Immunological Regulation Research Articles

Studying T Cell Responses to Hepatotropic Viruses in the Liver Microenvironment.

T cells play an important role in the clearance of hepatotropic viruses but may also cause liver injury and contribute to disease progression in chronic hepatitis B and C virus infections which affect millions of people worldwide. The liver provides a unique microenvironment of immunological tolerance and hepatic immune regulation can modulate the functional properties of T cell subsets and influence the outcome of a virus infection. Extensive research over the last years has advanced our understanding of hepatic conventional CD4+ and CD8+ T cells and unconventional T cell subsets and their functions in the liver environment during acute and chronic viral infections. The recent development of new small animal models and technological advances should further increase our knowledge of hepatic immunological mechanisms. Here we provide an overview of the existing models to study hepatic T cells and review the current knowledge about the distinct roles of heterogeneous T cell populations during acute and chronic viral hepatitis.

Genetic heterogeneity of colorectal cancer and the microbiome

In 2020, the International Agency for Research on Cancer and the World Health Organization's GLOBOCAN database ranked colorectal cancer (CRC) as the third most common cancer in the world. Most cases of CRC (> 95%) are sporadic and develop from colorectal polyps that can progress to intramucosal carcinoma and CRC. Increasing evidence is accumulating that the gut microbiota can play a key role in the initiation and progression of CRC, as well as in the treatment of CRC, acting as an important metabolic and immunological regulator. Factors that may determine the microbiota role in CRC carcinogenesis include inflammation, changes in intestinal stem cell function, impact of bacterial metabolites on gut mucosa, accumulation of genetic mutations and other factors. In this review, I discuss the major mechanisms of the development of sporadic CRC, provide detailed characteristics of the bacteria that are most often associated with CRC, and analyze the role of the microbiome and microbial metabolites in inflammation initiation, activation of proliferative activity in intestinal epithelial and stem cells, and the development of genetic and epigenetic changes in CRC. I consider long-term studies in this direction to be very important, as they open up new opportunities for the treatment and prevention of CRC.

Placental leukocyte infiltration accompanies gestational changes induced by hyperthyroidism.

The endocrine and immunological disruption induced by hyperthyroidism could alter gestation, placenta, and fetal development. This study suggests an immunological role of thyroid hormones in gestation. Thyroid dysfunctions lead to metabolic, angiogenic, and developmental alterations at the maternal-fetal interface that cause reproductive complications. Thyroid hormones (THs) act through their nuclear receptors that interact with other steroid hormone receptors. Currently, immunological regulation by thyroid status has been characterized to a far less extent. It is well known that THs exert regulatory function on immune cells and modulate cytokine expression, but how hyperthyroidism (hyper) modulates placental immunological aspects leading to placental alterations is unknown. This work aims to throw light on how hyper modulates immunological and morphological placental aspects. Control and hyper (induced by a daily s.c. injection of T4 0.25 mg/kg) Wistar rats were mated 8 days after starting T4 treatment and euthanized on days 19 (G19) and 20 (G20) of pregnancy. We removed the placenta to perform qPCR, flow cytometry, immunohistochemistry, Western blot and histological analysis, and amniotic fluid and serum to evaluate hormone levels. We observed that hyper increases the fetal number, fetal weight, and placental weight on G19. Moreover, hyper induced an endocrine imbalance with higher serum corticosterone and changed placental morphology, specifically the basal zone and decidua. These changes were accompanied by an increased mRNA expression of glucocorticoid receptor and monocyte chemoattractant protein-1, an increased mRNA and protein expression of prolactin receptor, and an increase in CD45+ infiltration. Finally, by in vitro assays, we evidenced that TH induced immune cell activation. In summary, we demonstrated that hyper modulates immunological and morphological placental aspects and induces fetal phenotypic changes, which could be related to preterm labor observed in hyper.

Immunomodulatory activity of manganese dioxide nanoparticles: Promising for novel vaccines and immunotherapeutics.

Manganese (Mn), a nutrient inorganic trace element, is necessary for a variety of physiological processes of animal body due to their important roles in oxidative regulation effects and other aspects of activities. Moreover, manganese ion (Mn2+) has widely reported to be crucial for the regulations of different immunological responses, thus showing promising application as potential adjuvants and immunotherapeutics. Taking the advantages of Mn-based biological and immunological activities, Manganese dioxide nanoparticles (MnO2 NPs) are a new type of inorganic nanomaterials with numerous advantages, including simple preparation, low cost, environmental friendliness, low toxicity, biodegradable metabolism and high bioavailability. MnO2 NPs, as a kind of drug carrier, have also shown the ability to catalyze hydrogen peroxide (H2O2) to produce oxygen (O2) under acidic conditions, which can enhance the efficacy of radiotherapy, chemotherapy and other therapeutics for tumor treatment by remodeling the tumor microenvironment. More importantly, MnO2 NPs also play important roles in immune regulations both in innate and adaptive immunity. In this review, we summarize the biological activities of Manganese, followed by the introduction for the biological and medical functions and mechanisms of MnO2 NPs. What's more, we emphatically discussed the immunological regulation effects and mechanisms of MnO2 NPs, as well as their potentials to serve as adjuvants and immunomodulators, which might benefit the development of novel vaccines and immunotherapies for more effective disease control.

Human umbilical cord mesenchymal stem cell-derived TGFBI attenuates streptozotocin-induced type 1 diabetes mellitus by inhibiting T-cell proliferation

MSCs have been demonstrated to have a great benefit for type 1 diabetes mellitus (T1DM) due to their strong immunosuppressive and regenerative capacity. However, the comprehensive mechanism is still unclear. Our previous study indicated that transforming growth factor beta induced (TGFBI) is highly expressed in human umbilical cord-derived mesenchymal stem or stromal cells (hUC-MSCs), which are also implicated in T1DM. In this study, we found that infusion of TGFBI knockdown hUC-MSCs displayed impaired therapeutic effects in T1DM mice and decreased immunosuppressive capability. TGFBI knockdown hUC-MSCs could increase the proportion of T-cell infiltration while increasing the expression of IFN-gamma and interleukin-17A in the spleen. In addition, we also revealed that hUC-MSC-derived TGFBI could repress activated T-cell proliferation by interfering with G1/S checkpoint CyclinD2 expression. Our results demonstrate that TGFBI plays a critical role in MSC immunologic regulation. TGFBI could be a new immunoregulatory molecule controlling MSC function for new treatments of T1DM.Graphical Schematic Representation of the Immunosuppression capacity of hUC-MSC by TGFBI

Severe Sarcoidosis Exhibits Loss of Immunological Regulation In MAPK, WNT, and PI3K Pathways

Sarcoidosis is a complex immunological disorder with varied progression. Disease course can vary greatly between mild and severe cases, with severe cases leading to systemic spread and organ damage. We hypothesized that the transcriptomic regulation of immune function differentiates severe and mild cases.

Trichosanthin Promotes Anti-Tumor Immunity through Mediating Chemokines and Granzyme B Secretion in Hepatocellular Carcinoma.

Trichosanthin (TCS) is a type I ribosome-inactivating protein extracted from the tuberous root of the plant Trichosanthes. TCS shows promising potential in clinical drug abortion, anti-tumor and immunological regulation. However, the molecular mechanisms of its anti-tumor and immune regulation properties are still not well discovered. In the present study, we investigated the anti-tumor activity of TCS in hepatocellular carcinoma (HCC), both in vitro and in vivo. Both HCC cell lines and xenograft tumor tissues showed considerable growth inhibition after they were treated with TCS. TCS provoked caspase-mediated apoptosis in HCC cells and xenograft tumor tissues. The recruitment of CD8+ T cells to HCC tissues and the expression of chemokines, CCL2 and CCL22, were promoted upon TCS treatment. In addition, TCS induced an upregulation of Granzyme B (GrzB), TNF-α and IFN-γ in HCC tissues, which are the major cytotoxic mediators produced by T cells. Furthermore, TCS also resulted in an increase of mannose-6-phosphate receptor (M6PR), the major receptor of GrzB, in HCC tissues. In summary, these results suggest that TCS perhaps increases T-cell immunity via promoting the secretion of chemokines and accelerating the entry of GrzB to HCC cells, which highlights the potential role of TCS in anti-tumor immunotherapy.

Alpha-Fetoprotein as an Immunoregulator and Immune Response Modifier: Historical Background and Current Update

The various immunological roles of human alpha-fetoprotein (HAFP) and its correlation with hepatomas, i.e., hepatocellular carcinomas (HCCs), are not always addressed together in the biomedical literature even though HAFP has long been utilized as a biomarker for hepatomas. Although the well-being of the newborn, infant, and juvenile can be monitored by the measurement of age-dependent HAFP in biological fluid levels throughout these stages, the majority of clinical reports in these age groups do not include hepatomas (except hepatoblastomas) because of their later onset. However, reports concerning the interaction of HAFP and immune-associated proteins and cells in HCC patients in both applied clinical research and investigational settings has gradually increased over the years; thus ,it has expanded our base knowledge of mounting an immunotherapeutic response against AFP in hepatomas. The different immune-associated proteins (cytokines, chemokines, interleukin, kinins) interacting with HAFP has remained less reported due to limitations of appropriate in vitro and in vivo models. Concomitantly, the advances in elucidating the various immunological activities of AFP are opening new vistas of knowledge regarding the physiological roles of AFP in the growth of HCC. The present review surveys HAFP as an immunologic response modifier and regulator for HCC and its use in the generation of AFP – sensitized lymphocytes. An attempt is also made to relate the AFP activities to HCC progression following immunotherapies. Hence, the present review was divided into two major sections; I) AFP structure and homologies in the immune response, and II) the therapeutic use of AFP in HCC patients in adult stages in both in vivo and in vitro models

10th Anniversary of Cells: Advances in Cellular Immunology—Regulation of Autoimmune Response and Antitumor Reactivity: Are They Two Side of the Same Coin?

The innate and adaptive arms of the immune system are involved in maintaining organism homeostasis [...].

Pan-cancer illumination of TRIM gene family reveals immunology regulation and potential therapeutic implications

BackgroundThe tripartite motif (TRIM) proteins function as important regulators in innate immunity, tumorigenesis, cell differentiation and ontogenetic development. However, we still lack knowledge about the genetic and transcriptome alterations landscape of TRIM proteins across cancer types.MethodsWe comprehensively reviewed and characterized the perturbations of TRIM genes across > 10,000 samples across 33 cancer types. Genetic mutations and transcriptome of TRIM genes were analyzed by diverse computational methods. A TRIMs score index was calculated based on the expression of TRIM genes. The correlation between TRIMs scores and clinical associations, immune cell infiltrations and immunotherapy response were analyzed by correlation coefficients and gene set enrichment analysis.ResultsAlterations in TRIM genes and protein levels frequently emerge in a wide range of tumors and affect expression of TRIM genes. In particular, mutations located in domains are likely to be deleterious mutations. Perturbations of TRIM genes are correlated with expressions of immune checkpoints and immune cell infiltrations, which further regulated the cancer- and immune-related pathways. Moreover, we proposed a TRIMs score index, which can accurately predict the clinical outcome of cancer patients. TRIMs scores of patients are correlated with clinical survival and immune therapy response across cancer types. Identifying the TRIM genes with genetic and transcriptome alterations will directly contribute to cancer therapy in the context of predictive, preventive, and personalized medicine.ConclusionsOur study provided a comprehensive analysis and resource for guiding both mechanistic and therapeutic analyses of the roles of TRIM genes in cancer.

Evolving roles of CD38 metabolism in solid tumour microenvironment.

Given that plenty of clinical findings and reviews have already explained in detail on the progression of CD38 in multiple myeloma and haematological system tumours, here we no longer give unnecessary discussion on the above progression. Though therapeutic antibodies have been regarded as a greatest breakthrough in multiple myeloma immunotherapies due to the durable anti-tumour responses in the clinic, but the role of CD38 in the immunologic regulation and evasion of non-hematopoietic solid tumours are just initiated and controversial. Therefore, we will focus on the bio-function of CD38 enzymatic substrates or metabolites in the variety of non-hematopoietic malignancies and the potential therapeutic value of targeting the CD38-NAD+ or CD38-cADPR/ADPR signal axis. Though limited, we review some ongoing researches and clinical trials on therapeutic approaches in solid tumour as well.

Association of Non-Hodgkin Lymphoma (NHL), Comorbidity and Death Due to Other Cancers in 30,000 Older Adults from SEER-Medicare

Introduction: NHL is a heterogeneous disease which frequently occurs in older adults. Patients (pts) with NHL have an increased risk of non-NHL malignancies (NNM; Morton, JCO, 2010) and published guidelines emphasize the importance of standard of care cancer screening in this population (Hallek, Blood, 2018). Comorbidities are associated with a more aggressive clinical course and shorter survival in pts with NHL. We hypothesized that comorbidities, measured using the three-factor risk estimate scale (TRES; Gordon, CCR, 2021), would be associated with increased risk of death due to NNM. These findings could have important implications for cancer screening in comorbid pts with NHL. Methods: We included pts in SEER-Medicare with NHL (ICD-O-3/WHO recodes 25012, 33041 and 33042) diagnosed between 2008-2017. Medicare claims were available through 2019. All cases had a pathologically confirmed diagnosis of NHL, age at cancer diagnosis >65 years and continuous coverage in Medicare parts A, B and D with no HMO coverage for the 12 months preceding diagnosis and for 12 months, or death if sooner, after diagnosis. Pts were excluded who were diagnosed on death certificate or at autopsy. Other cancers were identified in SEER. Comorbidities were assessed using the TRES comorbidity score, previously known as CLL-CI (Gordon, CCR, 2021). This index evaluates endocrine, vascular and upper gastrointestinal organ systems, assigning pts to low, intermediate and high-risk groups based on overall survival. Chi-square or t-test was used to compare pt characteristic distributions. Kaplan-Meier estimate and multivariable Cox regression with competing risk were used to test the association between NNM and TRES score. Results: Our cohort consisted of 40,486 pts with NHL. Median age was 77 years, 49.5% were female, 91% were white, 3.3% Hispanic and 2.5% black. 51% were unmarried. 62% received treatment for NHL during the study period, the most common type of treatment was chemoimmunotherapy (31%). TRES score was low in 41%, intermediate in 37% and high in 22%. 23.6% had a cancer diagnosis prior to NHL and 10.4% after. The most common types of cancer preceding NHL diagnosis were prostate (29%), breast (16%), melanoma (9%), colorectum (6%), bladder (6%) and lung (5%). The most common cancer types after NHL diagnosis were colorectal (16%), head and neck (11%), lung (7%), bladder (5%), MDS/AML (5%) and melanoma (5%). Cause of death was reported and analyzed in 30,155 pts which were included in the primary analysis of NNM specific survival. After a median follow up of 33 months, a total of 14,473 deaths occurred, 48% of all subjects in whom cause of death was reported. The most common cause of death was NHL (49%, N=7,110) followed by NNM in 36% (N=5,183) and other causes in 15% (N=2,180). Compared to pts with a low TRES score, intermediate and high-risk scores were associated with an increase in NNM (p<0.001, Figure 1). In multivariable models, hazard ratios (HR) were 1.41 (95%CI 1.32-1.51) for intermediate and 1.94 (95%CI 1.80-2.08) in high risk pts. Other variables associated with non-NHL cancer mortality were NHL subtype, stage, age, gender, marital status and initial treatment type. The most common NHL subtypes were chronic lymphocytic leukemia (CLL N=8,368), diffuse large B cell lymphoma (DLBCL, N=8,292), follicular lymphoma (FL, N=3,870), marginal zone lymphoma (MZL, N=2,597), mantle cell lymphoma (MCL, N=1,208), peripheral T cell lymphoma (PTCL, N=851), cutaneous T cell lymphoma (N=773) and lymphoplasmacytic lymphoma (LPL, N=495). TRES score was associated with NNM in all NHL subtypes, except for PTCL (Table 1). In pts who died, the percent due to NNM by NHL subtype was 50% in CLL, 25% in DLBCL, 40% in FL, 50% in MZL, 18% in MCL, 21% in PTCL, 39% in CTCL and 74% in LPL. The most frequently cited causes of death from NNM were MDS/AML, colorectal, lung and head and neck cancers. Discussion: Other cancers are a common cause of death in older adults with NHL, particularly in pts with indolent B cell subtypes (range, 40%-74%), and comorbidities further increase the risk of death from NNM. This may be due to the combinatorial effects of NHL and comorbidity on immunologic and metabolic regulation. These results have important implications for the treatment of older adults with NHL and highlight the need for close monitoring and the development of adapted cancer screening guidelines in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

An integrated multi-omics analysis of topoisomerase family in pan-cancer: Friend or foe?

BackgroundTopoisomerases are nuclear enzymes that get to the bottom of topological troubles related with DNA all through a range of genetic procedures. More and more studies have shown that topoisomerase-mediated DNA cleavage plays crucial roles in tumor cell death and carcinogenesis. There is however still a lack of comprehensive multi-omics studies related to topoisomerase family genes from a pan-cancer perspective.MethodsIn this study, a multiomics pan-cancer analysis of topoisomerase family genes was conducted by integrating over 10,000 multi-dimensional cancer genomic data across 33 cancer types from The Cancer Genome Atlas (TCGA), 481 small molecule drug response data from cancer therapeutics response portal (CTRP) as well as normal tissue data from Genotype-Tissue Expression (GTEx). Finally, overall activity-level analyses of topoisomerase in pan-cancers were performed by gene set variation analysis (GSVA), together with differential expression, clinical relevancy, immune cell infiltration and regulation of cancer-related pathways.ResultsDysregulated gene expression of topoisomerase family were related to genomic changes and abnormal epigenetic modifications. The expression levels of topoisomerase family genes could significantly impact cancer progression, intratumoral heterogeneity, alterations in the immunological condition and regulation of the cancer marker-related pathways, which in turn caused the differences in potential drugs sensitivity and the distinct prognosis of patients.ConclusionIt was anticipated that topoisomerase family genes would become novel prognostic biomarkers for cancer patients and provide new insights for the diagnosis and treatment of tumors.

Dual immunological and proliferative regulation of immune checkpoint FGL1 in lung adenocarcinoma: The pivotal role of the YY1–FGL1–MYH9 axis

RationalLung cancer is the most common tumor worldwide, with the highest mortality rate and second highest incidence. Immunotherapy is one of the most important treatments for lung adenocarcinoma (LUAD); however, it has relatively low response rate and high incidence of adverse events. Herein, we explored the therapeutic potential of fibrinogen-like protein 1 (FGL1) for LUAD.MethodsData from GEPIA and ACLBI databases were assessed to explore gene–gene correlations and tumor immune infiltration patterns. A total of 200 patients with LUAD were recruited. FGL1 levels in the serum and cellular supernatant were determined by enzyme-linked immunosorbent assay. In vitro and in vivo experiments were performed to assess the effect FGL1 on the proliferation of LUAD cells. Cocultures were performed to explore the effect of FGL1 knockdown in lung cancer cells on T cells, concerning cytokine secretion and viability. PROMO and hTFtarget databases were used for transcription factor prediction. Quantitative polymerase chain reaction (qPCR), chromatin immunoprecipitation, and dual luciferase reporter assays were performed to validate the identified transcription factor of FGL1. Immunoprecipitation, mass spectrometry and gene ontology analysis were performed to explore the downstream partners of FGL1.ResultsFGL1 expression in LUAD was positively associated with PDL1, but not for PD1 expression. Moreover, FGL1 was positively associated with the CD3D expression and negatively associated with FOXP3, S100A9, and TPSB2 within the tumor site. FGL1 promotes the secretion of interleukin-2 by T cells in vitro, simultaneously inducing their apoptosis. Indeed, YY1 is the upstream molecule of FGL1 was found to be transcriptionally regulated by YY1 and to directly by to MYH9 to promote the proliferation of LUAD cells in vitro and in vivo.ConclusionsFGL1 is involved in the immunological and proliferative regulation of LUAD cells by controlling the secretion of important immune-related cytokines via the YY1–FGL1–MYH9 axis. Hence, targeting FGL1 in LUAD may pave the way for the development of new immunotherapies for tackling this malignancy.

Comprehensive analysis for cellular senescence-related immunogenic characteristics and immunotherapy prediction of acute myeloid leukemia.

In malignancies, cellular senescence is critical for carcinogenesis, development, and immunological regulation. Patients with acute myeloid leukemia (AML) have not investigated a reliable cellular senescence-associated profile and its significance in outcomes and therapeutic response. Cellular senescence-related genes were acquired from the CellAge database, while AML data were obtained from the GEO and TCGA databases. The TCGA-AML group served as a training set to construct a prognostic risk score signature, while the GSE71014 set was used as a testing set to validate the accuracy of the signature. Through exploring the expression profiles of cellular senescence-related genes (SRGs) in AML patients, we used Lasso and Cox regression analysis to establish the SRG-based signature (SRGS), which was validated as an independent prognostic predictor for AML patients via clinical correlation. Survival analysis showed that AML patients in the low-risk score group had a longer survival time. Tumor immune infiltration and functional enrichment analysis demonstrated that AML patients with low-risk scores had higher immune infiltration and active immune-related pathways. Meanwhile, drug sensitivity analysis and the TIDE algorithm showed that the low-risk score group was more susceptible to chemotherapy and immunotherapy. Cell line analysis in vitro further confirmed that the SRGs in the proposed signature played roles in the susceptibility to cytarabine and YM155. Our results indicated that SRGS, which regulates the immunological microenvironment, is a reliable predictor of the clinical outcome and immunotherapeutic response in AML.

Osteoporosis and vascular calcification – An immunological link

Background and Aims : Osteoporosis and low bone mineral density were identified as independent risk factors for enhanced vascular calcification and cardiovascular diseases, associated with increasing mortality. Common risk factors for both disorders, such as age, lack of physical activity, and menopause are insufficient to explain a mutual pathogenic mechanism. However, broad evidence emphasises the important role of systemic inflammation in both diseases, indicating a pathologically immunological regulation.

A CSDE1/Unr gene from Penaeus monodon: Molecular characterization, expression and association with tolerance to low salt stress

The RNA-containing cold shock domain binding protein E1 (CSDE1) has been found to have a key function in immunological stress regulation. In this work, a novel CSDE1 homologue, PmCSDE1, was identified in Penaeus monodon. The full length is 4251 bp, containing a 5’-UTR of 925 bp, a 3’-UTR of 323 bp, and a 31-base poly A tail. The ORF (Open reading frame) is 3003 bp and encodes 1000 amino acids. Its relative molecular mass is 110.91 kD, and its pI is 6.77. The PmCSDE1 polypeptide sequence has five CSP structural domains and one SUZ-C motif, which may have synergistic or retrograde functions in mRNA transcriptional regulation. The results of homology analysis and phylogenetic tree analysis showed that PmCSDE1 was most closely related to P. vannamei and clustered into one group (similarity up to 95.8%), and CSDE1 was highly conserved evolutionarily among different species. Quantitative analysis showed PmCSDE1 was widely expressed in all tissues examined. After low salt stress, PmCSDE1 was significantly downregulated in hepatopancreas and gill tissues. The knockdown of PmCSDE1 resulted in a significant increase in shrimp mortality. In addition, we screened two SNPs in the genome of PmCSDE1, PmCSDE1-In3-476 and PmCSDE1-E7-166, that may be significantly associated with low-salt tolerance by chi-square tests (χ2 (P) < 0.05). The findings are expected to provide a foundation for P. monodon resistance breeding research as well as preliminary data for the investigation of low-salt tolerant strains.

A Review of Polygonatum Mill. Genus: Its Taxonomy, Chemical Constituents, and Pharmacological Effect Due to Processing Changes.

Ethnopharmacological relevance: The genus Polygonatum Tourn, ex Mill. contains numerous chemical components, such as steroidal saponins, polysaccharides, flavonoids, alkaloids, and others, it possesses diverse pharmacological activities, such as anti-aging, anti-tumor, immunological regulation, as well as blood glucose management and fat reducing properties. Aim of the review: This study reviews the current state of research on the systematic categorization, chemical composition, pharmacological effects, and processing changes of the plants belonging to the genus Polygonatum, to provide a theoretical foundation for their scientific development and rational application. Materials and methods: The information was obtained by searching the scientific literature published between 1977 and 2022 on online databases (including PubMed, CNKI, SciFinder, and Web of Science) and other sources (such as the Chinese Pharmacopoeia 2020 edition, and Chinese herbal books). Results: The genus Polygonatum contains 79 species, and 233 bioactive chemical compounds were identified in them. The abundance of pharmacological activities, such as antioxidant activities, anti-fatigue activities, anti-inflammatory activities, etc., were revealed for the representatives of this genus. In addition, there are numerous processing methods, and many chemical constituents and pharmacological activities change after the unappropriated processing. Conclusions: This review summarizes the taxonomy classification, chemical composition, pharmacological effects, and processing of the plants belonging to the genus Polygonatum, providing references and research tendencies for plant-based drug development and further clinical applications.

Immunomodulatory roles of selenium nanoparticles: Novel arts for potential immunotherapy strategy development.

Current chemotherapy strategies used in clinic appear with lots of disadvantages due to the low targeting effects of drugs and strong side effects, which significantly restricts the drug potency, causes multiple dysfunctions in the body, and even drives the emergence of diseases. Immunotherapy has been proved to boost the body’s innate and adaptive defenses for more effective disease control and treatment. As a trace element, selenium plays vital roles in human health by regulating the antioxidant defense, enzyme activity, and immune response through various specific pathways. Profiting from novel nanotechnology, selenium nanoparticles have been widely developed to reveal great potential in anticancer, antibacterial, and anti-inflammation treatments. More interestingly, increasing evidence has also shown that functional selenium nanoparticles can be applied for potential immunotherapy, which would achieve more effective treatment efficiency as adjunctive therapy strategies for the current chemotherapy. By directly interacting with innate immune cells, such as macrophages, dendritic cells, and natural killer cells, selenium nanoparticles can regulate innate immunity to intervene disease developments, which were reported to boost the anticancer, anti-infection, and anti-inflammation treatments. Moreover, selenium nanoparticles can also activate and recover different T cells for adaptive immunity regulations to enhance their cytotoxic to combat cancer cells, indicating the potential of selenium nanoparticles for potential immunotherapy strategy development. Here, aiming to enhance our understanding of the potential immunotherapy strategy development based on Se NPs, this review will summarize the immunological regulation effects of selenium nanoparticles and the application of selenium nanoparticle-based immunotherapy strategies. Furthermore, we will discuss the advancing perspective of selenium nanoparticle-based potential immunotherapy as a kind of novel adjunctive therapy to enhance the efficiency of current chemotherapies and also introduce the current obstacles for the development of selenium nanoparticles for potential immunotherapy strategy development. This work is expected to promote the future research on selenium nanoparticle-assisted immunotherapy and finally benefit the more effective disease treatments against the threatening cancer and infectious and chronic diseases.

Vitamin D receptor enhances NLRC4 inflammasome activation by promoting NAIPs-NLRC4 association.

Inflammasomes are cytosolic multiprotein complexes that initiate host defense against bacterial pathogens. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family caspase-associated recruitment domain-containing protein 4 (NLRC4) inflammasomes plays a critical role in the inflammatory response against intracellular bacterial infection. The NLR family apoptosis inhibitory proteins (NAIPs) detect Flagellin or type III secretion system (T3SS) microbial components to activate NLRC4 inflammasome. However, the underlying mechanism of NLRC4 inflammasome activation is not completely understood. Here, we show that the vitamin D receptor (VDR) is an essential immunological regulator of the NLRC4 inflammasome. Conditional VDR knockout mice (VDRflox/flox lyz2-Cre) exhibited impaired clearance of pathogens after acute Salmonella Typhimurium infection leading to poor survival. In macrophages, VDR deficiency reduced caspase-1 activation and IL-1β secretion upon S. Typhimurium infection. For NAIPs act as upstream sensors for NLRC4 inflammasome assembly, the further study demonstrated that VDR promoted the NAIP-NLRC4 association and triggered NAIP-NLRC4 inflammasome activation, not NLRP3 activation. Moreover, Lys123 residue of VDR is identified as the critical amino acid for VDR-NLRC4 interaction, and the mutant VDR (K123A) effectively attenuates the NLRC4 inflammasome activation. Together, our findings suggest that VDR is a critical regulator of NAIPs-NLRC4 inflammasome activation, mediating innate immunity against bacterial infection.