Chlorogenic acid alleviates renal fibrosis by reducing lipid accumulation in diabetic kidney disease through suppressing the Notch1 and Stat3 signaling pathway.

AIMS: Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis. METHODS: This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein. RESULTS: In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was -6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1. CONCLUSION: CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.

20( S )-Protopanaxatriol Improves Atherosclerosis by Inhibiting Low-Density Lipoprotein Receptor Degradation in ApoE KO Mice.

ABSTRACT: Atherosclerosis (AS) is a chronic progressive disease caused by various factors and causes various cerebrovascular and cardiovascular diseases (CVDs). Reducing the plasma levels of low-density lipoprotein cholesterol is the primary goal in preventing and treating AS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in regulating low-density lipoprotein cholesterol metabolism. Panax notoginseng has potent lipid-reducing effects and protects against CVDs, and its saponins induce vascular dilatation, inhibit thrombus formation, and are used in treating CVDs. However, the anti-AS effect of the secondary metabolite, 20( S )-protopanaxatriol (20( S )-PPT), remains unclear. In this study, the anti-AS effect and molecular mechanism of 20( S )-PPT were investigated in vivo and in vitro by Western blotting, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence staining, and other assays. The in vitro experiments revealed that 20( S )-PPT reduced the levels of PCSK9 in the supernatant of HepG2 cells, upregulated low-density lipoprotein receptor protein levels, promoted low-density lipoprotein uptake by HepG2 cells, and reduced PCSK9 mRNA transcription by upregulating the levels of forkhead box O3 protein and mRNA and decreasing the levels of HNF1α and SREBP2 protein and mRNA. The in vivo experiments revealed that 20( S )-PPT upregulated aortic α-smooth muscle actin expression, increased the stability of atherosclerotic plaques, and reduced aortic plaque formation induced by a high-cholesterol diet in ApoE -/- mice (high-cholesterol diet-fed group). Additionally, 20( S )-PPT reduced the aortic expression of CD68, reduced inflammation in the aortic root, and alleviated the hepatic lesions in the high-cholesterol diet-fed group. The study revealed that 20( S )-PPT inhibited low-density lipoprotein receptor degradation via PCSK9 to alleviate AS.

Soft bioelectronics for diagnostic and therapeutic applications in neurological diseases.

Physical and chemical signals in the central nervous system yield crucial information that is clinically relevant under both physiological and pathological conditions. The emerging field of bioelectronics focuses on the monitoring and manipulation of neurophysiological signals with high spatiotemporal resolution and minimal invasiveness. Significant advances have been realized through innovations in materials and structural design, which have markedly enhanced mechanical and electrical properties, biocompatibility, and overall device performance. The diagnostic and therapeutic potential of soft bioelectronics has been corroborated across a diverse array of pre-clinical settings. This review summarizes recent studies that underscore the developments and applications of soft bioelectronics in neurological disorders, including neuromonitoring, neuromodulation, tumor treatment, and biosensing. Limitations and outlooks of soft devices are also discussed in terms of power supply, wireless control, biocompatibility, and the integration of artificial intelligence. This review highlights the potential of soft bioelectronics as a future platform to promote deciphering brain functions and clinical outcomes of neurological diseases.

Gallic Acid Can Promote Low-Density Lipoprotein Uptake in HepG2 Cells via Increasing Low-Density Lipoprotein Receptor Accumulation.

Gallic acid (GA) is a type of polyphenolic compound that can be found in a range of fruits, vegetables, and tea. Although it has been confirmed it improves non-alcoholic fatty liver disease (NAFLD), it is still unknown whether GA can improve the occurrence of NAFLD by increasing the low-density lipoprotein receptor (LDLR) accumulation and alleviating cholesterol metabolism disorders. Therefore, the present study explored the effect of GA on LDLR and its mechanism of action. The findings indicated that the increase in LDLR accumulation in HepG2 cells induced by GA was associated with the stimulation of the epidermal growth factor receptor-extracellular regulated protein kinase (EGFR-ERK1/2) signaling pathway. When the pathway was inhibited by EGFR mab cetuximab, it was observed that the activation of the EGFR-ERK1/2 signaling pathway induced by GA was also blocked. At the same time, the accumulation of LDLR protein and the uptake of LDL were also suppressed. Additionally, GA can also promote the accumulation of forkhead box O3 (FOXO3) and suppress the accumulation of hepatocyte nuclear factor-1α (HNF1α), leading to the inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) mRNA expression and protein accumulation. This ultimately results in increased LDLR protein accumulation and enhanced uptake of LDL in cells. In summary, the present study revealed the potential mechanism of GA's role in ameliorating NAFLD, with a view of providing a theoretical basis for the dietary supplementation of GA.

STING directly recruits WIPI2 for autophagosome formation during STING-induced autophagy.

The cGAS-STING pathway plays an important role in host defense by sensing pathogen DNA, inducing type I IFNs, and initiating autophagy. However, the molecular mechanism of autophagosome formation in cGAS-STING pathway-induced autophagy is still unclear. Here, we report that STING directly interacts with WIPI2, which is the key protein for LC3 lipidation in autophagy. Binding to WIPI2 is necessary for STING-induced autophagosome formation but does not affect STING activation and intracellular trafficking. In addition, the specific interaction between STING and the PI3P-binding motif of WIPI2 leads to the competition of WIPI2 binding between STING and PI3P, and mutual inhibition between STING-induced autophagy and canonical PI3P-dependent autophagy. Furthermore, we show that the STING-WIPI2 interaction is required for the clearance of cytoplasmic DNA and the attenuation of cGAS-STING signaling. Thus, the direct interaction between STING and WIPI2 enables STING to bypass the canonical upstream machinery to induce LC3 lipidation and autophagosome formation.

Caffeine can alleviate non-alcoholic fatty liver disease by augmenting LDLR expression via targeting EGFR.

Increasing low-density lipoprotein receptor (LDLR) protein levels represents a key strategy for the prevention and treatment. Berberine can reportedly alleviate non-alcoholic fatty liver disease (NAFLD) by increasing the LDLR expression in an ERK1/2 signaling-dependent manner of NAFLD. Studies have shown that caffeine can inhibit fat deposition in the livers of mice; however, caffeine has not been reported to alleviate NAFLD by augmenting the LDLR expression via targeting EGFR. Here, an MTT assay, western blotting, RT-qPCR, immunohistochemistry, and surface plasmon resonance (SPR) analysis were used to investigate the role of caffeine in low-density lipoprotein cholesterol (LDL-C) clearance both in vitro and in vivo. In vitro, we found that caffeine could activate the EGFR-ERK1/2 signaling pathway in HepG2 cells, leading to increased LDLR mRNA and protein expression, and this effect could be inhibited by cetuximab. The SPR assay results have indicated that caffeine may increase the LDLR expression by directly binding to the EGFR extracellular domain and activating the EGFR-ERK1/2 signaling pathway. In vivo, caffeine markedly improved fatty liver and related blood indices in ApoE KO mice with high-fat-diet-induced NAFLD. Consistent with our in vitro results, we found that caffeine could also activate EGFR-ERK1/2 signaling and promote the LDLR expression in ApoE KO mice. In summary, caffeine can enhance the LDLR expression by directly binding to EGFR and activating the EGFR-ERK1/2 signaling pathway. EGFR signaling may represent a novel target for the prevention and treatment of NAFLD.

Alkyne Insertion Enabled Vinyl to Acyl 1,5-Palladium Migration: Rapid Access to Substituted 5-Membered-Dihydrobenzofurans and Indolines.

"Through space" palladium/hydrogen shift is an efficient strategy to achieve selective functionalization of a specific remote C-H bond. Compared with relatively extensive exploited 1,4-palladium migration process, the relevant 1,5-Pd/H shift was far less investigated. We herein report a novel 1,5-Pd/H shift pattern between a vinyl and an acyl group. Through the pattern, rapid access to 5-membered-dihydrobenzofuran and indoline derivatives has been achieved. Further studies have unveiled an unprecedented trifunctionalization (vinylation, alkynylation and amination) of a phenyl ring through 1,5-palladium migration relayed decarbonylative Catellani type reaction. A series of mechanistic investigations and DFT calculations have provided insights into the reaction pathway. Notably, it was unveiled that the 1,5-palladium migration in our case prefers a stepwise mechanism involving a PdIV intermediate.

20(S)-Protopanaxadiol decreases atherosclerosis in ApoE KO mice by increasing the levels of LDLR and inhibiting its binding with PCSK9.

Chinese medicinal and edible plants such as Panax notoginseng and ginseng are widely used for the treatment of atherosclerosis (AS). AS is the main pathological basis of cardiac-cerebral vascular disease, which seriously threatens human health and quality of life. Low-density lipoprotein (LDL) is the main pathogenic factor of AS. The LDL receptor (LDLR) is an important protein that functions to mediate the uptake and degradation of plasma LDL. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) can mediate the internalization and degradation of LDLR. So, increasing the LDLR level by inhibiting PCSK9 is an important means of prevention and treatment of AS. In this study, by combining interaction technology (surface plasmon resonance, SPR) of small molecule compounds with membrane receptor proteins, cell experiments, and in vivo experiments, it is proved for the first time that 20(S)-protopanaxadiol (PPD), as a hydrolytic product of Panax notoginseng saponins in the intestinal tract, can bind to the extracellular domain of LDLR and inhibit the role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in mediating LDLR degradation. The results showed that PPD significantly reduced aortic plaques and hepatic steatosis in HFD-fed ApoE KO mice. LDLR protein levels were elevated in the liver tissues isolated from PPD-treated HFD-fed ApoE KO mice and PPD-treated HepG2 cells. Our findings demonstrated that PPD significantly increased LDLR levels and reduced AS in the HFD-fed ApoE KO mice on account of LDLR degradation being inhibited by PPD inhibiting the interaction between PCSK9 and LDLR.

Synthesis and in vitro biological evaluation of novel dendrocandin analogue as potential anti-tumor agent.

Dendrocandins are characteristic chemical structures of D. officinale and have strong physiological bioactivities. In this study, a dendrocandin analogue (1) has been prepared by total synthesis (9 steps, 12.6% overall yield) in which coupling reaction and Wittig reaction as the key steps. Compound 1 was also evaluated for its anticancer activity in vitro against six human cancer cells (MCF-7, A549, A431, SW480, HepG-2 and HL-60) using MTT assays. Compound 1 showed potent cytotoxicity, with the IC50 value 16.27 ± 0.26 µM. The expression levels of apoptotic proteins indicated that compound 1 can up-regulate the expression of apoptotic proteins, leading to apoptosis. This compound suggested that it's potential as anticancer agent for further development.

Schottky Junctions with Bi Cocatalyst for Taming Aqueous Phase N2 Reduction toward Enhanced Solar Ammonia Production.

Solar-powered N2 reduction in aqueous solution is becoming a research hotspot for ammonia production. Schottky junctions at the metal/semiconductor interface have been effective to build up a one-way channel for the delivery of photogenerated electrons toward photoredox reactions. However, their applications for enhancing the aqueous phase reduction of N2 to ammonia have been bottlenecked by the difficulty of N2 activation and the competing H2 evolution reaction (HER) at the metal surface. Herein, the application of Bi with low HER activity as a robust cocatalyst for constructing Schottky-junction photocatalysts toward N2 reduction to ammonia is reported. The introduction of Bi not only boosts the interfacial electron transfer from excited photocatalysts due to the built-in Schottky-junction effect at the Bi/semiconductor interface but also synchronously facilitates the on-site N2 adsorption and activation toward solar ammonia production. The unidirectional charge transfer to the active site of Bi significantly promotes the photocatalytic N2-to-ammonia conversion efficiency by 65 times for BiOBr. In addition, utilizing Bi to enhance the photocatalytic ammonia production can be extended to other semiconductor systems. This work is expected to unlock the promise of engineering Schottky junctions toward high-efficiency solar N2-to-ammonia conversion in aqueous phase.

Proliferation of MDA-MB-231 can be suppressed by dimeric-epigallocatechin gallate through competitive inhibition of amphiregulin-epidermal growth factor receptor signaling.

Triple-negative breast cancer (TNBC) is highly aggressive, with high rates of early relapse and very poor overall prognosis. Amphiregulin (AREG) is the most abundant epidermal growth factor receptor (EGFR) agonist in MDA-MB-231 TNBC cells, whose proliferation can be inhibited by (-)-epigallocatechin gallate (EGCG), a constituent of green tea that is prone to oxidative polymerization. The effect of dimeric-EGCG, a dimer of oxidized and polymerized EGCG, on MDA-MB-231 cell the proliferation warrants further exploration. In the present study, MTT, flow cytometry, migration scratch, transwell, western blotting, and surface plasmon resonance assays were used to evaluate the effect of dimeric-EGCG on MDA-MB-231 cells and explore the underlying mechanism. MDA-MB-231 cell proliferation and migration were significantly inhibited by dimeric-EGCG at concentrations as low as 10 µM. Levels of EGFR and p44/42 MAPK phosphorylation in MDA-MB-231 cells were significantly reduced by treatment with 10 µM dimeric-EGCG (P < 0.01). In addition, the levels of phosphorylation induced by exogenous AREG were also inhibited by dimeric-EGCG (P < 0.01); however, no significant effects of dimeric-EGCG were observed on epidermal growth factor or transforming growth factor-alpha signaling. Surface plasmon resonance analysis demonstrated that 10 µM dimeric-EGCG bound directly to the extracellular domain of EGFR, competitively inhibiting the binding of AREG to EGFR. These results suggest a novel mechanism underlying the inhibitory effect of dimeric-EGCG on MDA-MB-231 cells, with potential application in the development of drugs for the treatment of TNBC.

Caffeine Targets SIRT3 to Enhance SOD2 Activity in Mitochondria.

Caffeine is chemically stable and not readily oxidized under normal physiological conditions but also has antioxidant effects, although the underlying molecular mechanism is not well understood. Superoxide dismutase (SOD) 2 is a manganese-containing enzyme located in mitochondria that protects cells against oxidative stress by scavenging reactive oxygen species (ROS). SOD2 activity is inhibited through acetylation under conditions of stress such as exposure to ultraviolet (UV) radiation. Sirtuin 3 (SIRT3) is the major mitochondrial nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, which deacetylates two critical lysine residues (lysine 68 and lysine 122) on SOD2 and promotes its antioxidative activity. In this study, we investigated whether the antioxidant effect of caffeine involves modulation of SOD2 by SIRT3 using in vitro and in vivo models. The results show that caffeine interacts with SIRT3 and promotes direct binding of SIRT3 with its substrate, thereby enhancing its enzymatic activity. Mechanistically, caffeine bound to SIRT3 with high affinity (K D = 6.858 × 10-7 M); the binding affinity between SIRT3 and its substrate acetylated p53 was also 9.03 (without NAD+) or 6.87 (with NAD+) times higher in the presence of caffeine. Caffeine effectively protected skin cells from UV irradiation-induced oxidative stress. More importantly, caffeine enhanced SIRT3 activity and reduced SOD2 acetylation, thereby leading to increased SOD2 activity, which could be reversed by treatment with the SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP) in vitro and in vivo. Taken together, our results show that caffeine targets SIRT3 to enhance SOD2 activity and protect skin cells from UV irradiation-induced oxidative stress. Thus, caffeine, as a small-molecule SIRT3 activator, could be a potential agent to protect human skin against UV radiation.

EGCG targeting Notch to attenuate renal fibrosis via inhibition of TGFß/Smad3 signaling pathway activation in streptozotocin-induced diabetic mice.

Renal fibrosis is a characteristic of diabetic nephropathy, which is a serious complication of diabetes. It has been reported that (-)-epigallocatechin gallate (EGCG) attenuates renal fibrosis. However, the molecular mechanism of regulation by EGCG in this process remains unclear. Previous studies showed that abnormal activation of Notch signaling contributes to the development of renal fibrosis. Previous studies have demonstrated that EGCG attenuates Notch1 expression. In this study, we found that the levels of fibronectin and Notch1 expression were decreased in human embryonic kidney cells after treatment with EGCG. We also observed that the type II transforming growth factor beta receptor (TGFßRII) and Smad3 pathway were inhibited in kidney cells by treatment with EGCG. In the diabetic kidney, we found that the activation of Notch signaling was attenuated by administration of EGCG. Moreover, TGFßRII and Smad3 phosphorylation could be inhibited by treatment with EGCG in the kidney. These results indicated that EGCG may improve renal fibrosis by targeting Notch via inhibition of the TGFß/Smad3 pathway in diabetic mice. Our findings provide insight into the therapeutic strategy for diabetes-induced renal fibrosis, and suggest EGCG to be a novel potential medicine for the treatment of chronic kidney disease in patients with diabetes.

Corrigendum: Dendrobium officinale Orchid Extract Prevents Ovariectomy-Induced Osteoporosis In Vivo and Inhibits RANKL-Induced Osteoclast Differentiation In Vitro.

[This corrects the article DOI: 10.3389/fphar.2017.00966.].

Corrigendum: Effect of Black Tea Extract and Thearubigins on Osteoporosis in Rats and Osteoclast Formation in vitro.

[This corrects the article DOI: 10.3389/fphys.2018.01225.].

Support interactions dictated active edge sites over MoS2-carbon composites for hydrogen evolution.

The rational design and synthesis of MoS2-based electrocatalysts with desirable active sites for the hydrogen evolution reaction have been actively pursued. Herein, we demonstrate a microwave-assisted steam heating method for the rapid and efficient synthesis of lamellar MoS2-based materials with favorable exposed active edge sites. Based on this new strategy, we have further separately introduced reduced graphene oxide (rGO) and carbon nanotubes (CNTs), two typical carbon allotropes widely used to boost the electrocatalytic activity of MoS2, to comparatively assess the support interactions and their effects on the electrocatalytic activity of MoS2. It was found that as compared to rGO, the CNTs afford favorable support interactions, which not only benefit to suppress the oriented in-plane growth of MoS2 to maximize the exposed edge sites but also ensure the maintainence of their intrinsic activity, thereby synergistically facilitating the exertion of the potential of MoS2 for HER. Our work conceptually highlights the importance of the support interactions for taming the active edge sites of MoS2 and is expected to inspire the rational design of layered metal dichalcogenide-based electrocatalysts with favorable active edges for HER.

Acetyltransferase GCN5 regulates autophagy and lysosome biogenesis by targeting TFEB.

Accumulating evidence highlights the role of histone acetyltransferase GCN5 in the regulation of cell metabolism in metazoans. Here, we report that GCN5 is a negative regulator of autophagy, a lysosome-dependent catabolic mechanism. In animal cells and Drosophila, GCN5 inhibits the biogenesis of autophagosomes and lysosomes by targeting TFEB, the master transcription factor for autophagy- and lysosome-related gene expression. We show that GCN5 is a specific TFEB acetyltransferase, and acetylation by GCN5 results in the decrease in TFEB transcriptional activity. Induction of autophagy inactivates GCN5, accompanied by reduced TFEB acetylation and increased lysosome formation. We further demonstrate that acetylation at K274 and K279 disrupts the dimerization of TFEB and the binding of TFEB to its target gene promoters. In a Tau-based neurodegenerative Drosophila model, deletion of dGcn5 improves the clearance of Tau protein aggregates and ameliorates the neurodegenerative phenotypes. Together, our results reveal GCN5 as a novel conserved TFEB regulator, and the regulatory mechanisms may be involved in autophagy- and lysosome-related physiological and pathological processes.

Nitrogen-doped Carbon with Modulated Surface Chemistry and Porous Structure by a Stepwise Biomass Activation Process towards Enhanced Electrochemical Lithium-Ion Storage.

Controllable conversion of biomass to value-added carbon materials is attractive towards a wide variety of potential applications. Herein, hydrothermal treatment and KOH activation are successively employed to treat the cheap and abundant camellia oleifera shell as a new carbon raw material. It is shown that this stepwise activation process allows the production of porous nitrogen-doped carbon with optimized surface chemistry and porous structure compared to the counterparts prepared by a single activation procedure. Benefiting from the modulated porous structure, the as-produced porous nitrogen-doped carbon electrode delivered a high reversible capacity of 1080 mAh g-1 at a current density of 100 mA g-1, which is 3.3 and 5.8 times as high as that of the carbon materials prepared by bare hydrothermal treatment or KOH activation, respectively. Moreover, the optimized surface composition of the porous nitrogen-doped carbon endows it with a highest initial Coulombic efficiency among the three samples, showing great potentials for practical applications. This work is expected to pave a new avenue to upgrade biomass to carbon materials with tunable surface properties and microstructures for target applications.

Visual Semantic Landmark-Based Robust Mapping and Localization for Autonomous Indoor Parking.

Autonomous parking in an indoor parking lot without human intervention is one of the most demanded and challenging tasks of autonomous driving systems. The key to this task is precise real-time indoor localization. However, state-of-the-art low-level visual feature-based simultaneous localization and mapping systems (VSLAM) suffer in monotonous or texture-less scenes and under poor illumination or dynamic conditions. Additionally, low-level feature-based mapping results are hard for human beings to use directly. In this paper, we propose a semantic landmark-based robust VSLAM for real-time localization of autonomous vehicles in indoor parking lots. The parking slots are extracted as meaningful landmarks and enriched with confidence levels. We then propose a robust optimization framework to solve the aliasing problem of semantic landmarks by dynamically eliminating suboptimal constraints in the pose graph and correcting erroneous parking slots associations. As a result, a semantic map of the parking lot, which can be used by both autonomous driving systems and human beings, is established automatically and robustly. We evaluated the real-time localization performance using multiple autonomous vehicles, and an repeatability of 0.3 m track tracing was achieved at a 10 kph of autonomous driving.

Facile synthesis of Camellia oleifera shell-derived hard carbon as an anode material for lithium-ion batteries.

A comparatively facile and ecofriendly process has been developed to synthesize porous carbon materials from Camellia oleifera shells. Potassium carbonate solution (K2CO3) impregnation is introduced to modify the functional groups on the surface of Camellia oleifera shells, which may play a role in promoting the development of pore structure during carbonization treatment. Moreover, a small amount of naturally embedded nitrogen and sulfur in the Camellia oleifera shells can also bring about the formation of pores. The Camellia oleifera shell-derived carbon has a large specific surface area of 1479 m2 g-1 with a total pore volume of 0.832 cm3 g-1 after being carbonized at 900 °C for 1 h. Furthermore, when used as an anode for lithium-ion batteries, the sample shows superior electrochemical performance with a specific capacity of 483 mA h g-1 after 100 cycles measured at 200 mA g-1 current density. Surprisingly, the specific capacity is even gradually increased with cycling. In addition, this sample exhibits almost 100% retention capacity after 250 cycles at a current density of 200 mA g-1.