Antiseptic Functions of CGK012 against HMGB1-Mediated Septic Responses.

High mobility group box 1 (HMGB1), a protein with important functions, has been recognized as a potential therapeutic target for the treatment of sepsis. One possible mechanism for this is that inhibiting HMGB1 secretion can exert antiseptic effects, which can restore the integrity of the vascular barrier. (7S)-(+)-cyclopentyl carbamic acid 8,8-dimethyl-2-oxo-6,7-dihydro-2H,8H-pyrano[3,2-g]chromen-7-yl-ester (CGK012) is a newly synthesized pyranocoumarin compound that could function as a novel small-molecule inhibitor of the Wnt/ß-catenin signaling pathway. However, no studies have yet determined the effects of CGK012 on sepsis. We investigated the potential of CGK012 to attenuate the excessive permeability induced by HMGB1 and enhance survival rates in a mouse model of sepsis with reduced HMGB1 levels following lipopolysaccharide (LPS) treatment. In both LPS-stimulated human endothelial cells and a mouse model exhibiting septic symptoms due to cecal ligation and puncture (CLP), we assessed proinflammatory protein levels and tissue damage biomarkers as indicators of reduced vascular permeability. CGK012 was applied after induction in human endothelial cells exposed to LPS and the CLP-induced mouse model of sepsis. CGK012 effectively mitigated excessive permeability and suppressed HMGB1 release, resulting in improved vascular stability, decreased mortality, and enhanced histological conditions in the mouse model of CLP-induced sepsis. In conclusion, our findings indicate that CGK012 treatment in mice with CLP-induced sepsis diminished HMGB1 release and increased the survival rate, suggesting its potential as a pharmaceutical intervention for sepsis.

Therapeutic Effects of Cornuside on Particulate Matter-Induced Lung Injury.

Particulate matter (PM) is a mixture comprising both organic and inorganic particles, both of which are hazardous to health. The inhalation of airborne PM with a diameter of ≤2.5 µm (PM2.5) can cause considerable lung damage. Cornuside (CN), a natural bisiridoid glucoside derived from the fruit of Cornus officinalis Sieb, exerts protective properties against tissue damage via controlling the immunological response and reducing inflammation. However, information regarding the therapeutic potential of CN in patients with PM2.5-induced lung injury is limited. Thus, herein, we examined the protective properties of CN against PM2.5-induced lung damage. Mice were categorized into eight groups (n = 10): a mock control group, a CN control group (0.8 mg/kg mouse body weight), four PM2.5+CN groups (0.2, 0.4, 0.6, and 0.8 mg/kg mouse body weight), and a PM2.5+CN group (0.2, 0.4, 0.6, and 0.8 mg/kg mouse body weight). The mice were administered with CN 30 min following intratracheal tail vein injection of PM2.5. In mice exposed to PM2.5, different parameters including changes in lung tissue wet/dry (W/D) lung weight ratio, total protein/total cell ratio, lymphocyte counts, inflammatory cytokine levels in the bronchoalveolar lavage fluid (BALF), vascular permeability, and histology were examined. Our findings revealed that CN reduced lung damage, the W/D weight ratio, and hyperpermeability caused by PM2.5. Moreover, CN reduced the plasma levels of inflammatory cytokines produced because of PM2.5 exposure, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and nitric oxide, as well as the total protein concentration in the BALF, and successfully attenuated PM2.5-associated lymphocytosis. In addition, CN substantially reduced the expression levels of Toll-like receptors 4 (TLR4), MyD88, and autophagy-related proteins LC3 II and Beclin 1, and increased protein phosphorylation of the mammalian target of rapamycin (mTOR). Thus, the anti-inflammatory property of CN renders it a potential therapeutic agent for treating PM2.5-induced lung injury by controlling the TLR4-MyD88 and mTOR-autophagy pathways.

Ameliorative Effect of Ginsenoside Rg6 in Periodontal Tissue Inflammation and Recovering Damaged Alveolar Bone.

Periodontal disease is a chronic disease with a high prevalence, and in order to secure natural materials to prevent oral diseases, new materials that protect periodontal tissue from inflammation are being sought. Genes were identified using real-time quantitative polymerase chain reaction (RT-qPCR), and proteins were confirmed using Western blot. Dichlorodihydrofluorescein diacetate (DCF-DA) analysis was used, and the antibacterial effects were confirmed through Minimum Inhibitory Concentration (MIC) and Minimal Bactericidal Concentration (MBC) analysis. To confirm this effect in vivo, Sprague-Dawley rats, in which periodontitis was induced using ligation or Lipopolysaccharide of Porphyromonas gingivalis (PG-LPS), were used. In vitro experiments using human periodontal ligament (HPDL) cells stimulated with PG-LPS showed that Ginsenoside Rg6 (G-Rg6) had anti-inflammatory, antibacterial, antioxidant, and osteoblast differentiation properties. In vivo, G-Rg6 was effective in Sprague-Dawley rats in which periodontitis was induced using ligation or PG-LPS. Therefore, Ginsenoside Rg6 shows potential effectiveness in alleviating periodontitis.

Egg White Protein Promotes Developmental Growth in Rodent Muscle Independently of Leucine Content.

BACKGROUND: Leucine has unique anabolic properties, serving as a nutrient signal that stimulates muscle protein synthesis. OBJECTIVE: We tested whether the leucine concentration is the only factor determining protein quality for muscle development. METHODS: We selected 3 dietary proteins: casein (CAS), egg white protein (EWP), and albumin (ALB), representing the leucine concentrations of ∼8.3%, 7.7%, and 6.7% of the total protein (wt:wt), respectively. In the chronic feeding experiment, these proteins were pair-fed to growing male Wistar rats [110-135 g body weight (BW)] for 14 d as a protein source, providing 10% of total energy intake, after which soleus and extensor digitorum longus (EDL) muscles were used to estimate muscle growth. In the acute administration experiment, we injected CAS, ALB, and EWP to rats by oral gavage (0.3 g protein/100 g BW), and after 1 or 3 h EDL muscle was excised for capillary electrophoresis-MS-based metabolomics. In another chronic feeding experiment, rats were pair-fed either CAS or a CAS diet supplemented with arginine to the same level as in the EWP diet for 14 d. RESULTS: At the end of the 14-d feeding, soleus and EDL muscle weight was 20% and 17% higher, respectively, when rats were fed EWP as compared with CAS (P < 0.05). In addition, the 14-d EWP diet increased the expression of p70S6K by 117% compared with CAS (P < 0.05). These results suggest the possibility that some amino acids (excluding leucine), derived from EWP, promote muscle growth. Metabolomics analysis showed that muscle arginine concentration, following acute protein administration, appeared to match muscle growth over the 14-d feeding period. In addition, 14-d arginine supplementation to a CAS diet increased EDL muscle weight by 15% when compared with the plain CAS diet (P < 0.05). CONCLUSIONS: EWP promotes rat developmental muscle growth compared with CAS, which can be partly explained by the arginine-rich EWP.

Short-term running exercise alters DNA methylation patterns in neuronal nitric oxide synthase and brain-derived neurotrophic factor genes in the mouse hippocampus and reduces anxiety-like behaviors.

Running exercise has beneficial effects on brain health. However, the effects of relatively short-term running exercise (STEx) on behavior, and its underlying signaling pathways, are poorly understood. In this study, we evaluated the possibility that the regulation by STEx of brain-derived neurotrophic factor (BDNF) and neuronal nitric oxide synthase (nNOS, encoded by NOS1), which are important molecules for anxiety regulation, might involve mechanisms of epigenetic modification, such as DNA methylation. C57BL/6J male mice were divided into sedentary (SED, n = 12) and STEx (EX, n = 15) groups; STEx was conducted with the mice for a duration of 11 days. STEx reduced anxiety-like behaviors, and STEx reduced Nos1α and increased Bdnf exon I and IV mRNA levels in the hippocampus. Interestingly, behavioral parameters were associated with Bdnf exon I and IV and Nos1α mRNA levels in the ventral, but not dorsal, hippocampal region. However, STEx had no effect on peroxisome proliferator-activated receptor-γ coactivator 1α (Pgc-1α) or fibronectin type III domain-containing 5 (Fndc5) mRNA levels, which are relatively long-term exercise-induced upstream regulators of BDNF. In parallel with gene expression changes, we found, for the first time, that STEx downregulated Bdnf promoter IV and upregulated Nos1 DNA methylation levels in the hippocampus, and these patterns were partially different between the dorsal and ventral regions. These findings suggest that the beneficial effects of running exercise on mood regulation may be controlled by alterations in epigenetic mechanisms, especially in the ventral hippocampus. These effects occur even after a relatively short-term period of exercise.

Taurine supplementation enhances endurance capacity by delaying blood glucose decline during prolonged exercise in rats.

Taurine enhances physical performance; however, the underlying mechanism remains unclear. This study examined the effect of taurine on the overtime dynamics of blood glucose concentration (BGC) during endurance exercise in rats. Male F344 rats were subjected to transient treadmill exercise until exhaustion following 3 weeks of taurine supplementation or non-supplementation (TAU and CON groups). Every 10 min during exercise, BGC was measured in blood collected through cannulation of the jugular vein. Gluconeogenesis-, lipolysis-, and fatty acid oxidation-related factors in the plasma, liver, and skeletal muscles were also analyzed after 120-min run. Exercise time to exhaustion was significantly longer with taurine supplementation. BGC in the two groups significantly increased by 40 min and gradually and significantly decreased toward the respective exhaustion point. The decline in BGC from the peak at 40 min was significantly slower in the TAU group. The time when the once-increased BGC regressed to the 0-time level was significantly and positively correlated with exercise time until exhaustion. At the 120-min point, where the difference in BGC between the two groups was most significant, plasma free fatty acid concentration and acetyl-carnitine and N-acetyltaurine concentrations in skeletal muscle were significantly higher in the TAU group, whereas glycogen and glucogenic amino acid concentrations and G6Pase activity in the liver were not different between the two groups. Taurine supplementation enhances endurance capacity by delaying the decrease in BGC toward exhaustion through increases of lipolysis in adipose tissues and fatty acid oxidation in skeletal muscles during endurance exercise.

Ultrasound-guided bilateral subcostal transversus abdominis plane block in gastric cancer patients undergoing laparoscopic gastrectomy: a randomised-controlled double-blinded study.

BACKGROUND: The effectiveness of subcostal transversus abdominis plane block (TAPB) in laparoscopic gastric cancer surgery is unknown. We aimed to investigate its opioid-sparing and pain-relief effects in laparoscopic gastrectomy for gastric cancer. METHOD: One hundred and twelve patients undergoing elective laparoscopic gastrectomy were randomised to the TAPB or control group. The TAPB group received ultrasound-guided bilateral subcostal TAPB at the end of surgery, while the control group did not. We investigated fentanyl consumption administered via intravenous patient-controlled analgesia and as a rescue analgesic, the numeric rating scale (NRS) pain scores at rest and during coughing, and the opioid-related side effects at 6, 12, 24, and 48 h postoperatively. The primary outcome was cumulative fentanyl consumption at 24 h postoperatively. RESULTS: The study included 53 patients in each group. The cumulative fentanyl consumption 24 h postoperatively was significantly lower in the TAPB group than in the control group (median difference -170 mcg, P = 0.03, 95% CI -360 to -15 mcg). Subcostal TAPB also significantly reduced the resting NRS score at 48 h postoperatively (median difference -1, 95% CI -1 to 0, P = 0.01) and coughing NRS score at all time points (all median difference -1, 95% CI -2 to 0, P < 0.01, P  = 0.02, 0.01, and 0.01, respectively). However, it did not reduce the occurrence of opioid-related side effects, except the use of antiemetics during the first 6 h postoperatively (TAPB, 1.9% vs. Control, 15.1%, P = 0.03). CONCLUSION: Ultrasound-guided bilateral subcostal TAPB provides efficient postoperative analgesia with an opioid-sparing effect after laparoscopic gastrectomy.

Effect of Taurine on the Regulation of Glucose Uptake in the Skeletal Muscle.

Diabetes is so common in Japan as to be called a national disease. Taurine, a free amino acid found abundantly in mammalian tissues that is also a key ingredient of many "energy drinks," has been shown to be effective in improving the hyperglycemic state caused by diabetes. Taurine administration is associated with increased insulin secretion from the pancreas, higher levels of insulin signaling-related factors, and higher expression of the glucose transporter, GLUT4. Skeletal muscle is the main target organ of insulin: Via cell surface GLUT4 molecules, myocytes take up blood glucose, enabling skeletal muscle contraction. The enhancing effect of taurine on blood glucose uptake in skeletal muscle has not been fully studied, and little is known about its mechanism. This review article summarizes what is known about the effects of taurine on insulin secretion from the pancreas and especially blood glucose uptake in skeletal muscle.

Inhibitory Activities of Rare Ginsenoside Rg4 on Cecal Ligation and Puncture-Induced Sepsis.

Sepsis is an uncontrolled response to inflammatory infection and is associated with high levels of mortality and morbidity. Rg4 is a rare ginsenoside mainly found in the leaves of Panax ginseng C. A. Meyer and the major protopanaxatriol-type ginsenoside of black ginseng. In this study, we determined whether Rg4 affects cecal ligation and puncture (CLP)-induced sepsis. Animals were separated into the following six groups: control group, CLP-operated group, CLP plus maslinic acid (MA), and CLP plus Rg4 (5, 10, or 15 mg/kg). Survival rate, body weight changes, inflammatory cytokines, and histological analyses were assessed. Human endothelial cells were activated with the high-mobility group box 1 (HMGB1) protein and Rg4. Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Enzyme-linked immunosorbent assay (ELISA) and Western blot analysis were used to assess inflammation and gene expression, respectively. After CLP surgery, the Rg4-administered group exhibited a higher survival rate and body weight compared with the untreated control group. Rg4 treatment reduced cytokine levels, including tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, as well as nitric oxide (NO) levels and renal inflammation. After Rg4 treatment of HMGB1-activated cells, the expressions of toll-like receptor (TLR) 4 and TNF-α were decreased, and the activation of phosphoinositide 3-kinase (PI3K)/AKT signaling increased cell viability. In summary, Rg4 inhibited inflammation and exhibited a protective effect against CLP-induced sepsis, thereby reinforcing cell survival against septic responses.

Barrier protective functions of hederacolchiside-E against HMGB1-mediated septic responses.

The role of high mobility group box 1 (HMGB1) has been recognized as important, and suppression of HMGB1 release and restoration of vascular barrier integrity are regarded as potentially promising therapeutic strategies against sepsis. Hederacolchiside-E (HCE), namely 3-O-{α-L-rhamnopyranosyl (1→2)-[ß-D-glucopyranosyl(1→4)]-α-L-arabinopyranosyl}-28-O-[α-L-rhamnopyranosyl (1→4)-ß-D-glucopyranosyl(1→6)-ß-D-glucopyranosyl ester, is a bidesmosidic oleanane saponin first isolated in 1970 from the leaves of Hedera colchica. We tested our hypothesis that HCE inhibits HMGB1-induced vascular hyperpermeability and thereby increases the survival of septic mouse model from suppression of HMGB1 release upon lipopolysaccharide (LPS)-stimulation. In LPS-activated human endothelial cells and a sepsis mouse model by cecal ligation and puncture (CLP), antiseptic activity of HCE was investigated from suppression of vascular permeability, pro-inflammatory proteins, and tissue injury markers. Post-treatment of HCE significantly suppressed HMGB1 release both in LPS-activated human endothelial cells and the CLP-induced sepsis mouse model. HCE inhibited hyperpermeability and alleviated HMGB1-mediated vascular disruptions, and reduced sepsis-related mortality and tissue injury in mice. Our results suggest that reduction of HMGB1 release and septic mortality by HCE may be useful for the drug candidate of sepsis, indicating a possibility of successful repositioning of HCE.

The impact of total intravenous anesthesia versus inhalation anesthesia on acute kidney injury after major abdominal surgery: a propensity score analysis.

PURPOSE: The effect of anesthetic types on postoperative acute kidney injury (AKI) remains unclear particularly in patients undergoing non-cardiac surgery. The purpose of this retrospective study was to compare total intravenous anesthesia (TIVA) and inhalation anesthesia in terms of the risk of AKI after open major abdominal surgery (MAS). METHODS: Adult patients who underwent open MAS (gastrectomy, hepatectomy, colectomy, or pancreatectomy) at our institute from 2016 to 2018 were included. Using the multivariable logistic regression, the risk of postoperative AKI was compared among patients who underwent TIVA (TIVA group) and inhalation anesthesia (inhalation group) both in the total cohort and in the propensity score-matched cohort. Additional multivariable logistic regression analysis was performed with inverse probability of treatment weighting (IPTW) using the propensity score. RESULTS: In total, 3616 patients were analyzed. The incidence of postoperative AKI was 5.0% (77/1546) and 7.8% (161/2070) in the TIVA and inhalation groups, respectively. The risk of AKI was significantly higher in the inhalation group [adjusted odds ratio (aOR) 1.72; 95% confidence interval (CI) 1.27-2.35; P = 0.002] than the TIVA group. In the matched cohort (n = 1518 in each group), the inhalation group also had a higher risk of AKI (aOR 1.66; 95% CI 1.20-2.31; P = 0.002). The multivariable logistic regression with IPTW showed similar results (aOR 1.59; 95% CI 1.30-1.95; P < 0.001). CONCLUSIONS: The risk of AKI after open MAS differed significantly according to the anesthetic used. Patients receiving inhalation anesthesia may have a greater risk of postoperative AKI than those undergoing TIVA.

mtDNA depletion-like syndrome in Wilson disease.

BACKGROUND AND AIMS: Wilson disease (WD) is caused by mutations in the copper transporter ATP7B, with its main pathology attributed to copper-mediated oxidative damage. The limited therapeutic effect of copper chelators and the early occurrence of mitochondrial deficits, however, undermine the prevalence of this mechanism. METHODS: We characterized mitochondrial DNA copy number and mutations as well as bioenergetic deficits in blood from patients with WD and in livers of tx-j mice, a mouse model of hepatic copper accumulation. In vitro experiments with hepatocytes treated with CuSO4 were conducted to validate in vivo studies. RESULTS: Here, for the first time, we characterized the bioenergetic deficits in WD as consistent with a mitochondrial DNA depletion-like syndrome. This is evidenced by enriched DNA synthesis/replication pathways in serum metabolomics and decreased mitochondrial DNA copy number in blood of WD patients as well as decreased mitochondrial DNA copy number, increased citrate synthase activity, and selective Complex IV deficit in livers of the tx-j mouse model of WD. Tx-j mice treated with the copper chelator penicillamine, methyl donor choline or both ameliorated mitochondrial DNA damage but further decreased mitochondrial DNA copy number. Experiments with copper-loaded HepG2 cells validated the concept of a direct copper-mitochondrial DNA interaction. CONCLUSIONS: This study underlines the relevance of targeting the copper-mitochondrial DNA pool in the treatment of WD separate from the established copper-induced oxidative stress-mediated damage.

Ilimaquinone inhibits neovascular age-related macular degeneration through modulation of Wnt/ß-catenin and p53 pathways.

Neovascular age-related macular degeneration (nAMD) is a common cause of irreversible vision loss in the elderly. Anti-vascular endothelial growth factor has been effective in treating pathological ocular neovascularization, but it has limitations including the need for repeated intraocular injections for the maintenance of therapeutic effects in most patients and poor or non-response to this agent in some patients. in vitro cellular studies were conducted using retinal pigment epithelial cell lines (ARPE-19 and hTERT-RPE1), human umbilical vein endothelial cells (HUVECs), and human umbilical vein smooth muscle cells (HUVSMCs). in vivo efficacy of ilimaquinone (IQ) was tested in laser-induced choroidal neovascularization mouse and rabbit models. Tissue distribution study was performed in male C57BL6/J mice. IQ, 4,9-friedodrimane-type sesquiterpenoid isolated from the marine sponge, repressed the expression of angiogenic/inflammatory factors and restored the expression of E-cadherin in retinal pigment epithelial cells by inhibiting the Wnt/ß-catenin pathway. In addition, it selectively inhibited proliferation and tube formation of HUVECs by activating the p53 pathway. Topical and intraperitoneal administration of IQ significantly reduced choroidal neovascularization in rabbits and mice with laser-induced choroidal neovascularization. Notably, IQ by the oral route of exposure was highly permeable to the eyes and suppressed abnormal vascular leakage by downregulation of ß-catenin and stabilization of p53 in vivo. Our findings demonstrate that IQ functions through regulation of p53 and Wnt/ß-catenin pathways with conceivable advantages over existing cytokine-targeted anti-angiogenic therapies.

Relationship between early-onset muscle soreness and indirect muscle damage markers and their dynamics after a full marathon.

BACKGROUND/OBJECTIVE: Muscle soreness and damage occurs after completing a full marathon. Here we refer to muscle soreness induced by prolonged running as early-onset muscle soreness (EOMS) because muscle soreness and damage markers induced after prolonged running are different from delayed-onset muscle soreness (DOMS) and muscle damage markers induced after eccentric contraction, such as resistance exercise. The dynamics and relationship between muscle damage markers and EOMS are unclear; therefore, in this study, we aimed to elucidate the relationship between EOMS and indirect muscle damage markers, and their dynamics after a full marathon. METHODS: The following measurements were performed in 19 subjects who completed a full marathon: perceived muscle soreness (using a numeric rating scale), thigh circumference (CIR), hip joint range of motion (ROM), jump height (JH) and muscle damage marker activities in the blood (CK, AST, LDH, ALD) before (Pre), after (Post) and every day for 4 days after a full marathon (D1-4). RESULTS: EOMS was induced, as determined by the numeric rating scale score peaking immediately after a full marathon. ROM and JH significantly decreased and all muscle damage markers significantly increased after a full marathon. Serum CK and AST peaked at D1. Serum LDH and ALD peaked at Post and D3. Each marker showed different dynamics. CIR significantly decreased after a full marathon. CONCLUSION: Muscle soreness peaked and muscle damage markers in the blood showed different dynamics after a full marathon. In other words, this is different from DOMS.

JH-4 reduces HMGB1-mediated septic responses and improves survival rate in septic mice.

Inhibition of high mobility group box 1 (HMGB1) and restoration of endothelial integrity are emerging as attractive therapeutic strategies for the management of severe vascular inflammatory diseases. Recently, we found that JH-4, a synthesized decursin derivative, exhibited a strong anti-Hutchinson-Gilford progeria syndrome by efficiently blocking progerin-lamin A/C binding. In this study, we examined the effects of JH-4 on HMGB1-mediated septic responses and the survival rate in a mouse sepsis model. The anti-inflammatory activities of JH-4 were monitored based on its effects on lipopolysaccharide- or cecal ligation and puncture (CLP)-mediated release of HMGB1. The antiseptic activities of JH-4 were determined by measuring permeability, leukocyte adhesion, migration, and the activation of proinflammatory proteins in HMGB1-activated human umbilical vein endothelial cells and mice. JH-4 inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses in human endothelial cells. JH-4 also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with JH-4 reduced CLP-induced release of HMGB1, sepsis-related mortality, and pulmonary injury in vivo. Our results indicate that JH-4 is a possible therapeutic agent to treat various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway.

Sustainable Low-Temperature Hydrogen Production from Lignocellulosic Biomass Passing through Formic Acid: Combination of Biomass Hydrolysis/Oxidation and Formic Acid Dehydrogenation.

Hydrogen production from renewable resources, such as lignocellulosic biomass, is highly desired, under the most sustainable and mildest reaction conditions. In this study, a new sustainable three-step process for the production of hydrogen has been proposed. In the first step, a crude formic acid (CF) solution, which included typical reaction byproducts, in particular, acetic acid, levulinic acid, saccharides, 5-hydroxymethylfurfural, furfural, and lignin, was obtained through the combined hydrolysis/oxidation of the biomass, in the presence of diluted sulfuric acid/hydrogen peroxide, as homogeneous catalysts. In the second one, the distilled formic acid (DF) solution was obtained by distillation of the CF solution, for example, by isolating liquid byproducts, or the lignin-free CF (LCF) solution was recovered by CF filtration for the elimination of only solid lignin particles. In the final step, hydrogen was produced from the DF or LCF solutions through formic acid dehydrogenation over Pd supported on amine-functionalized mesoporous silica catalysts, in the presence of sodium formate, as an additive. The clean hydrogen, which is produced from biomass passing through formic acid, could be applied as an energy source of fuel cells. This new hydrogen production process is smart, allowing the hydrogen production with mild reaction conditions, eventually starting from different lignocellulosic feedstocks, and it could be integrated within the existing hydrothermal technology for levulinic acid production, which has been already recognized as efficient and sustainable. In addition to the production of hydrogen as an energy source of fuel cells, formic acid derived from biomass could be utilized as a platform chemical for chemical, agricultural, textile, leather, pharmaceutical, and rubber industries.

Inhibitory effects of protopanaxatriol type ginsenoside fraction (Rgx365) on particulate matter-induced pulmonary injury.

Inhalation of fine particulate matter (PM2.5) is associated with elevated pulmonary injury attributed to the loss of vascular barrier integrity. Black ginseng (BG), steamed 9 times and dried ginseng, and its major protopanaxatriol type ginsenosides (ginsenoside Rg4, Rg6, Rh4, Rh1, and Rg2) exhibited various biological activities including anti-septic, anti-diabetic, wound healing, immune-stimulatory, and anti-antioxidant activity. The aim of this study was to investigate the beneficial effects of Rgx365 (a protopanaxatriol type rare ginsenosides fraction) on PM-induced lung endothelial cell (EC) barrier disruption and pulmonary inflammation. Permeability, leukocyte migration, activation of proinflammatory proteins, generation of reactive oxygen species (ROS), and histology were examined in PM2.5-treated EC and mice. Rgx365 significantly scavenged PM2.5-induced ROS, inhibited ROS-induced activation of p38 mitogen-activated protein kinase (MAPK), activated Akt in purified pulmonary EC, which helped maintain endothelial integrity. Further, Rgx365 reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in bronchoalveolar lavage fluids in PM-induced mouse lung tissues. Data suggested that Rgx365 might exhibit protective effects in PM-induced inflammatory lung injury and vascular hyperpermeability.

Effects of Taurine Supplementation on Vascular Endothelial Function at Rest and After Resistance Exercise.

High-intensity resistance exercise has been shown to increase arterial stiffness and reduce vascular endothelial function. Taurine supplementation has a favorable effect on maintaining vascular function. We had previously reported that taurine supplementation attenuated increases in resistance exercise-induced arterial stiffness. In the present study, we further investigate the effects of taurine supplementation on vascular endothelial function at rest and after resistance exercise.Twenty-nine healthy men were recruited and randomly assigned to either the placebo supplement group (n = 14) or the taurine supplement group (n = 15) in a double-blinded manner. Subjects were required to ingest 6 g of either a placebo or the taurine supplement for 2 weeks prior to and 3 days following the exercise. Two weeks after the commencement of supplementation, the subjects were asked to perform 2 sets of 20 repetitive unilateral maximal-effort resistance exercise of the elbow flexors on a Biodex isokinetic dynamometer, with each contraction lasting 3 s, with 1 repetition performed every 9 s and 4 min rest in between sets. We evaluated the changes in brachial artery flow-mediated dilation (FMD) in the non-exercised arm as an index of vascular endothelial function. Relative and absolute FMDs were measured prior to supplementation, before exercise, and 24, 48, and 96 h after exercise.Two weeks of taurine supplementation significantly increased both relative and absolute FMDs. Baseline diameter significantly increased at 96 h following the exercise in both groups. However, there was no change in the peak diameter. Consequently, both relative and absolute FMDs were significantly reduced at 96 h after the exercise in both groups. Taurine supplementation does not affect resistance exercise-induced reduction in FMD.Two weeks of taurine supplementation (6 g/day) significantly increased vascular endothelial function at rest; however, taurine supplementation did not improve resistance exercise-induced reduction in FMD.

LKY-047: First Selective Inhibitor of Cytochrome P450 2J2.

Highly selective cytochrome P450 CYP2J2 (CYP2J2) inhibitors suitable for reaction phenotyping are currently not available. (7S)-(+)-(4-Nitro-phenyl)-acrylic acid, 8,8-dimethyl-2-oxo-6,7-dihydro-2H,8H-pyrano[3,2-g]chromen-7-yl-ester (LKY-047), a decursin derivative, was synthesized, and its inhibitor potencies toward CYP2J2 as well as other cytochrome P450 (P450) enzymes in human liver microsomes (HLM) were evaluated. LKY-047 was demonstrated to be a strong competitive inhibitor of CYP2J2-mediated astemizole O-demethylase and terfenadine hydroxylase activity, with Ki values of 0.96 and 2.61 µM, respectively. It also acted as an uncompetitive inhibitor of CYP2J2-mediated ebastine hydroxylation with a Ki value of 3.61 µM. Preincubation of LKY-047 with HLMs and NADPH did not alter inhibition potency, indicating that it is not a mechanism-based inhibitor. LKY-047 was found to be a selective CYP2J2 inhibitor with no inhibitory effect on other human P450s, such as CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A (IC50 > 50 µM). These in vitro data support the use of LKY-047 as a selective CYP2J2 inhibitor with potential application in the identification of P450 isoforms responsible for drug metabolism in reaction phenotyping assays.

Warburg effect linked to cognitive-executive deficits in FMR1 premutation.

A 55-200 CGG repeat expansion in the 5'-UTR of the fragile X mental retardation 1 (FMR1) gene is known as a premutation. Some carriers are affected by the neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS), primary ovarian insufficiency, and neurobehavioral impairments. Based on the mitochondrial dysfunction observed in fibroblasts and brain samples from carriers, as well as in neurons and brains from a mouse model of the premutation, we evaluated the presence of the Warburg effect in peripheral blood mononuclear cells (PBMCs) from 30 premutation carriers with either a rebalance of the metabolism [increasing glycolysis while decreasing oxidative phosphorylation (oxphos)] or a metabolic amplification (increasing glycolysis while maintaining/increasing oxphos). Deficits in oxphos-more pronounced in FXTAS-affected subjects-were accompanied by a shift toward glycolysis, suggesting increased glycolysis despite aerobic conditions. Differential proteomics extended these findings, unveiling a decreased antioxidant response, translation, and disrupted extracellular matrix and cytoskeleton organization with activation of prosenescence pathways. Lower bioenergetics segregated with increased incidence of low executive function, tremors, below-average IQ, and FXTAS. The combination of functional and proteomic data unveiled new mechanisms related to energy production in the premutation, showing the potential of being applicable to other psychiatric disorders to identify endophenotype-specific responses relevant to neurobiology.-Napoli, E., Song, G., Schneider, A., Hagerman, R., Eldeeb, M. A. A. A., Azarang, A., Tassone, F., Giulivi, C. Warburg effect linked to cognitive-executive deficits in FMR1 premutation.