Search Results (371)

The Cucurbitaceae family includes several edible species that are consumed globally as fruits and vegetables. These species produce high volumes of seeds that are often discarded as waste. In this study, we investigate the chemical composition and biological activity of three seed oils from Cucurbitaceae plants, namely, cantaloupe, honeydew, and zucchini, in comparison to the widely used pumpkin seed oil for their ability to enhance and accelerate wound healing in rats. Our results showed that honeydew seed oil (HSO) was effective in accelerating wound closure and enhancing tissue repair, as indicated by macroscopic, histological, and biochemical analyses, as compared with pumpkin seed oil (PSO). This effect was mediated by down-regulation of the advanced glycation end products (AGE) and its receptor (RAGE) cue, activating the cytoprotective enzymes nuclear factor erythroid 2 (Nrf2) and heme oxygenase-1 (HO-1), suppressing the inflammatory mediators tumor necrosis factor (TNF)-α, nuclear factor kappa B (NF-κB), and nod-like receptor protein 3 (NLRP3), and reducing the levels of the skin integral signaling protein connexin (CX)-43. Furthermore, immunohistochemical staining for epidermal growth factor (EGF) showed the lowest expression in the skin after treatment with HSO, indicating a well-organized and complete healing process. Other seed oils from cantaloupe and zucchini exhibited favorable activity when compared with untreated rats; however, their efficacy was comparatively lower than that of PSO and HSO. Gas chromatographic analysis of the derivatized oils warranted the superior activity of HSO to its high nutraceutical content of linoleic acid, which represented 65.9% of the fatty acid content. This study’s findings validate the use of honeydew seeds as a wound-healing fixed oil and encourage further investigation into the potential of Cucurbitaceae seeds as sources of medicinally valuable plant oils. Full article

Pyroptosis represents a type of cell death mechanism notable for its cell membrane disruption and the subsequent release of proinflammatory cytokines. The Nod-like receptor family pyrin domain containing inflammasome 3 (NLRP3) plays a critical role in the pyroptosis mechanism associated with various diseases resulting from particulate matter (PM) exposure. Tert-butylhydroquinone (tBHQ) is a synthetic antioxidant commonly used in a variety of foods and products. The aim of this study is to examine the potential of tBHQ as a therapeutic agent for managing sinonasal diseases induced by PM exposure. The occurrence of NLRP3 inflammasome-dependent pyroptosis in RPMI 2650 cells treated with PM < 4 µm in size was confirmed using Western blot analysis and enzyme-linked immunosorbent assay results for the pyroptosis metabolites IL-1β and IL-18. In addition, the inhibitory effect of tBHQ on PM-induced pyroptosis was confirmed using Western blot and immunofluorescence techniques. The inhibition of tBHQ-mediated pyroptosis was abolished upon nuclear factor erythroid 2-related factor 2 (Nrf2) knockdown, indicating its involvement in the antioxidant mechanism. tBHQ showed potential as a therapeutic agent for sinonasal diseases induced by PM because NLRP3 inflammasome activation was effectively suppressed via the Nrf2 pathway. Full article

Epilepsy is one of the most prevalent and serious brain disorders and affects over 70 million people globally. Antiseizure medications (ASMs) relieve symptoms and prevent the occurrence of future seizures in epileptic patients but have a limited effect on epileptogenesis. Addressing the multifaceted nature of epileptogenesis and its association with the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires a comprehensive understanding of the underlying mechanisms of these medications for the development of targeted therapeutic strategies beyond conventional antiseizure treatments. Several types of NLRP3 inhibitors have been developed and their effect has been validated both in in vitro and in vivo models of epileptogenesis. In this review, we discuss the advances in understanding the regulatory mechanisms of NLRP3 activation as well as progress made, and challenges faced in the development of NLRP3 inhibitors for the treatment of epilepsy. Full article

Porcine astrovirus (PAstV) has a potential zoonotic risk, with a high proportion of co-infection occurring with porcine epidemic diarrhea virus (PEDV) and other diarrheal pathogens. Despite its high prevalence, the cellular mechanism of PAstV pathogenesis is ill–defined. Previous proteomics analyses have revealed that the differentially expressed protein NOD–like receptor X1 (NLRX1) located in the mitochondria participates in several important antiviral signaling pathways in PAstV–4 infection, which are closely related to mitophagy. In this study, we confirmed that PAstV–4 infection significantly up-regulated NLRX1 and mitophagy in Caco–2 cells, while the silencing of NLRX1 or the treatment of mitophagy inhibitor 3–MA inhibited PAstV–4 replication. Additionally, PAstV–4 infection triggered the activation of the extracellular regulated protein kinases/ myosin light-chain kinase (ERK/MLCK) pathway, followed by the down-regulation of tight–junction proteins (occludin and ZO–1) as well as MUC–2 expression. The silencing of NLRX1 or the treatment of 3–MA inhibited myosin light-chain (MLC) phosphorylation and up-regulated occludin and ZO–1 proteins. Treatment of the ERK inhibitor PD98059 also inhibited MLC phosphorylation, while MLCK inhibitor ML-7 mitigated the down-regulation of mucosa-related protein expression induced by PAstV–4 infection. Yet, adding PD98059 or ML–7 did not affect NLRX1 expression. In summary, this study preliminarily explains that NLRX1 plays an important role in the disruption of intestinal mucosal function triggered by PAstV–4 infection via the ERK/MLC pathway. It will be helpful for further antiviral drug target screening and disease therapy. Full article

Background: Haemonchus contortus is a parasite widely distributed in tropical, subtropical, and warm temperate regions, causing significant economic losses in the livestock industry worldwide. However, little is known about the genetics of H. contortus resistance in livestock. In this study, we monitor the dynamic immune cell responses in diverse peripheral blood mononuclear cells (PBMCs) during H. contortus infection in goats through single-cell RNA sequencing (scRNA-Seq) analysis. Methods and Results: A total of four Boer goats, two goats with oral infection with the L3 larvae of H. contortus and two healthy goats as controls, were used in the animal test. The infection model in goats was established and validated by the fecal egg count (FEC) test and qPCR analysis of the gene expression of IL-5 and IL-6. Using scRNA-Seq, we identified seven cell types, including T cells, monocytes, natural killer cells, B cells, and dendritic cells with distinct gene expression signatures. After identifying cell subpopulations of differentially expressed genes (DEGs) in the case and control groups, we observed the upregulation of multiple inflammation-associated genes, including NFKBIA and NFKBID. Kyoto Encyclopedia of the Genome (KEGG) enrichment analysis revealed significant enrichment of NOD-like receptor pathways and Th1/Th2 cell differentiation signaling pathways in CD4 T cells DEGs. Furthermore, the analysis of ligand–receptor interaction networks showed a more active state of cellular communication in the PBMCs from the case group, and the inflammatory response associated MIF–(CD74 + CXCR4) ligand receptor complex was significantly more activated in the case group, suggesting a potential inflammatory response. Conclusions: Our study preliminarily revealed transcriptomic profiling characterizing the cell type specific mechanisms in host PBMCs at the single-cell level during H. contortus infection. 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

The average life of a dog is generally maintained at ten to fifteen years, and tumours are the predominant reason that leads to the death of dogs, especially canine mammary carcinoma. Therefore, early diagnosis of tumours is very important. In this study, tumor size, morphology, and texture could be seen through general clinical examination, tumor metastasis could be seen through imaging examination, inflammatory reactions could be seen through hematological examination, and abnormal cell morphology could be seen through cytological and histopathological examination. In the 269 malignant cases and 179 benign cases, we randomly selected 30 cases each, and an additional 30 healthy dogs were selected for the experiment (healthy dogs: dogs in good physical condition without any tumor or other diseases). We used RT-qPCR and ELISA to determine the relative expression of vascular endothelial growth factor (VEGF), tumor protein P53 (P53), serum ferritin (SF), and NOD-like receptor protein 3 (NLRP3) in 30 healthy dogs, 30 dogs with benign mammary tumours, and 30 dogs with malignant mammary tumours. In the results, the same expression trend was obtained both in serum and tissues, and the expression of the four markers was the highest in malignant mammary tumours, with highly significant differences compared with the benign and healthy/paracancerous groups. By plotting the ROC curves, it was found that the results of combined tests were better than a single test and the combination of the four markers was the best for the early diagnosis. In conclusion, this can assist the clinical early diagnosis to a certain extent, and also provides some references and assistance for the development of tumor detection kits in clinical practice. 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

Emerging evidence has demonstrated a strong correlation between vitamin D status and fatty liver disease. Aberrant hepatic fat infiltration contributes to oxidant overproduction, promoting metabolic dysfunction, and inflammatory responses. Vitamin D supplementation might be a good strategy for reducing hepatic lipid accumulation and inflammation in non-alcoholic fatty liver disease and its associated diseases. This study aimed to investigate the role of the most biologically active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D), in hepatic fat accumulation and inflammation in palmitic acid (PA)-treated AML-12 hepatocytes. The results indicated that treatment with 1,25(OH)2D significantly decreased triglyceride contents, lipid peroxidation, and cellular damage. In addition, mRNA levels of apoptosis-associated speck-like CARD-domain protein (ASC), thioredoxin-interacting protein (TXNIP), NOD-like receptor family pyrin domain-containing 3 (NLRP3), and interleukin-1β (IL-1β) involved in the NLRP3 inflammasome accompanied by caspase-1 activity and IL-1β expression were significantly suppressed by 1,25(OH)2D in PA-treated hepatocytes. Moreover, upon PA exposure, 1,25(OH)2D-incubated AML-12 hepatocytes showed higher sirtulin 1 (SIRT1) expression and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. A SIRT1 inhibitor alleviated the beneficial effects of 1,25(OH)2D on PA-induced hepatic fat deposition, IL-1β expression, and caspase-1 activity. These results suggest that the favorable effects of 1,25(OH)2D on hepatic fat accumulation and inflammation may be, at least in part, associated with the SIRT1. Full article

In Asian regions, areca nuts are tropical fruits that are extensively consumed. The areca nut contains a lot of polyphenols and its safety is unknown. In this research, we investigated the effects of lipopolysaccharides (LPS) and areca nut polyphenols (ANP) on normal RAW264.7 cells. The results showed that LPS stimulated adverse effects in normal cells by affecting cytokine production. The GO analysis results mainly affected DNA repair, cell division, and enzyme activities. In the KEGG analysis results, the NOD-like receptor signaling pathway, which is related to NF-κB, MAPK, and the pro-inflammatory cytokines, is the most significant. In the protein–protein interaction network (PPI) results, significant sub-networks in all three groups were shown to be related to cytokine–cytokine receptor interaction. Collectively, our findings showed a comprehensive understanding of LPS-induced toxicity and the protective effects of ANP by RNA sequencing. Full article

Elizabethkingia miricola (E. miricola) is a significant pathogen that causes the crooked head disease in black spotted frogs. This disease has plagued numerous frog farms in China and has resulted in substantial losses to the frog farming industry. Nonetheless, the exact mechanism that causes the disease in frogs remains unknown. In this study, transcriptomic and microbiomic analyses were conducted to analyze frog samples infected with E. miricola to reveal the infection mechanism of the pathogen. Liver transcriptomic analysis indicated that the livers of infected frogs had 1469 differentially expressed genes when compared with an uninfected group. These DEGs are mainly involved in immunity and metabolism, including neutrophil extracellular trap formation, the NOD-like receptor signaling pathway, leukocyte transendothelial migration, chemokine signaling pathway, Fc gamma R-mediated phagocytosis, and “metabolism”-related pathways such as the pentose phosphate pathway, carbon metabolism, glycerophospholipid metabolism, and glycerolipid metabolism. Similarly, 4737 DEGs were found in the kidney of infected frogs. These DEGs are mainly involved in immunity, including neutrophil extracellular trap formation, the NOD-like receptor signaling pathway, B cell receptor signaling pathway, C-type lectin receptor signaling pathway, complement and coagulation cascade, and Toll-like receptor signaling pathway. Ten immune-associated DEGs were screened in liver and kidney DEGs, respectively. And it was hypothesized that E. miricola infection could influence the host immune response. Microbiome analysis results showed that some opportunistic pathogens such as Citrobacter, Shigella, and Providencia were significantly elevated (p < 0.05) in infected frogs. Additionally, functional prediction confirmed that most of the microbiota in infected frogs were linked to metabolism-related KEGG pathways. In this study, the screened genes linked to immunity showed an association with the gut microbiome. The majority of these genes were found to be linked with the abundance of opportunistic pathogens. The results showed that E. miricola infection led to the downregulation of immune and metabolic-related genes, which led to the inhibition of immune function and metabolic disorder, and then increased the abundance of opportunistic pathogens in the gut microbiota. The findings of this study offer a preliminary foundation for comprehending the pathogenic processes of E. miricola infection in black spotted frogs. Full article

Inflammatory bowel disease (IBD) is a chronic inflammatory bowel disease with unknown pathogenesis which has been gradually considered a public health challenge worldwide. Peptides derived from Rapana venosa have been shown to have an anti-inflammatory effect. In this study, peptide LLTRAGL derived from Rapana venosa was prepared by a solid phase synthesis technique. The protective effects of LLTRAGL were studied in a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced zebrafish colitis model. The underlying mechanisms of LLTRAGL were predicted and validated by transcriptome, real-time quantitative PCR assays and molecular docking. The results showed that LLTRAGL reduced the number of macrophages migrating to the intestine, enhanced the frequency and rate of intestinal peristalsis and improved intestinal inflammatory damage. Furthermore, transcriptome analysis indicated the key pathways (NOD-like receptor signal pathway and necroptosis pathway) that link the underlying protective effects of LLTRAGL’s molecular mechanisms. In addition, the related genes in these pathways exhibited different expressions after TNBS treatment. Finally, molecular docking techniques further verified the RNA-sequencing results. In summary, LLTRAGL exerted protective effects in the model of TNBS-induced colitis zebrafish. Our findings provide valuable information for the future application of LLTRAGL in IBD. Full article

Background: Hyperuricaemia (HUA) is a disorder of purine metabolism in the body. We previously synthesized a hesperitin (Hsp)-Cu(II) complex and found that the complex possessed strong uric acid (UA)-reducing activity in vitro. In this study we further explored the complex’s UA-lowering and nephroprotective effects in vivo. Methods: A mouse with HUA was used to investigate the complex’s hypouricemic and nephroprotective effects via biochemical analysis, RT-PCR, and Western blot. Results: Hsp-Cu(II) complex markedly decreased the serum UA level and restored kidney tissue damage to normal in HUA mice. Meanwhile, the complex inhibited liver adenosine deaminase (ADA) and xanthine oxidase (XO) activities to reduce UA synthesis and modulated the protein expression of urate transporters to promote UA excretion. Hsp-Cu(II) treatment significantly suppressed oxidative stress and inflammatory in the kidney, reduced the contents of cytokines and inhibited the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) inflammatory pathway. Conclusions: Hsp-Cu(II) complex reduced serum UA and protected kidneys from renal inflammatory damage and oxidative stress by modulating the NLRP3 pathway. Hsp-Cu(II) complex may be a promising dietary supplement or nutraceutical for the therapy of hyperuricemia. Full article

Type 2 diabetes mellitus (T2DM) is an epidemiological risk factor for dementia and has been implicated in multifactorial pathologies, including neuroinflammation. In the present study, we aimed to elucidate the potential anti-inflammatory effects of imeglimin, a novel antidiabetic agent, on high-glucose (HG)-stimulated microglia. Mouse microglial BV2 cells were stimulated with HG in the presence or absence of imeglimin. We examined the effects of imeglimin on the levels of proinflammatory cytokines, intracellular reactive oxygen species (ROS), mitochondrial integrity, and components related to the inflammasome or autophagy pathways in these cells. Our results showed that imeglimin suppressed the HG-induced production of interleukin-1beta (IL-1β) by reducing the intracellular ROS levels, ameliorating mitochondrial dysfunction, and inhibiting the activation of the thioredoxin-interacting protein (TXNIP)–NOD-like receptor family pyrin domain containing 3 (NLRP3) axis. Moreover, the inhibitory effects of imeglimin on the TXNIP–NLRP3 axis depended on the imeglimin-induced activation of ULK1, which also exhibited novel anti-inflammatory effects without autophagy induction. These findings suggest that imeglimin exerted novel suppressive effects on HG-stimulated microglia through the ULK1–TXNIP–NLRP3 axis, and may, thereby, contribute to the development of innovative strategies to prevent T2DM-associated cognitive impairment. Full article

Nucleotide-binding oligomerization domain-like (NOD) receptors rely on the interface between immunity and metabolism. Dietary factors constitute critical players in the activation of innate immunity and modulation of the gut microbiota. The latter have been involved in worsening or improving the control and promotion of diseases such as obesity, type 2 diabetes, metabolic syndrome, diseases known as non-communicable metabolic diseases (NCDs), and the risk of developing cancer. Intracellular NODs play key coordinated actions with innate immune ‘Toll-like’ receptors leading to a diverse array of gene expressions that initiate inflammatory and immune responses. There has been an improvement in the understanding of the molecular and genetic implications of these receptors in, among others, such aspects as resting energy expenditure, insulin resistance, and cell proliferation. Genetic factors and polymorphisms of the receptors are determinants of the risk and severity of NCDs and cancer, and it is conceivable that dietary factors may have significant differential consequences depending on them. Host factors are difficult to influence, while environmental factors are predominant and approachable with a preventive and/or therapeutic intention in obesity, T2D, and cancer. However, beyond the recognition of the activation of NODs by peptidoglycan as its prototypical agonist, the underlying molecular response(s) and its consequences on these diseases remain ill-defined. Metabolic (re)programming is a hallmark of NCDs and cancer in which nutritional strategies might play a key role in preventing the unprecedented expansion of these diseases. A better understanding of the participation and effects of immunonutritional dietary ingredients can boost integrative knowledge fostering interdisciplinary science between nutritional precision and personalized medicine against cancer. This review summarizes the current evidence concerning the relationship(s) and consequences of NODs on immune and metabolic health. Full article