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ALKBH5 is the main enzyme for m 6 A-based demethylation of RNAs and it has been implicated in many biological and pathophysiological processes. Here, we aimed to explore the potential involvement of ALKBH5 in osteosarcoma and decipher the underlying cellular/molecular mechanisms. We discovered downregulated levels of demethylase ALKBH5 were correlated with increased m 6 A methylation in osteosarcoma cells/tissues compared with normal osteoblasts cells/tissues. ALKBH5 overexpression significantly suppressed osteosarcoma cell growth, migration, invasion, and trigged cell apoptosis. In contrast, inhibition of ALKBH5 produced the opposite effects. Whereas ALKBH5 silence enhanced m 6 A methylations of pre-miR-181b-1 and YAP-mRNA exerting oncogenic functions in osteosarcoma. Moreover, upregulation of YAP or downregulation of mature miR-181b-5p displayed a remarkable attenuation of anti-tumor activities caused by ALKBH5. Further results revealed that m 6 A methylated pre-miR-181b-1 was subsequently recognized by m 6 A-binding protein YTHDF2 to mediate RNA degradation. However, methylated YAP transcripts were recognized by YTHDF1 to promote its translation. Therefore, ALKBH5-based m 6 A demethylation suppressed osteosarcoma cancer progression through m 6 A-based direct/indirect regulation of YAP. Thus, ALKBH5 overexpression might be considered a new approach of replacement therapy for osteosarcoma treatment.

Equitable distribution of urban park green space benefits public health and improves quality of life. From the perspective of landscape justice, this study establishes a subjective and objective comprehensive fairness evaluation method and analyzes the fairness of the spatial distribution of park green space in the Daxing part of Yizhuang New Town, Beijing and its relationship with the economic level of residents. The results show that: (1) the green space in the Daxing part of Yizhuang New Town is concentrated in the town center and distributed more sparsely in surrounding areas; (2) urban park green space is not equitable in quantity, area, disaster prevention and avoidance, or accessibility; (3) high-grade apartment complexes have higher quality of services than low-grade apartment complexes, and the number of parks, per capita park area, disaster prevention and avoidance, and park accessibility are all higher for high-grade than for low-grade apartment complexes. Medium-grade apartment complexes have a high level of green space services, and the number of parks, total area, and accessibility are 1.06, 2.58, and 1.13 times higher than those of high-grade apartment complexes, respectively. Conversely, disaster prevention and avoidance and park area per capita of medium-grade apartment complexes are lower than in high-grade apartment complexes, at 0.81 and 0.12 times, respectively. This study provides a new perspective for exploring society and landscape equity and concludes with suggestions for improving park green space public services.

Abstract The development of osteoporosis is often accompanied by autophagy disturbance, which also causes new osteoblast defects from bone marrow mesenchymal stem cells (BMSCs). However, the underlying molecular mechanisms are still not fully understood. Methyltransferase-like 14 (METTL14) is the main enzyme for N6-methyladenosine (m6A), the most prevalent internal modification in mammalian mRNAs, and it has been implicated in many bioprocesses. Herein, we demonstrate that METTL14 plays a critical role in autophagy induction and hinders osteoporosis process whose expression is decreased both in human osteoporosis bone tissue and ovariectomy (OVX) mice. In vivo, METTL14+/− knockdown mice exhibit elevated bone loss and impaired autophagy similar to the OVX mice, while overexpression of METTL14 significantly promotes bone formation and inhibits the progression of osteoporosis caused by OVX surgery. In vitro, METTL14 overexpression significantly enhances the osteogenic differentiation ability of BMSCs through regulating the expression of beclin-1 depending on m6A modification and inducing autophagy; the opposite is true with METTL14 silencing. Subsequently, m6A-binding proteins IGF2BP1/2/3 recognize m6A-methylated beclin-1 mRNA and promote its translation via mediating RNA stabilization. Furthermore, METTL14 negatively regulates osteoclast differentiation. Collectively, our study reveals the METTL14/IGF2BPs/beclin-1 signal axis in BMSCs osteogenic differentiation and highlights the critical roles of METTL14-mediated m6A modification in osteoporosis. Graphical Abstract METTL14 inhibits osteoporosis development via regulating the dynamic balance between osteoblasts and osteoclasts. m6A modification of beclin-1 mediated by METTL14/IGF2BPs promotes its RNA stability and translation, which further activates autophagy and promotes osteogenic differentiation of BMSCs.

Resource, environmental, and ecological issues have become major constraints to the development of many regions. The Yellow River Basin is an important barrier for maintaining ecological security in northern China, but it has been impacted by problems such as severe soil erosion and declining biodiversity. The rational construction of ecological security patterns is important to enhance ecosystem functions and maintain regional ecological security. In this study, a comprehensive ecological security assessment system was constructed by selecting ecosystem service importance, ecological sensitivity, and landscape connectivity to assess the ecological security of Xiliu Ditch, an ecologically fragile region of the Inner Mongolia section of the Yellow River Basin in China. The assessment results showed significant spatial heterogeneity, with medium- and low-security value areas dominating, while high-security value areas accounted for only 18.7% of the study area. Seventeen ecological sources were identified from the high-security areas, which were mainly composed of grassland, woodland, and water bodies, most of which are distributed in the southern part of the study area. Twenty ecological corridors were selected by the minimum cumulative resistance model and gravity model and classified into 15 construction corridors and 5 potential corridors. Forty-six ecological nodes were defined, including twenty strategic points, nine potential strategic points, and seventeen break points. On this basis, we constructed an ecological security pattern of “two belts, three cores, six zones, multiple corridors and multiple nodes” and proposed corresponding ecological governance measures. This study explores the ecological security pattern at the small watershed scale, which helps to realize the fine management of the Xiliu Ditch basin and, on this basis, can provide scientific support for the ecological protection and sustainable development of the Yellow River basin. In addition, the ecological security assessment system proposed in this study can provide new ideas for the construction of ecological security patterns in similar ecologically fragile areas around the globe.

Chemotherapy-induced cardiac damage remains a leading cause of death amongst cancer survivors. Anthracycline-induced cardiotoxicity is mediated by severe mitochondrial injury, but little is known about the mechanisms by which cardiomyocytes adaptively respond to the injury. We observed the translocation of selected mitochondrial tricarboxylic acid (TCA) cycle dehydrogenases to the nucleus as an adaptive stress response to anthracycline-cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes and in vivo. The expression of nuclear-targeted mitochondrial dehydrogenases shifts the nuclear metabolic milieu to maintain their function both in vitro and in vivo. This protective effect is mediated by two parallel pathways: metabolite-induced chromatin accessibility and AMP-kinase (AMPK) signaling. The extent of chemotherapy-induced cardiac damage thus reflects a balance between mitochondrial injury and the protective response initiated by the nuclear pool of mitochondrial dehydrogenases. Our study identifies nuclear translocation of mitochondrial dehydrogenases as an endogenous adaptive mechanism that can be leveraged to attenuate cardiomyocyte injury. Chemotherapy can cause severe damage to cardiomyocytes in some patients but it is unclear how cardiomyocytes protect themselves against such stress. Here the authors show that cardiomyocytes initiate an endogenous protective response when exposed to chemotherapeutic agents by translocating mitochondrial enzymes to the nucleus.

Bone marrow-derived mesenchymal stem cells (BMSCs) have been suggested to possess the capacity to differentiate into different cell lineages. Maintaining a balanced stem cell differentiation program is crucial to the bone microenvironment and bone development. MicroRNAs (miRNAs) have played a critical role in regulating the differentiation of BMSCs into particular lineage. However, the role of miR-149-3p in the adipogenic and osteogenic differentiation of BMSCs has not been extensively discovered. In this study, we aimed to detect the expression levels of miR-149-3p during the differentiation of BMSCs and investigate whether miR-149-3p participated in the lineage choice of BMSCs or not. Compared with mimic-negative control (NC), miR-149-3p mimic decreased the adipogenic differentiation potential of BMSCs and increased the osteogenic differentiation potential. Further analysis revealed that overexpression of miR-149-3p repressed the expression of fat mass and obesity-associated (FTO) gene through binding to the 3ʹ UTR of the FTO mRNA. Also, the role of miR-149-3p mimic in inhibiting adipogenic lineage differentiation and potentiating osteogenic lineage differentiation was mainly through targeting FTO, which also played an important role in regulating body weight and fat mass. In addition, BMSCs treated with miR-149-3p anti-miRNA oligonucleotide (AMO) exhibited higher potential to differentiate into adipocytes and lower tendency to differentiate into osteoblasts compared with BMSCs transfected with NC. In summary, our results detected the effects of miR-149-3p in cell fate specification of BMSCs and revealed that miR-149-3p inhibited the adipogenic differentiation of BMSCs via a miR-149-3p/FTO regulatory axis. This study provided cellular and molecular insights into the observation that miR-149-3p was a prospective candidate gene for BMSC-based bone tissue engineering in treating osteoporosis.

Osteoporosis is closely associated with the dysfunction of bone metabolism, which is caused by the imbalance between new bone formation and bone resorption. Osteogenic differentiation plays a vital role in maintaining the balance of bone microenvironment. The present study investigated whether melatonin participated in the osteogenic commitment of bone marrow mesenchymal stem cells (BMSCs) and further explored its underlying mechanisms. Our data showed that melatonin exhibited the capacity of regulating osteogenic differentiation of BMSCs, which was blocked by its membrane receptor inhibitor luzindole. Further study demonstrated that the expression of miR‐92b‐5p was up‐regulated in BMSCs after administration of melatonin, and transfection of miR‐92b‐5p accelerated osteogenesis of BMSCs. In contrast, silence of miR‐92b‐5p inhibited the osteogenesis of BMSCs. The increase in osteoblast differentiation of BMSCs caused by melatonin was attenuated by miR‐92b‐5p AMO as well. Luciferase reporter assay, real‐time qPCR analysis and western blot analysis confirmed that miR‐92b‐5p was involved in osteogenesis by directly targeting intracellular adhesion molecule‐1 (ICAM‐1). Melatonin improved the expression of miR‐92b‐5p, which could regulate the differentiation of BMSCs into osteoblasts by targeting ICAM‐1. This study provided novel methods for treating osteoporosis.

A potential therapeutic target to curb obesity and diabetes is thermogenic beige adipocytes. However, beige adipocytes quickly transition into white adipocytes upon removing stimuli. Here, we define the critical role of cyclin dependent kinase inhibitor 2A (Cdkn2a) as a molecular pedal for the beige-to-white transition. Beige adipocytes lacking Cdkn2a exhibit prolonged lifespan, and male mice confer long-term metabolic protection from diet-induced obesity, along with enhanced energy expenditure and improved glucose tolerance. Mechanistically, Cdkn2a promotes the expression and activity of beclin 1 (BECN1) by directly binding to its mRNA and its negative regulator BCL2 like 1 (BCL2L1), activating autophagy and accelerating the beige-to-white transition. Reactivating autophagy by pharmacological or genetic methods abolishes beige adipocyte maintenance induced by Cdkn2a ablation. Furthermore, hyperactive BECN1 alone accelerates the beige-to-white transition in mice and human. Notably, both Cdkn2a and Becn1 exhibit striking positive correlations with adiposity. Hence, blocking Cdkn2a -mediated BECN1 activity holds therapeutic potential to sustain beige adipocytes in treating obesity and related metabolic diseases. Beige adipocytes quickly transition into white adipocytes upon the removal of stimuli, limiting their therapeutic potential for chronic metabolic diseases. In this study, the authors show that inhibiting Cdkn2a-Becn1 mediated autophagy can maintain beige adipocytes and provide long term metabolic health benefits in mice.

Translational control shapes the proteome and is particularly important in regulating gene expression under stress. A key source of endothelial stress is treatment with tyrosine kinase inhibitors (TKIs), which lowers cancer mortality but increases cardiovascular mortality. Using a human induced pluripotent stem cell-derived endothelial cell (hiPSC-EC) model of sunitinib-induced vascular dysfunction combined with ribosome profiling, we assessed the role of translational control in hiPSC-ECs in response to stress. We identified staphylococcal nuclease and tudor domain-containing protein 1 (SND1) as a sunitinib-dependent translationally repressed gene. SND1 translational repression was mediated by the mTORC1/4E-BP1 pathway. SND1 inhibition led to endothelial dysfunction, whereas SND1 OE protected against sunitinib-induced endothelial dysfunction. Mechanistically, SND1 transcriptionally regulated UBE2N, an E2-conjugating enzyme that mediates K63-linked ubiquitination. UBE2N along with the E3 ligases RNF8 and RNF168 regulated the DNA damage repair response pathway to mitigate the deleterious effects of sunitinib. In silico analysis of FDA-approved drugs led to the identification of an ACE inhibitor, ramipril, that protected against sunitinib-induced vascular dysfunction in vitro and in vivo, all while preserving the efficacy of cancer therapy. Our study established a central role for translational control of SND1 in sunitinib-induced endothelial dysfunction that could potentially be therapeutically targeted to reduce sunitinib-induced vascular toxicity.

The use of pharmaceuticals to treat human and animal diseases has resulted in the increase of antibiotic traces in the water system and soil, thus raising concerns about the environmental aspect. In this study, sodium alginate (SA) and carboxymethyl chitosan (CMCS) hydrogel microbeads were developed to enhance the adsorption of antibiotics by applying electrostatic spray in the fabrication of microbeads. Two hydrogel microbead sizes, SC-400 (~400 µm) and SC-2000 (~2000 µm), were used for the adsorption of tetracycline (TC) and ciprofloxacin (CIP) antibiotics in single and binary systems. The microbeads exhibited a good adsorption capacity and were able to achieve a maximum adsorption at pH 7 and 25 °C. Adsorption kinetics expressed suitability in the pseudo-second-order kinetic model for TC and CIP antibiotics. These results demonstrate that both single and binary systems align well with the Freundlich and Temkin isotherm models, indicating their suitability in explaining the adsorption mechanisms. These mechanisms predominantly involve electrostatic interactions between the SA/CMCS hydrogel microbeads and the antibiotics TC and CIP. This study highlights the capability of using SA/CMCS hydrogel microbeads for antibiotic removal and other environmental applications.