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Dollar spot, caused by Clarireedia spp. (formerly Sclerotinia homoeocarpa F.T. Bennett), is the most economically important turfgrass disease causing considerable damage on golf courses. While cultural practices are available for reducing dollar spot infection, chemical fungicide use is often necessary for maintaining optimal turf quality. Since the release of boscalid in 2003, the succinate dehydrogenase inhibitor (SDHI) class has become an invaluable tool for managing dollar spot. However, resistance to this class has recently been reported in Clarireedia spp. and many other plant pathogenic fungi. After SDHI field failure on four golf courses and one university research plot, a total of six unique SDH mutations conferring differential in vitro sensitivities to SDHIs have been identified in Clarireedia spp. In 2018 and 2019, turf research plots were inoculated with sensitive, non-mutated isolates of Clarireedia spp., as well as resistant isolates harboring each unique identified mutation. Fungicide efficacy trials were conducted on inoculated plots to assess differential sensitivity to five SDHI active ingredients (boscalid, fluxapyroxad, isofetamid, fluopyram, and pydiflumetofen) across mutations under field conditions. Results indicate unique mutations are associated with distinct SDHI field efficacy profiles as shown in in-vitro sensitivity assays. Isolate populations with B subunit mutations (H267Y/R) were more sensitive to fluopyram, whereas isolate populations with C subunit mutations (C-G91R, C-G150R) showed resistance to all SDHIs tested. Mutation-associated differential sensitivity observed under field conditions indicates a need for a nation-wide survey and frequent monitoring of SDHI sensitivity of dollar spot populations on golf courses in the USA. Further, the information gained from this study will be useful in providing sustainable management recommendations for controlling site-specific resistant populations of Clarireedia spp.

Dollar spot, caused by the ascomycete fungus Clarireedia (formerly Sclerotinia), is one of the most resource-demanding diseases on amenity turfgrasses in North America. Differential resistance to the succinate dehydrogenase inhibitor (SDHI) fungicide class, conferred by singular point mutations on the SdhB, SdhC, and SdhD subunits of the succinate dehydrogenase enzyme (SDH), has been reported in dollar spot as well as many other plant-pathogenic fungal diseases. Four unique mutations were previously reported from Clarireedia field isolates collected from two different cool-season golf courses in Japan and Rhode Island: an amino acid substitution H267Y and a silent mutation (CTT to CTC) at codon 181 on the SdhB subunit gene, and amino acid substitutions G91R and G150R on the SdhC subunit gene. To properly diagnose and monitor SDHI resistance in the field, a rapid detection system for known mutations is crucial. As part of this study, additional SDHI-resistant Clarireedia isolates were collected from Rutgers University research plots and in vitro sensitivity to four SDHI active ingredients was assessed. SdhB, SdhC, and SdhD subunits of these isolates were sequenced to reveal an additional mutation on the SdhB subunit gene, H267R, not previously observed in Clarireedia. Cleaved amplified polymorphic sequence (CAPS) and derived CAPS molecular markers were developed to detect five mutations conferring SDHI resistance in Clarireedia isolates and validated using samples from two additional golf courses in Connecticut and Wisconsin experiencing SDHI field failure. This PCR-based molecular detection system will be useful for continued monitoring, assessment, and delay of SDHI resistance in the field.

The blood exhibits a dynamic flux of proteins that are secreted by the tissues and cells of the body. To identify novel aging-related circulating proteins, we compared the plasma proteomic profiles of young and old mice using tandem mass spectrometry. The expression of 134 proteins differed between young and old mice. We selected seven proteins that were expressed at higher levels in young mice, and confirmed their plasma expression in immunoassays. The plasma levels of anthrax toxin receptor 2 (ANTXR2), cadherin-13 (CDH-13), scavenger receptor cysteine-rich type 1 protein M130 (CD163), cartilage oligomeric matrix protein (COMP), Dickkopf-related protein 3 (DKK3), periostin, and secretogranin-1 were all confirmed to decrease with age. We then investigated whether any of the secreted proteins influenced bone metabolism and found that CDH-13 inhibited osteoclast differentiation. CDH 13 treatment suppressed the receptor activator of NF-κB ligand (RANKL) signaling pathway in bone marrow-derived macrophages, and intraperitoneal administration of CDH-13 delayed age-related bone loss in the femurs of aged mice. These findings suggest that low plasma CDH-13 expression in aged mice promotes aging-associated osteopenia by facilitating excessive osteoclast formation. Thus, CDH-13 could have therapeutic potential as a protein drug for the prevention of osteopenia.

Recently, the involvement of the nervous system in the pathology of allergic diseases has attracted increasing interest. However, the precise pathophysiological role of enteric neurons in food allergies has not been elucidated. We report the presence of functional high-affinity IgE receptors (FcεRIs) in enteric neurons. FcεRI immunoreactivities were observed in approximately 70% of cholinergic myenteric neurons from choline acetyltransferase-eGFP mice. Furthermore, stimulation by IgE-antigen elevated intracellular Ca2+ concentration in isolated myenteric neurons from normal mice, suggesting that FcεRIs are capable of activating myenteric neurons. Additionally, the morphological investigation revealed that the majority of mucosal mast cells were in close proximity to enteric nerve fibers in the colonic mucosa of food allergy mice. Next, using a newly developed coculture system of isolated myenteric neurons and mucosal-type bone-marrow-derived mast cells (mBMMCs) with a calcium imaging system, we demonstrated that the stimulation of isolated myenteric neurons by veratridine caused the activation of mBMMCs, which was suppressed by the adenosine A3 receptor antagonist MRE 3008F20. Moreover, the expression of the adenosine A3 receptor gene was detected in mBMMCs. Therefore, in conclusion, it is suggested that, through interaction with mucosal mast cells, IgE-antigen-activated myenteric neurons play a pathological role in further exacerbating the pathology of food allergy.

Sclerotinia homoeocarpa isolates were collected from golf courses in Japan and the United States (2016–2017). Japan isolates were collected during a monitoring study and the U.S. isolates were collected due to field failure. Five succinate dehydrogenase inhibitor (SDHI) active ingredients (boscalid, fluopyram, fluxapyroxad, isofetamid, and penthiopyrad) were examined using in vitro sensitivity assays to determine cross-resistance. Sequence analysis revealed a point mutation leading to an amino acid substitution (H267Y) and a silent mutation (CTT to CTC) at codon 181 in the SdhB subunit gene. Isolates with the B-H267Y (n = 10) mutation were resistant to boscalid and penthiopyrad and had increased sensitivity to fluopyram. SdhB silent mutation 181C>T isolates (n = 2) were resistant to boscalid, isofetamid, and penthiopyrad. Sequence analysis revealed 3 mutations leading to an amino acid substitution (G91R, n = 5; G150R, n = 1; G159W, n = 1) in the SdhC subunit gene. Isolates harboring the SdhC (G91R or G150R) mutations were resistant to boscalid, fluxapyroxad, isofetamid, and penthiopyrad. A genetic transformation system was used to generate mutants from a SDHI sensitive isolate to confirm the B-H267Y and C-G91R mutations were direct determinants of SDHI resistance and associated with in vitro sensitivity assay results.

Inflammatory bowel disease (IBD) is a chronic relapsing disorder modulated by numerous factors. Recent failures of drugs targeting single factors suggest that multitargeting drugs could be useful for the treatment of IBD. Natural medicines may be an alternative option for the treatment of IBD, owing to the complex nature of the disease. However, most natural medicines have poor in vitro and in vivo translational potential because of inadequate pharmacokinetic study. KM1608, a mixture of the medicinal plants Aucklandia lappa, Terminalia chebula, and Zingiber officinale, was examined for its anti-colitis effects and biodistribution using bioimaging. Dehydrocostus lactone, as a marker compound, was analyzed to assess the biodistribution of KM1608. KM1608 significantly attenuated the disease activity of dextran sodium sulfate-induced colitis in mice and suppressed inflammatory mediators such as myeloperoxidase, proinflammatory cytokines (TNF-&alpha, and IL-6), and the Th2-type cytokine IL-4 in the colon. Optical fluorescence imaging revealed that KM1608 was distributed in the intestinal area as a target organ. Collectively, our findings suggest that KM1608 is a potential therapeutic formulation for IBD.

Polyacetylenic compounds isolated from Panax species are comprised of non-polar C17 compounds, exhibiting anti-inflammatory, antitumor, and antifungal activities. Panaxynol represents the major component of the essential oils of ginseng. We investigated whether panaxynol isolated from Panax vietnamensis (Vietnamese ginseng, VG) could prevent cisplatin-induced renal damage induced in vitro and in vivo. Cisplatin-induced apoptotic cell death was observed by staining with annexin V conjugated with Alexa Fluor 488, and western blotting evaluated the molecular mechanism. Panaxynol at concentrations above 0.25 &mu, M prevented cisplatin-induced LLC-PK1 porcine renal proximal tubular cell death. LLC-PK1 cells treated with cisplatin demonstrated an increase in apoptotic cell death, whereas pretreatment with 2 and 4 &mu, M panaxynol decreased this effect. Cisplatin demonstrated a marked increase in the phosphorylation of c-Jun N-terminal kinase (JNK), P38, and cleaved caspase-3. However, pretreatment with 2 and 4 &mu, M panaxynol reversed the upregulated phosphorylation of JNK, P38, and the expression of cleaved caspase-3. We confirmed that the protective effect of panaxynol isolated from P. vietnamensis in LLC-PK1 cells was at least partially mediated by reducing the cisplatin-induced apoptotic damage. In the animal study, panaxynol treatment ameliorated body weight loss and blood renal function markers and downregulated the mRNA expression of inflammatory mediators.

Accompanied by increased life span, aging-associated diseases, such as metabolic diseases and cancers, have become serious health threats. Recent studies have documented that aging-associated diseases are caused by prolonged cellular stresses such as endoplasmic reticulum (ER) stress, mitochondrial stress, and oxidative stress. Thus, ameliorating cellular stresses could be an effective approach to treat aging-associated diseases and, more importantly, to prevent such diseases from happening. However, cellular stresses and their molecular responses within the cell are typically mediated by a variety of factors encompassing different signaling pathways. Therefore, a target-based drug discovery method currently being used widely (reverse pharmacology) may not be adequate to uncover novel drugs targeting cellular stresses and related diseases. The connectivity map (CMap) is an online pharmacogenomic database cataloging gene expression data from cultured cells treated individually with various chemicals, including a variety of phytochemicals. Moreover, by querying through CMap, researchers may screen registered chemicals in silico and obtain the likelihood of drugs showing a similar gene expression profile with desired and chemopreventive conditions. Thus, CMap is an effective genome-based tool to discover novel chemopreventive drugs.

Human intestinal organoids (hIOs) derived from human pluripotent stem cells (hPSCs) have immense potential as a source of intestines. Therefore, an efficient system is needed for visualizing the st...

Collagen synthesis is decreased and matrix metalloproteinase-1 (MMP-1) levels are increased in naturally aged human skin, and these alterations cause changes such as skin wrinkling and decreased elasticity. As a part of our ongoing search for bioactive ingredients, MMP-1 inhibitory and type-1 procollagen synthesis inducing activities of aqueous methanolic extract of manufactured gambir product from Uncaria gambir were investigated in in vitro bioassay systems. In addition, total phenolic contents were quantified using a spectrophotometric method. Among tested samples, 40% MeOH eluate from 80% methanolic extract of manufactured U. gambir using open column chromatography packed with Diaion HP-20 resin showed significant MMP-1 inhibitory activities with an IC50 value of 15.6±1.3 μg/mL. Furthermore, type-1 procollagen synthesis promoting property of 40% MeOH eluate (IC50 value; 6.9±0.7 μg/mL) from 80% methanolic extract of manufactured gambir was higher than other eluates. Additionally, the present investigation revealed that 40% MeOH eluate of manufactured gambir product contained a high level of total phenolic compounds. The result suggests a distinct relationship between anti-wrinkle activity and total phenolic contents, and manufactured gambir product could be considered a new effective source of natural bioactive ingredients. Systematic investigation of manufactured gambir product will be performed for further development of its biological properties.

We studied the effect of ethyl acetate (EA) fraction from Acer okamotoanum on cognitive improvement and protective abilities in amyloid beta (Aβ)25–35 peptide-injected Alzheimer’s disease (AD) mice. EA was oral administration at 100 and 200 mg/kg/day during the 14 days. We studied the protective effect of EA against AD on the basis of behavioral tests including T-maze test, Novel object recognition test, and Morris water maze test. Control group injected with Aβ25–35 showed significant impairments in memory function. But the oral administration of EA (EA 100 and EA 200 groups) improved the cognition and memory function. In addition, EA against Aβ25–35 peptide has been shown to inhibit lipid peroxidation levels and nitric oxide production in tissues. Acetylcholinesterase (AChE) was elevated in the brain by Aβ25–35 peptide, whereas administration of EA (EA 100 and EA 200 groups) significantly decreased AChE level. Our results indicated that EA improves learning and long-term memory against Aβ25–35 peptide–caused deficit through attenuation of oxidative stress.

Lindera obtusiloba has been used in traditional herbal medicine for the treatment of blood stasis and inflammation. The leaves of Lindera obtusiloba have been reported to exhibit various physiological activities. However, there is little information available on their antiplatelet and antithrombotic activities. Thus, the present study aimed to evaluate the effect of Lindera obtusiloba leaf extract (LLE) on platelet activities, coagulation and thromboembolism. In a platelet aggregation study, LLE significantly inhibited various agonist-induced platelet aggregations in vitro and ex vivo. Furthermore, LLE significantly inhibited collagen-induced thromboxane A2 (TXA2) production in rat platelets. In addition, oral administration of LLE was protective in a mouse model of pulmonary thromboembolism induced by intravenous injection of a mixture of collagen and epinephrine. Interestingly, LLE did not significantly alter prothrombin time (PT) and activated partial thromboplastin time (aPTT). This study indicates that the antithrombotic effects of LLE might be due to its antiplatelet activities rather than anticoagulation. Taken together, these results suggest that LLE may be a candidate preventive and therapeutic agent in cardiovascular diseases associated with platelet hyperactivity.

Yes-associated protein (YAP)-1 is highly upregulated in pancreatic cancer and associated with tumor progression. However, little is known about the role of YAP1 and related genes in pancreatic cancer. Here, we identified target genes regulated by YAP1 and explored their role in pancreatic cancer progression and the related clinical implications. Analysis of different pancreatic cancer databases showed that Neuromedin U (NMU) expression was positively correlated with YAP1 expression in the tumor group. The Cancer Genome Atlas data indicated that high YAP1 and NMU expression levels were associated with poor mean and overall survival. YAP1 overexpression induced NMU expression and transcription and promoted cell motility in vitro and tumor metastasis in vivo via upregulation of epithelial&ndash, mesenchymal transition (EMT), whereas specific inhibition of NMU in cells stably expressing YAP1 had the opposite effect in vitro and in vivo. To define this functional association, we identified a transcriptional enhanced associate domain (TEAD) binding site in the NMU promoter and demonstrated that YAP1&ndash, TEAD binding upstream of the NMU gene regulated its transcription. These results indicate that the identified positive correlation between YAP1 and NMU is a potential novel drug target and biomarker in metastatic pancreatic cancer.

Curcumin is a polyphenol compound derived from the rhizomes of Curcuma longa that exhibits antioxidant, anti-inflammatory, anticancer, and antimicrobial properties. However, its low solubility in aqueous solutions, low absorption following oral administration, and rapid degradation limit its use as a functional food material. In this study, a hydroxypropyl methylcellulose-based solid dispersion of curcumin (DW-CUR 20) was prepared and its bioavailability was evaluated. In addition, its therapeutic efficacy as a hepatoprotective agent was investigated using the model of tert-butyl hydroperoxide (t-BHP)-induced hepatocyte damage. The rat plasma pharmacokinetic study showed that the oral curcumin bioavailability of DW-CUR 20 significantly increased compared to that of non-formulated curcumin. DW-CUR 20 showed a concentration-dependent hepatocyte protective effect on t-BHP-induced HepG2 cells. DW-CUR 20 inhibited the release of lactate dehydrogenase and decreased apoptosis-related proteins such as Poly (ADP-ribose) polymerase, cleaved caspase-7 and cleaved caspase-8 on t-BHP-treated HepG2 cells. These findings suggest that DW-CUR 20 could be a promising formulation for enhancing the therapeutic efficiency of curcumin and for improving the safety.

We investigated the protective activities of quercetin (Q) and quercetin-3-β-d-glucoside (Q3G) under Aβ25–35-injected Alzheimer’s disease (AD) model mice. To induce an AD-like disease in an in vivo model, mice were injected with Aβ25–35 via the intracerebroventricular route. Q and Q3G were administered orally for 14 days at 30 mg/kg/day. Learning and memory functions were evaluated using behavioral experiments that comprise tests like T-maze, Morris water maze, and novel object recognition. The administration of Q and Q3G improved memory and cognitive function, compared with Aβ25–35-injected control mice in the T-maze and object recognition test. Q and Q3G administration decreased time in order to get to the platform during the Morris water maze test. The group administered Q experienced higher protective effects from long-term spatial memory and learning ability impairments than the group administered Q3G. Furthermore, lipid peroxidation and NO formation in the brain were significantly elevated in Aβ25–35-injected control mice, and this was inhibited by Q and Q3G. These results demonstrated that Q and Q3G improved Aβ25–35-induced memory deficits and cognitive impairment and promoted protection in the brain against oxidative stress.

Pectolinarin was isolated from the ethyl acetate fraction of Cirsium setidens using open column chromatography and was analyzed using spectrometry. Pectolinarin content in Cirsium spp. was determined using HPLC/UV. Pectolinarin content in the aerial part of Cirsium spp. was higher than that in the root and pappus. Pectolinarin content was highest in the aerial part of C. chlorolepis (110.65mg/g extract). Consequently, the aerial part of C. chlorolepis has potential for use in new natural medicinal products, health supplements, and beverages.

Neurodegenerative diseases are often associated with oxidative damage in neuronal cells. This study was conducted to investigate the neuro-protective effect of methanolic (MeOH) extract of Perilla frutescens var. japonica and its one of the major compounds, rosmarinic acid, under oxidative stress induced by hydrogen peroxide (H2O2) in C6 glial cells. Exposure of C6 glial cells to H2O2 enhanced oxidative damage as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and thiobarbituric acid-reactive substance assays. The MeOH extract and rosmarinic acid prevented oxidative stress by increasing cell viability and inhibiting cellular lipid peroxidation. In addition, the MeOH extract and rosmarinic acid reduced H2O2-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the transcriptional level. Moreover, iNOS and COX-2 protein expression was down-regulated in H2O2-indcued C6 glial cells treated with the MeOH extract and rosmarinic acid. These findings suggest that P. frutescens var. japonica and rosmarinic acid could prevent the progression of neurodegenerative diseases through attenuation of neuronal oxidative stress.

This study was conducted to investigate the purification methods for high-yield of α-linolenic acid (ALA) from Perilla frutescens var. japonica oil (PO). PO was treated with 2 g of urea, cooled for 24 h, and 81.75 % of ALA was obtained after gas chromatography–flame ionization detector analysis. Urea complexation at low temperature (refrigeration) is a prospective method for the extraction of unsaturated fatty acids in high yields. Our results suggest that urea treatment with cooling at 10 °C could be used for purification of ALA from PO. It will be enhanced for the development of nutritional, medical, and cosmetic value.

Aucklandia lappa DC., Terminalia chebula Retz and Zingiber officinale Roscoe have been traditionally used in east Asia to treat chronic diarrhea and abdominal pain. This study aimed to evaluated the anti-inflammatory activity of KM1608, which is composed of three natural herbs in a mouse model of dextran sodium sulfate (DSS)-induced ulcerative colitis. The anti-inflammatory activity and underlying mechanism were assessed in vitro using LPS-treated RAW264.7 cells. The in vivo effect of KM1608 on DSS-induced colitis was examined after oral administration in mice. KM1608 significantly inhibited the inflammatory mediators such as nitric oxide, interleukin (IL)-6, monocyte chemotactic protein 1 (MCP-1) and tumor necrosis factor (TNF)-&alpha, in LPS-treated RAW264.7 cells. The inhibitory effect of KM1608 was attributed to the reduction of Akt phosphorylation in the LPS-treated cells. In the mouse model, oral administration of KM1608 significantly improved DSS-induced colitis symptoms, such as disease activity index (DAI), colon length, and colon weight, as well as suppressed the expression of IL-6, TNF-&alpha, and myeloperoxidase (MPO) in the DSS-induced colitis tissues. Taken together, KM1608 improved colitis through the regulation of inflammatory responses, suggesting that KM1608 has potential therapeutic use in the treatment of inflammatory diseases.

Natural killer (NK) cells are primary immune cells that target cancer cells and can be used as a therapeutic agent against pancreatic cancer. Despite the usefulness of NK cells, NK-cell therapy is limited by tumor cell inhibition of NK-cell homing to tumor sites, thereby preventing a sustained antitumor immune response. One approach to successful cancer immunotherapy is to increase trafficking of NK cells to tumor tissues. Here, we developed an antibody-based NK-cell–homing protein, named NK-cell–recruiting protein-conjugated antibody (NRP-body). The effect of NRP-body on infiltration of NK cells into primary and metastatic pancreatic cancer was evaluated in vitro and in murine pancreatic ductal adenocarcinoma models. The NRP-body increased NK-cell infiltration of tumors along a CXCL16 gradient (CXCL16 is cleaved from the NRP-body by furin expressed on the surface of pancreatic cancer cells). CXCL16 induced NK-cell infiltration by activating RhoA via the ERK signaling cascade. Administration of the NRP-body to pancreatic cancer model mice increased tumor tissue infiltration of transferred NK cells and reduced the tumor burden compared with that in controls. Overall survival of NRP-body–treated mice (even the metastasis models) was higher than that of mice receiving NK cells alone. In conclusion, increasing NK-cell infiltration into tumor tissues improved response to this cancer immunotherapy. The combination of an NRP-body with NK-cell therapy might be useful for treating pancreatic cancer.

The bacterial flagellum is assembled by a multicomponent transport apparatus categorized as a type III secretion system. The secretion of proteins that assemble into the flagellum is driven by the proton motive force. The periplasmic protein FlhE is a member of the flhBAE operon in the majority of bacteria where FlhE is found. FlhA and FlhB are established components of the flagellar type III secretion system. The absence of FlhE results in a proton leak through the flagellar system, inappropriate secretion patterns, and cell death, indicating that FlhE regulates an important aspect of proper flagellar biosynthesis. We isolated FlhE from the periplasm of Salmonella and solved its structure to 1.5 A resolution. The structure reveals a β-sandwich fold, with no close structural homologs. Possible roles of FlhE, including that of a chaperone, are discussed.

The present study aimed to quantify the content of trans-cinnamic acid (CA) in Cinnamomum japonicum, C. loureirii, and C. camphora and the commercial application of CA using high performance liquid chromatography (HPLC). A C18 column was used, with water/methanol as the mobile phase gradient. The highest content of CA was observed in the bark of C. loureirii (16.97 mg/g) and cinnamon powder A (47.60 mg/g). The lowest content of CA was observed in leaf and heartwood of C. japonicum (0.10 and 0.10 mg/g, respectively) and cinnamon powder C (22.87 mg/g). This result could be utilized as a guideline for the analysis of the commercial applications of Cinnamomum.

Objective Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) promotes hepatic gluconeogenesis by activating HNF4α and FoxO1. PGC-1α expression in the liver is highly elevated in obese and diabetic conditions, leading to increased hepatic glucose production. We previously showed that the spliced form of X-box binding protein 1 (XBP1s) suppresses FoxO1 activity and hepatic gluconeogenesis. The shared role of PGC-1α and XBP1s in regulating FoxO1 activity and gluconeogenesis led us to investigate the probable interaction between PGC-1α and XBP1s and its role in glucose metabolism. Methods We investigated the biochemical interaction between PGC-1α and XBP1s and examined the role of their interaction in glucose homeostasis using animal models. Results We show that PGC-1α interacts with XBP1s, which plays an anti-gluconeogenic role in the liver by suppressing FoxO1 activity. The physical interaction between PGC-1α and XBP1s leads to suppression of XBP1s activity rather than its activation. Upregulating PGC-1α expression in the liver of lean mice lessens XBP1s protein levels, and reducing PGC-1α levels in obese and diabetic mouse liver restores XBP1s protein induction. Conclusions Our findings reveal a novel function of PGC-1α as a suppressor of XBP1s function, suggesting that hepatic PGC-1α promotes gluconeogenesis through multiple pathways as a co-activator for HNF4α and FoxO1 and also as a suppressor for anti-gluconeogenic transcription factor XBP1s., Highlights • XBP1s suppresses FoxO1 activity and hepatic gluconeogenesis. • PGC-1α physically interacts with XBP1s and functions as a co-suppressor of XBP1s in the liver. • The suppression of XBP1s activity by PGC-1α leads to impaired glucose homeostasis in obese mice. • Hepatic PGC-1α promotes gluconeogenesis as a co-activator and also as a co-suppressor.

Background. Biological facilitation is a type of relationship between two taxa that benefits at least one of the participants and harms neither. Although invasive species are widely known to compete with native taxa, recent studies suggest that invasive and native species can have positive relationships. This study aims to examine the biological facilitation of the germination of invasive Miconia calvescens by giant tree fern Angiopteris evecta, native to French Polynesia. Methods. Field surveys were conducted to measure A. evecta and M. calvescens by applying the 10×10 m2 quadrat survey method. The density of seedlings, saplings, and matures of M. calvescens growing on the rhizomes of A. evecta and on bare soil was compared, and the correlation between the size of the rhizomes and the number of M. calvescens growing on them was verified. Two separate sets of nutrient measurements of substrates were performed to compare the nutrient of A. evecta rhizome and other environments (abiotic and potential biotic environments). Leaf decomposition rate of five dominant tree species was compared to verify whether A. evecta has quickly decomposing leaves, and therefore induce the germination of M. calvescens indirectly. Results. Field surveys show that there is a greater number of seedlings and saplings of M. calvescens growing on the rhizomes of A. evecta as compared to bare soil. Furthermore, there is a positive correlation between the size of rhizomes and the number of M. calvescens growing on them. Substrates of A. evecta had higher phosphorus and potassium contents compared to other soils and substrates, but did not differ from bark of other tree species that could potentially offer favorable microenvironments. A. evecta has quickly decomposing leaves. Discussion. A. evecta facilitates the germination of M. calvescens, supported by the much higher number of seedlings and saplings growing on the rhizomes and the positive correlation between the size of the rhizome and the number of M. calvescens growing on it. Microslopes on the rhizomes of A. evecta prevent leaf litter from accumulating on the rhizomes, and enable more sunlight to reach and facilitate the germination of M. calvescens seeds. Also, quickly decomposing leaves of A. evecta prevent the accumulation of leaf litter on the ground and enable more light to reach seed bank. Although the chemical components is not different from other tree species, physical structure of the rhizome and consequent higher light availability, and higher amount of potassium than bare soil would be the possible reason for the facilitation. Biological facilitation of the germination of invasive M. calvescens by native A. evecta can give better understanding on the invasion success and the relationship between the native and invasive species. Invasion of A. evecta can induce and promote further invasion of M. calvescens. Therefore, thorough management of ongoing invasion of A. evecta is particularly required.

In this study, we investigated the anti-inflammatory effects and mechanisms of cirsimaritin isolated from an ethanol extract of the aerial parts of Cirsium japonicum var. maackii Maxim. using RAW264.7 cells. The extract and its flavonoid cirsimaritin inhibited nitric oxide (NO) production and inducible nitric oxide synthase expression in RAW264.7 cells. Cirsimaritin inhibited interleukin-6, tumor necrosis factor-α, and NO production in a concentration-dependent manner in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. From a western blot study, pretreatment with cirsimaritin inhibited phosphorylation/degradation of IκBα and phosphorylation of Akt in LPS-stimulated RAW264.7 cells. Moreover, cirsimaritin suppressed activation of LPS-induced transcription factors, such as c-fos and signal transducer and activator of transcription 3 (STAT3), in RAW264.7 cells. Collectively, these results show that cirsimaritin possesses anti-inflammatory activity, which is regulated by inhibition of c-fos and STAT3 phosphorylation in RAW264.7 cells.

Introduction. Planarians are renowned for their regenerative ability due to pluripotent stem cells, as well as their peculiar photophobic response. However, few facts are known about their aggregational behavior. This study aims to reveal the effect of light on aggregational behavior. Reynierse (1966) suggested that light has a negative effect on the formation of aggregations. However, one of his objectives for aggregational behavior was inappropriate. This study reevaluated the effect of existence of light on aggregational behavior, as well as ascertained the effect of wavelength on the formation of aggregations. Methods. In this study, the ratio of individuals participating in aggregations was measured as a criterion to determine aggregational behavior. Aggregational behavior was measured after two hours from the initial exposure to different light sources. The behaviors under white LED light and under shade were compared, as well as the behaviors under five different light sources: infrared lamp, red, green, blue LED, and ultraviolet lamp. Results. The existence of light interfered the formation of aggregations (t-test, p < 0.0001), which supports the former study of Reynierse. Also, aggregational behavior differed under different wavelengths (ANOVA, p < 0.0001). Except for the infrared light which emitted a wide range of wavelengths, the behavior showed hierarchy: decreasing aggregational behavior in accordance with decreasing wavelength. UV light has the most significant negative effect on the formation of aggregations. Discussion. Exposure to light caused negative effects on performing aggregational behavior. Participation in aggregations appears to be influenced by photophobic response, especially under lights of short wavelength. Disintegrating aggregations under exposure to lights can potentially bring evolutionary benefit. This behavior possibly makes the aggregating planarians altogether exposed to a higher risk or predation, considering that they lack defense mechanisms. Planarians can lower the risk and continue the populations by disintegrating the aggregational behavior under the existence of UV and lights of higher wavelength, which are indicatives of daytime. Understanding aggregational behavior of animals of a lower order would give better insight on general herding behavior, and potentially help interpreting more complex behaviors of higher animals.

Ramie (Boehmeria nivea) is a perennial herbaceous plant belonging to the family Urticaceae. It was used in folk remedies for diuretic or anti-pyretic purposes and as an hepatoprotective, anti-oxidant, and anti-inflammation agent. In this study, we investigated the composition of free sugars, amino acids, fatty acids, organic acids, and total polyphenol contents in parts of ramie (root, stem, and leaf) and different harvest areas (10 areas). Overall, free sugars were found as sucrose, glucose, fructose, and galactose at concentrations ranging from 24.5 to 1173.8 mg/g. Amino acids lysine, threonine, tyrosine, phenylalanine, and histidine were detected at concentrations of 33.8 to 3735.3 mg/g. Major fatty acids were linoleic acid, palmitic acid, and linolenic acid at concentrations of 7.3 to 364.4 mg/g. In organic acids, the concentration of malic acid was highest of all with 672.2 mg/g. The content of free sugars, amino acids, fatty acids, organic acids, and total polyphenol was higher in leaves than in roots and stems. In contrast, the total polyphenol content was higher in roots with 33.7 - 219.4 mg/g than in leaves or in stems. As seen in collecting region, the contents of free sugars, amino acids, fatty acids, organic acids, and total polyphenol of Bn-33, 39, 55, 65, and 90 were higher than other samples. Chemical compositions of different parts of ramie are important factors to consider in manufacturing functional foods. The results of this study provide fundamental information on the chemical compositions of ramie parts and would help develop new functional foods from ramie leaves or the whole plant.

Increased mammalian target of rapamycin complex 1 (mTORC1) activity has been suggested to play important roles in development of insulin resistance in obesity. mTORC1 hyperactivity also increases endoplasmic reticulum (ER) stress, which in turn contributes to development of insulin resistance and glucose intolerance. Increased IRS1 phosphorylation at Ser307 in vitro is correlated with mTORC1- and ER stress-induced insulin resistance. This phosphorylation site correlates strongly with impaired insulin receptor signaling in diabetic mice and humans. In contrast, evidence from knock-in mice suggests that phosphorylation of IRS1 at Ser307 is actually required to maintain insulin sensitivity. To study the involvement of IRS1(Ser307) phosphorylation in mTORC1-mediated glucose intolerance and insulin sensitivity in vivo, we investigated the effects of liver specific TSC1 depletion in IRS1(Ser307Ala) mice and controls. Our results demonstrate that blockade of IRS1(Ser307) phosphorylation in vivo does not prevent mTORC1-mediated glucose intolerance and insulin resistance.

Misfolding of exportable proteins can trigger endocrinopathies. For example, misfolding of insulin can result in autosomal dominant mutant INS gene–induced diabetes of youth, and misfolding of thyroglobulin can result in autosomal recessive congenital hypothyroidism with deficient thyroglobulin. Both proinsulin and thyroglobulin normally form homodimers; the mutant versions of both proteins misfold in the ER, triggering ER stress, and, in both cases, heterozygosity creates potential for cross-dimerization between mutant and WT gene products. Here, we investigated these two ER-retained mutant secretory proteins and the selectivity of their interactions with their respective WT counterparts. In both cases and in animal models of these diseases, we found that conditions favoring an increased stoichiometry of mutant gene product dominantly inhibited export of the WT partner, while increased relative level of the WT gene product helped to rescue secretion of the mutant partner. Surprisingly, the bidirectional consequences of secretory blockade and rescue occur simultaneously in the same cells. Thus, in the context of heterozygosity, expression level and stability of WT subunits may be a critical factor influencing the effect of protein misfolding on clinical phenotype. These results offer new insight into dominant as well as recessive inheritance of conformational diseases and offer opportunities for the development of new therapies.

Food allergy (FA) is a common allergic disease without any currently available effective drug therapies. Mucosal mast cells (MMCs) play a particularly important role in FA, and the increase in their cytosolic Ca2+ concentration ([Ca2+]cyt) is considered to be a principal component of the degranulation process. However, the mechanisms governing Ca2+ influx remain poorly understood in MMCs. Recent reports have highlighted the functions of the transient receptor potential melastatin 2 (TRPM2) channel in immunocytes, including its role in monocyte chemokine production and macrophage phagocytic activity. Although TRPM2 gene expression has been demonstrated in mast cells, the significance of such expression remains virtually unknown. In this study, we found that antigen-stimulated degranulation was significantly reduced in mucosal-type bone marrow-derived mast cells (mBMMCs) prepared from TRPM2-knockout (TRPM2-KO) mice (TRPM2-KO mBMMCs) and was suppressed following the administration of three TRPM2 inhibitors with different chemical structures, including econazole, flufenamic acid (FFA), and 2-aminoethoxydiphenyl borate. Furthermore, the antigen-stimulated increase in [Ca2+]cyt was significantly decreased in TRPM2-KO mBMMCs and was also suppressed by the TRPM2 inhibitors econazole and FFA. In addition, thapsigargin-induced increase in [Ca2+]cyt was significantly decreased in TRPM2-KO mBMMCs. These results suggest that TRPM2 may participate in antigen-induced extracellular Ca2+ influx and subsequent degranulation. In addition, TRPM2 inhibitors were shown to improve food allergic reactions in a mouse model. Together, these results suggest that TRPM2 inhibitors suppress MMC degranulation via regulation of the increase in [Ca2+]cyt. Thus, TRPM2 may play a key role in degranulation by modulating intracellular Ca2+ in MMCs.

Recent advances in neuroscience and immunology have revealed a bidirectional interaction between the nervous and immune systems. Therefore, the gastrointestinal tract may be modulated by neuro-immune interactions, but little information about this interaction is available. Intrinsic and extrinsic primary afferent neurons play an important role in this interaction because of their abilities to sense, process and transmit various information in the intestinal microenvironment. Calcitonin gene-related peptide (CGRP) is exclusively contained in intrinsic and extrinsic primary afferent neurons in the mouse intestine. Therefore, we investigated CGRP-immunoreactive nerve fibers in the colonic mucosa of mice induced to develop food allergy. CGRP-immunoreactive nerve fibers were specifically increased with the development of food allergy, and the fibers were juxtaposed to mucosal mast cells in the colonic mucosa of food allergy mice. Denervation of the extrinsic afferent neurons using neonatal capsaicin treatment did not affect the development of food allergy or the density and distribution of CGRP-immunoreactive nerve fibers in the colonic mucosa of food allergy mice. Furthermore, the mRNA and plasma level of CGRP was increased in food allergy mice. These results suggest that the activation of intrinsic primary afferent neurons in the intestine contributes to the development and pathology of food allergy.

flhE belongs to the flhBAE flagellar operon in Enterobacteria, whose first two members function in Type III secretion (T3S). In Salmonella enterica, absence of FlhE affects swarming, but not swimming, motility. Based on a chance observation of a 'green' colony phenotype of flhE mutants on pH indicator plates containing glucose, we have established that this phenotype is associated with lysis of flagellated cells in an acidic environment created by glucose metabolism. The flhE mutant phenotype of Escherichia coli is similar overall to that of S. enterica but is seen in the absence of glucose and, unlike in S. enterica, causes a substantial growth defect. flhE mutants have a lowered cytoplasmic pH in both bacteria, indicative of a proton leak. GFP reporter assays indicate that the leak is dependent on the flagellar system, is present before the T3S system switches to secretion of late substrates, and gets worse after the switch and upon filament assembly, leading to cell lysis. We show that FlhE is a periplasmic protein that co-purifies with flagellar basal bodies. FlhE may act as a plug or a chaperone to regulate proton flow through the flagellar T3S system.

Here we show that p38 mitogen-activated protein kinase (p38 MAPK) phosphorylates the spliced form of X-box binding protein 1 (Xbp1s) on its Thr48 and Ser61 residues and greatly enhances its nuclear migration in mice, whereas mutation of either residue to alanine substantially reduces its nuclear translocation and activity. We also show that p38 MAPK activity is markedly reduced in the livers of obese mice compared with lean mice. Further, we show that activation of p38 MAPK by expression of constitutively active MAP kinase kinase 6 (MKK6Glu) greatly enhances nuclear translocation of Xbp1s, reduces endoplasmic reticulum stress and establishes euglycemia in severely obese and diabetic mice. Hence, our results define a crucial role for phosphorylation on Thr48 and Ser61 of Xbp1s in the maintenance of glucose homeostasis in obesity, and they suggest that p38 MAPK activation in the livers of obese mice could lead to a new therapeutic approach to the treatment of type 2 diabetes.

Increased endoplasmic reticulum (ER) stress is one of the central mechanisms that lead to dysregulated metabolic homeostasis in obesity. It is thus crucial to understand the underpinnings of the mechanisms that lead to the development of ER stress. A high level of ER Ca 2+ is imperative for maintenance of normal ER function and this high Ca 2+ concentration of ER is maintained by sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA). Here, we show that SERCA2b protein and mRNA levels are dramatically reduced in the liver of obese mice and restoration of SERCA2b in the liver of obese and diabetic mice alleviates ER stress, increases glucose tolerance, and significantly reduces the blood glucose levels. Furthermore, overexpression of SERCA2b in the liver of obese mice significantly reduces the lipogenic gene expression and the triglyceride content in the liver. Our results document the importance of SERCA2b in dysregulated glucose and lipid homeostasis in the liver of obese mice and suggest development of drugs to increase SERCA2b activity for treatment of type 2 diabetes and nonalcoholic steatohepatitis.

Gentians (Gentiana triflora, G. scabra) are one of the most important ornamental plants, however, repellent odor emitted from their flowers makes them undesirable in indoor floral utilization. It is necessary to understand the component of their flower scent for breeding of new cultivars without repellent odor. Floral scent compounds of gentians were analyzed by the method of Head Space-Solid Phase Micro Extraction with GC-MS (HS-SPME/GC-MS). The level of scent emission from gentian flowers increased with the age of the flower and reached a maximum at three days after anthesis and decreased thereafter. Their flowers emitted volatiles throughout the day, and the amounts were higher at night than during the day. A total of 98 compounds were detected in 13 genotypes examined, and quantitative and qualitative variations were found. Of these compounds, several kinds of lilac aldehydes (terpenoids) were only detected in G. scabra. The results of principal component analysis showed that cultivars/lines classified in the same species were grouped with each other. Of the 13 genotypes, Ashiro-no-Natsu emitted the most abundant volatiles and has strong unpleasant odor. 2-Methylbutanoic acid is considered to be one of the major constituents responsible for the unpleasant odor of gentians.

This study was conducted to investigate the sex pheromone composition of Palpita (=Diaphania) indica (Saunders) (Lepidoptera: Pyralidae) in Korea. Two sex pheromone components, E11-16:Al and E,E-10,12-16:Al, were identified by GC and GC-EAD analysis of sex pheromone gland extracts. The mean ratios of the two components, E11-16:Al and E,E-10,12-16:Al, were about 6.5:3.5 and 7.5:2.5 in gland extracts and in SPME collection, respectively. In field bioassays, maximum attraction occurred in traps baited with a 7:3 ratio of E11-16:Al and E,E-10,12-16:Al. The head extracts of P. indica stimulated the sex pheromone production of P. indica, as well as Hez-PBAN and PssPT, indicating that a PBAN-like substance exists in the head extracts of P. indica. Whole-mount immunocytochemistry showed that three groups of neurosecretory cells showed PBAN-like immunoreactivity in the SEG of P. indica. The PBAN-like immunoreactivity connected to the Corpora Cardiaca, a neurohemal organ. Also, PBAN-like immunoreactivity was found in the brain and in the thoracic and third/fourth abdominal ganglia. The addition of sex pheromone components of Peridroma saucia to the sex pheromone of P. indica greatly improved the attraction of P. indica males. The mixing of the sex pheromone components of S. exigua did not significantly increase the catches of P. indica, while the sex pheromone of H. armigera completely inhibited the attractiveness.

It has been suggested that a thyroglobulin (Tg)-R19K missense mutation may be a newly identified cause of human congenital goiter, which is surprising for this seemingly conservative substitution. Here, we have examined the intracellular fate of recombinant mutant Tg expressed in COS-7 cells. Incorporation of the R19K mutation largely blocked Tg secretion, and this mutant was approximately 90% degraded intracellularly over a 24-h period after synthesis. Before its degradation, the Tg-R19K mutant exhibited abnormally increased association with molecular chaperones BiP, calnexin, and protein disulfide isomerase, and was unable to undergo anterograde advance from the endoplasmic reticulum (ER) through the Golgi complex. Inhibitors of proteasomal proteolysis and ER mannosidase-I both prevented ER-associated degradation of the Tg-R19K mutant and increased its association with ER molecular chaperones. ER quality control around Tg residue 19 is not dependent upon charge but upon side-chain packing, because Tg-R19Q was efficiently secreted. Whereas a Tg mutant truncated after residue 174 folds sufficiently well to escape ER quality control, introduction of the R19K point mutation blocked its secretion. The data indicate that the R19K mutation induces local misfolding in the amino-terminal domain of Tg that has global effects on Tg transport and thyroid hormonogenesis.

Dendritic cell (DC) based cancer vaccines represent a promising immunotherapeutic strategy against cancer. To enhance the modest immunogenicity of DC vaccines, various adjuvants are often incorporated. Particularly, most of the common adjuvants are derived from bacteria. In the current study, we evaluate the use of a human pancreatic cancer derived protein, pancreatic adenocarcinoma upregulated factor (PAUF), as a novel DC vaccine adjuvant. We show that PAUF can induce activation and maturation of DCs and activate NFkB by stimulating the Toll-like receptor signaling pathway. Furthermore, vaccination with PAUF treated DCs pulsed with E7 or OVA peptides leads to generation of E7 or OVA-specific CD8+ T cells and memory T cells, which correlate with long term tumor protection and antitumor effects against TC-1 and EG.7 tumors in mice. Finally, we demonstrated that PAUF mediated DC activation and immune stimulation are dependent on TLR4. Our data provides evidence supporting PAUF as a promising adjuvant for DC based therapies, which can be applied in conjunction with other cancer therapies. Most importantly, our results serve as a reference for future investigation of human based adjuvants.

Mannan endo-1,4-β-mannosidase (commonly known as β-mannanase) catalyzes a random cleavage of the β-d-1,4-mannopyranosyl linkage in mannan polymers. The enzyme has been utilized in biofuel production from lignocellulose biomass, as well as in production of mannooligosaccharides (MOS) for applications in feed and food industries. We aimed to obtain a β-mannanase, for such mannan polymer utilization, from actinomycetes strains isolated in Indonesia. Strains exhibiting high mannanase activity were screened, and one strain belonging to the genus Kitasatospora was selected. We obtained a β-mannanase from this strain, and an amino acid sequence of this Kitasatospora β-mannanase showed a 58–71% similarity with the amino acid sequences of Streptomyces β-mannanases. The Kitasatospora β-mannanase showed a significant level of activity (944 U/mg) against locust bean gum (0.5% w/v) and a potential for oligosaccharide production from various mannan polymers. The β-mannanase might be beneficial particularly in the enzymatic production of MOS for applications of mannan utilization. Electronic supplementary material The online version of this article (doi:10.1186/s13568-017-0401-6) contains supplementary material, which is available to authorized users.

Type 2 diabetes (T2D) is a worldwide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1α acetylation in the liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC-1α acetylation in cells and identified small molecules that increase PGC-1α acetylation, suppress gluconeogenic gene expression, and reduce glucose production in hepatocytes. On the basis of potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity, and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D.

Ulcerative colitis is a chronic inflammatory disease that frequently progresses to colon cancer. The tumor-promoting effect of inflammation is now widely recognized and understood. Recent studies have revealed that treatment with nicotine ameliorates colitis in humans and experimental murine models, whereas the effect of nicotine on colitis-associated colonic tumorigenesis remains unclear. In the present study, we examined the effect of nicotine on the development of acute colitis and colitis-associated cancer (CAC). The acute colitis model was induced by treatment with 3% dextran sulfate sodium (DSS) for 7 days, whereas the CAC model was induced by a combination of azoxymethane and repeated DSS treatment. Nicotine and a selective agonist of the α7-nicotinic acetylcholine receptor (α7-nAChR) reduced the severity of DSS-induced acute colonic inflammation. In addition, the suppressive effect of nicotine on acute colitis was attenuated by an antagonist of α7-nAChR. Furthermore, nicotine inhibited the IL-6 production of CD4 T cells in the DSS-induced inflamed colonic mucosa. We found that nicotine significantly reduced the number and size of colonic tumors in mice with CAC. Nicotine markedly inhibited the elevation of TNF-α and IL-6 mRNA as well as phosphorylated signal transducer and activator of transcription (Stat) 3 expression in the colons of the tumor model mice. These results demonstrate that nicotine suppresses acute colitis and colitis-associated tumorigenesis, and this effect may be associated with the activation of α7-nAChR. Furthermore, it is presumed that nicotine downregulates the expression of inflammatory mediators such as IL-6/Stat3 and TNF-α, thereby reducing the colonic tumorigenesis associated with chronic colitis.

Neuro-immune interaction in the gut is substantially involved in the maintenance of intestinal immune homeostasis and the pathology of intestinal immune diseases. We have previously demonstrated that mucosal mast cells and nerve fibers containing CGRP, a neurotransmitter of intrinsic enteric sensory neurons, are markedly increased and exist in close proximity to each other in the colon of food allergy (FA) mice. In the present study, a CGRP-receptor antagonist BIBN4096BS significantly alleviated allergic symptoms in the murine FA model. In addition, the elevated numbers of mucosal mast cells in the proximal colon of FA mice were significantly decreased in that of BIBN4096BS-treated FA mice. Thus, we investigated the effects of CGRP on calcium-independent process in degranulation of mucosal mast cells since CGRP increases intracellular cAMP levels, but not Ca(2+) concentration. CGRP did not alter a calcium ionophore A23187-increased cytosolic Ca(2+) concentration in mucosal-type bone marrow-derived mast cells (mBMMCs), but did augment microtubule reorganization in resting and A23187-activated mBMMCs. Furthermore, CGRP alone failed to cause the degranulation of mBMMCs, but CGRP significantly enhanced the degranulation of mBMMCs induced by A23187. Together, these data indicate that CGRP- enhanced microtubule reorganization augments IgE-independent/non-antigenic stimuli-induced mucosal mast cell degranulation, thereby contributing to the development of FA.

It is widely believed that inflammation associated with obesity has an important role in the development of type 2 diabetes. IκB kinase beta (IKKβ) is a crucial kinase that responds to inflammatory stimuli such as Tumor Necrosis Factor α (TNFα), by initiating a variety of intracellular signaling cascades, and is considered to be a key element in the inflammation-mediated development of insulin resistance. We show here, contrary to expectation, that IKKβ-mediated inflammation is a positive regulator of hepatic glucose homeostasis. IKKβ phosphorylates the spliced form of X-Box Binding Protein 1 (XBP1s) and increases the activity of XBP1s. We have used three experimental approaches to enhance the IKKβ activity in the liver of obese mice, and observed increased XBP1s activity, reduced ER stress, and a significant improvement in insulin sensitivity and consequently in glucose homeostasis. Our results reveal a beneficial role of IKKβ-mediated hepatic inflammation in glucose homeostasis.

The endoplasmic reticulum (ER) is a central organelle for protein biosynthesis, folding, and traffic. Perturbations in ER homeostasis create a condition termed ER stress and lead to activation of the complex signaling cascade called the unfolded protein response (UPR). Recent studies have documented that the UPR coordinates multiple signaling pathways and controls various physiologies in cells and the whole organism. Furthermore, unresolved ER stress has been implicated in a variety of metabolic disorders, such as obesity and type 2 diabetes. Therefore, intervening in ER stress and modulating signaling components of the UPR would provide promising therapeutics for the treatment of human metabolic diseases.

Targeted molecular imaging with hyaluronic acid (HA) has been highlighted in the diagnosis and treatment of CD44-overexpressing cancer. CD44, a receptor for HA, is closely related to the growth of cancer including proliferation, metastasis, invasion, and angiogenesis. For the efficient detection of CD44, we fabricated a few kinds of HA-modified MnFe2O4 nanocrystals (MNCs) to serve as specific magnetic resonance (MR) contrast agents (HA-MRCAs) and compared physicochemical properties, biocompatibility, and the CD44 targeting efficiency. Hydrophobic MNCs were efficiently phase-transferred using aminated polysorbate 80 (P80) synthesized by introducing spermine molecules on the hydroxyl groups of P80. Subsequently, a few kinds of HA-MRCAs were fabricated, conjugating different ratios of HA on the equal amount of phase-transferred MNCs. The optimized conjugation ratio of HA against magnetic content was identified to exhibit not only effective CD44 finding ability but also high cell viability through in vitro experiments. The results of this study demonstrate that the suggested HA-MRCA shows strong potential to be used for accurate tumor diagnosis.

CTHRC1 (collagen triple-helix repeat-containing 1), a protein secreted during the tissue-repair process, is highly expressed in several malignant tumors, including pancreatic cancer. We recently showed that CTHRC1 has an important role in the progression and metastasis of pancreatic cancer. Although CTHRC1 secretion affects tumor cells, how it promotes tumorigenesis in the context of the microenvironment is largely unknown. Here we identified a novel role of CTHRC1 as a potent endothelial activator that promotes angiogenesis by recruiting bone marrow-derived cells to the tumor microenvironment during tumorigenesis. Recombinant CTHRC1 (rCTHRC1) enhanced endothelial cell (EC) proliferation, migration and capillary-like tube formation, which was consistent with the observed increases in neovascularization in vivo. Moreover, rCTHRC1 upregulated angiopoietin-2 (Ang-2), a Tie2 receptor ligand, through ERK-dependent activation of AP-1 in ECs, resulting in recruitment of Tie2-expressing monocytes (TEMs) to CTHRC1-overexpressing tumor tissues. Treatment with a CTHRC1-neutralizing antibody-abrogated Ang-2 expression in the ECs in vitro. Moreover, administration of a CTHRC1-neutralizing antibody to a xenograft mouse model reduced the tumor burden and infiltration of TEMs in the tumor tissues, indicating that blocking the CTHRC1/Ang-2/TEM axis during angiogenesis inhibits tumorigenesis. Collectively, our findings support the hypothesis that CTHRC1 induction of the Ang-2/Tie2 axis mediates the recruitment of TEMs, which are important for tumorigenesis and can be targeted to achieve effective antitumor responses in pancreatic cancers.