Search Results (563)

The type IV secretion system (T4SS) is an important virulence factor of Brucella. T4SS secretes 16 effector proteins, which affect the intracellular transport of Brucella-containing vacuoles and regulate the host immune response, helping Brucella survive and replicate in host cells. In our previous crotonylation proteomics data of HEK-293T cell proteins triggered by BspF, we found BspF crotonylated on TRIM38, which is an important modulator in the pathways of inflammation, and the crotonylation site is K142. Therefore, it is speculated that BspF may be involved in the regulation of host inflammatory response during Brucella infection. In this study, we found that BspF-mediated TRIM38K142 crotonylation promotes the ubiquitination of tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6), leading to the degradation of TRAF6 and thereby inhibiting the transduction of Nuclear factor-kappaB (NF-κB), p38 Mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinases (JNK) MAPK signaling pathways and the secretion of pro-inflammatory factors IL-6 and IL-8, which finally helps Brucella promote intracellular survival. This study provides a new theoretical basis for the intracellular survival of host innate immunity through the T4SS, provides new insights into the pathogenic mechanism and treatment of Brucella, and provides an important reference for the study of non-histone crotonylation function. Full article

Background: Chemoresistance is an existing challenge faced in the treatment of the hairy cell leukemia variant (HCL-v). Classical hairy cell leukemia (HCL-c) is very sensitive to the standard of care with purine nucleoside analogs (PNAs) cladribine (cDa) and pentostatin. However, almost half of these patients eventually become less sensitive to chemotherapy and relapse. HCL-variant (HCL-v) is a biologically distinct entity from HCL-c that is not sensitive to frontline PNA therapy, and this treatment is not recommended for these patients. To address these treatment challenges, we investigated the role of B-cell activating factor (BAFF) in promoting HCL-v cell chemoresistance. Methods: Flow cytometry and quantitative PCR were used to measure the levels of BAFF and its receptors. To determine BAFF activated pathways in HCL-c and HCL-v, the Bonna-12 HCL-c cell line or HCL-v patient-derived cancer cells were stimulated with recombinat BAFF and activation of common BAFF-activated pathways, including the nonclassical nuclear factor kappa B (NF-κB) pathway, the Extracellular Signal-Regulated Kinase (Erk) and phosphatidylinositol-3 (PI-3) kinase (PI3K)/AKT serine/threonine kinase (AKT) pathways were measured by western blotting. To test whether BAFF signaling promotes chemoresistance in HCL-v, we stimulated patient-derived HCL-v cells with BAFF and performed RNA sequencing. Lastly, to confirm the functional implications of BAFF signaling in HCL-v, we treated patient-derived HCL-v cells with exogenous BAFF before treatment with cladribine. Results: We found that HCL-v patient-derived cancer cells express receptors of BAFF at varying degrees and express relatively lower levels of membrane-bound BAFF ligand expression. BAFF stimulation of these cells resulted in substantial activation of the nonclassical NF-κB pathway, which is known to promote anti-apoptotic and pro-survival effects in B-cell cancers. Conversely, in the Bonna-12 cell line, we observed constitutive activation of the nonclassical NF-κB pathway. Through RNA sequencing, we found that BAFF upregulates a myriad of genes that are known to promote chemoresistance in various cancers, including IL1, CXCL1/2, CXCL5, CXCL8, TRAF3, and PTGS2. Lastly, we found that BAFF protects these cells from cladribine-induced cell death in vitro. Conclusions: We conclude that BAFF provides chemo-protection in HCL-v cells by activating nonclassical NF-κB signaling, which results in the upregulation of multiple pro-survival or anti-apoptotic genes. Our results highlight an important role of BAFF in HCL-v resistance to chemotherapy and suggest that the BAFF blockade may enhance the chemosensitivity to PNAs in drug-resistant HCL-v patients. Full article

Osteoclastogenesis is tightly regulated by receptor activator of nuclear factor kappa-B ligand (RANKL) signaling, yet the role of matrix metalloproteinase-9 (MMP-9) in this process remains controversial. We established a high-yield osteoclastogenesis system using cryopreserved rabbit bone marrow cells (1 × 10⁹ cells/femur) treated with Macrophage colony-stimulating factor (M-CSF) and RANKL. Bone marrow cells from MMP-9 transgenic rabbits (macrophage-specific overexpression) and MMP-9-transfected RAW264.7 macrophages were compared to wild-type controls. MMP-9 overexpression increased osteoclastogenesis 5.5-fold (20 ng/mL RANKL, * p < 0.01) while suppressing inflammatory cytokines (IL-1β, TNF-α). RAW264.7 macrophages stably transfected with human MMP-9 similarly exhibited reduced inflammatory cytokine levels and enhanced osteoclastogenesis. MMP-9 acts as a dual regulator of osteoclastogenesis and inflammation, suggesting therapeutic potential for osteoporosis management. Full article

Osteoclast differentiation inhibition is a viable treatment strategy for osteoporosis because osteoclasts play a vital role in disease progression. Rhusflavone (Rhus), a biflavonoid, exhibits a sedative–hypnotic effect via the positive allosteric modulation of GABA(A) receptors. Although several biflavonoids possess activities that help prevent bone loss, the potential effects of Rhus on osteoclastogenesis have not been reported yet. In this study, we investigated the effects and underlying biological mechanisms of Rhus isolated from the dried roots of Rhus succedanea on osteoclastogenesis in primary cultured bone marrow-derived macrophages. No cytotoxicity was observed in bone marrow macrophages (BMMs) or during osteoclast differentiation. However, Rhus reduced the number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts during receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis. The results of F-actin ring formation demonstrated that Rhus suppresses the bone resorption activity of osteoclasts. Additionally, Rhus inhibits the expression of osteoclast differentiation marker proteins, specifically c-Fos and NF-ATc1. Western blot analysis revealed that Rhus primarily attenuated RANKL-mediated key signaling pathways, particularly the AKT signaling pathway. Furthermore, we found that the AKT activator and inhibitor pharmacologically abolished and enhanced the inhibitory effects of Rhus on osteoclast differentiation, respectively. Taken together, our findings provide evidence that Rhus is a promising biologically active compound that regulates osteoclast differentiation by inhibiting the AKT signaling pathway, which may contribute to future drug development. Full article

Osteoporosis is a prevalent metabolic bone disorder characterized by decreased bone mineral density and increased fracture risk, particularly among aging populations. While conventional pharmacological treatments exist, they often have adverse effects, necessitating the search for alternative therapies. Resveratrol, a naturally occurring polyphenol, has gained significant attention for its potential osteoprotective properties through various molecular mechanisms. This systematic review aims to comprehensively analyze the molecular pathways through which resveratrol protects against osteoporosis. Using an advanced search strategy in the Scopus, PubMed, and Web of Science databases, we identified 513 potentially relevant articles. After title and abstract screening, followed by full-text review, 28 studies met the inclusion criteria. The selected studies comprised 14 in vitro studies, 8 mixed in vitro and in vivo studies, 6 in vivo studies, and 1 cross-sectional study in postmenopausal women. Our findings indicate that resveratrol exerts its osteoprotective effects by enhancing osteoblast differentiation through the activation of the Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/Akt), Sirtuin 1 (SIRT1), AMP-Activated Protein Kinase (AMPK), and GATA Binding Protein 1 (GATA-1) pathways while simultaneously inhibiting osteoclastogenesis by suppressing Mitogen-Activated Protein Kinase (MAPK) and TNF Receptor-Associated Factor 6/Transforming Growth Factor-β-Activated Kinase 1 (TRAF6/TAK1). Additionally, resveratrol mitigates oxidative stress and inflammation-induced bone loss by activating the Hippo Signaling Pathway/Yes-Associated Protein (Hippo/YAP) and Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) pathways and suppressing Reactive Oxygen Species/Hypoxia-Inducible Factor-1 Alpha (ROS/HIF-1α) and NADPH Oxidase 4/Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (Nox4/NF-κB). Despite promising preclinical findings, the low bioavailability of resveratrol remains a significant challenge, highlighting the need for novel delivery strategies to improve its therapeutic potential. This review provides critical insights into the molecular mechanisms of resveratrol in bone health, supporting its potential as a natural alternative for osteoporosis prevention and treatment. Further clinical studies are required to validate its efficacy and establish optimal dosing strategies. Full article

Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a member of the G-protein-coupled receptor (GPCR) family, has been implicated in various regulatory functions across multiple differentiation stages and numerous target sites in bone diseases. Therefore, LGR4 is a potential regulator of nuclear factor-κB ligand (RANKL) during osteoclast differentiation. However, a comprehensive investigation of its functions and applications in bone immunology is lacking. This review discusses the molecular characteristics, signaling pathways, and role of LGR4 in osteoimmunology, with a particular focus on its interactions with RANKL during osteoclast differentiation, while identifying gaps that warrant further research. Full article

This study was conducted to investigate the effects and mechanisms of all-trans lycopene on intestinal health by establishing lipopolysaccharide-induced (LPS-induced) jejunal inflammation model. Dietary lycopene supplementation enhanced serum and jejunum antioxidant capacity. Lycopene significantly reduced LPS-induced upregulation of toll-like receptor-4 (TLR-4) and nuclear factor kappa-B (NF-κB), suggesting that lycopene reduced the activation of TLR-4/NF-κB signaling pathway induced by LPS challenge, and further protected mice from LPS induced jejunal inflammation. Furthermore, lycopene increased jejunal zonula occludens-1 (ZO-1) protein expression that was reduced by LPS challenge, and increased abundance of Rikenella, Lachnospiraceae_NK4A136_group and Mucispirillum potentially associated with reducing gut inflammation. Overall, these results showed that pretreatment with lycopene can improve jejunal inflammation and ensure intestinal health in mice by improving antioxidant capacity, intestinal barrier function, microorganisms potentially associated with anti-inflammatory effects and reducing the activation of TLR-4/NF-κB signaling pathway by LPS. We provided a new insight into lycopene prevented LPS-induced jejunal inflammation by corresponding alterations in serum metabolites and gut microbiota, improving antioxidant capacity and regulating the TLR-4/NF-κB signaling pathway in mice. Full article

Inflammation is associated with the pathophysiology of type 2 diabetes and COVID-19. Phytochemicals have the potential to modulate inflammation, expression of SARS-CoV-2 viral entry receptors (angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2)) and glucose transport in the gut. This study assessed the impact of phytochemicals on these processes. We screened 12 phytochemicals alongside 10 pharmaceuticals and three plant extracts, selected for known or hypothesised effects on the SARS-CoV-2 receptors and COVID-19 risk, for their effects on the expression of ACE2 or TMPRSS2 in differentiated Caco-2/TC7 human intestinal epithelial cells. Genistein, apigenin, artemisinin and sulforaphane were the most promising ones, as assessed by the downregulation of TMPRSS2, and thus they were used in subsequent experiments. The cells were then co-stimulated with pro-inflammatory cytokines interleukin-1 beta (IL-1β) and tumour necrosis factor-alpha (TNF-α) for ≤168 h to induce inflammation, which are known to induce multiple pathways, including the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Target gene expression (ACE2, TMPRSS2, SGLT1 (sodium-dependent glucose transporter 1) and GLUT2 (glucose transporter 2)) was measured by droplet digital PCR, while interleukin-1 (IL-6), interleukin-1 (IL-8) and ACE2 proteins were assessed using ELISA in both normal and inflamed cells. IL-1β and TNF-α treatment upregulated ACE2, TMPRSS2 and SGLT1 gene expression. ACE2 increased with the duration of cytokine exposure, coupled with a significant decrease in IL-8, SGLT1 and TMPRSS2 over time. Pearson correlation analysis revealed that the increase in ACE2 was strongly associated with a decrease in IL-8 (r = −0.77, p < 0.01). The regulation of SGLT1 gene expression followed the same pattern as TMPRSS2, implying a common mechanism. Although none of the phytochemicals decreased inflammation-induced IL-8 secretion, genistein normalised inflammation-induced increases in SGLT1 and TMPRSS2. The association between TMPRSS2 and SGLT1 gene expression, which is particularly evident in inflammatory conditions, suggests a common regulatory pathway. Genistein downregulated the inflammation-induced increase in SGLT1 and TMPRSS2, which may help lower the postprandial glycaemic response and COVID-19 risk or severity in healthy individuals and those with metabolic disorders. Full article

Background and Objectives: 5-Fluorouracil (5-FU) is a widely prescribed and effective chemotherapeutic drug, but its cardiotoxic side effects pose a significant challenge to its use. Identifying a protective agent that does not affect its anticancer efficacy is essential. Our study aimed to investigate the cardioprotective effect of N-acetyl cysteine (NAC) against 5-FU-induced cardiac injury and to elucidate the underlying mechanisms. Materials and Methods: This study included four experimental groups, each with eight rats (n = 8): Group I (control group), Group II (NAC group), Group III (5-FU group), and Group IV (combined group 5-FU+NAC). Cardiac enzymes, oxidative stress, inflammatory, and apoptotic markers were investigated, and cardiac sections from the different groups were histologically examined. Results: Co-treatment of 5-FU with NAC resulted in significantly lower levels of cardiac enzymes (alanine transaminase (ALT) by 62.1%, aspartate transaminase (AST) by 73.6%, lactate dehydrogenase (LDH) by 55.8%, and creatine kinase (CK) by 57.3%) compared to the 5-FU group, along with marked improvements in heart tissue histology. Additionally, NAC enhanced the activity of cardiac antioxidant enzymes (superoxide dismutase (SOD) by 295.6%, catalase (CAT) by 181%, and glutathione peroxidase (GPx) by 320.9%) while decreasing malondialdehyde (MDA) by 51.1%, a marker of membranous lipid peroxidation. This might be due to significant upregulation of the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway at the gene and protein levels. The combined treatment significantly decreased the gene expression of the toll-like receptor 4 (TLR4)/nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) pathway. Furthermore, it downregulated the protein levels of inflammatory markers, including tumor necrosis factor-alpha (TNF-α) by 29.9%, interleukin-1 beta (IL-1β) by 21.9%, and interleukin-6 (IL-6) by 49.3%. Moreover, it upregulated the antiapoptotic marker B-cell lymphoma 2 (Bcl-2) protein levels by 269% and decreased apoptotic indicators Bcl-2-associated protein x (Bax) by 57.9% and caspase-3 by 30.6% compared to the 5-FU group. Conclusions: This study confirmed that NAC prevented the cardiotoxic effect of 5-FU through its antioxidant, anti-inflammatory, and antiapoptotic properties, suggesting its potential application as an adjuvant therapy in chemotherapy to alleviate 5-FU-induced cardiotoxicity. Full article

Ischemic stroke ranks as the second leading cause of global mortality. The limited time for effective thrombolytic treatment has prompted the exploration of alternative prevention approaches. Eucommia ulmoides (E. ulmoides) Oliv. bark has shown multiple pharmacological effects, including neuroprotection, anti-inflammation and autophagy modulation. This study aims to elucidate the neuroprotective effects of water extract of E. ulmoides (WEU) supplementation in a middle cerebral artery occlusion (MCAO) mouse model and to further explore the underlying molecular mechanisms. Seven bioactive compounds in WEU—aucubin, chlorogenic acid, geniposidic acid, quercetin, protocatechuic acid, betulin and pinoresinol diglucoside—were identified using HPLC-MS. Our results showed that WEU supplementation significantly decreased infarct volume and ameliorated neurological dysfunction in mice following MCAO/reperfusion (MCAO/R) injury. Furthermore, the administration of WEU significantly attenuated microglia activation induced by cortical ischemia in mice and inhibited the production of pro-inflammatory mediators, including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Importantly, in contrast with the vehicle group, the protein expression levels of Toll-like receptor 4 (TLR4), phospho-p38 (p-p38) and nuclear factor kappa B (NF-κB) were reduced in the WEU group. Therefore, this present study provides evidence that E. ulmoides improves neurological behaviors by suppressing neuroinflammation and inhibiting the activation of the TLR4/ p38 MAPK and NF-κB pathways in mice after ischemia, which indicates that E.ulmoides is a promising candidate for alleviating gray matter ischemic change. Full article

The interplay between oxidative stress and adipogenesis is a critical factor in the development of obesity and its associated metabolic disorders. Excessive reactive oxygen species (ROS) disrupt key transcription factors such as peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (C/EBPα), impairing lipid metabolism, promoting adipocyte dysfunction, and exacerbating inflammation and insulin resistance. Antioxidants, classified as endogenous (e.g., glutathione, superoxide dismutase, and catalase) and exogenous (e.g., polyphenols, flavonoids, and vitamins C and E), are pivotal in mitigating these effects by restoring redox balance and preserving adipocyte functionality. Endogenous antioxidants neutralize ROS and safeguard cellular structures; however, under heightened oxidative stress, these defenses are often insufficient, necessitating dietary supplementation. Exogenous antioxidants derived from plant-based sources, such as polyphenols and vitamins, act through direct ROS scavenging, upregulation of endogenous antioxidant enzymes, and modulation of key signaling pathways like nuclear factor kappa B (NF-κB) and PPARγ, reducing lipid peroxidation, inflammation, and adipocyte dysfunction. Furthermore, they influence epigenetic regulation and transcriptional networks to restore adipocyte differentiation and limit lipid accumulation. Antioxidant-rich diets, including the Mediterranean diet, are strongly associated with improved metabolic health, reduced obesity rates, and enhanced insulin sensitivity. Advances in personalized antioxidant therapies, guided by biomarkers of oxidative stress and supported by novel delivery systems, present promising avenues for optimizing therapeutic interventions. This review, “Crosstalk Between Antioxidants and Adipogenesis: Mechanistic Pathways and Their Role in Metabolic Health”, highlights the mechanistic pathways by which antioxidants regulate oxidative stress and adipogenesis to enhance metabolic health. Full article

Protease-activated receptor 2 (PAR2) is a seven-transmembrane, G-protein-coupled receptor that is activated by coagulation proteases such as factor VIIa and factor Xa and other serine proteases. It is a potential therapeutic target for kidney injury, as it enhances inflammatory and fibrotic responses via the nuclear factor-kappa B and mitogen-activated protein kinase cascades. The body of knowledge regarding the role of PAR2 in kidney disease is currently growing, and its role in various kidney disease models, such as acute kidney injury, renal fibrosis, diabetic kidney disease, aging, and thrombotic microangiopathy, has been reported. Here, we review the literature to better understand the various aspects of PAR2 in kidney disease. Full article

Artemisia ordosica Krasch. represents a medicinal species traditionally and extensively employed in traditional medicine for treating ailments such as rheumatic arthritis, sore throat, and inflammation. This study initially focuses on the extraction, purification, and characterization of Artemisia ordosica Krasch. polysaccharides (AOP). The purified AOP exhibits a molecular mass corresponding to 9.00 kDa and consists of multiple monosaccharide units, with glucose (54.08%) as the predominant component, followed by arabinose (13.75%), mannose (13.43%), galactose (12.79%), xylose (3.15%), glucuronic acid (0.93%), galacturonic acid (0.67%), ribose (0.63%), and fucose (0.56%), respectively. Furthermore, to explore the immune-regulatory mechanisms of AOP, peripheral blood lymphocytes (PBLs) were cultured and exposed to inhibitors targeting receptors and signaling molecules. The results indicated that TLR4 serves as a potential target through which AOP exerts its immunomodulatory functions. AOP mitigates immune stress in PBLs triggered by LPS by disrupting the interaction between LPS and TLR and downregulating the over-activation of the nuclear factor kappa B (NF-κB) signaling pathway. In summary, AOP shows promise as a feed additive to protect animals from immune stress. Full article

Atopic dermatitis (AD) is a common inflammatory skin disease characterized by recurrent eczema and chronic itching, affecting a significant portion of the global population. This study investigated the effects of Corydalis Tuber 70% ethanol extract (CTE) on tumor necrosis factor-α- and interferon-γ (TI)-stimulated human keratinocytes (HaCaT) and a house dust mite-induced AD mouse model, elucidating its mechanism via transcriptome analysis. A total of 13 compounds, including columbamine, corydaline, dehydrocorydaline, and glaucine, were identified in CTE using ultra performance liquid chromatography-tandem mass spectrometry. CTE downregulated pathways related to cytokine signaling and chemokine receptors in TI-stimulated HaCaT cells. It significantly inhibited C-C motif chemokine ligand (CCL)5, CCL17, and CCL22 levels by blocking the Janus kinase-signal transducers and activators of transcription and nuclear factor kappa-light-chain-enhancer of activated B cells pathways. In the AD mouse model, topical CTE significantly decreased dermatitis scores, epidermal thickening, and inflammatory cell infiltration. Plasma levels of histamine, immunoglobulin E, CCL17, CCL22, corticosterone, and cortisol were reduced. Lesions showed decreased thymic stromal lymphopoietin, CD4⁺ T cells, interleukin-4, and intercellular adhesion molecule-1 expression. The findings demonstrate that CTE alleviates AD by modulating inflammatory mediators, cytokines, and chemokines, reducing inflammatory cell infiltration, and alleviating stress-related factors. Full article

Pulmonary and extrapulmonary manifestations have been reported following infection with SARS-CoV-2, the causative agent of COVID-19. The virus persists in multiple organs due to its tropism for various tissues, including the skeletal system. This study investigates the effects of SARS-CoV-2 infection, including both ancestral and Omicron viral strains, on differentiating mesenchymal stem cells (MSCs), the precursor cells, into osteoblasts. Although both viral strains can productively infect osteoblasts, precursor cell infection remained abortive. Viral exposure during osteoblast differentiation demonstrates that both variants inhibit mineral and organic matrix deposition. This is accompanied by reduced expression of runt-related transcription factor 2 (RUNX2) and increased levels of interleukin-6 (IL-6), a cytokine that negatively regulates osteoblast differentiation. Furthermore, the upregulation of receptor activator of nuclear factor kappa B ligand (RANKL) strongly suggests that the ancestral and Omicron variants may disrupt bone homeostasis by promoting osteoclast differentiation, ultimately leading to the formation of bone-resorbing cells. This process is dependent of spike glycoprotein since its neutralization significantly reduced the effect of infective SARS-CoV-2 and UV-C inactivated virus. This study underscores the capacity of ancestral and Omicron SARS-CoV-2 variants to disrupt osteoblast differentiation, a process essential for preserving the homeostasis and functionality of bone tissue. Full article