Nuclear factor-kappaB Signaling Research Articles

Interleukin-33 increases the sensitivity of multiple myeloma cells to the proteasome inhibitor bortezomib through reactive oxygen species-mediated inhibition of nuclear factor kappa-B signal and stemness properties.

The proteasome inhibitor bortezomib (BTZ) is the first-line therapy for multiple myeloma (MM). BTZ resistance largely limits its clinical application in MM. Interleukin-33 (IL-33) exerts antitumor effects through various mechanisms, including enhancing antitumor immunity and promoting the apoptosis of cancer cells. Here, the synergistic anti-MM effect of IL-33 and BTZ was verified, and the underlying mechanisms were elucidated. Bioinformatic analysis indicated that IL-33 expression levels were downregulated in MM, and that BTZ-treated MM patients with high IL-33 levels had better prognosis than those with low IL-33 levels. Moreover, the patients with high IL-33 levels had a better treatment response to BTZ. Further immune analysis suggested that IL-33 can enhance the anti-MM immunity. IL-33 and BTZ synergistically inhibited proliferation and induced apoptosis of MM cells, which was mediated by the excessive accumulation of cellular reactive oxygen species (ROS). Furthermore, increased ROS hindered the nuclear translocation of NF-κB-p65, thereby decreasing the transcription of target stemness-related genes (SOX2, MYC, and OCT3/4). These effects induced by the combination therapy could be reversed by eliminating ROS by N-acetylcysteine. In conclusion, our results indicated that IL-33 enhanced the sensitivity of MM to BTZ through ROS-mediated inhibition of nuclear factor kappa-B (NF-κB) signal and stemness properties.

Effect of Shenqi Jieyu formula on inflammatory response pathway in hippocampus of postpartum depression rats

AimTo investigate whether SJF functions in similar manner as the key substance in the inflammatory process, soluble epoxide hydrolase (sEH) inhibitor, to inhibit the arachidonic acid metabolic pathway and nuclear factor kappa-B(NF-κB) signal path in the hippocampi of postpartum depression rats. MethodsThe rats were subcutaneous injected estradiol benzoate and progesterone to build PPD rat model. SJF, paroxetine hydrochloride and sEH inhibitor (AUDA) were used to treat PPD rats for 3 weeks. Then the morphological changes of hippocampi and various proteins were observed after that behavioral test were conducted in all 36 SD rats in six group: SJF, paroxetine, AUDA, PPD, sham and normal group. ResultsWeight, results of sucrose preference, upright times, total and center squares crossing decreased significantly (P < 0.01), whereas immobility time increased (P < 0.01). Results above were reversed in animals that in the SJF, paroxetine and AUDA groups. Hippocampal neurons in PPD rats partially degenerated with narrowed nuclei, increased autophagy and mitochondria bound to lysosomes were visible while the autophagy of hippocampal neurons in the paroxetine and AUDA group decreased, with a small amount of lysosomes. sEH, COX-2, 5-LOX, TNF-α, IL-1, IL-6, NF-κB p65, and Cor increased in hippocampi of PPD rats while EETs and 5-HT decreased. Protein expressions of Ibal, GFAP, p-IκBα, p65, and p-p65(S536)increased in PPD animals. Those changes were reversed by SJF, paroxetine and AUDA. Gene expressions of TNF-α, IL-1β, IL-6, 5-LOX, COX-2 and p65 increased in PPD rats and the changes of expression in these genes were reversed by paroxetine and AUDA. SJF reversed the gene expression changes of COX-2, TNF-α, and IL-1β. ConclusionSJF may have an analogous effect as sEH inhibitor to relieve depressive symptoms by suppressing inflammatory signaling pathways in hippocampi of PPD rats, which involves AA metabolic pathway and NF-κB signal pathway.

Cascade Reactions Catalyzed by Gold Hybrid Nanoparticles Generate CO Gas Against Periodontitis in Diabetes.

The treatment ofdiabetic periodontitis poses a significant challenge due to the presence of local inflammation characterized by excessive glucose concentration, bacterial infection, and high oxidative stress. Herein, mesoporous silica nanoparticles (MSN) are embellished with gold nanoparticles (Au NPs) and loaded with manganese carbonyl to prepare a carbon monoxide (CO) enhanced multienzyme cooperative hybrid nanoplatform (MSN-Au@CO). The Glucose-like oxidase activity of Au NPs catalyzes the oxidation of glucose to hydrogen peroxide (H2O2) and gluconic acid，and then converts H2O2 to hydroxyl radicals (•OH) by peroxidase-like activity to destroy bacteria. Moreover, CO production in response to H2O2, together with Au NPs exhibited a synergistic anti-inflammatory effect in macrophages challenged by lipopolysaccharides. The underlying mechanism can be the induction of nuclear factor erythroid 2-related factor 2 to reduce reactive oxygen species, and inhibition of nuclear factor kappa-B signaling to diminish inflammatory response. Importantly, the antibacterial and anti-inflammation effects of MSN-Au@CO are validated in diabetic rats with ligature-induced periodontitis by showing decreased periodontal bone loss with good biocompatibility. To summarize, MSN-Au@CO is fabricate to utilize glucose-activated cascade reaction to eliminate bacteria, and synergize with gas therapy to regulate the immune microenvironment, offering a potential direction for the treatment of diabetic periodontitis.

Tanshinone IIA improves Alzheimer's disease via RNA nuclear-enriched abundant transcript 1/microRNA-291a-3p/member RAS oncogene family Rab22a axis.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by oxidative stress and neuroinflammation. Tanshinone IIA (Tan-IIA), a bioactive compound isolated from Salvia miltiorrhiza plants, has shown potential neuroprotective effects; however, the mechanisms underlying such a function remain unclear. To investigate potential Tan-IIA neuroprotective effects in AD and to elucidate their underlying mechanisms. Hematoxylin and eosin staining was utilized to analyze structural brain tissue morphology. To assess changes in oxidative stress and neuroinflammation, we performed enzyme-linked immunosorbent assay and western blotting. Additionally, the effect of Tan-IIA on AD cell models was evaluated in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Genetic changes related to the long non-coding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1)/microRNA (miRNA, miR)-291a-3p/member RAS oncogene family Rab22a axis were assessed through reverse transcription quantitative polymerase chain reaction. In vivo, Tan-IIA treatment improved neuronal morphology and attenuated oxidative stress and neuroinflammation in the brain tissue of AD mice. In vitro experiments showed that Tan-IIA dose-dependently ameliorated the amyloid-beta 1-42-induced reduction of neural stem cell viability, apoptosis, oxidative stress, and neuroinflammation. In this process, the lncRNA NEAT1 - a potential therapeutic target - is highly expressed in AD mice and downregulated via Tan-IIA treatment. Mechanistically, NEAT1 promotes the transcription and translation of Rab22a via miR-291a-3p, which activates nuclear factor kappa-B (NF-κB) signaling, leading to activation of the pro-apoptotic B-cell lymphoma 2-associated X protein and inhibition of the anti-apoptotic B-cell lymphoma 2 protein, which exacerbates AD. Tan-IIA intervention effectively blocked this process by inhibiting the NEAT1/miR-291a-3p/Rab22a axis and NF-κB signaling. This study demonstrates that Tan-IIA exerts neuroprotective effects in AD by modulating the NEAT1/miR-291a-3p/Rab22a/NF-κB signaling pathway, serving as a foundation for the development of innovative approaches for AD therapy.

Galangin Prevents Against Ethanol-Induced Intestinal Barrier Dysfunction and NLRP3 Inflammasome Activation via NF-κB/MAPK Signaling Pathways in Mice and Caco-2 Cells.

The potential of natural phytochemicals in addressing ethanol-related public safety concerns has been garnering attention. Galangin, a potent flavonoid renowned for its antioxidative and anti-inflammatory characteristics, is derived from the galanga plant, and propolis is derived from bees. Here, we documented the effects of galangin on ethanol-stimulated intestinal tight junction damage and investigated its potential protective mechanism in both in vivo and in vitro models, which has not been extensively investigated. Our results revealed that galangin efficaciously mitigated ethanol-induced intestine injury and dysfunction of the intestinal barrier. Concurrently, galangin significantly counteracted the ethanol-induced upregulation of NLRP3 inflammasome-associated proteins and activated the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways in both the mouse colon and Caco-2 cells. Interestingly, similar to galangin, inhibitors of MAPKs and the NF-κB p65 reduced ethanol-induced NLRP3 inflammasome activation and intestinal tight junction damage. To sum up, our results showed that galangin blocks the ethanol-induced perturbation of the intestinal barrier and activation of the NLRP3 inflammasome via the NF-κB/MAPK signaling pathways.

Rutin alleviates Sjogren's syndrome via CaR/NLRP3/NF-κB signal pathway.

Sjogren's syndrome (SS) is an autoimmune disease. Its mechanism and treatment methods are unclear. The purpose of this study was to investigate the effects of rutin (Ru) on SS. Proteomics was used to detect differential proteins in the submandibular glands of normal mice and SS mice. Salivary secretion (SAS) and salivary gland index (SGI) were detected. Oxidative stress and inflammatory cytokine in submandibular glands were detected. The levels of NLRP3, ASC, Caspase-1, IL-1β, and p-NF-κBp65 in submandibular gland tissues and submandibular gland cells of overexpressedcalcium-sensing receptor (over-CaR) mice and overexpressed CaR primary submandibular gland cells (over-CaR-PSGs) were detected. In total, 327 differential proteins were identified in the submandibular gland tissues of SS mice compared to control mice. CaR was one of the most differential proteins and significantly increased compared to control mice. Ru could significantly increase SGI and SGI, and inhibit oxidative stress and inflammatory cytokine in submandibular glands. In addition, Ru was shown to further improve SS via regulation of the CaR/NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/nuclear factor kappa-B (NF-κB) signal pathway. Overexpression of CaR counteracted partial activity of Ru. CaR may be an important target for the treatment of SS. In addition, Ru improved the SS via the CaR/NLRP3/NF-κB signal pathway. This study provides a basis for the treatments for SS.

Potential Targets and Signaling Mechanisms of Cinnamaldehyde Enhancing Intestinal Function and Nutritional Regulation in Fat Greenling (Hexagrammos otakii)

Cinnamaldehyde is an ideal feed additive with good immune enhancement and anti-inflammatory regulation effects. However, the anti-inflammatory regulation mechanism in fat greenling (Hexagrammos otakii, H. otakii) remains unclear. The nine targets of cinnamaldehyde were gathered in identified by the Traditional Chinese Medicine Systems Pharmacology database and Uniprot database, and 1,320 intestinal inflammation disease (IIF)-related proteins were screened from DrugBank, Online Mendelian Inheritance in Man (OMIM), Genecards, and Pharmacogenetics and Pharmacogenomics Knowledge Base (PHARMGKB) Databases. According to the Gene Ontology enrichment results and Kyoto Encyclopedia of Genes and Genomes pathway results, cinnamaldehyde may regulated the responses to bacteria, lipopolysaccharide, an inflammatory cytokine, and external stimuli via the nuclear factor kappa-B (NFκB) signaling pathway within on inflammatory network. In addition, the protein–protein interaction analysis assisted in obtaining the closely related inflammatory regulatory proteins, including the C5a anaphylatoxin chemotactic receptor 1 (C5aR1), transcription factor p65 (RELA), prostaglandin G/H synthase 2 (PTGS2), and toll-like receptor 4 (TLR4), which were confirmed as the bottleneck nodes of the network to be more deeply verified via the molecular docking. Moreover, a cinnamaldehyde feeding model was established for evaluating the anti-inflammatory effect of cinnamaldehyde in vivo. According to the current findings implied that cinnamaldehyde may play a protective role against IIF H. otakii by reducing inflammation through the C5 complement (C5)/C5aR1/interleukin-6 (IL-6) and TLR4/NFκB/PTGS2 pathway. The study focused on investigating the action mechanism of cinnamaldehyde on IIF through combining pharmacology and experimental verification in vivo, which provided a fresh perspective on the promoting effect of cinnamaldehyde on IIF in fish.

Activation of farnesoid X receptor enhances the efficacy of normothermic machine perfusion in ameliorating liver ischemia-reperfusion injury

The shortage of transplant organs remains a severe global issue. Normothermic machine perfusion (NMP) has the potential to increase organ availability, yet its efficacy is hampered by the inflammatory response during machine perfusion. Mouse liver ischemia-reperfusion injury (IRI) models, discarded human liver models, and porcine marginal liver transplantation models were utilized to investigate whether farnesoid X receptor (FXR) activation could mitigate inflammation-induced liver damage. FXR expression levels before and after reperfusion were measured. Gene editing and coimmunoprecipitation techniques were employed to explore the regulatory mechanism of FXR in inflammation inhibition. The expression of FXR correlates with the extent of liver damage after reperfusion. Activation of FXR significantly suppressed the inflammatory response triggered by IRI, diminished the release of proinflammatory cytokines, and improved liver function recovery during NMP, assisting discarded human livers to reach transplant standards. Mechanistically, FXR disrupts the interaction between p65 and p300, thus inhibiting modulating the nuclear factor kappa-B signaling pathway, a key instigator of inflammation. Our research across multiple species confirms that activating FXR can optimize NMP by attenuating IRI-related liver damage, thereby improving the utilization of marginal livers for transplantation.

Synthesis and in vitro characterization of naproxen derivatives as novel anti-inflammatory agents

Naproxen, one type of non-steroidal anti-inflammatory drugs, has excellent anti-inflammatory activity. However, long-term use of it causes serious adverse effects. Inspired by the biological diversification of cinnamic acid, novel naproxen derivatives containing cinnamic acid are synthesized and used to improve their anti-inflammatory activity and safety. Our results indicated that thirty naproxen derivatives have different inhibitory effects on RAW264.7 macrophage cells. It is showed that most of the target naproxen derivatives possess the lower degree of cytotoxicity than that of naproxen. Further studies indicated that compound 22 (IC50 = 8.74 ± 2.13 μM) concentration-dependently inhibits the over-expression of iNOS, COX-2 and IL-1β by blocking the activation of nuclear factor kappa-B (NF-κB) signaling pathway and NLRP-3 inflammasome, respectively. Docking studies showed that the binding of compound 22 to NLRP3 using a well-fitting mode. It is found that compound 22 will be a novel anti-inflammatory agent to treat inflammatory diseases with an improved safety profile.

Shikonin attenuates cerebral ischemia/reperfusion injury via inhibiting NOD2/RIP2/NF-κB-mediated microglia polarization and neuroinflammation

ObjectivesMicroglia-mediated neuroinflammation plays a crucial role in the pathophysiological process of multiple neurological disorders such as ischemic stroke, which still lacks effective therapeutic agents. Shikonin possesses anti-inflammatory and neuroprotective properties. However, its underlying mechanism remains elusive. This study aimed to investigate whether Shikonin confers protection against cerebral ischemia/reperfusion (I/R) injury by modulating microglial polarization and elucidate the associated mechanisms. MethodsThis study employed an oxygen-glucose deprivation and reoxygenation (OGD/R) BV2 microglial cellular model and a middle cerebral artery occlusion/reperfusion (MCAO/R) animal model to investigate the protection and underlying mechanism of Shikonin against ischemic stroke. ResultsThe results demonstrated that Shikonin treatment significantly reduced brain infarction volume and improved neurological function in MCAO/R rats. Simultaneously, Shikonin treatment significantly reduced microglial proinflammatory phenotype and levels of proinflammatory markers (inducible-NO synthase (iNOS), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6), increased microglial anti-inflammatory phenotype and levels of anti-inflammatory markers (Arginase-1 (Arg1), transforming growth factor-beta (TGF-β), and IL-10), reversed the expression of Nucleotide-binding oligomerization domain 2 (NOD2) and phosphorylation receptor interacting protein 2 (p-RIP2), and suppressed nuclear factor kappa-B (NF-κB) signaling activation in the ischemic penumbra regions. These effects of Shikonin were further corroborated in OGD/R-treated BV2 cells. Furthermore, overexpression of NOD2 markedly attenuated the neuroprotective effects of Shikonin treatment in MCAO/R rats. NOD2 overexpression also attenuated the regulatory effects of Shikonin on neuroinflammation, microglial polarization, and NF-κB signaling activation. ConclusionThis study illustrates that Shikonin mitigates inflammation mediated by microglial proinflammatory polarization by inhibiting the NOD2/RIP2/NF-κB signaling pathway, thereby exerting a protective role. The findings uncover a potential molecular mechanism for Shikonin in treating ischemic stroke.

Eucalyptol regulates Nrf2 and NF-kB signaling and alleviates gentamicin-induced kidney injury in rats by downregulating oxidative stress, oxidative DNA damage, inflammation, and apoptosis

Gentamicin, an aminoglycoside antibiotic, is nowadays widely used in the treatment of gram-negative microorganisms. The antimicrobial, anti-inflammatory, and antioxidant activities of eucalyptol, a type of saturated monoterpene, have been reported in many studies. The aim of this study was to examine the possible effects of eucalyptol on gentamicin-induced renal toxicity. A total of 32 rats were divided into 4 groups; Control (C), Eucalyptol (EUC), Gentamicin (GEN), and Gentamicin + Eucalyptol (GEN + EUC). In order to induce renal toxicity, 100 mg/kg gentamicin was administered intraperitoneally (i.p.) for 10 consecutive days in the GEN and GEN + EUC groups. EUC and GEN + EUC groups were given 100 mg/kg orally of eucalyptol for 10 consecutive days. Afterwards, rats were euthanized and samples were taken and subjected to histopathological, biochemical, immunohistochemical, and real-time PCR examinations. The blood urea nitrogen (BUN) and creatinine (CRE) levels were significantly decreased in the GEN + EUC group (0.76 and 0.69-fold, respectively) compared to the GEN group. The glutathione peroxidase (GPx) and catalase (CAT) activities were significantly increased in the GEN + EUC group (1.35 and 2.67-fold, respectively) compared to the GEN group. In GEN group, Nuclear factor kappa B (NF-kB), Interleukin 1-beta (IL-1β), Inducible nitric oxide synthase (iNOS), Tumor necrosis factor-α (TNF-α), Caspase-3, 8-Hydroxy-2′-deoxyguanosine (8-OHdG) and Nuclear factor erythroid 2–related factor (Nrf2) expression levels were found to be quite irregular. GEN + EUC group decreased the expressions of NF-kB, IL-1β, iNOS, TNF-α, Caspase-3, and 8-OHdG (0.55, 0.67, 0.54, 0.54, 0.63 and 0.67-fold, respectively), while it caused increased expression of Nrf2 (3.1 fold). In addition, eucalyptol treatment ameliorated the histopathological changes that occurred with gentamicin. The results of our study show that eucalyptol has anti-inflammatory, antioxidative, antiapoptotic, nephroprotective, and curative effects on gentamicin-induced nephrotoxicity.

Chemical characterisation of essential oil from Sambucus williamsii Hance leaves and its hepatoprotective effects

This study is the first to examine the effect of leaves of Sambucus williamsii Hance essential oil on acute liver injury. According to gas chromatography–mass spectrometry analysis, the major constituents of S. williamsii essential oil (SEO)were (S)-falcarinol (62.66%), 17-pentatriacontene (7.78%) and tetrapentacontane (8.64%). Mice were pre-treated with SEO for 6 days followed by inducing liver injury with CCl4. The results indicated that SEO protected the liver against CCl4-induced injuries. Elevated levels of alanine-aminotransferase (ALT), aspartate amino-transferase (AST), alkaline phosphatase (ALP) in serum were significantly reduced on SEO pre-treatment. SEO pre-treatment significantly inhibited the oxidative stress and inflammation. Furthermore, toll-like receptor-4 (TLR4)/nuclear factor kappa-B (NF-κB) signalling pathways were significantly modulated by SEO in the liver tissue. The findings demonstrate that the essential oil of S. williamsii has enhancing the resistance to CCl4-induced liver injury.

Sini decoction alleviates inflammation injury after myocardial infarction through regulating arachidonic acid metabolism

ObjectiveMyocardial inflammation during myocardial infarction (MI) could be inhibited by regulating arachidonic acid (AA) metabolism. Recent studies demonstrated that Sini Decoction (SND) was identified to be an effective prescription for treating heart failure (HF) caused by MI. But the anti-inflammatory mechanism of SND remained unclear. The work was designed to investigate the anti-inflammatory mechanism of SND through the AA metabolism pathway in vitro and in vivo experiments. MethodsAn inflammatory injury model of H9c2 cells was established by lipopolysaccharide (LPS)-stimulated macrophage-conditioned medium (CM). The MI model was built by the ligation of left anterior descending (LAD) branch of coronary artery in rat. Meanwhile, the rats were divided into five groups: sham group, MI group, MI + Celecoxib group, MI + low-dose SND group (SND-L) and MI + high-dose SND group (SND-H). Cardiac function, histopathological changes and serum cytokines were examined four weeks later. Western blot analysis was conducted to verify the key enzymes levels in the AA metabolic pathway, including phospholipase A2 (PLA2), cyclooxygenases (COXs) and lipoxygenases (LOXs). ResultsThese in vivo results demonstrated that SND could improve the cardiac function and pathological changes of rats with MI, and regulate the key inflammatory molecules in the AA metabolism pathway, including sPLA2, COX-1, COX-2, 5-LOX and 15-LOX. In vitro, SND could decrease the release of pro-inflammatory cytokines including TNF-α and IL-6 and inhibit cell apoptosis in CM-induced H9c2 cells. Moreover, SND could protect H9c2 cells from the damage of CM by regulating nuclear factor kappa-B (NF-κB) signal pathway and the expression of COX-2. ConclusionSND may be a drug candidate for anti-inflammatory treatment during MI by regulating the multiple targets in the AA metabolism pathway.

Long- and short-term dietary β-glucan improves intestinal health and disease resistance in pearl gentian grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀).

β-Glucans are immunostimulants and are widely used in aquaculture industry. The present study was conducted to evaluate the effects of different periods of β-glucan management on growth performance, intestinal health, and disease resistance in pearl gentian grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀). A commercial feed was used as control diet (CD), and the β-glucan diet (βD) was based on CD and further supplemented with 0.1% β-glucan. Grouper in control and long-term β-glucan diet (LGD) groups were fed with CD and βD for 8 weeks, respectively. Groupers in short-term β-glucan diet (SGD) group were fed with CD for the first 4 weeks and βD for the last 4 weeks. We found that LGD and SGD had no effect on growth performance but reduced the mortalities of grouper after challenging with Vibrio harveyi. In addition, both LGD and SGD increased intestinal morphology, enhanced antioxidant capacity, enhanced immunity, inhibited apoptosis, altered the transcriptional profile, and activated mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathway in the intestine of grouper. Furthermore, the effect of LGD on most of the above parameters was comparable to that of SGD. In conclusion, LGD and SGD did not affect growth rate parameters but enhanced the intestinal health and disease resistance of pearl gentian grouper.

ACOX1 deficiency-induced lipid metabolic disorder facilitates chronic interstitial fibrosis development in renal allografts

Chronic interstitial fibrosis presents a significant challenge to the long-term survival of transplanted kidneys. Our research has shown that reduced expression of acyl-coenzyme A oxidase 1 (ACOX1), which is the rate-limiting enzyme in the peroxisomal fatty acid β-oxidation pathway, contributes to the development of fibrosis in renal allografts. ACOX1 deficiency leads to lipid accumulation and excessive oxidation of polyunsaturated fatty acids (PUFAs), which mediate epithelial–mesenchymal transition (EMT) and extracellular matrix (ECM) reorganization respectively, thus causing fibrosis in renal allografts. Furthermore, activation of Toll-like receptor 4 (TLR4)-nuclear factor kappa-B (NF-κB) signaling induced ACOX1 downregulation in a DNA methyltransferase 1 (DNMT1)-dependent manner. Overconsumption of PUFA resulted in endoplasmic reticulum (ER) stress, which played a vital role in facilitating ECM reorganization. Supplementation with PUFAs contributed to delayed fibrosis in a rat model of renal transplantation. The study provides a novel therapeutic approach that can delay chronic interstitial fibrosis in renal allografts by targeting the disorder of lipid metabolism.

The relevance between abnormally elevated serum ceramide and cognitive impairment in Alzheimer's disease model mice and its mechanism.

The plasma ceramide levels in Alzheimer's disease (AD) patients are found abnormally elevated, which is related to cognitive decline. This research was aimed to investigate the mechanisms of aberrant elevated ceramides in the pathogenesis of AD. The ICR mice intracerebroventricularly injected with Aβ1-42 and APP/PS1 transgenic mice were employed as AD mice. The cognitive deficiency, impaired episodic and spatial memory were observed without altered spontaneous ability. The serum levels of p-tau and ceramide were evidently elevated. The modified expressions and activities of glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) influenced the serum content of p-tau. The levels of ceramide synthesis-related genes including sptlc1, sptlc2, cers2, and cers6 in the liver of AD mice were increased, while the ceramide degradation-related gene asah2 did not significantly change. The regulations of these genes were conducted by activated nuclear factor kappa-B (NF-κB) signaling. NF-κB, promoted by free fatty acid (FFA), also increased the hepatic concentrations of proinflammatory cytokines. The FFA amount was modulated by fatty acid synthesis-related genes acc1 and srebp-1c. Besides, the decreased levels of pre-proopiomelanocortin (pomc) mRNA and increased agouti-related protein (agrp) mRNA were found in the hypothalamus without significant alteration of melanocortin receptor 4 (MC4R) mRNA. The bioinformatic analyses proved the results using GEO datasets and AlzData. Ceramide was positively related to the increased p-tau and impaired cognitive function. The increased generation of ceramide and endoplasmic reticulum stress in the hypothalamus was positively related to fatty acid synthesis and NF-κB signaling via brain-liver axis.

Electroacupuncture targeting the immune system to alleviate sepsis

Sepsis is a life-threatening inflammatory syndrome with high morbidity and mortality rates. However, options for sepsis are still limited to general treatment in intensive care units (ICUs), and effective therapies that improve sepsis survival are required. Immune disturbances play a vital role in the pathology of sepsis and are associated with protracted inflammation, susceptibility to infections, and death. Therefore, many investigators have focused on the potential benefits of immunomodulation therapy for sepsis. Electroacupuncture (EA) has been practiced in clinics for many years and has shown advantages in treating infectious diseases. Over the last few decades, our understanding of the efficacy and mechanisms of EA in sepsis has undergone considerable developments. We searched the literature regarding “CNKI, Wan Fang Data, VIP Database, PubMed, and Ingenta Connect” from 2010 to 2023, using the keywords “sepsis” “septic” and “electroacupuncture” and 336 sources were searched. Finally, we included 82 studies that targeted the immune system to determine EA’s anti-inflammatory and immunomodulatory effects on sepsis. In this review, we found that EA has clinical benefits in relieving septic inflammation, improving immune function, and attenuating related multi-organ injury through several mechanisms, such as activation of the cholinergic anti-inflammatory pathway (CAP), vagal-adrenal axis, inhibition of the nuclear factor Kappa-B (NF-κB) signaling pathway, signal transducers and activators of transcription (STAT) signaling pathway, and improvement of immune cell function. Therefore, EA may be a promising complementary therapy for sepsis treatment. We also expect these data will contribute to further studies on EA in sepsis.

Knockdown of IFIT3 ameliorates multiple sclerosis via selectively regulating M1 polarization of microglia in an experimental autoimmune encephalomyelitis model

The key to the treatment of multiple sclerosis (MS) is to promote the transition from inflammation-induced demyelination to remyelination. Polarization of microglia towards M1 or M2 phenotype is critical in this transition. Interferon induced protein with tetratricopeptide repeats 3 (IFIT3) is involved in inflammatory reaction and up-regulated in M1-polarized macrophages. However, its effect on microglia during MS has not been reported. In this paper, we demonstrated the important role of IFIT3 in selectively regulating microglia polarization. The expression of IFIT3 was increased when microglia were polarized towards M1, but did not change under M2 polarization. The knockdown of IFIT3 selectively inhibited M1 polarization, while M2 polarization was not affected by IFIT3 silencing. Furthermore, the activation of signal transducer and activator of transcription 1 (STAT1) and nuclear factor kappa-B (NF-ĸB) signaling in M1 polarized microglia was suppressed by downregulating IFIT3. In experimental autoimmune encephalitis (EAE) mice, an animal model of MS, IFIT3 expression was upregulated. The disease progression, inflammatory infiltration and demyelination in the EAE mice were alleviated by silencing IFIT3. The inhibitory effects of IFIT3 knockdown on M1 polarization and STAT1 and NF-ĸB pathways were also confirmed in the spinal cord of EAE mice. In summary, our findings suggest that IFIT3 selectively intensified microglia polarization towards the pro-inflammatory M1 phenotype, and may contribute to the progression of MS.

Conjugated Network Supporting Highly Surface-Exposed Ru Site-Based Artificial Antioxidase for Efficiently Modulating Microenvironment and Alleviating Solar Dermatitis.

Solar dermatitis, a form of acute radiation burn that affects the skin, results from overexposure to ultraviolet B (UVB) radiation in strong sunlight. Cell damage caused by the accumulation of reactive oxygen species (ROS) produced by UVB radiation plays an important role in UVB-induced inflammation in the skin. Here, for efficiently scavenging excess ROS, modulating the microenvironment, and alleviating solar dermatitis, a π-conjugated network polyphthalocyanine supporting a highly surface-exposed Ru active site-based artificial antioxidase (HSE-PPcRu) is designed and fabricated with excellent ROS-scavenging, antioxidant, and anti-inflammatory capabilities. In photodamaged human keratinocyte cells, HSE-PPcRu could modulate mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B signaling pathways, prevent DNA damage, suppress apoptosis, inhibit pro-inflammatory cytokine secretion, and alleviate cell damage. In vivo animal experiments reveal the higher antioxidant and anti-inflammatory efficacies of HSE-PPcRu by reversing the activation of p38 and c-Jun N-terminal kinase, inhibiting expression of cyclooxygenase-2, interleukin-6, interleukin-8, and tumor necrosis factor-α. This work not only provides an idea for alleviating solar dermatitis via catalytically scavenging ROS and modulating the microenvironment but also offers a strategy to design an intelligent conjugated network-based artificial antioxidase with a highly surface-exposed active site.

Kynurenic Acid Plays a Protective Role in Hepatotoxicity Induced by HFPO-DA in Male Mice.

Following its introduction as an alternative to perfluorooctanoic acid, hexafluoropropylene oxide dimer acid (HFPO-DA) has been extensively detected in various environmental matrices. Despite this prevalence, limited information is available regarding its hepatotoxicity biomarkers. In this study, toxicokinetic simulations indicated that under repeated treatment, HFPO-DA in mice serum reached a steady state by the 4th day. To assess its subacute hepatic effects and identify potential biomarkers, mice were administered HFPO-DA orally at doses of 0, 0.1, 0.5, 2.5, 12.5, or 62.5 mg/kg/d for 7 d. Results revealed that the lowest observed adverse effect levels were 0.5 mg/kg/d for hepatomegaly and 2.5 mg/kg/d for hepatic injury. Serum metabolomics analysis identified 34, 58, and 118 differential metabolites in the 0.1, 0.5, and 2.5 mg/kg/d groups, respectively, compared to the control group. Based on weighted gene coexpression network analysis, eight potential hepatotoxicity-related metabolites were identified; among them, kynurenic acid (KA) in mouse serum exhibited the highest correlation with liver injury. Furthermore, liver-targeted metabolomics analysis demonstrated that HFPO-DA exposure induced metabolic migration of the kynurenine pathway from KA to nicotinamide adenine dinucleotide, resulting in the activation of endoplasmic reticulum stress and the nuclear factor kappa-B signaling pathway. Notably, pretreatment with KA significantly attenuated liver injury induced by HFPO-DA exposure in mice, highlighting the pivotal roles of KA in the hepatotoxicity of HFPO-DA.