tbuckley/cabot-search huggingface dataset:
PINK1-mediated mitophagy attenuates pathological cardiac hypertrophy by suppressing the mtDNA release-activated cGAS-STING pathway
Authors: Haobin Zhou, Xiao Wang, Tianyu Xu, Daojing Gan, Zhuang Ma, Hao Zhang, Jian Zhang, Qingchun Zeng, Dingli Xu
Journal: Cardiovascular Research (2024)

Abstract Aims Sterile inflammation is implicated in the development of heart failure (HF). Mitochondria play important roles in triggering and maintaining inflammation. Mitophagy is important for regulation of mitochondrial quality and maintenance of cardiac function under pressure overload. The association of mitophagy with inflammation in HF is largely unclear. As PINK1 is a central mediator of mitophagy, our objective was to investigate its involvement in cardiac hypertrophy, and the effect of PINK1-mediated mitophagy on cGAS-STING activation during cardiac hypertrophy. Methods and results PINK1 knockout and cardiac-specific PINK1-overexpressing transgenic mice were created and subsequently subjected to transverse aortic constriction (TAC) surgery. In order to explore whether PINK1 regulates STING-mediated inflammation during HF, PINK1/STING (stimulator of interferon genes) double-knockout (DKO) mice were created. Pressure overload was induced by TAC. Our findings indicate a significantly decline in PINK1 expression in TAC-induced hypertrophy. Cardiac hypertrophic stimuli caused the release of mitochondrial DNA (mtDNA) into the cytosol, activating the cGAS-STING signalling, which in turn initiated cardiac inflammation and promoted the progression of cardiac hypertrophy. PINK1 deficiency inhibited mitophagy activity, promoted mtDNA release, and then drove the overactivation of cGAS-STING signalling, exacerbating cardiac hypertrophy. Conversely, cardiac-specific PINK1 overexpression protected against hypertrophy thorough inhibition of the cGAS-STING signalling. DKO mice revealed that the effects of PINK1 on hypertrophy were dependent on STING. Conclusion Our findings suggest that PINK1-mediated mitophagy plays a protective role in pressure overload-induced cardiac hypertrophy via inhibiting the mtDNA-cGAS-STING pathway.
Epitranscriptomic regulation of cardiac fibrosis via YTHDF1-dependent <i>PIEZO2</i> mRNA m6A modification
Authors: Ji-Fei Ding, Bin Tu, Kai Song, Zhen-Yu Liu, Li-Chan Lin, Zhi-Yan Liu, Yan Shi, Jing-Jing Yang, Jian-Yuan Zhao, Hui Tao
Journal: Cardiovascular Research (2024)

Abstract Aims Mechanosensitive (MS) ion channels play a key role in heart development, physiology, and disease. However, little is known about the molecular mechanisms of the MS non-selective cationic channel Piezo family in cardiac fibrosis. Methods and results Mice were treated with ISO/Ang-II/TAC to induce cardiac fibrosis. AAV9 carrying POSTN promoter-driven small hairpin RNA targeting YTHDF1, and Piezo2 were administered to ISO mice to investigate their roles in cardiac fibrosis. RNA-seq, single-cell sequencing, and histological and biochemical analyses were performed to determine the mechanism by which YTHDF1 regulates Piezo2 expression in cardiac fibrosis. Piezo2 was reconstituted in YTHDF1-deficient cardiac fibroblasts (CFs) and mouse hearts to study its effects on CF autophagy and fibrosis. Piezo2 but not Piezo1 expression increased in experimental cardiac fibrosis and TGF-β1-induced CFs. Fibroblast-specific Piezo2 deficiency ameliorated fibroblast activation and autophagy and inhibited cardiac fibrosis. Mechanistically, Piezo2 up-regulation was associated with elevated m6A mRNA levels. Site-specific m6A modifications at peak_26355 were crucial for regulating the binding of YTHDF1 to Piezo2 mRNA and inducing Piezo2 translation. Notably, Piezo2 epitranscriptomic repression ameliorated experimental cardiac fibrosis. Conclusions We demonstrated a novel epitranscriptomic mechanism through which YTHDF1 recognizes Piezo2 and controls cardiac fibroblast autophagy and fibrosis through m6A-dependent modulation. Our findings provide new insights for the development of preventive measures for cardiac fibrosis.
Causal cardiovascular risk factors for dementia – insights from observational and genetic studies
Authors: Emilie Westerlin Kjeldsen, Ruth Frikke-Schmidt
Journal: Cardiovascular Research (2024)

Abstract The escalating prevalence of dementia worldwide necessitates preventive strategies to mitigate its extensive health, psychological, and social impacts. As the prevalence of dementia continues to rise, gaining insights into its risk factors and causes becomes paramount, given the absence of a definitive cure. Cardiovascular disease has emerged as a prominent player in the complex landscape of dementia. Preventing dyslipidaemia, unhealthy western-type diets, hypertension, diabetes, being overweight, physical inactivity, smoking, and high alcohol intake have the potential to diminish not only cardiovascular disease but also dementia. The purpose of this review is to present our current understanding of cardiovascular risk factors for Alzheimer’s disease and vascular dementia (VaD) by using clinical human data from observational, genetic studies and clinical trials, while elaborating on potential mechanisms. Hypertension and Type 2 diabetes surface as significant causal risk factors for both Alzheimer’s disease and VaD, as consistently illustrated in observational and Mendelian randomization studies. Anti-hypertensive drugs and physical activity have been shown to improve cognitive function in clinical trials. Important to note is that robust genome-wide association studies are lacking for VaD, and indeed more and prolonged clinical trials are needed to establish these findings and investigate other risk factors. Trials should strategically target individuals at the highest dementia risk, identified using risk charts incorporating genetic markers, biomarkers, and cardiovascular risk factors. Understanding causal risk factors for dementia will optimize preventive measures, and the implementation of well-known therapeutics can halt or alleviate dementia symptoms if started early. Needless to mention is that future health policies should prioritize primordial prevention from early childhood to prevent risk factors from even occurring in the first place. Together, understanding the role of cardiovascular risk factors in dementia, improving genome-wide association studies for VaD, and advancing clinical trials are crucial steps in addressing this significant public health challenge.
Neuroimmune cross-talk in heart failure
Authors: Sabrina Montuoro, Francesco Gentile, Alberto Giannoni
Journal: Cardiovascular Research (2024)

Abstract Heart failure (HF) is characterized by autonomic nervous system (ANS) imbalance and low-grade chronic inflammation. The bidirectional relationship between the ANS and immune system (IS) is named ‘neuroimmune cross-talk’ (NICT) and is based on common signaling molecules, receptors, and pathways. NICT may be altered in HF, and neuroinflammation seems to be a main driver of HF progression. In HF, heightened sympathetic nerve activity triggers inflammatory cascades that lead to cardiomyocyte death and myocardial interstitial fibrosis. Concurrently, parasympathetic withdrawal may impair the cholinergic anti-inflammatory pathway, with a less effective immune response to infections or inflammatory events. Additionally, microglial activation and inflammatory molecules contribute to autonomic imbalance by acting on central nuclei and peripheral visceral feedbacks, which in turn promote adverse cardiac remodeling, HF decompensation, and potentially life-threatening arrhythmias. Therefore, neuroinflammation has been identified as a potential target for treatment. Pharmacological antagonism of the neurohormonal system remains the cornerstone of chronic HF therapy. While some drugs used in HF management may have additional benefits due to their anti-inflammatory properties, clinical trials targeting inflammation in patients with HF have so far produced inconclusive results. Nevertheless, considering the pathophysiological relevance of NICT, its modulation seems an appealing strategy to optimize HF management. Current research is therefore investigating novel pharmacological targets for anti-inflammatory drugs, and the immunomodulatory properties of denervation approaches and bioelectronic medicine devices targeting NICT and neuroinflammation in HF. A deeper understanding of the complex relationship between the ANS and IS, as outlined in this review, could therefore facilitate the design of future studies aimed at improving outcomes by targeting NICT in patients with HF.
Cardiovascular Considerations During Cancer Therapy
Authors: Darryl P Leong, Sarah Waliany, Husam Abdel-Qadir, Katelyn M Atkins, Tomas G Neilan, Ninian N Lang, Jennifer E Liu, Anne H Blaes, Hira S Mian, Heather N Moore, Ludhmila A Hajjar, Alicia K Morgans, Peter M Ellis, Susan Dent
Journal: JACC CardioOncology (2024)
Predictors of Atrial Fibrillation After Thoracic Radiotherapy
Authors: Santino Butler, Hyunsoo No, Felicia Guo, Gibran Merchant, Natalie J Park, Scott Jackson, Daniel Eugene Clark, Lucas Vitzthum, Alex Chin, Kathleen Horst, Richard T Hoppe, Billy W Loo, Maximilian Diehn, Michael Sargent Binkley
Journal: JACC CardioOncology (2024)

Atrial fibrillation (AF) has been associated with thoracic radiotherapy, but the specific risk with irradiating different cardiac substructures remains unknown. This study sought to examine the relationship between irradiation of cardiac substructures and the risk of clinically significant (grade ≥3) AF. We analyzed data from patients who underwent definitive radiotherapy for localized cancers (non-small cell lung, breast, Hodgkin lymphoma, or esophageal) at our institution between 2004 and 2022. The 2-Gy fraction equivalent dose was calculated for cardiac substructures, including the pulmonary veins (PVs), left atrium, sinoatrial node, and left coronary arteries (the left main, left anterior descending, and left circumflex arteries). Competing risk models (subdistribution HRs [sHRs]) for AF incidence were adjusted for the Mayo AF risk score (MAFRS). Among 539 patients, the median follow-up was 58.8 months. The 5-year cumulative incidence of AF was 11.1% for non-small cell lung cancer, 8.3% for esophageal cancer, 1.3% for breast cancer, and 0.8% for Hodgkin lymphoma. Increased AF risk was associated with a higher PV maximum dose (d PV d
Incident Myocardial Infarction, Heart Failure, and Oncologic Outcomes in Breast Cancer Survivors
Authors: Oscar Calvillo-Argüelles, Paaladinesh Thavendiranathan, Yue Chen, Jiming Fang, Peter C Austin, Eitan Amir, Douglas S Lee, Husam Abdel-Qadir
Journal: JACC CardioOncology (2024)

Cardiovascular disease (CVD) is associated with higher rates of incident cancer. Data are scarce regarding the association of incident CVD with oncologic outcomes after a cancer diagnosis. This study sought to determine whether incident myocardial infarction (MI) or heart failure (HF) in breast cancer survivors is associated with oncologic outcomes. This was a population-based cohort study in Ontario, Canada, using linked administrative data sets of women diagnosed with first breast cancer between April 1, 2007, and March 31, 2015. A landmark analysis was conducted of women alive 2 years after breast cancer diagnosis, aged ≥40 years, and with available staging data and without recurrent/distant disease or preceding CVD. The exposure was a composite of MI and/or HF after the landmark date. The outcomes were cancer mortality, new non-breast malignancy diagnosis, and new chemotherapy initiation. Multivariable cause-specific hazards regression was used to determine the association of incident MI/HF (time-varying exposure) with outcomes. A total of 30,694 women (median age of 60 years) were included, of whom 1,346 developed incident MI/HF at a median of 3.9 years after the landmark date. At 5 years, the cumulative incidence was 5.9% (95% CI: 5.6%-6.1%) for cancer death, 4.3% (95% CI: 4.1%-4.6%) for non-breast malignancy, and 25.7% (95% CI: 25.2%-26.2%) for new chemotherapy. Incident MI/HF was associated with a higher hazard of cancer death (HR: 3.94; 95% CI: 3.38-4.59), non-breast malignancy (HR: 1.39; 95% CI: 1.06-1.82), and new chemotherapy (HR: 1.25; 95% CI: 1.02-1.53). Incident MI and/or HF after breast cancer treatment are associated with higher hazards of adverse oncologic outcomes, highlighting the need to prioritize care for these patients.
Liver transplantation for nonstandard oncological indications: Are we there yet?
Authors: Beat Moeckli, Joana Rodrigues Ribeiro, Christian Toso
Journal: Hepatology (2024)

Department of surgery, University of Geneva, Geneva University Hospitals, Geneva Switzerland Abbreviations: CRLM, Colorectal Liver Metastases; iCC, Intrahepatic Cholangiocarcinoma; IPD, Individual Patient Data; LT, Liver Transplantation; NELM, neuroendocrine tumor liver metastasis (NELM); phCC, Perihilar Cholangiocarcinoma; TO, Transplant Oncology; UNOS, United Network for Organ Sharing. Correspondence Christian Toso, Division of Digestive Surgery, Department of Surgery, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland. E-mail: [email protected]
Effects of Obesity and Hyperglycemia on Postprandial Insulin-Mediated and Non–Insulin-Mediated Glucose Disposal
Authors: Bettina Mittendorfer, Bruce W. Patterson, Gordon I. Smith, Mihoko Yoshino, Samuel Klein
Journal: Diabetes Care (2024)

OBJECTIVE To evaluate total, insulin-mediated, and non–insulin-mediated glucose disposal (TGD, IMGD, and NIMGD) after ingesting glucose in people with obesity and different glycemic status. RESEARCH DESIGN AND METHODS We developed and validated a new glucose tracer model in conjunction with an oral glucose tolerance test to determine IMGD, NIMGD, and TGD (sum of IMGD and NIMGD) after glucose ingestion in four groups of people: 1) lean with normal glucose tolerance (NGT), 2) obese with insulin resistance and NGT due to hyperinsulinemia (Ob-NGT group), 3) obese with insulin resistance and impaired glucose tolerance (IGT) due to inadequate hyperinsulinemia (Ob-IGT group), and 4) obese with insulin resistance and type 2 diabetes due to marked insulin insufficiency (Ob-T2D group). In addition, we evaluated the effect of intensive lifestyle therapy (ILT) that caused ∼15% weight loss on IMGD and NIMGD in people with obesity and type 2 diabetes (T2D). RESULTS IMGD progressively decreased and NIMGD progressively increased from lean to Ob-NGT to Ob-IGT to Ob-T2D. IMGD accounted for about 70%, 65%, 50%, and 20% of TGD, and NIMGD accounted for ∼40%, 35%, 50%, and 80% of TGD in lean, Ob-NGT, Ob-IGT and Ob-T2D, respectively. Although NIMGD was approximately twofold and approximately threefold higher in Ob-IGT and Ob-T2D compared with Ob-NGT, NIMGD only partially compensated for markedly impaired IMGD in the Ob-IGT and Ob-T2D. ILT in people with obesity and T2D increased IMGD and decreased NIMGD. CONCLUSIONS NIMGD is a major mechanism of postprandial TGD in people with insulin resistance and inadequate insulin secretion.
Recent Advances in Nanomaterial‐Mediated Cell Death for Cancer Therapy
Authors: Min Luo, Yuan‐min Wang, Fu‐kun Zhao, Yong Luo
Journal: Advanced Healthcare Materials (2024)

Abstract Nanomedicine has shown great anticancer potential by disrupting redox homeostasis and increasing the levels of oxidative stress, but the therapeutic effect is limited by factors including the intrinsic self‐protection mechanism of tumors. Cancer cell death can be induced by the exploration of different cell death mechanisms, such as apoptosis, pyroptosis, necroptosis, cuproptosis, and ferroptosis. The merging of nanotechnology with biomedicine has provided tremendous opportunities to construct cell death‐based nanomedicine for innovative cancer therapy. Nanocarriers are not only used for the targeted delivery of cell death inducers, but also as therapeutic components to induce cell death to achieve efficient tumor treatment. This review focuses on seven cell death modalities mediated by nanomaterials, such as apoptosis, pyroptosis, necroptosis, ferroptosis, cuprotosis, immunogenic cell death, and autophagy. The mechanisms of these seven cell death modalities are described in detail, as well as the preparation of nanomaterials that induce them and the mechanisms, they used to exert their effects. Finally, this work describes the potential future development based on the current knowledge related to cell death induced by nanomaterials.
Structural variation reshapes population gene expression and trait variation in 2,105 Brassica napus accessions
Authors: Yuanyuan Zhang, Zhiquan Yang, Yizhou He, Dongxu Liu, Yueying Liu, Congyuan Liang, Meili Xie, Yupeng Jia, Qinglin Ke, Yongming Zhou, Xiaohui Cheng, Junyan Huang, Lijiang Liu, Yang Xiang, Harsh Raman, Daniel J. Kliebenstein, Shengyi Liu, Qing-Yong Yang
Journal: Nature Genetics (2024)

Although individual genomic structural variants (SVs) are known to influence gene expression and trait variation, the extent and scale of SV impact across a species remain unknown. In the present study, we constructed a reference library of 334,461 SVs from genome assemblies of 16 representative morphotypes of neopolyploid Brassica napus accessions and detected 258,865 SVs in 2,105 resequenced genomes. Coupling with 5 tissue population transcriptomes, we uncovered 285,976 SV-expression quantitative trait loci (eQTLs) that associate with altered expression of 73,580 genes. We developed a pipeline for the high-throughput joint analyses of SV-genome-wide association studies (SV-GWASs) and transcriptome-wide association studies of phenomic data, eQTLs and eQTL-GWAS colocalization, and identified 726 SV-gene expression-trait variation associations, some of which were verified by transgenics. The pervasive SV impact on how SV reshapes trait variation was demonstrated with the glucosinolate biosynthesis and transport pathway. The study highlighting the impact of genome-wide and species-scale SVs provides a powerful methodological strategy and valuable resources for studying evolution, gene discovery and breeding.
Spatially resolved gene signatures of white matter lesion progression in multiple sclerosis
Authors: Astrid M. Alsema, Marion H. C. Wijering, Anneke Miedema, Janssen M. Kotah, Mirjam Koster, Merel Rijnsburger, Hilmar R. J. van Weering, Helga E. de Vries, Wia Baron, Susanne M. Kooistra, Bart J. L. Eggen
Journal: Nature Neuroscience (2024)
Investigation of the diagnostic accuracy of basophil activation test for allergic phenotypes of rhinitis
Authors: Almudena Testera‐Montes, Adriana Ariza, Rosa Alba Sola‐Martinez, Carlos Jose Aranda, Guillermo Bentabol‐Ramos, Dulce Sanchez‐Torralvo, Cristobalina Mayorga, Maria Jose Torres, Ibon Eguiluz‐Gracia, Carmen Rondon
Journal: Allergy (2024)

Basophil activation test (BAT) might be an alternative to nasal allergen challenge (NAC) to identify the allergic etiology in rhinitis patients. Here, we investigate the diagnostic performance of BAT for allergic phenotypes of rhinitis.
Foreign Body Immune Response to Zwitterionic and Hyaluronic Acid Granular Hydrogels Made with Mechanical Fragmentation
Authors: Maryam Asadikorayerm, Patrick Weber, František Surman, Anna Puiggalí‐Jou, Marcy Zenobi‐Wong
Journal: Advanced Healthcare Materials (2024)

Abstract Granular hydrogels have recently attracted the attention for diverse tissue engineering applications due to their versatility and modularity. Despite previous studies showing enhanced viability and metabolism of cells encapsulated in these hydrogels, the in vitro immune response and long‐term fibrotic response of these scaffolds have not been well characterized. Here, bulk and granular hydrogels are studied based on synthetic zwitterionic (ZI) and natural polysaccharide hyaluronic acid (HA) made with mechanical fragmentation. In vitro, immunomodulatory studies show an increased stimulatory effect of HA granular hydrogels compared to bulk, while both bulk and granular ZI hydrogels do not induce an inflammatory response. Subcutaneous implantation in mice shows that both ZI and HA granular hydrogels resulted in less collagen capsule deposition around implants compared to bulk HA hydrogels 10 weeks after implantation. Moreover, the HA granular hydrogels are infiltrated by host cells, including macrophages and mature blood vessels, in a porosity‐dependent manner. However, a large number of cells, including multinucleated giant cells as well as blood vessels, surround bulk and granular ZI hydrogels and are not able to infiltrate. Overall, this study provides new insights on the long‐term stability and fibrotic response of granular hydrogels, paving the way for future studies and applications.
Synthetic Nanocapsules with Tailored Surface Chemistry for Lung‐Specific Protein Delivery and Cancer Immunotherapy
Authors: Qizhen Zheng, Rui Yao, Ji Liu, Tianli Luo, Tianyu Ma, Ming Wang
Journal: Advanced Healthcare Materials (2024)

Abstract Efficient delivery of therapeutic proteins remains a major challenge in developing effective immunotherapies and treatments for genetic disorders due to the limited tissue targeting capability of native proteins. In this study, the design and synthesis of protein nanocapsules (NCs) that achieve lung‐specific delivery of therapeutic proteins are reported. These NCs are synthesized through a surface modification process that involves coating protein with functional monomers and cross‐linkers, followed by in situ polymerization to create a protective shell on the protein surface with tailored surface chemistry. This approach preserves protein integrity and significantly enhances delivery efficiency and tissue specificity. Notably, it is shown that protein@NC with guanidine‐rich surfaces exhibit exceptional lung‐targeting capabilities. This is likely attributed to the formation of a vitronectin‐rich protein corona, which facilitates receptor‐mediated endocytosis by lung cells. The platform effectively delivers various proteins, such as ovalbumin, to antigen‐presenting cells (APCs) in the lung, thereby enhancing antigen presentation and offering a promising strategy for cancer immunotherapy. These findings provide a significant advancement in tissue‐specific protein delivery and hold the potential for targeted cancer immunotherapy.
Engineering Injectable and Highly Interconnected Porous Silk Fibroin Microspheres for Tissue Regeneration
Authors: Ji Ding, Zhaojun Cheng, Yulong Ma, Tongxing Zhang, Lilong Du, Xiaobing Jiang, Meifeng Zhu, Wen Li, Baoshan Xu
Journal: Advanced Healthcare Materials (2024)

Abstract Injectable porous microspheres represent a promising therapeutic platform for cell delivery, drug delivery, and tissue regeneration. Yet, the engineering of silk fibroin microspheres with a highly interconnected porous structure remains an unsolved challenge. In this study, a simple and efficient method is developed that does not require the use of organic solvents to prepare silk fibroin microspheres with a predictable structure. Through extensive screening, the addition of glucose is found to direct the formation of a highly interconnected porous structure from the interior to the surface of silk fibroin microspheres. Compared to silk fibroin microspheres (SF microspheres) produced through a combination of electro‐spray, cryopreservation, and freeze drying, silk fibroin‐glucose microspheres (SF‐Glu microspheres) demonstrates enhanced capabilities in promoting cell adhesion and proliferation in vitro. Both SF‐Glu and SF microspheres exhibit the capacity to maintain the sustained release kinetics of the loaded model drug. Furthermore, SF‐Glu microspheres facilitate the recruitment of endogenous cells, capillary migration, and macrophage phenotype switch following subcutaneous injection in the rats. This study opens a new avenue for the construction of porous silk fibroin microspheres, which could lead to a broader range of applications in regenerative medicine.