Actinidia chinensis polysaccharide interferes with the epithelial-mesenchymal transition of gastric cancer by regulating the nuclear transcription factor-κB pathway to inhibit invasion and metastasis.

OBJECTIVE: To investigate the mechanisms of the effect of Actinidia chinensis polysaccharide (ACPS) on the invasion and metastasis of gastric cancer cells. METHODS: BGC-823-Luc gastric cancer cells stably transfected with a luciferase gene were used to establish an insitutransplanted tumor mouse model. A live mouse imaging system was used to observe tumor growth, and hematoxylin and eosin staining was applied to analyze tissue histopathology. Transwell and scratch wound assays were performed to examine the invasive and migratory ability of BGC-823 cells. Immunofluorescence, confocal microscopy, immunohistochemistry, and Western blot assays were used to analyze the expressions of the nuclear transcription factor-κB (NF-κB) signaling pathway and epithelial-mesenchymal transition (EMT)-related proteins. RESULTS: ACPS significantly inhibited the growth of subcutaneously transplanted BGC-823-Luc gastric cancer tumors in nude mice and reduced inflammatory cell infiltration in tumor tissues. ACPS inhibited Epidermal Growth Factor-induced invasion, migration, and morphological changes in the cytoskeleton of BGC-823 cells. ACPS inhibited gastric cancer EMT and decreased the expression of matrix metallopeptidase 9, N-cadherin and p-NF-κB p65 in transplanted tumor tissues. ACPS inhibited the expression of matrix metalloproteinases and vascular adhesion factors in BGC-823 cells, promoted p65-NF-κB nuclear translocation, and regulated proteins associated with the NF-κB p65 pathway. CONCLUSIONS: ACPS inhibited gastric cancer invasion and metastasis both in vivo and in vitro, which evidenced the inhibition of gastric cancer EMT viaregulating the NF-κB inflammatory pathway.

Role of toll-like receptor 4/mutant myeloid differentiation primary response 88/nuclear factor kappa-B mediated inflammation in diabetes mellitus with Northwest dryness syndrome.

OBJECTIVE: To investigate the role of toll-like receptor 4 (TLR4)/mutant myeloid differentiation primary response 88 (MyD88)/nuclear factor kappa-B (NF-κB) signaling pathway-mediated inflammation in diabetes mellitus with Northwest dryness syndrome. METHODS: Rats were randomly divided into the normal control, type 2 diabetes (T2DM) model, Northwest dryness syndrome + T2DM (Northwest dryness), and simple internal dampness + T2DM (internal dampness) groups. Enzyme-linked immunosorbent assay was used to detect biochemical indexes and inflammatory factors. The histopathological observation was performed. Quantitative real-time polymerase chain reaction and Western blot analysis were used to detect the mRNA and protein expression levels, respectively. RESULTS: Compared with the T2DM group, the glycosylated hemoglobin A1c, insulin, glucose tolerance, the homeostasis model assessment of insulin resistance, tumor necrosis factor-α, interleukin 1ß, interleukin 16, malondialdehyde, blood lipid, alanine aminotransferase, and aspartate aminotransferase were significantly elevated in the internal dampness group. Their levels were significantly elevated in the Northwest dryness group than in the T2DM and internal dampness groups. The superoxide dismutase, glutathione peroxidase, liver glycogen, and organ-to-weight ratio were significantly declined in the internal dampness group and the Northwest dryness group than in the T2DM group. However, these levels were elevated in the Northwest dryness group than in the internal dampness group. Moreover, the mRNA expression levels of interferon regulatory factor 5 and NF-κB p65, and the protein expression levels of TLR4, MyD88, and NF-κB were significantly higher in the internal dampness and the Northwest dryness groups than the T2DM group. Additionally, the mRNA and protein levels were significantly higher in the Northwest dryness group than in the internal dampness group. CONCLUSION: Northwest dryness syndrome-mediated TLR4/MyD88/NF-κB pathway and chronic inflammation might be associated with the occurrence and development of T2DM.

Trends and research foci in immunoregulatory mechanisms of allergic rhinitis: a bibliometric analysis (2014-2024).

Background: This study aims to provide a comprehensive bibliometric analysis of research trends, hotspots, and future directions in the immunoregulatory mechanisms of allergic rhinitis (AR) from 2014 to 2024. Methods: Data were sourced from the Web of Science Core Collection (WoSCC), covering articles and reviews published between April 1, 2014, and March 31, 2024. The search terms included "Allergic Rhinitis," "AR," and related terms along with specific keywords related to immune cells and inflammatory mediators. Bibliometric tools such as CiteSpace, VOSviewer, and SCImago Graphica were used to analyze institutional cooperation networks, keyword co-occurrence, citation bursts, and research topic evolution. Microsoft Excel 2019 was employed to display annual publication trends. Results: A total of 2200 papers met the inclusion and exclusion criteria. The number of publications showed an upward trend over the past decade, with a significant peak in 2021. China (583 papers) and the United States (454 papers) were the major contributing countries. Imperial College London emerged as the leading institution. Key research frontiers identified include the roles of NF kappa B and air pollution in AR. Keyword burst analysis revealed emerging topics such as respiratory allergy and personalized treatment strategies. Notable limitations include the exclusive use of the WoSCC database and the restriction to English-language publications. Conclusion: The field of immunoregulatory mechanisms in allergic rhinitis has seen significant growth, with China and the United States leading the research. Future research should focus on developing personalized treatment plans and understanding the comprehensive impact of environmental factors. Continued interdisciplinary collaboration and international cooperation will be essential for advancing therapeutic strategies in AR.

PM2.5 Induces Pyroptosis via Activation of the ROS/NF-κB Signaling Pathway in Bronchial Epithelial Cells.

Background and Objectives: Fine particulate matter, PM2.5, is becoming a major threat to human health, particularly in terms of respiratory diseases. Pyroptosis is a recently discovered and distinct form of cell death, characterized by pore formation in the cell membrane and secretions of proinflammatory cytokines. There has been little research on the effect of PM2.5 on pyroptosis, especially in airway epithelium. We investigated whether PM2.5-related oxidative stress induces pyroptosis in bronchial epithelial cells and defined the underlying mechanisms. Materials and Methods: After exposure of a BEAS-2B cell line to PM2.5 concentration of 20 µg/mL, reactive oxygen species (ROS) levels, parameters related to pyroptosis, and NF-κB signaling were measured by Western blotting, immunofluorescence, and ELISA (Enzyme-linked immunosorbent assay). Results: PM2.5 induced pyroptotic cell death, accompanied by LDH (Lactate dehydrogenase) release and increased uptake of propidium iodide in a dose-dependent manner. PM2.5 activated the NLRP3-casp1-gasdermin D pathway, with resulting secretions of the proinflammatory cytokines IL-1ß and IL-18. The pyroptosis activated by PM2.5 was alleviated significantly by NLRP3 inhibitor. In PM2.5-exposed BEAS-2B cells, levels of intracellular ROS and NF-κB p65 increased. ROS scavenger inhibited the expression of the NLRP3 inflammasome, and the NF-κB inhibitor attenuated pyroptotic cell death triggered by PM2.5 exposure, indicating that the ROS/NF-κB pathway is involved in PM2.5-induced pyroptosis. Conclusions: These findings show that PM2.5 exposure can cause cell injury by NLRP3-inflammasome-mediated pyroptosis by upregulating the ROS/NF-κB pathway in airway epithelium.

Shoutai Wan treatment upregulates the expression of TNFAIP3 and improves T cell immune tolerance at maternal-fetal interface.

Shoutai Wan (STW) is a traditional Chinese medicine formula used to treat various conditions. The objective of this study was to evaluate the impact of STW on the abortion rate in the URSA mouse model and elucidate its underlying molecular mechanisms. Female CBA/J mice were mated with male DBA/2 mice to establish the URSA model. Network pharmacological analysis was employed to investigate the potential molecular mechanisms of STW. Hematoxylin-eosin staining, immunofluorescence, and ELISA were performed to examine placental microenvironmental changes, protein expression related to TNFAIP3 and the NF-κB signaling pathway. Treatment with STW reduced the abortion rate in URSA model mice and improved trophoblast development. TNFAIP3 was identified as a potential target of STW for treating URSA, as STW enhanced TNFAIP3 protein expression while decreasing IL-6 and TNF-α secretion in the placenta. Moreover, STW upregulated TNFAIP3 protein expression and Foxp3 mRNA levels, increased the production of anti-inflammatory cytokines such as IL-10 and TGF-ß1, and decreased p-NF-κB expression in CD4+ cells at the placenta. The findings of this study indicate that STW treatment reduces the abortion rate in the URSA mouse model. These effects are likely mediated by increased TNFAIP3 expression and decreased NF-κB signaling pathway activity at the maternal-fetal interface. These molecular changes may contribute to the regulation of T cell immunity and immune tolerance during pregnancy.

Aucubin suppresses TLR4/NF-κB signalling to shift macrophages toward M2 phenotype in glucocorticoid-associated osteonecrosis of the femoral head.

In this study, we investigated whether the ability of aucubin to mitigate the pathology of GONFH involves suppression of TLR4/NF-κB signalling and promotion of macrophage polarization to an M2 phenotype. In necrotic bone tissues from GONFH patients, we compared levels of pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages as well as levels of TLR4/NF-κB signalling. In a rat model of GONFH, we examined the effects of aucubin on these parameters. We further explored its mechanism of action in a cell culture model of M1 macrophages. Necrotic bone tissues from GONFH patients contained a significantly increased macrophage M1/M2 ratio, and higher levels of TLR4, MYD88 and NF-κB p65 than bone tissues from patients with hip osteoarthritis. Treating GONFH rats with aucubin mitigated bone necrosis and demineralization as well as destruction of trabecular bone and marrow in a dose-dependent manner, based on micro-computed tomography. These therapeutic effects were associated with a decrease in the overall number of macrophages, decrease in the proportion of M1 macrophages, increase in the proportion of M2 macrophages, and downregulation of TLR4, MYD88 and NF-κB p65. These effects in vivo were confirmed by treating cultures of M1 macrophage-like cells with aucubin. Aucubin mitigates bone pathology in GONFH by suppressing TLR4/NF-κB signalling to shift macrophages from a pro- to anti-inflammatory phenotype.

The dual role of CCND1 in heterotopic ossification: A Non-canonical Pathway for Celecoxib treatment.

Objective: To explore the effective targets of Celecoxib in the treatment of heterotopic ossification using network pharmacology methods. Methods: Potential molecules related to heterotopic ossification were obtained by retrieving the GEO and CTD databases and intersecting them. Potential binding targets of Celecoxib were acquired from the STITCH database. A protein-protein interaction network was constructed between potential binding targets of Celecoxib and potential related molecules of heterotopic ossification using the STRING database. Molecules in the protein-protein interaction network were further analyzed using GO and KEGG enrichment analysis in R software, followed by enrichment analysis of active molecules in the Celecoxib-heterotopic ossification target dataset. Hub genes were selected based on the "degree" value and enrichment within the protein-protein interaction network. The binding affinity of hub genes to Celecoxib was observed using molecular docking techniques. Finally, in vitro experiments were conducted to validate the effectiveness of hub genes and explore their regulatory role in the progression of heterotopic ossification. Additionally, the therapeutic effect of Celecoxib, which modulates the expression of the hub genes, was investigated in the treatment of heterotopic ossification. Results: 568 potential molecules related to heterotopic ossification and 76 potential binding targets of Celecoxib were identified. After intersection, 13 potential functional molecules in Celecoxib's treatment of heterotopic ossification were obtained. KEGG analysis suggested pathways such as Rheumatoid arthritis, NF-kappa B signaling pathway, Pathways in cancer, Antifolate resistance, MicroRNAs in cancer play a role in the treatment of heterotopic ossification by Celecoxib. Further enrichment analysis of the 13 potential functional molecules identified 5 hub genes: IL6, CCND1, PTGS2, IGFBP3, CDH1. Molecular docking results indicated that Celecoxib displayed excellent binding affinity with CCND1 among the 5 hub genes. Experimental validation found that CCND1 is highly expressed in the progression of heterotopic ossification, promoting heterotopic ossification in the early stages and inhibiting it in the later stages, with Celecoxib's treatment of heterotopic ossification depending on CCND1. Conclusion: In the process of treating heterotopic ossification with Celecoxib, immune and inflammatory signaling pathways play a significant role. The therapeutic effect of Celecoxib on heterotopic ossification depends on the hub gene CCND1, which plays different roles at different stages of the progression of heterotopic ossification, ultimately inhibiting the occurrence of heterotopic ossification.

ISGylation enhances dsRNA-induced interferon response and NFκB signaling in fallopian tube epithelial cells.

Heritable mutations in BRCA1 associate with increased risk of high-grade serous tubo-ovarian cancer. Nongenetic risk factors associated with this cancer, which arises from fallopian tube epithelial (FTE) cells, suggests a role for repetitive ovulation wherein FTE cells are exposed to inflammatory signaling molecules within follicular fluid. We previously reported increased NFκB and EGFR signaling in BRCA1-deficient primary FTE cells, with follicular fluid exposure further increasing abundance of interferon-stimulated gene (ISG) transcripts, including the ubiquitin-like protein ISG15 and other ISGylation pathway members. Both NFκB and type I interferon signaling are upregulated by stimulation of cGAS-STING or MDA5 and RIGI pattern recognition receptors. Since some pattern recognition receptors and their signal transduction pathway members are ISGylated, we tested the impact of ISG15 and ISGylation on interferon regulatory factor 3 (IRF3) and NFκB signaling through cGAS-STING or RIGI and MDA5 activation. Expression of ISG15 or UBA7, the E1-like ISG15-activating enzyme, in immortalized FTE cells was disrupted by CRISPR gene editing. Activation of IRF3 by RIGI or MDA5 but not cGAS-STING was attenuated by loss of either ISG15 or UBA7 and this was reflected by a similar effect on NFκB activation and downstream targets. Loss of ISGylation decreased levels of both MDA5 and RIGI, with knockdown of RIGI but not MDA5, decreasing IRF3 and NFκB activation in parental cells. These finding indicate that ISGylation enhances the ability of dsRNA to activate cytokine release and proinflammatory signaling. Further work to explore ISGylation as a target for prevention of high-grade serous tubo-ovarian cancer in BRCA1 mutation carriers is warranted.

Tongqiao Yizhi granule repress the nuclear factor kappa-b/nucleotide oligomerization domain-like receptors 3/caspase-1 pyroptosis pathway in the hippocampus to counter vascular dementia in rats.

OBJECTIVE: To explore the mechanism by which Tongqiao Yizhi granule (, TQYZKL) intervenes pyroptosis to treat vascular dementia (VaD) in a rat model. METHODS: The rat model of VaD was established by two-vessel occlusion (2VO). The rats were randomly divided into Sham group, Model group, Nimodipine group, TQYZKL (6.2 g?kg-1?d-1), TQYZKL (12.4 g?kg-1?d-1), TQYZKL (24.8 g?kg-1?d-1). The Morris water maze (MWM) test was carried out to test the learning and memory function; Hematoxylin-eosin staining and transmission electron microscopy (TEM) to observe the pathological damage in the hippocampus; Tunel fluorescence staining to detect neuronal pyroptosis in the hippocampus. The expression levels of pyroptosis-related proteins, namely Golgi peripheral membrane protein p65 (P65), nucleotide oligomerization domain-like receptors 3 (NLRP3), caspase-1 and Gasdermin D (GSDMD), were detected using Western blotting and reverse transcription polymerase chain reaction. Moreover, the serum levels of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) were determined through the enzyme-linked immunosorbent assay. RESULTS: The study revealed that TQYZKL effectively improved the ability of VaD ratsto learn and memorize, relieved the pathological damage in the hippocampus, restored neuronal morphology, and reduced the expression of pyroptosis-related proteins P65, NLRP3, caspase-1, GSDMD-N, IL-18 and IL-1ß (P < 0.05). CONCLUSION: TQYZKL inhibits neuronal pyroptosis in the hippocampus of VaD rats by regulating nuclear factor kappa-B/NLRP3/caspase-1 signaling pathway, thus exerting a therapeutic effect on VaD in the rats.

USP36 inhibits apoptosis by deubiquitinating cIAP1 and survivin in colorectal cancer cells.

Chemotherapeutic agents for treating colorectal cancer (CRC) primarily induce apoptosis in tumor cells. The ubiquitin-proteasome system is critical for apoptosis regulation. Deubiquitinating enzymes (DUBs) remove ubiquitin from substrates to reverse ubiquitination. Although over 100 DUB members have been discovered, the biological functions of only a small proportion of DUBs have been characterized. Here, we aimed to systematically identify the DUBs that contribute to the development of CRC. Among the DUBs, ubiquitin-specific protease 36 (USP36) is upregulated in CRC. We showed that the knockdown of USP36 induces intrinsic and extrinsic apoptosis. Through gene silencing and coimmunoprecipitation techniques, we identified survivin and cIAP1 as USP36 targets. Mechanistically, USP36 binds and removes lysine-11-linked ubiquitin chains from cIAP1 and lysine-48-linked ubiquitin chains from survivin to abolish protein degradation. Overexpression of USP36 disrupts the formation of the XIAP-second mitochondria-derived activator of caspase complex and promotes receptor-interacting protein kinase 1 ubiquitination, validating USP36 as an inhibitor to intrinsic and extrinsic apoptosis through deubiquitinating survivin and cIAP1. Therefore, our results suggest that USP36 is involved in CRC progression and is a potential therapeutic target.

Whole-genome DNA methylation profiling revealed epigenetic regulation of NF-κB signaling pathway involved in response to Vibrio alginolyticus infection in the Pacific oyster, Crassostrea gigas.

DNA methylation, an essential epigenetic alteration, is tightly linked to a variety of biological processes, such as immune response. To identify the epigenetic regulatory mechanism in Pacific oyster (Crassostrea gigas), whole-genome bisulfite sequencing (WGBS) was conducted on C. gigas at 0 h, 6 h, and 48 h after infection with Vibrio alginolyticus. At 6 h and 48 h, a total of 11,502 and 14,196 differentially methylated regions (DMRs) were identified (p<0.05, FDR<0.001) compared to 0 h, respectively. Gene ontology (GO) analysis showed that differentially methylated genes (DMGs) were significantly enriched in various biological pathways including immunity, cytoskeleton, epigenetic modification, and metabolic processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that transcription machinery (ko03021) is one of the most important pathways. Integrated transcriptome and methylome analyses allowed the identification of 167 and 379 DMG-related DEGs at 6 h and 48 h, respectively. These genes were significantly enriched in immune-related pathways, including nuclear factor kappa B (NF-κB) signaling pathway (ko04064) and tumor necrosis factor (TNF) signaling pathway (ko04668). Interestingly, it's observed that the NF-κB pathway could be activated jointly by TNF Receptor Associated Factor 2 (TRAF2) and Baculoviral IAP Repeat Containing 3 (BIRC3, the homolog of human BIRC2) which were regulated by DNA methylation in response to the challenge posed by V. alginolyticus infection. Through this study, we provided insightful information about the epigenetic regulation of immunity-related genes in the C. gigas, which will be valuable for the understanding of the innate immune system modulation and defense mechanism against bacterial infection in invertebrates.

Umbelliferone reduces inflammation and ligature-induced osteoclastic alveolar bone resorption in mice.

AIMS: This study aimed to investigate the effects of Umbelliferone (UMB) on the inflammation underlying alveolar bone resorption in mouse periodontitis. METHODS: Male Swiss mice subjected to a ligature of molars were grouped as non-treated (NT), received UMB (15, 45, or 135 mg/kg) or saline daily for 7 days, respectively, and were compared with naïve mice as control. Gingival tissues were evaluated by myeloperoxidase (MPO) activity and interleukin-1ß level by ELISA. The bone resorption was directly assessed on the region between the cement-enamel junction and the alveolar bone crest. Microscopically, histomorphometry of the furcation region, immunofluorescence for nuclear factor-kappa B (NF-ĸB), and immunohistochemistry for tartrate-resistant acid phosphatase (TRAP), and cathepsin K (CTSK) were performed. Systemically, body mass variation and leukogram were analyzed. RESULTS: Periodontitis significantly increased MPO activity, interleukin-1ß level, and NF-ĸB+ immunofluorescence, and induced severe alveolar bone and furcation resorptions, besides increased TRAP+ and CTSK+ cells compared with naïve. UMB significantly prevented the inflammation by reducing MPO activity, interleukin-1ß level, and NF-ĸB+ intensity, besides reduction of resorption of alveolar bone and furcation area, and TRAP+ and CTSK+ cells compared with the NT group. Periodontitis or UMB treatment did not affect the animals systemically. CONCLUSION: UMB improved periodontitis by reducing inflammation and bone markers.

In Silico Analyses Indicate a Lower Potency for Dimerization of TLR4/MD-2 as the Reason for the Lower Pathogenicity of Omicron Compared to Wild-Type Virus and Earlier SARS-CoV-2 Variants.

The SARS-CoV-2 Omicron variants have replaced all earlier variants, due to increased infectivity and effective evasion from infection- and vaccination-induced neutralizing antibodies. Compared to earlier variants of concern (VoCs), the Omicron variants show high TMPRSS2-independent replication in the upper airway organs, but lower replication in the lungs and lower mortality rates. The shift in cellular tropism and towards lower pathogenicity of Omicron was hypothesized to correlate with a lower toll-like receptor (TLR) activation, although the underlying molecular mechanisms remained undefined. In silico analyses presented here indicate that the Omicron spike protein has a lower potency to induce dimerization of TLR4/MD-2 compared to wild type virus despite a comparable binding activity to TLR4. A model illustrating the molecular consequences of the different potencies of the Omicron spike protein vs. wild-type spike protein for TLR4 activation is presented. Further analyses indicate a clear tendency for decreasing TLR4 dimerization potential during SARS-CoV-2 evolution via Alpha to Gamma to Delta to Omicron variants.

Effects of Chronic Inflammatory Activation of Murine and Human Arterial Endothelial Cells at Normal Lipoprotein and Cholesterol Levels In Vivo and In Vitro.

The activation of endothelial cells is crucial for immune defense mechanisms but also plays a role in the development of atherosclerosis. We have previously shown that inflammatory stimulation of endothelial cells on top of elevated lipoprotein/cholesterol levels accelerates atherogenesis. The aim of the current study was to investigate how chronic endothelial inflammation changes the aortic transcriptome of mice at normal lipoprotein levels and to compare this to the inflammatory response of isolated endothelial cells in vitro. We applied a mouse model expressing constitutive active IκB kinase 2 (caIKK2)-the key activator of the inflammatory NF-κB pathway-specifically in arterial endothelial cells and analyzed transcriptomic changes in whole aortas, followed by pathway and network analyses. We found an upregulation of cell death and mitochondrial beta-oxidation pathways with a predicted increase in endothelial apoptosis and necrosis and a simultaneous reduction in protein synthesis genes. The highest upregulated gene was ACE2, the SARS-CoV-2 receptor, which is also an important regulator of blood pressure. Analysis of isolated human arterial and venous endothelial cells supported these findings and also revealed a reduction in DNA replication, as well as repair mechanisms, in line with the notion that chronic inflammation contributes to endothelial dysfunction.

Protective effect of modified Huangqi Chifeng decoction on immunoglobulin A nephropathy through toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-kappa B signaling pathway.

OBJECTIVE: To examine the nephroprotective mechanism of modified Huangqi Chifeng decoction (, MHCD) in immunoglobulin A nephropathy (IgAN) rats. METHODS: To establish the IgAN rat model, the bovine serum albumin, lipopolysaccharide, and carbon tetrachloride 4 method was employed. The rats were then randomly assigned to the control, model, telmisartan, and high-, medium-, and low-dose MHCD groups, and were administered the respective treatments via intragastric administration for 8 weeks. The levels of 24-h urinary protein, serum creatinine (CRE), and blood urea nitrogen (BUN) were measured in each group. Pathological alterations were detected. IgA deposition was visualized through the use of immunofluorescence staining. The ultrastructure of the kidney was observed using a transmission electron microscope. The expression levels of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-ß1 (TGF-ß1) were examined by immunohistochemistry and quantitative polymerase chain reaction. Levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB) P65, were examined by immunohistochemistry, Western blotting, and quantitative polymerase chain reaction. RESULTS: The 24-h urine protein level in each group increased significantly at week 6, and worsen from then on. But this process can be reversed by treatments of telmisartan, and high-, medium-, and low-dose of MHCD, and these treatments did not affect renal function. Telmisartan, and high-, and medium-dose of MHCD reduced IgA deposition. Renal histopathology demonstrated the protective effect of high-, medium-, and low-dose of MHCD against kidney injury. The expression levels of MCP-1, IL-6, and TGF-ß1 in kidney tissues were downregulated by low, medium and high doses of MHCD treatment. Additionally, treatment of low, medium and high doses of MHCD decreased the protein and mRNA levels of TLR4, MyD88, and NF-κB. CONCLUSIONS: MHCD exerted nephroprotective effects on IgAN rats, and MHCD regulated the expressions of key targets in TLR4/MyD88/NF-κB signaling pathway, thereby alleviating renal inflammation by inhibiting MCP-1, IL-6 expressions, and ameliorating renal fibrosis by inhibiting TGF-ß1 expression.

Ginsenoside Rb1 alleviates lipopolysaccharide-induced inflammation in human dental pulp cells via the PI3K/Akt, NF-κB, and MAPK signalling pathways.

AIM: Among numerous constituents of Panax ginseng, a constituent named Ginsenoside Rb1 (G-Rb1) has been studied to diminish inflammation associated with diseases. This study investigated the anti-inflammatory properties of G-Rb1 on human dental pulp cells (hDPCs) exposed to lipopolysaccharide (LPS) and aimed to determine the underlying molecular mechanisms. METHODOLOGY: The KEGG pathway analysis was performed after RNA sequencing in G-Rb1- and LPS-treated hDPCs. Reverse-transcription polymerase chain reaction (RT-PCR) and western blot analysis were used for the assessment of cell adhesion molecules and inflammatory cytokines. Statistical analysis was performed with one-way ANOVA and the Student-Newman-Keuls test. RESULTS: G-Rb1 did not exhibit any cytotoxicity within the range of concentrations tested. However, it affected the levels of TNF-α, IL-6 and IL-8, as these showed reduced levels with exposure to LPS. Additionally, less mRNA and protein expressions of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were shown. With the presence of G-Rb1, decreased levels of PI3K/Akt, phosphorylated IκBα and p65 were also observed. Furthermore, phosphorylated ERK and JNK by LPS were diminished within 15, 30 and 60 min of G-Rb1 exposure; however, the expression of non-phosphorylated ERK and JNK remained unchanged. CONCLUSIONS: G-Rb1 suppressed the LPS-induced increase of cell adhesion molecules and inflammatory cytokines, while also inhibiting PI3K/Akt, phosphorylation of NF-κB transcription factors, ERK and JNK of MAPK signalling in hDPCs.

Regulatory mechanism of FCGR2A in macrophage polarization and its effects on intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) poses a significant health burden, necessitating a deeper understanding of its molecular underpinnings. Transcriptomic analysis reveals 485 differentially expressed genes (DEGs) associated with IDD, underscoring the importance of immune regulation. Weighted gene co-expression network analysis (WGCNA) identifies a yellow module strongly correlated with IDD, intersecting with 197 DEGs. Protein-protein interaction (PPI) analysis identifies ITGAX, MMP9 and FCGR2A as hub genes, predominantly expressed in macrophages. Functional validation through in vitro and in vivo experiments demonstrates the pivotal role of FCGR2A in macrophage polarization and IDD progression. Mechanistically, FCGR2A knockdown suppresses M1 macrophage polarization and NF-κB phosphorylation while enhancing M2 polarization and STAT3 activation, leading to ameliorated IDD in animal models. This study sheds light on the regulatory function of FCGR2A in macrophage polarization, offering novel insights for IDD intervention strategies. KEY POINTS: This study unveils the role of FCGR2A in intervertebral disc (IVD) degeneration (IDD). FCGR2A knockdown mitigates IDD in cellular and animal models. Single-cell RNA-sequencing uncovers diverse macrophage subpopulations in degenerated IVDs. This study reveals the molecular mechanism of FCGR2A in regulating macrophage polarization. This study confirms the role of the NF-κB/STAT3 pathway in regulating macrophage polarization in IDD.

Gochujang, a traditional Korean fermented food, protects through suppressed inflammatory pathways and histological structure disruption in dextran sodium sulfate (DSS)-induced colitis mice.

The mechanisms underlying chronic inflammatory diseases remain unclear. Therefore, researchers have explored the mechanisms underlying colitis using diverse materials. Recently, there has been an increasing interest in fermented products and bioconversion materials, their potential efficacy is being actively studied. Gochujang, a traditional Korean fermented product, is crafted by blending fermented Meju powder, gochu (Korean chili) powder, glutinous rice, and salt. In our study, we explored the effectiveness of Gochujang (500 mg/kg; Cheongju and Hongcheon, Korea) in dextran sulfate sodium (DSS)-induced colitis mice model. Gochujang was orally administered for 2 weeks, followed by the induction of colitis using 3% DSS in the previous week. During our investigation, Gochujang variants (TCG22-25, Cheongju and TCG22-48, Hongcheon) did not exhibit significant inhibition of weight reduction (p = 0.061) but notably (p = 0.001) suppressed the reduction in large intestine length in DSS-induced colitis mice. In the serum from colitis mice, TCG22-48 demonstrated reduced levels of the inflammatory cytokines interleukin (IL)-6 (p = 0.001) and tumor necrosis factor (TNF)-α (p = 0.001). Additionally, it inhibited the phosphorylation of Erk (p = 0.028), p38, and NF-κB (p = 0.001) the inflammatory mechanism. In our study, TCG22-25 demonstrated a reduction in the IL-6 level (p = 0.001) in serum and inhibited the phosphorylation of p38 and NF-κB (p = 0.001). Histological analysis revealed a significant (p = 0.001) reduction in the pathological score of the large intestine from TCG22-25 and TCG22-48. In conclusion, the intake of Gochujang demonstrates potent anti-inflammatory effects, mitigating colitis by preventing the large intestine length reduction of animals with colitis, lowering serum levels of TNF-α and IL-6 cytokines, and inhibiting histological disruption and inflammatory mechanism phosphorylation.

Anti-inflammatory and anti-arthritic potential of Coagulansin-A: in vitro and in vivo studies.

The current work was designed to evaluate the anti-inflammatory and anti-arthritic potential of Coagulansin-A (Coag-A) using mouse macrophages and arthritic mice. In the LPS-induced RAW 264.7 cells, the effects of Coag-A on the release of nitric oxide (NO), reactive oxygen species (ROS), and pro-inflammatory cytokines were analyzed. In addition, the mediators involved in the nuclear factor-kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways were evaluated by the RT-qPCR and western blotting. Coag-A did not show significant cytotoxicity in the RAW 264.7 cells in the tested concentration range (1-100 µM). Coag-A significantly inhibited the production of NO, ROS, and key pro-inflammatory cytokines. The anti-inflammatory effects of Coag-A might be through inhibiting the NF-κB pathway and activating the Nrf2 pathway. In the arthritic mouse models, behavioral studies and radiological and histological analyses were performed. We found that the i.p. injection of Coag-A dose-dependently (1-10 mg/kg) reduced the Carrageenan-induced acute inflammation in the mice. In Complete Freund's Reagent-induced arthritic mouse model, Coag-A (10 mg/kg) showed significant anti-inflammatory and anti-arthritic effects in terms of the arthritic index, hematological parameters, and synovium inflammation. After the Coag-A treatment, the bone and tissue damage was ameliorated significantly in the arthritic mice. Moreover, immunohistochemistry of mouse paw tissues revealed a significant reduction in the expression of pro-inflammatory cytokines in the NF-κB pathway, confirming Coag-A's therapeutic potential and mechanism.