bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extracellular vesicles and immunogenic stress in cancer
Authors: Wu Qi , Zhang Hanpu , Sun Si , Wang Lijun , Sun Shengrong 
Published: October 2021

AbstractTumor progression requires bidirectional cell-to-cell communication within a complex tumor microenvironment (TME). Extracellular vesicles (EVs) as carriers have the capacity to shuttle regulatory molecules, including nucleic acids, proteins, and lipids, between cancer cells and multiple stromal cells, inducing remarkable phenotypic alterations in the TME. Recently proposed the concept “immunogenic stress”, which means in some stressed microenvironment, cancer cells can release EVs containing specific immunoregulatory mediators, depending on the initiating stress-associated pathway, thereby provoking the changes of immune status in the TME. Considerable evidence has revealed that the intracellular mechanisms underlying the response to diverse stresses are mainly autophagy, endoplasmic reticulum (ER) stress reactions and the DNA damage response (DDR). In addition, the activation of immunogenic stress responses endows hosts with immune surveillance capacity; in contrast, several cargoes in EVs under immunogenic stress trigger a passive immune response by mediating the function of immune cells. This review discusses the current understanding of the immunogenic stress pathways in cancer and describes the interrelation between EVs and immunogenic stress to propose potential treatment strategies and biomarkers.
Suppression of lncRNA NLRP3 inhibits NLRP3-triggered inflammatory responses in early acute lung injury
Authors: Luo Deqiang , Dai Wei , Feng Xiaojin , Ding Chengzhi , Shao Qiang , Xiao Rui , Zhao Ning , Peng Wei , Yang Ying , Cui Yamei , Liu Fen , Qian Kejian 
Published: October 2021

AbstractAcute lung injury (ALI) is a common lung pathology that is accompanied by alveolar macrophage (AM) activation and inflammatory response. This study investigated the role of the long non-coding RNA NONRATT004344 (hereafter named lncRNA NLRP3) in regulating the Nod-like receptor protein 3 (NLRP3)-triggered inflammatory response in early ALI and the underlying mechanism as well. We established LPS-induced ALI models to explore their interactive mechanisms in vitro and in vivo. Luciferase reporter assays were performed to determine that miR-138-5p could bind to lncRNA NLRP3 and NLRP3. We observed increased lncRNA NLRP3 expression, decreased miR-138-5p expression, NLRP3 inflammasome activation, and upregulated caspase-1, IL-1β, and IL-18 expression in the LPS-induced ALI model. Furthermore, lncRNA NLRP3 overexpression activated the NLRP3 inflammasome and promoted IL-1β and IL-18 secretion; the miR-138-5p mimic abolished these effects in vivo and in vitro. Consistently, miR-138-5p inhibition reversed the effects of lncRNA NLRP3 silencing on the expression of NLRP3-related molecules and inhibition of the NLRP3/caspase-1/IL-1β signalling pathway. Mechanistically, lncRNA NLRP3 sponging miR-138-5p facilitated NLRP3 activation through a competitive endogenous RNA (ceRNA) mechanism. In summary, our results suggested that lncRNA NLRP3 binding miR-138-5p promotes NLRP3-triggered inflammatory response via lncRNA NLRP3/miR-138-5p/NLRP3 ceRNA network (ceRNET) and provides insights into the treatment of early ALI.
Chidamide triggers BTG1-mediated autophagy and reverses the chemotherapy resistance in the relapsed/refractory B-cell lymphoma
Authors: Xue Kai , Wu Ji-Chuan , Li Xi-Ya , Li Ran , Zhang Qun-ling , Chang Jin-Jia , Liu Yi-Zhen , Xu Chun-Hui , Zhang Jia-Ying , Sun Xiao-Jian , Gu Juan J. , Guo Wei-Jian , Wang Lan 
Published: October 2021

AbstractRituximab/chemotherapy relapsed and refractory B cell lymphoma patients have a poor overall prognosis, and it is urgent to develop novel drugs for improving the therapy outcomes. Here, we examined the therapeutic effects of chidamide, a new histone deacetylase (HDAC) inhibitor, on the cell and mouse models of rituximab/chemotherapy resistant B-cell lymphoma. In Raji-4RH/RL-4RH cells, the rituximab/chemotherapy resistant B-cell lymphoma cell lines (RRCL), chidamide treatment induced growth inhibition and G0/G1 cell cycle arrest. The primary B-cell lymphoma cells from Rituximab/chemotherapy relapsed patients were sensitive to chidamide. Interestingly, chidamide triggered the cell death with the activation of autophagy in RRCLs, likely due to the lack of the pro-apoptotic proteins. Based on the RNA-seq and chromatin immunoprecipitation (ChIP) analysis, we identified BTG1 and FOXO1 as chidamide target genes, which control the autophagy and the cell cycle, respectively. Moreover, the combination of chidamide with the chemotherapy drug cisplatin increased growth inhibition on the RRCL in a synergistic manner, and significantly reduced the tumor burden of a mouse lymphoma model established with engraftment of RRCL. Taken together, these results provide a theoretic and mechanistic basis for further evaluation of the chidamide-based treatment in rituximab/chemotherapy relapsed and refractory B-cell lymphoma patients.
Modulation of oxidative phosphorylation augments antineoplastic activity of mitotic aurora kinase inhibition
Authors: Zhang Zijian , Zeng Deshun , Zhang Wei , Chen Ailin , Lei Jie , Liu Fang , Deng Bing , Zhuo Junxiao , He Bin , Yan Min , Lei Xinxing , Wang Shulan , Lam Eric W.-F. , Liu Quentin , Wang Zifeng 
Published: September 2021

AbstractUncontrolled mitosis is one of the most important features of cancer, and mitotic kinases are thought to be ideal targets for anticancer therapeutics. However, despite numerous clinical attempts spanning decades, clinical trials for mitotic kinase-targeting agents have generally stalled in the late stages due to limited therapeutic effectiveness. Alisertib (MLN8237) is a promising oral mitotic aurora kinase A (AURKA, Aurora-A) selective inhibitor, which is currently under several clinical evaluations but has failed in its first Phase III trial due to inadequate efficacy. In this study, we performed genome-wide CRISPR/Cas9-based screening to identify vulnerable biological processes associated with alisertib in breast cancer MDA-MB-231 cells. The result indicated that alisertib treated cancer cells are more sensitive to the genetic perturbation of oxidative phosphorylation (OXPHOS). Mechanistic investigation indicated that alisertib treatment, as well as other mitotic kinase inhibitors, rapidly reduces the intracellular ATP level to generate a status that is highly addictive to OXPHOS. Furthermore, the combinational inhibition of mitotic kinase and OXPHOS by alisertib, and metformin respectively, generates severe energy exhaustion in mitotic cells that consequently triggers cell death. The combination regimen also enhanced tumor regression significantly in vivo. This suggests that targeting OXPHOS by metformin is a potential strategy for promoting the therapeutic effects of mitotic kinase inhibitors through the joint targeting of mitosis and cellular energy homeostasis.
NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner
Authors: Huang Can , Santofimia-Castaño Patricia , Liu Xi , Xia Yi , Peng Ling , Gotorbe Célia , Neira Jose Luis , Tang Daolin , Pouyssegur Jacques , Iovanna Juan 
Published: October 2021

AbstractFerroptosis is an iron-dependent cell death characterized by the accumulation of hydroperoxided phospholipids. Here, we report that the NUPR1 inhibitor ZZW-115 induces ROS accumulation followed by a ferroptotic cell death, which could be prevented by ferrostatin-1 (Fer-1) and ROS-scavenging agents. The ferroptotic activity can be improved by inhibiting antioxidant factors in pancreatic ductal adenocarcinoma (PDAC)- and hepatocellular carcinoma (HCC)-derived cells. In addition, ZZW-115-treatment increases the accumulation of hydroperoxided lipids in these cells. We also found that a loss of activity and strong deregulation of key enzymes involved in the GSH- and GPX-dependent antioxidant systems upon ZZW-115 treatment. These results have been validated in xenografts induced with PDAC- and HCC-derived cells in nude mice during the treatment with ZZW-115. More importantly, we demonstrate that ZZW-115-induced mitochondrial morphological changes, compatible with the ferroptotic process, as well as mitochondrial network disorganization and strong mitochondrial metabolic dysfunction, which are rescued by both Fer-1 and N-acetylcysteine (NAC). Of note, the expression of TFAM, a key regulator of mitochondrial biogenesis, is downregulated by ZZW-115. Forced expression of TFAM is able to rescue morphological and functional mitochondrial alterations, ROS production, and cell death induced by ZZW-115 or genetic inhibition of NUPR1. Altogether, these results demonstrate that the mitochondrial cell death mediated by NUPR1 inhibitor ZZW-115 is fully rescued by Fer-1 but also via TFAM complementation. In conclusion, TFAM could be considered as an antagonist of the ferroptotic cell death.
Hsa_circ_0011385 knockdown represses cell proliferation in hepatocellular carcinoma
Authors: Ni Chuangye , Yang Shikun , Ji Yang , Duan Yunfei , Yang Wenjie , Yang Xinchen , Li Min , Xie Jun , Zhang Chuanyong , Lu Yunjie , Lu Hao 
Published: October 2021

AbstractCircular RNAs (circRNAs), continuous loops of single-stranded RNA, regulate gene expression during the development of various cancers. However, the function of circRNAs in hepatocellular carcinoma (HCC) is rarely discussed. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the mRNA levels of circ_0011385, miR-361-3p, and STC2 in 96 pairs of HCC tissues (tumor tissues and adjacent normal tissues), HCC cell lines, and L02 (human normal liver cell line) cells. The relationships between circ_0011385 expression and clinical features of HCC were evaluated. Functional experiments in vitro or in vivo were used to evaluate the biological function of circ_0011385. Bioinformatics analysis was performed to predict miRNAs and mRNAs sponged by circ_0011385. RNA immunoprecipitation (RIP) and dual-luciferase reporter gene assays were used to elucidate the interactions among circ_0011385, miR-361-3p, and STC2 (stanniocalcin 2). ChIP and dual-luciferase reporter gene assays were used to identify the upstream regulator of circ_0011385. High expression of circ_0011385 was observed in HCC tissues and cell lines and was significantly associated with tumor size, TNM stage, and prognosis. In addition, inhibition of circ_0011385 expression prevented the proliferation of HCC cells in vitro and in vivo. Circ_0011385 sponged miR-361-3p, thereby regulating the mRNA expression of STC2. In addition, the transcription of circ_0011385 was regulated by SP3. Circ_0011385 knockdown suppressed cell proliferation and tumor activity in HCC. Circ_0011385 may therefore serve as a new biomarker in the diagnosis and treatment of HCC.
The blood–brain barrier in systemic infection and inflammation
Authors: Galea Ian 
Published: September 2021

AbstractThe vascular blood–brain barrier is a highly regulated interface between the blood and brain. Its primary function is to protect central neurons while signaling the presence of systemic inflammation and infection to the brain to enable a protective sickness behavior response. With increasing degrees and duration of systemic inflammation, the vascular blood–brain barrier becomes more permeable to solutes, undergoes an increase in lymphocyte trafficking, and is infiltrated by innate immune cells; endothelial cell damage may occasionally occur. Perturbation of neuronal function results in the clinical features of encephalopathy. Here, the molecular and cellular anatomy of the vascular blood–brain barrier is reviewed, first in a healthy context and second in a systemic inflammatory context. Distinct from the molecular and cellular mediators of the blood–brain barrier’s response to inflammation, several moderators influence the direction and magnitude at genetic, system, cellular and molecular levels. These include sex, genetic background, age, pre-existing brain pathology, systemic comorbidity, and gut dysbiosis. Further progress is required to define and measure mediators and moderators of the blood–brain barrier’s response to systemic inflammation in order to explain the heterogeneity observed in animal and human studies.
Nonvolatile voltage-controlled magnetization reversal in a spin-valve multiferroic heterostructure
Authors: Liu Mengli , Du Wei , Su Hua , Zhang Huaiwu , Liu Bo , Meng Hao , Tang Xiaoli 
Published: October 2021

AbstractPure voltage-controlled magnetism, rather than a spin current or magnetic field, is the goal for next-generation ultralow power consumption spintronic devices. To advance toward this goal, we report a voltage-controlled nonvolatile 90° magnetization rotation and voltage-assisted 180° magnetization reversal in a spin-valve multiferroic heterostructure. Here, a spin valve with a synthetic antiferromagnetic structure was grown on a (110)-cut Pb(Mg1/3Nb2/3)0.7Ti0.3O3 (PMN-PT) substrate, in which only the magnetic moment of the free layer can be manipulated by an electric field (E-field) via the strain-mediated magnetoelectric coupling effect. As a result of selecting a specified PMN-PT substrate with defect dipoles, nonvolatile and stable magnetization switching was achieved by using voltage impulses. Accordingly, a giant, reversible and nonvolatile magnetoresistance modulation was achieved without the assistance of a magnetic field. In addition, by adopting a small voltage impulse, the critical magnetic field required for complete 180° magnetization reversal of the free layer can be tremendously reduced. A magnetoresistance ratio as large as that obtained by a magnetic field or spin current under normal conditions is achieved. These results indicate that E-field-assisted energy-efficient in-plane magnetization switching is a feasible strategy. This work is significant to the development of ultralow-power magnetoresistive memory and spintronic devices.
Tetraketide α-pyrone reductases in sporopollenin synthesis pathway in Gerbera hybrida: diversification of the minor function
Authors: Zhu Lingping , Zhang Teng , Teeri Teemu H 
Published: October 2021

Abstract
The structurally robust biopolymer sporopollenin is the major constituent of the exine layer of pollen wall and plays a vital role in plant reproductive success. The sporopollenin precursors are synthesized through an ancient polyketide biosynthetic pathway consisting of a series of anther-specific enzymes that are widely present in all land plant lineages. Tetraketide α-pyrone reductase 1 (TKPR1) and TKPR2 are two reductases catalyzing the final reduction of the carbonyl group of the polyketide synthase-synthesized tetraketide intermediates to hydroxylated α-pyrone compounds, important precursors of sporopollenin. In contrast to the functional conservation of many sporopollenin biosynthesis associated genes confirmed in diverse plant species, TKPR2’s role has been addressed only in Arabidopsis, where it plays a minor role in sporopollenin biosynthesis. We identified in gerbera two non-anther-specific orthologues of AtTKPR2, Gerbera reductase 1 (GRED1) and GRED2. Their dramatically expanded expression pattern implies involvement in pathways outside of the sporopollenin pathway. In this study, we show that GRED1 and GRED2 are still involved in sporopollenin biosynthesis with a similar secondary role as AtTKPR2 in Arabidopsis. We further show that this secondary role does not relate to the promoter of the gene, AtTKPR2 cannot rescue pollen development in Arabidopsis even when controlled by the AtTKPR1 promoter. We also identified the gerbera orthologue of AtTKPR1, GTKPR1, and characterized its crucial role in gerbera pollen development. GTKPR1 is the predominant TKPR in gerbera pollen wall formation, in contrast to the minor roles GRED1 and GRED2. GTKPR1 is in fact an excellent target for engineering male-sterile gerbera cultivars in horticultural plant breeding.
The NAM/ATAF1/2/CUC2 transcription factor PpNAC.A59 enhances PpERF.A16 expression to promote ethylene biosynthesis during peach fruit ripening
Authors: Guo Zhi-Hua , Zhang You-Jia , Yao Jia-Long , Xie Zhi-Hua , Zhang Yu-Yan , Zhang Shao-Ling , Gu Chao 
Published: October 2021

AbstractPeach is a typical climacteric fruit that releases ethylene during fruit ripening. Several studies have been conducted on the transcriptional regulation of ethylene biosynthesis in peach fruit. Herein, an ethylene response factor, PpERF.A16, which was induced by exogenous ethylene, could enhance ethylene biosynthesis by directly inducing the expression of1-aminocyclopropane-1-carboxylic acid synthase(PpACS1) and1-aminocyclopropane-1-carboxylic acid oxidase(PpACO1) genes. Moreover, the NAM/ATAF1/2/CUC2 (NAC) transcription factor (TF)PpNAC.A59was coexpressed withPpERF.A16in all tested peach cultivars. Interestingly, PpNAC.A59 can directly interact with the promoter ofPpERF.A16to induce its expression but not enhanceLUCactivity driven by any promoter ofPpACS1orPpACO1. Thus, PpNAC.A59 can indirectly mediate ethylene biosynthesis via the NAC-ERF signaling cascade to induce the expression of bothPpACS1andPpACO1. These results enrich the genetic network of fruit ripening in peach and provide new insight into the ripening mechanism of other perennial fruits.
The role of watermelon caffeic acid O-methyltransferase (ClCOMT1) in melatonin biosynthesis and abiotic stress tolerance
Authors: Chang Jingjing , Guo Yanliang , Yan Jingyi , Zhang Zixing , Yuan Li , Wei Chunhua , Zhang Yong , Ma Jianxiang , Yang Jianqiang , Zhang Xian , Li Hao 
Published: October 2021

AbstractMelatonin is a pleiotropic signaling molecule that regulates plant growth and responses to various abiotic stresses. The last step of melatonin synthesis in plants can be catalyzed by caffeic acid O-methyltransferase (COMT), a multifunctional enzyme reported to have N-acetylserotonin O-methyltransferase (ASMT) activity; however, the ASMT activity of COMT has not yet been characterized in nonmodel plants such as watermelon (Citrullus lanatus). Here, a total of 16 putative O-methyltransferase (ClOMT) genes were identified in watermelon. Among them, ClOMT03 (Cla97C07G144540) was considered a potential COMT gene (renamed ClCOMT1) based on its high identities (60.00–74.93%) to known COMT genes involved in melatonin biosynthesis, expression in almost all tissues, and upregulation under abiotic stresses. The ClCOMT1 protein was localized in the cytoplasm. Overexpression of ClCOMT1 significantly increased melatonin contents, while ClCOMT1 knockout using the CRISPR/Cas-9 system decreased melatonin contents in watermelon calli. These results suggest that ClCOMT1 plays an essential role in melatonin biosynthesis in watermelon. In addition, ClCOMT1 expression in watermelon was upregulated by cold, drought, and salt stress, accompanied by increases in melatonin contents. Overexpression of ClCOMT1 enhanced transgenic Arabidopsis tolerance against such abiotic stresses, indicating that ClCOMT1 is a positive regulator of plant tolerance to abiotic stresses.
The NAC transcription factor ClNAC68 positively regulates sugar content and seed development in watermelon by repressing ClINV and ClGH3.6
Authors: Wang Jinfang , Wang Yanping , Zhang Jie , Ren Yi , Li Maoying , Tian Shaowei , Yu Yongtao , Zuo Yi , Gong Guoyi , Zhang Haiying , Guo Shaogui , Xu Yong 
Published: October 2021

Abstract
NAC (NAM, ATAF1/2, and CUC2) transcription factors play important roles in fruit ripening and quality. The watermelon genome encodes 80 NAC genes, and 21 of these NAC genes are highly expressed in both the flesh and vascular tissues. Among these genes, ClNAC68 expression was significantly higher in flesh than in rind. However, the intrinsic regulatory mechanism of ClNAC68 in fruit ripening and quality is still unknown. In this study, we found that ClNAC68 is a transcriptional repressor and that the repression domain is located in the C-terminus. Knockout of ClNAC68 by the CRISPR-Cas9 system decreased the soluble solid content and sucrose accumulation in mutant flesh. Development was delayed, germination was inhibited, and the IAA content was significantly decreased in mutant seeds. Transcriptome analysis showed that the invertase gene ClINV was the only gene involved in sucrose metabolism that was upregulated in mutant flesh, and expression of the indole-3-acetic acid-amido synthetase gene ClGH3.6 in the IAA signaling pathway was also induced in mutant seeds. EMSA and dual-luciferase assays showed that ClNAC68 directly bound to the promoters of ClINV and ClGH3.6 to repress their expression. These results indicated that ClNAC68 positively regulated sugar and IAA accumulation by repressing ClINV and ClGH3.6. Our findings provide new insights into the regulatory mechanisms by which NAC transcription factors affect fruit quality and seed development.
The CaCIPK3 gene positively regulates drought tolerance in pepper
Authors: Ma Xiao , Li Yang , Gai Wen-Xian , Li Chuang , Gong Zhen-Hui 
Published: October 2021

AbstractDrought stress is a major agricultural problem restricting the growth, development, and productivity of plants. Calcineurin B-like proteins (CBLs) and CBL-interacting protein kinases (CIPKs) significantly influence the plant response to different stresses. However, the molecular mechanisms of CBL–CIPK in the drought stress response of pepper are still unknown. Here, the function ofCaCIPK3in the regulation of drought stress in pepper (Capsicum annuumL.) was explored. Transcriptomic data and quantitative real-time PCR (qRT-PCR) analysis revealed thatCaCIPK3participates in the response to multiple stresses. Knockdown ofCaCIPK3in pepper increased the sensitivity to mannitol and methyl jasmonate (MeJA). Transient overexpression ofCaCIPK3improved drought tolerance by enhancing the activities of the antioxidant system and positively regulating jasmonate (JA)-related genes. Ectopic expression ofCaCIPK3in tomato also improved drought and MeJA resistance. As the CaCIPK3-interacting partner, CaCBL2 positively influenced drought resistance. Additionally, CaWRKY1 and CaWRKY41 directly bound theCaCIPK3promoter to influence its expression. This study shows thatCaCIPK3acts as a positive regulator in drought stress resistance via the CBL–CIPK network to regulate MeJA signaling and the antioxidant defense system.