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.
Pandemics have become more frequent and more complex during the twenty-first century. Posttraumatic stress disorder (PTSD) following pandemics is a significant public health concern. We sought to ...provide a reliable estimate of the worldwide prevalence of PTSD after large-scale pandemics as well as associated risk factors, by a systematic review and meta-analysis. We systematically searched the MedLine, Embase, PsycINFO, Web of Science, CNKI, WanFang, medRxiv, and bioRxiv databases to identify studies that were published from the inception up to August 23, 2020, and reported the prevalence of PTSD after pandemics including sudden acute respiratory syndrome (SARS), H1N1, Poliomyelitis, Ebola, Zika, Nipah, Middle Eastern respiratory syndrome coronavirus (MERS-CoV), H5N1, and coronavirus disease 2019 (COVID-19). A total of 88 studies were included in the analysis, with 77 having prevalence information and 70 having risk factors information. The overall pooled prevalence of post-pandemic PTSD across all populations was 22.6% (95% confidence interval (CI): 19.9-25.4%, I
: 99.7%). Healthcare workers had the highest prevalence of PTSD (26.9%; 95% CI: 20.3-33.6%), followed by infected cases (23.8%: 16.6-31.0%), and the general public (19.3%: 15.3-23.2%). However, the heterogeneity of study findings indicates that results should be interpreted cautiously. Risk factors including individual, family, and societal factors, pandemic-related factors, and specific factors in healthcare workers and patients for post-pandemic PTSD were summarized and discussed in this systematic review. Long-term monitoring and early interventions should be implemented to improve post-pandemic mental health and long-term recovery.
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.
Infectious diseases, including COVID-19, are crucial public health issues and may lead to considerable fear among the general public and stigmatization of, and discrimination against, specific ...populations. This meta-analysis aimed to estimate the pooled prevalence of stigma in infectious disease epidemics. We systematically searched PubMed, PsycINFO, Embase, MEDLINE, Web of Science, and Cochrane databases since inception to June 08, 2021, and reported the prevalence of stigma towards people with infectious diseases including SARS, H1N1, MERS, Zika, Ebola, and COVID-19. A total of 50 eligible articles were included that contributed 51 estimates of prevalence in 92722 participants. The overall pooled prevalence of stigma across all populations was 34% 95% CI: 28-40%, including enacted stigma (36% 95% CI: 28-44%) and perceived stigma (31% 95% CI: 22-40%). The prevalence of stigma in patients, community population, and health care workers, was 38% 95% CI: 12- 65%, 36% 95% CI: 28-45%, and 30% 95% CI: 20-40%, respectively. The prevalence of stigma in participants from low- and middle-income countries was 37% 95% CI: 29-45%, which is higher than that from high-income countries (27% 95% CI: 18-36%) though this difference was not statistically significant. A similar trend of prevalence of stigma was also observed in individuals with lower education (47% 95% CI: 23-71%) compared to higher education level (33% 95% CI: 23-4%). These findings indicate that stigma is a significant public health concern, and effective and comprehensive interventions are needed to counteract the damaging effects of the infodemics during infectious disease epidemics, including COVID-19, and reduce infectious disease-related stigma.
A Mn(III)‐mediated radical cyclization reaction of o‐vinylaryl isocyanides and arylboronic acids or diphenylphosphine oxides to access various 2‐functionalized quinolines under mild conditions was ...developed. With the introduction of radical stabilizing substituents (e. g. aryl and methyl group) on vinyl group, this reaction provides a regiospecific 6‐endo‐trig radical cyclization of o‐vinylaryl isocyanides, giving a number of structurally unique and biologically potential 2‐functionalized quinoline derivatives.
Forsythiaside A, a phenylethanoid glycoside monomer extracted from
, shows anti-inflammatory, anti-infective, anti-oxidative, and antiviral pharmacological effects. The precise mechanism underlying ...the antiviral action of forsythiaside A is not completely clear. Therefore, in this study, we aimed to determine whether the anti-influenza action of forsythiaside A occurs via the retinoic acid-inducible gene-I-like receptors (RLRs) signaling pathway in the lung immune cells. Forsythiaside A was used to treat C57BL/6J mice and
mice infected with mouse-adapted influenza A virus FM1 (H1N1, A/FM1/1/47 strain), and the physical parameters (body weight and lung index) and the expression of key factors in the RLRs/NF-κB signaling pathway were evaluated. At the same time, the level of virus replication and the ratio of Th1/Th2 and Th17/Treg of T cell subsets were measured. Compared with the untreated group, the weight loss in the forsythiaside A group in the C57BL/6J mice decreased, and the histopathological sections showed less inflammatory damage after the infection with the influenza A virus FM1 strain. The gene and protein expression of retinoic acid-inducible gene-I (RIG-I), MAVS, and NF-κB were significantly decreased in the forsythiaside A group. Flow cytometry showed that Th1/Th2 and Th17/Treg differentiated into Th2 cells and Treg cells, respectively, after treatment with forsythiaside A. In conclusion, forsythiaside A reduces the inflammatory response caused by influenza A virus FM1 strain in mouse lungs by affecting the RLRs signaling pathway in the mouse lung immune cells.
Alteration in reproductive hormones profile is associated with the increasing risk of menopausal depression in women. Serum follicle-stimulating hormone (FSH) level is changed during the menopause ...transition, while the effect of FSH on menopausal depression has remained undefined. In this study we investigated whether or how FSH affected menopausal depression in postmenopausal (ovariectomized) FSHR knockout mice (Fshr
). We found that Fshr
mice displayed aggravated depression-like behaviors, accompanied by severe oxidative stress in the whole brain, resulted from significantly reduced glutamate cysteine ligase modifier subunit (GCLm) in glutathione synthesis and glucose-6-phosphate dehydrogenase (G6PD) in NADP/NADPH transition. Importantly, administration of ROS scavenger N-acetyl cysteine (NAC, 150 mg · kg
· d
, i.p. for 12 weeks) attenuated the depression-like behaviors of Fshr
mice. Consistent with these in vivo experiment results, we found that pretreatment with FSH (50, 100 ng/mL) dose-dependently increased protein levels of GCLm and G6PD, and decreased the ROS production in N2a mouse neuroblastoma cells. These findings demonstrate that FSH signaling is involved in pathogenesis of menopausal depression, and likely to maintain the redox-optimized ROS balance in neurons.
Purpose
To evaluate the effect of soft contact lens with concentric ring bifocal and peripheral add multifocal designs on controlling myopia progression in school‐aged children.
Methods
We ...systematically searched MEDLINE, EMBASE, Cochrane Library and reference lists of included trials. Methodological quality of included trials was assessed using Jadad Scale and Newcastle‐Ottawa Quality Assessment Scale items.
Results
We identified five randomised controlled trials (RCTs) and three cohort studies with a total of 587 myopic children. Compared with the control group, concentric ring bifocal soft contact lenses showed less myopia progression with a weighted mean difference (WMD) of 0.31 D (95% CI, 0.05~0.57 D, p = 0.02) and less axial elongation with a WMD of −0.12 mm (95% CI, approximately −0.18 to −0.07 mm, p < 0.0001) at 12 months. Relative to the control group, peripheral add multifocal soft contact lenses showed less myopia progression with a WMD of 0.22 D (95% CI 0.14~0.31 D, p < 0.0001) and less axial elongation of −0.10 mm (95% CI −0.13~0.07 mm, p < 0.0001) at 12 months, respectively. The soft contact lenses with concentric ring bifocal and peripheral add multifocal designs produced additional myopia control rates of 30~38% for slowing myopia progression and 31~51% for lessening axial elongation within 24 months.
Conclusions
Both concentric ring bifocal and peripheral add multifocal soft contact lenses are clinically effective for controlling myopia in school‐aged children, with an overall myopia control rates of 30~50% over 2 years. Concentric ring bifocal soft contact lenses seem to have greater effect than peripheral add multifocal soft contact lenses.
To explore the effects of breast cancer (BC)-derived exosomes on invasion and migration of BC cells.
Exosomes (Exo-MA, Exo-M7, Exo-M1) were extracted from normal breast epithelial cells (MCF-10A), BC ...cells (MCF-7/MDA-MB-231) and BC cells with miR-146a overexpression or knockdown using multi-step differential centrifugation. Morphologies and sizes of exosomes were observed by transmission electron microscope (TEM) and particle size analysis respectively. BC mouse models were injected with DIR labeled Exo-MA, Exo-M7 or Exo-M1. The epithelial-mesenchymal transition (EMT) in BC cells was determined by PCR and Western blot. PKH67 labeled Exo-MA, Exo-M7 and Exo-M1 were incubated with NFs or MCF-7 to measure the activation of CAFs. Cell invasion and migration abilities were determined by scratch test and Transwell assay.
Exo-MA, Exo-M7, Exo-M1 were successfully extracted with positive expressions of Alix, CD63 and TSG101. Contents of Ki67, N-cadherin, Vimentin and Snail-1 were increased but E-cadherin was decreased, compared to Exo-MA group. Exo-M7 or Exo-M1 could increase BC cell proliferation and enhance EMT in nude mouse. Exo-M7 and Exo-M1 could accelerate the transformation of NFs into CAFs and promote the recruitment of CAFs in MCF-7. Transfection of miR-146a could promote the transformation of NFs into CAFs and promote cell invasion and migration of MCF-7 cells. As a target gene of miR-146a, TXNIP could inhibit the activation of CAFs. miR-146a overexpression or TXNIP silence enhance the activation of Wnt signal pathway.
BC-derived exosomes promote the activation of CAFs through miR-146a/TXNIP axis to activate Wnt pathway, which in turn enhances invasion and metastasis of BC cells.
•BC-derived exosomes promote activation of CAFs.•MiR-146a overexpressed in BC-derived exosomes.•MiR-146a and TXNIP regulate activation of CAFs.•MiR-146a negatively targets TXNIP.•BC-derived exosomes promote invasion and metastasis via miR-16a to activate Wnt pathway.
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