Search Results (94)

The NOD-like receptor (NLR) signaling pathway may influence human immunodeficiency virus (HIV) clearance and CD4⁺ T cell recovery through inflammatory responses, but its specific mechanism requires further investigation. A deeper understanding of genetic variations can provide new insights into the biological mechanisms underlying the occurrence and development of immunodeficiency syndrome (AIDS). By utilizing multiple bioinformatic analyses and functional annotations, we identified single-nucleotide polymorphisms (SNPs) in the NLR signaling pathway that may affect HIV-1 infection and AIDS progression. Then, a case–control study was performed to screen risk-related variants by genotyping candidate SNPs in a sample of 500 men who have sex with men (MSM) with HIV-1 and 500 healthy controls from the Han population in Northern China. The results revealed significant association between five SNPs (NLRP3 rs4612666, MAVS rs17857295, MAVS rs6084497, MAVS rs16989000, and JAK1 rs4244165) and HIV-1 infection. Interestingly, the gene–gene interaction model composed of five SNPs exhibited a cumulative effect on the disease. Specially, the increase in risk alleles carried by the samples elevated the risk of contracting HIV-1. In addition, three SNPs (IL1B rs1143623, STAT1 rs1467199 and STAT1 rs2066804) were associated with CD4⁺ T cell counts in patients with AIDS. Three SNPs (OAS1 rs1131454, NLRP3 rs10754558, and MAVS rs867335) were found to be related to the clinical staging of AIDS. This finding provides insights into the genetic variants in NLR signaling pathway genes in HIV-1 infection and AIDS progression among MSM in Northern China. Full article

The side effects associated with the chemotherapy of triple-negative breast cancer (TNBC), such as nucleotide-binding oligomerization domain (NOD)-like receptor family (NLR), pyrin domain containing 3 (NLRP3) inflammasome activity, are responsible for the treatment failure and high mortality rates. Therefore, advanced delivery systems have been developed to improve the transport and targeted administration of anti-tumor agents at the tumor sites using tissue engineering approaches. Implantable delivery systems based on biodegradable polymers are an effective alternative due high biocompatibility, porosity, and mechanical strength. Moreover, the use of paclitaxel (PTX)-cyclodextrin complexes increases the solubility and permeability of PTX, enhancing the bioavailability and efficacy of the drug. All of these properties contribute to the efficient encapsulation and controlled release of drugs, preventing the damage of healthy tissues. In the current study, we detailed the synthesis process and evaluation of 3D scaffolds based on gelatin functionalized with methacryloyl groups (GelMA) and pectin loaded with PTX–cyclodextrin inclusion complexes on TNBC pathogenesis in vitro and in vivo. Bio-physio-chemical analysis of the proposed scaffolds revealed favorable mechanical and biological properties for the cellular component. To improve the drug solubility, a host–guest interaction was performed by the complexation of PTX with a cyclodextrin derivative prior to scaffold synthesis. The presence of PTX suppressed the growth of breast tumor cells and promoted caspase-1 activity, the release of interleukin (IL)-1β, and the production of reactive oxygen species (ROS), conditioning the expression levels of the genes and proteins associated with breast tumorigenesis and NLRP3 inflammasome. The in vivo experiments suggested the activation of pyroptosis tumor cell death, confirming the in vitro experiments. In conclusion, the bio-mechanical properties of the GelMA and pectin-based scaffolds as well as the addition of the PTX–cyclodextrin complexes allow for the targeted and efficient delivery of PTX, suppressing the viability of the breast tumor cells via pyroptosis cell death initiation. Full article

Atherosclerosis, a chronic inflammatory disease, is driven by complex molecular mechanisms involving inflammatory cytokines and immune pathways. According to recent research, tricyclic antidepressants (TCAs), which are typically prescribed to treat depressive disorders, have strong anti-inflammatory effects. TCAs, including imipramine and amitriptyline, alter inflammatory signaling cascades, which include lowering the levels pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6 and inhibiting NF-κB activation. By inhibiting the NLRP3 inflammasome and suppressing pathways including JAK/STAT, MAPK, and PI3K, these effects are produced, improving endothelial function and reducing oxidative stress. The intricacy of TCAs’ anti-inflammatory actions has demonstrated by the existence of contradictory findings about how they alter IL-6 levels. The dependence of the heterogeneity of the reaction on the use of particular TCAs and experimental settings is shown by the fact that some studies show reduced IL-6 production, while others indicate increases or no changes. This review explores the multifaceted mechanisms through which TCAs modulate inflammatory pathways. TCAs inhibit NF-κB activation, reduce oxidative stress, and suppress the production of key inflammatory mediators, including IL-6 and TNF-α. They also regulate Toll-like receptor (TLR) signaling and NOD-, LRR-, and NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome activation, reducing the release of IL-1β and IL-18, critical drivers of endothelial dysfunction and plaque instability. Given their capacity to target critical inflammatory molecules and pathways, TCAs provide great potential in the therapy of atherosclerosis, particularly for individuals with associated depression and cardiovascular risk factors. Nevertheless, further research is essential to clarify the precise molecular mechanisms, resolve inconsistencies in current findings, and establish the clinical applicability of TCAs as anti-inflammatory agents in atherosclerosis management. Full article

Current knowledge about Alzheimer’s disease highlights the accumulation of β-amyloid plaques (Aβ1–42) and neurofibrillary tangles composed of hyperphosphorylated Tau, which lead to the loss of neuronal connections. Microglial activation and the release of inflammatory mediators play a significant role in the progression of Alzheimer’s pathology. Recent advances have identified the involvement of inflammasomes, particularly NOD-like receptor NLR family pyrin domain containing 3 (NLRP3), whose activation promotes the release of proinflammatory cytokines and triggers pyroptosis, exacerbating neuroinflammation. Aggregates of Aβ1–42 and hyperphosphorylated Tau have been shown to activate these inflammasomes, while the apoptosis-associated speck-like protein (ASC) components form aggregates that further accelerate Aβ aggregation. Defects in the autophagic clearance of inflammasomes have also been implicated in Alzheimer’s disease, contributing to sustained inflammation. This review explores strategies to counteract inflammation in Alzheimer’s, emphasizing the degradation of ASC specks and the inhibition of NLRP3 inflammasome activation. Notably, the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor emerges as a promising therapeutic target due to its dual role in mitigating oxidative stress and directly inhibiting NLRP3 inflammasome formation. By reducing inflammasome-driven inflammation, Nrf2 offers significant potential for addressing the neuroinflammatory aspects of Alzheimer’s disease. Full article

NOD-like receptors (NLRs) are a family of cytosolic pattern recognition receptors (PRRs) implicated in the innate immune sensing of pathogens and damage signals. NLRs act as sensors in multi-protein complexes called inflammasomes. Inflammasome activity is necessary for the maintenance of intestinal homeostasis, although their aberrant activation contributes to the pathogenesis of several gastrointestinal diseases. In this review, we summarize the main features of the predominant types of inflammasomes involved in gastrointestinal immune responses and their implications in intestinal disease, including Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), celiac disease, and Colorectal Cancer (CRC). In addition, we report therapeutic discoveries that target the inflammasome pathway, highlighting promising novel therapeutic strategies in the treatment of intestinal diseases. Collectively, our understanding of the mechanisms of intestinal inflammasome activation and their interactions with other immune pathways appear to be not fully elucidated. Moreover, the clinical relevance of the efficacy of inflammasome inhibitors has not been evaluated. Despite these limitations, a greater understanding of the effectiveness, specificity, and reliability of pharmacological and natural inhibitors that target inflammasome components could be an opportunity to develop new therapeutic options for the treatment of intestinal disease. Full article

The article characterises platelets, pointing out the role and contribution of their numerous receptors determining their specific and broad immune activity. Three types of platelet receptors are described, that is, extracellular and intracellular receptors—TLR (toll-like receptors), NLR (NOD-like receptor), and RLR (RIG-I-like receptor); extracellular receptors—selectins and integrins; and their other extracellular receptors—CLR (C-type lectin receptor), CD (cluster of differentiation), TNF (tumour necrosis factor), among others. Outlining the contribution of these numerous platelet receptors to the intravascular immunity, it has been shown that they are formed by their fusion with pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and lifestyle-associated molecular patterns (LAMPs). They are initiating and effector components of signal transduction of these cells, and their expression and quantity determine the specific and broad functions of platelets towards influencing vascular endothelial cells, but mainly PRRs (pattern recognition receptors) of blood immune cells. These facts make platelets the fundamental elements that shape not only intravascular homeostasis, as previously indicated, but they become the determinants of immunity in blood vessels. Describing the reactions of the characterised three groups of platelet receptors with PAMP, DAMP and LAMP molecules, the pathways and participation of platelets in the formation and construction of intravascular immune status, in physiological states, but mainly in pathological states, including bacterial and viral infections, are presented, making these cells essential elements in the health and disease of mammals, including humans. Full article

Periodontal disease remains a significant global health concern, characterized by complex host–pathogen interactions leading to tissue destruction. This review explored the role of pattern recognition receptors (PRRs) in the pathogenesis of periodontal disease, synthesizing current knowledge on their molecular mechanisms and potential as therapeutic targets. We examined the diverse family of PRRs, focusing on toll-like receptors (TLRs) and NOD-like receptors (NLRs), elucidating their activation by periodontal pathogens and subsequent downstream signaling cascades. This review highlights the intricate interplay between PRR-mediated pathways, including NF-κB and MAPK signaling, and their impact on inflammatory responses and bone metabolism in periodontal tissues. We discussed the emerging concept of PRR crosstalk and its implications for periodontal homeostasis and disease progression. Furthermore, this review addressed the potential of PRR-targeted therapies, exploring both challenges and opportunities in translating molecular insights into clinical applications. By providing an overview of PRRs in periodontal health and disease, this review aims to stimulate future research directions and inform the development of novel diagnostic and therapeutic strategies in periodontology. Full article

Fowl adenovirus serotype 4 (FAdV-4) outbreaks have caused significant economic losses in the Chinese poultry industry since 2015. The relationships among viral structural proteins in infected hosts are relatively unknown. To explore the role of different parts of the fiber-1 protein in FAdV-4-infected hosts, we truncated fiber-1 into fiber-1-Δ1 (73–205 aa) and fiber-1-Δ2 (211–412 aa), constructed pEF1α-HA-fiber-1-Δ1 and pEF1α-HA-fiber-1-Δ2 and then transfected them into leghorn male hepatocyte (LMH) cells. After FAdV-4 infection, the roles of fiber-1-Δ1 and fiber-1-Δ2 in the replication of FAdV-4 were investigated, and transcriptome sequencing was performed. The results showed that the fiber-1-Δ1 and fiber-1-Δ2 proteins were the shaft and knob domains, respectively, of fiber-1, with molecular weights of 21.4 kDa and 29.6 kDa, respectively. The fiber-1-Δ1 and fiber-1-Δ2 proteins were mainly localized in the cytoplasm of LMH cells. Fiber-1-Δ2 has a greater ability to inhibit FAdV-4 replication than fiber-1-Δ1, and 933 differentially expressed genes (DEGs) were detected between the fiber-1-Δ1 and fiber-1-Δ2 groups. Functional analysis revealed these DEGs in a variety of biological functions and pathways, such as the phosphoinositide 3-kinase–protein kinase b (PI3K–Akt) signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, cytokine–cytokine receptor interactions, Toll-like receptors (TLRs), the Janus tyrosine kinase–signal transducer and activator of transcription (Jak–STAT) signaling pathway, the nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) signaling pathway, and other innate immune pathways. The mRNA expression levels of type I interferons (IFN-α and INF-β) and proinflammatory cytokines (IL-1β, IL-6 and IL-8) were significantly increased in cells overexpressing the fiber-1-Δ2 protein. These results demonstrate the role of the knob domain of the fiber-1 (fiber-1-Δ2) protein in FAdV-4 infection and provide a theoretical basis for analyzing the function of the fiber-1 protein of FAdV-4. Full article

Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) inflammasomes are multiprotein signaling platforms that control the inflammatory response and coordinate antimicrobial defense. In the present study, the distribution of NLR, Caspase-1, and gasdermin (GSDM) homologues and their structural characteristics and evolutionary relationships were systematically analyzed in metazoa according to the genomes of species. In invertebrates, there were only NLRC and/or NLRD presented from sponge to amphioxus, and according to the evolutionary tree, NLR from sponge located in the most primitive position. Caspase-1 existed in some metazoan phyla (Brachiopoda, Ectoprocta, Arthropoda, Mollusca, Annelia, Nematoda, Platyelminthes, Coelenterate, and Porifera) and its activation sites were relatively conserved. The amino acid sequences and three-dimensional structures of N-terminal CARD/Death domain of NLR and Caspase-1 were similar in species from sponge to human. NLR and Caspase-1 co-existed in species of Brachiopoda, Mollusca, Annelia, Coelenterate, and Porifera. There was only GSDME or PJVK found in some phyla of invertebrates and their cleavage sites were conserved (DxxD). And it was predicted that the NLR inflammasome in inducing pyroptosis could occur in species of Brachiopoda, Mollusca, Annelia, and Coelenterate. These studies indicated that NLR inflammasome emerged early in sponges of metazoa, and NLR inflammasome in inducing pyroptosis first appeared in Coelenterate, suggesting that inflammasome and its mediated pyroptosis had existed in the early stage of metazoa, but they had been lost in many species during evolution. Full article

Cardiovascular disease (CVD) may be inherited, as recently shown with the identification of single nucleotide polymorphisms (SNPs or “snips”) on a 250 kb DNA fragment that encodes 92 proteins associated with CVD. CVD is also triggered by microbial dysbiosis, microbial metabolites, metabolic disorders, and inflammatory intestinal epithelial cells (IECs). The epithelial cellular adhesion molecule (Ep-CAM) and trefoil factor 3 (TFF3) peptide keeps the gut wall intact and healthy. Variations in Ep-CAM levels are directly linked to changes in the gut microbiome. Leptin, plasminogen activator inhibitor 1 (PAI1), and alpha-1 acid glycoprotein 1 (AGP1) are associated with obesity and may be used as biomarkers. Although contactin 1 (CNTN1) is also associated with obesity and adiposity, it regulates the bacterial metabolism of tryptophan (Trp) and thus appetite. A decrease in CNTN1 may serve as an early warning of CVD. Short-chain fatty acids (SCFAs) produced by gut microbiota inhibit pro-inflammatory cytokines and damage vascular integrity. Trimethylamine N-oxide (TMAO), produced by gut microbiota, activates inflammatory Nod-like receptors (NLRs) such as Nod-like receptor protein 3 (NLRP3), which increase platelet formation. Mutations in the elastin gene (ELN) cause supra valvular aortic stenosis (SVAS), defined as the thickening of the arterial wall. Many of the genes expressed by human cells are regulated by gut microbiota. The identification of new molecular markers is crucial for the prevention of CVD and the development of new therapeutic strategies. This review summarizes the causes of CVD and identifies possible CVD markers. Full article

Inflammation is the body’s non-specific response to injury or infection. It is a natural defense mechanism that helps to maintain homeostasis and promotes tissue repair. However, excessive inflammation can lead to cellular, tissue, or organ dysfunction, as well as contribute to the development of acute vascular events and diseases like Crohn’s disease, psoriasis, obesity, diabetes, and cancer. The initial response to injury involves the activation of platelets and coagulation mechanisms to stop bleeding. This is followed by the recruitment of immune cells and the release of cytokines to promote tissue repair. Over time, the injured tissue undergoes remodeling and returns to its pre-injury state. Inflammation is characterized by the activation of inflammatory signaling pathways involving cytokines, chemokines, and growth factors. Mast cells play a role in initiating inflammatory responses. Pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and nucleotide-binding domain (NOD)-like receptors (NLRs) are involved in the activation of these inflammatory pathways. Inflammasomes, which are cytoplasmic complexes, also contribute to inflammation by activating cytokines. Inflammation can also be triggered by factors like dietary components and the composition of the gut microbiota. Dysregulation of the gut microbiome can lead to excessive inflammation and contribute to diseases like atherosclerosis and irritable bowel syndrome (IBS). The immune system and gut-associated lymphoid tissue (GALT) play crucial roles in the inflammatory response and the development of conditions like colorectal cancer. Anti-inflammatory therapy can play a significant role in reducing or inducing the remission of inflammatory diseases such as Crohn’s disease and ulcerative colitis. The fetal origin of adult diseases theory suggests that conditions during fetal development, such as low birth weight and maternal obesity, can influence the risk of cardiometabolic diseases later in life. All of the known risk factors associated with cardiometabolic diseases such as hypertension, excess weight, obesity, type-2 diabetes, and vascular diseases are accompanied by chronic low-grade inflammation. Inflammation seems to have a role in precipitating even acute vascular events such as heart attacks and stroke. Common markers of inflammation associated with cardiometabolic disease include interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF-α), C-reactive protein (CRP), and soluble TNF receptors such as sTNFR1 and sTNFR2. These markers serve as indicators of systemic inflammation. However, these markers are not disease-specific but provide an insight into the overall chronic inflammatory status. In fact, inflammation has been identified as a potential target for future treatments to reduce or reverse the risk of atherosclerosis-related complications. The regulation of inflammation is complex, and further research is needed to better understand its mechanisms and develop strategies for managing inflammatory disorders. In summary, inflammation is a natural response to injury or infection, but excessive or prolonged inflammation can lead to the progression of various diseases. Understanding the underlying mechanisms of inflammation is important for developing treatments and preventive measures for inflammatory disorders. Full article

Mycotoxins are secondary metabolites produced by several fungi and moulds that exert toxicological effects on animals including immunotoxicity, genotoxicity, hepatotoxicity, teratogenicity, and neurotoxicity. However, the toxicological mechanisms of mycotoxins are complex and unclear. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a multimeric cytosolic protein complex composed of the NLRP3 sensor, ASC adapter protein, and caspase-1 effector. Activation of the NLRP3 inflammasome plays a crucial role in innate immune defence and homeostatic maintenance. Recent studies have revealed that NLRP3 inflammasome activation is linked to tissue damage and inflammation induced by mycotoxin exposure. Thus, this review summarises the latest advancements in research on the roles of NLRP3 inflammasome activation in the pathogenesis of mycotoxin exposure. The effects of exposure to multiple mycotoxins, including deoxynivalenol, aflatoxin B1, zearalenone, T-2 toxin, ochratoxin A, and fumonisim B1, on pyroptosis-related factors and inflammation-related factors in vitro and in vivo and the pharmacological inhibition of specific and nonspecific NLRP3 inhibitors are summarized and examined. This comprehensive review contributes to a better understanding of the role of the NLRP3 inflammasome in toxicity induced by mycotoxin exposure and provides novel insights for pharmacologically targeting NLRP3 as a novel anti-inflammatory agent against mycotoxin exposure. Full article

While existing local therapies partially restore vision loss from diabetic retinopathy (DR), there is currently no reliable treatment to prevent the onset or stop the progression of the disease. This review seeks to explore the inflammatory molecular mechanisms underpinning DR pathogenesis, which have not been targeted by current interventions. Specifically, this review explores the role of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) protein 3 (NLRP3) inflammasome in DR onset and progression. Evidence through clinical trials has begun to note that specific drugs (fenofibrate, metformin) appear effective in slowing DR progression independent of lipid or glucose-lowering, respectively, suggesting that other mechanisms are at play. Novel therapeutics that inhibit the activation of the NLRP3 inflammasome pathway may provide a novel treatment for halting DR progression. Full article

The lung is prone to infections from respiratory viruses such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). A challenge in combating these infections is the difficulty in targeting antiviral activity directly at the lung mucosal tract. Boosting the capability of the respiratory mucosa to trigger a potent immune response at the onset of infection could serve as a potential strategy for managing respiratory infections. This study focused on screening immunomodulators to enhance innate immune response in lung epithelial and immune cell models. Through testing various subfamilies and pathways of pattern recognition receptors (PRRs), the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family was found to selectively activate innate immunity in lung epithelial cells. Activation of NOD1 and dual NOD1/2 by the agonists TriDAP and M-TriDAP, respectively, increased the number of IL-8+ cells by engaging the NF-κB and interferon response pathways. Lung epithelial cells showed a stronger response to NOD1 and dual NOD1/2 agonists compared to control. Interestingly, a less-pronounced response to NOD1 agonists was noted in PBMCs, indicating a tissue-specific effect of NOD1 in lung epithelial cells without inducing widespread systemic activation. The specificity of the NOD agonist pathway was confirmed through gene silencing of NOD1 (siRNA) and selective NOD1 and dual NOD1/2 inhibitors in lung epithelial cells. Ultimately, activation induced by NOD1 and dual NOD1/2 agonists created an antiviral environment that hindered SARS-CoV-2 replication in vitro in lung epithelial cells. Full article

In pathogen recognition, the nucleotide-binding domain (NBD) and leucine rich repeat receptors (NLRs) have noteworthy functions in the activation of the innate immune response. These receptors respond to several viral infections, among them NOD2, a very dynamic NLR, whose role in dengue virus (DENV) infection remains unclear. This research aimed to determine the role of human NOD2 in THP-1 macrophage-like cells during DENV-2 infection. NOD2 levels in DENV-2 infected THP-1 macrophage-like cells was evaluated by RT-PCR and Western blot, and an increase was observed at both mRNA and protein levels. We observed using confocal microscopy and co-immunoprecipitation assays that NOD2 interacts with the effector protein MAVS (mitochondrial antiviral signaling protein), an adaptor protein promoting antiviral activity, this occurring mainly at 12 h into the infection. After silencing NOD2, we detected increased viral loads of DENV-2 and lower levels of IFN-α in supernatants from THP-1 macrophage-like cells with NOD2 knock-down and further infected with DENV-2, compared with mock-control or cells transfected with Scramble-siRNA. Thus, NOD2 is activated in response to DENV-2 in THP-1 macrophage-like cells and participates in IFN-α production, in addition to limiting virus replication at the examined time points. Full article