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BACKGROUND: Cartilage harvest and transplantation is a common surgery using costal, auricular, and septal cartilage for craniofacial reconstruction. However, absorption and warping of the cartilage grafts can occur due to inflammatory factors associated with wound healing. Transcription factor nuclear factor-κB (NF-κB) is activated by the various stimulation such as interleukin-1 (IL-1), and plays a central role in the transactivation of this inflammatory cytokine gene. Inhibition of NF-κB may have anti-inflammatory effects. The aim of this study was to explore the potential of an NF-κB decoy oligodeoxynucleotide (Decoy) as a chondroprotective agent. MATERIALS AND METHODS: Safe and efficacious concentrations of Decoy were assessed using rabbit nasal septal chondrocytes (rNSChs) and assays for cytotoxicity, proteoglycan (PG) synthesis, and PG turnover were carried out. The efficacious concentration of Decoy determined from the rNSChs was then applied to human nasal septal cartilage (hNSC) in vitro and analyzed for PG turnover, the levels of inflammatory markers, and catabolic enzymes in explant-conditioned culture medium. RESULTS: Over the range of Decoy conditions and concentrations, no inhibition of PG synthesis or cytotoxicity was observed. Decoy at 10 μM effectively inhibited PG degradation in the hNSC explant, prolonging PG half-life by 63% and decreasing matrix metalloprotease 3 (MMP-3) by 70.7% (p = 0.027). CONCLUSIONS: Decoy may be considered a novel chondroprotective therapeutic agent in cartilage transplantation due to its ability to inhibit cartilage degradation due to inflammation cytokines.

Gwakhyangjeonggi-san (GJS) is a traditional herbal medicine used in East Asia for the treatment of symptoms involving lower intestinal abnormalities; however, the effects of GJS on innate immunity and its cellular mechanisms of action have not been elucidated. In this study, we assessed the immune-enhancing activity and underlying mechanisms of GJS using RAW 264.7 murine macrophages. The results showed that GJS treatment significantly increased the secretion of nitric oxide and cytokines and their mRNA expression in macrophage RAW 264.7 cells without causing cytotoxicity. GJS treatment also significantly increased the production of reactive oxygen species, as well as inducing phagocytic activity, adhesion function, and migration ability, all of which improved the immune response. In addition, GJS activated nuclear factor-κB by promoting the phosphorylation and degradation of inhibitor of nuclear factor-κB alpha. Furthermore, GJS markedly increased the phosphorylation of mitogen-activated protein kinase in RAW 264.7 cells. These findings indicate that GJS has potential value as a dietary supplement for strengthening immunity. [ABSTRACT FROM AUTHOR]

Introduction: Nuclear factor kappa (NF-κB) plays a key role in cancer cell proliferation; thus, small molecule inhibitors of NF-κB activity can effectively inhibit breast cancer (BC) progression. We have previously reported oxazine and piperazine-linked pyrimidines as novel anti-cancer agents that can suppress NF-κB activation in BC cells. Moreover, the TRX-01 compound, an oxazine-linked pyrimidine, inhibited MCF-7 cells at a concentration of 9.17 µM in the Alamar Blue assay. Methods: This work involved the analysis of frontier molecular orbitals, HOMO-LUMO interactions, and molecular electrostatic potential for the TRX-01 structure. Additionally, the TRX-01 compound was studied for cytotoxicity, and migration as well as invasion assays were performed on BC cells. Results: Finally, TRX-01 blocked the translocation of NF-κB from the cytoplasm to the nucleus in MCF-7 cells and reduced NF-κB and IκBα levels in a dose-dependent manner. It also suppressed migratory and invasive properties of BC cells. Conclusion: Overall, the data indicates that TRX-01 can function as a novel blocker of BC growth and metastasis by targeting NF-κB activation. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) play a pivotal role in a variety of physiologically relevant processes, including lung inflammation. Recent attention has been directed toward EV-derived microRNAs (miRNAs), such as miR-191-5p, particularly in the context of inflammation. Here, we investigated the impact of miR-191-5p-enriched EVs on the activation of NF-κB and the expression of molecules associated with inflammation such as interleukin-8 (IL-8). To this aim, cells of bronchial epithelial origin, 16HBE, were transfected with miR-191-5p mimic and inhibitor and subsequently subjected to stimulations to generate EVs. Then, bronchial epithelial cells were exposed to the obtained EVs to evaluate the activation of NF-κB and IL-8 levels. Additionally, we conducted a preliminary investigation to analyze the expression profiles of miR-191-5p in EVs isolated from the plasma of patients diagnosed with chronic obstructive pulmonary disease (COPD). Our initial findings revealed two significant observations. First, the exposure of bronchial epithelial cells to miR-191-5p-enriched EVs activated the NF-kB signaling and increased the synthesis of IL-8. Second, we discovered the presence of miR-191-5p in peripheral blood-derived EVs from COPD patients and noted a correlation between miR-191-5p levels and inflammatory and functional parameters. Collectively, these data corroborate and further expand the proinflammatory role of EVs, with a specific emphasis on miR-191-5p as a key cargo involved in this process. Consequently, we propose a model in which miR-191-5p, carried by EVs, plays a role in airway inflammation and may contribute to the pathogenesis of COPD. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mesenchymal stem cells possess characteristics such as rapid renewal, targeted homing, tissue repair, and immune regulation, which provide potential for the treatment of inflammatory diseases. In most inflammatory diseases, interleukin-1β is highly expressed. Both exogenous and endogenous mesenchymal stem cells unavoidably exist in an environment with high interleukin -1β concentration. OBJECTIVE: To study the interaction of interleukin-1β with mesenchymal stem cells in inflammatory environment and the mechanism of its influence on the migration and adhesion of mesenchymal stem cells to provide a theoretical basis for adjusting stem cell therapy strategies. METHODS: The first author searched for studies involving interleukin-1β enhancing migration and adhesion of mesenchymal stem cells by computer on CNKI, WanFang, VIP, PubMed, and Web of Science using search terms “interleukin-1β, mesenchymal stem cell, nuclear factor-κB, MAPK, ERK, p38, migration, adhesion” in Chinese and English. The literature tracing method was also used to search for some of the literature. Finally, 65 articles were included in the review analysis. RESULTS AND CONCLUSION: (1) In the inflammatory environment, interleukin-1β can regulate the migration and adhesion ability of mesenchymal stem cells. This effect may be achieved by recruiting IRAK1 through interleukin-1RI and then activating TAK1 and IKK in turn. After IKK phosphorylation, nuclear factor-κB and ERK signaling pathways are activated or CXCR expression is upregulated through the p38 pathway to promote mesenchymal stem cell migration and adhesion. However, further standardized research needs to be carried out based on the genetic background of mesenchymal stem cells, the dose and processing time of interleukin-1β. (2) In vitro experiments using pre-stimulated mesenchymal stem cells with interleukin-1β can change the survival environment of mesenchymal stem cells and alter their secretion factors to make them develop towards a more anti-inflammatory direction. On the other hand, under the premise of producing higher levels of anti-inflammatory and pro-nutrient factors, extracted mesenchymal stem cell exosomes can exert antiinflammatory effects. (3) It has been observed in various animal disease models that pre-stimulating mesenchymal stem cells with interleukin-1β regulates their immune regulation ability, thereby affecting the development and outcome of inflammation. However, this is limited to preclinical basic research only; further verification on efficacy and safety of stem cell therapy with interleukin-1β pre-treated mesenchymal stem cells is required in clinical settings. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a rare and progressive disorder that affects the pulmonary vasculature. Although recent developments in pharmacotherapy have extended the life expectancy of PAH patients, their 5‐year survival remains unacceptably low, underscoring the need for multitarget and more comprehensive approaches to managing the disease. This should incorporate not only medical, but also lifestyle interventions, including dietary changes and the use of nutraceutical support. Among these strategies, n‐3 polyunsaturated fatty acids (n‐3 PUFAs) are emerging as promising agents able to counteract the inflammatory component of PAH. In this narrative review, we aim at analysing the preclinical evidence for the impact of n‐3 PUFAs on the pathogenesis and the course of PAH. Although evidence for the role of n‐3 PUFAs deficiencies in the development and progression of PAH in humans is limited, preclinical studies suggest that these dietary components may influence several aspects of the pathobiology of PAH. Further clinical research should test the efficacy of n‐3 PUFAs on top of approved clinical management. These studies will provide evidence on whether n‐3 PUFAs can genuinely serve as a valuable tool to enhance the efficacy of pharmacotherapy in the treatment of PAH. [ABSTRACT FROM AUTHOR]

To investigate the effect and mechanism of sanguinarine (SAN) on osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) treated with tumor necrosis factor-α (TNF-α). hPDLSCs were divided into 6 groups: Control group, TNF-α group, TNF-α+0.1SAN group, TNF-α+1SAN group, TNF-α+10SAN group and TNF-α+100SAN group. All hPDLSCs were cultured in osteogenic induction medium. Except Control group, 10 ng/mL TNF-α was added to the culture medium of other groups. 0, 0.1, 1, 10, 100 μmol/L sanguinarine were added to the culture medium of TNF-α+0.1SAN group, TNF-α+1SAN group, TNF-α+10SAN group and TNF-α+100SAN group, respectively. HPDLSCs of all groups were cultured at 37 ℃ and 5% CO2 for 21 days. The activity of alkaline phosphatase (ALP) was detected by visible light colorimetry. The formation of calcified nodules was observed by alizarin red staining, and OD562 nm (representing the amount of calcified nodules) was counted. The transcription levels of Runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), osterix (OSX), cementum attachment protein (CAP) and Smad4 were detected by qRT-PCR. The phosphorylation level of NF-kappa B (NF-κB) p65 was detected by Western blot. Compared with that in the Control group, the relative ALP activity, amount of calcified nodules, and the relative expression of RUNX2, OCN, OSX, CAP and Smad4 mRNA in TNF-α group decreased (P<0.05), while p-NF-κB p65/NF-κB p65 increased (P<0.05). Compared with that in the TNF-α group, the relative ALP activity, amount of calcified nodules, RUNX2, OCN, OSX, CAP and Smad4 mRNA expression of TNF-α+1SAN group, TNF-α+10SAN group and TNF-α+100SAN group increased (P<0.05), while p-NF-κB p65/NF-κB p65 decreased (P<0.05). Sanguinarine can promote the osteogenic differentiation of hPDLSCs treated with TNF-α, and the mechanism may be related to the inhibition of the activation of NF-κB. Sanguinarine may be a candidate drug to promote the osteogenic differentiation of hPDLSCs in inflammatory microenvironment. [ABSTRACT FROM AUTHOR]

Objective To observe the neuroinflammatory response and the expression of PI3K/AKT signaling pathway-related proteins in brain tissues of rats with intracerebral hemorrhage (ICH ) after intraperitoneal injection of kaempferol in order to explore the inhibitory effect and mechanism of kaempferol on the neuroinflammatory response after ICH in rats. Methods Seventy-two SD rats were randomly divided into four groups： the kaempferol group, the kaempferol + PI3K inhibitor LY294002 group (inhibitor group), the ICH group, and the sham operation group, respectively. The model of ICH was established in the kaempferol group, and then kaempferol 20 mg/(kg. d) was injected intraperitoneally once a day for 3 consecutive days. In the inhibitor group, PI3K inhibitor LY294002(10 µL, 10 mmol/L) was injected into the lateral ventricle before ICH was induced, and the other steps were the same as those in the kaempferol group. After the ICH model was established, the rats in the ICH group were intraperitoneally injected with the same volume of normal saline once a day for 3 consecutive days. The ICH model was not established in the sham operation group, and the equal volume of normal saline was injected intraperitoneally with the same method as the ICH group. At the end of the treatment, the neuroinflammatory response of brain tissues in each group was observed, including the degree of neurological deficit (mNSS score), the proportion of water content in the brain tissues, the morphological structure of tissue around cerebral hematoma, the number and morphology of microglia in brain tissue, the expression levels of microglia marker Iba-1 and interleukin-1β(IL-1β), interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α) in the brain tissues, and the expression of phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) signaling pathway-related proteins (P-PI3K/PI3K, PAKT/AKT, P-NF-κB p65/NF-κB p65) in the brain tissues. Results Compared with the sham operation group, the neurological function score and the proportion of water content in brain tissue increased (all P<0. 05), and the tissue arrangement around the hematoma was disordered, the intercellular space was enlarged, a large number of inflammatory cells and red blood cells were infiltrated, and activated microglia were observed under immunofluorescence, the relative expression of Iba-1 protein in brain tissue increased, and the expression levels of inflammatory factors such as IL-1β, IL-6 and TNF-α in the brain tissue increased in the ICH group (all P<0. 05). Compared with the ICH group, the nerve function score and brain tissue water proportion decreased (all P<0. 05), and brain tissue pathological morphology was improved, the microglia tended to resting state changes, Iba-1 protein expression was lower, and the expression levels of IL-1β, IL-6 and TNFα in the brain tissues decreased in the kaempferol group (all P<0. 05). Compared with the kaempferol group, the neurological function score and the proportion of water content in the brain tissues significantly increased, the tissues around the hematoma were more disorderly arranged, with more inflammatory cells and red blood cells infiltration and increased activated microglia, the relative expression of Iba-1 protein in brain tissue increased, and the levels of IL-1β, IL-6 and TNF-α in the brain tissues increased in the inhibitor group (all P<0. 05). Compared with the sham operation group, the P-PI3K/ PI3K and P-AKT/AKT decreased, and the P-NF-κB p65/NF-κB p65 increased in the ICH group (all P<0. 05). Compared with the ICH group, the ratios of P-PI3K/PI3K and P-AKT/AKT increased, and the ratio of P-NF-κb p65/NF-κB p65 decreased in the kaempferol group (all P<0. 05). Compared with the kaempferol group, the ratio of P-PI3K/PI3K and P-AKT/AKT decreased, and the ratio of the P-NF-κb p65/NF-κB p65 increased in the inhibitor group (all P<0. 05). Conclusions Intraperitoneal injection of kaempferol can reduce the neuroinflammatory response and activate PI3K/AKT signaling pathway in the brain tissues of rats with ICH. Kaempferol can effectively inhibit the neuroinflammatory response after ICH in rats possibly by regulating the PI3K/AKT signaling pathway. [ABSTRACT FROM AUTHOR]

BACKGROUND: Inflammation is one of the important factors that induce cerebral ischemia-reperfusion injury. Studies have shown that electroacupuncture can effectively reduce inflammation after ischemic stroke and improve the symptoms of neurological deficits, but the mechanism is not clear. OBJECTIVE: To observe the effect of electroacupuncture on Toll-like receptor 4/nuclear factor-κB in rats with cerebral ischemia-reperfusion injury. METHODS: Forty-eight male Sprague-Dawley rats were randomly divided into sham operation group, model group and electroacupuncture group, with 16 rats in each group. The rat model of cerebral ischemia-reperfusion injury was prepared by middle cerebral artery occlusion. At 24 hours after modeling, the rats in the electroacupuncture group were treated with electroacupuncture, once a day, 20 minutes each time, for a total of 5 days. The sham operation group and the model group did not do any intervention. After 5 days of intervention, Longa method was used to evaluate the degree of neurological injury in rats. Triphenyl tetrazolium chloride staining and hematoxylin-eosin staining were used to measure the volume of cerebral infarction and the pathological changes of brain tissue in rats. Serum interleukin-6, interleukin-18 and tumor necrosis factor-α were detected by ELISA. Expressions of Toll-like receptor 4 and nuclear factor-κB in the cerebral cortex at mRNA and protein levels were detected by fluorescence quantitative PCR and western blot, respectively. RESULTS AND CONCLUSION: Compared with the sham operation group, the neurological function scores, serum interleukin-6, interleukin-18, and tumor necrosis factor-α levels, Toll-like receptor 4 and nuclear factor-κB mRNA and protein expression levels were significantly higher in the model group (P < 0.01). Compared with the model group, electroacupuncture significantly reduced the neurological function scores, serum interleukin-6, interleukin-18, and tumor necrosis factor-α levels, Toll-like receptor 4 and nuclear factor-κB mRNA and protein expression levels (P < 0.05, P < 0.01). Compared with the sham operation group, the volume of cerebral infarction in the model group increased significantly (P < 0.01). Compared with the model group, the volume of cerebral infarction in the electroacupuncture group decreased (P < 0.05). In the model group, the arrangement of neurons was disordered, some nerve cells disappeared, nuclei presented with pyknosis and incomplete structure. After electroacupuncture intervention, the degree of neuronal degeneration and neuronal loss in the cerebral cortex of rats were reduced compared with those in the model group. To conclude, electroacupuncture can significantly improve the neurobehavior of rats with cerebral ischemia-reperfusion injury, reduce brain tissue injury, and effectively reduce the level of serum inflammatory factors. The mechanism may be related to the inhibition of Toll-like receptor 4/nuclear factor-κB signaling pathway. [ABSTRACT FROM AUTHOR]

BACKGROUND: The nuclear factor-κB signaling pathway plays an important role in the pathogenesis of osteoporosis. In recent years, increasing studies have shown that terpenoid herbal monomer compounds can inhibit the activity of bone resorbing cells and promote the differentiation of bone forming cells via the nuclear factor-κB signaling pathway, thus reducing bone resorption and increasing bone formation, which has certain preventive and therapeutic effects on osteoporosis. OBJECTIVE: By analyzing and summarizing the domestic and international literature, to investigate the relationship between nuclear factor-κB signaling pathway and osteoporosis in depth, elucidate the mechanism of terpenoid monomer compounds in regulating the nuclear factor-κB signaling pathway to prevent osteoporosis, and systematically summarize the terpenoid monomer compounds targeting to regulate the nuclear factor-κB signaling pathway to prevent osteoporosis. METHODS: According to the proposed inclusion and exclusion criteria, two researchers searched for relevant articles published from database inception to December 2022 in CNKI and PubMed using the search terms “NF-κB, osteoporosis, osteoblasts, osteoclasts, angiogenesis, traditional Chinese medicine, terpenoid” in Chinese and English, respectively. A third researcher summarized and organized the literature and 75 articles were finally included for a systematic review. RESULTS AND CONCLUSION: The nuclear factor-κB signaling pathway mediates the onset and progression of osteoporosis by regulating the differentiation and proliferation of osteoblasts and osteoclasts, as well as angiogenesis. Activation of the nuclear factor-κB signaling pathway negatively regulates the proliferation and differentiation of osteoblasts. Activation of the nuclear factor-κB signaling pathway enhances osteoclast activity and inhibits osteoblast growth, thereby inhibiting compensatory bone production to maintain bone homeostasis. However, over-activation of the nuclear factor-κB signaling pathway can lead to osteoporosis. The nuclear factor-κB signaling pathway is involved in the “angiogenesis-osteogenesis” coupling by upregulating the expression levels of cytokines such as angiopoietin-1, platelet-derived growth factor BB and vascular endothelial growth factor, which promote the growth of blood vessels in bone. The terpenoid herbal monomer compounds are used in the field of tissue engineering to promote the proliferation and differentiation of bone cells, thereby promoting the growth and repair of bone tissue. Terpenoid herbal monomer compounds can prevent and treat osteoporosis by inhibiting the degradation of nuclear factor-κB inhibitor, blocking nuclear factor-κB/p65 phosphorylation and nuclear translocation, thereby weakening the nuclear factor-κB signaling pathway, promoting osteoblast differentiation and inhibiting osteoclast formation. Currently, research on the regulation of nuclear factor-κB signaling pathway by monomeric compounds of terpenoids to prevent osteoporosis is mainly based on in vitro cellular experiments and animal models, and there is a lack of research on the complex physiological and pathological processes in humans. In the future, more clinical trials and studies are needed to further clarify the mechanism of action and efficacy of the nuclear factor-κB signaling pathway involved in the intervention of osteoporosis. [ABSTRACT FROM AUTHOR]

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), inositolrequiring enzyme 1a (IRE1a), 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. [ABSTRACT FROM AUTHOR]

Objective: To discuss the effects of leucovorin on tumor growth and angiogenesis in the mice with lung cancer transplantation tumor, and to elucidate its mechanism. Methods: Thirty-two healthy C57BL/6 mice were selected to prepare the Lewis lung cancer transplantation tumor models. The mice were randomly divided into model group (0. 9% NaCl), low dose of leucovrin group (25 mg·kg -1 leucovrin), high dose of leucovrin group (50 mg·kg -1 leucovrin) and positive control group (60 mg·kg-1 cyclophosphamide), and there were 8 mice in each group. The levels of interleukin-2 (IL-2), interferon-γ (INF- γ) and tumor necrosis factor- α (TNF- α) in serum of the mice in various groups were detected by enzyme linked immunosorbent assay (ELISA) method; the expression of vascular endothelial growth factor (VEGF) in tumor tissue of the mice in various groups were detected by immunohistochemistry, and the microvascular density (MVD) and VEGF protein expression scores were calculated; the expression levels of nuclear factor- κB (NF- κB) and hypoxia inducible factor-1α (HIF-1α) in tumor tissue of the mice in various groups were detected by Western blotting method. Results: Compared with model group, the transplantation tumor masses of the mice in low and high doses of leucovorin groups and positive control group were decreased (P<0. 05); compared with low dose of leucovorin group, the transplantation tumor masses of the mice in high dose of leucovorin group and positive control group were decreased (P<0. 05), and the tumor inhibitory rates were increased (P<0. 05); compared with high dose of leucovorin group, the transplantation tumor mass of the mice in positive control group was decreased (P<0. 05), and the tumor inhibitory rate was increased (P<0. 05). Compared with model group, the spleen indexes and thymus indexes of the mice in low and high doses of leucovorin groups and positive control group were increased (P<0. 05); compared with low dose of leucovorin group, the spleen indexes and thymus indexes of the mice in high dose of leucovorin group and positive control group were increased (P<0. 05); compared with high dose of leucovorin group, the spleen index and thymus index of the mice in positive control group were increased (P<0. 05). The ELISA method results showed that compared with model group, the levels of IL-2, INF- γ and TNF- α in serum of the mice in low and high doses of leucovorin groups and positive control group were increased (P<0. 05); compared with low dose of leucovorin group, the levels of IL-2, INF- γ and TNF- α in serum of the mice in high dose of leucovorin group and positive control group were increased (P<0. 05); compared with high dose of leucovorin group, the levels of IL-2, INF- γ and TNF- α in serum of the mice in positive control group were increased (P<0. 05). Compared with model group, the MVD in tumor tissue of the mice in low and high dose of leucovorin groups and positive control group was decreased (P<0. 05); compared with low dose of leucovorin group, the MVD in tumor tissue of the mice in high dose of leucovorin group and positive control group was decreased (P< 0. 05); compared with high dose of leucovorin group, the MVD in tumor tissue of the mice in positive control group was decreased (P<0. 05). Compared with model group, the expression amounts of VEGF protein in tumor tissue of the mice in low and high dose of leucovorin groups and positive control group were decreased; compared with low dose of leucovorin group, the expression amounts of VEGF protein in tumor tissue of the mice in high dose of leucovorin group and positive control group were decreased; compared with high dose of leucovorin group, the expression amount of VEGF protein in tumor tissue of the mice in positive control group was decreased. The differences in VEGF protein expression scores between model group, low dose of leucovorin group, high dose of leucovorin group and positive control group were statistically significant (P<0. 05). Compared with model group, the expression levels of NF-κB and HIF1α in tumor tissue of the mice in low and high doses of leucovorin groups and positive control group were decreased (P<0. 05); compared with low dose of leucovorin group, the expression levels of NF- κB and HIF-1α in tumor tissue of the mice in high dose of leucovorin group and positive control group were decreased (P<0. 05); compared with high dose of leucovorin group, the expression levels of NF-κB and HIF-1 α in tumor tissue of the mice in positive control group were decreased (P<0. 05). Conclusion: Leucolorin can inhibit the tumor growth, protect the immune organs and suppress the tumor angiogenesis in the Lewis lung cancer transplantation tumor mice, and may exert the therapeutic effect by targeting NF- κB/HIF-1α signaling pathway and down-regulating the expression levels of NF- κB and HIF-1α proteins. [ABSTRACT FROM AUTHOR]

Progressive renal fibrosis is the hallmark of chronic kidney disease, which possesses heavy public health burden globally. Both diabetic and non-diabetic kidney diseases are the major causes for development of chronic kidney disease. MicroRNAs （miRNAs）, short noncoding RNAs, exert their regulatory roles at a post-transcription level and have been studied for renal fibrosis progression in diabetic and non-diabetic nephropathy. In this review, the pattern of miRNA expression alternations in diabetic and non-diabetic kidney diseases is summarized followed by discussion on the roles of miRNAs in renal fibrosis through interacting with various signaling pathways, such as transforming growth factor-β, nuclear factor-κB, Janus kinase/signal transducer and activator of transcription, tissue inhibitor of metalloproteinase 3, and SRY-box transcription factor 6. The potential of physical exercise in protection of renal dysfunction by regulating miRNAs is briefly discussed. [ABSTRACT FROM AUTHOR]

Rationale: Electroconvulsive therapy (ECT) is an effective treatment modality for schizophrenia. However, its antipsychotic-like mechanism remains unclear. Objectives: To gain insight into the antipsychotic-like actions of ECT, this study investigated how repeated treatments of electroconvulsive seizure (ECS), an animal model for ECT, affect the behavioral and transcriptomic profile of a neurodevelopmental animal model of schizophrenia. Methods: Two injections of MK-801 or saline were administered to rats on postnatal day 7 (PN7), and either repeated ECS treatments (E10X) or sham shock was conducted daily from PN50 to PN59. Ultimately, the rats were divided into vehicle/sham (V/S), MK-801/sham (M/S), vehicle/ECS (V/E), and MK-801/ECS (M/E) groups. On PN59, prepulse inhibition and locomotor activity were tested. Prefrontal cortex transcriptomes were analyzed with mRNA sequencing and network and pathway analyses, and quantitative real-time polymerase chain reaction (qPCR) analyses were subsequently conducted. Results: Prepulse inhibition deficit was induced by MK-801 and normalized by E10X. In M/S vs. M/E model, Egr1, Mmp9, and S100a6 were identified as center genes, and interleukin-17 (IL-17), nuclear factor kappa B (NF-κB), and tumor necrosis factor (TNF) signaling pathways were identified as the three most relevant pathways. In the V/E vs. V/S model, mitophagy, NF-κB, and receptor for advanced glycation end products (RAGE) pathways were identified. qPCR analyses demonstrated that Igfbp6, Btf3, Cox6a2, and H2az1 were downregulated in M/S and upregulated in M/E. Conclusions: E10X reverses the behavioral changes induced by MK-801 and produces transcriptional changes in inflammatory, insulin, and mitophagy pathways, which provide mechanistic insight into the antipsychotic-like mechanism of ECT. [ABSTRACT FROM AUTHOR]

Pulmonary thromboembolism caused by thrombi blocking major pulmonary artery and its branches, is a frequently encountered phenomenon and an important cause of high morbidity and mortality in lung diseases and may develop into persistent pulmonary hypertension (PH). Nuclear factor‐κB (NF‐κB) signaling pathway had been reported participated in the formation and development of PH by promoting inflammatory response. The aim of this study was to investigate the effects of NF‐κB activation on the serum levels of tumor necrosis factor α (TNF‐α) and interleukin‐1β (IL‐1β) in acute pulmonary microthromboembolism (APMTE) rats. Rats were randomized into five groups. APMTE group received jugular vein injection of autologous thrombus, while control group rats received normal saline injection. Pulmonary hemodynamic parameters were measured through ECHO‐guided transthoracic puncture. Pulmonary vascular morphological changes were analyzed by HE. The expression changes of NF‐κB and serum TNF‐α、IL‐1β levels were detected by enzyme‐linked immunosorbent assay. Protein expression of the MAPK/NF‐κB signaling pathway including p‐IκBα, p‐p38 MAPK, p‐NF‐κB p65, IκBα, p38 MAPK, and NF‐κB p65 was determined using western blot analysis. Compared with control group, the expression of NF‐κB in lung tissue and the levels of serum TNF‐α and IL‐1β rats were higher, a significant reduction in IκBα and elevation in the phosphorylation of IκBα, p38 MAPK, and NF‐κB p65 were found in APMTE group rats. And UK administration reversed the APMTE‐induced increase in TNF‐α, IL‐1β, p‐IκBα, p‐MAPK, and p‐NF‐κB protein. Furthermore, the levels of NF‐κB, TNF‐α, and IL‐1β were positively correlated with mean pulmonary artery. And the levels of TNF‐α and IL‐1β were positively correlated with NF‐κB. These findings suggest that the activation of MAPK/NF‐κB pathway as a critical driver of increasing TNF‐α and IL‐1β level in APMTE rats and UK exerted protective effects against APMTE‐induced PH may be related to the downregulation of the MAPK/NF‐κB signaling pathway. [ABSTRACT FROM AUTHOR]

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Macrophages are important for maintaining tissue homeostasis and defending against pathogens in periodontal tissues. However, these tissues are often vulnerable to damage due to local inflammatory responses within the host tissues. This study aimed to investigate the role of G protein-coupled receptor 91(GPR91) during the inflammatory response to Porphyromonas gingivalis (P. gingivalis) in bone marrow-derived macrophages (BMDMs). To this end, we examined expression levels of GPR91 genes in human periodontal tissues affected by periodontitis. Utilizing primary mouse BMDMs from wild-type (WT) and GPR91 knockout (GPR91−/−) mice infected with P. gingivalis, we demonstrated that GPR91 accumulates in inflamed gingival tissues. Additionally, P. gingivalis can induce intercellular succinate accumulation, inflammatory mediator generation, reactive oxygen species (ROS) production, lipid peroxidation, and superoxide dismutase activity in WT-BMDMs. Moreover, inhibition of GPR91 by the specific inhibitor 4C as well as knockdown of GPR91 reduced inflammation and oxidative stress in P. gingivalis-infected BMDMs. Furthermore, we discovered that GPR91-mediated inflammation in P. gingivalis-infected BMDMs is activated via the Erk/Nuclear Factor-κB pathway. These findings provide new insights into the metabolic pathogenesis of periodontal inflammation.

AIM: To observe the effects of N-acetylserotonin (NAS) administration on retinal ischemia-reperfusion (RIR) injury in rats and explore the underlying mechanisms involving the high mobility group box 1 (HMGB1)/receptor for advanced glycation end-products (RAGE)/nuclear factor-kappa B (NF-κB) signaling pathway. METHODS: A rat model of RIR was developed by increasing the pressure of the anterior chamber of the eye. Eighty male Sprague Dawley were randomly divided into five groups: sham group (n=8), RIR group (n=28), RIR+NAS group (n=28), RIR+FPS-ZM1 group (n=8) and RIR+NAS+ FPS-ZM1 group (n=8). The therapeutic effects of NAS were examined by hematoxylin-eosin (H&E) staining, and retinal ganglion cells (RGCs) counting. The expression of interleukin 1 beta (IL-1β), HMGB1, RAGE, and nod-like receptor 3 (NLRP3) proteins and the phosphorylation of nuclear factor-kappa B (p-NF-κB) were analyzed by immunohistochemistry staining and Western blot analysis. The expression of HMGB1 protein was also detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: H&E staining results showed that NAS significantly reduced retinal edema and increased the number of RGCs in RIR rats. With NAS therapy, the HMGB1 and RAGE expression decreased significantly, and the activation of the NF-κB/NLRP3 pathway was antagonized along with the inhibition of p-NF-κB and NLRP3 protein expression. Additionally, NAS exhibited an anti-inflammatory effect by reducing IL-1β expression. The inhibitory of RAGE binding to HMGB1 by RAGE inhibitor FPS-ZM1 led to a significant decrease of p-NF-κB and NLRP3 expression, so as to the IL-1β expression and retinal edema, accompanied by an increase of RGCs in RIR rats. CONCLUSION: NAS may exhibit a neuroprotective effect against RIR via the HMGB1/RAGE/NF-κB signaling pathway, which may be a useful therapeutic target for retinal disease.

Objective: The objective of this study was to investigate the effects and possible mechanisms of action of ginseng on cerebral vasospasm and early brain injury (EBI) following hemorrhagic stroke. Materials and Methods: Sprague-Dawley (SD) rats (n = 48) were randomly divided into sham operation (sham group), subarachnoid hemorrhage (SAH) model (SAH group), normal saline (NS group), and Ginaton (Extract of Ginkgo Biloba Leaves Drops) intervention (gin group) groups. MCP-1 mRNA and tumor necrosis factor levels were detected using reverse transcription–polymerase chain reaction. The relative expression of mRNA was detected by Western blotting. Results: (1) Compared with the sham group, the SAH, NS, and gin groups had different degrees of neurological dysfunction. Compared with the SAH and NS groups, the neurological deficits in the gin group were significantly improved (P < 0.05). (2) Compared with the sham group, the relative expression levels of MCP-1 mRNA in the SAH, NS, and gin groups were 5.1 ± 0.9, 3.4 ± 0.6, and 2.5 ± 0.4, respectively; the relative expression levels of mRNA were 13.3 ± 2.4, 11.2 ± 1.8, and 3.8 ± 0.6, respectively. (3) The apoptosis rates of brain tissue in the sham, SAH, NS, and gin groups were 4.8 ± 0.7, 54.2 ± 10.3, 50.1 ± 7.4, and 28.4 ± 4.5, respectively. (4) Western blot showed that the relative expression levels of toll-like receptor-4 (TLR-4) protein in the sham, SAH, NS, and gin groups were 0.29 ± 0.03, 0.87 ± 0.15, 0.65 ± 0.13, and 0.41 ± 0.17, respectively; the relative expression levels of B protein were 0.21 ± 0.04, 0.96 ± 0.14, 0.73 ± 0.18, and 0.30 ± 0.05, respectively. Gin treatment could inhibit TLR-4 and nuclear factor-κB (NF-κB) protein expression. Conclusions: Dona tablets may inhibit activation of the NF-κB signaling pathway, and SAH-induced inflammatory response, so as to reduce cerebral vasospasm and EBI.

The P-glycoprotein (P-gp) plays a major role in the efflux of chemotherapeutic drugs and significantly limits chemotherapy efficacy. Chemosensitizers augment the therapeutic effects of anticancer agents by overcoming drug resistance mechanisms. In this study, the chemosensitizing property of andrographolide (Andro) in P-gp overexpressing multidrug-resistant (MDR) colchicine-selected KBChR 8-5 cells was evaluated. Molecular docking studies showed Andro exhibits higher binding interaction with P-gp than the other two ABC-transporters studied. Further, it inhibits P-gp transport function in a concentration dependant manner in the colchicine-selected KBChR 8-5 cells. Moreover, Andro downregulates P-gp overexpression via NF-κB signaling in these MDR cell lines. MTT-based cell-based assay illustrates that Andro treatment augments the PTX effect in the KBChR 8-5 cells. Further, the Andro plus PTX combination showed enhanced apoptotic cell death in KBChR 8-5 cells compared with PTX alone treatment. Therefore, the results showed that Andro enhances PTX therapeutic effect in the drug-resistant KBChR 8-5 cells. [ABSTRACT FROM AUTHOR]

Objective To explore the potential relationship between ubiquitination of transforming growth factor kinase 1 (TAK1)/nuclear factor-κB (NF-κB) signaling pathway mediated by ring finger protein 99 (RNF99) and septic acute respiratory distress syndrome (ARDS). Methods Plasmid and siRNA transfection were conducted to overexpress or knock down RNF99 in MLE12, and expressions of p65 phosphate and p65 protein were analyzed. The protein interaction between RNF99 and TRAF6 or TAK1 was analyzed by immunoprecipitation assay. Forty mice were randomly divided into WT plus PBS, WT plus LPS, RNF99 specific expression (TG) plus PBS, and TG plus LPS groups, with 10 mice in each group. Sepsis was induced by intraperitoneal injection of 30 mg/kg LPS. Results As compared with vector group, protein expression levels of TRAF6 and TAK1 in MLE12 cells decreased significantly in RNF99 group (P < 0.05). Ubiquitinated TRAF6 protein increased in MLE12 cells with RNF99 knockdown. As compared with LPS plus vector group, phosphorylation level of p65 in MLE12 cells was significantly lower in LPS plus RNF99 group (P < 0.05). As compared with si-NC group, protein expression levels of RNF99 and IκBα in si-RNF99 group decreased significantly (P < 0.05). As compared with LPS plus si-NC group, phosphorylation level of p65 in LPS plus si-RNF99 group increased significantly (P < 0.05). The staining percentage of CD68 macrophages in lung tissues was significantly lower in TG plus LPS group than in WT plus LPS group (P < 0.05). Phosphorylation level of p65 in lung tissues was significantly lower in TG plus LPS group than in WT plus LPS group (P < 0.05). Conclusion RNF99 regulates NF-κB signaling pathway by interacting with the key regulator of NF-κB signaling pathway (TRAF6/TAK1), and improves lung injury after intraperitoneal injection of LPS in mice. [ABSTRACT FROM AUTHOR]

Objective: To observe the effect of astragalus polysaccharides on liver injury in mice with viral hepatitis, and to investigate whether it can regulate the expression of nucleotide-binding oligomerization domain 1 (NOD1)/receptor-interacting protein 2 (RIP2)/nuclear factor-κB (NF-κB) immune inflammation mediated by signaling pathway plays a protective role in liver. Methods: Sixty female C3H/HeJ mice were divided into modeling group (50 mice) and normal group (10 mice) using a random number table. The mouse model of viral hepatitis was established by intraperitoneal injection of mouse hepatitis virus type 3 (MHV-3) in the modeling group. After the successful modeling was confirmed, the surviving mice were divided into thymus peptide group (10 µg), astragalus polysaccharide low, medium and high dose groups (100, 200, 400 mg/kg astragalus polysaccharide lyophilized in 1 ml/100 g body weight saline) and model group by random number table. Model group and normal group were given the same amount of normal saline intraperitoneal injection, each group was given once a day for 1 month. Results: The model was confirmed by HE staining of liver tis-sue and detection of viral plaque. Compared with the normal group, the liver index, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and tumor necrosis factor-α (TNF-α), IL-1β and IL-8, viral plaques in liver tissue, NOD1, RIP2 and NF-κB p65 expressions and p-NF-κ B p65 level in the model group increased (P<0.05), and the liver tissue showed severe pathological changes. Compared with the model group, the liver indexes, serum ALT, AST, TBIL and TNF-α, IL-1β and IL-8, viral plaques in liver tissue, NOD1, RIP2 and NF-κB p65 expressions and p-NF-κB p65 level in the thymosin group and astragalus polysaccharide each 3-dose groups decreased (P<0.05), and the pathological changes of liver tissue were alleviated. The effect of astragalus polysaccharide was dose-dependent, and there were no significant differences in these indexes between thymosin group and astragalus polysaccharide medium dose group (P>0.05). Conclusion: Astragalus polysaccharides can improve the liver function of mice with viral hepatitis, reduce the inflammatory response and pathological changes of liver tissue, reduce the level of virus, speculate and inhibit NOD1/RIP2/NF-κB pathway and down-regulate NOD1, RIP2 and NF-κB p65 expressions, inhibit p-NF-κB p65 level, and high dose of astragalus polysaccharide has the best effect, which is better than thymosin-α1. [ABSTRACT FROM AUTHOR]

Objective To explore the effect of Huangqi Yanghe Decoction on wound healing of diabetic foot ulcer (DFU) rats based on phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor- κB (NF- κB) signal pathway. Methods DFU rat model was constructed, and 48 rats successfully modeled were randomly divided into the model group, the Huangqi Yanghe Decoction low (8.5 g/kg) group, the Huangqi Yanghe Decoction high (17 g/kg) dose group and the Huangqi Yanghe Decoction high dose (17 g/kg)+LY294002 (PI3K/AKT pathway inhibitor, 0.3 mg/kg) group. There were 12 rats in each group. Another 12 rats were selected as the control group. Rats in each group were given corresponding drug intervention for 4 weeks. After the 14th and 28th day-administration, the general state and wound changes of rats were observed, and the wound healing rate was calculated. The fasting blood glucose (FBG) level of rats was measured, and the percutaneous partial pressure of oxygen (TcpO2) of tissue around the wound was detected. Serum levels of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1α (HIF-1α), C-reactive protein (CRP) and interleukin (IL)-6 were determined by enzyme linked immunosorbent assay. Histopathological changes of the wound were observed by hematoxylin-eosin staining. Immunohistochemical staining was used to measure the microvascular density of rat wound tissue. The protein expression levels of PI3K, phosphorylated PI3K (p-PI3K), AKT, phosphorylated AKT (p-AKT), NF-κB p65, phosphorylated NF- κB p65 (p-NF- κB p65) and NF- κB inhibitory protein α (IκB- α) in rat wound tissue were determined by Western blot assay. Results Rats in the control group had smooth hair color, normal diet, drinking water and excretion, more active, wound healing fast, less inflammatory reaction in wound tissue, and there were more new blood vessels. Fibroblasts and collagen matrix were abundant in granulation tissue. In the model group, the fur color of rats was dull and matte, and the activity was reduced. The symptoms of polydipsia, polyphagia and polyuria were appeared in the model group, the wound color was dark, and edema and ulcer appeared in the surrounding tissue, a large number of inflammatory cells infiltrated in the wound tissue, accompanied by tissue necrosis and exudation, fewer neovascularization and fibroblasts were observed. Wound healing rate, TcpO2 in wound surrounding tissue, serum VEGF, HIF-1α, microvascular density, pPI3K, p-AKT and IκB-α protein expression levels in wound tissue were decreased, and FBG, serum CRP, IL-6, p-NF-κB p65 protein expression in wound tissue were increased (P＜0.05). Compared with the model group, the state of rats was gradually improved in the Huangqi Yanghe Decoction low and high dose groups, and the lesion degree of wound tissue was reduced successively, wound healing rate, TcpO2 in wound surrounding tissue, serum VEGF, HIF-1α, microvascular density, p-PI3K, p-AKT and IκB-α protein expression levels in wound tissue were increased in turn (P＜0.05). The FBG, serum CRP, IL-6 and p-NF- κB p65 protein expression in wound tissue were decreased in turn (P＜0.05). LY294002 could partially reverse the therapeutic effect of high-dose Huangqi Yanghe Decoction on DFU rats (P＜0.05). Conclusion Huangqi Yanghe Decoction can regulate PI3K/AKT/NF-κB pathway, inhibit inflammatory response in DFU rats, promote angiogenesis and thus promote wound healing. [ABSTRACT FROM AUTHOR]

Objective: To discuss the effect of silencing Forkhead box K1 (FOXK1) on the proliferation, migration, and invasion of the gastric cancer HGC-27 cells, and to clarify the possible mechanism. Methods: The expression levels of FOXK1 mRNA in gastric cancer tissue and normal gastric tissue were consulted based on the Gene Expression Profiling Interactive Analysis (GEPIA) Database; the synthetic si-FOXK1 was used to transfect the gastric cancer HGC-27 cells in vitro, and the cells were divided into blank control group, nc-FOXK1 group, and si-FOXK1 group. Western blotting method was used to detect the transfection efficiencies of the cells in various groups; MTT assay was used to detect the proliferation abilities of the HGC-27 gastric cancer cells in various groups after transfected with si-FOXK1. The clone formation assay was used to detect the number of clone-forming of the HGC-27 gastric cancer cells after transfected with si-FOXK1; wound healing assay was used to detect the migration rates of the gastric cancer HGC-27 cells in various groups after transfected with si-FOXK1; Transwell chamber assay was used to detect the numbers of migration and invasion cells in various groups; Western blotting method was used to detect the expression levels of NF- κB pathway-related proteins [nuclear factor κB p65 (NF- κB p65) and phosphorylated NF- κB p65 (p-NF- κB p65)] in the gastric cancer HGC-27 cells in various groups after transfected with si-FOXK1. Results: The GEPIA Database results showed that compared with normal gastric tissue, the expression level of FOXK1 mRNA in gastric cancer tissue was increased (P<0. 05) . The Western blotting method results showed that the expression level of FOXK1 protein in the gastric cancer HGC-27 cells was higher than that in normal gastric mucosal GES-1 cells (P<0. 01). Compared with blank control group and nc-FOXK1 group, the expression level of FOXK1 protein in the cells in si-FOXK1 group was significantly decreased (P<0. 01). The MTT assay results showed that compared with blank control group and nc-FOXK1 group, the proliferation ability of the gastric cancer HGC-27 cells in si-FOXK1 group was decreased (P<0. 05) . The clone formation assay results showed that compared with blank control group and nc-FOXK1 group, the number of clone-forming of the gastric cancer HGC-27 cells in si-FOXK1 group was decreased (P<0. 05). The cell scratch healing results showed that compared with blank control group and nc-FOXK1 group, the migration rate of the gastric cancer HGC-27 cells in si-FOXK1 group was decreased (P<0. 05). The Transwell chamber assay results showed that compared with blank control group and nc-FOXK1 group, the number of invasion cells of the gastric cancer HGC-27 cells in si-FOXK1 group was decreased (P<0. 05). The Western blotting results showed that compared with blank control group and nc-FOXK1 group, the expression level of p-NF-κB p65 protein in the cells in si-FOXK1 group was decreased (P<0. 05). Conclusion: FOXK1 is highly expressed in the gastric cancer HGC-27 cells, and silencing FOXK1 can inhibit the proliferation, migration, and invasion abilities of the HGC-27 gastric cancer cells; its mechanism is possibly associated with the NF-κB pathway. [ABSTRACT FROM AUTHOR]

Cathepsin B (CatB) is thought to be essential for the induction of Porphyromonas gingivalis lipopolysaccharide (Pg LPS)-induced Alzheimer's disease-like pathologies in mice, including interleukin-1β (IL-1β) production and cognitive decline. However, little is known about the role of CatB in Pg virulence factor-induced IL-1β production by microglia. We first subjected IL-1β-luciferase reporter BV-2 microglia to inhibitors of Toll-like receptors (TLRs), IκB kinase, and the NLRP3 inflammasome following stimulation with Pg LPS and outer membrane vesicles (OMVs). To clarify the involvement of CatB, we used several known CatB inhibitors, including CA-074Me, ZRLR, and human β-defensin 3 (hBD3). IL-1β production in BV-2 microglia induced by Pg LPS and OMVs was significantly inhibited by the TLR2 inhibitor C29 and the IκB kinase inhibitor wedelolactonne, but not by the NLRPs inhibitor MCC950. Both hBD3 and CA-074Me significantly inhibited Pg LPS-induced IL-1β production in BV-2 microglia. Although CA-074Me also suppressed OMV-induced IL-1β production, hBD3 did not inhibit it. Furthermore, both hBD3 and CA-074Me significantly blocked Pg LPS-induced nuclear NF-κB p65 translocation and IκBα degradation. In contrast, hBD3 and CA-074Me did not block OMV-induced nuclear NF-κB p65 translocation or IκBα degradation. Furthermore, neither ZRLR, a specific CatB inhibitor, nor shRNA-mediated knockdown of CatB expression had any effect on Pg virulence factor-induced IL-1β production. Interestingly, phagocytosis of OMVs by BV-2 microglia induced IL-1β production. Finally, the structural models generated by AlphaFold indicated that hBD3 can bind to the substrate-binding pocket of CatB, and possibly CatL as well. These results suggest that Pg LPS induces CatB/CatL-dependent synthesis and processing of pro-IL-1β without activation of the NLRP3 inflammasome. In contrast, OMVs promote the synthesis and processing of pro-IL-1β through CatB/CatL-independent phagocytic mechanisms. Thus, hBD3 can improve the IL-1β-associated vicious inflammatory cycle induced by microglia through inhibition of CatB/CatL. [ABSTRACT FROM AUTHOR]

Inflammatory and immune pathways play a crucial role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD). Sitagliptin blocks the dipeptidyl peptidase-4 (DPP-4) enzyme, mechanisms that alter inflammatory pathways and the innate immune system, and by which Sitagliptin affects the pathogenesis of NAFLD weren't previously discussed. This study aims to understand the interaction between Sitagliptin and innate immune response in order to meliorate NAFLD. Thirty- two Wistar male albino rats were categorised into four groups. Rats have received a standard diet or a high-fat diet either with or without Sitagliptin. Serum HMGB1, protein and mRNA expressions of hepatic TLR4 and NF-κB, inflammatory cytokines, and histopathological changes were analysed. An ameliorative action of Sitagliptin in NAFLD was demonstrated via decreasing HMGB1-mediated TLR4/NF-κB signalling in order to suppress inflammation and reduce insulin resistance. Sitagliptin may in fact prove to be a beneficial therapeutic intervention in NAFLD. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a serious central nervous system disease. Traumatic SCI often causes persistent neurological deficits below the injury level. Epigenetic changes occur after SCI. Studies have shown DNA methylation to be a key player in nerve regeneration and remodeling, and in regulating some pathophysiological characteristics of SCI. Curcumin is a natural polyphenol from turmeric. It has anti-inflammatory, antioxidant, and neuroprotective effects, and can mitigate the cell and tissue damage caused by SCI. This report analyzed the specific functions of DNA methylation in central nervous system diseases, especially traumatic brain injury and SCI. DNA methylation can regulate the level of gene expressions in the central nervous system. Therefore, pharmacological interventions regulating DNA methylation may be promising for SCI. [ABSTRACT FROM AUTHOR]

Introduction: Osteoarthritis (OA) is a common inflammatory joint disease characterised by progressive cartilage destruction. Management of this condition remains a significant challenge, and new therapies are required. We investigated the protective effects of miR-106a mimics in a murine model of OA. Material and methods: This study was performed using both in vitro and in vivo OA models. Primary chondrocytes were isolated from female rats, with inflammation induced via treatment with lipopolysaccharide (LPS). Then the effects of a miR-106a mimic were examined based on the level of inflammatory cytokine production and apoptotic signalling following LPS stimulation. An in vivo rat model of OA was generated by injecting LPS into the anterior cruciate ligament, followed by treatment with miR-106a mimics. Then, inflammatory and apoptotic protein expression was assessed in the cartilage tissue. Results: Treatment with miR-106a mimic reduced the levels of inflammatory cytokines and apoptotic proteins in cartilage tissues following LPS-induced inflammation. Furthermore, the mimic ameliorated the expression of DR-6 mRNA and DR6, IkBα, and p65 proteins in chondrocytes. Similar effects were seen in the in vivo model, with the mimic attenuating expression of NF-κB, p65, IkBα, and DR6 proteins and improving histopathological outcomes in the chondrocytes of OA rats. Conclusions: Treatment with miR-106a mimic ameliorates inflammation in cartilage tissues of OA subjects by activating death receptor 6 via the NF-κB signalling pathway. [ABSTRACT FROM AUTHOR]

Abstract Pulmonary thromboembolism caused by thrombi blocking major pulmonary artery and its branches, is a frequently encountered phenomenon and an important cause of high morbidity and mortality in lung diseases and may develop into persistent pulmonary hypertension (PH). Nuclear factor‐κB (NF‐κB) signaling pathway had been reported participated in the formation and development of PH by promoting inflammatory response. The aim of this study was to investigate the effects of NF‐κB activation on the serum levels of tumor necrosis factor α (TNF‐α) and interleukin‐1β (IL‐1β) in acute pulmonary microthromboembolism (APMTE) rats. Rats were randomized into five groups. APMTE group received jugular vein injection of autologous thrombus, while control group rats received normal saline injection. Pulmonary hemodynamic parameters were measured through ECHO‐guided transthoracic puncture. Pulmonary vascular morphological changes were analyzed by HE. The expression changes of NF‐κB and serum TNF‐α、IL‐1β levels were detected by enzyme‐linked immunosorbent assay. Protein expression of the MAPK/NF‐κB signaling pathway including p‐IκBα, p‐p38 MAPK, p‐NF‐κB p65, IκBα, p38 MAPK, and NF‐κB p65 was determined using western blot analysis. Compared with control group, the expression of NF‐κB in lung tissue and the levels of serum TNF‐α and IL‐1β rats were higher, a significant reduction in IκBα and elevation in the phosphorylation of IκBα, p38 MAPK, and NF‐κB p65 were found in APMTE group rats. And UK administration reversed the APMTE‐induced increase in TNF‐α, IL‐1β, p‐IκBα, p‐MAPK, and p‐NF‐κB protein. Furthermore, the levels of NF‐κB, TNF‐α, and IL‐1β were positively correlated with mean pulmonary artery. And the levels of TNF‐α and IL‐1β were positively correlated with NF‐κB. These findings suggest that the activation of MAPK/NF‐κB pathway as a critical driver of increasing TNF‐α and IL‐1β level in APMTE rats and UK exerted protective effects against APMTE‐induced PH may be related to the downregulation of the MAPK/NF‐κB signaling pathway.

Abstract Background Interplay between gut microbiota and heart, termed “gut-heart” axis, has a crucial role in the pathogenesis of atherosclerosis. Our previous study showed that lycopene possesses anti-inflammatory and anti-atherosclerotic effects, but its link to the gut microbiota is poorly understood. Herein, we surmised that lycopene could regulate the gut microbiota, exert anti-atherosclerotic effect by regulating the “gut-heart” axis. Methods Male ApoE−/− mice were fed a high-fat diet (HFD) with or without lycopene (0.1% w/w) for 19 weeks. Gut microbiota was analyzed by 16 S rRNA sequencing, the protein levels of zonula occludens-1 (ZO-1), occludin, toll-like receptor 4 (TLR4) and phospho-nuclear factor-κB (NF-κB) p65 were measured by Western blotting, the levels of serum inflammatory factors including monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 were assayed using ELISA kits. Also, the concentrations of serum lipopolysaccharide (LPS), D-lactic acid (D-LA) and diamine peroxidase (DAO) were measured through ELISA method. Results The aortic sinus sections revealed that lycopene supplementation significantly reduced the extent of atherosclerotic lesions and inhibited atherosclerosis development caused by HFD. The analysis of gut microbiota showed that lycopene reduced the ratio of Firmicutes/Bacteroides and increased the relative abundance of Verrucomicrobia, Akkermansia and Alloprevotella, which were related to elevated intestinal barrier function and reduced inflammation. Moreover, lycopene up-regulated the expression of intestinal ZO-1 and occludin and decreased serum LPS, D-LA and DAO levels. In addition, lycopene inhibited the expression of TLR4 and phospho-NF-κB p65 in aortic sinus plaque, serum MCP-1, TNF-α, IL-1β, and IL-6 levels were also lowered by lycopene treatment. Conclusions Our results indicated the protective effect of lycopene against atherosclerosis induced by HFD and further revealed that its mechanism might be its prebiotic effect on maintaining gut microbiota homeostasis and improving intestinal barrier function, consequently reducing serum LPS-triggered inflammatory response in the heart.

Abstract Background Overproduction and activation of osteoclasts result in various bone diseases, such as osteoporosis, Paget's disease, and rheumatoid arthritis. Thus, inhibiting osteoclast formation and overactivation may effectively prevent osteoclast‐related bone diseases, especially osteoporosis. Madecassic acid, one of the most important active ingredients in Centella asiatica, has various biological effects, but its role in osteoclastogenesis remains unknown. Methods RAW 264.7 cells were stimulated with receptor activator of nuclear factor (NF)‐κΒ ligand (RANKL, 25 ng/mL) to differentiate into multi‐nucleated osteoclasts. Subsequently, osteoclasts were treated with or without varying concentrations of madecassic acid (1, 2.5, 5, and 10 μmol/L). Results Madecassic acid significantly inhibited RANKL‐induced osteoclastogenesis in a concentration‐dependent manner. In addition, it reduced the percentage of bone resorptive area compared with the control, confirming that madecassic acid can inhibit osteoclast function. Furthermore, luciferase reporter gene studies indicate that madecassic acid could decrease the transcriptional activity of NF of activated T cells (NFAT) and NF‐κB in a dose‐dependent manner. Quantitative real‐time polymerase chain reaction results show that madecassic acid attenuated the expression of osteoclast‐associated genes, including V‐ATPase‐d2, cathepsin K, tartrate‐resistant acid phosphatase (TRAP), NFAT cytoplasmic 1 (NFATc1). Western blot analysis shows that madecassic acid inhibited RANKL‐mediated degradation of IκBα and NFATc1 expression, as well as phosphorylation of c‐Jun N‐terminal kinase (JNK) in RAW 264.7 cells. Conclusion Madecassic acid inhibited osteoclast formation and function in vitro by suppressing NF‐κB, JNK, and NFAT signaling pathways, indicating its potential as a novel drug for the treatment of osteoclast‐related bone diseases, especially osteoporosis.

Gwakhyangjeonggi-san (GJS) is a traditional herbal medicine used in East Asia for the treatment of symptoms involving lower intestinal abnormalities; however, the effects of GJS on innate immunity and its cellular mechanisms of action have not been elucidated. In this study, we assessed the immune-enhancing activity and underlying mechanisms of GJS using RAW 264.7 murine macrophages. The results showed that GJS treatment significantly increased the secretion of nitric oxide and cytokines and their mRNA expression in macrophage RAW 264.7 cells without causing cytotoxicity. GJS treatment also significantly increased the production of reactive oxygen species, as well as inducing phagocytic activity, adhesion function, and migration ability, all of which improved the immune response. In addition, GJS activated nuclear factor-κB by promoting the phosphorylation and degradation of inhibitor of nuclear factor-κB alpha. Furthermore, GJS markedly increased the phosphorylation of mitogen-activated protein kinase in RAW 264.7 cells. These findings indicate that GJS has potential value as a dietary supplement for strengthening immunity.

Extracellular vesicles (EVs) play a pivotal role in a variety of physiologically relevant processes, including lung inflammation. Recent attention has been directed toward EV-derived microRNAs (miRNAs), such as miR-191-5p, particularly in the context of inflammation. Here, we investigated the impact of miR-191-5p-enriched EVs on the activation of NF-κB and the expression of molecules associated with inflammation such as interleukin-8 (IL-8). To this aim, cells of bronchial epithelial origin, 16HBE, were transfected with miR-191-5p mimic and inhibitor and subsequently subjected to stimulations to generate EVs. Then, bronchial epithelial cells were exposed to the obtained EVs to evaluate the activation of NF-κB and IL-8 levels. Additionally, we conducted a preliminary investigation to analyze the expression profiles of miR-191-5p in EVs isolated from the plasma of patients diagnosed with chronic obstructive pulmonary disease (COPD). Our initial findings revealed two significant observations. First, the exposure of bronchial epithelial cells to miR-191-5p-enriched EVs activated the NF-kB signaling and increased the synthesis of IL-8. Second, we discovered the presence of miR-191-5p in peripheral blood-derived EVs from COPD patients and noted a correlation between miR-191-5p levels and inflammatory and functional parameters. Collectively, these data corroborate and further expand the proinflammatory role of EVs, with a specific emphasis on miR-191-5p as a key cargo involved in this process. Consequently, we propose a model in which miR-191-5p, carried by EVs, plays a role in airway inflammation and may contribute to the pathogenesis of COPD.

PurposeHIV infection is consistently associated with an increased risk of atherosclerotic cardiovascular disease, but the underlying mechanisms remain elusive. HIV protein Tat, a transcriptional activator of HIV, has been shown to activate NF-κB signaling and promote inflammation in vitro. However, the atherogenic effects of HIV Tat have not been investigated in vivo. Macrophages are one of the major cell types involved in the initiation and progression of atherosclerosis. We and others have previously revealed the important role of IκB kinase β (IKKβ), a central inflammatory coordinator through activating NF-κB, in the regulation of macrophage functions and atherogenesis. This study investigated the impact of HIV Tat exposure on macrophage functions and atherogenesis.MethodsTo investigate the effects of Tat on macrophage IKKβ activation and atherosclerosis development in vivo, myeloid-specific IKKβ-deficient LDLR-deficient (IKKβΔMyeLDLR-/-) mice and their control littermates (IKKβF/FLDLR-/-) were exposed to recombinant HIV protein Tat.ResultsExposure to Tat significantly increased atherosclerotic lesion size and plaque vulnerability in IKKβF/FLDLR-/- but not IKKβΔMyeLDLR-/- mice. Deficiency of myeloid IKKβ attenuated Tat-elicited macrophage inflammatory responses and atherosclerotic lesional inflammation in IKKβΔMyeLDLR-/- mice. Further, RNAseq analysis demonstrated that HIV protein Tat affects the expression of many atherosclerosis-related genes in vitro in an IKKβ-dependent manner.ConclusionsOur findings reveal atherogenic effects of HIV protein Tat in vivo and demonstrate a pivotal role of myeloid IKKβ in Tat-driven atherogenesis.

BACKGROUND: In recent years, it has been found that nuclear factor-κB signaling pathway aggravates ischemia-reperfusion injury of skin flaps by regulating downstream cytokines, and traditional Chinese medicine can inhibit the activation of nuclear factor-κB, thereby reducing ischemia-reperfusion injury of skin flaps. OBJECTIVE: To review the research progress in the regulation of nuclear factor-κB signaling pathway by Chinese medicine, its active ingredients and Chinese medicine compound against skin flap ischemia-reperfusion injury. METHODS: The first author searched for the relevant literatures published in CNKI and PubMed databases from January 2012 to October 2022 using the keywords of “Traditional Chinese Medicine (TCM), NF-κB, Skin flaps, vascular endothelial cell (VEC)” in Chinese and English, respectively. After screening, 45 articles were finally summarized for review. RESULTS AND CONCLUSION: Activated nuclear factor-κB signaling pathway can promote the release of inflammatory factors and adhesion molecules in tissue cells to anti-fibrinolytic and coagulant substances through the transcription of a variety of cytokines, and aggravate the inflammatory cascade reaction between ischemia-reperfusion-damaged flap tissue and vascular endothelial cells, leukocyte adhesion and microthrombus formation, leading to flap necrosis. Traditional Chinese medicine, its compounds and effective components (flavonoids, terpenoids, saponins, phenols, etc.) inhibit the activation of nuclear factor-κB signaling pathway, alleviate the inflammatory cascade reaction between the ischemia-reperfusion-damaged flap and vascular endothelial cells, leukocyte adhesion and thrombosis, and thereby inhibit ischemia-reperfusion injury of skin flaps. Research on the mechanism of nuclear factor-κB signaling pathway regulated by traditional Chinese medicine against ischemia-reperfusion injury of skin flaps provides a new idea for the drug research and development of skin flap ischemiareperfusion injury, and provides reference and theoretical basis for the clinical prevention and treatment of skin flap ischemia-reperfusion injury by traditional Chinese medicine and the acceleration of skin flap healing. [ABSTRACT FROM AUTHOR]

BACKGROUND: The pathogenesis of periodontitis is still unclear, and its therapeutic target remains to be explored. Recent studies have showed that miR-185- 5p has anti-inflammatory effects in many diseases. However, it is unclear whether miR-185-5p can influence the inflammatory response in periodontitis. OBJECTIVE: To investigate the effect of regulating miR-185-5p expression on inflammatory response in experimental periodontitis in mice. METHODS: Twenty-four C57B/6J mice were randomly divided into normal control group, periodontitis control group, periodontitis miR-NC group and periodontitis miR-mimics group (n=6 per group). Except for the normal control group, other groups were induced into experimental periodontitis. Four weeks after modeling, in the periodontitis miR-mimics group, 100 μL of normal saline containing 0.5 mmol/L miR-185-5p mimics was injected into the proximal and distal gingival papillae of bilateral mandibular second molars of mice. In the periodontitis miR-NC group, 100 μL of normal saline containing 0.5 mmol/L negative control miR-NC was injected. In the normal control group and the periodontitis control group, the same amount of normal saline was injected. After 8 weeks of administration, all mice were sacrificed. Micro-CT was used to detect the left mandibles, and qRT-PCR was used to detect the gene expression of miR-185-5p, marginal zone B and B-1 cell-specific protein (MZB1), tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) in the gingiva of left mandibles. Immunohistochemical staining was used to detect the protein expression of MZB1, phospho-p65 NF-κB (pp65), TNF-α and IL-6 in the gingiva of right mandibles. RESULTS AND CONCLUSION: Micro-CT examination results showed that compared with the periodontitis control group and periodontitis miR-NC group, alveolar bone loss in the periodontitis miR-mimics group was decreased (P < 0.05). qRT-PCR results showed that the expression of miR-185-5p in the periodontitis miR-mimics group was higher than that in the normal control group, periodontitis control group, and periodontitis miR-NC group (P < 0.05). Compared with the periodontitis control group and periodontitis miR-NC group, the mRNA expression of MZB1, TNF-α, and IL-6 was decreased in the periodontitis miR-mimics group (P < 0.05). Immunohistochemical staining results showed that compared with the periodontitis control group and periodontitis miR-NC group, the protein expression of MZB1, pp65, TNF-α and IL-6 was decreased in the periodontitis miR-mimics group (P < 0.05). Therefore, increasing the expression of miR-185-5p can inhibit the inflammatory response in periodontitis and the resorption of alveolar bone, which may be associated with the suppression of MZB1 and nuclear fctor-κB pathway in the gingival tissue. [ABSTRACT FROM AUTHOR]

Background: Endothelial cell (EC) inflammation plays a crucial role in the development of several cardiovascular disorders (CD), including atherosclerosis and sepsis. Ligustrazine (Lig), a bioactive constituent derived from Traditional Chinese Medicine Ligusticum chuanxiong Hort, has exhibited in vivo anti-inflammatory properties. Despite the observed positive outcomes, the exact mechanisms underlying these beneficial effects remain unidentified. Aim: The goal of this research is to investigate the influence and potential mechanism of Lig on lipopolysaccharide (LPS)-induced inflammatory responses in human umbilical vein endothelial cells (HUVECs). Introduction: These experiments investigate the effectiveness of Lig in preventing LPS-induced damage in HUVECs, with the goal of elucidating the underlying processes at work. Materials and Methods: To evaluate HUVECs' viability, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was conducted. Enzyme-linked immunosorbent assay (ELISA) was employed to measure changes in ICAM-1, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein (MCP-1) levels. Real-time polymerase chain reaction (RT-PCR) was used to determine the levels of ICAM-1, IL-6, TNF-α, MCP-1, and toll-like receptors (TLR4) mRNA. Additionally, we performed WB analysis to assess the levels of nuclear factor-κB (NF-κB) p65, TLR4, IκBα, and p-IκBα. Results: The findings demonstrated significantly suppressed cell viability due to LPS treatment, while Lig treatment increased cell viability in a concentration-dependent manner. Lig also effectively reduced the mRNA levels of ICAM-1, TNF-α, IL-6, and MCP-1. Furthermore, Lig pretreatment led to downregulation of TLR4, p-IκBα, and NF-κB p65 in HUVECs. Discussion: The findings indicate that Lig reduces LPS-induced inflammation in HUVECs, and that the TLR4/NF-κB pathway is critical in increasing cell survival and minimizing inflammatory damage. This provides possible anti-inflammatory techniques for treating CD. Conclusion: In conclusion, our work demonstrates Lig's anti-inflammatory actions on LPS-stimulated HUVECs. The data suggest that Lig lowers inflammation via regulating the TLR4/NF-B pathway, boosting cell survival, and decreasing inflammatory responses. [ABSTRACT FROM AUTHOR]

Background: Interplay between gut microbiota and heart, termed "gut-heart" axis, has a crucial role in the pathogenesis of atherosclerosis. Our previous study showed that lycopene possesses anti-inflammatory and anti-atherosclerotic effects, but its link to the gut microbiota is poorly understood. Herein, we surmised that lycopene could regulate the gut microbiota, exert anti-atherosclerotic effect by regulating the "gut-heart" axis. Methods: Male ApoE−/− mice were fed a high-fat diet (HFD) with or without lycopene (0.1% w/w) for 19 weeks. Gut microbiota was analyzed by 16 S rRNA sequencing, the protein levels of zonula occludens-1 (ZO-1), occludin, toll-like receptor 4 (TLR4) and phospho-nuclear factor-κB (NF-κB) p65 were measured by Western blotting, the levels of serum inflammatory factors including monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 were assayed using ELISA kits. Also, the concentrations of serum lipopolysaccharide (LPS), D-lactic acid (D-LA) and diamine peroxidase (DAO) were measured through ELISA method. Results: The aortic sinus sections revealed that lycopene supplementation significantly reduced the extent of atherosclerotic lesions and inhibited atherosclerosis development caused by HFD. The analysis of gut microbiota showed that lycopene reduced the ratio of Firmicutes/Bacteroides and increased the relative abundance of Verrucomicrobia, Akkermansia and Alloprevotella, which were related to elevated intestinal barrier function and reduced inflammation. Moreover, lycopene up-regulated the expression of intestinal ZO-1 and occludin and decreased serum LPS, D-LA and DAO levels. In addition, lycopene inhibited the expression of TLR4 and phospho-NF-κB p65 in aortic sinus plaque, serum MCP-1, TNF-α, IL-1β, and IL-6 levels were also lowered by lycopene treatment. Conclusions: Our results indicated the protective effect of lycopene against atherosclerosis induced by HFD and further revealed that its mechanism might be its prebiotic effect on maintaining gut microbiota homeostasis and improving intestinal barrier function, consequently reducing serum LPS-triggered inflammatory response in the heart. [ABSTRACT FROM AUTHOR]

Objective To observe the intervention of propofol on high glucose-induced injury in podocytes and to explore the related mechanisms based on nuclear factor κB (NF-κB) signaling pathway. Methods Human glomerular podocytes (HGPC) were cultured in vitro and the cells in the logarithmic growth phase were divided into the normal glucose group, high glucose group, propofol group, inhibitor group, propofol + inhibitor group, and propofol + activator group, respectively. Cells in the normal glucose group were treated with 5 mmol/L D-glucose. Cells in the other groups were treated with 30 mmol/L D-glucose, and cells in the propofol group were additionally given propofol (25, 50, 100 µmol/L), cells in the inhibitor group were given NF-κB signaling pathway inhibitor BAY 11-7082, cells in the propofol + inhibitor group were given propofol and BAY 11-7082, and cells in the propofol + activator group were given propofol and NF-κB signaling pathway activator Prostratin. After 24 h of intervention, CCK-8 was used to detect cell viability and we se-lected the optimal concentration of propofol. The cell morphology of each group was observed by inverted microscope. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β in the supernatant of each group were determined by ELI-SA. The cell proliferation rate and cell migration number were measured by 5-acetylidene-2 'deoxyuracil nucleoside method and Transwell cell chamber method, respectively. Western blotting was used to determine epithelial-mesenchymal transformation (EMT) and NF-κB signaling pathway-related proteins in each group. Results The cross connections between the foot processes were reduced, the cell bodies were reduced, and the cell spacing increased in the high glucose group. Podocyte morphological changes in the propofol group and the inhibitor group were less than those in the high glucose group； podocyte morphological changes in the propofol + inhibitor group were less than those in the propofol group, and podocyte morphological changes in the propofol + activator group were more than those in the propofol group. The expression levels of TNF-α, IL-6, IL-1β, N-cadherin, Vimentin, p-NF-κB p65 protein and the number of migrating cells in the high glucose group were higher than those in the normal glucose group, while the cell proliferation rate and E-cadherin expression were lower than those in the normal glucose group (all P<0. 05). The expression levels of TNF-α, IL-6, IL1β, N-cadherin, Vimentin, p-NF-κB p65 protein and the number of migrating cells in the propofol group and the inhibitor group were lower than those in the high glucose group, and the cell proliferation rate and E-cadherin protein expression were higher than those in the high glucose group (all P<0. 05). The expression levels of TNF-α, IL-6, IL-1β, N-cad‐herin, Vimentin, p-NF-κB p65 protein and the number of migrating cells in the propofol + inhibitor group were lower than those in the propofol group, and the cell proliferation rate and E-cadherin protein expression were higher than those in the propofol group (all P<0. 05). The expression levels of TNF-α, IL-6, IL-1β, N-cadherin, Vimentin, p-NF-κB p65 protein and the number of migrating cells in the propofol + activator group were higher than those in the propofol group, and the cell proliferation rate and E-cadherin protein expression were lower than those in the propofol group (all P<0. 05). Conclusion Propofol could maintain the normal morphology of podocytes induced by high glucose, reduce inflammatory response, promote cell proliferation, inhibit cell migration and EMT, which may be related to the inhibition of NF-κB sig-naling transduction pathway. [ABSTRACT FROM AUTHOR]

Objective: To explore effect of ginsenoside Rg1 on nuclear factor-κB(NF-κB) phosphorylation and inflammationrelated pathways in rats with myocardial injury caused by sepsis. Methods: Rat sepsis myocardial injury model was established by cecal ligation and puncture(CLP). Sixty rats were randomly divided into sham operation(sham) group, CLP group, ginsenoside Rg1 low-dose(CLP+Rg1L ) group, ginsenoside Rg1 medium-dose(CLP+Rg1M) group, ginsenoside Rg1 high-dose(CLP+Rg1H ) group and risatovir(CLP+TAK-242) group, with 10 rats in each group. Sepsis cardiomyocyte model in vitro was constracted by LPS. H9C2 cells were divided into control group, LPS group, LPS+Rg1L group, LPS+Rg1M group, LPS+Rg1H group, LPS+TAK-242 group. Right common carotid artery cannulation method was used to detect mean arterial blood pressure(MABP), heart rate×left ventricular development pressure(LVDP×HR), and maximal increase/decrease rate of left ventricular pressure(±dp/dtmax) in each group. Myocardial histopathological changes was observed by HE staining. Apoptosis of myocardial tissues and H9C2 cells were detected by Annexin VFITC/PI double staining. Creatine kinase(CK), lactate dehydrogenase(LDH), aspartate aminotransferase(AST), cardiac troponin Ⅰ(cTnⅠ), tumor necrosis factor-α(TNF-α), IL-6, IL-1β levels in rat serum and H9C2 cells were detected by ELISA. Proliferation ability of H9C2 cells was detected by CCK-8 and EdU staining. RT-qPCR detected myocardial tissues Toll-like receptor 4(TLR4), NF- κB p65, p38 mitogen activated protein kinase(p38MAPK) mRNA expressions. Western blot detected protein expressions of TLR4, NF-κB p65, p-NF-κB p65, p38MAPK, p-p38MAPK and nucleotide binding oligomerization domain-like receptor protein 3(NLRP3) in myocardial tissues. Results: Ginsenoside Rg1 could increase levels of MABP, LVDP×HR and ±dp/dtmax, decrease activities of CK, LDH and AST, and decrease levels of cTnⅠ, TNF-α, IL-6, IL-1β, TLR4, NF-κB p65, p38MAPK mRNA and TLR4, NF-κB p65, p-p38MAPK/p38MAPK, NLRP3 proteins(P<0.05), promote cardiomyocyte proliferation, inhibit apoptosis and inflammation, and improve myocardial injury. Conclusion: Ginsenoside Rg1 can inhibit myocardial tissue cell apoptosis and inflammation, improve cardiac function, and reduce myocardial injury caused by sepsis, whose mechanism may be related to TLR4/NF- κB and p38MAPK signaling pathways. [ABSTRACT FROM AUTHOR]

Background: Natural products have been recommended as a complementary therapy for type 2 diabetes mellitus (T2DM) due to constraints of safety and tolerability of existing anti-diabetic agents. Luteolin exhibits anti-diabetic and anti-inflammatory effects. Hence, the impact of luteolin on glucose homoeostasis and organ damage was investigated in high-fat diet (HFD) and streptozotocin (STZ) induced T2DM in rats. Methods and results: Male Wistar rats were maintained on HFD (provided 55% energy as fat) for 10 days. Subsequently, a single dose of 40 mg/kg STZ was injected intraperitoneally on the 11th day. Seventy-two hours after STZ administration, diabetic rats with established hyperglycemia (fasting serum glucose > 200 mg/dL) were randomized into different groups having six rats each and orally administered either 0.5% hydroxy propyl cellulose or pioglitazone (10 mg/kg) or luteolin (50 mg/kg or 100 mg/kg) once daily for 28 days, while continuing HFD for respective groups. Luteolin significantly reduced hyperglycaemia, homoeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) levels, and improved hypoinsulinemia and HOMA of b-cell function (HOMA-B) in a dose-dependent manner. Increased TNF-α, IL-6 and NFκB levels in diabetic rats were significantly regulated. Additionally, luteolin significantly augmented PPAR-γ expression while attenuating sterol regulatory element binding protein-1c (SREBP-1c) expression. Histopathological scrutiny validated that luteolin effectively attenuated HFD-STZ-induced injury in pancreatic β-cells and kidneys to near normalcy. Conclusion: Our study showed that luteolin ameliorated hyperglycemia and improved hypoinsulinemia, β-cell dysfunction, and renal impairment in HFD-STZ-induced diabetic rats by attenuating inflammation and dysregulated cytokine secretion through modulation of PPAR-γ, TNF-α, IL-6 and NF-kB expression and down-regulation of SREBP-1c. [ABSTRACT FROM AUTHOR]

Objective To observe the preventive and therapeutic effect of intraperitoneal and subcutaneous injection of allopregnanolone (Allo) on postoperative delirium (POD) in aged male mice and to explore its possible mechanism. Methods Ninety-six 6-month-old male C57BL/6J mice were randomly divided into groups A, B, C and control group, with 24 in each. Mice in the control group were fed normally, and mice in the groups A, B and C underwent internal fixation of tibial fracture of right lower limb (POD animal model preparation method is commonly used). Mice in the group A were intraperitoneally injected with 8 mg/kg allopregnenolone at 1 h after surgery, and then were subcutaneously injected with 8 mg/kg allopregnenolone at 6, 24 and 48 h after surgery, respectively. Mice in the group B were intraperitoneally injected with 2-hydroxypropyl-β-cyclodextrin at 1 h after surgery, and subcutaneously injected with 2-hydroxypropyl-β-cyclodextrin at 6, 24 and 48 h after surgery, respectively. Mice in the group C were not given any drugs after surgery. Morris water maze test was used to evaluate the spatial learning and memory ability of mice before surgery and at the 1, 3 and 7 days after surgery, respectively. After the test, six mice were randomly killed in each group. Hippocampal tissues were taken to detect inflammatory factors and phosphorylated p38 mitogen-activated protein kinase (p-p38MAPK), nuclear factor κB (NF-κB), and NOD-like receptor protein 3 (NLRP3) pathway-related proteins in the hippocampal tissues of mice in each group. Results Compared with the control group, the escape latency of mice in group C was longer and the number of platform crossing was smaller on the 1st, 3rd and 7th days after operation (all P<0. 05). Compared with the group C, the escape latency of mice in the group A was shorter and the number of platform crossing was lager on day 1, 3 and 7 after operation (all P<0. 05). Compared with the control group, the expression levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), p-p38MAPK, NF-κB, and NLRP3 in the hippocampal tissues of group C were higher on day 1, 3 and 7 after surgery (all P<0. 05). Compared with the group C, the expression levels of TNF-α, IL-1β, p-p38MAPK, NF-κB and NLRP3 in the hippocampal tissues of the group A were lower on day 1, 3 and 7 after surgery (all P<0. 05). Conclusion Intraperitoneal and subcutaneous injection of allopregnenolone can reduce POD after internal fixation of tibial fracture of right lower limb in aged male mice probably by inhibiting the expression levels of TNF-α, IL-1β, p-p38MAPK, NF-κB, and NLRP3 in the hippocampal tissues. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor-1 alpha (HIF-1α) is usually regarded as a core regulator of hypoxic response. Persistent inflammation and impaired wound healing are common manifestations of diabetic foot ulcer (DFU). In normal wounds, HIF-1α and its related regulatory molecules, such as vascular endothelial growth factor and inducible nitric oxide synthase, are activated by hypoxia signals, which in turn promote wound healing. However, abnormal regulation of the HIF-1α signaling pathway by hyperglycemia leads to impaired wound healing in DFU. In this review, we highlight the tissue-specific and stage-specific effects of the HIF-1α signaling pathway in DFU. In the early stage of DFU, HIF-1α in inflammatory cells is over-upregulated by hyperglycemia, causing the activation of nuclear factor-κB and the inducible nitric oxide synthase-mediated pro-inflammatory signaling pathway, leading to sustained inflammation, which is deleterious. In the late stage of DFU, HIF-1α in endothelial cells and keratinocytes is inhibited by hyperglycemia, which leads to the downregulation of vascular endothelial growth factor expression, resulting in insufficient angiogenesis and difficult healing at the wound site. In this review, we discuss recent advances in the knowledge of the HIF-1α signaling pathway and the key targeted molecules in impaired wound healing of DFU. We also summarize the drugs currently in clinical trials that target HIF-1α or its downstream molecules, recapitulate current gaps in our knowledge, and propose rational therapeutic strategies for DFU based on the action characteristics of HIF-1α. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is characterized by inflammation of joints and degradation of articular cartilage matrix. As involvement of damage-associated molecular patterns (DAMPs) in the pathogenesis of OA has been reported, the present study comprehensively investigated the regulation of inflammatory mediator expression in chondrocytes mediated by Toll-like receptor 4 (TLR4), a receptor for DAMPs. Treatment of cultured rat chondrocytes with lipopolysaccharide (LPS) induced the mRNA expression of proinflammatory cytokines (interleukin [IL]-1β, IL-6, tumor necrosis factor [TNF]), matrix degradation enzymes (metalloproteinase [MMP] 3, MMP13), and inducible nitric oxide synthase (iNOS) through TLR4. Transforming growth factor β-activated kinase-1 (TAK1) and nuclear factor-κB (NF-κB) were crucial for the upregulated expression of these inflammatory mediators. The induction of IL-1β and TNF was regulated by extracellular signal-regulated kinase (ERK), while the induction of IL-6 was mediated by Tank-binding kinase 1 (TBK1) and c-Jun N-terminal kinase (JNK). The induction of MMP3 and MMP13 was regulated by TBK1, ERK, and JNK, while the induction of iNOS was mediated by ERK and JNK. In summary, some of the regulatory mechanisms underlying the expression of key inflammatory mediators for OA pathogenesis have been demonstrated. Further clarification may allow these signaling molecules to become new therapeutic targets for OA treatment strategies.

Objective To investigate the expression levels and significance of serum interleukin-17 （IL-17） and nuclear factor-κB （NF-κB） in Mycoplasma pneumoniae pneumonia （MPP） children in acute stage with lung consolidation. Methods Sixty-four children diagnosed with MPP in acute stage were selected. According to the imaging features of chest CT scan or chest X-ray upon admission， all patients were divided into the lung consolidation group （n = 32） and non-lung consolidation group （n = 32）. The serum levels of IL-17 and NF-κB in MPP children were detected and compared between two groups. The relationship between IL-17 and NF-κB was analyzed. The receiver operating characteristic （ROC） curve was drawn. The diagnostic efficacy of serum IL-17 and NF-κB levels for lung consolidation was assessed in MPP children in acute stage. Results The serum levels of IL-17 and NF-κB in the lung consolidation group were higher than those in the non-lung consolidation group （both P < 0.05）. Spearman correlation analysis showed that IL-17 level was positively correlated with NF-κB level in MPP children （rs = 0.818， P < 0.05）. When the serum level of IL-17 was 10.45 pg/mL， the area under the ROC curve （AUC） was 0.806， and the sensitivity and specificity for the diagnosis of lung consolidation in MPP children were 75.0% and 78.1%. When the serum level of NF-κB was 534.13 pg/mL， the AUC was 0.951， and the sensitivity and specificity for the diagnosis of lung consolidation in children with MPP were 90.6% and 84.4%. Conclusions The expression levels of IL-17 and NF-κB are up-regulated in MPP children with lung consolidation in acute stage. Early detection of serum levels of IL-17 and NF-κB has certain diagnostic efficacy for lung consolidation in MPP.

BACKGROUND: Astrocytes can be activated into A1 and A2 subtypes of reactive astrocytes, which are completely different in gene, molecule and function, and have different specific roles in spinal cord injury repair. High-mobility group box 1 (HMGB1) has been proven to be an important inflammatory and immune factor after spinal cord injury, which can cause cell edema, inflammatory reaction and apoptosis; however, its effect on reactive astrocytes remains unclear. OBJECTIVE: To investigate the activation of rat spinal cord astrocytes into reactive astrocytes after oxygen-glucose deprivation/restoration (OGD/R) and to explore the effect of HMGB1 on different subtypes of reactive astrocytes and the relevant mechanism. METHODS: Rat spinal cord astrocytes were cultured to the third generation. Cell morphology was observed after OGD/R treatment, activation of reactive astrocytes was detected by western blot assay, and migration ability of the cells was detected by cell scratch assay. After inhibition of HMGB1, the cells were divided into five groups: normal group, OGD6 h/R6 h group, HMGB1 interference group, negative sequence group, and OGD6 h/R6 h+12 μmol/L ethyl pyruvate group (an HMGB1 inhibitor). Western blot assay and immunofluorescence method were used to detect the expression of C3 and S100A10 in different subtypes of reactive astrocytes, and cell scratch assay was used to detect the migration of reactive astrocytes. To explore the possible mechanism underlying the effect of HMGB1 on reactive astrocytes, the cells were divided into four groups: normal group, OGD6 h/R6 h group, OGD6 h/R6 h+5 µmol/L CLI-095 group (a toll-like receptor 4 inhibitor), and OGD6 h/R6 h+5 µmol/L BAY 11-7082 group (a nuclear factor-κB inhibitor). Western blot assay was used to detect the expression of toll-like receptor 4, nuclear factor-B, C3, and S100A10. RESULTS AND CONCLUSION: (1) Oxygen-glucose deprived cells were shrunk in size and had an increased migration capacity. After reoxygen-glucose treatment, the cell volume was increased and A1 and A2 reactive astrocytes were activated. S100A10 expression was the highest at OGD6 h/R6 h and C3 expression was peaked at OGD6 h/R12 h (P < 0.05). (2) Effects of silencing or inhibition of HMGB1 expression on reactive astrocytes: Compared with the OGD6 h/R6 h group, inhibition of HMGB1 significantly reduced the expression of C3 (P < 0.05), increased the expression of S100A10 (P < 0.05), and enhanced cell migration ability. (3) Compared with the OGD6 h/R6 h group, the expression of toll-like receptor 4 decreased in the OGD6 h/R6 h+CLI 095 group (P < 0.05), while the expression of nuclear factor-κB and C3 decreased and the expression of S100A10 increased in the OGD6 h/R6 h+CLI 095 group and OGD6 h/R6 h+BAY 11-7082 group (P < 0.05). (4) To conclude, astrocytes can be activated into two different subtypes of reactive astrocytes after OGD/R. Inhibition of HMGB1 can reduce A1 reactive astrocytes, increase A2 reactive astrocytes, and enhance cell migration ability through the toll-like receptor 4/nuclear factor-κB pathway. [ABSTRACT FROM AUTHOR]

Introduction: Lipopolysaccharide (LPS) tolerance is the downregulation of LPS signaling after pre-exposure to LPS, and it provides protection against hyperactive inflammation. Cytokine production decreases during LPS tolerance, and the phenotype of LPS-tolerant monocytes shifts toward M2 (anti-inflammatory) type. Magnesium sulfate (MgSO4) is a widely used anti-inflammatory agent. Although MgSO4 inhibits LPS signaling, the effect of MgSO4 on LPS tolerance is unknown. In the present study, we investigated the in vitro effects of MgSO4 on LPS tolerance. Methods: To induce LPS tolerance, THP-1 cells were stimulated with LPS (200 ng/mL, 2 h) after pre-exposure to LPS (200 ng/mL, 24 h) with or without pre-treatment of MgSO4 (20 mM, 24 h). Results: Our results revealed that MgSO4 enhanced LPS tolerance by downregulating nuclear factor-κB (NF-κB)-induced tumor necrosis factor-α or interleukin-6, and upregulating cluster of differentiation 163 (a M2-associated marker). Furthermore, the LPS-triggered upregulation of phosphoinositide 3-kinase (PI3K) was significantly increased during LPS tolerance. MgSO4 activated PI3K, but inhibited NF-κB in LPS-stimulated cells. Notably, MgSO4 mitigated the signaling of both PI3K and NF-κB in LPS-tolerant cells, suggesting the effect of MgSO4 on LPS tolerance relies on the modulation of the crosstalk between PI3K and NF-κB. Conclusion: MgSO4 enhanced LSP tolerance, thus providing evidence for a novel underlying mechanism of the anti-inflammatory effects of MgSO4. [ABSTRACT FROM AUTHOR]