The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory ...pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia‐telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1‐Bcl‐2 autophagy‐regulatory complex formation in a ROS‐dependent fashion. We further demonstrate that CHK2‐mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2−/− mice display aggravated infarct phenotypes and reduced Beclin 1 p‐Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2‐induced autophagy in cell survival. Taken together, these results indicate that the ROS‐ATM‐CHK2‐Beclin 1‐autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress‐induced tissue damage.
Synopsis
Whether hypoxia and nutrient starvation are coupled to cellular autophagy remains unclear. Here, DNA damage response kinases ATM and CHK2 are shown to trigger autophagy in response to reactive oxygen species (ROS) accumulation, suggesting a novel physiological adaptation pathway toward metabolic stress.
Depletion of CHK2 or ATM impairs oxidative stress‐induced autophagy in MEFs.
CHK2 binds and phosphorylates Beclin1 at Ser90/Ser93, suppressing Beclin1‐Bcl‐2 autophagy regulatory complex formation.
CHK2‐induced autophagy limits intracellular ROS levels by clearing damaged mitochondria.
CHK2‐induced autophagy protects against cell death and tissue damage following cerebral ischemia.
ROS accumulation activates protective autophagy to prevent stress‐induced tissue damage.
The long‐term inflammatory microenvironment is one of the main obstacles to inhibit acute spinal cord injury (SCI) repair. The natural adipose tissue‐derived extracellular matrix hydrogel shows ...effective anti‐inflammatory regulation because of its unique protein components. However, the rapid degradation rate and removal of functional proteins during the decellularization process impair the lasting anti‐inflammation function of the adipose tissue‐derived hydrogel. To address this problem, adipose tissue lysate provides an effective way for SCI repair due to its abundance of anti‐inflammatory and nerve regeneration‐related proteins. Thereby, human adipose tissue lysate‐based hydrogel (HATLH) with an appropriate degradation rate is developed, which aims to in situ long‐term recruit and induce anti‐inflammatory M2 macrophages through sustainedly released proteins. HATLH can recruit and polarize M2 macrophages while inhibiting pro‐inflammatory M1 macrophages regardless of human or mouse‐originated. The axonal growth of neuronal cells also can be effectively improved by HATLH and HATLH‐induced M2 macrophages. In vivo experiments reveal that HATLH promotes endogenous M2 macrophages infiltration in large numbers (3.5 × 105/100 µL hydrogel) and maintains a long duration for over a month. In a mouse SCI model, HATLH significantly inhibits local inflammatory response, improves neuron and oligodendrocyte differentiation, enhances axonal growth and remyelination, as well as accelerates neurological function restoration.
Human adipose tissue lysate is utilized as raw material to prepare human adipose tissue lysate‐based hydrogel. This hydrogel has the unique ability to sustainably recruit and polarize M2 macrophages through slow degradation, while also inhibiting M1 macrophages. It induces a long‐term anti‐inflammatory microenvironment that significantly improves neural differentiation, enhances axon regeneration, and accelerates the recovery of neurological function after spinal cord injury.
As a new material with excellent mechanical properties and good stability, slide‐ring gels have attracted attention and research. However, they cannot be widely used due to their relatively ...complicated synthesis. Herein, we use 6‐acrylamidomethylether‐modified α‐cyclodextrin (αCDAAmMe) and PEG20000 diacrylate (PEG20000DA) to construct a polypseudorotaxane. Then, the polypseudorotaxane reacts with acrylamide via a photo‐initiated polymerization in situ to conveniently obtain a slide‐ring hydrogel with good elastic property and high recovery property. The hydrogel can be easily stretched to 22.5 times of its original length but recovered rapidly and almost reversibly. These results enable the application of hydrogel to make an intrinsically stretchable and compressible supercapacitor after doping ions and the adhesion of commercially available carbon nanotube (CNT) paper as electrodes, giving the ionic conductivity of 17.0 mS cm−1 (comparable to that of the commercial PVA/H3PO4 electrolyte) and the capacitance of 0.87 μF cm−2 (at the scan speed of 100 mV s−1), and its capacitance can be further enhanced under stretching.
At a stretch: A highly elastic slide‐ring hydrogel with good recovery was obtained by a two‐step method. The threading of 6‐acrylamidomethylether‐modified α‐cyclodextrins (αCDAAmMe) on the PEG20000 diacrylate (PEG20000DA) produces a polypseudorotaxane, then the polypseudorotaxane co‐polymerizes with the acrylamide monomer via a photo‐initiated polymerization. The hydrogel can be used to construct a stretchable supercapacitor after doping with 1 m Li2SO4 and the adhesion of carbon nanotube (CNT) paper as electrodes.
Diabetes is a disorder of glucose metabolism, and over 90% are type 2 diabetes. Diabetic cardiomyopathy (DCM) is one of the type 2 diabetes complications, usually accompanied by changes in myocardial ...structure and function, together with cardiomyocyte apoptosis. Our study investigated the effect of curcumin on regulating oxidative stress (OS) and apoptosis in DCM. In vivo, diabetes was induced in an experimental rat model by streptozoticin (STZ) together with high‐glucose and high‐fat (HG/HF) diet feeding. In vitro, H9c2 cardiomyocytes were cultured with high‐glucose and saturated free fatty acid palmitate. Curcumin was orally or directly administered to rats or cells, respectively. Streptozoticin ‐induced diabetic rats showed metabolism abnormalities and elevated markers of OS (superoxide dismutase SOD, malondialdehyde MDA, gp91phox, Cyt‐Cyto C), enhanced cell apoptosis (Bax/Bcl‐2, Cleaved caspase‐3, TUNEL‐positive cells), together with reduced Akt phosphorylation and increased Foxo1 acetylation. Curcumin attenuated the myocardial dysfunction, OS and apoptosis in the heart of diabetic rats. Curcumin treatment also enhanced phosphorylation of Akt and inhibited acetylation of Foxo1. These results strongly suggest that apoptosis was increased in the heart of diabetic rats, and curcumin played a role in diabetic cardiomyopathy treatment by modulating the Sirt1‐Foxo1 and PI3K‐Akt pathways.
Dendrobium is known for its pharmacological actions including anti-cancer effect, anti-fatigue effect, gastric ulcer protective effect, and so on. At present, only studies on endophytic fungi of ...Dendrobium affecting the metabolites of host plants have been reported, very little research has been done on endophytic bacteria. In this study, we have demonstrated the great diversity of endophytic bacteria in 6 Dendrobium samples from different origins and cultivars. According to the results of the culture-independent method, the endophytic bacterial community in Dendrobium stems showed obvious different in the 6 samples and was influenced by origin and cultivar. Some bacteria including Ralstonia, Comamonas and Lelliottia were first detected in Dendrobium in this study. Based on the culture-dependent method, a total of 165 cultivable endophytic bacteria isolates were isolated from the sterilized Dendrobium stems, and were classified into 43 species according to the 16S rRNA gene sequence analysis. Moreover, 14 of the 43 strains showed antimicrobial activity against phytopathogen using the Kirby-Bauer method. Strain NA-HTong-7 (Bacillus megaterium, 99.12%) showed the highest antimicrobial activity. This study was the first comprehensive study on endophytic bacteria of Dendrobium from different origins and cultivars, which provides new insights into the endophytic bacteria from Dendrobium.
Both Xp11 translocation renal cell carcinomas and the corresponding mesenchymal neoplasms are characterized by a variety of gene fusions involving TFE3. It has been known that tumors with different ...gene fusions may have different clinicopathologic features; however, further in-depth investigations of subtyping Xp11 translocation-associated cancers are needed in order to explore more meaningful clinicopathologic correlations. A total of 22 unusual cases of Xp11 translocation-associated cancers were selected for the current study; 20 cases were further analyzed by RNA sequencing to explore their TFE3 gene fusion partners. RNA sequencing identified 17 of 20 cases (85%) with TFE3-associated gene fusions, including 4 ASPSCR1/ASPL-TFE3, 3 PRCC-TFE3, 3 SFPQ/PSF-TFE3, 1 NONO-TFE3, 4 MED15-TFE3, 1 MATR3-TFE3, and 1 FUBP1-TFE3. The results have been verified by fusion fluorescence in situ hybridization (FISH) assays or reverse transcriptase polymerase chain reaction (RT-PCR). The remaining 2 cases with specific pathologic features highly suggestive of MED15-TFE3 renal cell carcinoma were identified by fusion FISH assay. We provide the detailed morphologic and immunophenotypic description of the MED15-TFE3 renal cell carcinomas, which frequently demonstrate extensively cystic architecture, similar to multilocular cystic renal neoplasm of low malignant potential, and expressed cathepsin K and melanotic biomarker Melan A. This is the first time to correlate the MED15-TFE3 renal cell carcinoma with specific clinicopathologic features. We also report the first case of the corresponding mesenchymal neoplasm with MED15-TFE3 gene fusion. Additional novel TFE3 gene fusion partners, MATR3 and FUBP1, were identified. Cases with ASPSCR1-TFE3, SFPQ-TFE3, PRCC-TFE3, and NONO-TFE3 gene fusion showed a wide variability in morphologic features, including invasive tubulopapillary pattern simulating collecting duct carcinoma, extensive calcification and ossification, and overlapping and high columnar cells with nuclear grooves mimicking tall cell variant of papillary thyroid carcinoma. Furthermore, we respectively evaluated the ability of TFE3 immunohistochemistry, TFE3 FISH, RT-PCR, and RNA sequencing to subclassify Xp11 translocation-associated cancers. In summary, our study expands the list of TFE3 gene fusion partners and the clinicopathologic features of Xp11 translocation-associated cancers, and highlights the importance of subtyping Xp11 translocation-associated cancers combining morphology, immunohistochemistry, and multiple molecular techniques.
Many serious ecological problems and changes in urban spatial structure in coal resource-based cities in China are attributable to rapid urbanization and human coal mining activities. Therefore, ...optimizing urban spatial structure and functions can help balance the opposing requirements of urban built-up areas and ecosystems. This research first used restricted ecological areas in the three scenarios and embedded them in the PLUS model. Subsequently, the Markov chain model combined with the ecosystem service value maximization optimization model predicted the land-use demand in two scenarios. Through the LEAS function of the PLUS model, the 19 influencing factors under the “pressure-state-response (PSR)” framework were analyzed. The important driving factors affecting land use were obtained and embedded in the PLUS model. Finally, the urban growth boundary (UGB) for the Jining Metropolitan Area (JMA) in 2030 to optimize the urban spatial structure and ecological functions was determined for four scenarios: natural development (ND), ecological security (ES), multiregulation integrity (MR), and ecosystem health (EH). After comparing the UGB in these four scenarios, we found that the ES scenario ensured ES in the JMA. Additionally, under the EH scenario, the urban spatial structure and functions were further optimized. Our research could provide new ideas and technical support for the rational layout of the spatial structure and functions of coal resource-based cities.
•The fundamental problems faced by China's coal resource-based cities are urbanization and coal mining activities.•Based on the problems, the integrated PLUS model is used to construct UGB to optimization of urban structure and function.•Propose an analysis framework, and then provide suggestions and strategies for the development of coal resource-based cities.
Abstract
Vasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of neuronal, metabolic, and inflammatory ...diseases. However, our understanding of its mechanism of action and the potential of drug discovery targeting this receptor is limited by the lack of structural information of VIP1R. Here we report a cryo-electron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, whose complex assembly is stabilized by a NanoBiT tethering strategy. Comparison with other class B GPCR structures reveals that PACAP27 engages VIP1R with its N-terminus inserting into the ligand binding pocket at the transmembrane bundle of the receptor, which subsequently couples to the G protein in a receptor-specific manner. This structure has provided insights into the molecular basis of PACAP27 binding and VIP receptor activation. The methodology of the NanoBiT tethering may help to provide structural information of unstable complexes.
Two parallel sequence batch reactors (SBRs) were operated, with and without TCS addition, to research the causes of sludge reduction by uncouplers. Three possible mechanisms of sludge reduction by ...TCS were studied: (1) occurrence of metabolic uncoupling, (2) consumption of more energy to resist the infection of TCS, (3) promotion of lysis-cryptic growth by TCS addition. Results showed the remarkable reduction of electronic transport system (ETS) activity and specific cellular ATP (SATP) in TCS reactor, which proved the occurrence of metabolic uncoupling. The increasing amounts of extracellular polymeric substances (EPS), as measured by chemical methods and excitation-emission matrix (EEM) fluorescence spectra, implied microorganisms consumed more energy to resist TCS. The similar DNA concentrations of the effluents in two reactors indicated sludge lysis was not intensified by TCS. Therefore, uncoupler might not only cause metabolic uncoupling but also induce more energy consumption in the production of some substances to resist uncoupler.
FeSx@MoS2-x (FM-x, x implied real Mo/Fe content ratios) in which FeSx derived from MIL-88A deposited on the surface of MoS2 with a tight heterogeneous interface were synthesized for peroxymonosulfate ...(PMS) activation to degrade atrazine (ATZ). The catalytic performance of FM-0.96 was greatly improved due to the rapid regeneration of Fe2+ resulting from the interfacial interaction. FM-0.96 could completely degrade 10.0 mg/L ATZ within 1.0 min, and the toxicities for most of its intermediates were greatly reduced. The k value of FM-0.96 was 320 and 40 times higher than that of the MoS2 and FeSx, respectively. The SO4·−, ·OH and 1O2 were mainly responsible for ATZ degradation in FM-0.96/PMS system, and the conversion pathway of 1O2 was analyzed. Furthermore, the long-term continuous operation for ATZ degradation was achieved using a fixed membrane reactor. This work provides deep insights into metal sulfide composites derived from metal-organic frameworks for removing pollutants by activating PMS.
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•FeSx@MoS2-x heterojunction catalyst was synthesized adopting MIL-88A as precursor.•The rapid regeneration of Fe2+ greatly promoted the SR-AOP performance.•The continuous ATZ degradation was achieved via fixed bed reactor.
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