Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, ...pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor's glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1β secretion compared to sulfonylurea accompanied by increased serum β-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects.
Sarcopenia is associated with nonalcoholic fatty liver disease (NAFLD). This study investigated whether sarcopenia is associated with significant liver fibrosis in subjects with NAFLD. Data from the ...Korean National Health and Nutrition Examination Surveys 2008‐2011 database were analyzed. NALFD was defined by NAFLD liver fat score, comprehensive NAFLD score, or hepatic steatosis index. Degree of liver fibrosis was assessed by NAFLD fibrosis score (NFS), FIB‐4, and Forns index. Significant liver fibrosis was defined as FIB‐4 ≥2.67 and the highest quartile values of NFS and Forns index. Sarcopenia index (= total appendicular skeletal muscle mass kg/body mass index (kg/m2) was calculated using dual‐energy X‐ray absorptiometry. Using the NAFLD liver fat score, NAFLD was identified in 2761 (28.5%) of 9676 subjects. Of subjects with NAFLD, sarcopenia was identified in 337 (12.2%). Sarcopenia was significantly associated with significant liver fibrosis assessed in fibrosis prediction models (all P < 0.05). In subgroups stratified according to body mass index and homeostasis model assessment of insulin resistance, a significant association between sarcopenia and significant liver fibrosis by NFS was consistently present (odds ratio = 1.76‐2.68 depending on the subgroup, all P < 0.05). Multivariate logistic regression analysis demonstrated an independent association between SI and significant liver fibrosis by NFS after adjusting for other confounders (odds ratio = 0.52‐0.67, all P < 0.01). Other NAFLD (comprehensive NAFLD score, hepatic steatosis index) and fibrosis prediction models (FIB‐4 and Forns index) produced similar results. Conclusion: Sarcopenia is associated with significant liver fibrosis in subjects with NAFLD, and the association is independent of obesity and insulin resistance. (Hepatology 2016;63:776–786)
Current methods for functional group interconversion have, for the most part, relied on relatively strong driving forces which often require highly reactive reagents to generate irreversibly a ...desired product in high yield and selectivity. These approaches generally prevent the use of the same catalytic strategy to perform the reverse reaction. Here we describe a catalytic functional group metathesis approach to interconvert, under CO-free conditions, two synthetically important classes of electrophiles that are often employed in the preparation of pharmaceuticals and agrochemicals-aroyl chlorides (ArCOCl) and aryl iodides (ArI). Our reaction design relies on the implementation of a key reversible ligand C-P bond cleavage event, which enables a non-innocent, metathesis-active phosphine ligand to mediate a rapid aryl group transfer between the two different electrophiles. Beyond enabling a practical and safer approach to the interconversion of ArCOCl and ArI, this type of ligand non-innocence provides a blueprint for the development of a broad range of functional group metathesis reactions employing synthetically relevant aryl electrophiles.
A high‐performance, transparent, and extremely thin (<15 nm) hydrogen (H2) gas sensor is developed using 2D electron gas (2DEG) at the interface of an Al2O3/TiO2 thin film heterostructure grown by ...atomic layer deposition (ALD), without using an epitaxial layer or a single crystalline substrate. Palladium nanoparticles (≈2 nm in thickness) are used on the surface of the Al2O3/TiO2 thin film heterostructure to detect H2. This extremely thin gas sensor can be fabricated on general substrates such as a quartz, enabling its practical application. Interestingly, the electron density of the Al2O3/TiO2 thin film heterostructure can be tailored using ALD process temperature in contrast to 2DEG at the epitaxial interfaces of the oxide heterostructures such as LaAlO3/SrTiO3. This tunability provides the optimal electron density for H2 detection. The Pd/Al2O3/TiO2 sensor detects H2 gas quickly with a short response time of <30 s at 300 K which outperforms conventional H2 gas sensors, indicating that heating modules are not required for the rapid detection of H2. A wide bandgap (>3.2 eV) with the extremely thin film thickness allows for a transparent sensor (transmittance of 83% in the visible spectrum) and this fabrication scheme enables the development of flexible gas sensors.
A high‐performance, transparent, and extremely thin (≈15 nm) hydrogen (H2) gas sensor is developed using 2D electron gas at the interface of an Al2O3/TiO2 thin film heterostructure. This extremely thin gas sensor can be fabricated on general substrates such as a glass using atomic layer deposition, and this fabrication scheme enables the development of flexible gas sensors.
A completely atom economical palladium‐catalyzed addition reaction has been developed to stereoselectively access functionalized tetrasubstituted alkenyl iodides. The palladium catalyst, which bears ...an electron‐poor bidentate ligand rarely employed in catalysis, is essential to promote the high yielding and chemoselective intermolecular reaction between equimolar amounts of an alkyne and an aryl iodide. This new carbohalogenation reaction is an attractive alternative to traditional synthetic methods, which rely on multistep synthetic sequences and protecting‐group manipulations.
An atom‐economical palladium‐catalyzed addition reaction has been developed to stereoselectively access tetrasubstituted alkenyl iodides. A palladium catalyst bearing 1,2‐bisbis(pentafluorophenyl)phosphinoethane (dArFpe), an electron‐poor bidentate ligand, is essential to promote the high yielding and chemoselective reaction between alkynes and aryl iodides.
Additional surgeries for implantable biomedical devices are inevitable to replace discharged batteries, but repeated surgeries can be a risk to patients, causing bleeding, inflammation, and ...infection. Therefore, developing self‐powered implantable devices is essential to reduce the patient's physical/psychological pain and financial burden. Although wireless communication plays a critical role in implantable biomedical devices that contain the function of data transmitting, it has never been integrated with in vivo piezoelectric self‐powered system due to its high‐level power consumption (microwatt‐scale). Here, wireless communication, which is essential for a ubiquitous healthcare system, is successfully driven with in vivo energy harvesting enabled by high‐performance single‐crystalline (1 − x)Pb(Mg1/3Nb2/3)O3−(x)Pb(Zr,Ti)O3 (PMN‐PZT). The PMN‐PZT energy harvester generates an open‐circuit voltage of 17.8 V and a short‐circuit current of 1.74 µA from porcine heartbeats, which are greater by a factor of 4.45 and 17.5 than those of previously reported in vivo piezoelectric energy harvesting. The energy harvester exhibits excellent biocompatibility, which implies the possibility for applying the device to biomedical applications.
In vivo self‐powered wireless transmission using a flexible single‐crystalline piezoelectric energy harvester is demonstrated. The high‐performance energy harvester generates an output voltage of 17.8 V and a current of 1.75 µA from the contraction and relaxation motion of porcine heart. The energy from in vivo physiological motion enables self‐powered wireless transmission, thus realizing practical application in the ubiquitous healthcare system.
Background Recent studies have reported improved diastolic function in patients administered sodium-glucose cotransporter 2 inhibitors (SGLT2i). We aimed to investigate the effect of dapagliflozin on ...left ventricular (LV) diastolic function in a diabetic animal model and to determine the molecular and cellular mechanisms underlying its function. Methods A total of 30 male New Zealand white rabbits were randomized into control, diabetes, or diabetes+dapagliflozin groups (n = 10/per each group). Diabetes was induced by intravenous alloxan. Cardiac function was evaluated using echocardiography. Myocardial samples were obtained for histologic and molecular evaluation. For cellular evaluation, fibrosis-induced cardiomyoblast (H9C2) cells were obtained, and transfection was performed for mechanism analysis (serum and glucocorticoid-regulated kinase 1 (SGK1) signaling analysis). Results The diabetes+dapagliflozin group showed attenuation of diastolic dysfunction compared with the diabetes group. Dapagliflozin inhibited myocardial fibrosis via inhibition of SGK1 and epithelial sodium channel (ENaC) protein, which was observed both in myocardial tissue and H9C2 cells. In addition, dapagliflozin showed an anti-inflammatory effect and ameliorated mitochondrial disruption. Inhibition of SGK1 expression by siRNA decreased and ENaC and Na+/H+ exchanger isoform 1 (NHE1) expression was confirmed as significantly reduced as siSGK1 in the diabetes+dapagliflozin group. Conclusions Dapagliflozin attenuated left ventricular diastolic dysfunction and cardiac fibrosis via regulation of SGK1 signaling. Dapagliflozin also reduced macrophages and inflammatory proteins and ameliorated mitochondrial disruption. Keywords: Heart failure, Diabetes mellitus, Sodium-glucose cotransporter 2 inhibitor, Left ventricular diastolic function
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dopamine is a key molecule in neurotransmission and has been known to be responsible for several neurological diseases. Hence, its sensitive and selective detection is important for the early ...diagnosis of diseases related to abnormal levels of dopamine. In this study, we reported a new cylindrical gold nanoelectrode (CAuNE) platform fabricated via sequential laser interference lithography and electrochemical deposition. Among the fabricated electrodes, CAuNEs with a diameter of 700 nm, 150 s deposited, was found to be the best for electrochemical dopamine detection. According to cyclic voltammetry results, the linear range of the CAuNE-700 nm was 1-100 µM of dopamine with a limit of detection (LOD) of 5.83 µM. Moreover, owing to the homogeneous periodic features of CAuNEs, human neural cells were successfully cultured and maintained for more than 5 days in vitro without the use of any extracellular matrix proteins and dopamine was detectable in the presence of these cells on the electrode. Therefore, we concluded that the developed dopamine sensing platform CAuNE can be used for many applications including early diagnosis of neurological diseases; function tests of dopaminergic neurons derived from various stem cell sources; and toxicity assessments of drugs, chemicals, and nanomaterials on human neuronal cells.
Aim
We aimed to evaluate the metabolite ratios that could predict the clinical incidence or remission of type 2 diabetes mellitus (T2D).
Methods
The Cox proportional hazards regression model was used ...to assess 1813 individuals without T2D to test the predictive value of metabolite ratios for T2D incidence and 451 newly diagnosed T2D for remission. The receiver operating characteristic curve analysis was performed to determine the best cut‐off values for the metabolite ratios. Survival analyses were performed to compare the four subgroups defined by baseline metabolite ratios and clinical status of obesity.
Results
The alanine/glycine was the most significant marker for T2D incidence (hazard ratio per SD: 1.24; p < .001). On the other hand, metabolite hydroxy sphingomyelin C22:2 was most specific for T2D remission (hazard ratio per SD: 1.32; p = .029). Survival analysis of T2D incidence among the subgroups defined by the combination of alanine/glycine and obesity showed the group with a high alanine/glycine and obesity had the highest risk of T2D incidence (p < .001). The alanine/glycine as a T2D risk marker was also validated in the independent external data.
Conclusions
The combination of obesity and the alanine/glycine ratio can be used to evaluate the diabetes risk.
Lipotoxicity, induced by saturated fatty acid (SFA)-mediated cell death, plays an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The KEAP1 (kelch like ECH associated ...protein 1)-NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) pathway is a pivotal defense mechanism against lipotoxicity. We previously reported that SQSTM1/p62 has a cytoprotective role against lipotoxicity through activation of the noncanonical KEAP1- NFE2L2 pathway in hepatocytes. However, the underlying mechanisms and physiological relevance of this pathway have not been clearly defined. Here, we demonstrate that NFE2L2-mediated induction of SQSTM1 activates the noncanonical KEAP1-NFE2L2 pathway under lipotoxic conditions. Furthermore, we identified that SQSTM1 induces ULK1 (unc-51 like autophagy activating kinase 1) phosphorylation by facilitating the interaction between AMPK (AMP-activated protein kinase) and ULK1, leading to macroautophagy/autophagy induction, followed by KEAP1 degradation and NFE2L2 activation. Accordingly, the activity of this SQSTM1-mediated noncanonical KEAP1-NFE2L2 pathway conferred hepatoprotection against lipotoxicity in the livers of conventional sqstm1- and liver-specific sqstm1-knockout mice. Moreover, this pathway activity was evident in the livers of patients with nonalcoholic fatty liver. This axis could thus represent a novel target for NAFLD treatment.
Abbreviations: ACACA: acetyl-CoA carboxylase alpha; ACTB: actin beta; BafA1: bafilomycin A
1
; CM-H2DCFDA:5-(and-6)-chloromethyl-2ʹ,7ʹ-dichlorodihydrofluorescein diacetate; CQ: chloroquine; CUL3: cullin 3; DMSO: dimethyl sulfoxide; FASN: fatty acid synthase; GSTA1: glutathione S-transferase A1; HA: hemagglutinin; Hepa1c1c7: mouse hepatoma cells; HMOX1/HO-1: heme oxygenase 1; KEAP1: kelch like ECH associated protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MTORC1: mechanistic target of rapamycin kinase complex 1; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NAC: N-acetyl-L-cysteine; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; NQO1: NAD(P)H quinone dehydrogenase 1; PA: palmitic acid; PARP: poly (ADP-ribose) polymerase 1; PRKAA1/2: protein kinase AMP-activated catalytic subunits alpha1/2; RBX1: ring-box 1; ROS: reactive oxygen species; SESN2: sestrin 2; SFA: saturated fatty acid; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1; TBK1: TANK binding kinase 1; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; ULK1: unc-51 like autophagy activating kinase.
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