Search

Background and Purpose Experimental approach Key Results Conclusions and Implications Dihydro‐resveratrol (DHR), a polyphenol derivative, that has been demonstrated to suppress inflammation‐mediated injury. However, it is still unknown whether it has anti‐neuroinflammatory and neuroprotective effects, and a therapeutic action in Alzheimer's disease (AD).The anti‐inflammatory and anti‐Alzheimer's disease actions of dihydro‐resveratrol were investigated using lipopolysaccharide (LPS) and AD mice models, and primary microglial cells. The changes in behaviour in mice were detected by the Morris water maze test and open‐field test. Flow cytometry assay, western blotting, immunofluorescence assays and co‐immunoprecipitation were used to investigate the changes in the NLRP3 inflammasome activation and mitophagy.In this study, in vivo observations indicated that the administration of dihydro‐resveratrol (DHR) dramatically restored spatial learning, memory ability, autophagy and mitophagy, attenuated NLRP3 inflammasome activation, neuroinflammation and amyloid precursor protein pathology in LPS mice and AD mice. In addition, the inhibition of autophagy and mitophagy, or the activation of NLRP3 in vivo greatly abolished DHR‐generated therapeutic efficacy on neuroinflammation, amyloid precursor protein pathology and cognitive loss. Further examination indicated that the application of DHR after the LPS and ATP exposure significantly inhibited the NLRP3 inflammasome activation, neuroinflammation and enhanced autophagic and mitophagic activation in microglia. Additionally, in vitro results show that DHR protects microglial cells against LPS and ATP‐induced cytotoxicity by inhibiting NLRP3 inflammasome through activating Bnip3‐dependent mitophagy and ULK phosphorylation.In summary, these findings suggest that dihydro‐resveratrol (DHR) possesses potent anti‐neuroinflammatory property and can act as a potential therapeutic agent for the treatment of AD. [ABSTRACT FROM AUTHOR]

Hypersensitivity pneumonitis (HP) is an immune‐mediated interstitial lung disease (ILD) relating to specific occupational, environmental or medication exposures. Disease behaviour is influenced by the nature of exposure and the host response, with varying degrees of lung inflammation and fibrosis seen within individuals. The differentiation of HP from other ILDs is important due to distinct causes, pathophysiology, prognosis and management implications. This Thoracic Society of Australia and New Zealand (TSANZ) position statement aims to provide an up‐to‐date summary of the evidence for clinicians relating to the diagnosis and management of HP in adults, in the Australian and New Zealand context. This document highlights recent relevant findings and gaps in the literature for which further research is required. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a respiratory disease characterized by pulmonary and systemic inflammation. Inflammatory mediators show relationships with shortness of breath, exercise intolerance and health related quality of life. Pulmonary rehabilitation (PR), a comprehensive education and exercise training programme, is the most effective therapy for COPD and is associated with reduced exacerbation and hospitalization rates and increased survival. Exercise training, the primary physiological intervention within PR, is known to exert a beneficial anti‐inflammatory effect in health and chronic diseases. The question of this review article is whether exercise training can also make such a beneficial anti‐inflammatory effect in COPD. Experimental studies using smoke exposure mice models suggest that the response of the immune system to exercise training is favourably anti‐inflammatory. However, the evidence about the response of most known inflammatory mediators (C‐reactive protein, tumour necrosis factor α, interleukin 6, interleukin 10) to exercise training in COPD patients is inconsistent, making it difficult to conclude whether regular exercise training has an anti‐inflammatory effect in COPD. It is also unclear whether COPD patients with more persistent inflammation are a subgroup that would benefit more from hypothesized immunomodulatory effects of exercise training (i.e., personalized treatment). Nevertheless, it seems that PR combined with maintenance exercise training (i.e., lifestyle change) might be more beneficial in controlling inflammation and slowing disease progress in COPD patients, specifically in those with early stages of disease. [ABSTRACT FROM AUTHOR]

ABSTRACT Mandarin fish ranavirus (MRV) is widely spread in China and causes huge economic losses to the mandarin fish (Siniperca chuatsi) aquaculture. However, the pathogenesis of MRV is still unclear. In the present study, mandarin fish were artificially infected with MRV, and then different gut compartments from diseased fish were subjected to histologic analysis by H&E staining, quantification of proinflammatory genes and MRV copies by qPCR. MRV‐MCP protein expression was assessed using indirect fluorescence assay (IFA) and immunohistochemistry. Proliferation of IgM+ B cells was evaluated by indirect fluorescence assay (IFA). Then, we found that MRV infection caused serious histologic lesions along with inflammatory cell infiltration, especially in the foregut. A significant accumulation of IgM+ B cells was detected in the foregut (~6.5‐fold) and hindgut (~3.3‐fold), respectively. The expression of inflammation‐related genes such as IL‐1β, IL‐6, IL‐8, TNF‐α, CSF1r and NCF1 was significantly upregulated in the foregut, varying from ~2.8‐fold to ~11.9‐fold. In addition, MRV exhibited foregut tropism, according to the investigation of viral loads and MCP protein expression. Overall, our findings indicated that MRV‐induced hyperinflammation in the gut eventually led to enteritis. This study provided new insights into uncovering the pathogenesis of MRV infection. [ABSTRACT FROM AUTHOR]

The Carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1, also CD66a), a transmembrane glycoprotein of the immunoglobulin superfamily, is a pivotal mediator of various physiological and pathological processes, including oncologic disorders. However, its precise role in tumorigenicity is contradictory discussed by several clinical studies. This review aims to elucidate the clinical significance of CEACAM1 in different cancer entities focusing on tumour formation, progression and metastasis as well as on CEACAM1‐mediated treatment resistance. Furthermore, we discuss the contribution of CEACAM1 to cancer immunity and modulation of the inflammatory microenvironment and finally provide a comprehensive review of treatment regimens targeting this molecule. [ABSTRACT FROM AUTHOR]

Astrocytes are important regulators of neuronal development and activity. Their activation plays a key role in the response to many central nervous system (CNS) pathologies. However, reactive astrocytes are a double‐edged sword as their chronic or excessive activation may negatively impact CNS physiology, for example, via abnormal modulation of synaptogenesis and synapse function. Accordingly, astrocyte activation has been linked to neurodegenerative and neurodevelopmental disorders. Therefore, the attenuation of astrocyte activation may be an important approach for preventing and treating these disorders. Since zinc deficiency has been consistently linked to increased pro‐inflammatory signaling, we aimed to identify cellular zinc‐dependent signaling pathways that may lead to astrocyte activation using techniques such as immunocytochemistry and protein biochemistry to detect astrocyte GFAP expression, fluorescent imaging to detect oxidative stress levels in activated astrocytes, cytokine profiling, and analysis of primary neurons subjected to astrocyte secretomes. Our results reveal a so far not well‐described pathway in astrocytes, the platelet activation factor receptor (PAFR) pathway, as a critical zinc‐dependent signaling pathway that is sufficient to control astrocyte reactivity. Low zinc levels activate PAFR signaling‐driven crosstalk between astrocytes and neurons, which alters excitatory synapse formation during development in a PAFR‐dependent manner. We conclude that zinc is a crucial signaling ion involved in astrocyte activation and an important dietary factor that controls astrocytic pro‐inflammatory processes. Thus, targeting zinc homeostasis may be an important approach in several neuroinflammatory conditions. [ABSTRACT FROM AUTHOR]

Diabetic polyneuropathy (DPN) is a multifactorial disease associated not only with hyperglycaemia but also with circulatory disturbances such as hypertension. A close interaction between the immune system and hypertension is known. It remains unclear whether the inflammatory response is associated with hypertension in the pathology of human DPN. Autopsied patients were evaluated: 7 non‐diabetic patients (nDM), 11 non‐diabetic patients with hypertension (nDMHT), 6 patients with diabetes (DM) and 9 patients with hypertension and diabetes (DMHT). Intraepidermal nerve fibre density (IENFD) was examined by immunofluorescent staining. Dissected sural nerve (SNs) were morphometrically quantified. Dermal and endoneurial macrophage infiltration was evaluated by double immunostaining using anti‐CD68 and anti‐CD206 antibodies. IENFD was significantly decreased in DM compared to nDM (p < 0.05) and was further decreased in DMHT (p < 0.05). Myelinated nerve fibre density (MNFD) in the SN was significantly decreased in DM compared with nDM (p < 0.05) and further decreased in DMHT (p < 0.01 vs. DM). The infiltration of CD206−/CD68+ proinflammatory macrophages in the SN was significantly increased in DM compared to nDM (p < 0.05), whilst the number of CD206+/CD68+ anti‐inflammatory macrophages was decreased in DM (p < 0.05). Hypertension had no impact on macrophage infiltration. The ratio of CD206− and CD206+ macrophage was negatively correlated with MNFD (r = 0.42, p < 0.05) but not IENFD (r = 0.30, p = 0.09). Dermal CD206+ macrophage infiltration was similar amongst all groups. Diabetes complicated by hypertension significantly increased the total diffusion barrier thickness (p < 0.01 vs. DM). Total diffusion barrier thickness was inversely correlated with both IENFD (r = ‐0.59, p < 0.01) and MNFD (r =‐0.62, p < 0.01). Our results suggest that vascular factors and inflammation might be synergistically involved in pathological changes in human diabetic patients through different mechanisms. [ABSTRACT FROM AUTHOR]

Malaria is a mosquito‐borne disease caused by Plasmodium parasites, responsible for a significant impact on public health in several tropical and sub‐tropical countries. The majority of infection cases are classified as uncomplicated malaria, causing mild symptoms such as fever and headache. However, the disease may progress to severe malaria and death if the infection is not properly treated. Furthermore, malaria poses a major concern for children, pregnant women and immunosuppressed individuals. Exacerbated inflammation is characteristic of severe malaria cases. The C–C chemokine receptor type 5 (CCR5) is an important molecule for leukocyte migration and regulation of inflammation. Although widely known as an HIV‐1 co‐receptor, CCR5 also affects the susceptibility and progression of autoimmune and inflammatory diseases. There is evidence supporting the participation of CCR5 in malaria manifestations, with the evaluation of CCR5 gene expression levels suggested as a marker to monitor malaria severity. Certain genetic variants in the CCR5 gene affect CCR5 expression, potentially altering CCR5‐mediated inflammatory responses during malaria infection. However, the complex influences of CCR5 on malaria remain underexplored. Therefore, this review examines and updates the role of CCR5 in various contexts of malaria infection, including uncomplicated malaria, Plasmodium/HIV co‐infection, pregnancy and severe (cerebral) malaria. [ABSTRACT FROM AUTHOR]

Infection by bacteria leads to tissue damage and inflammation, which need to be tightly controlled by host mechanisms to avoid deleterious consequences. It is previously reported that TMEM16F, a calcium‐activated lipid scramblase expressed in various immune cell types including T cells and neutrophils, is critical for the control of infection by bacterium Listeria monocytogenes (Lm) in vivo. This function correlated with the capacity of TMEM16F to repair the plasma membrane (PM) damage induced in T cells in vitro, by the Lm toxin listeriolysin O (LLO). However, whether the protective effect of TMEM16F on Lm infection in vivo is mediated by an impact in T cells, or in other cell types, is not determined. Herein, the immune cell types and mechanisms implicated in the protective effect of TMEM16F against Lm in vivo are elucidated. Cellular protective effects of TMEM16F correlated with its capacity of lipid scrambling and augment PM fluidity. Using cell type‐specific TMEM16F‐deficient mice, the indication is obtained that TMEM16F expressed in liver Kupffer cells (KCs), but not in T cells or B cells, is key for protection against Listeria in vivo. In the absence of TMEM16F, Listeria induced PM rupture and fragmentation of KCs in vivo. KC death associated with greater liver damage, inflammatory changes, and dysregulated liver metabolism. Overall, the results uncovered that TMEM16F expressed in Kupffer cells is crucial to protect the host against Listeria infection. This influence is associated with the capacity of Kupffer cell‐expressed TMEM16F to prevent excessive inflammation and abnormal liver metabolism. [ABSTRACT FROM AUTHOR]

Background and Objective Methods Results Conclusion Chronic obstructive pulmonary disease (COPD) exhibits diverse patterns of disease progression, due to underlying disease activity. We hypothesized that changes in static hyperinflation or KCO % predicted would reveal subgroups with disease progression unidentified by preestablished markers (FEV1, SGRQ, exacerbation history) and associated with unique baseline biomarker profiles. We explored 18‐month measures of disease progression associated with 18–54‐month mortality, including changes in hyperinflation parameters and transfer factor, in a large German COPD cohort.Analysing data of 1364 patients from the German observational COSYCONET‐cohort, disease progression and improvement patterns were assessed for their impact on mortality via Cox hazard regression models. Association of biomarkers and COPD Assessment test items with phenotypes of disease progression or improvement were evaluated using logistic regression and random forest models.Increased risk of 18–54‐month mortality was linked to decrease in KCO % predicted (7.5% increments) and FEV1 (20 mL increments), increase in RV/TLC (2% increments) and SGRQ (≥6 points), and an exacerbation grade of 2 at 18 months. Decrease in KCO % predicted ≥7.5% and an increase of RV/TLC ≥2% were the most frequent measures of 18‐month disease progression occurring in ~52% and ~46% of patients, respectively. IL‐6 and CRP thresholds exhibited significant associations with medium‐ and long‐term disease measures.In a multicentric cohort of COPD, new markers of current disease activity predicted mid‐term mortality and could not be anticipated by baseline biomarkers. [ABSTRACT FROM AUTHOR]

Summary Menstruation is an inflammatory process that involves changes in women's physiology leading to mental and physical complaints. Sleep is essential for optimal hormonal release, immune response, and wellbeing, becoming an important factor to be evaluated. We compared sleep, inflammatory mediators, fatigue, anxiety and depression symptoms, and quality of life in menstruating and non‐menstruating women. We used the polysomnographic data of 232 women from EPISONO 2007, an epidemiological study from São Paulo city, Brazil. Women were distributed into menstruating (N = 61) and non‐menstruating groups (N = 171). We applied questionnaires related to sleep quality, sleepiness, insomnia, fatigue, anxiety and depression symptoms, and quality of life. The serum levels of interleukin 6, tumour necrosis factor‐alpha, and C‐reactive protein were analysed. For statistical analysis the significance level adopted was p < 0.05. Sleep efficiency was statistically lower in menstruating women (81% ± 13) compared with the non‐menstruating group (84.2% ± 13.3, p < 0.023). No statistical differences between the two groups were found in respect to the other parameters analysed. Both groups scored for fatigue symptoms, but no statistical significance was observed between the groups. Our findings indicate that menstruation was associated with lower objective sleep efficiency, suggesting that menstruation may be a physiological factor impairing sleep. Further studies evaluating menstrual variables, and each phase of the menstrual cycle, should be undertaken to detect the main factors associated with sleep complaints, fatigue, and objective parameters of sleep. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Adolescents exposed to victimization are at an increased risk for a variety of adverse mental health outcomes, including depressive symptoms. Yet, the biological pathways underlying these associations remain poorly understood. Focusing on within‐person processes, we examined whether low‐grade systemic inflammation mediated the longitudinal associations between peer victimization and depressive symptoms in adolescence.207 adolescents (at baseline Mage = 12.69 years; SD = 0.49; 43.5% female) participated in a multi‐wave longitudinal study, with assessments repeated every 6 months over 1.5 years. At each assessment wave, participants self‐reported their peer victimization experiences and depressive symptoms. Dried blood spots were collected at each wave using a finger prick procedure to assay a key marker of low‐grade systemic inflammation, interkeukin‐6 (IL‐6). Data were analyzed using random‐intercept cross‐lagged panel models.The cross‐lagged paths from IL‐6 to depressive symptoms were significant across all models and waves (β12 = .13; β23 = .12; β34 = .08), indicating that when adolescents' levels of low‐grade systemic inflammation were above their person‐specific average, they reported increased levels of depressive symptoms in the subsequent months. However, no significant cross‐lagged within‐person associations emerged between peer victimization and either IL‐6 or depressive symptoms.The findings provide no evidence for the hypothesized mediating role of inflammation in the within‐person associations between peer victimization and depressive symptoms. Nevertheless, they extend prior research by indicating that elevated levels of low‐grade systemic inflammation predict the development of depressive symptoms in adolescence. [ABSTRACT FROM AUTHOR]

Cancer detection and inflammation monitoring during photothermal therapy (PTT) enable timely cancer intervention and precise inflammation control, advancing to address inflammation‐related tumor recurrence and metastasis associated with PTT. This can be achieved through real‐time monitoring biomarker for cancer and inflammation, like hypochlorous acid (HOCl), a highly reactive oxygen species (hROS) in body with elevated levels in inflammation. Here, a HOCl‐responsive theranostic nanoprobe is introduced, AuNRs@SiO2‐CAA for ratiometric photoacoustic (PA) cancer detection and inflammation monitoring during PTT. AuNRs@SiO2‐CAA emits PA signals at 680 and 820 nm, with only PA680 undergoing changes in the presence of HOCl, enabling precise HOCl imaging via recording changes of ratiometric PA signals (PA680/PA820). AuNRs@SiO2‐CAA exhibits high selectivity and sensitivity, with a detection limit of 0.34 µM for ratiometric PA imaging of HOCl. In vivo, it effectively detects tumor, drives PTT, and monitors inflammation during PTT by sensing HOCl. The successful development of AuNRs@SiO2‐CAA offers a novel theranostic nanoprobe system for cancer diagnosis, poised to enhance PTT through precise inflammation control. [ABSTRACT FROM AUTHOR]

Background Materials and Methods Results Conclusions α‐1 blockers and dutasteride are widely used as agents to treat benign prostatic hyperplasia (BPH); the impact of these drugs on prostatic inflammation is still unclear. Herein, we investigated the impact of α‐1 blockers and dutasteride treatment of BPH in terms of the degree of prostatic inflammation.Tissue specimens were obtained from 143 BPH patients who were administered α‐1 blockers up until their operation. Thirty‐three of the patients had also been treated with dutasteride before the procedure. The degree of prostatic inflammation was quantified histologically by the ratio of high endothelial venule (HEV)‐like vessels. We divided this retrospective cohort into α‐1 blocker monotherapy and combination therapy (α‐1 blockers + dutasteride) groups and evaluated clinical parameters of the two groups in relation to the degree of chronic prostatic inflammation. At the same time, we assessed factors exacerbating chronic prostatic inflammation.Comparison of the monotherapy and combination therapy groups showed no significant differences in the parameters of the urodynamic study or degree of chronic prostatic inflammation, whereas the IPSS total score, voiding subscore, nocturia, intermittency, weak stream, and straining were significantly lower in the combination than the monotherapy group. The duration of α‐1 blockers administration was not correlated with the ratio of HEV‐like vessels, while that of dutasteride was strongly correlated (correlation coefficient = 0.595; p < 0.001). Multiple regression analysis demonstrated that the duration of dutasteride administration was a key factor exacerbating the degree of chronic prostatic inflammation.The present study showed that despite their ameliorating effect on prostatic hyperplasia, dutasteride contributed significantly to chronic prostatic inflammation. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Design Setting Population Methods Main Outcome Measures Results Conclusions To identify a microbial signature for endometriosis for use as a diagnostic non‐invasive biomarker.Prospective cohort pilot study.Nepean Hospital and UNSW Microbiome Research Centre, Australia.Sixty‐four age‐ and sex‐matched subjects (n = 19 healthy control (HC); n = 24 non‐endometriosis (N‐ENDO) and n = 21 confirmed endometriosis (ENDO)). All study participants, besides healthy controls, underwent laparoscopic surgical assessment for endometriosis, and histology was performed on excised lesions.Oral, stool and, vaginal samples were self‐collected at a single time point for healthy controls, and preoperatively for patients undergoing laparoscopy. Samples underwent 16S rRNA amplicon sequencing, followed by bioinformatics analysis.Compositional differences between cohorts as identified by diversity analyses, and differentially abundant microbial taxa, as identified by LEfSE analysis.The composition of the oral (adjusted p = 0.003), and stool (adjusted p = 0.042) microbiota is different between the three cohorts. Differentially abundant taxa are present within each cohort as identified by LEfSE analysis. Particularly, Fusobacterium was enriched in the oral samples of patients with moderate/severe endometriosis.Taxonomic and compositional differences were found between the microbiota in the mouth, gut and, vagina of patients with and without endometriosis and healthy controls. Fusobacterium was enriched in patients with moderate/severe endometriosis. Fusobacterium is noted as a key pathogen in periodontal disease, a common comorbidity in endometriosis. These findings suggest a role for the oral, stool and, vaginal microbiome in endometriosis, and present potential for microbial‐based treatments and the design of a diagnostic swab. [ABSTRACT FROM AUTHOR]

Chronic inflammation with progressive age, called inflammaging, contributes to the pathogenesis of cardiovascular diseases. Previously, we have shown increased vascular expression of the Carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) in aged mice and humans, presumably via mutual upregulation with the pro‐inflammatory cytokine TNF‐α. CEACAM1 is critical for aging‐associated vascular alterations like endothelial dysfunction, fibrosis, oxidative stress, and sustained inflammation and can be regarded as a main contributor to vascular inflammaging. This study was conducted to elucidate the mechanisms underlying endothelial CEACAM1 upregulation by TNF‐α in detail. Using wildtype (WT) and TNF‐α knockout (Tnf−/−) mice, we confirmed that the aging‐related upregulation of endothelial CEACAM1 critically depends on TNF‐α. The underlying mechanisms were analyzed in an endothelial cell culture model. TNF‐α time‐dependently upregulated CEACAM1 in vitro. In pharmacological experiments, we identified an early NF‐κB‐ and a delayed β‐catenin‐mediated response. Involvement of β‐catenin was further substantiated by siRNA‐mediated knockdown of the β‐catenin‐targeted transcription factor TCF4. Both signaling pathways acted independent from each other. Elucidating the delayed response, co‐immunoprecipitation analysis revealed release of β‐catenin from adherens junctions by TNF‐α. Finally, TNF‐α activated Akt kinase by increasing its Ser473 phosphorylation. Consequently, Akt kinase facilitated β‐catenin signaling by inhibiting its degradation via phosphorylation of GSK3β at Ser9 and by increased phosphorylation of β‐catenin at Ser552 that augments its transcriptional activity. Taken together, our study provides novel mechanistic insights into the aging‐related, inflammation‐mediated endothelial upregulation of CEACAM1. Beyond the pathogenesis of cardiovascular diseases, these findings may be significant to all fields of inflammaging. [ABSTRACT FROM AUTHOR]

Enteric glia are a heterogeneous population of peripheral glia within the enteric nervous system and play pivotal roles in gut homeostasis, tissue integrity, coordination of motility, and intestinal immune responses. Under physiological conditions, they communicate with enteric neurons to control intestinal motility. In contrast, enteric glia undergo reactive changes in response to inflammatory signals during enteric neuroinflammation and participate in immune control. In this state, these glia are called reactive enteric glia, which promote cytokine and chemokine secretion and perpetuate immune cell recruitment, thereby affecting disease progression. Interestingly, reactive glia exhibit a huge plasticity and adapt to or shape the immune environment towards a resolving phenotype during inflammation and neuropathies. Recent studies revealed a bidirectional communication between enteric glia and resident and infiltrating immune cells under healthy conditions and in the context of inflammation‐based intestinal disorders and neuropathies. While recent reviews give a superb general overview of enteric glial reactivity, we herein discuss the latest evidence on enteric glial reactivity in two prominent inflammatory conditions: acute postoperative inflammation, resulting in postoperative ileus, and chronic inflammation in inflammatory bowel diseases. We define their plasticity during inflammation and the interplay between reactive enteric glia and intestinal macrophages. Finally, we sketch important questions that should be addressed to clarify further the impact of enteric glial reactivity on intestinal inflammation. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Angiogenesis is a pathological component of neovascular age‐related macular degeneration. Current therapies, although successful, are prone to high levels of patient non‐response and a loss of efficacy over time, indicating the need to explore other therapeutic avenues. We have shown that an interaction between syndecan‐2 and the tyrosine phosphatase receptor CD148 (RTP Type J) results in the ablation of angiogenesis. Here we exploit this pathway to develop a peptide activator of CD148 as a therapy for neovascular age‐related macular degeneration.We tested a peptide (QM107) derived from syndecan‐2 in a variety of angiogenesis models and a pre‐clinical model of neovascular age‐related macular degeneration. We assessed the toxicological and inflammatory profiles of QM107 and its stability in vitreous humour.QM107 inhibits angiogenesis in ex vivo sprouting assays and disrupts endothelial microcapillary formation via inhibition of cell migration. QM107 acts through CD148, leading to changes in GSK3A phosphorylation and β1 integrin activation. QM107 elicits a negligible inflammatory response and exhibits limited toxicity in cultured cells, and is stable in vitreous humour. Finally, we show proof of concept that QM107 blocks angiogenesis in vivo using a model of neovascular age‐related macular degeneration.We have developed a CD148 activating peptide which shows promise in inhibiting angiogenesis in models of neovascular age‐related macular degeneration. This treatment could either represent an alternative or augment existing therapies, and owing to its distinct mode of action be used in patients who do not respond to existing treatments. [ABSTRACT FROM AUTHOR]

Vitex trifolia L. is widely used as a traditional medicine owing to its secondary metabolites. This study aimed to determine the phytochemical profiling of the ethanolic extract of V. trifolia leaves (EEVL). Additionally, biological activities were investigated, supported by molecular docking studies. The total flavonoid and phenolic contents of the EEVL were 35.25 ± 0.13 mg QE/g extract and 39.55 ± 1.43 mg GAE/g extract, respectively. The EEVL exhibits anti‐inflammatory activity with a half‐maximal inhibitory concentration (IC50) value of 153.59 µg/mL. The antioxidant activity of the EEVL exhibited an IC50 value of 20.41 ± 0.08 µg/mL with the 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) radical scavenging method, a half‐maximal effective concentration value of 80.85 ± 0.39 µg/mL with the cupric‐reducing antioxidant capacity (CUPRAC) method, and a capacity of 180.58 mg QE/g extract with the ferric‐reducing antioxidant power (FRAP) method. At 16% concentration, the EEVL exhibited an antibacterial activity against some pathogenic bacteria. Molecular docking studies reported that casticin interacts with sodium diclofenac similarly toward 1PXX. However, artemitin exhibited better affinity toward 1HD2 than ascorbic acid. Thus, the EEVL has significant potential as a natural source for treating various diseases related to inflammation, oxidation, and infection. Moreover, screening of its active compounds is necessary for further exploration. [ABSTRACT FROM AUTHOR]

ABSTRACT Fermented and aged mountain‐cultivated ginseng sprouts (FAMCGS) exhibit superior antioxidant and anti‐inflammatory properties compared to mountain‐cultivated ginseng sprouts (MCGS). However, the mechanisms behind these properties of FAMCGSE remain unclear. This study explores the anti‐inflammatory effects of FAMCGS extract (FAMCGSE) on LPS‐stimulated RAW 264.7 macrophages and the underlying mechanisms. The MTT assay confirmed that FAMCGSE (0 to 0.1%) maintained cell viability without inducing morphological changes. Pretreatment with FAMCGSE significantly mitigated LPS‐induced morphological alterations dose‐dependently. RT‐PCR and Western blot analyses showed that FAMCGSE significantly reduced the mRNA and protein levels of proinflammatory mediators such as TNF‐α, IL‐1β, IL‐6, iNOS, and COX‐2. Additionally, FAMCGSE decreased the production of TNF‐α, IL‐1β, IL‐6, nitric oxide, and PGE2 in LPS‐activated RAW264.7 cells. Mechanistically, FAMCGSE inhibited the phosphorylation of mitogen‐activated protein kinases (MAPKs; ERK, p38, and JNK) and prevented the LPS‐induced nuclear translocation of NF‐κB, with effects comparable to compound K (CK) or dexamethasone. Notably, FAMCGSE was particularly effective in inhibiting ERK and JNK activation, with less impact on p38, suggesting a specific inhibitory action on certain MAPK pathways. These findings highlight FAMCGSE's potential as an inhibitor of MAPK and NF‐κB pathways, indicating that FAMCGSE, including its main component CK, may be a promising therapeutic agent for inflammation‐related conditions. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion 2,3‐bisphosphoglycerate mutase (BPGM) is traditionally recognized for its role in modulating oxygen affinity to hemoglobin in erythrocytes. Recent transcriptomic analyses, however, have indicated a significant upregulation of BPGM in acutely injured murine and human kidneys, suggesting a potential renal function for this enzyme. Here we aim to explore the physiological role of BPGM in the kidney.A tubular‐specific, doxycycline‐inducible Bpgm‐knockout mouse model was generated. Histological, immunofluorescence, and proteomic analyses were conducted to examine the localization of BPGM expression and the impact of its knockout on kidney structure and function. In vitro studies were performed to investigate the metabolic consequences of Bpgm knockdown under osmotic stress.BPGM expression was localized to the distal nephron and was absent in proximal tubules. Inducible knockout of Bpgm resulted in rapid kidney injury within 4 days, characterized by proximal tubular damage and tubulointerstitial fibrosis. Proteomic analyses revealed involvement of BPGM in key metabolic pathways, including glycolysis, oxidative stress response, and inflammation. In vitro, Bpgm knockdown led to enhanced glycolysis, decreased reactive oxygen species elimination capacity under osmotic stress, and increased apoptosis. Furthermore, interactions between nephron segments and immune cells in the kidney suggested a mechanism for propagating stress signals from distal to proximal tubules.BPGM fulfills critical functions beyond the erythrocyte in maintaining glucose metabolism in the distal nephron. Its absence leads to metabolic imbalances, increased oxidative stress, inflammation, and ultimately kidney injury. [ABSTRACT FROM AUTHOR]

Key points The present study was designed to test the potential utility of regional cerebral oxygen saturation (rcSO2) in detecting term infants with brain injury. The study also examined whether quantitative rcSO2 features are associated with grade of hypoxic ischaemic encephalopathy (HIE). We analysed 58 term infants with HIE (>36 weeks of gestational age) enrolled in a prospective observational study. All newborn infants had a period of continuous rcSO2 monitoring and magnetic resonance imaging (MRI) assessment during the first week of life. rcSO2 Signals were pre‐processed and quantitative features were extracted. Machine‐learning and deep‐learning models were developed to detect adverse outcome (brain injury on MRI or death in the first week) using the leave‐one‐out cross‐validation approach and to assess the association between rcSO2 and HIE grade (modified Sarnat – at 1 h). The machine‐learning model (rcSO2 excluding prolonged relative desaturations) significantly detected infant MRI outcome or death in the first week of life [area under the curve (AUC) = 0.73, confidence interval (CI) = 0.59−0.86, Matthew's correlation coefficient = 0.35]. In agreement, deep learning models detected adverse outcome with an AUC = 0.64, CI = 0.50−0.79. We also report a significant association between rcSO2 features and HIE grade using a machine learning approach (AUC = 0.81, CI = 0.73−0.90). We conclude that automated analysis of rcSO2 using machine learning methods in term infants with HIE was able to determine, with modest accuracy, infants with adverse outcome. De novo approaches to signal analysis of NIRS holds promise to aid clinical decision making in the future. Hypoxic‐induced neonatal brain injury contributes to both short‐ and long‐term functional deficits. Non‐invasive continuous monitoring of brain oxygenation using near‐infrared‐ spectroscopy offers a potential new insight to the development of serious injury. In this study, characteristics of the NIRS signal were summarised using either predefined features or data‐driven feature extraction, both were combined with a machine learning approach to predict short‐term brain injury. Using data from a cohort of term infants with hypoxic ischaemic encephalopathy, the present study illustrates that automated analysis of regional cerebral oxygen saturation rcSO2, using either machine learning or deep learning methods, was able to determine infants with adverse outcome. [ABSTRACT FROM AUTHOR]

Summary The NLRP3 inflammasome is a multiprotein complex that upon activation by the innate immune system drives a broad inflammatory response. The primary initial mediators of this response are pro‐IL‐1β and pro‐IL‐18, both of which are in an inactive form. Formation and activation of the NLRP3 inflammasome activates caspase‐1, which cleaves pro‐IL‐1β and pro‐IL‐18 and triggers the formation of gasdermin D pores. Gasdermin D pores allow for the secretion of active IL‐1β and IL‐18 initiating the organism‐wide inflammatory response. The NLRP3 inflammasome response can be beneficial to the host; however, if the NLRP3 inflammasome is inappropriately activated it can lead to significant pathology. While the primary components of the NLRP3 inflammasome are known, the precise details of assembly and activation are less well defined and conflicting. Here, we discuss several of the proposed pathways of activation of the NLRP3 inflammasome. We examine the role of subcellular localization and the reciprocal regulation of the NLRP3 inflammasome by autophagy. We focus on the roles of mitochondria and mitophagy in activating and regulating the NLRP3 inflammasome. Finally, we detail the impact of pathologic NLRP3 responses in the development and manifestations of pulmonary disease. [ABSTRACT FROM AUTHOR]

Hypertension drives the development of concentric left ventricular hypertrophy (LVH). However, the relative contribution of pentraxin‐3 (PTX‐3), a novel marker for inflammatory cardiovascular disease, in the hypertrophic response to pressure overload has not been adequately elucidated. We investigated the role of PTX‐3 in the development of LVH in spontaneously hypertensive rats (SHR), untreated and treated with either captopril (an ACE inhibitor) or hydralazine (a non‐specific vasodilator). Three‐month‐old SHR received either 20 mg/kg/day hydralazine (SHR + H, n = 6), 40 mg/kg/day captopril (SHR + C, n = 6), or plain gelatine cubes (untreated SHR, n = 7) orally for 4 months. Wistar Kyoto rats (WKY, n = 7) were used as the normotensive controls. Blood pressure (BP) was measured using the tail‐cuff method. Cardiac geometry and function were determined using M‐mode echocardiography. Circulating concentrations of inflammatory markers were measured in plasma by ELISA. LV fibrosis and cardiomyocyte width were assessed by histology. Relative mRNA expression of PTX‐3 was determined in the LV by RT‐PCR. Untreated SHR exhibited greater systolic BP and relative wall thickness (RWT) compared to WKY. Captopril and hydralazine normalized BP but only captopril reversed RWT in SHR. Circulating PTX‐3 and VCAM‐1 levels were elevated in untreated SHR and reduced with captopril and hydralazine. Circulating PTX‐3 was positively associated with systolic BP but lacked independent relations with indices of LVH. LV relative mRNA expression of PTX‐3 was similar between the groups. PTX‐3 may not be involved in the development of LVH in SHR, but plausibly reflects the localized inflammatory milieu associated with hypertension. [ABSTRACT FROM AUTHOR]

Goto‐Kakizaki (GK) rats develop a well‐defined insulin resistance (IR) and type 2 diabetes mellitus (T2DM) without presenting obesity. The lymphocyte profile in nonobese diabetic conditions is not yet characterized. Therefore, GK rats were chosen to explore T lymphocyte (TL) dynamics at various stages (21, 60, and 120 days) compared to Wistar rats. GK rats exhibit progressive disruption of glucose regulation, with early glucose intolerance at 21 days and reduced insulin sensitivity at 60 days, confirming IR. Glucose transporter 1 (GLUT1) expression was consistently elevated in GK rats, suggesting heightened TL activation. T‐regulatory lymphocyte markers diminished at 21 days. However, GK rats showed increased Th1 markers and reduced Gata‐3 expression (crucial for Th2 cell differentiation) at 120 days. These findings underscore an early breakdown of anti‐inflammatory mechanisms in GK rats, indicating a proinflammatory TL profile that may worsen chronic inflammation in T2DM. [ABSTRACT FROM AUTHOR]

The intestine is populated by a complex and dynamic assortment of microbes, collectively called gut microbiota, that interact with the host and contribute to its metabolism and physiology. Diet is considered a key regulator of intestinal microbiota, as ingested nutrients interact with and shape the resident microbiota composition. Furthermore, recent studies underscore the interplay of dietary and microbiota‐derived nutrients, which directly impinge on intestinal stem cells regulating their turnover to ensure a healthy gut barrier. Although advanced sequencing methodologies have allowed the characterization of the human gut microbiome, mechanistic studies assessing diet–microbiota–host interactions depend on the use of genetically tractable models, such as Drosophila melanogaster. In this review, we first discuss the similarities between the human and fly intestines and then we focus on the effects of diet and microbiota on nutrient‐sensing signaling cascades controlling intestinal stem cell self‐renewal and differentiation, as well as disease. Finally, we underline the use of the Drosophila model in assessing the role of microbiota in gut‐related pathologies and in understanding the mechanisms that mediate different whole‐body manifestations of gut dysfunction. [ABSTRACT FROM AUTHOR]

Pre‐clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth. These anti‐oncogenic effects of exercise were associated with the exercise‐mediated release of myokines such as interleukin (IL)‐15. However, no study has quantified the acute IL‐15 response in human cancer survivors, and whether physiological adaptations to exercise training (i.e. body composition and cardiorespiratory fitness) influence this response. In the present study breast, prostate and colorectal cancer survivors (n = 14) completed a single bout of high‐intensity interval exercise (HIIE) [4×4 min at 85–95% heart rate (HR) peak, 3 min at 50–70% HR peak] before and after 7 months of three times weekly high‐intensity interval training (HIIT) on a cycle ergometer. At each time point venous blood was sampled before and immediately after HIIE to assess the acute myokine (IL‐15, IL‐6, IL‐10, IL‐1ra) responses. Markers of inflammation, cardiorespiratory fitness and measures of body composition were obtained at baseline and 7 months. An acute bout of HIIE resulted in a significant increase in IL‐15 concentrations (pre‐intervention: 113%; P = 0.013, post‐intervention: 102%; P = 0.005). Post‐exercise IL‐15 concentrations were associated with all other post‐exercise myokine concentrations, lean mass (P = 0.031), visceral adipose tissue (P = 0.039) and absolute V̇O2${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ peak (P = 0.032). There was no significant effect of 7 months of HIIT on pre‐ or post‐HIIE IL‐15 concentrations (P > 0.05). This study demonstrates HIIE is a sufficient stimulus to increase circulating IL‐15 and other myokines including IL‐6, IL‐10 and IL‐1ra which may be clinically relevant in the anti‐oncogenic effect of exercise and repetitive exposure to these effects may contribute to the positive relationship between exercise and cancer recurrence. Key points: Exercise has been demonstrated to reduce the risk of cancer recurrence.Pre‐clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth, mediated by exercise‐induced myokines (IL‐6 and IL‐15).High‐intensity interval exercise significantly increased myokines associated with the anti‐oncogenic effect of exercise and the magnitude of response was associated with lean mass, but training did not appear to influence this response.Given IL‐15 has been implicated in the anti‐oncogenic effect of exercise and is being explored as an immunotherapy agent, high‐intensity interval exercise may improve outcomes for people living beyond cancer through IL‐15‐mediated pathways.Interventions that increase lean mass may also enhance this response. [ABSTRACT FROM AUTHOR]

Folate (FT) is a suitable targeting ligand for folate receptors (FOLR) overexpressed on inflamed cells. Thus, FT‐loaded polymers can be used as FOLRs‐targeted immunotherapy to positively modulate the inflammatory process. A novel biodegradable imprinted polymer with a FT delivery mechanism driven by pH changes [PCL‐MIP@FT] is designed with molecularly imprinted technology. The pH mechanism is validated in vitro, demonstrating that an acidic environment accelerated and increased the release of FT for a period of 7 days (∼100 µg mL−1). For the first time, FT receptors (FOLR‐1 and FOLR‐3) are discovered and also overexpressed on activated human gingival fibroblasts, representing a favorable target in the oral environment. Although FT itself does not have antimicrobial effects, the nanomechanical properties of biofilm are changed after topical FT administration. In vivo systemic toxicity of PCL‐MIP@FT has been demonstrated to be a safe biomaterial (up to 1.3 mg kg−1). When the PCL‐MIP@FT is assessed in the subcutaneous tissue, it promoted an alleviating inflammation and may be able to stimulate tissue repair. The present findings have demonstrated the reliable in vitro and in vivo anti‐inflammatory actions of FT‐loaded polymer and support its use as a novel drug‐free therapeutic platform for modulating and mitigating inflammatory responses in dental implant‐related infections. [ABSTRACT FROM AUTHOR]

Neutrophil extracellular traps (NETs) are highly associated with inflammatory response and vascular injury after ischemic stroke. As the primary degrader of NETs, DNase 1 is limited by easy deactivation and low efficiency of crossing the blood‐brain barrier (BBB). Here, CD206+ M2‐like macrophages‐derived exosomal (M2exo) system is developed for DNase 1 delivery to achieve enhanced ischemic stroke therapy. The nanoplatform can cross the BBB through transcytosis of exosomes, subsequently clearing NETs by DNase 1 to inhibit inflammatory factors release and prevent vascular injury. Moreover, M2exo induces the polarization of M1 microglia to M2 phenotype, alleviating neuroinflammation via producing anti‐inflammatory cytokines. This nanoplatform exhibits significant efficiency in reducing brain infarct area, improving long‐term neurologic outcomes, and promoting BBB remodeling. The mechanism for the synergistic effect from M2exo and DNase 1 is unveiled at the genetic level through transcriptome analysis. This work provides a paradigm for improving the effectiveness of ischemic stroke therapy. [ABSTRACT FROM AUTHOR]

Two novel ibuprofen cystamine salts (IBU‐CYS 1 and IBU‐CYS 2) are synthesized by coupling the anion of ibuprofen with cystamine dihydrochloride in 1 : 1 and 2 : 1 ratio to improve the solubility and bioavailability of ibuprofen. The salts are characterized by 1H NMR, FT‐IR and UV‐Vis spectroscopy, differential scanning calorimetry (DSC), thermogravimetry (TGA, DTA) and X‐ray diffraction measurements. IBU‐CYS 1 and IBU‐CYS 2 show higher solubility (6.11 and 7.81 mg/mL) compared to ibuprofen (0.04 mg/mL) in water. IBU‐CYS2 was encapsulated into 2‐hydroxyethyl methacrylate: poly (ethylene glycol) acrylate hydrogels for enhanced delivery. The in vitro studies in PBS (pH 7.4) indicate that the salts are effective in relieving inflammatory responses induced by lipopolysaccharide in RAW264.7 macrophage cells (nitrite inhibition percentages of IBU‐CYS 1, IBU‐CYS 2 and ibuprofen: approximately 34.29, 27.03 and 31.50 respectively) while indicating no cytotoxicity. Therefore, these salts may be promising candidates for the development of effective formulations of this drug. [ABSTRACT FROM AUTHOR]

Background and Purpose: Depression is closely linked with microglial activation and neuro‐inflammation. Peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) plays an important role in M2 activation of microglia. Forkhead box (FOX) O3a has been implicated in the regulation of mood‐relevant behaviour. However, little is known about the inflammatory mechanisms of in the microglia of the brain. Here, we have investigated the role of microglial FOXO3a/PPAR‐γ in the development of depression. Experimental Approach: The effect of FOXO3a on microglia inflammation was analysed in vitro and in lipopolysaccharide (LPS)‐induced depression‐like behaviours in vivo. ChIP‐seq and Dual‐luciferase reporter assays were used to confirm the interaction between FOXO3a and PPAR‐γ. Behavioural changes were measured, while inflammatory cytokines, microglial phenotype and morphological properties were determined by ELISA, qRT‐PCR, western blotting and immunostaining. Key Results: Overexpression of FOXO3a significantly attenuated expression of PPAR‐γ and enhanced the microglial polarization towards the M1 phenotype, while knockdown of FOXO3a had the opposite effect. FOXO3a binds to the promoters of PPAR‐γ and decreases its transcription activity. Importantly, deacetylation and activation of FOXO3a regulate LPS‐induced neuro‐inflammation by inhibiting the expression of PPAR‐γ in microglia cells, supporting the antidepressant potential of histone deacetylase inhibitors. Microglial FOXO3a deficiency in mice alleviated LPS‐induced neuro‐inflammation and depression‐like behaviours but failed to reduce anxiety behaviour, whereas pharmacological inhibition of PPAR‐γ by GW9662 restored LPS‐induced microglial activation and depressive‐like behaviours in microglial FOXO3a‐deficient mice. Conclusion and Implications: FOXO3a/PPAR‐γ axis plays an important role in microglial activation and depression, identifying a new therapeutic avenue for the treatment of major depression. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Non‐selective beta‐blockers (NSBB) are a well‐established treatment in patients with clinically significant portal hypertension. However, their potential role after insertion of a transjugular intrahepatic portosystemic shunt (TIPS) still needs to be determined. Of note, recent studies suggested that favourable anti‐inflammatory effects of NSBB might be independent from pressure reduction. This study aimed to evaluate whether NSBB‐treatment is associated with amelioration of systemic inflammation (SI), hepatic decompensation and survival after TIPS‐insertion. Methods: In a retrospective study comprising 305 consecutive patients, we investigated the impact of NSBB‐intake at TIPS‐placement on periinterventional cirrhosis‐associated complications and continued NSBB‐treatment after discharge on complications including hepatic decompensation and mortality during 1‐year follow‐up, employing multivariable competing‐risk‐analyses. In a prospective cohort including 45 patients, we performed a comprehensive analysis of SI analysing 48 soluble inflammatory markers (SIMs) at baseline plus 3 and 6 months after TIPS‐insertion. Results: Overall, 175 (57.4%) patients received NSBB‐therapy prior to TIPS‐insertion; upon discharge, this decreased to 131 (22.9%), with 36 (27.5%) discontinuing NSBB within 1‐year follow‐up. Neither NSBB‐therapy at TIPS‐insertion nor treatment‐continuation after discharge were associated with lower risks for hepatic decompensation, individual cirrhosis‐associated complications or mortality neither in the periinterventional period nor during follow‐up. Similarly, in the prospective cohort NSBB‐intake was not linked to lower levels or a more prominent change of WBC, CRP or any other SIM at any of the investigated time points. Conclusion: NSBB‐therapy at the time of TIPS‐insertion and its (dis‐)continuation afterwards seems to have no significant impact on SI, development of hepatic decompensation and survival. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the relationship between the amount of ultra‐processed food (UPF) in the diet and low‐grade inflammation in children. This cross‐sectional study was conducted in 50 healthy children recruited from children attending the Social Paediatrics Outpatient Clinic for follow‐up of normal developmental stages. Low‐grade inflammation was calculated by INFLA‐score, dietary intake by three 24‐h dietary recalls and dietary content analyses by BeBiS™ software. The mean age of the 50 children included in our study was 10.18 ± 3.98 years (5–17 years). UPF accounted for 24.5% of the total daily energy intake of children. In children with higher inflammation scores (INFLA‐score ≥ 2), the amount in grams of UPF and the percentage of total energy from UPF were found to be significantly higher (p = 0.030 and p = 0.015, respectively). A weak positive correlation was found between the INFLA‐score and the percentage of daily dietary energy intake coming from UPFs (r = 0.350, p < 0.01), the average daily energy intake from UPFs (r = 0.313, p < 0.05), and the average daily amount of UPF consumed (r = 0.260, p < 0.05). The linear regression model revealed that every one‐unit increase (1%) in the percentage of total daily energy intake coming from UPF caused an increase in β = 0.154‐unit in the INFLA‐score. It was found that obesity was not a mediator in the association between the percentages of total energy intake from UPF on the INFLA‐score, instead, the energy intake from UPF had a significant direct association with the INFLA‐score. The average amount of UPF consumed daily showed an increasing pattern in parallel with inflammation‐score quartile classes (Q1 to Q4) with 33.3% in Q1, 38.5% in Q2, 53.8% in Q3 and 66.7% in Q4 (p = 0.049). In conclusion, a positive association was found between low‐grade inflammation and UPF consumption in children, independent of obesity. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) represents a severe neurological condition often coupled with a drastic secondary inflammatory response, which further exacerbates the damage in most cases. Due to their unique electrical and mechanical compatibilities with the spinal cord, the utilization of conductive hydrogels through injection for SCI repair, particularly in scenarios involving non‐uniform and large gaps, has emerged as a promising approach. Herein, leveraging the acidic microenvironment characteristic of acute SCI sites, an injectable conductive hydrogel with pH‐responsive immunoregulation is engineered for SCI repair. Based on the dynamic Schiff base chemistry and covalent photo‐crosslinking, this composite hydrogel, composed of gelatin methacryloyl, oxidized dextran, and MoS2, exhibits adjustable mechanical and conductive properties, enabling a customized match with the natural spinal cord's attributes. Additionally, the incorporation of Wnt5a and its selective release in acidic conditions prompt the immediate suppression of inflammatory factors and enhances neural differentiation and regeneration. In the 2‐mm hemisection mouse SCI model, the optimized conductive hydrogel can effectively bridge the injury gap, establish nerve connections and signal, mitigate inflammatory response, and promoted recovery of mobility. This novel injectable conductive hydrogel system offers a promising advance in therapeutic materials for SCI repair. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusion This study aimed to investigate the relationship between advanced lung cancer inflammation index (ALI) and non‐alcoholic fatty liver disease (NAFLD) and advanced liver fibrosis (AF).A total of 5642 individuals from the National Health and Nutrition Examination Survey (NHANES) between 2017 and 2020 were examined. Limited cubic spline regression model, and weighted logistic regression were employed to determine if ALI levels were related to the prevalence of NAFLD and AF. Additionally, a mediating analysis was conducted to investigate the role of lipid biomarkers, such as total cholesterol (TC) and high‐density lipoprotein cholesterol (HDL‐C), in the effects of ALI on the prevalence of NAFLD and AF.After adjusting for potential confounders, a significant positive association was found between ALI with NAFLD and AF prevalence. Compared with those in ALI Tertile 1, participants in Tertile 3 had higher odds of NAFLD prevalence (odds ratio [OR]: 3.16; 95% confidence interval [CI]: 2.52–3.97) and AF (OR: 3.17; 95% CI: 2.30–4.36). Participants in both Tertile 2 and Tertile 3 had lower odds of developing AF (P for trend = 0.005). Moreover, we discovered a nonlinear association between ALI and NAFLD. An inflection point of 74.25 for NAFLD was identified through a two‐segment linear regression model. Moreover, TC and HDL‐C levels mediated the association between ALI and NAFLD by 10.2% and 4.2%, respectively (both P < 0.001).Our findings suggest that higher ALI levels are positively associated with an increased prevalence of NAFLD and AF, partly mediated by lipid biomarkers. [ABSTRACT FROM AUTHOR]

Infection and subsequent inflammatory processes negatively impact prognosis in individuals with traumatic brain injury (TBI). Tissue repair following TBI is tightly regulated by microglia, promoting or, importantly, preventing astrocyte‐mediated repair processes, depending on the activation state of the neuroimmune cells. This study investigated the poorly understood mechanism linking proinflammatory microglia activation and astrocyte‐mediated tissue repair using an in vitro mechanical injury model in mixed cortical cultures of rat neurons and glia. We hypothesized that proinflammatory activation disrupts the microglial response to colony‐stimulating factor 1 (CSF‐1), which stimulates microglia migration and proliferation, both essential for astrocyte‐mediated tissue repair. Following mechanical damage, cultures were treated with lipopolysaccharide (LPS) and interferon‐gamma (IFNγ) to induce a proinflammatory state. Immunocytochemical and biochemical analyses were used to evaluate glial repair. Proinflammatory activation dramatically impeded wound closure, reducing microglial levels via upregulation of the zinc‐dependent disintegrin and metalloprotease 17 (ADAM17), leading to the cleavage of the CSF‐1 receptor (CSF‐1R). Indeed, pharmacological inhibition of ADAM17 effectively promoted wound closure during inflammation. Moreover, zinc chelation prevented ADAM17‐mediated cleavage of CSF‐1R and induced the release of trophic factors, dramatically improving tissue recovery. Our findings strongly identify ADAM17 as a primary regulator of CSF‐1R‐mediated signaling and establish a mechanism defining the association between pro‐inflammatory microglial activation and tissue repair following injury. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Allergic contact dermatitis (ACD) is a dermal inflammatory disease caused by allergic reactions to substances that contact the skin. The hyperactivation of T cells plays an important role in its pathogenesis. Photobiomodulation (PBM) is an efficacious therapeutic approach for suppressing inflammatory diseases.This study aimed to evaluate the potentially beneficial role of PBM in ACD models and investigate its possible mechanisms.In this study, the ACD model of C57BL/6 mice was produced and treated with PBM, and the number of T cells was evaluated. In an in vitro study, naïve T cells were isolated and intervened with PBM. The markers of T cell activation were detected by flow cytometer. Transforming growth factor‐β (TGF‐β) and reactive oxygen species (ROS) were detected to investigate the mechanism.PBM effectively inhibited the inflammatory response by impeding the number of T cells in the ACD model. And in vitro studies showed that PBM could directly moderate the activation of naïve T cells and possess the capability to impede T cell activation via TGF‐beta signaling pathway.Our finding elucidates the potential mechanism underlying the inhibitory effects of PBM in inflammatory diseases and furnishes a theoretical foundation for its clinical application. [ABSTRACT FROM AUTHOR]

Graft‐versus‐host disease (GVHd) remains a significant challenge following allogeneic hematopoietic stem cell transplantation (HSCT). Prevention of GVHd relies mainly on the use of calcineurin inhibitors, notably ciclosporin that exhibits complex pharmacokinetics influenced by many factors including drug‐drug interactions (DDIs). Due to the downregulation of drug metabolizing enzymes and transporters, it has been postulated that inflammation may be a contributing factor to the variability observed in ciclosporin pharmacokinetics.This study aimed to assess the impact of inflammation, as indicated by C‐reactive protein (CRP) levels, on the metabolism of ciclosporin in adult allogeneic HSCT recipients. A retrospective observational study was conducted at Rennes University Hospital involving 71 adult HSCT patients. The relationship between the intensity of inflammation (no‐to‐mild, moderate, and severe), and the metabolism of ciclosporin (estimated by the concentration/dose ratio) was assessed. Severe inflammation significantly decreased the metabolism of ciclosporin, as evidenced by higher concentration/dose ratios. Thanks to the daily dose adjustment, inflammation did not influence the blood levels of ciclosporin. Interestingly, DDIs did not emerge as a significant covariate in influencing ciclosporin metabolism. This is likely because the CYP3A4 inhibitory potential of interacting drugs may be masked in HSCT patients where metabolism is already upstream downregulated by inflammation.The study highlights the intricate relationship between inflammation and ciclosporin pharmacokinetics in HSCT patients. This underscores the necessity for therapeutic monitoring and the potential adjustment of dosage strategies based on the inflammatory status. These insights could contribute to the development of more personalized, optimized, and effective management strategies for HSCT recipients. [ABSTRACT FROM AUTHOR]

The prevalence of many chronic noncommunicable diseases has been steadily rising over the past six decades. During this time, over 350,000 new chemical substances have been introduced to the lives of humans. In recent years, the epithelial barrier theory came to light explaining the growing prevalence and exacerbations of these diseases worldwide. It attributes their onset to a functionally impaired epithelial barrier triggered by the toxicity of the exposed substances, associated with microbial dysbiosis, immune system activation, and inflammation. Diseases encompassed by the epithelial barrier theory share common features such as an increased prevalence after the 1960s or 2000s that cannot (solely) be accounted for by the emergence of improved diagnostic methods. Other common traits include epithelial barrier defects, microbial dysbiosis with loss of commensals and colonization of opportunistic pathogens, and circulating inflammatory cells and cytokines. In addition, practically unrelated diseases that fulfill these criteria have started to emerge as multimorbidities during the last decades. Here, we provide a comprehensive overview of diseases encompassed by the epithelial barrier theory and discuss evidence and similarities for their epidemiology, genetic susceptibility, epithelial barrier dysfunction, microbial dysbiosis, and tissue inflammation. [ABSTRACT FROM AUTHOR]

Persistent inflammation, characterized by the intense interplay of inflammatory chemokine secretion and immune cell infiltration, is a hallmark of many skin disorders including diabetic wounds and psoriasis with inadequate therapeutic interventions. Monocyte chemotactic protein‐1 (MCP‐1) is an inflammatory chemokine that plays a key role in recruiting and polarizing monocytes into pro‐inflammatory macrophages to establish a vicious cycle that worsens the inflamed tissue microenvironment. Here, the sponge‐like microneedles (HPMN) technology is described to alleviate inflammatory skin disorders. Heparin/4‐arm PEG‐NH2 network crosslinked onto microneedle surface spatially attracted and sequestered multiple inflammatory chemokines including MCP‐1. Enrichment of MCP‐1 on microneedles recruits and traps inflammatory monocytes within the porous structure of microneedles. Subsequent removal of microneedles not only depletes inflammatory chemokine, MCP‐1, but also its cellular source. As a result, HPMN treatment facilitates 47.1% smaller open wound area in mice and 27.2% shorter wound length in pigs. To demonstrate the versatility of the HPMN technology, it is also shown that combining the method with standard‐of‐care immunosuppressants reduces 45.1% epidermis thickening and attenuated immune cell influx in a mouse psoriasis model. Overall, the HPMN technology is a novel demonstration of employing inflammatory chemokine and cell extraction to treat a broad range of inflammatory skin disorders. [ABSTRACT FROM AUTHOR]

Current therapeutic drug exploring targeting at myocardial ischemia/reperfusion (I/R) injury is limited due to the lack of humanized cardiac models that resemble myocardial damage and inflammatory response. Herein, we develop ventricular cardiac organoids from human induced pluripotent stem cells (hiPSCs) and simulate I/R injury by hypoxia/reoxygenation (H/R), which results in increased cardiomyocytes apoptosis, elevated oxidative stress, disrupted morphological structure and decreased beat amplitude. RNA‐seq reveals a potential role of type I interferon (IFN‐I) in this I/R injury model. We then introduce THP‐1 cells and reveal inflammatory responses between monocytes/macrophages and H/R‐induced ventricular cardiac organoids. Furthermore, we demonstrate Anifrolumab, an FDA approved antagonist of IFN‐I receptor, effectively decreases IFN‐I secretion and related gene expression, attenuates H/R‐induced inflammation and oxidative stress in the co‐culture system. This study advances the modelling of myocardial I/R injury with inflammatory response in human cardiac organoids, which provides a reliable platform for preclinical study and drug screening. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusions Maternal socioeconomic status (SES) is an important predictor of adverse birth outcomes and postnatal health across global populations. Chronic inflammation is implicated in cardiometabolic disease risk in high‐income contexts and is a potential pathway linking maternal adversity to offspring health trajectories. To clarify how socioeconomic inequality shapes pregnancy inflammation in middle‐income settings, we investigated SES as a predictor of inflammatory cytokines in late gestation in a sample from the Cebu Longitudinal Health Nutrition Survey in Cebu, Philippines.We used multiple regression to evaluate maternal SES, reflected in household assets, as a predictor of general inflammation (C‐reactive protein), inflammatory cytokines (interleukin‐6, interleukin‐10), and inflammatory balance (n = 407). Inflammatory markers were measured at 29.9 weeks gestation in dried blood spots, and a measure reflecting relative balance of IL6 and IL10 was calculated to capture pro‐ versus anti‐inflammatory skewed immune profiles.Greater household assets significantly predicted lower IL6 concentration (p <  0.001), with a trend toward lower IL6 relative to IL10 (p = 0.084). C‐reactive protein and IL10 were not individually related to SES.The inverse relationship between SES and pregnancy inflammation in Cebu is consistent with results from high‐income settings. These findings further highlight the influence of socioeconomic conditions on immune regulation during pregnancy. Given the evidence that gestational inflammation impacts offspring fetal growth, our results suggest that social and economic effects on immune function may be an important pathway for the intergenerational transmission of health disparities. [ABSTRACT FROM AUTHOR]

Background Results Conclusion Maintaining low concentrations of plasma low‐density lipoprotein cholesterol (LDLc) over time decreases the number of LDL particles trapped within the artery wall, slows the progression of atherosclerosis and delays the age at which mature atherosclerotic plaques develop. This substantially reduces the lifetime risk of atherosclerotic cardiovascular disease (ASCVD) events. In this context, plaque development and vulnerability result not only from lipid accumulation but also from inflammation.Changes in the composition of immune cells, including macrophages, dendritic cells, T cells, B cells, mast cells and neutrophils, along with altered cytokine and chemokine release, disrupt the equilibrium between inflammation and anti‐inflammatory mechanisms at plaque sites. Considering that it is not a competition between LDLc and inflammation, but instead that they are partners in crime, the present narrative review aims to give an overview of the main inflammatory molecular pathways linked to raised LDLc concentrations and to describe the impact of lipid‐lowering approaches on the inflammatory and lipid burden. Although remarkable changes in LDLc are driven by the most recent lipid lowering combinations, the relative reduction in plasma C‐reactive protein appears to be independent of the magnitude of LDLc lowering.Identifying clinical biomarkers of inflammation (e.g. interleukin‐6) and possible targets for therapy holds promise for monitoring and reducing the ASCVD burden in suitable patients. [ABSTRACT FROM AUTHOR]

High‐fat diet (HFD)‐induced obesity induces peripheral inflammation and hypothalamic pathogenesis linking the activation of astrocytes and microglia. Clinical evidence indicates a positive correlation between obesity and psychiatric disorders, such as depression. The connectivity of the frontal‐striatal (FS) circuit, involving the caudate putamen (CPu) and anterior cingulate cortex (ACC) within the prefrontal cortex (PFC), is known for its role in stress‐induced depression. Thus, there is a need for a thorough investigation into whether chronic obesity‐induced gliosis, characterized by the activation of astrocytes and microglia, in these brain regions of individuals with chronic obesity. The results revealed increased S100β+ astrocytes and Iba1+ microglia in the CPu and ACC of male obese mice, along with immune cell accumulation in meningeal lymphatic drainage. Activated GFAP+ astrocytes and Iba1+ microglia were observed in the corpus callosum of obese mice. Gliosis in the CPu and ACC was linked to elevated cleaved caspase‐3 levels, indicating potential neural cell death by chronic HFD feeding. There was a loss of myelin and adenomatous polyposis coli (APC)+ oligodendrocytes (OLs) in the corpus callosum, an area known to be linked with injury to the CPu. Additionally, reduced levels of aquaporin‐4 (AQP4), a protein associated within the glymphatic systems, were noted in the CPu and ACC, while ciliary neurotrophic factor (CNTF) gene expression was upregulated in these brain regions of obese mice. The in vitro study revealed that high‐dose CNTF causing a trend of reduced astrocytic AQP4 expression, but it significantly impaired OL maturation. This pathological evidence highlights that prolonged HFD consumption induces persistent FS gliosis and demyelination in the corpus callosum. An elevated level of CNTF appears to act as a potential regulator, leading to AQP4 downregulation in the FS areas and demyelination in the corpus callosum. This cascade of events might contribute to neural cell damage within these regions and disrupt the glymphatic flow. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Chronic inflammation triggers tissue remodeling in human nasal epithelial (HNE) cells. S100A9, a protein secreted by inflammatory cells, exhibits potent proinflammatory activity. However, its effect on HNE cell remodeling, such as squamous metaplasia, remains unclear. Therefore, this study aimed to determine the effects and underlying pathways of S100A9 on HNE cell remodeling and investigate its clinical implications in chronic rhinosinusitis (CRS).Cultured HNE cells were treated with S100A9. Bulk RNA sequencing was performed to analyze gene ontology (GO). Ingenuity pathway analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were also analyzed. Additionally, immunohistochemistry and multiplex immunofluorescence were performed on tissue samples obtained from 60 patients, whose clinical informations were also reviewed.GO enrichment analysis indicated that S100A9 induced tissue remodeling in HNE cells toward squamous metaplasia. IPA and KEGG commonly showed that S100A9 affected HNE cells associated with the IL‐17 signaling pathway, including target molecules such as matrix metalloproteinase 1 (MMP1) and small proline‐rich protein 2A (SPRR2A). Squamous metaplasia with a marked expression of S100A9 was observed in 50% of CRS with nasal polyps (CRSwNPs). In addition, in multiplex immunofluorescence, the S100A9 in sub‐epithelium was co‐expressed with myeloperoxidase, a neutrophil marker, and MMP1 and SPRR2A were strongly expressed in epithelial remodeling. Clinically, the expression of S100A9 correlated with sino‐nasal outcome test‐22 (r = 0.294, p = 0.022) and Lund–Mackay scores (r = 0.348, p = 0.006).S100A9 induces tissue remodeling in HNE cells. Its increased expression in CRSwNP, particularly squamous epithelium, correlates with disease severity. This suggests the clinical potential of S100A9 as a biomarker for CRS severity. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications FGF, VEGFR‐2 and CSF1R signalling pathways play a key role in the pathogenesis of multiple sclerosis (MS). Selective inhibition of FGFR by infigratinib in MOG35‐55‐induced experimental autoimmune encephalomyelitis (EAE) prevented severe first clinical episodes by 40%; inflammation and neurodegeneration were reduced, and remyelination was enhanced. Multi‐kinase inhibition of FGFR1‐3, CSFR and VEGFR‐2 by fexagratinib (formerly known as AZD4547) may be more efficient in reducing inflammation, neurodegeneration and regeneration in the disease model.Female C57BL/6J mice were treated with fexagratinib (6.25 or 12.5 mg·kg−1) orally or placebo over 10 days either from time of EAE induction (prevention experiment) or onset of symptoms (suppression experiment). Effects on inflammation, neurodegeneration and remyelination were assessed at the peak of the disease (Day 18/20 post immunization) and the chronic phase of EAE (Day 41/42).In the prevention experiment, treatment with 6.25 or 12.5 mg·kg−1 fexagratinib prevented severe first clinical episodes by 66.7% or 84.6% respectively. Mice treated with 12.5 mg·kg−1 fexagratinib hardly showed any symptoms in the chronic phase of EAE. In the suppression experiment, fexagratinib resulted in a long‐lasting reduction of severe symptoms by 91 or 100%. Inflammation and demyelination were reduced, and axonal density, numbers of oligodendrocytes and their precursor cells, and remyelinated axons were increased by both experimental approaches.Multi‐kinase inhibition by fexagratinib in a well‐tolerated dose of 1 mg·kg−1 in humans may be a promising approach to reduce inflammation and neurodegeneration, to slow down disease progression and support remyelination in patients. [ABSTRACT FROM AUTHOR]

Aim Materials and Methods Results Conclusions To investigate the independent and combined effects of muscle strength and visceral adiposity on prediabetes and type 2 diabetes incidence among midlife women.In this prospective study of midlife women (mean age 56.4 years), visceral adiposity, defined as visceral adipose tissue (VAT) >131 cm2 measured by dual energy X‐ray absorptiometry, and poor combined muscle strength, defined as handgrip strength <18 kg and/or five‐time repeated chair stand test performance ≥12 s, were determined at baseline between 2014 and 2016. After 6.6 years, the effects of VAT and muscle strength on risk of incident prediabetes (fasting blood glucose 5.6–6.9 mmol/L) and type 2 diabetes (fasting blood glucose levels ≥7 mmol/L, medication use, or physician diagnosis) were examined using modified Poisson regression analysis.Among the 733 initially normoglycaemic participants, 150 (20.5%) developed prediabetes or type 2 diabetes. Women with both poor combined muscle strength and high VAT had the highest risk for both prediabetes and type 2 diabetes (adjusted relative risk [aRR] 2.63, 95% confidence interval [CI] 1.81–3.82). In comparison, high VAT alone increased risk by 1.78‐fold (95% CI 1.12–2.84). Stratification analyses showed that among women with low muscle strength, high VAT demonstrated increased risks of prediabetes and type 2 diabetes (aRR 2.84, 95% CI 1.95–4.14) compared to those with normal strength (aRR 1.66, 95% CI 1.04–2.65).Low combined muscle strength with high VAT poses a greater risk for the development of prediabetes and type 2 diabetes than high VAT alone. Muscle strengthening should be promoted alongside weight loss in diabetes prevention. [ABSTRACT FROM AUTHOR]

Objectives: Systemic lupus erythematosus (SLE) is a chronic and severe autoimmune disease characterised by persistent inflammation. Hydroxychloroquine (HCQ) and glucocorticoids (GCs) are the primary agents commonly used in combination as the first‐line treatment for SLE. Nevertheless, the specific mechanisms responsible for the effectiveness of this combined therapy with HCQ and GCs have not been fully elucidated. This study aimed to reveal the mechanism behind combined HCQ and GC treatment in lupus. Methods: An SLE IgG‐induced inflammation model was used to investigate the anti‐inflammatory effects of HCQ and dexamethasone (DXM). A glucocorticoid‐induced osteoporosis (GIOP) model was used to investigate the inhibitory effect of HCQ on osteoclastogenesis. Inflammation was assessed by haematoxylin and eosin staining. Bone metabolism was determined structurally via microcomputer tomography and in bone marrow‐derived osteoclast cultures. Results: An SLE IgG‐induced inflammation model demonstrated that HCQ could not ameliorate inflammation alone but could enhance the anti‐inflammatory effect of GCs by decreasing the expression of FcγRI on macrophages. HCQ inhibited osteoclastogenesis induced by GCs and RANKL by upregulating nuclear factor erythroid 2‐related factor 2 and limiting reactive oxygen species formation, which mitigated GC‐induced bone loss. Conclusion: The results indicate that HCQ improved the anti‐inflammatory effects of GCs and inhibits the osteoclastogenesis in experimental lupus. This study offers valuable insights into the mechanisms underlying the combined treatment of lupus with HCQ and GCs. [ABSTRACT FROM AUTHOR]

Renowned for their role in haemostasis and thrombosis, platelets are also increasingly recognized for their contribution in innate immunity, immunothrombosis and inflammatory diseases. Platelets express a wide range of receptors, which allows them to reach a variety of activation endpoints and grants them immunomodulatory functions. Activated platelets release extracellular vesicles (PEVs), whose formation and molecular cargo has been shown to depend on receptor‐mediated activation and environmental cues. This study compared the immunomodulatory profiles of PEVs generated via activation of platelets by different receptors, glycoprotein VI, C‐type lectin‐like receptor 2 and combining all thrombin‐collagen receptors. Functional assays in vivo in zebrafish and in vitro in human macrophages highlighted distinct homing and secretory responses triggered by the PEVs. In contrast, omics analyses of protein and miRNA cargo combined with physicochemical particle characterization found only subtle differences between the activated PEV types, which were insufficient to predict their different immunomodulatory functions. In contrast, constitutively released PEVs, formed in the absence of an exogenous activator, displayed a distinct immunomodulatory profile from the receptor‐induced PEVs. Our findings underscore that PEVs are tunable through receptor‐mediated activation. To truly comprehend their role(s) in mediating platelet functions among immune cells, conducting functional assays is imperative. [ABSTRACT FROM AUTHOR]