Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage.

Cerebrospinal fluid (CSF) in the subarachnoid space around the brain has long been known to drain through the lymphatics to cervical lymph nodes1-17, but the connections and regulation have been challenging to identify. Here, using fluorescent CSF tracers in Prox1-GFP lymphatic reporter mice18, we found that the nasopharyngeal lymphatic plexus is a major hub for CSF outflow to deep cervical lymph nodes. This plexus had unusual valves and short lymphangions but no smooth-muscle coverage, whereas downstream deep cervical lymphatics had typical semilunar valves, long lymphangions and smooth muscle coverage that transported CSF to the deep cervical lymph nodes. α-Adrenergic and nitric oxide signalling in the smooth muscle cells regulated CSF drainage through the transport properties of deep cervical lymphatics. During ageing, the nasopharyngeal lymphatic plexus atrophied, but deep cervical lymphatics were not similarly altered, and CSF outflow could still be increased by adrenergic or nitric oxide signalling. Single-cell analysis of gene expression in lymphatic endothelial cells of the nasopharyngeal plexus of aged mice revealed increased type I interferon signalling and other inflammatory cytokines. The importance of evidence for the nasopharyngeal lymphatic plexus functioning as a CSF outflow hub is highlighted by its regression during ageing. Yet, the ageing-resistant pharmacological activation of deep cervical lymphatic transport towards lymph nodes can still increase CSF outflow, offering an approach for augmenting CSF clearance in age-related neurological conditions in which greater efflux would be beneficial.

Artificial neuromorphic cognitive skins based on distributed biaxially stretchable elastomeric synaptic transistors.

Cephalopod (e.g., squid, octopus, etc.) skin is a soft cognitive organ capable of elastic deformation, visualizing, stealth, and camouflaging through complex biological processes of sensing, recognition, neurologic processing, and actuation in a noncentralized, distributed manner. However, none of the existing artificial skin devices have shown distributed neuromorphic processing and cognition capabilities similar to those of a cephalopod skin. Thus, the creation of an elastic, biaxially stretchy device with embedded, distributed neurologic and cognitive functions mimicking a cephalopod skin can play a pivotal role in emerging robotics, wearables, skin prosthetics, bioelectronics, etc. This paper introduces artificial neuromorphic cognitive skins based on arrayed, biaxially stretchable synaptic transistors constructed entirely out of elastomeric materials. Systematic investigation of the synaptic characteristics such as the excitatory postsynaptic current, paired-pulse facilitation index of the biaxially stretchable synaptic transistor under various levels of biaxial mechanical strain sets the operational foundation for stretchy distributed synapse arrays and neuromorphic cognitive skin devices. The biaxially stretchy arrays here achieved neuromorphic cognitive functions, including image memorization, long-term memorization, fault tolerance, programming, and erasing functions under 30% biaxial mechanical strain. The stretchy neuromorphic imaging sensory skin devices showed stable neuromorphic pattern reinforcement performance under both biaxial and nonuniform local deformation.

Imeglimin attenuates NLRP3 inflammasome activation by restoring mitochondrial functions in macrophages.

Imeglimin is a novel oral antidiabetic drug for treating type 2 diabetes. However, the effect of imeglimin on NLRP3 inflammasome activation has not been investigated yet. Here, we aimed to investigate whether imeglimin reduces LPS-induced NLRP3 inflammasome activation in THP-1 macrophages and examine the associated underlying mechanisms. We analyzed the mRNA and protein expression levels of NLRP3 inflammasome components and IL-1ß secretion. Additionally, reactive oxygen species (ROS) generation, mitochondrial membrane potential, and mitochondrial permeability transition pore (mPTP) opening were measured by flow cytometry. Imeglimin inhibited NLRP3 inflammasome-mediated IL-1ß production in LPS-stimulated THP-1-derived macrophages. In addition, imeglimin reduced LPS-induced mitochondrial ROS production and mitogen-activated protein kinase phosphorylation. Furthermore, imeglimin restored the mitochondrial function by modulating mitochondrial membrane depolarization and mPTP opening. We demonstrated for the first time that imeglimin reduces LPS-induced NLRP3 inflammasome activation by inhibiting mPTP opening in THP-1 macrophages. These results suggest that imeglimin could be a promising new anti-inflammatory agent for treating diabetic complications.

T18/S19 diphosphorylation of myosin regulatory light chain impairs pulmonary artery relaxation in monocrotaline-induced pulmonary hypertensive rats.

Phosphorylation of Ser19 (S19-p) on the myosin regulatory light chain (MLC2) is critical for arterial contraction. It has been shown that elevated RhoA-dependent kinase (ROCK) activity or decreased MLC phosphatase (MLCP) activity leads to further phosphorylation of Thr18 (T18/S19-pp), which has been linked to vasospastic diseases. However, this phenomenon has not yet been studied in the context of pulmonary arterial hypertension (PAH). In the monocrotaline-induced PAH (PAH-MCT) rat model, we observed a significant delay in pulmonary artery (PA) relaxation following high potassium-induced contraction, which persisted even with the use of an L-type calcium channel blocker or in a calcium-free solution. Immunoblot analysis showed increased levels of both S19-p and T18/S19-pp in unstimulated PAs from PAH-MCT rats. Proteomics analysis revealed a reduction in soluble guanylate cyclase (sGC) and protein kinase G (PKG) levels, and immunoblotting confirmed decreased levels of MYPT1 (a component of MLCP) and increased ROCK in PAH-MCT. In the control PAs, the pharmacological inhibition of sGC with ODQ resulted in a prominent delay of relaxation and increased T18/S19-pp as in PAH-MCT. The delayed relaxation and the T18/S19-pp in PAH-MCT were reversed by ROCK inhibitor, Y27632, while not by membrane permeable 8-Br-cGMP. The delayed relaxation and T18/S19-diP in the ODQ-treated control PA were also reversed by Y27632. Taken together, the decreased sGC and MLCP, and increased ROCK increased T18/S19-pp, which leads to the decreased ability of PA to relax in PAH-MCT rats. PA specific inhibition of ROCK or activation of MLCP are expected to serve as potential drugs in the treatment of PAH.

NADPH Oxidase 1 Mediates Acute Blood Pressure Response to Angiotensin II by Contributing to Calcium Influx in Vascular Smooth Muscle Cells.

BACKGROUND: Reactive oxygen species (ROS) and calcium ions (Ca2+) are among the major effectors of Ang II (angiotensin II) in vascular smooth muscle cells. ROS are related to Ca2+ signaling or contraction induced by Ang II, but little is known about their detailed functions. Here, NOX (NADPH oxidase), a major ROS source responsive to Ang II, was investigated regarding its contribution to Ca2+ signaling. METHODS: Vascular smooth muscle cells were primary cultured from rat aorta. Ca2+ and ROS were monitored mainly using fura-2 and HyPer family probes' respectively. Signals activating NOX were examined with relevant pharmacological inhibitors and genetic manipulation techniques. RESULTS: Ang II-induced ROS generation was found to be biphasic: the first phase of ROS production, which was mainly mediated by NOX1, was small and transient, preceding a rise in Ca2+, and the second phase of ROS generation, mediated by NOX1 and NOX4, was slow but sizeable, continuing over tens of minutes. NOX1-derived superoxide in the first phase is required for Ca2+ influx through nonselective cation channels. AT1R (Ang II type 1 receptor)-Gßγ-PI3Kγ (phosphoinositide 3-kinase γ) signaling pathway was responsible for the rapid activation of NOX1 in the first phase, while in the second phase, NOX1 was further activated by a separate AT1R-Gαq/11-PLC (phospholipase C)-PKCß (protein kinase C ß) signaling axis. Consistent with these observations, aortas from NOX1-knockout mice exhibited reduced contractility in response to Ang II, and thus the acute pressor response to Ang II was also attenuated in NOX1-knockout mice. CONCLUSIONS: NOX1 mediates Ca2+ signal generation and thereby contributes to vascular contraction and blood pressure elevation by Ang II.

Amphiregulin Induces iNOS and COX-2 Expression through NF-κB and MAPK Signaling in Hepatic Inflammation.

Background: Inflammation is a major cause of hepatic tissue damage and accelerates the progression of nonalcoholic fatty liver disease (NAFLD). Amphiregulin (AREG), an epidermal growth factor receptor ligand, is associated with human liver cirrhosis and hepatocellular carcinoma. We aimed to investigate the effects of AREG on hepatic inflammation during NAFLD progression, in vivo and in vitro. Methods: AREG gene expression was measured in the liver of mice fed a methionine choline-deficient (MCD) diet for 2 weeks. We evaluated inflammatory mediators and signaling pathways in HepG2 cells after stimulation with AREG. Nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were analyzed using an enzyme-linked immunosorbent assay and western blotting. Nuclear transcription factor kappa-B (NF-κB) and mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase, were analyzed using western blotting. Results: Proinflammatory cytokines (interleukin (IL)-6, IL-1ß, and IL-8) and immune cell recruitment (as indicated by L3T4, F4/80, and ly6G mRNA expression) increased, and expression of AREG increased in the liver of mice fed the MCD diet. AREG significantly increased the expression of IL-6 and IL-1ß and the production of NO, PGE2, and IL-8 in HepG2 cells. It also activated the protein expression of iNOS and COX-2. AREG-activated NF-κB and MAPKs signaling, and together with NF-κB and MAPKs inhibitors, AREG significantly reduced the protein expression of iNOS and COX-2. Conclusion: AREG plays a role in hepatic inflammation by increasing iNOS and COX-2 expression via NF-κB and MAPKs signaling.

KATP channels in lymphatic function.

KATP channels function as negative regulators of active lymphatic pumping and lymph transport. This review summarizes and critiques the evidence for the expression of specific KATP channel subunits in lymphatic smooth muscle and endothelium, the roles that they play in normal lymphatic function, and their possible involvement in multiple diseases, including metabolic syndrome, lymphedema, and Cantú syndrome. For each of these topics, suggestions are made for directions for future research.

Mitochondrial protease ClpP supplementation ameliorates diet-induced NASH in mice.

BACKGROUND & AIMS: Mitochondrial dysfunction is considered a pathogenic linker in the development of non-alcoholic steatohepatitis (NASH). Inappropriate mitochondrial protein-quality control, possibly induced by insufficiency of the mitochondrial matrix caseinolytic protease P (ClpP), can potentially cause mitochondrial dysfunction. Herein, we aimed to investigate hepatic ClpP levels in a diet-induced model of NASH and determine whether supplementation of ClpP can ameliorate diet-induced NASH. METHODS: NASH was induced by a high-fat/high-fructose (HF/HFr) diet in C57BL/6J mice. Stress/inflammatory signals were induced in mouse primary hepatocytes (MPHs) by treatment with palmitate/oleate (PA/OA). ClpP levels in hepatocytes were reduced using the RNAi-mediated gene knockdown technique but increased through the viral transduction of ClpP. ClpP activation was induced by administering a chemical activator of ClpP. RESULTS: Hepatic ClpP protein levels in C57BL/6J mice fed a HF/HFr diet were lower than the levels in those fed a normal chow diet. PA/OA treatment also decreased the ClpP protein levels in MPHs. Overexpression or activation of ClpP reversed PA/OA-induced mitochondrial dysfunction and stress/inflammatory signal activation in MPHs, whereas ClpP knockdown induced mitochondrial dysfunction and stress/inflammatory signals in these cells. On the other hand, ClpP overexpression or activation improved HF/HFr-induced NASH characteristics such as hepatic steatosis, inflammation, fibrosis, and injury in the C57BL/6J mice, whereas ClpP knockdown further augmented steatohepatitis in mice fed a HF/HFr diet. CONCLUSIONS: Reduced ClpP expression and subsequent mitochondrial dysfunction are key to the development of diet-induced NASH. ClpP supplementation through viral transduction or chemical activation represents a potential therapeutic strategy to prevent diet-induced NASH. LAY SUMMARY: Western diets, containing high fat and high fructose, often induce non-alcoholic steatohepatitis (NASH). Mitochondrial dysfunction is considered pathogenically linked to diet-induced NASH. We observed that the mitochondrial protease ClpP decreased in the livers of mice fed a western diet and supplementation of ClpP ameliorated western diet-induced NASH.

Hepatoprotective effects of gemigliptin and empagliflozin in a murine model of diet-induced non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) includes a broad spectrum of liver diseases characterized by steatosis, inflammation, and fibrosis. This study aimed to investigate the potential of dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors in alleviating the progression of NAFLD. The NAFLD model was generated by feeding male C57BL/6J mice a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 7 weeks. After 2 weeks of CDAHFD feeding, the NAFLD model mice were assigned to four groups, namely (ⅰ) VEHICLE, (ⅱ) gemigliptin (GEMI), (ⅲ) empagliflozin (EMPA), and (ⅳ) GEMI + EMPA. For the next 5 weeks, mice received the vehicle or the drug based upon the group to which they belonged. Thereafter, the triglyceride concentration, extent of fibrosis, and the expression of genes encoding inflammatory cytokines, chemokines, and antioxidant enzymes were analyzed in the livers of mice. The NAFLD activity score and hepatic fibrosis grade were assessed via hematoxylin and eosin and Sirius Red staining of the liver tissue samples. All mice belonging to the GEMI, EMPA, and GEMI + EMPA groups showed improvements in the accumulation of liver triglycerides and the expression of inflammatory cytokines and chemokines. Additionally, the oxidative stress was reduced due to inhibition of the c-Jun N-terminal kinase pathway and upregulation of the antioxidant enzymes. Furthermore, in these three groups, the galectin-3 and interleukin 33-induced activity of tumor necrosis factor-α was inhibited, thereby preventing the progression of liver fibrosis. These findings suggest that the GEMI, EMPA, and GEMI + EMPA treatments ameliorate hepatic steatosis, inflammation, oxidative stress, and fibrosis in CDAHFD-induced NAFLD mouse models.

Nanoceria-based lateral flow immunoassay for hydrogen peroxide-free colorimetric biosensing for C-reactive protein.

During the recent several decades, lateral flow immunoassay (LFIA) constructed with gold nanoparticle (AuNP) has been widely utilized to conveniently detect target analyte. However, AuNP-based LFIA has limitations, such as limited detection sensitivity and quantification capability. Herein, to overcome these constraints, we have developed cerium oxide nanoparticle (nanoceria)-based LFIA for C-reactive protein (CRP) detection in human serum samples. It was fabricated with nanoceria, a notable nanozyme that shows an oxidase activity to quickly oxidize organic substrate, such as 3,3',5,5'-tetramethylbenzidine (TMB), to produce colored product without any oxidizing agent (e.g., hydrogen peroxide), which is advantageous for realizing point-of-care testing (POCT) applications. By employing human blood serum spiked with CRP, the nanoceria-based LFIA showed two blue-colored lines on the test and control region within 3 min via TMB oxidation, by the captured nanoceria through antigen-antibody interaction. The produced blue-colored lines were distinguished by naked eyes and quantitated with real images acquired by a conventional smartphone with the ImageJ software. With this strategy, target CRP was specifically determined down to 117 ng mL-1 with high detection precisions yielding coefficient of variation of 9.8-11.3% and recovery of 90.7-103.2% using human blood serum samples. This investigation demonstrates the potential of oxidase-like nanoceria for developing LFIA, which is particularly useful in instrumentation-free POCT environments.

In Vivo Two-Photon Imaging Analysis of Dynamic Degradation of Hepatic Lipid Droplets in MS-275-Treated Mouse Liver.

The accumulation of hepatic lipid droplets (LDs) is a hallmark of non-alcoholic fatty liver disease (NAFLD). Appropriate degradation of hepatic LDs and oxidation of complete free fatty acids (FFAs) are important for preventing the development of NAFLD. Histone deacetylase (HDAC) is involved in the impaired lipid metabolism seen in high-fat diet (HFD)-induced obese mice. Here, we evaluated the effect of MS-275, an inhibitor of HDAC1/3, on the degradation of hepatic LDs and FFA oxidation in HFD-induced NAFLD mice. To assess the dynamic degradation of hepatic LDs and FFA oxidation in fatty livers of MS-275-treated HFD C57BL/6J mice, an intravital two-photon imaging system was used and biochemical analysis was performed. The MS-275 improved hepatic metabolic alterations in HFD-induced fatty liver by increasing the dynamic degradation of hepatic LDs and the interaction between LDs and lysozyme in the fatty liver. Numerous peri-droplet mitochondria, lipolysis, and lipophagy were observed in the MS-275-treated mouse fatty liver. Biochemical analysis revealed that the lipolysis and autophagy pathways were activated in MS-275 treated mouse liver. In addition, MS-275 reduced the de novo lipogenesis, but increased the mitochondrial oxidation and the expression levels of oxidation-related genes, such as PPARa, MCAD, CPT1b, and FGF21. Taken together, these results suggest that MS-275 stimulates the degradation of hepatic LDs and mitochondrial free fatty acid oxidation, thus protecting against HFD-induced NAFLD.

Development and psychometric evaluation of a new brief scale to measure eHealth literacy in people with type 2 diabetes.

BACKGROUND: The internet has become a major source of health information, and obtaining appropriate information requires various abilities and skills, labeled as electronic health literacy (eHealth literacy). The existing instruments for measuring eHealth literacy are outdated because they were developed during the Web 1.0 era, or not sufficiently sensitive for people with a specific condition or disease because they were designed to assess eHealth literacy over a broad range for a general population. Approximately one in ten adults worldwide live with diabetes. Health professionals have a responsibility to identify patients with low eHealth literacy to prevent them from obtaining misleading internet diabetes information. AIMS: The aims were to develop a condition-specific eHealth literacy scale for diabetes and to evaluate its psychometric properties among people with type 2 diabetes. METHODS: An instrument development design was used. This study recruited 453 people diagnosed with type 2 diabetes at the outpatient clinics of hospitals in 2021. Psychometric properties (internal consistency, measurement invariance, and content, structural, convergent, and known-groups validities) were analyzed. RESULTS: An expert panel assessed content validity. Exploratory factor analysis, exploratory graph analysis, and confirmatory factor analysis (CFA) for structural validity yielded a two-factor solution (CFI = 0.977, SRMR = 0.029, RMSEA = 0.077). Cronbach's alpha and omega values were excellent for each factor (0.87-0.94). Multigroup CFA yielded configural and metric measurement invariance across the gender, age, and glycemic control status groups. Convergent validity with a comparator instrument to measure health literacy was supported by a moderate correlation, and known-groups validity determined using groups with different internet-use frequencies was satisfied with a high effect size. CONCLUSION: A new condition-specific eHealth literacy scale for people with type 2 diabetes was developed, comprising 10 items. The scale exhibited good psychometric properties; however, test-retest reliability must be determined for the stability of the scale and cross-cultural validity is required among different languages. The brief scale has the merits of being feasible to use in busy clinical practice and being less burdensome to respondents. The scale can be applied in clinical trials of internet-based diabetes interventions for assessing the eHealth literacy of respondents.

Valorization of Click-Based Microporous Organic Polymer: Generation of Mesoionic Carbene-Rh Species for the Stereoselective Synthesis of Poly(arylacetylene)s.

This work reports the functionalization of azide-alkyne click-based microporous organic polymer (CMOP). The generation of triazolium salts and successive deprotonation induced mesoionic carbene species in hollow CMOP (H-CMOP). Rh(I) species could be coordinated to the mesoionic carbene species to form H-CMOP-Rh, showing excellent heterogeneous catalytic performance in the stereoselective polymerization of arylacetylenes.

Visfatin exacerbates hepatic inflammation and fibrosis in a methionine-choline-deficient diet mouse model.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to non-alcoholic steatohepatitis, which is characterized by hepatic inflammation that can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. Visfatin, an adipocytokine, was reported to induce pro-inflammatory cytokines and can be associated with liver fibrosis. We investigated the role of visfatin on hepatic inflammation and fibrosis in a methionine-choline-deficient (MCD)-diet-induced steatohepatitis mouse model. METHODS: Eight-week-old male C57BL/6 J mice were randomly assigned into one of three groups: (1) saline-injected control diet group; (2) saline-injected MCD diet group; and (3) visfatin-injected MCD diet group (n = 8 per group). Mice were administered intravenous saline or 10 µg/kg of recombinant murine visfatin for 2 weeks. Histologic assessment of liver and biochemical and molecular measurements of endoplasmic reticulum (ER) stress, reactive oxidative stress (ROS), inflammation, and fibrosis were performed in livers from these animals. RESULTS: Visfatin injection aggravated hepatic steatosis and increased plasma alanine aminotransferase and aspartate aminotransferase concentrations. Visfatin increased inflammatory cell infiltration (as indicated by F4/80, CD68, ly6G, and CD3 mRNA expression) and expression of chemokines in the liver. Visfatin also increased the expression of pro-inflammatory cytokines (IL-1ß, TNF-α, and IL-6) and activated fibrosis markers (CTGF, TIMP1, collagen 1α2, collagen 3α2, αSMA, fibronectin, and vimentin) in liver. Livers of visfatin-injected mice showed upregulation of ER stress and ROS and activation of JNK signaling. CONCLUSIONS: These results suggest that visfatin aggravates hepatic inflammation together with induction of ER and oxidative stress and exacerbates fibrosis in an MCD-diet-fed mouse model of NAFLD.

Colorimetric determination of phenolic compounds using peroxidase mimics based on biomolecule-free hybrid nanoflowers consisting of graphitic carbon nitride and copper.

Hybrid nanoflowers consisting of graphitic carbon nitride (GCN) and copper were successfully constructed without the involvement of any biomolecule, by simply mixing them at room temperature to induce proper self-assembly to achieve a flower-like morphology. The resulting biomolecule-free GCN-copper hybrid nanoflowers (GCN-Cu NFs) exhibited an apparent peroxidase-mimicking activity, possibly owing to the synergistic effect from the coordination of GCN and copper, as well as their large surface area, which increased the number of catalytic reaction sites. The peroxidase-mimicking GCN-Cu NFs were then employed in the colorimetric determination of selected phenolic compounds hydroquinone (HQ), methylhydroquinone (MHQ), and catechol (CC). For samples without phenolic compounds, GCN-Cu NFs catalyzed the oxidation of the peroxidase substrate 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of H2O2, producing an intense blue color signal. Conversely, in the presence of phenolic compounds, the oxidation of TMB was inhibited, resulting in a significant reduction of the color signal. Using this strategy, HQ, MHQ, and CC were selectively and sensitively determined in a linear range up to 100 µM with detection limits down to 0.82, 0.27, and 0.36 µM, respectively. The practical utility of this assay system was also validated by using it to detect phenolic compounds spiked in tap water, yielding a good recovery of 97.1-108.9% and coefficient of variation below 3.0%, demonstrating the excellent reliability and reproducibility of this strategy. Colorimetric determination of phenolic compounds using peroxidase mimics based on biomolecule-free hybrid nanoflowers consisting of graphitic carbon nitride and copper.

Acute Glucose Shift Induces the Activation of the NLRP3 Inflammasome in THP-1 Cells.

We aimed to investigate the effect of acute glucose shift on the activation of the NLRP3 inflammasome, IL-1ß secretion, and underlying signaling pathways in THP-1 cells. THP-1 cells were divided into four groups and exposed to the following glucose concentrations for 24 h: constant normal glucose (NG, 5.5 mM), constant high glucose (HG, 25 mM), normal to high glucose shift (NG-to-HG, 5.5 to 25 mM), and high to normal glucose shift (HG-to-NG, 25 to 5.5 mM). Cell viability, oxidative stress, and the levels of NLRP3 inflammasome components were assessed. Both directions of the acute glucose shift increased the activation of the NLRP3 inflammasome, generation of reactive oxygen species (ROS), and expression of phosphorylated p38 MAPK, JNK, and NF-κB compared with either constant NG or HG. Treatment with N-acetylcysteine, a pharmacological antioxidant, inhibited the acute glucose shift-induced generation of ROS, activation of NLRP3 inflammasome, and upregulation of MAPK-NF-κB. Further analysis using inhibitors of p38 MAPK, JNK, and NF-κB indicated that acute glucose shifts promoted IL-1ß secretion by activating the signaling pathway in a ROS-MAPK-NF-κB-NLRP3 inflammasome in THP-1 cells. These findings suggested that acute changes in glucose concentration might cause monocyte inflammation, which is associated with diabetic complications.

Synthesis of 2D Germanane (GeH): a New, Fast, and Facile Approach.

Germanane (GeH), a germanium analogue of graphane, has recently attracted considerable interest because its remarkable combination of properties makes it an extremely suitable candidate to be used as 2D material for field effect devices, photovoltaics, and photocatalysis. Up to now, the synthesis of GeH has been conducted by substituting Ca by H in a ß-CaGe2 layered Zintl phase through topochemical deintercalation in aqueous HCl. This reaction is generally slow and takes place over 6 to 14 days. The new and facile protocol presented here allows to synthesize GeH at room temperature in a significantly shorter time (a few minutes), which renders this method highly attractive for technological applications. The GeH produced with this method is highly pure and has a band gap (Eg ) close to 1.4 eV, a lower value than that reported for germanane synthesized using HCl, which is promising for incorporation of GeH in solar cells.

Kir6.1-dependent KATP channels in lymphatic smooth muscle and vessel dysfunction in mice with Kir6.1 gain-of-function.

KEY POINTS: Spontaneous contractions are essential for normal lymph transport and these contractions are exquisitely sensitive to the KATP channel activator pinacidil. KATP channel Kir6.1 and SUR2B subunits are expressed in mouse lymphatic smooth muscle (LSM) and form functional KATP channels as verified by electrophysiological techniques. Global deletion of Kir6.1 or SUR2 subunits results in severely impaired lymphatic contractile responses to pinacidil. Smooth muscle-specific expression of Kir6.1 gain-of-function mutant (GoF) subunits results in profound lymphatic contractile dysfunction and LSM hyperpolarization that is partially rescued by the KATP inhibitor glibenclamide. In contrast, lymphatic endothelial-specific expression of Kir6.1 GoF has essentially no effect on lymphatic contractile function. The high sensitivity of LSM to KATP channel GoF offers an explanation for the lymphoedema observed in patients with Cantú syndrome, a disorder caused by gain-of-function mutations in genes encoding Kir6.1 or SUR2, and suggests that glibenclamide may be an appropriate therapeutic agent. ABSTRACT: This study aimed to understand the functional expression of KATP channel subunits in distinct lymphatic cell types, and assess the consequences of altered KATP channel activity on lymphatic pump function. KATP channel subunits Kir6.1 and SUR2B were expressed in mouse lymphatic muscle by PCR, but only Kir6.1 was expressed in lymphatic endothelium. Spontaneous contractions of popliteal lymphatics from wild-type (WT) (C57BL/6J) mice, assessed by pressure myography, were very sensitive to inhibition by the SUR2-specific KATP channel activator pinacidil, which hyperpolarized both mouse and human lymphatic smooth muscle (LSM). In vessels from mice with deletion of Kir6.1 (Kir6.1-/- ) or SUR2 (SUR2[STOP]) subunits, contractile parameters were not significantly different from those of WT vessels, suggesting that basal KATP channel activity in LSM is not an essential component of the lymphatic pacemaker, and does not exert a strong influence over contractile strength. However, these vessels were >100-fold less sensitive than WT vessels to pinacidil. Smooth muscle-specific expression of a Kir6.1 gain-of-function (GoF) subunit resulted in severely impaired lymphatic contractions and hyperpolarized LSM. Membrane potential and contractile activity was partially restored by the KATP channel inhibitor glibenclamide. In contrast, lymphatic endothelium-specific expression of Kir6.1 GoF subunits had negligible effects on lymphatic contraction frequency or amplitude. Our results demonstrate a high sensitivity of lymphatic contractility to KATP channel activators through activation of Kir6.1/SUR2-dependent channels in LSM. In addition, they offer an explanation for the lymphoedema observed in patients with Cantú syndrome, a disorder caused by gain-of-function mutations in genes encoding Kir6.1/SUR2.

Revealing molecular-level surface redox sites of controllably oxidized black phosphorus nanosheets.

Bulk and two-dimensional black phosphorus are considered to be promising battery materials due to their high theoretical capacities of 2,600 mAh g-1. However, their rate and cycling capabilities are limited by the intrinsic (de-)alloying mechanism. Here, we demonstrate a unique surface redox molecular-level mechanism of P sites on oxidized black phosphorus nanosheets that are strongly coupled with graphene via strong interlayer bonding. These redox-active sites of the oxidized black phosphorus are confined at the amorphorized heterointerface, revealing truly reversible pseudocapacitance (99% of total stored charge at 2,000 mV s-1). Moreover, oxidized black-phosphorus-based electrodes exhibit a capacitance of 478 F g-1 (four times greater than black phosphorus) with a rate capability of ~72% (compared to 21.2% for black phosphorus) and retention of ~91% over 50,000 cycles. In situ spectroelectrochemical and theoretical analyses reveal a reversible change in the surface electronic structure and chemical environment of the surface-exposed P redox sites.

Comparison of heart failure risk and medical costs between patients with type 2 diabetes mellitus treated with dapagliflozin and dipeptidyl peptidase-4 inhibitors: a nationwide population-based cohort study.

BACKGROUND: Dapagliflozin is one of the novel glucose-lowering agents, which has recently been reported to reduce the risk of hospitalization for heart failure (hHF). The present study aimed to compare the differences between the risk of hHF after using dapagliflozin and dipeptidyl peptidase-4 inhibitors (DPP-4i) as second-line drugs for the treatment of type 2 diabetes mellitus using the latest nationwide population data in Korea. Additionally, we aimed to examine the impact of clinical outcomes on direct medical costs in the two groups. METHODS: The present population-based, retrospective cohort study was conducted using the nationwide claims data between September 01, 2014 and June 30, 2018. New users of dapagliflozin and DPP-4i were identified from the database and the differences in patients' characteristics between the two groups were analyzed using propensity score-weighted analysis. Cox proportional hazards regression analysis was used to estimate the risk of hHF. A simple model was used for the estimation of direct medical costs for 3 years. RESULTS: In total, 23,147 patients in the dapagliflozin group and 237,187 patients in the DPP-4i group were selected for the analysis. The incidence rates of hHF were 3.86 and 6.79 per 1000 person-years in the dapagliflozin and DPP-4i groups, respectively. In the entire study population, the hazard ratio for hHF in the dapagliflozin group compared to the DPP-4i group was 0.58 (95% confidence interval 0.46-0.74), with 0.55 (95% confidence interval 0.41-0.74) among patients with underlying cardiovascular disease and 0.66 (95% confidence interval 0.46-0.95) among patients without underlying cardiovascular disease. The direct medical costs were $57,787 lower in the dapagliflozin group than in the DPP-4i group for 3 years. CONCLUSIONS: This study showed that dapagliflozin lowers the risk for hHF and subsequently reduces direct medical costs compared to DPP-4i. The protective effect against hHF was more evident among patients with underlying cardiovascular disease.