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Organophosphorus flame retardants (OPFRs) can damage the brain and may cause abnormal behaviors. There was no population-based study to reveal the relationship between OPFRs and the occurrence of depression. This study utilized a publicly available database to investigate the correlation between OPFRs exposure and the risk of depression, and the mediation effect of inflammation on the correlation. Data in this study was from the database of the National Health and Nutrition Examination Survey. Multifactorial logistic regression was used to estimate the relationship between OPFRs exposure and the risk of depression, and a mediation effect model was constructed to explore the impact of inflammation on the correlation. Data of 1273 participants was included in the study. It was found that individuals with high urinary concentration of bis-(2-chloroethyl) phosphate had an increased risk of developing depression (OR = 1.217, 95 % CI: 1.032–1.435). Combined exposure to OPFRs was significantly associated with the increased risk of depression than single OPFRs exposure. Subgroup analyses based on inflammatory levels in the body revealed that inflammation might exert the mediation effect on the association between OPFRs exposure and the risk of depression, with the contribution proportion of 8.23 %. Cross-sectional data and rapid metabolism of OPFRs lead to uncertainty in revealing long-term exposure in the body. There was a correlation between OPFRs exposure and the risk of depression, which may be mediated by inflammation in the body to some extent. • OPFRs exposure is a risk factor for depression. • Combined exposure to OPFRs causes a higher risk of depression than single exposure. • The inflammatory status may be involved in the depression caused by OPFRs. [ABSTRACT FROM AUTHOR]

The liver serves as the central organ for lipid metabolism, making it a crucial component of chicken physiology. However, the intricate regulation of lipid absorption, synthesis, decomposition, and transport within the liver is influenced by various factors, such as environmental conditions, diet, and genetics. Recent research has suggested that numerous functional genes and transcription factors play a pivotal role in liver metabolism via different molecular mechanisms. In this study, we examined the transcriptomes of both healthy and fatty chicken livers to better understand the role of functional genes in chicken liver fat metabolism. Our bioinformatics analysis of RNA-seq data revealed differential expression of SLCO1B3 in healthy liver and fatty liver, with lower ex-pression levels observed in fatty liver. To further investigate the potential role of SLCO1B3 in liver metabolism, we conducted in vitro experiments to knock down its expression in primary hepatocytes. Our results indicated that SLCO1B3 could suppress lipogenesis, hepatocyte apoptosis, and inflammation. These findings provide insight into the molecular mechanism of SLCO1B3 as a functional gene capable of regulating fat metabolism in chicken liver, and may contribute to ad-dressing the issue of fatty liver in chicken. [ABSTRACT FROM AUTHOR]

Background/purpose: Rosacea has been linked to inflammatory bowel disease and small bowel bacterial overgrowth. We aimed to investigate the fecal microbial profiling and the potential gene functions between rosacea and non-rosacea subjects.Methods: A case-control study. Fecal microbiome and predicted genetic function inferred from high-throughput 16S ribosomal RNA sequencing were analyzed between rosacea (n = 11) and age-, gender- and body mass index-matched non-rosacea subjects (n=110). The correlation between altered microbiome as well as lifestyle and diet were also investigated.Results: A significant reduction of fecal microbial richness was found in rosacea patients. A distinct fecal microbial community structure was demonstrated in rosacea patients. The discriminating enriched genera in rosacea patients included Rhabdochlamydia, CF231, Bifidobacterium, Sarcina, Ruminococcus, belonging to the phylum of Chlamydiae, Bacteroidetes, Actinobacteria, and Lentisphaerae. The discriminating reduced abundant genera included Lactobacillus, Megasphaerae, Acidaminococcus, Hemophilus, Roseburia, Clostridium, belong to the phylum of Firmicutes; and Citrobacter, belonging to the phylum of Proteobacteria. The distinct fecal microbial composition might be related to sulfur metabolism, cobalamin, and carbohydrate transport.Conclusion: An altered fecal microbial richness and composition were observed in rosacea patients. The distinct microbial composition might be related to sulfur metabolism, cobalamin and carbohydrate transport. [ABSTRACT FROM AUTHOR]

Oxidative stress induces a senescence-associated secretory phenotype in chondrocytes. Hesperidin decreases mRNA levels of inflammatory mediators in H 2 O 2 -stimulated chondrocytes. Hesperidin modulates Foxo1, Foxo3 and Nrf2 signaling pathways to H 2 O 2 -exposed chondrocytes. Hesperidin enhances cellular antioxidant capacity. Excessive levels of oxidative stress can induce a senescence-associated secretory phenotype in chondrocytes which is characterized by the secretions of inflammatory mediators. Citrus flavonoid hesperidin (Hsd) is known to have anti-inflammatory and antioxidant capacities. Accordingly, we demonstrated the antioxidant property of Hsd against hydrogen peroxide (H 2 O 2)-induced oxidative stress damages to chondrocytes in this study. Primary human chondrocytes were cultured in media supplemented with Hsd (5, 10, 50 and 100 μM) to evaluate the dose-dependent cytotoxicity. Subsequently, cells were stimulated by H 2 O 2 and supplied with Hsd to study chondroprotective effects. Results showed that high-dose of Hsd (50 and 100 μM) has a deleterious effect on normal cells, whilst low Hsd (5 and 10 μM) supplements improved mitochondrial activity, cytotoxicity, proliferation kinetic, survival and cell senescence in H 2 O 2 -stimulated chondrocytes. Real-time PCR revealed that Hsd downregulated the mRNA levels of COX-2 , IL-1β , TNF-α , MMP-3 , MMP-9 , and upregulated IL-10 , TIMP-1 , SOX9. Western blotting further revealed that Hsd modulates Foxo1, Foxo3 and Nrf2 signaling pathways. Furthermore, Hsd improved total antioxidant capacity, and restored superoxide dismutases and glutathione peroxidase activities in H 2 O 2 -stimulated chondrocytes. In conclusion, our findings suggest that Hsd has the potential to improve antioxidant capacity in human chondrocytes. [ABSTRACT FROM AUTHOR]

In addition to airborne particulate matter (PM), exposure to spray paint PMs (SPPMs) may also be associated with pulmonary dysfunction. In this study, we employed human normal bronchial epithelial BEAS-2B cells to elucidate the association between pulmonary toxicity and different sizes of SPPMs (SPPM 10-3.2 , SPPM 3.2-1 and SPPM 1) under realistic environmental concentrations in a spray paint factory. Results indicated that all SPPMs (20–100μg/cm2) induced significant decreases in cell viability (> 70% compared to the control), except for low-dose SPPM 10-3.2 (20 and 50μg/cm2). Almost all SPPMs (20μg/cm2 and 100μg/cm2) induced oxidative stress (2–4 times that of the control), which increased the production of proinflammatory cytokines (1.5–4.5 times that of the control) as well as increased α1-antitrypsin expression (3–4.5 times that of the control). Moreover, we found that almost all SPPMs induced pulmonary epithelial barrier dysfunction (0.77–0.11 times that of the control) through the depletion of zonula occludens proteins (0.8–0.65 times that of the control). In conclusion, smaller SPPMs induced more severe adverse pulmonary adverse effects. Exposure to SPPM 1 was a potential major risk factor for pulmonary epithelial barrier dysfunction. Our evidence demonstrates that exposure to SPPMs, especially SPPM 1 , may increase the risk of pulmonary dysfunction. [ABSTRACT FROM AUTHOR]

Abstract Chronic stress can provoke depressive-like behaviors through activation of inflammation and apoptosis, leading to a reduction of neurons. Antidepressant therapy may contribute to inhibiting inflammation responses and have neuroprotective effects. Baicalin (BA) has an antidepressant effect in the chronic unpredictable mild stress (CUMS) animal model and exerts anti-inflammation, anti-apoptosis, as well as neuroprotective effects in many central nervous system (CNS)-related diseases. But the effects of BA on neuroprotection, apoptosis, and neuroinflammation and the potential mechanisms in depression are unclear. Here, we focused on examining the therapeutic effects of BA in CUMS-induced depression rats and investigating the molecular mechanisms. Results showed that administration of BA improved depressive-like behaviors and significantly increased the levels of doublecortin (DCX), Neuron-specific enolase (NSE), and Brain-derived neurotrophic factor (BDNF) in hippocampus. Furthermore, administration of BA increased the cell survival by reducing the level of malondialdehyde (MDA) and increasing the level of superoxide dismutase (SOD). Finally, administration of BA significantly decreased CUMS-induced apoptosis and inflammatory cytokines (caspase-1 and IL-1β) in hippocampus. These responses were mediated by Glycogen synthase kinase-3 (GSK3) β/Nuclear factor-κB (NF-κB)/Nucleotide-binding domain, leucine-rich repeat, pyrin domain containing protein 3 (NLRP3) signal pathway. Taken together, these results indicate that BA could promote neuronal maturation and rescue neurons from apoptosis via inhibiting activation of GSK3β/NF-κB/NLRP3 signal pathway that is known to be associated with inflammation, thus exerting neuroprotective effects and preventing CUMS-induced depressive-like behaviors. Highlights • CUMS procedure was used to establish a rat depression model. • Administration of BA improved the depressive-like behaviors. • Administration of BA protected hippocampal neurons. • Administration of BA decreased apoptosis and protected cells from oxidative stress. • BA ameliorated CUMS-induced neuroinflammation via inhibiting activation of GSK3β/NF-κB/NLRP3 signaling. [ABSTRACT FROM AUTHOR]

Abstract Background/Purpose Oral lichen planus (OLP) is a common chronic inflammatory disease characterized by a T cell-mediated immune response against epithelial cells. The epidemiological survey of OLP in Taiwanese population was scarce. In this study, we investigated the time trend of prevalence stratified by gender, age, urbanization, and income of OLP based on National Health Insurance Research Database (NHIRD). Materials and methods We studied the claims data of Taiwanese population from NHIRD 1996 to 2013. Patients with the diagnosis of OLP based on the International Classification of Diseases, Ninth Clinical Modification (ICD-9-CM) code: 697.0 were recruited in this study. Demographic characteristics were analyzed by multi-variate Poisson regression. Results The prevalence of OLP increased significantly from 1.3 (per 105) in 1996 to 12.8 (per 105) in 2013 (p for trend < 0.001). The prevalence was higher among female than male (RR: 2.13; 95% CI: 2.07–2.18, p < 0.001). The subjects living in suburban area had a lower risk of OLP than those living in urban area (RR: 0.80; 95% CI: 0.78–0.82, p < 0.001). The higher income group had higher risk of OLP compared with the lower income group (RR, 2.27; 95% CI, 2.17–2.36, p < 0.001). Conclusion The prevalence of OLP in Taiwan significantly increased over the past 18 years. The mean age with OLP was shown in an increased pattern. In addition, OLP occurs more frequently in women than in men. [ABSTRACT FROM AUTHOR]

Background Macrophage migration inhibitory factor (MIF) has been implicated in inflammation. We clarified whether serum MIF could be used as a marker of inflammation, brain damage and outcome after aneurysmal subarachnoid hemorrhage (aSAH). Methods Serum samples from 102 aSAH adults and 102 healthy controls were determined. The World Federation of Neurological Surgeons (WFNS) scale was used for neurological evaluation and radiological severity was estimated in accordance with the Fisher scale. Results Serum MIF, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and S100B concentrations were significantly higher in patients than in controls. Serum MIF concentrations correlated with WFNS scores and Fisher scores and serum concentrations of CRP, IL-6, TNF-α and S100B. Serum MIF was identified as an independent predictor for 6-month unfavorable outcome (defined as Extended Glasgow Outcome Scale score of 1–4). Area under receiver operating characteristic curve of serum MIF concentrations was similar to those of WFNS scores, Fisher scores and serum S100B concentrations and significantly exceeded those of serum CRP, IL-6 and TNF-α concentrations. Conclusions Serum MIF provides information about inflammation, brain injury severity and outcome after aSAH, which can be useful as a complement to clinical data. [ABSTRACT FROM AUTHOR]

Emodin is an anthraquinone derived from Chinese herb that exerts anti-inflammation effects. This study aimed to investigate whether emodin provides the protection for jejunum injury by inhibiting inflammation. We established a model of sepsis caused by cecal ligation and puncture. Forty-eight male Wistar rats were divided into four groups (n = 12). Jejunum injury was assessed by pathological examination. The activity of pJAK1/pSTAT3 and protein levels of Bcl-2 and Bax were detected by Western blot analysis. Inflammatory factors IL-6, TNF-α and procalcitonin were detected by ELISA. Apoptosis was detected by TUNEL. We found that emodin alleviated jejunum damage and apoptosis induced by sepsis and decreased the levels of IL-6, TNF-α and procalcitonin in septic rats. Furthermore, we observed that emodin increased the levels of pJAK1 and of pSTAT3, which were decreased in rats with sepsis. In addition, emodin enhanced the expression of Bcl-2 which was downregulated by sepsis and decreased the expression of Bax which was upregulated by sepsis. In conclusion, these results indicate that emodin suppresses inflammatory response induced by sepsis. Emodin activates JAK1/STAT3 signaling pathway and regulates Bcl-2 and Bax expression to protect the jejunum in rats with sepsis. [ABSTRACT FROM AUTHOR]

Probiotics are reported to provide protective health benefits against various disorders. In this study, we established a high-calorie diet animal model with a diet prepared by fortifying normal diet with soybean oil and condensed milk and the animals were supplemented with different dose of probiotic Lactobacillus reuteri GMNL-263(Lr263) for 8 weeks to investigate the protective function. We measured the lipid levels in plasma, liver and faecal; heart weight, function and collagen accumulation and biochemical markers of cardiac disease. Lr263 reversed high-calorie diet-induced cardiac weight gain, systolic malfunction and prevented heart inflammation by decreasing inflammation proteins NF-κB and COX-2. Moreover, Lr263 reduced cardiac eccentric hypertrophy and the levels of cardiac fibrosis markers CTGF and SP1 in high-calorie diet-fed rat hearts. Thus, Lr263 is considered as a functional food that provides anti-inflammatory, anti-hypertrophic, anti-fibrotic functions and identified specific biologic effects in reducing the characteristics of the high-calorie diet-induced progression to heart failure. [ABSTRACT FROM AUTHOR]

Bromodomains (BRDs) are evolutionarily conserved protein interaction modules that specifically recognise acetyl-lysine on histones and other proteins, facilitating roles in regulating gene transcription. BRD-containing proteins bound to chromatin loci such as enhancers are often deregulated in disease leading to aberrant expression of proinflammatory cytokines and growth-promoting genes. Recent developments targeting the bromo and extraterminal (BET) subset of BRD proteins demonstrated remarkable efficacy in murine models providing a compelling rationale for drug development and translation to the clinic. Here we summarise recent advances in our understanding of the roles of BETs in regulating gene transcription in normal and diseased tissue as well as the current status of their clinical translation. [ABSTRACT FROM AUTHOR]

Background Rosacea is a chronic inflammatory skin disease. Inflammation plays a prominent role in atherosclerosis and its complications. Objective We sought to investigate the associations of rosacea with cardiovascular disease risk factors and cardiovascular diseases from a nationwide population-based database. Methods A total of 33,553 patients with rosacea and 67,106 age- and gender-matched control subjects were identified from the National Health Insurance Research Database in Taiwan from 1997 to 2010. Multivariate logistic regressions were performed to compare the odds of comorbidities between the 2 groups. Results Dyslipidemia (odds ratio 1.41; 95% confidence interval 1.36-1.46), coronary artery disease (odds ratio 1.35, 95% confidence interval 1.29-1.41), and hypertension (odds ratio 1.17, 95% confidence interval 1.12-1.21) were significantly associated with rosacea. Coronary artery disease remained independently associated with rosacea after adjustment for hypertension, diabetes mellitus, and dyslipidemia. Male patients with rosacea had higher risks for all comorbidities than female patients with rosacea. Limitations The National Health Insurance Research Database does not contain information regarding rosacea subtypes or disease severity, or laboratory data. Conclusion Patients with rosacea are more likely to have dyslipidemia and hypertension. They are also at increased risk of coronary artery disease after adjustment for cardiovascular disease risk factors. [ABSTRACT FROM AUTHOR]

Background: 5-FU-induced intestinal mucositis (FUIIM) is a common gastrointestinal side effect of chemotherapy, leading to gastric pain in clinical cancer patients. In a previous study, we demonstrated that neutrophil elastase (NE) inhibitors could alleviate FUIIM and manipulate the homeostasis of the gut microbiota. The root of Melastoma malabathricum, also called Ye-Mu-Dan, has been used as a traditional Chinese medicine for gastrointestinal disease. Water extract of the roots of M. malabathricum exhibits an inhibitory effect on NE, with an IC50 value of 9.13 μg/ml.Purpose: In this study, we aimed to isolate an anti-NE compound from the root of M. malabathricum and to determine the protective effect of the bioactive component on a mouse model of FUIIM with respect to tissue damage, inflammation, intestinal barrier dysfunction, and gut microbiota dysbiosis.Methods: A water extract of the roots of M. malabathricum was prepared and its major bioactive compound, was identified using bioactivity-guided fractionation. The effects of samples on the inhibition of NE activity were evaluated using enzymatic assays. To evaluate the effects of the bioactive compound in an FUIIM animal model, male C57BL/6 mice treated with or without casuarinin (50 and 100 mg/kg/day, p.o.), and then received of 5-fluorouracil (50 mg/kg/day) intraperitoneally for 5 days to induce FUIIM. Histopathological staining was used to monitor the tissue damage, proliferation of intestinal crypts, and expression of tight junction proteins. The inflammation score was estimated by determining the levels of oxidative stress, neutrophil-related proteases, and proinflammatory cytokines in tissue and serum. The ecology of the gut microbiota was evaluated using 16S rRNA gene sequencing.Results: Casuarinin had the most potent and selective effect against NE, with an IC50 value of 2.79 ± 0.07 μM. Casuarinin (100 mg/kg/day, p.o.) significantly improved 5-FU-induced body weight loss together with food intake reduction, and it also significantly reversed villus atrophy, restored the proliferative activity of the intestinal crypts, and suppressed inflammation and intestinal barrier dysfunction in the mouse model of FUIIM. Casuarinin also reversed 5-FU-induced gut microbiota dysbiosis, particularly the abundance of Actinobacteria, Candidatus Arthromitus, and Lactobacillus murinus, and the Firmicutes-to-Bacteroidetes ratio.Conclusion: This study firstly showed that casuarinin isolated from the root part of M. malabathricum could be used as a NE inhibitor, whereas it could improve FUIIM by modulating inflammation, intestinal barrier dysfunction, and gut microbiota dysbiosis. In summary, exploring anti-NE natural product may provide a way to find candidate for improvement of FUIIM. [ABSTRACT FROM AUTHOR]

• Diabetes-induced organ damage is associated with altered immunophenotype. • Chlorpyrifos enhances hepatic infiltration of neutrophils and regulatory T cells. • Chlorpyrifos may promote apoptosis of T cells in the spleen. • Chlorpyrifos may impair the immunosuppressive ability of regulatory T cells. Hyperglycemia induces low-grade systemic inflammation and immune dysregulation, leading to overstated reactions to immune stimuli and diabetes-related organ damage. Tissue inflammation is characterized by leukocyte infiltration, and T cells play crucial roles in directing leukocyte-mediated inflammatory responses. The aim of the study was to investigate the effects of dietary exposure to chlorpyrifos (CPF) on systemic and hepatic immune-cell phenotypes in C57BL/6 mice with streptozotocin (STZ)-induced diabetes. Mice received an intraperitoneal injection of STZ for 5 consecutive days to induce diabetes, and diabetic mice were given either an AIN-93-based control diet or a CPF-containing diet at doses of 0.5, 1, or 2 mg/kg body weight/day for 28 days. Results showed that dietary exposure to CPF had no influence on the body weight or the erythrocyte hemoglobin A1c level in diabetic mice. Both blood and hepatic neutrophil populations were enhanced by CPF exposure. CPF-exposed groups had lower percentages of blood T cells without altering the proportions of CD4+ and CD8+ T-cell subsets, and lower expression levels of the Bcl-2 antiapoptotic gene in the spleen. CPF exposure reduced the percentage of blood regulatory T cells (Tregs); however, the Treg population was upregulated in the liver even when hepatic T cells were not affected by CPF in diabetic mice. Hepatic expressions of Treg-related genes were suppressed in all CPF-exposed groups. Higher plasma levels of aspartate aminotransferase and expression levels of the hepatic interleukin-1β gene were observed in diabetic mice exposed to medium and high doses of CPF. These findings suggest that dietary exposure to CPF affects the distribution of both myeloid and lymphoid immune cells in the blood and liver under hyperglycemic conditions, which may lead to hyperinflammation when encountering immune stimuli. [ABSTRACT FROM AUTHOR]

As microplastics (MPs) dispersed into the environment, people might be exposed to MPs. Most pollutants either pass through or concentrate in the kidney. Therefore, nephrotoxicity tests are needed to verify the toxic potential of MPs. Here we used human embryonic kidney 293 (HEK293) cells to determine the association between nephrotoxicity and round-shape polystyrene MPs (PSMPs) (3.54 ± 0.39 μ m) under realistic environmental exposure concentrations. Results revealed that PSMPs can adhere to the cell membrane and get entirely engulfed by HEK293 cells. PSMPs can induce cytotoxicity by oxidative stress via inhibition of the antioxidant haem oxygenase-1. Depolarisation of the mitochondrial membrane potential and formation of autophagosomes confirmed that apoptosis and autophagy can be simultaneously induced by PSMPs. The inflammatory factor was only activated (33 cytokines) by noncytotoxic concentration of PSMPs (3 ng/mL); however, the cytotoxic concentration (300 ng/mL) of PSMPs induced autophagy, which might further reduce NLRP3 expression, thus contributing to dampening inflammation (35 cytokines) in HEK293 cells. PSMPs (300 ng/mL) can impair kidney barrier integrity and increase the probability of developing acute kidney injury through the depletion of the zonula occludens-2 proteins and α1-antitrypsin. Altogether, our results demonstrated that environmental exposure to PSMPs may lead to an increased risk of renal disease. [Display omitted] • PSMPs can adhere to the cell membrane and be entirely engulfed by HEK293 cells. • PSMPs can induce cytotoxicity by ROS through the inhibition of antioxidant enzyme. • Apoptosis and autophagy can be simultaneously induced in HEK293 cells by PSMPs. • PSMP-induced autophagy can diminish inflammatory responses via NLRP-3 inhibition. • PSMPs can impair kidney barrier integrity and increase the risk of kidney injury. [ABSTRACT FROM AUTHOR]

Abstract: Contemporary pharmacological research has demonstrated that puerarin, the most important phytoestrogen extracted from Pueraria lobata(Willd.) Ohwi, has protecting functions on the cardiovascular system, nervous system, osteoporosis, liver injury, and inflammation in vivo and in vitro. Most of these research studies focused on inhibiting oxidative stress and apoptosis through regulating various bioactivators and signal pathways. Among these, superoxide dismutase (SOD), endothelial nitric oxide synthase (eNOS) and malondialdehyde (MDA), and PI3K/Akt, MAPK, and NF-κB are of great importance. The data cited in this review were mainly obtained from articles listed in PubMed and Elsevier SDOL published from 1959 to 2013, and the search term used was “puerarin”. [Copyright &y& Elsevier]

Abstract: Background: Deep venous thrombosis (DVT) and inflammation are two closely related entities. The objective of this study was to evaluate a possible association between interleukin-10 (IL-10) -1082A/G, -819C/T and -592C/A polymorphisms with DVT. Methods: A case-control study was carried out in 660 patients with DVT and 660 age- and gender-matched healthy controls. Polymerase chain reaction restriction fragment length polymorphism (PCR–RFLP) assay was applied to identify the polymorphisms mentioned. Results: Patients with DVT had a significantly lower frequency of IL-10 -1082GG genotype [odds ratio (OR)=0.59, 95% confidence interval (CI)=0.39, 0.89; P =0.01] than healthy controls. When stratifying by family history of DVT, it was found that patients with positive family history of DVT had a significantly lower frequency of IL-10 -1082GG genotype (OR=0.13, 95% CI=0.02, 0.95; P =0.04). When stratifying by smoking status, presence of varicose veins, type 2 diabetes mellitus and any hormone administration before, no significant differences were found in any groups. Conclusions: This study provides evidence that IL-10 -1082A/G polymorphism associated with risk of DVT. However, no association of the IL-10 -592C/A or -819C/T polymorphism with DVT risk was found. Additional well-designed large studies were required for the validation of our results. [Copyright &y& Elsevier]

Abstract: Inflammation and hepatic stellate cell (HSC) activation are the most crucial steps in the formation of hepatic fibrosis. Hepatocytes damaged by viral or bacterial infection, alcohol or toxic chemicals initiate an inflammatory response that activates collagen production by HSCs. Recent studies indicate curcumin has liver-protective effects due to its anti-inflammatory, antioxidant and anticancer activities; however, the mechanisms are not well understood. In this study, we show that curcumin protected against hepatic fibrosis in BALB/c mice in vivo by inhibiting HSC activation, inflammatory responses and inducing apoptosis of damaged hepatocytes. Using the thioacetamide (TAA)-induced hepatic fibrosis animal model, we found that curcumin treatment up-regulated P53 protein expression and Bax messenger RNA (mRNA) expression and down-regulated Bcl-2 mRNA expression. Together, these responses increased hepatocyte sensitivity to TAA-induced cytotoxicity and forced the damaged cells to undergo apoptosis. Enhancing the tendency of damaged hepatocytes to undergo apoptosis may be the protective mechanism whereby curcumin suppresses inflammatory responses and hepatic fibrogenesis. These results provide a novel insight into the cause of hepatic fibrosis and the cytoprotective effects curcumin has on hepatic fibrosis suppression. [Copyright &y& Elsevier]

Abstract: Tissue type plasminigen activator (t-PA) is one of the important proteolysis factors in the pathogenesis of pulpal inflammation. However, the mechanisms and signal transduction pathways involved in the production of t-PA in human pulp cells are not fully understood. The purpose of this study was to investigate the t-PA activity in human pulp cells stimulated with various pharmacological agents. IL-1α was used to evaluate t-PA activity in human pulp cells using casein zymography and enzyme-linked immunosorbent assay (ELISA). Furthermore, to search possible signal transduction pathways, p38 inhibitor SB203580, MEK inhibitor U0126, and phosphatidylinositaol 3-kinase (PI3K) inhibitor LY294002 were added to test how they modulated the t-PA activity. The main casein secreted by human pulp cells migrated at 70 kDa and represented t-PA. Secretion of t-PA was found to be stimulated with IL-1α during 2 day cultured period (p < 0.05). From the results of casein zymography and ELISA, SB203580, U0126, and LY294002 significantly reduced the IL-1α-stimulated t-PA production, respectively (p < 0.05). Our findings demonstrated that IL-1α enhance t-PA production in human pulp cells, and the signal transduction pathways p38, MEK, and PI3K are involved in the inhibition of t-PA. SB203580, U0126, and LY294002 suppress t-PA activity and may also have important implication for pharmacological intervention. [Copyright &y& Elsevier]

Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is a type II acute-phase protein; however, the role of pulmonary ITIH4 after exposure to air pollution remains unclear. In this study, we investigated the role of ITIH4 in the lungs in response to air pollution. ITIH4 expression in bronchoalveolar lavage fluid (BAL) of 47 healthy human subjects and of Sprague-Dawley rats whole-body exposed to air pollution was determined, and the underlying antiapoptotic and matrix-stabilizing pathways in alveolar epithelial A549 cells induced by diesel exhaust particles (DEPs) as well as ITIH4-knockdown were investigated. We found that an interquartile range (IQR) increase in PM 2.5 was associated with a decrease of 2.673 ng/mL in ITIH4, an increase of 1.104 pg/mL of 8-isoprostane, and an increase of 6.918 pg/mL of interleukin (IL)-6 in human BAL. In rats, increases in 8-isoprostane, IL-6, and p53 and a decrease in sirtuin-1 (Sirt1) in the lungs and decreases in ITIH4 in the BAL, lungs, and serum were observed after PM 2.5 and gaseous exposure. ITIH4 levels in lung lysates were correlated with levels in BAL samples (r = 0.377, p < 0.01), whereas ITIH4 levels in BAL were correlated with IL-6 levels (r = −0.420, p < 0.01). ITIH4 expression was significantly reduced in alveolar epithelial A549 cells by DEP in a dose-dependent manner. A decrease in Sirt1 and increases in phosphorylated extracellular signal-regulated kinase (p-ERK) and caspase-3 were observed after DEP exposure and ITIH4-knockdown. In conclusion, air pollution decreased ITIH4 expression in the lungs, which was associated with alveolar epithelial cell senescence and apoptosis. ITIH4 could be a vital protein in regulating alveolar cell destruction and its inhibition after exposure to air pollution. [Display omitted] • PM 2.5 was associated with an ITIH4 deficiency in the lungs. • Decrease of ITIH4 by PM 2.5 presented in alveolar epithelial cells of rats. • Loss of ITIH4 activated apoptosis and senescence in alveolar epithelial cells. • ITIH4 may be a specific protein in response to PM 2.5 in alveolar epithelium. Capsule of main finding : The significance and novelty of this study are that ITIH4 regulates alveolar cell destruction by air pollution and thus could be an indicator of lung injury due to air pollution. [ABSTRACT FROM AUTHOR]

To investigate the improvement and mechanisms of silymarin on renal injury in mouse podocytes and streptozotocin (STZ)-induced diabetic nephropathy model (DN) rats. Firstly, the effects of silymarin on the cell viability and cellular injury-related indicators of high-glucose incubated mouse podocytes MPC-5 were assessed by CCK-8 and western blotting (WB) methods, respectively. The STZ-induced diabetic rats with DN were treated with silymarin nanoliposomes at three doses for consecutive 8-week. General metabolic indicators, renal functions and lipid accumulation-related factors were all measured. The renal tissue sections were stained and observed via hematoxylin-eosin (H&E) staining method. Real-time RT-PCR and WB methods were utilized to measure the expression of JAK2/STAT3/SOCS1 and TGF-β/Smad signaling pathway related factors. Silymarin significantly improve the high-glucose induced up-regulation of podoxin and nephrin, as well as the expression of inflammatory cytokines IL-6, ICAM-1 and TNF-α, and the cell survival rates were also significantly increased in a dose-dependent manner. Significant improvement on body weight/kidney ratio, renal functions and lipid profiles in renal tissues were observed in STZ-induced diabetic rats after chronic silymarin treatment. The H&E staining exhibited that the pathological damages in renal tissues were obviously improved. Moreover, silymarin nanoliposomes treatment notably suppressed expression levels of inflammation-related proteins as well as IL-6 and ICAM-1, and regulated JAK2/STAT3/SOCS1 and TGF-β/Smad signaling pathway, thereby exhibited protective effects on kidney of DN model rats. Silymarin nanoliposomes ameliorate STZ-induced kidney injury by improving oxidative stress, renal fibrosis, and co-inhibiting JAK2/STAT3/SOCS1 and TGF-β/Smad signaling pathways in diabetic rats. [ABSTRACT FROM AUTHOR]

Maternal hypercholesterolemia induces early onset of cardiovascular diseases in offspring; however, its underlying mechanism remains poorly understood. We hypothesized that maternal hypercholesterolemia increases offspring susceptibility to atherosclerosis in adulthood through developmental modifications of macrophages. Female apolipoprotein E (ApoE)-deficient mice were fed a Western-type diet (WD) or a control diet (CD) prior to and throughout gestation and lactation. The offspring were all fed a WD after weaning. Sixteen-week-old female offspring of WD-fed dams showed a significant increase in atherosclerotic lesions of the aorta and aortic root compared with those of CD-fed dams. This effect was associated with increased macrophage accumulation within lesions, macrophage inflammation and an increase in circulating Ly6Chigh monocyte and F4/80 macrophage counts. We further evidenced that in utero WD exposure promoted macrophage polarization toward the M1 phenotype by elevating M1 markers (Cd86, Inos/Nos2) without affecting M2 markers (Cd206, Arg1). Proinflammatory cytokine synthesis was also enhanced in response to LPS. Finally, maternal WD intake strongly inhibited the macrophage expression of Pparg and Lxra, which was associated with aberrant DNA methylation of Lxra promoter. Our findings demonstrate that maternal hypercholesterolemia exacerbates atherosclerosis, in part by altering the epigenetic state of the macrophage genome of the offspring, imprinting gene expression, and changing macrophage polarization, which ultimately contributes to plaque macrophage burden. [ABSTRACT FROM AUTHOR]

HKUST-1 is currently studied for a very diverse range of applications. Despite its exciting potential, significant concerns remain regarding the safety of HKUST-1. Therefore, human embryonic kidney 293 (HEK293) cells were used to verify the renal toxicity of HKUST-1. In this study, HKUST-1 induced concentration-dependent cytotoxic effects in HEK293 cells. The depolarization of mitochondrial membrane potential and formation of apoptotic bodies and autophagic vesicles were observed in HKUST-1–treated HEK293 cells. Oxidative (oxidative stress and haem oxygenase-1 activation) and inflammatory responses (NF-κB and NLRP3 activation) in HEK293 cells were induced by HKUST-1 exposure. In addition, the observed reduction in NAD(P)H levels in HKUST-1–treated HEK293 cells may be attributable to PARP-1 activation following DNA single- and double-strand breaks. The HKUST-1–induced depletion of zonula occludens proteins in HEK293 cells might lead to altered renal barrier integrity. The variations of α1-antitrypsin, oxidised α1-antitrypsin and NLRP3 protein expression in HEK293 cells suggested that HKUST-1 increases the risk of chronic kidney diseases. However, most of these adverse effects were significantly induced only by high HKUST-1 concentration (100 μg/mL), which do not reflect the actual exposure. Thus, the toxic risk of HKUST-1 appears to be negligible. Image 1 • HKUST-1 induces apoptosis and autophagy in HEK293 cells. • HKUST-1 decreases intracellular NAD(P)H due to DNA strand breaks in HEK293 cells. • HKUST-1 is associated with impaired renal barrier by depleting ZO proteins. • HKUST-1 increases the risk for chronic kidney disease. • Almost all of these adverse responses were induced by high level of HKUST-1. [ABSTRACT FROM AUTHOR]

• Citicoline promotes random skin flap survival in rats. • Citicoline upregulates VEGF expression, stimulates angiogenesis and improves the blood supply. • Citicoline reduces tissue inflammation, antagonizes tissue lipid peroxidation, and inhibits flap ischemia reperfusion injury. Medical therapy for flap survival has been extensively investigated. In this study, we explored the effect of citicoline (CDP-choline, CDPC), used for clinical treatment of cerebral trauma, on random skin flap survival in rats. Sixty rats were divided into three groups: low-dose (CDPC-L), high-dose (CDPC-H), and control. The CDPC-L and CDPC-H groups were intraperitoneally injected with 100 mg/kg and 300 mg/kg CDPC every day, respectively; the control group was injected with an equivalent volume of normal saline. The survival region was assessed on the 7th day after the flap operation. The microvascular density and neutrophil density were measured by hematoxylin and eosin staining. Lead angiography was used to detect angiogenesis, and laser Doppler was used to detect blood perfusion. Expression levels of vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, Toll-like receptor (TLR) 4, and nuclear factor kappa B (NF-κB) were detected by immunohistochemistry. Malondialdehyde and superoxide dismutase were used to determine the lipid peroxidation level. The average survival region of the flap was significantly larger in the CDPC-H group than in CDPC-L and control groups, with less ischemic necrosis. VEGF expression, microvascular density, angiogenesis, blood perfusion, and superoxide dismutase in the flap were higher in the CDPC-H group than in the CDPC-L and control groups. In addition, levels of neutrophil density, IL-1β, IL-6, TNF-α, TLR4, NF-κB, and malondialdehyde decreased significantly in the CDPC-H group. High-dose CDPC injection after a random flap operation is beneficial for flap survival. [ABSTRACT FROM AUTHOR]

Diet-induced obesity is the most widely used animal model for studying nonalcoholic fatty liver disease (NAFLD). However, the physiological effects of a high-fat diet (HFD) are inconsistent between different studies. To elucidate this mystery, mice raised with conventional (CONV), specific pathogen-free (SPF) and gentamicin (G) treatments and fed with standard diet (STD) or HFD were analyzed in terms of their physiology, gut microbiota composition, hepatic steatosis and inflammation. Serum biochemistry showed increased levels of cholesterol and aspartate aminotransferase in the G-STD and CONV-HFD groups, respectively. The CONV-HFD group exhibited more inflammatory foci compared to the SPF-HFD and G-HFD groups. Furthermore, immunohistochemistry staining revealed the infiltration of Kupffer cells in the liver, consistent with increased mRNA levels of MCP-1, CD36 and TLR4. Principal coordinate analysis and the cladogram of LEfSe showed that the distinguished clusters of gut microbiota were dependent on housing conditions. The Rikenellaceae, F16 and Desulfovibrionaceae were strongly correlated with hepatic inflammation. Otherwise, higher NAFLD activity score correlated with altered relative abundances of Bacteroidetes and Firmicutes. In conclusion, gut microbiota varying with housing condition may be pivotal for the host response to HFD. [ABSTRACT FROM AUTHOR]

Thyroid hormone, L-thyroxine (T 4), induces inflammatory genes expressions and promotes cancer growth. It also induces expression of the checkpoint programmed death-ligand 1 (PD-L1), which plays a vital role in cancer progression. On the other hand, resveratrol inhibits inflammatory genes expressions. Moreover, resveratrol increases nuclear inducible cyclooxygenase (COX)-2 accumulation, complexes with p53, and induces p53-dependent anti-proliferation. In this study, we investigated the effect of T 4 on resveratrol-induced anti-proliferation in oral cancer. T 4 increased the expression and cytoplasmic accumulation of PD-L1. Increased expressions of pro-inflammatory genes, interleukin (IL) -1β and transforming growth factor (TGF) -β1 , were shown to stimulate PD-L1 expression. T 4 stimulated pro-inflammatory and proliferative genes expressions, and oral cancer cells proliferation. In contrast, resveratrol inhibited those genes and activated anti-proliferative genes. T 4 retained resveratrol-induced COX-2 in cytoplasm and prevented COX-2 nuclear accumulation when resveratrol treated cancer cells. A specific signal transducer and activator of transcription 3 (STAT3) inhibitor, S31-201, blocked T 4 -induced inhibition and restored resveratrol-induced nuclear COX-2 accumulation. By inhibiting the T 4 -activated STAT3 signal transduction axis with S31-201, resveratrol was able to sequentially reestablish COX-2/p53-dependent gene expressions and anti-proliferation. These findings provide a novel understanding of the inhibitory effects of T 4 on resveratrol-induced anticancer properties via the sequential expression of PD-L1 and inflammatory genes. [ABSTRACT FROM AUTHOR]

Abstract: The matrix metalloproteinases (MMPs) participate in a wide variety of extracellular matrix degradation. Detailed knowledge of MMPs may be important for understanding the pathogenesis of pulpal inflammation. The purpose of this study was to compare MMP-9 expression in clinically healthy human pulp and inflamed human pulp tissue specimens. We compared the levels of MMP-9 between clinically healthy pulp and inflamed pulp tissues by using the semi-quantitative reverse-transcriptase polymerase chain reaction analysis. In addition, immunohistochemistry was used to identify the in situ localization of MMP-9 expression in pulp specimens. MMP-9 mRNA gene was found to be increased in inflamed pulps as compared with clinically healthy pulp tissues (p < 0.05). The results from immunohistochemistry demonstrated that MMP-9 expression was significantly higher in the inflamed pulps than clinically healthy pulps (p < 0.05). MMP-9 stain was detected in the odontoblasts, fibroblasts, inflammatory infiltrates, and endothelial cells. Taken together, MMP-9 may play an important role in the pathogenesis of pulpal inflammation. [Copyright &y& Elsevier]

Chronic diabetic wounds pose a serious threat to human health and safety because of their refractory nature and high recurrence rates. The formation of refractory wounds is associated with wound microenvironmental factors such as increased expression of proinflammatory factors and oxidative stress. Bilirubin is a potent endogenous antioxidant, and morin is a naturally active substance that possesses anti-inflammatory and antioxidant effects. Both hold the potential for diabetic wound treatment by intervening in pathological processes. In this study, we developed bilirubin/morin-based carrier-free nanoparticles (BMn) to treat chronic diabetic wounds. In vitro studies showed that BMn could effectively scavenge overproduced reactive oxygen species and suppress elevated inflammation, thereby exerting a protective effect. BMn was then loaded into a collagen/polyvinyl alcohol gel (BMn@G) for an in vivo study to maintain a moist environment for the skin and convenient biomedical applications. BMn@G exhibits excellent mechanical properties, water retention capabilities, and in vivo safety. In type I diabetic mice, BMn@G elevated the expression of the anti-inflammatory factor IL-10 and concurrently diminished the expression of the proinflammatory factor TNF-α in the tissues surrounding the wounds. Furthermore, BMn@G efficiently mediated macrophage polarization from the M1-type to the M2-type, thereby fostering anti-inflammatory effects. Additionally, BMn@G facilitated the conversion of type III collagen fiber bundles to type I collagen fiber bundles, resulting in a more mature collagen fiber structure. This study provides a promising therapeutic alternative for diabetic wound healing. [ABSTRACT FROM AUTHOR]

• Serum sTREM-1 levels are significantly raised after ICH. • Serum sTREM-1 levels are highly correlated with severity of ICH. • Serum sTREM-1 levels are tightly correlated with degree of inflammation after ICH. • Serum sTREM-1 levels are independently associated with early neurologic deterioration after ICH. • Serum sTREM-1 levels are independently associated with functional outcome after ICH. Triggering receptor expressed on myeloid cells-1 (TREM-1) participates in neuroinflammation. We intended to ascertain whether serum soluble TREM-1 (sTREM-1) could be utilized as a biomarker of inflammation, severity, early neurologic deterioration (END) and outcome after primary intracerebral hemorrhage (ICH). Serum sTREM-1 levels were gauged in 104 ICH patients and 104 healthy controls. END was diagnosed when the National Institutes of Health Stroke Scale (NIHSS) score increased ≥ 4 points or death between admission and 24 h after admission. Patients with a modified Rankin scale score of > 2 at 3 months were considered to have poor outcome. As compared to controls, patients exhibited significantly elevated serum sTREM-1 levels (median: 309.0 vs 67.9 pg/ml). Serum sTREM-1 concentrations were intimately correlated with NIHSS score (r = 0.574), hematoma volume (r = 0.554), blood leukocyte count (r = 0.529) and serum C-reactive protein concentrations (r = 0.509). Serum sTREM-1 concentrations > 309.0 pg/ml independently predicted END and poor outcome with odds ratio values of 4.054 and 4.721 respectively. Serum sTREM-1 concentrations distinguished END and poor outcome with areas under receiver operating characteristic curve of 0.789 and 0.813 respectively. Serum sTREM-1 may represent a promising inflammatory biomarker for assessment of severity and prediction of END and poor outcome after ICH. [ABSTRACT FROM AUTHOR]

Abstract: Cardiomyocyte stretching has been reported to be a major trigger for brain natriuretic peptide (BNP) release; however, an increase in circulating BNP is observed in patients with acute myocardial ischemia in the absence of increased left ventricular wall stress or cardiomyocyte stretching. In the present study, to investigate the direct and independent effects of acute myocardial ischemia on BNP expression and its mechanism, we established an in vitro glucose-free ischemia and hypoxia injured model of cultured rat cardiomyotes and proved hypoxia upregulated expressions of interleukin-6(il-6) and BNP. Further treatment with il-6 elicited dose- and time-dependent increases in BNP mRNA and protein expression as well as an upregulation in transforming growth factor-β1 (TGF-β1)/Smad2 expression, which was partially suppressed by a neutralizing antibody. In conclusion, our study showed that acute myocardial ischemia can directly upregulate BNP expression at the translational and transcriptional levels through the action of il-6, and this process is associated with the upregulation of TGF-β1/Smad2 signal path. [Copyright &y& Elsevier]

• Polystyrene microplastics (PS-MPs) cause pulmonary cytotoxicity by inducing ROS. • PS-MPs is associated with impaired pulmonary barrier by depleting ZO proteins. • PS-MPs inhalation increases the risk for chronic obstructive pulmonary disease. Microplastics (MPs) have become a global environmental concern. Recent studies have shown that MPs, of which the predominant type is often polystyrene (PS; known as PS-MPs), can extend to and affect remote, sparsely inhabited areas via atmospheric transport. Although exposure to inhaled MPs may induce lung dysfunction, further experimental verification of the pulmonary toxic potential of MPs and the mechanism underlying the toxicity is needed. Here we used normal human lung epithelial BEAS-2B cells to clarify the association between pulmonary toxicity and PS-MPs. Results revealed that PS-MPs can cause cytotoxic and inflammatory effects in BEAS-2B cells by inducing reactive oxygen species formation. PS-MPs can decrease transepithelial electrical resistance by depleting zonula occludens proteins. Indeed, decreased α1-antitrypsin levels in BEAS-2B cells suggest that exposure to PS-MPs increases the risk for chronic obstructive pulmonary disease, and high concentrations of PS-MPs can induce these adverse responses. While low PS-MP levels can only disrupt the protective pulmonary barrier, they may also increase the risk for lung disease. Collectively, our findings indicate that PS-MP inhalation may influence human respiratory health. [ABSTRACT FROM AUTHOR]

The obesity-regulated gene, leptin, is essential for diet. Leptin resistance causes obesity and related diseases. Certain types of diet are able to decrease leptin resistance. However, leptin has been shown to be correlated with inflammation and stimulate proliferation of various cancers. Two synthetic leptin derivatives (mimetics), OB3 and [D-Leu-4]-OB3, show more effective than leptin in reducing obesity and diabetes in mouse models. OB3 inhibits leptin-induced proliferation in ovarian cancer cells. However, effects of these mimetics in hepatocellular carcinoma (HCC) have not been investigated. In the present study, we examined the effects of OB3 and [D-Leu-4]-OB3 on cell proliferation and gene expressions in human HCC cell cultures. In contrast to what was reported for leptin, OB3 and [D-Leu-4]-OB3 reduced cell proliferation in hepatomas. Both OB3 and [D-Leu-4]-OB3 stimulated expression of pro-apoptotic genes. Both compounds also inhibited expressions of pro-inflammatory, proliferative and metastatic genes and PD-L1 expression. In combination with leptin, OB3 inhibited leptin-induced cell proliferation and expressions of pro-inflammation-, and proliferation-related genes. Furthermore, the OB3 peptide inhibited phosphoinositide 3-kinase (PI3K) activation which is essential for leptin-induced proliferation in HCC. These results indicate that OB3 and [D-Leu-4]-OB3 may have the potential to reduce leptin-related inflammation and proliferation in HCC cells. • OB3 and [D-leu-4]-OB3 derivatives of leptin stimulated expression of pro-apoptotic genes and inhibited PD-L1 expression. • OB3 and [D-leu-4]-OB3 inhibited gene expression of genes involved in pro-inflammation, proliferation and metastasis. • OB3 inhibited leptin-induced proliferation and expressions of pro-inflammation-, and proliferation-related genes in HCC. • OB3 peptide inhibited phosphoinositide 3-kinase (PI3K) activation which is essential for leptin-induced proliferation. • OB3 and [D-Leu-4]-OB3 may have the potential to inhibit leptin-related inflammation and proliferation. [ABSTRACT FROM AUTHOR]

To explore how hypochlorous acid (HClO) affects human health, a highly sensitive, selective, and trace detection method for hypochlorite (ClO−) is crucial for determining its non-negligible function in both environment and living systems. Herein, a dicyanoisophorone-phenylboronic acid-based novel ratiometric near-infrared fluorescent probe (Probe 1) was designed for the rapid and specific detection of ClO− based on the intramolecular charge transfer (ICT) mechanism. Excess addition of HClO to the Probe 1 solution, 186-times ratio (I 652 / I 582) augment were gained. And this probe provided a colorimetric and ratiometric fluorescence response to ClO− with a high selectivity, a rapid response (within 30 s), and had an extremely low detection limit (15.7 nM). In addition, owing to the good sensing properties and low cytotoxicity of Probe 1 , it can be used to expediently visualize exogenous ClO− in HepG2 cells and endogenous ClO− in RAW264.7 macrophage cells. Furthermore, the probe was successfully used for the bioimaging of zebrafish with an acute inflammation. Thus, Probe 1 is a promising vehicle to identify the level of HClO in animals with associated diseases. A new ratiometric and colorimetric NIR fluorescent probe (Probe 1) for the specific detection of ClO− has been designed and synthesized on the basis of dicyanoisophorone-phenylboronic acid. And it was endowed with the following outstanding advantages: one-step synthesis, a long-wavelength emission, naked-eye assay, ratio fluorescent dual-channel detection, and feasibility in living cells and zebrafish. Image 1 • A new ratiometric dicyanoisophorone fluorescent Probe 1 was synthesized. • Probe 1 displays high selectivity and sensitivity to ClO− over other relevant ROS and common ions. • Probe 1 responses quickly to ClO− through distinct color change and ratiometric fluorescence variation. • Probe 1 has low cytotoxicity and is applicable for ClO− detection in living cells. • Probe 1 is successfully used for the detection of endogenous and exogenous ClO− in zebrafish. [ABSTRACT FROM AUTHOR]

Asthma is a chronic airway inflammatory disease. Current treatment of mainstream medications has significant side effects. There is growing evidence that the refractoriness of asthma is closely related to common changes in the lung and intestine. The lungs and intestines, as sites of frequent gas exchange in the body, are widely populated with gas signaling molecules NO and CO, which constitute NO–CO metabolism and may be relevant to the pathogenesis of asthma in the lung and intestine. The Chinese herbal formula Tingli Dazao Xiefei Decoction (TD) is commonly used in clinical practice to treat asthma with good efficacy, but there are few systematic evaluations of the efficacy of asthma on NO–CO metabolism, and the mode of action of its improving effect on the lung and intestine is unclear. To investigate the effect of TD on the lung and intestine of asthmatic rats based on NO–CO metabolism. In vivo , we established a rat asthma model by intraperitoneal injection of sensitizing solution with OVA atomization, followed by intervention by gavage administration of TD. We simultaneously examined alterations in basal function, pathology, NO–CO metabolism, inflammation and immune cell homeostasis in the lungs and intestines of asthmatic rats, and detected changes in intestinal flora by macrogenome sequencing technology, with a view to multi-angle evaluation of the treatment effects of TD on asthmatic rats. In vitro , lung cells BEAS-2B and intestinal cells NCM-460 were used to establish a model of lung injury causing intestinal injury using LPS and co-culture chambers, and lung cells or intestinal cells TD-containing serum was administered to intervene. Changes in inflammatory, NO–CO metabolism-related, cell barrier-related and oxidative stress indicators were measured in lung cells and intestinal cells to evaluate TD on intestinal injury by way of amelioration and in-depth mechanism. In vivo , our results showed significant basal functional impairment in the lung and intestine of asthmatic rats, and an inflammatory response, immune cell imbalance and intestinal flora disturbance elicited by NO–CO metabolic disorders were observed (P < 0.05 or 0.01). The administration of TD was shown to deliver a multidimensional amelioration of the impairment induced by NO–CO metabolic disorders (P < 0.05 or 0.01). In vitro , the results showed that LPS-induced lung cells BEAS-2B injury could cause NO–CO metabolic disorder-induced inflammatory response, cell permeability damage and oxidative stress damage in intestinal cells NCM-460 (P < 0.01). The ameliorative effect on intestinal cells NCM-460 could only be exerted when TD-containing serum interfered with lung cells BEAS-2B (P < 0.01), suggesting that the intestinal ameliorative effect of TD may be exerted indirectly through the lung. TD can ameliorate NO–CO metabolism in the lung and thus achieve the indirectly amelioration of NO–CO metabolism in the intestine, ultimately achieving co-regulation of lung and intestinal inflammation, immune imbalance, cellular barrier damage, oxidative stress and intestinal bacterial disorders in asthma in vivo and in vitro. Targeting lung and intestinal NO–CO metabolic disorders in asthma may be a new therapeutic idea and strategy for asthma. Tingli Dazao Xiefei Decoction can ameliorate lung and intestinal inflammation, immune imbalance, cellular barrier damage, oxidative stress and intestinal bacterial disorders caused by asthma through addressing NO-CO metabolic disorders, and its ameliorating effect on intestinal damage is indirectly through the lung. This suggests that targeting lung and intestinal NO-CO metabolic disorders in asthma may be a new therapeutic idea and strategy for asthma. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Our previous studies have shown that recombinant human phospholipase D2 (rhPLD2) plays a modulator role on NF-κB and PKC signaling pathways. It also inhibits IL-5-induced inflammatory response in chronic asthmatic guinea pigs. Additionally, increasing evidence also has revealed that the adoptive transfer of induced regulatory T cells (Tregs) may be a therapeutic solution to airway allergic diseases. To investigate the epigenetic, transcriptomic and phenotypic variability of Treg population in an ovalbumin (OVA)-induced airway inflammation model derived from the induction of rhPLD2, OVA-induced asthmatic murine model is used in this study. The lung inflammation, eosinophil infiltration, the differentiation and proliferation of T helper cells and the amplification of Tregs were examined in this mouse model with and without rhPLD2 induction. Our data showed that rhPLD2 administration in asthmatic mice significantly increases CD4+CD25+ Foxp3+ Treg cell numbers and alleviates lung inflammation. The addition of rhPLD2 in vitro enhanced the demethylation of Treg-specificdemethylated region (TSDR) in iTregs, suggesting that rhPLD2 protein may be involved in improving the quality and quantity of Treg cells that eventually significantly reduces lung inflammation in asthmatic murine model. These results suggest that rhPLD2 could have a clinical impact treating patients with allergic airway inflammation via promoting and stabilizing iTreg differentiation and function. [ABSTRACT FROM AUTHOR]

The choroid plexus is able to modulate the cognitive function, through changes in the neuroinflammatory response and in brain immune surveillance. However, whether lycopene is involved in inflammatory responses at the choroid plexus in the early stages of Alzheimer's disease, and its molecular underpinnings are elusive. In this rat study, lycopene was used to investigate its protective effects on inflammation caused by β-amyloid. We characterized the learning and memory abilities, cytokine profiles of circulating TNF-α, IL-1β and IL-6β in the serum and the expressions of Toll like receptor 4 and nuclear factor-κB p65 mRNA and protein at the choroid plexus. The results showed that functional deficits of learning and memory in lycopene treatment groups were significantly improved compared to the control group without lycopene treatment in water maze test. The levels of serum TNF-α, IL-1β and IL-6β were significantly increased, and the expressions of TLR4 and NF-κB p65 mRNA and protein at the choroid plexus were up-regulated, indicating inflammation response was initiated following administration of Aβ1-42. After intragastric pretreatment with lycopene, inflammatory cytokines were significantly reduced and lycopene also reversed the Aβ1-42 induced up-regulation of TLR4 and NF-κB p65 mRNA and protein expressions at the choroid plexus. These results provided a novel evidence that lycopene significantly improved cognitive deficits and were accompanied by the attenuation of inflammatory injury via blocking the activation of NF-κB p65 and TLR4 expressions and production of cytokines, thereby endorsing its usefulness for diminishing β-amyloid deposition in the hippocampus tissues. [ABSTRACT FROM AUTHOR]

The ketogenic diet (KD) might improve cardiac function in diabetic cardiomyopathy, but the mechanisms remain unclear. This study investigated the effects of KD on myocardial fatty acid (FA), glucose, and ketone metabolism in diabetic cardiomyopathy. Echocardiograms, biochemistry, and micro-positron emission tomography were performed to evaluate cardiac function and glucose uptake in control rats and streptozotocin-induced diabetes mellitus (DM) rats with normal diet (ND) or KD for 6 weeks. Histopathology, adenosine triphosphate measurement, and Western blot were performed in the ventricular myocytes to analyze fibrosis, FA, ketone body, and glucose utilization. The ND-fed DM rats exhibited impaired left ventricular systolic function and increased chamber dilatation, whereas control and KD-fed DM rats did not. The KD reduced myocardial fibrosis and apoptosis in the DM rats. Myocardial glucose uptake in the micro-positron emission tomography was similar between ND-fed DM rats and KD-fed DM rats and was substantially lower than the control rats. Compared with the control rats,  ND-fed DM rats had increased phosphorylation of acetyl CoA carboxylase and higher expressions of CD-36, carnitine palmitoyltransferase-1β, tumor necrosis factor-α, interleukin-1β, interleukin6, PERK, and e-IF2α as well as more myocardial fibrosis and apoptosis (assessed by Bcl-2, BAX, and caspase-3 expression); these increases were attenuated in the KD-fed DM rats. Moreover, ND-fed DM rats had significantly lower myocardial adenosine triphosphate, BHB, and OXCT1 levels than the control and KD-fed DM rats. The KD may improve the condition of diabetic cardiomyopathy by suppressing FA metabolism, increasing ketone utilization, and decreasing endoplasmic reticulum stress and inflammation. [ABSTRACT FROM AUTHOR]

Liver fibrosis is an important pathologic process in response to chronic or repetitive liver injury. It can advance to liver cirrhosis. Both peroxisome proliferator-activated receptor gamma (PPARγ) and Nogo-B play critical roles in fibrogenesis, while PPARγ is essential for the development. However, the effect of Nogo-B deficiency on the development of liver fibrosis in cell-specific PPARγ deficient mice remains unknown. In this study, hepatocyte or macrophage PPARγ deficient (hPPARγ KO or mPPARγ KO) mice, Nogo-B deficient mice, and cell-specific PPARγ plus Nogo-B double deficient (hPPARγ/Nogo-B DKO or mPPARγ/Nogo-B DKO) mice were induced liver fibrosis by CCl 4 injection. We found hPPARγ KO mice showed enhanced liver fibrotic signatures compared to mPPARγ KO mice after CCl 4 administration. Hepatocyte or macrophage PPARγ deficiency further enhanced CCl 4 -induced severe inflammation infiltration, apoptosis and M1 macrophage polarization in the liver. In contrast, Nogo-B deficiency effectively ameliorated PPARγ deficiency-aggravated liver injury and fibrosis. It ameliorated PPARγ deficiency-aggravated liver inflammation and fibrosis by suppressing hepatic stellate cell activation, TLR4-NF-κB/TNF-α signaling and M1 macrophage polarization. In conclusion, our study demonstrates that PPARγ deficiency increases susceptibility of mice to develop CCl 4 -induced liver injury/fibrosis, which is potently reduced by Nogo-B deficiency, indicating Nogo-B inhibition might be a therapeutic approach for liver fibrosis treatment. [Display omitted] • Lack of PPARγ in hepatocytes or macrophages aggravates CCl 4 -induced liver fibrosis. • Lack of PPARγ enhances liver inflammation, apoptosis and M1 macrophage polarization. • Nogo-B deficiency reduces CCl 4 or CCl 4 plus PPARγ deficiency-induced liver fibrosis. • Lack of Nogo-B inhibits HSC activation and TLR4-NF-κB-TNF-α signaling pathway. • Nogo-B inhibition and PPARγ activation might be used for liver fibrosis treatment. [ABSTRACT FROM AUTHOR]

To better understand the pharmacological characters of syringaldehyde (SA), which is a key-odorant compound of whisky and brandy, this review article is the first to compile the published literature for molecular docking that were subsequently validated by in vitro and in vivo assays to predict and develop insights into the medicinal properties of SA in terms of anti-oxidation, anti-inflammation, and anti-diabetes. The molecular docking displayed significantly binding affinity for SA towards tumor necrosis factor-α, interleukin-6, and antioxidant enzymes when inflammation from myocardial infarction and spinal cord ischemia. Moreover, SA nicely docked with dipeptidyl peptidase-IV, glucagon-like peptide 1 receptor, peroxisome proliferator-activated receptor, acetylcholine M2 receptor, and acetylcholinesterase in anti-diabetes investigations. These are associated with (1) an increase glucose utilization and insulin sensitivity to an anti-hyperglycemic effect; and (2) to potentiate intestinal contractility to abolish the α-amylase reaction when concurrently reducing retention time and glucose absorption of the intestinal tract to achieve a glucose-lowering effect. In silico screening of multi-targets concomitantly with preclinical tests could provide a potential exploration for new indications for drug discovery and development. [Display omitted] • Syringaldehyde (SA) presents in various plants and non-plants sources. • Molecular simulation intensely investigates the pharmaceutical evolution of phenolic SA. • SA virtually docked with anti-oxidative, and anti-inflammatory relate target molecules. • SA employs an anti-diabetic beneficial effect via in silico , in vitro, and in vivo. • In silico screening of multi-targets with preclinical tests explore a new indication drug. [ABSTRACT FROM AUTHOR]

Background We tested the hypothesis that tissue plasminogen activator (tPA) deficiency protected against acute ischemic stroke (AIS)-induced brain injury. Methods and Results Wild-type mice (n = 54) were categorized into group 1 (sham control, n = 18) and group 3 [AIS by permanent ligation of left common carotid artery (CCA) and cramping right CCA for 1 h and then reperfusion followed by hypoxia (11% of oxygen supply for 2 h), n = 36]. Similarly, tPA knockout (tPA −/− ) mice (n = 54) were randomized into group 2 (sham control, n = 18) and group 4 (AIS, n = 36). By day 28 after AIS procedure, mortality rate was higher in group 3 (77.8%) than in group 4 (38.9%) and lowest in groups 1 (0%) and 2 (0%) (p < 0.001). By days 3 and 28, MRI demonstrated a pattern of changes in brain-infarct volume identical to that of mortality among four groups (p < 0.001). By day 28, protein expressions of inflammatory (MMP-9, TNF-α, NF-κB, iNOS, PAI-1, RANTES), oxidative (NOX-1, NOX-2, oxidized protein), apoptotic (cleaved caspase-3 & PARP, Bax), and fibrotic (Smad3, TGF-β) biomarkers and cellular expressions of inflammation (CD11, F4/80, GFAP), DNA-damage (γ-H2AX) and brain-edema (AQP4) markers exhibited an identical pattern compared to that of mortality (all p < 0.001), whereas protein expressions of endothelial (eNOS, CD31), anti-fibrotic (Smad1/5, BMP-2) biomarkers, and number of small vessels displayed an opposite pattern (all p < 0.001) among four groups. Expressions of protein and cellular angiogenesis markers (VEGF, SDF-1α, CXCR4) were progressively increased from groups 1 and 2 to group 4 (all p < 0.0001). Conclusion tPA deficiency protected the brain from AIS injury. [ABSTRACT FROM AUTHOR]

Cardiorenal syndrome (CRS) remains the leading cause of death in hospitalized patients for all disease entities. Sacubitril/Valsartan (Sac/Val) therapy has been proved to improve prognostic outcome in patients with heart failure or chronic kidney disease. This study tested the hypothesis that combined levosimendan and Sac/Val was superior to just one therapy on protecting the heart and kidney against simultaneous heart and kidney ischemia (I) (for 50-min)-reperfusion (R) (for 7-days) (i.e., double IR) injury (defined as CRS). Adult-male Spraque-Dawley rats (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (double IR), group 3 [double IR+levosimendan (10 mg/kg by intra-peritoneum administration at 30 min/followed by days 1–5 once daily after IR procedure)], group 4 [double IR+Sac/Val (10 mg/kg, orally at 30 min/followed by days 1–5 twice daily after IR procedure)], and group 5 (double IR+Sac/Val+levosimendan). By day 7 after double-IR, the left-ventricular-ejection fraction (LVEF)/left-ventricular-fraction-shortening (LVFS) were highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3/4, but they showed no difference between groups 3/4, whereas the circulatory heart-failure (brain-natriuretic peptide)/proinflammatory (suppression of tumorigenicity-2) biomarkers, blood-urea-nitrogen/creatinine and ratio of urine protein to creatinine (all p < 0.0001) exhibited an opposite pattern of LVEF among the groups. The protein expressions of inflammatory (tumor necrosis factor-α/interleukin-1ß/matrix metalloproteinase-9)/oxidative-stress (NOX-1/NOX-2/NOX-4)/apoptotic (mitochondrial-Bax/caspase-3/poly-(ADP-ribose)-polymerase)/fibrotic (Smad3/transforming growth factor-ß)/mitochondrial-damaged (cytosolic-cytochrome-C)/myocardial-hypertrophic (ß-MHC) biomarkers in LV myocardium exhibited an opposite pattern of LVEF among the groups (all p < 0.0001). The cellular expressions of inflammatory (CD68)/DNA-damaged (γ-H2AX) biomarkers and infarct/fibrotic areas in LV myocardium and kidney displayed an opposite pattern of LVEF among the groups (all p < 0.0001). Combined levosimendan and Sac/Val was superior to merely one therapy on protecting the heart and kidney as well as preserving their functions against double IR injury. [Display omitted] • Levosimendan/entresto effectively protected heart against cardiorenal syndrome. • This combination reduced proteinuria & heart failure in cardiorenal syndrome. • This combination offered synergic effect on preserving heart and kidney function. [ABSTRACT FROM AUTHOR]

The aim of this study was to address the effects of shaking stress (a.k.a. physical agitation) on burn-induced remote organ injury and to evaluate the application of delayed fluid resuscitation to treat severe burns under shaking conditions. Healthy adult male rabbits, weighing 2.50±0.40kg, were randomly assigned to the following groups: control group, burn group, and burn+shaking group. One half of burned animals received a 6-h delayed fluid resuscitation and the other half remained untreated. Cardiovascular hemodynamics and functional and pathological changes of the heart and kidney were examined. Compared to normal controls, untreated burned animals showed decreased hemodynamic parameters, increased serum lactic acid, and severe myocardial inflammation. The burn-induced hemodynamic abnormalities and cardiac injury were aggravated by shaking stress. Burn injury led to reduced urine volume, elevated serum creatinine and blood urea nitrogen, and formation of erythrocyte casts in renal tubules. Shaking stimulation worsened the burn-associated functional and pathological changes of the kidney. Fluid resuscitation markedly mitigated cardiac and renal injury in burned animals, and, to a lesser extent, in the presence of shaking stimulation. Shaking stimulation aggravates burn-induced cardiovascular and renal disturbances. Delayed fluid resuscitation attenuates cardiac and renal damages in burn injury under shaking conditions. [Copyright &y& Elsevier]

Abstract: The effects of taurine (Tau) in regulation of lipid metabolism and decreasing inflammation in chronic alcohol-fed rats was investigated. Rats were randomly divided into three groups: (1) isocaloric solution; (2) 3g alcohol/kg BW/day; (3) 3g alcohol/kg BW/day+1g Tau/kg BW/day for 6weeks. Liver size and serum/liver lipids of alcohol-fed rats were decreased (p <0.05) by Tau supplementation, but daily fecal lipid/bile acid outputs were increased (p <0.05). Regarding de novo lipogenesis, Tau downregulated (p <0.05) fatty-acid biosynthesis and upregulated (p <0.05) cholesterol metabolism (CYP7A1) and energy expenditure (PPAR-α). Serum AST and ALT, and hepatic TNF-α levels and MMP-9 activity of alcohol-fed rats were decreased (p <0.05) by Tau supplementation which may be related to the maintenance of higher (p <0.05) antioxidant levels (lower thiobarbituric-acid-reactive-substances values and higher trolox equivalent antioxidant capacity) in serum and livers. Our study indicates that Tau downregulates lipogenesis, oxidative stress, and inflammation in chronic alcohol-fed rats. [Copyright &y& Elsevier]

Abstract: Carotenoids are effective antioxidants, which can quench singlet oxygen, suppress lipid peroxidation, and prevent oxidative damage. Both Pseudorabies virus (PRV) and human Herpes simplex virus (HSV) are DNA viruses, and their pathogenesis and immunobiology are similar. However, PRV does not infect humans. Therefore, PRV was used to infect murine macrophages (RAW264.7 cells), to mimic HSV-induced inflammation. Meanwhile, the influence of β-carotene on PRV-induced inflammation was also investigated. Results indicated that β-carotene inhibited (p <0.05) NO, IL-1β, IL-6, and MCP-1 production in PRV-infected RAW264.7 cells. β-Carotene also suppressed (p <0.05) NF-κB (p50 and p65), phosphorylation of extracellular-signal-related kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) expression. It could be concluded that the anti-inflammatory effect of β-carotene is mainly through a suppression of cytokine expression in PRV-induced inflammation, which results from NF-κB inactivation. β-Carotene can be considered a potential anti-inflammatory agent for DNA-virus infection. [Copyright &y& Elsevier]

Abstract: The carbohydrate polymer, hyaluronan, is a major component of the extracellular matrix in animal tissues. Exogenous hyaluronan has been used to treat osteoarthritis (OA), a degenerative joint disease involving inflammatory changes. The underlying mechanisms of hyaluronan in OA are not fully understood. Pro-inflammatory interleukin (IL)-1β downregulates peroxisome proliferator-activated receptor gamma (PPARγ), and increases expression of matrix metalloproteinases (MMPs) which are responsible for the degeneration of articular cartilage. The effects of low- and high-molecular-weight hyaluronan (oligo-HA and HMW-HA) on the inflammatory genes were determined in human SW-1353 chondrosarcoma cells. HMW-HA antagonized the effects of IL-1β by increasing PPARγ and decreasing cyclooxygenase (COX)-2, MMP-1, and MMP-13 levels. It promoted Akt, but suppressed mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NFκB) signaling, indicating anti-inflammatory effects. In contrast, the cells had overall opposite responses to oligo-HA. In conclusion, HMW-HA and oligo-HA exerted differential inflammatory responses via PPARγ in IL-1β-treated chondrosarcoma cells. [Copyright &y& Elsevier]

Abstract: Growing evidence suggests that proinflammatory responses will be a crucial issue for developing neuropsychiatric disorders. Recent clinical trials demonstrated that adjunctive therapy of cyclo-oxygenase (COX)-2 inhibitor was effective for major depression. Here, we present the case of an elderly depressed woman with acute cognitive deficit who was refractory to multiple antidepressants but only responsive to celecoxib, a COX-2 inhibitor, in acute treatment and sustaining remission for a 5-year treatment course. Our finding suggests that a therapeutic effect of celecoxib exists for major depressive disorder comorbid with neurocognitive dysfunction. [Copyright &y& Elsevier]

Abstract: N-n-Butyl haloperidol iodide (F2), a novel compound derived from haloperidol, protects against the damaging effects of ischemia/reperfusion (I/R) injury in vitro and in vivo. We tested whether the myocardial protection of F2 on cardiomyocyte hypoxia/reoxygenation (H/R) injury is mediated by modulating protein kinase C (PKC) activity in primary cultured cardiomyocytes. Primary cultures of ventricular cardiomyocytes underwent 2-h hypoxia and 30-min reoxygenation. Total PKC activity was measured, and the translocation pattern of PKCα, βII, δ and ɛ isoforms was assessed by fractionated western blot analysis. We investigated the association of PKC isoform translocation and H/R-induced injury in the presence and absence of the specific inhibitors and activator. Measurements included cell damage evaluated by creatine kinase (CK) release, and apoptosis measured by annexin V-FITC assay. In primary cultured cardiomyocytes exposed to H/R, PKCα, δ and ɛ were translocated, with no change in PKCβII activity. Total PKC activity, CK release and apoptosis were increased after H/R. Treatment with the conventional PKC inhibitor Gő6976 reduced early growth response-1 (Egr-1) protein expression and attenuated apoptosis. The PKCɛ inhibitor peptide ɛV1–2 increased H/R injury without influencing Egr-1 expression. Pretreatment with F2 inhibited translocation of PKCα, increased translocation of PKCɛ, and relieved the CK release and apoptosis. The protection of F2 was blocked in part by the conventional PKC activator thymeleatoxin (TXA) and ɛV1–2 peptide. F2 significantly alleviated H/R-induced injury, which might be attributed to the combined benefits of inhibiting PKCα and activating PKCɛ. [Copyright &y& Elsevier]

Background: Phospholipase A2 (PLA2) and cyclooxygenase 2 (COX2) are the two key enzymes in the metabolism of polyunsaturated fatty acids, which in turn play an important role in cytokine-induced depression and sickness behavior. Methods: Patients with chronic hepatitis C viral infection (n = 132) were assessed to examine the effects of seven single nucleotide polymorphisms in COX2 and PLA2 genes on the development of depression during interferon (IFN)-α treatment; a subsample (n = 63) was assessed for the erythrocyte levels of the three main polyunsaturated fatty acids, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid. An independent “replication” sample of patients with major depression unrelated to cytokine treatment (n = 82) was also examined. Results: Twenty-eight percent of participants developed INF-α–induced depression. Participants with the PLA2 BanI GG or the COX2 rs4648308 AG genotypes had a higher risk of IFN-α–induced depression (odds ratio = 3.1 and 3.5, respectively). The “at risk” PLA2 genotype was associated with lower EPA levels, and the “at risk” COX2 genotype was associated with lower DHA levels, during IFN-α treatment. The PLA2 BanI GG polymorphism was also associated with more somatic symptoms of depression, both in patients with INF-α–induced depression and in the replication sample of patients with major depression. Conclusions: Genetic variations in the COX2 and PLA2 genes increase the risk of IFN-α–induced depression, possibly by affecting the levels of EPA and DHA. Moreover, PLA2 genotype is associated with somatic symptoms in depression. Our study confirms the role of inflammatory mechanisms in major depression. [Copyright &y& Elsevier]