MiR‐146a regulates PM1‐induced inflammation via NF‐κB signaling pathway in BEAS‐2B cells

Exposure to particulate matter (PM) leads to kinds of cardiopulmonary diseases, such as asthma, COPD, arrhythmias, lung cancer, etc., which are related to PM‐induced inflammation. We have found that PM_2.5 (aerodynamics diameter <2.5 µm) exposure induces inflammatory response both in vivo and in vitro. Since the toxicity of PM is tightly associated with its size and components, PM₁ (aerodynamics diameter <1.0 µm) is supposed to be more toxic than PM_2.5. However, the mechanism of PM₁‐induced inflammation is not clear. Recently, emerging evidences prove that microRNAs play a vital role in regulating inflammation. Therefore, we studied the regulation of miR‐146a in PM₁‐induced inflammation in human lung bronchial epithelial BEAS‐2B cells. The results show that PM₁ induces the increase of IL‐6 and IL‐8 in BEAS‐2B cells and up‐regulates the miR‐146a expression by activating NF‐κB signaling pathway. Overexpressed miR‐146a prevents the nuclear translocation of p65 through inhibiting the IRAK1/TRAF6 expression, and downregulates the expression of IL‐6 and IL‐8. Taken together, these results demonstrate that miR‐146a can negatively feedback regulate PM₁‐induced inflammation via NF‐κB signaling pathway in BEAS‐2B cells.     

Angiotensin‐(1–7) treatment ameliorates angiotensin II‐induced apoptosis of human umbilical vein endothelial cells

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Role of NF‐κB activation and Th1/Th2 imbalance in pulmonary toxicity induced by nano NiO

With the progress of nanotechnology, nano nickel oxide (NiO) has been extensively used as sensors, battery electrodes, catalysts, and cosmetics. Previous researches verified that nano NiO could exert pulmonary toxicity, but its mechanism was unclear. To shed light upon this, the role of nuclear factor‐κ B (NF‐κ B) activation and Th1/Th2 imbalance were to explore in pulmonary damage induced by nano NiO. Male Wistar rats were randomized into control group, nano NiO groups (0.015, 0.06, and 0.24 mg kg^?1) and micro NiO group (0.024 mg kg^?1) and treated by intratracheal instillation twice a week for 6 weeks. The results showed that the abnormal changes induced by nano NiO were found on indicators of nitrative stress (NO, TNOS, and iNOS), inflammatory cytokines (TNF‐α , IL‐2, and IL‐10) and cytokine‐induced neutrophil chemoattractants (CINC‐1, CINC‐2αβ , and CINC‐3) in lung tissue. In addition, nano NiO instillation induced the upregulated mRNA and protein expression of NF‐κ B, inhibitor of κB kinase‐α (IKK‐α ) and nuclear factor‐inducing kinase (NIK). The protein content of GATA‐3 increased as well as T‐bet decreased in nano NiO groups, and the ratio of T‐bet/GATA‐3, as a key evaluation indicator of Th1/Th2 balance, was lower than the control group. The findings indicated that nano NiO could enhance the nitrative stress and inflammatory response in lung tissue, and its mechanism was related to the NF‐κ B activation and Th1/Th2 imbalance. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1354–1362, 2017.     

Hyperforin induces apoptosis through extrinsic/intrinsic pathways and inhibits EGFR/ERK/NF‐κB‐mediated anti‐apoptotic potential in glioblastoma

Glioblastoma is the most common primary brain tumor with poor survival rate and without effective treatment strategy. Notably, amplification and active mutation of epidermal growth factor receptor (EGFR) occur frequently in glioblastoma patient that may be a potential treatment target. Several studies indicated that various type of herbal compounds not only regulate anti‐depressant effect but also shown capacity to suppress glioblastoma growth via inducing apoptosis and inhibiting oncogene signaling transduction. Hyperforin, an herb compound derived from St. John's wort was used to treat depressive disorder by inhibiting neuronal reuptake of several neurotransmitters. Although hyperforin can reduce matrix metallopeptidases‐2 (MMPs) and ‐9‐mediated metastasis of glioblastoma, the detail mechanism of hyperforin on glioblastoma is remaining unclear. Here, we suggested that hyperforin may induce extrinsic/intrinsic apoptosis and suppress anti‐apoptotic related proteins expression of glioblastoma. We also indicated that hyperforin‐mediated anti‐apoptotic potential of glioblastoma was correlated to inactivation of EGFR/extracellular signal‐regulated kinases (ERK)/nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) signaling.     

Diallyl sulfide alleviates cisplatin‐induced nephrotoxicity in rats via suppressing NF‐κB downstream inflammatory proteins and p53/Puma signalling pathway

Despite being a potent anticancer drug, nephrotoxicity is an adverse effect which renders the clinical use of cisplatin (Cis) limited. The protective role of diallyl sulfide (DAS); a naturally occurring organo‐sulfide, present in garlic, in cisplatin‐induced nephrotoxicity has been reported earlier. However, the mechanism through which DAS exerts its nephroprotective activity remains elusive. The aim of the current study was to elucidate the possible mechanisms underlying the reno‐protective effect of DAS in cisplatin‐induced nephrotoxicity in rats. DAS was given at 2 dose levels; 50 and 100 mg/kg, orally for 4 consecutive days, starting 1 hour after administration of single dose of cisplatin (3.5 mg/kg, intraperitoneally [i.p.]). The Cis‐induced elevation in serum urea and creatinine, degree of histopathological alterations was significantly ameliorated in cisplatin groups co‐treated with DAS. In addition, DAS significantly restored Cis‐depleted glutathione (GSH) content and superoxide dismutase (SOD) activity and attenuated Cis‐elevated Malondialdehyde (MDA) level. Also, DAS significantly reduced Cis‐increased renal expression of nuclear factor kappa B (NF‐κB) and subsequent pro‐inflammatory mediators; tumour necrosis factor alpha (TNF‐α), interleukin‐1β (IL‐1β), intercellular adhesion molecule‐1 (ICAM‐1) and inducible nitric oxide synthase (iNOS) in kidney tissues. Moreover, co‐treatment with DAS significantly inhibited Cis‐increased caspase‐8 and ‐9 levels. Additionally, DAS significantly mitigated Cis‐induced protein expression of p53, Puma, and Bax while, it significantly restored Cis‐reduced protein expression of Bcl‐xL compared to the Cis group. In conclusion, these results demonstrate that DAS ameliorates cisplatin‐induced nephrotoxicity in rats through enhancement of antioxidant defense, reduction of inflammatory cytokine tissue levels as well as inhibition of apoptosis via p53/Puma signalling pathway.     

NF‐κB/p53‐activated inflammatory response involves in diquat‐induced mitochondrial dysfunction and apoptosis

Inflammation generated by environmental toxicants including pesticides could be one of the factors underlying neuronal cell damage in neurodegenerative diseases. In this study, we investigated the mechanisms by which inflammatory responses contribute to apoptosis in PC12 cells treated with diquat. We found that diquat induced apoptosis, as demonstrated by the activation of caspases and nuclear condensation, inhibition of mitochondrial complex I activity, and decreased ATP level in PC12 cells. Diquat also reduced the dopamine level, indicating that cell death induced by diquat is due to cytotoxicity of dopaminergic neuronal components in these cells. Exposure of PC12 cells to diquat led to the production of reactive oxygen species (ROS), and the antioxidant N‐acetyl‐cystein attenuated the cytotoxicity of caspase‐3 pathways. These results demonstrate that diquat‐induced apoptosis is involved in mitochondrial dysfunction through production of ROS. Furthermore, diquat increased expression of cyclooxygenase‐2 (COX‐2) and tumor necrosis factor‐α (TNF‐α) via inflammatory stimulation. Diquat induced nuclear accumulation of NF‐κB and p53 proteins. Importantly, an inhibitor of NF‐κB nuclear translocation blocked the increase of p53. Both NF‐κB and p53 inhibitors also blocked the diquat‐induced inflammatory response. Pretreatment of cells with meloxicam, a COX‐2 inhibitor, also blocked apoptosis and mitochondrial dysfunction. These results represent a unique molecular characterization of diquat‐induced cytotoxicity in PC12 cells. Our results demonstrate that diquat induces cell damage in part through inflammatory responses via NF‐κB‐mediated p53 signaling. This suggests the potential to generate mitochondrial damage via inflammatory responses and inflammatory stimulation‐related neurodegenerative disease.     

C‐phycocyanin protects against ethanol‐induced gastric ulcers in rats: Role of HMGB1/NLRP3/NF‐κB pathway

Gastric ulcer is a widespread inflammatory disease with high socio‐economic burden. C‐phycocyanin is one of the active constituents of Spirulina microalgae, and although it is well known for its antioxidant and anti‐inflammatory properties, its protective effects against gastric ulcer have not yet been identified. High‐mobility group box 1 (HMGB1) is a nuclear protein that, once secreted extracellularly, initiates several inflammatory reactions, and it is involved in the pathogenesis of gastric ulcer. The aim of the present study was to investigate the anti‐inflammatory and anti‐ulcerogenic effects of C‐phycocyanin against ethanol‐induced gastric ulcer targeting HMGB1/NLRP3/NF‐κB pathway. Ulcer induction showed increase in HMGB1 expression through activation of nucleotide‐binding domain and leucine‐rich repeat‐containing protein 3 (NLRP3) inflammasome and nuclear factor kappa p65 (NF‐κB p65). Moreover, oxidative stress and inflammatory markers were elevated in the ulcer‐treated group compared to the normal control group. However, pre‐treatment with C‐phycocyanin significantly reduced HMGB1 expression via suppression of NLRP3/NF‐κB, oxidative markers, IL‐1β, tumour necrosis factor‐α (TNF‐α) and ulcer index value. These results were consistent with histopathological and immunohistochemistry examination. Thus, C‐phycocyanin is a potential therapeutic strategy with anti‐inflammatory and anti‐ulcerogenic effects against ethanol‐induced gastric ulcer.     

Angiotensin‐(1–7) upregulates expression of adenosine triphosphate‐binding cassette transporter A1 and adenosine triphosphate‐binding cassette transporter G1 through the Mas receptor through the liver X receptor alpha signalling pathway in THP‐1 macrophages treated with angiotensin‐II

Adenosine triphosphate‐binding cassette transporter A1 (ABCA1) and ABCG1 play crucial roles in reverse cholesterol transport, and have anti‐atherosclerosis effects, and liver X receptor alpha (LXRα) can stimulate cholesterol efflux through these transporters. Angiotensin (Ang)‐(1–7) can protect endothelial cells, inhibit smooth muscle cell growth, ameliorate inflammation and exert anti‐atherosclerotic effects. In the present study, we attempted to clarify the effect of Ang‐(1–7) on expression of ABCA1 and ABCG1, and explored the role of LXRα in the regulation of ABCA1 and ABCG1 in THP‐1 macrophages that had been incubated with angiotensin‐II (AngII). Ang‐(1–7) increased ABCA1 and ABCG1 expression in a concentration‐dependent manner at both the mRNA and protein levels, promoted cholesterol efflux, and decreased cholesterol content in THP‐1 macrophages treated with AngII. Furthermore, Ang‐(1–7) upregulated the expression of LXRα in a concentration‐dependent manner in these cells. LXRα small interfering RNA, as well as the Mas receptor antagonist A‐779, completely abolished these effects of Ang‐(1–7). In summary, Ang‐(1–7) upregulates ABCA1 and ABCG1 expression in THP‐1 macrophages treated with AngII through the Mas receptor, via the LXRα pathway. This novel insight into the molecular mechanism underlying Ang‐(1–7) and AngII interaction could prove useful for developing new strategies for treatment of cardiovascular diseases.     

The toll like receptor 4‐myeloid differentiation factor 88 pathway is essential for particulate matter‐induced activation of CD4‐positive cells

Asian sand dust (ASD), a type of particulate matter (PM) found in Asia, can be transported to East Asia. We recently found that acute splenic inflammation is induced by ASD in mouse models. In this study, we examined the effect of sub‐chronic ASD exposure on mouse immune cells. Mice were intratracheally administered ASD once every 2 weeks for 8 weeks and killed 24 hours after the final administration. Wild‐type (WT) mice showed increased cell viability after ASD administration. In contrast, ASD administration induced splenocyte activation in toll‐like receptor (TLR)2^?/?, but not TLR4^?/? mice. Furthermore, concanavalin A‐induced interleukin‐2 production increased after ASD administration in WT and TLR2^?/? mice, but not in TLR4^?/? or myeloid differentiation factor (MyD)88^?/? mice. Immunoblotting demonstrated that nuclear factor κB (NF‐κB) was activated in WT mice, but not in TLR4^?/? or MyD88^?/? mice. The NF‐κB‐dependent gene products CDK2 and intercellular cell adhesion molecule‐1 were upregulated upon ASD administration in WT mice, but not in TLR4^?/? or MyD88^?/? mice. Furthermore, the particles themselves, rather than particle constituents, activated NF‐κB in CD4‐positive cells through the TLR4 or MyD88 pathway. Taken together, these results indicate that particle‐induced splenic inflammation occurs via TLR4‐MyD88 signaling.     

Regorefenib induces extrinsic/intrinsic apoptosis and inhibits MAPK/NF‐κB‐modulated tumor progression in bladder cancer in vitro and in vivo

The aim of the present study is to investigate anticancer effect and mechanism of regorafenib in bladder cancer in vitro and in vivo. Human bladder cancer TSGH 8301 cells were treated with regorafenib, NF‐κB, AKT, or mitogen‐activated protein kinase (MAPK) inhibitors for different time. The changes of cell viability, NF‐κB activation, apoptotic signaling transduction, and expression of tumor progression‐associated proteins were evaluated with MTT, NF‐κB reporter gene assay, flow cytometry, and Western blotting assay. TSGH 8301 tumor bearing mice were established and treated with vehicle (140 μL of 0.1% DMSO) or regorafenib (10 mg/kg/day by gavage) for 15 days. The changes of tumor volume, body weight, NF‐κB activation, MAPK activation, and tumor progression‐associated proteins (MMP‐9, XIAP, VEGF, and Cyclin‐D1) after regorafenib treatment were evaluated with digital caliper, digital weight, and ex vivo Western blotting assay. Our results demonstrated NF‐κB activation and protein levels of MMP‐9, XIAP, VEGF, and Cyclin‐D1 were significantly reduced by NF‐κB (QNZ), ERK (PD98059), and P38 (SB203580) inhibitors. Regorafenib also significantly induced extrinsic and intrinsic apoptotic signaling transduction in bladder cancer in vitro. In addition, regorafenib significantly inhibited tumor growth, NF‐κB, p38, ERK activation and expression of tumor progression‐associated proteins in bladder cancer in vitro and in vivo. Taken together, these results proved that regorafenib not only induced apoptosis through extrinsic and intrinsic pathways and but suppressed MAPK/ NF‐κB‐modulated tumor progression in bladder cancer.     

Maternal marginal iodine deficiency limits dendritic growth of cerebellar purkinje cells in rat offspring by NF‐κB signaling and MAP1B

Iodine deficiency (ID) during early pregnancy had an adverse effect on children's psychomotor and motor function. It is worth noting that maternal marginal ID tends to be a common public health problem. Whether marginal ID potentially had adverse effects on the development of cerebellum and the underlying mechanisms remain unclear. Therefore, our aim was to study the effects of marginal ID on the dendritic growth in filial cerebellar Purkinje cells (PCs) and the underlying mechanism. In the present study, we established Wistar rat models by feeding dam rats with a diet deficient in iodine and deionized water supplemented with potassium iodide. We examined the total dendritic length using immunofluorescence, and Western blot analysis was conducted to investigate the activity of nuclear factor‐κB (NF‐κB) signaling and microtubule‐associated protein 1B (MAP1B). Our results showed that marginal ID reduced the total dendritic length of cerebellar PCs, slightly down‐regulated the activity of NF‐κB signaling and decreased MAP1B in cerebellar PCs on postnatal day (PN) 7, PN14, and PN21. Our study may support the hypothesis that decreased T₄ induced by marginal ID limits PCs dendritic growth, which may involve in the disturbance of NF‐κB signaling and MAP1B on the cerebellum. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1241–1251, 2017.     

Knockdown of cathepsin D protects dopaminergic neurons against neuroinflammation‐mediated neurotoxicity through inhibition of NF‐κB signalling pathway in Parkinson's disease model

Parkinson's disease (PD) is a progressive neurodegenerative disorder pathologically characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Chronic neuroinflammation is one of the hallmarks of PD pathophysiology. Cathepsin D (CathD), a soluble aspartic protease, has been reported to play an important role in neurodegenerative diseases such as PD. This research focuses on the role of CathD and the molecular mechanisms involved in the process of neuroinflammation and neurotoxicity. We use 1‐methyl‐4phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP)‐challenged mice and lipopolysaccharide (LPS)‐induced murine microglia BV2 cells as the in vivo and in vitro models, respectively. The effect of CathD on the neuroinflammation, cytotoxicity and the underlying mechanisms associated with NF‐κB signalling pathway are investigated. Data showed that MPTP induces motor deficit, inflammation and depletion of dopaminergic neurons in PD model mice. Notably, cathD was overexpressed in the SNpc of MPTP‐induced PD mice and was highly expressing in LPS‐stimulated primary microglial cells and BV‐2 cells. Furthermore, knockdown of CathD with lentiviral transduction inhibited LPS‐induced neuroinflammation through inhibition of NF‐κB signalling pathway primarily by regulating the NF‐κB p65 nuclear translocation both in BV‐2 and primary microglial cells. Additionally, knockdown of CathD protected the activated‐microglia induced dopaminergic neurons MN9D cells from neurotoxicity as well as apoptosis. Our findings bring a new insight into understanding the complex mechanisms underlying the pathogenesis of PD and provide a novel target to attenuate the excessive neuroinflammatory responses in the treatment of PD.     

Apoptosis induction and ERK/NF‐κB inactivation are associated with magnolol‐inhibited tumor progression in hepatocellular carcinoma in vivo

Although hepatitis B and/or hepatitis C virus were recognized as major risk factor for the development of hepatocellular carcinoma (HCC), certain occupational, environmental, and lifestyle factors also play key roles in HCC tumorigenesis. Moreover, in molecular signaling route, extracellular signal‐regulated kinase (ERK)/nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) signaling was found to be overexpressed and linked to poor prognosis in HCC. Thus, to identify possible nature compound that can suppress ERK/NF‐κB may be benefit to HCC patient. Magnolol, a natural compound derived from herbal plant Magnolia officinalis, has been recognized as a liver protection and antitumor reagent. However, whether magnolol‐inhibited HCC progression correlates with disruption of ERK/NF‐κB signaling is remained unclear. In this studies, we performed SK‐Hep1/luc2 HCC bearing animal model to investigate the anticancer efficacy and mechanism of magnolol on tumor progression. Tumor size and tumor growth rate were dramatically suppressed after treatment of magnolol. In addition, expression of phospho‐ERK (p‐ERK), NF‐κB p65 (Ser536), and tumor progression‐associated proteins, such as matrix metallopeptidase 9 (MMP‐9), vascular endothelial growth factor (VEGF), X‐linked inhibitor of apoptosis protein (XIAP), and CyclinD1 were all significantly decreased by magnolol. Most important, major extrinsic and intrinsic apoptosis signaling factors, including active caspase‐8 and caspase‐9 were both enhanced by magnolol. This study indicated that apoptosis induction through extrinsic/intrinsic pathways and blockage of ERK/NF‐κB activation were associated with magnolol‐inhibited tumor progression in HCC in vivo.     

The role of GSH in microcystin‐induced apoptosis in rat liver: Involvement of oxidative stress and NF‐κB

Microcystins (MCs) are potent and specific hepatotoxins produced by cyanobacteria in eutrophic waters, representing a health hazard to animals and humans. The objectives of this study are to determine the relationship between oxidative stress and NF‐κB activity in MC‐induced apoptosis in rat liver and the role of glutathione (GSH). Sprague‐Dawley rats were intraperitoneally (i.p.) injected with microcystin‐LR (MC‐LR) at 0.25 and 0.5 LD₅₀ with or without pretreatment of buthionine‐(S,R)‐sulfoximine (BSO), a specific GSH synthesis inhibitor. MC‐LR induced time‐dependent alterations of GSH levels in rat liver. Increased malondialdehyde (MDA) and significant changes of antioxidant enzymes including GSH peroxidase (GPX) and GSH reductase (GR) were also observed, particularly at 24 h post‐exposure. The results indicated that acute exposure to MC‐LR induced oxidative stress, and GSH depletion (BSO pretreatment) enhanced the level of oxidative stress. Furthermore, the modulation of pro‐apoptotic gene p53 and Bax and anti‐apoptotic gene Bcl‐2 was observed in 0.5 LD₅₀ group at 24 h, and the alteration was more pronounced by BSO injection before MC‐LR treatment, suggesting that GSH played a protective role against MC‐induced toxicity. Additionally, electrophoretic mobility shift assay (EMSA) showed that NF‐κB was induced at 0.25 LD₅₀ but inhibited at 0.5 LD₅₀. The above results indicated that the possible crosstalk of oxidative stress and NF‐κB activity was associated with MC‐LR‐induced hepatocytes apoptosis in vivo. Our data will provide a new perspective for understanding the mechanisms of MC‐induced liver injury. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 552–560, 2016.