Inflammation Research最新文献

Objective: To investigate the association of genetic polymorphisms in MB21D1 (Mab-21 domain-containing 1), TMEM173 (Transmembrane Protein 173), IFNB1 (Interferon beta 1), IFNGR1 (Interferon gamma receptor 1), IFNGR2 (Interferon gamma receptor 2), IRF3 (Interferon Regulatory Factor 3), and IRF8 (Interferon Regulatory Factor 8) with susceptibility to non-tuberculous mycobacteria pulmonary disease (NTM-PD) as well as their correlation with the treatment outcomes and immune status of patients.

Methods: Forty-four tagSNPs from the candidate genes were genotyped in a 2-phase cohort study including an initial discovery phase involving 707 NTM-PD patients and 726 healthy controls and a replication phase involving 357 NTM-PD patients and 400 controls. The frequencies and distributions of genotypes were compared between the case and control groups. Treatment success rates, sputum culture conversion rates, imaging characteristics, and peripheral blood immunological indices were compared among patients with different genotypes.

Results: Individuals with the IFNGR1 rs2234711 A/A genotype were more susceptible to MAC-PD compared to those with the G/G genotype (discovery phase OR = 1.752, P.adj = 0.025; replication phase OR = 2.143, P.adj = 0.019). Patients with the rs2234711 A/A genotype exhibited significantly lower treatment success rates and sputum culture conversion rates, along with elevated levels of peripheral blood heparin-binding protein (HBP), erythrocyte sedimentation rate, and interleukin-10, but significantly decreased interleukin-1β levels (all P < 0.05). Individuals with the IRF8 rs2280378 A/A genotype were more susceptible to MAB-PD (discovery phase OR = 2.302, P.adj = 0.014; replication phase OR = 2.465, P.adj = 0.015). Compared to G/G genotype patients, those with the rs2280378 A/A genotype exhibited lower treatment success rates and sputum culture conversion rates, were more likely to develop pulmonary cavities and multiple lung field involvement, and showed elevated levels of peripheral blood HBP and C-reactive protein, along with significantly reduced levels of serum interleukin-12 P70, tumor necrosis factor-α, and CD8 + T lymphocytes (all P < 0.05).

Conclusion: In the Chinese Han population, IFNGR1 genetic polymorphisms are closely associated with MAC-PD susceptibility, while IRF8 genetic polymorphisms are associated with MAB-PD susceptibility. Variants in IFNGR1 and IRF8 significantly affect the immune status and treatment outcomes of MAC-PD and MAB-PD patients, respectively.

Background: Hepatocellular carcinoma (HCC) is the predominant type of liver cancer with a poor prognosis. Treatment methods include surgery, ablation, liver transplantation, and immunotherapy. Programmed cell death (PCD) plays a significant role in the occurrence and treatment of HCC, and disulfidoptosis, as a novel type of PCD, is associated with tumor prognosis and anti-tumor immunity. The purpose of this study is to explore the role and molecular mechanisms of disulfidoptosis-related genes (DRGs) in the occurrence and development of HCC.

Methods: We developed an HCC prognostic signature comprising three DRGs: RPN1, SLC7A11, and GYS1, using the TCGA database. The mRNA expression levels of the signature genes in peripheral blood mononuclear cells (PBMCs) of 196 patients were detected by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR), and the expression of RPN1 in 23 pairs of HCC tissues and adjacent non-tumor tissues were validated by RT-qPCR and immunohistochemistry (IHC). Additionally, the role of RPN1 in HCC was investigated through EdU Assay, CCK8 Assay, wound Healing Test, transwell experiments. The changes of cell cycle were detected by flow cytometry, and the changes of Cyclin (CDK1, CDK2, Cyclin D1, Cyclin E1) were detected by Western blot. We carried out in vivo experiments in a BALB/c nude mice model of HCC established through subcutaneous injection.

Results: RPN1 was significantly upregulated in paired HCC tissues (p < 0.001). HCC group was also significantly higher in PBMCs than healthy group (p < 0.001). Interestingly, RPN1 expression were higher in the HBV group and HBV-LC group than in HBV-HCC group (p < 0.001). IHC experiments confirmed that RPN1 was also up-regulated in HCC tissues (p < 0.05). In vitro experiments showed that knockdown of RPN1 promoted the proliferation and migration of HCC cells, while overexpression of RPN1 inhibited these functions. Flow cytometry and Western blot confirmed that knockdown of RPN1 in HCCLM3 and Huh7 cells resulted in a decrease in the proportion of G0/G1 phase cells and an increase in the proportion of G2/M phase cells. Meanwhile, the expression levels of cell cycle proteins (CDK1, CDK2, Cyclin D1, and Cyclin E1) were significantly elevated. In vivo, overexpression of RPN1 in Hep3B cells can inhibit tumor growth.

Conclusions: In vitro and in vivo experiments confirmed that the overexpression of RPN1 can significantly suppresses the progression of HCC by regulating the cell cycle. RPN1 could potentially serve as a new therapeutic target for HCC.

Inflammation is a crucial pathological process in many diseases. Mechanosensitive ion channels, like the Piezo family and TRPV4, play a significant role in the inflammatory response. They sense mechanical stimuli and convert them into intracellular signals, regulating physiological processes. During inflammation, their activation is linked to inflammatory signal transduction. By modulating intracellular calcium levels and activating pathways such as NF-κB and MAPK, these channels promote the release of inflammatory factors, which exacerbate the inflammatory response. These ion channels are involved in the pathogenesis of various inflammatory-related diseases, including cardiovascular, respiratory, digestive, and neurological disorders. Animal and cell experiments, such as gene manipulation and drug intervention, have been used to explore their relationship with inflammation. Targeting these channels shows therapeutic potential, but the safety and efficacy of such treatments need to be evaluated. In summary, mechanosensitive ion channels are important research targets in inflammation. Although further study is required to fully understand their mechanisms and therapeutic applications, they hold promise for treating inflammatory diseases.

Background: Toxoplasmosis promotes acute and chronic symptoms ranging from ocular to severe congenital or neurotoxoplasmosis. A proper host immune response and a healthy gut microbiota control the pathophysiology of toxoplasmosis, presenting an opportunity for pro-resolving mediators.

Objective: Here, we evaluated the role of the anti-inflammatory/pro-resolving protein annexin (Anx)A1 in Toxoplasma gondii (Tg) infection.

Results: AnxA1 levels increase in the brain during Tg infection, and AnxA1 knockout (KO) mice display higher susceptibility to disease, an increased number of brain cysts, an inflammatory response, severe lesions, and brain permeability, along with lower claudin-5 and occludin expression. Notably, AnxA1 deficiency increased the number of IBA-1⁺ cells in the brain, macrophages/neutrophils/dendritic cells producing IL-10 and TNF, and Th2 and CD8 T cells producing IL-17 compared to wild-type cells. An increased number of Tregs and innate cells producing TNF has been observed in the spleen. Moreover, the absence of AnxA1 increases gut inflammation, alters microbiota composition, reduces mucus production, increases intestinal permeability, and promotes bacterial translocation from the gut to the liver. Furthermore, imipenem treatment restored animal survival, prevented bacterial translocation into the liver, and reduced brain inflammation. = CONCLUSION: Collectively, our data demonstrate that AnxA1 is critical for regulating the pathogenesis of Tg infection and unveils a possible therapeutic target for this disease.

Background: Atherosclerosis (AS) and Alzheimer's disease (AD) are both multifactorial in nature and share many risk factors. Vascular dementia and AD may occur together, and a substantial proportion of AD cases also have signs of cardiovascular disease, a relationship well-established by cohort studies. The risk factors could contribute to persistent smoldering inflammation, including activation of complement at sites of endothelial injury and/or by accumulation of molecular aggregates.

Methods: To examine the possible bridging points between AD and AS, we constructed a comprehensive narrative review.

Results: A connecting point between AD and AS is inflammation. Contrary to prior assumptions, a significant linkage exists between systemic inflammation and neuroinflammation. Activities of complement, a key effector of innate immunity, are of special interest in the pathogenesis of both diseases.

Conclusion: AS and AD share a partially overlapping array of pathophysiological mechanisms.

Background: Fibulins belong to the family of secreted glycoproteins regulating several cellular processes. Fibulin7 (Fbln7) is one of its recent members, and it was first identified in the developing tooth. Fbln7 is also expressed in specialized tissues such as cartilage, eye, and the placenta. Previous reports have suggested that its C-terminal (Fbln7-C) fragment and not the full-length protein can inhibit angiogenesis, and modulate systemic inflammation and cancer.

Method: We have performed a literature review based on published original and review articles that encompass the significant effect of Fbln7 and its bioactive fragments on immune cell functions from central databases, including PubMed and Google Scholar.

Results and conclusion: Recent reports have also shown that several shorter peptides of Fbln7-C, such as FC-10, regulate innate immune cell functionality and have anti-angiogenic properties. Since the discovery of Fbln7, many research groups have improved our understanding of the role of Fbln7, Fbln7-C, and short peptides in immunoregulation and pathophysiology of many disease conditions, such as sepsis, kidney injury, and different cancers (e.g., murine breast tumors and glioblastoma). This review will present an updated overview of the research findings on the immunomodulatory, anti-angiogenic, and other regulatory properties of Fbln7 and its fragments, which will provide further insight into its significance, mode of action, and possible implications for future research and therapeutics.

Achieving better clinical outcomes in cancer research requires a deeper understanding of tumoral biology and the application of this knowledge within a clinic setting. The aim of this review is to briefly summarize the current knowledge on H₃R molecular pharmacology, the clinical use of H₃R antagonists, and the most recent findings reporting H₃R role in cancer biology. We will discuss in detail the current landscape and clinical perspectives of the modulation of this H₃R on cancer progression and treatment. We propose H₃R as a promising molecular target for cancer drug repurposing and development.

Pyroptosis contributes to activation of the innate immunity system and defense against infection by pathogens. Endotoxemia is the host inflammatory storm occurring in response to severe and life-threatening infections caused by endotoxin from gram-negative bacilli. However, whether pyroptosis is involved in intestinal epithelial cell (IEC) or intestinal stem cell (ISC) injury induced by endotoxemia remains unclear. Mice with NF-κB p65 deletion in IECs (p65^IEC - KO) were used to investigate the role of NF-κB-mediated pyroptosis in endotoxemia-induced intestinal injury. Morphology, pyroptosis, permeability, inflammation, endoplasmic reticulum stress in the intestine and survival were evaluated in WT and p65^IEC - KO mice. Pyroptosis was found in intestinal epithelial cells of mice treated with lipopolysaccharide (LPS), but was significantly reduced in p65^IEC - KO mice. Mice with endotoxemia exhibited morphological alterations in intestinal tissue, with a shortened villus length and crypt depth, increased intestinal permeability, increased inflammatory factors, and reduced survival rate, all of which were markedly improved in p65^IEC - KO mice. Importantly, ER stress was found to be downregulated in IECs of p65^IEC - KO mice with endotoxemia. Furthermore, the ER stress activator tunicamycin markedly enhanced IEC pyroptosis and aggravated intestinal injury in p65^IEC - KO mice with endotoxemia. NF-κB p65-mediated pyroptosis participates in IEC injury in response to endotoxemia via regulation of ER stress. It may provide a potential therapeutic target for protecting against endotoxemia-induced intestinal injury.

Objective and design: Immune defence requires systemic metabolic changes to redirect energy and nutrients to activated immune cells. The circadian clock is known to control the immune response, but its role in regulating metabolic adaptations following the immune challenge remains poorly understood. We aimed to examine the inflammatory and metabolic responses in rat liver and visceral white adipose tissue (vWAT) after time-of-day-dependent endotoxin stimulation under a regular light/dark cycle or dim artificial light at night (ALAN; ~2 lx), which disrupts immune and metabolic rhythms. Male rats were challenged with lipopolysaccharide (LPS) either during the day or night and acute changes in metabolic pathways and the peripheral metabolic clocks were analysed at both systemic and molecular levels.

Results: In the control light/dark cycle, we observed higher fatty acid (FA) mobilization in vWAT after daytime than nighttime LPS injection. Similarly, hepatic glucose metabolism was more responsive to daytime than nighttime LPS, while the opposite trend was observed for FA uptake and synthesis. This daily variability in metabolic changes was associated with the inflammatory response, involving nuclear factor interleukin-3 regulated (NFIL3) in the liver and nuclear factor-kappa B (NF-κB)/NLR family, pyrin domain containing 3 (NLRP3) inflammasome pathway in vWAT. Hepatic and adipose clocks also showed time-of-day-dependent response to LPS, indicating a direct link to circadian regulation. Disruption of metabolic clocks by ALAN impaired the capacity of rats to maintain lipid metabolic adaptations during inflammation.

Conclusions: Together, our results highlight the role of circadian clocks in LPS-induced responses of glucose and FA metabolism and their susceptibility to disruption by ALAN.

Objective: Autoimmune diseases (AIDs) are a spectrum of chronic conditions characterized by abnormal immune responses directed against the body's own tissues. Current therapeutic strategies still rely on broad-spectrum immunosuppression, which often produces severe adverse effects and is ineffective in targeting comorbidities. The complement system, a key component of innate immunity, has been increasingly recognized for its role in the pathogenesis and progression of AIDs. This review aims to assess the diagnostic and therapeutic potential of targeting the complement system in AIDs.

Methods: A comprehensive literature review was conducted using the PubMed, Medscape, and ClinicalTrials.gov databases. The analysis included both original research and review articles, as well as data from ongoing and completed clinical trials focused on complement-targeted therapies.

Results: Complement activation contributes to inflammation, tissue injury, and amplification of adaptive immunity in AIDs. Current and emerging complement-targeted therapies, including monoclonal antibodies and small-molecule inhibitors has shown promising preliminary outcomes in reducing disease activity with fewer adverse effects.

Conclusion: Targeting the complement system represents a promising and more precise strategy for the treatment of AIDs. Ongoing clinical evaluation is essential to establish its long-term safety and efficacy, with the potential to significantly advance future therapeutic approaches.