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Hepatocellular carcinoma (HCC) remains a major global health problem with high incidence and mortality. Diagnosis of HCC at late stages and tumour heterogeneity in patients with different genetic profiles are known factors that complicate the disease treatment. HCC therapy becomes even more challenging in patients with drug resistance such as resistance to sorafenib, which is a common drug used in HCC patients. Sorafenib resistance can further aggravate HCC by regulating various oncogenic pathways such as autophagy and nuclear factor-kappa Beta (NF-ĸβ) signalling. Sirtuin 1 (SIRT1), is a nicotinamide adenosine dinucleotide (NAD)-dependent histone deacetylases that regulates various metabolic and oncogenic events such as cell survival, apoptosis, autophagy, tumourigenesis, metastasis and drug resistance in various cancers, but its role in HCC, particularly in sorafenib resistance is underexplored. In this study, we generated sorafenib-resistant HepG2 and Huh-7 liver cancer cell models to investigate the role of SIRT1 and its effect on autophagy and nuclear factor-kappa Beta (NF-ĸβ) signalling pathways. Western blot analysis showed increased SIRT1, altered autophagy pathway and activated NF-ĸβ signalling in sorafenib-resistant cells. SIRT1-silenced HCC cells demonstrated down-regulated autophagy in both parental and chemoresistant cells. This may occur through the deacetylation of key autophagy molecules such as FOXO3, beclin 1, ATGs and LC3 by SIRT1, highlighting the role of SIRT1 in autophagy induction. Silencing of SIRT1 also resulted in activated NF-ĸβ signalling. This is because SIRT1 failed to deacetylate p65 subunit of NF-κB, translocate the NF-κB from nucleus to cytoplasm, and suppress NF-κB activity due to the silencing. Hence, the NF-κB transcriptional activity was restored. These findings summarize the role of SIRT1 in autophagy/NF-ĸβ regulatory axis, with a similar trend observed in both parental and sorafenib-resistant cells. The present work promotes a better understanding of the role of SIRT1 in autophagy and NF-ĸβ signalling in HCC and sorafenib-resistant HCC. As some key proteins in these pathways are potential therapeutic targets, a better understanding of SIRT1/autophagy/NF-ĸβ axis could further improve the therapeutic strategies against HCC. [ABSTRACT FROM AUTHOR]

Background: Cervical cancer is a common gynecologic malignant tumor, but the critical factors affecting cervical cancer progression are still not well demonstrated. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has been widely recognized as an anti-inflammatory factor to regulate macrophage polarization. In this study, the effect and mechanism of MANF on cervical cancer were preliminarily explored. Methods and results: Kaplan–Meier curve was used to show the overall survival time of the involved cervical cancer patients with high and low MANF expression in cervical cancer tissues. MANF was highly expressed in peritumoral tissues of cervical carcinoma by using immunohistochemistry and western blot. MANF mRNA level was detected by using qRT-PCR. Dual-labeled immunofluorescence showed MANF was mainly expressed in macrophages of cervical peritumoral tissues. Moreover, MANF-silenced macrophages promoted HeLa and SiHa cells survival, migration, invasion and EMT via NF-κB signaling activation. The results of tumor formation in nude mice indicated MANF-silenced macrophages promoted cervical tumor formation in vivo. Conclusion: Our study reveals an inhibitory role of MANF in cervical cancer progression, indicating MANF as a new and valuable therapeutic target for cervical cancer treatment. [ABSTRACT FROM AUTHOR]

Inositol-requiring enzyme-1 (IRE1) is the master regulator of the unfolded protein response pathway, associated with the endoplasmic reticulum (ER) in sensing and regulating cell stress. The activity of IRE1 is highly explored and well-characterized in cancer and other cells. However, the IRE1 molecular mechanism in chondrocytes is poorly understood. The present study explored the effect of IRE1 on chondrocytes regarding its chondrogenic gene expression and its correlation with different cellular pathways and cell behavior. Chondrocytes transfected with the cDNA of IRE1 reduced the expression of type II collagen, disrupting chondrocyte differentiation as confirmed by western blotting and immunofluorescence. Upon siRNA treatment, the influence of IRE1 on chondrocyte differentiation is restored by reviving the normal expression of type II collagen. Different molecular pathways were explored to investigate the role of IRE1 in causing chondrocyte dedifferentiation. However, we found no significant correlation, as IRE1 induces dedifferentiation through independent pathways. In response to various endoplasmic reticulum (ER) agonists (2-deoxy-D-glucose), and ER stress antagonists (tauroursodeoxycholic acid and salubrinal), IRE1 overexpression did not affect GRP78/94, as implicated in the pathogenesis of ER stress. Moreover, when IRE1 overexpression was correlated with the inflammation pathway, nuclear factor-kappa B (NFκB), IRE1 substantially increased the expression of p50 while decreasing the expression of nuclear factor kappa light polypeptide alpha (IκBα). These results suggest that IRE1 induces dedifferentiation in chondrocytes by modulating inflammatory pathways that cause dedifferentiation by disrupting type II collagen expression. [ABSTRACT FROM AUTHOR]

Background: Benign prostatic hyperplasia (BPH) is a prevalent and chronic progressive disease in aging males with lower urinary tract symptoms. Shikonin is known as traditional herb extracts, which have the capacity of anti-oxidation, anti-inflammation, and antitumor. However, little is known about the effect of shikonin on BPH. Objective: The BPH animal model was established by orchiectomy and testosterone propionate injection. After the end of animal model, the weight of prostate and the histologic structure of prostate tissues were examined. ELISA and immunoblotting were performed to detect the levels of steroid hormones, inflammatory cytokines, and oxidative factors as well as proteins. TUNEL was utilized to detect apoptotic cells in prostate tissues. Results: The administration of shikonin in BPH rats reduced the weight gain of prostate tissues, decreased the levels of DHT, testosterone, and PSA, and also restored the histologic change of prostate tissues. Also, in BPH rats, the IL-6, IL-1β, TNF-α, and MDA levels of prostate tissues were higher than control rats, while shikonin treatment reduced these biochemical changes. There were a lower apoptosis rate and lower expression of Bcl-2 in BPH rats, which was reversed by shikonin treatment. An increase in Nrf2, NQO1, and HO-1 of BPH prostate tissues was induced by shikonin supplement. The NF-κB pathway was activated in BPH prostate tissues, which was then inhibited by shikonin treatment. Conclusion: Our data revealed that shikonin treatment had a beneficial effect on the inflammation response, apoptotic process, and oxidative stress of BPH via the Nrf2-ARE and NF-κB pathways. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a set of metabolic diseases defined by a persistently high blood sugar level. Mesenchymal stem cells (MSCs) are a novel potential therapeutic intervention in treatments of various diseases, which is also referred to as regenerative medicine. We aimed to compare the pro-inflammatory cytokines' levels during bone marrow mesenchymal stem cells (BM-MSCs) transplantation in rats with induced type I (T1D) and type II diabetes (T2D). Thirty-five male Sprague dawley rats were divided into: Group I: the healthy control group, group II: untreated rats with streptozotocin (STZ)-induced T1D (65 mg/kg), group III: BM-MSCs treated rats with STZ-induced T1D, group IV: untreated rats with high-fat diet (HFD)/STZ-induced T2D (40 mg/kg), group V: BM-MSCs-treated rats with HFD/STZ-induced T2D. Biochemical, histopathological and immunohistochemical studies were applied. Our results showed that transplantation reduced hyperglycemia and increased insulin levels in both induced T1D and T2D. Also, reductions in the levels of inflammatory markers were noticed after transplantation that was coincided with nuclear factor-kappa B (NF-кB) immunohistochemical results; which showed negative or moderate cytoplasmic reactivity in treated groups III and V. These results indicated the ability of BM-MSCs transplantation to modulate the pro-inflammatory cytokine profile during treatment of both T1D and T2D. Key points: BM-MSCs transplantation, in both T1D and T2D, led to the reduction in blood glucose levels. The biochemical and histological findings indicated an improvement in pancreatic islets. The immunomodulatory effect of BM-MSCs allowed the islets to neogenesis. [ABSTRACT FROM AUTHOR]

Spinal cord edema is a quick-onset phenomenon with long-term effects. This complication is associated with inflammatory responses, as well as poor motor function. No effective treatment has been developed against spinal edema, which urges the need to provide novel therapies. Astaxanthin (AST) is a fat-soluble carotenoid with anti-inflammatory effects and a promising candidate for treating neurological disorders. This study aimed to investigate the underlying mechanism of AST on the inhibition of spinal cord edema, astrocyte activation, and reduction of inflammatory responsesin a rat compression spinal cord injury (SCI) model. Male rats underwent laminectomy at thoracic 8–9, and the SCI model was induced using an aneurysm clip. After SCI, rats received dimethyl sulfoxide or AST via intrathecal injection. The effects of AST were examined on the motor function, spinal cord edema, integrity of blood-spinal cord barrier (BSCB), and expression of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), glial fibrillary acidic protein (GFAP), and aquaporin-4 (AQP4), and matrix metallopeptidase- 9 (MMP-9) post-SCI. We showed that AST potentially improved the recovery of motor function and inhibited the spinal cord edema via maintaining the integrity of BSCB, reducing the expression of HMGB1, TLR4, and NF-κB, MMP-9 as well as downregulation of astrocyte activation (GFAP) and AQP4 expression. AST improves motor function and reduces edema and inflammatory responses in the spinal tissue. These effects are mediated by suppression of the HMGB1/TLR4/NF-κB signaling pathway, suppressing post-SCI astrocyte activation, and decreasing AQP4 and MMP-9 expression. [ABSTRACT FROM AUTHOR]

Pectolinarigenin (PEC), a natural flavonoid present in cirsium chanroenicum and citrus fruits, has possess the distinct pharmacological activities. However, its molecular mechanisms and pharmacological effects on intestinal illness have not been elucidated. In the present study, we investigated the potential beneficial effects of pectolinarigenin (PEC) on lipopolysaccharide (LPS)-induced macrophage cells and the dextran sulfate sodium (DSS)-induced colitis model. Our findings showed that PEC pretreatment inhibits the LPS-induced nuclear factor-kappa B (NF-κB) activation by interfering with the degradation of IκB-α. Further, increased Nrf2 protein expression was reported on PEC treated RAW 264.7 and THP1 cell lines. In addition, we revealed that PEC mediated the NF-κB/Nrf2 pathway regulation, which in turn inhibits the synthesis of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), interleukin-1beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) on RAW 264.7 and THP1 cells. Furthermore, PEC dose-dependently reduced the DSS-induced inflammation in the colon by regulating NF-κB/Nrf2 signaling pathway and enhancing the myeloperoxidase (MPO) activity and redox regulators such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and lipid peroxidation byproduct malondialdehyde (MDA) in DSS-induced inflamed colon. Similarly, we reported the minimal pathological damages in the PEC-treated mice colon, as well as increase goblet cell population and mucin-2 production. In conclusion, our findings demonstrate that PEC reduces the DSS-induced colitis in mice by regulating the NF-κB/Nrf2 pathway. Thus, PEC might be a promising therapeutic agent for the treatment of inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of seabuckthorn berries extract (SBE) on pulmonary vascular hyperpermeability in the mice model of acute lung injury (ALI) induced by lipopolysaccharide (LPS). Methods: Sixty Kunming mice were allocated into 6 groups by a random number table, including control, LPS, dexamethasone (Dex, 1 mg/kg), and 120, 240 and 480 mg/kg SBE groups, 10 mice in each group. Except the control group, mice were pre-treated with Dex and SBE, respectively, for 7 days before LPS was intraperitoneally injected to induce ALI. Pulmonary vascular hyperpermeability was evaluated by histopathologic observation and transvascular leakage determination. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) levels in serum were measured using enzyme-linked immunosorbent assay. The expression of nuclear factor-kappa B (NF-κB) p65 in lung cells was determined by immunofluorescence analysis. The contents of cytoplasmic inhibitor of nuclear factor-κB kinase (IKK) and nuclear p65, as well as downstream proteins of E-selectin (CD62E) and intercellular adhesion molecule-1 (ICAM-1), were determined using Western blot analysis. Results: Histopathological observation confirmed SBE treatment alleviated morphological lesion induced by LPS. Compared with the LPS group, 480 mg/kg SBE significantly decreased the water content of lung, Evans blue accumulation in lung tissue, and protein concentration and neutrophils count in bronchoalveolar lavage fluid (P<0.01); moreover, 480 mg/kg SBE significantly suppressed release of TNF-α and IL-6, and down-regulated expressions of IKK, nuclear p65, ICAM-1 and CD62E (P<0.01). Conclusion: SBE maintained alveolar-capillary barrier integrity under endotoxin challenge in mice by suppressing the key factors in the pathogenesis of ALI. [ABSTRACT FROM AUTHOR]

Background: Plant-derived phytochemicals have been reported to exert anticancer activity. This study investigated the antitumor role of silymarin (Silybum marianum) (SMN) and its molecular targets in Ehrlich solid tumor xenografts in vivo. Methods and results: Female Swiss albino mice were divided into three groups (of five animals each) that were engrafted with Ehrlich tumor (ET) cells with or without SMN treatment. The 3rd groups treated with DMSO only vehicle control group. A significant reduction in animal body mass and tumor volume/weight were observed in xenografted mice treated with SMN. SMN modulated oxidative stress in tumors while enhancing the antioxidant levels in mouse serum. SMN activated both mitochondrial and death receptor-related apoptosis pathways and induced cell cycle arrest, marked by a significant downregulation of cyclin D1 in SMN-treated tumors. Significant decreases in RNA content and protein expression levels of Ki-67 and proliferating cell nuclear antigen were observed in ET cells. Additionally, SMN downregulated vascular endothelial growth factor and nuclear factor-kappa B levels indicating anti-angiogenesis activity of this agent. SMN upregulated the expression of E-cadherin in tumor tissue suggesting, that SMN has potential ability to inhibit metastasis. Tumor tissue from SMN-treated animals showed a remarkable degeneration and reduction in the neoplastic cell density. Conclusions: The anticancer effect was associated with apparent apoptosis in neoplastic cells with abundance of multifocal necrotic areas. SMN was found to inhibit ET growth via enhancing apoptosis, inhibition of cell division and reduction in angiogenesis in vivo. Hypothetical scheme of SMN antitumor effects (mechanism of signaling) in solid ET in vivo. SMN anticancer effect may be mediated by molecular mediators that affect proliferation, cell cycle activity, apoptotic pathways, angiogenesis, and metastasis. [ABSTRACT FROM AUTHOR]

Previous studies have verified that celastrol (Cel) protects against rheumatoid arthritis (RA) by inhibiting the NLRP3 inflammasome signaling pathway, but the molecular mechanism by which Cel regulates NLRP3 has not been clarified. This study explored the specific mechanisms of Cel in vitro and in vivo. A type II collagen-induced arthritis (CIA) mouse model was used to study the antiarthritic activity of Cel; analysis of paw swelling, determination of the arthritis score, and pathological examinations were performed. The antiproliferative and antimigratory effects of Cel on TNF-α induced fibroblast-like synoviocytes (FLSs) were tested. Proinflammatory factors were evaluated using enzyme-linked immunosorbent assay (ELISA). The expression of NF-κB/NLRP3 pathway components was determined by western blotting and immunofluorescence staining in vitro and in vivo. The putative binding sites between Cel and Hsp90 were predicted through molecular docking, and the binding interactions were determined using the Octet RED96 system and coimmunoprecipitation. Cel decreased arthritis severity and reduced TNF-α-induced FLSs migration and proliferation. Additionally, Cel inhibited NF-κB/NLRP3 signaling pathway activation, reactive oxygen species (ROS) production, and proinflammatory cytokine secretion. Furthermore, Cel interacted directly with Hsp90 and blocked the interaction between Hsp90 and NLRP3 in FLSs. Our findings revealed that Cel regulates NLRP3 inflammasome signaling pathways both in vivo and in vitro. These effects are induced through FLSs inhibition of the proliferation and migration by blocking the interaction between Hsp90 and NLRP3. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a significant public health issue that imposes numerous burdens on patients and society. Uncontrolled excessive inflammation in the second pathological phase of SCI can aggravate the injury. In this paper, we hypothesized that suppressing inflammatory pathways via autophagy could aid functional recovery, and prevent spinal cord tissue degeneration following SCI. To this end, we examined the effects of intrathecal injection of all-trans retinoic acid (ATRA)-preconditioned bone marrow mesenchymal stem cells (BM-MSCs) (ATRA-MSCs) on autophagy activity and the HMGB1/NF-κB/NLRP3 inflammatory pathway in an SCI rat model. This study demonstrated that SCI increased the expression of Beclin-1 (an autophagy-related gene) and NLRP3 inflammasome components such as NLRP3, ASC, Caspase-1, and pro-inflammatory cytokines IL-1β, IL-18, IL-6, and TNF-α. Additionally, following SCI, the protein levels of key autophagy factors (Beclin-1 and LC3-II) and HMGB1/NF-κB/NLRP3 pathway factors (HMGB1, p-NF-κB, NLRP3, IL-1β, and TNF-α) increased. Our findings indicated that ATRA-MSCs enhanced Beclin-1 and LC3-II levels, regulated the HMGB1/NF-κB/NLRP3 pathway, and inhibited pro-inflammatory cytokines. These factors improved hind limb motor activity and aided in the survival of neurons. Furthermore, ATRA-MSCs demonstrated greater beneficial effects than MSCs in treating spinal cord injury. Overall, ATRA-MSC treatment revealed beneficial effects on the damaged spinal cord by suppressing excessive inflammation and activating autophagy. Further research and investigation of the pathways involved in SCI and the use of amplified stem cells may be beneficial for future clinical use. [ABSTRACT FROM AUTHOR]

Neuroimmune alterations have important implication in the neuropsychiatric symptoms and biochemical changes associated with lead-induced neurotoxicity. It has been suggested that inhibition of neuroinflammatory-mediated lead-induced neurotoxicity by phytochemicals enriched with antioxidant activities would attenuate the deleterious effects caused by lead. Hence, this study investigated the neuroinflammatory mechanism behind the effect of Ginkgo biloba supplement (GB-S) in lead-induced neurotoxicity in mice brains. Mice were intraperitoneally pretreated with lead acetate (100 mg/kg) for 30 min prior the administration of GB-S (10 and 20 mg/kg, i.p.) and ethylenediaminetetraacetic acid (EDTA) (50 mg/kg, i.p.) for 14 consecutive days. Symptoms of neurobehavioral impairment were evaluated using open field test (OFT), elevated plus maze (EPM), and tail suspension test (TST) respectively. Thereafter, mice brain hippocampi were sectioned for myeloperoxidase activity (MPO), pro-inflammatory cytokine (TNF-α and IL-6) estimation and inflammatory protein (NF-κB) expression. Furthermore, histomorphormetric studies (Golgi impregnation and Cresyl violet stainings) were carried out. GB-S (10 and 20 mg/kg) significantly restores neurobehavioral impairments based on improved locomotion, reduced anxiety- and depressive-like behavior. Moreover, GB-S reduced the MPO activity, inhibits TNF-α, IL-6 release, and downregulates NF-κB immunopositive cell expression in mice hippocampus. Histomorphometrically, GB-S also prevents the loss of pyramidal neuron in the hippocampus. The endpoint of this findings suggest that GB-S decreases neuropsychiatric symptoms induced by lead acetate through mechanisms related to inhibition of release of pro-inflammatory mediators and suppression of hippocampal pyramidal neuron degeneration in mice. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is chronic inflammatory autoimmune disease. The crucial role of long non-coding RNA (lncRNA) in the progression of RA has been highlighted. Hence, this study was designed to explore the specific downstream mechanism of lncRNA nuclear-enriched abundant transcript 1 (NEAT1) in RA. Initially, the expression of NEAT1, p-p65, p300, and IL-18 in clinical tissues and cells was determined. Then, interactions among p65, NEAT1, p300, CBP, and IL-18 were investigated by immunofluorescence staining, dual luciferase reporter gene assay, RT-qPCR assay ChIP assay, and RIP assay followed by the analysis of their effects on RA in vivo and in vitro after expression alteration. The expressions of NEAT1, p-p65, p300, and IL-18 were all upregulated in the synovial tissues from the mice and patients with RA. NEAT1 silencing reduced the infiltration of CD4+ T cells and macrophages in synovial tissues, downregulated expression of blood inflammatory factors, relieved RA severity, and lowered incidence of RA in mice. Further, p-p65 could increase the expression of NEAT1 by binding to the NEAT1 promoter region, NEAT1 could co-locate and interact with p300, thus regulating the expression of IL-18 by regulating histone acetylation modification in IL-18 promoter region. NEAT1 aggravated RA via p300/CBP/IL-18 axis, representing a promising therapeutic target in RA. [ABSTRACT FROM AUTHOR]

Bacterial myocarditis is a key cause leading to myocardial damage and cardiac dysfunction. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has been found to be an anti-inflammatory factor. This study is to explore the effect of MANF on LPS-induced myocardial inflammation and macrophage differentiation. The myocarditis mouse model was constructed by LPS treatment. Myocardial damage and serum inflammatory factors were evaluated by ELISA. RT-qPCR was used to detect mRNA of M1/M2 macrophage markers. Western blot, immunohistochemical, and immunofluorescent staining were used to examine myocardial M1/M2 macrophages and NF-κB activation. Mono-macrophage-derived MANF deficiency enhanced LPS-induced inflammatory response and increased M1 macrophages in myocardium tissues, further causing more severe myocardial injury and lower survival rate of mice. Also, LPS-induced myocardial NF-κB activation was strengthened after mono-macrophage-derived MANF knockout. Mono-macrophage-derived MANF inhibits bacterial myocarditis and myocardial M1 macrophage differentiation, which is potential to be used for bacterial myocarditis treatment clinically. [ABSTRACT FROM AUTHOR]

A prenylated flavonoid, cudraflavanone B, is isolated from Cudrania tricuspidata. In this study, we investigated its anti-inflammatory and anti-neuroinflammatory effects in lipopolysaccharide (LPS)-induced RAW264.7 and BV2 cells. In our initial study of the anti-inflammatory effects of cudraflavanone B the production of nitric oxide and prostaglandin E2 was attenuated in LPS-stimulated RAW264.7 and BV2 cells. These inhibitory effects were related to the downregulation of inducible nitric oxide synthase and cyclooxygenase-2. In addition, cudraflavanone B suppressed the production of pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-α in LPS-induced RAW264.7 and BV2 cells. Moreover, the evaluation of the molecular mechanisms underlying the anti-inflammatory effects of cudraflavanone B revealed that the compound attenuated the nuclear factor-kappa B signaling pathway in LPS-induced RAW264.7 and BV2 cells. In addition, cudraflavanone B inhibited the phosphorylation of extracellular signal-regulated kinase mitogen-activated protein kinase signaling pathways in these LPS-stimulated cells. Thus, cudraflavanone B suppressed nuclear factor-κB, and extracellular signal-regulated kinase mitogen-activated protein kinase mediated inflammatory pathways, demonstrating its potential in the treatment of neuroinflammatory conditions. [ABSTRACT FROM AUTHOR]

Purpose: Emerging evidence has shown that interleukin (IL)-17A is implicated in the pathogenesis of allergic rhinitis (AR). Thymic stromal lymphopoietin (TSLP) orchestrates the immune response toward a Th2 phenotype. Although increased TSLP is found in AR, the contribution of IL-17A in TSLP production by nasal fibroblasts is not well understood. We aimed to investigate the effect and mechanism of IL-17A on TSLP production by human nasal fibroblasts (HNFs) from AR patients. Methods: HNFs from AR patients were cultured and stimulated with IL-17A in the absence or presence of a Janus kinase (JAK) 2 or JAK1/3 inhibitor. Western blotting was used to assay phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and nuclear factor-kappa B (NF-κB) p65 in HNFs. The TSLP expression in the cells and culture supernatants was evaluated by real-time polymerase chain reaction and enzyme-linked immunoassay. Results: Stimulation with IL-17A induced STAT3 phosphorylation, which was inhibited by the pretreatment with JAK2 inhibitor AZD1480 or JAK1/3 inhibitor tofacitinib. IL-17A promoted the nuclear translocation of NF-κBp65 protein, leading to increased TSLP production, while the pre-incubation with AZD1480 prior to IL-17A attenuated these effects. However, the pre-incubation with tofacitinib before IL-17A stimulation had no impact on the expression of NF-κBp65 and TSLP. Conclusions: IL-17A up-regulated TSLP production by HNFs through JAK2/NF-κB pathway. Although IL-17A induced STAT3 activation through JAK1/2/3, IL-17A-mediated TSLP expression was not dependent on STAT3 signaling. These observations would provide mechanistic insight into therapeutic strategies to improve the immune and inflammation associated with Th17A in the management of AR. [ABSTRACT FROM AUTHOR]

Adjuvant arthritis is a chronic, autoimmune and inflammatory disorder of the joints. The occurrence of disorder causes a severe damage to the connective tissue eventually leading to progressive physical disability and eventual death. The recent years of evidence suggests the anti-inflammatory properties of stevioside, a diterpene glycoside. However, the effect of stevioside against adjuvant arthritis, a chronic inflammatory disorder is not known. Hence, the present study was designed to study the effect of stevioside against Freund's complete adjuvant induced arthritis model in rats. The acute anti-inflammatory effect of stevioside also studied by employing carrageenan-induced paw oedema model in rats. The biochemical markers, haematological parameters, lipid peroxidation, myeloperoxidase activity, lipoxygenase activity, the levels of PGE2 and pro-inflammatory (TNF-α, IL-6 & IL-1β) and anti-inflammatory cytokine (IL-10) were analysed. The protein expression of NF-κB (p65) COX-2 and iNOS in paw tissues were estimated by western blotting. Stevioside treatment significantly ameliorates the adjuvant induced arthritic scoring, histological alterations, paw volume, elevation of biochemical (AST, ALT, ALP and glucose levels) and haematological (haemoglobin, differential and platelet count) parameters and restored the endogenous anti-oxidant (SOD, CAT, GSH and GST) activities. Treatment with stevioside also significantly prevented the adjuvant induced elevation of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), pro-inflammatory protein expressions (iNOS, COX-2, NF-κB (p65) and pIκB/IκB ratio), prevented the increase in myeloperoxidase activity and significantly restored the anti-inflammatory (IL-10) cytokine level in paw tissues. Collectively, our findings suggest that stevioside may serve as anti-inflammatory agent and could serve as a potential adjunct therapeutic option in treating adjuvant arthritis. [ABSTRACT FROM AUTHOR]

Activation of glial cells (including microglia and astrocytes) appears central to the initiation and progression of neuroinflammation in Alzheimer's disease (AD). The low-density lipoprotein receptor-related protein 1 (LRP1) is a major receptor for amyloid-β (Aβ), which plays a critical role in AD pathogenesis. LRP1 regulates inflammatory response by modulating the release of pro-inflammatory cytokines and phagocytosis. However, the effects of LRP1 on microglia- and astrocytic cell-mediated neuroinflammation and their underlying mechanisms in AD remain unclear. Therefore, using APP/PS1 transgenic mice, we found that LRP1 is downregulated during disease progression. Silencing of brain LRP1 markedly exacerbated AD-related neuropathology including Aβ deposition, neuroinflammation, and synaptic and neuronal loss, which was accompanied by a decline in spatial cognitive ability. Further mechanistic study revealed that silencing of LRP1 initiated neuroinflammation by increasing microgliosis and astrogliosis, enhancing pro-inflammatory cytokine production, and regulating toll-like receptor 4 (TLR4)-mediated activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Taken together, these findings indicated that LRP1 suppresses microglia and astrocytic cell activation by modulating TLR4/NF-κB/MAPK signaling pathways. Our results further provide insights into the role of LRP1 in AD pathogenesis and highlight LRP1 as a potential therapeutic target for the treatment of AD. [ABSTRACT FROM AUTHOR]

Methylene blue (MethyB) was shown to protect against different brain pathologies. In this study, the effect of acute administration of MethyB on epileptic seizures, brain oxidative stress, and neuronal injury induced in rats by pentylenetetrazole (PTZ) was studied. Rats received repeated intraperitoneal (i.p.) injections of PTZ until the development of status epilepticus and were i.p. treated once with MethyB at doses of 50 or 100 mg/kg, 30 min prior to the first PTZ injection. Results indicated that compared with the PTZ control group, the administration of MethyB at 50 and 100 mg/kg decreased the mean seizure score over the study period by 48.8% and 55.1%, respectively. The development of myoclonic jerks and generalized tonic-clonic seizures was inhibited by 90.0–85.0% and 45.4–56.3%, respectively, compared with the PTZ control group. The mean latency to develop status epilepticus increased by 43.1% after treatment with MethyB at 100 mg/kg. MethyB had no significant effect on the mean threshold dose of PTZ required to reach status epilepticus. MethyB showed inhibitory effects on the increase in brain lipid peroxidation (malondialdehyde), and nitric oxide induced PTZ by 16.7–24.0% and 25.2–32.6%, respectively. Meanwhile, the decrease in reduced glutathione and paraoxonase-1 (PON-1) activity and the increase in nuclear factor-kappa B (NF-κB) in the brain of PTZ-treated rats were attenuated by MethyB. Brain acetylcholinesterase (AChE) concentration decreased by PTZ and showed further decrements after treatment with either dose of MethyB. PTZ caused neuronal atrophy in the hippocampus and cerebral cortex and decreased neuronal size and number in the substantia nigra. These pathological changes were prevented by MethyB given at 100 mg/kg. These data indicate that treatment with MethyB inhibits the PTZ-induced seizures in rats and increases the latency to develop status epilepticus. In addition, MethyB decreases brain oxidative stress and protects against neuronal atrophy in this experimental model of generalized epilepsy. [ABSTRACT FROM AUTHOR]

Background/aims: The proton pump inhibitor lansoprazole (LPZ) is clinically used to reduce gastric acid secretion, but little is known about its possible hepatoprotective effects. This study aimed to investigate the hepatoprotective effects of LPZ and its potential mechanisms using in vitro and in vivo rat models of liver injury.Methods: For the in vitro model of liver injury, primary cultured rat hepatocytes were treated with interleukin-1β in the presence or absence of LPZ. The influence of LPZ on inducible nitric oxide synthase (iNOS) induction and nitric oxide (NO) production and on the associated signaling pathways was analyzed. For the in vivo model, rats were treated with D-galactosamine (GalN) and lipopolysaccharide (LPS). The effects of LPZ on survival and proinflammatory mediator expression (including iNOS and tumor necrosis factor-α) in these rats were examined.Results: LPZ inhibited iNOS induction partially through suppression of the nuclear factor-kappa B signaling pathway in hepatocytes, thereby reducing potential liver injury from excessive NO levels. Additionally, LPZ increased survival by 50% and decreased iNOS, tumor necrosis factor-α, and cytokine-induced neutrophil chemoattractant-1 mRNA expression in the livers of GalN/LPS-treated rats. LPZ also inhibited nuclear factor-kappa B activation by GalN/LPS.Conclusions: LPZ inhibits the induction of several inflammatory mediators (including cytokines, chemokines, and NO) partially through suppression of nuclear factor-kappa B, resulting in the prevention of fulminant liver failure. The therapeutic potential of LPZ for liver injuries warrants further investigation. [ABSTRACT FROM AUTHOR]

Bioreactor-cultured adventitious roots (ARs) of the endangered medicinal plant Oplopanax elatus Nakai is a novel alternative plant material. To utilize ARs in the product production, the present study investigated the anti-inflammatory effect of O. elatus ARs. In the in vivo experiment, lipopolysaccharide (LPS)-induced acute lung injury disease model was established and several inflammatory indexes were determined. For the LPS-stimulated mice, after pretreatment of AR crude extract (200 mg/kg), cell infiltration in lungs was decreased, the production of proinflammatory mediators, including nitric oxide (NO), tumor necrosis factor (TNF)-α, and interleukin (IL)-6, and 1β in the bronchoalveolar lavage fluid was evidently reduced, which indicated that O. elatus ARs had an anti-inflammatory effect. In the in vitro experiment, ethyl acetate (EtOAc) fractions (12.5, 25, and 50 μg/mL) were used to treat LPS-induced peritoneal macrophages (PMs) of mice. The production of NO, prostaglandin E2, TNF-α, IL-6, and IL-1β in LPS-stimulated PMs was obviously inhibited (p < 0.05) after pretreatment with EtOAc fractions, and the expression of the inducible nitric oxide synthase and cyclooxygenase were also suppressed. To clarify the anti-inflammatory mechanism, effects of EtOAc fraction on changes of proteins related to the pathways of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) were investigated. The phosphorylation of extracellular regulated protein kinases, c-jun n-terminal kinase, and p38 MAPK in LPS-induced PMs was inhibited after pretreatment of EtOAc fractions. In addition, EtOAc fractions enhanced inhibitor of nuclear factor-kappa B-α expression and decreased nuclear translocation of p65 NF-κB. Thus, EtOAc from O. elatus ARs is involved in regulating MAKP and NF-κB signaling pathways to inhibit LPS-induced inflammation. [ABSTRACT FROM AUTHOR]

Clinical trials and animal experimental studies have demonstrated an association of arterial baroreflex impairment with the prognosis and mortality of cardiovascular diseases and diabetes. As a primary part of the arterial baroreflex arc, the pressure sensitivity of arterial baroreceptors is blunted and involved in arterial baroreflex dysfunction in cardiovascular diseases and diabetes. Changes in the arterial vascular walls, mechanosensitive ion channels, and voltage-gated ion channels contribute to the attenuation of arterial baroreceptor sensitivity. Some endogenous substances (such as angiotensin II and superoxide anion) can modulate these morphological and functional alterations through intracellular signaling pathways in impaired arterial baroreceptors. Arterial baroreceptors can be considered as a potential therapeutic target to improve the prognosis of patients with cardiovascular diseases and diabetes. [ABSTRACT FROM AUTHOR]

Maresin 1 is a novel pro-resolving mediator derived from docosahexaenoic acid (DHA), with potent anti-inflammation effects against several animal models, including brain ischemia, sepsis, and lung fibrosis. However, its effect against motor neuron cell death is still not investigated. Therefore, we investigated the effects of maresin 1 on several stress-induced motor neuron cell death. Maresin 1 suppressed combinatorial stress which was evoked by superoxide dismutase 1 (SOD1)G93A and serum-free, -induced motor neuron cells death in a concentration-dependent manner, and had a stronger neuroprotective effective than DHA. Maresin 1 also had neuroprotective effects against transactivation response DNA-binding protein (TDP)-43A315T and serum-free stress, H2O2, and tunicamycin-induced cell death. Maresin 1 reduced the reactive oxygen species (ROS) production caused by SOD1G93A or TDP-43A315T. Moreover, maresin 1 suppressed the NF-κB activation induced by SOD1G93A and serum-free stress. These data indicate that maresin 1 has motor neuron protective effects against several stresses by reduction of ROS production or attenuation of the NF-κB activation. Maresin 1 also had neuroprotective effects against H2O2, and tunicamycin-induced cell death in a concentration-dependent manner. Finally, maresin 1 ameliorated the motor function deficits of spinal muscular atrophy model in which endoplasmic reticulum stress was upregulated. Thus, maresin 1 may be beneficial to protect against motor neuron diseases. [ABSTRACT FROM AUTHOR]

Studies have shown that the removal of the cholinergic innervation to the hippocampus induces dysfunction of the hypothalamic-pituitary-adrenocortical axis and decreases the number of glucocorticoid receptors (GRs). Subsequent studies have revealed that the loss of cholinergic input to the hippocampus reduces the expression of GRs and activates nuclear factor-kappa B (NF-κB) signaling through interactions with the cytoplasmic catalytic subunit of protein kinase A (PKAc). We examined the effects of chronic stress on cognitive status and GR-PKAc-NF-κB signaling in rats with a loss of cholinergic input to the hippocampus and cortex. Male Sprague-Dawley rats received 192 IgG-saporin injections to selectively eliminate cholinergic neurons in their basal forebrain. Two weeks later, rats were subjected to 1 h of restraint stress per day for 14 days. Rats subjected to both chronic stress and cholinergic depletion showed more severe memory impairments compared to those that received either treatment alone. The reduction in nuclear GR levels induced by cholinergic depletion was unaffected by chronic stress. The activation of NF-κB signaling in the hippocampus and the cerebral cortex induced by cholinergic depletion was augmented by chronic stress, resulting in the increased expression of pro-inflammatory markers, such as inducible nitric oxide synthase and cyclooxygenase-2. The activation of NF-κB induced by cholinergic depletion appears to be aggravated by chronic stress, and this might explain the increased susceptibility of patients with Alzheimer’s disease to stress since activation of NF-κB is associated with stress. [ABSTRACT FROM AUTHOR]

This study was conducted to isolate the anti-neuroinflammatory component(s) in the 80% EtOH extract of P. tinctoria, and to investigate underlying molecular mechanism of the anti-neuroinflammatory component(s) in LPS-induced BV2 microglial cells. To isolate the active component(s) in the extract, various chromatographic methods were employed, and the structures of the isolated secondary metabolites were determined mainly by analysis of spectroscopic data such as NMR and MS data. Tryptanthrin (1), isolated from P. tinctoria extract, significantly inhibited the protein expression of iNOS and COX-2, and reduced the levels of their products (NO and PGE2) in LPS-stimulated BV2 microglial cells. Tryptanthrin (1) also downregulated the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. These anti-neuroinflammatory effects of tryptanthrin (1) was elucidated to be correlated with inactivating NF-κB pathway by interrupting the phosphorylation and degradation of the inhibitor of κB-α protein, and inhibiting the DNA binding activity of NF-κB. In addition, tryptanthrin (1) suppressed the activation of p38 MAPK pathway. Furthermore, tryptanthrin (1) inhibited the TLR4 and MyD88 protein expression in LPS-stimulated BV2 microglial cells. Taken together, it was suggested that tryptanthrin (1) have anti-neuroinflammatory effect by regulating TLR4-MyD88-mediated several inflammatory pathways including p38 and NF-κB pathways in LPS-induced BV2 microglial cells. [ABSTRACT FROM AUTHOR]

Scutellaria root, the root of Scutellaria baicalensis Georgi, is a crude drug used for inflammatory diseases. In our previous report, the combination of flavonoids contained in Scutellaria root have been found to inhibit PGE production more strongly than individual flavonoids. Here, to investigate the mechanism of the synergistic effect, we examined the effects of an equimolar mixture (F-mix) of baicalein ( 1), wogonin ( 2) and oroxylin A ( 3) on the production of PGE in LPS-treated J774.1 cells. Although 1 and 3 inhibited COX-2 activity, the F-mix showed no synergistic effect on COX-2 inhibition. Therefore, we investigated the steps leading to the activation of COX-2 protein. Compounds 1- 3 and F-mix inhibited the expression of COX-2 protein. However, only 2 inhibited the expression of COX-2 mRNA among the flavonoids, and the F-mix showed no synergistic effect. Only 1 inhibited NF-κB translocation into the nucleus, and the F-mix showed no synergistic effect. Although 2 did not affect NF-κB translocation, it strongly inhibited NF-κB-dependent transcriptional activity, and the F-mix inhibited the activity slightly more than 2. Compounds 1- 3 also inhibited NO production, and the F-mix showed a synergistic effect. However, the effects of each flavonoid on the expression of iNOS mRNA were not consistent with those on COX-2 mRNA. Because the flavonoids inhibit different steps in the production of PGE and NO, and their mixture did not show apparent synergistic effects in each step, we conclude that the synergistic effect of the flavonoid mixture reflects the total effect of the flavonoids inhibiting different steps in the NF-κB signalling pathway. [ABSTRACT FROM AUTHOR]

Neuronal autophagy and inflammatory responses are important in the pathogenesis of traumatic brain injury (TBI), and toll-like receptor 4 (TLR4) may play an important role in the related molecular cascade. The present study investigated the protective effect of apocynin, an inhibitor of NADPH oxidase, in a TBI rat model and further examined neuronal autophagy and the TLR4-mediated pathway. Adult male Sprague-Dawley rats were subjected to controlled cortical impact injury and intraperitoneally injected with apocynin (50 mg/kg) immediately after the trauma. In addition to motor and behavioral studies, brain water content and histology analyses were performed. Expression of autophagy-related proteins as well as TLR4/NF-κB signaling and inflammatory mediators was analyzed. The apocynin treatment significantly attenuated TBI-induced motor and behavioral impairment, brain edema and neuronal damage in rats. Immunohistochemical and Western blot analyses revealed that apocynin treatment significantly reduced the expression of NOX, LC3 and Beclin1 in the hippocampus at 12-48 h after injury. Double immunolabeling demonstrated that apocynin decreased the co-localization of LC3 or TLR4-positive cells with hippocampal neurons at 24 h following TBI. In addition, CD11b (microglial marker) and GFAP (astrocyte marker)-immunopositive cells were also clearly decreased in hippocampal tissues. Meanwhile, protein levels of TLR4, NF-κB p65, TNF-α and IL-1β were found to be significantly downregulated by Western blot analysis. In conclusion, our findings indicate that the protective effects of apocynin may be related to modulation of neuronal autophagy and the TLR4/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Ischemic preconditioning (IPC) provides neuroprotection against subsequent severe ischemic insults by specific mechanisms. We tested the hypothesis that IPC attenuates post-ischemic neuronal death in the gerbil hippocampal CA1 region (CA1) throughout hypoxia inducible factor-1α (HIF-1α) and its associated factors such as vascular endothelial growth factor (VEGF) and nuclear factor-kappa B (NF-κB). Lethal ischemia (LI) without IPC increased expressions of HIF-1α, VEGF, and p-IκB-α (/and translocation of NF-κB p65 into nucleus) in CA1 pyramidal neurons at 12 h and/or 1-day post-LI; thereafter, their expressions were decreased in the CA1 pyramidal neurons with time and newly expressed in non-pyramidal cells (pericytes), and the CA1 pyramidal neurons were dead at 5-day post-LI, and, at this point in time, their immunoreactivities were newly expressed in pericytes. In animals with IPC subjected to LI (IPC/LI)-group), CA1 pyramidal neurons were well protected, and expressions of HIF-1α, VEGF, and p-IκB-α (/and translocation of NF-κB p65 into nucleus) were significantly increased compared to the sham-group and maintained after LI. Whereas, treatment with 2ME2 (a HIF-1α inhibitor) into the IPC/LI-group did not preserve the IPC-mediated increases of HIF-1α, VEGF, and p-IκB-α (/and translocation of NF-κB p65 into nucleus) expressions and did not show IPC-mediated neuroprotection. In brief, IPC protected CA1 pyramidal neurons from LI by upregulation of HIF-1α, VEGF, and p-IκB-α expressions. This study suggests that IPC increases HIF-1α expression in CA1 pyramidal neurons, which enhances VEGF expression and NF-κB activation and that IPC may be a strategy for a therapeutic intervention of cerebral ischemic injury. [ABSTRACT FROM AUTHOR]

Objective and design: An animal experiment was performed to demonstrate the anti-inflammatory effects of an alpha-lipoic acid (ALA) derivative, dihydrolipoyl histidinate zinc complex (DHLHZn) for acute lung injury (ALI) and to investigate the mechanism of action. Material: Rats were randomly divided into three experimental groups: control group ( n = 17), DHLHZn(−) group ( n = 11, ALI model rats), and DHLHZn(+) group ( n = 12, ALI model rats treated by DHLHZn). Treatment: Lipopolysaccharides (LPS, 10 mg/kg) were administered intratracheally in the DHLHZn(−) group and the DHLHZn(+) group. For the DHLHZn(+) group, DHLHZn (100 mg/kg) was administered intraperitoneally 2 h prior to LPS administration. Methods: Four hours after LPS administration, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The findings were analyzed using the Mann-Whitney U test. Results: Total number of cells, number of neutrophils and lymphocytes, levels of various inflammatory cytokines, and NF-kB p65 concentration of BALF were significantly lower in the DHLHZn(+) group than in the DHLHZn(−) group ( p < 0.05). ALI pathology scores were significantly lower in the DHLHZn(+) group than in the DHLHZn(−) group ( p < 0.001). Conclusions: Anti-inflammatory effects of DHLHZn for ALI were demonstrated by BALF and histopathological findings. The mechanism of action of DHLHZn was considered to be via inhibition of the NF-kB signaling pathway. DHLHZn is thus suggested to be a new prophylactic agent for ALI. [ABSTRACT FROM AUTHOR]

Drug-resistance epilepsy (DRE) is attributed to the brain P-glycoprotein (P-gp) overexpression. We previously reported that nuclear factor-kappa B (NF-κB) played a critical role in regulating P-gp expression at the brain of the acute seizure rats. This study was extended further to investigate the interaction effect of NF-κB and pregnane X receptor (PXR) on P-gp expression at the brain of chronic epileptic rats treated with carbamazepine (CBZ). The chronic epileptic models were induced by the micro-injection of kainic acid (KA) into rats' hippocampus. Subsequently, the successful models were treated with different intervention agents of CBZ; PMA(a non-specific PXR activity inhibitor) or PDTC(a specific NF-κB activity inhibitor) respectively. The expression levels of P-gp and its encoded gene mdr1a/ b were significantly up-regulated on the brain of KA-induced chronic epilepsy rats or the epilepsy rats treated with CBZ for 1 week, meanwhile with a high expression of PXR. The treatment of PMA dramatically reduced both PXR and P-gp expressions at the protein and mRNA levels in the chronic epilepsy brain. By compared to the epilepsy model group, the P-gp expression was not markedly attenuated by the inhibition of NF-κB activity with PDTC treatment, nevertheless with a decrease of NF-κB expression in this intervention group. Higher levels of proinflammatory cytokines(IL-1β, IL-6, TNF-α) were found both in the brain tissue and the serum in the epilepsy rats of each group. There was a declined trend of the pro-inflammatory cytokines expression of the PDTC treatment group but with no statistical significance. This study demonstrates for the first time that P-gp up-regulation is due to increase PXR expression in the chronic phase of epilepsy, differently from that NF-κB signaling may induce the P-gp expression in the acute seizure phase. Our results offer insights into the mechanism underlying the development of DRE using or not using CBZ treatment. [ABSTRACT FROM AUTHOR]

Objective: To investigate the mechanism of action of Fuzheng Huayu Formula (扶正化瘀方, FZHY) against renal interstitial fibrosis (RIF) relating to oxidative injury and nuclear factor-kappa B (NF-κB) activity. Methods: Thirty-two Sprague-Dawley rats were randomly divided into 3 groups: normal group, model group and FZHY treatment group. The RIF model was induced by oral administration of HgCl at a dose of 8 mg/kg body weight once a day for 9 weeks. Meanwhile, rats in FZHY treatment group orally took FZHY at a dose of 4.0 g/kg rat weight for 9 weeks. The content of hydroxyproline (Hyp) and collagen deposition in kidney were observed. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), the content of glutathione (GSH) and malondialdehyde (MDA) of kidney were tested. The expressions of inhibitor-κappa B (IκB), phospho-IκB (p-IκB), tumor necrosis factor-α (TNF-α), matrix metalloproteinase-2 (MMP-2) and α-smooth muscle actin (α-SMA) were analyzed by Western blot. α-SMA expression was also observed by immunofluorescent staining. MMP-2 activity was measured by gelatin zymography. NF-κB activation was determined by electrophoretic mobility shift assay. Results: Renal interstitial fibrosis was induced by HgCl, demonstrated by remarkably increased Hyp contents and excessive collagen deposition in kidney ( P<0.01). FZHY significantly inhibited renal interstitial collagen deposition and reduced Hyp content of the HgCl-treated rats ( P<0.01). GSH content decreased obviously, and MDA content increased signifificantly in HgCl-treated rats compared with that of normal rats ( P<0.01). FZHY significantly increased GSH content and decreased MDA content in the model rats ( P<0.01). The expression α-SMA was increased in model rats compared with that of normal rats, FZHY signifificantly decreased its expression ( P<0.01). The expressions of p-IκB and TNF-α and MMP-2, MMP-2 activity, and NF-κB activation were increased in model group compared with that in normal group ( P<0.01), FZHY signifificantly decreased NF-κB activation, MMP-2 activity and p-IκB and TNF-α expressions ( P<0.01). Conclusions: FZHY could protect kidney from oxidative injury intoxicated by HgCl, and antagonized oxidative stress-stimulated NF-κB activity through inhibition of IκB phosphorylation in the interstitial fibrotic kidney, these effects importantly contributed to FZHY action mechanism against renal interstitial fifibrosis. [ABSTRACT FROM AUTHOR]

Objective: Visfatin is an adipocytokine that plays a role in regulating periodontal inflammation by as yet identified mechanisms. It has been suggested that visfatin mediates inflammation via activation of the nuclear factor-kappa B (NF-κB) and phosphatidylinositol 3-kinase (PI3k) signaling pathways which play a role in the inhibition of neutrophil apoptosis. The aim of this study was to investigate the expression of visfatin, NF-κB (NF-κB and NF-κB), PI3k, tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β) in the tissue of healthy individuals and patients with periodontitis. Materials and methods: Tissue biopsy samples were obtained from 21 patients with chronic periodontitis and from the gingiva of 19 healthy individuals undergoing crown lengthening. The mRNA expression levels of visfatin, NF-κB, PI3k, TNF-α, and IL-1β were evaluated by quantitative real-time PCR (qPCR). Also, visfatin protein expression was measured by immunohistochemistry. Results: Both qPCR and immunohistochemistry results revealed that the visfatin expression was higher in the tissues with periodontitis than in healthy tissues ( P < 0.01). Similarly, the mRNA expression levels of NF-κB, PI3k, and IL-1β were higher in tissues with periodontitis than in healthy gingival tissues ( P < 0.01). Visfatin was positively correlated with the levels of NF-κB ( r = 0.549, P < 0.05), NF-κB ( r = 0.636, P < 0.05), PI3k ( r = 0.682, P < 0.01), TNF-α ( r = 0.558, P < 0.05), and IL-1β ( r = 0.686, P < 0.01) in the tissues with periodontitis. Conclusions: Our results demonstrated that increased visfatin was associated with the expression of NF-κB and PI3k which may play a role in the pathogenesis of periodontitis. We suggest that increased visfatin may contribute to the inhibition of neutrophil apoptosis via the NF-κB and PI3k signaling pathways. Clinical relevance: Understanding the role of visfatin in periodontitis will enable the development of new treatment methods for inflammation. [ABSTRACT FROM AUTHOR]

Carfilzomib is a proteasome inhibitor, commonly used in multiple myeloma, but its clinical use may be limited due to cardiotoxicity. This study was aimed to evaluate the influence of rutin in carfilzomib-induced cardiotoxicity in rats. Wistar albino male rats weighing 200-250 g (approximately 10 weeks old) were taken for this study. Animals were divided into four groups of six animals each. Group 1 served as normal control (NC), received normal saline; group 2 animals received carfilzomib (dissolved in 1 % DMSO) alone; group 3 animals received rutin (20 mg/kg) + carfilzomib; and group 4 animals received rutin (40 mg/kg) + carfilzomib. Hematological changes, biochemical changes, oxidative stress, hypertrophic gene expression, apoptotic gene expression, NFκB and IκB-α protein expression and histopathological evaluation were done to confirm the finding of carfilzomib-induced cardiotoxicity. Treatment with rutin decreased the carfilzomib-induced changes in cardiac enzymes such as lactate dehydrogenase, creatine kinase (CK) and CK-MB. For the assessment of cardiotoxicity, we further evaluated cardiac hypertrophic gene and apoptotic gene expression such as α-MHC, β-MHC and BNP and NF-κB and p53 gene expression, respectively, using RT-PCR. Western blot analysis showed that rutin treatment prevented the activation of NF-κB by increasing the expression of IκB-α. Rutin also attenuated the effects of carfilzomib on oxidant-antioxidant including malondialdehyde and reduced glutathione. Histopathological study clearly confirmed that rutin attenuated carfilzomib-induced cardiotoxicity in rats. [ABSTRACT FROM AUTHOR]

Neougonin A is a prenylated flavonoid isolated from the whole plants of Helminthostachys zeylanica (Ophioglossaceae), which was usually used as traditional Chinese herbal medicine for the treatment of fever and inflammation. In this study, the pharmacological effects and underlying molecular mechanisms of neougonin A on lipopolysaccharide (LPS)-induced inflammatory responses were investigated. We observed that neougonin A reduced the production of inflammatory mediators (TNFα, PGE, NO, IL-1β, and IL-6; P < 0.001) and inflammation-related proteins (iNOS and COX-2) induced by LPS in murine macrophage RAW 264.7 cells. Furthermore, Western blot and immunofluorescence analysis indicated that neougonin A could inhibit the phosphorylation of IkBα and block the translocation of NF-kB/p65 into the nucleus even at 1.25 μM ( P < 0.05), but have no effect on JNK, ERK1/2, and p38MAPK phosphorylation. It was suggested that the anti-inflammatory actions of neougonin A might be due to the downregulation of TNFα, IL-1β, IL-6, NO, and PGE via the suppression of NF-kB signal transduction pathway. [ABSTRACT FROM AUTHOR]

Objective and design: Nuclear factor-kappa B (NF-κB) has multiple physiological and pathological functions. The role of NF-κB can be protective or destructive. We aim to investigate the biphasic activation of NF-κB in brain after subarachnoid hemorrhage (SAH). Material or subjects: Eighty male New Zealand rabbits are assigned to control, SAH, vehicle, and pyrrolidine dithiocarbamate (PDTC) groups. Treatment: PDTC (3 mg/kg, dissolved in saline) was injected into cisterna magna. Methods: Immunofluorescence and electrophoretic mobility shift assay experiments were performed to assess the activation of NF-κB. The levels of inflammatory and apoptosis mediators were detected by ELISA and real-time polymerase chain reaction. Nissl and immunofluorescent stain was performed to evaluate neuron injury. Results: NF-κB activity in the brain cortex showed two peaks after SAH. Inflammatory mediators exhibited similar time course. PDTC could significantly inhibit the NF-κB activity and inflammatory mediators. Suppressing the early NF-κB activity significantly decreased neuron injury, while inhibiting the late one could statistically increase neuron injury. Conclusions: The biphasic NF-κB activation in the brain cortex after SAH played a decisive role on neuronal fate through the inflammatory signaling pathway. The early NF-κB activity contributed to neuron damage after SAH. Nevertheless, the late activated NF-κB may serve as a protector. [ABSTRACT FROM AUTHOR]

The mimic of manganese superoxide dismutase (MnSODm) has been synthesized and reported to have anti-inflammatory properties. However, whether MnSODm has anti-inflammatory effects on colitis and any underlying mechanisms are poorly understood. This study was to investigate therapeutic effects and mechanism of MnSODm on 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced colitis model in rats. Rats were intragastrically administered MnSODm (10, 20, and 40 mg/kg) per day for 7 days after colitis was induced by TNBS. After treated with MnSODm, the colonic macroscopic and microscopic damage scores and colonic weight/length ratios were significantly decreased compared with colitis model group. Myeloperoxidase (MPO) activity, malonyldialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-8 levels in colon tissues were also significantly decreased in MnSODm treatment groups. However, superoxide dismutase (SOD) activity significantly increased and phosphorylated inhibitory kappa B-alpha (IκBα), inhibitor kappa B kinase (IKKα/β), and nuclear factor-kappa Bp65 (NF-κBp65) as well as Toll-like receptor 4 (TLR4) and myeloid differentiation actor 88 (MyD88) in the colonic mucosa were significantly inhibited by MnSODm treatment. Thus, MnSODm was protective against colitis via antioxidant activity and by inhibiting inflammatory mediators by down-regulating TLR4/MyD88/NF-κB signaling pathways. These data suggest a potential therapeutic effect of MnSODm in colitis. [ABSTRACT FROM AUTHOR]

Makgeolli is a Korean traditional alcoholic beverage prepared by fermenting rice starch using nuruk. It is known for its health benefits, but the mechanisms underlying its inhibitory effects on cancer remain unclear. Here a 70% ethanol extract of Makgeolli suldeot (70EMS) was tested for its inhibitory activities against cancer metastasis. This extract interrupted the formation of the neovasculature and reduced the migratory and invasive activity of breast cancer cells. Furthermore, it dose-dependently suppressed the activity of matrix metalloproteinase (MMP)-9 and phosphorylation of ERK1/2, JNK, and Akt. Moreover, 70EMS strongly inhibited the translocation of nuclear factor-kappa B (NF-κB) into the nucleus and expression of activator protein-1 (AP-1). These data indicate that the anti-invasive effect of 70EMS may be related to the inhibition of ERK1/2, phosphorylation of JNK, and reduced expression of NF-κB and AP-1, thereby attenuating MMP-9 in human breast cancer cells. [ABSTRACT FROM AUTHOR]

The potential neuroprotective value of sulforaphane (SFN) in Huntington's disease (HD) has not been established yet. We investigated whether SFN prevents and improves the neurological impairment and striatal cell death in a 3-nitropropionic acid (3-NP)-induced mouse model of HD. SFN (2.5 and 5.0 mg/kg/day, i.p.) was given daily 30 min before 3-NP treatment (pretreatment) and from onset/progression/peak points of the neurological scores. Pretreatment with SFN (5.0 mg/kg/day) produced the best neuroprotective effect with respect to the neurological scores and lethality among other conditions. The protective effects due to pretreatment with SFN were associated with the following: suppression of the formation of a lesion area, neuronal death, succinate dehydrogenase activity, apoptosis, microglial activation, and mRNA or protein expression of inflammatory mediators, including tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase, and cyclooxygenase-2 in the striatum after 3-NP treatment. Also, pretreatment with SFN activated the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway and inhibited the mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) pathways in the striatum after 3-NP treatment. As expected, the pretreatment with activators (dimethyl fumarate and antioxidant response element inducer-3) of the Keap1-Nrf2-ARE pathway decreased the neurological impairment and lethality after 3-NP treatment. Our findings suggest that SFN may effectively attenuate 3-NP-induced striatal toxicity by activating the Keap1-Nrf2-ARE pathway and inhibiting the MAPKs and NF-κB pathways and that SFN has a wide therapeutic time-window for HD-like symptoms. [ABSTRACT FROM AUTHOR]

Objective: To investigate the anti-tumor activity and molecular mechanism of Tonglian Decoction (通莲汤, TLD) on esophageal carcinoma Eca109 cells. Methods: Eca109 cells were treated with TLD and its separated formulae, including the clearing-heat and detoxification formula (Q), activating-blood and promoting-qi formula (H) and nourishing-yin and blood formula (Z). Cell proliferation was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, cell morphology was observed using a microscope, the cell cycle was measured using flow cytometry and the activity of the nuclear factor-kappa B (NF-κB) signal pathway was detected by Western blot. Results: The half maximal inhibitory concentrations of TLD, Q and H were 386, 771 and 729 mg/L, respectively. TLD, Q and H significantly inhibited cell proliferation, with 69.43%, 60.84% and 61.90% of treated cells in the G phase of the cell cycle. The percentage of cells in S phase increased significantly after treatment with TLD, Q, and H compared with the control group ( P<0.05), and TLD showed the strongest effect. Z had no influence on the cell cycle compared with the control group ( P>0.05). Western blot detection indicated slight differences in the inhibition of the NF-κB pathway by the different formulae. TLD formula strongly inhibited IKKβ, NF-κB, interleukin-6 and tumor necrosis factor-α expression compared with the control group. Conclusions: TLD inhibited Eca109 cell proliferation by arresting cells in S phase. The possible mechanism might be related to inhibiting the NF-κB transduction cascade. The combination of the herbs found in the three separate formulae, H, Q and Z, work synergistically in TLD to produce the inhibitory effects of TLD treatment on Eca109 proliferation. [ABSTRACT FROM AUTHOR]

Inflammatory responses play critical roles in carbon monoxide (CO) poisoning-induced cerebral injury. The present study investigated whether erythropoietin (EPO) modulates the toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) inflammatory signaling pathways in brain injury after acute CO poisoning. EPO (2500 and 5000 U/kg) was injected subcutaneously twice a day after acute CO poisoning for 2 days. At 48 h after treatment, the expression levels of TLR4 and NF-κB as well as the levels of inflammatory cytokines in the hippocampal tissues were measured. Our results showed that CO poisoning induced a significant upregulation of TLR4, NF-κB, and inflammatory cytokines in the injured rat hippocampal tissues. Treatment with EPO remarkably suppressed the gene and protein expression levels of TLR4 and NF-κB, as well as the concentrations of TNF-α, IL-1β, and IL-6 in the hippocampal tissues. EPO treatment ameliorated CO poisoning-induced histological edema and neuronal necrosis. These results suggested that EPO protected against CO poisoning-induced brain damage by inhibiting the TLR4-NF-κB inflammatory signaling pathway. [ABSTRACT FROM AUTHOR]

Objective: To examine the mechanism underlying the beneficial role of cinnamaldehyde on oxidative damage and apoptosis in high glucose (HG)-induced dorsal root ganglion (DRG) neurons in vitro. Methods: HG-treated DRG neurons were developed as an in vitro model of diabetic neuropathy. The neurons were randomly divided into five groups: the control group, the HG group and the HG groups treated with 25, 50 and 100 nmol/L cinnamaldehyde, respectively. Cell viability was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and apoptosis rate was evaluated by the in situ TdT-mediated dUTP nick end labeling (TUNEL) assay. The intracellular level of reactive oxygen species (ROS) was measured with flow cytometry. Expression of nuclear factor-kappa B (NFB), inhibitor of B (IB), phosphorylated IB (p-IB), tumor necrosis factor (TNF), interleukin-6 (IL-6) and caspase-3 were determined by western blotting and real-time quantitative reverse transcription polymerase chain reaction (RT-PCR). Expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) were also measured by western blotting. Results: Cinnamaldehyde reduced HG-induced loss of viability, apoptosis and intracellular generation of ROS in the DRG neurons via inhibiting NFB activity. The western blot assay results showed that the HG-induced elevated expressions of NFB, IB and p-IB were remarkably reduced by cinnamaldehyde treatment in a dose-dependent manner ( P <0.01). The HG-induced over-expression of NFB p65 mRNA was remarkably attenuated after cinnamaldehyde treatment in a dose-dependent manner ( P <0.01). However, the expressions of Nrf2 and HO-1 were not upregulated. Treatment with cinnamaldehyde not only attenuated caspase-3 activation and the caspase cleavage cascade in DRG neurons, but also lowered the elevated IL-6, TNF, cyclo-oxygenase and inducible nitric oxide synthase levels, indicating a reduction in inflammatory damage. Conclusions: Cinnamaldehyde protected DRG neurons from the deleterious effects of HG through inactivation of NF-κB pathway but not through activation of Nrf2/HO-1. And thus cinnamaldehyde may have potential application as a treatment for DPN. [ABSTRACT FROM AUTHOR]

Our previous studies demonstrated that propofol protects rat brain against focal cerebral ischemia. However, whether propofol attenuates early brain injury after subarachnoid hemorrhage in rats remains unknown until now. The present study was performed to evaluate the effect of propofol on early brain injury after subarachnoid hemorrhage in rats and further explore the potential mechanisms. Sprague-Dawley rats underwent subarachnoid hemorrhage (SAH) by endovascular perforation then received treatment with propofol (10 or 50 mg/kg) or vehicle after 2 and 12 h of SAH. SAH grading, neurological scores, brain water content, Evans blue extravasation, the myeloperoxidase activity, and malondialdehyde (MDA) content were measured 24 h after SAH. Expression of nuclear factor erythroid-related factor 2 (Nrf2), nuclear factor-kappa B (NF-κB) p65, and aquaporin 4 (AQP4) expression in rat brain were detected by Western blot. Expression of cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9) were determined by reverse transcription-polymerase chain reaction (RT-PCR). Expressions of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were assessed by ELISA. Neurological scores, brain water content, Evans blue extravasation, the myeloperoxidase activity, and MDA content were significantly reduced by propofol. Furthermore, expression of Nrf2 in rat brain was upregulated by propofol, and expression of NF-κB p65, AQP4, COX-2, MMP-9, TNF-α, and IL-1β in rat brain were attenuated by propofol. Our results demonstrated that propofol improves neurological scores, reduces brain edema, blood-brain barrier (BBB) permeability, inflammatory reaction, and lipid peroxidation in rats of SAH. Propofol exerts neuroprotection against SAH-induced early brain injury, which might be associated with the inhibition of inflammation and lipid peroxidation. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that tumor necrosis factor-alpha (TNF-α) in the red nucleus (RN) plays a facilitated role in the development of neuropathic pain. Here, we further investigated the expression changes and roles of the downstream signaling molecules of the red nucleus TNF-α, including nuclear factor-kappa B (NF-κB), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), in the initiation and maintenance of neuropathic pain induced by spared nerve injury (SNI). Immunohistochemistry demonstrated that increased expressions of NF-κB, phospho-ERK (p-ERK) and p-p38 MAPK were observed in the RN contralateral (but not ipsilateral) to the nerve injury side at 3 days after SNI compared with sham-operated and normal rats, the up-regulations of NF-κB and p-ERK but not p-p38 MAPK remained at high levels till 14 days later. An elevated expression of p-JNK occurred at 14 days (but not 3 and 7 days) after SNI, which was later than those of NF-κB, p-ERK and p-p38 MAPK. The up-regulations of NF-κB, p-ERK, p-p38 MAPK and p-JNK all could be abolished by microinjection of anti-TNF-α antibody into the RN of rats with SNI. Microinjection of NF-κB inhibitor PDTC, ERK inhibitor PD98059, p38 MAPK inhibitor SB203580 but not JNK inhibitor SP600125 into the RN contralateral to the nerve injury side at 3 days postinjury significantly alleviated SNI-induced mechanical allodynia. In addition, microinjection of PDTC, PD98059 and SP600125 but not SB203580 into the RN at 14 days postinjury significantly alleviated SNI-induced mechanical allodynia. These results suggest that the red nucleus TNF-α produces the algesic effect through activating NF-κB, ERK and p38 MAPK in the early initiation stage but relying on the activation of NF-κB, ERK and JNK in the later maintenance stage of SNI-induced neuropathic pain. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effect of total flavonoids of Choerospondias axillaris (TFC) on myocardial infarction (MI)-induced cardiac dysfunction, interstitial fibrosis and inflammatory reaction and further to clarify the potential signaling pathway involved. Rats were subjected to MI via coronary artery occlusion. The model establishment was confirmed by the occurrence of ST-segment elevation in electrocardiogram. Then, TFC was administrated at doses of 75, 150 and 300 mg/kg for 28 consecutive days (gavage). Body weight and heart weight were recorded. Hemodynamics, infarct size and myocardial fibrosis were examined. Blood samples were collected to determine tumor necrosis factor- α (TNF- α) and interleukin 6, 10 (IL-6, IL-10) levels. The expressions of matrix metalloproteinases-2, 9 (MMP-2, 9), phosphor-IKB α (p-IKB α) and transforming growth factor-β1 (TGF-β1) were assayed by Western blot. The results indicated that TFC significantly improved cardiac dysfunction, the heart coefficient and myocardial fibrosis in MI rat. TFC also decreased the levels of TNF- α and IL-6, but increased IL-10 content. Moreover, treatment with TFC protected the heart from chronic MI injury by decreasing the expressions of MMP-2, 9, TGF-β1 and p-IKB α. The results suggested that TFC attenuated cardiac dysfunction and myocardial interstitial fibrosis by modulating nuclear factor-kappa B (NF-κB) signaling pathway. [ABSTRACT FROM AUTHOR]

Ischemic preconditioning (IPC) has been demonstrated to provide a neuroprotection against brain damage produced by focal cerebral ischemia. However, it is elusive whether ischemic preconditioning attenuates ischemic brain damage through modulating phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. In the present study, we first explored the best scheme of repetitive ischemic preconditioning (RIPC) to protect rat brain against ischemic damage and then further investigated the underlying mechanisms in RIPC's neuroprotection. Adult male Sprague-Dawley rats underwent ischemic preconditioning or (and) middle cerebral artery occlusion (MCAO). LY294002 or (and) PD98059 were injected intracerebroventricularly to selectively inhibit the activation of PI3K/Akt or ERK1/2. Neurological deficit scores, cerebral infarct volume, and morphological characteristic were detected at corresponding time after cerebral ischemia. The enzymatic activity of myeloperoxidase (MPO) was measured 24 h after cerebral ischemia. Expressions of p-Akt, t-Akt, p-ERK1/2, t-ERK1/2, nuclear factor-kappa B (NF-κB) p65, and cyclooxygenase-2 (COX-2) in ischemic brain were determined by Western blot. The release of tumor necrosis factor-α (TNF-α) in blood was examined by ELISA. In the various schemes of RIPC, IPC2 × 5 min causes less neuronal damage in the cortex and subcortex of ischemic brain and provides an obvious alleviation of cerebral infarction and neurological deficit after lethal ischemia. IPC2 × 5 min significantly reduces cerebral infarct volume, neurological deficit scores, and MPO activity; all of which were diminished by LY294002 or (and) PD98059. IPC2 × 5 min significantly upregulates the expressions of p-Akt and p-ERK1/2, which were inhibited by LY294002 or (and) PD98059. IPC2 × 5 min significantly downregulates the expressions of NF-κB p65 and COX-2 and attenuates the release of TNF-α; all of which were abolished by LY294002 or (and) PD98059. IPC2 × 5 min is the best scheme of RIPC to protect rat brain against cerebral ischemia. IPC2 × 5 min attenuates brain damage in rats subjected to lethal ischemia, and this neuroprotection is associated with inhibition of neuroinflammation through modulating PI3K/Akt and ERK1/2 signaling pathway. [ABSTRACT FROM AUTHOR]

Recent studies show that nuclear factor-kappa B (NF-κB) signaling pathway plays a key role in contributing to the development of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Tetrahydrocoptisine is one of the main active components of Chelidonium majus L. and has been described to be effective in suppressing inflammation. The aim of the present study is to evaluate the protective effect of tetrahydrocoptisine on LPS-induced ALI in rats and clarify its underlying mechanisms of action. We found that in vivo pretreatment with tetrahydrocoptisine to rats 30 min before inducing ALI by LPS markedly decreased the mortality rate, lung wet weight to dry weight ratio, and ameliorated lung pathological changes. Meanwhile, tetrahydrocoptisine significantly inhibited the increase of the amounts of inflammatory cells, total protein content, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) secretion in the bronchoalveolar lavage fluids (BALFs). Furthermore, tetrahydrocoptisine inhibited myeloperoxidase (MPO) accumulation in lung tissue and alleviated TNF-α and IL-6 production in serum. Additionally, immunohistochemistry showed that tetrahydrocoptisine efficiently reduced nuclear factor-kappa B (NF-κB) activation by inhibiting the translocation of NF-κBp65. In conclusion, our results demonstrate that tetrahydrocoptisine possesses a protective effect on LPS-induced ALI through inhibiting of NF-κB signaling pathways, which may involve the inhibition of pulmonary inflammatory process. [ABSTRACT FROM AUTHOR]

Genistein possesses a wide variety of biological activities, and it is best known for its ability to inhibit cancer progression. Its cancer-preventive effect has been attributed to various mechanisms, including the induction of cell cycle arrest and apoptosis as well as the antioxidant functions. Nuclear factor kappa-B (NF-κB) is a signaling pathway that controls transcriptional activation of genes important for the tight regulation of many cellular processes and is aberrantly expressed in many types of cancer. Inhibitors of NF-κB pathway have shown potential anti-tumor activities. However, it is not fully elucidated in colon cancer. In the present study, we demonstrated that genistein could induce apoptosis in human colon cancer LoVo and HT-29 cells through inhibiting NF-κB pathway, as well as downregulation of Bcl-2 and upregulation of Bax, thus providing basis for clinical application of genistein in colon cancer cases. [ABSTRACT FROM AUTHOR]

Toll-like receptors 2 and 4 (TLR2/4) and the downstream nuclear factor-kappa B (NF-κB) signaling pathway, which mediate the inflammatory reaction in cerebral ischemia, were demonstrated to be involved in the extension of cerebral infarction and the aggravation of ischemic brain damage. Reports showed that curcumin provides neuroprotection against ischemic brain damage. In this study, we investigated whether curcumin inhibits the activation of TLR2/4-NF-κB signaling pathway in rats of permanent focal cerebral ischemia. Adult male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (pMCAO). Curcumin was administered by intraperitoneal injection twice at 2 and 12 h after the onset of ischemia. Neurological deficit scores, cerebral infarct size, morphological characteristic, and cerebral water content were measured after 24 h of pMCAO. The enzymatic activity of myeloperoxidase (MPO) was assessed after 24 h of pMCAO. Expression of TLR2 and TLR4 in ischemic brain was determined by western blot. Expression of NF-κB p65 in ischemic brain was detected by immunohistochemistry and western blot. The release of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in blood was examined by ELISA. Curcumin significantly reduced neurological deficit scores, cerebral infarct size, neuronal damage, cerebral water content, and MPO activity. It also inhibited the expression of TLR2/4 and decreased the expression and activity of NF-κB p65 in rat brain. In addition, curcumin attenuated the release of TNF-α and IL-1β in blood. Our results suggest that curcumin reduces inflammatory reaction and brain damage in a rat model of permanent focal cerebral ischemia. The neuroprotective effect and anti-inflammatory property of curcumin in cerebral ischemia might be associated with the inhibition of TLR2/4-NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs) proliferate abnormally and resist apoptosis. Bufalin inhibits cell proliferation and induces apoptosis in human cancer cells. In this study, we explored the effects of bufalin on interleukin-1beta (IL-1β)-induced proliferation and apoptosis of RAFLSs. The cell proliferation and apoptosis were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay and annexin V/propidium iodide staining, respectively. Bufalin dose-dependently inhibited IL-1β-induced RAFLS proliferation. Mechanistically, bufalin decreased the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB), both of which are involved in IL-1β-mediated RAFLS proliferation. Moreover, bufalin induced apoptosis and mitochondrial damage of RAFLSs, which was associated with Bcl-2 downregulation, Bax upregulation, mitochondrial cytochrome c release, and enhanced cleavages of caspase-3 and poly-(ADP-ribose) polymerase. Collectively, our results reveal that bufalin suppresses IL-1β-induced proliferation of RAFLSs through MAPK and NF-κB signaling pathways and induces RAFLS apoptosis via the mitochondria-dependent pathway. [ABSTRACT FROM AUTHOR]

The activation of microglia is crucially associated with the neurodegeneration observed in many neuroinflammatory pathologies, including multiple sclerosis, Parkinson's disease, and Alzheimer's disease. Therefore, the inhibition of microglial activation may alleviate certain neurodegenerative processes. We previously demonstrated the protective actions of a new drug, 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride (KHG26377), against glutamate-induced excitotoxicity and ischemic neuronal damage in in vivo rat brain study. The current investigation explored the possible mechanisms underlying the anti-inflammatory effects of this compound against lipopolysaccharide (LPS)-stimulated activation of cultured BV-2 microglial cells. The results showed that KHG26377 reduced the production of prostaglandin E (PGE), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), reactive oxygen species (ROS), and nitric oxide (NO) in LPS-activated microglia. Furthermore, KHG26377 attenuated LPS-mediated increases in the protein expression levels of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), toll-like receptor 4 (TLR4), phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK). The compound also prevented the LPS-provoked translocation of the nuclear factor-kappa B (NF-κB) p65 subunit (NF-κB-p65) from the cytosol into the nucleus of BV-2 cells. These findings suggest that KHG26377 may find utility as a therapeutic agent that can be further developed for the management of various neuroinflammatory conditions. [ABSTRACT FROM AUTHOR]