Production Of Pro-inflammatory Mediators Research Articles

Targeting Dectin-1 and or VISTA enhances anti-tumor immunity in melanoma but not colorectal cancer model.

Acquired resistance to immune checkpoint blockers (ICBs) is a major barrier in cancer treatment, emphasizing the need for innovative strategies. Dectin-1 (gene Clec7a) is a C-type lectin receptor best known for its ability to recognize β-glucan-rich structures in fungal cell walls. While Dectin-1 is expressed in myeloid cells and tumor cells, its significance in cancer remains the subject of controversy. Using Celc7a-/- mice and curdlan administration to stimulate Dectin-1 signaling, we explored its impact. VISTA KO mice were employed to assess VISTA's role, and bulk RNAseq analyzed curdlan effects on neutrophils. Our findings reveal myeloid cells as primary Dectin-1 expressing cells in the tumor microenvironment (TME), displaying an activated phenotype. Strong Dectin-1 co-expression/co-localization with VISTA and PD-L1 in TME myeloid cells was observed. While Dectin-1 deletion lacked protective effects, curdlan stimulation significantly curtailed B16-F10 tumor progression. RNAseq and pathway analyses supported curdlan's role in triggering a cascade of events leading to increased production of pro-inflammatory mediators, potentially resulting in the recruitment and activation of immune cells. Moreover, we identified a heterogeneous subset of Dectin-1+ effector T cells in the TME. Similar to mice, human myeloid cells are the prominent cells expressing Dectin-1 in cancer patients. Our study proposes Dectin-1 as a potential adjunctive target with ICBs, orchestrating a comprehensive engagement of innate and adaptive immune responses in melanoma. This innovative approach holds promise for overcoming acquired resistance to ICBs in cancer treatment, offering avenues for further exploration and development.

Type I Cystatin Derived from Cysticercus pisiformis—Stefins, Suppresses LPS-Mediated Inflammatory Response in RAW264.7 Cells

Cysticercus pisiformis is a kind of tapeworm larvae of Taenia pisiformis, which parasitizes the liver envelope, omentum, mesentery, and rectum of rodents such as rabbits. Cysteine protease inhibitors derived from helminth were immunoregulatory molecules of intermediate hosts and had an immunomodulatory function that regulates the production of inflammatory factors. Thus, in the present research, the recombinant Stefin of C. pisiformis was confirmed to have the potential to fight inflammation in LPS-Mediated RAW264.7 murine macrophages. CCK8 test showed that rCpStefin below 50 μg/mL concentration did not affect cellular viability. Moreover, the NO production level determined by the Griess test was decreased. In addition, the secretion levels of IL-1β, IL-6, and TNF-α as measured by ELISA were decreased. Furthermore, it exerted anti-inflammatory activity by decreasing the production of proinflammatory cytokines and proinflammatory mediators, including IL-1β, IL-6, TNF-α, iNOS, and COX-2 at the gene transcription level, as measured by qRT-PCR. Therefore, Type I cystatin derived from C. pisiformis suppresses the LPS-Mediated inflammatory response of the intermediate host and is a potential candidate for the treatment of inflammatory diseases.

Wogonoside alleviates microglia-mediated neuroinflammation via TLR4/MyD88/NF-κB signaling axis after spinal cord injury

Wogonoside (WG) is a natural flavonoid extracted from Scutellariae Radix, recognized for its established anti-inflammatory properties. However, the role of WG in the context of neuroinflammation after spinal cord injury (SCI) remains inadequately elucidated. This study employed in silico, in vitro, and in vivo methodologies to investigate the impact of WG on microglia-mediated neuroinflammation after SCI. In the in silico experiment, we identified 15 potential target genes of WG associated with SCI. These genes were linked to the regulation of inflammatory response and immune defense. Molecular docking maps revealed toll-like receptor 4 as a molecular target for WG, demonstrating binding through a hydrogen bond (Lys263, Ser120). In lipopolysaccharide-stimulated BV2 cells and SCI mice, WG significantly attenuated microglial activation and facilitated a phenotype shift from M1 to M2. This was evidenced by the reversal of the increased expressions of Iba1, GFAP, and iNOS, as well as the decreased expression of Arg1. WG also suppressed the production of pro-inflammatory mediators (NO, TNF-α, IL-6, IL-1α, IL-1β, C1q). WG exerted these effects by suppressing the TLR4/MyD88/NF-κB signaling axis in microglia. Furthermore, by reducing levels of TNF-α, IL-1α, and C1q in supernatant of LPS-induced microglia, WG indirectly induced astrocytes change to A2 phenotype, evidenced by transcriptome sequencing result of primary mouse astrocytes. All these events above collectively created a favorable microenvironment, contributing to a significant alleviation of weight loss and neuronal damage at the lesion site of SCI mice. Our findings substantiate the efficacy of WG in mitigating neuroinflammation after SCI, thereby warranting further exploration.

Inflammation and Exosomes in Fabry Disease Pathogenesis.

Fabry Disease (FD) is one of the most prevalent lysosomal storage disorders, resulting from mutations in the GLA gene located on the X chromosome. This genetic mutation triggers glo-botriaosylceramide (Gb-3) buildup within lysosomes, ultimately impairing cellular functions. Given the role of lysosomes in immune cell physiology, FD has been suggested to have a profound impact on immunological responses. During the past years, research has been focusing on this topic, and pooled evidence strengthens the hypothesis that Gb-3 accumulation potentiates the production of pro-inflammatory mediators, revealing the existence of an acute inflammatory process in FD that possibly develops to a chronic state due to stimulus persistency. In parallel, extracellular vesicles (EVs) have gained attention due to their function as intercellular communicators. Considering EVs' capacity to convey cargo from parent to distant cells, they emerge as potential inflammatory intermediaries capable of transporting cytokines and other immunomodulatory molecules. In this review, we revisit the evidence underlying the association between FD and altered immune responses and explore the potential of EVs to function as inflammatory vehicles.

The inositol-requiring enzyme 1 (IRE1) endoplasmic reticulum stress pathway promotes MDA-MB-231 cell survival and renewal in response to the aryl-ureido fatty acid CTU

Current treatment options for triple-negative breast cancer (TNBC) are limited to toxic drug combinations of low efficacy. We recently identified an aryl-substituted fatty acid analogue, termed CTU, that effectively killed TNBC cells in vitro and in mouse xenograft models in vivo without producing toxicity. However, there was a residual cell population that survived treatment. The present study evaluated the mechanisms that underlie survival and renewal in CTU-treated MDA-MB-231 TNBC cells. RNA-seq profiling identified several pro-inflammatory signaling pathways that were activated in treated cells. Increased expression of cyclooxygenase-2 and the cytokines IL-6, IL-8 and GM-CSF was confirmed by real-time RT-PCR, ELISA and Western blot analysis. Increased self-renewal was confirmed using the non-adherent, in vitro colony-forming mammosphere assay. Neutralizing antibodies to IL-6, IL-8 and GM-CSF, as well as cyclooxygenase-2 inhibition suppressed the self-renewal of MDA-MB-231 cells post-CTU treatment. IPA network analysis identified major NF-κB and XBP1 gene networks that were activated by CTU; chemical inhibitors of these pathways and esiRNA knock-down decreased the production of pro-inflammatory mediators. NF-κB and XBP1 signaling was in turn activated by the endoplasmic reticulum (ER)-stress sensor inositol-requiring enzyme 1 (IRE1), which mediates the unfolded protein response. Co-treatment with an inhibitor of IRE1 kinase and RNase activities, decreased phospho-NF-κB and XBP1s expression and the production of pro-inflammatory mediators. Further, IRE1 inhibition also enhanced apoptotic cell death and prevented the activation of self-renewal by CTU. Taken together, the present findings indicate that the IRE1 ER-stress pathway is activated by the anti-cancer lipid analogue CTU, which then activates secondary self-renewal in TNBC cells.

The acute phase reactant orosomucoid-2 directly promotes rheumatoid inflammation

Acute phase proteins involved in chronic inflammatory diseases have not been systematically analyzed. Here, global proteome profiling of serum and urine revealed that orosomucoid-2 (ORM2), an acute phase reactant, was differentially expressed in rheumatoid arthritis (RA) patients and showed the highest fold change. Therefore, we questioned the extent to which ORM2, which is produced mainly in the liver, actively participates in rheumatoid inflammation. Surprisingly, ORM2 expression was upregulated in the synovial fluids and synovial membranes of RA patients. The major cell types producing ORM2 were synovial macrophages and fibroblast-like synoviocytes (FLSs) from RA patients. Recombinant ORM2 robustly increased IL-6, TNF-α, CXCL8 (IL-8), and CCL2 production by RA macrophages and FLSs via the NF-κB and p38 MAPK pathways. Interestingly, glycophorin C, a membrane protein for determining erythrocyte shape, was the receptor for ORM2. Intra-articular injection of ORM2 increased the severity of arthritis in mice and accelerated the infiltration of macrophages into the affected joints. Moreover, circulating ORM2 levels correlated with RA activity and radiographic progression. In conclusion, the acute phase protein ORM2 can directly increase the production of proinflammatory mediators and promote chronic arthritis in mice, suggesting that ORM2 could be a new therapeutic target for RA.

Synthesis, characterization, and anti-inflammatory activity of tetrahydropiperine, piperic acid, and tetrahydropiperic acid via down regulation of NF-κB pathway

The present study describes the synthesis, characterization, and evaluation of tetrahydropiperine (THP), piperic acid (PA), and tetrahydropiperic acid (THPA) as anti-inflammatory agents. THPA demonstrated potent anti-inflammatory activity among all the compounds. The anti-inflammatory potential was investigated in both in-vitro and in-vivo experimental models. Our findings demonstrated that THPA effectively suppressed the production of pro-inflammatory mediators, including nitric oxide and pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) in both in vitro and in vivo. Additionally, THPA attenuated the expression of i-NOS and COX-2 in RAW 264.7 macrophages. The oral administration of THPA significantly reduced carrageenan induced paw edema thickness and alleviated liver, lung, and kidney injury induced by LPS. THPA also reduced the infiltration of inflammatory cells, prevented the occurrence of significant lesions, and mitigated tissue damage. Moreover, THPA significantly improved the survival rate of mice challenged with LPS. Our western blot studies also found that LPS induced NF-κB activation was downregulated by treatment with THPA in an in vivo system. These results collectively illustrated the potential of THPA as a therapeutic agent for treating inflammatory diseases.

Vitamin D supply, respiratory viral infections and persistent wheezing in children: how significant is the relationship?

The review discusses the multifaceted effect of vitamin D on antiviral immunity, induction of antimicrobial peptides, functional activity of immunocompetent cells, autophagy processes, clearance of viruses and viral fragments. The relationship between vitamin D and allergic inflammatory cells, its modulating and tolerogenic potential is considered. The inhibitory effect of vitamin D on eosinophils, mast cells, the production of pro-inflammatory and proallergic mediators, and the synthesis of IgE has been shown. The protective role of vitamin D in the development of remodeling and hyperresponsiveness of the respiratory tract has been established by reducing the number of goblet cells, mucus hypersecretion, and the expression of metalloproteinases. The effects of vitamin D on the replication of respiratory viruses and experimental resistance to them through the induction of antimicrobial peptides and other mechanisms have been demonstrated. Data from clinical studies on the preventive effect of vitamin D on the incidence of respiratory infections and episodes of persistent wheezing in children are presented. Children with respiratory syncytial infection and vitamin D deficiency were more likely to require respiratory support and mechanical ventilation. The preventive role of vitamin D in the development of obstructive bronchitis in children and severe bronchiolitis in infants has been shown. It has been established that normal levels of 25(OH)D in the mother significantly reduce the risk of developing bronchial obstruction in the child. Alternative data that do not support a protective effect of vitamin D on respiratory morbidity and wheezing in children are discussed. Further monitoring studies that take into account geographic location and analysis of the dose of cholecalciferol used to assess its preventive role in the development of wheezing and bronchial asthma in children are advisable.

Sp1 Regulates the M1 Polarization of Microglia Through the HuR/NF-κB Axis after Spinal Cord Injury

The M1 polarization of microglia, followed by the production of pro-inflammatory mediators, hinders functional recovery after spinal cord injury (SCI). Our previous study has illuminated that specificity protein 1 (Sp1) expression is increased following SCI, whereas the function and regulatory mechanism of Sp1 during M1 polarization of microglia following SCI remain unknown. RNA binding protein, HuR, has been shown to be up-regulated in the injured spinal cord through analysis of the GEO database. Further investigation using Chip-Atlas data suggests a binding between Sp1 and HuR. Emerging evidence indicates that HuR plays a pivotal role in neuroinflammation after SCI. In this research, Sp1 and HuR levels in mice with SCI and BV2 cells treated with lipopolysaccharide (LPS) was determined by using quantitative real-time polymerase chain reaction and Western blotting techniques. A series of in vitro assays were performed to investigate the function of Sp1 during M1 polarization of microglia. The association between Sp1 and its target gene HuR was confirmed through gene transfection and luciferase reporter assay. Enhanced expression of HuR was observed in both SCI mice and LPS-treated BV2 cells, while Sp1 knockdown restrained M1 polarization of microglia and its associated inflammation by inhibiting the NF-κB signaling pathway. Silencing Sp1 also suppressed microglia activation and its mediated inflammatory response, which could be reversed by overexpression of HuR. In conclusion, silencing Sp1 restrains M1 polarization of microglia through the HuR/NF-κB axis, leading to neuroprotection, and thus promotes functional restoration following SCI.

Structural Characterization and In Vitro Anti-Inflammatory Activity of Polysaccharides Isolated from the Fruits of Rosa laevigata.

RLPa-2 (Mw 15.6 kDa) is a polysaccharide isolated from Rosa laevigata Michx. It consists of arabinose (Ara), galactose (Gal), rhamnose (Rha), glucose (Glc), xylose (Xyl), and galacturonic acid (Gal-UA) with a molar ratio of 1.00:0.91:0.39:0.34:0.25:0.20. Structural characterization was performed by methylation and NMR analysis, which indicated that RLPa-2 might comprise →6)-α-D-Galp-(1→, →4)-α-D-GalpA-(1→, α-L-Araf-(1→, →2,4)-α-D-Glcp-(1→, β-D-Xylp, and α-L-Rhap. In addition, the bioactivity of RLPa-2 was assessed through an in vitro macrophage polarization assay. Compared to positive controls, there was a significant decrease in the expression of M1 macrophage markers (CD80, CD86) and p-STAT3/STAT3 protein. Additionally, there was a down-regulation in the production of pro-inflammatory mediators (NO, IL-6, TNF-α), indicating that M1 macrophage polarization induced with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) stimulation could be inhibited by RLPa-2. These findings demonstrate that the RLPa-2 might be considered as a potential anti-inflammatory drug to reduce inflammation.

Amlexanox attenuates LPS-induced neuroinflammatory responses in microglial cells via inhibition of NF–κB and STAT3 signaling pathways

Amlexanox is an anti-inflammatory and anti-allergic agent used clinically for the treatment of aphthous ulcers, allergic rhinitis, and asthma. Recent studies have demonstrated that amlexanox, a selective inhibitor of IkB kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1), suppresses a range of diseases or inflammatory conditions, such as obesity-related metabolic dysfunction and type 2 diabetes. However, the effects of amlexanox on neuroinflammatory responses to amlexanox have not yet been comprehensively studied. In this study, we investigated the novel therapeutic effect of amlexanox on LPS-induced neuroinflammation in vivo, and intraperitoneal injection of amlexanox markedly reduced LPS-induced IKKε levels, proinflammatory cytokines, and microglial activation, as evidenced by ionized calcium-binding adapter molecule 1 (Iba1) immunostaining. Furthermore, amlexanox significantly reduced proinflammatory cytokines and chemokines in LPS-induced bone marrow-derived macrophages (BMDM), murine BV2, and human HMC3 microglial cells. This data provided considerable evidence that amlexanox can be used as a preventive and curative therapy for neuroinflammatory and neurodegenerative diseases. In terms of mechanism aspects, our results demonstrated that the anti-inflammatory action of amlexanox in BV2 microglial cells was through the downregulation of NF-κB and STAT3 signaling pathways. In addition, the combination of amlexanox and SPI (a STAT3 selective inhibitor) showed high efficiency in inhibiting the production of neurotoxic and pro-inflammatory mediators. Overall, our data provide rational insights into the mechanisms of amlexanox as a potential therapeutic strategy for neuroinflammation-related diseases.

Diffusive mediator feedbacks control the health-to-disease transition of skin inflammation.

The spatiotemporal dynamics of inflammation provide vital insights into the understanding of skin inflammation. Skin inflammation primarily depends on the regulatory feedback between pro- and anti-inflammatory mediators. Healthy skin exhibits fading erythema. In contrast, diseased skin exhibits expanding erythema with diverse patterns, which are clinically classified into five types: circular, annular, arcuate, gyrate, and polycyclic. Inflammatory diseases with expanding erythema are speculated to result from the overproduction of pro-inflammatory mediators. However, the mechanism by which feedback selectively drives the transition from a healthy fading erythema to each of the five types of diseased expanding erythema remains unclear. This study theoretically elucidates the imbalanced production between pro- and anti-inflammatory mediators and prospective treatment strategies for each expanding pattern. Our literature survey showed that eleven diseases exhibit some of the five expanding erythema, thereby suggesting a common spatiotemporal regulation underlying different patterns and diseases. Accordingly, a reaction-diffusion model incorporating mediator feedback reproduced the five observed types of diseased expanding and healthy fading patterns. Importantly, the fading pattern transitioned to the arcuate, gyrate, and polycyclic patterns when the productions of anti-inflammatory and pro-inflammatory mediators were lower and higher, respectively than in the healthy condition. Further depletion of anti-inflammatory mediators caused a circular pattern, whereas further overproduction of pro-inflammatory mediators caused an annular pattern. Mechanistically, the bistability due to stabilization of the diseased state exhibits circular and annular patterns, whereas the excitability exhibits the gyrate, polycyclic, arcuate, and fading patterns as the threshold of pro-inflammatory mediator concentration relative to the healthy state increases. These dynamic regulations of diffusive mediator feedback provide effective treatment strategies for mediator production wherein skins recover from each expanding pattern toward a fading pattern. Thus, these strategies can estimate disease severity and risk based on erythema patterns, paving the way for developing noninvasive and personalized treatments for inflammatory skin diseases.

Flavonoid Rutin Presented Anti-Glioblastoma Activity Related to the Modulation of Onco miRNA-125b Expression and STAT3 Signaling and Impact on Microglia Inflammatory Profile.

Glioblastoma (GBM) is the most aggressive and treatment-resistant brain tumor. In the GBM microenvironment, interaction with microglia is associated with the dysregulation of cytokines, chemokines, and miRNAs, contributing to angiogenesis, proliferation, anti-apoptosis, and chemoresistance. The flavonoid rutin can inhibit glioma cell growth associated with microglial activation and production of pro-inflammatory mediators by mechanisms that are still poorly understood. The present study investigated the effect of rutin on viability, regulation of miRNA-125b, and the STAT3 expression in GBM cells, as well as the effects on the modulation of the inflammatory profile and STAT3 expression in microglia during indirect interaction with GBM cells. Human GL15-GBM cells and human C20 microglia were treated or not with rutin for 24 h. Rutin (30-50 μM) significantly reduced the viability of GL15 cells; however, it did not affect the viability of microglia. Rutin (30 μM) significantly reduced the expression of miRNA-125b in the cells and secretome and STAT3 expression. Microglia submitted to the conditioned medium from GBM cells treated with rutin showed reactive morphology associated with reduced expression of IL-6, TNF, and STAT3. These results reiterate the anti-glioma effects of the flavonoid, which may also modulate microglia towards a more responsive anti-tumor phenotype, constituting a promising molecule for adjuvant therapy to GBM.

Menopause-Associated Depression: Impact of Oxidative Stress and Neuroinflammation on the Central Nervous System-A Review.

Perimenopausal depression, occurring shortly before or after menopause, is characterized by symptoms such as emotional depression, anxiety, and stress, often accompanied by endocrine dysfunction, particularly hypogonadism and senescence. Current treatments for perimenopausal depression primarily provide symptomatic relief but often come with undesirable side effects. The development of agents targeting the specific pathologies of perimenopausal depression has been relatively slow. The erratic fluctuations in estrogen and progesterone levels during the perimenopausal stage expose women to the risk of developing perimenopausal-associated depression. These hormonal changes trigger the production of proinflammatory mediators and induce oxidative stress, leading to progressive neuronal damage. This review serves as a comprehensive overview of the underlying mechanisms contributing to perimenopausal depression. It aims to shed light on the complex relationship between perimenopausal hormones, neurotransmitters, brain-derived neurotrophic factors, chronic inflammation, oxidative stress, and perimenopausal depression. By summarizing the intricate interplay between hormonal fluctuations, neurotransmitter activity, brain-derived neurotrophic factors, chronic inflammation, oxidative stress, and perimenopausal depression, this review aims to stimulate further research in this field. The hope is that an increased understanding of these mechanisms will pave the way for the development of more effective therapeutic targets, ultimately reducing the risk of depression during the menopausal stage for the betterment of psychological wellbeing.

Eugenol alleviates the symptoms of experimental autoimmune encephalomyelitis in mice by suppressing inflammatory responses

Eugenol is a principal compound in essential clove oil, known for its anti-inflammatory and antioxidant properties. While recent studies have demonstrated its neuroprotective effects on central nervous system (CNS) injuries, such as brain ischemia/reperfusion injuries, but its potential impact on multiple sclerosis (MS), an autoimmune disease of the CNS, has not yet been explored. We evaluated the therapeutic effects of eugenol on experimental autoimmune encephalomyelitis (EAE), an established animal model of MS. EAE was induced in C57BL/6 mice using the myelin oligodendrocyte glycoprotein (MOG)35–55 peptide. Clinical symptoms, including paralysis, were monitored daily, and levels of pro-inflammatory mediators were evaluated using real-time quantitative polymerase chain reaction, Western blot analyses, and immunohistochemistry. Daily oral administration of eugenol to MOG-induced EAE mice led to a notable decline in the severity of clinical symptoms. Eugenol inhibited EAE-related immune cell infiltration and the production of pro-inflammatory mediators. Histological examinations confirmed its ability to mitigate inflammation and demyelination in the spinal cord post-EAE induction. Eugenol alleviates neuroinflammation in the spinal cords of EAE-induced mice, primarily through anti-inflammatory action.

Correlation of C-Reactive Protein and Severity of Peri-Implant Diseases.

Peri-implant disease pathogenesis is similar to periodontal disease pathogenesis resulting in production of pro-inflammatory mediators. These mediators are released during the inflammation phase, among which C-reactive protein (CRP) is one of the acute phase reactants. The aim of the study was to correlate the levels of CRP with the severity of peri-implant diseases. The present observational study was carried out from June 2022 to December 2022 in the Department of Implantology, Saveetha Dental College and Hospitals, Chennai, India. A total of 60 patients with peri-implant health (n = 20), peri-mucositis (n = 20) and peri-implantitis (n = 20) were enrolled. Unstimulated salivary samples were collected and subjected to latex agglutination assay for CRP analysis. CRP levels were then correlated with severity of peri-implant diseases. The mean CRP level in peri-implant health, peri-implant mucositis, peri-implantitis were 0.25 ± 0.36 mg/dl, 3.56 ± 0.85 mg/dl and 5.07 ± 0.74 mg/dl, respectively. Pearson correlation coefficient analysis revealed a strong positive correlation between CRP and peri-implant parameters suggesting that the CRP level increased as the severity of peri-implant disease increased. CRP level increases with severity of peri-implant diseases and there exists a positive correlation between CRP level and peri-implant parameters. Therefore, CRP can be used as a diagnostic marker for peri-implant diseases.

Autophagy in Neuroinflammation: A Focus on Epigenetic Regulation.

Neuroinflammation, characterized by the secretion of abundant inflammatory mediators, pro-inflammatory polarization of microglia, and the recruitment of infiltrating myeloid cells to foci of inflammation, drives or exacerbates the pathological processes of central nervous system disorders, especially in neurodegenerative diseases. Autophagy plays an essential role in neuroinflammatory processes, and the underlaying physiological mechanisms are closely correlated with neuroinflammation-related signals. Inhibition of mTOR and activation of AMPK and FOXO1 enhance autophagy and thereby suppress NLRP3 inflammasome activity and apoptosis, leading to the relief of neuroinflammatory response. And autophagy mitigates neuroinflammation mainly manifested by promoting the polarization of microglia from a pro-inflammatory to an anti-inflammatory state, reducing the production of pro-inflammatory mediators, and up-regulating the levels of anti-inflammatory factors. Notably, epigenetic modifications are intimately associated with autophagy and the onset and progression of various brain diseases. Non-coding RNAs, including microRNAs, circular RNAs and long noncoding RNAs, and histone acetylation have been reported to adjust autophagy-related gene and protein expression to alleviate inflammation in neurological diseases. The present review primarily focuses on the role and mechanisms of autophagy in neuroinflammatory responses, as well as epigenetic modifications of autophagy in neuroinflammation to reveal potential therapeutic targets in central nervous system diseases.

Long-term supplementation with EPA and DHA changes the fatty acid profile of rat tissues, upregulates NRF2 expression and downregulates TGFβ expression

We studied the influence of long-term treatment with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the liver, and kidney lipogenesis, inflammation and antioxidative gene expression. Male Wistar rats were divided into three groups on the basis of the different n6/n3 fatty acid ratios achieved by using different dietary oil blends: the control (CON, n6/n3 ratio was ~7), the N6 group (n6/n3 ratio was ~50) and the DHA group (n6/n3 ~1). Treatment significantly influenced the fatty acid profile of the liver and kidney tissues. The most characteristic changes were an increased content of EPA and DHA in the DHA group in both tissues, of the kidney and liver. The expression of transforming growth factor beta (TGF-ß) was downregulated in the liver tissue by long-term EPA/DHA supplementation. This could be attributed to a decrease in the production of arachidonic acid-derived proinflammatory mediators, and an increase in EPA and DHA derived eicosanoids. DHA and EPA supplementation also significantly increased expression of the NRF 2 gene. This finding suggests that n3 PUFA could influence the activation of the NRF 2 pathway, which is important in cell antioxidative defense. In conclusion, we have shown that long-term dietary supplementation with DHA and EPA could influence lipid metabolism, inflammation and antioxidative defense. Therefore, the long-term addition of dietary DHA and EPA could potentially influence the most important pathological processes in aging.

Early growth response 1/Krüppel-like factor 5 pathway inhibitor alleviates lipopolysaccharide-induced lung injury by promoting autophagy

Early transcription factors play critical roles in the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Early growth response 1 (EGR1) is a transcription factor essential for various biological processes, including regulation of metabolism, differentiation, and inflammation. However, its role in ALI has been poorly reported. In this study, we aimed to determine the effect of EGR1 on ALI to gain insights into the theoretical basis for further treatment of ALI. By employing concerted molecular biology techniques, we showed that EGR1 protein was upregulated in mice. EGR1 protein was upregulated in mice and human lung epithelial cells in response to lipopolysaccharide (LPS) stimulation. EGR1 knockdown promoted autophagy and reduced LPS-induced pro-inflammatory mediator production. EGR1 was preferentially bound to the GCGTGGGCG motif region and EGR1-binding peak-related genes were mainly enriched in autophagy and injury stress-related pathways. Additionally, EGR1 promoted Krüppel-like factor 5 (KLF5) transcription by binding to the KLF5 promoter region, and KLF5 knockdown significantly decreased inflammatory damage, suggesting that EGR1 promotes ALI progression by regulating KLF5 expression. Furthermore, ML264, an inhibitor of the EGR1/KLF5 pathway axis, displayed a protective role in ALI to reduce inflammation. In conclusion, our findings demonstrate the potential of EGR1 knockdown to inhibit KLF5 and promote autophagy, further reducing the inflammatory response to mitigate ALI/ARDS. The EGR1/KLF5 pathway axis may be a valuable therapeutic target for the treatment of ALI/ARDS.

Inhibition of voltage-gated Hv1 alleviates LPS-induced neuroinflammation via regulation of microglial metabolic reprogramming

A growing body of evidence highlights the crucial role of metabolic reprogramming in activated immune cells, significantly contributing to both the initiation and progression of neuroinflammation and neurodegenerative diseases. The voltage-gated H channel (Hv1) has been reported to be involved in microglial activation and acts as a key driver of neuroinflammation. This study aimed to explore how Hv1-mediated metabolic reprogramming contributes to neuroinflammation and to assess the therapeutic potential of the Hv1 inhibitor 2-GBI in a model of lipopolysaccharide (LPS)-induced neuroinflammation. We investigated the influence of 2-GBI on the generation of ROS, metabolic reprogramming, and pro-inflammatory mediator production in vitro and examined the therapeutic effect of 2-GBI on microglial activation and hippocampal neuroinflammation in vivo. The results indicated that 2-GBI attenuated the LPS-induced pro-inflammatory response and aerobic glycolysis in microglia, specifically mitigating HIF1α-mediated upregulation of glycolysis. 2-GBI exerted a protective effect against LPS-induced neuroinflammation through HIF1α pathway-regulated aerobic glycolysis. Using a transwell coculture system, we demonstrated that 2-GBI reversed PC12 cell death caused by BV2-mediated neuroinflammation. In vivo experiments further suggested that 2-GBI mitigated neuroinflammatory processes and cognitive dysfunction via microglial metabolic reprogramming. Collectively, our results highlight the potential of Hv1 inhibition as a therapeutic strategy for alleviating LPS-induced neuroinflammation by modulating microglial metabolic reprogramming.