with surgery, diagnosis is often confirmed at a late stage and efficacious drugs are lacking. Recent progress in immune-based therapies has focused on dendritic cells (DCs), aiming to elicit tumor-specific responses by inducing immunological memory. Our previous microarray study indicated that a biomarker, termed lymphocyte antigen-6E (LY6E), is commonly overexpressed in two potentially lethal GI cancers: those of colon and stomach. In this study, we examined the antigenic potency of LY6E in stimulating DCs.Methods: Following isolation, differentiation, and maturation of mononuclear cells, DCs were pulsed with LY6E peptide, a protein related to major histocompatibility complex (MHC) class I/II. Subsequently, DCs were co-cultured with mouse splenocytes to assess antigen-specific T-cell proliferation. Elucidated cytotoxic T-lymphocyte responses were assessed using subcutaneous colorectal murine tumor models.Results: Our in vitro results suggest that DCs loaded with LY6E peptide antigen are capable of stimulating and inducing proliferation of murine T-cells. Furthermore, our in vivo results demonstrate that LY6E peptide has a substantial impact on provoking immune responses against induced colon cancer in mice.Discussion: In conclusion, based on the overexpression of LY6E in colorectal, gastric, and pancreatic cancers, the role of this peptide should be further investigated with a goal of developing new therapies for these challenging diseases.Keywords: dendritic cell, colorectal cancer, LY6E, dendritic cell tumor-associated antigen therapy

Pulmonary fibrosis leads to increased mortality but is poorly understood. Fibrotic progression is associated with abnormal wound repair and an increase in myofibroblast cell populations. Here we investigate how the myofibroblast population is impacted by unique compression-induced apoptosis derived from mechanical strain characteristic of asthma. Using a mechanical device, both static and dynamic mechanical strains were applied to alginate/gelatin/CaCl 2 scaffolds containing fibroblasts and myofibroblasts. As cell groups were stimulated with 30 % static strain for 12 h, fibroblast and myofibroblast cell groups showed increased cell apoptosis by 5.55 % and 19.56 %, respectively, compared to control groups. Additionally, myofibroblasts exhibited higher susceptibility to apoptosis induction than did fibroblasts. Comparing dynamic and static loading modes, dynamic loading resulted in a higher apoptosis rate of fibroblast and myofibroblast cells, indicating its potential to induce apoptosis effectively. These findings suggest that mechanical stimulation can be considered a promising approach to induce apoptosis in myofibroblasts, thus offering the potential for future approaches to treating pulmonary fibrosis. Moreover, mechanical loads can be designed for other diseases, selectively reducing or increasing apoptosis in either hard or soft cell groups, based on specific application needs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Statement of Problem: The clinical success of ceramic veneers cemented with preheated composite resin has been reported to be acceptable. Although the cementing technique requires sufficient light energy to activate its polymerization, the ability of light to penetrate through ceramic restorations of different thicknesses is unclear., Purpose: The purpose of this in vitro study was to evaluate the polymerization quality and bond joint thickness of a dual-component adhesive and a heated composite resin when bonding ceramic onlays of varying thicknesses., Material and Methods: Sixty noncarious maxillary premolars, extracted for orthodontic or periodontal reasons, were divided into 6 groups (n=10) and sectioned apically to the marginal ridge. Computer-aided design and computer-aided manufacturing (CAD-CAM) was used to create onlays of varying thicknesses. Following the manufacturers ' instructions, the onlays were cemented using a dual-polymerizing resin for group DP1, DP2, and DP3 groups and preheated light-polymerizing resin for groups LP1, LP2, and LP3. The numbers indicate onlay thickness in each group. Vickers testing was performed 24 hours after polymerization, with a 0.49-N static load applied for 10 seconds. Film thickness was analyzed under an optical microscope, and temperature changes were measured using a thermal imaging camera. Statistical analysis was done with the 2-factor mixed ANOVA tests (α=.05)., Results: The Vickers hardness of a dual-polymerizing cement was lower compared with heated light-polymerizing cement (P<.05). Moreover, the thickness of the resin-ceramic restoration did not significantly affect the polymerization of a dual-polymerizing cement. However, the polymerization of the preheated light-polymerizing composite resin in group LP3 was significantly lower compared with other thicknesses (P<.05). In group LP3, the Vickers hardness of the tooth adjacent to the surface of the cement (DX2) was lower compared with indentations closer to the restoration surface (DX3, DX6), demonstrating a reduction in polymerization in the internal part. In addition, the mean film thickness of the dual-polymerizing groups (96 ±18 µm) was significantly lower than of the heated light-polymerizing groups (294 ±64 µm) (P<.05). A temperature reduction of 15 °C in the heated composite resin was also observed after 8 seconds CONCLUSIONS: The thickness of the ceramic restoration did not significantly affect the polymerization of a dual-polymerizing cement. However, the polymerization of the preheated light-polymerizing composite resin under the same ceramic restoration with a thickness of 3 mm was significantly lower. In addition, the mean film thickness for the dual-polymerizing composite resin groups was significantly lower than for the heated light-polymerizing composite resin groups., (Copyright © 2024 Editorial Council for The Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

Exosomes (Exos), natural nanovesicles released by various cell types, show potential as an effective drug delivery platform due to their intrinsic role as transporters of biomolecules between different cells. However, Exos functionalization with targeting ligands is a critical step to enhance their targeting capability, which could be challenging. In this study, Exos were modified to specifically bind to CD44-positive cells by anchoring chondroitin sulfate (CS) to their surface. Exo modification was facilitated with CS conjugation with alpha-tocopherol succinate (TOS) as an anchorage. The modified Exos were utilized for delivering curcumin (Cur) to pancreatic cancer (PC) cells. In vitro Cur release studies revealed that Exos play a crucial role in maintaining Cur within themselves, demonstrating their potential as effective carriers for drug delivery to targeted locations. Notably, Cur loaded into the modified Exos exhibited enhanced cytotoxicity compared to unmodified Exo-Cur. Meanwhile, Exo-Cur-TOS-CS induced apoptosis more effectively in AsPC-1 cells than unmodified Exos (70.2 % versus 56.9 %). It is worth mentioning that with CD44-mediated cancer-specific targeting, Exo-CS enabled increased intracellular accumulation in AsPC-1 cells, showing promise as a targeted platform for cancer therapy. These results confirm that Exo modification has a positive impact on enhancing the therapeutic efficacy and cytotoxicity of drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Photobiomodulation (PBM) and Akkermansia muciniphila have been shown to be effective in improving inflammatory conditions with positive effects on increasing the population of anti-inflammatory M2 macrophages (MQs). In this study, gliadin-stimulated THP-1 derived MQs were treated with A. muciniphila and PBM to evaluate their effects on promoting the polarization of M2 MQs. Methods: The human monocyte cell line (THP-1) was differentiated to MQs. MQs were stimulated with 200 μg/mL gliadin for 24 hours and then treated with PBM 810 nm alone and in combination with A. muciniphila for the following 24 hours to evaluate their effects on MQs polarization. THP-1 derived MQs were also treated with PBM and A. muciniphila to evaluate their effects on non-stimulated MQs. CD11b, CD80, and CD206 levels were evaluated by using the flow cytometry technique. Moreover, the expression of some M1 and M2-related cytokines was determined. Results: PBM therapy of gliadin-stimulated MQs decreased IL-6 and increased TGF-β, IL-10 and TNF-α expression compared with gliadin exposed MQs. PBM along with A. muciniphila treatment induced IL-6, TNF-α, and IL-10 expression in MQs in comparison to the untreated group. It also elevated TGF-β, IL-10 and TNF-α levels in gliadin-triggered MQs in comparison to gliadin-stimulated MQ cells. Conclusion: The result of this study showed the potential of PBMT and A. muciniphila for modulating inflammatory responses and MQs polarization. This may open new perspectives to find possible therapeutic targets for celiac diseases., Competing Interests: No potential conflict of interest was reported by the authors., (Copyright © 2024 J Lasers Med Sci.)

Exosomes are small extracellular vesicles (30-150 nm) that are formed by endocytosis containing complex RNA as well as protein structures and are vital in intercellular communication and can be used in gene therapy and drug delivery. According to the cell sources of origin and the environmental conditions they are exposed to, these nanovesicles are very heterogeneous and dynamic in terms of content (cargo), size and membrane composition. Exosomes are released under physiological and pathological conditions and influence the pathogenesis of cancers through various mechanisms, including angiogenesis, metastasis, immune dysregulation, drug resistance, and tumor growth/development. Gastrointestinal cancer is one of the deadliest types of cancer in humans and can involve organs e.g., the esophagus and stomach, or others such as the liver, pancreas, small intestine, and colon. Early diagnosis is very important in this field because the overall survival of patients is low due to diagnosis in late stages and recurrence. Also, various therapeutic strategies have failed and there is an unmet need for the new therapeutic agents. Exosomes can become promising candidates in gastrointestinal cancers as biomarkers and therapeutic agents due to their lower immunity and passing the main physiological barriers. In this work, we provide a general overview of exosomes, their biogenesis and biological functions. In addition, we discuss the potential of exosomes to serve as biomarkers, agents in cancer treatment, drug delivery systems, and effective vaccines in immunotherapy, with an emphasis on gastrointestinal cancers., (© 2024. The Author(s).)

Objectives:  Using finite element analysis (FEA), this study aimed to determine the effect of nonrigid connectors (NRCs) and their position on the success of tooth and implant-supported fixed prostheses in the maxillary posterior region., Materials and Methods:  Three three-dimensional FEA models were designed, presuming maxillary second premolar and first molar to be extracted. Implant (replacing first molar), abutment, bone (spongious and cortical), first premolar (containing dentin, root cement, gutta-percha, and casting post and core), periodontal ligament, and three three-unit cemented porcelain-fused-to-metal prostheses (a rigid one and two nonrigid) were modeled. The NRC was once on the tooth side and once on the implant side. The prostheses were loaded twice. The first molar (180 N) and premolars (120 N) teeth were subjected to progressive vertical and oblique (12-degree) loads, and maximum von Mises stress and strain in teeth and connectors were calculated for each model., Results:  The findings of the current study showed evidence that tooth-implant design with an NRC has significantly increased the average stress in the tooth. The average stress in dentin was 769.02 for the mesial connector and 766.95 for the distal connector, and this was only 731.59 for rigid connector. Furthermore, it was observed that rigid connector has considerably minimized the stress within the tooth-implant-supported fixed partial denture. The average stress for the crown and metal frame is 346.22 and 526.41 in rigid connector, while it is 1,172.9 and 2,050.9 for the nonrigid mesial connector., Conclusion:  Although distal NRC was more efficient than mesial NRC, using NRC will only reduce the stress applied to cortical bone and is not recommended in the posterior region of the maxilla., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Hepatocellular carcinoma (HCC) is the most frequent form of liver malignancy, and curing it is very challenging. Restoring tumor suppressor microRNAs could trigger the initiation of cellular anticancer mechanisms. Exosomes are nanosized biocarriers capable of fusing with cell membranes and delivering their cargo. The main goal of the current study was to explore the potential of human embryonic kidney cells (HEK293) cell-derived exosomes to provide an anticancer therapy based on the restoration of tumor suppressor miR-365a downregulated in HepG2 cells. To accomplish this aim, exosomes were isolated from the HEK293 cell line culture and characterized, enriched by Homo sapiens (hsa) miR-365a-3p mimics. Exosomes enabled an efficient loading and intracellular delivery of hsa-miR-365a mimics, which translated into G0/G1 cell cycle arrest, induction of oxidative stress, reduction of migration capacity, and high apoptosis rate. The findings indicate that the delivery of miR-365a-3p by HEK293-derived exosomes may act as an innovative and effective therapeutic strategy against HCC., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background: The isolation of Mesenchymal Stem Cells (MSCs) from various tissues is possible, with the umbilical cord emerging as a competitive alternative to bone marrow. In order to fulfill the demands of cell therapy, it is essential to generate stem cells on a clinical scale while minimizing time, cost, and contamination. Here is a simple and effective protocol for isolating MSC from Wharton's Jelly (WJ-MSC) using the explant method with various supplements., Methods: Utilizing the explant method, small fragments of Wharton's jelly from the human umbilical cord were cultured in a flask. The multipotency of the isolated cells, were confirmed by their differentiation ability to osteocyte and adipocyte. Additionally, the immunophenotyping of WJ-MSCs showed positive expression of CD73, CD90, and CD105, while remaining negative for hematopoietic markers CD34 and CD45, meeting the criteria for WJ-MSC identification. Following that, to evaluate cells' proliferative capacity, various supplements, including basic Fibroblast Growth Factor (bFGF), Non-Essential amino acids (NEA), and L-Glutamine (L-Gln) were added to either alpha-Minimal Essential Medium (α-MEM) or Dulbecco's Modified Eagle's Medium-F12 (DMEM-F12), as the basic culture media., Results: WJ-MSCs isolated by the explant method were removed from the tissue after seven days and transferred to the culture medium. These cells differentiated into adipocyte and osteocyte lineages, expressing CD73, CD90, and CD105 positively and CD34 and CD45 negatively. The results revealed that addition of bFGF to α-MEM or DMEMF12 media significantly increased the proliferation of MSCs when compared to the control group. However, there were no significant differences observed when NEA or LGln were added., Conclusion: Although bFGF considerably enhances cell proliferation, our study demonstrates that MSCs can grow and expand when properly prepared Wharton's jelly tissues of the human umbilical cord., (Copyright© 2024 Avicenna Research Institute.)

Introduction: In in-vitro dental radiographic research, simulation of soft tissue is required to replicate the clinical condition as close as possible. This study aimed to find out which soft tissue simulation material have been studied to use in dentomaxillofacial radiology and showed similarity in radiodensity to the soft tissues of the maxillofacial region., Methods: In this scoping review, Web of Science, Embase, Scopus, Google scholar and PubMed databases were searched on April 9, 2023, considering the following PICOS: Population: soft tissue simulants, Intervention: X-ray-based imaging, Comparison: -, Outcome: properties of the soft tissue simulants, Study design: in-vitro studies. Screening, study selection, and data extraction were performed by two independent researchers. A third team member was consulted in the case of disagreement. Quality assessment of the included studies was made using Quality Assessment Tool For In-Vitro Studies (QUIN Tool)., Results: Of the initial 1172 articles retrieved in the database search, 13 studies were included in the review. Seven studies had a low risk of bias. In 8 studies, computed tomography (CT) or cone beam computed tomography (CBCT), in 4 studies intraoral radiography, and in 2 studies panoramic radiography was used (one study has used CT/CBCT and panoramic radiography). The studies varied in the radiographic modality, acquisition parameters, selected outcomes, and gold standard. In the majority of the studies (n = 10, 77%), acrylic resin derivatives were used in the soft tissue simulant formula alone or as a major component. Wax was used in the simulant material in 8 studies (62%). In addition, in 3 studies (23%) ice/water was used as the main simulant., Conclusion: Ballistic gelatin, expanded 2-cm thick polystyrene with or without 1-cm utility wax, and 0.5 cm of acrylic resin were shown to have a radiographic density similar to soft tissue in standardized studies employing CBCT scanning. For intraoral radiographs, using self-polymerizing acrylic resin, utility wax, and wood, as well as a polymethylmethacrylate box filled with water in thicknesses ranging from 4 to 45 mm, provides suitable radiographic contrast. However, for 4 and 8 mm of wax and 4 mm of water, the radiographic contrast is not appropriate. In addition, 13-17 mm wax and 14.5 mm acrylic resin showed acceptable soft tissue densities in intraoral radiography. Further studies using different imaging modalities with standardized conditions and objective metrics are required to confirm the most appropriate soft tissue simulant material for in-vitro dental radiographic research., (© 2023. The Author(s) under exclusive licence to Japanese Society for Oral and Maxillofacial Radiology.)

Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver diseases, affecting more than one-quarter of people worldwide. Hepatic steatosis can progress to more severe forms of NAFLD, including NASH and cirrhosis. It also may develop secondary diseases such as diabetes and cardiovascular disease. Genetic and environmental factors regulate NAFLD incidence and progression, making it a complex disease. The contribution of various environmental risk factors, such as type 2 diabetes, obesity, hyperlipidemia, diet, and sedentary lifestyle, to the exacerbation of liver injury is highly understood. Nevertheless, the underlying mechanisms of genetic variations in the NAFLD occurrence or its deterioration still need to be clarified. Hence, understanding the genetic susceptibility to NAFLD is essential for controlling the course of the disease. The current review discusses genetics' role in the pathological pathways of NAFLD, including lipid and glucose metabolism, insulin resistance, cellular stresses, and immune responses. Additionally, it explains the role of the genetic components in the induction and progression of NAFLD in lean individuals. Finally, it highlights the utility of genetic knowledge in precision medicine for the early diagnosis and treatment of NAFLD patients., (© 2024. The Author(s).)

Celiac Disease (CeD) is an autoimmune disorder with various symptoms upon gluten exposure. Dendritic cells (DCs) play a crucial role in gliadin-induced inflammation. Vitamin A (retinol; Ret) and its metabolite, retinoic acid (RA), along with tryptophan (Trp) and its metabolite, kynurenic acid (KYNA), are known to influence the immune function of DCs and enhance their tolerogenicity. This research aims to assess the impact of gliadin on DC maturation and the potential of vitamin A and tryptophan to induce immune tolerance in DCs. The monocyte cells obtained from peripheral blood mononuclear cells (PBMCs) of celiac disease patients were differentiated into DCs in the absence or presence of Ret, RA, Trp, KYNA, and then stimulated with peptic and tryptic (PT) digested of gliadin. We used flow cytometry to analyze CD11c, CD14, HLA-DR, CD83, CD86, and CD103 expression. ELISA was carried out to measure TGF-β, IL-10, IL-12, and TNF-α levels. qRT-PCR was used to assess the mRNA expression of retinaldehyde dehydrogenase 2 (RALDH2) and integrin αE (CD103). The mRNA and protein levels of Indoleamine 2, 3-dioxygenase (IDO) was analyzed by qRT-PCR and Western blot assays, respectively. Our findings demonstrate that PT-gliadin enhances the expression of maturation markers, i.e. CD83, CD86 and HLA-DR and promote the secretion of TNF-α and IL-12 in DCs. Interestingly, vitamin A, tryptophan, and their metabolites increase the expression of CD103, while limiting the expression of HLA-DR, CD83, and CD86. They also enhance RALDH2 and IDO expression and promote the secretion of TGF-β and IL-10, while limiting IL-12 and TNF-α secretion. These findings suggest that vitamin A and tryptophan have beneficial effects on PT-gliadin-stimulated DCs, highlighting their potential as therapeutic agents for celiac disease. However, further research is needed to fully understand their underlying mechanisms of action in these cells., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Individuals with Coronavirus Disease 2019 (COVID-19) may show no symptoms to moderate or severe complications. This variation may be due to differences in the strength of the immune response, including a delayed interferon (IFN) response in asymptomatic patients and higher IFN levels in severe patients. Some long non-coding RNAs (lncRNAs), as regulators of the IFN pathway, may contribute to the emergence of different COVID-19 symptoms. This study aimed to comparatively investigate the relationship between lncRNAs (eosinophil granule ontogeny transcript (EGOT), negative regulator of antiviral response (NRAV), and negative regulator of interferon response (NRIR)), alongside interferon-stimulated genes (ISGs) like ISG-15 and interferon-induced transmembrane protein 3 (IFITM3) in COVID-19 patients with asymptomatic, moderate, and severe symptoms. Buffy coat samples were collected from 17 asymptomatic, 23 moderate, 22 severe patients, and 44 healthy controls. Quantitative real-time PCR was utilized to determine the expression levels. In a comparison between COVID-19 patients and healthy individuals, higher expression levels of EGOT and NRAV were observed in severe and moderate patients. NRIR expression was increased across all patient groups. Meanwhile, ISG15 expression decreased in all patient groups, and the moderate group showed a significant decrease in IFITM3 expression. Comparing COVID-19 patient groups, EGOT expression was significantly higher in moderate COVID-19 patients compared to asymptomatic patients. NRAV was higher in moderate and severe patients compared to asymptomatic. NRIR levels did not differ significantly between the COVID-19 patient groups. ISG15 was higher in moderate and severe patients compared to asymptomatic. IFITM3 expression was significantly higher in severe patients compared to the moderate group. In severe COVID-19 patients, EGOT expression was positively correlated with NRAV levels. EGOT and NRAV showed a significant positive correlation in asymptomatic patients, and both were positively correlated with IFITM3 expression. This study suggests that EGOT, NRAV, NRIR, ISG15, and IFITM3 may serve as diagnostic biomarkers for COVID-19. The lncRNA NRAV may be a good biomarker in a prognostic panel between asymptomatic and severe patients in combination with other high-sensitivity biomarkers. EGOT, NRAV, and ISG15 could also be considered as specific biomarkers in a prognostic panel comparing asymptomatic and moderate patients with other high-sensitivity biomarkers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The pentaspan transmembrane glycoprotein CD133, prominin-1, is expressed in cancer stem cells in many tumors and is promising as a novel target for the delivery of cytotoxic drugs to cancer-initiating cells. In this study, we prepared a mouse library of single-chain variable fragment (scFv) antibodies using mRNAs isolated from mice immunized with the third extracellular domain of a recombinant CD133 (D-EC3). First, the scFvs were directly exposed to D-EC3 to select a new specific scFv with high affinity against CD133 using the ribosome display method. Then, the selected scFv was characterized by the indirect enzyme-linked immunosorbent assay (ELISA), immunocytochemistry (ICC), and in silico analyses included molecular docking and molecular dynamics simulations. Based on ELISA results, scFv 2 had a higher affinity for recombinant CD133, and it was considered for further analysis. Next, the immunocytochemistry and flow cytometry experiments confirmed that the obtained scFv could bind to the CD133 expressing HT-29 cells. Furthermore, the results of in silico analysis verified the ability of the scFv 2 antibody to bind and detect the D-EC3 antigen through key residues employed in antigen-antibody interactions. Our results suggest that ribosome display could be applied as a rapid and valid method for isolation of scFv with high affinity and specificity. Also, studying the mechanism of interaction between CD133's scFv and D-EC3 with two approaches of experimental and in silico analysis has potential importance for the design and development of antibody with improved properties., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The routine application of dental implants for replacing missing teeth has revolutionized restorative and prosthetic dentistry. However, cone beam computed tomography (CBCT) evaluations of structures adjacent to the implants are limited by metal artifacts. There are several methods for reducing metal artifacts, but this remains a challenging task. This study aimed to examine the effectiveness of metal artifact reduction (MAR) algorithms in identifying injuries of implants to the inferior alveolar canal in CBCT images., Method: In this in vitro study, mono-cortical bone windows were created and the inferior alveolar canal was revealed. Using 36 implants, pilot drill and penetration damage of the implant tip into the canal was simulated and compared to the control implants with distance from the canal. CBCT images were evaluated by four experienced observers with and without the MAR algorithm and compared to direct vision as the gold standard. The values of accuracy, sensitivity, and specificity were obtained and compared by receiver operating characteristic (ROC) curve (α = 0.05)., Result: The area under the ROC curve values for detection of pilot drill injuries varied between 0.840-0.917 and 0.639-0.854 in the active and inactive MAR conditions, respectively. The increase in ROC area was only significant for one of the observers (P = 0.010). For diagnosing penetrative injuries, the area under the ROC curve values was between 0.990-1.000 and 0.722-1.000 in the active and inactive MAR conditions, respectively. The improvement of ROC curve values in active MAR mode was only significant for one of the observers (P = 0.006)., Conclusion: Activation of MAR improved the diagnostic values of CBCT images in detecting both types of implant-related injuries to the inferior alveolar canal. However, for most observers, this increase was not statistically significant., (© 2024. The Author(s).)

Long-term clinical outcomes of short dental implants (≤6 mm) supporting single crowns or short fixed partial dentures have been reported differently in different studies and need more clarification. This systematic study evaluated the rate of bone loss (BL), the durability of implants equal to or shorter than 6 mm supporting single crowns or short fixed partial dentures, and prosthetic-related side effects during 5 years of follow-up. Five databases (PubMed, MEDLINE, Scopus, Google Scholar, and Cochrane) were electronically and manually searched for longitudinal studies with a follow-up period of 5 years or more until January 2023. The study question was, "Does the implant equal to or shorter than 6 mm affect BL and survival rate of the implant-supported prosthesis after 5 years of follow-up?". From 752 identified articles, nine studies were selected for further evaluation. After 5 years of follow-up, most studies had more than 90% survival rate and the maximum BL was 0.54 mm. Still, in internal and external connections, these changes were not substantial. For example, screw loosening was the most common problem with implanted prostheses. Implants of 6 mm or shorter are a suitable treatment option in atrophic ridges with good durability and fewer side effects during a follow-up period of more than 5 years., Competing Interests: None declared, (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Background: One of the main reasons for cancer resistance to chemotherapy is the presence of cancer stem cells (CSCs) in cancer tissues. It is also believed that CSCs are the unique originators of all tumor cells. On the other hand, the Epithelial-Mesenchymal Transition pathway (EMT) can act as the main agent of metastasis. Therefore, it is possible that targeting CSCs as well as the EMT pathway could help in cancer therapy. Considering that CSCs constitute only a small percentage of the total tumor mass, enrichment before study is necessary. In our previous study, CSCs were enriched in the human colon cancer cell line HT29 by induction of EMT. These CSC-enriched HT29 cells with mesenchymal morphology were named "HT29-shE". In the present study, these cells were used to investigate the effect of pioglitazone (Pio) and Cetuximab (Cet) in order to find CSC and EMT targeting agents., Method: The viability and IC50 rate of cells treated with different concentrations of Pio and Cet were evaluated using the MTT test. EMT and CSC markers and cell morphology were assessed in Pio and Cet treated and untreated HT29-shE cells using flow cytometry, realtime PCR, immunocytochemistry, and microscopic monitoring., Results: The findings showed that Pio and Cet at concentrations of 250 μM and 40 μg/ml, respectively, decrease cell viability by 50%. Also, they were able to reduce the expression of CSC markers (CD133 and CD44) in the CSC enriched HT29 cell line. Furthermore, Pio and Cet could efficiently reduce the expression of vimentin as a mesenchymal marker and significantly upregulate the expression of E-cadherin as an epidermal marker of EMT and its reverse mesenchymal-- to-epithelial transition (MET). In addition, the mesenchymal morphology of HT29-shE changed into epithelial morphology after Cet treatment., Conclusion: Pio and Cet could inhibit EMT and reduce CSC markers in the EMT induced/CSC enriched cell line. We expect that focus on finding EMT/CSC-targeting agents like these drugs can be helpful for cancer treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Statement of Problem: With the growing importance of implant brand detection in clinical practice, the accuracy of machine learning algorithms in implant brand detection has become a subject of research interest. Recent studies have shown promising results for the use of machine learning in implant brand detection. However, despite these promising findings, a comprehensive evaluation of the accuracy of machine learning in implant brand detection is needed., Purpose: The purpose of this systematic review and meta-analysis was to assess the accuracy, sensitivity, and specificity of deep learning algorithms in implant brand detection using 2-dimensional images such as from periapical or panoramic radiographs., Material and Methods: Electronic searches were conducted in PubMed, Embase, Scopus, Scopus Secondary, and Web of Science databases. Studies that met the inclusion criteria were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Meta-analyses were performed using the random-effects model to estimate the pooled performance measures and the 95% confidence intervals (CIs) using STATA v.17., Results: Thirteen studies were selected for the systematic review, and 3 were used in the meta-analysis. The meta-analysis of the studies found that the overall accuracy of CNN algorithms in detecting dental implants in radiographic images was 95.63%, with a sensitivity of 94.55% and a specificity of 97.91%. The highest reported accuracy was 99.08% for CNN Multitask ResNet152 algorithm, and sensitivity and specificity were 100.00% and 98.70% respectively for the deep CNN (Neuro-T version 2.0.1) algorithm with the Straumann SLActive BLT implant brand. All studies had a low risk of bias., Conclusions: The highest accuracy and sensitivity were reported in studies using CNN Multitask ResNet152 and deep CNN (Neuro-T version 2.0.1) algorithms., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Gastric cancer is a complex heterogeneous disease with different molecular subtypes that have clinical implications. It is characterized by high mortality rates and limited effective therapies. Microsatellite instability (MSI) has been recognized as a subgroup with a good prognosis based on TCGA and ACRG categorizations. Besides its prognostic and predictive value, gastric cancers with high MSI exhibit different clinical behaviors. The prevalence of high MSI has been assessed in gastric cancer worldwide, especially in East Asia, but there is a lack of such information in the Middle East. Therefore, this study aimed to investigate the incidence and status of MSI in Iranian gastric cancer patients using 53 samples collected from 2015 to 2020 at Taleghani Hospital Medical Center. DNA from tumoral and normal tissues were extracted and assessed through multiplex-PCR based on five mononucleotide repeats panel. Clinicopathological variables, including age, sex, Lauren classification, lymph node involvement, TNM stage, differentiation, localization, and tumor size, were also analyzed. With 2 males and 2 females, high microsatellite instability represented a small subgroup of almost 7.5% of the samples with a median age of 60.5 years. High microsatellite instability phenotypes were significantly associated with patients aged 68 years and older (p‑value of 0.0015) and lower lymph node involvement (p‑value of 0.0004). Microsatellite instability was also more frequent in females, with distal gastric location, bigger tumor size, and in the intestinal type of gastric cancer rather than the diffuse type., (© 2023. The Author(s).)

End-stage of liver fibrosis as a precancerous state could lead to cirrhosis and hepatocellular carcinoma which liver transplantation is the only effective treatment. Previous studies have indicated that farnesoid X receptor (FXR) agonists, such as obeticholic acid (OCA) protect against hepatic injuries. However, free OCA administration results in side effects in clinical trials that could be alleviated by applying bio carriers such as MSC-derived exosomes (Exo) with the potential to mimic the biological regenerative effect of their parent cells, as proposed in this study. Loading OCA into the Exo was conducted via water bath sonication. Ex vivo bio distribution studies validated the Exo-loaded OCA more permanently accumulated in the liver. Using CCL4-induced liver fibrosis, we proposed whether Exo isolated from human Warton's Jelly mesenchymal stem cells loaded with a minimal dosage of OCA can facilitate liver recovery. Notably, Exo-loaded OCA exerted additive anti-fibrotic efficacy on histopathological features in CCL4-induced fibrotic mice. Compared to baseline, Exo-mediated delivery OCA results in marked improvements in the fibrotic-related indicators as well as serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations. Accordingly, the synergistic impact of Exo-loaded OCA as a promising approach is associated with the inactivation of hepatic stellate cells (HSCs), extracellular matrix (ECM) remodeling, and Fxr-Cyp7a1 cascade on CCL4-induced liver fibrosis mice. In conclusion, our data confirmed the additive protective effects of Exo-loaded OCA in fibrotic mice, which suggests a valuable therapeutic strategy to combat liver fibrosis. Furthermore, the use of Exo for accurate drug delivery to the liver tissue can be inspiring., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a major public health concern worldwide due to its rapidly rising prevalence and its potential to progress into end-stage liver disease. While the precise pathophysiology underlying NAFLD remains incompletely understood, it is strongly associated with various environmental triggers and other metabolic disorders. Epigenetics examines changes in gene expression that are not caused by alterations in the DNA sequence itself. There is accumulating evidence that epigenetics plays a key role in linking environmental cues to the onset and progression of NAFLD. Our understanding of how epigenetic mechanisms contribute to NAFLD pathophysiology has expanded considerably in recent years as research on the epigenetics of NAFLD has developed. This review summarizes recent insights into major epigenetic processes that have been implicated in NAFLD pathogenesis including DNA methylation, histone acetylation, and microRNAs that have emerged as promising targets for further investigation. Elucidating epigenetic mechanisms in NAFLD may uncover novel diagnostic biomarkers and therapeutic targets for this disease. However, many questions have remained unanswered regarding how epigenetics promotes NAFLD onset and progression. Additional studies are needed to further characterize the epigenetic landscape of NAFLD and validate the potential of epigenetic markers as clinical tools. Nevertheless, an enhanced understanding of the epigenetic underpinnings of NAFLD promises to provide key insights into disease mechanisms and pave the way for novel prognostic and therapeutic approaches., Competing Interests: Declaration of Competing Interest All authors declare no potential competing interest., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background: Helicobacter pylori outer membrane vesicles (OMVs) are nano-sized structures, which have been recently suggested to play a crucial role in H. pylori pathogenesis. There are growing evidence indicating the relationship of H. pylori infection with extra-gastroduodenal diseases, especially liver-related disorders. This study was aimed to investigate the effects of H. pylori-derived OMVs on autophagy in hepatic stellate cells (HSCs)., Material and Methods: A selection of five clinical strains of H. pylori with different virulence genotypes were included. The OMVs were isolated by ultracentrifugation and characterized by scanning electron microscopy (SEM) and dynamic light scattering (DLS). The protein concentration of OMVs was measured by BCA assay. MTT assay was used to determine the viability of LX-2 cells (human HSCs) treated with OMVs. The expression level of MTOR, AKT, PI3K, BECN1, ATG16 and LC3B genes was assessed in OMVs-treated LX-2 cells using quantitative real-time PCR. Moreover, immunocytochemistry was performed to evaluate the protein expression of MTOR and LC3B autophagy markers., Results: H. pylori strains produced round shape nano-vesicles ranging from 50 to 500 nm. Treatment of HSCs with H. pylori-derived OMVs at concentration of 10 μg/mL for 24 h significantly elevated the expression of autophagy inhibitory markers (PI3K, AKT, and MTOR) and suppressed the mRNA expression level of autophagy core proteins (BECN1, ATG16 and LC3B). Immunocytochemistry also presented a substantial reduction in the concentration of LC3B autophagy core protein, and a marked elevation in the amount of MTOR autophagy inhibitory protein., Conclusion: This study revealed that H. pylori-derived OMVs could potentially suppress autophagy flux in HSCs as a novel mechanism for H. pylori-mediated liver autophagy impairment and liver disease development. Further studies are required to elucidate the exact role of OMV-carried contents in liver autophagy, and liver-associated disorders., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Liver fibrosis is characterized by the excessive deposition and accumulation of extracellular matrix components, mainly collagens, and occurs in response to a broad spectrum of triggers with different etiologies. Under stress conditions, autophagy serves as a highly conserved homeostatic system for cell survival and is importantly involved in various biological processes. Transforming growth factor-β1 (TGF-β1) has emerged as a central cytokine in hepatic stellate cell (HSC) activation and is the main mediator of liver fibrosis. A growing body of evidence from preclinical and clinical studies suggests that TGF-β1 regulates autophagy, a process that affects various essential (patho)physiological aspects related to liver fibrosis. This review comprehensively highlights recent advances in our understanding of cellular and molecular mechanisms of autophagy, its regulation by TGF-β, and the implication of autophagy in the pathogenesis of progressive liver disorders. Moreover, we evaluated crosstalk between autophagy and TGF-β1 signalling and discussed whether simultaneous inhibition of these pathways could represent a novel approach to improve the efficacy of anti-fibrotic therapy in the treatment of liver fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hydatidosis is a disease caused by the larval stage of Echinococcus granulosus, which involves several organs of intermediate hosts. Evidence suggests a communication between hydatid cyst (HC) and hosts via extracellular vesicles. However, a little is known about the communication between EVs derived from HC fluid (HCF) and host cells. In the current study, EVs were isolated using differential centrifugation from sheep HCF and characterized by western blot, electron microscope and size distribution analysis. The uptake of EVs by human monocyte cell line (THP-1) was evaluated. The effects of EVs on the expression levels of pro- and anti-inflammatory cytokines were investigated using quantitative real-time PCR (RT-PCR), 3 and 24 h after incubation. Moreover, the cytokine level of IL-10 was evaluated in supernatant of THP-1 cell line at 3 and 24 h. EVs were successfully isolated and showed spherical shape with size distribution at 130.6 nm. After 3 h, the expression levels of pro-inflammatory cytokine genes (IL1Β, IL15 and IL8) were upregulated, while after 24 h, the expression levels of pro-inflammatory cytokines were decreased and IL13 gene expression showed upregulation. A statistically significant increase was seen in the levels of IL-10 after 24 h. The main mechanism of the communication between EVs derived from HCF and their host remains unclear; however, time-dependent anti-inflammatory effects in our study suggest that HC may modulate the immune responses via EVs., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Treatment of Helicobacter pylori (H. pylori) infection has become challenging following the development of primary antibiotic resistance. A primary therapeutic regimen for H. pylori eradication includes clarithromycin; however, the presence of point mutations within the 23S rRNA sequence of H. pylori contributes to clarithromycin resistance and eradication failure. Thus, we aimed to develop a rapid and precise method to determine clarithromycin resistance-related point mutations using the pyrosequencing method., Methods and Results: H. pylori was isolated from 82 gastric biopsy samples and minimal inhibitory concentration (MIC) was evaluated using the agar dilution method. Clarithromycin resistance-associated point mutations were detected by Sanger sequencing, from which 11 isolates were chosen for pyrosequencing. Our results demonstrated a 43.9% (36/82) prevalence in resistance to clarithromycin. The A2143G mutation was detected in 8.3% (4/48) of H. pylori isolates followed by A2142G (6.2%), C2195T (4.1%), T2182C (4.1%), and C2288T (2%). Although the C2195T mutation was only detected by Sanger sequencing, the overall results from pyrosequencing and Sanger sequencing platforms were comparable., Conclusions: Pyrosequencing could be used as a rapid and practical platform in clinical laboratories to determine the susceptibility profile of H. pylori isolates. This might pave the way for efficient H. pylori eradication upon detection., (© 2023. The Author(s).)

Liver fibrosis is the excessive accumulation of extracellular matrix proteins. Due to the lack of an accurate test for an early diagnosis of liver fibrosis and the invasiveness of the liver biopsy procedure, there is an urgent need for effective non-invasive biomarkers for screening the patients. we aimed to evaluate the diagnostic performance of circulating miRNAs (miR-146b, -194, -214) and their related mechanisms in the pathogenesis of liver fibrosis. The expression levels of miR-146b, -194, and -214 were quantified in whole blood samples from NAFLD patients using real-time PCR. The competing endogenous RNA (ceRNA) network was constructed and a gene set enrichment analysis (GSEA) was performed for HSC activation-related genes. Also, the transcription factor (TF)-miR co-regulatory network and the survival plot for three miRNAs and core genes were illustrated. The qPCR results showed that the relative expression of miR-146b and miR-214 significantly increased in NAFLD patients, while miR-194 showed significant down-regulation. The ceRNA network analysis implicated NEAT1 and XIST as sponge candidates for these miRNAs. The GSEA results identified 15 core genes involved in HSC activation, primarily enriched in NF-κB activation and autophagy pathways. STAT3, TCF3, RELA, and RUNX1 were considered potential transcription factors connected to miRNAs in the TF-miR network. Our study elucidated three candidate circulating miRNAs differentially expressed in NAFLD that could serve as a promising non-invasive diagnostic tool for early detection strategies. Also, NF-κB activation, autophagy, and negative regulation of the apoptotic process are the main potential underlying mechanisms regulated by these miRNAs in liver fibrosis pathogenesis., Competing Interests: The authors declare that they have no competing interests., (© 2023 The Authors.)

Liver fibrosis is a significant cause of morbidity and mortality without approved treatment. The therapeutic effects of Imatinib as a tyrosine kinase inhibitor on reversing liver fibrosis have already been shown. However, considering the conventional route of Imatinib administration, the amount of drug to be used is very high, and its side effects are raised. Therefore, we designed an efficient pH-sensitive polymer for the targeted delivery of Imatinib in treating a carbon tetrachloride (CCl4)-induced liver fibrosis. This nanotherapeutic system-based Vitamin A (VA)-modified Imatinib-loaded poly (lactic-co-glycolic acid)/Eudragit S100 (PLGA-ES100) has been successfully fabricated by adapting the solvent evaporation technique. The applying ES100 on the surface of our desired nanoparticles (NPs) protects drug release at the acidic pH of the gastric and guarantees the effective release of Imatinib at a higher pH of the intestine. Besides, VA-functionalized NPs could be an ideal efficient drug delivery system due to the high capacity of hepatic cell lines to absorb VA. For induction of liver fibrosis, CCL4 was intraperitoneally (IP) injected twice a week for six weeks in BALB/c mice. Oral administration of VA-targeted PLGA-ES100 NPs loaded with Rhodamine Red™ by live animal imaging showed a preferential accumulation of the selected NPs in the liver of mice. Besides, administrating targeted Imatinib-loaded NPs significantly decreased serum levels of ALT, and AST, and also reduced the expression of extracellular matrix components, including collagen I, collagen III, and α-SMA, considerably. Interestingly, histopathological evaluation of liver tissues through H&E and Masson's trichrome staining showed that oral administration of targeted Imatinib-loaded NPs reduced hepatic damage by enhancing hepatic structure condition. Also, the Sirius-red staining indicated a reduction in collagen expression during treatment with targeted NP containing Imatinib. The immunohistochemistry result on liver tissue shows a significant decrease in the expression of α-SMA in groups treated with targeted NP. In the meantime, administration of a very scarce dose of Imatinib via targeted NP caused a substantial decline in the expression of fibrosis marker genes (Collagen I, Collagen III, α-SMA). Our results confirmed that novel pH-sensitive VA-targeted PLGA-ES100 NPs could efficiently deliver Imatinib to the liver cells. Loading Imatinib in the PLGA-ES100/VA might overcome many challenges facing conventional Imatinib therapy, including gastrointestinal pH, the low concentration at the target region, and toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Liver fibrosis is a significant challenge to global health that results in organ failure through inflammation and the release of fibrotic biomarkers. Due to the lack of effective treatments for liver fibrosis, anti-fibrotic and anti-inflammatory therapies are being developed. Since there has been an association between aberrant expression of miR-124 and liver disease progression, we investigated whether delivery of miR-124 through human Wharton's jelly mesenchymal stem cells derived-exosomes (hWJMSC-Exo) can improve liver fibrosis., Methods: We established a 6-week carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis, then we administered hWJMSC-Exo and miR-124-3p-enriched exosomes (ExomiR-124) for three weeks. The extent of fibrosis and inflammation was assessed by histology, biochemistry, Real-time PCR, immunohistochemistry, and Enzyme-linked immunoassays (ELISA). The inflammatory status of the spleen was also investigated using flow cytometry., Results: Based on the gene and protein expression measurement of IL-6, IL-17, TGF-β, STAT3, α-SMA, and COL1, In vivo administration of Exo and ExomiR-124 effectively reduce collagen accumulation and inhibition of inflammation. Regarding histopathology findings, the therapeutic effect of ExomiR-124 against liver fibrosis was significantly greater than hWJMSC-Exo. In addition, we found that Exo and ExomiR-124 was capable of phenotype switching of splenic monocytes from inflammatory Ly6C hi to restorative Ly6C lo ., Conclusions: MSC-derived exosomes demonstrated anti-inflammatory effect via different aspects. Aside from the therapeutic approach, enrichment of exosomes as a nanocarrier by miR-124 revealed the down-regulation of STAT3, which plays a crucial role in liver fibrosis. The anti-inflammatory and anti-fibrotic properties of ExomiR-124 could be a promising option in liver fibrosis combination therapies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Non-Alcoholic fatty liver disease is characterized by the accumulation of excess fat in the liver, chronic inflammation, and cell death, ranging from simple steatosis to fibrosis, and finally leads to cirrhosis and hepatocellular carcinoma. The effect of Fibroblast growth factor 2 on apoptosis and ER stress inhibition has been investigated in many studies. In this study, we aimed to investigate the effect of FGF2 on the NAFLD in-vitro model in the HepG2 cell line., Methods: The in-vitro NAFLD model was first induced on the HepG2 cell line using oleic acid and palmitic acid for 24 h and evaluated by ORO staining and Real-time PCR. The cell line was then treated with various concentrations of fibroblast growth factor 2 for 24 h, total RNA was extracted and cDNA was consequently synthesized. Real-time PCR and flow cytometry was applied to evaluate gene expression and apoptosis rate, respectively., Results: It was shown that fibroblast growth factor 2 ameliorated apoptosis in the NAFLD in-vitro model by reducing the expression of genes involved in the intrinsic apoptosis pathway, including caspase 3 and 9. Moreover, endoplasmic reticulum stress was decreased following upregulating the protective ER-stress genes, including SOD1 and PPARα., Conclusions: FGF2 significantly reduced ER stress and intrinsic apoptosis pathway. Our data suggest that FGF2 treatment could be a potential therapeutic strategy for NAFLD., (© 2023. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)

Extracellular vesicles (EVs) are a promising drug delivery vehicle candidate because of their natural origin and intrinsic function of transporting various molecules between different cells. Several advantages of the EV delivery platform include enhanced permeability and retention effect, efficient interaction with recipient cells, the ability to traverse biological barriers, high biocompatibility, high biodegradability, and low immunogenicity. Furthermore, EV membranes share approximately similar structures and contents to the cell membrane, which allows surface modification of EVs, an approach to enable specific targeting. Enhanced drug accumulation in intended sites and reduced adverse effects of chemotherapeutic drugs are the most prominent effects of targeted drug delivery. In order to improve the targeting ability of EVs, chemical modification and genetic engineering are the most adopted methods to date. Diverse chemical methods are employed to decorate EV surfaces with various ligands such as aptamers, carbohydrates, peptides, vitamins, and antibodies. In this review, we introduce the biogenesis, content, and cellular pathway of natural EVs and further discuss the genetic modification of EVs, and its challenges. Furthermore, we provide a comprehensive deliberation on the various chemical modification methods for improved drug delivery, which are directly related to increasing the therapeutic index., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The activation of hepatic stellate cells is the primary function of facilitating liver fibrosis. Interfering with the coordinators of different signaling pathways in activated hepatic stellate cells (aHSCs) could be a potential approach in ameliorating liver fibrosis. Regarding the illustrated anti-fibrotic effect of imatinib in liver fibrosis, we investigated the imatinib's potential role in inhibiting HSC activation through miR-124 and its interference with the STAT3/hepatic leukemia factor (HLF)/IL-6 circuit. The anti-fibrotic effect of imatinib was investigated in the LX-2 cell line and carbon tetrachloride (CCl 4 )-induced Sprague-Dawley rat. The expression of IL-6, STAT3, HLF, miR-124, and α-smooth muscle actin (α-SMA) were quantified by quantitative real-time PCR (qRT-PCR) and the protein level of α-SMA and STAT3 was measured by western blot analysis both in vitro and in vivo. The LX-2 cells were subjected to immunocytochemistry (ICC) for α-SMA expression. After administering imatinib in the liver fibrosis model, histopathological examinations were done, and hepatic function serum markers were checked. Imatinib administration alleviated mentioned liver fibrosis markers. The expression of miR-124 was downregulated, while IL-6/HLF/STAT3 circuit agents were upregulated in vitro and in vivo. Notably, imatinib intervention decreased the expression of IL-6, STAT3, and HLF. Elevated expression of miR-124 suppressed the expression of STAT3 and further inhibited HSCs activation. Our results demonstrated that imatinib not only ameliorated hepatic fibrosis through tyrosine kinase inhibitor (TKI) activity but also interfered with the miR-124 and STAT3/HLF/IL-6 pathway. Considering the important role of miR-124 in regulating liver fibrosis and HSCs activation, imatinib may exert its anti-fibrotic activity through miR-124., (© 2023 International Federation for Cell Biology.)

Introduction: Helicobacter pylori is a prevalent pathogenic bacterium that resides in the human stomach. Outer membrane vesicles (OMVs) are known as nanosized cargos released by H. pylori , which have been proposed to have a key role in disease progression, pathogenesis, and modulation of the immune system. There are multiple evidences for the role of H. pylori in extragastroduodenal illnesses especially liver-related disorders. However, the precise mechanism of H. pylori extragastroduodenal pathogenesis still remains unclear. In the current study, we aimed to determine the impact of H. pylori -isolated OMVs on hepatic stellate cell (HSC) activation and expression of liver fibrosis markers., Materials and Methods: Five H. pylori clinical strains with different genotype profiles were used. Helicobacter pylori OMVs were isolated using ultracentrifugation and were analyzed by scanning electron microscopy (SEM) and dynamic light scattering (DLS). Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis was applied to determine protein components of H. pylori -derived OMVs. Cell viability of LX-2 human hepatic stellate cell line exposed to OMVs was measured by MTT assay. LX-2 cells were treated with OMVs for 24 h. The gene expression of α -SMA, E-cadherin, vimentin, snail, and β -catenin was analyzed using quantitative real-time PCR. The protein expression of α -SMA, as a well-studied profibrotic marker, was evaluated with immunocytochemistry., Results: Our results showed that H. pylori strains released round shape nanovesicles ranging from 50 to 500 nm. Totally, 112 various proteins were identified in OMVs by proteomic analysis. The isolated OMVs were negative for both CagA and VacA virulence factors. Treatment of HSCs with H. pylori -derived OMVs significantly increased the expression of fibrosis markers., Conclusions: In conclusion, the present study demonstrated that H. pylori -derived OMVs could promote HSC activation and induce the expression of hepatic fibrosis markers. Further research is required to elucidate the definite role of H. pylori -derived OMVs in liver fibrosis and liver-associated disorders., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023 Shahin Bolori et al.)

Non-alcoholic steatohepatitis (NASH) is associated with intrahepatic lipid accumulation, inflammation, and hepatocyte death. Several studies have indicated that high-fat diets increase ceramide synthases-6 (CerS-6) expression and a concomitant elevation of C16-ceramides, which can modulate endoplasmic reticulum (ER) stress and further contribute to the progression of NASH. Ceramide levels have reportedly been impacted by basic fibroblast growth factor (bFGF) in various diseases. This study looked into the role of bFGF on CerS6/C16-ceramide and ER stress-related pathways in a mouse model of NASH. Male C57BL/6J mice were fed a western diet (WD) combined with carbon tetrachloride (CCl4) for eight weeks. Next, bFGF was injected into the NASH mice for seven days of continuous treatment. The effects of bFGF on NASH endpoints (including steatosis, inflammation, ballooning, and fibrosis), ceramide levels and ER-stress-induced inflammation, reactive oxygen species (ROS) production, and apoptosis were evaluated. Treatment with bFGF significantly reduced CerS-6/C16-ceramide. Further, the inflammatory condition was alleviated with reduction of nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) gene expression. ROS level was also reduced. ER stress-related cell death diminished by reducing C/EBP homologous protein (CHOP) mRNA expression and caspase 3 activity. Furthermore, activation of the hepatic stellate cells was inhibited in the bFGF-treated mice by lowering the amount of alpha-smooth muscle actin (α-SMA) at the mRNA and protein level. According to our findings, CerS-6/C16-ceramide alteration impacts ER stress-mediated inflammation, oxidative stress, and apoptosis. The bFGF treatment effectively attenuated the development of NASH by downregulating CerS-6/C16-ceramide and subsequent ER stress-related pathways., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Macrophages (MQs) pro-inflammatory phenotype is triggered by gliadin peptides. Akkermansia muciniphila (A. muciniphila) showed to enhance the anti-inflammatory phenotype of MQs. This study aimed to investigate the anti-inflammatory effects of A. muciniphila, on gliadin stimulated THP-1 derived macrophages. THP-1 cell line monocytes were differentiated into MQs by phorbol 12-myristate 13-acetate (PMA). MQs were treated with A. muciniphila before and after stimulation with gliadin (pre- and post-treat). CD11b, as a marker of macrophage differentiation, and CD206 and CD80, as M1 and M2 markers, were evaluated by flow cytometry technique. The mRNA expression of TGF-β, IL-6, and IL-10 and protein levels of IL-10 and TNF-α were measured by RT-PCR and ELISA techniques, respectively. Results show an increased percentage of M1 phenotype and release of proinflammatory cytokines (like TNF-α and IL-6) by macrophages upon incubation with gliadin. Pre- and post-treatment of gliadin-stimulated macrophages with A. muciniphila induced M2 phenotype associated with decreased proinflammatory (IL-6, TNF-α) and increased anti-inflammatory (IL-10, TGF-β) cytokines expression relative to the group that was treated with gliadin alone. This study suggests the potential beneficial effect of A. muciniphila on gliadin-stimulated MQs and the importance of future studies focusing on their exact mechanism of action on these cells., (© 2023. The Author(s).)

Natural killer cells are members of the innate immune system and promote cytotoxic activity against tumor or infected cells independently from MHC recognition. NK cells are modulated by the expression of activator/inhibitory receptors. The ratio of this activator/inhibitory receptors is responsible for the cytotoxic activity of NK cells toward the target cells. Owing to the potent anti-tumor properties of NK cells, they are considered as interesting approach in tumor treatment. Colorectal cancer (CRC) is the second most common cause of death in the world and the incidence is about 2 million new cases per year. Metastatic CRC is accompanied by a poor prognosis with less than three years of overall survival. Chemotherapy and surgery are the most adopted treatments. Besides, targeted therapy and immune checkpoint blockade are novel approach to CRC treatment. In these patients, circulating NK cells are a prognostic marker. The main target of CRC immune cell therapy is to improve the tumor cell's recognition and elimination by immune cells. Adaptive NK cell therapy is the milestone to achieve the purpose. Allogeneic NK cell therapy has been widely investigated within clinical trials. In this review, we focus on the NK related approaches including CAR NK cells, cell-based vaccines, monoclonal antibodies and immunomodulatory drugs against CRC tumoral cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ghazvinian, Abdolahi, Tokhanbigli, Tarzemani, Piccin, Reza Zali, Verdi and Baghaei.)

Liver fibrosis is a disorder in which inflammatory reactions play an important role, and central to the progression and pathogenesis of this disease are the immune-specific cells known as macrophages. Macrophage types are distinguished from each other by the expression of a series of surface markers. STAT6 and Arg1 play an important role in the polarization of macrophages, so these two factors are downstream of interleukin 4 (IL-4) and IL-13 cytokines and cause to differentiate M2. Therefore, this study aimed to compare the independent effects of imatinib and mesenchymal cell treatment on the polarization of macrophages in rat models of liver fibrosis. The liver fibrosis was induced by the injection of CCL4 for 6 weeks in Sprague-Dawley rats. Then, rats were divided into four different groups, and the effects of imatinib and mesenchymal cells on the expression of Arg1, Ly6c, and STAT6 were evaluated. Histopathology experiments considered the amelioration effect of treatments. Our results showed that Arg1 expression was significantly increased in the groups treated with mesenchymal cells and imatinib compared to the control group. On the other hand, expression of STAT6 was significantly increased in the imatinib-treated mice compared to mesenchymal and control groups. Moreover, the expression of LY6C significantly decreased in imatinib and mesenchymal treated groups compared to the control group. Therefore, our data showed that mesenchymal stem cells and imatinib significantly modulate the fibrotic process in rat models of fibrosis, probably by polarizing macrophages towards an anti-inflammatory profile and increasing the frequency of these cells in liver tissue., (© 2022 International Federation for Cell Biology.)