bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity
Authors: Fang Xing , Jiang Shujun , Wang Jiangong , Bai Yu , Kim Chung Sub , Blake David , Weintraub Neal L. , Lei Yun , Lu Xin-Yun 
Published: January 2021

AbstractPrevious studies have shown that AgRP neurons in the arcuate nucleus (ARC) respond to energy deficits and play a key role in the control of feeding behavior and metabolism. Here, we demonstrate that chronic unpredictable stress, an animal model of depression, decreases spontaneous firing rates, increases firing irregularity and alters the firing properties of AgRP neurons in both male and female mice. These changes are associated with enhanced inhibitory synaptic transmission and reduced intrinsic neuronal excitability. Chemogenetic inhibition of AgRP neurons increases susceptibility to subthreshold unpredictable stress. Conversely, chemogenetic activation of AgRP neurons completely reverses anhedonic and despair behaviors induced by chronic unpredictable stress. These results indicate that chronic stress induces maladaptive synaptic and intrinsic plasticity, leading to hypoactivity of AgRP neurons and subsequently causing behavioral changes. Our findings suggest that AgRP neurons in the ARC are a key component of neural circuitry involved in mediating depression-related behaviors and that increasing AgRP neuronal activity coule be a novel and effective treatment for depression.
Metformin exhibits antiproliferation activity in breast cancer via miR-483-3p/METTL3/m6A/p21 pathway
Authors: Cheng Lin , Zhang Xu , Huang Yu-Zhou , Zhu Yu-Lan , Xu Ling-Yun , Li Zhi , Dai Xin-Yuan , Shi Liang , Zhou Xu-Jie , Wei Ji-Fu , Ding Qiang 
Published: January 2021

AbstractEvidence suggests that metformin might be a potential candidate for breast cancer treatment. Yet, its relevant molecular mechanisms remain to be fully investigated. We found that metformin could suppress the N6-methyladenosine (m6A) level in breast cancer cells significantly. The latter has an essential role in breast cancer progression and is newly considered as a therapeutic target. In this study, we measured the m6A level by m6A colorimetric analysis and dot blot assay. We then performed qRT-PCR, western blot, MeRIP, dual-luciferase reporter assay, and others to explore the m6A-dependent pathway associated with metformin. In vivo effect of metformin was investigated using a mouse tumorigenicity model. In addition, breast cancer and normal tissues were used to determine the role of METTL3 in breast cancer. Metformin could reduce the m6A level via decreasing METTL3 expression mediated by miR-483-3p in breast cancer. METTL3 is known to be able to promote breast cancer cell proliferation by regulating the p21 expression by an m6A-dependent manner. Metformin can take p21 as the main target to inhibit such effect. To specify, this study exhibited that metformin can inhibit breast cancer cell proliferation through the pathway miR-483-3p/METTL3/m6A/p21. Our findings suggest that METTL3 may be considered as a potential therapeutic target of metformin for breast cancer.
Feedback activation of STAT3 limits the response to PI3K/AKT/mTOR inhibitors in PTEN-deficient cancer cells
Authors: Wang Jian , Lv Xiaoye , Guo Xiutian , Dong Yanbo , Peng Peipei , Huang Fang , Wang Peng , Zhang Haoqian , Zhou Jianguang , Wang Youliang , Wei Bo , Shang Zeng-Fu , Li Shanhu 
Published: January 2021

AbstractThe PI3K/AKT/mTOR signaling pathway is constitutively active in PTEN-deficient cancer cells, and its targeted inhibition has significant anti-tumor effects. However, the efficacy of targeted therapies is often limited due to drug resistance. The relevant signaling pathways in PTEN-deficient cancer cells treated with the PI3K/mTOR inhibitor BEZ235 were screened using a phosphokinase array, and further validated following treatment with multiple PI3K/AKT/mTOR inhibitors or AKT knockdown. The correlation between PTEN expression levels and STAT3 kinase phosphorylation in the tissue microarrays of gastric cancer patients was analyzed by immunohistochemistry. Cell proliferation and clonogenic assays were performed on the suitably treated PTEN-deficient cancer cells. Cytokine arrays, small molecule inhibition and knockdown assays were performed to identify related factors. PTEN-deficient tumor xenografts were established in nude mice that were treated with PI3K/AKT/mTOR and/or STAT3 inhibitors. PTEN deficiency was positively correlated with low STAT3 activity. PI3K/mTOR inhibitors increased the expression and secretion of macrophage migration inhibitory factor (MIF) and activated the JAK1/STAT3 signaling pathway. Both cancer cells and in vivo tumor xenografts showed that the combined inhibition of PI3K/AKT/mTOR and STAT3 activity enhanced the inhibitory effect of BEZ235 on the proliferation of PTEN-deficient cancer cells. Our findings provide a scientific basis for a novel treatment strategy in cancer patients with PTEN deficiency.
PBK phosphorylates MSL1 to elicit epigenetic modulation of CD276 in nasopharyngeal carcinoma
Authors: Wang Meng-Yao , Qi Bin , Wang Fang , Lin Zhi-Rui , Li Ming-Yi , Yin Wen-Jing , Zhu Yan-Yi , He Lu , Yu Yi , Yang Fang , Liu Jin-Quan , Chen Dong-Ping 
Published: January 2021

AbstractCD276 (also known as B7–H3, an immune checkpoint molecule) is aberrantly overexpressed in many cancers. However, the upregulation mechanism and in particular, whether oncogenic signaling has a role, is unclear. Here we demonstrate that a pro-oncogenic kinase PBK, the expression of which is associated with immune infiltration in nasopharyngeal carcinoma (NPC), stimulates the expression of CD276 epigenetically. Mechanistically, PBK phosphorylates MSL1 and enhances the interaction between MSL1 and MSL2, MSL3, and KAT8, the components of the MSL complex. As a consequence, PBK promotes the enrichment of MSL complex on CD276 promoter, leading to the increased histone H4 K16 acetylation and the activation of CD276 transcription. In addition, we show that CD276 is highly upregulated and associated with immune infiltrating levels in NPC. Collectively, our findings describe a novel PBK/MSL1/CD276 signaling axis, which may play an important role in immune evasion of NPC and may be targeted for cancer immunotherapy.
Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder
Authors: Nunes Abraham , Stone William , Ardau Raffaella , Berghöfer Anne , Bocchetta Alberto , Chillotti Caterina , Deiana Valeria , Degenhardt Franziska , Forstner Andreas J. , Garnham Julie S. , Grof Eva , Hajek Tomas , Manchia Mirko , Mattheisen Manuel , McMahon Francis , Müller-Oerlinghausen Bruno , Nöthen Markus M. , Pinna Marco , Pisanu Claudia , O’Donovan Claire , Rietschel Marcella D. C. , Rouleau Guy , Schulze Thomas , Severino Giovanni , Slaney Claire M. , Squassina Alessio , Suwalska Aleksandra , Turecki Gustavo , Uher Rudolf , Zvolsky Petr , Cervantes Pablo , del Zompo Maria , Grof Paul , Rybakowski Janusz , Tondo Leonardo , Trappenberg Thomas , Alda Martin 
Published: January 2021

AbstractPredicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with “exemplary phenotypes”—those whose clinical features are reliably associated with LiR and non-response (LiNR)—are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a “clinical exemplar score,” which measures the degree to which a subject’s clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the “best clinical exemplars”) were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the “poor clinical exemplars”). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer’s amyloid–secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers.
Multi-environment gene interactions linked to the interplay between polysubstance dependence and suicidality
Authors: Polimanti Renato , Levey Daniel F. , Pathak Gita A. , Wendt Frank R. , Nunez Yaira Z. , Ursano Robert J. , Kessler Ronald C. , Kranzler Henry R. , Stein Murray B. , Gelernter Joel 
Published: January 2021

AbstractSubstance dependence diagnoses (SDs) are important risk factors for suicidality. We investigated the associations of multiple SDs with different suicidality outcomes, testing how genetic background moderates these associations. The Yale-Penn cohort (N = 15,557) was recruited to investigate the genetics of SDs. The Army STARRS (Study to Assess Risk and Resilience in Servicemembers) cohort (N = 11,236) was recruited to evaluate mental health risk and resilience among Army personnel. We applied multivariate logistic regression to investigate the associations of SDs with suicidality and, in the Yale-Penn cohort, we used the structured linear mixed model (StructLMM) to study multivariate gene–environment interactions. In Yale-Penn, lifetime polysubstance dependence was strongly associated with lifetime suicidality: having five SDs showed an association with suicidality, from odds ratio (OR) = 6.77 (95% confidence interval, CI = 5.74–7.99) for suicidal ideation (SI) to OR = 3.61 (95% CI = 2.7–4.86) for suicide attempt (SA). In Army STARRS, having multiple substance use disorders for alcohol and/or drugs was associated with increased suicidality ranging from OR = 2.88 (95% CI = 2.6–3.19) for SI to OR = 3.92 (95% CI = 3.19–4.81) for SA. In Yale-Penn, we identified multivariate gene–environment interactions (Bayes factors, BF > 0) of SI with respect to a gene cluster on chromosome 16 (LCAT, p = 1.82 × 10–7; TSNAXIP1, p = 2.13 × 10−7; CENPT, p = 2.32 × 10−7; PARD6A, p = 5.57 × 10−7) for opioid dependence (BF = 12.2), cocaine dependence (BF = 12.1), nicotine dependence (BF = 9.2), and polysubstance dependence (BF = 2.1). Comorbidity of multiple SDs is a significant associated with suicidality and heritability of suicidality is partially moderated by multivariate gene interactions.
Osteoclast-derived apoptotic bodies couple bone resorption and formation in bone remodeling
Authors: Ma Qinyu , Liang Mengmeng , Wu Yutong , Luo Fei , Ma Zaisong , Dong Shiwu , Xu Jianzhong , Dou Ce 
Published: January 2021

AbstractBone remodeling is precisely coordinated by bone resorption and formation. Apoptotic osteoclasts generate large amounts of apoptotic bodies (ABs) marking the end of the bone resorption phase, whereas the functions of osteoclast-derived ABs remain largely unknown. Here, we identified the molecular profile of ABs derived from osteoclasts at distinct differentiation stages and investigated their corresponding functions. ABs were isolated from apoptotic bone marrow macrophages, preosteoclasts, and mature osteoclasts induced by staurosporine. Proteomic signature analysis with liquid chromatography-tandem mass spectrometry suggested marked protein cargo differences among the different ABs. Further bioinformatic analysis showed that the proteomic signatures of the ABs were highly similar to those of their parental cells. Functionally, pOC-ABs induced endothelial progenitor cell differentiation and increased CD31hiEmcnhi endothelial cell formation in a murine bone defect model via their PDGF-BB cargo. mOC-ABs induced osteogenic differentiation of mesenchymal stem cells and facilitated osteogenesis via RANKL reverse signaling. In summary, we mapped the detailed proteomic landscapes of ABs derived from osteoclasts and showed that their potential biological roles are important in coupling bone formation with resorption during bone remodeling.
LncRNA linc00312 suppresses radiotherapy resistance by targeting DNA-PKcs and impairing DNA damage repair in nasopharyngeal carcinoma
Authors: Guo Zhen , Wang You-Hong , Xu Heng , Yuan Chun-Su , Zhou Hong-Hao , Huang Wei-Hua , Wang Hui , Zhang Wei 
Published: January 2021

AbstractRadioresistance is the main obstacle in the clinical management of nasopharyngeal carcinoma (NPC). linc00312 is deregulated in a number of human cancers, including NPC. However, the detailed functions and underlying mechanisms of linc00312 in regulating radiosensitivity of NPC remains unknown. In this study, cox regression analysis was used to assess the association between linc00312 and NPC patients’ survival after radiotherapy. Our results reveal that linc00312 is significantly down-regulated in NPC tissues and patients with higher expression of linc00312 are significantly associated with longer overall survival and better short-term radiotherapy efficacy. Overexpression of linc00312 could increase the sensitivity of NPC cells to ionizing radiation, as indicated by clonogenic survival assay, comet assay, and flow cytometry. Mechanistically, RNA pull down and RNA immunoprecipitation were performed to investigate the binding proteins of linc00312. linc00312 directly binds to DNA-PKcs, hinders the recruitment of DNA-PKcs to Ku80, and inhibits phosphorylation of AKT–DNA–PKcs axis, therefore inhibiting the DNA damage signal sensation and transduction in the NHEJ repair pathway. In addition, linc00312 impairs DNA repair and cell cycle control by suppressing MRN–ATM–CHK2 signal and ATR–CHK1 signal. In summary, we identified DNA-PKcs as the binding protein of linc00312 and revealed a novel mechanism of linc00312 in the DNA damage response, providing evidence for a potential therapeutic strategy in NPC.
The HIV protease inhibitor Saquinavir attenuates sepsis-induced acute lung injury and promotes M2 macrophage polarization via targeting matrix metalloproteinase-9
Authors: Tong Yao , Yu Zhuang , Chen Zhixia , Zhang Renlingzi , Ding Xibing , Yang Xiaohu , Niu Xiaoyin , Li Mengzhu , Zhang Lingling , Billiar Timothy R. , Pitt Bruce R. , Li Quan 
Published: January 2021

AbstractImbalance of macrophage polarization plays an indispensable role in acute lung injury (ALI), which is considered as a promising target. Matrix metalloproteinase-9 (MMP-9) is expressed in the macrophage, and has a pivotal role in secreting inflammatory cytokines. We reported that saquinavir (SQV), a first-generation human immunodeficiency virus-protease inhibitor, restricted exaggerated inflammatory response. However, whether MMP-9 could regulate macrophage polarization and inhibit by SQV is still unknown. We focused on the important role of macrophage polarization in CLP (cecal ligation puncture)-mediated ALI and determined the ability of SQV to maintain M2 over M1 phenotype partially through the inhibition of MMP-9. We also performed a limited clinical study to determine if MMP-9 is a biomarker of sepsis. Lipopolysaccharide (LPS) increased MMP-9 expression and recombinant MMP-9 (rMMP-9) exacerbated LPS-mediated M1 switching. Small interfering RNA to MMP-9 inhibited LPS-mediated M1 phenotype and SQV inhibition of this switching was reversed with rMMP-9, suggesting an important role for MMP-9 in mediating LPS-induced M1 phenotype. MMP-9 messenger RNA levels in peripheral blood mononuclear cells of these 14 patients correlated with their clinical assessment. There was a significant dose-dependent decrease in mortality and ALI after CLP with SQV. SQV significantly inhibited LPS-mediated M1 phenotype and increased M2 phenotype in cultured RAW 264.7 and primary murine bone marrow-derived macrophages as well as lung macrophages from CLP-treated mice. This study supports an important role for MMP-9 in macrophage phenotypic switching and suggests that SQV-mediated inhibition of MMP-9 may be involved in suppressing ALI during systemic sepsis.
Mtu1 defects are correlated with reduced osteogenic differentiation
Authors: He Qiufen , Zhao Qiong , Li Qianqian , Pan Ruolang , Li Xiongfeng , Chen Ye 
Published: January 2021

AbstractAccumulating evidence has revealed that mitochondria dynamics and function regulation is essential for the successful mesenchymal stem cell (MSC) differentiation. In the present study, the researchers reported for the first time that Mtu1 defects are correlated with reduced osteogenic differentiation. Using in vitro cultured bone marrow MSCs and stromal cell line MS5, we demonstrated that depressed Mtu1 expression was associated with reduced 2-thiouridine modification of the U34 of mitochondrial tRNAGln, tRNAGlu, and tRNALys, which led to respiratory deficiencies and reduced mitochondrial ATP production, and finally suppressed osteogenic differentiation. As expected, these Mtu1-deficient mice exhibited obvious osteopenia. Therefore, our findings in this study provide new insights into the pathophysiology of osteopenia.
SP1-induced long non-coding RNA SNHG6 facilitates the carcinogenesis of chondrosarcoma through inhibiting KLF6 by recruiting EZH2
Authors: Pu Fei-Fei , Shi De-Yao , Chen Ting , Liu Yu-Xuan , Zhong Bin-Long , Zhang Zhi-Cai , Liu Wei-Jian , Wu Qiang , Wang Bai-Chuan , Shao Zeng-Wu , He Tong-Chuan , Liu Jian-Xiang 
Published: January 2021

AbstractSmall nucleolar RNA host gene 6 (SNHG6) is a newly discovered long non-coding RNA (lncRNA), while the regulatory mechanism of SNHG6 in chondrosarcoma is largely unknown. Here we found that SNHG6 expression was upregulated and showed positive correlation with the progression of chondrosarcoma. Functional assays demonstrated that SNHG6 was required for the proliferation, migration, and invasion of chondrosarcoma cells. Mechanistic study revealed that SNHG6 could recruit EZH2 and maintain high level of H3K27me3 to repress the transcription of tumor-suppressor genes, including KLF6. KLF6 was found to bind to the promoter region of SP1 and restrained its transcription, while SP1 could be recruited to the promoter region of SNHG6 and promoted its transcription to form a positive loop. In summary, this study reveals that SP1-induced SNHG6 forms a positive loop to facilitate the carcinogenesis of chondrosarcoma through the suppression of KLF6 by recruiting EZH2, which manifests the oncogenic function of SNHG6 in chondrosarcoma.
Necroptosis is active and contributes to intestinal injury in a piglet model with lipopolysaccharide challenge
Authors: Liu Yulan , Xu Qiao , Wang Yang , Liang Tianzeng , Li Xiangen , Wang Dan , Wang Xiuying , Zhu Huiling , Xiao Kan 
Published: January 2021

AbstractNecroptosis, a newly discovered form of programmed cell death that combines the features of apoptosis and necrosis, is important in various physiological and pathological disorders. However, the role of necroptosis on intestinal injury during sepsis has been rarely evaluated. This study aimed to investigate the presence of necroptosis in intestinal injury, and its contribution to intestinal injury in a piglet model challenged with Escherichia coli lipopolysaccharide (LPS). Firstly, a typical cell necrotic phenomenon was observed in jejunum of LPS-challenged pigs by transmission electron microscope. Protein expression of necroptosis signals including receptor-interacting protein kinase (RIP) 1, RIP3, and phosphorylated mixed-lineage kinase domain-like protein (MLKL), mitochondrial proteins including phosphoglycerate mutase family member 5 (PGAM5) and dynamin-related protein 1 (DRP1), and cytoplasmic high-mobility group box 1 (HMGB1) were time-independently increased in jejunum of LPS-challenged piglets, which was accompanied by the impairment of jejunal morphology, and digestive and barrier function indicated by lower activities of jejunal disaccharidases and protein expression of jejunal tight junction proteins claudin-1 and occludin. Pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 were also dynamically induced in serum and jejunum of piglets after LPS challenge. Moreover, pretreatment with necrostatin-1 (Nec-1), an specific inhibitor of necroptosis, inhibited necroptosis indicated by decreased necrotic ultrastructural changes and decreased protein expression of RIP1, RIP3, and phosphorylated MLKL as well as PGAM5, DRP1, and cytoplasmic HMGB1. Nec-1 pretreatment reduced jejunal morphological injury, and improved digestive and barrier function. Nec-1 pretreatment also decreased the levels of serum and jejunal pro-inflammatory cytokines and the numbers of jejunal macrophages and monocytes. These findings indicate for the first time that necroptosis is present and contributes to LPS-induced intestinal injury. Nec-1 may have a preventive effect on intestinal injury during sepsis.
CHIP promotes Wnt signaling and regulates Arc stability by recruiting and polyubiquitinating LEF1 or Arc
Authors: Liu Yuchun , Sun Yao , Huang Yonghui , Cheng Kang , Xu Yuming , Tian Qingnan , Zhang Shoutao 
Published: January 2021

AbstractThe carboxyl terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase, participates in many cellular processes such as protein degradation, trafficking, autophagy, apoptosis, and multiple signaling transductions. The mutant of CHIP (p.T246M) causes the spinocerebellar autosomal recessive 16 (SCAR16), a neurodegenerative disease characterized by spinocerebellar atrophy. Previous studies have shown that Wnt signaling and activity-regulated cytoskeleton-associated protein (Arc) play important roles in neurodegenerative diseases. However, the mechanisms by which CHIP regulates Wnt signaling and the stability of Arc that may affect SCAR16 are still unclear. We show that overexpression of CHIP promoted the activation of Wnt signaling, and enhanced the interaction between LEF1 and β-catenin through heightening the K63-linked polyubiquitin chains attached to LEF1, while the knockdown of CHIP had the opposite effect. Moreover, we verified that Wnt signaling was inhibited in the rat models of SCAR16 induced by the CHIP (p.T246M) mutant. CHIP also accelerated the degradation of Arc and regulated the interaction between Arc and GSK3β by heightening the K48- or K63-linked polyubiquitin chains, which further potentiated the interaction between GSK3β and β-catenin. Our data identify that CHIP is an undescribed regulator of Wnt signaling and Arc stability which may be related to the occurrence of SCAR16.