Immune evasion and therapeutic opportunities based on natural killer cells

Natural killer(NK)cells can elicit an immune response against malignantly transformed cells without recognizing antigens,and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy.Although several studies have shown the promising antitumor effects of NK cells in immunotherapy,their function is often limited in the tumor microenvironment because tumor cells can easily escape NK cell-induced death.Thus,for efficient tumor immunotherapy,the mechanism by which tumor cells escape NK cell-induced cytotoxicity must be fully understood.Various novel molecules and checkpoint receptors that mediate the disruption of NK cells in the tumor microenvironment have been discovered.In this review,we analyze and detail the major activating and inhibitory receptors on the surface of NK cells to delineate the mechanism by which tumor cells suppress NKG2D ligand expression and increase tumor receptor and inhibitory receptor expression[NKG2A,programmed cell death1(PD-1),and T-cell immunoglobulin and immunoreceptor tyrosine inhibitory motif(TIGIT)]on the NK cell surface,and thus inhibit NK cell activity.We also reviewed the current status of treatments based on these surface molecules.By comparing the therapeutic effects related to the treatment status and bypass mechanisms,we attempt to identify optimal single or combined treatments to suggest new treatment strategies for tumor immunotherapy.

Mushroomβ-glucan and polyphenol formulations as natural immunity boosters and balancers:nature of the application

Mushrooms are experiencing a kind of renaissance as a part of the contemporary human diet.These valuable organisms are more than food,they fit in perfectly as a novel market group known as nutra-mycoceuticals.Immune-balancing mushroom dietary fibers and secondary metabolites such as polyphenols are the main focus of the healthcare industry.Wellness and cosmetic companies are increasingly using mushroom extracts rich in these ingredients.This review considers the basic molecular immunomodulatory mechanisms of action of the most commonly used mushroom dietary fibers,β-glucans.The literature data on their bioavailability,metabolic transformations,preclinical and human clinical research,and safety are discussed.Immunomodulatory mechanisms of polyphenol ingredients are also considered.These molecules present great potential in the design of the new immunity balancer formulations according to their widespread structural diversity.Finally,we draw attention to the perspectives of modern trends in mushroom nutraceutical and cosmeceutical formulations to strengthen and balance immunity.

Revolutionizing gastric cancer treatment:The potential of immunotherapy

Gastric cancer,a prevalent malignancy worldwide,ranks sixth in terms of frequency and third in fatality,causing over a million new cases and 769000 annual deaths.Predominant in Eastern Europe and Eastern Asia,risk factors include family medical history,dietary habits,tobacco use,Helicobacter pylori,and Epstein-Barr virus infections.Unfortunately,gastric cancer is often diagnosed at an advanced stage,leading to a grim prognosis,with a 5-year overall survival rate below 5%.Surgical intervention,particularly with D2 Lymphadenectomy,is the mainstay for early-stage cases but offers limited success.For advanced cases,the National Comprehensive Cancer Network recommends chemotherapy,radiation,and targeted therapy.Emerging immunotherapy presents promise,especially for unresectable or metastatic cases,with strategies like immune checkpoint inhibitors,tumor vaccines,adoptive immunotherapy,and nonspecific immunomodulators.In this Editorial,with regards to the article“Advances and key focus areas in gastric cancer immunotherapy:A comprehensive scientometric and clinical trial review”,we address the advances in the field of immunotherapy in gastric cancer and its future prospects.

Pharmacological Investigation on the Qi-Invigorating Action of Schisandrin B: Effects on Mitochondrial ATP Generation in Multiple Tissues and Innate/Adaptive Immunity in Mice

Schisandrae Fructus, containing schisandrin B (Sch B) as its main active component, is recognized in traditional Chinese medicine (TCM) for its Qi-invigorating properties in the five visceral organs. Our laboratory has shown that the Qi-invigorating action of Chinese tonifying herbs is linked to increased mitochondrial ATP generation and an enhancement in mitochondrial glutathione redox status. To explore whether Sch B can exert Qi-invigorating actions across various tissues, we investigated the effects of Sch B treatment on mitochondrial ATP generation and glutathione redox status in multiple mouse tissues ex vivo. In line with TCM theory, which posits that Zheng Qi generation relies on the Qi function of the visceral organs, we also examined Sch B’s impact on natural killer cell activity and antigen-induced splenocyte proliferation, both serving as indirect measures of Zheng Qi. Our findings revealed that Sch B treatment consistently enhanced mitochondrial ATP generation and improved mitochondrial glutathione redox status in mouse tissues. This boost in mitochondrial function was associated with stimulated innate and adaptive immune responses, marked by increased natural killer cell activity and antigen-induced T/B cell proliferation, potentially through the increased generation of Zheng Qi.

Are Ni/and Ni5Fe1/biochar catalysts suitable for synthetic natural gas production?A comparison with g-Al2O3 supported catalysts

Among challenges implicit in the transition to the post-fossil fuel energetic model,the finite amount of resources available for the technological implementation of CO_(2) revalorizing processes arises as a central issue.The development of fully renewable catalytic systems with easier metal recovery strategies would promote the viability and sustainability of synthetic natural gas production circular routes.Taking Ni and NiFe catalysts supported over g-Al_(2)O_(3) oxide as reference materials,this work evaluates the potentiality of Ni and NiFe supported biochar catalysts for CO_(2) methanation.The development of competitive biochar catalysts was found dependent on the creation of basic sites on the catalyst surface.Displaying lower Turn Over Frequencies than Ni/Al catalyst,the absence of basic sites achieved over Ni/C catalyst was related to the depleted catalyst performances.For NiFe catalysts,analogous Ni_(5)Fe_(1) alloys were constituted over both alumina and biochar supports.The highest specific activity of the catalyst series,exhibited by the NiFe/C catalyst,was related to the development of surface basic sites along with weaker NiFe-C interactions,which resulted in increased Ni0:NiO surface populations under reaction conditions.In summary,the present work establishes biochar supports as a competitive material to consider within the future low-carbon energetic panorama.

EZH2 identifies the precursors of human natural killer cells with trained immunity

Objective:Trained immunity of natural killer(NK)cells has shown great potential in the treatment of cancers by eliciting enhanced effector responses to restimulation by cytokines or cancer cells for long time periods after preactivation.However,the human NK cells responsible for the generation and maintenance of trained immunity are largely unknown.We hypothesized that heterogeneous human NK cells would respond differentially to stimulation with a combination of IL-12,IL-15,and IL-18,and that an NK cell subset might exist that is mainly responsible for the induction of trained immunity.On the basis of our hypothesis,we aimed to identify the subset from which cytokine-trained human NK cells originate and to explore possible regulatory targets for drug intervention.Methods:Flow cytometry assays were performed to analyze the functions of cytokine-trained NK cells and examine cell division and protein expression in NK cell subsets.Single-cell RNA sequencing(scRNA-seq)plus TotalSeq™technology was used to track the heterogeneity of NK cells during the induction of trained immunity.Results:Traditional developmental markers for peripheral NK cells were unable to identify the precursors of human NK cells with trained immunity.Therefore,we used scRNA-seq plus TotalSeq™technology to track the heterogeneity of NK cells during the induction of trained immunity and identified a unique cluster of CD57−NKG2A+EZH2+IFNG+MKI67+IL12R+IL15R+IL18R+NK cells.Enrichment and pseudotime trajectory analyses suggested that this cluster of NK cells contained the precursor of trained NK cells.We then used flow cytometry to further investigate the role of EZH2 in trained NK precursors and found that CD57−NKG2A+EZH2+NK cells had faster cell cycles and an enhanced trained phenotype,and EZH2 inhibition significantly impaired the induction of trained immunity in NK cells.These results suggested that EZH2 is a unique epigenetic marker of precursors of human NK cells with trained immunity.Conclusions:Our work revealed human NK heterogeneity in the induction of trained immunity,identified the precursor subset for trained NK cells,and demonstrated the critical role of EZH2 in the induction of trained immunity in human NK cells.

To resolve recent natural immune defense effects of antimicrobial peptides in the gastrointestinal tract

The human gut is the normal habitat of a lot of microorganisms; in the long process of evolution they have developed a symbiotic relationship with the host. Under normal circumstances they do not damage the health, which totally owes to the barrier functions of the integral intestinal mucosa. Intestinal lnucosal barriers are mainly composed of four parts： mechanical barrier, immune barrier, chemical and biological barrier. Each of these functions has corresponding structural basis, an important barrier to prevent harmful substances and pathogens in the gut into the inner environment of the body, and to maintain a stable internal environment.

Differential Effects of Yin- and Yang-Chinese Tonifying Herbs on Innate and Adaptive Immunity

The present study investigated the effect of treatment with methanolic extracts of Yin- and Yang-Chinese tonifying herbs on concanavalin A (Con A)/lipopolysaccharide (LPS)-stimulated splenocyte proliferation (adaptive immunity) and natural killer (NK) cell activity (innate immunity) in an ex vivo mouse model. The results indicated that while treatment with most Yin herbal extracts potentiated the Con A/LPS-stimulated splenocyte proliferation, only Yang (but not Yin) herbal extracts stimulated NK cell activity. The differential effects of Yin- and Yang-Chinese tonifying herbs on innate and adaptive immunity are consistent with the Chinese medicine theory which depicts the Yin and Yang functional components of Zheng Qi (vital energy), with the Yang component being responsible for the first line of defense against invading microorganisms (i.e., innate immunity) and the Yin oner serving as a follow-up defensive response (adaptive immunity).

Natural Passivity of Amorphous Fe_(40)Ni_(40)P_(14)B_6 and Fe_(54.6)Ni_(38)Si_(4.1)B_(2.3)V_1 Alloys

The natural passive films forrned on Fe_(40)Ni_(40)P_(14)B_6 and Fe_(54.6)Ni_(38)Si_(4.1)B_(2.3)V_1 amorphous alloys long-term exposed in air have been studied by X-ray photoelectron spectroscopy (XPS) and Auger electron (including Ar+ ion depth profiling) spectroscopy (AES). The following aspects have been investigated: (1) chemical states of the elements in the films. binding energies and the chemical shifts measured by XPSf (2) structure and composition of the films fand (3) thickness of the passive films determined by AES depth profiling and XPS analysis.

Adsorption of Nickel in Aqueous Solution onto Natural Maghnite

Maghnite clay obtained from Tlemcen, Algeria was investigated to remove heavy metal ion from wastewater. Thus, the present study includes the adsorption of Ni(II) in aqueous solution on maghnite clay through the process of adsorption under various conditions (with variable concentration of metal ion, temperature, pH and mixing time). Increasing pH favours the removal of metal ions till they are precipitated as the insoluble hydroxides. The uptake is rapid with maximum adsorption being observed within 10 min for Ni(II). In addition, the results obtained from adsorption isotherm indicated that these data can be better fitted with the Langmuir and Freundlich equations than the Dubinin-Radushke- vich (D-R) equation.

The Skin Whitening Effect of Co-Cultured Conditioned Medium: Involvement of Synergy between Stem Cells and Immune Cells

Many researchers have described that mesenchymal stem cells conditioned medium and immune cells conditioned medium have a clear whitening effect when they are used as cosmetic ingredients. In this study, we confirmed the whitening efficacy of various concentrations of immune cells and stem cell conditioned media. The author tried to study a conditioned medium that has a strong whitening effect even with a composition of less than 20% (the most used concentration in cosmetics). Because of the fact that the conditioned medium contains various cytokines and growth factors secreted by stem cells or immune cells, it is known to have effects such as wound healing, antioxidant, and whitening effect. Recently, stem cells have been used not only in the development of cosmetic raw materials but also in skincare procedures, and there are reports being released of cosmetics using immune cells conditioned medium. The concentration-dependent whitening effect equivalently increased as the concentration of the mono-cultured conditioned medium was obtained through the stem cells or immune cells culture. In the case of co-culture, whitening results are like the effect of positive control such as arbutin in the medium carrying only 10% of the co-cultured conditioned medium. It is possible that enhanced whitening efficiency in co-cultured conditioned medium leads to a major innovation in the global cosmetic market.

Modulation of Lianbizi Injection (Andrographolide ) on Some Immune Functions

Objective: To study the effects of andrographolide on immune functions and the immune mechanism in clinical therapy.Methods: The amounts of IFN-α,IFN-γ, TNF-α, IL-8 in the peripheral blood mononuclear cells (PBMC) culture supernatants dealt with by different concentrations of LianBiZhi (LBZ) injection, the effective component of which is andrographolide, were detected by biological activity test or ELISA in vitro. The effects of LBZ injection on macrophage phagocytotic function and natural killer cells cytotoxicity were examined by means of macrophage to phagocytize cock erythrocyte and measurement of lactate dehydrogenase (LDH) activity released from the damaged cells, respectively.Results: The LBZ injection could not only enhance the phagocytosis activity of peritoneal macrophage from guinea pig to phagocytosis cock erythrocytes, but also augment the cytotoxicity mediated by natural killer cells from PBMCs.Conclusion: Andrographolide is an immunostimulant agent which can modulate both antigen specific and nonspecific immune function by means of its natural killer cells, macrophage and cytokines.

基于NIS的异常检测算法

该文根据生物免疫系统的免疫识别机理提出了一种基于NIS的异常检测算法来识别计算机系统运行的性能异常,将健康的系统状态作为“自我”,不健康的系统状态作为“非我”,多次应用阴性选择充当过滤器,并以遗传算法进化检测子,最后仿真实验验证了算法具备较好的检测性能。

Cellular immune function and liver damage in post hepatitic cirrhosis

AIM To study the cellular immune function in patients with post hepatitic cirrhosis (PHC) and its relation with different liver damages.

Roles of liver innate immune cells in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease in the United States and other developed countries and is expected to increase in the next few years. Emerging data suggest that some patients with NAFLD may progress to nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma. NAFLD can also promote the development and progression of disease in other organ systems, such as the cardiovascular and endocrine (i.e. diabetes) systems. Thus, understanding the pathogenesis of NAFLD is of great clinical importance and is critical for the prevention and treatment of the disease. Although the "two-hit hypothesis" is generally accepted, the exact pathogenesis of NAFLD has not been clearly established. The liver is an important innate immune organ with large numbers of innate immune cells, including Kupffer cells (KCs), natural killer T (NKT) cells and natural killer (NK) cells. Recent data show that an imbalance in liver cytokines may be implicated in the development of fatty liver disease. For example, Th1 cytokine excess may be a common pathogenic mechanism for hepatic insulin resistance and NASH. Innate immune cells in the liver play important roles in the excessive production of hepatic Th1 cytokines in NAFLD. In addition, liver innate immune cells participate in the pathogenesis of NAFLD in other ways. For example, activated KCs can generate reactive oxygen species, which induce liver injury. This review will focus primarily on the possible effect and mechanism of KCs, NKT cells and NK cells in the development of NAFLD.

Fat:A matter of disturbance for the immune system

Obesity is increasingly being recognized as a risk factor for a number of benign and malignant gastrointestinal conditions. However, literature on the underlying pathophysiological mechanisms is sparse and ambiguous. There is compelling evidence that both overnutrition and undernutrition negatively interfere with the immune system. Overnutrition has been found to increase susceptibility to the development of inflammatory diseases, autoimmune diseases and cancer. In the regulation of immune and in? ammatory processes, white adipose tissue plays a critical role, not only as an energy store but also as an important endocrine organ. The obese state is characterised by a low-grade systemic in? ammation, mainly as a result of increased adipocytes as well as fat resident-and recruited-macrophage activity. In the past few years, various products of adipose tissue including adipokines and cytokines have been characterised and a number of pathways linking adipose tissue metabolism with the immune system have been identified. Activation of the innate immune system plays a major role in hepatic steatosis. Non-alcoholic fatty liver disease includes a wide spectrum of diseases, from pure steatosis to non-alcoholic steato-hepatitis in the absence of signif icant alcohol consumption. Although steatosis is considered a non-progressive disease, non-alcoholic steatohepatitis may deteriorate in advanced chronic liver diseases, cirrhosis, and hepatocellular carcinoma. An important parallel between obesityrelated pathology of adipose tissue and liver pertains to the emerging role of macrophages, and growing evidence suggests that Kupffer cells critically contribute to progression of non-alcoholic fatty liver disease. Moreover, a close link between specif ic immune activation and atherosclerosis has been well established, suggesting that fat can directly trigger immune responses. This review discusses the role of fat as "a matter of disturbance for the immune system" with a focus on hepatic steatosis.

Hepatitis B virus-persistent infection and innate immunity defect: Cell-related or virus-related?

The outcomes of hepatitis B virus(HBV) infection are closely related to the age at which infection was acquired. Infection acquired in adult life tends to be selflimited, in contrast to perinatal acquirement, for which chronic persistence of the HBV is a general outcome. Innate immunity plays an indispensable role in early virus infection, facilitating virus clearance. However, it has been reported that HBV is under-recognized and poorly eliminated by the innate immune system in the early stages of infection, possibly explaining the long-lasting persistence of viremia afterwards. Furthermore, due to the existence of covalently closed circular DNA, chronic HBV clearance is very difficult, even when patients are given interferon-α and nucleotide/nucleoside analogs for antiviral therapy. The mechanism by which HBV evades innate immune recognition and establishes persistent infection remains a subject of debate. Besides, some researchers are becoming more interested in how to eradicate chronic HBV infection by restoring or boosting innate immunity. This review aimed to summarize the current knowledge on how intrahepatocyte signaling pathways and innate immune cells act after the onset of HBV infection and how these actions are related to the persistence of HBV. We anticipate the insights presented herein to be helpful for future development of novel immune therapeutic strategies to fight HBV infection.

Innate and adaptive immune responses that control lymph-borne viruses in the draining lymph node

The interstitial fluids in tissues are constantly drained into the lymph nodes(LNs)as lymph through afferent lymphatic vessels and from LNs into the blood through efferent lymphatics.LNs are strategically positioned and have the appropriate cellular composition to serve as sites of adaptive immune initiation against invading pathogens.However,for lymph-borne viruses,which disseminate from the entry site to other tissues through the lymphatic system,immune cells in the draining LN(dLN)also play critical roles in curbing systemic viral dissemination during primary and secondary infections.Lymph-borne viruses in tissues can be transported to dLNs as free virions in the lymph or within infected cells.Regardless of the entry mechanism,infected myeloid antigen-presenting cells,including various subtypes of dendritic cells,inflammatory monocytes,and macrophages,play a critical role in initiating the innate immune response within the dLN.This innate immune response involves cellular crosstalk between infected and bystander innate immune cells that ultimately produce type I interferons(IFN-Is)and other cytokines and recruit inflammatory monocytes and natural killer(NK)cells.IFN-I and NK cell cytotoxicity can restrict systemic viral spread during primary infections and prevent serious disease.Additionally,the memory CD8+T-cells that reside or rapidly migrate to the dLN can contribute to disease prevention during secondary viral infections.This review explores the intricate innate immune responses orchestrated within dLNs that contain primary viral infections and the role of memory CD8+T-cells following secondary infection or CD8+T-cell vaccination.

Natural killer cells in hepatitis C:Current progress

Patients infected with the hepatitis C virus(HCV) are characterized by a high incidence of chronic infection, which results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The functional impairment of HCV-specific T cells is associated with the evolution of an acute infection to chronic hepatitis. While T cells are the important effector cells in adaptive immunity, natural killer(NK) cells are the critical effector cells in innate immunity to virus infections. The findings of recent studies on NK cells in hepatitis C suggest that NK cell responses are indeed important in each phase of HCV infection. In the early phase, NK cells are involved in protective immunity to HCV. The immune evasion strategies used by HCV may target NK cells and might contribute to the progression to chronic hepatitis C. NK cells may control HCV replication and modulate hepatic fibrosis in the chronic phase. Further investigations are, however, needed, because a considerable number of studies observed functional impairment of NK cells in chronic HCV infection. Interestingly, the enhanced NK cell responses during interferon-α-based therapy of chronic hepatitis C indicate successful treatment. In spite of the advances in research on NK cells in hepatitis C, establishment of more physiological HCV infection model systems is needed to settle unsolved controversies over the role and functional status of NK cells in HCV infection.

Impairment of innate immune responses in cirrhotic patients and treatment by branched-chain amino acids

It has been reported that host defense responses, such as phagocytic function of neutrophils and natural killer (NK) cell activity of lymphocytes, are impaired in cirrhotic patients. This review will concentrate on the impairment of innate immune responses in decompensated cirrhotic patients and the effect of the treatment by branched-chain amino acids (BCAA) on innate immune responses. We already reported that phagocytic function of neutrophils was significantly improved by 3-mo BCAA supplementation. In addition, the changes of NK activity were also significant at 3 mo of supplementation compared with before supplementation. Also, Fisher’s ratios were reported to be significantly increased at 3 mo of BCAA supplementation compared with those before oral supplementation. Therefore, administration of BCAA could reduce the risk of bacterial and viral infection in patients with decompensated cirrhosis by restoring impaired innate immune responses of the host. In addition, it was also revealed that BCAA oral supplementation could reduce the risk of development of hepatocellular carcinoma in cirrhotic patients. The mechanisms of the effects will also be discussed in this review article.