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.
SUMMARY
The color of purple carrot taproots mainly depends on the anthocyanins sequestered in the vacuoles. Glutathione S‐transferases (GSTs) are key enzymes involved in anthocyanin transport. ...However, the precise mechanism of anthocyanin transport from the cytosolic surface of the endoplasmic reticulum (ER) to the vacuoles in carrots remains unclear. In this study, we conducted a comprehensive analysis of the carrot genome, leading to the identification of a total of 41 DcGST genes. Among these, DcGST1 emerged as a prominent candidate, displaying a strong positive correlation with anthocyanin pigmentation in carrot taproots. It was highly expressed in the purple taproot tissues of purple carrot cultivars, while it was virtually inactive in the non‐purple taproot tissues of purple and non‐purple carrot cultivars. DcGST1, a homolog of Arabidopsis thaliana TRANSPARENT TESTA 19 (TT19), belongs to the GSTF clade and plays a crucial role in anthocyanin transport. Using the CRISPR/Cas9 system, we successfully knocked out DcGST1 in the solid purple carrot cultivar ‘Deep Purple’ (‘DPP’), resulting in carrots with orange taproots. Additionally, DcMYB7, an anthocyanin activator, binds to the DcGST1 promoter, activating its expression. Compared with the expression DcMYB7 alone, co‐expression of DcGST1 and DcMYB7 significantly increased anthocyanin accumulation in carrot calli. However, overexpression of DcGST1 in the two purple carrot cultivars did not change the anthocyanin accumulation pattern or significantly increase the anthocyanin content. These findings improve our understanding of anthocyanin transport mechanisms in plants, providing a molecular foundation for improving and enhancing carrot germplasm.
Significance Statement
These findings improve our understanding of anthocyanin transport mechanisms in plants, providing a molecular foundation for improving and enhancing carrot germplasm.
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.
A scheme for nonreciprocal mechanical squeezing (NMS) based on the three‐mode optomechanical interaction is proposed. In this scheme, a mechanical mode couples to a spinning whispering‐gallery‐cavity ...(WGC) mode and to an optical mode. An external laser is coupled into and thus drives the WGC via a waveguide. Mechanical squeezing results from the joint effect of the mechanical intrinsic nonlinearity and the quadratic optomechanical coupling, which, in the presence of strong thermal noise, is still considerable, while the nonreciprocity originates from the optical Sagnac effect. There are two NMS areas in the parametric space, one works for the laser driving from the left of the waveguide and another, from the right. For a given spinning speed of the WGC, the squeezing values in these two areas are equal if the corresponding detunings of the WGC differ from each other by two‐times of the Sagnac–Fizeau shift. At the red‐detuning resonance, the analytical results for the mechanical squeezing and cooling are obtained. The NMS scheme is robust to the thermal noise of the mechanical environment.
A scheme for nonreciprocal mechanical squeezing (NMS) based on the three‐mode optomechanical interaction in the presence of the optical Sagnac effect is proposed. The NMS is robust to the thermal noise for the mechanical mode and may apply to a phonon switch for classical‐quantum‐state transformation, phonon‐based information processing and communication, etc.
Vascular calcification refers to the pathological deposition of calcium and phosphate minerals into the vasculature. It is prevalent in atherosclerosis, ageing, type 2 diabetes mellitus and chronic ...kidney disease, thus, increasing morbidity and mortality from these conditions. Vascular calcification shares similar mechanisms with bone mineralization, with smooth muscle cells playing a critical role in both processes. In the last decade, a variety of microRNAs have been identified as key regulators for the differentiation, phenotypic switch, proliferation, apoptosis, cytokine production and matrix deposition in vascular smooth muscle cells during vascular calcification. Therefore, this review mainly discusses the roles of microRNAs in the pathophysiological mechanisms of vascular calcification in smooth muscle cells and describes several interventions against vascular calcification by regulating microRNAs. As the exact mechanisms of calcification remain not fully elucidated, having a better understanding of microRNA involvement in vascular calcification may give impetus to development of novel therapeutics for the control and treatment of vascular calcification.
Adipocyte differentiation of bone marrow mesenchymal stem/stromal cells (BMSCs) instead of osteoblast formation contributes to age- and menopause-related marrow adiposity and osteoporosis. Vascular ...calcification often occurs with osteoporosis, a contradictory association called "calcification paradox". Here we show that extracellular vesicles derived from aged bone matrix (AB-EVs) during bone resorption favor BMSC adipogenesis rather than osteogenesis and augment calcification of vascular smooth muscle cells. Intravenous or intramedullary injection of AB-EVs promotes bone-fat imbalance and exacerbates Vitamin D3 (VD3)-induced vascular calcification in young or old mice. Alendronate (ALE), a bone resorption inhibitor, down-regulates AB-EVs release and attenuates aging- and ovariectomy-induced bone-fat imbalance. In the VD3-treated aged mice, ALE suppresses the ovariectomy-induced aggravation of vascular calcification. MiR-483-5p and miR-2861 are enriched in AB-EVs and essential for the AB-EVs-induced bone-fat imbalance and exacerbation of vascular calcification. Our study uncovers the role of AB-EVs as a messenger for calcification paradox by transferring miR-483-5p and miR-2861.
A practical protocol for the preparation of quinoxaline‐2,3(1H,4H)‐diones through direct C(sp2)−H hydroxylation of quinoxalin‐2(1H)‐ones in recyclable DL‐α‐Tocopherol methoxypolyethylene glycol ...succinate solution (2 wt% in water) (TPGS‐750‐M/H2O) was developed. The target products were exclusively generated and could be collected through extraction and recrystallization.
A modified Hayward black hole is a nonsingular black hole. It is proposed that it would form when the pressure generated by quantum gravity can stop matter’s collapse as the matter reaches the Planck ...density. Strong deflection gravitational lensing occurring nearby its event horizon might provide some clues of these quantum effects in its central core. We investigate observables of the strong deflection lensing, including angular separations, brightness differences and time delays between its relativistic images, and we estimate their values for the supermassive black hole in the Galactic center. We find that it is possible to distinguish the modified Hayward black hole from a Schwarzschild one, but it demands a very high resolution, beyond current stage.
Pulmonary endometriosis is a rare form of thoracic endometriosis. We herein describe a 29-year-old woman with recurrent hemoptysis associated with her menstrual cycle. The patient had a 4-month ...history of catamenial hemoptysis without thoracic pain, respiratory embarrassment, cough, fever, night sweating, or loss of appetite. Chest computed tomography revealed exudation shadows in the right lower pulmonary lobe and small fiber lesions in the right middle lobe and left lung. Thoracoscopic wedge resection of the right lower pulmonary lobe was performed, and the pathological result was pulmonary endometriosis. No evidence of hemoptysis during menstruation was found following the operation.
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.
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