Inflammation Research最新文献

Importance: Studies have reported an association among systemic immune inflammation index (SII), all-cause and cause-specific mortality, but the results are inconsistent.

Objective: To comprehensively explore the association between Systemic Immune Inflammation (SII) and the risk of all-cause mortality, cardiovascular disease (CVD), and cancer mortality.

Evidence review: A meta-analysis was conducted by reviewing existing literature. The search encompassed prominent databases including PubMed, Embase, Cochrane, and the Web of Science, with the cutoff date set at March 1, 2024. Furthermore, subgroup analyses and dose-response assessments were undertaken to provide a nuanced exploration of mortality risk factors.

Findings: A total of 33 articles were included (427,819 participants). In the study, SII was associated with an increased risk of all-cause mortality (HR = 1.45, 95%CI [1.36,1.54], P < 0.05). SII increased the risk of CVD mortality (HR = 1.44, 95%CI [1.29,1.60], P < 0.05). The Linear independence shows that for every 100 units increase in SII, the risk of all-cause and CVD death increases by 5% and 6%. SII was not associated with a statistically significant risk of cancer death (HR = 1.09, 95%CI [0.96,1.23], P < 0.05).

Conclusions and relevance: Meta-analysis showed that SII was associated with all-cause mortality and CVD mortality. More data and basic research are needed to confirm the association.

Objective: This study sought to investigate the cellular and molecular alterations during the injury and recovery periods of ALI and develop effective treatments for ALI.

Methods: Pulmonary histology at 1, 3, 6, and 9 days after lipopolysaccharide administration mice were assessed. An unbiased single-cell RNA sequencing was performed in alveoli tissues from injury (day 3) and recovery (day 6) mice after lipopolysaccharide administration. The roles of Fpr2 and Dpp4 in ALI were assessed.

Results: The most severe lung injury occurred on day 3, followed by recovery entirely on day 9 after lipopolysaccharide administration. The numbers of Il1a⁺ neutrophils, monocytes/macrophages, and Cd4⁺ and Cd8⁺ T cells significantly increased at day 3 after LPS administration; subsequently, the number of Il1a⁺ neutrophils greatly decreased, the numbers of monocytes/macrophages and Cd4⁺ and Cd8⁺ T cells continuously increased, and the number of resident alveolar macrophages significantly increased at day 6. The interactions between monocytes/macrophages and pneumocytes during the injury period were enhanced by the Cxcl10/Dpp4 pair, and inhibiting Dpp4 improved ALI significantly, while inhibiting Fpr2 did not.

Conclusions: Our results offer valuable insights into the cellular and molecular mechanisms underlying its progression and identify Dpp4 as an effective therapeutic target for ALI.

Background: Lower back pain, as a typical clinical symptom of spinal degenerative diseases, is emerging as a major social problem. According to recent researches, the primary cause of this problem is intervertebral disc degeneration (IVDD). IVDD is closely associated with factors such as age, genetics, mechanical stimulation (MS), and inadequate nutrition. In recent years, an increasing number of studies have further elucidated the relationship between MS and IVDD. However, the exact molecular mechanisms by which MS induces IVDD remain unclear, highlighting the need for in-depth exploration and study of the relationship between MS and IVDD.

Methods: Search for relevant literature on IVDD and MS published from January 1, 2010, to the present in the PubMed database.

Results: One of the main causes of IVDD is MS, and loading modalities have an impact on the creation of matrix metalloproteinase, the metabolism of the cellular matrix, and other biochemical processes in the intervertebral disc. Nucleus pulposus cell death induced by MS, cartilage end-plate destruction accompanied by pyroptosis, apoptosis, iron death, senescence, autophagy, oxidative stress, inflammatory response, and ECM degradation interact with one another to form a cooperative signaling network.

Conclusion: This review discusses the molecular mechanisms of the changes in the microenvironment of intervertebral discs caused by mechanical pressure, explores the interaction between mechanical pressure and IVDD, and provides new insights and approaches for the clinical prevention and treatment of IVDD.

Background: One mechanism by which antiphospholipid syndrome (APS) IgG contribute to thrombotic events in patients with APS is through the potentiation of neutrophil extracellular traps (NETs) release. However, the exact mechanism by which APS IgG induces NETs formation and thrombosis has not been fully elucidated.

Methods: We conducted untargeted metabolomics on serum samples from thrombotic APS patients to identify metabolic changes. The effect of 5-oxoETE on NETs formation and oxidative stress was evaluated in vitro by treating neutrophils with various concentrations of 5-oxoETE. The involvement of the PLC/PKC/ERK signaling pathway in 5-oxoETE-induced NETs formation was examined using pharmacological inhibitors. In vivo, we assessed the effects of inhibiting 5-oxoETE synthesis or blocking its receptor (OXE-R) on NETs formation and thrombosis in APS mouse models.

Results: Serum metabolomics revealed significantly elevated levels of 5-oxoETE in APS patients. In vitro experiments demonstrated that 5-oxoETE, via OXE-R activation of the PLC/PKC/ERK signaling pathway, increased NETs formation and oxidative stress in a dose-dependent manner. In vivo, inhibiting 5-oxoETE synthesis or OXE-R reduced NETs formation and attenuated venous thrombosis in APS mice models.

Conclusion: This study identifies 5-oxoETE as a critical mediator of NET formation and thrombosis in APS. Targeting 5-oxoETE or OXE-R may offer a promising therapeutic approach for thrombotic APS and other NET-associated autoimmune diseases.

Background: AC-186 (4-[4-4-Difluoro-1-(2-fluorophenyl) cyclohexyl] phenol) is a neuroprotective non-steroidal selective oestrogen receptor modulator. This study investigated whether inhibition of neuroinflammation contributed to neuroprotective activity of this compound.

Methods: BV-2 microglia were treated with AC-186 (0.65-5 μM) prior to stimulation with LPS (100 ng/mL). Levels of pro-inflammatory mediators and proteins were then evaluated.

Results: Treatment of LPS-activated BV-2 microglia with AC-186 resulted in significant (p < 0.05) reduction in TNFα, IL-6, NO, PGE₂, iNOS and COX-2. Further investigations showed that AC-186 decreased LPS-induced elevated levels of phospho-p65, phospho-IκBα and acetyl-p65 proteins, while blocking DNA binding and luciferase activity of NF-κB. AC-186 induced significant (p < 0.05) increase in protein expression of ERβ, while enhancing ERE luciferase activity in BV-2 cells. Effects of the compound on oestrogen signalling in the microglia was confirmed in knockdown experiments which revealed a loss of anti-inflammatory activity following transfection with ERβ siRNA. In vitro neuroprotective activity of AC-186 was demonstrated by inhibition of activated microglia-mediated damage to HT-22 neurons.

Conclusions: This study established that AC-186 produces NF-κB-mediated anti-inflammatory activity, which is proposed as a contributory mechanism involved in its neuroprotective actions. It is suggested that the anti-inflammatory activity of this compound is linked to its agonist effect on ERβ.

Objective and design: This observational study investigated the regulatory mechanism of Pim-1 in inflammatory signaling pathways.

Materials: THP-1, RAW 264.7, BV2, and Jurkat human T cell lines were used.

Treatment: None.

Methods: Lipopolysaccharide (LPS) was used to induce inflammation, followed by PIM1 knockdown. Western blot, immunoprecipitation, immunofluorescence, and RT-PCR assays were used to assess the effect of PIM1 knockdown on LPS-induced inflammation.

Results: PIM1 knockdown in macrophage-like THP-1 cells suppressed LPS-induced upregulation of pro-inflammatory cytokines, inducible nitric oxide synthase, cyclooxygenase-2, phosphorylated Janus kinase, signal transducer and activator of transcription 3, extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, and nuclear factor kappa B p65 (NF-κB p65). It also suppressed upregulation of inhibitor of NF-κB kinase α/β and enhanced the nuclear translocation of NF-κB p65. Moreover, it inhibited the upregulation of Nod-like receptor family pyrin domain-containing 3 (NLRP3) and cleavage of caspase-1 induced by co-treatment of LPS with adenosine triphosphate. Additionally, p-transforming growth factor-β-activated kinase 1 (TAK1) interacted with Pim-1. All three members of Pim kinases (Pim-1, Pim-2, and Pim-3) were required for LPS-mediated inflammation in macrophages; however, unlike Pim-1 and Pim-3, Pim-2 functioned as a negative regulator of T cell activity.

Conclusions: Pim-1 interacts with TAK1 in LPS-induced inflammatory responses and is involved in MAPK/NF-κB/NLRP3 signaling pathways. Additionally, considering the negative regulatory role of Pim-2 in T cells, further in-depth studies on their respective functions are needed.

Objective: Intestinal mucositis is one of the common side effects of anti-cancer chemotherapy. However, the molecular mechanisms involved in mucositis development remain incompletely understood. In this study, we investigated the function of receptor-interacting protein kinase 3 (RIP3/RIPK3) in regulating doxorubicin-induced intestinal mucositis and its potential mechanisms.

Methods: Intestinal mucositis animal models were induced in mice for in vivo studies. Rat intestinal cell line IEC-6 was used for in vitro studies. RNA‑seq was used to explore the transcriptomic changes in doxorubicin-induced intestinal mucositis. Intact glycopeptide characterization using mass spectrometry was applied to identify α-1,2-fucosylated proteins associated with mucositis.

Results: Doxorubicin treatment increased RIP3 expression in the intestine and caused severe intestinal mucositis in the mice, depletion of RIP3 abolished doxorubicin-induced intestinal mucositis. RIP3-mediated doxorubicin-induced mucositis did not depend on mixed lineage kinase domain-like (MLKL) but on α-1,2-fucosyltransferase 2 (FUT2)-catalyzed α-1,2-fucosylation on inflammation-related proteins. Deficiency of MLKL did not affect intestinal mucositis, whereas inhibition of α-1,2-fucosylation by 2-deoxy-D-galactose (2dGal) profoundly attenuated doxorubicin-induced inflammation and mucositis.

Conclusions: RIP3-FUT2 pathway is a central node in doxorubicin-induced intestinal mucositis. Targeting intestinal RIP3 and/or FUT2-mediated α-1,2-fucosylation may provide potential targets for preventing chemotherapy-induced intestinal mucositis.

Objective: Ischemic stroke is a leading cause of death and disability in individuals worldwide. Cerebral ischemia-reperfusion injury (CIRI) typically results in severe secondary injury and complications following reperfusion therapy. Microglia play critical roles in the inflammatory reaction of CIRI. However, less attention has been given to microglial death in this process. Our study aims to explore microglial death in CIRI and the effects and mechanism of minocycline treatment on microglia.

Methods: A middle cerebral artery occlusion (MCAO) model was applied to induce CIRI in rats. At 0 h, 24 h and 48 h post-operation, rats were intraperitoneally injected with 45 mg/kg minocycline. Neurological deficit scoring, 2,3,5-triphenyltetrazolium chloride (TTC) staining, assessment of activated microglia and examination of mitochondrial structure were conducted and checked at 72 h after reperfusion. Additionally, an in vitro model of oxygen-glucose deprivation/reperfusion (OGD/R) model was established. BV-2 cells were treated with various pharmacological inhibitors of cell death or minocycline. Cell viability, lipid peroxidation, mitochondrial structure and function, and labile Fe²⁺ and ferroptosis-associated gene/protein levels were measured. Hemin was used for further validation after transcriptome analysis.

Results: In the MCAO and OGD/R models, ferroptosis was identified as a major form of microglial death. Minocycline inhibited microglia ferroptosis by reducing HO-1 expression. In addition, minocycline improved mitochondrial membrane potential, mitochondrial structures and microglial survival in vivo. Minocycline also decreased labile Fe²⁺ levels, lipid peroxidation, and expression of ferritin heavy chain (FTH) and it improved mitochondrial structure and function in vitro. Upregulation of HO-1 counteracted the protective effect of minocycline.

Conclusion: Ferroptosis is a major form of microglial death in CIRI. The protective mechanism of minocycline in CIRI partially hinges on its ability to effectively ameliorate microglia ferroptosis by downregulating HO-1 expression. Consequently, targeting microglia ferroptosis is a promising treatment for CIRI.

Acute lung injury (ALI) is caused by a variety of intrapulmonary and extrapulmonary factors and is associated with high morbidity and mortality. Oxidative stress is an important part of the pathological mechanism of ALI. Ferroptosis is a mode of programmed cell death distinguished from others and characterized by iron-dependent lipid peroxidation. This article reviews the metabolic regulation of ferroptosis, its role in the pathogenesis of ALI, and the use of ferroptosis as a therapeutic target regarding the pharmacological treatment of ALI.

Background and objective: Neuropathic pain is a chronic condition characterized by aberrant signaling within the somatosensory system, affecting millions of people worldwide with limited treatment options. Herein, we aim at investigating the potential of a sigma-1 receptor (σ1R) antagonist in managing neuropathic pain.

Methods: A Chronic Constriction Injury (CCI) model was used to induce neuropathic pain. The potential of (+)-MR200 was evaluated following daily subcutaneous injections of the compound. Its mechanism of action was confirmed by administration of a well-known σ1R agonist, PRE084.

Results: (+)-MR200 demonstrated efficacy in protecting neurons from damage and alleviating pain hypersensitivity in CCI model. Our results suggest that (+)-MR200 reduced the activation of astrocytes and microglia, cells known to contribute to the neuroinflammatory process, suggesting that (+)-MR200 may not only address pain symptoms but also tackle the underlying cellular mechanism involved. Furthermore, (+)-MR200 treatment normalized levels of the gap junction (GJ)-forming protein connexin 43 (Cx43), suggesting a reduction in harmful intercellular communication that could fuel the chronicity of pain.

Conclusions: This approach could offer a neuroprotective strategy for managing neuropathic pain, addressing both pain symptoms and cellular processes driving the condition. Understanding the dynamics of σ1R expression and function in neuropathic pain is crucial for clinical intervention.