Immunological Functions Research Articles

Apoptosis: A Comprehensive Overview of Signaling Pathways, Morphological Changes, and Physiological Significance and Therapeutic Implications

Cell survival and death are intricately governed by apoptosis, a meticulously controlled programmed cell death. Apoptosis is vital in facilitating embryonic development and maintaining tissue homeostasis and immunological functioning. It is a complex interplay of intrinsic and extrinsic signaling pathways that ultimately converges on executing the apoptotic program. The extrinsic pathway is initiated by the binding of death ligands such as TNF-α and Fas to their respective receptors on the cell surface. In contrast, the intrinsic pathway leads to increased permeability of the outer mitochondrial membrane and the release of apoptogenic factors like cytochrome c, which is regulated by the Bcl-2 family of proteins. Once activated, these pathways lead to a cascade of biochemical events, including caspase activation, DNA fragmentation, and the dismantling of cellular components. Dysregulation of apoptosis is implicated in various disorders, such as cancer, autoimmune diseases, neurodegenerative disorders, and cardiovascular diseases. This article focuses on elucidating the molecular mechanisms underlying apoptosis regulation, to develop targeted therapeutic strategies. Modulating apoptotic pathways holds immense potential in cancer treatment, where promoting apoptosis in malignant cells could lead to tumor regression. This article demonstrates the therapeutic potential of targeting apoptosis, providing options for treating cancer and neurological illnesses. The safety and effectiveness of apoptosis-targeting drugs are being assessed in ongoing preclinical and clinical trials (phase I–III), opening the door for more effective therapeutic approaches and better patient outcomes.

A pan-cancer study of ADAM9’s immunological function and prognostic value particularly in liver cancer

A pan-cancer analysis summarizing the overall changes in mRNA and protein stability of ADM9, as well as its oncogenic function on immune cell line modulation and checkpoints within the tumor microenvironment (TME), is lacking, despite the fact that ADM9 up-regulation is correlated with the progression of many cancers. Therefore, in this study, we comprehensively analyzed the role of ADAM9 expression and its prognostic value in different cancers to fill this gap. Multiple bioinformatics databases such as Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) were used to evaluate the ADAM9 genetic alternation, phosphorylation, and methylation, and indicated highly positive correlated genes that might play a critical interaction with ADAM9 and their molecular function with GO analysis. We also evaluate the effect of higher ADAM9 with prominent immune modulatory genes and immune infiltration especially in liver cancer pathogenesis stimulates lower NK cell effector functions based on its role in MICA shedding and increasing the Tregs infiltration. Immunohistochemistry (IHC) staining from 90 pathologically verified samples proved the positive correlation between ADAM9 and tumor stages and proved the higher expression of ADAM9 correlated genes (SNX9, APP, TNF, CDH1, ITGAV, MAD2L2) in HCC pathogenesis. In conclusion, this pan-cancer study provides a comprehensive understanding of the prognostic value of ADAM9 in various tumors emphasizing its importance to be considered as an innovative treatment approach, especially in tumor immunity shortly.

Structural Characteristics and Immunological Function of a New Non-Starch Polysaccharide from Red Sprout Taro

Taro is a tuber crop that is used for nutritional and medicinal purposes due to its abundance of non-starch polysaccharides (NSPs). Red Sprout taro is a local variety in Southern China, but the characteristics and bioactivities of its NSPs are currently unknown. In this study, NSPs were isolated from the corms of Red Sprout taro using hot-water extraction, ion-exchange chromatography, and ethanol precipitation; their molecular weight, monosaccharide composition, structural formulae, and immunomodulatory effects were examined. A novel NSP named Colocasia esculenta polysaccharide 1 (CEP1) was purified and characterized and was shown to mainly consist of glucose (60.49%) and galactose (25.92%) and have a molecular weight of 4556.272 kDa. The backbone of CEP1 consisted primarily of →4)-α-D-Glcp-(1→, →4,6)-β-D-Galp-(1→, and →3)-β-D-Galp-(1→ residues, with a branch consisting of the β-D-Glcp-(1→ residue. In addition, 25–400 µg/mL CEP1 was shown to have immunomodulatory effects on RAW264.7 macrophages. CEP1 not only increased cell viability, phagocytic capacity, inducible nitric oxide synthase secretion, and nitric oxide generation in RAW264.7 cells, but it also activated M1 and M2 macrophages to generate tumor necrosis factor α, interleukin 6, transforming growth factor β, and interleukin 10. These findings could lead to the use of CEP1 from Red Sprout taro as a possible immunomodulatory polysaccharide in functional foods.

Inflammation as a shared mechanism of chronic stressrelated disorders with potential novel therapeutic targets.

Stress is a subjective experience that varies across individuals depending on their sensitivity, resilience, and length of exposure to stressors. Stress may be categorised as acute (positive stress) or chronic (negative stress). Acute stress is advantageous for the human body, but chronic stress results in changes in cardiovascular, neuroendocrine, autonomic, and immunological functions, eventually causing different illnesses. The specific process relating stress to chronic stress associated diseases is still a topic of continuing debate. Inflammation has been recognised as a new and fascinating physiological mechanism that connects chronic stress and its associated illnesses. This article explored the relationships between chronic stress, inflammation, and chronic illnesses, including depression, cancer, and cardiovascular disease. This article also emphasises on various possible therapeutic targets for the management of chronic stressrelated illnesses by targeting inflammation, namely lipoxins and alpha7 nicotinic receptors. These therapeutic targets may be useful in developing new and safe therapies for the management of chronic stressrelated dysfunctions.

Enhancing Broiler Growth and Carcass Quality: Impact of Diets Enriched with Moringa oleifera Leaf Powder Conjugated with Zinc Nanoparticles

This study evaluated the effects of Moringa oleifera leaf powder extract stabilized with zinc nanoparticles (ZnNPs-MLPE) as a natural growth promoter in broiler diets. Randomly assigned 264 one-day-old Ross 308 chicks to four different feeding treatments, with each group being subdivided into six replicates, each comprising 11 unsexed chicks. The control group was fed a basic diet without additives, while the experimental groups were supplemented with 1.0, 2.0, or 3.0 cm³ of ZnNPs-MLPE/L of diet. The findings demonstrated that 2.0 and 3.0 cm³/L ZnNPs-MLPE supplementation significantly enhanced live body weight (LBW) and weight gain (BWG). Feed intake (FI) and feed conversion ratio (FCR) did not show significant differences between the treated groups and the control, indicating that the additive did not negatively affect feed efficiency. However, an increase in abdominal fat was noted in the ZnNPs-MLPE treatments relative to the control. Blood analysis revealed that the ZnNPs-MLPE groups had significantly lower levels of "total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and alanine transaminase (ALT) compared to the control group. In contrast, total protein (TP), albumin, and the albumin/globulin (A/G) ratio" were higher in the ZnNPs-MLPE groups. Immunoglobulins IgY and IgM, as well as superoxide dismutase (SOD) levels, were elevated. Malondialdehyde (MDA) levels were reduced, indicating improved antioxidant capacity and immune function in the ZnNPs-MLPE-treated groups. In conclusion, supplementation with ZnNPs-MLPE at 2.0 and 3.0 cm³/L positively impacted broiler growth efficiency, antioxidant capacity, and immunological functionality. These findings support the potential of ZnNPs-MLPE as an effective natural growth enhancer for producing healthier poultry products.

Citizen science observations shed light on how anthropogenic food sources influence wildlife disease.

Research Highlight: Knutie, S., Bahouth, R., Bertone, M., Webb, C., Mehta, M., Nahom, M., Barta, R., Ghai, S., Love, A., Horan, S., Soldo, A., Cochrane, E., Bartholomew, J., Cowan, E., Bjerke, H., Balenger, S., Butler, M., Cornell, A., Kennedy, A., Rolland, V., Schultz, E., Stanback, M., Taff, C., Albery, G. (2024). Understanding spatiotemporal effects of food supplementation on host-parasite interactions using community-based science. Journal of Animal Ecology. https://doi.org/10.1111/1365-2656.14155. Wildlife have become increasingly dependent on anthropogenic food supplementation, resulting in altered nutritional intake and inter- and intraspecific interactions. Subsequently, supplemental feeding can affect both the immunological function of individuals and transmission dynamics among individuals and species. The magnitude of the effect supplemental feeding has on disease is likely to vary across time and space with the nutritional demands of hosts. However, the broad temporal or spatial scale effects of supplementation are poorly understood. Recently, Knutie etal. (2024) introduced their citizen science program, the Nest Parasite Community Project, a broadscale coordinated effort by scientists and the public to monitor box nesting wild birds and their ectoparasites across the eastern United States. The authors amassed an impressive 4-year data set with hundreds of nests spanning the entire US breeding range of Eastern bluebirds (Sialia sialis). In the first study to come from the project, the authors demonstrate that the effects of food supplementation on host-parasite interactions vary across time and space and do not consistently influence host-parasite outcomes, highlighting that host-parasite interactions are often context dependent and influenced by many environmental factors (e.g. weather and habitat quality). The authors also found that supplemental feeding increases host fitness, regardless of parasitism. The study provides strong evidence that citizen science projects can help broaden our understanding of how human food sources influence wildlife disease in various environmental contexts.

Distinct Cutibacterium acnes subspecies defendens strains classified by multi-omics dissection alleviate inflammatory skin lesions of a rosacea-like mouse model

IntroductionCutibacterium acnes (C. acnes) resides in various organs such as the skin, prostate, eye, nose, stomach, and intestine, indicating the possibility of extensive crosstalk between this bacterium and the human body. C. acnes strains are classified into three subspecies based on phylogenetics and distinguishable phenotypes. Among them, C. acnes subsp. defendens strains are characterized by anti-inflammatory features, raising expectations for their potential as future microbiome therapeutics. However, the heterogeneity of C. acnes subsp. defendens and its corresponding immunological functions have not been clearly addressed.MethodsThe genetic diversity of the strains was assessed using single- and multi-locus sequence typing. Their immune-modulatory functions were evaluated in vitro using 2D and 3D assays with immune and epithelial cells. The anti-inflammatory effects were further confirmed in vivo using a rosacea-like mouse model. Comparative genomic and transcriptomic analyses were conducted to uncover mechanisms underlying the immunosuppressive activity of the strains.ResultsWe demonstrated that the newly isolated C. acnes subsp. defendens strains, exhibiting phenotypic heterogeneity, are distinctly clustered using single- and multi-locus sequence typing methods. These strains showed strong immune-regulatory functions in immune and epithelial cell-based 2D and 3D in vitro assays. Furthermore, their anti-inflammatory role was functionally confirmed in vivo using a rosacea-like mouse model, where they alleviated skin lesions characterized by hyperplasia and dermal inflammation. Comparative transcriptomics revealed that these strains may exert their immunosuppressive effects through the enhanced expression of acnecins and transcriptional variation in envelope stress regulators (specifically the two-component systems, CesSR homologs). Additionally, we propose that these C. acnes type II strains produce anti-inflammatory metabolites or peptides smaller than 3 kDa, which are associated with elevated pyrimidine and reduced L-arginine biosynthesis.DiscussionThe newly isolated C. acnes subsp. defendens strains demonstrate significant anti-inflammatory properties both in vitro and in vivo, suggesting their potential as microbiome-based therapeutics. Their unique genomic and transcriptomic profiles, including the production of small bioactive compounds and specific transcriptomic patterns, underpin their immunosuppressive capabilities. These findings provide a foundation for developing novel treatments for inflammatory skin conditions, such as rosacea.

Hypothetical proteins of chicken-isolated Limosilactobacillus reuteri subjected to in silico analyses induce IL-2 and IL-10

Lactic acid bacteria (LAB) probiotics are health-promoting but their characteristics, safety profile and functional mechanisms are not fully understood. Hence, this study aimed to characterize some hypothetical proteins of the chicken-isolated Limosilactobacillus reuteri genome and unravel their IL-2 and IL-10-inducing potential to understand mechanisms of their immunological functionality for sustainable applications. The selected proteins were subjected to in silico analyses for transmembrane topology, sub-cellular localization, IL-2 and IL-10-inducing ability and IL-2 and IL-10 gene expression across various conditions. IL-2 and IL-10-inducing mutants were statistically analyzed using a one-way analysis of variance of a general linear model of SAS and statistical significance was set at p < 0.05. The analyzed proteins are stable under a wide temperature range. All the hypothetical proteins are IL-2 and IL-10-inducing but QHPv.2.12, QHPv.2.13 and QHPv.2.15 are non-immunogenic. The evaluated mutants are IL-2 and IL-10-inducers but QHPv.2.13 and QHPv.2.15 are not immunogenic. This study sheds light on understanding the functional mechanisms of chicken-isolated L. reuteri and suggests it or its proteins as potent candidates for feed additive and therapeutic purposes.

The effect of baby touch on premature infants

Objective: Premature infants require special attention during nursing. This study aimed to explore the effects of baby touch on the growth, immunity, sleep and communication in premature infants. Methods: This was a retrospective study. A total of 64 premature infants with a gestational age of 30-36 weeks were selected at Maternity &amp; Child Care Center of Qinhuangdao from June 2022 to May 2023, and randomly divided into experimental group and control group. The control group received routine comprehensive nursing care for newborns, while the experimental group was additionally treated with touch intervention using the international standard touch method. The effects of the three months touch on the growth and development, immunological function, sleep quality, and emotional communication of the premature infants were observed. Results: No statistically significant differences were found in gender, gestational age, birth weight, birth length, or head circumference at birth between the two groups (p&gt; 0.05). In the third month, the increases in body weight, body length and head circumference were significantly more obvious, the immunological function indicators including CD3+, CD4+, CD8+, IgG, IgA and IgM were all significantly higher, the sleep time and sleep quality were both significantly superior, and the interaction time and intimacy with parents were significantly superior in the experimental group compared with the control group, with statistically significant differences (p&lt; 0.05). Conclusion: Baby touch can promote growth and development, strengthen immunological function, improve sleep quality and enhance the emotional communication abilities of premature infants, and help them better adapt to the environment and grow. doi: https://doi.org/10.12669/pjms.40.10.9275 How to cite this: Du Q, Zhu H, Guo M, Yang Q, Yang H, Ma Y. The effect of baby touch on premature infants. Pak J Med Sci. 2024;40(10):2256-2260. doi: https://doi.org/10.12669/pjms.40.10.9275 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The role of preoperative immunonutrition on morbidity and immune response after cystectomy: protocol of a multicenter randomized controlled trial (INCyst Trial)

IntroductionCancer, malnutrition, and surgery negatively impact patient’s immune system. Despite standardized surgical technique and the development of new perioperative care protocols, morbidity after cystectomy remains a serious challenge for urologists. Most common postoperative complications, such as infections and ileus, often lead to longer length of stay and worse survival. The immune system and its interaction with the gut microbiota play a pivotal role in cancer immunosurveillance and in patient’s response to surgical stress. Malnutrition has been identified as an independent and modifiable risk factor for both mortality and morbidity. Immunonutrition (IN) may improve the nutritional status, immunological function, and clinical outcome of surgical patients. Aims of the study are (1) to evaluate the impact of IN on morbidity and mortality at 30 and 90 days after cystectomy and (2) to determine immune and microbiota signature that would predict IN effect.MethodsThis is a randomized, multicentric, controlled, pragmatic, parallel-group comparative study, supported by the Swiss National Science Foundation. A total of 232 patients is planned to be enrolled between April 2023 and June 2026. Three participating centers (Lausanne, Bern, and Riviera-Chablais) have been selected. All patients undergoing elective radical and simple cystectomy will be randomly assigned to receive 7 days of preoperative IN (Oral Impact®, Nestlé, Switzerland) versus standard of care (control group) and followed for 90 days after surgery. For the exploratory outcomes, blood, serum, urine, and stool samples will be collected in patients treated at Lausanne. In order to determine the impact of IN on immune fitness, patients enrolled at Lausanne will be vaccinated against influenza and the establishment of the vaccine-specific immune response will be followed. Analysis of the microbiota and expression of argininosuccinate synthetase 1 as potential biomarker will also be performed.Discussion and conclusionStrengths of the INCyst study include the randomized, multicenter, prospective design, the large number of patients studied, and the translational investigation. This study will challenge the added value of preoperative IN in patients undergoing cystectomy, assessing the clinical effect of IN on the onset of postoperative morbidity and mortality after cystectomy. Furthermore, it will provide invaluable data on the host immune response and microbiota composition.Trial registrationClinicalTrials.gov NCT05726786. Registered on March 9, 2023.

Key genes and immune pathways in T-cell mediated rejection post-liver transplantation identified via integrated RNA-seq and machine learning

Liver transplantation is the definitive treatment for end-stage liver disease, yet T-cell mediated rejection (TCMR) remains a major challenge. This study aims to identify key genes associated with TCMR and their potential biological processes and mechanisms. The GSE145780 dataset was subjected to differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning algorithms to pinpoint key genes associated with TCMR. Gene Set Enrichment Analysis (GSEA), immune infiltration analysis, and regulatory networks were constructed to ascertain the biological relevance of these genes. Expression validation was performed using single-cell RNA-seq (scRNA-seq) data and liver biopsy tissues from patients. We identified 5 key genes (ITGB2, FCER1G, IL-18, GBP1, and CD53) that are associated with immunological functions, such as chemotactic activity, antigen processing, and T cell differentiation. GSEA highlighted enrichment in chemokine signaling and antigen presentation pathways. A lncRNA-miRNA-mRNA network was delineated, and drug target prediction yielded 26 potential drugs. Evaluation of expression levels in non-rejection (NR) and TCMR groups exhibited significant disparities in T cells and myeloid cells. Tissue analyses from patients corroborated the upregulation of GBP1, IL-18, CD53, and FCER1G in TCMR cases. Through comprehensive analysis, this research has identified 4 genes intimately connected with TCMR following liver transplantation, shedding light on the underlying immune activation pathways and suggesting putative targets for therapeutic intervention.

Inflammasome-mediated pyroptosis in defense against pathogenic bacteria.

Macrophages, neutrophils, and epithelial cells are pivotal components of the host's immune response against bacterial infections. These cells employ inflammasomes to detect various microbial stimuli during infection, triggering an inflammatory response aimed at eradicating the pathogens. Among these inflammatory responses, pyroptosis, a lytic form of cell death, plays a crucial role in eliminating replicating bacteria and recruiting immune cells to combat the invading pathogen. The immunological function of pyroptosis varies across macrophages, neutrophils, and epithelial cells, aligning with their specific roles within the innate immune system. This review centers on elucidating the role of pyroptosis in resisting gram-negative bacterial infections, with a particular focus on the mechanisms at play in macrophages, neutrophils, and intestinal epithelial cells. Additionally, we underscore the cell type-specific roles of pyroptosis invivo in these contexts during defense.

Bidirectional regulation of the cGAS-STING pathway in the immunosuppressive tumor microenvironment and its association with immunotherapy.

Adaptive anti-tumor immunity is currently dependent on the natural immune system of the body. The emergence of tumor immunotherapy has improved prognosis and prolonged the survival cycle of patients. Current mainstream immunotherapies, including immune checkpoint blockade, chimeric antigen receptor T-cell immunotherapy, and monoclonal antibody therapy, are linked to natural immunity. The cGAS-STING pathway is an important natural immunity signaling pathway that plays an important role in fighting against the invasion of foreign pathogens and maintaining the homeostasis of the organism. Increasing evidence suggests that the cGAS-STING pathway plays a key role in tumor immunity, and the combination of STING-related agonists can significantly enhance the efficacy of immunotherapy and reduce the emergence of immunotherapeutic resistance. However, the cGAS-STING pathway is a double-edged sword, and its activation can enhance anti-tumor immunity and immunosuppression. Immunosuppressive cells, including M2 macrophages, MDSC, and regulatory T cells, in the tumor microenvironment play a crucial role in tumor escape, thereby affecting the immunotherapy effect. The cGAS-STING signaling pathway can bi-directionally regulate this group of immunosuppressive cells, and targeting this pathway can affect the function of immunosuppressive cells, providing new ideas for immunotherapy. In this study, we summarize the activation pathway of the cGAS-STING pathway and its immunological function and elaborate on the key role of this pathway in immune escape mediated by the tumor immunosuppressive microenvironment. Finally, we summarize the mainstream immunotherapeutic approaches related to this pathway and explore ways to improve them, thereby providing guidelines for further clinical services.

Splenic Trauma: Concepts and Technique for Interventional Management

AbstractThe spleen is the most commonly involved organ in abdominal trauma, especially in blunt mode of injury. High vascularity and a thin capsule predispose to rapid and fatal bleeding, which could be acute as well as delayed at onset. FAST is usually the first line of investigation required to see for fluid and screen patients suffering abdominal trauma. Triple-phase contrast-enhanced computed tomography of the abdomen further aids in diagnosing and grading splenic trauma as per the American Association for the Surgery of Trauma (AAST) guidelines. Hemodynamic stability and AAST grade are the main guiding parameters for management. Treatment options include surgical and nonsurgical (endovascular intervention) management. The recent concept of endovascular resuscitation and trauma management, which dwells on creating a hybrid suite, is coming up fast and will play a pivotal role in offering splenic preserving management in trauma cases. In this review article, authors have bought insights about managing splenic trauma as a multidisciplinary concept to achieve splenic preservation and maintain this vital organ's immunological functions.

Ultrarare Variants in DNA Damage Repair Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome or Acute Behavioral Regression in Neurodevelopmental Disorders.

Acute onset of severe psychiatric symptoms or regression may occur in children with premorbid neurodevelopmental disorders, although typically developing children can also be affected. Infections or other stressors are likely triggers. The underlying causes are unclear, but a current hypothesis suggests the convergence of genes that influence neuronal and immunological function. We previously identified 11 genes in Pediatric Acute-Onset Neuropsychiatry Syndrome (PANS), in which two classes of genes related to either synaptic function or the immune system were found. Among the latter, three affect the DNA damage response (DDR): PPM1D, CHK2, and RAG1. We now report an additional 17 cases with mutations in PPM1D and other DDR genes in patients with acute onset of psychiatric symptoms and/or regression that their clinicians classified as PANS or another inflammatory brain condition. The genes include clusters affecting p53 DNA repair (PPM1D, ATM, ATR, 53BP1, and RMRP), and the Fanconi Anemia Complex (FANCE, SLX4/FANCP, FANCA, FANCI, and FANCC). We hypothesize that defects in DNA repair genes, in the context of infection or other stressors, could contribute to decompensated states through an increase in genomic instability with a concomitant accumulation of cytosolic DNA in immune cells triggering DNA sensors, such as cGAS-STING and AIM2 inflammasomes, as well as central deficits on neuroplasticity. In addition, increased senescence and defective apoptosis affecting immunological responses could be playing a role. These compelling preliminary findings motivate further genetic and functional characterization as the downstream impact of DDR deficits may point to novel treatment strategies.

Genome-wide diversity, linkage disequilibrium, and admixture in the main Colombian Creole pig breeds

Colombian Creole pigs have adapted to tropical conditions for over 500 years. They have been modified by natural and artificial selection in different regions. At present, the diversity and current introgression status are unknown. The objective was to estimate the genomic diversity, linkage disequilibrium, population structure, and admixture of four Colombian pig breeds and their relationship with other breeds worldwide. Three Colombian pig breeds (SPE-San Pedreño, 11 samples; ZUN-Zungo, 11 samples; CM-Casco de Mula, ten samples) from the conservation nucleus and one biotype not recognized as a breed (CCH-Criollo Chocoano, seven samples) were genotyped using the Illumina GGP-Porcine80K chip. Open-access data from seven international breeds were also included. Colombian Creole pigs showed moderate genetic differentiation (FST 0.14) globally, but several groups of animals separated, suggesting local clustering due to geographical isolation or different founding effects. Colombian Creole pigs showed breed imprinting and specific grouping in all analyses except for CCH, which, like the Ecuadorian Creole, was a cluster of admixtures. The Colombian Creole pigs revealed a significant relationship with the Iberian pig and some other breeds to varying degrees. However, good maintenance of the conservation nucleus was evidenced. Potential adaptive genes, mainly related to immunological functions, were found, according to FST and pcadapt analyses. This study provides a foundation and scientific data for policy decisions on zoogenetic resources.

The β2-adrenergic biased agonist nebivolol inhibits the development of Th17 and the response of memory Th17 cells in an NF-κB-dependent manner.

Adrenergic receptors regulate metabolic, cardiovascular, and immunological functions in response to the sympathetic nervous system. The effect of β2-adrenergic receptor (AR) as a high expression receptor on different subpopulations of T cells is complex and varies depending on the type of ligand and context. While traditional β2-AR agonists generally suppress T cells, they potentially enhance IL-17A production by Th17 cells. The effects of pharmacological drugs that count as biased agonists of AR like nebivolol are not completely understood. We investigated the impact of nebivolol on human memory CD4+ T (Th1, Th2, Th17) cells and polarized naive Th17 cells, highlighting its potential for IL-17A suppression via a non-canonical β2-AR cell signaling pathway. The effects of nebivolol were tested on healthy human peripheral blood mononuclear cells, purified memory Th cells, and polarized naive Th17 cells activated with anti-CD3/anti-CD28/anti-CD2 ImmunoCult reagent. IFN-γ, IL-4, and IL-17A, which are primarily derived from Th1, Th2, and Th17 cells, respectively, were quantified by ELISA and flow cytometry. IL-10 was measured by ELISA. Gene expression of RORC, ADRB1, ADRB2, and ADRB3 was evaluated by qPCR. The ADRB2 gene was knocked out in memory Th cells using CRISPR/Cas9. Protein expression of phosphorylated serine133-CREB and phosphorylated NF-κB p65 was assessed by Western blot. Proliferation was assessed by fluorescent dye loading and flow cytometry. Nebivolol treatment decreased IL-17A and IFN-γ secretion by activated memory Th cells and elevated IL-4 levels. Nebivolol reduced the proportion of IL-17A+ Th cells and downregulated RORC expression. Unlike the β2-AR agonist terbutaline, nebivolol inhibited the shift of naive CD4+ T cells toward the Th17 phenotype. IL-10 and the proliferation index remained unchanged. Nebivolol-treated β2-knockout memory Th cells showed significant inhibition of β2-AR-mediated signaling, evidenced by the absence of IL-17A suppression compared to controls. Phosphorylation of the NF-κB p65 subunit was inhibited by nebivolol, but CREB phosphorylation was not changed, suggesting a selective transcriptional control. The findings demonstrate that nebivolol acts through a β2-AR-mediated signaling pathway, as a distinctive anti-inflammatory agent capable of selectively shifting Th17 cells and suppressing the phosphorylation of NF-κB. This highlights nebivolol's potential for therapeutic interventions in chronic autoimmune conditions with elevated IL-17A levels.

Two homologous genes encoding interleukin (IL)-34 in the common carp (Cyprinus carpio L.): Roles in inflammatory modulation and anti-bacterial defense

In mammals, interleukin 34 (IL-34) is a ligand for macrophage colony-stimulating factor receptor (M-CSFR), promoting inflammatory responses and inducing the synthesis and secretion of various cytokines. However, studies on its function in lower vertebrates is limited, and its evolutionary relationship with homologous molecules in mammals remains unclear. In this study, two IL-34-encoding genes were cloned and identified in common carp (Cyprinus carpio L.), designated as CcIL-34A and CcIL-34B, with an amino acid sequence similarity of 77.7 %. Gene synteny analysis revealed that the IL-34 gene loci are relatively conserved, and both are located downstream of SF3B3. The expression patterns of CcIL-34s were analyzed using qRT-PCR, and this showed that they are expressed across all tested tissues, with higher levels in the liver, spleen, and head kidney and lower levels in the gills and intestines. Following infection with Aeromonas hydrophila, the mRNA expression levels of CcIL-34s in the gills, head kidney, intestines, and spleen were significantly upregulated. Immunofluorescence was also employed to assess changes in CcIL-34 protein expression, showing a significant increase in carp spleens 24 h after A. hydrophila infection, suggesting that CcIL-34s contribute to host defense against this bacterium. To investigate the immunological function of IL-34 in vivo, pc-CcIL-34A and pc-CcIL-34B eukaryotic expression plasmids were constructed and injected intramuscularly into fish. Five days after injection, the expression levels of inflammation-related cytokines in the head kidney and spleen were significantly altered. Furthermore, 24 h post-A. hydrophila infection, the bacterial loads in the liver, spleen, and kidneys were significantly reduced. Ten days post-infection, the survival rates in the groups with CcIL-34A and CcIL-34B overexpression were 40 % and 36.7 %, respectively, compared to 16.7 % in the control group. These findings suggest that CcIL-34s are involved in modulating inflammatory responses, enhancing the immune response, and improving survival rates in fish following bacterial infection, thus supporting the potential use of IL-34 molecules in aquaculture.

Targeting CD3-CD16+CD56+ NK Cells and NK Cell Activity by Intralipid in the Management of Reproductive Failure

Immunological risk factors in recurrent pregnancy loss include autoantibodies, alterations in NK cell number and function, regulatory T cells, the human leukocyte antigen system (HLA), etc., where the treatment options aim to regulate immune dysfunction. Intralipid is a synthetic product traditionally used as a dietary supplement consisting of soybean oil combined with refined egg phospholipids. It has been shown that intralipid exerts physiologic activities, including altering immunological functions, that may benefit patients with certain types of infertility. In this review, we summarize the current state of the art of targeting NK cells and NK cell activity in women with implantation failure or/and recurrent pregnancy loss. We focus on intralipid mechanisms of action and outcomes of clinical trials regarding the efficacy and safety of intralipid infusions in women with reproductive failure. More studies are needed to reveal all the aspects of the safety and effectiveness of intralipid administration in reproductive failure treatment.

Effect of Phyto Constitutes of &lt;i&gt;Ayurveda&lt;/i&gt; and &lt;i&gt;Siddha&lt;/i&gt; Herbs on SARS-CoV-2/CoVID-19 Management by Modulating the Human Gut Microbiome

The therapeutic plants used in Ayurveda and Siddha medicine primarily function as immunomodulators to combat viral infection. The majority of the Indian states adopted an integrative approach to the treatment strategy for COVID-19 infection during the COVID-19 outbreak. A large percentage of Indians consume Ayurvedic and Siddha herbs as preventative medication or immune boosters during the COVID outbreak. ACE-2 receptor, Mpro, Nsp15, endoribonuclease, ACE-2-RBD interface, RBD complex, helicase inhibitors, and ACE-2-RBD interface are the main targets of the phytochemicals of medicinal plants, which also have the potential to limit their action and lower infection rates. The phytonutrients also preserve the permeability of the gut epithelial membrane and improve gut barrier proteins including occludin, Zo-1, and claudin. The phytonutrients also help probiotic bacteria flourish, such as Faecalibacterium, Rikenellaceae, Lactobacillus and Lachnospiraceae, which may lower proinflammatory cytokines and improve immunological function. A small number of opportunistic bacteria, such as Pseudomonas aeruginosa and Klebsiella pneumonia, co-infect with the SARS-CoV-2 virus and increase the frequency of hospital stays and severity of the illness. The co-infections or secondary infections may be reduced by the antibacterial and anti-inflammatory activities of phytochemicals.