Journal Of Inflammation (London, England)[JOURNAL]
Sun
200 papers
Current perspectives on the pathogenesis of cerebral atherosclerosis.
Zhu C, Lu J, Zhang J … +2 more , Li W, Han J
J Inflamm (Lond) · 2025 Oct · PMID 41057855 · Full text
PURPOSE OF REVIEW: To summarize the current understanding of the pathogenesis of cerebral atherosclerosis to provide a basis for developing effective treatments and exploring future research directions for clinical appli...
PURPOSE OF REVIEW: To summarize the current understanding of the pathogenesis of cerebral atherosclerosis to provide a basis for developing effective treatments and exploring future research directions for clinical application. RECENT FINDINGS: (1) Pathophysiological processes: Endothelial dysfunction and oxidative stress are crucial in the early stage of atherosclerotic plaque formation. Lipid accumulation, especially of low-density lipoprotein, promotes plaque growth and instability. Inflammatory responses exacerbate vascular damage, resulting in plaque rupture and thrombosis. (2) Genetic factors: Genetic studies have identified several loci associated with increased susceptibility to cerebral atherosclerosis, indicating potential therapeutic targets, including APOEε4, RNF213, NTNG1, and CYP2C19. (3) Daily diet also plays a role in the development of the disease. Healthy patterns (Mediterranean, DASH) with good nutrients and less bad fats/sodium can reduce cerebral atherosclerosis risk and improve cerebrovascular health. (1) This review presents recent progress in understanding the mechanisms of intracranial atherosclerosis, covering genetics, inflammation, comorbidities, diet, and exercise aspects. It reveals that managing blood pressure, lipids, glucose, and consistent moderate-intensity physical activity benefits vascular health. Controlling inflammation spread and maintaining cerebral vessel structure are linked to slowing the disease, suggesting therapeutic and genetic targets. (2) Nevertheless, there are gaps. Most mechanisms come from small-scale, single-center clinical studies, mainly focusing on extracranial atherosclerosis and plaque formation. Their reliability needs large-scale, multi-center validation. Besides, basic research is hampered by challenges of intracranial atherosclerosis animal models, like long duration, instability, and tissue-collecting difficulty. (3) Thus, large - scale clinical imaging can better describe intracranial atherosclerosis features. Also, specific animal models should be developed to offer more stable and reliable evidence and guidance for treating this disease.
Baicalein inhibits mycobacterium tuberculosis-induced macrophage M1 polarization depending on the regulation of YY1/RAB10/TLR4 pathway.
Zhou Q, Chen S, Shu L … +5 more , Wang Q, Yuan T, Ou Y, Qing L, He X
J Inflamm (Lond) · 2025 Oct · PMID 41057834 · Full text
BACKGROUND: Baicalein (Bai) has been found to alleviate the progression of tuberculosis (TB) by inhibiting mycobacterium tuberculosis (M.tb)-induced macrophage pyroptosis, so it may be used as an adjuvant treatment for T...
BACKGROUND: Baicalein (Bai) has been found to alleviate the progression of tuberculosis (TB) by inhibiting mycobacterium tuberculosis (M.tb)-induced macrophage pyroptosis, so it may be used as an adjuvant treatment for TB. However, the underlying molecular mechanism of Bai remains unclear. METHODS: THP-1 macrophages were infected with M.tb and treated with Bai. The viability and apoptosis of macrophages were examined with CCK8 assay, flow cytometry and TUNEL staining. The levels of inflammatory cytokines were tested by ELISA. Macrophage M1 polarization was assessed by detecting CD86 cell rate using flow cytometry. The protein levels of RAB10, YY1, TLR4, MYD88, p-P65/P65 and p-IκBα/IκBα were determined using western blot. The interaction between RAB10 and YY1 or TLR4 was confirmed by ChIP assay, dual-luciferase reporter assay and Co-IP assay. RESULTS: M.tb promoted macrophage M1 polarization, apoptosis and inflammation, while this effect was abolished by Bai treatment. Bai decreased RAB10 expression, and RAB10 overexpression reversed the anti-TB effect of Bai. YY1 enhanced the transcription of RAB10, and YY1 knockdown inhibited M.tb-induced macrophage M1 polarization by reducing RAB10 expression. Also, Bai could decrease YY1 expression, and YY1 overexpression eliminated the regulation of Bai on M.tb-induced macrophage M1 polarization. Moreover, RAB10 could interact with TLR4 to activate TLR4/MYD88/NF-κB pathway, thus promoting M.tb-induced macrophage M1 polarization. CONCLUSION: Bai might play anti-TB effect by regulating YY1/RAB10/TLR4/MYD88/NF-κB pathway, providing a novel idea for the treatment of TB.
Immunological response and tissue loss in a rodent model of chronic traumatic brain injury treated with resolvin.
Kiwanuka O, Cheung J, Hånell A … +1 more , Lindblad C
J Inflamm (Lond) · 2025 Oct · PMID 41039416 · Full text
BACKGROUND: Traumatic brain injury (TBI) triggers neuroinflammation both acutely and chronically, the latter which might be involved in neurodegenerative disorders. Resolvins are neuroinflammatory modulators, hypothesize...
BACKGROUND: Traumatic brain injury (TBI) triggers neuroinflammation both acutely and chronically, the latter which might be involved in neurodegenerative disorders. Resolvins are neuroinflammatory modulators, hypothesized to improve resolution of inflammation. This study sought to explore sustained immunological responses after delayed treatment with resolvins utilizing novel tools for automated cellular assessments. MATERIALS AND METHODS: Twenty-five rodents (Sprague-Dawley rats) were exposed to a penetrating TBI, following which delayed treatment with resolvin was initiated. Assessments of tissue loss, and persistent neuroinflammatory activation, was assessed at 6 weeks post-injury utilizing histological and immunohistochemical methods. We also developed a novel computational tool to count and automatically assess cell counts across treatment groups. RESULTS: The TBI model elicited a substantial brain injury, as expected. The lesion cavity volume was not affected by resolvin or vehicle treatment. Notably, both microglial and macrophage responses were also similar between treatment groups, as deemed by state-of-the-art computational models. CONCLUSION: Resolvins administered in a delayed fashion following severe TBI did not affect the extent of chronic microglial or macrophage responses, but warrants future corroboration. Dosing and timing of resolvin treatment warrants further study.
Loss of tuberous sclerosis complex 2 confers inflammation via dysregulation of nuclear factor kappa-light-chain-enhancer of activated B cells.
McPhail DK, Alzahrani MAM, Martin KR … +5 more , Calver BL, Harwood AJ, MacKeigan JP, Davies DM, Tee AR
J Inflamm (Lond) · 2025 Sep · PMID 41013689 · Full text
BACKGROUND: Aberrant activation of mTORC1 is clearly defined in TSC and causes uncontrolled cell growth. While mTORC1 inhibitors show efficacy in stabilising tumour growth in patients with TSC, they are not fully curativ...
BACKGROUND: Aberrant activation of mTORC1 is clearly defined in TSC and causes uncontrolled cell growth. While mTORC1 inhibitors show efficacy in stabilising tumour growth in patients with TSC, they are not fully curative. Disease facets of TSC that are not restored with mTOR inhibitors might involve NF-κB. This study aimed to characterise NF-κB in the context of TSC. RESULTS: Enrichment of NF-κB-regulated genes was observed in TSC patient tumours, SEN/SEGAs, cortical tubers, and a TSC tumour-derived cell line (621 − 101). Highlighting an inflammatory component of TSC, TSC cell models exhibit elevated NF-κB and STAT3 activation. Herein, we report a dysregulated inflammatory phenotype in TSC2-deficient cells in which NF-κB promotes autocrine signalling involving IL-6. Notably, mTORC1 inhibition does not block this inflammatory signal to promote STAT3, while NF-κB inhibition is much more effective. Combined mTORC1 and NF-κB inhibition potently prevented the anchorage-independent growth of TSC2-deficient cells, whereas mTORC1 inhibition alone was insufficient to prevent colony regrowth after cessation of treatment. CONCLUSION: This study reveals autocrine signalling crosstalk between NF-κB and STAT3 in TSC cell models. Furthermore, the data presented indicate that NF-κB pathway inhibitors could be a viable adjunct therapy to the currently available mTORC1 inhibitors for treating TSC.
Beyond energy: how TCA cycle-derived metabolites regulate gene expression and inflammation in the nucleus.
Randhawa J, Pålsson-McDermott EM
J Inflamm (Lond) · 2025 Sep · PMID 41013544 · Full text
Immune cells can rewire their metabolism in response to various stimuli. Crosstalk between the nucleus and mitochondria allows for tight regulation of this metabolic reprogramming. Research has emerged showing several TC...
Immune cells can rewire their metabolism in response to various stimuli. Crosstalk between the nucleus and mitochondria allows for tight regulation of this metabolic reprogramming. Research has emerged showing several TCA cycle-derived metabolites exhibiting moonlighting functions in the nucleus, modulating chromatin modifications in order to control inflammation. These TCA cycle-derived metabolites include acetyl-CoA, α-ketoglutarate, succinate, fumarate, itaconate, and succinyl-CoA which can modify DNA or histone to drive or inhibit gene expression. In this review, we look at the mechanisms of TCA cycle metabolites' non-canonical functions in the nucleus in the context of inflammation. In addition, we discuss the known and possible links between these metabolites' nuclear moonlighting functions and the pathogenesis of diseases, including inflammatory diseases and cancers.
In-depth investigation of the mechanism in rats with alcoholic acute pancreatitis via DNA methylation, intestinal flora, and fecal metabolomics.
Dong H, Ying W, Zhu S
J Inflamm (Lond) · 2025 Sep · PMID 40999405 · Full text
BACKGROUND: Alcohol consumption is the main cause of acute pancreatitis (AP). Alcohol combined with cerulein (CI) exerts direct damage to pancreas, with its mechanism undefined. METHODS: Rats were randomly divided into t...
BACKGROUND: Alcohol consumption is the main cause of acute pancreatitis (AP). Alcohol combined with cerulein (CI) exerts direct damage to pancreas, with its mechanism undefined. METHODS: Rats were randomly divided into three subgroups, with subgroup I including Control and Alcohol groups at weeks 6, 8, and 10, subgroup II including Control and Alcohol groups administered CI (12.5, 25, and 50 µg/kg), and subgroup III including Control and Alcohol groups administered CI (50 µg/kg). Following measurement of liver and kidney function indicators, pathological damage of liver, kidney, lung, and intestine was detected using HE staining. Methylation-Specific PCR, Sequenom MassARRAY methylation, ELISA, Western blot, and correlation analysis of 16S rRNA sequencing and metabolomics were performed. RESULTS: Compared to Control group, Alcohol + CI group increased pathological damage, serum aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, blood urea nitrogen, alkaline phosphatase, amylase, lipase, TNF-α, IL-6, and IL-1β levels (P < 0.01). Meanwhile, p-mTOR/mTOR, hypoxia-inducible factor 1 alpha (HIF-1α), and vascular endothelial growth factor were enhanced, with lower creatinine and HIF-1α DNA methylation (P < 0.01). Alcohol at week 8 caused higher HIF-1α-25_CpG_35 methylation (P = 0.0222), which were reduced by further CI (50 µg/kg, P = 0.0034). Moreover, strong correlation was reported between key flora (Methanobrevibacter_A, Ruminococcus_C_59129, Lactobacillus, Eubacterium_Q, and Phascolarctobacterium_A) and metabolites (Homocysteine, Aspartic acid, Agmatine, 6-Ketoprostaglandin e1, Stearic acid, and Palmitic acid). CONCLUSION: HIF-1α-25_CpG_35 methylation, intestinal flora, and metabolites involved in regulating AP pathogenesis. Methanobrevibacter_A, Ruminococcus_C_59129, Lactobacillus, Eubacterium_Q, Phascolarctobacterium_A, Homocysteine, Aspartic acid, Agmatine, 6-Ketoprostaglandin e1, Stearic acid, and Palmitic acid were the potential biomarkers, offering new insights into the pathogenesis of AP.
Identification of neutrophil extracellular traps-related genes for the diagnosis of acute myocardial infarction based on bioinformatics and experimental verification.
Yuan HJ, Yu YD, Liu WW … +5 more , Liu XJ, Han QC, Shi JL, Xue YT, Li Y
J Inflamm (Lond) · 2025 Aug · PMID 40866955 · Full text
BACKGROUND: Neutrophil extracellular traps (NETs) have been demonstrated to play an important role in acute myocardial infarction (AMI), but their specific mechanisms in the development of AMI have not been investigated....
BACKGROUND: Neutrophil extracellular traps (NETs) have been demonstrated to play an important role in acute myocardial infarction (AMI), but their specific mechanisms in the development of AMI have not been investigated. METHODS: The AMI datasets were screened from the GEO database. The hub genes in differentially expressed NET-related genes (DE-NRGs) were screened using bioinformatics and machine learning algorithms, and the nomogram model was constructed based on this. Functional enrichment analysis clarified the biological function and signaling pathways of NETs-mediated AMI. Immune infiltration analysis was performed on the AMI datasets. Finally, the AMI model was constructed using Wistar rats, evaluated by echocardiography and HE staining, and hub genes expression was verified by real-time quantitative PCR (RT-qPCR) and western blot. RESULTS: Based on the bioinformatics analysis, 23 DE-NRGs were obtained. The hub genes were screened by machine learning algorithms for NFIL3, MMP9 and S100A8. Immune infiltration analysis demonstrated the relative abundance of immune cells in the sample and their expression levels in hub genes. The experimental results showed that LVEF and FS were significantly reduced in the AMI group, cardiac function was impaired, and there were disturbances in the arrangement of cardiomyocytes and interstitial edema with inflammatory infiltration. NFIL3, MMP9 and S100A8 were significantly elevated in the AMI group compared to the Sham group. CONCLUSION: This study identified the hub genes of NETs-mediated AMI and constructed a diagnostic model through bioinformatics and experimental verification, which provided a new idea for the molecular mechanisms of AMI development and treatment.
The metabolic intersection between immunosenescence and neuroinflammation in amyotrophic lateral sclerosis.
Tsang VSK, Malaspina A, Henson SM
J Inflamm (Lond) · 2025 Aug · PMID 40866928 · Full text
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons. Although it is traditionally viewed as a neuron-centric disease, neurodegeneration is increasingl...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons. Although it is traditionally viewed as a neuron-centric disease, neurodegeneration is increasingly linked to immunosenescence and age-related immune dysfunction, but the mechanisms connecting immune ageing to neurodegeneration remain poorly understood. In this review, we explore how metabolic reprogramming, especially the loss of metabolic plasticity in senescent immune cells, drives neuroinflammation in ALS. Senescent immune cells, including microglia and T cells, exhibit mitochondrial dysfunction, redox imbalance, impaired autophagy, and altered nutrient-sensing pathways that impair their homeostatic and reparative capacities. These cells adopt a metabolically demanding pro-inflammatory phenotype, sustaining an inflammatory secretome while promoting glial activation and neuronal damage. Finally, we discuss how targeting immunometabolic pathways may offer new therapeutic opportunities to restore immune balance, mitigate neuroinflammation, and potentially slow ALS progression. Understanding the metabolic basis of immune ageing is essential for developing effective, age-tailored interventions for ALS.
Long-term risk of de novo malignancy with tumor necrosis factor alpha (TNF) inhibitor immunosuppression: a multicenter, retrospective cohort study.
Driscoll CB, Rich JM, Yang C … +10 more , Nicolas J, Isaacson D, Silberman P, Mi X, Kumar SKSR, Zhang H, Belknap S, Temps WH, Schaeffer EM, Kundu SD
J Inflamm (Lond) · 2025 Aug · PMID 40814047 · Full text
BACKGROUND: Tumor necrosis factor-alpha (TNF) is an inflammatory cytokine implicated in the development of many chronic inflammatory diseases and TNF-α inhibitors (TNF-I) are frequently prescribed as treatment. Their mal...
BACKGROUND: Tumor necrosis factor-alpha (TNF) is an inflammatory cytokine implicated in the development of many chronic inflammatory diseases and TNF-α inhibitors (TNF-I) are frequently prescribed as treatment. Their malignancy risk is debated, with pro-oncogenic effects of decreased immune surveillance and anti-oncogenic effects of decreasing chronic inflammation. As such, the literature is inconclusive in the malignancy risk of these medications. Here we investigate the malignancy risk in patients with chronic TNF-I exposure. METHODS: This is a single health system, retrospective non-matched cohort study of patients with chronic inflammatory conditions between 1996 and 2023. Patients exposed to TNF-I were identified using the generic medication names and the chronic inflammatory disease indication. The unmatched control cohort consisted of patients with the same chronic inflammatory conditions but without TNF-I exposure. Malignancies in this population were identified using ICD-9 and ICD-10 codes. TNF-I exposure was analyzed as a time-varying covariate prior to model fitting. Hazard ratios (HR) for TNF-I exposure on overall and individual cancer risk were estimated using two-sided Cox proportional hazards regression. RESULTS: There were 12,941 patients exposed to TNF-I and 37,402 patients unexposed to TNF-I. TNF-I exposure was not associated with overall cancer risk (HR 1.05, 95% CI 0.92-1.19). TNF-I exposure was positively associated with melanoma (HR 1.45, 95% CI 1.01-2.08), basal cell carcinoma (BCC) (HR 1.6, 95% CI 1.18-2.15) and squamous cell carcinoma (SCC) (HR 1.8, 95% CI 1.15-2.83), and negatively associated with prostate cancer (PCa) (HR = 0.51, 95% CI 0.29-0.91), leukemia (HR 0.12, 95% CI 0.02-0.83), and non-Hodgkin lymphoma (NHL) (HR 0.36, 95% CI 0.13-0.98). There was an increased risk of overall malignancy in TNF-I exposed patients with Psoriasis (HR 1.53, 95% CI 1.15-2.03, p = 0.003) but not in other inflammatory conditions. CONCLUSIONS: Patients with TNF-I exposure had higher risk of melanoma, skin SCC and BCC along with lower risk of leukemia, NHL, and PCa. This is consistent with previous melanoma, skin SCC and BCC data and demonstrates novel findings for leukemia, NHL, and PCa. There may need to be differential cancer screening algorithms for patients with different inflammatory conditions and TNF-I exposure.
Hydroxychloroquine reduces metastatic tumor burden in pancreatic adenocarcinoma through myeloperoxidase inhibition.
Niemann B, Rao P, Hopen Q … +5 more , Landreth K, Basnet A, Geldenhuys W, Liu TW, Boone BA
J Inflamm (Lond) · 2025 Aug · PMID 40797324 · Full text
BACKGROUND: Metastatic pancreatic adenocarcinoma has a 5-year survival of only 3%. Neutrophil extracellular traps are formed when neutrophils expel their intracellular contents and have been intricately linked to metasta...
BACKGROUND: Metastatic pancreatic adenocarcinoma has a 5-year survival of only 3%. Neutrophil extracellular traps are formed when neutrophils expel their intracellular contents and have been intricately linked to metastases. Hydroxychloroquine is an FDA-approved anti-malarial drug and neutrophil extracellular trap inhibitor with high potential for clinical translation. This study investigates the impact of hydroxychloroquine treatment on pancreatic metastases. RESULTS: Hydroxychloroquine reduced metastatic tumor burden via a neutrophil extracellular trap independent mechanism and resulted in prolonged survival. Hydroxychloroquine inhibited the function of myeloperoxidase in vitro via direct binding with a Kd of 9.74 mM. Myeloperoxidase inhibition via hydroxychloroquine in vivo was the direct result of suppressed activity. Hydroxychloroquine mediated myeloperoxidase inhibition was also demonstrated in metastatic pancreatic adenocarcinoma patients receiving neoadjuvant chemotherapy. CONCLUSION: Hydroxychloroquine suppressed pancreatic metastases growth through myeloperoxidase inhibition, leading to a significant increase in survival. Corroborative data supports this mechanism in metastatic pancreatic adenocarcinoma patients treated with hydroxychloroquine. These data provide important insight into the role of myeloperoxidase in pancreatic metastases and the potential use of hydroxychloroquine in metastatic pancreatic adenocarcinoma treatment.
C-reactive protein modulates lipid mediators in a pro-inflammatory direction.
Kurano M, Tsukamoto K, Isago H … +2 more , Hara M, Yatomi Y
J Inflamm (Lond) · 2025 Aug · PMID 40797222 · Full text
BACKGROUND: C-reactive protein (CRP) is a risk factor for atherosclerosis. Although inflammation may confound this association, CRP itself has been hypothesized to possess both pro-atherosclerotic and pro-inflammatory pr...
BACKGROUND: C-reactive protein (CRP) is a risk factor for atherosclerosis. Although inflammation may confound this association, CRP itself has been hypothesized to possess both pro-atherosclerotic and pro-inflammatory properties. In this study, we aimed to elucidate the mechanism by which CRP may modulate bioactive lipid mediators. RESULTS: We found that the overexpression of human CRP increased plasma IL-6 and TNF-a levels in mice. Moreover, the conditioned medium of CRP-overexpressing HepG2 cells increased the release of these cytokines from RAW264.7 cells to a greater degree than recombinant CRP. Lipidomics analyses then revealed that the overexpression of CRP increased the total levels of plasma lysophosphatidic acid, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, and sphingosine 1-phosphate in mice. It also increased the levels of pro-inflammatory arachidonic acid derivatives, including PGE2 metabolites, LTA4 metabolites, and oxylipids, and decreased the levels of anti-inflammatory eicosapentaenoic acid- and docosahexaenoic acid-derived mediators. In regard to the mechanisms, analyses of CRP-overexpressing HepG2 cells suggested that CRP may increase the hepatic production of glycero-lysophospholipids, and may also modulate eicosanoids and related mediators outside the liver. Finally, analyses of the fraction separated using anti-CRP IgG suggested that CRP can bind several lipid mediators including sphingosine 1-phosphate, PGE2, and PGF2a. CONCLUSIONS: CRP may modulate lysophospholipids, and eicosanoids, and related mediators in pro-atherosclerotic and pro-inflammatory directions.
Associations of leucocyte subtypes and platelet parameters with kidney cancer risk in the UK Biobank cohort.
Christakoudi S, Tsilidis KK, Gunter MJ … +1 more , Riboli E
J Inflamm (Lond) · 2025 Aug · PMID 40790491 · Full text
BACKGROUND: Kidney cancer is related to obesity and inflammation and platelets are involved in thrombo-inflammation, but the prospective associations of individual leucocyte subtypes and platelet parameters with kidney c...
BACKGROUND: Kidney cancer is related to obesity and inflammation and platelets are involved in thrombo-inflammation, but the prospective associations of individual leucocyte subtypes and platelet parameters with kidney cancer risk are unclear. METHODS: Using data from the UK Biobank cohort and multivariable Cox proportional hazards models, we obtained hazard ratios (HR per one standard deviation increase) with 95% confidence intervals (95%CI) for the mutually adjusted associations of inflammatory markers and platelet parameters (log-transformed), and allometric obesity indices (body mass index (BMI), a body shape index (ABSI), hip index) with kidney cancer risk (overall, by sex, and by follow-up time with a cut-off at 6 years). RESULTS: During a mean follow-up of 10.4 years, 1086 kidney cancers were ascertained in 396,482 participants. Conditional on each other and covariates, neutrophil count (HR = 1.12; 95%CI = 1.04 - 1.20), C-reactive protein (HR = 1.11; 95%CI = 1.04 - 1.19), platelet count (HR = 1.18; 95%CI = 1.10 - 1.27), platelet distribution width (HR = 1.16; 95%CI = 1.09 - 1.24), and BMI (HR = 1.22; 95%CI = 1.14 - 1.30) were positively associated, while lymphocyte count (HR = 0.90; 95%CI = 0.84 - 0.96) and hip index (HR = 0.88; 95%CI = 0.83 - 0.93) were inversely associated with kidney cancer risk in participants overall, but there was little evidence for an association with ABSI (HR = 1.05; 95%CI = 0.99 - 1.12). There were no major sex differences, but the positive association with C-reactive protein was observed only for shorter follow-up time (HR = 1.26; 95%CI = 1.14 - 1.38; p-follow-up = 0.0006). CONCLUSIONS: Our findings support two separate longer-acting pathways in kidney cancer development- a pathway related to general rather than abdominal obesity and an immune-cell-related pathway involving neutrophils assisted by activated platelets, as well as a cancer-induced thrombo-inflammation closer to kidney cancer diagnosis.
NAD + metabolism and function in innate and adaptive immune cells.
Mann R, Stavrou V, Dimeloe S
J Inflamm (Lond) · 2025 Aug · PMID 40751253 · Full text
Nicotinamide adenine dinucleotide (NAD+) plays a central role in cellular metabolism and energy production, supporting many biological processes. Recent studies highlight the significance of NAD + in regulation of immune...
Nicotinamide adenine dinucleotide (NAD+) plays a central role in cellular metabolism and energy production, supporting many biological processes. Recent studies highlight the significance of NAD + in regulation of immune cell function, with implications for our understanding of immune homeostasis, inflammation, and disease. This review reports our current understanding on the role of NAD + in the immune system, specifically in macrophages and T cells, facilitating their metabolic reprogramming during differentiation and activation. It offers an overview of NAD + biosynthesis within these immune cells, describes its role in the modulation of immune cell metabolism and effector function, and highlights potential therapeutic applications of NAD + modulation in immunological disorders including autoimmune diseases and cancer.
Unveiling the anti-inflammatory potential of RF16, an interleukin 8-derived therapeutic peptide in macrophages.
Chang CC, Tu HY, Peng SY … +2 more , Hsu HJ, Jiang SJ
J Inflamm (Lond) · 2025 Jul · PMID 40722163 · Full text
BACKGROUND: Interleukin 8 (IL-8, also known as CXCL-8) regulates inflammation and breast cancer formation by activating its cognate receptor CXCR1/2. In our previous study, a RF16 peptide, derived from the IL-8 binding r...
BACKGROUND: Interleukin 8 (IL-8, also known as CXCL-8) regulates inflammation and breast cancer formation by activating its cognate receptor CXCR1/2. In our previous study, a RF16 peptide, derived from the IL-8 binding region of CXCR1/2, was synthesized to inhibit IL-8-stimulated and LPS-induced adhesion and transmigration of monocytes. However, the anti-inflammatory effects of RF16 on THP-1 cells remain unknown. METHODS: THP-1 cells were differentiated with PMA overnight, followed by an one hour pretreatment of the IL-8 antagonist peptide RF16. IL-8 or TNF-α was then added for further incubation. The supernatant, mRNA, and protein of the cells were harvested. The secretion of TNF-α, IL-1β, and IL-6 was measured, along with assessment of ROS production and oxLDL uptake. Protein expression of different signaling pathways was analyzed. RF16 was also treated in a mouse model of acute sepsis to evaluate the white blood cell (WBC) count and serum IL-6 levels. RESULTS: Our results indicate that RF16 was able to reduce mRNA and protein expression of inflammatory cytokines including TNF-α, IL-8, IL-6, and IL-1β levels in TNF-α/IL-8-induced THP-1 cells, with some results showing a dose-dependent trend. We found that RF16 was able to inhibit TNF-α/IL-8-induced ROS generation, thereby suppressing the inflammatory response. Moreover, a higher concentration (1 uM) of RF16 can alleviate oxLDL uptake induced by TNF-α and IL-8. Further investigation revealed that NF-κB, PI3K, and MAPK signaling pathways were the main mechanism responsible for the inhibition of inflammation. In addition, using the LPS-induced sepsis animal model, RF16 was able to reduce the number of white blood cells in peripheral blood, and subsequently reduce IL-6 levels. CONCLUSION: Our results demonstrated that RF16 has the ability to suppress the expressions and secretions of TNF-α, IL-8, and LPS-induced pro-inflammatory cytokines in both in vitro and in vivo.
Verteporfin attenuates NLRP3 inflammasome activation to alleviate gout arthritis flares.
Shippy DC, Ulland TK
J Inflamm (Lond) · 2025 Jul · PMID 40671118 · Full text
BACKGROUND: Gout arthritis (GA) is an inflammatory disorder characterized by the deposition of monosodium urate (MSU) crystals within synovial joints due to increased urate concentrations in the body. The NLRP3 inflammas...
BACKGROUND: Gout arthritis (GA) is an inflammatory disorder characterized by the deposition of monosodium urate (MSU) crystals within synovial joints due to increased urate concentrations in the body. The NLRP3 inflammasome drives a majority of the inflammatory response to MSU crystals; therefore, we hypothesize pharmaceutical agents that attenuate NLRP3 inflammasome activation could be used to treat GA flares. RESULTS: We screened a drug library containing 875 FDA-approved drugs and identified five drugs that reduced NLRP3 inflammasome activation without causing cytotoxic effects in bone marrow-derived macrophages (BMDM). The best performing and therefore leading candidate, verteporfin, used to treat macular degeneration and other eye disorders, reduced Nlrp3- and Caspase-1-dependent IL-1β and IL-18 secretion by BMDM. Additionally, verteporfin-treated mice showed a marked reduction in paw swelling and pro-inflammatory cytokine/chemokine induction, including inflammasome markers (IL-1β and IL-18), in a MSU-induced mouse model of GA flares. CONCLUSION: Collectively, these data suggest verteporfin is a NLRP3 inflammasome inhibitor that could be repurposed as a treatment for GA.
Curcumin and omega-3 ameliorate experimental osteoarthritis progression in terms of joint pain and mitochondrial dysfunction.
Jhun J, Lee D, Na HS … +7 more , Cho KH, Lee SY, Lee JS, Lee YJ, Kim SJ, Park SH, Cho ML
J Inflamm (Lond) · 2025 Jul · PMID 40665304 · Full text
BACKGROUND: Osteoarthritis (OA), a chronic degenerative disorder, induces pain, joint inflammation, and destruction of the articular cartilage matrix. Curcumin and omega-3 have been used as dietary supplements for OA due...
BACKGROUND: Osteoarthritis (OA), a chronic degenerative disorder, induces pain, joint inflammation, and destruction of the articular cartilage matrix. Curcumin and omega-3 have been used as dietary supplements for OA due to their anti-inflammatory and antioxidant properties. However, there is no evidence demonstrating a synergistic effect in OA. The current study aimed to investigate the therapeutic effects and underlying mechanism of a combination of curcumin and omega-3 in the treatment of OA. METHODS: Wistar rats were injected with monosodium iodoacetate to induce OA. Oral treatments of a vehicle, curcumin, curcumin and omega 3, or celecoxib were administered. Pain was analyzed according to the paw withdrawal latency, paw withdrawal threshold, and weight bearing ability. The joint was isolated from OA rats, and cartilage damage was evaluated using histomorphological techniques, the Mankin scoring system, and micro computed tomography analysis. Protein expression in the joint was examined using immunohistochemistry. The expression levels of catabolic markers were measured in curcumin and omega-3-treated OA chondrocytes. RESULTS: The OA animal model revealed diminished pain and cartilage conservation in response to the combined treatment. mRNA levels of matrix metalloproteinase 1 (MMP1), MMP3, and MMP13 were reduced in interleukin-1 beta-simulated human OA chondrocytes. Additionally, mitochondrial markers, cytochrome c oxidase 4, and TOMM20, were increased by the combination treatment. CONCLUSIONS: These findings suggest promising therapeutic outcomes for the combined treatment of curcumin and omega-3 in OA patients.
The potential role of 1,25(OH)D (Active vitamin D) in modulating macrophage function; implications for chronic obstructive pulmonary disease (COPD).
Thai H, Hassanen R, Whittall T … +1 more , Kirkham P
J Inflamm (Lond) · 2025 Jul · PMID 40598381 · Full text
Macrophages play an important role in tissue homeostasis, inflammation, and repair, displaying remarkable plasticity by polarising towards pro-inflammatory M1 or anti-inflammatory M2 phenotypes. In chronic obstructive pu...
Macrophages play an important role in tissue homeostasis, inflammation, and repair, displaying remarkable plasticity by polarising towards pro-inflammatory M1 or anti-inflammatory M2 phenotypes. In chronic obstructive pulmonary disease (COPD), this regulatory balance is disrupted, resulting in sustained tissue damage and impaired repair capability. Defective efferocytosis and dysregulated macrophage phenotypes are key contributors to COPD pathogenesis. Emerging evidence suggests that vitamin D3, particularly its active form 1,25(OH)2D3, has an immunomodulatory effect on reprogramming macrophages towards an M2 phenotype. This review examines the molecular mechanisms through which 1,25(OH)2D3 is reported to influence macrophage metabolism, surface marker expression, and intracellular signalling. Overall, the review suggests that 1,25(OH)2D3-mediated reprogramming of macrophage phenotype and function offers a potential therapeutic approach to mitigate persistent inflammation and tissue destruction in COPD. Moreover, future research should focus on exploring the detailed molecular pathway of 1,25(OH)2D3 action in COPD macrophages and validating its clinical effects as part of personalised treatment strategies.Evidence suggests that 1,25(OH)2D3 enhances mitochondrial function and shift macrophage metabolism from glycolysis to oxidative phosphorylation through metabolic reprogramming facilitating M1-to-M2 polarisation. 1,25(OH)2D3 also modulates macrophage phenotype by regulating M2-associated surface markers (CD36, CD163, CD206, TIM-3) and downregulating pro-inflammatory mediators (CD86, iNOS, HLA-DR). It promotes the secretion of anti-inflammatory cytokines IL-10 and TGF-β while suppressing IL-1β, IL-6 and TNF production. Mechanistically, 1,25(OH)2D3 regulates macrophage polarisation through multiple signalling pathways and suppresses pro-inflammatory responses by inhibiting NF-κB and MAPK activation, while promoting anti-inflammatory signalling via STAT6 and VDR-PPARγ axis. Deficiency in 1,25(OH)2D3 is strongly associated with increased inflammation and oxidative stress in COPD correlating with increased disease severity. Conversely, restoring vitamin D3 levels reduces oxidative damage, suppresses pro-inflammatory gene expression, and improves alveolar macrophage function highlighting its therapeutic potential in modulating inflammation.
The soluble epoxide hydrolase inhibitor TPPU alleviates Aβ-mediated neuroinflammatory responses in Drosophila melanogaster and cellular models of alzheimer's disease.
Sun X, Liu H, Li W … +9 more , Li L, Tian Q, Cao Q, Meng Y, Shen Y, Che F, Chiu JC, Yu J, Hammock BD
J Inflamm (Lond) · 2025 Jun · PMID 40551105 · Full text
BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disease, and its pathogenesis is closely associated with neuroinflammation. The control of neuroinflammation in AD is the focus of current research. solu...
BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disease, and its pathogenesis is closely associated with neuroinflammation. The control of neuroinflammation in AD is the focus of current research. soluble epoxide hydrolase (sEH) protein is increased in the brain tissues of patients with AD and has been targeted by multiple genome wide association studies as a prime target for treating AD. Since sEH induces nerve inflammation by degrading epoxyeicosatrienoic acids (EETs), application of sEH inhibitor and sEH gene knockout are effective ways to improve the bioavailability of EETs and inhibit or even resolve neuroinflammation in AD. 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) is a potent sEH inhibitor that has been shown to be effective in preclinical animal models of a variety of chronic inflammatory diseases. This study aims to further explore whether TPPU can alleviate AD neuroinflammation. METHODS: We established an Aβ42-transgenic Drosophila melanogaster model using the galactose-regulated upstream promoter element 4 (GAL4) / upstream active sequence (UAS) expression system and investigated the protective and anti-neuroinflammatory effects of TPPU against Aβ toxicity. We detected behavioral indexes (survival time, crawling ability, and olfactory memory) and biochemical indexes malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in brain tissues of Aβ42 transgenic flies. Finally, we explored the anti-neuroinflammatory effect of TPPU and its possible mechanism by stimulating cocultures of human SH-SY5Y cells and HMC3 cells with Aβ(25-35) to model neuronal cell inflammation, and evaluated the cells by fluorescence microscopy, ELISA, Western Blot, and Real-time PCR. RESULTS: We found that TPPU improved the survival time, crawling ability, and olfactory memory of Aβ42-transgenic flies. We also observed reduction of MDA content and elevation of SOD activity in the brain tissues of these flies. In human cell models, we found that TPPU improved cell viability, reduced cell apoptosis, decreased lipid oxidation, inhibited oxidative damage, thus playing a neuroprotective role. The inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and interleukin-18 (IL-18) were downregulated, and the mRNA expression of the M2 microglia markers CD206 and SOCS3 were upregulated by TPPU; thus, TPPU inhibited neuroinflammatory responses. TPPU exerted neuroprotective and anti-inflammatory effects by decreasing the protein expression of the sEH-encoding gene EPHX2 and increasing the levels of 11,12-epoxyeicosatrienoic acid (11,12-EET) and 14,15-epoxyeicosatrienoic acid (14,15-EET). The inhibitory effect of TPPU on Aβ(25-35)-mediated neuroinflammation was associated with inhibition of the toll like receptor 4 (TLR4)/nuclear transcription factor-κB (NF-κB) pathway and p38 mitogen activated protein kinases (MAPK)/NF-κB pathway. CONCLUSIONS: We report that the sEH inhibitor TPPU exerts neuroprotective and anti-neuroinflammatory effects in AD models, and it is expected that this drug could potentially be used for the prevention and treatment of AD.
Intermittent methionine restriction and selenium supplementation protect against inflammation and the development of dermatitis.
Plummer JD, Johnson JE
J Inflamm (Lond) · 2025 Jun · PMID 40537808 · Full text
Dietary methionine restriction (MR) produces multiple metabolic health benefits and extends the healthspan of several model organisms, including rodents. MR is feasible for humans, and studies have reported that methioni...
Dietary methionine restriction (MR) produces multiple metabolic health benefits and extends the healthspan of several model organisms, including rodents. MR is feasible for humans, and studies have reported that methionine-restricted human subjects receive similar benefits to rodents. However, long-term adherence to continuous MR is likely to be challenging (if not impossible) for many individuals. Another obstacle to the successful translation of this intervention is the fact that multiple deleterious effects of continuous MR have been reported for mice and humans, including loss of musculoskeletal mass, increased bone marrow adipogenesis, and an increased incidence of fractures. To address these issues, we developed two novel interventions that produce similar health benefits to continuous MR, but without the same deleterious side effects. The first is an intermittent form of MR (IMR) that requires only 3 days of reduced methionine intake per week; the second involves supplementation of an otherwise normal diet with sodium selenite. For the current study, we considered the possibility that these interventions might also prevent and/or ameliorate diet-induced chronic inflammation, as well as pathologies that result from this condition. Accordingly, we tested whether IMR or selenium supplementation were able to protect high-fat diet-fed mice against both inflammation and the development of inflammation-induced ulcerative dermatitis. Here, we show that high-fat diet-fed mice undergoing both interventions not only have relatively low levels of inflammation, but are also protected against the development of dermatitis. We also propose a model for the mechanistic basis of such benefits, which involves reduced activation of leptin-responsive pro-inflammatory pathways.
Mesenchymal stem cell-derived exosomal CBLB ameliorates infantile pneumonia progression probably by ubiquitinating MAPK14.
Guo F, Song F, Chen Z … +4 more , Niu N, Sun L, Yan M, Liu M
J Inflamm (Lond) · 2025 Jun · PMID 40537786 · Full text
BACKGROUND: Infantile pneumonia (IP) is a significant cause of morbidity and mortality in young children. Mesenchymal stem cells (MSCs) have emerged as potential therapeutic agents in pneumonia due to their immunomodulat...
BACKGROUND: Infantile pneumonia (IP) is a significant cause of morbidity and mortality in young children. Mesenchymal stem cells (MSCs) have emerged as potential therapeutic agents in pneumonia due to their immunomodulatory properties. The study analyzed the role of MSCs from bone marrow in IP and the underlying mechanism. METHODS: Human embryonic lung fibroblasts (WI-38) were stimulated using lipopolysaccharide (LPS) to mimic an IP cell model. This study employed flow cytometry to analyze the expression of hematopoietic markers and marker proteins on MSCs. The differentiation potential of MSCs was assessed through microscopy, oil red O staining, and alkaline phosphatase (ALP) assays. The localization of exosomes in WI-38 cells was observed using the cell membrane green fluorescent probe DIO. Quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting and immunohistochemistry assays were used to analyze the expression of mRNA or protein. Cell viability, proliferation, and apoptosis were evaluated using Cell counting kit-8, 5-Ethynyl-2'-deoxyuridine, and flow cytometry assays, respectively. Enzyme-linked immunosorbent assays were conducted to measure cytokine levels. A mouse model of pneumonia was utilized to assess the therapeutic potential of MSC-derived exosomes on lung injury. Co-immunoprecipitation (Co-IP) assay was performed to study the interaction between Cbl proto-oncogene B (CBLB) and mitogen-activated protein kinase 14 (MAPK14). RESULTS: MSC-derived exosomes could be transferred into LPS-induced WI-38 cells, where they mitigated the inhibitory effects of LPS on CBLB mRNA expression. These exosomes improved WI-38 cell proliferation, reduced apoptosis, and decreased the production of pro-inflammatory cytokines including IL-6, IL-1β, and TNF-α by regulating CBLB after LPS treatment. Moreover, in a mouse model, MSC-derived exosomes protected against LPS-induced lung injury, whereas the effect was reversed after treatment with the exosomes isolated from CBLB-deficient MSCs. In addition, CBLB was found to destabilize MAPK14 protein expression in WI-38 cells. Further, overexpression of CBLB ameliorated LPS-induced inhibitory effect on cell proliferation and promoting effects on cell apoptosis and inflammation in WI-38 cells by regulating MAPK14. CONCLUSION: MSC-derived exosomal CBLB has therapeutic potential in ameliorating the progression of IP probably by ubiquitinating MAPK14, which could lead to novel clinical interventions for treating this condition.
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