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Sepsis-associated acute kidney injury (SA-AKI) results in significant morbidity and mortality, and ferroptosis may play a role in its pathogenesis. Our aim was to examine the effect of exogenous H2S (GYY4137) on ferroptosis and AKI in in vivo and in vitro models of sepsis and explore the possible mechanism involved. Sepsis was induced by cecal ligation and puncture (CLP) in male C57BL/6 mice, which were randomly divided into the sham, CLP, and CLP + GYY4137 group. The indicators of SA-AKI were most prominent at 24 h after CLP, and analysis of the protein expression of ferroptosis indicators showed that ferroptosis was also exacerbated at 24 h after CLP. Moreover, the level of the endogenous H2S synthase CSE (Cystathionine-γ-lyase) and endogenous H2S significantly decreased after CLP. Treatment with GYY4137 reversed or attenuated all these changes. In the in vitro experiments, LPS was used to simulate SA-AKI in mouse renal glomerular endothelial cells (MRGECs). Measurement of ferroptosis-related markers and products of mitochondrial oxidative stress showed that GYY4137 could attenuate ferroptosis and regulate mitochondrial oxidative stress. These findings imply that GYY4137 alleviates SA-AKI by inhibiting ferroptosis triggered by excessive mitochondrial oxidative stress. Thus, GYY4137 may be an effective drug for the clinical treatment of SA-AKI.

Bacterial induced wound infection is very common in real life, but the abuse of antibiotics means that is poses a potential threat to human health. The development of non-antibiotic type antibacterial materials appears to be of importance. Herein, a microenvironment-responsive and biodegradable hydrogel complex, consisting of an acid-degradable antibacterial hydrogel and a hydrogen peroxide (H

Alcohol-associated liver disease (ALD) encompasses a wide range of pathologies from simple steatosis to cirrhosis and hepatocellular carcinoma and is a global health problem. Currently, there are no effective pharmacological treatments for ALD. We have previously demonstrated that aging exacerbates the pathogenesis of ALD, but the underlying mechanisms are still poorly understood. Cellular repressor of E1A-stimulated genes 1 protein (CREG1) is a recently identified small glycoprotein that has been implicated in aging process by promoting cellular senescence and activating stress kinases. Thus, the current study aimed to explore the role of aging associated CREG1 in ALD pathogenesis and CREG1 as a potential therapeutic target. Hepatic and serum CREG1 protein levels were elevated in ALD patients. Elevation of hepatic CREG1 protein and mRNA was also observed in a mouse model of Gao-binge alcohol feeding. Genetic deletion of the

Background Natural killer (NK) cells typically function as frontline lymphocytes against cancer although little is known about their engagement in non–small cell lung cancer (NSCLC). This study compared the performance and activity of NK cells and their subsets in the peripheral blood of NSCLC sufferers and healthy participants. Methods In total, 67 healthy controls (40 men; 59.7%) and 56 patients with NSCLC (35 men; 62.5%) were included (mean age, 66.6 years). Flow cytometry identified NK cells and their subpopulations in external blood, and the total number, proportion, activity, surface activating and inhibitory receptor expression levels were determined. Results NK cell surface receptors CD107a, IFN-γ, and TNF-α activity were markedly reduced in lung cancer patients compared to healthy controls. The number and ratio of NK cells within the lymphocyte population were decreased in patients. The concentration of the inhibitory receptors TIGIT, TIM-3, CD96, PD-1, and Siglec-7 were increased in patients, whereas the expression level of the activating receptor NKP30 was decreased. Moreover, the expression levels of IFN-γ, TIGIT, CD96, PD-1, and TIM-3 were correlated with the clinical phase of NSCLC.Conclusions NSCLC patients have decreased number and function of external blood NK cells, and the proportion of most of the inhibitory receptors assessed on NK cells in this study increased as the disease progressed. These findings suggest that surface receptors from NK cells are likely to be involved in the evolution of NSCLC.

CD39-mediated inhibition of natural killer (NK) cell activity has been demonstrated, but the characteristics of CD39

Background Lung squamous cell carcinoma (LSCC) is the most common histological subtype of all lung cancer. Although the overall prognosis of lung cancer has improved, the predictable nomogram model of LSCC has not improved significantly. Our study aimed to construct and validate a nomogram model and to predict overall survival (OS) for patients with LSCC undergoing surgical treatment. Methods A total of 8,078 patients identified to have LSCC between 2010 and 2015 were selected from the Surveillance, Epidemiology and End Results (SEER) database. They were further randomly divided into training and validation cohorts. Univariable and multivariable Cox regression analyses were used to identify the risk factors affecting the prognosis for constructing the nomogram. The discrimination and calibration of the established nomogram were evaluated using receiver operating characteristic (ROC) curve, area under ROC curve (AUC), and calibration plots. In addition, decision curve analysis (DCA) was performed to evaluate the clinical utility. Finally, we plotted Kaplan-Meier survival curves and developed risk stratification systems. Results Seven variables were selected to establish the nomogram for LSCC. The AUC value in the ROC curve analysis revealed 0.658, 0.651, and 0.647 in the training cohort and 0.673, 0.667, and 0.658 in the validation cohort at 1-, 2-, and 3-year survival, respectively. The calibration curves showed satisfactory consistencies between nomogram-predicted and observed survival probability at 1-, 2-, and 3- year OS in training and validation cohorts. The DCA curve showed the established nomogram had great clinical net benefit, indicating high clinical application value. In risk stratification systems, patients were divided into three risk groups: low risk (total points༜95), middle risk (95 ≤ total points༜143), high risk (total points ≥ 143). The Kaplan-Meier survival curves indicated that significant difference in OS were observed among the three groups (P༜0.001). Conclusions A prognostic nomogram for OS of LSCC patients after surgical treatment was developed and validated, which may assist clinicians in evaluating prognosis of and facilitate doctors to provide highly individualized therapy.

Objective Natural killer (NK) cells have gained considerable attention due to their potential in treating "cold tumors," and are therefore considered as one of the new strategies for curing cancer, by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products. Methods We constructed a trispecific killer engager (TriKE) consisting of anti-CD16, IL-15, and anti-CD19. This TriKE was designed to attract CD19+ tumor cells to CD16+ NK cells, whereas IL-15 sustained the proliferation, development, and survival of NK cells. Results Treatment with 161519 TriKE in the presence of CD19+ targets upregulated expression of CD69, CD107a, TRAIL, IFN-γ, and TNF-α in NK cells, and significantly improved the proliferation and cytotoxicity of NK cells. NK cells "armed" with 161519 TriKE showed stronger cytolysis against CD19+ targets compared with that of "unarmed" NK cells. A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE, when compared with that in control mice or mice treated with 1619 BiKE. Combined use of IL-2 was a more effective treatment with 1619 BiKE, when compared with that using 161519 TriKE. Conclusions The newly generated 161519 TriKE enhanced the proliferation, activation, cytokine secretion, and cytotoxicity of NK cells in the presence of CD19+ tumor cells. The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts, and could be used to treat CD19-positive cancers.

Natural killer (NK) cells play a crucial role in the control of human viral infections but their activity is significantly impaired in patients infected with chronic hepatitis B (CHB). The mechanism that contributes to NK cell dysfunction in CHB needs further elucidation. In this study, we analyzed the expression and function of the novel inhibitory receptor immunoglobulin-like transcript-2 (ILT2) on NK cells from 131 CHB patients and 36 healthy controls. We observed that ILT2 expression on circulating CD56

Summary Major histocompatibility complex class I (MHC-I)-dependent inhibitory receptors on natural killer (NK) cells have been found to contribute to NK cell dysfunction in hepatocellular carcinoma (HCC). However, the roles of MHC-I-independent inhibitory receptors on NK cells in HCC remain poorly defined. In this study, we analyzed the expression of the MHC-I-independent inhibitory receptors sialic acid-binding immunoglobulin-like lectin (Siglec)-7 and Siglec-9 on NK cells by analyzing the peripheral blood of 35 HCC patients and 63 healthy donors. We observed that HCC patients had lower frequencies and total numbers of NK cells in the peripheral blood. Importantly, both the expression levels of Siglec-7 on NK cells and the frequencies of Siglec-7+ NK cells were significantly reduced in HCC patients, which was accompanied by a decrease in activating receptor and an increase in inhibitory receptor expression on NK cells. Moreover, Siglec-7+ NK cells expressed higher levels of activating receptors and displayed stronger effector functions, compared with Siglec-7− NK cells. Our findings demonstrate for the first time that reduced Siglec-7 expression predicts NK cell dysfunction in HCC patients, suggesting that Siglec-7 may be a potential marker of functional NK cell subset in HCC patients.

Although T cell centered immune checkpoint blockade (ICB) therapies have shown unprecedented success in various cancer types, only a minority of patients benefit from these treatments due to the lack of neoantigen burden and exhaustion of tumor-infiltrating immune stimulating cells. Inspired by the crucial role of NK cell based immunity and potential immunostimulating effect of chemotherapeutic drugs, the therapeutic efficiency on tumor inhibition through combination of doxorubicin (DOX) and blockade of TIGIT (T-cell Ig and ITIM domain), a co-inhibitory receptor expressed by both NK and T cells, in a matrix metalloproteinase 2 (MMP-2)-degradable hydrogel was thoroughly evaluated in this study. Due to the distinct release kinetics from destructed framework of hydrogels, the differentially released DOX and anti-TIGIT monoclonal antibody (aTIGIT) molecules could elicit immunogenic tumor microenvironment and reverse the exhaustion of NK and effector T cells to realize not only durable localized tumor inhibition but also systemic and long-lasting immune memory responses. Thus, our work pioneered the union of chemotherapeutic drugs and NK cell centered ICB therapies for activating cascade-like anti-tumor immune responses through eliciting immunogenic tumor microenvironment and boosting both innate and adaptive immunity. This article is protected by copyright. All rights reserved.

Increasing evidence demonstrates that IL-17A promotes tumorigenesis, metastasis, and viral infection. Natural killer (NK) cells are critical for defending against tumors and infections. However, the roles and mechanisms of IL-17A in regulating NK cell activity remain elusive. Herein, our study demonstrated that IL-17A constrained NK cell antitumor and antiviral activity by restraining NK cell maturation. It was observed that the development and metastasis of tumors were suppressed in IL-17A–deficient mice in the NK cell-dependent manner. In addition, the antiviral activity of NK cells was also improved in IL-17A–deficient mice. Mechanistically, ablation of IL-17A signaling promoted generation of terminally mature CD27(−)CD11b(+) NK cells, whereas constitutive IL-17A signaling reduced terminally mature NK cells. Parabiosis or mixed bone marrow chimeras from Il17a(−/−)and wild-type (WT) mice could inhibit excessive generation of terminally mature NK cells induced by IL-17A deficiency. Furthermore, IL-17A desensitized NK cell responses to IL-15 and suppressed IL-15–induced phosphorylation of signal transducer and activator of transcription 5 (STAT5) via up-regulation of SOCS3, leading to down-regulation of Blimp-1. Therefore, IL-17A acts as the checkpoint during NK cell terminal maturation, which highlights potential interventions to defend against tumors and viral infections.

Natural killer (NK) cells are reported to have immunological memory, with CD49a+ liver-resident NK cells shown to confer hapten-specific memory responses, but how this memory is induced or maintained is unclear. Here we show that memory type I innate lymphoid cells (ILC1s), which express IL-7Rα, are generated in the lymph nodes (LNs) and require IL-7R signaling to maintain their longevity in the liver. Hapten sensitization initiates CXCR3-dependent recruitment of IL-7Rα+ ILC1s into skin-draining LNs, where they are primed and acquire hapten-specific memory potential. Memory IL-7Rα+ ILC1s then exit draining LNs and are preferentially recruited, via CXCR6, to reside in the liver. Moreover, long-term blockade of IL-7R signaling significantly reduces ILC1-mediated memory responses. Thus, our results identify a memory IL-7Rα+ ILC1 population and reveal a LN-liver axis that is essential for ILC1 memory generation and long-term maintenance. Natural killer cells may respond better on second antigen encounters, but how this memory is induced or maintained in vivo is not clear. Here the authors show that memory NK cells expressing interleukin-7 (IL-7) receptor are induced in the lymph nodes but later recruited to liver for long term, IL-7 dependent survival and memory maintenance.

Mucosal-associated invariant T (MAIT) cells are an invariant T cell subset, which have been reported to play an antimicrobial role in infectious diseases. However, little is known about it in malignant diseases and tumors, especially in gastric cancer (GC). So in this study, we aim to examine the frequency, phenotype, partial functional capacity and clinical relevance of this cells from GC patients’ peripheral blood by flow cytometry. It was shown that the frequency of peripheral blood MAIT cells was negatively correlated with their increasing age in healthy adults. Importantly, comparing to the healthy controls (HC), the frequency and the absolute number of MAIT cells from GC patients’ peripheral blood with or without chemotherapy were both significantly lower than those. For the phenotype, the proportion of CD4−MAIT cell subset in GC patients without chemotherapy was lower than in HC, but higher than in GC patients with chemotherapy. Whereas, the proportion of CD4−CD8+MAIT cell subset in GC patients without chemotherapy was significantly lower than that in HC. Finally, the level of Granzyme-B (GrB), a molecule associated with MAIT cells was markedly lower in GC patients. But the correlation between the serum levels of GC-associated tumor antigens and the percentages of MAIT cells in GC patients was not observed. In conclusion, our study shows the decreased frequency, changed phenotypes and partial potentially impaired function of MAIT cells in GC patients, suggesting a possible MAIT cell-based immunological surveillance of GC.

CD3+CD56+ NKT-like cells play pivotal roles in the anti-tumor immune defense response. However, little is known regarding circulating NKT-like cells in patients with primary hepatocellular carcinoma (HCC). In the present study, we demonstrate that circulating NKT-like cells in HCC patients are functionally impaired and anti-PD-1 blockade improves their anti-tumor potency. Circulating NKT cells were mainly comprised of CD8+ T cells. The frequencies and absolute counts of circulating NKT-like cells were comparable between HCC patents compared to healthy donors. NKT-like cells in HCC patients were impaired in their production of TNF-α and IFN-γ as well as cytotoxicity. The level of activating receptor NKG2D was significantly decreased on NKT-like cells in HCC patients. In contrast, the expression of inhibitory receptors PD-1, Tim-3, and CTLA-4 were markedly increased on NKT-like cells in HCC patients. Meanwhile, the expression of PD-L1 was also upregulated on NKT-like cells in HCC patients. In detail, PD-1+ NKT-like cells expressed lower levels of NKG2D, higher levels of Tim-3, and CTLA-4, and less IFN-γ when compared with PD-1− NKT-like cells. Importantly, PD-1 blocked with anti-PD-1 antibody effectively improved the effector function of NKT-like cells from HCC patients or healthy donors. Our findings unveil the functional characterization of NKT-like cells in HCC patients and provide the potential targets to improve their function, which might benefit the optimization of HCC immunotherapy.

Tourism activities have brought overexploitation of natural ecotourism resources and ecological pressure challenge though it exactly contributes to the economic prosperity of a region. Research on tourism ecological safety is of great importance for tourist destinations to balance the relationship between environmental protection and tourism development. Qilian Mountains National Park (QMNP) has a prominent ecological status and is a vital ecological barrier in the northwest of China, which attracts large numbers of tourists every year for its rich tourism resources in the Zhangye (ZY) region. However, there is still a lack of systematic research on the environmental impact of tourism activities and on achieving sustainable development of ecotourism in national parks. We took QMNP-ZY as the study object, establishing the system of indicators based on the PSR model for the comprehensive evaluation of tourism ecological safety and the diagnosis of the main obstacles. Moreover, the autoregressive integrated moving average (ARIMA) model was introduced to forecast the evolutionary trends of tourism ecological security in QMNP-ZY. The results showed that (1) The tourism ecological security composite values of the QMNP-ZY exhibited a “U”-type evolution of “first fall-then rise” feature, and the pressure layer gradually became the dominant factor. (2) For the main barrier factors, there had been a shift from response factors. (3)The output of the ARIMA model demonstrated that the level of tourism ecological security would rise in a short period and then decline a few years later. Especially, the contribution degree of economic to the tourism eco-security development will weaken with the region’s economy growing.

γδ T cells display unique developmental, distributional, and functional patterns and can rapidly respond to various insults and contribute to diverse diseases. Different subtypes of γδ T cells are produced in the thymus prior to their migration to peripheral tissues. γδ T cells are enriched in the liver and exhibit liver-specific features. Accumulating evidence reveals that γδ T cells play important roles in liver infection, non-alcoholic fatty liver disease, autoimmune hepatitis, liver fibrosis and cirrhosis, and liver cancer and regeneration. In this study, we review the properties of hepatic γδ T cells and summarize the roles of γδ T cells in liver diseases. We believe that determining the properties and functions of γδ T cells in liver diseases enhances our understanding of the pathogenesis of liver diseases and is useful for the design of novel γδ T cell-based therapeutic regimens for liver diseases.

Immune dysfunction is an established risk factor in acute myeloid leukemia (AML). The cytotoxicity of natural killer (NK) cells is greatly impaired in AML, and the profile of NK cell receptors is markedly altered in AML; however, this is not yet well characterized. In this study, we found the downregulation of Siglec-7 could be utilized as a potential marker of NK cell dysfunction in AML. The absolute numbers and percentages of NK cells were declined in the peripheral blood of patients with AML, and the levels of activating receptors NKG2D, NKp46, and NKp30 were reduced in NK cells from patients with AML compared with healthy controls. In contrast, the levels of inhibitory receptors TIM-3, ILT-4, ILT-5, and PD-1 were increased in NK cells from patients with AML. Of note, the level of Siglec-7 in NK cells from patients with AML was significantly lower than that in NK cells from healthy controls, and Siglec-7+ NK cells displayed higher levels of activating receptors and stronger cytotoxicity when compared with Siglec-7- NK cells. Our data indicate that decreased Siglec-7 level may predict NK cell dysfunction in AML, and NK cells may be promising targets of immunotherapy for AML.

Paraquat is a poisoning herbicide that primarily targets lung, leading to severe acute lung injury characterized by extensive neutrophil infiltration. However, the mechanisms underlying the neutrophil infiltration is not clear. In this study, we demonstrated the significance of the signaling cascade from high-mobility group box 1 (HMGB1), to Toll-like receptor 4 (TLR4), interleukin-23 (IL-23), and lastly to IL-17A during the paraquat-induced neutrophil infiltration and the subsequent lung injury in mice. Paraquat challenge significantly elevated serum levels of IL-17A and IL-23, the percentage of IL-17A-producing γδT cells in the lung, and the level of HMGB1 in bronchoalveolar lavage fluid. Reducing IL-17A production using an anti-γδT antibody, targeting IL-23 with the neutralizing antibody against IL-23p19, and blocking HMGB1 signaling by using glycyrrhizin or TLR4−/− mice all dramatically inhibited the infiltration of neutrophils and attenuated lung injury. These novel findings not only reveal the critical role of HMGB1-TLR4-IL-23-IL-17A axis in the pathogenesis of paraquat-induced acute lung injury, but also provide promising therapeutic targets for treating paraquat poisoning.

Natural killer (NK) cells are reported to have immunological memory, with CD49a+ liver-resident NK cells shown to confer hapten-specific memory responses, but how this memory is induced or maintained is unclear. Here we show that memory type I innate lymphoid cells (ILC1s), which express IL-7Rα, are generated in the lymph nodes (LNs) and require IL-7R signaling to maintain their longevity in the liver. Hapten sensitization initiates CXCR3-dependent recruitment of IL-7Rα+ ILC1s into skin-draining LNs, where they are primed and acquire hapten-specific memory potential. Memory IL-7Rα+ ILC1s then exit draining LNs and are preferentially recruited, via CXCR6, to reside in the liver. Moreover, long-term blockade of IL-7R signaling significantly reduces ILC1-mediated memory responses. Thus, our results identify a memory IL-7Rα+ ILC1 population and reveal a LN-liver axis that is essential for ILC1 memory generation and long-term maintenance., Natural killer cells may respond better on second antigen encounters, but how this memory is induced or maintained in vivo is not clear. Here the authors show that memory NK cells expressing interleukin-7 (IL-7) receptor are induced in the lymph nodes but later recruited to liver for long term, IL-7 dependent survival and memory maintenance.