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Linear ubiquitin chain assembly complex (LUBAC) is a ubiquitin E3 ligase complex composed of HOIP, HOIL-1L, and SHARPIN that catalyzes the formation of linear/M1- linked ubiquitin chain. It has been shown to play a pivotal role in the nuclear factor (NF)- κB signaling induced by proinflammatory stimuli. Here, we found that tumor susceptibility gene (TSG101) physically interacts with HOIP, a catalytic component of LUBAC, and potentiates LUBAC activity. Depletion of TSG101 expression by RNA interference decreased TNFa-induced linear ubiquitination and the formation of TNFa receptor 1 signaling complex (TNF- RSC). Furthermore, TSG101 facilitated the TNFa-induced stimulation of the NF-κB pathway. Thus, we suggest that TSG101 functions as a positive modulator of HOIP that mediates TNFa-induced NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Abnormal placental inflammation has a role in the pathophysiology of preeclampsia. Magnesium sulfate (MgSO4) has anti-inflammatory properties and is a fetal neuroprotective agent. MgSO4 is often used to treat severe preeclampsia; however, the specificmechanisms of action underlyingthistherapeutic effect remain unclear. The objective of this study was to investigate the effects of MgSO4 (270 mg/kg) on placental inflammation in a rat model of lipopolysaccharide (LPS; 1.0 µg/kg)-induced preeclampsia. Compared to normal pregnant rats, LPS-treated pregnant rats had higher blood pressure, proteinuria, and expression of the anti-angiogenic factor sFlt-1 and the pro-inflammatory factors interleukin-1β (IL-1β) and IL-12 in placental tissue. LPS-treated pregnant rats had placental insufficiency, poor fetal outcomes, and significantly decreased expression of the anti-inflammatory factors apolipoprotein E (APOE) and IL-10 in placental tissue. MgSO4 treatment had favorable effects on maternal and fetal outcomes. MgSO4 treatment improved placental function by repressing an exaggerated inflammatory response in the placenta and promoting angiogenesis via the NF-κB pathway. These findings suggest MgSO4 has a potential role in the prevention of preeclampsia and in the treatment of mild and moderate preeclampsia. [ABSTRACT FROM AUTHOR]

Excessive inflammation in bovine mammary endothelial cells (BMEC) due to mastitis leads to disease progression and eventual culling of cattle. Sirtuin 3 (SIRT3), a mitochondrial deacetylase, downregulates pro-inflammatory cytokines in BMEC exposed to high concentrations of nonesterified fatty acids by blunting nuclear factor-κB (NFκB) signaling. In nonruminants, SIRT3 is under the control of PGC1α, a transcriptional cofactor. Specific aims were to study (1) the effect of SIRT3 on inflammatory responses of lipopolysaccharide (LPS)-challenged bovine mammary epithelial cells (bovine mammary alveolar cells-T, MAC-T) models, and (2) the role of PGC1α in the attenuation of NFκB signaling via SIRT3. To address these objectives, first, MAC-T cells were incubated in triplicate with 0, 50, 100, 150, or 200 μg/mL LPS (derived from Escherichia coli O55:B5) for 12 h with or without a 2-h incubation of the NFκB inhibitor ammonium pyrrolidine dithiocarbamate (APDC, 10 μ M). Second, SIRT3 was overexpressed using adenoviral expression (Ad-SIRT3) at different multiplicity of infection (MOI) for 6 h followed by a 12 h incubation with 150 μg/mL LPS. Third, cells were treated with the PGC1α agonist ZLN005 (10 μg/mL) for 24 h and then challenged with 150 μg/mL LPS for 12 h. Fourth, cells were initially treated with the PGC1α inhibitor SR-18292 (100 μ M) for 6 h followed by a 6-h culture with or without 50 MOI Ad-SIRT3 and a challenge with 150 μg/mL LPS for 12 h. Data were analyzed using one-way ANOVA with subsequent Bonferroni correction. Linear and quadratic contrasts were used to determine dose-responses to LPS. There were linear and quadratic effects of LPS dosage on cell viability. Incubation with 150 and 200 μg/mL LPS for 12 h decreased cell viability to 78.6 and 34.9%, respectively. Compared with controls, expression of IL1B , IL6 , and TNFA was upregulated by 5.2-, 5.9-, and 2.7-fold with 150 μg/mL LPS; concentrations of IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) in cell medium also increased. Compared with the LPS group, LPS+APDC increased cell viability and reversed the upregulation of IL1B , IL6 , and TNFA expression. However, mRNA and protein abundance of SIRT3 decreased linearly with increasing LPS dose. Ad-SIRT3 infection (50 MOI) reduced IL1B , IL6 , and TNFA expression and also their concentrations in cell medium, and decreased pNFκB P65/NFκB P65 ratio and nuclear abundance of NFκB P65. The PGC1α agonist increased SIRT3 expression, whereas it decreased cytokine expression, pNFκB P65/NFκB P65 ratio, and prevented NFκB P65 nuclear translocation. Contrary to the agonist, the PGC1α inhibitor had opposite effects, and elevated the concentrations of IL-1β, IL-6, and TNF-α in cell medium. Overall, data suggested that SIRT3 activity could attenuate LPS-induced inflammatory responses in mammary cells via alterations in the PGC1α-NFκB pathway. As such, there may be potential benefits for targeting SIRT3 in vivo to help prevent or alleviate negative effects of mastitis. [ABSTRACT FROM AUTHOR]

• Inflammation serves as an important factor in the development of diabetes and diabetic peripheral polyneuropathy. • The activation of advanced glycation end products (AGEs)/receptor for AGE plays a key part in the activation of the intracellular signaling cascade leading to cytokine release. • Increased release of inflammatory cytokines is related to diabetes, diabetic neuropathy and neuropathic pain. • Anti-inflammatory therapy shows promise for the treatment of diabetic symmetrical polyneuropathy. Diabetic distal symmetric polyneuropathy is the most common type of peripheral neuropathy complication of diabetes mellitus. Neuroinflammation is emerging as an important contributor to diabetes-induced neuropathy. Long-term hyperglycemia results in increased production of advanced glycation end products (AGEs). AGEs interact with their receptors to activate intracellular signaling, leading to the release of various inflammatory cytokines. Increased release of inflammatory cytokines is associated with diabetes, diabetic neuropathy, and neuropathic pain. Thus, anti-inflammatory intervention is a potential therapy for diabetic distal symmetric polyneuropathy. Further characterization of inflammatory mechanisms might identify novel therapeutic targets to mitigate diabetic neuropathy. [ABSTRACT FROM AUTHOR]

The excessive release of proinflammatory chemokines promotes cell proliferation and tumor growth in colorectal cancer. However, their regulatory functions and molecular pathogenesis have not been well elucidated. Here, we observed the upregulation of chemokine (C-X-C motif) ligand 13 (CXCL13) in human colorectal cancers and mouse intestinal tumors. Both CXCL13 deficiency and blockade of CXCL13 signaling ameliorated disease progression. CXCL13 promoted intestinal tumorigenesis through the activation of the AKT signaling pathway in a C-X-C chemokine receptor type 5 (CXCR5)-dependent manner. Intestinal microbiota translocation drove CXCL13 production in dendritic cells through the activation of NF-κB signaling. Inhibition of microbiota translocation decreased CXCL13 production and ameliorated intestinal tumorigenesis. Together, the results of this study identify a role for the CXCL13-CXCR5 axis is involved in the crosstalk between chemokines and cell growth during the development of intestinal tumorigenesis, which also provides a therapeutic strategy for targeting CXCL13/CXCR5 in the future clinical treatment of intestinal tumors. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is a highly fatal malignancy with few effective therapies currently available. Recent studies have shown that PD-L1 inhibitors could be potential therapeutic targets for the treatment of PC. The present study aims to investigate the effect of Shikonin on immune evasion in PC with the involvement of the PD-L1 degradation. Initially, the expression patterns of PD-L1 and NF-κB in PC were predicted in-silico using the GEPIA database, and were subsequently validated using PC tissues. Thereafter, the correlation of NF-κB with STAT3, CSN5 and PD-L1 was examined. PC cells were treated with Shikonin, NF-κB inhibitor, STAT3 activator, and CSN5 overexpression plasmid to investigate effects on PD-L1 glycosylation and immune evasion in PC. Finally, in vivo tumor formation was induced in C57BL/6J mice, in order to verify the in vitro results. PD-L1, NF-κB, NF-κB p65, STAT3, and CSN5 were highly expressed in PC samples, and NF-κB was positively correlated with STAT3/CSN5/PD-L1. Inhibition of NF-κB decreased PD-L1 glycosylation and increased PD-L1 degradation, whereas activated STAT3 and overexpressed CSN5 reversed these trends. Shikonin blocked immune evasion in PC, and lowered the expression of PD-L1, NF-κB, NF-κB p65, STAT3 and CSN5 in vivo and in vitro. The findings indicated Shikonin inhibited immune evasion in PC by inhibiting PD-L1 glycosylation and activating the NF-κB/STAT3 and NF-κB/CSN5 signaling pathways. These effects of Shikonin on PC cells may bear important potential therapeutic implications for the treatment of PC. [ABSTRACT FROM AUTHOR]

Syzygium cumini (L.) Skeels (SC) , an ancient medicinal plant, is used as a complementary and alternative medicine for treating diabetes mellitus and its associated complications, such as diabetic nephropathy (DN). Phytochemicals present in SC homeopathic formulations possess anti-glycemic, anti-glycation, anti-inflammatory, and antioxidant properties. Additionally, the non-enzymatic formation of advanced glycation end products (AGEs) increases during hyperglycemia in diabetes. AGEs interaction with their receptor of AGEs (RAGE) promotes inflammation via Nuclear Factor-κB (NF-κB) and the accumulation of Extracellular Matrix (ECM) proteins, contributing to the renal dysfunction in DN. However, the molecular mechanism through which SC formulations interact with the AGEs-RAGE–NF–κB pathway has not yet been investigated. This study aims to examine the impact of SC formulations on the RAGE–NF–κB pathway and ECM protein modifications in glycation-induced DN using a molecular approach. Human serum albumin (10 mg/ml) was glycated with MGO (55 mM) in the presence of SC formulations - Mother tincture (MT), 30C, 200C for 7 days. Glycated samples were added to renal cells (HEK 293) for 24 h. Subsequently, cellular gene and protein expressions of RAGE, NF-κB, vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), collagen IV (Col IV), and fibronectin were determined using RT-qPCR and Western blot analysis. The immunofluorescence, luciferase assay, and chromatin immunoprecipitation techniques were employed to gain insights into glycation-induced NF-κB nuclear translocation, transcriptional activity, and its effect on RAGE promoter activity in SC-treated cells. SC formulations significantly downregulated glycation-induced elevated levels of RAGE and NF-κB. Mechanistically, SC formulations prevented NF-κB nuclear translocation, transcriptional activity, and RAGE promoter activity. Also, SC formulations significantly attenuated glycation-enhanced expressions of inflammatory cytokines (IL-6, TNF-α, and VEGF) and ECM proteins (Col IV and fibronectin). Our findings enlighten the molecular mechanism of SC in DN by targeting the AGEs-RAGE–NF–κB signaling pathway, inflammatory responses, and ECM accumulation. Hence, the study validates the protective role of SC formulations and signifies its novel potential for treating DN. [Display omitted] • S. cumini formulations ameliorate glycation induced diabetic nephropathy. • S. cumini formulations inhibit RAGE–NF–κB signaling pathway. • S. cumini reduced inflammatory response and extracellular matrix accumulation. • Mechanistically, S. cumini is beneficial to alleviate diabetic nephropathy. [ABSTRACT FROM AUTHOR]

The roots of Averrhoa carambola L. (Oxalidaceae) have a long history of medical use in traditional Chinese medicine for treating diabetes and diabetic nephropathy. 2-dodecyl-6-methoxycyclohexa-2, 5-diene-1, 4-dione (DMDD) was isolated from the tuberous roots of Averrhoa carambola L. The purpose of this study was to investigate the beneficial effect of DMDD on the advanced glycation end-product-mediated renal injury in type 2 diabetic KKAy mice with regard to prove its efficacy by local traditional practitioners in the treatment of kidney frailties in diabetics. KKAy mice were orally administrated DMDD (12.5, 25, 50 mg/kg body weight/d) or aminoguanidine (200 mg/kg body weight/d) for 8 weeks. Hyperglycemia, renal AGE formation, and the expression of related proteins, such as the AGE receptor, nuclear factor-κB, transforming growth factor-β1, and Nε-(carboxymethyl)lysine, were markedly decreased by DMDD. Diabetes-dependent alterations in proteinuria, serum creatinine, creatinine clearance, and serum urea-N and glomerular mesangial matrix expansion were attenuated after treatment with DMDD for 8 weeks. The activities of superoxide dismutase and glutathione peroxidase, which are reduced in the kidneys of KKAy mice, were enhanced by DMDD. These findings suggest that DMDD may inhibit the progression of diabetic nephropathy and may be a therapeutic agent for regulating several pharmacological targets to treat or prevent of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

• M. tuberculosis EsxL induces the production of TNF-α, IL-6 cytokines and MIP-1 α, MIP-1β, MCP-1 α and RANTES chemokines. • M. tuberculosis EsxL induces TNF-α via phosphorylation of p38 and ERK1/2 MAPK and NF-kB dependent pathways. • M. tuberculosis EsxL induces TNF-α synthesis through TLR2. Mycobacterium tuberculosis (Mtb) employs distinct strategies to circumvent host immune responses during the infection process. Various Mtb cell-wall associated and secretory proteins are known to play a critical role in the orchestration of host innate immune responses through modulation of signaling pathways. Mtb genome encodes for 23 (EsxA-EsxW) proteins belonging to the ESAT-6 like family; however, most of them are functionally unknown. Here, we show that Mtb EsxL induces tumor necrosis factor-alpha (TNF-α) production by activating nuclear translocation of nuclear factor-κB (NF-κB) via interaction with Toll-like Receptor 2 (TLR2). Blocking or silencing of TLR2 abrogated nuclear translocation of NF-kB and TNF-α production. Treatment with recombinant purified EsxL (rEsxL) activated mitogen-activated protein kinase (MAPK) pathway by inducing the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 kinase (p38) pathways. At the same time, inhibition of ERK and p38 down-regulated the expression of TNF-α in rEsxL exposed murine macrophages. Besides TNF-α, EsxL also induced the production of IL-6 proinflammatory cytokine. Taken together, these results suggest that EsxL is able to induce TNF-α secretion via TLR2 through activation of NF-κB and MAPK signaling. This study will help in deducing therapeutic strategies for better control of the disease. [ABSTRACT FROM AUTHOR]

Bone diseases such as osteoporosis and periodontitis are induced by excessive osteoclastic activity, which is closely associated with inflammation. Benzydamine (BA) has been used as a cytokine-suppressive or non-steroidal anti-inflammatory drug that inhibits the production of pro-inflammatory cytokines or prostaglandins. However, its role in osteoclast differentiation and function remains unknown. Here, we explored the role of BA in regulating osteoclast differentiation and elucidated the underlying mechanism. BA inhibited osteoclast differentiation and strongly suppressed interleukin-1 β (IL-1 β) production. BA inhibited osteoclast formation and bone resorption when added to bone marrow-derived macrophages and differentiated osteoclasts, and the inhibitory effect was reversed by IL-1 β treatment. The reporter assay and the inhibitor study of IL-1 β transcription suggested that BA inhibited nuclear factor- κ B and activator protein-1 by regulating I κ B kinase, extracellular signal regulated kinase and P38, resulting in the down-regulation of IL-1 β expression. BA also promoted osteoblast differentiation. Furthermore, BA protected lipopolysaccharide- and ovariectomy-induced bone loss in mice, suggesting therapeutic potential against inflammation-induced bone diseases and postmenopausal osteoporosis. The role of BA was explored in regulating osteoclast differentiation and the underlying mechanism was elucidated. BA inhibits osteoclast differentiation and resorption by suppressing IL-1 β synthesis via down-regulation of IKK, ERK and P38, and promotes osteoblast differentiation. Image 1 [ABSTRACT FROM AUTHOR]

Despite strong evidence that high-density lipoproteins (HDLs) modulate the immune response, the role of HDL in allergies is still poorly understood. Many patients with allergic rhinitis (AR) develop a late-phase response, characterized by infiltration of monocytes and eosinophils into the nasal submucosa. Functional impairment of HDL in AR-patients may insufficiently suppress inflammation and cell infiltration, but the effect of AR on the composition and function of HDL is not understood. We used apolipoprotein (apo) B-depleted serum as well as isolated HDL from AR-patients (n = 43) and non-allergic healthy controls (n = 20) for detailed compositional and functional characterization of HDL. Both AR-HDL and apoB-depleted serum of AR-patients showed decreased anti-oxidative capacity and impaired ability to suppress monocyte nuclear factor-κB expression and pro-inflammatory cytokine secretion, such as interleukin (IL)-4, IL-6, IL-8, tumor necrosis factor alpha and IL-1 beta. Sera of AR-patients showed decreased paraoxonase and cholesteryl-ester transfer protein activities, increased lipoprotein-associated phospholipase A2 activity, while lecithin-cholesterol acyltransferase activity and cholesterol efflux capacity were not altered. Surprisingly, apoB-depleted serum and HDL from AR-patients showed an increased ability to suppress eosinophil effector responses upon eotaxin-2/CCL24 stimulation. Mass spectrometry and biochemical analyses showed reduced levels of apoA-I and phosphatidylcholine, but increased levels of apoA-II, triglycerides and lyso-phosphatidylcholine in AR-HDL. The changes in AR-HDL composition were associated with altered functional properties. In conclusion, AR alters HDL composition linked to decreased anti-oxidative and anti-inflammatory properties but improves the ability of HDL to suppress eosinophil effector responses. Unlabelled Image • HDL of allergic rhinitis (AR) patients has impaired PON and anti-oxidative capacity. • AR-HDL is defective in suppressing NF-κB expression and cytokine secretion. • AR-HDL shows an improved ability to suppress eosinophil effector responses. • LPC and triglyceride content of AR-HDL is linked to altered AR-HDL functionality. • Activity of enzymes involved in HDL metabolism is altered in AR. [ABSTRACT FROM AUTHOR]

Oxidative stress and inflammation have been implicated in hepatic fibrosis. Antioxidant and anti-inflammatory activities are among the pharmacological effects of hyperoside. This study aimed to evaluate the impact of hyperoside on hepatic fibrosis and elucidate the underlying processes that perpetuate this relationship. The findings indicated that hyperoside significantly protects mouse livers against damage, inflammation, and fibrosis. Specifically, attenuation of hepatic fibrosis is associated with lower expression of HMGB1 protein and reduced expression of Toll-like receptor 4, PARP-1, and nuclear factor-kB (NF-κB) p65 mRNA and protein. Furthermore, hyperoside inhibited the cytoplasmic translocation of HMGB1 and nuclear localization of NF-κB p65 in the hepatic tissues of mice. The results of this study indicate that hyperoside may impose a blocking or reversing effect on hepatic fibrosis; additionally, the corresponding hyperoside-dependent mechanism may be linked to PARP-1-HMGB1 pathway regulation. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy is triggered by an initial insult, such as status epilepticus, that initiates the process of epilepsy development. Heat shock protein 70 (Hsp70) is a ubiquitously expressed molecular chaperone, involved in the inflammatory response that is upregulated after status epilepticus. Hsp70 has been described as an endogenous intracellular ligand of Toll-like receptor 4. It is released from damaged or necrotic tissue and by activated immune cells after an inflammatory event. So far, the time course and the pattern of epileptogenesis-associated alterations in Hsp70 expression have not been described in detail. Thus, we investigated immunohistochemical expression of Hsp70 in hippocampus, parahippocampal cortex, parietal cortex, amygdala, and thalamus following status epilepticus in a rat model of temporal lobe epilepsy. The impact of status epilepticus on Hsp70 expression varied during different phases of epileptogenesis, displaying a stronger effect in the early post-insult phase, a milder and more localized effect in the latency phase and no relevant effect in the chronic phase. Cellular-level characterization revealed that Hsp70 colocalized with the neuronal marker NeuN and with Toll-like receptor 4. No colocalization with the astrocytic marker GFAP or the microglia marker Iba1 was found. The intense neuronal Hsp70 upregulation during the early post-insult phase might contribute to the onset of excessive inflammation triggering molecular and cellular reorganization and generation of a hyperexcitable epileptic network. Therefore, development of multi-targeting strategies aiming at prevention of epileptogenesis should consider Hsp70 modulation in the early days following an epileptogenic insult. Unlabelled Image • Hsp70 is upregulated in the acute post-SE phase and with minor extent in the latency phase of epileptogenesis. • Hsp70i co-localize with Toll-like receptor 4 and with principal neuron markers in hippocampus and parahippocampal cortex. • Hsp70i does not colocalize with astrocytes and with microglia markers in hippocampus and parahippocampal cortex. [ABSTRACT FROM AUTHOR]

• Nontoxic concentrations of OTA aggravated DON-induced intestinal barrier dysfunction in IPEC-J2 cells. • Nontoxic concentrations of OTA aggravated DON-induced inflammatory response in IPEC-J2 cells. • Inhibitor of NF-κB reversed the aggravating effects of OTA on DON-induced intestinal inflammation and barrier dysfunction. • NF-κB signaling pathway is involved in OTA aggravated DON-induced intestinal barrier dysfunction and inflammatory response. Deoxynivalenol (DON) is well-known enteropathogenic mycotoxin which can alter intestinal barrier functions. Consistently, Ochratoxin A (OTA) ingestion has been found to induce intestinal injuries, including inflammation and diarrhea. However, little is known whether OTA aggravates DON-induced toxicity. This study is designed to explore the effects of OTA on DON-induced intestinal barrier function and involved mechanism. Our results showed either DON or OTA could disrupt intestinal barrier function in a time- and dose-dependent manner, as demonstrated by decreased transepithelial electrical resistance (TEER) and increased paracellular permeability to 4 kDa dextran. However, to eliminate the involvement of cell death, nonlethal concentrations of DON and OTA were used in following experiments. The nontoxic concentration of OTA was observed to aggravate DON-induced intestinal barrier dysfunction, accompanied with tight junction disruption (Claudin-3 and Claudin-4). Moreover, nontoxic concentrations of OTA aggravated DON-induced up-regulation of pro-inflammatory cytokines expression and activated nuclear factor-κB (NF-κB) in IPEC-J2 cells. Adding NF-κB inhibitor (PDTC) alleviated the aggravating effects of nontoxic concentrations of OTA on DON-induced intestinal barrier dysfunction and inflammation. These findings indicate that nontoxic concentrations of OTA promoted DON-induced barrier dysfunction via NF-κB signaling pathway. Our experiment suggests that exposure to nontoxic concentrations of toxins also poses potentially harmful effects. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is one of the most common health threatening disorders. Patients with chronic diabetes are at high risk of contracting oral diseases, including dental pulp damage. In this study, we reviewed how Teneligliptin, a commonly used anti-diabetic agent, protected dental pulp cells from lipopolysaccharide (LPS)-induced cytotoxicity and improved their viability. The dental pulp cells treated with Teneligliptin were resistant to LPS-induced reactive oxygen species (ROS) and its byproduct 4-hydroxynonenal (4-HNE) generation. The Teneligliptin recovered LPS-induced a reduction of cellular glutathione and produced cytokine including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Mechanistically, we found that Teneligliptin suppressed LPS- that caused an expression of the cell surface receptor toll like receptor 4 (TLR-4) and the activation of JNK kinase and activator protein 1 (AP1) as well as the nuclear factor-κB (NF-κB) signal pathways. Collectively, our study demonstrates that the molecular mechanism Teneligliptin is a protective anti-diabetic agent in dental pulp cells and it has the potential to treat diabetes-associated dental pulp diseases. • Teneligliptin protects LPS-induced cell death of human dental pulp cells. • Teneligliptin ameliorates LPS-induced oxidative stress in human dental pulp cells. • Teneligliptin reduces LPS-induced generation of pro-inflammatory cytokines. • Teneligliptin inhibits LPS-induced activation of TLR4. • Teneligliptin inhibits LPS-induced activation of JNK/AP1/NF-κB signaling. [ABSTRACT FROM AUTHOR]

Modified Da-chai-hu Decoction (MDD), a traditional Chinese medicinal formulation, which was empirically generated from Da-chai-hu decoction, has been utilized to treat severe acute pancreatitis (SAP) for decades. The aim of the present study was to explore its potential organprotective mechanism in SAP. In the present study, rat SAP model was induced by retrograde injection of 3.5% sodium taurocholate into the biliopancreatic duct, MDD (23.35 g/kg body weight, twelve times the clinical dose) were orally given at 2 h before and 10 h after injection. At 12 h after model induction, blood was taken from vena cava for analysis of amylase, diamine oxidase (DAO), pulmonary surfactant protein-A (SP-A), and C-reactive protein (CRP). Histopathological change of pancreas, ileum and lung was assayed by H&E staining, myeloperoxidase (MPO) activity were determinated using colorimetric assay, and the expressions of occludin and nuclear factor-κB (NF-κB) were detected by real-time RT-PCR and western blot, respectively. In addition, the tissue concentrations of tumor necrosis factor-α (TNF- α), interleukin-1 β (IL-1 β), and monocyte chemoattractant protein-1 (MCP-1) were measured by enzyme-linked immunosorbent assay (ELISA). The results showed that in SAP rats, MDD significantly alleviated histopathological damage, depressed the MPO activity and the concentrations of TNF- α , IL-1 β , and MCP-1 of pancreas, ileum and lung, and reduced the serum levels of amylase [(3283.4 ± 585.5) U·L–1 vs (5626.4 ± 795.1)U·L–1], DAO [(1100.1 ± 334.3) U·L–1 vs (1666.4 ± 525.3) U·L–1] and CRP [(7.6 ± 1.2) μg·mL–1 vs (17.8 ± 3.8) μg·mL–1]. However, the serum SP-A concentration [(106.1 ± 16.6) pg·mL–1 vs (90.1 ± 14.9) pg·mL–1] was elevated when treated SAP rats with MDD. Furthermore, MDD increased the occludin expression and reduced the NF-κB expression in pancreas, ileum and lung of SAP rats. Our findings suggested that MDD administration was an effective therapeutic approach for SAP treatment. It could up-regulate occludin expression to protect intercellular tight junction and down-regulate NF-κB expression to inhibit inflammatory reaction of pancreas, ileum and lung. [ABSTRACT FROM AUTHOR]

Highlights • KPF inhibits LPS-induced inflammatory response by modulating NFκB signaling pathway. • KPF effectively suppresses IL-1β-activated NF-κB signaling events mechanistically through reducing polyubiquitination on TLR4 pathway. • KPF significantly extends the survival of LPS-challenged mice and alleviates ALI by blocking K63-linked polyubiquitination in lung tissue. • KPF-responsive pathways may be an excellent target to pursue for the development of therapies for ALI. Abstract Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), pose a major clinical challenge. The major driving force in this syndrome is pulmonary inflammation. Recent studies have shown that the naturally occurring flavonoid kaempferol (KPF) reduces endotoxin-induced inflammatory responses in mice. However, the mechanisms of these anti-inflammatory activities are not currently known. Here, we show that enhanced inflammatory cytokine production in response to lipopolysaccharide (LPS) is due to increased TGF-β-activated kinase-1 (TAK1) phosphorylation with subsequent activation of nuclear factor-κB (NF-κB). KPF attenuates LPS-mediated production of cytokines as well as activation of NF-κB. Furthermore, we identified that KPF prevents increased K63-linked polyubiquitination on TNF receptor associated factor-6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1). K63-linked polyubiquitination is a signal leading to enhanced activation of downstream pathways including TAK1. Our study shows that KPF is effective in reducing lung damage induced by LPS by modulating TRAF6 polyubiquitination. Furthermore, our findings may provide novel molecular targets to alleviate acute lung injury. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Ficus is an important commercial crop not only for its nutritive value but also, for its medicinal value. Several Ficus species have been traditionally used in the Egypt, Indian and Chinese as carminative, astringent, antibacterial, hepatoprotective, and hypolipidemic agents. Aim of the study To standardize and compare the possible hepatoprotective potential of the ethanolic extract of leaves of five tested Ficus species namely: Ficus mysorensis Roth ex Roem. & Schult, Ficus pyriformis Hook. & Arn., Ficus auriculata Lour., Ficus trigonata L., and Ficus spragueana Mildbr. & Burret in the intrahepatic cholestasis rat model induced by 17α-Ethinylestradiol (EE) and to explore the mechanism of action with respect to their phytochemical constituents. Materials and methods Determination of the total phenolic and flavonoid contents, chromatographic examination and acute oral toxicity test were performed on the tested Ficus extracts. Animals were divided into 8 groups. Group 1 , served as control for 2 weeks. Group 2 , untreated cholestatic rats. Groups 3–8 , pretreated with Ficus extracts (100 mg/Kg/day, p.o) or ursodeoxycholic acid (as reference drug) for 2 weeks and injected by EE in the last 5 days. Serum liver function test, 5′-nucleotidase (5′-N), total bile acids (TBA), total cholesterol (T.C) and phospholipids were assayed. Also, hepatic Na+/K+-ATPase, nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), hepatocyte growth factor (HGF), hemeoxygenase-1 (HO-1), and markers of oxidative stress were investigated. Furthermore, molecular docking study was performed to explore the ability of the major constituents of Ficus to interact with Farnesoid X receptor (FXR). Results Four phenolic compounds (gallic, chlorogenic acid, caffeic acids and rutin) were identified. Chlorogenic acid and rutin represented the major constituents of Ficus extracts. Simultaneous administration of Ficus extracts with EE effectively: i- preserved liver function, TBA, T.C and phospholipids, ii- suppressed the pro-inflammatory cytokines (NF-κB and TNF-α), iii- enhanced hepatic regeneration (HGF) and antioxidant defense system. Furthermore, molecular docking reveals that rutin and chlorogenic acid effectively act as FXR agonists. Conclusion Among the tested extracts, Ficus spragueana Mildbr. & Burret enriched with phenolics exhibited a pronounced hepatoprotective activity and may provide a new therapeutic approach for estrogen-induced cholestasis. Graphical abstract fx1 Highlights • HPLC analysis of phenolics in the leaf extracts of five Ficus species. • Quantification of chlorogenic acid and rutin by HPLC. • Five Ficus species were tested for their hepatoprotective potential. • Modulation of the NF-κB, and FXR signaling pathways. • A new strategy approach for estrogen-induced cholestasis. [ABSTRACT FROM AUTHOR]

Abstract Gastric cancer (GC), one of the most common cancers of the digestive system, results in high morbidity and mortality, but the molecular mechanisms underlying GC remain largely unknown. Cadherin-17 (CDH17) is a nonclassical member of the cadherin (CDH) superfamily of calcium-dependent proteins. Despite recent advances in the understanding of CDH17 biology, the mechanism of CDH17 in GC proliferation, migration, and invasion has not been extensively studied. In the present study, we observed that CDH17 expression was increased in GC tissues compared with para-carcinoma tissues and was correlated with lymph node metastasis and the AJCC stage. Additionally, a significant correlation was found between CDH17 protein expression and the number of blood and lymph vessels in GC tissues. Furthermore, in vitro suppression of CDH17 expression using short-interfering RNA (siRNA) decreased AGS cell proliferation, migration and invasion. Conversely, overexpression of CDH17 through plasmid transfection enhanced the malignant activity of AGS cells. Moreover, CDH17 increased the matrix metallopeptidase 2 (MMP-2) levels via the canonical nuclear factor-kappaB (NF-κB) pathway. Our findings offer new insights into the mechanism of the CDH17/NF-κB/MMP-2 axis, and the associated signalling pathways might represent novel targets for the treatment of GC. Highlights • CDH17 is a useful marker for the histological diagnosis of human gastric cancer. • Abnormal expression of CDH17 can strongly affect the malignant biological characteristics of AGS cells. • CDH17 activates the canonical NF-κB pathway to influence the MMP-2 level in AGS cells. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance A multi-herb Chinese medicinal formula consisting of a variety of medicinal and edible materials has long been consumed as a hot drink and immune enhancer for its efficiency to increase disease resistance in Xinjiang, China. However, no fundamental data has been collected associated with traditional consumption. The present work was designed to evaluate the immunostimulatory role of Xinjiang herbal tea (XMT-WE) in RAW 264.7 macrophages and cyclophosphamide (CTX)-induced immunosuppression mice model. Materials and methods RAW 264.7 cells were treated with various concentrations of XMT-WE. Nitric oxide (NO) levels were determined using Griess reagents, and pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α were investigated with a cytometric bead array kit. The effects on mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and TNF-α were investigated. Furthermore, activation of nuclear factor (NF)-κB and AP-1 mitogen-activated protein kinase (MAPK) signaling pathways was investigated. Results Pre-treatment with XMT-WE significantly increased secretion of NO, IL-6, and TNF-α. In addition, XMT-WE markedly increased expression of iNOS, COX-2, and TNF-α as well as AP-1 and NF-κB translocation from the cytoplasm into the nucleus, which was associated with an increase of phosphorylated ERK, JNK, and p38 as well as membrane receptors such as toll-like receptor (TLR) 2 and TLR4. Moreover, XMT-WE promoted the secretion of interleukin-2 (IL-2) and interferon-γ (IFN-γ) in cyclophosphamide (CTX)-induced immunosuppressive mice. Conclusion These results indicated that XMT-WE at 50 µg/ml exerts immunomodulatory activity via TLR2/4-mediated MAPK signaling pathways in RAW 264.7 cells. Furthermore, in vivo experiments revealed that XMT-WE at the dose of 50 and 100 mg/kg strongly stimulated inflammatory cytokines. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Senkyunolide H (SNH) helped attenuate PC12 cell apoptosis induced by MPP+. • SNH protected PC12 cells by inhibiting NF-κB and AP-1 activation. • The neuroprotective effect of SNH was related to suppression of MAPKs pathways. Abstract Senkyunolide H (SNH) is a phthalide isolated from the rhizome of Ligusticum chuanxiong Hort. that has been reported to have several pharmacological activities, including anti-atherosclerotic, antiproliferative, and cytoprotective effects. In this study, we investigated the neuroprotective effects and potential mechanisms of SNH against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress. We demonstrated that SNH pretreatment significantly attenuated MPP+-induced neurotoxicity and apoptosis in PC12 cells. In addition, SNH attenuated the effect of MPP+ on the expression of the pro-apoptotic factors Bax and caspase-3. Meanwhile, SNH prevented oxidative stress by reducing reactive oxygen species generation, mitochondrial membrane potential loss, cytochrome C release, and malondialdehyde levels while increasing antioxidant enzyme activity (e.g., superoxide dismutase, catalase, and glutathione peroxidase). In addition, SNH inhibited nuclear accumulation of nuclear factor-κB and c-Jun N-terminal kinase and phosphorylation p38 mitogen-activated protein kinases (MAPKs). Overall, this investigation provides novel evidence that SNH exerts neuroprotective effects via the ROS-mediated MAPK pathway and represents a potential preventive or therapeutic agent for neuronal disorders. [ABSTRACT FROM AUTHOR]

Highlights • Disrupted BBB integrity involves in MMP-9 upregulation in 1,2-DCE poisoned mice. • Activated P38 MAPK involves in MMP-9 upregulation in 1,2-DCE poisoned mice. • NF-κB and AP-1 is activated and mediated by p38 MAPK in 1,2-DCE poisoned mice. Abstract Accumulated data have revealed that subacute poisoning of 1,2-dichloroethane (1,2-DCE), an industrial solvent used in some countries can cause encephalopathy, in which brain edema is the main pathological change. However, the underlying mechanisms are unclear. In the present study, we hypothesized that the p38 MAPK (p38) signaling pathway could be activated in 1,2-DCE-intoxicated mice, which in turn stimulates transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), and then enhances the expression of proinflammatory factors, including matrix metalloproteinase-9 (MMP-9), finally leading to blood-brain barrier (BBB) disruption and brain edema formation. Our results revealed that brain water content and BBB permeability increased significantly in the intoxicated mice. Meanwhile, the levels of phosphorylated p38 (p-p38) and inhibitory κBα (p-IκB), as well as the expression levels of MMP-9, c-jun, c-fos, and p65, also increased markedly in the brains of intoxicated mice. Conversely, the protein levels of ZO-1, occludin and claudin-5 in these mice decreased markedly, but their JAM-1 protein levels increased dramatically. Our results revealed that p-p38 levels in the brains of intoxicated mice were suppressed by pretreatment with a p38 inhibitor. In response to suppressed p-p38 levels, the brain water contents and DNA binding activities of NF-κB and AP-1, as well as the expression levels of MMP-9, c-jun, c-fos, p65, p-IκB and JAM-1, decreased, whereas the protein levels of ZO-1, occludin and claudin-5 increased markedly. Taken together, our findings indicated that the p38 signaling pathway might be activated and involved in the course of brain edema in 1,2-DCE-intoxicated mice. [ABSTRACT FROM AUTHOR]

IκB, a cytoplasmic inhibitor of nuclear factor-κB (NF-κB), is reportedly degraded via the proteasome. However, we recently found that long-term incubation with proteasome inhibitors (PIs) such as PS-341 or MG132 induces iκBα degradation via an alternative pathway, lysosome, which results in NF-κB activation and confers resistance to Pl-induced lung cancer cell death. To enhance the anti-cancer efficacy of Pis, elucidation of the regulatory mechanism of PI-induced iκBα degradation is necessary. Here, we demonstrated that PI up-regulates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) via both de nouo protein synthesis and Kelch-like ECH-associated protein 1 (KEAP1) degradation, which is responsible for iκBα degradation via macroautophagy activation. Pis increased the protein level of light chain 3B (LC3B, macroautophagy marker), but not lysosome-associated membrane protein 2a (Lamp2a, the receptor for chaperone-mediated autophagy) in NCI-H157 and A549 lung cancer cells. Pretreatment with macroautophagy inhibitor or knock-down of LC3B blocked PI-induced iKBa degradation. Pis up-regulated Nrf2 by increasing its transcription and mediating degradation of KEAP1 (cytoplasmic inhibitor of Nrf2). Overexpression of dominantnegative Nrf2, which lacks an N-terminal transactivating domain, or knock-down of Nrf2 suppressed Pi-induced LC3B protein expression and subsequent iKBa degradation. Thus, blocking of the Nrf2 pathway enhanced PI-induced cell death. These findings suggest that Nrf2-driven induction of LC3B plays an essential role in Pi-induced activation of the IκB/NF-κB pathway, which attenuates the anti-tumor efficacy of Pis. [ABSTRACT FROM AUTHOR]

Abstract Really interesting new gene finger protein (RING) finger protein 121 (RNF-121) is an E3 ubiquitin ligase involved in the regulation of several signaling pathways. Among those signaling pathways, nuclear factor-κB (NF-κB) signaling pathway is known to play a critical role in tumorigenesis. However, the relevance between RNF121 and cancer development remains poorly understood. In this study, we found that RNF121 was less expressed in tumor tissues than adjacent normal tissues of renal cell carcinoma (RCC) patients. Overexpression of RNF121 inhibited the growth of human RCC cells (768-O cell line) in vivo. Moreover, RNF121 impeded the proliferation, migration and invasion of human RCC cells in vitro. In addition, we found that RNF121 activated NF-κB signaling pathway via promoting IκBα degradation in human RCC cells. Our findings reveal a previously unrecognized role of RNF121 in RCC development, and provide new insights into RCC prognosis and therapy. Highlights • RNF121 expression was downregulated in RCC. • Overexpression of RNF121 inhibited tumor growth. • RNF121 activated NF-κB signaling pathway in RCC. [ABSTRACT FROM AUTHOR]

Abstract Allergic rhinitis (AR) is a global health problem because of its steadily increasing incidence and prevalence that currently affects about 30% of people worldwide. β-eudesmol has various beneficial effects, including anti-cancer and anti-allergic activities. However, the effects of β-eudesmol on AR have not yet been clarified; thus, we investigated the effects of β-eudesmol in an ovalbumin-induced AR animal model using enzyme-linked immunosorbent assay, histamine assay, Western blotting, and hematoxylin and eosin staining methods. β-eudesmol reduced the nasal rubs score and levels of histamine and immunoglobulin E in serum of AR mouse. In addition, the levels of thymic stromal lymphopoietin, interleukin-1β, tumor necrosis factor-α, and macrophage inflammatory protein-2 were down-regulated and infiltration of eosinophils and the level of intercellular adhesion molecule-1 were inhibited by β-eudesmol administration. β-eudesmol administration also reduced active caspase-1 and nuclear factor-κB DNA binding activity in nasal mucosa tissues of AR mice. Taken together, these results indicate that β-eudesmol would be effective for the treatment of allergic and inflammatory diseases, such as AR. Highlights • β-eudesmol reduced nasal rubs score, histamine, and IgE in an allergic rhinitis (AR) murine model. • β-eudesmol inhibited TSLP level and eosinophil infiltration in AR mice. • β-eudesmol decreased caspase-1 activation and NF-kB activity in nasal mucosa tissues of AR mice. [ABSTRACT FROM AUTHOR]

Abstract Among five major anthocyanin compounds, delphinidin exhibited the most potent and selective cytocidal effect against HL-60, a trivalent arsenic (As(III))-resistant cell line. Co-treatment with delphinidin and As(III) resulted in the reduction of IC 50 value for As(III) from 11.2 to 1.5 μM, which was considered as clinically achieved concentrations of As(III). The combination treatment strongly preferred to selectively enhance the cytotoxicity of As(III) against HL-60 cells rather than human peripheral blood mononuclear cells. The induction of apoptosis as evidenced by the increase of sub-G 1 cells, DNA fragmentation, annexin V-positive cells and the activation of caspase-8, -9 and -3 was observed in HL-60 cells co-treated with As(III) and delphinidin. Similar to the activation pattern of caspases, a substantial decrease in the expression level of Bid along with the loss of mitochondrial membrane potential was also observed. These results suggested that the combination treatment triggered a convergence of the intrinsic and extrinsic pathways of apoptosis via the activation of caspase-8 and cleaved Bid. Delphinidin itself significantly decreased the intracellular GSH ([i]GSH) and nuclear factor-κB (NF-κB) binding activity, and further returned As(III)-triggered increment of [i]GSH and enhancement of NF-κB binding activity to control level. Additionally, buthionine sulfoximine, a GSH depletor; JSH-23, a NF-κB inhibitor, also mimicked the capacity of delphinidin to significantly induce the reduction of [i]GSH along with the potentiation of As(III) cytotoxicity in HL-60 cells. These observations suggested that delphinidin-induced sensitization of HL-60 cells to As(III) was caused by the reduction of [i]GSH, which was probably associated with the inhibitory effect of delphinidin on NF-κB binding activity. These findings further suggest that delphinidin-induced sensitization of HL-60 cells to As(III) may lead to dose reduction of As(III) in clinical application, and ultimately contribute to minimizing its side effects. Graphical abstract Image 1 Highlights • Effect of five anthocyanins on trivalent arsenic (As(III))-resistant cells HL-60. • Delphinidin exhibited the most potent and selective cytocidal effect against HL-60. • Delphinidin prominently sensitized the cells to As(III)-mediated cytocidal effects. • Apoptosis induction, reduced [i]GSH and NF-κB activity involved in the sensitization. [ABSTRACT FROM AUTHOR]

Abstract Introduction In this study, we examined the effect of mineral trioxide aggregate (MTA) on macrophage polarization and the potential involvement of Axl/nuclear factor kappa B (NF-κB) signaling in mediating the effect of MTA. Methods The human monocyte cell line THP-1 was cultured with MTA solution for 1, 2, or 3 days, and the population change of M2 macrophages was analyzed by flow cytometry. Expression of M2 cytokines was examined by enzyme-linked immunosorbent assay. Phagocytosis and angiogenesis-induction ability were also assayed. The involvement of Axl/NF-κB signaling in MTA-treated cells was examined by analyzing phosphorylation status of Axl, Akt, IKKα/β, and IκBα. Specific inhibitors for Axl/Akt/NF-κB signaling were added to MTA-treated THP-1 cells, and their cytokine expression change was examined. Results Flow cytometry analysis showed that MTA treatment increased CD206＋ cells in a time-dependent way. After MTA treatment, the expression of M2-related cytokines was up-regulated. MTA also enhanced phagocytic ability and the ability of THP-1 cells to induce angiogenesis. Treatment of MTA led to activate Axl/Akt/NF-kB signal axis by phosphorylation of Axl, Akt, IKKα/β, IκBα, and p65. In addition, MTA-induced interleukin 10, transforming growth factor beta, and vascular endothelial growth factor expression was suppressed as specific inhibitors were added. Conclusions Our findings indicate that MTA is able to induce macrophage polarization toward the M2 phenotype, with up-regulation of interleukin 10, transforming growth factor beta, and vascular endothelial growth factor, and that Axl/Akt/NF-κB signaling participates in this process. These results provide the cellular and molecular basis of MTA's anti-inflammatory action in clinical applications. Highlights • MTA is able to induce macrophage polarization toward the M2 phenotype. • MTA upregulate the macrophage to secrete IL-10, TGF-b, and VEGF. • Axl/Akt/NF-κB signaling participates in the process of MTA affect macrophage polarization and cytokine expression. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are the primary cause of mortality in patients with diabetes and obesity. Hyperglycemia and hyperlipidemia in diabetes alters cardiac function, which is associated with broader cellular processes such as aberrant inflammatory signaling. Recent studies have shown that a pattern recognition receptor called Dectin-1, expressed on macrophages, mediates pro-inflammatory responses in innate immunity. In the present study, we examined the role of Dectin-1 in the pathogenesis of diabetic cardiomyopathy. We observed increased Dectin-1 expression in heart tissues of diabetic mice and localized the source to macrophages. We then investigated the cardiac function in Dectin-1-deficient mice with STZ-induced type 1 diabetes and high-fat-diet-induced type 2 diabetes. Our results show that Dectin-1 deficient mice are protected against diabetes-induced cardiac dysfunction, cardiomyocyte hypertrophy, tissue fibrosis, and inflammation. Mechanistically, our studies show that Dectin-1 is important for cell activation and induction of inflammatory cytokines in high-concentration glucose and palmitate acid (HG + PA)-challenged macrophages. Deficiency of Dectin-1 generate fewer paracrine inflammatory factors capable of causing cardiomyocyte hypertrophy and fibrotic responses in cardiac fibroblasts. In conclusion, this study provides evidence that Dectin-1 mediates diabetes-induced cardiomyopathy through regulating inflammation. Dectin-1 may be a potential target to combat diabetic cardiomyopathy. [Display omitted] • Dectin-1 is upregulated in cardiac tissue of diabetic mice. • Dectin-1 aggravates diabetic cardiomyopathy via regulating Syk/NF-κB activation and cardiac inflammatory response. • Dectin-1-mediated cytokines in macrophages promote hypertrophy in cardiomyocytes and fibrosis in cardiac fibroblasts. • Targeting Dectin-1 may offer new promises in diabetes-induced cardiac injuries. [ABSTRACT FROM AUTHOR]

Cbf-14 with the sequence RLLRKFFRKLKKSV, is an effective antimicrobial peptide derived from a cathelin-like domain. Previous reports have demonstrated that Cbf-14 not only exerts antimicrobial activity against penicillin-resistant bacteria but also alleviates bacterial-induced inflammation in E. coli BL21 (DE3)-NDM-1-infected mice. In this article, we demonstrated that Cbf-14 can effectively reduce RAW 264.7 intracellular infection caused by clinical strain E. coli and alleviate the inflammatory response of cells and improve cell survival after infection. Therefore, we established the LPS-stimulated RAW 264.7 cell inflammation model to uncover the molecular mechanisms of the peptide Cbf-14 in anti-inflammatory activity. The results reveal that Cbf-14 can decrease LPS-induced ROS secretion by blocking the membrane translocation of p47-phox subunits and suppressing p47-phox protein phosphorylation. Meanwhile, this peptide can down-regulate the over-expression of iNOS, and finally inhibit the NO excessive secretion from RAW 264.7 macrophages stimulated by LPS. Moreover, Cbf-14 also down-regulates the expression levels of p-IκB and p-p65 and inhibits the nuclear translocation of NF-κB through blocking MAPK- and/or PI3K-Akt signaling pathways. Overall, Cbf-14 exhibits anti-inflammatory activity through inhibiting NF-κB activity and ROS production via PI3K- Akt signaling pathway. • Cbf-14 can effectively eliminate bacteria inside of the RAW 264.7 macrophages. • Cbf-14 can improve cell viability and relieve inflammation after infection. • Cbf-14 can decrease ROS and iNOS production. • This activity is mediated by PI3K- Akt /ROS/ NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] Improved therapies for inflammatory bowel diseases are sorely needed. Novel therapeutic agents and the development of controlled release systems for targeted tissue delivery are interesting approaches to overcome these barriers. We investigated the activity of trans -chalcone (T) in acetic acid-induced colitis in mice and developed, characterized, and determined the therapeutic effect of pectin/casein polymer microcapsules containing T (MT) in a colitis mouse model. In vitro , compound release was achieved in simulated intestinal fluid but not in the simulated gastric fluid. In vivo , since T at the dose of 3 mg/kg but not 0.3 mg/kg ameliorated colitis, we next tested the effects of MT at 0.3 mg/kg (non-effective dose). MT, but not free T at 0.3 mg/kg, significantly improved colitis outcomes such as neutrophil recruitment, antioxidant capacity, cytokine production, and NF-kB activation. This translated into reduced macro and microscopic damage in the colon. T release from the microcapsules is mediated by a pH-dependent and pectinase-regulated mechanism that provide controlled and prolonged release of T. Moreover, MT lowered the required dose for T therapeutic effect, indicating that could be a suitable pharmaceutical approach to colitis treatment. This is the first demonstration that T or MT is effective at reducing the signs of colitis. [ABSTRACT FROM AUTHOR]

Despite advances in overall medical care, sepsis and its sequelae continue to be an embarrassing clinical entity with an unacceptably high mortality rate. The central reason for high morbidity and high mortality of sepsis and its sequelae is the lack of an effective treatment. Previous clinical trials have largely failed to identify an effective therapeutic target to improve clinical outcomes in sepsis. Thus, the key goal favoring the outcome of septic patients is to devise innovative and evolutionary therapeutic strategies. Gene therapy can be considered as one of the most promising novel therapeutic approaches for nasty disorders. Since a number of transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), play a pivotal role in the pathophysiology of sepsis that can be characterized by the induction of multiple genes and their products, sepsis may be regarded as a gene-related disorder and gene therapy may be considered a promising novel therapeutic approach for treatment of sepsis. In this review article, we provide an up-to-date summary of the gene-targeting approaches, which have been developed in animal models of sepsis. Our review sheds light on the molecular basis of sepsis pathology for the development of novel gene therapy approaches and leads to the conclusion that future research efforts may fully take into account gene therapy for the treatment of sepsis. [ABSTRACT FROM AUTHOR]

Endometritis is the inflammation of the endometrium that is associated with lower conception rates, increased intervals from calving to first service, and more culls for failure to conceive, which leads to serious economic losses in the dairy industry. Leonurine, a natural active compound of Leonurus cardiaca , has been proved to possess various biological activities. However, there is still no study about its anti-inflammatory effects on LPS-induced endometritis. The present study aimed to demonstrate the underlying mechanism responsible for the anti-inflammatory effects of leonurine on LPS induced endometritis in mice and in bovine endometrial epithelial cells (bEECs). The results of pathological section displayed that leonurine alleviated LPS induced uterine injury. qRT-PCR and ELISA experiments suggested that leonurine inhibited the expression levels of TNF-α and IL-1β in uterus tissues and bEECs. Molecular studies showed that TLR4 expression and nuclear factor (NF)-κB activation were both inhibited by leonurine treatment. These results suggested that the therapeutic effects of leonurine on LPS-induced endometritis in mice and bEECs may act by inhibiting the expression of TLR4 and its downstream mediated NF-κB pathway. Accordingly, leonurine may serve as an effective drug in preventing and treating LPS induced endometritis. [ABSTRACT FROM AUTHOR]

HIPK2 is considered to be a tumor suppressor. It also has been implicated in several functions such as apoptosis and inflammation that are linked to spinal cord injury (SCI). However, whether HIPK2 ameliorates the neurological pain of SCI remains unclear. Here, we investigated the effects of HIPK2 on neurological function, oxidative stress, levels of inflammatory cytokines and expression of Bcl-2/Bax in an SCI model. Firstly, we evaluated the therapeutic effects of HIPK2 on neurological pain in the SCI rat using the Basso, Beattie and Bresnahan scores and H & E staining. Overexpression of HIPK2 significantly elevated the levels of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), and reduced the mRNA expression of Nogo-A and RhoA in SCI rats. Furthermore, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays showed that overexpression of HIPK2 significantly reduced the number of apoptotic cells. Overexpression of HIPK2 also decreased expression of Bax and Caspase-3 and elevated expression of Bcl-2 in the SCI model, indicating that HIPK2 exhibited its protective activity by inhibiting SCI-induced apoptosis. Then, we measured the serum concentrations of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX). We also determined the mRNA and protein levels of nuclear factor-κB p65 unit, tumor necrosis factor-α (TNF-α), and interleukin (IL)-1β. HIPK2 overexpression reduced oxidative stress and the levels of inflammatory cytokines compared with SCI control animals. Additionally, acetylation of HIPK2 was reduced in SCI rats. Overexpression of HIPK2 could enhance autophagy by elevating the expression of Beclin-1 and LC3-II while autophagy is regarded as a beneficial regulator to improve spinal cord injury. Together, overexpression of HIPK2 improved contusive SCI induced pain by modulating oxidative stress, Bcl‑2 and Bax signaling, and inflammation, and also regulating autophagy. [ABSTRACT FROM AUTHOR]

Sargassum serratifolium has been known to contain high concentration of meroterpinoids as anti-inflammatory compounds. We investigated the protective effects of the meroterpinoid-rich fraction of the ethanol extract from S. serratifolium (MES) on vascular inflammation using tumor necrosis factor (TNF)-α-induced human umbilical vein endothelial cells (HUVECs) and high cholesterol diet (HCD)-fed C57BL/6J mice. The in vitro results showed that MES inhibited the adhesion of monocytes to TNF-α-stimulated HUVECs by reduced levels of cell adhesion molecules, monocyte chemoattractant protein-1, and matrix metalloproteinase-9. Decreased levels of these proteins by MES were associated with down-regulated translocation of nuclear factor kappa B. Active compounds in MES were identified as sargahydroquinoic acid, sargacromenol and sargaquinoic acid based on the inhibition of adhesion molecules. In vivo study, MES supplementation remarkably decreased levels of vascular inflammatory proteins in serum and aorta tissue in HCD-fed mice. These results suggest that MES could be a potential supplement as an anti-atherogenic dietary agent for the prevention of atherosclerosis. [ABSTRACT FROM AUTHOR]

Astrocytes and microglia appear central to the initiation and progression of neuroinflammation in Alzheimer's disease (AD). In this study, inflammation was mimicked by Aβ 1–42 treatment of rat astrocytes (RA) and N9 microglia cell lines. Inflammation induced by Aβ 1–42 can be inhibited by pyrrolidine dithiocarbamic acid (PDTC), indicating that the NF-κB signal pathway is involved in inflammation. Then, the inhibitive effects of resveratrol (Res) on the inflammation in RA and N9 cells were assessed by observing the changes in inflammatory factors, chemokines, cell cycle and adhesion molecules on the cell surface. 17β-Estradiol was used as an estrogen-positive control because Res is one of the selective estrogen receptor modulators. In RA cells, TNF-α, IL-1β and MCP-1 in the supernatant and the proliferation index in the cell cycle were decreased by 5, 12.5, and 25 μM Res and 20 nM 17β-estradiol treatment 24 h before Aβ 1–42 . Similarly, in N9 microglial, the levels of IL-1β, IL-6 and NO in the supernatant and CD40 and MHCII in the 10, 20, and 40 μM Res and 20 nM 17β-estradiol treatment groups decreased markedly compared with the Aβ 1–42 treatment group. In addition, Res decreased the nuclear translocation of NF-κB/p65 when checked by immunofluorescence. Furthermore, Res increased the expression of NF-κB/p65 and decreased the expression of p-IκB in the cytoplasm in both RA and N9 microglia. Taken together, the present data indicate that Res reduces inflammation in RA and N9 microglia, and the anti-NF-κB signal pathway may be one of the target mechanisms. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD), which is characterized by chronic intestinal inflammation and leads to an increased risk of colon cancer. There are many studies using phyto-ingredients as a novel approach for the treatment of UC. The plant Andrographis paniculata (Acanthaceae) is a safe and edible vegetable that has been extensively adopted in traditional Chinese medicine for conditions involving inflammation, and the most active phytochemical agent is andrographolide. The andrographolide derivative 3,14,19-triacetyl andrographolide, which is known as CX-10 (a hemi chemical synthesized from andrographolide), has been found to possess strong anti-inflammatory properties. In the present study, we investigated the therapeutic potential of CX-10 as a complementary and alternative medicine against dextran sulphate sodium (DSS)-induced ulcerative colitis in mice. Our results revealed that CX-10 treatment reduced body weight loss, reduced colon length shortening, decreased colon weight, decreased the spleen index, decreased the disease activity index (DAI), and alleviated histological damage in the colon. The expression of TNF-α and IL-6 and the activity of myeloperoxidase (MPO) in colonic tissues were significantly reduced in CX-10 supplemented mice. It is noteworthy that the efficacy of 200 mg/kg of CX-10 was equivalent to that of the mesalazine positive control (200 mg/kg). Furthermore, western blot analysis revealed that CX-10 treatment reduced the expression of nuclear factor-κB (NF-κB) p65 and p-IκBα, increased the expression of IκBα and down-regulated the phosphorylation of p38 mitogen-activated protein kinase (MAPK), ERK and JNK. In conclusion, CX-10 treatment attenuated DSS-induced UC in mice through inhibiting the activation of NF-κB and MAPK pathways and reducing TNF-α and IL-6 levels, suggesting that CX-10 is a potential therapeutic drug for UC. [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used as the first-line treatment for advanced NSCLC; however, the efficacy of drug delivery remains unknown. Hence, we successfully developed erlotinib-conjugated iron oxide nanoparticles (FeDC-E NPs) as theranostic probe that can potentially provide a new avenue for monitoring drug delivering through noninvasive magnetic resonance imaging. MRI ΔR2* relaxivity measurements offer an opportunity to quantitatively evaluate the uptake of FeDC-E NPs at cellular and tumoral levels. Additionally, NF-κB reporter gene system provides NF-κB activation status monitoring to validate the therapeutic efficiency of FeDC-E NPs. FeDC-E NPs not only inhibit the tumor growth and NF-κB-modulated antiapoptotic mechanism but also trigger extrinsic and intrinsic apoptotic pathways. Taken together, dual functional FeDC-E NPs offer diagnostic and therapeutic benefits against lung cancers, indicating that our presented probe could be applied in clinical. [ABSTRACT FROM AUTHOR]

Bisphenol S (BPS) and bisphenol F (BPF) have been increasingly used as alternatives to bisphenol A (BPA) owing to health concerns. The present study aims to evaluate the impact of these two BPA analogs on oxidative stress and the immune system during zebrafish embryonic and larval development. Environmentally relevant levels of BPS and BPF exposure could increase reactive oxygen species (ROS) content, nitric oxide (NO) content, nitric oxide synthase (NOS) activity, and the expression of immunity-related genes in concentration dependent manners during the early developmental stages in zebrafish. At a concentration of 100 μg/L, BPS and BPF showed similar effects on the immune toxicity of zebrafish as that of BPA. Moreover, BPS and BPF induced both erα and nf-κb expression, and antagonists of estrogen receptor and NF-κB blocked the effects on immunity-related gene expression, providing evidence that the two pathways mediate the actions of BPS and BPF on fish immune response and functions. Thus we conclude that the presence of BPS and BPF in the environment, similar to BPA, may also pose risks to ecosystem and human health and cannot be widely used without limitations and precautions. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is an inflammatory lung disease caused by sepsis, infection, or ischemia-reperfusion. The receptor for advanced glycation end-products (RAGE) signaling pathway plays an important role in ALI. In this study, a novel RAGE-antagonist peptide (RAP) was produced as an inhibitor of the RAGE signaling pathway based on the RAGE-binding domain of high mobility group box-1 (HMGB1). Recombinant RAP was over-expressed and purified using nickel-affinity chromatography. In lipopolysaccharide- or HMGB1-activated RAW264.7 macrophage cells, RAP reduced the levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). RAP decreased the levels of cell surface RAGE and inhibited the nuclear translocation of nuclear factor-κB (NF-κB). These results imply that RAP decreases RAGE-mediated NF-κB activation and subsequent inflammatory reaction. For in vivo evaluation, RAP was delivered to the lungs of ALI-model animals via intratracheal administration. As a result, RAGE was down-regulated in the lung tissues by pulmonary delivery of RAP. Consequently, TNF-α, IL-6, and IL-1β were also reduced in broncoalveolar lavage fluid and the lung tissues of RAP-treated animals. Hematoxylin and eosin staining indicated that inflammation was decreased in RAP-treated animals. Collectively, these results suggest that RAP may be a useful treatment for ALI. [ABSTRACT FROM AUTHOR]

Aims: To investigate TAp63 expression in patients with type 2 diabetes mellitus (T2DM) and the potential correlations between TAp63 and proinflammatory cytokines production and other clinical parameters.Methods: Peripheral blood mononuclear cells (PBMCs) and plasma were collected from 72 T2DM (cases) and 72 healthy subjects (controls). Fasting blood glucose (FBG), fasting insulin (FIN) and a blood lipid profile were measured. The homeostasis model assessment (HOMA) was used to estimate insulin resistance (IR). Plasma tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were determined. PBMCs isolated from healthy subjects were cultured with or without 33.3 mmol/l glucose or 0.5 mmol/l palmitic acid (PA) for 6 h, 24 h, 48 h, and 72 h. The expression of TAp63 at mRNA and protein levels in PBMCs was analyzed using real-time qRT-PCR and western blots, respectively.Results: TAp63 expression was significantly lower in T2DM patients compared with that of the controls. In addition, TAp63 expression showed a negative correlation with FBG, FIN, HbA1c, HOMA-IR, FFAs, TNF-α, and IL-6 levels. Treatment with 33.3 mmol/l glucose or 0.5 mmol/l PA increased TAp63 expression in the cultured PBMCs.Conclusions: TAp63 level may be correlated with chronic inflammatory state and perturbed glucose and lipid metabolism in T2DM. [ABSTRACT FROM AUTHOR]

To investigate the immunostimulatory effects of chitosan sulfates, we prepared α- and β-chitosan sulfates with different molecular weights and compared their immunostimulatory activities in RAW 264.7 macrophages. Results suggest that β-chitosan sulfates were more active than α-chitosan in promoting nitric oxide (NO) production. Further study show that β-chitosan sulfate significantly promoted the production of NO, prostaglandin E 2 , tumor necrosis factor (TNF)-α, interleukin-6 and interleukin-1β at the levels of transcription and translation. Moreover, Western blots revealed that it induced the phosphorylation of p85 and Akt, and the nuclear translocation of p50/p65 and c-Fos/c-Jun. The luciferase activity of cells pretreated with β-chitosan sulfate further confirmed the nuclear translocation of p50/p65 and c-Fos/c-Jun. Determination of Toll-like receptor (TLR) 4 expression suggested that β-chitosan sulfate at least partly bound to TLR4. In conclusion, β-chitosan sulfates activate RAW 264.7 cells through the PI3K-Akt pathway, which is dependent on activator protein-1 and nuclear factor-κB activation. [ABSTRACT FROM AUTHOR]

Aims The present study aimed to investigate whether puerarin regulated tissue factor (TF) expression induced by oxidative low-density lipoprotein (ox-LDL), an independent risk factor for atherosclerosis, and its mechanisms. Main methods TF expression at the mRNA level was determined by reverse transcription-quantitative polymerase chain reaction, and its expression at the protein level, as well as other target proteins, was assessed by western blotting. Nitric oxide (NO) production was measured by a nitrate reduction method. Key findings Results demonstrated that treatment with ox-LDL (50 mg/l) for 24 h significantly increased ( P < 0.01) TF expression at the mRNA and protein levels in human umbilical vein endothelial cells (HUVECs). Such an ox-LDL exposure also triggered the dephosphorylation of Akt, resulting in a reduction of NO production and activated the extracellular signal-regulated kinase (ERK)1/2 and nuclear factor (NF)-κB signaling pathways. Pre-treatment with puerarin (50–200 μM) for 1 h significantly attenuated the ox-LDL-induced TF expression, augmented the phosphorylation of Akt, with a resultant increase of the NO production, and inhibited the activation of ERK1/2 and NF-κB ( P < 0.01). However, this beneficial effect of puerarin (100 μM) was abolished by LY294002 (10 μM), an inhibitor of phosphoinositide 3-kinase (PI3K), or NG-nitro-L-arginine methyl ester (100 μM), an inhibitor of NO synthase. Significance These results suggested that puerarin suppressed TF expression in HUVECs through activating the PI3K/Akt/endothelial nitric oxide synthase signaling pathway and inhibiting the activation of ERK1/2 and NF-κB. These findings suggested that puerarin possessed certain anticoagulation and may be a potential novel therapeutic drug for thrombosis in coronary artery disease. [ABSTRACT FROM AUTHOR]

Aims Cellular senescence and matrix metalloproteinases (MMPs) play an important role in liver diseases. The source and regulating factors of MMPs in senescent hepatocytes are not known. We investigated whether senescent hepatocytes secreted MMPs and if this was regulated by nuclear factor (NF)-κB. Materials and methods The TGF-α transgenic mouse hepatocyte line AML12 was treated with H 2 O 2 to induce senescence. NF-κB signaling was examined by Western blotting and luciferase reporter assays. Quantitative reverse transcription polymerase chain reaction was used to evaluated expression of MMP-2, -9 and -13. Key findings AML12 cells treated with H 2 O 2 showed the characteristic morphology of senescence. The activity of NF-κB and expression of MMP-2, -9 and -13 were increased in senescent AML12 cells. The NF-κB inhibitor BAY 11-7082 decreased the levels of MMPs. Significance These results suggest that senescent hepatocytes are involved in the pathology of liver diseases through remodeling the extracellular matrix. [ABSTRACT FROM AUTHOR]

Pinocembrin, one of the primary flavonoids in propolis, possesses many biological activities, including anti-inflammation, anti-oxidation and immunoregulation. This study aimed to evaluate whether pinocembrin could attenuate ovalbumin (OVA)-induced allergic airway inflammation in mice and to explore the possible mechanism. BALB/c mice sensitized and challenged with OVA were administered intraperitoneally with pinocembrin. Airway inflammation and airway hyperresponsiveness were examined. T-helper type (Th) 2 cytokines in bronchoalveolar lavage fluid (BALF) and OVA-specific immunoglobulin E (IgE) in serum were determined. The activation of nuclear factor kappa B (NF-κB) p65 were also measured. Our results showed that pinocembrin resulted in significant inhibition of pathophysiological signs of allergic asthma, including increased pulmonary eosinophilia infiltration, mucus hypersecretion and airway hyperresponsiveness (AHR). Treatment with pinocembrin significantly reduced Th2 cytokines interleukin (IL)-4, IL-5 and IL-13 in BALF, and OVA-specific IgE in serum. Moreover, pinocembrin treatment suppressed phosphorylation of inhibitor-κBα (IκBα) and NF-κB subunit p65 activation in lung tissue of OVA-sensitized mice. These data suggest that pinocembrin may inhibit allergic airway inflammation, and providing potential benefits in the treatment of inflammatory disease. [ABSTRACT FROM AUTHOR]

Aims Optic neuritis (ON) is an inflammatory disease of the optic nerve, which often occurs in patients with multiple sclerosis (MS) and leads to retinal ganglion cell (RGC) death and even severe visual loss. Valproic acid (VPA) is a short-chain branched fatty acid with anti-epileptic, neuro-protective and anti-inflammatory effects. Here, we examined the effects of VPA in experimental autoimmune encephalomyelitis (EAE) rats and explored the underlying mechanisms. Main methods EAE was induced by subcutaneous injection with myelin basic protein, emulsified with complete Freund’s adjuvant and Mycobacterium tuberculosis H37Ra into the Lewis rats. Subsequently, animals in the VPA groups were treated orally with VPA (250 or 500 mg/kg) once a day for 13 days. Key findings VPA treatment significantly attenuated inflammation and microgliosis in optic nerve in EAE-ON rats, as evidenced by the decrease in the mRNA levels of interferon (INF)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-17, and inducible nitric oxide synthase (iNOS), the suppression in nuclear factor (NF)-κB signal pathway as well as the down-regulation of CD11b expression in optic nerve. Additionally, the apoptotic RGCs were remarkably increased in the EAE retina, which was inhibited by VPA treatment. Consistent with the TUNEL staining, VPA administration also obviously suppressed the ratio of Bax: Bcl-2 and the expression of cleaved caspase-3 and PARP in optic nerve in EAE rats. Significance Our findings demonstrated that VPA treatment could prevent inflammation responses and RGC apoptosis in optic nerve in EAE-ON rats, suggesting that VPA may be available for optic nerve protection during ON. [ABSTRACT FROM AUTHOR]

Objective: Investigated the correlation of nuclear factor-κB, regulatory cells and transforming growth factor-β with rheumatoid arthritis. Methods: Included 65 cases of RA patients admitted in our hospital from June 2015 to December 2016 into case group, and included 50 healthy people into control group during the same period. Collected the peripheral detection of nuclear factor-κB, regulatory cells and transforming growth factor beta levels, and compared them between two groups. Results: The percentage of CD4 + , CD25 + T cells in the case group was significantly lower than that in the control group ( P  < .05); There was no significant difference in the percentage of CD4 + , CD25 + CD127 low/− , T cells between groups ( P  > .05); The levels of TGF - beta and NF - kappa B in the case group were higher than those in the control group, and the difference between the two groups was statistically significant ( P  < .05); The levels of ESR, CRP and RF in the case group were higher than those in the control group ( P  < .05). There was a negative correlation between the expression of nuclear factor-κB, transforming growth factor-β and RF level in RA patients by pearson correlation analysis, r = −0.652, P  < .05. Conclusion: The expression levels of CD4 + , CD25 + T cells in patients with RA are significantly decrease, which has a negative correlation with RA activity index RF, and showed that the pathogenesis of RA is related to the regulation of immune system. [ABSTRACT FROM AUTHOR]

Inflammation has been considered as a major risk factor for various kinds of human diseases. Macrophages play substantial roles in host defense against infection. It can be activated by lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria. The current study aims to investigate the anti-inflammatory effects of ethyl acetate fraction isolated from T. bellerica (EFTB) in LPS stimulated RAW 264.7 macrophage cell lines. The inhibitory effects of EFTB on total cyclooxygenase (COX), 5-lipoxygenase (5-LOX) activity, nitrate and inducible nitric oxide synthase (iNOS) level, reactive oxygen species (ROS) production were studied. The gene level expression of COX-2, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and Nuclear factor-κB (NF-κB) were also studied in LPS stimulated RAW 264.7 cells. EFTB (100 μg/mL) inhibited all inflammatory markers in dose dependent manner. Moreover, EFTB down regulated the mRNA expression of TNF-α, IL-6, COX-2 and NF-κB against LPS stimulation. Our results demonstrated that EFTB is able to attenuate inflammatory response possibly via suppression of ROS and NO species, inhibiting the production of arachidonic acid metabolites, proinflammatory mediators and cytokines release. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a life-threatening disease characterized by increased pulmonary vascular permeability because of alveolar capillary barrier dysfunction and increased immune responses. This study determined the anti-inflammatory effect of tyrosol on lipopolysaccharide (LPS)-induced ALI and its underlying mechanisms of action. BALB/c mice were orally administered with tyrosol (0.1, 1, and 10 mg/kg) 1 h before an intratracheal injection of LPS (25 μg/50 μL). Oral treatment with tyrosol inhibited lung vascular permeability, histopathological changes, wet/dry lung weight ratio, and pulmonary vascular cell infiltration. The LPS-induced imbalance in the activity of enzymes, such as superoxide dismutase and myeloperoxidase, was regulated by tyrosol. Pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, were reduced by tyrosol in bronchoalveolar lavage fluid and lung tissue. The activation of inflammatory molecules, including inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and phosphorylated-IκBα, was suppressed by the presence of tyrosol in the lung tissue. In addition, tyrosol attenuated the production of NO, the expression of pro-inflammatory cytokines, the expression of iNOS and COX-2, and the nuclear translocation of nuclear factor-κB in LPS-stimulated RAW 264.7 macrophages. These results suggested that tyrosol is a potential therapeutic agent for treating inflammatory lung diseases. [ABSTRACT FROM AUTHOR]

Osteoclasts are bone-resorbing cells that are derived from hematopoietic precursor cells and require macrophage-colony stimulating factor and receptor activator of nuclear factor-κB ligand (RANKL) for their survival, proliferation, differentiation, and activation. The binding of RANKL to its receptor RANK triggers osteoclast precursors to differentiate into osteoclasts. This process depends on RANKL-RANK signaling, which is temporally regulated by various adaptor proteins and kinases. Here we summarize the current understanding of the mechanisms that regulate RANK signaling during osteoclastogenesis. In the early stage, RANK signaling is mediated by recruiting adaptor molecules such as tumor necrosis factor receptor-associated factor 6 (TRAF6), which leads to the activation of mitogen-activated protein kinases (MAPKs), and the transcription factors nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). Activated NF-κB induces the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), which is the key osteoclastogenesis regulator. In the intermediate stage of signaling, the co-stimulatory signal induces Ca2+ oscillation via activated phospholipase Cγ2 (PLCγ2) together with c-Fos/AP-1, wherein Ca2+ signaling facilitates the robust production of NFATc1. In the late stage of osteoclastogenesis, NFATc1 translocates into the nucleus where it induces numerous osteo-clast-specific target genes that are responsible for cell fusion and function. [ABSTRACT FROM AUTHOR]

Background Retinal ischemia/reperfusion (I/R) injury is one of significant cause of visual dysopia and causes inflammatory response. Dexmedetomidine is widely applied to general/local anaesthesia and has been reported to have extensive anti-inflammatory effect. However, the role of dexmedetomidine in retinal I/R injury is currently unknown. This study investigates the effect of dexmedetomidine preconditioning on retinal I/R injury and explore the related signal mechanism toll-like receptor 4 (TLR4) pathway. Methods Retinal I/R injury model were established with SD rats through periocular injection. Retinal damage was quantified by measuring the thickness of retinal layers, cell counts of retinal ganglion cells (RGCs) and electroretinography (ERG). Apoptosis of retinal cell was detected by TUNEL assay. Protein and mRNA expression of glial fibrillary acidic protein (GFAP) were measured by western blot and real-time quantitate PCR. Bax, Bcl-2 and nuclear factor-κB (NF-κB) in retinas were detected by western blot. Results ERG and HE staining showed that dexmedetomidine preconditioning significantly inhibited the histologic damage induced by I/R injury, which expresses apparent concentration dependent. TUNEL demonstrated that apoptosis of retinal cells were reduced by dexmedetomidine. The expression of NF-κB and GFAP were decreased compared I/R blank group. Conclusion Dexmedetomidine preconditioning suppresses retinal I/R injury and shows effective anti-inflammatory effect by inhibiting TLR4/NF-κB expression. [ABSTRACT FROM AUTHOR]