tbuckley/cabot-search huggingface dataset:
Agency in the Anthropocene: education for planetary health
Authors: Peta J White, Nicole M Ardoin, Chris Eames, Martha C Monroe
Journal: The Lancet Planetary Health (2024)

Collective action is essential to address planetary health as current and future environmental challenges are socioecological and require coordinated, informed, and sustained action from all societal sectors. Education that engages intergenerational communities is a crucial means of building collective action as it provides opportunities to develop an informed citizenry capable of making the necessary decisions to work towards planetary health. Schools are valuable sites of community learning and action, and will benefit from a new orientation towards and commitment to educator training, curriculum development, and youth agency. This orientation is supported by the Organisation for Economic Co-operation and Development's Programme for International Student Assessment's (PISA) 2025 Science Framework, which measures the competence (skills and knowledge) of 15-year-old students. This Personal View describes a new concept, Agency in the Anthropocene, a contributing element of the 2025 Science Framework that defines the way science education could develop agency and hope in this era of socioecological challenges that are impacting planetary health.
Gut ribotoxic stress responses facilitate dyslipidemia via metabolic reprogramming: an environmental health prediction
Authors: Juil Kim, Hoyoung Jeong, Navin Ray, Ki-Hyung Kim, Yuseok Moon
Journal: Theranostics (2024)

Rationale:The gut and its accessory organ, the liver, are crucial determinants of metabolic homeostasis via the regulation of circulating lipids for cardiovascular health.In response to environmental insults, cells undergo diverse adaptation or pathophysiological processes via stress-responsive eukaryotic initiation factor 2 alpha (eIF2α) kinase signaling and subsequent cellular reprogramming.We noted that patients with inflammatory gut distress display enhanced levels of ribosomal stress-responsive eIF2α kinase, which is notably associated with lipid metabolic process genes.Based on an assumption that eukaryotic ribosomes are a promising stress-responsive module for molecular reprogramming, chemical ribosome-inactivating stressors (RIS) were assessed for their involvement in enterohepatic lipid regulation.Methods: Experimental assessment was based on prediction using the clinical transcriptome and single-cell RNA-sequencing analysis of inflammatory bowel diseases and obesity.The prediction was verified using RIS exposure models of mice, gut organoids, and intestinal cells.The lipidomic profiling was performed to address RIS-induced intracellular fat alterations.Biochemical processes of the mechanisms were evaluated using RT-PCR, western blot analysis, luciferase reporter assays, and confocal microscopy of genetically ablated or chemically inhibited mice, organoids, and cells.Results: Chemical RIS including deoxynivalenol promoted enterohepatic lipid sequestration while lowering blood LDL cholesterol in normal and diet-induced obese mice.Although ribosomal stress caused extensive alterations in cellular lipids and metabolic genes, the cholesterol import-associated pathway was notably modulated.In particular, ribosomal stress enhanced gut levels of the low-density lipoprotein receptor (LDLR) via both transcriptional and post-transcriptional regulation.Subsequently, LDLR facilitated enterohepatic cholesterol accumulation, leading to dyslipidemia in response to ribosomal stress.Moreover, genetic features of stress-responsive LDLR modulators were consistently proven in the inflammation-and obesity-associated gut model. Conclusion:The elucidated ribosome-linked gut lipid regulation provides predictive insights into stress-responsive metabolic rewiring in chronic human diseases as an environmental health prediction.
Pattern recognition of microcirculation with super-resolution ultrasound imaging provides markers for early tumor response to anti-angiogenic therapy
Authors: Jingyi Yin, Feihong Dong, Jian An, Tianyu Guo, Heping Cheng, Jiabin Zhang, Jue Zhang
Journal: Theranostics (2024)

Rationale: Cancer treatment outcome is traditionally evaluated by tumor volume change in clinics, while tumor microvascular heterogeneity reflecting tumor response has not been fully explored due to technical limitations.Methods: We introduce a new paradigm in super-resolution ultrasound imaging, termed pattern recognition of microcirculation (PARM), which identifies both hemodynamic and morphological patterns of tumor microcirculation hidden in spatio-temporal space trajectories of microbubbles.Results: PARM demonstrates the ability to distinguish different local blood flow velocities separated by a distance of 24 μm.Compared with traditional vascular parameters, PARM-derived heterogeneity parameters prove to be more sensitive to microvascular changes following anti-angiogenic therapy.Particularly, PARM-identified "sentinel" microvasculature, exhibiting evident structural changes as early as 24 hours after treatment initiation, correlates significantly with subsequent tumor volume changes (|r| > 0.9, P < 0.05).This provides prognostic insight into tumor response much earlier than clinical criteria.Conclusions: The ability of PARM to noninvasively quantify tumor vascular heterogeneity at the microvascular level may shed new light on early-stage assessment of cancer therapy.
MAGL protects against renal fibrosis through inhibiting tubular cell lipotoxicity
Authors: Shan Zhou, Xian Ling, Jielin Zhu, Ye Liang, Qijian Feng, Chao Xie, Jiemei Li, Qiyan Chen, Shuangqin Chen, Jinhua Miao, Mengyao Zhang, Zhiru Li, Weiwei Shen, Xiaolong Li, Qinyu Wu, Xiaoxu Wang, Ruiyuan Liu, Cheng Wang, Fan Fan Hou, Yaozhong Kong, Youhua Liu, Lili Zhou
Journal: Theranostics (2024)

Rationale: Renal fibrosis, with no therapeutic approaches, is a common pathological feature in various chronic kidney diseases (CKD).Tubular cell injury plays a pivotal role in renal fibrosis.Commonly, injured tubular cells exhibit significant lipid accumulation.However, the underlying mechanisms remain poorly understood.Methods: 2-arachidonoylglycerol (2-AG) levels in CKD patients and CKD model specimens were measured using mass spectrometry.2-AG-loaded nanoparticles were infused into unilateral ureteral obstruction (UUO) mice.Lipid accumulation and renal fibrosis were tested.Furthermore, monoacylglycerol lipase (MAGL), the hydrolyzing enzyme of 2-AG, was assessed in CKD patients and models.Tubular cell-specific MAGL knock-in mice were generated.Moreover, MAGL recombination protein was also administered to unilateral ischemia reperfusion injury (UIRI) mice.Besides, a series of methods including RNA sequencing, metabolomics, primary cell culture, lipid staining, etc. were used.Results: 2-AG was increased in the serum or kidneys from CKD patients and models.Supplement of 2-AG further induced lipid accumulation and fibrogenesis through cannabinoid receptor type 2 (CB2)/β-catenin signaling.β-catenin knockout blocked 2-AG/CB2-induced fatty acid β-oxidation (FAO) deficiency and lipid accumulation.Remarkably, MAGL significantly decreased in CKD, aligning with lipid accumulation and fibrosis.Specific transgene of MAGL in tubular cells significantly preserved FAO, inhibited lipid-mediated toxicity in tubular cells, and finally retarded fibrogenesis.Additionally, supplementation of MAGL in UIRI mice also preserved FAO function, inhibited lipid accumulation, and protected against renal fibrosis.Conclusion: MAGL is a potential diagnostic marker for kidney function decline, and also serves as a new therapeutic target for renal fibrosis through ameliorating lipotoxicity.
Global metabolomics revealed deviations from the metabolic aging clock in colorectal cancer patients
Authors: Long Zhang, Shaobo Mo, Xiurui Zhu, C. James Chou, Bo Jin, Zhi Han, James Schilling, Weili Liao, Sheeno Thyparambil, Ruben Y. Luo, John C. Whitin, Lu Tian, Seema Nagpal, Scott R. Ceresnak, Harvey J. Cohen, Doff B. McElhinney, Karl G. Sylvester, Yangming Gong, Chen Fu, Xuefeng B. Ling, Junjie Peng
Journal: Theranostics (2024)

Background: Markers of aging hold promise in the context of colorectal cancer (CRC) care.Utilizing high-resolution metabolomic profiling, we can unveil distinctive age-related patterns that have the potential to predict early CRC development.Our study aims to unearth a panel of aging markers and delve into the metabolomic alterations associated with aging and CRC.Methods: We assembled a serum cohort comprising 5,649 individuals, consisting of 3,002 healthy volunteers, 715 patients diagnosed with colorectal advanced precancerous lesions (APL), and 1,932 CRC patients, to perform a comprehensive metabolomic analysis.Results: We successfully identified unique age-associated patterns across 42 metabolic pathways.Moreover, we established a metabolic aging clock, comprising 9 key metabolites, using an elastic net regularized regression model that accurately estimates chronological age.Notably, we observed significant chronological disparities among the healthy population, APL patients, and CRC patients.By combining the analysis of circulative carcinoembryonic antigen levels with the categorization of individuals into the "hypo" metabolic aging subgroup, our blood test demonstrates the ability to detect APL and CRC with positive predictive values of 68.4% (64.3%, 72.2%) and 21.4% (17.8%, 25.9%), respectively.Conclusions: This innovative approach utilizing our metabolic aging clock holds significant promise for accurately assessing biological age and enhancing our capacity to detect APL and CRC.
Degraders in epigenetic therapy: PROTACs and beyond
Authors: Xing-Jie Dai, Shi-Kun Ji, Meng-Jie Fu, Gao-Zhi Liu, Hui-Min Liu, Shao-Peng Wang, Liang Shen, Ning Wang, Piet Herdewijn, Yi-Chao Zheng, Sai-Qi Wang, Xiao-Bing Chen
Journal: Theranostics (2024)

Epigenetics refers to the reversible process through which changes in gene expression occur without changing the nucleotide sequence of DNA. The process is currently gaining prominence as a pivotal objective in the treatment of cancers and other ailments. Numerous drugs that target epigenetic mechanisms have obtained approval from the Food and Drug Administration (FDA) for the therapeutic intervention of diverse diseases; many have drawbacks, such as limited applicability, toxicity, and resistance. Since the discovery of the first proteolysis-targeting chimeras (PROTACs) in 2001, studies on targeted protein degradation (TPD)-encompassing PROTACs, molecular glue (MG), hydrophobic tagging (HyT), degradation TAG (dTAG), Trim-Away, a specific and non-genetic inhibitor of apoptosis protein (IAP)-dependent protein eraser (SNIPER), antibody-PROTACs (Ab-PROTACs), and other lysosome-based strategies-have achieved remarkable progress. In this review, we comprehensively highlight the small-molecule degraders beyond PROTACs that could achieve the degradation of epigenetic proteins (including bromodomain-containing protein-related targets, histone acetylation/deacetylation-related targets, histone methylation/demethylation related targets, and other epigenetic targets) via proteasomal or lysosomal pathways. The present difficulties and forthcoming prospects in this domain are also deliberated upon, which may be valuable for medicinal chemists when developing more potent, selective, and drug-like epigenetic drugs for clinical applications.
The combination of calreticulin-targeting L-ASNase and anti-PD-L1 antibody modulates the tumor immune microenvironment to synergistically enhance the antitumor efficacy of radiotherapy
Authors: Ying Zhang, Venu Akhil, Ho Seong Seo, Hae Ran Park, Soo Hyun Kim, Sung-Hwan You, Zhipeng Liu, So-young Kim, Rukhsora D. Sultonova, Jung-Joon Min, Yeongjin Hong
Journal: Theranostics (2024)

Radiotherapy (RT) triggers immunogenic cell death (ICD).L-ASNase, which catalyzes the conversion of asparagine (Asn), thereby depleting it, is used in the treatment of blood cancers.In previous work, we showed that CRT3LP and CRT4LP, PASylated L-ASNases conjugated to the calreticulin (CRT)-specific monobodies CRT3 and CRT4, increase the efficacy of ICD-inducing chemotherapy.Here, we assessed their efficacy in tumor-bearing mice treated with RT.Methods: Monobody binding was evaluated by in silico molecular docking analysis.The expression and cellular localization of ecto-CRT were assessed by confocal imaging and flow cytometry.The antitumor effect and the roles of CRT3LP and CRT4LP in irradiation (IR)-induced ICD in tumors were analyzed by ELISA, immunohistochemistry, and immune analysis methods.Results: Molecular docking analysis showed that CRT3 and CRT4 monobodies were stably bound to CRT.Exposure to 10 Gy IR decreased the viability of CT-26 and MC-38 tumor cells in a time-dependent manner until 72 h, and increased the expression of the ICD marker ecto-CRT (CRT exposed on the cell surface) and the immune checkpoint marker PD-L1 until 48 h.IR enhanced the cytotoxicity of CRT3LP and CRT4LP in CT-26 and MC-38 tumor cells, and increased reactive oxygen species (ROS) levels.In mice bearing CT-26 and MC-38 subcutaneous tumors treated with 6 Gy IR, Rluc8-conjugated CRT-specific monobodies (CRT3-Rluc8 and CRT4-Rluc8) specifically targeted tumor tissues, and CRT3LP and CRT4LP increased total ROS levels in tumor tissues, thereby enhancing the antitumor efficacy of RT.Tumor tissues from these mice showed increased mature dendritic, CD4 + T, and CD8 + T cells and pro-inflammatory cytokines (IFNγ and TNFα) and decreased regulatory T cells, and the expression of tumor cell proliferation markers (Ki67 and CD31) was downregulated.These data indicate that the combination of IR and CRT-targeting L-ASNases activated and reprogramed the immune system Ivyspring International Publisher of the tumor microenvironment.Consistent with these data, an immune checkpoint inhibitor (anti-PD-L1 antibody) markedly increased the therapeutic efficacy of combined IR and CRT-targeting L-ASNases.Conclusion: CRT-specific L-ASNases are useful as additive drug candidates in tumors treated with RT, and combination treatment with anti-PD-L1 antibody increases their therapeutic efficacy.
20-HETE mediated TRPV1 activation drives allokinesis via MrgprA3<sup>+</sup> neurons in chronic dermatitis
Authors: Guang Yu, Pei Liu, Xiaobao Huang, Mingxin Qi, Xue Li, Weimeng Feng, Erxin Shang, Yuan Zhou, Changming Wang, Yan Yang, Chan Zhu, Fang Wang, Zongxiang Tang, Jinao Duan
Journal: Theranostics (2024)

Rationale: Noxious stimuli are often perceived as itchy in patients with chronic dermatitis (CD); however, itch and pain mechanisms of CD are not known.Methods: TRPV1 involvement in CD was analyzed using a SADBE induced CD-like mouse model, and several loss-and gain-of-function mouse models.Trigeminal TRPV1 channel and MrgprA3 + neuron functions were analyzed by calcium imaging and whole-cell patch-clamp recordings.Lesional CD-like skin from mice were analyzed by unbiased metabolomic analysis.20-HETE availability in human and mouse skin were determined by LC/MS and ELISA.And finally, HET0016, a selective 20-HETE synthase inhibitor, was used to evaluate if blocking skin TRPV1 activation alleviates CD-associated chronic itch or pain.Results: While normally a pain inducing chemical, capsaicin induced both itch and pain in mice with CD condition.DREADD silencing of MrgprA3 + primary sensory neurons in these mice selectively decreased capsaicin induced scratching, but not pain-related wiping behavior.In the mice with CD condition, MrgprA3 + neurons showed elevated ERK phosphorylation.Further experiments showed that MrgprA3 + neurons from MrgprA3;Braf mice, which have constitutively active BRAF in MrgprA3 + neurons, were significantly more excitable and responded more strongly to capsaicin.Importantly, capsaicin induced both itch and pain in MrgprA3;Braf mice in an MrgprA3 + neuron dependent manner.Finally, the arachidonic acid metabolite 20-HETE, which can activate TRPV1, was significantly elevated in the lesional skin of mice and patients with CD.Treatment with the selective 20-HETE synthase inhibitor HET0016 alleviated itch in mice with CD condition. Conclusion:Our results demonstrate that 20-HETE activates TRPV1 channels on sensitized MrgprA3 + neurons, and induces allokinesis in lesional CD skin.Blockade of 20-HETE synthesis or silencing of TRPV1-MrgprA3 + neuron signaling offers promising therapeutic strategies for alleviating CD-associated chronic itch.
Tumor cell senescence-induced macrophage CD73 expression is a critical metabolic immune checkpoint in the aging tumor microenvironment
Authors: Yue Deng, Qinyan Chen, Xiao Yang, Yajie Sun, Bin Zhang, Wenwen Wei, Suke Deng, Jingshu Meng, Yan Hu, Yijun Wang, Zhanjie Zhang, Lu Wen, Fang Huang, Chao Wan, Kunyu Yang
Journal: Theranostics (2024)

Background:The role of senescent cells in the tumor microenvironment (TME) is usually bilateral, and diverse therapeutic approaches, such as radiotherapy and chemotherapy, can induce cellular senescence.Cellular interactions are widespread in the TME, and tumor cells reprogram immune cells metabolically by producing metabolites.However, how senescent cells remodel the metabolism of TME remains unclear.This study aimed to explore precise targets to enhance senescent cells-induced anti-tumor immunity from a metabolic perspective. Methods:The in vivo senescence model was induced by 8 Gy×3 radiotherapy or cisplatin chemotherapy, and the in vitro model was induced by 10 Gy-irradiation or cisplatin treatment.Metabonomic analysis and ELISA assay on tumor interstitial fluid were performed for metabolites screening.Marker expression and immune cell infiltration in the TME were analyzed by flow cytometry.Cell co-culture system and senescence-conditioned medium were used for crosstalk validation in vitro.RNA sequencing and rescue experiments were conducted for mechanism excavation.Immunofluorescence staining and single-cell transcriptome profiling analysis were performed for clinical validation.Results: We innovatively reveal the metabolic landscape of the senescent TME, characterized with the elevation of adenosine.It is attributed to the senescent tumor cell-induced CD73 upregulation of tumor-associated macrophages (TAMs).CD73 expression in TAMs is evoked by SASP-related pro-inflammatory cytokines, especially IL-6, and regulated by JAK/STAT3 pathway.Consistently, a positive correlation between tumor cells senescence and TAMs CD73 expression is identified in lung cancer clinical specimens and databases.Lastly, blocking CD73 in a senescent background suppresses tumors and activates CD8 + T cell-mediated antitumor immunity.Conclusions: TAMs expressed CD73 contributes significantly to the adenosine accumulation in the senescent TME, suggesting targeting CD73 is a novel synergistic anti-tumor strategy in the aging microenvironment.
Enhancing anti-tumor potential: low-intensity vibration suppresses osteosarcoma progression and augments MSCs' tumor-suppressive abilities
Authors: Xue Xiong, Qingji Huo, Kexin Li, Changpeng Cui, Chunyi Chang, Charles Park, BonHeon Ku, Chin-Suk Hong, HeeChang Lim, Pankita H. Pandya, M. Reza Saadatzadeh, Khadijeh Bijangi-Vishehsaraei, Chien-Chi Lin, Melissa A. Kacena, Karen E. Pollok, Andy Chen, Jing Liu, William R. Thompson, Xue-Lian Li, Bai-Yan Li, Hiroki Yokota
Journal: Theranostics (2024)

Rationale: Osteosarcoma (OS), a common malignant bone tumor, calls for the investigation of novel treatment strategies.Low-intensity vibration (LIV) presents itself as a promising option, given its potential to enhance bone health and decrease cancer susceptibility.This research delves into the effects of LIV on OS cells and mesenchymal stem cells (MSCs), with a primary focus on generating induced tumor-suppressing cells (iTSCs) and tumor-suppressive conditioned medium (CM).Methods: To ascertain the influence of vibration frequency, we employed numerical simulations and conducted experiments to determine the most effective LIV conditions.Subsequently, we generated iTSCs and CM through LIV exposure and assessed the impact of CM on OS cells.We also explored the underlying mechanisms of the tumor-suppressive effects of LIV-treated MSC CM, with a specific focus on vinculin (VCL).We employed cytokine array, RNA sequencing, and Western blot techniques to investigate alterations in cytokine profiles, transcriptomes, and tumor suppressor proteins.Results: Numerical simulations validated LIV frequencies within the 10-100 Hz range.LIV induced notable morphological changes in OS cells and MSCs, confirming its dual role in inhibiting OS cell progression and promoting MSC conversion into iTSCs.Upregulated VCL expression enhanced MSC responsiveness to LIV, significantly bolstering CM's efficacy.Notably, we identified tumor suppressor proteins in LIV-treated CM, including procollagen C endopeptidase enhancer (PCOLCE), histone H4 (H4), peptidylprolyl isomerase B (PPIB), and aldolase A (ALDOA).Consistently, cytokine levels decreased significantly in LIV-treated mouse femurs, and oncogenic transcript levels were downregulated in LIV-treated OS cells.Moreover, our study demonstrated that combining LIV-treated MSC CM with chemotherapy drugs yielded additive anti-tumor effects.Conclusions: LIV effectively impeded the progression of OS cells and facilitated the transformation of MSCs into iTSCs.Notably, iTSC-derived CM demonstrated robust anti-tumor properties and the Ivyspring International
Discovery of novel antibacterial agent for the infected wound treatment: all-hydrocarbon stapling optimization of LL-37
Authors: Yanan Zhang, Mengjun Zheng, Zhe Wang, Zhinan Liu, Sumeng Chen, Xiang Li, Yejiao Shi, Honggang Hu
Journal: Theranostics (2024)

Rationale: Antimicrobial peptide LL-37 has been recognized as a favorable alternative to antibiotics due to its broad antibacterial spectrum, low resistance development and diverse biological activities.However, its high manufactory cost, poor proteolytic stability, and unpredictable cytotoxicity seriously hindered its medical translation.Methods: To push the frontiers of its clinical application, all-hydrocarbon stapling strategy was exploited here for the structural modification of KR-12, the core and minimal fragment of LL-37.Results: Based on a library of KR-12 derivatives that designed and synthesized to be stapled at positions of either i, i+4 or i, i+7, structure to activity relationship was investigated.Among them, KR-12(Q5, D9) with the glutamine and aspartic acid residues stapled displayed increased helical content and positive charge.The reinforced α-helical conformation not only protected it from proteolytic hydrolysis but also improved its antibacterial efficacy via effective membrane perturbation and anti-inflammatory efficacy via compact LPS binding.Besides, the increased positive charge endowed it with an enhanced therapeutic index.On infected wound mouse model, it was demonstrated to eliminate bacteria and promote wound closure and regeneration effectively. Conclusion:Overall, the all-hydrocarbon stapling was proven to lay the foundation for the future development of antibacterial agents.KR-12(Q5, D9) could serve as a lead compound for the clinical treatment of bacterial infections.