Lysosomes have fundamental physiological roles and have previously been implicated in Parkinson's disease
. However, how extracellular growth factors communicate with intracellular organelles to ...control lysosomal function is not well understood. Here we report a lysosomal K
channel complex that is activated by growth factors and gated by protein kinase B (AKT) that we term lysoK
. LysoK
consists of a pore-forming protein TMEM175 and AKT: TMEM175 is opened by conformational changes in, but not the catalytic activity of, AKT. The minor allele at rs34311866, a common variant in TMEM175, is associated with an increased risk of developing Parkinson's disease and reduces channel currents. Reduction in lysoK
function predisposes neurons to stress-induced damage and accelerates the accumulation of pathological α-synuclein. By contrast, the minor allele at rs3488217-another common variant of TMEM175, which is associated with a decreased risk of developing Parkinson's disease-produces a gain-of-function in lysoK
during cell starvation, and enables neuronal resistance to damage. Deficiency in TMEM175 leads to a loss of dopaminergic neurons and impairment in motor function in mice, and a TMEM175 loss-of-function variant is nominally associated with accelerated rates of cognitive and motor decline in humans with Parkinson's disease. Together, our studies uncover a pathway by which extracellular growth factors regulate intracellular organelle function, and establish a targetable mechanism by which common variants of TMEM175 confer risk for Parkinson's disease.
Owing to the harmful nature of 4-nitrochlorobenzene (4-NCB, one toxic organic pollutant) and the low cost, high sensitivity and ease of operation of electrochemical method, it is highly desirable to ...develop effect electrochemical sensor for the detection of 4-NCB. Herein, by partially unzipping carbon nanohorns (CNHs) via a simple wet-chemistry method, CNHs and graphene oxide (GO) (CNHs/GO) nanohybrids were produced for sensing 4-NCB with synergistic properties. While the retained CNHs offer a path for rapid electron transport, the GO sheets formed by partially unzipping CNHs provide abundant active sites, further increase in surface area as well as improved dispersibility of the CNHs/GO. Our results show that the CNHs/GO modified electrode has excellent sensitivity to 4-NCB with a wide linear response range and a detection limit as low as 10 nM.
•Carbon nanohorns and graphene oxide nanohybrids were produced by partially unzipping carbon nanohorns.•The obtained nanohybrids were applied to electrochemically detect 4-NCB.•Highly sensitive electrochemical sensor of 4-NCB was successfully achieved.•Carbon nanohorns/graphene oxide nanohybrids have promising applications in electrochemical sensing and other fields.
Abstract The suppressor of cytokine signaling 3 (SOCS3) is an established negative feedback regulation transcription factor associated with leptin, tumor necrosis factor-α (TNF-α), interferon-γ ...(IFN-γ) and growth hormone (GH). However, the regulatory mechanism of SOCS3 on inflammation and apoptosis of adipocyte is still not clear. In this study, we found an increased expression of adipocyte inflammatory cytokines TNF-α and IL-6 due to leptin treatment. Meanwhile Caspase3, a key executioner of apoptosis, was also elevated in this process. In addition, we observed that SOCS3 could promote inflammation whereas SOCS3 interference reversed this effect in LPS-induced adipocytes inflammatory model. Moreover, the expression of apoptosis-associated genes Bax, cleaved-Caspase9 and cleaved-Caspase3 were elevated along with decreased Bcl-2 expression as detected with Western blot and ELISA assay. The phosphorylation level of JAK2/STAT3 signal was inhibited by SOCS3 along with the elevated expression of IL-6, TNF-α and Caspase3. We also demonstrated that stable knockdown of SOCS3 along with SD1008, a specific inhibitor of JAK2/STAT3 signaling pathway, could significantly inhibit inflammation and apoptosis of adipocyte. Altogether, these results inferred that SOCS3 promotes adipocyte apoptosis by both aggravating inflammation and inhibiting the activity of JAK2/STAT3 signaling pathway.
Sirtuin type 1 (Sirt1) and protein kinase B (Akt2) are associated with development of obesity and inflammation, but the molecular mechanisms of Sirt1 and Akt2 interaction on adipose inflammation ...remain unclear. To explore these mechanisms, a mouse model was used. Mice were fed with a high-fat diet (HFD) for 8 weeks, with interventions of resveratrol (RES) or nicotinamide (NAM) during the last 15 days. The HFD reduced Sirt1 mRNA in adipose tissue and elevated interleukin-6 (IL-6) expression. RES reduced the adipose tissue weight, increased the Sirt1 mRNA level, and reduced both mRNA and protein levels of IL-6, MCP-1, inducible nitric oxide synthase, and TNF-α by inhibiting phosphorylation of Akt2 in adipose tissue. Additionally, macrophage type I marker genes were reduced while macrophage type II marker genes were elevated by RES addition. Moreover, activation of Akt2 signal by using insulin significantly blunted the inhibitory effect of RES on adipose inflammation. Immunoprecipitation assay demonstrated that RES enhances the protein-protein interaction between Sirt1 and Akt2, but NAM inhibits this interaction. Furthermore, Sirt1 significantly reduced the levels of raptor and inactivated mammalian target of rapamycin (mTOR)C1 signal by interacting with Akt2, and confirmed that RES attenuated adipose inflammation by inhibiting the mTOR/S6K1 pathway via rapamycin.
Forkhead box C2 (Foxc2) protein is a transcription factor in regulation of development, metabolism, and immunology. However, the regulatory mechanisms of Foxc2 on proliferation and apoptosis of ...preadipocytes are unclear. In this study, we found that high-fat-diet-induced obesity elevated the expression of Foxc2 and cyclin E after 6 weeks. Additionally, Foxc2 suppressed preadipocyte differentiation, increased cell counts and augmented G1-S transition of preadipocytes, along with the elevation of cyclin E expression and the reduction levels of p27 and p53. Furthermore, Foxc2 knockdown reduced early apoptotic cells with accompanying reduction of mitochondrial membrane potential and increased fragmentation of genomic DNA. We show that Foxc2 reduces the expression of Bax, caspase-9, and caspase-3 in both serum-starved and palmitic acid-induced cell apoptotic models, which confirms the anti-apoptotic role of Foxc2. Moreover, the protein kinase B (Akt)/mammalian target of rapamycin (mTOR)C1 signaling pathway and the ERK/mTORC1 signaling pathway were activated along with preadipocyte proliferation in response to Foxc2 overexpression, whereas apoptosis marker genes were downregulated during this process. Those effects were blocked by the interference of Foxc2 or signal pathways specific inhibitors. These data collectively reveal that Foxc2 enhances proliferation of preadipocytes and inhibits apoptosis of preadipocytes by activating the Akt/mTORC1 and ERK/mTORC1 signaling pathways.
Lysosomes are membrane-bound organelles with an acidic lumen and are traditionally characterized as a recycling center in cells. Lysosomal ion channels are integral membrane proteins that form pores ...in lysosomal membranes and allow the influx and efflux of essential ions. Transmembrane protein 175 (TMEM175) is a unique lysosomal potassium channel that shares little sequence similarity with other potassium channels. It is found in bacteria, archaea, and animals. The prokaryotic TMEM175 consists of one six-transmembrane domain that adopts a tetrameric architecture, while the mammalian TMEM175 is comprised of two six-transmembrane domains that function as a dimer in lysosomal membranes. Previous studies have demonstrated that the lysosomal K
conductance mediated by TMEM175 is critical for setting membrane potential, maintaining pH stability, and regulating lysosome-autophagosome fusion. AKT and B-cell lymphoma 2 regulate TMEM175's channel activity through direct binding. Two recent studies reported that the human TMEM175 is also a proton-selective channel under normal lysosomal pH (4.5-5.5) as the K
permeation dramatically decreased at low pH while the H
current through TMEM175 greatly increased. Genome-wide association studies and functional studies in mouse models have established that TMEM175 is implicated in the pathogenesis of Parkinson's disease, which sparks more research interests in this lysosomal channel.
Hypoxia represent a condition in which an adequate amount of oxygen supply is missing in the body, and it could be caused by a variety of diseases, including gastrointestinal disorders. This review ...is focused on the role of hypoxia in the maintenance of the gut homeostasis and related treatment of gastrointestinal disorders. The effects of hypoxia on the gut microbiome and its role on the intestinal barrier functionality are also covered, together with the potential role of hypoxia in the development of gastrointestinal disorders, including inflammatory bowel disease and irritable bowel syndrome. Finally, we discussed the potential of hypoxia-targeted interventions as a novel therapeutic approach for gastrointestinal disorders. In this review, we highlighted the importance of hypoxia in the maintenance of the gut homeostasis and the potential implications for the treatment of gastrointestinal disorders.
To promote the activity and stability of immobilized porcine pancreatic lipase (PPL), novel carrier was combined with special immobilization method. Enzymatic activity was enhanced after immobilized ...onto ionic liquid modified magnetic Fe
3
O
4
by electrostatic adsorption. Activity of immobilized enzyme (PPL-IM/BF
4
-Fe
3
O
4
@CA) reached 596 U/g PPL. Through the combination of electrostatic adsorption and embedding immobilization methods, we improve binding force between the carrier and enzyme, and further enhance the efficiency and stability of immobilized enzyme. The activity of PPL-IM/BF
4
-Fe
3
O
4
@CA after repeated third use was 78%. After storage at room temperature for 5 days, the residual activity was 89%. Enzymatic properties and catalytic kinetics of immobilized enzymes were studied, and the effect mechanism of ionic liquid modified Fe
3
O
4
on PPL was revealed. The effect of ionic liquid on the carrier structure was investigated by characterization of XRD, FT-IR, SEM and TG. The mechanism and enzymatic properties of immobilized PPL via electrostatic adsorption and embedding were analyzed. A novel and efficient immobilized PPL was developed.
Due to the large differences in physico-mechanical properties of composite strata, jamming, head sinking and other serious consequences occur frequently during tunnel boring machine (TBM) excavation. ...To analyse the stability of surrounding rocks in composite strata under the disturbance of TBM excavation, a geomechanical model test was carried out based on the Lanzhou water supply project. The evolution patterns and distribution characteristics of the strain, stress, and tunnel deformation and fracturing were analysed. The results showed that during TBM excavation in the horizontal composite formations (with upper soft and lower hard layers and with upper hard and lower soft layers), a significant difference in response to the surrounding rocks can be observed. As the strength ratio of the surrounding rocks decreases, the ratio of the maximum strain of the hard rock mass to that of the relatively soft rock mass gradually decreases. The radial stress of the relatively soft rock mass is smaller than that of the hard rock mass in both types of composite strata, indicating that the weak rock mass in the composite formation results in the difference in the mechanical behaviours of the surrounding rocks. The displacement field of the surrounding rocks obtained by the digital speckle correlation method (DSCM) and the macro-fracture morphology after tunnel excavation visually reflected the deformation difference of the composite rock mass. Finally, some suggestions and measures were provided for TBM excavation in composite strata, such as advance geological forecasting and effective monitoring of weak rock masses.
The Jinsha River flows through one of the most geologically complex regions in western China with extremely high altitudes and capricious climates. Frequent landslides (e.g., the Baige landslides on ...11 October and 3 November 2018) occurred along its stretch which posed severe damage to bridges, dams, and roads, and put the safety of local residents at risk. Systematic and comprehensive landslide detection has been rarely carried out in the Jinsha River corridor because it is a wide and hard-to-reach region. With 30 years of development, InSAR has become an effective way to map ground motion, which in turn makes it feasible to detect active landslides over wide regions. However, several challenges remain in applying InSAR in the Jinsha River corridor, such as low coherence due to dense vegetation and/or large gradient surface movements, and atmospheric effects due to the spatio-temporal variations of the atmosphere (especially the part due to tropospheric water vapor). In this paper, we propose a framework to overcome the limitations of conventional InSAR through the integration of GACOS-assisted InSAR, advanced SBAS InSAR, and SAR pixel offset tracking techniques. This integrated framework enables us to detect active landslides under complex topographic and climate conditions. Our results show that the detected active landslides are largely controlled by active faults, most of them are found at elevations of 2500–4000 m, their slopes fall between
25
and
45
∘
facing southwest and northwest, and 83.3% of the active landslides have a NDVI value of less than 0.3. Furthermore, precipitation is one critical triggering factor of active landslides, evidenced by the high temporal correlation between average precipitation and surface displacement time series.
PDF
