Mediators of Inflammation最新文献

The excessive accumulation of lipid droplets within hepatocytes stands as a hallmark characteristic of metabolic-associated fatty liver disease (MAFLD). Selenium (Se) nanoparticles (NPs) have garnered considerable attention for their notable bioavailability, minimal toxicity, and exceptional antioxidant properties. However, a critical limitation lies in the propensity of SeNPs to aggregate into the biologically inactive elemental Se, thereby constraining their utility. Here, we utilized Stevioside (SV), a natural sweetener, to modify SeNPs and obtained the SV-SeNPs with a size of about 187 ± 7 nm. We aimed to investigate the effect of SV-SeNPs on high fructose-palmitate (HFP) induced lipid accumulation in HepG2 cells. Noteworthy is the absence of overt cytotoxicity attributed to SV-SeNPs on normal HepG2 cells. Of significance, our findings delineate the profound inhibitory effects of SV-SeNPs on the expression of key genes implicated in de novo lipogenesis, such as fatty-acid synthase (FASN), acetyl-CoA-carboxylase 1 (ACC1), and stearoyl-CoA desaturase-1 (SCD1) within HFP-induced HepG2 cells. Furthermore, our investigation reveals that SV-SeNPs mediate a significant reduction in lipid accumulation by activating the PI3K/AKT/Nrf2 signaling cascades. Additionally, the antioxidative properties of SV-SeNPs are underscored by their ability to counteract oxidative stress via the upregulation of two pivotal antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GSHPx). In conclusion, our study unveils the potential beneficial effects of SV-SeNPs on the prevention and treatment of MAFLD by effectively suppressing lipid accumulation and ameliorating oxidative stress.

Amyotrophic lateral sclerosis (ALS) is a multicomplex neurodegenerative disorder characterized by motor neuron death, muscle atrophy, and respiratory failure. Owing to its multicomplex mechanisms and multifactorial nature in the skeletal muscle and spinal cord (SC), no effective therapy has been developed. However, herbal medicines, known for their multitarget properties, have demonstrated promising efficacy with limited side effects in treating various diseases. Specifically, Paeonia lactiflora Pallas has been demonstrated to exhibit analgesic, antidepressant, anti-inflammatory, and neuroprotective effects. However, the pharmacological mechanisms underlying the beneficial effects of P. lactiflora in hSOD1^G93A animal models remain unexplored. Therefore, this study was conducted to investigate the multitarget effects of P. lactiflora in hSOD1^G93A transgenic mice, an ALS model. Footprint tests, western blot assays, and immunohistochemical analysis were used to assess the effect of P. lactiflora on the tibia anterior (TA), gastrocnemius (GC), and SC. The results revealed that P. lactiflora augmented motor function and decreased motor neuron loss in hSOD1^G93A mice. Furthermore, P. lactiflora significantly lowered the expression of proteins associated with inflammation and oxidative stress in the skeletal muscle (TA and GC) and SC. P. lactiflora also regulated autophagy function by reducing the levels of key markers, such as P62/sequestosome 1 (SQSTM1), microtubule-associated proteins 1A/1B light chain 3B, and SMAD family member 2, in the muscle and SC. Overall, P. lactiflora treatment improved motor function, prevented motor neuron death, and exhibited anti-inflammatory and antioxidative effects in the skeletal muscle and SC of ALS mouse models. These results suggest that P. lactiflora could serve as a promising multitarget therapeutic agent for systemic and multipathological diseases.

Endothelial dysfunction is a significant factor in the pathogenesis of various diseases. In pathological states, endothelial cells (ECs) undergo activation, resulting in dysfunction characterized by the stimulation of inflammatory responses, oxidative stress, cell proliferation, blood coagulation, and vascular adhesions. Interleukin-35 (IL-35), a novel member of the IL-12 family, is primarily secreted by regulatory T cells (Tregs) and regulatory B cells (Bregs). The role of IL-35 in immunomodulation, antioxidative stress, resistance to apoptosis, control of EC activation, adhesion, and angiogenesis in ECs remains incompletely understood, as the specific mechanisms of IL-35 action and its regulation have yet to be fully elucidated. Therefore, this systematic review aims to comprehensively investigate the impact of IL-35 on ECs and their physiological roles in a range of conditions, including cardiovascular diseases, tumors, sepsis, and rheumatoid arthritis (RA), with the objective of elucidating the potential of IL-35 as a therapeutic target for these ailments.

Psoriasis is an inflammatory skin disease mediated by multiple immune cells, including T cells, macrophages, and dendritic cells, which exhibit complex pathologies and limited clinical treatment. Here, we found that salt-inducible kinase 1 (SIK1) was upregulated in the imiquimod (IMQ)-induced psoriasis mouse model. This increment may be due to a higher level of interleukin-17, which promoted the expression of SIK1 in keratinocytes. Inhibition of SIK1 kinase activity using a small molecular inhibitor (HG-9-91-01 or YKL-06-062) dramatically alleviated IMQ-induced psoriasis, showing reduced epidermal thickness, inflammation, and hyperproliferative epidermal keratinocytes. Our data demonstrated that SIK1 inhibitors HG-9-91-01 or YKL-06-062 blocked the expression of IL-17-induced proinflammatory cytokines and chemokines, including Il6, Kc, and Ccl20. Mechanistically, we found that SIK1 inhibitor HG-9-91-01 or YKL-06-062 suppressed the phosphorylation of Iκbα and P38. Consistently, SIK1 overexpression in keratinocytes promoted the activation of Iκbα and P38. Collectively, our results reveal that SIK1 participates to promote IL17-induced signaling through enhancing activation of NF-κB and MAPKs and exacerbates psoriasis-like skin inflammation. Thus, inhibition of SIK1 presents a potential new therapeutic target for psoriasis.

Background: Geniposide, a prominent iridoid glycoside derived from Gardenia jasminoides J. Ellis, has garnered attention due to its association with hepatotoxicity despite its well-documented pharmacological efficacy in preclinical and clinical contexts. The NOD-like receptor protein 3 (NLRP3) inflammasome is implicated in numerous pathological conditions, including drug-induced liver injury. This study aims to explore the involvement of the NLRP3 inflammasome in geniposide-induced liver toxicity. Methods: Rats were administered geniposide for 5 days, concurrently treated with or without glibenclamide (GLY), an in vivo inhibitor of NLRP3. In vitro, HL-7702 cells were exposed to genipin (a metabolite of geniposide via hepatointestinal circulation), with or without GLY supplement. Liver tissue was examined through pathological sections. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GT), and total bilirubin (T-Bil) levels were determined using the enzyme plate method. IL-1β and IL-18 levels in the supernatant and serum were quantified through ELISA. Apoptosis-associated speck-like protein (ASC), NLRP3, caspase-1, pro-IL-1β, and pro-IL-18 mRNA levels in cells or the liver were assessed by RT-PCR. Protein levels of ASC, NLRP3, caspase-1, pro-IL-1β, and pro-IL-18 in cells or the liver were analyzed by Western blot. Results: Rats treated with geniposide displayed notable liver damage characterized by inflammatory infiltration, elevated serum transaminases, and heightened levels of inflammatory factors IL-1β and IL-18. This liver damage was concomitant with NLRP3 inflammasome activation within the liver. Furthermore, genipin induction led to reduced cell viability, increased transaminases in the cell supernatant, and an upsurge in inflammatory factors, resulting in heightened NLRP3 inflammasome expression within the cells. However, GLY effectively curtailed excessive NLRP3 activation, dampened the production of inflammatory factors IL-1β and IL-18, and ameliorated liver damage caused by geniposide. Conclusions: Our findings collectively elucidate that geniposide induces hepatotoxicity by triggering NLRP3 inflammasome signaling. Inhibition of the inflammasome presents a promising novel therapeutic target for mitigating geniposide-induced hepatotoxicity.

Background: Chronic actinic dermatitis (CAD) is a skin inflammation triggered by light exposure, occurring at the exposed site and potentially causing widespread inflammation throughout the body. While we hypothesize that severe CAD could progress to atopic dermatitis, the exact inflammatory mechanisms and pathogenesis remain unclear. Objective: We aimed to investigate the relationships between CAD severity and clinical and immunological parameters. Methods: CAD patients were classified into two groups based on severity: mild CAD and severe CAD. We assessed total IgE levels, eosinophil count in peripheral blood (PB), the ratio of Th2 cell percentage to Th1 cell percentages (Th2/Th1), and cytokine/chemokine levels in both PB and skin lesions. Results: In our study, eosinophil counts in patients with severe CAD and mild CAD were significantly higher than those in the control group (p  < 0.05). It was exhibited a higher Th2/Th1 ratio in severe-CAD patients compared with mild-CAD patients and control group (p  < 0.05). There were significant increases in the levels of IL-4, IL-5, IL-8, IL-31, and IFN-γ in the lesions of severe CAD patients compared to the control group (p  < 0.05). Additionally, the level of CD63 exosomes in the PB of severe-CAD patients was significantly elevated compared to the control group (p  < 0.05). Persistent elevations of CD63 exosomes in severe CAD patients were associated with the Th2/Th1 balance status in PB (p  < 0.05). Conclusion: Severe CAD demonstrates a shift toward Th2 immunity from Th2/Th1, accompanied by elevated with inflammatory factors such as IL-4, IL-5, IL-31, IL-8, and IFN-γ in skin lesions, as well as increased CD63 exosomes in PB. Thus, consequently, exosomes and Th2/Th1 imbalance may contribute to the systemic manifestations observed in CAD patients.

Background: Trapa natans L. fruits and leaf extracts have a broad range of immunomodulatory, anti-inflammatory, and antioxidant effects; however, their effects on cardiac protection have not been investigated. Objective: The study aims to test the biological activity of Trapa natans L. extract (TNE) in cisplatin (CDDP)-induced cardiotoxicity. Methods: Wistar albino rats received a single dose of CDDP intraperitoneally and TNE ones per day for 2 weeks orally. Cardiac inflammation, necrosis, and fibrosis were determined by histological and immunohistochemical analyses. Cytokines in rat sera and cardiac tissue were detected by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time (qRT)-PCR. Rat macrophages cultured in the presence of TNE for 48 h were harvested for flow cytometry, while supernatants were collected for cytokine and reactive oxygen species (ROS) measurement. Results: Application of TNE significantly attenuated CDDP induced cardiotoxicity as demonstrated by biochemical and histopathological analysis. Administration of TNE once daily for 14 days decreased level of proinflammatory (TNF-α, IFN-γ, and IL-6) and prooxidative parameters (NO₂, O₂, and H₂O₂), while increased level of immunosuppressive IL-10 and antioxidative glutathione (GSH), catalase (CAT) and uperoxide dismutase (SOD) in the systemic circulation. TNE treatment resulted in attenuated heart inflammation and fibrosis accompanied with the reduced infiltration of macrophages and reduced expression of proinflammatory and profibrotic genes in heart tissue of CDDP-treated animals. In vitro lipopolysaccharide (LPS)-stimulated macrophages cultured in the presence of TNE adopted immunosuppressive phenotype characterized by decreased production of proinflammatory cytokines and prooxidative mediators. Conclusion: Our study provides the evidence that TNE ameliorates cisplatin-induced cardiotoxicity in rats by reducing inflammation and oxidative stress via promoting M2 macrophage polarization.

Background: This study aims to reveal the potential molecular mechanisms of modified Gegen Qinlian decoction (MGQD) in relieving ulcerative colitis (UC). Methods: C57BL/6J mice were used to establish experimental colitis via dextran sodium sulfate (DSS). Body weight, disease activity index (DAI), spleen weight, colon length, and histopathologic features were measured to evaluate the therapeutic effects of MGQD on mice with UC. The ELISA kits were employed to assess the concentrations of interleukin (IL)-6, IL-1β, tumor necrosis factor-α (TNF-α), glutathione (GSH), reactive oxygen species (ROS), and malondialdehyde (MDA). Western blot analyses were used to assess the levels of IκBα, p65, p-IκBα, p-p65, HO-1, and Nrf2. Moreover, the protein levels of Nrf2 and p-p65 were assessed by immunofluorescence. Results: Colitis-related symptoms in mice were significantly alleviated by MGQD. Moreover, MGQD inhibited the levels of TNF-α, IL-1β, IL-6, MDA, and ROS and increased the level of GSH in mice with UC. Mechanistically, MGQD prevented the activation of the NF-κB pathway and concomitantly promoted the activation of the Nrf2/HO-1 pathway. Conclusion: MGQD alleviated UC by suppressing inflammation and oxidative stress via the modulation of NF-κB and Nrf2/HO-1 pathways, suggesting that MGQD may be a candidate therapy for UC.

Background: Tobacco smoke is known to contain numerous harmful chemicals, and epidemiological evidence has firmly established smoking as a potent risk factor for hypertension and myocardial infarction (MI). However, the precise mechanisms by which smoking contributes to cardiovascular disease are not fully understood. The aim of this study is to identify common molecular signatures in blood that link smoking to acute MI (AMI). Methods: We extracted transcriptome data from seven blood microarray datasets in the Gene Expression Omnibus (GEO) database, encompassing a total of 403 patients. Employing both individual dataset analysis and a combined meta-analysis approach, we conducted a thorough examination of blood transcriptome profiles associated with AMI and smoking, uncovering numerous differentially expressed genes (DEGs). Results: Functional enrichment analysis indicated that DEGs associated with AMI and smoking were significantly enriched in overlapping biological processes, such as immune response and inflammation. Moreover, three genes-PTGDR, PYHIN1, and PRSS23-were consistently altered in both conditions and were validated as dysregulated in AMI using an independent GEO dataset. Furthermore, quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) validation further confirmed the differential expression of PYHIN1 and PRSS23 in AMI patients. Conclusions: Our findings suggest that gene expression changes induced by smoking in blood may contribute to the heightened risk of AMI. These identified genes are likely to play critical roles in the pathogenesis of AMI. Given the accessibility of peripheral blood samples, the expression levels of these genes could potentially serve as biomarkers for assessing cardiovascular health, particularly in individuals with a history of long-term exposure to cigarette smoke.

Objective: This study aims to investigate the mechanism of Tetrastigma hemsleyanum Diels et Gilg flavonoids (THF) on acute hepatic injury (AHI). Methods: First, high-performance liquid chromatography (HPLC) fingerprints were established to obtain the main chemical components of THF. According to the network pharmacology databases, collect active targets of AHI and potential targets. Using interaction targets to construct a protein-protein interaction (PPI) network, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Finally, the affinity between the core targets and the main active ingredients was verified by molecular docking. Next, verified network pharmacology predictions with animal experiments. Mice were treated with THF (20, 40, and 80 mg/kg) for 7 days, and then built an acute liver injury model (lipopolysaccharide [LPS], 10 mg/kg). Detecting the liver biochemical indices, observe the liver pathological changes, and verify the key signaling pathway targets. Results: HPLC showed that the main components of THF were quercetin and kaempferol. Seven active ingredients and 193 potential targets were screened, and 259 disease targets related to acute liver injury, quercetin, and kaempferol may be the main active ingredients in THF. PPI network analysis showed that tumor necrosis factor (TNF), interleukin-6 (IL-6), and tumor protein 53 (TP53) were potential targets of THF for the treatment of AHI. KEGG analysis showed that the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway might be one of the main pathways in the treatment of AHI. The molecular docking results showed that active compounds both have strong binding activity with potential targets in PPI. In vivo experiments showed that THF could reduce the fibrosis and inflammation of liver tissue etc. Meanwhile, it could downregulate the alanine aminotransferase (ALT), aspartate aminotransferase (AST), IL-6, tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP) levels, and the protein expressions of phosphorylated phosphoinositide 3-kinase (p-PI3K), phosphorylated protein kinase B (p-AKT), and the ratio of BCL2-associated X (BAX)/B-cell lymphoma-2 (BCL-2) in the liver tissue of the mice with acute liver injury and upregulate the level of interleukin-10 (IL-10). Conclusion: The treatment of acute liver injury with THF is characterized by multicomponents and multitargets, and its mechanism may be related to the alleviation of the inflammatory response, reduction of apoptosis, and regulation of the PI3K/AKT signaling pathway.