Inflammation最新文献

Cholestasis is a multifactorial hepatobiliary disorder, characterized by obstruction of bile flow and accumulation of bile, which in turn causes damage to liver cells and other tissues. In severe cases, it can result in the development of life-threatening conditions, including cirrhosis and liver cancer. Paeoniflorin (PF) has been demonstrated to possess favourable therapeutic potential for the treatment of cholestasis. The objective of this research was to examine the molecular mechanism of PF in the treatment of ANIT-induced cholestasis and to propose novel avenues for further research on the pharmacological effects of PF. In vivo and in vitro models of cholestasis were developed. The histopathological changes in the bile ducts and liver were evaluated through the use of hematoxylin and eosin (HE) staining. The extent of apoptosis was evaluated through the use of immunofluorescence (IF), immunoblotting (WB), and electron microscopy. The JNK signalling pathway was identified as the direct mechanism of action of PF through the utilisation of HuProt™ 20 K chips and other technologies. The present study demonstrated that PF markedly alleviated liver injury in an ANIT-induced cholestasis model. Specifically, PF was observed to attenuate cholestasis-induced liver injury by reducing the abnormal elevation of liver function indices and suppressing the expression of inflammatory mediators. Furthermore, PF exhibited anti-apoptotic properties in both in vivo and in vitro experiments, thereby mitigating cholestasis-induced hepatocyte apoptosis. These protective effects are attributable to the fact that PF exerts its action through direct interaction with the JNK pathway. It has been demonstrated that PF is capable of binding directly to MAPK8 (JNK1) and MAPK9 (JNK2), thereby inhibiting JNK activation and reducing apoptosis. With regard to the protection of bile ducts, PF may indirectly inhibit hepatocyte apoptosis by maintaining the structural integrity and tight junctions of bile duct cells. PF improved cholestasis by inhibiting hepatocyte apoptosis directly by targeting the JNK signaling pathway and indirectly inhibited hepatocyte apoptosis by improving the tight junctions of bile duct cells to regulate the bile duct microenvironment.

Inflammatory bone resorption represents a pathological condition marked by an increase in bone loss, commonly associated with chronic inflammatory conditions such as rheumatoid arthritis and periodontitis. Current therapies primarily focus on anti-inflammatory drugs and bisphosphonates; however, these treatments are limited due to side effects, inadequate efficacy, and unpredictable long-term complications. Kurarinone (KR), a bioactive compound isolated from the traditional Chinese herb Sophora flavescens, exhibits a range of biological activities, including anti-inflammatory, anticancer, and cardiovascular protective effects. To address the limitations of existing therapies and enhance drug utilization, this study explores the potential of KR as a therapeutic agent for inflammatory bone resorption and delineates its underlying mechanisms. In vitro experiments reveal that KR notably inhibits osteoclastogenesis and reduces the expression of osteoclastic markers. Additionally, KR decreases the levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, while downregulating NADPH oxidase 1 (NOX1) and Kelch-like ECH-associated protein 1 (Keap1) to diminish ROS production. Furthermore, KR activates the nuclear factor erythroid 2-related factor 2 (Nrf2), which enhances the activity of heme oxygenase-1 (HO-1) and catalase (CAT), facilitating the clearance of excess ROS. The compound also hinders osteoclast formation and functionality by inhibiting the PI3K/AKT/GSK-3β signaling pathway. Lentiviral knockdown of CAT can partially reverse these effects of KR. Meanwhile, in vivo experiments indicate that KR effectively mitigates bone loss in an LPS-induced inflammatory bone resorption model. In summary, KR is a promising new star in breaking through the limitations of previous drugs and treating inflammatory bone resorption.

KW-2449 is a novel multitargeted kinase inhibitor that has been reported to alleviate chronic inflammation and altered immunity during the treatment of autoimmune diseases. The aim of the study was to investigate the effect of KW-2449 on sepsis-induced cardiomyopathy (SIC). A rat model of moderate SIC was induced using the cecal ligation and puncture (CLP) method. KW-2449 was administered to rats at 10 mg/kg for 3 consecutive days by intraperitoneal injection. At 24 hours after CLP, echocardiography, electrocardiogram, and hemodynamic analyses were performed. Blood and cardiac tissues were collected for further analysis. RNA sequencing (RNA-seq) analyses were used to identify the key genes affected by KW-2449 treatment during SIC. KW-2449 improved the liver dysfunction in septic rats. KW-2449 significantly improved left ventricular (LV) systolic function and hemodynamics compared to the CLP group. KW-2449 suppressed the systemic inflammatory response, decreased myocardial inflammation and cell apoptosis in the CLP rats. RNA-seq analyses indicated that there were a total of 2256 differentially expressed genes in the CLP group compared to the Control group, among which 63 genes were down-regulated and 59 genes were up-regulated by KW-2449. Specifically, Pparα was identified as a key target gene of KW-2449 in the treatment of SIC by RNA-seq analysis.KW-2449 also significantly upregulated the protein expression of Pparα in the LV tissue of septic rats. KW-2449 reduced systemic inflammation, cardiac inflammation, and improved cardiac dysfunction in the CLP-induced SIC rat model. The underlying mechanism of the cardio-protective role of KW-2449 in the CLP-induced SIC might be related to Pparα.

Parkinson's disease (PD) stands as the sec most prevalent incapacitating neurodegenerative disorder characterized by deterioration of dopamine-producing neurons in the substantia nigra. Coenzyme Q10 (CoQ10) has garnered attention as a potential antioxidant, anti-inflammatory agent and enhancer of mitochondrial complex-I activity. This study aimed to examine and compare the effectiveness of liposomal and non-encapsulated CoQ10 in rotenone induced-PD mouse model over a 21-day treatment duration. 30 mice were divided into 5 equal groups: Group I (mice receiving normal saline), Group II (rotenone was administered to mice), Group III (standard CoQ10 was given to mice), Group IV (mice were treated with non-encapsulated CoQ10) and Group V (mice were treated with CoQ10 Liposomes). Motor performance, the preservation of dopaminergic neurons, levels of neuroinflammation, oxidative stress, neurotransmitter levels, RT-qPCR analysis of PD-linked genes and histopathology were evaluated. The Liposomal CoQ10 group exhibited superior outcomes in behavioral tests such as reduced anxiety in the open field test, enhanced balance and coordination in beam balance test and improved cognitive performance in Y-maze test. Liposomal Coenzyme Q10 displayed pronounced antioxidative effects, evidenced by a significant (p < 0.001) increase in superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) activities. In contrast, the non-encapsulated CoQ10 group showed a delayed response in mitigating the inflammation and oxidative stress. CoQ10 Liposomes demonstrated superior efficacy (p < 0.0001) in restoring dopamine and noradrenaline levels, reducing acetylcholinesterase activity, and downregulating Synuclein Alpha (SNCA) gene expression (0.722-fold change) compared to oral CoQ10, highlighting its potential in suppressing PD symptoms. The results of this study indicated that the liposomal CoQ10 effectively averted motor impairments, memory lapses, oxidative stress, as well as neuroinflammation triggered by rotenone.

Fibroblasts play a pivotal role in key processes within the heart, particularly in cardiac remodeling that follows both ischemic and non-ischemic injury. During remodeling, fibroblasts drive fibrosis and inflammation by reorganizing the extracellular matrix and modulating the immune response, including toll-like receptor (TLR) activation, to promote tissue stabilization. Building on findings from our prior research on heart tissue from patients with advanced coronary artery disease and aortic valve disease, this study sought to explore specific effects of TLR1, TLR3, and TLR7 activation on NF-κB signaling, proinflammatory cytokine production, and γ-protocadherin expression in cardiac fibroblasts. Human cardiac fibroblasts were exposed to agonists for TLR1, TLR3, or TLR7 for 24 h, followed by an analysis of NF-κB signaling, cytokine production, and γ-protocadherin expression. The activation of these TLRs triggered distinct responses in the NF-κB signaling pathway, with TLR3 showing a stronger activation profile compared to TLR1 and TLR7, particularly in downregulating γ-protocadherin expression. These findings highlight a potential role for TLR3 in amplifying inflammatory responses and reducing γ-protocadherin levels in cardiac fibroblasts, correlating with the enhanced inflammation and lower γ-protocadherin expression observed in diseased myocardium from patients with coronary artery disease and aortic valve disease. Consequently, TLR3 represents a potential therapeutic target for modulating immune responses in cardiovascular diseases.

Toxoplasma gondii (T. gondii) induces gut barrier integrity impairment, which is crucial to the establishment of long-term infection in hosts. Cellular senescence is an imperative event that drives disease progression. Several studies have indicated that T. gondii induces oxidative stress and cell cycle blockade in the tissues of hosts, suggesting cellular senescence induced by the parasite. Here, we explored whether cell senescence is involved in T. gondii-mediated colonic barrier integrity damage in mice. C57BL/6J mice were infected with 10 cysts of T. gondii. Senolytic therapy (dasatinib and quercetin, DQ, a combination therapy for reducing senescent cells) was given by oral gavage 4 weeks post-infection. Alcian blue staining, immunofluorescence, western blot, quantitative PCR (qPCR), and enzyme-linked immunosorbent assay (ELISA) were employed to evaluate the thickness of the colonic mucus layer, the expression profiles of genes and proteins related to tight junction function and cellular senescence in the colonic tissues, and the levels of serum lipopolysaccharides (LPS), respectively. T. gondii-infected mice exhibited deteriorated secreted mucus, shortened length, decreased expression of zonula occludens-1 (ZO-1) and occludin in the colon, accompanied by elevated levels of serum LPS. Moreover, the infection upregulated cell senescence-related markers (p16^INK4A, p21^CIP1) while inhibiting Lamin B1 expression. In addition, the expression levels of senescence-associated secretory phenotypes (SASPs), including IL-1β, TNF-α, IL-6, MMP9 and CXCL10, were upregulated post-infection. Notably, reducing cell senescence with DQ administration, significantly ameliorated the colonic pathological alterations induced by T. gondii infection. This study uncovers for the first time that cellular senescence contributes to the colonic barrier integrity damage induced by chronic T. gondii infection. Importantly, we provide evidence that senolytic therapy exerts a therapeutic effect on the intestinal pathological lesions.

The inflammatory response mediated by alveolar macrophages plays a crucial role in the development of acute lung injury. Numerous studies have reported that lncRNAs are highly expressed in acute lung injury in mouse models and cell lines, and acute lung injury (ALI) can be effectively alleviated by targeting these lncRNAs. The aim of this study was to explore the mechanism by LncRNA Gm26917 regulates the inflammatory response in alveolar macrophages during acute lung injury mouse model. We initially observed a significant upregulation of Gm26917 expression in both ALI conditions and in MH-S cells treated with LPS. Furthermore, the silencing of Gm26917 via lentivirus-mediated methods conferred protection against LPS-induced ALI. Additionally, siRNA-mediated knockdown of Gm26917 attenuated LPS-induced inflammatory responses and modulated the function of alveolar macrophages. Subsequent mechanistic studies revealed that Gm26917 interacts with NKRF, and its knockdown suppressed NKRF ubiquitination, thereby enhancing NKRF binding to p50 and subsequently inhibiting the NF-κB signaling pathway. In conclusion, our findings demonstrate that silencing Gm26917 can mitigate LPS-induced ALI by modulating the NF-κB signaling pathway in alveolar macrophages through interactions with NKRF.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by chronic inflammation of the synovium and progressive joint damage. Fibroblast-like synoviocytes (FLSs) exhibit excessive proliferative and aggressive phenotypes and play a major role in the pathophysiology of RA. Previous studies have confirmed the pathologic role of L-selectin in cell adhesion and migration. In rheumatoid arthritis models, L-selectin regulates leukocyte homing, which leads to joint inflammation. Moreover, in L-selectin knockout mice, there is a reduction in joint inflammation. However, the associations of L-selectin with FLSs in RA remain unclear. This study aims to reveal the effect of L-selectin on RA-FLSs and to investigate the molecular mechanism of L-selectin in RA. Our findings indicated that L-selectin was significantly expressed in RA synovial tissues and RA-FLSs. L-selectin silencing reduced RA-FLSs migration and invasion and attenuated the secretion of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in vitro. Moreover, investigations into mechanisms revealed that L-selectin activated the nuclear factor kappa-B (NF-κB) signaling pathway while blocking this signaling pathway could compromise the effects of L-selectin. Finally, in vivo experiments with a collagen-induced arthritis rat model revealed that silencing L-selectin alleviated inflammatory infiltration of the synovium and cartilage destruction, and validated the NF-κB signaling pathways findings observed in vitro. In summary, we show that L-selectin enhances the migration and invasion of RA-FLSs through the activation of NF-κB signaling pathways, ultimately worsening the progression of RA.

Atopic dermatitis (AD) is a multifaceted inflammatory skin condition characterized by the involvement of various cell types, such as keratinocytes, macrophages, neutrophils, and mast cells. Research indicates that flavonoids possess anti-inflammatory properties that may be beneficial in the management of AD. However, the investigation of the glycoside forms for anti-AD therapy is limited. We aimed to assess the ability of quercetin-3-O-glycosides in treating AD-like lesions through in silico-, cell-, and animal-based platforms. The glycosylated flavonols of quercitrin, isoquercitrin, and rutin were used in this study. We also tried to understand the influence of glycone type on the bioactivity and skin delivery of glycosides. The glycosides effectively reduced the overexpression of proinflammatory effectors such as interleukin (IL)-6, chemokine (C-X-C motif) ligand (CXCL)1, CXCL8, regulated upon activation normal T cell expressed and secreted (RANTES), and thymus and activation-regulated chemokine (TARC) in the activated keratinocytes. This reduction could be due to the inhibition of extracellular signal-regulated kinase (ERK) and p38 phosphorylation. Isoquercitrin (but not quercitrin and rutin) could arrest the upregulated IL-6 and CCL5 in the macrophage model. The glycosides significantly prevented histamine release from RBL-2H3 cells. The skin absorption examination showed a greater permeation of quercitrin and isoquercitrin than rutin with dual sugar moieties due to the smaller molecular volume and higher lipophilicity. The skin deposition of quercitrin and isoquercitrin was enhanced by about 11-fold in the stripped and delipidized skins, which mimicked AD lesions. The in vivo dinitrochlorobenzene (DNCB)-induced AD mouse model demonstrated less erosion, scaling, and epidermal hyperplasia after topical isoquercitrin treatment. The concentration of cytokines/chemokines in the lesion was decreased by isoquercitrin. These effects were similar to those of tacrolimus ointment. The immunohistochemistry (IHC) displayed the reduction of epidermal hyperproliferation and immune cell infiltration by topical isoquercitrin. The results indicated that the delivery of quercetin glycosides could provide an efficient and safe way to treat AD inflammation.