Regulation Of Immune Responses Research Articles

Interaction mechanism of lipid metabolism remodeling, oxidative stress, and immune response mediated by Epinephelus coioides SRECII

Scavenger receptors (SRs), a category of pattern recognition receptors primarily expressed on the surface of myeloid cells, play pivotal roles in oxidation response and lipid metabolism. However, current research on Scavenger Receptor class F type II (SRECⅡ) revolves around Van Den Ende-Gupta Syndrome (VDEG), the potential function of SRECII, particularly in regulating lipid metabolism and oxidative stress processes, remains elusive. Herein, we elucidate that SRECII from Epinephelus coioides (EcSRECII) may modulate fatty acid oxidation and oxidative stress levels via interactions with lipoprotein particles. EcSRECII mediates the internalization of oxidized Low-Density Lipoprotein (oxLDL), thereby inducing lipid accumulation. This process upregulates the expression of genes associated with lipid synthesis and concurrently suppresses those involved in lipolysis. Additionally, EcSRECII exacerbates the production of Reactive Oxygen Species (ROS) following oxLDL exposure, evidenced by significantly heightened activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), increased accumulation of malondialdehyde (MDA), and enhanced total antioxidant capacity (T-AOC). Furthermore, we reveal that EcSRECII-mediated oxLDL internalization culminates in apoptosis and necrosis in GS cells. Ultimately, we demonstrate that EcSRECII augments oxLDL-induced cellular oxidative stress and inflammatory responses, effects that are notably mitigated by EcSRECII knockdown or pretreatment with the fatty acid synthase (FAS) inhibitor C75. Collectively, our study underscores the role of EcSRECII in facilitating oxLDL internalization and subsequent lipid metabolism remodeling, thereby participating in the intricate regulation of intracellular oxidative stress and immune responses.

Advances in roles of Parabacteroides distasonis and its regulation by traditional Chinese medicines

Parabacteroides distasonis is a gram-negative bacterium initially isolated from a clinical specimen in the 1930s. The strain was re-classified to form the new genus Parabacteroides in 2006. P. distasonis can regulate intestinal barrier function and plays a key role in immune response and metabolic regulation of bodies. Traditional Chinese medicine(TCM) is closely related to the intestinal microbiota. Polysaccharides, saponins, and other ingredients of TCM can treat diseases by interacting with P. distasonis, but the specific mechanisms underlying these processes are still unclear, requiring further exploration. This study reviewed the roles and related mechanisms of P. distasonis in inflammatory-immune diseases, metabolic diseases, cardiovascular disease, neuropsychiatric diseases, cancer, and other diseases and summarized the relevant research results of TCM to prevent and treat diseases by regulating P. distasonis. This study provides a reference for subsequent exploration of P. distasonis and research on the interaction between TCM and intestinal microbiota.

New Insights into the Pleiotropic Actions of Dipeptidyl Peptidase-4 Inhibitors Beyond Glycaemic Control.

Dipeptidyl peptidase-4 (DPP-4) is a multifunctional serine ectopeptidase that cleaves and modifies a plethora of substrates, including regulatory peptides, cytokines and chemokines. DPP-4 is implicated in the regulation of immune response, viral entry, cellular adhesion, metastasis and chemotaxis. Regarding its numerous substrates and extensive expression inside the body, multitasking DPP-4 has been assumed to participate in different pathophysiological mechanisms. DPP-4 inhibitors or gliptins are increasingly used for the treatment of type 2 diabetes mellitus. Several reports from experimental and clinical studies have clarified that DPP-4 inhibitors exert many beneficial pleiotropic effects beyond glycaemic control, which are mediated by anti-inflammatory, anti-oxidant, anti-fibrotic and anti-apoptotic actions. The present review will highlight the most recent findings in the literature about these pleiotropic effects and the potential mechanisms underlying these benefits, with a specific focus on the potential effectiveness of DPP-4 inhibitors in coronavirus disease-19 and diabetic kidney disease.

Bridging the Gap Between Tolerogenic Dendritic Cells In Vitro and In Vivo: Analysis of Siglec Genes and Pathways Associated with Immune Modulation and Evasion.

Dendritic cells (DCs) are master regulators of the adaptive immune response. Inflammatory DCs (inflamDCs) can prime inflammatory T cells in, for instance, cancer and infection. In contrast, tolerogenic DCs (tolDCs) can suppress the immune system through a plethora of regulatory mechanisms in the context of autoimmunity. We successfully generated tolDCs in vitro to durably restore immune tolerance to an islet autoantigen in type 1 diabetes patients in a clinical trial. However, cancers can induce inhibitory DCs in vivo that impair anti-tumor immunity through Siglec signaling. To connect in vivo and in vitro tolDC properties, we tested whether tolDCs generated in vitro may also employ the Siglec pathway to regulate autoimmunity by comparing the transcriptomes and protein expression of immature and mature inflamDCs and tolDCs, generated from monocytes. Both immature DC types expressed most Siglec genes. The expression of these genes declined significantly in mature inflamDCs compared to mature tolDCs. Surface expression of Siglec proteins by DCs followed the same pattern. The majority of genes involved in the different Siglec pathways were differentially expressed by mature tolDCs, as opposed to inflamDCs, and in inhibitory pathways in particular. Our results show that tolDCs generated in vitro mimic tumor-resident inhibitory DCs in vivo regarding Siglec expression.

Identification of ferroptosis-related genes associated with diffuse large B-cell lymphoma via bioinformatics and machine learning approaches

Ferroptosis has emerged as a critical mechanism in the development and progression of various tumors, particularly diffuse large B-cell lymphoma (DLBCL). However, the thorough characterization of ferroptosis-related genes in DLBCL remains inadequately explored. We retrieved datasets associated with DLBCL and ferroptosis gene sets from the Gene Expression Omnibus (GEO) database and the Ferroptosis Database (FerrDb), resulting in the identification of 27 differentially expressed ferroptosis-related genes (DE-FRGs) linked to DLBCL. Utilizing the LASSO and Support Vector Machine Recursive Feature Elimination (SVW-RFE) algorithms, we identified 10 genes—MT1G, MTOR, BRD4, ACO1, SAT1, PEBP1, LPIN1, ATM, SRXN1, and PRDX1—as key biomarker candidates with significant diagnostic potential. Functional enrichment analyses revealed that these biomarker genes are likely involved in regulating several critical biological pathways implicated in DLBCL pathogenesis, including immune response, oxidative phosphorylation, and cell cycle regulation. Moreover, we identified 246 potential therapeutic agents targeting these 10 biomarker genes. Concurrently, competitive endogenous RNA (ceRNA) network analysis uncovered a complex regulatory network centered on the identified biomarker genes. Additionally, CIBERSORT analysis highlighted notable alterations in the immune microenvironment of DLBCL patients. We propose a diagnostic strategy that provides novel insights into the molecular mechanisms underlying DLBCL. Nevertheless, further validation of the practical value of this strategy for DLBCL diagnosis is necessary before its clinical application.

Integrated Single-Cell Multiomic Profiling of Caudate Nucleus Suggests Key Mechanisms in Alcohol Use Disorder.

Alcohol use disorder (AUD) induces complex transcriptional and regulatory changes across multiple brain regions including the caudate nucleus, which remains understudied. Using paired single-nucleus RNA-seq and ATAC-seq on caudate samples from 143 human postmortem brains, including 74 with AUD, we identified 17 distinct cell types. We found that a significant portion of the alcohol-induced changes in gene expression occurred through altered chromatin accessibility. Notably, we identified novel transcriptional and chromatin accessibility differences in medium spiny neurons, impacting pathways such as RNA metabolism and immune response. A small cluster of D1/D2 hybrid neurons showed distinct differences, suggesting a unique role in AUD. Microglia exhibited distinct activation states deviating from classical M1/M2 designations, and astrocytes entered a reactive state partially regulated by JUND, affecting glutamatergic synapse pathways. Oligodendrocyte dysregulation, driven in part by OLIG2, was linked to demyelination and increased TGF-β1 signaling from microglia and astrocytes. We also observed increased microglia-astrocyte communication via the IL-1β pathway. Leveraging our multiomic data, we performed cell type-specific expression quantitative trait loci analysis, integrating that with public genome-wide association studies to identify AUD risk genes such as ADAL and PPP2R3C, providing a direct link between genetic variants, chromatin accessibility, and gene expression in AUD. These findings not only provide new insights into the genetic and cellular mechanisms in the caudate related to AUD but also demonstrate the broader utility of large-scale multiomic studies in uncovering complex gene regulation across diverse cell types, which has implications beyond the substance use field.

Construction and integrative analysis of miRNA-mRNA response to salinity stress in Oreochromis mossambicus cells

This study investigated the genetic response of tilapia (Oreochromis mossambicus) brain cells to hypertonic stress, focusing on miRNAs regulation. Three hundred and thirty-one known miRNAs and 163 novel miRNAs which responded to hypertonic stress were identified by high-throughput sequencing in tilapia brain cells. Differential expression analysis revealed that 16 miRNAs were significantly upregulated, while 11 miRNAs were significantly downregulated. These differentially expressed miRNAs are closely related to metabolism, immune response, and neural regulation. The target genes of these miRNAs are implicated in neurotrophic and synaptic signaling pathways, potentially affecting metabolic and apoptotic processes. GO and KEGG enrichment analyses provided insights into the biological processes and pathways affected by hypertonic stress. Furthermore, correlation analysis between mRNA and miRNA highlighted miRNA-mRNA interactions related to cell cycle and apoptosis regulation. These results indicated significant changes of miRNA expression under hypertonic stress and their crucial role in osmotic pressure regulation. This study offers a basis for further exploration of miRNA functions and molecular mechanisms in tilapia, potentially informing practices for aquaculture in challenging environments such as saline-alkaline waters.

Cannabidiol Enhances Atezolizumab Efficacy by Upregulating PD-L1 Expression via the cGAS-STING Pathway in Triple-Negative Breast Cancer Cells.

The treatment of patients with triple-negative breast cancer (TNBC) relies on cytotoxic therapy. Currently, atezolizumab and chemotherapy can be combined in patients with TNBC. However, this approach is not effective for all patients, with many tumors showing low responsiveness to atezolizumab. As there is a lack of alternative treatment options, new anticancer drugs are urgently needed to enhance atezolizumab activity against TNBC. Recent strategies have focused on regulating the expression of programmed cell death ligand 1 (PD-L1) or enhancing immune response activation by combining anticancer drugs with immune checkpoint inhibitors. Cannabidiol (CBD), a cannabinoid component derived from the cannabis plant, has been reported to have anticancer therapeutic potential because of its capacity to induce apoptotic cell death in tumor cells while avoiding cytotoxicity in normal cells. Previous studies have demonstrated the effects of CBD on apoptosis in various cancer cell types. However, the potential role of CBD as an immune modulator in the regulation of PD-L1 expression and anticancer immune responses remains to be explored. In this study, we found that CBD stimulated PD-L1 expression in TNBC cells and that this occurred downstream of CBD-mediated cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway activation. Taken together, we have demonstrated that the combination of CBD and anti-PD-L1 enhances the anticancer immune responses in in vitro and in vivo experiments. Our findings identified the mechanism of PD-L1 regulation by CBD in TNBC cells and suggested that CBD could be a potential candidate for the development of new combinatorial strategies with immune checkpoint inhibitors in patients with TNBC.

RGS10 Attenuates Systemic Immune Dysregulation Induced by Chronic Inflammatory Stress.

Regulator of G-protein signaling 10 (RGS10), a key homeostatic regulator of immune cells, has been implicated in multiple diseases associated with aging and chronic inflammation including Parkinson's Disease (PD). Interestingly, subjects with idiopathic PD display reduced levels of RGS10 in subsets of peripheral immune cells. Additionally, individuals with PD have been shown to have increased activated peripheral immune cells in cerebral spinal fluid (CSF) compared to age-matched healthy controls. However, it is unknown whether CSF-resident peripheral immune cells in individuals with PD also exhibit decreased levels of RGS10. Therefore, we performed an analysis of RGS10 levels in the proteomic database of the CSF from the Michael J. Fox Foundation Parkinson's Progression Markers Initiative (PPMI) study. We found that RGS10 levels are decreased in the CSF of individuals with PD compared to healthy controls and prodromal individuals. Moreover, we find that RGS10 levels decrease with age but not PD progression and that males have less RGS10 than females in PD. Importantly, studies have established an association between chronic systemic inflammation (CSI) and neurodegenerative diseases, such as PD, and known sources of CSI have been identified as risk factors for developing PD; however, the role of peripheral immune cell dysregulation in this process has been underexplored. As RGS10 levels are decreased in the CSF and circulating peripheral immune cells of individuals with PD, we hypothesized that RGS10 regulates peripheral immune cell responses to CSI prior to the onset of neurodegeneration. To test this, we induced CSI for 6 weeks in C57BL6/J mice and RGS10 KO mice to assess circulating and CNS-associated peripheral immune cell responses. We found that RGS10 deficiency synergizes with CSI to induce a bias for inflammatory and cytotoxic cell populations, a reduction in antigen presentation in peripheral blood immune cells, as well as in and around the brain that is most notable in males. These results highlight RGS10 as an important regulator of the systemic immune response to CSI and implicate RGS10 as a potential contributor to the development of immune dysregulation in PD.

Experimental and in silico analysis of LINC01279 expression in tumor of patients with breast cancer.

Breast cancer (BC) is characterized by the increase of malignant cells in the breast. The malignant cells begin in the lining of the breast milk glands or ducts (ductal epithelium). BC is the most frequent cancer in women, but it may also occur in males. Long non-coding RNAs (lncRNA) have been demonstrated to control the development and incidence of cancer. However, some lncRNAs experience potential changes in BC, but their role has not been well studied. LINC01279 is known as a valuable biomarker in gastric cancer but has not yet been studied in BC. Changes in LINC01279 expression levels in BC samples were investigated by microarray. Q-PCR was also used to evaluate the expression of LINC01279 in the tumor and normal adjacent samples of 30 BC patients. The LINC01279 co-expressed gene module was discovered using weighted gene correlation network analysis (WGCNA) on the relevant dataset. The top ten hub genes were determined using gene ontology (GO) functional enrichments on the co-expressed gene module. The results of the bioinformatics study showed an increase in LINC01279 expression levels (log2FC = 3.228749561, adj.P.Val = 1.69E - 12) in tumor samples compared to normal marginal tissue. Q-PCR results also showed a significant increase in LINC01279 expression (P-value = 0.0005) in tumor samples. WGCNA analysis identified that the black module is the LINC01279 co-expressed module, and functional annotation analysis of black module genes enriched in significant cancer-related pathways and processes, including cell growth and/or maintenance, regulation of immune response, regulation of cell proliferation, and epithelial-to-mesenchymal transition (EMT). Regarding the real-time PCR results, the analysis of expression patterns has illuminated a distinct association between the heightened expression levels of LINC01279, and the stages of cancer progression as well as the metastatic potential of tumors. However, intriguingly, our observations have failed to reveal any statistically significant correlations between the relative expression of LINC01279 and tumor grade classification, or the presence of ER, PR, and HER2 biomarkers. The present study could provide a new perspective on the molecular regulatory. Processes associated with BC pathogenic mechanisms are linked to the LINC01279, although further research is needed on the possible role of this lncRNA in BC.

Bitter taste receptors as sensors of gut luminal contents.

Taste is important in the selection of food and is orchestrated by a group of distinct receptors, the taste G protein-coupled receptors (GPCRs). Taste 1 receptors (Tas1rs in mice and TAS1Rs in humans; also known as T1Rs) detect sweet and umami tastes, and taste 2 receptors (Tas2rs in mice and TAS2Rs in humans; also known as T2Rs) detect bitterness. These receptors are also expressed in extraoral sites, including the gastrointestinal mucosa. Tas2rs/TAS2Rs have gained interest as potential targets to prevent or treat metabolic disorders. These bitter taste receptors are expressed in functionally distinct types of gastrointestinal mucosal cells, including enteroendocrine cells, which, upon stimulation, increase intracellular Ca2+ and release signalling molecules that regulate gut chemosensory processes critical for digestion and absorption of nutrients, for neutralization and expulsion of harmful substances, and for metabolic regulation. Expression of Tas2rs/TAS2Rs in gut mucosa is upregulated by high-fat diets, and intraluminal bitter 'tastants' affect gastrointestinal functions and ingestive behaviour through local and gut-brain axis signalling. Tas2rs/TAS2Rs are also found in Paneth and goblet cells, which release antimicrobial peptides and glycoproteins, and in tuft cells, which trigger type 2 immune response against parasites, thus providing a direct line of defence against pathogens. This Review will focus on gut Tas2r/TAS2R distribution, signalling and regulation in enteroendocrine cells, supporting their role as chemosensors of luminal content that serve distinct functions as regulators of body homeostasis and immune response.

NCOR1 orchestrates macrophage inflammation in heart failure with preserved ejection fraction: a translational study

Abstract Background/Introduction Inflammatory response is a key player in heart failure with preserved ejection fraction (HFpEF) but the underlying mechanisms are poorly understood. Recent studies have shown a critical involvement of cardiac macrophage activation in myocardial remodeling thus contributing to HFpEF. Purpose To investigate the role of cardiac macrophage inflammation in experimental and human HFpEF. Methods We employed a translational approach combining human and murine LV myocardial tissue, FACS analysis of cardiac immune cells, in vitro experiments in RAW 264.7 cells exposed to metabolic stress by palmitic acid (PA), bone marrow-derived macrophages from healthy and HFpEF mice, cardiomyocytes (H9c2), endothelial cells (HAECs) as well as ex vivo functional analyses in LV tissues. Human LV myocardial samples were used to evaluate the pro-inflammatory activity of macrophages in the HFpEF myocardium. Induction of HFpEF in mice was done through a validated mouse model combining metabolic (high-fat diet) and hemodynamic stress (L-NAME). Cardiac function was investigated by high resolution ultrasound imaging (Vevo3100) and the LV myocardial samples were used to study the macrophage polarization and their inflammatory activity. Based on interrogation of available RNA-seq datasets – showing the transcriptional repressor NCOR1 as a relevant signature in macrophages during cardiac inflammation, we generated myeloid cell-specific NCOR1 knockout (Ncor1-KO) transgenic mice to investigate the in vivo effects of NCOR1 deletion on the HFpEF phenotype. Results The expression of macrophage markers in human LV specimens showed an increase in pro-inflammatory macrophages (M1) and a decrease in regulatory macrophages (M2) as compared to age-matched control mice. HFpEF mice showed increased expression of vascular adhesion molecules (ICAM1, ICAM2, E-selectin) and a significant recruitment of M1 macrophages as proved by qPCR, WB, and flow cytometry analysis. Of interest, diastolic dysfunction - assessed by E/A ratio and isovolumic relaxation time (IVRT) – and lung congestion were significantly reduced in mice with macrophage NCOR1 deletion as compared to WT littermates, while exercise tolerance was significantly improved. These findings were associated with a reduction of myocardial inflammation (TNF-a, IL6, IL-1b) in Ncor1-KO mice. In vitro assays showed that stimulation of macrophages with PA induced M1 type switch and increased NCOR1, TNF-a, IL-6, and IL-1b levels, whereas NCOR1 depletion prevented detrimental changes of macrophage secretome (Fig.2). Conclusion NCOR1 is a crucial regulator of immune response and macrophage inflammation in the heart. Our findings highlight its potential as a target for therapies aimed at preventing myocardial damage in HFpEF.

PI3 kinase delta governs regulatory T-cell biology and thus confers protection against atherosclerosis progression in mice

Abstract Introduction and Purpose Atherosclerosis is a chronic inflammatory disease of arteries, critically involving innate and adaptive immune cells like macrophages as well as T and B lymphocytes. Macrophages are major drivers of disease through the ingestion of lipoproteins, foam cell formation, and secretion of inflammatory mediators. Although macrophages outnumber other leukocytes in atherosclerotic plaques, T and B cells can shape the course of disease by promoting or mitigating inflammatory responses. The phosphoinositide 3-kinase delta (PI3Kd) exerts a key role in the regulation of immune responses including activation, proliferation, differentiation, and effector function of lymphocytes. Therefore, PI3Kd may represent a promising target for the modulation of inflammatory diseases. Consequently, we aimed to analyse the role of PI3Kd during atherogenesis. Methods and Results To investigate the role of haematopoietic PI3Kd in atherosclerosis, bone marrow from PI3Kd-/- or PI3Kd+/+ mice was transplanted into Ldlr-/- mice. After a 6-weeks-challenge by high fat diet, PI3Kd-/- recipient Ldlr-/- mice displayed profoundly impaired CD4+ and CD8+ T-cell numbers, CD4+ T-cell activation, CD4+ effector T-cell differentiation, and proatherogenic CD4+ T-helper (Th) 1 responses in para-aortic lymph nodes and spleen compared with PI3Kd+/+ transplanted controls. Surprisingly, the net effect of PI3Kd deficiency was a substantial increase of aortic inflammation and atherosclerosis in Ldlr-/- mice. Whereas plaque content and functions of macrophages including foam cell formation, efferocytosis, and cytokine secretion remained largely unaffected, haematopoietic PI3Kd ablation strongly reduced mature B cells and serum immunoglobulins in Ldlr-/- mice. Importantly, PI3Kd deficiency severely impaired numbers, proliferation, immunosuppressive functions, and stability of regulatory CD4+ T cells (Tregs). Consequently, adoptive transfer of PI3Kd+/+ Tregs fully restrained the atherosclerotic plaque burden in PI3Kd-/- transplanted Ldlr-/- mice without affecting B-cell numbers and serum immunoglobulins, whereas transferred PI3Kd-/- Tregs failed to relieve atherosclerosis progression. Conclusions Here, we demonstrate that PI3Kd plays a crucial role in Tregs, Th1 cells, and B cells during atherogenesis. Lack of PI3Kd signalling specifically in atheroprotective Treg responses outplays its impact on B-cell and proatherogenic Th1 responses, thus leading to aggravated atherosclerosis. Hence, PI3Kd is a key regulator of Treg biology and thereby protects against atherosclerosis, suggesting that fine-tuning PI3Kd signalling may represent a promising target for Treg-directed therapy.

Cullin-Conciliated Regulation of Plant Immune Responses: Implications for Sustainable Crop Protection.

Cullins are crucial components of the ubiquitin-proteasome system, playing pivotal roles in the regulation of protein metabolism. This review provides insight into the wide-ranging functions of cullins, particularly focusing on their impact on plant growth, development, and environmental stress responses. By modulating cullin-mediated protein mechanisms, researchers can fine-tune hormone-signaling networks to improve various agronomic traits, including plant architecture, flowering time, fruit development, and nutrient uptake. Furthermore, the targeted manipulation of cullins that are involved in hormone-signaling pathways, e.g., cytokinin, auxin, gibberellin, abscisic acids, and ethylene, can boost crop growth and development while increasing yield and enhancing stress tolerance. Furthermore, cullins also play important roles in plant defense mechanisms through regulating the defense-associated protein metabolism, thus boosting resistance to pathogens and pests. Additionally, this review highlights the potential of integrating cullin-based strategies with advanced biological tools, such as CRISPR/Cas9-mediated genome editing, genetic engineering, marker-associated selections, gene overexpression, and gene knockout, to achieve precise modifications for crop improvement and sustainable agriculture, with the promise of creating resilient, high-yielding, and environmentally friendly crop varieties.

GmWRKY33A positively regulates disease resistance in soybean (Glycine max)

The WRKY transcription factor gene family is a plant-specific transcription factor that plays important roles defense responses. Studies in model plant Arabidopsis demonstrated that WRKYs function downstream of mitogen activated-protein kinase (MAPK) signaling cascade and participate in defense responses through activating the expression of defense-related genes. However, the roles of WRKYs in defense responses have not been previously investigated in paleopolyploidy soybean. Bioinfomatic analysis revealed that there are three pair of GmWRKY33 genes in the soybean genome. The identity of first two pair of GmWRKY33 genes is greater than 84% (named as GmWRKY33A). The identity of genes within the same pair is greater than 95%. A 300 bp fragment highly homologous to these four GmWRKY33A was chosen to clone into bean pod mosaic virus (BPMV)-based silencing vector (BPMV-VIGS) to achieve the goal of silencing four GmWRKY33A genes simultaneously. In this study, we simultaneously silenced four homologous genes of GmWRKY33A using a bean pod mottle virus (BPMV) vector carrying a single fragment of GmWRKY33A. Comparing the silenced plants with the vector control plants, no evident morphological phenotypes were observed. However, the GmWRKY33A-silenced plants exhibited significantly reduced resistance to Pseudomonas syringae pv. glycinea (Psg), Xanthomonas axonopodis pv. glycine (Xag), as well as to soybean mosaic virus (SMV). Furthermore, we demonstrated that silencing these GmWRKY33A genes significantly inhibited the activation of GmMPK3/GmMPK6 induced by Psg infection. Collectively, our results suggest that GmWRKY33As are involved in soybean immunity through regulating the transcription of GmMPK3/6 genes or activating the kinase activities of GmMPK3/6. Taken together, our results demonstrated that GmWRKY33As are positive regulators of soybean immune responses.

Assessment of toxicity changes induced by exposure of human cells to lunar dust simulant

The toxicity of lunar dust (LD) to astronauts' health has been confirmed in the Apollo missions and subsequent biological experiments. Therefore, it is crucial to understand the biological toxicity of lunar dust for future human missions to the Moon. In this study, we exposed human lung epithelial cells (BEAS-2B) and peripheral blood B lymphocytes (AHH-1) to varying concentrations (0, 500, 1000, and 1500 μg/ml) of a lunar dust simulant (LDS) called CLDS-i for 24 and 48 h. The results provided the following key findings: (1) LDS induction of cell damage occurred through oxidative stress, with the levels of reactive oxygen species (ROS) in BEAS-2B cells being dependent on the duration of exposure. (2) Necrosis and early apoptosis were observed in BEAS-2B cells and AHH-1 cells, respectively. In addition, both cells showed lysosomal damage. (3) Genes CXCL1, SPP1, CSF2, MMP1, and POSTN are implicated in immune response and cytoskeletal arrangement regulation in BEAS-2B cells. Considering the similarities in composition and properties between CLDS-i and real lunar dust, our findings not only enhance the understanding of LDS toxicity, but also contribute to a better comprehension of the genomic alterations and molecular mechanisms underlying cellular toxicity induced by LD. These insights will contribute to the development of a biotoxicology framework aimed at safeguarding the health of astronauts and, consequently, facilitating future human missions to the Moon.

Taxonomic Diversity, Predicted Metabolic Pathway, and Interaction Pattern of Bacterial Community in Sea Urchin Anthocidaris crassispina.

Bacterial assemblages associated with sea urchin are critical to their physiology and ecology within marine ecosystems. In this study, we characterized the bacterial communities in wild sea urchin Anthocidaris crassispina captured in Daya Bay, South China Sea. A total of 363 amplicon sequence variants belonging to nine phyla and 141 genera were classified from intestine, body surface, and surrounding seawater samples. Proteobacteria, Firmicutes, and Bacteroidetes were the dominant bacteria phyla found in this study. A network analysis of bacterial interspecies interactions revealed varying complexity, stability, connectivity, and relationship patterns across the samples, with the most intricate network observed in the surrounding seawater. Metagenomic predictions highlighted the distinct bacterial metabolic pathways, with significant differences between intestine and seawater samples. Notably, pathways associated with polysaccharide degradation, including chitin derivatives, starch, and CoM biosynthesis, were markedly abundant, underscoring the gut microbiota's key role in digesting algae. In addition, other metabolic pathways in intestine samples were linked to immune response regulation of sea urchins. Overall, this study provides a comprehensive overview of the bacterial community structure and potential functional roles in A. crassispina.

Comprehensive proteomic analysis of buffalo milk extracellular vesicles

Extracellular vesicles are secretory vesicles involved in cell-to-cell communication via their encapsulated cargo of proteins, lipids, and nucleic acids. Bovine milk provides a rich source of extracellular vesicles (mEVs) that have been studied as therapeutics and drug delivery systems. Therefore, insight into the mEV cargo, such as its proteome, may help in understanding the molecular mechanism underlying the potential health benefits attributed to the mEVs. Hence, mEVs were isolated from healthy buffalo milk after screening the milk somatic cell count. The total proteins of mEVs were analyzed using LC-MS, and 331 proteins were found commonly present among three buffalo milk samples. These proteins were primarily derived from extracellular regions and lysosomes. The major biological roles associated with the proteins were immune response, metabolism, and cell cycle regulation. The molecular functions of the proteins were transporter activity, catalytic activity, and GTPase activity. Further, comparative analysis with the previously available bovine mEVs proteome data showed 114 proteins to be newly identified in the buffalo mEVs. The biological pathways associated with these proteins may play a major role in muscle development. These findings shed a light on the potential health benefits of buffalo mEVs as therapeutics as well as drug delivery vehicles.

Interleukin-2 receptor α (IL-2Rα/CD25) shedding is differentially regulated by N- and O-glycosylation

The cytokine interleukin-2 (IL-2) is a critical regulator of immune responses, with an especially well-characterized role in regulating T-cell homeostasis. IL-2 signaling involves three distinct receptor subunits: the IL-2Rα (CD25), IL-2Rβ, and IL-2Rγ. The intracellular transduction of IL-2-induced signals is strictly dependent on IL-2Rβ and IL-2Rγ, while the IL-2Rα is not directly involved in signaling. Instead, it has the highest affinity towards IL-2 and is thus responsible for regulating the affinity of a cell for IL-2. In addition to the membrane-bound IL-2Rα, a soluble form of the receptor (sIL-2Rα) has been described, which is present in the blood of healthy individuals, increased under various pathological conditions, and able to bind IL-2 and thus modulate its function. The sIL-2Rα is generated by proteolytic cleavage of the membrane-bound receptor. Here, we analyze whether glycosylation of the IL-2Rα regulates its proteolysis. We find that constitutive IL-2Rα shedding is affected by glycosylation and discover distinct roles for N- and O-glycosylation. Furthermore, we show that induced shedding by the metalloproteases ADAM10 and ADAM17 is also differentially regulated by distinct types of glycans. Finally, we identify a specific role for an N-glycan at an exosite in ADAM17-mediated proteolysis that does not affect ADAM10, indicating distinct substrate recognition mechanisms. These results further the understanding of the mechanisms leading to sIL-2Rα generation, and thus offer the opportunity to specifically modulate the generation of the soluble receptor.

Effects of Free and Nanoencapsulated Benznidazole in Acute Trypanosoma cruzi Infection: Role of Cholinergic Pathway and Redox Status

Background/Objectives: The Trypanosoma cruzi infection promotes an intense inflammatory process that affects several tissues. The cholinergic system may exert a regulatory immune response and control the inflammatory process. This study aimed to evaluate the comparative effect of free and nanoencapsulated benznidazole in acute T. cruzi infection to assess hematological, biochemical, and oxidative status triggered by the cholinergic system. Methods: For this, fifty female Swiss mice were distributed in eight groups, i.e., uninfected and infected animals under four treatment protocols: untreated (control—CT); vehicle treatment (Eudragit L 100—EL-100); benznidazole treatment (BNZ); and nanoencapsulated benznidazole treatment (NBNZ). After eight treatment days, the animals were euthanized for sample collection. Results: The peak of parasitemia was at day 7 p.i., and the BNZ and NBNZ controlled and reduced the parasite rate but showed no efficacy in terms of total elimination of parasites analyzed by RT-PCR in both infected groups. The infection promotes significant anemia, leukopenia, and thrombocytopenia, which the BNZ improves. There was an increase in AChE activity during infection, leading to a pro-inflammatory response and an increase in M1 and M2 mACh receptors in the BNZ group, showing that the treatment interacted with the cholinergic pathway. In addition, a pro-oxidative response was characterized in the infection and mainly in the infected BNZ and NBNZ groups. The histopathological analysis showed significative splenomegaly and inflammatory infiltrate in the heart, liver, and spleen. Conclusions: The administration of the BNZ or NBNZ reverses hematological, hepatic, and renal alterations through cholinergic signaling and stimulates a pro-inflammatory response during acute T. cruzi infection.