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Colorectal cancer is the fourth leading cause of cancer-related deaths that has significantly increased over the past three decades. New therapeutic approaches, such as oncolytic viruses, have become very imperative recently to destroy cancer cells. The use of mesenchymal stem cells (MSCs) secretome that is produced in response to variant conditions involves different paracrine molecules secretion that has therapeutic potential in several chronic diseases. Mesenchymal stem cells and their derivatives are employed as regenerative medicine; nevertheless, there is ambiguity in the function of these cells in the control of malignancy. This study aimed to examine the apoptotic effect of secretomes derived from MSCs affected by encompassing oncolytic reoviruses. Mesenchymal stem cells were cultured after separation from abdominal adipose tissue of BALB/c mice. After three passages, the cells were infected by reovirus at the multiplicity of infection of 1 plaque-forming unit per cell. Uninfected and infected secretomes with reovirus were collected separately. The colorectal cancer CT26 cells were confronted with uninfected secretome, infected secretions, reovirus as a positive control, and Dulbecco's Modified Eagle Medium/High Glucose as negative control separately. Finally, apoptosis and necrosis were evaluated by flow cytometry. The infected secretome with reovirus was capable to induce apoptosis more than the uninfected secretome in CT26. However, the supernatant of reovirus infected cells was more capable to induce cell death, in comparison to the infected secretome. Infected MSCs with oncolytic reovirus produced a type of condition media that enhanced apoptosis induction and could have a therapeutic effect on cancer cells. Nonetheless, tumoral cells confronted with the oncolytic reovirus showed more capability in inducing apoptosis in CT26 cells. As a result, the use of oncolytic virus and infected secretome are more effective than uninfected secretome in inducing apoptosis. [ABSTRACT FROM AUTHOR]

This paper has solved the nonrelativistic equation with the external uniform electric potential and magnetic and Aharonov–Bohm (AB) fields in a dot. We have obtained the three-term recurrence relation for the expansion coefficients using the series method. In continuing, we have found two different conditions. Then, using the obtained conditions, we have calculated the energy eigenvalues and eigenfunction. We have then obtained the main thermodynamic quantities such as the free energy, mean energy, entropy, specific heat, magnetization and persistent currents for our system. Also, we extended the calculations to an interaction-free N -body system. The obtained analytic results are compared with other results, and some of the obtained results are discussed, too. [ABSTRACT FROM AUTHOR]

Recombinant cysteine peptidase vaccine can induce protective immunity against cutaneous leishmaniasis. However, the antigenic diversity and variable immunogenicity prevents them from being approved for general vaccination. Different approaches like adjuvant application and antigen delivery systems are studied to increase their efficacy. Nanoparticles can both stimulated antigen uptakes and affect direction of immune response. In this study the effect of PLGA nanoparticles were considered to enhance the immune response against recombinant CPA (CPA) and CPB (CPB). For this purpose, L . major CPA and CPB were prepared. PLGA were conjugated to the proteins using Aldehyde/Hydrazine Reaction. Conjugation efficacy and created nanoparticle morphology were determined by FTIR and SEM methods, respectively. BALB/c mice were received intraperitoneally three boosts of 7 μg/mouse of each antigen alone (CPA/CPB/CPA + CPB) or as PLGA conjugated form in different Study groups, at 3 weeks interval. After vaccination, mice were challenged with 10 6 L . major , subcutaneously. Time course study of lesion development demonstrated nanoparticle efficacy in parasite dissemination control that confirmed by spleen parasite burden assay. Significant induction of nitric oxide production by peritoneal macrophages and increase in splenocyte IFN-γ production showed the protective effect of PLGA-CPA/CPB vaccination in comparison to CPA and CPB alone. Current study demonstrated that the conjugation of the antigen with the PLGA can activate immune responses against L . major . However, further study is necessary to assess the long-term effect and other aspects of immune response. [ABSTRACT FROM AUTHOR]

Cancer cachexia is characterized by inflammation, loss of skeletal muscle and adipose tissue mass, and functional impairment. Oxidative stress and inflammation are believed to regulate pathways controlling skeletal muscle wasting. The aim of this study was to determine the effects of aerobic interval training and the purported antioxidant treatment, selenium nanoparticle supplementation, on expression of IL-15 and inflammatory cytokines in 4T1 breast cancer-bearing mice with cachexia. Selenium nanoparticle supplementation accelerated cachexia symptoms in tumor-bearing mice, while exercise training prevented muscle wasting in tumor-bearing mice. Also, aerobic interval training enhanced the anti-inflammatory indices IL-10/TNF-α ratio and IL-15 expression in skeletal muscle in tumor-bearing mice. However, combining exercise training and antioxidant supplementation prevented cachexia and muscle wasting and additionally decreased tumor volume in 4T1 breast cancer mice. These finding suggested that combining exercise training and antioxidant supplementation could be a strategy for managing tumor volume and preventing cachexia in breast cancer. [ABSTRACT FROM AUTHOR]

Due to the vital importance of the lungs, lung-related diseases and their control are very important. Severe inflammatory responses mediated by immune cells were among the leading causes of lung tissue pathology and damage during the COVID-19 pandemic. In addition, uncontrolled immune cell responses can lead to lung tissue damage in other infectious and non-infectious diseases. It is essential to control immune responses in a way that leads to homeostasis. Immunosuppressive drugs only suppress inflammatory responses and do not affect the homeostasis of reactions. The therapeutic application of mesenchymal stem cells (MSCs), in addition to restoring immune homeostasis, can promote the regeneration of lung tissue through the production of growth factors and differentiation into lung-related cells. However, the communication between MSCs and immune cells after treatment of pulmonary diseases is essential, and investigating this can help develop a clinical perspective. Different studies in the clinical phase showed that MSCs can reverse fibrosis, increase regeneration, promote airway remodeling, and reduce damage to lung tissue. The proliferation and differentiation potential of MSCs is one of the mechanisms of their therapeutic effects. Furthermore, they can secrete exosomes that affect the function of lung cells and immune cells and change their function. Another important mechanism is that MSCs reduce harmful inflammatory responses through communication with innate and adaptive immune cells, which leads to a shift of the immune system toward regulatory and hemostatic responses., 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 © 2024 Hazrati, Mirarefin, Malekpour, Rahimi, Khosrojerdi, Rasouli, Akrami and Soudi.)

Leishmaniasis is considered one of the most critical health concerns in the world. Unfortunately, no protective vaccines exist and conventional treatments are relatively ineffective. Therefore, new strategies are necessary against leishmaniasis. In recent years, exosomes have shown promising therapeutic outcomes in various diseases, including infectious diseases. In this regard, we aimed to explore the effect of the exosome, pyrimethamine and their combination on the anti-parasitic function of RAW264.7 cells against Leishmania major. Exosomes were isolated from the C57BL/6 peritoneal macrophages. L. major infected and non-infected RAW264.7 cells treated with exosomes, pyrimethamine (PM), and exosomes along with PM. The effect of the treatments was analysed on phagocytosis, efferocytosis, the intracellular parasite count, arginase activity, nitric oxide (NO) and reactive oxygen species (ROS) production. Exosomes could significantly elevate the phagocytosis, efferocytosis, NO and ROS in both infected and non-infected groups (Pv < 0.05). The exosomes reduced the arginase activity in both groups (Pv < 0.05). The intracellular parasite count was significantly lower after treatment with exosomes (Pv < 0.05). These results demonstrate that MQ-derived exosomes can enhance in vitro anti-parasitic responses against L. major. This provides a potential pathway for more effective treatments and underscores the importance of further research in this area., (© 2024 John Wiley & Sons Ltd.)

Background: Sepsis is a syndrome that occurs following an infection and marked by severe inflammatory responses, and if not treated in time, it can lead to multi-organ failure syndrome and death. This study examines the effects of a novel combination therapy using azithromycin and mesenchymal stem cell-derived extracellular vesicles (EVs) on a cecal ligation and puncture (CLP) model of sepsis., Methods: Human Wharton's jelly-mesenchymal stem cells were cultured, characterized, and used to extract EVs. The CLP sepsis model was induced in mice, followed by treatments: saline, AZM, EVs, and combination therapy (A+E). Clinical sepsis scores were recorded 24 h post-treatment. Serum, peritoneal fluid, and organ tissues (kidney, liver, lung) were collected and analyzed for biochemical parameters (AST ALT, and creatinine), inflammatory markers, bacterial load, and histopathological changes., Results: The A+E combined treatment improved the clinical scores of septic mice. The administration of A+E reduced bacterial loads in the peritoneum of septic mice, contributing to effective control of infection. Inflammatory markers of neutrophils-to-lymphocytes ratio (NLR) and TNF-α serum levels were significantly lower in the combinational therapy group, indicating significant anti-inflammatory effect of this combination. Additionally, combination of AZM and EVs alleviated organ damage mainly within liver, kidneys and lungs. Based on histopathological assessments and biochemical parameters, there was diminished tissue damage as well as reduced inflammation, which is correlated with improved functions of these vital organs., Conclusion: The combined use of azithromycin and EVs offers a promising therapeutic approach for sepsis by effectively controlling infection and modulating the inflammatory response., 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.)

Objective: Exosomes, membrane-enveloped vesicles found in various cell types, including Wharton's jelly mesenchymal stem cells, play a crucial role in intercellular communication and regulation. Their use as a cell-free nanotechnology and drug delivery system has attracted attention. Triple-negative breast cancer (TNBC) is a major global health problem and is characterized by a high mortality rate. This study investigates the potential of Wharton's Jelly mesenchymal stem cell-derived exosomes (WJ-Exo) as carriers of S3I-201 and their effects on STAT3 expression in breast cancer cell lines, and evaluates whether these exosomes can enhance the anti-tumor effect of S3I-201., Methods: The filtered WJ-Exos were analyzed by Transmission Electron Microscopy (TEM), Scanning electron microscopy (SEM), Dynamic Light Scattering (DLS), flow cytometry, and Western blotting. These exosomes were then used for loading with S3I-201, resulting in the nano-formulation WJ-Exo(S3I-201). The effect of WJ-Exo(S3I-201) on 4T1 cancer cells was investigated in vitro using MTT assay, flow cytometry, wound healing assay, Western blotting and Quantitative Real-Time Polymerase chain reaction (qPCR) analysis. Finally, the therapeutic efficacy of the nano-formulation was investigated in vivo using a tumor-bearing mouse model., Results: In vitro experiments showed that co-incubation of 4T1 cells with the nano-formulation resulted in a significant reduction in p-STAT3 levels, induction of apoptosis, modulation of Bcl-2, Bax and caspase-3 protein and gene expression, and inhibition of migration. In vivo, treatment of tumor-bearing mice with WJ-Exo(S3I-201) showed a strong antitumor effect that exceeded the efficacy observed in the S3I-201 group., Conclusion: Our results demonstrate that WJ-Exo is an effective carrier for targeting S3I-201 to tumor cells and enhances the therapeutic efficacy of S3I-201 in tumor-bearing mice., (© 2024. The Author(s).)

Aim: Sepsis is a life-threatening condition caused by a dysregulated immune response to infection. Broad-spectrum antibiotics are used to treat it. However, due to antibiotic resistance, alternative treatments are needed. Mesenchymal stem cells (MSCs) have become a promising therapeutic tool for sepsis due to their immunomodulatory properties. The limitations of MSC therapy have led to increased attention to cell derivatives such as conditioned medium (CM). This study investigates the immunomodulatory effects of young and old MSC-CM during the inflammatory phase of sepsis., Main Methods: The cecal ligation and puncture (CLP) model was used to induce sepsis in mice. The mice were divided into four groups: sham, CLP, CLP treated with young MSC-CM, and CLP treated with old MSC-CM. The CM was injected intraperitoneally at 2-, 12-, and 24-hours post-surgery. After 72 h, blood was collected and white blood cells (WBCs) were counted. In addition, serum and tissue were isolated, and the levels of alanine transaminase (ALT) and aspartate transaminase (AST) in serum, bacterial load in the spleen, concentration of pro- and anti-inflammatory cytokines, and histopathology of liver and lung were investigated., Key Findings: MSC-CM decreased serum AST and ALT levels, bacterial load in the spleen, and pro-inflammatory cytokines in serum. In addition, tissue damage was reduced, and the survival rate and WBC count increased. There was no significant difference between the young and old MSC-CM., Significance: MSC-CM effectively reduced inflammation-induced tissue damage in the liver and lungs during sepsis. Although young MSC-CM had better immunomodulatory effects than old MSC-CM, the difference was not significant., 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 Elsevier B.V. All rights reserved.)

Lymphoid organs are the main structural components of the immune system. In the current research, the mixture of poly lactic-co-glycolic acid (PLGA), polycaprolactone (PCL), and M13 phage or its RGD-modified form was used in the construction of a fibrillar scaffold using the electrospinning method. The constructs were transplanted intra-abdominally and examined for the formation of lymphoid-like tissues at different time intervals. The confocal and scanning electron microscopy demonstrate that M13 phage-containing scaffolds provide a suitable environment for lymph node-isolated fibroblasts. Morphological analysis demonstrate the formation of lymph node-like tissues in the M13 phage-containing scaffolds after transplantation. Histological analysis confirm both blood and lymph angiogenesis in the implanted construct and migration of inflammatory cells to the M13 phage-containing scaffolds. In addition, flow cytometry and immunohistochemistry analysis showed the homing and compartmentalization of dendritic cells (DCs), B and T lymphocytes within the PLGA/PCL/M13 phage-RGD based scaffolds and similar to what is seen in the mouse lymphoid tissues. It seems that the application of M13 phage could improve the generation of functional lymphoid tissues in the electrospun scaffolds and could be used for lymphoid tissue regeneration., 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. Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The undesirable inflammation and the excessive M1 macrophage activity may lead to inflammatory diseases. Corticosteroids and stem cell therapy are used in clinical practice to promote anti-inflammatory responses. However, this protocol has limitations and is associated with numerous side effects. In this study, the synergistic anti-inflammatory effects of dexamethasone (Dex) and mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) were evaluated to enhance the polarization of M1 inflammatory macrophages into the anti-inflammatory (M2) phenotype. Hence, we designed different combinations of Dex and EVs using three methods, including EVs isolated from Dex-preconditioned MSCs (Pre-Dex-EVs), EVs loaded with Dex (L-Dex-EVs), and EVs and Dex co-administration (Dex + EVs). All designed EVs had a significant effect on reducing the expression of M1-related genes (iNOS, Stat1, and IRF5), cytokines (IL6 and TNF-a), and CD markers (CD86) in lipopolysaccharide-stimulated macrophages. On the other hand, these combinations promoted the expression of alternative-activated M2-related genes (Arg-1, Stat6, and IRF4), cytokine (IL10), and CD markers (CD206).The combination of Dex and MSC-EVs enhances the effectiveness of both and synergistically promotes the conversion of inflammatory macrophages into an anti-inflammatory state., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Photodynamic inactivation (PDI) technology is a promising alternative to antibiotics. This technology is defined as the inhibition of bacterial growth with photosensitizers while irradiated with low-level laser light in the wavelength of 532 ± 2.08 nm. A challenging area in this field is selecting photosensitizers with antibacterial potential. In this paper, to enhance the antibacterial efficiency, the photosensitizers (the selected plant extracts) with a high absorption peak at the selected laser frequency, 532 nm, were prepared. Low-concentration ethanolic plant extracts of Hibiscus sabdariffa and Opuntia ficus-indica were found to exhibit significant antibacterial activity against, Acinetobacter baumannii ATCC 19606 and, Staphylococcus aureus ATCC 33591 as two important human pathogenic bacteria. The effectiveness of these natural photosensitizers was measured by determining their Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) values and by performing a time-killing assay in the absence and the presence of laser irradiation. Our results showed that the combination of low-level laser irradiation and the selected photosensitizers had excellent potential for treating in vitro bacterial infections. Therefore, PDI technology has great potential as a viable alternative to traditional antibiotics for combating bacterial infections. This study presents a promising avenue for further exploration of PDI and the use of laser technology in medical science., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Background and Objectives: Mesenchymal Stem Cells (MSCs) can repair gastrointestinal tract damage. The Secretome of MSCs has a high capacity to inhibit bacterial colonization and the subsequent inflammatory responses of Vibrio cholerae ., Materials and Methods: The Caco-2 cells were treated with adipose-derived MSCs (AD-MSCs) secretome and then infected with V. cholerae . Subsequently, the bacterial attachment and invasion, cholera toxin gene expression, PGE2 and IL-6 secretion, TNF-α, IL-1β, and IL-8 expression, and apoptosis of Caco-2 cells were evaluated., Results: The secretome of AD-MSCs significantly reduced the V. cholerae attachment and internalization on Caco-2 epithelial cells (P<0.0001). The cholera toxin (Ctx-B) gene expression (FR=4.56 ± 0.66) and PGE2 production (P=0.0007) were also significantly reduced. The production of NO and TNF-α, IL-1β, and IL-8 pro-inflammatory cytokines were significantly (P<0.05) reduced in exposure to the secretome of AD-MSCs. Secretome also improved a significant 81.33% increase in IL-6 production (128.1 ± 37.6 pg/mL) and showed a 12.36% significant decrease in epithelial cell apoptosis (P< 0.0001) after exposure to V. cholerae ., Conclusion: The secretome of AD-MSCs can play a critical role in inhibiting bacterial colonization, and subsequent inflammatory responses, and maintaining the integrity of the epithelial barrier. The secretome may be effective in the prevention of hypovolemic shock., (Copyright© 2024 The Authors. Published by Tehran University of Medical Sciences.)

Pathogen recognition receptors (PRRs), which play a crucial role in responding to pathogens, affect the function of mesenchymal stem cells (MSCs). One important group of PRRs is the toll-like receptors (TLRs). When PRRs are activated, they can alter the expression of specific surface markers, the ability of MSCs to differentiate, and the types of substances they secrete. These modifications in MSC function may have unexpected consequences for patients. In this study, we examined how Leishmania major (L. major) promastigotes affect the properties of MSCs. MSCs were isolated from adipose tissue and categorized into two groups: one group left untreated and the other group exposed to L. major. Giemsa staining was employed to accurately quantify the number of parasites that entered the cells. After 72 hours, real-time polymerase chain reaction was utilized to assess the expression of TLRs. Additionally, the flow cytometry technique was used to evaluate the expression of surface markers on the MSCs. Our results showed that MSCs can engulf parasites and increase the expression of TLR4 and TLR6. The pro-inflammatory cytokine increased, and the transforming growth factor-β decreased significantly. The parasite exposure increased reactive oxygen species production. Additionally, the percentage of cluster differentiation (CD) 73 decreased, and the mean fluorescent index of CD29 and CD73 was down-regulated by L. major. Exposure to parasites diminishes the immunomodulatory capacity of MSCs. This discovery holds significance for the application of MSCs in addressing parasite infections and underscores the need for additional research to enhance their therapeutic effectiveness.

Local adaptation commonly involves alleles of large effect, which experience fitness advantages when in positive linkage disequilibrium (LD). Because segregating inversions suppress recombination and facilitate the maintenance of LD between locally adapted loci, they are also commonly found to be associated with adaptive divergence. However, it is unclear what fraction of an adaptive response can be attributed to inversions and alleles of large effect, and whether the loci within an inversion could still drive adaptation in the absence of its recombination-suppressing effect. Here, we use genome-wide association studies to explore patterns of local adaptation in three species of sunflower: Helianthus annuus , Helianthus argophyllus , and Helianthus petiolaris , which each harbour a large number of species-specific inversions. We find evidence of significant genome-wide repeatability in signatures of association to phenotypes and environments, which are particularly enriched within regions of the genome harbouring an inversion in one species. This shows that while inversions may facilitate local adaptation, at least some of the loci can still harbour mutations that make substantial contributions without the benefit of recombination suppression in species lacking a segregating inversion. While a large number of genomic regions show evidence of repeated adaptation, most of the strongest signatures of association still tend to be species-specific, indicating substantial genotypic redundancy for local adaptation in these species., Competing Interests: SS, MJ, MT, GO, NB, LR, SY No competing interests declared, (© 2023, Soudi, Jahani et al.)

Malignancies contain a relatively small number of Mesenchymal stem/stromal cells (MSCs), constituting a crucial tumor microenvironment (TME) component. These cells comprise approximately 0.01-5% of the total TME cell population. MSC differentiation potential and their interaction with the tumor environment enable these cells to affect tumor cells' growth, immune evasion, metastasis, drug resistance, and angiogenesis. This type of MSC, known as cancer-associated mesenchymal stem/stromal cells (CA-MSCs (interacts with tumor/non-tumor cells in the TME and affects their function by producing cytokines, chemokines, and various growth factors to facilitate tumor cell migration, survival, proliferation, and tumor progression. Considering that the effect of different cells on each other in the TME is a multi-faceted relationship, it is essential to discover the role of these relationships for targeting in tumor therapy. Due to the immunomodulatory role and the tissue repair characteristic of MSCs, these cells can help tumor growth from different aspects. CA-MSCs indirectly suppress antitumor immune response through several mechanisms, including decreasing dendritic cells (DCs) antigen presentation potential, disrupting natural killer (NK) cell differentiation, inducing immunoinhibitory subsets like tumor-associated macrophages (TAMs) and Treg cells, and immune checkpoint expression to reduce effector T cell antitumor responses. Therefore, if these cells can be targeted for treatment so that their population decreases, we can hope for the treatment and improvement of the tumor conditions. Also, various studies show that CA-MSCs in the TME can affect other vital aspects of a tumor, including cell proliferation, drug resistance, angiogenesis, and tumor cell invasion and metastasis. In this review article, we will discuss in detail some of the mechanisms by which CA-MSCs suppress the innate and adaptive immune systems and other mechanisms related to tumor progression., 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 Hazrati, Malekpour, Mirsanei, Khosrojerdi, Rahmani-Kukia, Heidari, Abbasi and Soudi.)

Aim Sepsis is a medical emergency with no definitive treatment. Animal experiments have confirmed the therapeutic characteristics of exosomes in reducing inflammation and tissue damage. The study investigates the effect of MSC and hepatocyte-derived exosomes along with imipenem in controlling systemic and local (liver) inflammation in a mouse model of sepsis., Main Methods: To induce sepsis in C57BL/6 mice, the Cecal Ligation and Puncture (CLP) model was used. The mice were given various treatments, including imipenem, MSC-derived exosomes, hepatocyte-derived exosomes, and a mixture of exosomes. Blood and liver samples were collected and analyzed for cell blood count, liver enzymes, NO levels, cytokine concentrations, and bacterial presence. The percentages of TCD3 + CD4+/CD8+ and Treg in the spleen and mesenteric lymph nodes were also assessed using flow cytometry. The pathological changes were assessed in the liver, lung, and heart tissues. In addition, the cytokine content of exosomes was measured by ELISA., Key Findings: Our results demonstrated that MSC-derived exosomes+imipenem could control systemic and local inflammation and increase the TCD4+ and Treg populations. Hepatocyte-derived exosomes+imipenem reduced inflammation in the liver and increased the TCD8+ and Treg populations. The mixture of exosomes+imipenem had the best function in reducing inflammation, maintaining all T lymphocyte populations, reducing liver damage, and ultimately increasing the survival rate., Significance: The mixture of exosomes derived from MSCs and hepatocytes, along with imipenem, in the inflammatory phase of sepsis could be a promising therapeutic strategy in sepsis treatment., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Background: Rapid adaptation to new environments can facilitate species invasions and range expansions. Understanding the mechanisms of adaptation used by invasive disease vectors in new regions has key implications for mitigating the prevalence and spread of vector-borne disease, although they remain relatively unexplored., Results: Here, we integrate whole-genome sequencing data from 96 Aedes aegypti mosquitoes collected from various sites in southern and central California with 25 annual topo-climate variables to investigate genome-wide signals of local adaptation among populations. Patterns of population structure, as inferred using principal components and admixture analysis, were consistent with three genetic clusters. Using various landscape genomics approaches, which all remove the confounding effects of shared ancestry on correlations between genetic and environmental variation, we identified 112 genes showing strong signals of local environmental adaptation associated with one or more topo-climate factors. Some of them have known effects in climate adaptation, such as heat-shock proteins, which shows selective sweep and recent positive selection acting on these genomic regions., Conclusions: Our results provide a genome wide perspective on the distribution of adaptive loci and lay the foundation for future work to understand how environmental adaptation in Ae. aegypti impacts the arboviral disease landscape and how such adaptation could help or hinder efforts at population control., (© 2023. The Author(s).)

Cell therapy is one of the methods that have shown promising results in treating diseases in recent decades. However, the use of different types of cells comes with limitations. The application of immune cells in cell therapy can lead to cytokine storms and inappropriate responses to self-antigens. Also, the use of stem cells has the potential to create tumors. Also, cells may not migrate to the injury site after intravenous injection. Therefore, using exosomes from different cells as therapeutic candidates were proposed. Due to their small size and favorable characteristics, such as biocompatibility and immunocompatibility, the easy storage and isolation, exosomes have attracted much attention. They are used in treating many diseases, including cardiovascular diseases, orthopedic diseases, autoimmune diseases, and cancer. However, the results of various studies have shown that the therapeutic efficiency of exosomes (Exo) can be increased by loading different drugs and microRNAs inside them (encapsulated exosomes). Therefore, analyzing studies investigating encapsulated exosomes' therapeutic ability is critical. In this study, we have examined the studies related to the use of encapsulated exosomes in treating diseases such as cancer and infectious diseases and their use in regenerative medicine. Compared to intact exosomes, the results show that the application of encapsulated exosomes has a higher therapeutic ability. Therefore it is suggested to use this method depending on the treatment type to increase the treatment's efficiency., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Diabetes is a highly common metabolic disorder in advanced societies. One of the causes of diabetes is insulin resistance, which is associated with a loss of sensitivity to insulin-sensitive cells. Insulin resistance develops in the body of a person prone to diabetes many years before diabetes development. Insulin resistance is associated with complications such as hyperglycemia, hyperlipidemia, and compensatory hyperinsulinemia and causes liver inflammation, which, if left untreated, can lead to cirrhosis, fibrosis, and even liver cancer. Metformin is the first line of treatment for patients with diabetes, which lowers blood sugar and increases insulin sensitivity by inhibiting gluconeogenesis in liver cells. The use of metformin has side effects, including a metallic taste in the mouth, vomiting, nausea, diarrhea, and upset stomach. For this reason, other treatments, along with metformin, are being developed. Considering the anti-inflammatory role of mesenchymal stem cells (MSCs) derived exosomes, their use seems to help improve liver tissue function and prevent damage caused by inflammation. This study investigated the anti-inflammatory effect of Wharton's jelly MSCs derived exosomes in combination with metformin in the HepG2 cells insulin resistance model induced by high glucose. This study showed that MSCs derived exosomes as an anti-inflammatory agent in combination with metformin could increase the therapeutic efficacy of metformin without needing to change metformin doses by decreasing inflammatory cytokines production, including IL-1, IL-6, and TNF-α and apoptosis in HepG2 cells., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors.)

Mesenchymal stem cells (MSCs) are among the known cells that can control and modulate immune responses in different circumstances, including autoimmune diseases. Also, various studies have shown that they can prevent and reduces the pulmonary inflammation caused by infectious agents. In the case of tuberculosis and inflammation caused by BCG, the granuloma has destructive effects and improper orientation of the immune response. Therefore, it is possible to prevent airway damage by preventing harmful inflammatory responses and guiding the immune system responses. This study investigates the role of nasal administration of MSCs supernatant by designing an inflammatory model in the BALB/c mice lung with BCG. MSCs are isolated from mice adipose tissue in this study and evaluated for their phenotypic and differentiation properties. After the third passage, these cells' condition medium (CM) was collected. 20 mice were divided into four groups. Group 1 receive BCG (10 7  CFU in 5 ml volume for 15 min) nasal administration. Group 2 treated with CM, and group 3 initially were treated with CM (in 5 ml volume for 15 min) and, after 24 h, treated with BCG nasal administration. CM treatment was continued every five days for one month. The fourth group of mice was treated with PBS nasal administration of CM and BCG. One week after the last administration, the lung tissue of mice in each group was pathologically examined. In addition, secretion of IL1-β, IL-6, TNF-α, TGF-β, and IL-10 in the alveolar fluid and secretion of IL-4 and IFN-γ cytokines in the supernatant of splenocytes was evaluated by ELISA. The TNF-α/IL-10 ratio in the alveolar lung fluid of the BCG received group is 2/9 and decreased to 0.58 after successive CM treatment. Therefore, it can be concluded that inflammatory responses to BCG infection in the presence of CM are balanced and pave the way for the induction of effective immune responses by reducing lung tissue damage., 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.)

Abstract: Background: Sepsis is a life-threatening disorder that leads to the induction of inflammatory responses and organ failure. Phage therapy is a new approach to controlling infections resistant to common treatments, including sepsis. Several studies have shown the effect of lytic bacteriophages on infection control by reducing the bacterial load. The present study deals with lysogenic bacteriophage M13 on the inflammatory responses caused by cecal ligation and puncture (CLP)-induced sepsis in a mouse model. Methods Bacteriophage M13 harvested from ER2738, titrated, and confirmed by transmission electron microscopy analysis. In vitro toxicity and immunomodulatory effect of bacteriophage M13 were assessed on splenocytes by measurement of cell viability and the production level of cytokines, nitric oxide, and reactive oxygen species. For in vivo experiments, 8-weeks-old male C57BL/6 mice were randomly divided into the following three groups: CLP + NS (treated with normal saline), CLP + M13 (treated with an intraperitoneal injection of 10 9 PFU/mL of bacteriophage M13), and sham + NS (induced surgery but without ligation and puncture, treated with NS). The mice were killed at different time points after surgery (6, 24, 48, and 72, n = 10 for each time point of each group). The kidney, liver, and lungs were harvested for histopathological analysis, and blood was obtained for cytokine and liver enzyme assay. The spleen was used to assess the bacterial load using colony-forming unit assay. The rectal temperature and survival were evaluated during the study. Results According to the in vitro results, 10 9 PFU/mL of bacteriophage M13 was not toxic and did not affect the level of cytokine, nitric oxide, and reactive oxygen species production by splenocytes, but it reduced the inflammatory response of splenocytes in responses to LPS. In vivo studies indicated that the amount of proinflammatory cytokines, liver enzymes, bacterial load, and organ failure were decreased in the CLP + M13 group compared with CLP + NS, whereas the survival rate was increased. Conclusions These experiments demonstrated that bacteriophage M13 could lessen the consequences related to sepsis in CLP mice and can be considered a therapeutic approach in sepsis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by the Shock Society.)

Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Mesenchymal stromal/stem cells (MSCs) perform their therapeutic effects through various mechanisms, including their ability to differentiate, producing different growth factors, immunomodulatory factors, and extracellular vesicles (EVs). In addition to the mentioned mechanisms, a new aspect of the therapeutic potential of MSCs has recently been noticed, which occurs through mitochondrial transfer. Various methods of MSCs mitochondria transfer have been used in studies to benefit from their therapeutic potential. Among these methods, mitochondrial transfer after MSCs transplantation in cell-to-cell contact, EVs-mediated transfer of mitochondria, and the use of MSCs isolated mitochondria (MSCs-mt) are well studied. Pathological conditions can affect the cells in the damaged microenvironment and lead to cells mitochondrial damage. Since the defect in the mitochondrial function of the cell leads to a decrease in ATP production and the subsequent cell death, restoring the mitochondrial content, functions, and hemostasis can affect the functions of the damaged cell. Various studies show that the transfer of MSCs mitochondria to other cells can affect vital processes such as proliferation, differentiation, cell metabolism, inflammatory responses, cell senescence, cell stress, and cell migration. These changes in cell attributes and behavior are very important for therapeutic purposes. For this reason, their investigation can play a significant role in the direction of the researchers'., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Induction of a protective immune response against Leishmania major requires the activation of both TH1 and CD8 + T lymphocytes. Because L. major is an intra-phagosomal parasite, its antigens do not have access to MHC-I. The present study aimed to evaluate the effect of cysteine peptidase A (CPA)/cysteine peptidase B (CPB) conjugated to α-AL2O3 on autophagy induction in L. major infected macrophages and subsequent activation of cytotoxic CD8 + T lymphocytes., Methods: Recombinant CPA and CPB of L. major were produced in expression vectors and purified. Aldehyde functionalized α-AL2O3 were conjugated to hydrazine-modified CPA/CPB by a chemical bond was confirmed by Fourier-transform infrared spectroscopy (FTIR). The High efficient internalization of α-AL2O3 conjugated CPA/CPB to macrophages was confirmed using a fluorescence microscope and flowcytometry. Induction of the acidic autophagosome and LC3 conversion in macrophages was determined by acridine orange (AO) staining and western blot. Autophagy-activated macrophages were used for CD8 + T cell priming. Cytotoxic activity of the primed CD8 + T cell against L. major infected macrophages was measured using apoptosis assay., Results: α-AL2O3 conjugated CPA/CPB enhances macrophages antigen uptake and increases acidic vacuole formation and LC-3I to LC-3II conversion. Co-culture of autophagy-activated macrophages with CD8 + T cells augmented CD8 + T cells priming and proliferation more than in other study groups. These primed CD8 + T cells induce significant apoptotic death of L. major infected macrophages compared with non-primed CD8 + T cells., Conclusion: α-AL2O3 nanoparticles enhance the cross-presentation of L. major antigens to CD8 + T cells by inducing autophagy. This finding supports the positive role of autophagy and encourages the use of α-AL2O3 in vaccine design., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s).)

Cell therapy is one of the newest therapeutic approaches for treating tissue destruction diseases and replacing damaged parts in defective tissues. Among different cells, mesenchymal stem cells (MSCs) have received a lot of attention due to their advantages and desirable properties. Also, MSCs-derived secretome, which includes various growth factors, cytokines, and extracellular vesicles (EVs), is used in the treatment of different types of diseases. However, the application of MSCs in an intact form brings their functionality with limitations. For this reason, different methods are recommended to increase their efficiency and the extracellular vesicles derived from them. One of these methods is gene editing of these cells. Among the different techniques for MSCs gene editing, CRISPR/Cas9 can increase the therapeutic potential of MSCs in a targeted manner due to its advantages. In order to achieve the desired result, various genes have been manipulated in MSCs, including genes involved in stemness, aging, migration, proliferation, survival, and inflammatory responses. Engineering MSCs with this method affects the cells' characteristics, changes their cytokine and different growth factors secretions, and increases their therapeutic efficiency., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Sepsis is a debilitating systemic inflammation that resulted from infection or injury. Despite many advances in treatment, the resulting mortality rate has remained high due to increasing antibiotic resistance and aging communities. The present study investigated the effects of stem cell-derived exosomes in a mouse model of LPS-induced systemic inflammation., Materials and Methods: To induce sepsis, the LPS model was used. Mice were divided into three groups: normal, patient group (LPS + PBS), and treatment group (LPS + exosome). The treatment group received an intravenous exosome 1 h after induction of the model. Patient and treatment groups were sacrificed at 4, 6, 24, and 48 h after induction of the model, and their tissues were isolated. Blood samples were taken from animal hearts to perform biochemical and immunological tests. The study results were analyzed using Graph Pad Prism software version 9., Results: Mesenchymal stem cell-derived exosomes decreased serum levels of ALT and AST liver enzymes, decreased neutrophil to lymphocyte ratio (NLR), and improved kidney, liver, and lung tissue damage at 4, 6, and 24 h after model induction. At 24 h, the exosomes were able to reduce serum urea levels. This study revealed decreased levels of inflammatory cytokines such as IL-6, IL-1β, and TNF-α after exosome injection., Conclusion: Our findings suggest that treating mice with stem cell-derived exosomes can ameliorate the destructive effects of inflammation caused by sepsis by reducing inflammatory factors and tissue damage., 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 © 2022 Elsevier Inc. All rights reserved.)

This study investigated the role of medium (face-to-face, cyber) and publicity (public, private) in adolescents' perceptions of severity and coping strategies (i.e., avoidant, ignoring, helplessness, social support seeking, retaliation) for victimization, while accounting for gender and cultural values. There were 3432 adolescents (ages 11-15, 49% girls) in this study; they were from China, Cyprus, the Czech Republic, India, Japan, and the United States. Adolescents completed questionnaires on individualism and collectivism, and ratings of coping strategies and severity for public face-to-face victimization, private face-to-face victimization, public cyber victimization, and private cyber victimization. Findings revealed similarities in adolescents' coping strategies based on perceptions of severity, publicity, and medium for some coping strategies (i.e., social support seeking, retaliation) but differential associations for other coping strategies (i.e., avoidance, helplessness, ignoring). The results of this study are important for prevention and intervention efforts because they underscore the importance of teaching effective coping strategies to adolescents, and to consider how perceptions of severity, publicity, and medium might influence the implementation of these coping strategies.

Drawing on the social-ecological perspective, this longitudinal study investigated the potential moderating effect of gender in the relationships among Machiavellianism, popularity goals, and cyberbullying involvement (i.e. victimization, perpetration) among adolescents from China, Cyprus, India, and the United States. There were 2,452 adolescents ( M age = 14.85; SD = .53; 13-16 years old; 49.1% girls) from China, Cyprus, India, and the United States included in this study. They completed surveys on Machiavellianism, popularity goals, and cyberbullying victimization and perpetration during the fall of 2014 (Time 1). One year later, during the fall of 2015, adolescents completed surveys on cyberbullying victimization and perpetration. Findings revealed that Machiavellianism and popularity goals were both associated positively with Time 2 cyberbullying victimization and perpetration for all adolescents. The associations between Machiavellianism and Time 2 cyberbullying perpetration and between popularity goals and Time 2 cyberbullying perpetration were stronger for Chinese and Indian boys than girls. Opposite patterns were found for popularity goals and Time 2 cyberbullying perpetration for adolescents from the United States. Gender did not moderate any of the associations for Cypriot adolescents or for Time 2 cyberbullying victimization. The social-ecological perspective provides a useful understanding of how various contexts influence bullying.

Cell therapy is one of the new treatment methods in which mesenchymal stem/stromal cell (MSCs) transplantation is one of the cells widely used in this field. The results of MSCs application in the clinic prove their therapeutic efficacy. For this reason, many clinical trials have been designed based on the application of MSCs for various diseases, especially inflammatory disease and regenerative medicine. These cells perform their therapeutic functions through multiple mechanisms, including the differentiative potential, immunomodulatory properties, production of therapeutic exosomes, production of growth factors and cytokines, and anti-apoptotic effects. Exosomes are nanosized extracellular vesicles (EVs) that change target cell functions by transferring different cargos. The therapeutic ability of MSCs-derived exosomes has been demonstrated in many studies. However, some limitations, such as the low production of exosomes by cells and the need for large amounts of them and also their limited therapeutic ability, have encouraged researchers to find methods that increase exosomes' therapeutic potential. One of these methods is the spheroid culture of MSCs. Studies show that the three-dimensional culture (3DCC) of MSCs in the form of multicellular spheroids increases the therapeutic efficacy of these cells in laboratory and animal applications. In addition, the spheroid culture of MSCs leads to enhanced therapeutic properties of their exosomes and production rate. Due to the novelty of the field of using 3DCC MSCs-derived exosomes, examination of their properties and the results of their therapeutic application can increase our view of this field. This review discussed MSCs and their exosomes enhanced properties in spheroid culture., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Antibiotics are used to treat bacterial liver infections and the resulting inflammation. However, their use is limited due to their side effects, especially the development of antibiotic resistance. Mesenchymal stem cells (MSCs) are recognized for their immunomodulatory properties. In this study, we investigated the immunomodulatory effect of Wharton's jelly MSC-derived exosomes in combination with imipenem on HepG2 cells infected with Escherichia col i.MSC-derived exosomes were separated from MSCs, which were isolated by flow cytometry. Scanning electron microscopy and dynamic light scanning were used to confirm the presence of exosomes. Quantitative real-time PCR, ELISA, and nitric oxide assay were used to assess the inflammatory response in the infected cells. Annexin-PI was used to measure the extent of apoptosis. The results showed that the combination of imipenem and MSC-derived exosomes were more effective than imipenem or exosomes alone in reducing the production and secretion of inflammatory cytokines, nitric oxide, and apoptotic rate in E Coli-infected HepG2 cells.

The aim of this study was to evaluate the cytotoxicity and immune-stimulatory effect of Mesoporous silica nanoparticle (MSN) Nano-adjuvant on pro-inflammatory cytokines and pattern recognition receptors (PRR) genes expression in Caco-2/PBMC co-culture model. MSNs were synthesized and characterized by scanning electron microscope (SEM), Brunauer Emmett Teller (BET) and Barrett Joyner Halenda (BJH) techniques. The BET specific surface area of MSNs was around 947 m 2 /g and the total pore volume and average pore diameter were 1.5 cm 3 /g and 8.01 nm, respectively. At the concentration of 10 µg/mL, MSN showed a low and time-dependent cytotoxicity on Caco-2 cells, while no cytotoxic effect was observed for 0.1 and 1 µg/mL concentrations after 24, 48 and 72 h. The expression of pro-inflammatory cytokines genes (IL-1, IL-8 and TNF-α) in co-cultures treated with different concentrations of MSN showed a dose-dependent significant increase up to 17.44, 2.722 and 4.34 folds, respectively, while the expression augmentation of IL-1 gene was significantly higher than the others. This indicates slight stimulation of intestinal inflammation. Different concentrations of MSN significantly increased TLR4 and NOD2 expression to 4.14 and 2.14 folds, respectively. NOD1 was not affected significantly. It can be concluded that MSN might increase protective immune responses against antigens as a vaccine adjuvant candidate. It seems that stimulation of TNF-α, IL-1, and IL-8 expression in enterocytes probably transpires through the agonistic activity of MSN for TLRs including TLR4, while NOD2-associated signaling pathways are also involved. This study provides an overall picture of MSN as a novel and potent oral adjuvant for mucosal immunity., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Bacteriophages are one of the viral components of the human microbiome. M13 phages have recently been considered for immunotherapy because they can be detected by immune cells and stimulated immune responses. Macrophages are essential innate immune cells that respond to stimuli and direct subsequent immune responses. Therefore, it is crucial to evaluate the immunomodulatory effect of phage on macrophage function. For this purpose, peritoneal macrophages from BALB/c and C57BL/6 mice were cultured on the M13 phage, M13 phage-RGD, gelatin-coated, and un-coated wells. Then macrophages were examined for morphological characteristics, L. arginine metabolism, redox potential, inflammatory cytokine production, and phagocytic activity after two and seven days of culture. We observed that M13 phage-coated surfaces induced anti-inflammatory cytokines production and reduced inflammatory cytokines level of BALB/c and C57BL/6 macrophages at the steady-state and post LPS stimulation. In addition, L. arginine metabolism and phagocytic activity of macrophages were directed to the M2 phenotype by induction of arginase-1 and efferocytosis in the M13 phage-containing groups, respectively. The present study confirms the M13 phage's ability to polarize macrophages toward the M2 phenotype. However, using M13 phage in treating inflammatory diseases in animal models could determine their immunotherapy capacity in the future., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Exosomes, ranging in size from 30 to 150 nm as identified initially via electron microscopy in 1946, are one of the extracellular vesicles (EVs) produced by many cells and have been the subject of many studies; initially, they were considered as cell wastes with the belief that cells produced exosomes to maintain homeostasis. Nowadays, it has been found that EVs secreted by different cells play a vital role in cellular communication and are usually secreted in both physiological and pathological conditions. Due to the presence of different markers and ligands on the surface of exosomes, they have paracrine, endocrine and autocrine effects in some cases. Immune cells, like other cells, can secrete exosomes that interact with surrounding cells via these vesicles. Immune system cells-derived exosomes (IEXs) induce different responses, such as increasing and decreasing the transcription of various genes and regulating cytokine production. This review deliberate the function of innate and acquired immune cells derived exosomes, their role in the pathogenesis of immune diseases, and their therapeutic appliances., (© 2022. The Author(s).)

Various factors, including viral and bacterial infections, autoimmune responses, diabetes, drugs, alcohol abuse, and fat deposition, can damage liver tissue and impair its function. These factors affect the liver tissue and lead to acute and chronic liver damage, and if left untreated, can eventually lead to cirrhosis, fibrosis, and liver carcinoma. The main treatment for these disorders is liver transplantation. Still, given the few tissue donors, problems with tissue rejection, immunosuppression caused by medications taken while receiving tissue, and the high cost of transplantation, liver transplantation have been limited. Therefore, finding alternative treatments that do not have the mentioned problems is significant. Cell therapy is one of the treatments that has received a lot of attention today. Hepatocytes and mesenchymal stromal/stem cells (MSCs) are used in many patients to treat liver-related diseases. In the meantime, the use of mesenchymal stem cells has been studied more than other cells due to their favourable characteristics and has reduced the need for liver transplantation. These cells increase the regeneration and repair of liver tissue through various mechanisms, including migration to the site of liver injury, differentiation into liver cells, production of extracellular vesicles (EVs), secretion of various growth factors, and regulation of the immune system. Notably, cell therapy is not entirely excellent and has problems such as cell rejection, undesirable differentiation, accumulation in unwanted locations, and potential tumorigenesis. Therefore, the application of MSCs derived EVs, including exosomes, can help treat liver disease and prevent its progression. Exosomes can prevent apoptosis and induce proliferation by transferring different cargos to the target cell. In addition, these vesicles have been shown to transport hepatocyte growth factor (HGF) and can promote the hepatocytes'(one of the most important cells in the liver parenchyma) growths., 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 © 2022 Hazrati, Malekpour, Soudi and Hashemi.)

Background: Physical activity can improve brain health in people with multiple sclerosis (PwMS). One of the underlying mechanisms can be the modulation of gut bacteria. The association of different intensity of physical activity in a lifetime; and brain volume, lesion volume, and number, and gut bacteria counts were investigated in the current study., Methods: Forty-five PwMS were recruited, and magnetic resonance imagining was used to evaluate brain volume, lesion volume, and number. Also, stool samples were taken for evaluation faecalibacterium prausnitzii, akkermansia muciniphila, prevotella, and bacteroides count. Moreover, lifetime physical activity was assessed using the adapted version of the historical activity questionnaire., Results: Data revealed a significant association of physical activity with brain volume (r = 0.41), lesion volume (r=-0.35), lesion number (r=-0.37), akkermansia muciniphila (r=-0.34), prevotella (r = 0.52) and bacteroides (r=-0.32) count (p<0.05). Moderate-intensity of physical activity was associated with brain volume (r = 0.33), lesion volume (r=-0.38), prevotella (r = 0.35) and bacteroides (r=-0.40) count (p<0.05). Moreover, vigorous-intensity of physical activity was associated with brain volume (r = 0.38), lesion number (r=-0.39), akkermansia muciniphila (r=-0.30) and prevotella (r = 0.56) count (p<0.05)., Conclusion: Our results suggest that lifetime physical activity is associated with brain health and gut bacteria count in PwMS. Additionally, the heterogeneity of the association of the physical activity intensities with the studied variables indicates the importance of using different intensities of physical activity to greater benefit from physical activity., (Copyright © 2022. Published by Elsevier B.V.)

Cyclosporine A (CsA) is an immunosuppressive drug used in organ transplantation and treatment of autoimmune diseases. Effects of CsA on determining the direction of the immune response and pathogenesis of infections by altering immune responses particulary T cells functions have always been questionable. We evaluated the effect of different doses of CsA on course of infection in BALB/c mice infected with live Bacillus Calmette Guérin (BCG) (as an example of Mycobacterial infections). Four groups of mice (n = 5) receiving 5, 25, 125, and 0 mg/kg of CsA, three times a week, were infected with BCG aerosolly. Before BCG inhalation and 40-/60- days post-infection, cell proliferation and CD4 + CD25 + cell percentage were evaluated in splenocytes of mice after culture and stimulation with PHA or BCG lysate. The histopathological alterations and bacterial burden were assessed in lung tissue. Cells showed a dose-dependent decrease in proliferation and the percentage of CD4 + CD25 + cells. After BCG infection, in presence of dose 125 mg/kg, there were some exceptions. The number of bacteria and histopathological lesions and inflammation in lung tissues increased in a dose-dependent manner. CsA immunosuppressed BCG infected mice can be used as a safe model for studying Mycobacterium species pathogenesis and related cellular immune responses., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Vibrio cholerae is the causative agent of cholera, which is commonly associated with high morbidity and mortality, and presents a major challenge to healthcare systems throughout the world. Lipopolysaccharide (LPS) is required for full protection against V. cholerae but can induce inflammation and septic shock. Mesenchymal stem cells (MSCs) are currently used to treat infectious and inflammatory diseases. Therefore, this study aimed to evaluate the immune-modulating effects of the LPS-MSC-conditioned medium (CM) on V. cholerae LPS immunization in a murine model., Methods: After preconditioning MSCs with LPS, mice were immunized intraperitoneally on days 0 and 14 with the following combinations: LPS + LPS-MSC-CM; detoxified LPS (DLPS) + MSC-CM; LPS + MSC sup; LPS; LPS-MSC-CM; MSC supernatant (MSC sup); and PBS. The mouse serum and saliva samples were collected to evaluate antibody (serum IgG and saliva IgA) and cytokine responses (TNF-α, IL-10, IL-6, TGF-β, IL-4, IL-5, and B-cell activating factor (BAFF))., Results: The LPS + LPS-MSC-CM significantly increased total IgG and IgA compared to other combinations (P < 0.001). TNF-α levels, in contrast to IL-10 and TGF-β, were reduced significantly in mice receiving the LPS + LPS-MSC-CM compared to mice receiving only LPS. IL-4, IL-5, and BAFF levels significantly increased in mice receiving increased doses of LPS + LPS-MSC-CM compared to those who received only LPS. The highest vibriocidal antibody titer (1:64) was observed in LPS + LPS-MSC-CM-immunized mice and resulted in a significant improvement in survival in infant mice infected by V. cholerae O1., Conclusions: The LPS-MSC-CM modulates the immune response to V. cholerae LPS by regulating inflammatory and anti-inflammatory responses and inducing vibriocidal antibodies, which protect neonate mice against V. cholerae infection., (© 2021. The Author(s).)

Cancer has remained a major health problem around the world. Mesenchymal stem cells (MSCs)-based therapy exhibits a therapeutic effect via different mechanisms. By using MSCs as carrier cells, the major problem of clearance of oncolytic viruses is resolved by neutralizing antibodies before they react with cancer cells. The aim of this study was to characterize the effect of infected MSCs by reovirus type-3 Dearing (T3D) for in vitro cancer therapy. Adipose-derived MSCs (AD-MSCs) were infected with reovirus T3D and its biological properties were evaluated. Then, the effects of reovirus-infected AD-MSCs on cytokine profile, nitric oxide (NO) production, and apoptosis induction in TC-1 cells were assessed. Our results indicated that the differentiation potential of AD-MSCs was affected by reovirus. However, phenotypes were not affected after infection. Then, the effects of reovirus-infected AD-MSCs in TC-1 cells showed an increased amount of tumor necrosis factor-alpha (TNF-α) and NO production and a decreased amount of transforming growth factor-beta 1 (TGF-β1) and interleukin-10 (IL-10). Moreover, apoptosis significantly increased via coculturing of TC-1 cells with infected AD-MSCs, compared with control, and both internal and external apoptosis pathways are activated in experimental groups. In conclusion, the data showed that with increasing TNF-α and NO production and reducing IL-10 and TGF-β production, AD-MSCs can enhance the oncolytic effect of reovirus in cancer cells. Furthermore, the results suggested that AD-MSCs can be used as effective carrier cells candidate for reovirus T3D to maximize their anticancer cell activity., (© 2021 Wiley Periodicals LLC.)

Inflammation-induced by the interaction of the Vibrio cholerae with the epithelial cells is considered as a main cause of bacteria spreading through the gastrointestinal tract and its consequences. Because of the immunomodulatory and antibacterial properties of adipose-derived mesenchymal stem cells (AD-MSCs), this study aimed to investigate the effect of AD-MSCs on the interaction of the bacterial-epithelial cell. Caco-2 differentiated to intestinal epithelial cells co-cultured with AD-MSCs in a 1:1 ratio of the surface area of six-well plates, for 48 hours. After exposure to Vibrio cholerae, bacterial attachment and internalization were evaluated. Secretions of interleukin (IL) -6, prostaglandin E2 (PGE2), and nitric oxide (NO) were also measured using ELISA, and Griess assay, respectively. In addition, the expression of chloratoxin (Ctx-β) and inflammatory cytokines such as TNF-α, IL-1β, and IL-8 were evaluated by real-time polymerase chain reaction (RT-PCR). The rate of apoptosis was also evaluated by Annexin V-PI flow cytometry. Bacterial attachment and Ctx-β expression were significantly reduced in the co-culture group compared to the Vibrio cholerae-exposed Caco-2. IL-6 and PGE2 secretion increased in the co-culture group. NO, was also slightly reduced in exposure to Vibrio cholerae. An elevated level of bacterial internalization was observed in the co-culture group compared to the Caco-2 cells leading to an increase in the expression of pro-inflammatory cytokines. The rate of apoptosis was also increased significantly. Cell-to-cell contact of AD-MSCs and Caco-2 promoted inflammatory responses and disruption of the epithelium barrier by enhancing bacterial invasion. This may be due to the high expression of surface matrix metalloproteinases on MSCs.

Acquired forms of Aplastic anemia (AA) are characterized by T cell-mediated immune disease resulting in bone marrow (BM) failure and marrow hypoplasia. In these cases, it is a major challenge to modulate autoreactive T cell activity and thereby decrease the pro-inflammatory cytokine storm. Emerging evidence indicates that extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) control and modulate immunity. The therapeutic potential of MSC-EVs has not been investigated in acquired AA. Hence, in this study, we constructed an AA mice model through irradiation and splenocyte infusion to test the benefits of hypoxic MSC-EVs (Hx-EVs) and normoxic MSC-EVs (Nx-EVs). We found that MSC-EVs treatment significantly prolonged the survival rate and increased the platelet (PLT) counts of the AA mice. Immunohistochemical staining and colony assay confirmed amelioration of hypoplasia in the BM and increased numbers of hematopoietic stem cells (HSCs). These effects of MSC-EVs were mediated by T cell suppression and inhibition of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) production in the AA mouse model. In addition, an in vitro study revealed that MSC-EVs led to reduced IFN-γ and TNF-α levels and there was an association with decreased splenocyte viability. Previous studies examined the diagnostic and prognostic values of microRNAs (miRNAs) in AA and identified miR-199a, miR-146a, miR-223, and miR-126. We used quantitative real-time PCR to evaluate the expression of these miRNAs on isolated BM mononuclear cells (BM-MNCs) from treated and untreated AA mice. miR-223, miR-146a, and miR-199a expressions increased in the MSC-EVs treated AA mice. Treatment with MSC-EVs increased expression of miR-223 and miR-146a. Our findings showed that treatment with MSC-EVs significantly ameliorated immune destruction of HSCs in the AA mouse model and confirmed the importance of miRNAs in the clinical status of this model., (© 2021 Wiley Periodicals LLC.)

T-lymphocytes have critical functions in the immune responses against viral and intracellular bacterial infections as well as cancers. Antigen (Ag)-specific T-lymphocyte clones enriched and expanded in vitro are valuable tools in the study of immune responses in animal models and adoptive T-cell therapy of patients with cancer or infection. We described a method for inducing, enriching, and replicating Ag-specific poly-clonal T-cells from BALB/c mice infected with live Bacillus Calmette Guérin (BCG) bacterium. During a 7-8 days procedure, T-lymphocytes were purified from immune cells of lymph nodes stimulated with immunodominant Ag of BCG, TB10.4, and expanded by interleukin -2 cytokine. We evaluated the effect of Ag doses (1, 10, and 100 μg/mL) and exposure method of Ag presenting cells (APCs) to T-cells, on T-cells' proliferation, viability, and Interferon-gamma (IFN-γ) secretion at 2, 5, and 7 days after Ag stimulation. Increasing Ag concentration increased the average cell division, but at the highest dose of Ag (100 μg/mL), T-cell viability is decreased. Only clones induced by 10 μg/mL Ag produced a desirable amount of IFN-γ. Incubation of Ag and APCs, 24 h before T-lymphocytes addition, increased the proliferation and viability of cells. T cells are in a more favorable condition around day 5 of Ag stimulation in terms of proliferation and survival, and it is the desired time for T cell restimulation. For optimal preparation of specific T-cells for adoptive cell transfer, optimization of Ag dose, the order of APCs and T-cells exposure with Ag, and the duration of initial Ag stimulation, as well as the time for restimulation, is essential.

The aim of this study was to assess the modulatory effect of TcpA in the expression of CEACAM1 adhesin molecule and IL-1, IL-8, and TNF-α pro-inflammatory cytokines in the Coculture model of Caco-2/PBMC (peripheral blood mononuclear cell) that can mimic the intestinal milieu. The TcpA gene from Vibrio cholerae ATCC14035 was cloned in pET-28a and transformed into Escherichia coli Bl-21. The recombinant TcpA-His6 protein was expressed and purified using Ni-column chromatography. The sequencing of transformed plasmid and Western blot analysis of purified protein confirmed the identity of rTcp. The cytotoxicity of different concentrations of recombinant protein for human colon carcinoma cell line (human colorectal adenocarcinoma cell [Caco-2 cell]) was assessed by MTT assay and showed viability of 92%, 82%, and 70%, for 10 µg/mL of TcpA after 24, 48, and 72 h, respectively. Co-cultures of Caco-2 and PBMCs were used to mimic the intestinal milieu and treated with different concentrations of rTcpA (1, 5, 10, and 50 µg/mL). Our data showed about 2.04-, 3.37-, 3.68-, and 42.7-fold increase in CEACAM1 gene expression, respectively, compared with the nontreated Caco-2/PBMC Coculture. Moreover, the expression of IL-1, IL-8, and TNF-α genes was significantly increased up to 15.75-, 7.04-, and 80.95-folds, respectively. In conclusion, V. cholerae TcpA induces statistically significant dose-dependent stimulatory effect on TNF-α, IL-,1, and IL-8 pro-inflammatory cytokines expression. Of these, TNF-α was much more affected which, consequently, elevated the CEACAM1 expression level in IECs. This suggests that TcpA protein is a critical effector as an inducer of increased adhesion potential of V. cholera as well as inflammatory responses of host intestinal tissue., (© 2021 The Societies and John Wiley & Sons Australia, Ltd.)

Background and Aims: Several oncolytic viruses applications have been approved in the clinic or in different phases of clinical trials. However, these methods have some rudimentary problems. Therefore, to enhance the delivery and quality of treatment, considering the advantage of cell carrier-based methods such as Mesenchymal Stem Cells (MSC) have been proposed. This study was designed to evaluate the performance and quality of cancer treatment based on MSCs loaded by oncolytic reovirus in the cancerous C57BL/6 mouse model. Also, we evaluated MSCs migration potency in vitro and in vivo following the oncolytic reovirus infection., Methods: C57BL/6 mice were inoculated with TC-1 cell lines and tumors were established in the right flank. Mice were systemically treated with reovirus, MSCs-loaded with reovirus, MSCs, and PBS as a control in separated groups. Effects of infected AD-MSCs with reovirus on tumor growth and penetration in the tumor site were monitored. All groups of mice were monitored for two months in order to therapeutic and anticancer potential. After treatments, tumor size alteration and apoptosis rate, as well as cytokine release pattern was assessed., Results: The results of the current study indicated that the effect of reovirus infection on AD-MSCs is not devastating the migration capacity especially in MOI 1 and 5 while intact cells remain. On the other hand, MSCs play an efficient role as a carrier to deliver oncolytic virus into the tumor site in comparison with systemic administration of reovirus alone. Apoptosis intensity relies on viral titration and passing time. Followed by systemic administration, treatment with oncolytic reovirus-infected AD-MSCs and MSCs alone had shown significant inhibition in tumor growth. Also, treatment by reovirus causes an increase in IFN-γ secretion., Conclusion: The results of in vitro and in vivo study confirmed the tumor-homing properties of infected AD-MSCs and the significant antitumor activity of this platform. Hence, our results showed that the cell carrier strategy using oncolytic reovirus-loaded AD-MSCs enhanced virus delivery, infiltration, and antitumor activity can be effectively applied in most cancers.