Search

Background:: Melanoma, a highly malignant skin cancer, is a hot topic in oncology treatment research. Nowadays, tumor immunotherapy, especially immunotherapy combined with other therapies, has attracted more and more attention. Indoleamine 2,3-dioxygenase 2 (IDO2), a ratelimiting enzyme of the tryptophan metabolism pathway in the urine of dogs with immunosuppression, is highly expressed in melanoma tissue. Additionally, IDO2 significantly inhibits the anti-tumor immunity of the body and has become a novel target of melanoma treatment. Nifuroxazide, as an intestinal antibacterial agent, was found to be able to inhibit Stat3 expression and exert an anti-tumor effect. Therefore, the present study aimed to examine the therapeutic effect of a self-designed IDO2-small interfering RNA (siRNA) delivered by attenuated Salmonella combined with nifuroxazide on melanoma- bearing mice, as well as determine its underlying mechanism. Methods:: The effect of nifuroxazide on melanoma was detected by flow cytometry, CCK-8 and colony- forming ability assays, respectively, in vitro. The plasmid of siRNA-IDO2 was constructed, and the mice-bearing melanoma model was established. After the treatment, the tumor growth and survival rate were monitored, and the morphological changes of tumor tissue were detected by HE staining. The expression of related proteins was detected by Western blotting, and the expression of CD4 and CD8 positive T cells in tumor tissue was detected by IHC and IF, and the proportion of CD4 and CD8 positive T cells in spleen was detected by flow cytometry. Results:: The results demonstrated that the combination therapy effectively inhibited the phosphorylation of Stat3 and the expression level of IDO2 in melanoma cells, which effectively inhibited tumor growth and prolonged the survival time of tumor-bearing mice. The mechanistic study revealed that, compared with control groups and monotherapy groups, the combination treatment group reduced the atypia of tumor cells, increased the apoptotic rate, enhanced the infiltration of T lymphocytes in tumor tissue and increased the CD4+ and CD8+ T lymphocytes in the spleen, suggesting that the mechanism may be associated with the inhibition of tumor cell proliferation, the increase of apoptosis and the enhancement of the cellular immunity. Conclusion:: In conclusion, IDO2-siRNA combined with nifuroxazide therapy could serve a significant role in the treatment of melanoma-bearing mice, enhance the tumor immunity and provide an experimental basis for identifying a novel combination method for the treatment of melanoma clinically.

Background Endotoxin tolerance (ET) is a protective mechanism in the process of sepsis, septic shock, and their sequelae including uncontrolled inflammation. Accumulating evidence has shown that peripheral T cells contribute to the induction of ET. However, what and how T-cell development contributes to ET inductions remain unclear. Methods Mice were intraperitoneally injected with LPS at a concentration of 5 mg/kg to establish an LPS tolerance model and were divided into two groups: a group examined 72 h after LPS injection (72-h group) and a group examined 8 days after LPS injection (8-day group). Injection of PBS was used as a control. We performed high-throughput sequencing to analyze the characteristics and changes of CD4+SP TCRβ CDR3 repertoires with respect to V direct to J rearrangement during the ET induction. Moreover, the proportion and proliferation, as well as surface molecules such as CD80 and CD86, of F4/80+ macrophages were analyzed using FCM. Furthermore, ACT assay was designed and administered by the tail vein into murine LPS-induced mouse model to evaluate the role of F4/80+ macrophages on the development of CD4+SP thymocytes in ET condition. Results We found that the frequency and characteristics of the TCRβ chain CDR3 changed obviously under condition of ET, indicating the occurrence of TCR rearrangement and thymocyte diversification. Moreover, the absolute numbers of F4/80+ macrophages, but not other APCs, were increased in thymic medulla at 72-h group, accompanied by the elevated function-related molecules of F4/80+ macrophages. Furthermore, adoptively transferred OVA332-339 peptide-loaded macrophages into Rag-1−/− mice induced the clone deletion of OVA-specific CD4+SP, thereby ameliorating the pathology in lung tissue in LPS challenge. Conclusions These data reveal that the frequency and characteristics of the TCRβ chain CDR3 undergo dynamic programming under conditions of LPS tolerance. Furthermore, the peripheral macrophages may be a key factor which carry peripheral antigen to thymic medulla and affect the negative selection of T-cell population, thereby contributing to the formation of ET. These results suggest that the clone selection in thymus in ET may confer protection against microbial sepsis.

Targeted gene therapy has become a promising approach for lung cancer treatment. In our previous work, we reported that the targeted expression of microRNA-7 (miR-7) operated by thyroid transcription factor-1 (TTF-1) promoter inhibited the growth of human lung cancer cells in vitro and in vivo; however, the intervention efficiency needed to be further improved. In this study, we identified the core promoter of TTF-1 (from -1299 bp to -871 bp) by 5' deletion assay and screened out the putative transcription factors nuclear factor-1 (NF-1) and activator protein-1 (AP-1). Further analysis revealed that the expression level of NF-1, but not AP-1, was positively connected with the activation of TTF-1 core promoter in human non-small-cell lung cancer (NSCLC) cells. Moreover, the silencing of NF-1 could reduce the expression level of miR-7 operated by TTF-1 core promoter. Of note, we optimized four distinct sequences to form additional NF-1-binding sites (TGGCA) in the sequence of TTF-1 core promoter (termed as (opt) TTF-1 promoter), and verified the binding efficiency of NF-1 on the (opt) TTF-1 promoter by electrophoretic mobility shift assay (EMSA). As expected, the (opt) TTF-1 promoter could more effectively drive miR-7 expression and inhibit the growth of human NSCLC cells in vitro, accompanied by a reduced transduction of NADH dehydrogenase (ubiquinone) 1α subcomplex 4 (NDUFA4)/protein kinase B (Akt) pathway. Consistently, (opt) TTF-1 promoter-driven miR-7 expression could also effectively abrogate the growth and metastasis of tumor cells in a murine xenograft model of human NSCLC. Finally, no significant changes were detected in the biological indicators or the histology of some important tissues and organs, including heart, liver, and spleen. On the whole, our study revealed that the optimized TTF-1 promoter could more effectively operate miR-7 to influence the growth of human NSCLC cells, providing a new basis for the development of microRNA-based targeting gene therapy against clinical lung cancer.

Patterning is attractive for nanofabrication, electron devices, and bioengineering. However, achieving the molecular-scale patterns to meet the demands of these fields is challenging. Here, we propose a bubble-template molecular printing concept by introducing the ultrathin liquid film of bubble walls to confine the self-assembly of molecules and achieve ultrahigh-precision assembly up to 12 nanometers corresponding to the critical point toward the Newton black film limit. The disjoining pressure describing the intermolecular interaction could predict the highest precision effectively. The symmetric molecules exhibit better reconfiguration capacity and smaller preaggregates than the asymmetric ones, which are helpful in stabilizing the drainage of foam films and construct high-precision patterns. Our results confirm the robustness of the bubble template to prepare molecular-scale patterns, verify the criticality of molecular symmetry to obtain the ultimate precision, and predict the application potential of high-precision organic patterns in hierarchical self-assembly and high-sensitivity sensors.

Culture can be formed from habits acquired by humans as members of society. Indonesia has so many ethnic groups and produces different habits. From the habits carried out by the community; it is not uncommon to have bad habits and unique habits. This is what makes one of the videos with a cultural theme that is considered satire through one of the social media platforms, which is Youtube, entitled "Only in Indonesia" by LASTDAY Production, interesting to study. Using a descriptive qualitative methodology with Roland Barthes' semiotic analysis which focuses on the meaning of denotation, connotation, and myth; this study aims to determine the representation of Indonesian culture through the scenes in the Youtube video. The results show that there are five of the seven elements of universal culture, namely, social organization systems, technology and equipment systems, knowledge systems, arts, and religion. In addition, the representation of Indonesian culture contained in the video "Only in Indonesia" is a culture that can be said to be negative, seen from the depiction of people's habits. Keyword: Representation, Indonesia Culture, Youtube Video, Semiotics

Sensors based on RuOx/ZnO possess better gas sensing performance than ZnO and RuO2/ZnO based sensors and amorphous RuOx can work stably as a sensitizer at high temperature (210 °C).

Upon perception of pathogens, plants can rapidly close their stomata to restrict pathogen entry into internal tissue, leading to stomatal immunity as one aspect of innate immune responses. The actin cytoskeleton is required for plant defense against microbial invaders. However, the precise functions of host actin during plant immunity remain largely unknown. Here, we report that Arabidopsis villin3 (VLN3) is critical for plant resistance to bacteria by regulating stomatal immunity. Our in vitro and in vivo phosphorylation assays show that VLN3 is a physiological substrate of two pathogen-responsive mitogen-activated protein kinases, MPK3/6. Quantitative analyses of actin dynamics and genetic studies reveal that VLN3 phosphorylation by MPK3/6 modulates actin remodeling to activate stomatal defense in Arabidopsis. Plants can rapidly close stomata to restrict pathogen entry into leaves. Here the authors show that phosphorylation of villin3 by mitogen-activated protein kinases modulates actin remodeling to activate stomatal defense in Arabidopsis.

Thyroid transcription factor-1 (TTF-1/NKx2.1) is a member of the NKx2 tissue-specific transcription factor family, which is expressed in thyroid follicle, parathyroid gland, alveolar epithelium, and diencephalon which originated from ectoderm, and participates in the differentiation, development, and functional maintenance of the above organs. Recent studies have shown that the abnormal expression of TTF-1 is closely related to the occurrence of a variety of human diseases and can be used as a potential new target for the diagnosis and treatment of related diseases. In this article, in order to strengthen the systematic understanding of TTF-1 and promote the progress of related research, we reviewed the structure, expression regulation, biological functions of TTF-1, and its role in the occurrence and development of human-related clinical diseases. Meanwhile, we prospect the future research direction of TTF-1, which might ultimately contribute to the understanding of the pathogenesis of related clinical diseases and the development of new prevention and treatment strategies.

Icariin (ICA) is a kind of natural flavonoid compound monomer, which is derived from the extract of dried stems and leaves of Epimedium. Modern pharmacological studies have found that ICA has broad bioactive function in affecting the biological processes of a variety of cancers, including breast cancer, colorectal cancer, hepatocellular carcinoma, esophageal cancer and other cancers, which indicates that ICA has promising application value in the treatment of cancer patients in the future. Nevertheless, the targets and molecular mechanisms of ICA in cancer treatment have not been elucidated in detail. Therefore, in this review, we systematically summarizes the current research progress of ICA in a series of cancers. In particular, an emphasis is placed on the mechanism of ICA and its future development direction, aiming at providing relevant theoretical basis for the development and application of ICA in the future cancer treatment strategies.

Although the distribution of 8:2 polyfluoroalkyl phosphate diester (8:2 diPAP) in aquatic environments has been reported, details on its uptake, tissue specificity, and elimination in bivalve mollusks remain to be clarified. The present study is the first report on the accumulation and elimination of 8:2 diPAP in mussels (Mytilus galloprovincialis). The tissue-specific accumulation and depuration of 8:2 diPAP and its metabolites were investigated via semistatic seawater exposure (8:2 diPAP at a nominal concentration of 10 μg/L), through water-borne exposure with static daily renewal over a 72-h exposure period and a 360-h depuration period. The digestive gland was found to be the target organ where accumulation and biotransformation primarily occur. The bioaccumulation factor values (mL/g dry wt) in different organs were in the following order: digestive gland (1249) > adductor muscle (315) > gills (289) > gonad (82.9) > mantle (33.0). Moreover, the distribution of 8:2 diPAP among tissues may be related to the total protein content. The 8:2 diPAP tended to be excreted in feces. The compounds 8:2 fluorotelomer carboxylic acid, 8:2 fluorotelomer unsaturated carboxylic acid, 7:3 fluorotelomer carboxylic acid, perfluorooctanoic acid, and perfluoroheptanoic acid were detected and quantified as phase I metabolites, and the concentration of all phase I metabolites relative to the 8:2 diPAP concentration (72 h) was 0.304 mol%. A phase II metabolite, 8:2 fluorotelomer alcohol conjugated with sulfate, was detected but not quantitated in the digestive gland. A biotransformation pathway of 8:2 diPAP in M. galloprovincialis was proposed on the basis of the results obtained in the present study and previous studies. These findings improve our understanding of the accumulation of perfluorocarboxylic acids in bivalve mollusks. Environ Toxicol Chem 2021;40:1992-2004. © 2021 SETAC.

BACKGROUND AND AIMS Increasing evidence in recent years has suggested that microRNA-7 (miR-7) is an important gene implicated in the development of various diseases including HCC. However, the role of miR-7 in autoimmune hepatitis (AIH) is unknown. APPROACH AND RESULTS Herein, we showed that miR-7 deficiency led to exacerbated pathology in Concanavalin-A-induced murine acute autoimmune liver injury (ALI) model, accompanied by hyperactivation state of CD4+ T cells. Depletion of CD4+ T cells reduced the effect of miR-7 deficiency on the pathology of ALI. Interestingly, miR-7 deficiency elevated CD4+ T-cell activation, proliferation, and cytokine production in vitro. Adoptive cell transfer experiments showed that miR-7def CD4+ T cells could exacerbate the pathology of ALI. Further analysis showed that miR-7 expression was up-regulated in activated CD4+ T cells. Importantly, the transcription of pre-miR-7b, a major resource of mature miR-7 in CD4+ T cells, was dominantly dependent on transcription factor CCAAT enhancer binding protein alpha (C/EBPα), which binds to the core promoter region of the miR-7b gene. Global gene analysis showed that mitogen-activated protein kinase 4 (MAPK4) is a target of miR-7 in CD4+ T cells. Finally, the loss of MAPK4 could ameliorate the activation state of CD4+ T cells with or without miR-7 deficiency. Our studies document the important role of miR-7 in the setting of AIH induced by Concanavalin-A. Specifically, we provide evidence that the C/EBPα/miR-7 axis negatively controls CD4+ T-cell activation and function through MAPK4, thereby orchestrating experimental AIH in mice. CONCLUSIONS This study expands on the important role of miR-7 in liver-related diseases and reveals the value of the C/EBPα/miR-7 axis in CD4+ T-cell biological function for the pathogenesis of immune-mediated liver diseases.

The type I interferon (IFN-I) system is important for antiviral and anticancer immunity. Prolonged activation of IFN/JAK/STAT signaling is closely associated with autoimmune diseases. TRIM10 dysfunction may be associated closely with certain autoimmune disorders. Here, we observed that the serum TRIM10 protein level is lower in patients with systemic lupus erythematosus than in healthy control subjects. We speculated the possible involvement of TRIM10-induced modulation of the IFN/JAK/STAT signaling pathway in systemic lupus erythematosus. In line with our hypothesis, TRIM10 inhibited the activation of JAK/STAT signaling pathway triggered by various stimuli. TRIM10 restricted the IFN-I/JAK/STAT signaling pathway, which was independent of its E3 ligase activity. Mechanistically, TRIM10 interacted with the intracellular domain of IFNAR1 and blocked the association of IFNAR1 with TYK2. These data suggest the possible TRIM10 suppresses IFN/JAK/STAT signaling pathway through blocking the interaction between IFNAR1 and TYK2. Targeting TRIM10 is a potential strategy for treating autoimmune diseases.

Intermittent fasting (IF) is becoming a prevailing topic worldwide, as it can cause changes in the body's energy metabolism processes, improve health, and affect the progression of many diseases, particularly in the circumstance of oncology. Recent research has shown that IF can alter the energy metabolism of tumor cells, thereby inhibiting tumor growth and improving antitumor immune responses. Furthermore, IF can increase cancer sensitivity to chemotherapy and radiotherapy and reduce the side effects of these traditional anticancer treatments. IF is therefore emerging as a promising approach to clinical cancer treatment. However, the balance between long-term benefits of IF compared with the harm from insufficient caloric intake is not well understood. In this article, we review the role of IF in tumorigenesis and tumor therapy, and discuss some scientific problems that remain to be clarified, which might provide some assistance in the application of IF in clinical tumor therapy.

Oral squamous cell carcinoma is one of the most common malignant tumors of the head and neck. Increasing evidence suggests that various non-coding RNAs, such as circRNAs, are implicated in a myriad of biological processes supporting tumor progression. Recent studies have revealed that several circRNAs are dysregulated in oral squamous cell carcinoma (OSCC). However, their functional role in OSCC and the underlying mechanism remains to be further investigated. In this study, we aim to evaluate the biological role and survey the molecular mechanism of circBCL11B in regulating the progression of OSCC. We demonstrated that circBCL11B was significantly upregulated in OSCC tissues and cell lines, and the expression level was correlated with the malignancy. Silencing cirCBCL11B inhibited cell proliferation and migration, and also included cell apoptosis in OSCC cells. miR-145 was identified as a downstream target mediating the effect of circBCL11B by targeting LASP1. miR-145 negatively regulated LASP1 expression, which could be rescued by miR-145 inhibitor. Collectively, our study uncovered a functional role of circBCL11B/miR-579/LASP1 axis in OSCC, implying that targeting these molecules could be an intervention approach in OSCC treatment., Graphical Abtstract

Objective: LCAT (lecithin cholesterol acyltransferase) deficiency results in severe low HDL (high-density lipoprotein). Although whether LCAT is pro- or antiatherosclerosis was in debate in mouse studies, our previous study clearly shows that LCAT deficiency (LCAT −/− ) in hamster accelerates atherosclerotic development on high-fat diet. However, unlike in hypercholesterolemia and hypertriglyceridemia, whether LCAT deficiency could lead to spontaneous atherosclerosis has not been studied yet in animal models. We, therefore, sought to investigate the atherosclerosis in LCAT −/− hamsters on standard laboratory diet and explore the potential underlying mechanisms. Approach and Results: Young (16 months) male and female wild-type and LCAT −/− hamsters on standard laboratory diet were used. Compared with age- and sex-matched wild-type hamsters, LCAT −/− hamsters showed a complete loss of plasma HDL and an increase in triglyceride by 2- to 8-fold at different stages of age. In aged LCAT −/− hamsters, the lesion areas at the aortic roots were ≈40×10 4 μm 3 in males and 18×10 4 μm 3 in females, respectively, which were consistent with the en face plaques observed in male (1.2%) and (1.5%) female groups, respectively. The results of plasma malondialdehyde measurement showed that malondialdehyde concentrations were markedly elevated to 54.4 μmol/L in males and 30 μmol/L in females, which are significantly associated with the atherosclerotic lesions. Conclusions: Our study demonstrates the development of spontaneous atherosclerotic lesions in aged male and female LCAT −/− hamsters with higher plasma oxidative lipid levels independent of plasma total cholesterol levels, further confirming the antiatherosclerotic role of LCAT.

BackgroundAccumulating evidence has shown that microRNAs (miRNAs), one of the representative types of noncoding RNAs (ncRNAs), contribute to the development of non-small-cell lung cancer (NSCLC) and act as promising therapeutic targets in NSCLC. However, how to improve the efficiency of miRNA-based gene intervention against NSCLC remains largely unknown.MethodsA proliferation assay was used to assess the effect of miR-7 intervention on human NSCLC cells. RNA-seq was performed to analyze the global gene expression of miR-7-resistant cells. Mechanistically, coimmunoprecipitation (Co-IP), chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR) and western blotting were performed.ResultsUnder continuous intervention with miR-7, miR-7 levels in human NSCLC cells steadily increased, while its inhibition efficiency gradually decreased. The growth and metastatic capacity of miR-7-resistant human NSCLC cells displaying elevated activation of related signaling pathways were significantly enhanced in vitro and in vivo. Global gene analysis showed that the expression of paired box 6 (PAX6), a target molecule of miR-7, was obviously increased in these cells. Moreover, PAX6 silencing significantly impaired the aggressive behavior of miR-7-resistant human NSCLC cells, accompanied by decreased transduction of the PI3K/AKT pathway. Mechanistically, the histone acetyltransferase KAT8 regulated PAX6 expression via H4K16 acetylation, subsequently resulting in the activation of the PI3K/AKT pathway. Notably, PAX6 silencing significantly improved miR-7 intervention efficiency in human NSCLC cells in vitro and in vivo. Finally, the relatively higher miR-7 expression was correlated with PAX6 expression in clinical NSCLC tumors.ConclusionNSCLC cells acquired resistance to miR-7 intervention, orchestrated by KAT8 regulating PAX6 expression via H4K16 acetylation. Specifically, PAX6 silencing significantly improved miR-7 intervention efficiency in human NSCLC cells, thereby providing a feasible approach for miRNA-based intervention in NSCLC.

REC8 meiotic recombination protein (REC8) is a member of structural maintenance of chromosome (SMC) protein partners, which play an important role in meiosis, antitumor activity, and sperm formation. As the adaptor proteins of RIG-I-like receptor (RLR) signaling and cyclic GMP-AMP synthase (cGAS)-DNA signaling, the activity and stability of MAVS (mitochondrial antiviral signaling protein; also known as VISA, Cardif, and IPS-1) and STING (stimulator of interferon genes; also known as MITA) are critical for innate immunity. Here, we report that REC8 interacts with MAVS and STING and inhibits their ubiquitination and subsequent degradation, thereby promoting innate antiviral signaling. REC8 is upregulated through the JAK-STAT signaling pathway during viral infection. Knockdown of REC8 impairs the innate immune responses against vesicular stomatitis virus (VSV), Newcastle disease virus (NDV), and herpes simplex virus (HSV). Mechanistically, during infection with viruses, the SUMOylated REC8 is transferred from the nucleus to the cytoplasm and then interacts with MAVS and STING to inhibit their K48-linked ubiquitination triggered by RNF5. Moreover, REC8 promotes the recruitment of TBK1 to MAVS and STING. Thus, REC8 functions as a positive modulator of innate immunity. Our work highlights a previously undocumented role of meiosis-associated protein REC8 in regulating innate immunity. IMPORTANCE The innate immune response is crucial for the host to resist the invasion of viruses and other pathogens. STING and MAVS play a critical role in the innate immune response to DNA and RNA viral infection, respectively. In this study, REC8 promoted the innate immune response by targeting STING and MAVS. Notably, REC8 interacts with MAVS and STING in the cytoplasm and inhibits K48-linked ubiquitination of MAVS and STING triggered by RNF5, stabilizing MAVS and STING protein to promote innate immunity and gradually inhibiting viral infection. Our study provides a new insight for the study of antiviral innate immunity.

Background Acute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. Atypical mitogen activated protein kinases (MAPKs) play critical roles in the development of tissues and have been proposed as promising therapeutic targets for various diseases. However, the potential role of atypical MAPKs in ALI remains elusive. In this study, we investigated the role of atypical MAPKs family member MAPK4 in ALI using LPS-induced murine ALI model. Results We found that MAPK4 deficiency mice exhibited prolonged survival time after LPS challenge, accompanied by alleviated pathology in lung tissues, decreased levels of pro-inflammatory cytokines and altered composition of immune cells in BALF. Furthermore, the transduction of related signaling pathways, including MK5, AKT, JNK, and p38 MAPK pathways, was reduced obviously in LPS-treated MAPK4−/− mice. Notably, the expression of MAPK4 was up-regulated in lung tissues of ALI model, which was not related with MAPK4 promoter methylation, but negatively orchestrated by transcriptional factors NFKB1 and NR3C1. Further studies have shown that the expression of MAPK4 was also increased in LPS-treated macrophages. Meanwhile, MAPK4 deficiency reduced the expression of related pro-inflammatory cytokines in macrophage in response to LPS treatment. Finally, MAPK4 knockdown using shRNA pre-treatment could ameliorate the pathology of lung tissues and prolong the survival time of mice after LPS challenge. Conclusions Collectively, these findings reveal an important biological function of atypical MAPK in mediating the pathology of ALI, indicating that MAPK4 might be a novel potential therapeutic target for ALI treatment.

The ability to harness innate immunity is a promising solution for improving cancer immunotherapy. Interferon (IFN) induces expression of IFN-stimulated genes (ISGs) by activating the JAK-STAT signaling pathway to promote innate immunity and inhibit malignant tumor growth, but the functions and mechanisms of most ISGs in cancer regulation are unknown. As an innate immune effector, ISG12a promotes the innate immune response to viral infection. In this study, ISG12a was found to be expressed at low levels in gastrointestinal cancer, represented by hepatocellular cancer (HCC) and gastric cancer (GC), and it identified as a tumor suppressor that affects clinical prognosis. ISG12a silencing accelerated the malignant transformation and epithelial–mesenchymal transition of cancer cells. Mechanistically, ISG12a promoted β-catenin proteasomal degradation by inhibiting the degradation of ubiquitinated Axin, thereby suppressing the canonical Wnt/β-catenin signaling pathway. Notably, β-catenin was identified as a transcription factor for PD-L1. Inhibition of Wnt/β-catenin signaling by ISG12a suppressed expression of the immune checkpoint PD-L1, rendering cancer cells sensitive to NK cell-mediated killing. This study reveals a mechanism underlying the anticancer effects of IFN. Some ISGs, as represented by ISG12a, may be useful in cancer therapy and prevention. The identified interrelations among innate immunity, Wnt/β-catenin signaling, and cancer immunity may provide new insight into strategies that will improve the efficiency of immunotherapy.

High-resolution mass spectrometry (HRMS) analysis with the assistance of molecular networking was used to investigate intracellular toxin profiles of five Prorocentrum lima (P. lima) strains sampled from the north Yellow Sea and South China Sea. Mice were used as a model species for testing the acute toxicity of intracellular okadaic acid (OA) and dinophysistoxins (DTXs) in free and esterified states. Results showed that OA and DTX1 esterified derivatives were detected in all P. lima samples, accounting for 55%-96% of total toxins in five strains. A total of 24 esters and 1 stereoisomer of DTX1 (35S DTX1) were identified based on molecular networking and MS data analysis, 15 esters of which have been reported first. All P. lima strains displayed specific toxin profiles, and preliminary analysis suggested that toxin profiles of the five P. lima strains might be region-related. Moreover, acute toxicity in mice suggested higher toxicity of esters compared with free toxins, which highlights the importance and urgency of attention to esterified toxins in P. lima.