NF-κB Inflammatory Signaling Pathway Research Articles

SIRT1 exerts protective effects by inhibiting endoplasmic reticulum stress and NF-κB signaling pathways.

Silent information regulator two homolog 1 (SIRT1), an NAD + -dependent histone deacetylase, plays a pivotal regulatory role in a myriad of physiological processes. A growing body of evidence suggests that SIRT1 can exert protective effects in metabolic disorders and neurodegenerative diseases by inhibiting endoplasmic reticulum (ER) stress and the nuclear factor-κB (NF-κB) inflammatory signaling pathway. This review systematically elucidates the molecular mechanisms and biological significance of SIRT1 in regulating ER stress and the NF-κB pathway. On one hand, SIRT1 can deacetylate key molecules in the ER stress pathway, such as glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), PKR-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6), thereby alleviating ER stress. On the other hand, SIRT1 can directly or indirectly remove the acetylation modification of the NF-κB p65 subunit, inhibiting its transcriptional activity and thus attenuating inflammatory responses. Through these mechanisms, SIRT1 can ameliorate insulin resistance in metabolic diseases, exert cardioprotective effects in ischemia-reperfusion injury, and reduce neuronal damage in neurodegenerative diseases. However, it is important to note that while these findings are promising, the complex nature of the biological systems involved warrants further investigation to fully unravel the intricacies of SIRT1's regulatory mechanisms. Nevertheless, understanding the regulatory mechanisms of SIRT1 on ER stress and the NF-κB pathway is of great significance for expanding our knowledge of the pathogenesis of related diseases and exploring new preventive and therapeutic strategies targeting SIRT1.

Litchi Pericarp Extract Treats Type 2 Diabetes Mellitus by Regulating Oxidative Stress, Inflammatory Response, and Energy Metabolism.

Litchi pericarp is rich in polyphenols, and demonstrates significant biological activity. This study assessed the therapeutic effects of litchi pericarp extract (LPE) on type 2 diabetes mellitus in db/db mice. The results showed that LPE ameliorated symptoms of glucose metabolism disorder, oxidative stress, inflammatory response, and insulin resistance in db/db mice. The mechanistic studies indicated that LPE activates adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and suppresses the protein expression of phosphoenolpyruvate carboxykinase (PEPCK), thereby reducing hepatic gluconeogenesis. Additionally, LPE facilitates the translocation of nuclear factor erythroid2-related factor 2 (Nrf2) into the cell nucleus, initiating the transcription of antioxidant factors superoxide dismutase (SOD) and NAD(P)H: quinone oxidoreductase 1 (NQO1), which alleviate oxidative stress and reduce oxidative damage. Furthermore, LPE blocks nuclear factor kappa-B (NF-κB) nuclear translocation and subsequent inflammatory response initiation, thereby reducing inflammation. These findings indicate that LPE addresses type 2 diabetes mellitus by activating the AMPK energy metabolic pathway and regulating the Nrf2 oxidative stress and NF-κB inflammatory signaling pathways.

Forskolin-mediated cAMP activation upregulates TNF-α expression despite NF-κB downregulation in LPS-treated Schwann cells.

Although Schwann cells have been found to play a key role in inflammation and repair following nerve injury, the exact pathway is still unknown. To explore the mechanism by which Schwann cells exert their effects in the neuron microenvironment, we investigated two main inflammatory pathways: the NF-κB and cAMP pathways, and their downstream signaling molecules. In this study, lipopolysaccharide (LPS), a bacterial endotoxin, was used to activate the NF-κB pathway, and forskolin, a plant extract, was used to activate the cAMP pathway. The rat RT4-D6P2T Schwann cell line was treated with 0.1, 1, or 10 μg/mL of LPS, with or without 2 μM of forskolin, for 1, 3, 12, and 24 hours to determine the effects of elevated cAMP levels on LPS-treated cell viability. To investigate the effects of elevated cAMP levels on the expression of downstream signaling effector proteins, specifically NF-κB, TNF-α, AKAP95, and cyclin D3, as well as TNF-α secretion, RT4-D6P2T cells were incubated in the various treatment combinations for a 3-hour time period. Overall, results from the CellTiter-Glo viability assay revealed that forskolin increased viability in cells treated with smaller doses of LPS for 1 and 24 hours. For all time points, 10 μg/mL of LPS noticeably reduced viability regardless of forskolin treatment. Results from the Western blot analysis revealed that, at 10 μg/mL of LPS, forskolin upregulated the expression of TNF-α despite a downregulation of NF-κB, which was also accompanied by a decrease in TNF-α secretion. These results provide evidence that cAMP might regulate TNF-α expression through alternate pathways. Furthermore, although cAMP activation altered AKAP95 and cyclin D3 expression at different doses of LPS, there does not appear to be an association between the expression of AKAP95 or cyclin D3 and the expression of TNF-α. Exploring the possible interactions between cAMP, NF-κB, and other key inflammatory signaling pathways might reveal a potential therapeutic target for the treatment of nerve injury and inflammation.

Flavokawain B inhibits NF-κB inflammatory signaling pathway activation in inflammatory bowel disease by targeting TLR2

Inflammatory bowel disease (IBD) is characterized by recurrent inflammatory reactions in the intestinal mucosa, including ulcerative colitis (UC) and Crohn's disease (CD). The expression of Toll-like receptor 2 (TLR2) has been observed to increase during the progression of IBD. Flavokawain B (FKB), a natural chalcone with potent anti-inflammatory activity, exerts its effects through inhibition of the NF-κB pathway. In this study, we aimed to investigate the effects and mechanisms of FKB targeting TLR2 in IBD. C57BL/6 J mice were treated with 2.5% dextran sulfate sodium (DSS) for 7 days, with administration of FKB or TLR2 inhibitor C29 starting on day 2 to establish the model of IBD. In vitro, bone marrow-derived macrophages (BMDMs) were stimulated with the TLR2 agonist Pam3CSK4 to explore the therapeutic effect of FKB and its pharmacological mechanism. Compared with the model group, the FKB-treated group showed significant reductions in colitis-related injuries in the IBD mouse model, including weight gain, increased colon length and reduced inflammation. FKB decreased the formation of TLR2-MyD88 complex by targeting TLR2, leading to suppression of downstream NF-κB signaling pathway. Similar therapeutic effects were observed in the C29-treated group. Additionally, in vitro data suggested that FKB exerted its anti-inflammatory effect by targeting TLR2 and inhibiting Pam3CSK4-induced activation of the NF-κB pathway. The anti-inflammatory effects of FKB were demonstrated through drug affinity responsive target stability assay and cellular thermal shift assay, revealing its binding affinity to TLR2. By inhibiting the activation of the TLR2/NF-κB signaling pathway, FKB effectively prevented DSS-induced IBD and exhibited promising potential as a therapeutic candidate for IBD treatment.

Ski ameliorates synovial cell inflammation in monosodium iodoacetate-induced knee osteoarthritis

Knee osteoarthritis (KOA) is one of the most common degenerative diseases and is characterized by cartilage degeneration, synovial inflammation, joint stiffness and even loss of motor function. In the clinical treatment of arthritis, conventional analgesic and anti-inflammatory drugs have great side effects. We have evaluated the possibility of the endogenous transcription regulator Ski as an anti-inflammatory alternative in OA through experimental studies in animal models and in vivo and in vitro. Male Sprague‒Dawley rats were injected with monosodium iodoacetate (MIA) into the knee joints to induce symptoms identical to those of human OA. We isolated knee synovial tissue under sterile conditions and cultured primary synovial cells. In vitro, Ski inhibits the proinflammatory factors IL-1β, IL-6 and TNF-α mRNA and protein expression in lipopolysaccharide (LPS)-stimulated fibroblast-like synoviocytes (FLSs) and U-937 cells. In addition, Ski attenuates or inhibits OA-induced synovial inflammation by upregulating the protein expression of the anti-inflammatory factor IL-4 and downregulating the protein expression of downstream molecules related to the NF-κB inflammatory signaling pathway. In vivo, Ski downregulated proinflammatory factors and p–NF–κB p65 in KOA synovial tissue and alleviated pain-related behaviors in KOA rats. These experimental data show that Ski has strong anti-inflammatory activity. Ski is an endogenous factor, and if used in the clinical treatment of OA, the side effects are small. However, the anti-inflammatory mechanism of Ski must be further studied.

Membrane-bound Merkel cell polyomavirus middle T protein constitutively activates PLCγ1 signaling through Src-family kinases.

Merkel cell polyomavirus (MCV or MCPyV) is an alphapolyomavirus causing human Merkel cell carcinoma and encodes four tumor (T) antigen proteins: large T (LT), small tumor (sT), 57 kT, and middle T (MT)/alternate LT open reading frame proteins. We show that MCV MT is generated as multiple isoforms through internal methionine translational initiation that insert into membrane lipid rafts. The membrane-localized MCV MT oligomerizes and promiscuously binds to lipid raft-associated Src family kinases (SFKs). MCV MT-SFK interaction is mediated by a Src homology (SH) 3 recognition motif as determined by surface plasmon resonance, coimmunoprecipitation, and bimolecular fluorescence complementation assays. SFK recruitment by MT leads to tyrosine phosphorylation at a SH2 recognition motif (pMTY114), allowing interaction with phospholipase C gamma 1 (PLCγ1). The secondary recruitment of PLCγ1 to the SFK-MT membrane complex promotes PLCγ1 tyrosine phosphorylation on Y783 and activates the NF-κB inflammatory signaling pathway. Mutations at either the MCV MT SH2 or SH3 recognition sites abrogate PLCγ1-dependent activation of NF-κB signaling and increase viral replication after MCV genome transfection into 293 cells. These findings reveal a conserved viral targeting of the SFK-PLCγ1 pathway by both MCV and murine polyomavirus (MuPyV) MT proteins. The molecular steps in how SFK-PLCγ1 activation is achieved, however, differ between these two viruses.

PSIX-8 Increased Expression of ST6GAL1 and Vegfa Mediate the Inflammatory Signaling Pathway in Feline Hyperthyroidism

Abstract Hyperthyroidism in cats is characterized by increased production of thyroid hormones including thyroxine (T4) and triiodothyronine (T3) and decreased levels of thyroid stimulating hormone (TSH). Older cats are at greater risk of developing hyperthyroidism. The common clinical signs include increased appetite, body weight loss, increased thirst and urination, periodic vomiting, and rapid heart rate. While the etiology of this disease in cats is not clear, it is likely multi-factorial and environmental, nutritional, and immunological factors have been implicated. We assessed the levels of inflammatory markers in thyroid tissue from cats housed in the Hill’s colony, at the natural end-of-life after living full lives. Cats that were diagnosed as having hyperthyroidism by a veterinarian (n = 10, 12.1-18.9 yr) had greater circulating fT4 when compared with controls. Control cats showed no signs of hyperthyroidism (n = 10, 10.9 to 18.6 yr). Histopathological analysis of hematoxylin and eosin-stained thyroid sections showed an increase in follicular cells as well as evidence of colloid reabsorption in cats with hyperthyroid when compared with controls. RNA was extracted from samples collected from cats and gene expression was investigated using the NanoString nCounter platform. Analysis was performed using the nSolver software. There was a significant increase in ST6GAL1 sialyltransferase when compared with controls (1.22 fold; P < 0.05). ST6GAL1 is an enzyme that can post-translationally modify glycoproteins by adding α2-6-linked sialic acids to them. ST6GAL1 can also regulate the NFκB inflammatory signaling pathway by promoting its sustained activation that can potentially lead to inflammation. In the present study we also saw a decrease in NFκB1/p105 (-1.14, ns), a protein that is processed to produce p50, an NFκB binding protein, but a small increase in NFκB2/p100 (1.06, ns), a protein that is processed to produce p52 of the NFκB signaling pathway in hyperthyroid cats when compared with controls. NFκB1 is a transcriptional repressor and a decline in its expression has been reported to contribute to increased inflammation. Further, an increase in NFκB2 may lead to increased activation of NFκB signaling as p52/RelB dimer is a transcriptional activator of NFκB signaling. There was also an increase in VEGFA in hyperthyroid when compared with controls (1.79 fold; P < 0.05). VEGF is an angiogenesis factor and increasing evidence indicates that angiogenesis sustains inflammation. VEGF is produced by endothelial cells, macrophages and activated T-cells and is also a potent chemoattractant for monocytes. While VEGF induces several pro-inflammatory genes including IL-8 and MCP-1, both were downregulated in hyperthyroid in the present study, indicating that the effects of VEGF were likely not mediated by pro-inflammatory IL-8 or MCP-1 in feline hyperthyroidism. Our data indicate that the etiology of hyperthyroidism involves multiple inflammatory signaling pathways and these may represent important therapeutic targets for reducing inflammation in feline hyperthyroidism.

Tree Frog-Derived Cathelicidin Protects Mice against Bacterial Infection through Its Antimicrobial and Anti-Inflammatory Activities and Regulatory Effect on Phagocytes.

Due to excessive use or abuse in the food industry, agriculture, and medicine, many pathogens are developing resistance against conventional antibiotics. Antimicrobial peptides (AMPs) hold promise as effective therapeutic options for the treatment of bacterial infections. Herein, a novel cathelicidin antimicrobial peptide (Zs-CATH) was identified from the tree frog Zhangixalus smaragdinus. Zs-CATH mainly adopted an amphipathic β-sheet structure in a membrane-mimetic environment. It showed broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria in vitro and significantly protected mice from lethal infections induced by Gram-negative bacteria Escherichia coli ATCC 25922 or Gram-positive bacteria Staphylococcus aureus ATCC 25923 in vivo. In addition, Zs-CATH exerted a strong anti-inflammatory effect by neutralizing lipopolysaccharide (LPS) and lipoteichoic acid (LTA) and promoting macrophage M2 polarization, thus inhibiting the secretion of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) and enhancing the production of M2 macrophage markers IL-10, IL-4, and CD206. The MAPK and NF-κB inflammatory signaling pathways and transcriptional activator 6 (STAT6) were involved in this effect. In mice, Zs-CATH rapidly recruited neutrophils and monocytes/macrophages to the abdominal cavity but not T and B lymphocytes. Zs-CATH did not exhibit a direct chemoattractant effect on phagocytes but significantly promoted phagocyte migration in the presence of macrophages. Zs-CATH stimulated macrophages to secrete chemokines CXCL1, CXCL2, and CCL2, which mediated the recruitment of phagocytes. Furthermore, Zs-CATH promoted the production of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs), which are oxygen-dependent and oxygen-independent mechanisms of the microbicidal activity of neutrophils, respectively. Zs-CATH exhibited no toxic side effects on mammalian cells and mice. These findings show that in addition to direct antibacterial activity, Zs-CATH also possesses the ability to modulate immune and inflammatory processes during bacterial infection, showing potential for development as anti-infective and/or anti-inflammatory agents.

Maternal high-fat diet increases the susceptibility of offspring to colorectal cancer via the activation of intestinal inflammation.

A high-fat diet plays a key role in the pathogenesis of colorectal cancer, and this effect on the gut can also occur in the offspring of mothers with a high-fat diet. In this review, we discuss the role of a high-fat diet in the pathogenesis of colorectal cancer and summarize the effects of a maternal high-fat diet on the activation of inflammation and development of colorectal cancer in offspring. Studies have found that a maternal high-fat diet primarily induces an inflammatory response in the colorectal tissue of both the mother herself and the offspring during pregnancy. This leads to the accumulation of inflammatory cells in the colorectal tissue and the release of inflammatory cytokines, which further activate the NF-κb and related inflammatory signaling pathways. Research suggests that high levels of lipids and inflammatory factors from mothers with a high-fat diet are passed to the offspring through the transplacental route, which induces colorectal inflammation, impairs the intestinal microecological structure and the intestinal barrier, and interferes with intestinal development in the offspring. This in turn activates the NF-κb and related signaling pathways, which further aggravates intestinal inflammation. This process of continuous inflammatory stimulation and repair may promote the uncontrolled proliferation of colorectal mucosal cells in the offspring, thus increasing their susceptibility to colorectal cancer.

Abstract 1481: MAPK and NF-kappaB signaling converge on the epigenome to transcriptionally activate genes involved in pancreatic cancer metastasis

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent and highly aggressive type of pancreatic neoplasm. Unfortunately, most patients will present with unresectable, locally advanced, or metastatic disease at the time of diagnosis. Current treatment methods (gemcitabine and nab-paclitaxel, FOLFIRINOX) are not sufficient for patients with late-stage disease and only modestly improve survival. Difficulties in treating PDAC lie in the characteristics of PDAC tumors. They are highly heterogeneous, have multiple signaling pathway alterations, and are highly metastatic with a dense tumor microenvironment (TME). Hence, PDAC remains one of the most lethal malignancies with a 5-year survival rate below 10%.The KRAS mutation is a hallmark of PDAC, occurring early in 95% of pancreatic neoplasms. The mutant KRAS protein constitutively activates the mitogen-activated protein kinase (MAPK) signaling pathway to sustain PDAC pathogenesis. Although the mutant KRAS gene is the initiating molecular alteration, chronic inflammation accelerates PDAC progression to a highly aggressive and therapy-resistant cancer. Our study shows that MAPK and the nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) inflammatory signaling pathway synergize to promote PDAC progression. Live cell imaging analysis of PDAC cell lines after the simultaneous hyperactivation of MAPK and NF-κB signaling by epidermal growth factor (EGF) and tumor necrosis factor alpha respectively (TNF alpha), showed significant increases in cell migration. An integrated genome-wide epigenetic and transcriptomic analysis (ChIPseq and RNAseq) after the simultaneous stimulation of both pathways revealed significant increases in the occupancy of the active mark, H3K27ac. This was observed around transcription start sites of a subset of genes involved in cell polarity, migration, and subtype switch, processes known to be important for tumor aggressiveness. Epigenome mapping of the transcription factors FOSL1 and RELA, which are downstream targets of the MAPK and NF-κB signaling pathways respectively, show their co-occupancy in the H3K27ac-enriched regions. Furthermore, loss-of-function approaches show the synergistic effect of both MAPK and NF-κB hyperactivation on the migration capacity in vitro and in vivo. Based on these observations, we aim to delineate the molecular mechanism involved in the synergism, investigate the role of the TME, and decipher the signaling interactions between PDAC tumor cells and cells of the TME. This study is the first comprehensive analysis of the synergism between MAPK and NF-κB signaling and will provide novel insights into the development of mechanism-based therapeutic approaches. Citation Format: Joana E. Aggrey-Fynn, Feda H. Hamdan, Alexander Q. Wixom, Thomas L. Ekstrom, Steven A. Johnsen. MAPK and NF-kappaB signaling converge on the epigenome to transcriptionally activate genes involved in pancreatic cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1481.

Low vitamin D status is associated with inflammatory response in older patients with cerebral small vessel disease.

This study aimed to determine the association of the NF-κB inflammatory signaling pathway with vitamin D status in older cerebral small vessel disease (SVD) patients. We measured serum 25(OH)D, pro-and anti-inflammatory cytokines, and mRNA levels of the vitamin D-activating enzyme, CYP27B1, as well as NF-kB, COX-2, the chemokine-CCL2, IL-1β, IL-6, TNF-α, TGF-β, and IL-10, in cerebral SVD patients aged ≥60years presenting with vascular dementia and age and gender-matched healthy controls. Low vitamin D status (insufficiency: serum 25(OH)D 12-20ng/ml; deficiency: ≤12ng/ml) was more prevalent among patients compared to controls. The mRNA levels of NF-kB, COX-2, CCL2, IL-1β, and IL-6, and serum levels of pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, and TNF-α) were significantly higher in cases compared to controls. There was a significant correlation between CYP27B1 and NF-kB, COX-2, CCL2, and IL-1β gene expression. Serum IL-1α, IL-1β, and IL-6 concentrations and the expression of CCL-2, NF-kB2, and NF-kB3 genes were higher in vitamin D-deficient subjects compared to vitamin D-sufficient subjects. There was a significant negative correlation between serum 25(OH)D and IL-1α, IL-6, and TNF-α, and a positive correlation between 25(OH)D and IL-10. Low vitamin D is associated with an inflammatory response via NF-kB signaling, which could play a role in the etio-pathogenesis of SVD. Further large-scale studies are required to validate our findings.

Dl-3-n-Butylphthalide Protects against Memory Deficits in Vascular Dementia Rats by Attenuating Pyroptosis via TLR-4/NF-κB Signaling Pathway

Introduction: Inflammation is closely associated with the pathogenesis of vascular dementia (VD). Dl-3-n-butylphthalide (NBP) is a small molecule compound extracted from the seeds of Chinese celery, which have anti-inflammatory properties in animal models of acute ischemia and patients with stroke. In this experiment, we studied the protective effects of NBP in a rat model of VD induced by permanent bilateral occlusion of the common carotid arteries and investigated the role of the TLR-4/NF-κB inflammatory signaling pathway in the pathology of VD. Methods: The Morris water maze test was used to evaluate cognitive deficits in the VD rats. Western blot, immunohistochemistry, and PCR analyses were used to analyze the molecular basis of the inflammatory response. Results: NBP significantly improved the learning and memory ability of VD rats. With regard to the protective mechanism, the results showed that NBP significantly downregulated the relative expression of Cleaved Cas-1/Cas-1 and Cleaved GSDMD/GSDMD. Moreover, NBP decreased the levels of the TLR-4 and NF-κB (P65) protein and phosphorylation of P65 in the hippocampus of VD rats via the TLR-4/NF-κB signaling pathway. Conclusion: These findings demonstrate that NBP protects against memory deficits in permanent bilateral common carotid artery occlusion-induced VD rats by attenuating pyroptosis via the TLR-4/NF-κB signaling pathway.

The anti-inflammatory activity of GABA-enriched Moringa oleifera leaves produced by fermentation with Lactobacillus plantarum LK-1.

Gamma-aminobutyric acid (GABA), one of the main active components in Moringa oleifera leaves, can be widely used to treat multiple diseases including inflammation. In this study, the anti-inflammatory activity and the underlying anti-inflammatory mechanism of the GABA-enriched Moringa oleifera leaves fermentation broth (MLFB) were investigated on lipopolysaccharide (LPS)-induced RAW 264.7 cells model. The key active components changes like total flavonoids, total polyphenols and organic acid in the fermentation broth after fermentation was also analyzed. ELISA, RT-qPCR and Western blot results indicated that MLFB could dose-dependently inhibit the secretions and intracellular expression levels of pro-inflammatory cytokines like 1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α). Furthermore, MLFB also suppressed the expressions of prostaglandin E2 (PGE2) and inducible nitric oxide synthase (iNOS). Moreover, the mRNA expressions of the key molecules like Toll-like receptor 4 (TLR-4) and nuclear factor (NF)-κB in the NF-κB signaling pathway were also restrained by MLFB in a dose-dependent manner. Besides, the key active components analysis result showed that the GABA, total polyphenols, and most organic acids like pyruvic acid, lactic acid as well as acetic acid were increased obviously after fermentation. The total flavonoids content in MLFB was still remained to be 32 mg/L though a downtrend was presented after fermentation. Our results indicated that the MLFB could effectively alleviate LPS-induced inflammatory response by inhibiting the secretions of pro-inflammatory cytokines and its underlying mechanism might be associated with the inhibition of TLR-4/NF-κB inflammatory signaling pathway activation. The anti-inflammatory activity of MLFB might related to the relative high contents of GABA as well as other active constituents such as flavonoids, phenolics and organic acids in MLFB. Our study provides the theoretical basis for applying GABA-enriched Moringa oleifera leaves as a functional food ingredient in the precaution and treatment of chronic inflammatory diseases.

The Molecular Basis of the Anti-Inflammatory Property of Astragaloside IV for the Treatment of Diabetes and Its Complications.

Astragali Radix is a significant traditional Chinese medication, and has a long history of clinical application in the treatment of diabetes mellitus (DM) and its complications. AS-IV is an active saponin isolated from it. Modern pharmacological study shows that AS-IV has anti-inflammatory, anti-oxidant and immunomodulatory activities. The popular inflammatory etiology of diabetes suggests that DM is a natural immune and low-grade inflammatory disease. Pharmacological intervention of the inflammatory response may provide promising and alternative approaches for the prevention and treatment of DM and its complications. Therefore, this article focuses on the potential of AS-IV in the treatment of DM from the perspective of an anti-inflammatory molecular basis. AS-IV plays a role by regulating a variety of anti-inflammatory pathways in multiple organs, tissues and target cells throughout the body. The blockade of the NF-κB inflammatory signaling pathway may be the central link of AS-IV's anti-inflammatory effect, resulting in a reduction in the tissue structure and function damage stimulated by inflammatory factors. In addition, AS-IV can delay the onset of DM and its complications by inhibiting inflammation-related oxidative stress, fibrosis and apoptosis signals. In conclusion, AS-IV has therapeutic prospects from the perspective of reducing the inflammation of DM and its complications. An in-depth study on the anti-inflammatory mechanism of AS-IV is of great significance for the effective use of Chinese herbal medicine and the promotion of its status and influence on the world.

Discrimination of serum metabolomics profiles in infants with sepsis, based on liquid chromatography-mass spectrometer

Sepsis is one of the most important problems to be addressed in pediatrics, characterized by insidious onset, rapid progression, and high rates of severe infection and even mortality. Biomarkers with high sensitivity and robustness are urgently required for the early diagnosis of infant sepsis. Serum metabolomic approaches based on liquid chromatography-mass spectrometry were used to analyze the samples from 30 infants with sepsis at an early stage and 30 infants with noninfectious diseases. Multivariate statistical analysis was used to screen for differential metabolites and ROC curves were generated to find potential biomarkers. Six metabolites, including phosphatidic acid (PA (8:0/14:0)), phosphatidyl ethanolamine (PE (16:0/18:2(9Z,12Z))), cytidine 5'-diphosphocholine (CDP-CHO), sphingomyelin (SM (d18:0/16:1(9Z))), prolylhydroxyproline and phosphorylcholine (P-CHO), were identified between the two groups. ROC curve analysis showed that prolylhydroxyproline (AUC = 0.832) had potential diagnostic values for infant sepsis. The AUC value was 0.859 (CI: 0.764, 0.954) in the combined model. Prolylhydroxyproline were found to be correlated with CRP and PCT levels, while PE and CDP-CHO associated with PCT levels. Pathway analysis indicated that glycerophospholipid metabolism, aminoacyl-tRNA biosynthesis and necroptosis pathways played important roles in infant sepsis. Network analysis showed that the differential metabolites were linked to ERK/ MAPK, NF-κB, AMPK, mTOR, and other classical inflammatory and metabolic signaling pathways. This study identified serum metabolite profiles and three metabolites as potential biomarkers in infants with sepsis. The findings will help improve the early diagnosis of sepsis in infants.

A Co(II) compound: photocatalytic activity and application value in trigeminal neuralgia with minimally invasive interventional therapy guided by CT

ABSTRACT A new thermostable Co(II)-based compound, namely [Co3(L)2(HTEA)2]n (1, HL = isonicotinic acid, H3TEA = triethanolamine), has been successfully synthesized by the isomicotinic acid ligand and HTEA anion. The photocatalytic property of 1 was also investigated, indicating that it shows excellent photocatalytic activity for the degradation of Rhodamine B (MB) solution under the UV light irradiation. For the treatment of trigeminal neuralgia, the content of the inflammatory cytokines released into the trigeminal ganglion tissue fluid was measured with enzyme-linked immunosorbent assay (ELISA) assay. Then, the real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) was conducted and the activation of the nuclear factor kappa-B (NF-κB) inflammatory signaling pathway was measured.

MiR-210-3p Promotes Obesity-Induced Adipose Tissue Inflammation and Insulin Resistance by Targeting SOCS1-Mediated NF-κB Pathway.

Under the condition of chronic obesity, an increased level of free fatty acids along with low oxygen tension in the adipose tissue creates a pathophysiological adipose tissue microenvironment (ATenv), leading to the impairment of adipocyte function and insulin resistance. Here, we found the synergistic effect of hypoxia and lipid (H + L) surge in fostering adipose tissue macrophage (ATM) inflammation and polarization. ATenv significantly increased miR-210-3p expression in ATMs which promotes NF-κB activation-dependent proinflammatory cytokine expression along with the downregulation of anti-inflammatory cytokine expression. Interestingly, delivery of miR-210-3p mimic significantly increased macrophage inflammation in the absence of H + L co-stimulation, while miR-210-3p inhibitor notably compromised H + L-induced macrophage inflammation through increased production of suppressor of cytokine signaling 1 (SOCS1), a negative regulator of the NF-κB inflammatory signaling pathway. Mechanistically, miR-210 directly binds to the 3'-UTR of SOCS1 mRNA and silences its expression, thus preventing proteasomal degradation of NF-κB p65. Direct delivery of anti-miR-210-3p LNA in the ATenv markedly rescued mice from obesity-induced adipose tissue inflammation and insulin resistance. Thus, miR-210-3p inhibition in ATMs could serve as a novel therapeutic strategy for managing obesity-induced type 2 diabetes.

Piezo1 channel-mediated Ca2+ signaling inhibits lipopolysaccharide-induced activation of the NF-κB inflammatory signaling pathway and generation of TNF-α and IL-6 in microglial cells.

Microglial cells are crucial in maintaining central nervous system (CNS) homeostasis and mediating CNS disease pathogenesis. Increasing evidence supports that alterations in the mechanical properties of CNS microenvironments influence glial cell phenotypes, but the mechanisms regulating microglial cell function remain elusive. Here, we examined the mechanosensitive Piezo1 channel in microglial cells, particularly, how Piezo1 channel activation regulates pro-inflammatory activation and production of pro-inflammatory cytokines, using BV2 and primary microglial cells. Piezo1 expression in microglial cells was detected both at mRNA and protein levels. Application of Piezo1 channel activator Yoda1 induced Ca2+ flux to increase intracellular Ca2+ concentration that was reduced by treatment with ruthenium red, a Piezo1 inhibitor, or Piezo1-specific siRNA, supporting that Piezo1 functions as a cell surface Ca2+ -permeable channel. Priming with lipopolysaccharide (LPS) induced microglial cell activation and production of TNF-α and IL-6, which were inhibited by treatment with Yoda1. Furthermore, LPS priming induced the activation of ERK, p38 MAPKs, and NF-κB. LPS-induced activation of NF-κB, but not ERK and p38, was inhibited by treatment with Yoda1. Yoda1-induced inhibition was blunted by siRNA-mediated depletion of Piezo1 expression and, furthermore, treatment with BAPTA-AM to prevent intracellular Ca2+ increase. Collectively, our results support that Piezo1 channel activation downregulates the pro-inflammatory function of microglial cells, especially production of TNF-α and IL-6, by initiating intracellular Ca2+ signaling to inhibit the NF-κB inflammatory signaling pathway. These findings reveal Piezo1 channel activation as a previously unrecognized mechanism regulating microglial cell function, raising an interesting perspective on targeting this molecular mechanism to alleviate neuroinflammation and associated CNS pathologies.

Micellar nanoparticles inhibit the postoperative inflammation, recurrence and pulmonary metastasis of 4T1 breast cancer by blocking NF-κB pathway and promoting MDSCs depletion

The progression of breast cancer can stimulate the production of myeloid-derived suppressor cells (MDSCs). These cells with significant immunosuppressive activity play a key role in promoting the formation of pulmonary inflammatory and immunosuppressive microenvironment, namely pre-metastatic niche (PMN). Surgical resection of tumors often leads to strong inflammatory reactions, and the produced circulating tumor cells (CTCs) can implant into PMN to promote the recurrence and pulmonary metastasis of breast cancer. Therefore, we developed a hyaluronic acid (HA)-coated chitosan oligosaccharide-all-trans-retinoic-acid (COS-ATRA) micellar nanoparticle loaded with chemotherapeutic drug doxorubicin (DOX) (HA@CA/DOX NPs). The hydrophilic segment COS and hydrophobic segment ATRA both blocked NF-κB inflammatory signaling pathway in 4T1 tumor cells and MDSCs and alleviated the inflammation after resection. Besides, ATRA also significantly depleted MDSCs in lungs and tumors, thereby regulating the inflammatory and immunosuppressive microenvironment and inhibiting the formation of PMN. HA coated on the surface of nanoparticles shielded the excessive positive charge and achieved tumor targeting through CD44 on the surface of tumor cells. This drug delivery system combined with anti-inflammation and chemotherapy significantly inhibited the postoperative recurrence and pulmonary metastasis of breast cancer.

Specific PFKFB3 Inhibitor Memorably Ameliorates Intervertebral Disc Degeneration via Inhibiting NF-κB and MAPK Signaling Pathway and Reprogramming of Energy Metabolism of Nucleus Pulposus Cells.

Intervertebral disc (IVD) degeneration (IVDD) is a characteristic of the dominating pathological processes of nucleus pulposus (NP) cell senescence, abnormal synthesis and irregular distribution of extracellular matrix (ECM), and tumor necrosis factor-α (TNF-α) induced inflammation. Nowadays, IVD acid environment variation which accelerates the pathological processes mentioned above arouses researchers' attention. KAN0438757 (KAN) is an effective inhibitor of selective metabolic kinase phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) that has both energy metabolism reprogramming and anti-inflammatory effects. Therefore, a potential therapeutic benefit of KAN lies in its ability to inhibit the development of IVDD. This study examined in vitro KAN toxicity in NP primary cells (NPPs). Moreover, KAN influenced tumor necrosis factor-α (TNF-α) induced ECM anabolism and catabolism; the inflammatory signaling pathway activation and the energy metabolism phenotype were also examined in NPPs. Furthermore, KAN's therapeutic effect was investigated in vivo using the rat tail disc puncture model. Phenotypically speaking, the KAN treatment partially rescued the ECM degradation and glycolysis energy metabolism phenotypes of NPPs induced by TNF-α. In terms of mechanism, KAN inhibited the activation of MAPK and NF-κB inflammatory signaling pathways induced by TNF-α and reprogramed the energy metabolism. For the therapeutic aspect, the rat tail disc puncture model demonstrated that KAN has a significant ameliorated effect on the progression of IVDD. To sum up, our research successfully authenticated the potential therapeutic effect of KAN on IVDD and declaimed its mechanisms of both novel energy metabolism reprogramming and conventional anti-inflammation effect.