We pay particular attention to the delivery of therapeutic transgenes, such as CARs, to endogenous loci which prevents collateral damage and increases therapeutic effectiveness. Finally, we review creative innovations, including immune system repurposing, that facilitate safe and efficient genome surgery within the framework of clinical cancer immunotherapies.Liver fibrosis can result from various causes and could progress to cirrhosis and cancer; however, there are no effective treatments due to that its molecular mechanism is unclear. liver fibrosis model made by Schistosoma japonicum (S. japonicum) infection or Carbon tetrachloride (CCl4) intraperitoneal injection is a conventional model used in liver fibrosis-related studies for mechanism or pharmaceutical research purposes. But the differences in the pathological progression, immune responses and the underlying mechanism between the two liver fibrosis model have not been carefully compared and characterized, which hinders us from correctly understanding and making better use of the two models. In the present study, the pathological changes to the liver, and the cytokines, inflammatory factors, macrophages, and lymphocytes subsets involved were analyzed in the liver fibrosis model of S. japonicum infection or CCl4 intraperitoneal injection. Additionally, the pathological progression, immune responses and the uytokines and immune cells. The pathological progressions and immune responses to S. japonicum or CCl4 induced liver fibrosis were different, possibly because of their different injury mechanisms. The appropriate animal model should be selected according to the needs of different experiments and the pathogenic factors of liver fibrosis in the study.The COVID-19 is an acute and contagious disease characterized by pneumonia and ARDS. The disease is caused by SARS-CoV-2, which belongs to the family of Coronaviridae along with MERS-CoV and SARS-CoV-1. The virus has the positive-sense RNA as its genome encoding for ~26 proteins that work together for the virus survival, replication, and spread in the host. The virus gets transmitted through the contact of aerosol droplets from infected persons. The pathogenesis of COVID-19 is highly complex and involves suppression of host antiviral and innate immune response, induction of oxidative stress followed by hyper inflammation described as the "cytokine storm," causing the acute lung injury, tissue fibrosis, and pneumonia. Currently, several vaccines and drugs are being evaluated for their efficacy, safety, and for determination of doses for COVID-19 and this requires considerable time for their validation. Therefore, exploring the repurposing of natural compounds may provide alternatives against COVID-19. Several nutraceuticals have a proven ability of immune-boosting, antiviral, antioxidant, anti-inflammatory effects. #link# These include Zn, vitamin D, vitamin C, curcumin, cinnamaldehyde, probiotics, selenium, lactoferrin, quercetin, etc. Grouping some of these phytonutrients in the right combination in the form of a food supplement may help to boost the immune system, prevent virus spread, preclude the disease progression to severe stage, and further suppress the hyper inflammation providing both prophylactic and therapeutic support against COVID-19.The blockade of immunological negative regulators offered a novel therapeutic approach that revolutionized the immunotherapy of cancer. Still, a significant portion of patients fail to respond to anti-PD-1/PD-L1 and/or anti-CTLA-4 therapy or experience significant adverse effects. We propose that one of the major reasons that many patients do not respond to this form of therapy is due to the powerful physiological suppression mediated by hypoxia-adenosinergic signaling. Indeed, both inflamed and cancerous tissues are hypoxic and rich in extracellular adenosine, in part due to stabilization of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1α). Adenosine signals through adenosine A2A receptors (A2AR) to suppress anti-tumor and anti-pathogen immune responses. Several classes of anti-hypoxia-A2AR therapeutics have been offered to refractory cancer patients, with A2AR blockers, inhibitors of adenosine-generating enzymes such as CD39 and CD73, and hypoxia-targeting drugs now reaching the clinical stage. Clinical results have confirmed preclinical observations that blockade of the hypoxia-adenosine-A2AR axis synergizes with inhibitors of immune checkpoints to induce tumor rejection. Thus, https://www.selleckchem.com/products/arv-771.html provide a new hope for the majority of patients who are nonresponsive to current immunotherapeutic approaches including checkpoint blockade. Here, we discuss the discoveries that firmly implicate the A2AR as a critical and non-redundant biochemical negative regulator of the immune response and highlight the importance of targeting the hypoxia-adenosine-A2AR axis to manipulate anti-pathogen and anti-tumor immune responses.Atherosclerotic cardiovascular disease is part of chronic immunometabolic disorders such as type 2 diabetes and nonalcoholic fatty liver disease. Their common risk factors comprise hypertension, insulin resistance, visceral obesity, and dyslipidemias, such as hypercholesterolemia and hypertriglyceridemia, which are part of the metabolic syndrome. Immunometabolic diseases include chronic pathologies that are affected by both metabolic and inflammatory triggers and mediators. Important and challenging questions in this context are to reveal how metabolic triggers and their downstream signaling affect inflammatory processes and vice-versa. Along these lines, specific nuclear receptors sense changes in lipid metabolism and in turn induce downstream inflammatory and metabolic processes. link2 The transcriptional activity of these nuclear receptors is regulated by the nuclear receptor corepressors (NCORs), including NCOR1. In this review we describe the function of NCOR1 as a central immunometabolic regulator and focus on its role in atherosclerosis and associated immunometabolic diseases.Mitophagy has recently been implicated in bacterial infection but the underlying mechanism remains largely unknown. Here, we uncover a role of microRNA-302/367 cluster in regulating mitophagy and its associated host response against bacterial infection. We demonstrate that miR-302/367 cluster expression was significantly increased after Pseudomonas aeruginosa infection. Enhanced expression of miR-302/367 cluster accelerated the mitophagic response in macrophages, thus increasing clearance of invading P. aeruginosa by regulating production of reactive oxygen species (ROS), while application of miR-302/367 cluster inhibitors decreased bacterial clearance. Blocking mitophagy with siRNA against mitophagy receptor prohibitin 2 (PHB2) reduced the effect of miR-302/367 cluster on induction of mitophagy and its-associated P. aeruginosa elimination. In addition, we found that miR-302/367 cluster also increased bacterial clearance in mouse model. Mechanistically, we illustrate that miR-302/367 cluster binds to the 3'-untranslated region of nuclear factor kappa B (NF-κB), a negative regulator of mitophagy, accelerated the process of mitophagy by inhibiting NF-κB. Furthermore, inhibition of NF-κB in macrophages attenuated the ROS or cytokines production and may reduce cell injury by P. aeruginosa infection to maintain cellular homeostasis. Collectively, our findings elucidate that miR-302/367 cluster functions as potent regulators in mitophagy-mediated P. aeruginosa elimination and pinpoint an unexpected functional link between miRNAs and mitophagy.Macrophage-stimulating protein (MSP), a soluble protein mainly synthesized by the liver, is the only known ligand for recepteur d'origine nantais (RON), which is a member of the MET proto-oncogene family. Recent studies show that the MSP-RON signaling pathway not only was important in tumor behavior but also participates in the occurrence or development of many immune system diseases. Activation of RON in macrophages results in the inhibition of nitric oxide synthesis as well as lipopolysaccharide (LPS)-induced inflammatory response. MSP-RON is also associated with chronic inflammatory responses, especially chronic liver inflammation, and might serve as a novel regulator of inflammation, which may affect the metabolism in the body. Another study provided evidence of the relationship between MSP-RON and autoimmune diseases, suggesting a potential role for MSP-RON in the development of drugs for autoimmune diseases. Moreover, MSP-RON plays an important role in maintaining the stability of the tissue microenvironment and contributes to immune escape in the tumor immune microenvironment. Here, we summarize the role of MSP-RON in immunity, based on recent findings, and lay the foundation for further research.The systemic treatment landscape for advanced hepatocellular carcinoma (HCC) has experienced tremendous paradigm shift towards targeting tumor microenvironment (TME) following recent trials utilizing immune checkpoint blockade (ICB). However, limited success of ICB as monotherapy mandates the evaluation of combination strategies incorporating immunotherapy for improved clinical efficacy. Radiotherapy (RT) is an integral component in treatment of solid cancers, including HCC. link3 Radiation mediates localized tumor killing and TME modification, thereby potentiating the action of ICB. Several preclinical and clinical studies have explored the efficacy of combining RT and ICB in HCC with promising outcomes. Greater efforts are required in discovery and understanding of novel combination strategies to maximize clinical benefit with tolerable adverse effects. This current review provides a comprehensive assessment of RT and ICB in HCC, their respective impact on TME, the rationale for their synergistic combination, as well as the current potential biomarkers available to predict clinical response. We also speculate on novel future strategies to further enhance the efficacy of this combination.Clotting and inflammation are effective danger response patterns positively selected by evolution to limit fatal bleeding and pathogen invasion upon traumatic injuries. As a trade-off, thrombotic, and thromboembolic events complicate severe forms of infectious and non-infectious states of acute and chronic inflammation, i.e., immunothrombosis. Factors linked to thrombosis and inflammation include mediators released by platelet granules, complement, and lipid mediators and certain integrins. Extracellular deoxyribonucleic acid (DNA) was a previously unrecognized cellular component in the blood, which elicits profound proinflammatory and prothrombotic effects. Pathogens trigger the release of extracellular DNA together with other pathogen-associated molecular patterns. Dying cells in the inflamed or infected tissue release extracellular DNA together with other danger associated molecular pattern (DAMPs). Neutrophils release DNA by forming neutrophil extracellular traps (NETs) during infection, trauma or other forms of vascular injury. Fluorescence tissue imaging localized extracellular DNA to sites of injury and to intravascular thrombi. Functional studies using deoxyribonuclease (DNase)-deficient mouse strains or recombinant DNase show that extracellular DNA contributes to the process of immunothrombosis. Here, we review rodent models of immunothrombosis and the evolving evidence for extracellular DNA as a driver of immunothrombosis and discuss challenges and prospects for extracellular DNA as a potential therapeutic target.