Qingda granule ameliorates vascular remodeling and phenotypic transformation of adventitial fibroblasts via suppressing the TGF-ß1/Smad2/3 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Qingda granule (QDG) exhibits significant therapeutic effects on high blood pressure, vascular dysfunction, and elevated proliferation of vascular smooth muscle cells by inhibiting multiple pathways. However, the effects and underlying mechanisms of QDG treatment on hypertensive vascular remodeling are unclear. AIM OF THE STUDY: The aim of this study was to determine the role of QDG treatment in hypertensive vascular remodeling in vivo and in vitro. MATERIALS AND METHODS: An ACQUITY UPLC I-Class system coupled with a Xevo XS quadrupole time of flight mass spectrometer was used to characterize the chemical components of QDG. Twenty-five spontaneously hypertensive rats (SHR) were randomly divided into five groups, including SHR (equal volume of double distilled water, ddH2O), SHR + QDG-L (0.45 g/kg/day), SHR + QDG-M (0.9 g/kg/day), SHR + QDG-H (1.8 g/kg/day), and SHR + Valsartan (7.2 mg/kg/day) groups. QDG, Valsartan, and ddH2O were administered intragastrically once a day for 10 weeks. For the control group, ddH2O was intragastrically administered to five Wistar Kyoto rats (WKY group). Vascular function, pathological changes, and collagen deposition in the abdominal aorta were evaluated using animal ultrasound, hematoxylin and eosin and Masson staining, and immunohistochemistry. Isobaric tags for relative and absolute quantification (iTRAQ) was performed to identify differentially expressed proteins (DEPs) in the abdominal aorta, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Cell Counting Kit-8 assays, phalloidin staining, transwell assays, and western-blotting were performed to explore the underlying mechanisms in primary isolated adventitial fibroblasts (AFs) stimulated with transforming growth factor-ß 1 (TGF-ß1) with or without QDG treatment. RESULTS: Twelve compounds were identified from the total ion chromatogram fingerprint of QDG. In the SHR group, QDG treatment significantly attenuated the increased pulse wave velocity, aortic wall thickening, and abdominal aorta pathological changes and decreased Collagen I, Collagen III, and Fibronectin expression. The iTRAQ analysis identified 306 DEPs between SHR and WKY and 147 DEPs between QDG and SHR. GO and KEGG pathway analyses of the DEPs identified multiple pathways and functional processes involving vascular remodeling, including the TGF-ß receptor signaling pathway. QDG treatment significantly attenuated the increased cell migration, actin cytoskeleton remodeling, and Collagen I, Collagen III, and Fibronectin expression in AFs stimulated with TGF-ß1. QDG treatment significantly decreased TGF-ß1 protein expression in abdominal aortic tissues in the SHR group and p-Smad2 and p-Smad3 protein expression in TGF-ß1-stimulated AFs. CONCLUSIONS: QDG treatment attenuated hypertension-induced vascular remodeling of the abdominal aorta and phenotypic transformation of adventitial fibroblasts, at least partly by suppressing TGF-ß1/Smad2/3 signaling.

Specific separation and recovery of phosphate anions by a novel NiFe-LDH/rGO hybrid film based on electroactivity-variable valence.

Phosphorus is anon-renewable resource. Supplies are limited and muchphosphorusis currently wasted during the production and utilization process, causing concerns about future supplies and widespread environmental problems. To solve these problems, a new type of NiFe-LDH/rGO electrically switched ion-selective (ESIX) film is designed, based on the dominant mechanism of inner-sphere complexation. An ESIX process allows the NiFe-LDH/rGO hybrid film to achieve a controllably selective uptake and release of the phosphate anions. This route involves tuning potential steps to regulate the redox states of the composite film and the variable metal (e.g., Ni, Fe (II)/(III)) in coordination centers, as the inner-sphere complexation of the metals to phosphate anions is combined with the assistance of the outer electric field. A high absorption capacity (270 mg·g-1) and regeneration rate (>85%) were achieved, together with good cycle stability.

Deer antler extracts reduce amyloid-beta toxicity in a Caenorhabditis elegans model of Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Velvet antler extracts (VAE) are composed of a variety of active substances and growth factors, and have been reported to improve sleep quality and memory. AIM OF THE STUDY: We aimed to explore the protective effects and mechanism of action for VAE on Alzheimer's disease (AD) using a transgenic Caenorhabditis elegans model. MATERIALS AND METHODS: C. elegans were cultivated at 40% relative humidity on solid nematode growth medium (NGM) containing live E. coli (OP50) as the food source, with Strain N2 (normal) held at 20 °C and the CL4176s (transgenic) held at 16 °C. AD-like aggregation of Aß peptide in the CL4176s strain is induced by lifting the temperature to 25 °C. Nematodes were treated with three types of VAEs and Resveratrol (positive control). Analyses included qRT-PCR for quantification of gene transcripts of interest; ELISA for measuring levels of amyloid-ß protein; Thioflavin T fluorescent staining for localizing Aß depositions; assays for reactive oxygen species (ROS) and superoxide dismutase activity (SOD). RESULTS: VAEs reduced ß-amyloid peptide (Aß) toxicity in the transgenic C. elegans model. An enzymatically-digested VAE (EDVAE) was superior to both a cold-water VAE (CWVAE) and a hot-water VAE (HWVAE) from the same velvet antler. EDVAE treatment reduced the severity of the Aß-induced paralysis phenotype and decreased the amount of Aß deposits in the AD model nematodes, and these effects were found to be significantly better than that of the positive control Resveratrol. In addition, EDVAE treatment reduced production of ROS (induced by Aß), enhanced SOD activity, and elevated expression levels of antioxidant-related transcription factors, although it is not known whether these effects were achieved directly or indirectly. CONCLUSION: EDVAE had a protective role in Aß-induced toxicity in the transgenic AD nematodes, possibly through reducing accumulation of toxic Aß and enhancing the ability of nematodes to resist oxidative stress. Thus, EDVAE has potential to be an effective treatment to relieve the symptoms of AD.

Baicalin attenuates angiotensin II-induced blood pressure elevation and modulates MLCK/p-MLC signaling pathway.

Scutellaria baicalensis Georgi is an extensively used medicinal herb for the treatment of hypertension in traditional Chinese medicine. Baicalin, is an important flavonoid in Scutellaria baicalensis Georgi extracts, which exhibits therapeutic effects on anti-hypertension, but its underlying mechanisms remain to be further explored. Therefore, we investigated the effects and molecular mechanisms of Baicalin on anti-hypertension. In vivo studies revealed that Baicalin treatment significantly attenuated the elevation in blood pressure, the pulse propagation and thickening of the abdominal aortic wall in C57BL/6 mice infused with Angiotensin II (Ang II). Moreover, RNA-sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses identified 537 differentially expressed transcripts and multiple enriched signaling pathways (including vascular smooth muscle contraction and calcium signaling pathway). Consistently, we found that Baicalin pretreatment significantly alleviated the Ang II induced constriction of abdominal aortic ring, while promoted NE pre-contracted vasodilation of abdominal aortic ring at least partly dependent on L-type calcium channel. In addition, Ang II stimulation significantly increased cell viability and PCNA expression, while were attenuated after Baicalin treatment. Moreover, Baicalin pretreatment attenuated Ang II-induced intracellular Ca2+ release, Angiotensin II type 1 receptor (AT1R) expression and activation of MLCK/p-MLC pathway in vascular smooth muscle cells (VSMCs). The present work further addressed the pharmacological and mechanistic insights on anti-hypertension of Baicalin, which may help better understand the therapeutic effect of Scutellaria baicalensis Georgi on anti-hypertension.

Leaf extract from Vitis vinifera L. reduces high fat diet-induced obesity in mice.

Despite the health benefits of Vitis vinifera L. leaves, its anti-obesity potential has not been fully explored. In this work, we showed that Vitis vinifera L. leaf extract (VLE) inhibits the pancreatic lipase activity. Intragastric administration of VLE to mice led to a significant decrease in the body weight, tissue fat accumulation, levels of cholesterol, low-density lipoprotein and triglyceride compared to mice fed with high fat diet. We also found a lower level of neuropeptide-Y (NPY) in the serum and hypothalamus and a higher level of fibroblast growth factor 15 in mice supplemented with VLE. These results suggested that VLE regulates both the NPY-mediated pathway and the bile acid-FGF15 pathway to control energy metabolism and body weight gain. The composition of VLE was further investigated by a targeted metabolomics approach, which identified 21 compounds including phenolic acids, flavones, flavanols, flavanones, coumarins, and stilbenes. Taken together, we demonstrated the capacity of grape leaves in reducing obesity, which could be mediated by NPY and bile acids. Identification of putative active compounds in VLE also open the path for further studies to determine their effectiveness individually to treat obesity.

[Characteristics of Sludge and Associated Risk Assessment of Urban Sewage Treatment Plants].

In urban solid waste management, the scientific and reasonable disposal and utilization of sewage sludge is becoming more and more important. It can be said that the pollution status and chemical properties of sewage sludge in urban sewage treatment plants can provide a basis for the scientific disposal and utilization of sludge. In this study, the characteristics of pH, moisture content, Cd, Cr, Cu, Zn, Pb, As, Hg, Ni, mineral oil, volatile phenol, PAHs, organic matter, nitrogen, phosphorus, and potassium were evaluated in sewage sludge collected from 49 sewage treatment plants in a certain city. The pollution status of heavy metals and organic pollutants, the frequency distribution of pollutant concentrations, and changes in the nutrient content were analyzed. The Nemero index and Hakanson potential ecological hazard index were used to assess the potential ecological risks of heavy metals in the agricultural utilization process of sludge. The results showed that under the condition of neutral pH values and high moisture content, the order of heavy metal content was Zn > Cu > Cr > Pb > Ni > As > Hg > Cd. The principal component analysis (PCA) results indicated that Cd, Pb, Hg, Ni, and As constituted the main load factors of the first main component of heavy metal sources. The most concentrated contents of 8 heavy metal frequency distributions among the 49 samples were 38.9-1380.0, 62.6-182.7, 63.6-181.3, 0.0-97.8, 19.3-68.4, 0.8-29.2, 0.3-8.7, and 0.01-0.96 mg·kg-1. In addition, the most concentrated frequency distribution of mineral oil, volatile phenol, and PAH concentration were 87.0%, 87.9%, and 77.6%, respectively. Moreover, the nutrient content of sludge was higher than the average level in China, and the organic matter content was 67.4%, 75.9%, and 92.5% of that of pig manure, cow dung, and chicken manure, while the content of nitrogen, phosphorus, and potassium was not very different. The Nemero index and Hakanson ecological hazard index results showed that the sludge of urban sewage treatment plant in the city has certain ecological risks. However, four sewage treatment plants were heavily polluted or highly ecologically hazardous among the 44 plants in this study, which were in line with the Standards for pollutant control of agricultural sludge. In summary, there are certain potential ecological risks for the agricultural utilization of sludge in the city, and it is necessary to reduce the heavy metal content before resourcing. More importantly, on the premise that the sludge meets the agricultural standards, a comprehensive ecological risk assessment is required to select a reasonable sludge recycling method.

Retinoic Acid Synthesis Deficiency Fosters the Generation of Polymorphonuclear Myeloid-Derived Suppressor Cells in Colorectal Cancer.

Metabolism is reprogrammed in cancer to fulfill the demands of malignant cells for cancer initiation and progression. Apart from its effects within cancer cells, little is known about whether and how reprogramed metabolism regulates the surrounding tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSC) are key regulators of the TME and greatly affect tumor progression and therapeutic responses. In this study, our results revealed that retinol metabolism-related genes and enzymes were significantly downregulated in human colorectal cancer compared with adjacent colonic tissues, and tumors exhibited a defect in retinoic acid (RA) synthesis. Reduced ADH1-mediated retinol metabolism was associated with attenuated RA signaling and accumulated MDSCs in colorectal cancer tumors. Using an in vitro model, generating MDSCs from CD34+ myeloid precursors, we found that exogenous RA could abrogate the generation of polymorphonuclear MDSCs (PMN-MDSC) with negligible impact on myeloid differentiation. Mechanistically, RA could restrain the glycolytic capacity of myeloid cells, which in turn activated the AMP-activated protein kinase (AMPK) pathway, further impairing the suppressive capacity of myeloid cells. Supplementation with RA could significantly delay tumor growth, with reduced arginase-1-expressing myeloid cells and increased CD8+ and granzyme B+ T cells in both colitis-associated and implanted MC38 mouse colorectal cancer models. Our results indicated that the defect in ADH1-mediated RA synthesis could provide a possible mechanism that fosters the generation of PMN-MDSCs in colorectal cancer and that restoring RA signaling in the TME could serve as a promising therapeutic strategy to abrogate the generation of PMN-MDSCs.

Long-term, genome-wide kinetic analysis of the effect of the circadian clock and transcription on the repair of cisplatin-DNA adducts in the mouse liver.

Cisplatin is the most commonly used chemotherapeutic drug for managing solid tumors. However, toxicity and the innate or acquired resistance of cancer cells to the drug limit its usefulness. Cisplatin kills cells by forming cisplatin-DNA adducts, most commonly the Pt-d(GpG) diadduct. We recently showed that, in mice, repair of this adduct 2 h following injection is controlled by two circadian programs. 1) The circadian clock controls transcription of 2000 genes in liver and, via transcription-directed repair, controls repair of the transcribed strand (TS) of these genes in a rhythmic fashion unique to each gene's phase of transcription. 2) The excision repair activity itself is controlled by the circadian clock with a single phase at which the repair of the nontranscribed strand (NTS) and the rest of the genome takes place. Here, we followed the repair kinetic for long periods genome-wide both globally and at single nucleotide resolution by the Excision Repair-sequencing (XR-seq) method to better understand cisplatin DNA damage and repair. We find that transcription-driven repair is nearly complete after 2 days, whereas weeks are required for repair of the NTS and the rest of the genome. TS repair oscillates in rhythmically expressed genes up to 2 days post injection, and in all expressed genes, we see a trend in TS repair with time from the 5' to 3' end. These findings help to understand the circadian- and transcription-dependent and -independent control of repair in response to cisplatin, and should aid in designing cisplatin chemotherapy regimens with improved therapeutic indexes.

Responses of antioxidant defenses in the clam Mactra veneriformis to 2,2',4,4'­tetrabromodiphenyl ether exposure.

Antioxidant enzymes play essential roles against oxidative stress caused by 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), which is ubiquitous in marine environment and organisms. However, research on antioxidant responses to BDE-47 in marine bivalves is scarce. In this study, we identified the full-length cDNA of catalase (CAT), and glutathione peroxidase (GPx) in the clam Mactra veneriformis. Subsequently, the responses of CAT, GPx, and copper, zinc-superoxide dismutase (Cu, Zn-SOD) were investigated in the clams exposed to 0.1, 1, and 10 µg/L BDE-47 for 7 days, and then depurated in natural seawater for 3 days. MvCAT and MvGPx contained conserved sequences. The deduced amino acid sequences shared high similarity with CATs and GPxs in other mollusks. M. veneriformis accumulated BDE-47 in a dose-dependent manner and eliminated BDE-47 poorly. BDE-47 induced a time- and dose-dependent increase of malondialdehyde content. Both the dose and the duration had significant effect on mRNA expressions and activities of the three antioxidants. Cu, Zn-SOD responded to BDE-47 earlier than CAT and GPx. The antioxidant responses could recover after depuration. These results suggested that M. veneriformis could accumulate BDE-47 efficiently. Antioxidant enzymes were triggered to counter the oxidative stress generated by BDE-47. Cu, Zn-SOD acted as the first defense against oxidative stress, while CAT and GPx intervened later. This study is therefore helpful in understanding the antioxidant responses to PBDEs in marine bivalves.

Cisplatin-DNA adduct repair of transcribed genes is controlled by two circadian programs in mouse tissues.

Cisplatin is a major cancer chemotherapeutic drug. It kills cancer cells by damaging their DNA, mainly in the form of Pt-d(GpG) diadducts. However, it also has serious side effects, including nephrotoxicity and hepatotoxicity that limit its usefulness. Chronotherapy is taking circadian time into account during therapy to improve the therapeutic index, by improving efficacy and/or limiting toxicity. To this end, we tested the impact of clock time on excision repair of cisplatin-induced DNA damage at single-nucleotide resolution across the genome in mouse kidney and liver. We found that genome repair is controlled by two circadian programs. Repair of the transcribed strand (TS) of active, circadian-controlled genes is dictated by each gene's phase of transcription, which falls across the circadian cycle with prominent peaks at dawn and dusk. In contrast, repair of the nontranscribed strand (NTS) of all genes, repair of intergenic DNA, and global repair overall peaks at Zeitgeber time ZT08, as basal repair capacity, which is controlled by the circadian clock, peaks at this circadian time. Consequently, the TS and NTS of many genes are repaired out of phase. As most cancers are thought to have defective circadian rhythms, these results suggest that future research on timed dosage of cisplatin could potentially reduce damage to healthy tissue and improve its therapeutic index.

Radioprotective effects of dammarane sapogenins against 60 Co-induced myelosuppression in mice.

Radiotherapy frequently induces failure of hematopoietic system and leads to myelosuppression. The objective of this study was to investigate the protective effect of dammarane sapogenins (DS), the hydrolysed product of the constituent ginsenosides of Panax ginseng, which are produced by gut metabolism, on radiation-induced hematopoietic injury. Mice were exposed to 3.5 Gy 60 Co γ-rays of total body radiation at a dose rate of 1.60 Gy per minute and treated with DS or granulocyte colony-stimulating factor immediately after radiation. The general condition of the mice, the peripheral blood cell counts, multiple colony forming unit (CFU) assays of hematopoietic progenitor cells, hematopoietic stem cell counts, bone marrow histology, and spleen colony forming unit counts were then investigated. Our results indicated that administration with DS could ameliorate 60 Co-irradiation induced damage and significantly increase the number of peripheral blood cells (white blood cells and platelets), 5 types of hematopoietic progenitor cells CFU (CFU-GM, CFU-E, BFU-E, CFU-Meg, and CFU-GEMM), hematopoietic stem cell (Lin- c-kit+ Scal-1+ ) numbers, and CFUs in the spleen, as well as improved bone marrow histopathology. All together, these results confirmed the enhancement of DS on hematopoiesis.

The Protective Effect of Lavender Essential Oil and Its Main Component Linalool against the Cognitive Deficits Induced by D-Galactose and Aluminum Trichloride in Mice.

Lavender essential oil (LO) is a traditional medicine used for the treatment of Alzheimer's disease (AD). It was extracted from Lavandula angustifolia Mill. This study was designed to investigate the effects of lavender essential oil (LO) and its active component, linalool (LI), against cognitive impairment induced by D-galactose (D-gal) and AlCl3 in mice and to explore the related mechanisms. Our results revealed that LO (100 mg/kg) or LI (100 mg/kg) significantly protected the cognitive impairments as assessed by the Morris water maze test and step-though test. The mechanisms study demonstrated that LO and LI significantly protected the decreased activity of superoxide dismutase (SOD), glutathione peroxidase (GPX), and protected the increased activity of acetylcholinesterase (AChE) and content of malondialdehyde (MDA). Besides, they protected the suppressed nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression significantly. Moreover, the decreased expression of synapse plasticity-related proteins, calcium-calmodulin-dependent protein kinase II (CaMKII), p-CaMKII, brain-derived neurotrophic factor (BDNF), and TrkB in the hippocampus were increased with drug treatment. In conclusion, LO and its active component LI have protected the oxidative stress, activity of cholinergic function and expression of proteins of Nrf2/HO-1 pathway, and synaptic plasticity. It suggest that LO, especially LI, could be a potential agent for improving cognitive impairment in AD.

Ginsenoside Rc from Panax ginseng exerts anti-inflammatory activity by targeting TANK-binding kinase 1/interferon regulatory factor-3 and p38/ATF-2.

BACKGROUND: Ginsenoside Rc (G-Rc) is one of the major protopanaxadiol-type saponins isolated from Panax ginseng, a well-known medicinal herb with many beneficial properties including anticancer, anti-inflammatory, antiobesity, and antidiabetic effects. In this study, we investigated the effects of G-Rc on inflammatory responses in vitro and examined the mechanisms of these effects. METHODS: The in vitro inflammation system used lipopolysaccharide-treated macrophages, tumor necrosis factor-α/interferon-γ-treated synovial cells, and HEK293 cells transfected with various inducers of inflammation. RESULTS: G-Rc significantly inhibited the expression of macrophage-derived cytokines, such as tumor necrosis factor-α and interleukin-1ß. G-Rc also markedly suppressed the activation of TANK-binding kinase 1/IκB kinase ε/interferon regulatory factor-3 and p38/ATF-2 signaling in activated RAW264.7 macrophages, human synovial cells, and HEK293 cells. CONCLUSION: G-Rc exerts its anti-inflammatory actions by suppressing TANK-binding kinase 1/IκB kinase ε/interferon regulatory factor-3 and p38/ATF-2 signaling.

Antidepressant-like effects and cognitive enhancement of the total phenols extract of Hemerocallis citrina Baroni in chronic unpredictable mild stress rats and its related mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Depression induce distressed emotional state and cognitive deficits simultaneously, which both should be improved in the treatment. Hemerocallis citrina Baroni (HC) is a traditional herbal medicine in Eastern-Asia areas and the total phenols extract of HC (HCPE) contains the main active ingredients. It has been reported that HC has the emotional improvement effect. But the cognitive effect of HC was seldom researched. AIM OF THE STUDY: We designed to evaluate the antidepressant and cognitive improvement effect of HCPE using a chronic unpredictable mild stress (CUMS) model, and the potential mechanisms were explored by investigating the corticosterone (CORT), monoamine neurotansmitters, brain-derived neurotropic factor (BDNF) and oxidative stress. MATERIALS AND METHODS: The depression rats were induced by CUMS procedures and treated with HCPE (10, 20, 40mg/kg/day, by gastric gavage). The antidepressant effect was evaluated by sucrose preference test, open field test and body weight, while the cognitive improvement was investigated using morris water maze test. Besides, the levels of monoamine neurotransmitters in the hippocampus and frontal cortex were measured by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The serum CORT and BDNF in hippocampus were test using enzyme-linked immunosorbent assay (ELISA) kits. The oxidative stress indicators in frontal cortex were also analyzed. RESULTS: HCPE (40mg/kg) improved the emotion and cognition related behaviors in depression effectively. Moreover, HCPE increased the neurotransmitters concentration (5-HT, DA and NE) in the hippocampus and frontal cortex compared with CUMS rats. Meanwhile, the CUMS induced changes of serum corticosterone level and the hippocampus BDNF level were reversed. Besides, HCPE reduced malondialdehyde (MDA) in the frontal cortex of model rats. CONCLUSION: It suggested that HCPE could improve the depression-like emotional status and associated cognitive deficits in CUMS rats, which might be mediated by regulation of neurotransmitters and BDNF levels in brain, alleviation of corticosterone level as well as the alleviation of oxidative stress.

Ginsenoside Rc from Korean Red Ginseng (Panax ginseng C.A. Meyer) Attenuates Inflammatory Symptoms of Gastritis, Hepatitis and Arthritis.

Korean Red Ginseng (KRG) is an herbal medicine prescribed worldwide that is prepared from Panax ginseng C.A. Meyer (Araliaceae). Out of ginseng's various components, ginsenosides are regarded as the major ingredients, exhibiting anticancer and anti-inflammatory activities. Although recent studies have focused on understanding the anti-inflammatory activities of KRG, compounds that are major anti-inflammatory components, precisely how these can suppress various inflammatory processes has not been fully elucidated yet. In this study, we aimed to identify inhibitory saponins, to evaluate the in vivo efficacy of the saponins, and to understand the inhibitory mechanisms. To do this, we employed in vitro lipopolysaccharide-treated macrophages and in vivo inflammatory mouse conditions, such as collagen (type II)-induced arthritis (CIA), EtOH/HCl-induced gastritis, and lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-triggered hepatitis. Molecular mechanisms were also verified by real-time PCR, immunoblotting analysis, and reporter gene assays. Out of all the ginsenosides, ginsenoside Rc (G-Rc) showed the highest inhibitory activity against the expression of tumor necrosis factor (TNF)-[Formula: see text], interleukin (IL)-1[Formula: see text], and interferons (IFNs). Similarly, this compound attenuated inflammatory symptoms in CIA, EtOH/HCl-mediated gastritis, and LPS/D-galactosamine (D-GalN)-triggered hepatitis without altering toxicological parameters, and without inducing gastric irritation. These anti-inflammatory effects were accompanied by the suppression of TNF-[Formula: see text] and IL-6 production and the induction of anti-inflammatory cytokine IL-10 in mice with CIA. G-Rc also attenuated the increased levels of luciferase activity by IRF-3 and AP-1 but not NF-[Formula: see text]B. In support of this phenomenon, G-Rc reduced TBK1, IRF-3, and ATF2 phosphorylation in the joint and liver tissues of mice with hepatitis. Therefore, our results strongly suggest that G-Rc may be a major component of KRG with useful anti-inflammatory properties due to its suppression of IRF-3 and AP-1 pathways.

The Transcript Profile of a Traditional Chinese Medicine, Atractylodes lancea, Revealing Its Sesquiterpenoid Biosynthesis of the Major Active Components.

Atractylodes lancea (Thunb.) DC., named "Cangzhu" in China, which belongs to the Asteraceae family. In some countries of Southeast Asia (China, Thailand, Korea, Japan etc.) its rhizome, commonly called rhizoma atractylodis, is used to treat many diseases as it contains a variety of sesquiterpenoids and other components of medicinal importance. Despite its medicinal value, the information of the sesquiterpenoid biosynthesis is largely unknown. In this study, we investigated the transcriptome analysis of different tissues of non-model plant A. lancea by using short read sequencing technology (Illumina). We found 62,352 high quality unigenes with an average sequence length of 913 bp in the transcripts of A. Lancea. Among these, 43,049 (69.04%), 30,264 (48.53%), 26,233 (42.07%), 17,881 (28.67%) and 29,057(46.60%) unigenes showed significant similarity (E-value<1e(-5)) to known proteins in Nr, KEGG, SWISS-PROT, GO, and COG databases, respectively. Of the total 62,352 unigenes, 43,049 (Nr Database) open reading frames were predicted. On the basis of different bioinformatics tools we identify all the enzymes that take part in the terpenoid biosynthesis as well as five different known sesquiterpenoids via cytosolic mevalonic acid (MVA) pathway and plastidal methylerythritol phosphate (MEP) pathways. In our study, 6, 864 Simple Sequence Repeats (SSRs) were also found as great potential markers in A. lancea. This transcriptomic resource of A. lancea provides a great contribution in advancement of research for this specific medicinal plant and more specifically for the gene mining of different classes of terpenoids and other chemical compounds that have medicinal as well as economic importance.

Molecular mechanism of protopanaxadiol saponin fraction-mediated anti-inflammatory actions.

BACKGROUND: Korean Red Ginseng (KRG) is a representative traditional herbal medicine with many different pharmacological properties including anticancer, anti-atherosclerosis, anti-diabetes, and anti-inflammatory activities. Only a few studies have explored the molecular mechanism of KRG-mediated anti-inflammatory activity. METHODS: We investigated the anti-inflammatory mechanisms of the protopanaxadiol saponin fraction (PPD-SF) of KRG using in vitro and in vivo inflammatory models. RESULTS: PPD-SF dose-dependently diminished the release of inflammatory mediators [nitric oxide (NO), tumor necrosis factor-α, and prostaglandin E2], and downregulated the mRNA expression of their corresponding genes (inducible NO synthase, tumor necrosis factor-α, and cyclooxygenase-2), without altering cell viability. The PPD-SF-mediated suppression of these events appeared to be regulated by a blockade of p38, c-Jun N-terminal kinase (JNK), and TANK (TRAF family member-associated NF-kappa-B activator)-binding kinase 1 (TBK1), which are linked to the activation of activating transcription factor 2 (ATF2) and interferon regulatory transcription factor 3 (IRF3). Moreover, this fraction also ameliorated HCl/ethanol/-induced gastritis via suppression of phospho-JNK2 levels. CONCLUSION: These results strongly suggest that the anti-inflammatory action of PPD-SF could be mediated by a reduction in the activation of p38-, JNK2-, and TANK-binding-kinase-1-linked pathways and their corresponding transcription factors (ATF2 and IRF3).

ATF-2/CREB/IRF-3-targeted anti-inflammatory activity of Korean red ginseng water extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Korean Red Ginseng (KRG) is one of the representative traditional herbal medicines prepared from Panax ginseng Meyer (Araliaceae) in Korea. It has been reported that KRG exhibits a lot of different biological actions such as anti-aging, anti-fatigue, anti-stress, anti-atherosclerosis, anti-diabetic, anti-cancer, and anti-inflammatory activities. Although systematic studies have investigated how KRG is able to ameliorate various inflammatory diseases, its molecular inhibitory mechanisms had not been carried out prior to this study. MATERIALS AND METHODS: In order to investigate these mechanisms, we evaluated the effects of a water extract of Korean Red Ginseng (KRG-WE) on the in vitro inflammatory responses of activated RAW264.7 cells, and on in vivo gastritis and peritonitis models by analyzing the activation events of inflammation-inducing transcription factors and their upstream kinases. RESULTS: KRG-WE reduced the production of nitric oxide (NO), protected cells against NO-induced apoptosis, suppressed mRNA levels of inducible NO synthase (iNOS), cyclooxygenase (COX)-2, and interferon (IFN)-ß, ameliorated EtOH/HCl-induced gastritis, and downregulated peritoneal exudate-derived NO production from lipopolysaccharide (LPS)-injected mice. The inhibition of these inflammatory responses by KRG-WE was regulated through the suppression of p38, c-Jun N-terminal kinase (JNK), and TANK-binding kinase 1 (TBK1) and by subsequent inhibition of activating transcription factor (ATF)-2, cAMP response element-binding protein (CREB), and IRF-3 activation. Of ginsensides included in this extract, interestingly, G-Rc showed the highest inhibitory potency on IRF-3-mediated luciferase activity. CONCLUSION: These results strongly suggest that the anti-inflammatory activities of KRG-WE could be due to its inhibition of the p38/JNK/TBK1 activation pathway.

Functional roles of p38 mitogen-activated protein kinase in macrophage-mediated inflammatory responses.

Inflammation is a natural host defensive process that is largely regulated by macrophages during the innate immune response. Mitogen-activated protein kinases (MAPKs) are proline-directed serine and threonine protein kinases that regulate many physiological and pathophysiological cell responses. p38 MAPKs are key MAPKs involved in the production of inflammatory mediators, including tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). p38 MAPK signaling plays an essential role in regulating cellular processes, especially inflammation. In this paper, we summarize the characteristics of p38 signaling in macrophage-mediated inflammation. In addition, we discuss the potential of using inhibitors targeting p38 expression in macrophages to treat inflammatory diseases.

Hyperbaric oxygen therapy ameliorates local brain metabolism, brain edema and inflammatory response in a blast-induced traumatic brain injury model in rabbits.

Many studies suggest that hyperbaric oxygen therapy (HBOT) can provide some clinically curative effects on blast-induced traumatic brain injury (bTBI). The specific mechanism by which this occurs still remains unknown, and no standardized time or course of hyperbaric oxygen treatment is currently used. In this study, bTBI was produced by paper detonators equivalent to 600 mg of TNT exploding at 6.5 cm vertical to the rabbit's head. HBO (100% O2 at 2.0 absolute atmospheres) was used once, 12 h after injury. Magnetic resonance spectroscopy was performed to investigate the impact of HBOT on the metabolism of local injured nerves in brain tissue. We also examined blood-brain barrier (BBB) integrity, brain water content, apoptotic factors, and some inflammatory mediators. Our results demonstrate that hyperbaric oxygen could confer neuroprotection and improve prognosis after explosive injury by promoting the metabolism of local neurons, inhibiting brain edema, protecting BBB integrity, decreasing cell apoptosis, and inhibiting the inflammatory response. Furthermore, timely intervention within 1 week after injury might be more conducive to improving the prognosis of patients with bTBI.