Iron controls the development of airway hyperreactivity by regulating ILC2 metabolism and effector function.

Group 2 innate lymphoid cells (ILC2s) rapidly induce a type 2 inflammation in the lungs in response to allergens. Here, we focused on the role of iron, a critical nutritional trace element, on ILC2 function and asthma pathogenesis. We found that transferrin receptor 1 (TfR1) is rapidly up-regulated and functional during ILC2 activation in the lungs, and blocking transferrin uptake reduces ILC2 expansion and activation. Iron deprivation reprogrammed ILC2 metabolism, inducing a HIF-1α-driven up-regulation of glycolysis and inhibition of oxidative mitochondrial activity. Consequently, we observed that in vivo iron chelation or induction of hypoferremia reduced the development of airway hyperreactivity in experimental models of ILC2-driven allergic asthma. Human circulating ILC2s rapidly induced TfR1 during activation, whereas inhibition of iron uptake or iron deprivation reduced effector functions. Last, we found a negative relationship between circulating ILC2 TfR1 expression and airway function in cohorts of patients with asthma. Collectively, our studies define cellular iron as a critical regulator of ILC2 function.

Piezo1 channels restrain ILC2s and regulate the development of airway hyperreactivity.

Mechanosensitive ion channels sense force and pressure in immune cells to drive the inflammatory response in highly mechanical organs. Here, we report that Piezo1 channels repress group 2 innate lymphoid cell (ILC2)-driven type 2 inflammation in the lungs. Piezo1 is induced on lung ILC2s upon activation, as genetic ablation of Piezo1 in ILC2s increases their function and exacerbates the development of airway hyperreactivity (AHR). Conversely, Piezo1 agonist Yoda1 reduces ILC2-driven lung inflammation. Mechanistically, Yoda1 inhibits ILC2 cytokine secretion and proliferation in a KLF2-dependent manner, as we found that Piezo1 engagement reduces ILC2 oxidative metabolism. Consequently, in vivo Yoda1 treatment reduces the development of AHR in experimental models of ILC2-driven allergic asthma. Human-circulating ILC2s express and induce Piezo1 upon activation, as Yoda1 treatment of humanized mice reduces human ILC2-driven AHR. Our studies define Piezo1 as a critical regulator of ILC2s, and we propose the potential of Piezo1 activation as a novel therapeutic approach for the treatment of ILC2-driven allergic asthma.

Catalase-gold nanoaggregates manipulate the tumor microenvironment and enhance the effect of low-dose radiation therapy by reducing hypoxia.

Radiotherapy as a standard method for cancer treatment faces tumor recurrence and antitumoral unresponsiveness. Suppressive tumor microenvironment (TME) and hypoxia are significant challenges affecting efficacy of radiotherapy. Herein, a versatile method is introduced for the preparation of pH-sensitive catalase-gold cross-linked nanoaggregate (Au@CAT) having acceptable stability and selective activity in tumor microenvironment. Combining Au@CAT with low-dose radiotherapy enhanced radiotherapy effects via polarizing protumoral immune cells to the antitumoral landscape. This therapeutic approach also attenuated hypoxia, confirmed by downregulating hypoxia hallmarks, such as hypoxia-inducible factor α-subunits (HIF-α), vascular endothelial growth factor (VEGF), and EGF. Catalase stability against protease digestion was improved significantly in Au@CAT compared to the free catalase. Moreover, minimal toxicity of Au@CAT on normal cells and increased reactive oxygen species (ROS) were confirmed in vitro compared with radiotherapy. Using the nanoaggregates combined with radiotherapy led to a significant reduction of immunosuppressive infiltrating cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (T-regs) compared to the other groups. While, this combined therapy could significantly increase the frequency of CD8+ cells as well as M1 to M2 macrophages (MQs) ratio. The combination therapy also reduced the tumor size and increased survival rate in mice models of colorectal cancer (CRC). Our results indicate that this innovative nanocomposite could be an excellent system for catalase delivery, manipulating the TME and providing a potential therapeutic strategy for treating CRC.

In vitro investigation of wound healing performance of PVA/chitosan/silk electrospun mat loaded with deferoxamine and ciprofloxacin.

Electrospinning is an advanced method used for developing wound dressings. Biopolymer-based electrospun mats have been extensively studied in tissue engineering due to their similarity to the extracellular matrix. In this study, electrospun poly(vinyl alcohol)/chitosan/silk fibroin (PChS) mat demonstrated improved mechanical properties, including tensile strength, strain at break, and Young's modulus, compared to electrospun poly(vinyl alcohol) and poly(vinyl alcohol)/chitosan mats. Similarly, the swelling capability, thermal stability, and hydrophilicity were higher in the PChS mat compared to the other ones. Hence, the PChS mat was selected for further investigation. Ciprofloxacin (CIP) was added to the PChS electrospinning solution at 5 % and 10 % concentration, and deferoxamine (DFO) was immobilized on CIP-loaded mats at 1 and 2 g/L concentration using a polydopamine linker. Evaluating mats with the dimensions of 1 × 1 cm2 showed that those containing 5 % and 10 % CIP exhibited bactericidal activity against Escherichia coli and Staphylococcus aureus. Moreover, Human dermal fibroblast cells were compatible with the fabricated mats, as confirmed by the MTT assay. Finally, drug-loaded mats had a positive effect on wound healing in a scratch test, and mats with 10 % CIP and 2 g/L DFO showed the highest effect on promoting wound healing, indicating potential for use as a wound dressing.

Pentoxifylline changes the balance of immune cell population in breast tumor-infiltrating lymphocytes.

Immunotherapy utilizing tumor-infiltrating lymphocytes (TILs) is a promising approach for cancer treatment. Pentoxifylline (PTXF), a xanthine derivative, exhibits antitumor properties. This study aimed to investigate the impact of PTXF on the phenotype and function of TILs and splenocytes in a triple-negative breast cancer (TNBC) mouse model. TNBC was subcutaneously induced in BALB/c mice, followed by nine intraperitoneal injections of 100 mg/kg PTXF. TILs were then isolated by enzymatic digestion of tumors and cocultured with 4T1 cells. The proportion of regulatory T cells (Tregs) and cytotoxic T cells in TILs and splenocytes was assessed using flow cytometry. Transforming growth factor (TGF)-ß and interferon (IFN)-γ production in TILs and splenocytes cultures was measured by ELISA. Relative expression of t-bet, foxp3, gata-3, and ror-γt in TILs and splenocytes was evaluated using real-time PCR. Tumor growth in PTXF-treated mice was significantly lower than that in the controls (P < 0.01). The frequency of regulatory and cytotoxic TILs in PTXF-treated mice was approximately half (P < 0.01) and twice (P < 0.05) that of the control group, respectively. The level of TGF-ß and IFN-γ in the supernatant of PTXF-treated TILs was decreased and increased, respectively (P < 0.05). The relative expression of t-bet and foxp3 in the PTXF-treated mice compared to controls was increased and decreased, respectively (P < 0.05). Changes in the immune cell balance were less significant in the spleen compared to the TILs. PTXF treatment could limit the tumor growth and modify the regulatory-to-cytotoxic TILs ratio, as well as cytokine balance of TILs, in favor of antitumor responses.

A novel method for the separation of saponin from soybean meal by colloidal gas aphrons: optimization based on response surface methodology.

Natural surfactants, such as soy saponins, are rich in triterpenoid saponins, which have significant biological activities and are used in different applications, such as cosmetics, food, and pharmaceutical industries. In this research, it was used colloidal gas aphrons (CGAs) as a green and cost-effective method to concentrate soy saponin from soybean meal extract. The production of micro-nano bubbles, in conjunction with the investigation of the effect of different chemical and process variables, significantly impacted the purity and recovery of saponins in this method. The response surface methodology (RSM) was employed to optimize the process. The purity and recovery percentage of saponins were found to be 75.12 and 25.87 in optimal conditions, respectively. Furthermore, when the maximum value for both responses was selected, the purity and recovery reached 57.61% and 71.94%, respectively. Eventually, the results indicate that this method is technically promising, straightforward, and cost-effective in separating saponins for various applications.

Tumor-infiltrating lymphocytes for treatment of solid tumors: It takes two to tango?

Tumor-infiltrating lymphocytes (TILs), frontline soldiers of the adaptive immune system, are recruited into the tumor site to fight against tumors. However, their small number and reduced activity limit their ability to overcome the tumor. Enhancement of TILs number and activity against tumors has been of interest for a long time. A lack of knowledge about the tumor microenvironment (TME) has limited success in primary TIL therapies. Although the advent of engineered T cells has revolutionized the immunotherapy methods of hematologic cancers, the heterogeneity of solid tumors warrants the application of TILs with a wide range of specificity. Recent advances in understanding TME, immune exhaustion, and immune checkpoints have paved the way for TIL therapy regimens. Nowadays, TIL therapy has regained attention as a safe personalized immunotherapy, and currently, several clinical trials are evaluating the efficacy of TIL therapy in patients who have failed conventional immunotherapies. Gaining favorable outcomes following TIL therapy of patients with metastatic melanoma, cervical cancer, ovarian cancer, and breast cancer has raised hope in patients with refractory solid tumors, too. Nevertheless, TIL therapy procedures face several challenges, such as high cost, timely expansion, and technical challenges in selecting and activating the cells. Herein, we reviewed the recent advances in the TIL therapy of solid tumors and discussed the challenges and perspectives.

Anti-cancer therapeutic strategies based on HGF/MET, EpCAM, and tumor-stromal cross talk.

As an intelligent disease, tumors apply several pathways to evade the immune system. It can use alternative routes to bypass intracellular signaling pathways, such as nuclear factor-κB (NF-κB), Wnt, and mitogen-activated protein (MAP)/phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). Therefore, these mechanisms lead to therapeutic resistance in cancer. Also, these pathways play important roles in the proliferation, survival, migration, and invasion of cells. In most cancers, these signaling pathways are overactivated, caused by mutation, overexpression, etc. Since numerous molecules share these signaling pathways, the identification of key molecules is crucial to achieve favorable consequences in cancer therapy. One of the key molecules is the mesenchymal-epithelial transition factor (MET; c-Met) and its ligand hepatocyte growth factor (HGF). Another molecule is the epithelial cell adhesion molecule (EpCAM), which its binding is hemophilic. Although both of them are involved in many physiologic processes (especially in embryonic stages), in some cancers, they are overexpressed on epithelial cells. Since they share intracellular pathways, targeting them simultaneously may inhibit substitute pathways that tumor uses to evade the immune system and resistant to therapeutic agents.

Type-I interferons in the immunopathogenesis and treatment of Coronavirus disease 2019.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is currently the major global health problem. Still, it continues to infect people globally and up to the end of February 2022, over 436 million confirmed cases of COVID-19, including 5.95 million deaths, were reported to the world health organization (WHO). No specific treatment is currently available for COVID-19, and the discovery of effective therapeutics requires understanding the effective immunologic and immunopathologic mechanisms behind this infection. Type-I interferons (IFN-Is), as the critical elements of the immediate immune response against viral infections, can inhibit the replication and spread of the viruses. However, the available evidence shows that the antiviral IFN-I response is impaired in patients with the severe form of COVID-19. Moreover, the administration of exogenous IFN-I in different phases of the disease can lead to various outcomes. Therefore, understanding the role of IFN-I molecules in COVID-19 development and its severity can provide valuable information for better management of this disease. This review summarizes the role of IFN-Is in the pathogenesis of COIVD-19 and discusses the importance of autoantibodies against this cytokine in the spreading of SARS-CoV-2 and control of the subsequent excessive inflammation.

Decrease of Tumor-infiltrating Regulatory T Cells Using Pentoxifylline: An Ex Vivo Analysis in Triple-negative Breast Cancer Mouse Model.

Triple-negative breast cancer (TNBC) is the most aggressive type of BC with the highest percentage of tumor-infiltrating lymphocytes (TILs). Hence, TIL therapy is considered a promising approach to target TNBC. Depletion of regulatory T cells (Tregs) in TILs can improve the antitumor function of TIL therapy. Pentoxifylline (PTXF) is a xanthine derivative that can modulate the nuclear factor kappa B (NF-κB) signaling and probably affect the Treg proportion in TILs. We aimed to evaluate the ex vivo effect of PTXF on the proportion of Treg cells in the TILs derived from a mouse model of TNBC. The 4T1 cells were inoculated subcutaneously to BALB/c mice to induce TNBC. TILs were isolated from tumor tissue by enzymatic digestion and cultured alone or with 4T1 cells for 24, 48, and 72 h in the presence of interleukin (IL)-2 and different concentrations of PTXF. The toxicity of PTXF and its effects on Tregs proportion as well as cytokine production was evaluated using MTT assay, flow cytometry, and ELISA, respectively. PTXF had no significant impact on the viability of TILs. Both 500 and 1000 mg/mL of PTXF decreased the proportion of Tregs in a dose-dependent manner. The level of interferon-g and tumor growth factor-b in TILs supernatant was increased and decreased, respectively. Our data suggest that ex vivo treatment of TILs with pentoxifylline could decrease the proportion of Tregs in the conventional IL-2-mediated TIL expansion and change the cytokine balance of TILs in favor of antitumor immune response.

Estimation of CO2 flux components over northern hemisphere forest ecosystems by using random forest method through temporal and spatial data scanning procedures.

Modeling CO2 flux components is an important task in ecosystem analysis and terrestrial studies. Net ecosystem exchange (NEE), ecosystem respiration (R), and gross primary production (GPP) are three CO2 flux components. Despite the ecosystem land cover characteristics, climatic factors can make considerable impact on quantity and mechanism of these components. Nevertheless, such climatic factors are not available in most of the areas, especially in developing regions. Therefore, obtaining the models that can exempt using locally recorded variables would be of great importance. A modeling study was carried out here to simulate CO2 flux components using soft computing-based random forest (RF) model in both local and external (spatial) scales, assessed by k-fold validation procedure. Data from 11 sites located in three forest ecosystems, e.g. deciduous broad leaf (DBF), evergreen needle leaf (ENF), and mixed forest (MF), were used to simulate the flux components. The obtained results showed that the temperature-related parameters (e.g., air and soil temperature, vapor pressure deficit) along with the net radiation play key role in determining the flux components in all studied ecosystems. It was confirmed that a chronologic scan of the available patterns is needed for a thorough assessment of the performance accuracy of the local models. The external models provided promising results when compared with the locally trained models. This is a very great step forward in estimating CO2 flux components under data scarcity conditions.

Potential cytotoxicity of trace elements and polycyclic aromatic hydrocarbons bounded to particulate matter: a review on in vitro studies on human lung epithelial cells.

A large number of studies have been conducted for clarifying toxicological mechanisms of particulate matter (PM) aimed to investigate the physicochemical properties of PM and providing biological endpoints such as inflammation, perturbation of cell cycle, oxidative stress, or DNA damage. However, although several studies have presented some effects, there is still no consensus on the determinants of biological responses. This review attempts to summarize all past research conducted in recent years on the physicochemical properties of environmental PM in different places and the relationship between different PM components and PM potential cytotoxicity on the human lung epithelial cells. Among 447 papers with our initial principles, a total of 50 articles were selected from 1986 to April 2020 based on the chosen criteria for review. According to the results of selected studies, it is obvious that cytotoxicity in human lung epithelial cells is created both directly or indirectly by transition metals (such as Cu, Cr, Fe, Zn), polycyclic aromatic hydrocarbons (PAH), and ions that formed on the surface of particles. In the selected studies, the findings of the correlation analysis indicate that there is a significant relationship between cell viability reduction and secretion of inflammatory mediators. As a result, it seems that the observed biological responses are related to the composition and the physicochemical properties of the PMs. Therefore, the physicochemical properties of PM should be considered when explaining PM cytotoxicity, and long-term research data will lead to improved strategies to reduce air pollution.

Oncolytic virotherapy in hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) is a curative option for various hematologic malignancies. However, fatal complications, such as relapse and graft-versus-host disease (GVHD) hampered favorable HSCT outcomes. Cancer cells remained in the body following the conditioning regimen, or those contaminating the autologous graft can cause relapse. Although the relapse is much lesser in allogeneic HSCT, GVHD is still a life-threatening complication in this type of HSCT. Researchers are seeking various strategies to reduce relapse and GVHD in HSCT with minimum effects on the engraftment and immune-reconstitution. Oncolytic viruses (OVs) are emerging anti-cancer agents with promising results in battling solid tumors. OVs can selectively replicate in the malignant cells in which the antiviral immune responses have defected. Hence, they could be used as a purging agent to eradicate the tumoral contamination of autologous grafts with no damages to hematopoietic stem cells. Moreover, they have been shown to alleviate GVHD complications through modulating alloreactive T cell responses. Primary results promise using OVs as a strategy to reduce both relapse and GVHD in the HSCT without affecting hematologic and immunologic engraftment. Herein, we provide the latest findings in the field of OV therapy in HSCT and discuss their pros and cons.

Breast cancer immunotherapy: Current and novel approaches.

The crucial role of the immune system in the progression/regression of breast cancer (BC) should always be taken into account. Various immunotherapy approaches have been investigated for BC, including tumor-targeting antibodies (bispecific antibodies), adoptive T cell therapy, vaccines, and immune checkpoint blockade such as anti-PD-1. In addition, a combination of conventional chemotherapy and immunotherapy approaches contributes to improving patients' overall survival rates. Although encouraging outcomes have been reported in most clinical trials of immunotherapy, some obstacles should still be resolved in this regard. Recently, personalized immunotherapy has been proposed as a potential complementary medicine with immunotherapy and chemotherapy for overcoming BC. Accordingly, this review discusses the brief association of these methods and future directions in BC immunotherapy.

The fatty acid-binding protein (FABP) decreases the clinical signs and modulates immune responses in a mouse model of experimental autoimmune encephalomyelitis (EAE).

BACKGROUND: An increasing body of studies has shown that Fasciola hepatica can affect immune responses. This study explored whether the fatty acid-binding protein (FABP) of F. hepatica can modulate the immune system in a mouse model of experimental autoimmune encephalomyelitis (EAE). METHODS: EAE-induced C57BL/6 mice were treated with vehicle, F. hepatica total extract (TE) or FABP. The clinical signs, body weights, and the expression of IFN-γ, T-bet, IL-4, GATA3, IL-17, RORγ, TGF-ß, FOXP3, IL-10, TNF-α genes and proteins were determined in the isolated CD4+ splenocytes. Besides, the percentage of Treg cells and degree of demyelination were evaluated. RESULTS: We found that TE and FABP treatments decreased the clinical scores, lymphocyte infiltration rate, and demyelinated plaques in EAE mice. The expressions of IL-4 and GATA3 were increased, whereas IL-17 and TNF-α were down-regulated. FABP did not affect the expression of IFN-γ, RORγ, IL-10, and TGF-ß genes or proteins but reduced the expression of T-bet. TE administration did not affect the expression of IL-10 and the Tbet genes, and increased the expression levels of IFN-γ and FOXP3 in CD4+ lymphocytes. Both FABP and TE treatment did not affect the Treg cell percentage. CONCLUSION: This study indicates that F. hepatica FABP and TE can suppress the inflammatory responses in EAE-induced mice and shift the immune system toward Th2 responses. However, FABP exerts stronger anti-inflammatory effects and seems to be more effective than TE for EAE treatment.

PI3 kinase signaling pathway in hematopoietic cancers: A glance in miRNA's role.

Hematopoietic cancers are among the most common malignancies worldwide, which are divided into different types depending on the origin of tumor cells. In recent years, the pivotal role of different signaling pathways in the onset and progression of these cancer types has been well established. One of these pathways, whose role in blood malignancies has been well-defined, is PI3K/mTOR/AKT axis. The signaling pathway involves in a wide variety of important biological events in cells. It is clear that dysregulation of mediators involved in PI3 kinase signaling takes a pivotal role in cancer development. Considering the undeniable role of miRNAs, as one of the well-known families of non-coding RNAs, in gene regulation, we aimed to review the role of miRNAs in regulation of PI3 kinase signaling effectors in hematopoietic cancers.

Immune and metabolic checkpoints blockade: Dual wielding against tumors.

Recent advances in cancer immunotherapy have raised hopes for treating cancers that are resistant to conventional therapies. Among the various immunotherapy methods, the immune checkpoint (IC) blockers were more promising and have paved their way to the clinic. Tumor cells induce the expression of ICs on the immune cells and derive them to a hyporesponsive exhausted phenotype. IC blockers could hinder immune exhaustion in the tumor microenvironment and reinvigorate immune cells for an efficient antitumor response. Despite the primary success of IC blockers in the clinic, the growing numbers of refractory cases require an in-depth study of the cellular and molecular mechanisms underlying IC expression and function. Immunometabolism is recently found to be a key factor in the regulation of immune responses. Activated or exhausted immune cells exploit different metabolic pathways. Tumor cells can suppress antitumor responses via immunometabolism alteration. Therefore, it is expected that concurrent targeting of ICs and immunometabolism pathways can cause immune cells to restore their antitumor activity. In this review, we dissected the reciprocal interactions of immune cell metabolism with expression and signaling of ICs in the tumor microenvironment. Recent findings on dual targeting of ICs and metabolic checkpoints have also been discussed.

Risk Factors of Graft-Versus-Host Disease in the Iranian Allogeneic Hematopoietic Stem Cell Transplantation: A 10-Year Experience.

Background: Graft-versus-host disease (GVHD) is a serious complication associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Thus, it is necessary to evaluate the risk factors of GVHD in allo-HSCT. Herein, we studied the effects of some risk factors on GVHD incidence in patients with allo-HSCT. Methods: We retrospectively evaluated the GVHD incidences and risk factors in 199 patients diagnosed with hematological disorders who underwent allo-HSCT in Taleghani hospital, Tehran, Iran, between 2007 and 2017. The univariable and multivariable analyses of time to event data were performed using the Logistic regression model. Computations were performed using SAS, and the level of statistical significance for univariable and multivariable analyses was set at 20% and 10%, respectively. Results: Acute GVHD (aGVHD) was seen in 59 (29.6%) patients, and 18 (9%) patients developed chronic GVHD (cGVHD). The odds of GVHD incidence in male to female transplants was 3.49 times greater than the male-to-male transplantations (CI, 1.16, 11.5; p<0.001). The patients with body mass index (BMI) below 18.5 had 96% lower odds of GVHD incidence compared with those with BMI above 30 (CI, 0.007-0.27; p=0.013). The odds of GVHD incidence in patients who were negative for cytomegalovirus (CMV) antigen was 76% lower than patients with positive CMV antigen (CI, 0.06-0.93; p=0.081). Conclusion: In a nutshell, our results indicated that the donor-recipient gender disparity, the recipient's BMI, and CMV infection/reactivation status might be pivotal risk factors, which should be taken into account for prevention and management of GVHD.

Immunopathological similarities between COVID-19 and influenza: Investigating the consequences of Co-infection.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a global public health emergency since December 2019, and so far, more than 980,000 people (until September 24, 2020) around the world have died. SARS-CoV-2 mimics the influenza virus regarding methods and modes of transmission, clinical features, related immune responses, and seasonal coincidence. Accordingly, co-infection by these viruses is imaginable because some studies have reported several cases with SARS-CoV-2 and influenza virus co-infection. Given the importance of the mentioned co-infection and the coming influenza season, it is essential to recognize the similarities and differences between the symptoms, immunopathogenesis and treatment of SARS-CoV-2 and influenza virus. Therefore, we reviewed the virology, clinical features, and immunopathogenesis of both influenza virus and SARS-CoV-2 and evaluated outcomes in cases with SARS-CoV-2 and influenza virus co-infection.