Background & Aims Pharmacological approaches can potentially improve fatty liver condition in alcoholic and non-alcoholic fatty liver diseases. The salutary effects of reducing lipid synthesis or ...promoting lipid oxidation have been well reported, but the benefits of increasing lipid degradation have yet to be well explored. Macroautophagy is a cellular degradation process that can remove subcellular organelles including lipid droplets. We thus investigated whether pharmacological modulation of macroautophagy could be an effective approach to alleviate fatty liver condition and liver injury. Methods C57BL/6 mice were given ethanol via intraperitoneal injection (acute) or by a 4-week oral feeding regime (chronic), or high fat diet for 12 weeks. An autophagy enhancer, carbamazepine or rapamycin, or an autophagy inhibitor, chloroquine, was given before sacrifice. Activation of autophagy, level of hepatic steatosis, and blood levels of triglycerides, liver enzyme, glucose and insulin were measured. Results In both acute and chronic ethanol condition, macroautophagy was activated. Carbamazepine, as well as rapamycin, enhanced ethanol-induced macroautophagy in hepatocytes in vitro and in vivo . Hepatic steatosis and liver injury were exacerbated by chloroquine, but alleviated by carbamazepine. The protective effects of carbamazepine and rapamycin in reducing steatosis and in improving insulin sensitivity were also demonstrated in high fat diet-induced non-alcoholic fatty liver condition. Conclusions These findings indicate that pharmacological modulation of macroautophagy in the liver can be an effective strategy for reducing fatty liver condition and liver injury.
The behaviour of arsenic (As) from geogenic soil exposed to aerobic conditions is critical to predict the impact of As on the environment, which processes remain unresolved. The current study ...examined the depth profile of As in geologically derived subsoil cores from Hong Kong and investigated the mobilization, plant availability, and bioaccessibility of As in As-contaminated soil at different depths (0–45.8 m). Results indicated significant heterogeneity, with high levels of As in three layers of soil reaching up to 505 mg/kg at a depth of 5 m, 404 mg/kg at a depth of 15 m, and 1510 mg/kg at a depth of 27–32 m. Arsenic in porewater samples was <11.5 μg/L in the study site. X-ray absorption spectroscopy (XAS) indicated that main As species in soil was arsenate (As(V)), as adsorbed fraction to Fe oxides (41–69% on goethite and 0–8% on ferrihydrite) or the mineral form scorodite (30–57%). Sequential extraction procedure demonstrated that 0.5 ± 0.4% of As was exchangeable. Aerobic incubation experiments exhibited that a very small amount (0.14–0.48 mg/kg) of As was desorbed from the soil because of the stable As(V) complex structure on abundant Fe oxides (mainly goethite), where indigenous microbes partly (59 ± 18%) contributed to the release of As comparing with the sterilized control. Furthermore, no As toxicity in the soil was observed with the growth of ryegrass. The bioaccessibility of As was <27% in the surface soil using simplified bioaccessibility extraction test. Our systematic evaluation indicated that As in the geogenic soil profile from Hong Kong is relatively stable exposing to aerobic environment. Nevertheless, children and workers should avoid incidental contact with excavated soil, because high concentration of As was present in the digestive solution (<0.1–268 μg/L).
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•The soil cores from Hong Kong exhibit high level of arsenic (up to 1510 mg/kg) with significant heterogeneity.•Arsenic in the soil was mainly arsenate (>92%), primarily as adsorbed species on Fe oxides or the mineral form scorodite.•Only 0.14–0.48 mg/kg of As was released from soil during aerobic incubation tests.•An average of 59% of the released As was contributed by the soil indigenous microbe.•The bioaccessibility extraction test indicated probable As toxicity (268 μg/L) with incidental soil ingestion.
Geogenic arsenic is mainly arsenate (>98%), primarily as adsorbed species on Fe oxides, with low leachability in soil under aerobic conditions.
Solid-state 29Si, 113Cd, 119Sn, and 31P MAS NMR spectra are reported on a series of II-IV-P2 compounds. In favorable cases (e.g., high degree of crystallinity, low concentration of unpaired ...electrons), well-defined spectra, with sharp lines for each specific nearest-neighbor configuration, are observed; in such cases, expected J coupling patterns are also seen. High-resolution solid-state NMR studies of this type provide useful information on structure (disorder), doping, and electron-mediated coupling in semiconductor systems.
Predicting landslide displacement is challenging, but accurate predictions can prevent casualties and economic losses. Many factors can affect the deformation of a landslide, including the geological ...conditions, rainfall and reservoir water level. Time series analysis was used to decompose the cumulative displacement of landslide into a trend component and a periodic component. Then the least-squares support vector machine (LSSVM) model and genetic algorithm (GA) were used to predict landslide displacement, and we selected a representative landslide with episodic movement deformation as a case study. The trend component displacement, which is associated with the geological conditions, was predicted using a polynomial function, and the periodic component displacement which is associated with external environmental factors, was predicted using the GA-LSSVM model. Furthermore, based on a comparison of the results of the GA-LSSVM model and those of other models, the GA-LSSVM model was superior to other models in predicting landslide displacement, with the smallest root mean square error (RMSE) of 62.4146 mm, mean absolute error (MAE) of 53.0048 mm and mean absolute percentage error (MAPE) of 1.492 % at monitoring station ZG85, while these three values are 87.7215 mm, 74.0601 mm and 1.703 % at ZG86 and 49.0485 mm, 48.5392 mm and 3.131 % at ZG87. The results of the case study suggest that the model can provide good consistency between measured displacement and predicted displacement, and periodic displacement exhibited good agreement with trends in the major influencing factors.
Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of ...Smoothened (SMO). Here, we performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond. This modification was inhibited by Patched-1 (Ptch1) but enhanced by Hh. The SMO(D95N) mutation, which could not be cholesterol modified, was refractory to Hh-stimulated ciliary localization and failed to activate downstream signaling. Furthermore, homozygous SmoD99N/D99N (the equivalent residue in mouse) knockin mice were embryonic lethal with severe cardiac defects, phenocopying the Smo−/− mice. Together, the results of our study suggest that Hh signaling transduces to SMO through modulating its cholesterylation and provides a therapeutic opportunity to treat Hh-pathway-related cancers by targeting SMO cholesterylation.
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•SMO is covalently modified by cholesterol on the Asp95 (D95) residue•Cholesterol modification of SMO is inhibited by Ptch1 and enhanced by Hh•SMO cholesterylation is essential for Hh signaling and embryonic development
Xiao et al. identify that SMO is covalently modified by cholesterol. This modification is regulated by Ptch1 and Hh and is essential for Hh signaling. It suggests that Hh signaling transduces to SMO through modulating its cholesterylation and that targeting SMO cholesterylation may provide a therapeutic approach to treat Hh-pathway-related cancers.
Neuregulin 1 (NRG1) and its receptor ErbB4 are schizophrenia risk genes. NRG1-ErbB4 signaling plays a critical role in neural development and regulates neurotransmission and synaptic plasticity. ...Nevertheless, its cellular targets remain controversial. ErbB4 was thought to express in excitatory neurons, although recent studies disputed this view. Using mice that express a fluorescent protein under the promoter of the ErbB4 gene, we determined in what cells ErbB4 is expressed and their identity. ErbB4 was widely expressed in the mouse brain, being highest in amygdala and cortex. Almost all ErbB4-positive cells were GABAergic in cortex, hippocampus, basal ganglia, and most of amygdala in neonatal and adult mice, suggesting GABAergic transmission as a major target of NRG1-ErbB4 signaling in these regions. Non-GABAergic, ErbB4-positive cells were present in thalamus, hypothalamus, midbrain, and hindbrain. In particular, ErbB4 is expressed in serotoninergic neurons of raphe nuclei but not in norepinephrinergic neurons of the locus ceruleus. In hypothalamus, ErbB4 is present in neurons that express oxytocin. Finally, ErbB4 is expressed in a group of cells in the subcortical areas that are positive for S100 calcium binding protein β. These results identify novel cellular targets of NRG1-ErbB4 signaling.
Anatase TiO(2) having different percentages of (001)/(101) surface demonstrated different behaviors for Li(+) ions insertion and much enhanced rate performance of Li-ion batteries.
Herein, we report an efficient kinetic resolution of alkyl allylic alcohols enabled by an iridium-catalyzed enantioselective alkynylation of alkyl allylic alcohols with potassium ...alkynyltrifluoroborates. A wide range of chiral 1,4-enynes bearing various functional groups and unreacted enantioenriched allylic alcohols were obtained with excellent enantioselectivities and high kinetic resolution performance (
s
-factor up to 922). Additionally, this method is particularly effective for preparing some useful optically pure alkyl allylic alcohols, such as the key components towards the synthesis of prostaglandins and naturally occurring matsutakeols, which are difficult to access
via
other asymmetric reactions. Mechanistic studies revealed that the efficient kinetic resolution might be due to the significant distinction of the
η
2
-coordination between the (
R
)- and (
S
)-allylic alcohols with the iridium/(phosphoramidite, olefin) complex.
An efficient kinetic resolution of (±)-alkyl allylic alcohols has been realized by Ir/(
S
)-
L1
-catalyzed allylic alkynylation. The reaction of (±)-alkyl allylic alcohols and potassium alkynyltrifluoroborates provided enantioenriched 1,4-enynes and unreacted allylic alcohols.
High‐mobility group box 1 (HMGB1), a nonhistone nuclear protein, is released by macrophages into the extracellular milieu consequent to cellular activation. Extracellular HMGB1 has properties of a ...pro‐inflammatory cytokine through its interaction with receptor for advanced glycation endproducts (RAGE) and/or toll‐like receptors (TLR2 and TLR4). Although HMGB1 is highly expressed in macrophages and differentiating osteoclasts, its role in osteoclastogenesis remains largely unknown. In this report, we present evidence for a function of HMGB1 in this event. HMGB1 is released from macrophages in response to RANKL stimulation and is required for RANKL‐induced osteoclastogenesis in vitro and in vivo. In addition, HMGB1, like other osteoclastogenic cytokines (e.g., TNFα), enhances RANKL‐induced osteoclastogenesis in vivo and in vitro at subthreshold concentrations of RANKL, which alone would be insufficient. The role of HMGB1 in osteoclastogenesis is mediated, in large part, by its interaction with RAGE, an immunoglobin domain containing family receptor that plays an important role in osteoclast terminal differentiation and activation. HMGB1‐RAGE signaling seems to be important in regulating actin cytoskeleton reorganization, thereby participating in RANKL‐induced and integrin‐dependent osteoclastogenesis. Taken together, these observations show a novel function of HMGB1 in osteoclastogenesis and provide a new link between inflammatory mechanisms and bone resorption.
Neuregulin 1 (Nrg1) is a susceptibility gene of schizophrenia, a disabling mental illness that affects 1% of the general population. Here, we show that ctoNrg1 mice, which mimic high levels of NRG1 ...observed in forebrain regions of schizophrenic patients, exhibit behavioral deficits and hypofunction of glutamatergic and GABAergic pathways. Intriguingly, these deficits were diminished when NRG1 expression returned to normal in adult mice, suggesting that damage which occurred during development is recoverable. Conversely, increase of NRG1 in adulthood was sufficient to cause glutamatergic impairment and behavioral deficits. We found that the glutamatergic impairment by NRG1 overexpression required LIM domain kinase 1 (LIMK1), which was activated in mutant mice, identifying a pathological mechanism. These observations demonstrate that synaptic dysfunction and behavioral deficits in ctoNrg1 mice require continuous NRG1 abnormality in adulthood, suggesting that relevant schizophrenia may benefit from therapeutic intervention to restore NRG1 signaling.
•Mice modeling abnormal NRG1 level in patients show schizophrenia-like deficits•NRG1 overexpression causes synaptic dysfunction possibly by activating LIMK1•Deficits are alleviated when NRG1 expression is returned to normal in adult animals•Schizophrenia may benefit from therapeutic intervention to restore NRG1 signaling
Yin et al. demonstrate that NRG1 overexpression in adulthood, seen in schizophrenia patients, is critical for behavioral and synaptic deficits in mice. This study therefore suggests the potential of therapeutic intervention to restore NRG1 signaling.
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