217 results on '"Ping La"'
Search Results
2. Heme oxygenase-1 regulates postnatal lung repair after hyperoxia: Role of β-catenin/hnRNPK signaling
- Author
-
Guang Yang, Chhanda Biswasa, Qing Sara Lin, Ping La, Fumihiko Namba, Tiangang Zhuang, Manasa Muthu, and Phyllis A. Dennery
- Subjects
Heme oxygenase-1 ,Neonatal hyperoxic lung injury and repair ,β-catenin/hnRNPK ,DNA damage and repair ,Cell proliferation ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
In the newborn, alveolarization continues postnatally and can be disrupted by hyperoxia, leading to long-lasting consequences on lung function. We wanted to better understand the role of heme oxygenase (HO)-1, the inducible form of the rate-limiting enzyme in heme degradation, in neonatal hyperoxic lung injury and repair. Although it was not observed after 3 days of hyperoxia alone, when exposed to hyperoxia and allowed to recover in air (O2/air recovered), neonatal HO-1 knockout (KO) mice had enlarged alveolar spaces and increased lung apoptosis as well as decreased lung protein translation and dysregulated gene expression in the recovery phase of the injury. Associated with these changes, KO had sustained low levels of active β-catenin and lesser lung nuclear heterogeneous nuclear ribonucleoprotein K (hnRNPK) protein levels, whereas lung nuclear hnRNPK was increased in transgenic mice over-expressing nuclear HO-1. Disruption of HO-1 may enhance hnRNPK-mediated inhibition of protein translation and subsequently impair the β-catenin/hnRNPK regulated gene expression required for coordinated lung repair and regeneration.
- Published
- 2013
- Full Text
- View/download PDF
3. Expression level and subcellular localization of heme oxygenase-1 modulates its cytoprotective properties in response to lung injury: a mouse model.
- Author
-
Fumihiko Namba, Hayato Go, Jennifer A Murphy, Ping La, Guang Yang, Shaon Sengupta, Amal P Fernando, Mekdes Yohannes, Chhanda Biswas, Suzanne L Wehrli, and Phyllis A Dennery
- Subjects
Medicine ,Science - Abstract
Premature infants exposed to hyperoxia suffer acute and long-term pulmonary consequences. Nevertheless, neonates survive hyperoxia better than adults. The factors contributing to neonatal hyperoxic tolerance are not fully elucidated. In contrast to adults, heme oxygenase (HO)-1, an endoplasmic reticulum (ER)-anchored protein, is abundant in the neonatal lung but is not inducible in response to hyperoxia. The latter may be important, because very high levels of HO-1 overexpression are associated with significant oxygen cytotoxicity in vitro. Also, in contrast to adults, HO-1 localizes to the nucleus in neonatal mice exposed to hyperoxia. To understand the mechanisms by which HO-1 expression levels and subcellular localization contribute to hyperoxic tolerance in neonates, lung-specific transgenic mice expressing high or low levels of full-length HO-1 (cytoplasmic, HO-1-FL(H) or HO-1-FL(L)) or C-terminally truncated HO-1 (nuclear, Nuc-HO-1-TR) were generated. In HO-1-FL(L), the lungs had a normal alveolar appearance and lesser oxidative damage after hyperoxic exposure. In contrast, in HO-1-FL(H), alveolar wall thickness with type II cell hyperproliferation was observed as well worsened pulmonary function and evidence of abnormal lung cell hyperproliferation in recovery from hyperoxia. In Nuc-HO-1-TR, the lungs had increased DNA oxidative damage, increased poly (ADP-ribose) polymerase (PARP) protein expression, and reduced poly (ADP-ribose) (PAR) hydrolysis as well as reduced pulmonary function in recovery from hyperoxia. These data indicate that low cytoplasmic HO-1 levels protect against hyperoxia-induced lung injury by attenuating oxidative stress, whereas high cytoplasmic HO-1 levels worsen lung injury by increasing proliferation and decreasing apoptosis of alveolar type II cells. Enhanced lung nuclear HO-1 levels impaired recovery from hyperoxic lung injury by disabling PAR-dependent regulation of DNA repair. Lastly both high cytoplasmic and nuclear expression of HO-1 predisposed to long-term abnormal lung cellular proliferation. To maximize HO-1 cytoprotective effects, therapeutic strategies must account for the specific effects of its subcellular localization and expression levels.
- Published
- 2014
- Full Text
- View/download PDF
4. Inclusion of a short hairpin RNA targeting BCL11A into a β-globin expressing vector allows concurrent synthesis of curative adult and fetal hemoglobin
- Author
-
Danuta Jarocha, Janet L. Kwiatkowski, Tobias Raabe, Virginia Guzikowski, Silvia Pires Lourenco, Stefano Rivella, Yukio Nakamura, Amaliris Guerra, Kim Smith-Whitley, Alexandra Zezulin, Laura Breda, Ping La, Valentina Ghiaccio, and Osheiza Abdulmalik
- Subjects
Small hairpin RNA ,Text mining ,business.industry ,Fetal hemoglobin ,Hematology ,Globin ,Vector (molecular biology) ,Biology ,business ,Molecular biology - Published
- 2021
5. Impact of Wearable Device-Based Walking Programs on Gait Speed in Older Adults: A Systematic Review and Meta-Analysis
- Author
-
Ping Lai, Jing Zhang, Qing Lai, Jinfeng Li, and Zhengbo Liang
- Subjects
Orthopedic surgery ,RD701-811 ,Geriatrics ,RC952-954.6 - Abstract
Background As walking abilities are widely affected among the aging population, investigating the effectiveness of wearable device-based walking programs is essential. The intentions of this meta-analysis were to investigate their effects on gait speed among older adults, as well as to include subgroup analysis to evaluate potential effects on individuals with aging-related conditions such as Parkinson’s disease (PD) and stroke. Methods Systematic retrieval of Pubmed, The Cochrane Library, Embase and Web of Science databases were searched up to February 2024. Outcomes such as gait speed, balance, cadence, and stride length were extracted and analyzed. Study quality was evaluated using the Rob 2 tool and heterogeneity was tested using I 2 statistics through STATA 16. Results Nine studies with 284 participants were analyzed. The intervention group showed a significant improvement in gait speed (weighted mean difference (WMD) 0.12; 95% CI 0.03 to 0.21). There is a subgroup analysis suggesting differential effects: significant improvements in PD and stroke subgroups, but not in the normal aging group. Balance (WMD: 1.93; 95% CI: 0.20 to 3.66) and stride length (WMD: 8.58; 95% CI: 3.04 to 14.12) were also shown to improve, but the heterogeneity across the studies was moderate (I 2 = 63.91%). No significant changes were observed in the Timed Up and Go test, Gait Variability, and Step Width. Conclusions Wearable device-based walking programs improve gait speed in older adults, with top notch advantages in the ones tormented by PD or stroke. These findings advocate that such interventions can be a valuable part of individualized treatment strategies in geriatric care, aiming to enhance mobility and usual satisfactory of existence.
- Published
- 2024
- Full Text
- View/download PDF
6. The gut ileal mucosal virome is disturbed in patients with Crohn’s disease and exacerbates intestinal inflammation in mice
- Author
-
Zhirui Cao, Dejun Fan, Yang Sun, Ziyu Huang, Yue Li, Runping Su, Feng Zhang, Qing Li, Hongju Yang, Fen Zhang, Yinglei Miao, Ping Lan, Xiaojian Wu, and Tao Zuo
- Subjects
Science - Abstract
Abstract Gut bacteriome dysbiosis is known to be implicated in the pathogenesis of inflammatory bowel disease (IBD). Crohn’s disease (CD) is an IBD subtype with extensive mucosal inflammation, yet the mucosal virome, an empirical modulator of the bacteriome and mucosal immunity, remains largely unclear regarding its composition and role. Here, we exploited trans-cohort CD patients and healthy individuals to compositionally and functionally investigate the small bowel (terminal ileum) virome and bacteriome. The CD ileal virome was characterised by an under-representation of both lytic and temperate bacteriophages (especially those targeting bacterial pathogens), particularly in patients with flare-up. Meanwhile, the virome-bacteriome ecology in CD ileal mucosa was featured by a lack of Bifidobacterium- and Lachnospiraceae-led mutualistic interactions between bacteria and bacteriophages; surprisingly it was more pronounced in CD remission than flare-up, underlining the refractory and recurrent nature of mucosal inflammation in CD. Lastly, we substantiated that ileal virions from CD patients causally exacerbated intestinal inflammation in IBD mouse models, by reshaping a gut virome-bacteriome ecology preceding intestinal inflammation (microbial trigger) and augmenting microbial sensing/defence pathways in the intestine cells (host response). Altogether, our results highlight the significance of mucosal virome in CD pathogenesis and importance of mucosal virome restoration in CD therapeutics.
- Published
- 2024
- Full Text
- View/download PDF
7. Fatty Acid Oxidation Promotes Apoptotic Resistance and Proinflammatory Phenotype of CD4+ Tissue-resident Memory T cells in Crohn’s DiseaseSummary
- Author
-
Guanzhan Liang, Junfeng Huang, Jing Chen, Xiaofeng Wen, Ruibing Li, Hanlin Xie, Zongjin Zhang, Zexian Chen, Yongle Chen, Zhenyu Xian, Xiaowen He, Jia Ke, Lei Lian, Ping Lan, Xianrui Wu, and Tuo Hu
- Subjects
Fatty Acid Oxidation ,Crohn’s Disease ,CD4+ Tissue-resident Memory T Cell ,Proinflamatory Phenotype ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background & Aims: As the most abundant memory T cells and major source of tumor necrosis factor α in the intestinal mucosa of Crohn’s disease (CD) patients, CD4+ tissue-resident memory T (TRM) cells play a critical role in CD pathogenesis. We investigated the role of metabolic reprogramming in the regulation of proinflammatory and apoptosis-resistant phenotype for CD4+ TRM cells. Methods: CD4+ TRM cells were collected from intestinal resection tissues from control and CD patients. Transcriptomic and metabolomic analysis were performed to identify metabolic characteristics of CD4+ TRM cells. Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction experiments were used to assess cytokines level in CD4+ TRM cells; activation-induced cell apoptosis rate was evaluated by flow cytometry. Transwell assay and wound healing assay were performed to detect the effect of CD4+ TRM cells on the migration of normal intestinal epithelial cells. Results: Transcriptomic data combined with unbiased metabolomic analysis revealed an increased fatty acid oxidation (FAO) phenotype existed in CD4+ TRM cells from CD patients. The lipidomic data and stable isotope tracer experiments demonstrated that CD4+ TRM cells up-regulated their lipid lipolysis and fatty acid uptake to fuel FAO in CD patients. Mechanistically, the activated nuclear factor kappa B signaling increased transcription of genes involved in lipid lipolysis, fatty acid uptake, and oxidation in CD4+ TRM cells from CD patients. Targeting FAO of CD4+ TRM cells reversed their apoptosis-resistant and proinflammatory phenotype in CD patients. Conclusions: CD4+ TRM cells process an accelerated FAO mediated by activated nuclear factor kappa B signaling in CD patients; targeting FAO could reverse their apoptosis-resistant and proinflammatory phenotype. These findings shed a new light on the pathogenic mechanism investigation and novel therapy development in CD patients.
- Published
- 2024
- Full Text
- View/download PDF
8. Multi-kingdom microbial signatures in excess body weight colorectal cancer based on global metagenomic analysis
- Author
-
Xinyue Zhu, Pingping Xu, Ruixin Zhu, Wenxing Gao, Wenjing Yin, Ping Lan, Lixin Zhu, and Na Jiao
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Abstract Excess body weight (EBW) increases the risk of colorectal cancer (CRC) and is linked to lower colonoscopy compliance. Here, we extensively analyzed 981 metagenome samples from multiple cohorts to pinpoint the specific microbial signatures and their potential capability distinguishing EBW patients with CRC. The gut microbiome displayed considerable variations between EBW and lean CRC. We identify 44 and 37 distinct multi-kingdom microbial species differentiating CRC and controls in EBW and lean populations, respectively. Unique bacterial-fungal associations are also observed between EBW-CRC and lean-CRC. Our analysis revealed specific microbial functions in EBW-CRC, including D-Arginine and D-ornithine metabolism, and lipopolysaccharide biosynthesis. The best-performing classifier for EBW-CRC, comprising 12 bacterial and three fungal species, achieved an AUROC of 0.90, which was robustly validated across three independent cohorts (AUROC = 0.96, 0.94, and 0.80). Pathogenic microbial species, Anaerobutyricum hallii, Clostridioides difficile and Fusobacterium nucleatum, are EBW-CRC specific signatures. This work unearths the specific multi-kingdom microbial signatures for EBW-CRC and lean CRC, which may contribute to precision diagnosis and treatment of CRC.
- Published
- 2024
- Full Text
- View/download PDF
9. Mutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death
- Author
-
Chi Zhou, Wenxin Li, Zhenxing Liang, Xianrui Wu, Sijing Cheng, Jianhong Peng, Kaixuan Zeng, Weihao Li, Ping Lan, Xin Yang, Li Xiong, Ziwei Zeng, Xiaobin Zheng, Liang Huang, Wenhua Fan, Zhanzhen Liu, Yue Xing, Liang Kang, and Huashan Liu
- Subjects
Science - Abstract
Abstract Mutant KRAS (KRASMUT) is often exploited by cancers to shape tumor immunity, but the underlying mechanisms are not fully understood. Here we report that tumor-specific cytotoxic T lymphocytes (CTLs) from KRASMUT cancers are sensitive to activation-induced cell death (AICD). circATXN7, an NF-κB-interacting circular RNA, governs T cell sensitivity to AICD by inactivating NF-κB. Mechanistically, histone lactylation derived from KRASMUT tumor cell-produced lactic acid directly activates transcription of circATXN7, which binds to NF-κB p65 subunit and masks the p65 nuclear localization signal motif, thereby sequestering it in the cytoplasm. Clinically, circATXN7 upregulation in tumor-specific CTLs correlates with adverse clinical outcomes and immunotherapeutic resistance. Genetic ablation of circAtxn7 in CD8+ T cells leads to mutant-selective tumor inhibition, while also increases anti-PD1 efficacy in multiple tumor models in female mice. Furthermore, targeting circATXN7 in adoptively transferred tumor-reactive CTLs improves their antitumor activities. These findings provide insight into how lymphocyte-expressed circRNAs contribute to T-cell fate decisions and anticancer immunotherapies.
- Published
- 2024
- Full Text
- View/download PDF
10. Chemotherapy-induced microbiota exacerbates the toxicity of chemotherapy through the suppression of interleukin-10 from macrophages
- Author
-
Zhen He, Hongyu Xie, Haoyang Xu, Jinjie Wu, Wanyi Zeng, Qilang He, Christian Jobin, Sanqing Jin, and Ping Lan
- Subjects
Chemotherapy-induced toxicity ,microbiota ,interleukin-10 ,macrophage ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
ABSTRACTThe gut microbiota has been shown to influence the efficacy and toxicity of chemotherapy, thereby affecting treatment outcomes. Understanding the mechanism by which microbiota affects chemotherapeutic toxicity would have a profound impact on cancer management. In this study, we report that fecal microbiota transplantation from oxaliplatin-exposed mice promotes toxicity in recipient mice. Splenic RNA sequencing and macrophage depletion experiment showed that the microbiota-induced toxicity of oxaliplatin in mice was dependent on macrophages. Furthermore, oxaliplatin-mediated toxicity was exacerbated in Il10-/- mice, but not attenuated in Rag1-/- mice. Adoptive transfer of macrophage into Il10-/- mice confirmed the role of macrophage-derived IL-10 in the improvement of oxaliplatin-induced toxicity. Depletion of fecal Lactobacillus and Bifidobacterium was associated with the exacerbation of oxaliplatin-mediated toxicity, whereas supplementation with these probiotics alleviated chemotherapy-induced toxicity. Importantly, IL-10 administration and probiotics supplementation did not attenuate the antitumor efficacy of chemotherapy. Clinically, patients with colorectal cancer exposed to oxaliplatin exhibited downregulation of peripheral CD45+IL-10+ cells. Collectively, our findings indicate that microbiota-mediated IL-10 production influences tolerance to chemotherapy, and thus represents a potential clinical target.
- Published
- 2024
- Full Text
- View/download PDF
11. Lack of Gdf11 does not improve anemia or prevent the activity of RAP-536 in a mouse model of β-thalassemia
- Author
-
Callum R. Hamilton, Ana C. Martins, Carla Casu, Ping La, Mark D. Fleming, Paraskevi Rea Oikonomidou, Amaliris Guerra, Jianbing Zhang, Stefano Rivella, Sayantani Sinha, Laura Breda, Anoop K. Sendamarai, and Vania Lo Presti
- Subjects
0301 basic medicine ,business.industry ,Extramural ,Anemia ,Thalassemia ,Immunology ,Treatment outcome ,MEDLINE ,Cell Biology ,Hematology ,medicine.disease ,Bioinformatics ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Text mining ,030220 oncology & carcinogenesis ,GDF11 ,Medicine ,business - Abstract
There is a Blood Commentary on this article in this issue.
- Published
- 2019
12. Association of random glucose to albumin ratio with post-contrast acute kidney injury and clinical outcomes in patients with ST-elevation myocardial infarction
- Author
-
Ping Lai, Xiaoyan Gu, Xuhui Lin, Yu He, Yining Dai, Chongyang Duan, Yuanhui Liu, and Wenfei He
- Subjects
random glucose ,albumin ,post-contrast acute kidney injury ,ST-segment elevation myocardial infarction ,percutaneous coronary intervention ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
PurposeBoth glucose and albumin are associated with chronic inflammation, which plays a vital role in post-contrast acute kidney injury (PC-AKI). To explore the relationship between random glucose to albumin ratio (RAR) and the incidence of PC-AKI after percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI).Patients and methodsSTEMI patients who underwent PCI were consecutively enrolled from January, 01, 2010 to February, 28, 2020. All patients were categorized into T1, T2, and T3 groups, respectively, based on RAR value (RAR < 3.377; 3.377 ≤ RAR ≤ 4.579; RAR > 4.579). The primary outcome was the incidence of PC-AKI, and the incidence of major adverse clinical events (MACE) was the second endpoint. The association between RAR and PC-AKI was assessed by multivariable logistic regression analysis.ResultsA total of 2,924 patients with STEMI undergoing PCI were finally included. The incidence of PC-AKI increased with the increasing tertile of RAR (3.2% vs 4.8% vs 10.6%, P
- Published
- 2024
- Full Text
- View/download PDF
13. Inclusion of a short hairpin RNA targeting
- Author
-
Silvia, Pires Lourenco, Danuta, Jarocha, Valentina, Ghiaccio, Amaliris, Guerra, Osheiza, Abdulmalik, Ping, La, Alexandra, Zezulin, Kim, Smith-Whitley, Janet L, Kwiatkowski, Virginia, Guzikowski, Yukio, Nakamura, Tobias, Raabe, Laura, Breda, and Stefano, Rivella
- Subjects
Adult ,Repressor Proteins ,Humans ,gamma-Globins ,beta-Globins ,RNA, Small Interfering ,Letters to the Editor ,Fetal Hemoglobin ,Transcription Factors - Published
- 2020
14. MCCC2 is a novel mediator between mitochondria and telomere and functions as an oncogene in colorectal cancer
- Author
-
Wanjun Liu, Si Chen, Wenqing Xie, Qian Wang, Qianxin Luo, Minghan Huang, Minyi Gu, Ping Lan, and Daici Chen
- Subjects
MCCC2 ,Mitochondria ,Telomere ,Colorectal cancer ,Cytology ,QH573-671 - Abstract
Abstract Background The mitochondrial gene MCCC2, a subunit of the heterodimer of 3-methylcrotonyl-CoA carboxylase, plays a pivotal role in catabolism of leucine and isovaleric acid. The molecular mechanisms and prognostic value still need to be explored in the context of specific cancers, including colorectal cancer (CRC). Methods In vitro and in vivo cell-based assays were performed to explore the role of MCCC2 in CRC cell proliferation, invasion, and migration. Mitochondrial morphology, membrane potential, intracellular reactive oxygen species (ROS), telomerase activity, and telomere length were examined and analyzed accordingly. Protein complex formation was detected by co-immunoprecipitation (CO-IP). Mitochondrial morphology was observed by transmission electron microscopy (TEM). The Cancer Genome Atlas (TCGA) CRC cohort analysis, qRT-PCR, and immunohistochemistry (IHC) were used to examine the MCCC2 expression level. The association between MCCC2 expression and various clinical characteristics was analyzed by chi-square tests. CRC patients’ overall survival (OS) was analyzed by Kaplan–Meier analysis. Results Ectopic overexpression of MCCC2 promoted cell proliferation, invasion, and migration, while MCCC2 knockdown (KD) or knockout (KO) inhibited cell proliferation, invasion, and migration. MCCC2 KD or KO resulted in reduced mitochondria numbers, but did not affect the gross ATP production in the cells. Mitochondrial fusion markers MFN1, MFN2, and OPA1 were all upregulated in MCCC2 KD or KO cells, which is in line with a phenomenon of more prominent mitochondrial fusion. Interestingly, telomere lengths of MCCC2 KD or KO cells were reduced more than control cells. Furthermore, we found that MCCC2 could specifically form a complex with telomere binding protein TRF2, and MCCC2 KD or KO did not affect the expression or activity of telomerase reverse transcriptase (TERT). Finally, MCCC2 expression was heightened in CRC, and patients with higher MCCC2 expression had favorable prognosis. Conclusions Together, we identified MCCC2 as a novel mediator between mitochondria and telomeres, and provided an additional biomarker for CRC stratification.
- Published
- 2023
- Full Text
- View/download PDF
15. An Interpretable Target-Aware Vision Transformer for Polarimetric HRRP Target Recognition with a Novel Attention Loss
- Author
-
Fan Gao, Ping Lang, Chunmao Yeh, Zhangfeng Li, Dawei Ren, and Jian Yang
- Subjects
high-resolution range profile (HRRP) ,radar automatic target recognition (RATR) ,vision Transformer (ViT) ,polarimetric preprocessing ,attention loss ,Science - Abstract
Polarimetric high-resolution range profile (HRRP), with its rich polarimetric and spatial information, has become increasingly important in radar automatic target recognition (RATR). This study proposes an interpretable target-aware vision Transformer (ITAViT) for polarimetric HRRP target recognition with a novel attention loss. In ITAViT, we initially fuse the polarimetric features and the amplitude of polarimetric HRRP with a polarimetric preprocessing layer (PPL) to obtain the feature map as the input of the subsequent network. The vision Transformer (ViT) is then used as the backbone to automatically extract both local and global features. Most importantly, we introduce a novel attention loss to optimize the alignment between the attention map and the HRRP span. Thus, it can improve the difference between the target and the background, and enable the model to more effectively focus on real target areas. Experiments on a simulated X-band dataset demonstrate that our proposed ITAViT outperforms comparative models under various experimental conditions. Ablation studies highlight the effectiveness of polarimetric preprocessing and attention loss. Furthermore, the visualization of the self-attention mechanism suggests that attention loss enhances the interpretability of the network.
- Published
- 2024
- Full Text
- View/download PDF
16. Data Matters: Rethinking the Data Distribution in Semi-Supervised Oriented SAR Ship Detection
- Author
-
Yimin Yang, Ping Lang, Junjun Yin, Yaomin He, and Jian Yang
- Subjects
synthetic aperture radar ,semi-supervised learning ,oriented ship detection ,fuzzy comprehensive evaluation ,data distribution ,Science - Abstract
Data, in deep learning (DL), are crucial to detect ships in synthetic aperture radar (SAR) images. However, SAR image annotation limitations hinder DL-based SAR ship detection. A novel data-selection method and teacher–student model are proposed in this paper to effectively leverage sparse labeled data and improve SAR ship detection performance, based on the semi-supervised oriented object-detection (SOOD) framework. More specifically, we firstly propose a SAR data-scoring method based on fuzzy comprehensive evaluation (FCE), and discuss the relationship between the score distribution of labeled data and detection performance. A refined data selector (RDS) is then designed to adaptively obtain reasonable data for model training without any labeling information. Lastly, a Gaussian Wasserstein distance (GWD) and an orientation-angle deviation weighting (ODW) loss are introduced to mitigate the impact of strong scattering points on bounding box regression and dynamically adjusting the consistency of pseudo-label prediction pairs during the model training process, respectively. The experiments results on four open datasets have demonstrated that our proposed method can achieve better SAR ship detection performances on low-proportion labeled datasets, compared to some existing methods. Therefore, our proposed method can effectively and efficiently reduce the burden of SAR ship data labeling and improve detection capacities as much as possible.
- Published
- 2024
- Full Text
- View/download PDF
17. Function of resveratrol derived from transgenic plant expressing resveratrol synthase gene
- Author
-
Ping, La, Wenqi, Cai, Jiuchun, Zhang, Fengli, Zhang, and Rongxiang, Fang
- Published
- 2001
- Full Text
- View/download PDF
18. Enteral nutrition promotes the remission of colitis by gut bacteria-mediated histidine biosynthesisResearch in context
- Author
-
Wanyi Zeng, Jinjie Wu, Hongyu Xie, Haoyang Xu, Dayi Liang, Qilang He, Xiaoya Yang, Chen Liu, Junli Gong, Qiang Zhang, Zhanhao Luo, Yuan Chen, Zhen He, and Ping Lan
- Subjects
Exclusive enteral nutrition ,Crohn’s disease ,Faecalibaculum rodentium ,Histidine ,Biosynthesis ,Medicine ,Medicine (General) ,R5-920 - Abstract
Summary: Background: Exclusive enteral nutrition (EEN) is an important alternative strategy for patients with Crohn’s disease (CD), and during this process, microbiota alterations have been observed. However, the underlying mechanisms by which EEN reduces intestinal inflammation are currently unclear. Methods: The therapeutic potential of enteral nutrition (EN) was assessed using various mouse models. Fecal full-length 16S rDNA sequencing analysis and several CD metagenome datasets were used to identify the candidate therapeutic bacteria Faecalibaculum rodentium (F. rodentium). Whole genome sequencing of F. rodentium and widely-targeted metabolome analysis of the supernatant showed that EN-induced F. rodentium accumulation protected against colitis via histidine biosynthesis. Findings: The therapeutic potential of EN therapy was observed in both dextran sulfate sodium (DSS)-induced colitis and Il10−/− spontaneous colitis mouse models. Accumulation of F. rodentium after EN therapy was determined using full-length 16S rDNA sequencing and verified with several metagenome datasets from patients with CD. Colonization of an isolated F. rodentium could reduce colitis in Il10−/− mice. Significant histidine enrichment was observed in the F. rodentium culture supernatant, and a series of histidine biosynthesis genes were observed in the F. rodentium genome. Engineered Escherichia coli Nissle 1917 (EcN), encoding the heterologous hisG of F. rodentium (EcN-hisG), which was a key driver of histidine biosynthesis in F. rodentium, was found to protect against colitis. Interpretation: This study suggests that EN-induced F. rodentium accumulation protects against colitis in mice via gut bacteria-mediated histidine biosynthesis. Funding: A full list of funding bodies can be found in the Acknowledgements section.
- Published
- 2024
- Full Text
- View/download PDF
19. Loss of ESRP2 Activates TAK1‐MAPK Signaling through the Fetal RNA‐Splicing Program to Promote Hepatocellular Carcinoma Progression
- Author
-
Qian Yan, Xiaona Fang, Xiaoxia Liu, Sai Guo, Siqi Chen, Min Luo, Ping Lan, and Xin‐Yuan Guan
- Subjects
epithelial splicing regulatory protein 2 ,fetal reprogramming ,hepatocellular carcinoma ,RNA splicing ,TAK1/MAPK activation ,Science - Abstract
Abstract Tumors usually display fetal‐like characteristics, and many oncofetal proteins have been identified. However, fetal‐like reprogramming of RNA splicing in hepatocellular carcinoma (HCC) is poorly understood. Here, it is demonstrated that the expression of epithelial splicing regulatory protein 2 (ESRP2), an RNA splicing factor, is suppressed in fetal hepatocytes and HCC, in parallel with tumor progression. By combining RNA‐Seq with splicing analysis, it is identified that ESRP2 controls the fetal‐to‐adult switch of multiple splice isoforms in HCC. Functionally, ESRP2 suppressed cell proliferation and migration by specifically switching the alternative splicing (AS) of the TAK1 gene and restraining the expression of the fetal and oncogenic isoform, TAK1_ΔE12. Notably, aberrant TAK1 splicing led to the activation of p38MAPK signaling and predicted poor prognosis in HCC patients. Further investigation revealed that TAK1_ΔE12 protein interacted closely with TAB3 and formed liquid condensation in HCC cells, resulting in p38MAPK activation, enhanced cell migration, and accelerated tumorigenesis. Loss of ESRP2 sensitized HCC cells to TAK1 kinase inhibitor (TAK1i), promoting pyroptotic cell death and CD8+ T cell infiltration. Combining TAK1i with immune checkpoint therapy achieved potent tumor regression in mice. Overall, the findings reveal a previously unexplored onco‐fetal reprogramming of RNA splicing and provide novel therapeutic avenues for HCC.
- Published
- 2024
- Full Text
- View/download PDF
20. Combining perineural invasion with staging improve the prognostic accuracy in colorectal cancer: a retrospective cohort study
- Author
-
Bin Zhang, Yanyun Lin, Chao Wang, Zexian Chen, Tianze Huang, Hao Chen, Guannan Wang, Ping Lan, Xiaowen He, and Xiaosheng He
- Subjects
Perineural invasion ,Colorectal cancer ,Survival ,Tumor stage ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Current guidelines only propose the importance of perineural invasion(PNI) on prognosis in stage II colon cancer. However, the prognostic value of PNI in other stages of colorectal cancer (CRC) is ambiguous. Methods This single-center retrospective cohort study included 3485 CRC patients who underwent primary colorectal resection between January 2013 and December 2016 at the Sixth Affiliated Hospital of Sun Yat-sen University. Associations of PNI with overall survival (OS) and disease-free survival (DFS) were evaluated using multivariable Cox proportional hazards regression models. In addition, interaction analyses were performed to explore the prognostic effects of PNI in different clinical subgroups. Results After median follow-up of 61.9 months, we found PNI was associated with poorer OS (adjusted hazard ratio [aHR], 1.290; 95% CI, 1.087–1.531) and DFS (aHR, 1.397; 95% CI, 1.207–1.617), irrespective of tumor stage. Interestingly, the weight of PNI was found second only to incomplete resection in the nomogram for risk factors of OS and DFS in stage II CRC patients. Moreover, OS and DFS were insignificantly different between stage II patients with PNI and stage III patients (both P > 0.05). PNI was found to be an independent prognostic factor of DFS in stage III CRC (aHR: 1.514; 95% CI, 1.211–1.892) as well. Finally, the adverse effect of PNI on OS was more significant in female, early-onset, and diabetes-negative patients than in their counterparts (interaction P = 0.0213, 0.0280, and 0.0186, respectively). Conclusion PNI was an important prognostic factor in CRC, more than in stage II. The survival of patients with stage II combined with perineural invasion is similar with those with stage III. PNI in stage III CRC also suggests a worse survival.
- Published
- 2023
- Full Text
- View/download PDF
21. NFκB is Essential in Regulating Rev-erbα Promoter Activity in Hyperoxia: 374
- Author
-
Yang, Guang, Hinson, Maurice, Xiao, Haiyan, Ping, La, Lin, Sara Q, Wright, Clyde J, and Dennery, Phyllis A
- Published
- 2010
- Full Text
- View/download PDF
22. Lack of
- Author
-
Amaliris, Guerra, Paraskevi Rea, Oikonomidou, Sayantani, Sinha, Jianbing, Zhang, Vania, Lo Presti, Callum R, Hamilton, Laura, Breda, Carla, Casu, Ping, La, Ana C, Martins, Anoop K, Sendamarai, Mark, Fleming, and Stefano, Rivella
- Subjects
Growth Differentiation Factors ,Disease Models, Animal ,Mice ,Treatment Outcome ,Recombinant Fusion Proteins ,Bone Morphogenetic Proteins ,beta-Thalassemia ,Animals ,Anemia ,Mice, Transgenic ,Biomarkers - Published
- 2019
23. Terpinen-4-ol Improves Lipopolysaccharide-Induced Macrophage Inflammation by Regulating Glutamine Metabolism
- Author
-
Yanhui Liu, Xin Tang, Huazhen Zhang, Linyan Zheng, Ping Lai, Chang Guo, Jingfan Ma, Hongbo Chen, and Longxin Qiu
- Subjects
terpinen-4-ol ,lipopolysaccharide (LPS) ,inflammatory cytokines ,non-targeted metabolomics ,glutamine ,Chemical technology ,TP1-1185 - Abstract
Terpinen-4-ol (T-4-O) is an important component of tea tree oil and has anti-inflammatory effects. Currently, there are very few studies on the mechanisms by which T-4-O improves lipopolysaccharide (LPS)-induced macrophage inflammation. In this study, LPS-stimulated mouse RAW264.7 macrophages were used as a model to analyze the effects of T-4-O on macrophage inflammatory factors and related metabolic pathways in an inflammatory environment. The results showed that T-4-O significantly decreased the expression levels of inflammatory cytokines induced by LPS. Cellular metabolism results showed that T-4-O significantly decreased the ratio of the extracellular acidification rate and oxygen consumption rate. Non-targeted metabolomics results showed that T-4-O mainly affected glutamine and glutamate metabolism and glycine, serine, and threonine metabolic pathways. qPCR results showed that T-4-O increased the transcript levels of GLS and GDH and promoted glutamine catabolism. Western blotting results showed that T-4-O inhibited the mTOR and IκB, thereby decreasing NF-κB activity. The overall results showed that T-4-O inhibited mTOR phosphorylation to promote glutamine metabolism and increased cell oxidative phosphorylation levels, thereby inhibiting the expression of LPS-induced inflammatory cytokines.
- Published
- 2024
- Full Text
- View/download PDF
24. Tumor-secreted IFI35 promotes proliferation and cytotoxic activity of CD8+ T cells through PI3K/AKT/mTOR signaling pathway in colorectal cancer
- Author
-
Peisi Li, Dawang Zhou, Dongwen Chen, Yikan Cheng, Yuan Chen, Zhensen Lin, Xi Zhang, Zhihong Huang, Jiawei Cai, Wenfeng Huang, Yanyun Lin, Haoxian Ke, Jiahui Long, Yifeng Zou, Shubiao Ye, and Ping Lan
- Subjects
IFI35 ,CD8+ T cells ,Immunotherapy ,Colorectal cancer ,Medicine - Abstract
Abstract Background A large proportion of the patients with cancer do not respond to immunotherapies. Recent studies suggested an important role for tumor-infiltrating cytotoxic T lymphocytes (CTL) in enhancing response to immunotherapy. Here, we aim to identify gene that induce proliferative and cytotoxic states of CD8+ T cells, and to investigate its effect on CAR-T cells against colorectal cancer. Methods Correlation between the expression of IFI35 with the activation and cytotoxicity of CD8+ T cells was assessed with TCGA and proteomic databases. Then we constructed murine colon cancer cells over-expressing IFI35 and tested their effect on anti-tumor immunity in both immunodeficient and immunocompetent mouse models. Flow cytometry and immunohistochemistry were performed to assess the immune microenvironment. Western blot analysis was used to identify the potential down-stream signaling pathway regulated by IFI35. We further investigated the efficacy of the rhIFI35 protein in combination with immunotherapeutic treatment. Results The transcriptional and proteomic analysis of the activation and cytotoxicity of CD8+ T cells in human cancer samples demonstrated that IFI35 expression is correlated with increased CD8+ T cell infiltration and predicted a better outcome in colorectal cancer. The number and cytotoxicity of CD8+ T cells were significantly increased in IFI35-overexpressing tumors. Mechanistically, we identified that the IFNγ-STAT1-IRF7 axis stimulated IFI35 expression, and that IFI35-mediated regulation of CD8+ T cell proliferation and cytotoxicity was dependent on PI3K/AKT/mTOR signaling pathway in vitro. Furthermore, IFI35 protein enhanced the efficacy of CAR-T cells against colorectal cancer cells. Conclusion Our findings identify IFI35 as a new biomarker that can enhance the proliferation and function of CD8+ T cells, as well as increase the efficacy of CAR-T cells against colorectal cancer cells. Graphical Abstract
- Published
- 2023
- Full Text
- View/download PDF
25. High-throughput proteomics profiling-derived signature associated with chemotherapy response and survival for stage II/III colorectal cancer
- Author
-
Shu-Biao Ye, Yi-Kan Cheng, Pei-Si Li, Lin Zhang, Lian-Hai Zhang, Yan Huang, Ping Chen, Yi Wang, Chao Wang, Jian-Hong Peng, Li-Shuo Shi, Li Ling, Xiao-Jian Wu, Jun Qin, Zi-Huan Yang, and Ping Lan
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Adjuvant chemotherapy (ACT) is usually used to reduce the risk of disease relapse and improve survival for stage II/III colorectal cancer (CRC). However, only a subset of patients could benefit from ACT. Thus, there is an urgent need to identify improved biomarkers to predict survival and stratify patients to refine the selection of ACT. We used high-throughput proteomics to analyze tumor and adjacent normal tissues of stage II/III CRC patients with /without relapse to identify potential markers for predicting prognosis and benefit from ACT. The machine learning approach was applied to identify relapse-specific markers. Then the artificial intelligence (AI)-assisted multiplex IHC was performed to validate the prognostic value of the relapse-specific markers and construct a proteomic-derived classifier for stage II/III CRC using 3 markers, including FHL3, GGA1, TGFBI. The proteomics profiling-derived signature for stage II/III CRC (PS) not only shows good accuracy to classify patients into high and low risk of relapse and mortality in all three cohorts, but also works independently of clinicopathologic features. ACT was associated with improved disease-free survival (DFS) and overall survival (OS) in stage II (pN0) patients with high PS and pN2 patients with high PS. This study demonstrated the clinical significance of proteomic features, which serve as a valuable source for potential biomarkers. The PS classifier provides prognostic value for identifying patients at high risk of relapse and mortality and optimizes individualized treatment strategy by detecting patients who may benefit from ACT for survival.
- Published
- 2023
- Full Text
- View/download PDF
26. Laparoscopic surgery contributes to a decrease in short-term complications in surgical ulcerative colitis patients during 2008–2017: a multicenter retrospective study in China
- Author
-
Zerong Cai, Xiaosheng He, Jianfeng Gong, Peng Du, Wenjian Meng, Wei Zhou, Jinbo Jiang, Bin Wu, Weitang Yuan, Qi Xue, Lianwen Yuan, Jinhai Wang, Jiandong Tai, Jie Liang, Weiming Zhu, Ping Lan, and Xiaojian Wu
- Subjects
colitis, ulcerative ,surgery ,complication ,laparoscopy ,Medicine ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background/Aims The aim of this study was to analyze the chronological changes in postoperative complications in surgical ulcerative colitis patients over the past decade in China and to investigate the potential parameters that contributed to the changes. Methods Ulcerative colitis patients who underwent surgery during 2008–2017 were retrospectively enrolled from 13 hospitals in China. Postoperative complications were compared among different operation years. Risk factors for complications were identified by logistic regression analysis. Results A total of 446 surgical ulcerative colitis patients were analyzed. Fewer short-term complications (24.8% vs. 41.0%, P=0.001) and more laparoscopic surgeries (66.4% vs. 25.0%, P
- Published
- 2023
- Full Text
- View/download PDF
27. VSSP-activated macrophages mediate senescence and tumor inhibition in a preclinical model of advanced prostate cancer
- Author
-
Rydell Alvarez-Arzola, Nicoló Bancaro, Ping Lai, Giuseppe Attanasio, Laura Pellegrini, Martina Troiani, Manuel Colucci, Simone Mosole, Emiliano Pasquini, Andrea Alimonti, and Circe Mesa
- Subjects
Macrophages ,VSSP ,Prostate cancer ,Adoptive transfer ,Medicine ,Cytology ,QH573-671 - Abstract
Abstract Androgen deprivation therapy (ADT) is a standard therapy for prostate cancer (PCa). Though disseminated disease is initially sensitive to ADT, an important fraction of the patients progresses to castration-resistant prostate cancer (CRPC). For this reason, the identification of novel effective therapies for treating CRPC is needed. Immunotherapeutic strategies focused on macrophages as antitumor effectors, directly enhancing their tumoricidal potential at the tumor microenvironment or their adoptive transfer after ex vivo activation, have arisen as promising therapies in several cancer types. Despite several approaches centered on the activation of tumor-associated macrophages (TAMs) in PCa are under investigation, to date there is no evidence of clinical benefit in patients. In addition, the evidence of the effectiveness of macrophage adoptive transfer on PCa is poor. Here we find that VSSP, an immunomodulator of the myeloid system, decreases TAMs and inhibits prostatic tumor growth when administered to castrated Pten-deficient prostate tumor-bearing mice. In mice bearing castration-resistant Ptenpc−/−; Trp53pc−/− tumors, VSSP administration showed no effect. Nevertheless, adoptive transfer of macrophages activated ex vivo with VSSP inhibited Ptenpc−/−; Trp53pc−/− tumor growth through reduction of angiogenesis and tumor cell proliferation and induction of senescence. Taken together, our results highlight the rationale of exploiting macrophage functional programming as a promising strategy for CRPC therapy, with particular emphasis on ex vivo-activated proinflammatory macrophage adoptive transfer. Graphical abstract Video abstract
- Published
- 2023
- Full Text
- View/download PDF
28. MiR-196a regulates heme oxygenase-1 by silencing Bach1 in the neonatal mouse lung
- Author
-
Masato Ito, Guang Yang, Hayato Go, Kazuhiko Igarashi, Fumihiko Namba, Phyllis A. Dennery, Ping La, and Andrey Brydun
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Physiology ,Biology ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,chemistry.chemical_compound ,RNA interference ,Physiology (medical) ,microRNA ,medicine ,Animals ,Gene silencing ,RNA, Messenger ,3' Untranslated Regions ,Lung ,Heme ,Cells, Cultured ,Bronchopulmonary Dysplasia ,Mice, Knockout ,Hyperoxia ,Three prime untranslated region ,Gene Expression Regulation, Developmental ,Membrane Proteins ,Articles ,Cell Biology ,respiratory system ,Molecular biology ,respiratory tract diseases ,Cell biology ,Mice, Inbred C57BL ,Heme oxygenase ,MicroRNAs ,Basic-Leucine Zipper Transcription Factors ,030104 developmental biology ,medicine.anatomical_structure ,Animals, Newborn ,chemistry ,RNA Interference ,medicine.symptom ,Heme Oxygenase-1 - Abstract
In the lung, heme oxygenase-1 (HO-1) is developmentally regulated, with its highest expression in the first days of life. In addition, neonatal mice have limited HO-1 induction in hyperoxia compared with adults. However, few reports have addressed the functional effect of microRNAs (miRNAs) in the regulation of HO-1 in vivo. The aims of the present study were to characterize changes in lung miRNA expression during postnatal development and in response to hyperoxic exposure, and to identify miRNAs that target lung HO-1 gene expression. Neonatal (
- Published
- 2016
29. Modeling stream baseflow nitrate concentration in an agricultural watershed using neural network and bootstrap method
- Author
-
Ping Lan, Li Guo, Hailong Sun, Yaling Zhang, and Yanjia Jiang
- Subjects
Agricultural land use ,Bootstrap method ,Neural network ,Nitrate ,Nonpoint source pollution ,Water quality ,Ecology ,QH540-549.5 - Abstract
The evaluation of water resource vulnerability to nonpoint source pollution in the presence of uncertainty remains a crucial concern. To enhance the accuracy of the assessment and pinpoint the key factors that affect watershed water quality, the integration of an artificial neural network (ANN) into the evaluation process is imperative. The research involved the collection of streams baseflow samples from thirty-eight sites between 1994 and 1999 in the Tomorrow-Waupaca River Watershed in central Wisconsin, USA, with a focus on examining the relationship between nitrate concentrations and a range of environmental and land use variables extracted from the watershed GIS database. This study utilized ANN methodology, combined with a bootstrap technique that employed a random resampling approach from a single input dataset, to simulate monthly stream baseflow nitrate concentrations. The effectiveness and predictive ability of the ANN model were assessed by comparing it to conventional multivariate regression methods. Through the use of ANN, more precise outcomes can be achieved while taking into account the uncertainty associated with the analysis. The findings demonstrated that the ANN outperformed both the multivariate linear regression and nonlinear quadratic response surface models in explaining the variance of stream nitrate and in external prediction consistency. This study also highlighted several key variables, such as the areal percentage of agricultural land and grassland, stream order, and the average slope of the groundwater flow path, that significantly impacted the stream baseflow nitrate concentrations in this watershed that was dominated by dairy farming and groundwater. Of these variables, the percentage of agricultural land emerged as the most significant factor.
- Published
- 2023
- Full Text
- View/download PDF
30. Dietary iron modulates gut microbiota and induces SLPI secretion to promote colorectal tumorigenesis
- Author
-
Chen Liu, Junli Gong, Qiang Zhang, Guangyuan Chen, Shengmei Yin, Zhanhao Luo, Wanyi Zeng, Jing Yu, Ping Lan, and Zhen He
- Subjects
Excessive dietary iron ,gut microbiome ,colorectal cancer ,secretory leukocyte protease inhibitor ,tumorigenesis ,epithelium ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
ABSTRACTDietary iron intake is closely related to the incidence of colorectal cancer. However, the interactions among dietary iron, gut microbiota, and epithelial cells in promoting tumorigenesis have rarely been discussed. Here, we report that gut microbiota plays a crucial role in promoting colorectal tumorigenesis in multiple mice models under excessive dietary iron intake. Gut microbiota modulated by excessive dietary iron are pathogenic, irritating the permeability of the gut barrier and causing leakage of lumen bacteria. Mechanistically, epithelial cells released more secretory leukocyte protease inhibitor (SLPI) to combat the leaked bacteria and limit inflammation. The upregulated SLPI acted as a pro-tumorigenic factor and promoted colorectal tumorigenesis by activating the MAPK signaling pathway. Moreover, excessive dietary iron significantly depleted Akkermansiaceae in the gut microbiota; while supplementation with Akkermansia muciniphila could successfully attenuate the tumorigenic effect from excessive dietary iron. Overall, excessive dietary iron perturbs diet – microbiome–epithelium interactions, which contributes to intestinal tumor initiation.
- Published
- 2023
- Full Text
- View/download PDF
31. Elucidating the Role of IL6 in Stress Erythropoiesis and in the Development of Anemia Under Inflammatory Conditions
- Author
-
Ping La, Sara Gardenghi, Ritama Gupta, Amaliris Guerra, Jianbing Zhang, Sayantani Sinha, and Stefano Rivella
- Subjects
Ineffective erythropoiesis ,medicine.medical_specialty ,biology ,Anemia ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease_cause ,medicine.disease ,Biochemistry ,Proinflammatory cytokine ,medicine.anatomical_structure ,Endocrinology ,Iron-deficiency anemia ,Hepcidin ,Internal medicine ,medicine ,biology.protein ,Erythropoiesis ,Bone marrow ,business ,Anemia of chronic disease - Abstract
Anemia of inflammation, also known as anemia of chronic disease is the second most common anemia after iron deficiency anemia. The predominant regulators of AI are the cytokine-interleukin-6 (IL6) and the hormone hepcidin (Hamp). IL6 has been implicated in inducing expression of hepcidin. Published data from our lab have shown that lack of IL6 or hepcidin in knockout mouse models (IL6-KO and Hamp-KO) injected with the heat-killed pathogen Brucella abortus(BA) results in recovery from anemia but interestingly the pattern of the recovery was different in IL6-KO and Hamp-KO mice, suggesting that the two proteins contribute independently to AI. Here, we validated the independent role of IL6 and Hamp in AI by generating a double-knockout (DKO) mouse model lacking the expression of both. In the first few days following BA administration, we observed severe reduction in the total number of BM cells in each model followed by a slow recovery in erythroid and multilineage hematopoietic cells. The recovery, initially, was more sustained in the BA-treated-DKO model. In particular, in the first week, BA-treated-DKO mice showed an increased number of erythroblasts in the bone marrow (BM) and spleen as seen in comparison to IL6-KO and Hamp-KO. IL6-KO mice showed an intermediate recovery profile when compared to DKO and Hamp-KO, the last one showing the worst profile in the BM. Interestingly, when the reticulocyte count in the DKO mice was compared to that of IL6-KO and Hamp-KO mice, it showed a biphasic trend, with a significant increase in number during the 2nd week, followed by a significant reduction during the 3rd week. We hypothesized that the initial surge in reticulocyte count in DKO was due to lack of hepcidin, which increases iron availability to erythroid cells, and concurrent lack of IL6, which favors BM erythropoiesis in presence of inflammatory stimuli. However, we also speculated that the excess of iron (as NTBI), which accumulates during the first two weeks, leads to oxidative stress and erythroid cell death in presence of inflammatory cytokines, despite the absence of IL6. We also surmised that, during the second week, a second wave of inflammatory cytokines is triggered by the adaptive response in response to the BA that would explain the negative effect on erythropoiesis after the initial recovery. To assess this hypothesis, we utilized an inflammation panel to analyze the cytokine expression in WT animals treated with PBS or BA at 6 hours, 24 hours and then around ~2 weeks. The cytokine levels were normalized after 24 hours. However, around two weeks, we observed a novel surge of cytokines such as IFN-g and TNFa in the BA treated mice, indicating their role in innate (immediate effect; 6 hours) and adaptive immune response, which activated a second wave of inflammation (around 2 weeks, during the recovery of hematopoiesis in the BM). Interestingly, while we observed oxidative stress and defective erythropoiesis in the bone marrow, this was not seen in the spleen, where increased and extramedullary erythropoiesis sustained some level of RBC production. Since the BA-treated-IL6-KO did not show any major defect in the BM after two weeks, we challenged them with administration of iron dextran. Upon treatment, also the IL6-KO mice treated with both BA and iron dextran shown increased production of reactive oxygen species as well as a defect in bone marrow erythropoiesis, similarly as in DKO or Hamp-KO mice, thereby explaining the plausible reason of reduced erythropoiesis in the bone-marrow. Furthermore, to identify mechanisms leading to oxidative stress, we established an in-vitro culture system where primary murine bone marrow cells were cultured for 18-20 hours in presence of serum isolated after 6hrs from either PBS treated or BA treated C57BL/6 mice. With the help of confocal microscopy, we observed an increase in mitochondrial superoxide in the cells treated with BA serum; interestingly we have also seen a decrease in Ter 119 population in the cells cultured with BA treated serum implicating that the erythroid cells are dying. To further investigate the downstream players related to the death of erythroid progenitors we are currently investigating the role caspase 1 (a major regulator in pyroptosis) and Gata-1. In conclusion, this study is elucidating some of the mechanisms associated with the anemia triggered by inflammation with the potential to identify new targets and treatments. Disclosures Rivella: Disc medicine, Protagonist, LIPC, Meira GTx: Consultancy; Meira GTx, Ionis Pharmaceutical: Membership on an entity's Board of Directors or advisory committees.
- Published
- 2019
32. Reprogramming of palmitic acid induced by dephosphorylation of ACOX1 promotes β-catenin palmitoylation to drive colorectal cancer progression
- Author
-
Qiang Zhang, Xiaoya Yang, Jinjie Wu, Shubiao Ye, Junli Gong, Wai Ming Cheng, Zhanhao Luo, Jing Yu, Yugeng Liu, Wanyi Zeng, Chen Liu, Zhizhong Xiong, Yuan Chen, Zhen He, and Ping Lan
- Subjects
Cytology ,QH573-671 - Abstract
Abstract Metabolic reprogramming is a hallmark of cancer. However, it is not well known how metabolism affects cancer progression. We identified that metabolic enzyme acyl-CoA oxidase 1 (ACOX1) suppresses colorectal cancer (CRC) progression by regulating palmitic acid (PA) reprogramming. ACOX1 is highly downregulated in CRC, which predicts poor clinical outcome in CRC patients. Functionally, ACOX1 depletion promotes CRC cell proliferation in vitro and colorectal tumorigenesis in mouse models, whereas ACOX1 overexpression inhibits patient-derived xenograft growth. Mechanistically, DUSP14 dephosphorylates ACOX1 at serine 26, promoting its polyubiquitination and proteasomal degradation, thereby leading to an increase of the ACOX1 substrate PA. Accumulated PA promotes β-catenin cysteine 466 palmitoylation, which inhibits CK1- and GSK3-directed phosphorylation of β-catenin and subsequent β-Trcp-mediated proteasomal degradation. In return, stabilized β-catenin directly represses ACOX1 transcription and indirectly activates DUSP14 transcription by upregulating c-Myc, a typical target of β-catenin. Finally, we confirmed that the DUSP14-ACOX1-PA-β-catenin axis is dysregulated in clinical CRC samples. Together, these results identify ACOX1 as a tumor suppressor, the downregulation of which increases PA-mediated β-catenin palmitoylation and stabilization and hyperactivates β-catenin signaling thus promoting CRC progression. Particularly, targeting β-catenin palmitoylation by 2-bromopalmitate (2-BP) can efficiently inhibit β-catenin-dependent tumor growth in vivo, and pharmacological inhibition of DUSP14-ACOX1-β-catenin axis by Nu-7441 reduced the viability of CRC cells. Our results reveal an unexpected role of PA reprogramming induced by dephosphorylation of ACOX1 in activating β-catenin signaling and promoting cancer progression, and propose the inhibition of the dephosphorylation of ACOX1 by DUSP14 or β-catenin palmitoylation as a viable option for CRC treatment.
- Published
- 2023
- Full Text
- View/download PDF
33. Brain Activation Differences of Six Basic Emotions Between 2D Screen and Virtual Reality Modalities
- Author
-
Jialan Xie, Ping Lan, Shiyuan Wang, Yutong Luo, and Guangyuan Liu
- Subjects
Six basic emotions ,brain activation ,EEG ,virtual reality ,Medical technology ,R855-855.5 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
To our knowledge, it has been widely studied in Screen-2D modality for the six basic emotions proposed by Professor Paul Ekman, but there are only studies on their positive and negative valence in VR-3D modality. In this study, we will investigate whether the six basic emotions have stronger brain activation states in VR-3D modality than in Screen-2D modality. We designed an emotion-inducing experiment with six basic emotions (happiness, surprise, sadness, fear, anger, and disgust) to record the electroencephalogram (EEG) signals during watching VR-3D and Screen-2D videos. The power spectral density (PSD) was calculated to compare the brain activation differences between VR-3D and Screen-2D modalities during the induction of the six basic emotions. The results of statistical analysis of the relative power differences between VR-3D and Screen-2D modalities for each emotion revealed that both happiness and surprise presented greater differences in the $\alpha $ and $\gamma $ frequency bands, while sad, fear, disgust and anger all presented greater differences in the $\alpha $ and $\theta $ frequency bands, which are mainly observed in the frontal and occipital regions. On the other hand, the six emotions all yielded satisfactory classification accuracy (above 85%) by classification from a subset of power feature of the brain activation states in the same emotion between the two modalities. Overall, there are significant differences in the induction of same discrete emotions in VR-3D and Screen-2D modalities, with greater brain activation in VR-3D modalities. These findings provide a better understanding about the neural activity of discrete emotional tasks assessed in VR environments.
- Published
- 2023
- Full Text
- View/download PDF
34. RF Overdrive Burnout Behavior and Mechanism Analysis of GaN HEMTs Based on High Speed Camera
- Author
-
Chang Liu, Hong Xia Liu, Yi Qiang Chen, Yi Jun Shi, Yu Han Xie, Si Chen, Ping Lai, Zhi Yuan He, and Yun Huang
- Subjects
GaN HEMTs ,burnout ,RF overdrive stress ,Electrical engineering. Electronics. Nuclear engineering ,TK1-9971 - Abstract
In this work, a new method for failure analysis of electronic components, high speed camera, is used to investigate burnout failure location of GaN HEMTs under RF overdrive stress. Based on the high speed camera system and the RF test system, we can filter out most of the burn flashes, and clearly locate the weak parts of devices. To further explain the burnout mechanism, a long-term (100 h) RF overdrive stress experiment was carried out and the significant degradation was observed. The drain-source current decreases and the threshold voltage drifts forward. These phenomena show that the degradation of RF overdrive stress is based on hot electron effect (HEE), which is related to the electric field. Besides, Electroluminescence (EL) tests are used and the non-uniform but strong luminescence characteristics of the gate were found, which indicates the strong electric field is the main cause of burnout. We also explore the correlation between burnout and ambient temperature. It was found that the influence of ambient temperature on the burnout was limited. At last, a TCAD simulation is carried out to confirm the temperature and electric field distribution in the device when burnout. It can be found that the electric field inside the device exceeded the breakdown electric field of GaN, which further proves that the burnout caused by RF overdrive is mainly due to electric field rather than temperature.
- Published
- 2023
- Full Text
- View/download PDF
35. Briarane Diterpenoids from the Gorgonian Dichotella gemmacea
- Author
-
Hua Tang, Wen Zhang, Peng Sun, Ming-Ping La, Cui Li, Jiao Li, Chunlin Zhuang, Baoshu Liu, and Tie-Jun Li
- Subjects
China ,Circular dichroism ,South china ,Stereochemistry ,gorgonian ,Dichotella gemmacea ,Pharmaceutical Science ,Growth inhibitory ,Article ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,lcsh:QH301-705.5 ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,biology ,Spectrum Analysis ,tumor cell growth inhibitory activity ,structure elucidation ,Absolute configuration ,Anthozoa ,biology.organism_classification ,Gorgonian ,lcsh:Biology (General) ,briarane diterpenoids ,Diterpenes ,Spectrum analysis - Abstract
Seven new briarane diterpenoids, gemmacolides AS-AY (1–7), were isolated together with ten known analogues (8–17) from the South China Sea gorgonian Dichotella gemmacea. The structures of the new compounds were elucidated by the detailed analysis of spectroscopic data and comparison with reported data. The absolute configuration of compounds was determined based on electronic circular dichroism (ECD) experiments and genetic correlations as well. Compounds 15 and 16 were reported for the first time for the gorgonian. In the preliminary in vitro bioassays, compound 5 showed potential growth inhibitory activity against MG63 cells.
- Published
- 2014
36. Senescence‐based colorectal cancer subtyping reveals distinct molecular characteristics and therapeutic strategies
- Author
-
Min‐Yi Lv, Du Cai, Cheng‐Hang Li, Junguo Chen, Guanman Li, Chuling Hu, Baowen Gai, Jiaxin Lei, Ping Lan, Xiaojian Wu, Xiaosheng He, and Feng Gao
- Subjects
cancer subtype ,colorectal cancer ,multi‐omics ,senescence ,therapeutic strategy ,Medicine - Abstract
Abstract Cellular senescence has been listed as a hallmark of cancer, but its role in colorectal cancer (CRC) remains unclear. We comprehensively evaluated the transcriptome, genome, digital pathology, and clinical data from multiple datasets of CRC patients and proposed a novel senescence subtype for CRC. Multi‐omics data was used to analyze the biological features, tumor microenvironment, and mutation landscape of senescence subtypes, as well as drug sensitivity and immunotherapy response. The senescence score was constructed to better quantify senescence in each patient for clinical use. Unsupervised learning revealed three transcriptome‐based senescence subtypes. Cluster 1, characterized by low senescence and activated proliferative pathways, was sensitive to chemotherapeutic drugs. Cluster 2, characterized by intermediate senescence and high immune infiltration, exhibited significant immunotherapeutic advantages. Cluster 3, characterized by high senescence, high immune, and stroma infiltration, had a worse prognosis and maybe benefit from targeted therapy. We further constructed a senescence scoring system based on seven senescent genes through machine learning. Lower senescence scores were highly predictive of longer disease‐free survival, and patients with low senescence scores may benefit from immunotherapy. We proposed the senescence subtypes of CRC and our findings provide potential treatment interventions for each CRC senescence subtype to promote precision treatment.
- Published
- 2023
- Full Text
- View/download PDF
37. Research trends in cardiovascular tissue engineering from 1992 to 2022: a bibliometric analysis
- Author
-
Ping Lai, Ming Sheng, Jin-hua Ye, Zhi-xian Tang, Shuo Hu, Bei Wang, Jing-lin Yuan, Yi-hong Yang, Yi-ming Zhong, and Yong-ling Liao
- Subjects
cardiovascular tissue engineering ,potential research direction ,biomaterial ,bibliometric analysis ,VOSviewer ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
BackgroundCardiovascular tissue engineering (CTE) is a promising technique to treat incurable cardiovascular diseases, such as myocardial infarction and ischemic cardiomyopathy. Plenty of studies related to CTE have been published in the last 30 years. However, an analysis of the research status, trends, and potential directions in this field is still lacking. The present study applies a bibliometric analysis to reveal CTE research trends and potential directions.MethodsOn 5 August 2022, research articles and review papers on CTE were searched from the Web of Science Core Collection with inclusion and exclusion criteria. Publication trends, research directions, and visual maps in this field were obtained using Excel (Microsoft 2009), VOSviewer, and Citespace software.ResultsA total of 2,273 documents from 1992 to 2022 were included in the final analysis. Publications on CTE showed an upward trend from 1992 [number of publications (Np):1] to 2021 (Np:165). The United States (Np: 916, number of citations: 152,377, H-index: 124) contributed the most publications and citations in this field. Research on CTE has a wide distribution of disciplines, led by engineering (Np: 788, number of citations: 40,563, H-index: 105). “Functional maturation” [red cluster, average published year (APY): 2018.63, 30 times], “cell-derived cardiomyocytes” (red cluster, APY: 2018.43, 46 times), “composite scaffolds” (green cluster, APY: 2018.54, 41 times), and “maturation” (red cluster, APY: 2018.17, 84 times) are the main emerging keywords in this area.ConclusionResearch on CTE is a hot research topic. The United States is a dominant player in CTE research. Interdisciplinary collaboration has played a critical role in the progress of CTE. Studies on functional maturation and the development of novel biologically relevant materials and related applications will be the potential research directions in this field.
- Published
- 2023
- Full Text
- View/download PDF
38. Nuclear Heme Oxygenase-1 (HO-1) Modulates Subcellular Distribution and Activation of Nrf2, Impacting Metabolic and Anti-oxidant Defenses
- Author
-
Shaon Sengupta, Manasa Muthu, Chhanda Biswas, Amal P. Fernando, Guang Yang, Nidhi Shah, Phyllis A. Dennery, and Ping La
- Subjects
Proteasome Endopeptidase Complex ,NF-E2-Related Factor 2 ,Glucosephosphate Dehydrogenase ,Pentose phosphate pathway ,Biology ,medicine.disease_cause ,Biochemistry ,Antioxidants ,Glycogen Synthase Kinase 3 ,Mice ,chemistry.chemical_compound ,GSK-3 ,NAD(P)H Dehydrogenase (Quinone) ,medicine ,Animals ,Phosphorylation ,Molecular Biology ,Heme ,Transcription factor ,Cells, Cultured ,Cell Nucleus ,Mice, Knockout ,Glycogen Synthase Kinase 3 beta ,Membrane Proteins ,Cell Biology ,Cytoprotection ,Cell biology ,Heme oxygenase ,Oxidative Stress ,Cell nucleus ,medicine.anatomical_structure ,chemistry ,Proteolysis ,Heme Oxygenase-1 ,Oxidative stress ,Signal Transduction - Abstract
With oxidative injury as well as in some solid tumors and myeloid leukemia cells, heme oxygenase-1 (HO-1), the anti-oxidant, anti-inflammatory, and anti-apoptotic microsomal stress protein, migrates to the nucleus in a truncated and enzymatically inactive form. However, the function of HO-1 in the nucleus is not completely clear. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor and master regulator of numerous antioxidants and anti-apoptotic proteins, including HO-1, also accumulates in the nucleus with oxidative injury and in various types of cancer. Here we demonstrate that in oxidative stress, nuclear HO-1 interacts with Nrf2 and stabilizes it from glycogen synthase kinase 3β (GSK3β)-mediated phosphorylation coupled with ubiquitin-proteasomal degradation, thereby prolonging its accumulation in the nucleus. This regulation of Nrf2 post-induction by nuclear HO-1 is important for the preferential transcription of phase II detoxification enzymes such as NQO1 as well as glucose-6-phosphate dehydrogenase (G6PDH), a regulator of the pentose phosphate pathway. Using Nrf2 knock-out cells, we further demonstrate that nuclear HO-1-associated cytoprotection against oxidative stress depends on an HO-1/Nrf2 interaction. Although it is well known that Nrf2 induces HO-1 leading to mitigation of oxidant stress, we propose a novel mechanism by which HO-1, by modulating the activation of Nrf2, sets an adaptive reprogramming that enhances antioxidant defenses.
- Published
- 2014
39. Chemistry and Bioactivity of Briaranes from the South China Sea Gorgonian Dichotella gemmacea
- Author
-
Chunlin Zhuang, Peng Sun, Ming-Ping La, Wen Zhang, Baoshu Liu, Hua Tang, Yang-Hua Yi, and Cui Li
- Subjects
China ,Antifungal Agents ,Stereochemistry ,gorgonian ,briarane diterpenoids ,biological activity ,structure elucidation ,Dichotella gemmacea ,Pharmaceutical Science ,medicine.disease_cause ,01 natural sciences ,Article ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,medicine ,Escherichia coli ,Bioassay ,Animals ,Humans ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,lcsh:QH301-705.5 ,Bacillus megaterium ,biology ,010405 organic chemistry ,Chemistry ,Biological activity ,biology.organism_classification ,Anthozoa ,0104 chemical sciences ,Anti-Bacterial Agents ,010404 medicinal & biomolecular chemistry ,Gorgonian ,lcsh:Biology (General) ,A549 Cells ,Growth inhibition ,Diterpenes ,Antibacterial activity ,Bacteria - Abstract
Seven new briarane diterpenoids, gemmacolides AZ–BF (1–7), were isolated together with eight known analogues (8–15) from the South China gorgonian Dichotella gemmacea. Their structures were elucidated based on detailed spectroscopic analysis and a comparison with reported data. In an in vitro bioassay, these compounds exhibited different levels of growth inhibition activity against A549 and MG63 cells, giving continuous evidences about the biological contribution of functional groups at C-2, C-12, C-13, and C-16. These compounds were also evaluated for their antibacterial and antifungal activities. Compound 8 exhibited a potential antibacterial activity against both Gram-positive bacterium Bacillus megaterium and Gram-negative bacterium Escherichia coli.
- Published
- 2016
40. Analysis of glomerular PLA2R efficacy in evaluating the prognosis of idiopathic membranous nephropathy in the background of different serum anti-PLA2R levels
- Author
-
Yuemeng Sun, Ping Lan, Jie Feng, Zhigang Wang, Chao Liu, Liyi Xie, and Xiaoyang Yu
- Subjects
Membranous nephropathy ,glomerular PLA2R ,serum anti-PLA2R ,clinical remission ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Objective To verify glomerular PLA2R antigen and serum PLA2R antibody expression in membranous nephropathy as well as to explore glomerular PLA2R efficacy in evaluating the prognosis of idiopathic membranous nephropathy (IMN) in the background of different serum anti-PLA2R levels.Methods We retrospectively analyzed 155 patients who were diagnosed with IMN by kidney biopsy. Patients were divided into six groups according to their serum PLA2R antibody or glomerular PLA2R antigen positiveness and the level of serum anti-PLA2R titer. Both clinical features and pathological characteristics were recorded, and the remission time was compared among groups. Correlation between clinical figures and the anti-PLA2R titer or semi-quantity of glomerular PLA2R antigen was detected.Results A positive correlation between time to partial remission and serum anti-PLA2R titer was found. Among patients with serum anti-PLA2R titer
- Published
- 2022
- Full Text
- View/download PDF
41. Practical, Multigram Preparation of Synthetically Useful, Enantiomerically Pure Building-Blocks from Quinic Acid
- Author
-
Shen Tan, Ping Lan, Martin G. Banwell, and Lorenzo V. White
- Subjects
1,2-addition ,α,β-annulation ,cross-coupling ,cyclohexenone ,enantiomerically pure ,α-iodination ,quinic acid ,Chemistry ,QD1-999 - Abstract
The naturally abundant, enantiomerically pure cyclitol quinic acid has been converted into a synthetically useful enone in nearly quantitative yield using the operationally straightforward and reproducible protocols reported herein. The latter compound, which was obtained in multigram quantities, engages in a diastereoselective 1,2-addition reaction with a hydrazone-based nucleophile. Furthermore, a readily derived α-iodoenone participates in both cross-coupling and α,β-annulation reactions. The results reported here emphasize that the now practically accessible cyclohexenones are useful, enantiomerically pure building blocks for organic synthesis.
- Published
- 2022
- Full Text
- View/download PDF
42. AMPK Regulates the Expression of the Fe-S Cluster Assembly Enzyme (ISCU) and ALAS2, Modulating Cellular Iron Metabolism and Increasing Hemoglobin Synthesis
- Author
-
Laura Breda, Silvia Pires Lourenco, Stefano Rivella, and Ping La
- Subjects
biology ,Kinase ,Immunology ,AICA ribonucleotide ,AMPK ,Cell Biology ,Hematology ,Oxidative phosphorylation ,Mitochondrion ,Biochemistry ,Cell biology ,chemistry.chemical_compound ,chemistry ,biology.protein ,ISCU ,Protein kinase A ,Heme - Abstract
Iron-sulfur (Fe-S) clusters are iron-containing prosthetic groups and enzymatic cofactors. They are strong oxidants when unbound yet essential in many processes like facilitating ATP production in mitochondria, promoting DNA, RNA and protein syntheses during cell proliferation and enhancing DNA repair in antioxidant defense. In particular, Fe-S clusters are indispensable in erythropoiesis, where the majority of physiological iron is utilized and where Fe-S clusters are required for the heme synthesis. Deficient Fe-S cluster synthesis predisposes individual to various diseases, such as cancer, metabolic and neurodegeneration diseases and blood disorders. However, it is unclear how Fe-S cluster synthesis is regulated and coordinates with environmental and developmental needs to prevent oxidative damage. The 5' AMP-activated protein kinase (AMPK) is a kinase activated by oxidative stress and energy starvation and critical for maintaining redox and energy homeostasis. In this study, we investigated the role of AMPK on Fe-S clusters synthesis and function and extended our findings in normal and thalassemic erythroid cells. Through bioinformatic analysis, we found that the Fe-S cluster assembly enzyme (ISCU), a scaffold protein indispensable for Fe-S cluster biogenesis, contains putative AMPK phosphorylation motifs at serine (S) residues 14 and 29 (human numbering). Using the human cell line 293T, we confirmed that AMPK phosphorylates ISCU, while point mutations in these residues prevented this activity. Moreover, AMPK-mediated phosphorylation promoted ISCU binding to 14-3-3s, a family of proteins that, once associate with phosphorylated residues, modulates the stability and function of targeted proteins. Indeed, increased association with 14-3-3s stabilized ISCU proteins, corroborating the observation that AMPK promotes the activity of ISCU proteins. We extended our studies using A549 cells that do not have AMPK activity since they harbor a mutant LKB1 kinase, which is responsible for activating AMPK. By overexpression of wild type (WT)-LKB1 and LKB1 kinase-dead mutant (KDM), we found that only WT-LKB1 restored AMPK activity, binding of ISCU to 14-3-3s and stability of ISCU. Moreover, under hydrogen peroxide incubation and glucose starvation, ISCU protein levels and Fe-S cluster synthesis were both increased only in the presence of LKB1-WT, but not in cells harboring KMD. LKB1-WT overexpressed cells also survived hydrogen peroxide incubation and glucose starvation better than those with KMD. Together, these data suggest that AMPK activation stabilizes ISCU protein and preserves Fe-S cluster synthesis to maintain a healthy redox and energy homeostasis. We then explored the effect of AMPK on Fe-S cluster synthesis in erythropoiesis by using the drug AICAR, an AMPK activator, in murine erythroleukemia (MEL) cells. We found that in MEL cells, AICAR treatment stabilized ISCU, increased Fe-S cluster levels and promoted the synthesis of the aminolevulinic acid synthase 2 (ALAS2) protein, which represents the rate-limiting enzyme in erythroid heme synthesis. Furthermore, this was associated with increased heme and globin chain synthesis, with a trend in increasing β-globin mRNA and proteins more than α-globin. We further confirmed these observations in Human Umbilical Cord Blood-Derived Erythroid Progenitor (HUDEP-2) and CD34+ cells derived from peripheral blood isolated from both healthy individuals and ß-thalassemic patients. In these cells, we found that AMPK upregulation by AICAR administration not only increased ALAS2 expression and erythroid heme levels, but also enhanced the synthesis of both a- and ß-globin chains, though with a preference for increasing β-globin levels. Analysis using specimens from thalassemic mice is in progress. In conclusion, our work demonstrates that under redox and energetic stress, activated AMPK phosphorylates and stabilizes ISCU protein, thereby enhancing Fe-S cluster synthesis and maintaining their function. Moreover, AMPK activation with AICAR treatment increases erythroid heme synthesis and hemoglobin expression. Given that AMPK is the major kinase that responds to oxidative and energetic cues, our work provides a mechanistic explanation for how erythropoiesis responds to energy starvation and redox stress as well as a potential novel therapeutic target to treat blood and metabolic disorders. Disclosures Rivella: Ionis Pharmaceuticals, Inc: Consultancy; MeiraGTx: Other: SAB; Protagonist: Consultancy; Disc Medicine: Consultancy.
- Published
- 2018
43. An Orchestrated Balance between Mitochondria Biogenesis, Iron-Sulfur Cluster Synthesis and Cellular Iron Acquisition
- Author
-
Valentina Ghiaccio, Jianbing Zhang, Ping La, and Stefano Rivella
- Subjects
0301 basic medicine ,Chemistry ,Immunology ,chemistry.chemical_element ,Iron–sulfur cluster ,Transferrin receptor ,Cell Biology ,Hematology ,Mitochondrion ,Biochemistry ,Sulfur ,Aconitase ,Cell biology ,03 medical and health sciences ,chemistry.chemical_compound ,Cytosol ,030104 developmental biology ,Biogenesis ,Iron acquisition - Abstract
Fe-S clusters are essential cofactors for mitochondria functions, and mitochondria are required for Fe-S cluster synthesis. Additionally, mitochondria biogenesis demands cellular iron uptake, which is negatively regulated by Fe-S clusters. Fe-S clusters are synthesized in the mitochondria and cytosol by two different machineries. However, cytosolic Fe-S cluster synthesis necessitates the mitochondrial Fe-S cluster assembly machinery. PGC-1α is a transcriptional coactivator and a master regulator of mitochondria biogenesis. We confirmed that overexpression of PGC-1α in adipocytes and hepatocytes stimulated mitochondria biogenesis, as measured by Mitotrack Green and Deep Red staining, which label total and alive mitochondria, respectively. We further measured Fe-S cluster synthesis by monitoring the gene expression of Fe-S cluster assembly machinery. By using RT-qPCR and Western Blot analyses, we confirmed that PGC-1α expression increases expression of ABCB7, ISCA1, ISCA2, ISD11, Nfu1 and ISCU, components of the Fe-S assembly machinery, suggesting a coordination between mitochondria biogenesis and Fe-S cluster synthesis. Iron Regulatory Proteins (IRP1 and IRP2) control iron metabolism by binding to specific non-coding sequences within an mRNA, known as iron-responsive elements (IRE). In the absence of Fe-S clusters, IRP1 acts as an aconitase (aka ACO1), while IRP2 is degraded by ubiquitination. Aconitases, represented by the cytosolic form ACO1 and mitochondrial form ACO2, catalyze the isomerization of citrate to isocitrate and require Fe-S clusters to be enzymatically active. PGC-1α overexpression enhanced aconitase activity but not their protein levels, corroborating the notion that Fe-S cluster synthesis was increased. To explore whether this coordination solely depends on PGC-1α, we evaluated the Fe-S cluster synthesis status during brown adipocyte maturation, which is characterized by enhanced mitochondria biogenesis and has been suggested to be PGC-1α-independent. We found that the synthesis of Fe-S cluster assembly machinery increased during maturation in both wild-type and PGC-1α-knockout brown adipocytes, indicating that Fe-S cluster synthesis coordinates with mitochondria biogenesis even in the absence of PGC-1α. To explore the impact of Fe-S cluster synthesis on iron acquisition under enhanced mitochondria biogenesis, we evaluated the expression of the iron importer transferrin receptor 1 (TfR1). TfR1 mRNA contains IREs in the 3' untranslated region (UTR). These 3'UTR IREs can be bound by IRPs and responsible for the subsequent stabilization of TfR1 mRNA. Therefore, if IRP1 associates with Fe-S cluster and converted into ACO1, it is expected that both TfR1 mRNA and protein levels would decrease. In contrast, we found that stimulated Fe-S cluster synthesis increased levels of the TfR1 protein, despite reduced IRP1 activity and destabilized TfR1 mRNA. This suggests that Fe-S cluster synthesis coordinates with mitochondria biogenesis but does not block iron uptake. Moreover, we extended our work to erythropoiesis by using murine erythroleukemia (MEL) cells. Stimulated mitochondria biogenesis enhanced expression of the Fe-S cluster assembly machinery and Fe-S cluster synthesis in these cells. TfR1 protein levels were increased despite elevated Fe-S cluster synthesis and reduced IRP activity. We also found increases in heme levels and the expression of aminolevulinic acid synthase 2 (ALAS2), the rate-limiting enzyme for erythroid heme synthesis. Of note, the ALAS2 mRNA contains IRE at the 5'UTR; binding of IRPs to the IRE inhibits translation while high Fe-S cluster levels lead to release. Moreover, as α- and β-globins chain expression is stimulated by increased heme availability, we also observed that mitochondria biogenesis was associated with increased synthesis of these two proteins and hemoglobinization. These data suggests that erythroid heme synthesis, hemoglobin expression and hemoglobinization coordinates with mitochondria biogenesis via Fe-S cluster synthesis. In conclusion, our data show that Fe-S cluster synthesis coordinates with mitochondria biogenesis but does not block cellular iron uptake, thus suggesting a potential unidentified iron regulator to ensure adequate iron for mitochondria biogenesis. Moreover, our work suggests a mechanism underlying the essential role of mitochondria biogenesis in erythropoiesis. Disclosures Rivella: Disc Medicine: Consultancy; MeiraGTx: Other: SAB; Ionis Pharmaceuticals, Inc: Consultancy; Protagonist: Consultancy.
- Published
- 2018
44. Heme oxygenase-1 is required for iron homeostasis and mitochondrial respiration
- Author
-
Phyllis A. Dennery, Jennifer F. Carr, and Ping La
- Subjects
chemistry.chemical_classification ,biology ,Ferroportin ,Transferrin receptor ,Oxidative phosphorylation ,Biochemistry ,Aconitase ,Cell biology ,Heme oxygenase ,Ferritin ,chemistry.chemical_compound ,chemistry ,Transferrin ,Physiology (medical) ,biology.protein ,Heme - Abstract
Heme is an essential cofactor in several enzymes of the electron transport chain (ETC) where its primary function is the coordination of iron to facilitate redox reactions. Unbound, free heme is strongly oxidative such that the cell has evolved mechanisms to prevent it from causing oxidative damage. This includes the catalytic breakdown of heme by heme oxygenase (HO-1), generating antioxidants CO and biliverdin. However the catabolism of heme also releases highly toxic free iron which seems counter productive to the antioxidant effort. We sought to explore the role of HO-1 in iron homeostasis using HO-1 knockout mouse embryonic fibroblasts and HO-1 deficient human liver cells. By Western blot these cells showed dysregulated iron handling including increased expression of transferrin receptor and decreased expression of ferritin and ferroportin compared to wild type controls. Additionally cytosolic aconitase activity was decreased in HO-1 deficient cells while the mutually exclusive mRNA binding activity of aconitase was increased. This switch is indicative of reduced FeS cluster availability. Consistent with FeS cluster deficiency we observed decreased frataxin mRNA levels, the product of which is involved in FeS cluster assembly in the mitochondria. Because FeS clusters are important in the ETC we examined mitochondrial respiration with a Seahorse Bioanalyzer (Agilent) and found it to be markedly reduced in HO-1 knockout cells. Interestingly, this was partially rescued by exogenous iron (1nM transferrin). Our findings suggest that an additional and important role of HO-1 is the maintenance of cellular iron homeostasis via the release of iron upon breakdown of heme.
- Published
- 2018
45. Landscape of the gut archaeome in association with geography, ethnicity, urbanization, and diet in the Chinese population
- Author
-
Xiaowu Bai, Yang Sun, Yue Li, Maojuan Li, Zhirui Cao, Ziyu Huang, Feng Zhang, Ping Yan, Lan Wang, Juan Luo, Jing Wu, Dejun Fan, Hongxia Chen, Min Zhi, Ping Lan, Zhong Zeng, Xiaojian Wu, Yinglei Miao, and Tao Zuo
- Subjects
Archaea ,Gut ,Geography ,Ethnicity ,Urbanization ,Diet ,Microbial ecology ,QR100-130 - Abstract
Abstract Background and aims The human gut is home to a largely underexplored microbiome component, the archaeome. Little is known of the impact of geography, urbanization, ethnicity, and diet on the gut archaeome in association with host health. We aim to delineate the variation of the human gut archaeome in healthy individuals and its association with environmental factors and host homeostasis. Methods Using metagenomic sequencing, we characterized the fecal archaeomes of 792 healthy adult subjects from 5 regions in China, spanning 6 ethnicities (Han, Zang, Miao, Bai, Dai, and Hani), consisting of both urban and rural residents for each ethnicity. In addition, we sampled 119 host variables (including lifestyle, diet, and blood parameters) and interrogated the influences of those factors, individually and combined, on gut archaeome variations. Results Population geography had the strongest impact on the gut archaeome composition, followed by urbanization, dietary habit, and ethnicity. Overall, the metadata had a cumulative effect size of 11.0% on gut archaeome variation. Urbanization decreased both the α-diversity (intrinsic microbial diversity) and the β-diversity (inter-individual dissimilarities) of the gut archaeome, and the archaea-to-bacteria ratios in feces, whereas rural residents were enriched for Methanobrevibacter smithii in feces. Consumption of buttered milk tea (a characteristic diet of the rural Zang population) was associated with increased abundance of M. smithii. M. smithii was at the central hub of archaeal-bacterial interactions in the gut microecology, where it was positively correlated with the abundances of a multitude of short chain fatty acid (SCFA)-producing bacteria (including Roseburia faecis, Collinsella aerofaciens, and Prevotella copri). Moreover, a decreased abundance of M. smithii was associated with increased human blood levels of cholinesterase in the urban population, coinciding with the increasing prevalence of noncommunicable diseases (such as dementia) during urbanization. Conclusions Our data highlight marked contributions of environmental and host factors (geography, urbanization, ethnicity, and habitual diets) to gut archaeome variations across healthy individuals, and underscore the impact of urbanization on the gut archaeome in association with host health in modern society. Video Abstract
- Published
- 2022
- Full Text
- View/download PDF
46. Easily-injectable shear-thinning hydrogel provides long-lasting submucosal barrier for gastrointestinal endoscopic surgery
- Author
-
Yinxiang Tang, Minhui Hu, Fuxin Tang, Rongkang Huang, Hui Wang, Dingcai Wu, and Ping Lan
- Subjects
Shear-thinning ,Injectable hydrogel ,Gellan gum ,Long-lasting barrier ,Endoscopic surgery ,Materials of engineering and construction. Mechanics of materials ,TA401-492 ,Biology (General) ,QH301-705.5 - Abstract
Submucosal injection material has shown protective effect against gastrointestinal injury during endoscopic surgery in clinic. However, the protective ability of existing submucosal injection material is strictly limited by their difficult injectability and short barrier time. Herein, we report a shear-thinning gellan gum hydrogel that simultaneously has easy injectability and long-lasting barrier function, together with good hemostatic property and biocompatibility. Shear-thinning property endows our gellan gum hydrogel with excellent endoscopic injection performance, and the injection pressure of our gellan gum hydrogel is much lower than that of the small molecule solution (50 wt% dextrose) when injected through the endoscopic needle. More importantly, our gellan gum hydrogel shows much stronger barrier retention ability than normal saline and sodium hyaluronate solution in the ex vivo and in vivo models. Furthermore, our epinephrine-containing gellan gum hydrogel has a satisfactory hemostatic effect in the mucosal lesion resection model of pig. These results indicate an appealing application prospect for gellan gum hydrogel utilizing as a submucosal injection material in endoscopic surgery.
- Published
- 2022
- Full Text
- View/download PDF
47. Mammalian Target of Rapamycin Complex 1 (mTORC1)-mediated Phosphorylation Stabilizes ISCU Protein
- Author
-
Ping La, Guang Yang, and Phyllis A. Dennery
- Subjects
inorganic chemicals ,Scaffold protein ,biology ,Cell Biology ,mTORC1 ,Metabolism ,Biochemistry ,Serine ,biology.protein ,Phosphorylation ,TOR Serine-Threonine Kinases ,ISCU ,biological phenomena, cell phenomena, and immunity ,Molecular Biology ,PI3K/AKT/mTOR pathway - Abstract
The scaffold protein ISCU facilitates the assembly of iron-sulfur clusters (ISCs), which are essential cofactors for many vital metabolic processes. The mTOR pathways are central to nutrient and energy-sensing networks. Here, we demonstrate that mTORC1 associates with ISCU and phosphorylates ISCU at serine 14. This phosphorylation stabilized ISCU protein. Insufficiency of ISCU triggered by mTORC1 inhibition prevented ISC assembly. Sustained ISCU protein levels enhanced by mTORC1 sensitized TSC2-null cells to iron deprivation due to constitutive ISC biogenesis-triggered iron demand, which outstrips supply. We conclude that the mTORC1 pathway serves to modulate iron metabolism and homeostasis, and we speculate that iron deprivation may be an adjunct in the treatment of cancers characterized by constitutive mTORC1 activation.
- Published
- 2013
48. Current hotspot and study trend of innate immunity in COVID-19: a bibliometric analysis from 2020 to 2022
- Author
-
Ping Lai, Shuquan Xu, Jin-hua Xue, Hong-zhou Zhang, Yi-ming Zhong, and Yong-ling Liao
- Subjects
COVID-19 ,innate immunity ,bibliometric analysis ,WoSCC ,VOS viewer ,CiteSpace ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundSince the coronavirus disease 2019 (COVID-19) has spread throughout the world, many studies on innate immunity in COVID-19 have been published, and great progress has been achieved, while bibliometric analysis on hotspots and research trends in this field remains lacking.MethodsOn 17 November 2022, articles and reviews on innate immunity in COVID-19 were recruited from the Web of Science Core Collection (WoSCC) database after papers irrelevant to COVID-19 were further excluded. The number of annual publications and the average citations per paper were analyzed by Microsoft Excel. Bibliometric analysis and visualization of the most prolific contributors and hotspots in the field were performed by VOSviewer and CiteSpace software.ResultsThere were 1,280 publications that met the search strategy on innate immunity in COVID-19 and were published from 1 January 2020 to 31 October 2022. Nine hundred thirteen articles and reviews were included in the final analysis. The USA had the highest number of publications (Np) at 276 and number of citations without self-citations (Nc) at 7,085, as well as an H-index of 42, which contributed 30.23% of the total publications, followed by China (Np: 135, Nc: 4,798, and H-index: 23) with 14.79% contribution. Regarding Np for authors, Netea, Mihai G. (Np: 7) from the Netherlands was the most productive author, followed by Joosten, Leo A. B. (Np: 6) and Lu, Kuo-Cheng (Np: 6). The Udice French Research Universities had the most publications (Np: 31, Nc: 2,071, H-index: 13), with an average citation number (ACN) at 67. The journal Frontiers in Immunology possessed the most publications (Np: 89, Nc: 1,097, ACN: 12.52). “Evasion” (strength 1.76, 2021-2022), “neutralizing antibody” (strength 1.76, 2021-2022), “messenger RNA” (strength 1.76, 2021-2022), “mitochondrial DNA” (strength 1.51, 2021-2022), “respiratory infection” (strength 1.51, 2021-2022), and “toll-like receptors” (strength 1.51, 2021-2022) were the emerging keywords in this field.ConclusionThe study on innate immunity in COVID-19 is a hot topic. The USA was the most productive and influential country in this field, followed by China. The journal with the most publications was Frontiers in Immunology. “Messenger RNA,” “mitochondrial DNA,” and “toll-like receptors” are the current hotspots and potential targets in future research.
- Published
- 2023
- Full Text
- View/download PDF
49. Mesenteric Adipose Tissue‐Derived Klebsiella variicola Disrupts Intestinal Barrier and Promotes Colitis by Type VI Secretion System
- Author
-
Junli Gong, Jing Yu, Shengmei Yin, Jia Ke, Jinjie Wu, Chen Liu, Zhanhao Luo, Wai Ming Cheng, Yaozu Xie, Yuan Chen, Zhen He, and Ping Lan
- Subjects
colitis ,Crohn's disease ,Klebsiella variicola ,mesenteric adipose tissue ,type VI secretion system ,Science - Abstract
Abstract Mesenteric adipose tissue (MAT) in Crohn's disease (CD) is associated with transmural inflammation. Extended mesenteric excision can reduce surgical recurrence and improve long‐term outcomes, indicating that MAT plays an important role in the pathogenesis of CD. Bacterial translocation has been reported to occur in the MAT of patients with CD (CD‐MAT), but the mechanisms by which translocated bacteria lead to intestinal colitis remain unclear. Here it is shown that members of Enterobacteriaceae are highly enriched in CD‐MAT compared with non‐CD controls. Viable Klebsiella variicola in Enterobacteriaceae is isolated exclusively in CD‐MAT and can induce a pro‐inflammatory response in vitro and exacerbates colitis both in dextran sulfate sodium (DSS)‐induced colitis mice model and IL‐10−/− spontaneous colitis mice model. Mechanistically, active type VI secretion system (T6SS) is identified in the genome of K. variicola, which can impair the intestinal barrier by inhibiting the zonula occludens (ZO‐1) expression. Dysfunction of T6SS by CRISPR interference system alleviates the inhibitory effect of K. variicola on ZO‐1 expression and attenuated colitis in mice. Overall, these findings demonstrate that a novel colitis‐promoting bacteria exist in the mesenteric adipose tissue of CD, opening a new therapeutic avenue for colitis management.
- Published
- 2023
- Full Text
- View/download PDF
50. Three cerebrosides from the sea cucumber Cucumaria frondosa
- Author
-
Yang-Hua Yi, Jun-Jie Shao, Jian Jiao, and Ming-Ping La
- Subjects
Sea cucumber ,Cucumaria ,Chromatography ,biology ,Chemical constituents ,Botany ,General Medicine ,Glucocerebroside ,biology.organism_classification ,High-performance liquid chromatography ,Cerebroside - Abstract
Aim To study the chemical constituents of the sea cucumber Cucumaria frondosa. Methods Three sphingosine-type glucocerebrosides, CF-3-1, CF-3-2 and CF-3-3 were isolated by means of high performance liquid chromatography (HPLC) from a cerebroside molecular species 3 which was obtained from the less polar fraction of the 65% EtOH extract of the sea cucumber Cucumaria frondosa Gunnerus. Results The structures of these cerebrosides were determined on the basis of chemical and spectroscopic evidences. Conclusion Three compounds were isolated from the sea cucumber Cucumaria frondosa for the first time. CF-3-3 and CF-3-2 were obtained as pure compounds for the first time.
- Published
- 2012
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.