tbuckley/cabot-search huggingface dataset:
Nanoengineered cargo with targeted in vivo Foxo3 gene editing modulated mitophagy of chondrocytes to alleviate osteoarthritis
Authors: Manyu Chen, Yuan Liu, Quanying Liu, Siyan Deng, Yuhan Liu, Jiehao Chen, Yaojia Zhou, Xiaolin Cui, Jie Liang, Xingdong Zhang, Yujiang Fan, Qiguang Wang, Bin Shen
Journal: Acta Pharmaceutica Sinica B (2024)

Mitochondrial dysfunction in chondrocytes is a key pathogenic factor in osteoarthritis (OA), but directly modulating mitochondria in vivo remains a significant challenge. This study is the first to verify a correlation between mitochondrial dysfunction and the downregulation of the FOXO3 gene in the cartilage of OA patients, highlighting the potential for regulating mitophagy via FOXO3 gene modulation to alleviate OA. Consequently, we developed a chondrocyte-targeting CRISPR/Cas9-based FOXO3 gene-editing tool (FoxO3) and integrated it within a nanoengineered 'truck' (NETT, FoxO3-NETT). This was further encapsulated in injectable hydrogel microspheres (FoxO3-NETT@SMs) to harness the antioxidant properties of sodium alginate and the enhanced lubrication of hybrid exosomes. Collectively, these FoxO3-NETT@SMs successfully activate mitophagy and rebalance mitochondrial function in OA chondrocytes through the Foxo3 gene-modulated PINK1/Parkin pathway. As a result, FoxO3-NETT@SMs stimulate chondrocytes proliferation, migration, and ECM production in vitro, and effectively alleviate OA progression in vivo, demonstrating significant potential for clinical applications.
Heterozygous variant of CYP2C8*3 is a protective factor for developing post-ERCP pancreatitis
Authors: Mike J P De Jong, Romy N Kuipers, Joost P H Drenth, René H M Te Morsche, Foke Van Delft, Peter D Siersema, Christina J Sperna Weiland, Robert C Verdonk, Niels G Venneman, Muhammed Hadithi, Tanya M Bisseling, Marco J Bruno, Erwin-Jan M van Geenen
Journal: Clinical Gastroenterology and Hepatology (2024)
Deubiquitinases as novel therapeutic targets for diseases
Authors: Yali Xian, Jing Ye, Yu Tang, Nan Zhang, Cheng Peng, Wei Huang, Gu He
Journal: MedComm (2024)

Deubiquitinating enzymes (DUBs) regulate substrate ubiquitination by removing ubiquitin or cleaving within ubiquitin chains, thereby maintaining cellular homeostasis. Approximately 100 DUBs in humans counteract E3 ubiquitin ligases, finely balancing ubiquitination and deubiquitination processes to maintain cellular proteostasis and respond to various stimuli and stresses. Given their role in modulating ubiquitination levels of various substrates, DUBs are increasingly linked to human health and disease. Here, we review the DUB family, highlighting their distinctive structural characteristics and chain-type specificities. We show that DUB family members regulate key signaling pathways, such as NF-κB, PI3K/Akt/mTOR, and MAPK, and play crucial roles in tumorigenesis and other diseases (neurodegenerative disorders, cardiovascular diseases, inflammatory disorders, and developmental diseases), making them promising therapeutic targets Our review also discusses the challenges in developing DUB inhibitors and underscores the critical role of the DUBs in cellular signaling and cancer. This comprehensive analysis enhances our understanding of the complex biological functions of the DUBs and underscores their therapeutic potential.
Strengthening Romania's health workforce: leading by example
Authors: Rosemary James, Cris Scotter, Alexandru Florin Rogobete, Teodor Cristian Blidaru, Alexandru Rafila, Gareth Rees, Ioana Novac, Daphne Kaiteladou, Yanina Andersen, Khamis Al-Alawy, Olympia Konstantakopoulou, Natasha Azzopardi Muscat, Tomas Zapata, Nicolae Dragoș Garofil
Journal: The Lancet Regional Health - Europe (2024)
Expression profile of Bcl‐2 family proteins in newly diagnosed multiple myeloma patients
Authors: Cristina De Ramón, Elizabeta A. Rojas, Irena Misiewicz‐Krzeminska, Ignacio J. Cardona‐Benavides, Myriam Cuadrado, Isabel Isidro, María‐José Calasanz, Manuela Fernandez, Ramón García‐Sanz, Noemi Puig, M. Teresa Cedena, Bruno Paiva, Laura Rosiñol, Joaquín Martínez‐López, Joan Bladé, Juan J. Lahuerta, Jesús F. San Miguel, María V. Mateos, Luis A. Corchete, Norma C. Gutiérrez
Journal: HemaSphere (2024)

Abstract Antiapoptotic Bcl‐2 family proteins are involved in myeloma cell survival. To date, their expression in multiple myeloma (MM) patients has mostly been analyzed at the RNA level. In the present study, we quantified for the first time the protein expression of the Bcl2‐family members using a capillary electrophoresis immunoassay in 120 newly diagnosed MM patients, aged ≤65 years, treated in the context of the PETHEMA/GEM2012 study. We found that the pattern of expression of Bcl‐2 family proteins was highly heterogeneous among patients. Although cases with t(11;14) had significantly higher levels of Bcl‐2/Bcl‐xL and Bcl‐2+Bim+Bax/Bcl‐xL ratios than those without t(11;14), the presence of this translocation was not synonymous with such high levels of expression. Conversely, some patients with other genetic alterations also showed higher levels of those ratios. Survival analysis revealed that the high expression of Bad and Puma proteins was associated with significantly longer overall survival ( p = 0.001 and p &lt; 0.001, respectively). Bcl‐2 protein ratios predicting sensitivity to venetoclax in vitro were also able to distinguish patients with shorter time to progression after triplet‐based induction therapy and ASCT. This is the first study to assess the expression of the most important Bcl‐2 family proteins by a quantitative method in a large set of MM patients according to their cytogenetic abnormalities. We shed light on the impact of these proteins on MM prognosis, which could help to consider the levels of proteins involved in apoptosis in the development of new therapeutic strategies.
Radiomics and radiogenomics: extracting more information from medical images for the diagnosis and prognostic prediction of ovarian cancer
Authors: Song Zeng, Xin-Lu Wang, Hua Yang
Journal: Military Medical Research (2024)

Abstract Ovarian cancer (OC) remains one of the most lethal gynecological malignancies globally. Despite the implementation of various medical imaging approaches for OC screening, achieving accurate differential diagnosis of ovarian tumors continues to pose significant challenges due to variability in image performance, resulting in a lack of objectivity that relies heavily on the expertise of medical professionals. This challenge can be addressed through the emergence and advancement of radiomics, which enables high-throughput extraction of valuable information from conventional medical images. Furthermore, radiomics can integrate with genomics, a novel approach termed radiogenomics, which allows for a more comprehensive, precise, and personalized assessment of tumor biological features. In this review, we present an extensive overview of the application of radiomics and radiogenomics in diagnosing and predicting ovarian tumors. The findings indicate that artificial intelligence methods based on imaging can accurately differentiate between benign and malignant ovarian tumors, as well as classify their subtypes. Moreover, these methods are effective in forecasting survival rates, treatment outcomes, metastasis risk, and recurrence for patients with OC. It is anticipated that these advancements will function as decision-support tools for managing OC while contributing to the advancement of precision medicine.
Activated neutrophil membrane-coated tRF-Gly-CCC nanoparticles for the treatment of aortic dissection/aneurysm
Authors: Tian-Xiang Li, Yan-Yan Yang, Jin-Bao Zong, Min Li, Xiu-Xiu Fu, Xiao-Xin Jiang, Wen-Tao Wang, Xiao-Qian Li, Hong-Zhao Qi, Tao Yu
Journal: Journal of Controlled Release (2024)
Lighthouses Illuminating Tumor Metastasis: The Application of Fluorescent Probes in the Localization and Imaging Metastatic Lymph Nodes Across Various Tumors
Authors: Qi Dang, Linhao Zhang, Huipeng Ma, Xiaoshan Sun, Anguo Ren, Jiuyang Chen, Xiaohua Huang, Boyu Zhang, Wen Sun
Journal: Biomaterials (2024)
Vascular endothelial growth factor B-mediated fatty acid flux in the adipose-kidney axis contributes to lipotoxicity in diabetic kidney disease.
Authors: Erika Folestad, Annika Mehlem, Frank Chenfei Ning, Timo Oosterveld, Isolde Palombo, Jaskaran Singh, Hannes Olauson, Anna Witasp, Anders Thorell, Peter Stenvinkel, Kerstin Ebefors, Jenny Nyström, Ulf Eriksson, Annelie Falkevall
Journal: Kidney International (2024)

A common observation in diabetic kidney disease is lipid accumulation, but the mechanism(s) underlying this pathology is unknown. Inhibition of Vascular endothelial growth factor B (VEGF-B) signaling was shown to prevent glomerular lipid accumulation and ameliorated diabetic kidney disease in experimental models. Here, we examined kidney biopsies from patients with Type 2 (84 %) and Type 1 diabetes (16 %), combined with data mining of RNA-seq dataset analyses in patients with diabetic kidney disease. In glomeruli, mesangial cell-derived VEGF-B expression was increased, and glomerular lipid accumulation positively correlated with impaired kidney function. Tubular lipid accumulation also associated with kidney dysfunction but was independent of tubular-derived VEGF-B expression. In vitro, the uptake of the fatty acid analogue, BODIPY-FA, was quantified. VEGF-B treatment increased BODIPY-FA uptake in endothelial cells, whilst pre-incubation with neutralizing antibodies against VEGF-B and its receptor VEGFR1 abolished this uptake. Transcriptome analyses of kidney and white adipose tissue from diabetic macaques showed that VEGF-B expression was higher in white adipose tissue than in kidney, and expression of VEGF-B was increased in white adipose tissue from patients with diabetic kidney disease. Analyzes in diabetic transgenic mice demonstrated that expression of VEGF-B in adipocytes determined the lipolytic activity, dyslipidemia, kidney lipid accumulation and the development of diabetic kidney disease. Overall, VEGF-B is a regulator of kidney lipotoxicity in diabetic kidney disease, by controlling white adipose tissue lipolysis as well as endothelial fatty acid transport in glomeruli. Our data propose that assessment of kidney lipid accumulation, and VEGF-B expression can serve as biomarkers for early diabetic kidney disease.
Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors
Authors: Silvana Bazua-Valenti, Matthew R Brown, Jason Zavras, Magdalena Riedl Khursigara, Elizabeth Grinkevich, Eriene-Heidi Sidhom, Keith H Keller, Matthew Racette, Moran Dvela-Levitt, Catarina Quintanova, Hasan Demirci, Sebastian Sewerin, Alissa C Goss, John Lin, Hyery Yoo, Alvaro S Vaca Jacome, Malvina Papanastasiou, Namrata Udeshi, Steven A Carr, Nina Himmerkus, Markus Bleich, Kerim Mutig, Sebastian Bachmann, Jan Halbritter, Stanislav Kmoch, Martina Živná, Kendrah Kidd, Anthony J Bleyer, Astrid Weins, Seth L Alper, Jillian L Shaw, Maria Kost-Alimova, Juan Lorenzo B Pablo, Anna Greka
Journal: Journal of Clinical Investigation (2024)

The trafficking dynamics of uromodulin (UMOD), the most abundant protein in human urine, play a critical role in the pathogenesis of kidney disease. Monoallelic mutations in the UMOD gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), an incurable genetic disorder that leads to kidney failure. The disease is caused by the intracellular entrapment of mutant UMOD in kidney epithelial cells, but the precise mechanisms mediating disrupted UMOD trafficking remain elusive. Here, we report that transmembrane Emp24 protein transport domain-containing (TMED) cargo receptors TMED2, TMED9, and TMED10 bind UMOD and regulate its trafficking along the secretory pathway. Pharmacological targeting of TMEDs in cells, in human kidney organoids derived from patients with ADTKD-UMOD, and in mutant-UMOD-knockin mice reduced intracellular accumulation of mutant UMOD and restored trafficking and localization of UMOD to the apical plasma membrane. In vivo, the TMED-targeted small molecule also mitigated ER stress and markers of kidney damage and fibrosis. Our work reveals TMED-targeting small molecules as a promising therapeutic strategy for kidney proteinopathies.
Pathobiont-driven antibody sialylation through IL-10 undermines vaccination
Authors: Chih-Ming Tsai, Irshad A Hajam, J R Caldera, Austin Wt Chiang, Cesia Gonzalez, Xin Du, Biswa Choudhruy, Haining Li, Emi Suzuki, Fatemeh Askarian, Ty'Tianna Clark, Brian Lin, Igor H Wierzbicki, Angelica M Riestra, Douglas J Conrad, David J Gonzalez, Victor Nizet, Nathan E Lewis, George Y Liu
Journal: Journal of Clinical Investigation (2024)

The pathobiont Staphylococcus aureus (Sa) induces nonprotective antibody imprints that underlie ineffective staphylococcal vaccination. However, the mechanism by which Sa modifies antibody activity is not clear. Herein, we demonstrate that IL-10 is the decisive factor that abrogates antibody protection in mice. Sa-induced B10 cells drive antigen-specific vaccine suppression that affects both recalled and de novo developed B cells. Released IL-10 promotes STAT3 binding upstream of the gene encoding sialyltransferase ST3gal4 and increases its expression by B cells, leading to hyper-α2,3sialylation of antibodies and loss of protective activity. IL-10 enhances α2,3sialylation on cell-wall-associated IsdB, IsdA, and MntC antibodies along with suppression of the respective Sa vaccines. Consistent with mouse findings, human anti-Sa antibodies as well as anti-pseudomonal antibodies from cystic fibrosis subjects (high IL-10) are hypersialylated, compared with anti-Streptococcus pyogenes and pseudomonal antibodies from normal individuals. Overall, we demonstrate a pathobiont-centric mechanism that modulates antibody glycosylation through IL-10, leading to loss of staphylococcal vaccine efficacy.
Interleukin 10 drives Staphylococcus aureus imprinting and vaccine failure in murine models via antibody glycosylation
Authors: Victor J. Torres
Journal: Journal of Clinical Investigation (2024)

Despite many attempts, there is currently no approved vaccine to prevent Staphylococcus aureus infections. Preclinical vaccination models have failed to predict vaccine efficacy in humans as S. aureus exposure in humans imprints an immune response that is lacking in naive animals. In this issue of the JCI, Tsai and colleagues identify the cytokine IL-10 as the driver of humoral imprinting by S. aureus. Upon vaccination, S. aureus-experienced animals produced copious levels of IL-10, resulting in the hyper-α2,3 sialylation of antibodies, which interfered with the phagocytic-promoting properties of the vaccine-elicited anti-S. aureus antibodies. These findings correlate with the observation that hyperproduction of IL-10 in humans also induces hyper-α2,3 sialylation of antibodies and provide a possible mechanism for previous vaccine failures.
Balancing immune response: SHP1 controls neutrophil activation in inflamed lungs
Authors: Laxman Ghimire, Hongbo R. Luo
Journal: Journal of Clinical Investigation (2024)

Following respiratory infection or injury, neutrophil hyperactivation can damage surrounding lung tissue by releasing harmful compounds. In this issue of the JCI, Moussavi-Harami and colleagues identified tyrosine phosphatase SHP1 as a key negative regulator of neutrophil activation in acute respiratory distress syndrome (ARDS). Neutrophil-specific Shp1 disruption leads to hyperinflammation, pulmonary hemorrhage, and increased mortality in both sterile and pathogen-induced acute lung injury (ALI). Large intravascular neutrophil clusters and excessive PAD4-independent neutrophil extracellular traps (NETs) were identified as key features of lung injury. Mechanistically, Shp1 deficiency resulted in uncontrolled SYK kinase activation, driving chaotic neutrophil hyperactivation and inflammation.
The muscle stem cell case of Benjamin Button: rejuvenating muscle regenerative capacity through nutraceuticals
Authors: Taylor Peach, Mattia Quattrocelli
Journal: Journal of Clinical Investigation (2024)

Aging negatively affects the capacity of muscle stem cells (MuSCs) to regenerate muscle. In this issue of the JCI, Ancel, Michaud, and colleagues used a high-content imaging screen to identify nicotinamide and pyridoxine as promoters of MuSC function. The combination of the two compounds promoted MuSC function in vivo in aged mice and in primary cells isolated from older individuals. Furthermore, the two compounds were lower in the circulation of older men, paralleling decreases in lean mass and gait speed. These results advance the translational perspective of rejuvenating MuSC function through nutraceuticals.
Immune-molecular interactions in high-grade serous ovarian cancer distinguish long-term survivors
Authors: Jeanette E Boudreau
Journal: Journal of Clinical Investigation (2024)

The approach and efficacy of treatments for high-grade serous carcinoma (HGSC) of the ovary have changed little in decades. Although numerous studies demonstrated immune infiltration as frequent and prognostically beneficial, clinical trials of immunotherapies have generated benefit in fewer than 15% of patients. In this issue of the JCI, Nelson and colleagues compiled 1,233 HGSC samples from patients across four continents and compared the molecular and immunologic features that associate with long-term survival (greater than 10 years). Diversity among HGSC tumors is well defined, but this study explored the combined influence of immunologic and molecular features. Long-term survivors harbored tumors with high epithelial content and overrepresentation of the C4/differentiated molecular signature, with cytotoxic T and B cells infiltrating to the tumor epithelium and stroma, respectively. These findings highlight features that might underly poor responsiveness to existing immunotherapies of most HGSC tumors and considerations for the design of future, more precise treatments for HGSC.
SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts
Authors: Leigh Goedeke, Yina Ma, Rafael C Gaspar, Ali Nasiri, Jieun Lee, Dongyan Zhang, Katrine Douglas Galsgaard, Xiaoyue Hu, Jiasheng Zhang, Nicole Guerrera, Xiruo Li, Traci LaMoia, Brandon T Hubbard, Sofie Haedersdal, Xiaohong Wu, John Stack, Sylvie Dufour, Gina Marie Butrico, Mario Kahn, Rachel J Perry, Gary W Cline, Lawrence H Young, Gerald I Shulman
Journal: Journal of Clinical Investigation (2024)

Previous studies highlight the potential for sodium-glucose cotransporter type 2 (SGLT2) inhibitors (SGLT2i) to exert cardioprotective effects in heart failure by increasing plasma ketones and shifting myocardial fuel utilization toward ketone oxidation. However, SGLT2i have multiple in vivo effects and the differential impact of SGLT2i treatment and ketone supplementation on cardiac metabolism remains unclear. Here, using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology combined with infusions of [13C6]glucose or [13C4]βOHB, we demonstrate that acute SGLT2 inhibition with dapagliflozin shifts relative rates of myocardial mitochondrial metabolism toward ketone oxidation, decreasing pyruvate oxidation with little effect on fatty acid oxidation in awake rats. Shifts in myocardial ketone oxidation persisted when plasma glucose levels were maintained. In contrast, acute βOHB infusion similarly augmented ketone oxidation, but markedly reduced fatty acid oxidation and did not alter glucose uptake or pyruvate oxidation. After inducing heart failure, dapagliflozin increased relative rates of ketone and fatty acid oxidation, but decreased pyruvate oxidation. Dapagliflozin increased mitochondrial redox and reduced myocardial oxidative stress in heart failure, which was associated with improvements in left ventricular ejection fraction after 3 weeks of treatment. Thus, SGLT2i have pleiotropic effects on systemic and heart metabolism, which are distinct from ketone supplementation and may contribute to the long-term cardioprotective benefits of SGLT2i.
Beyond ketosis: the search for the mechanism underlying SGLT2-inhibitor benefit continues
Authors: Justin H Berger, Brian N Finck
Journal: Journal of Clinical Investigation (2024)

Despite the impressive clinical benefits and widespread adoption of sodium glucose cotransporter 2 inhibitors (SGLT2i) to treat all classes of heart failure, their cardiovascular mechanisms of action are poorly understood. Proposed mechanisms range broadly and include enhanced ketogenesis, where the mild ketosis associated with SGLT2i use is presumed to be beneficial. However, in this issue of the JCI, carefully conducted metabolic flux studies by Goedeke et al. comparing the effects of SGLT2i and exogenous ketones suggest differential effects. Thus, the mechanisms of action for SGLT2i are likely pleiotropic, and further work is needed to fully understand their beneficial effects.
Endothelial BMAL1 decline during aging leads to bone loss by destabilizing extracellular fibrillin-1
Authors: Ying Yin, Qingming Tang, Jingxi Yang, Shiqi Gui, Yifan Zhang, Yufeng Shen, Xin Zhou, Shaoling Yu, Guangjin Chen, Jiwei Sun, Zhenshuo Han, Luoying Zhang, Lili Chen
Journal: Journal of Clinical Investigation (2024)

The occurrence of aging is intricately associated with alterations in circadian rhythms that coincide with stem cell exhaustion. Nonetheless, the extent to which the circadian system governs skeletal aging remains inadequately understood. Here, we noticed that skeletal aging in male mice was accompanied by a decline in a core circadian protein, BMAL1, especially in bone marrow endothelial cells (ECs). Using male mice with endothelial KO of aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1), we ascertained that endothelial BMAL1 in bone played a crucial role in ensuring the stability of an extracellular structural component, fibrillin-1 (FBN1), through regulation of the equilibrium between the extracellular matrix (ECM) proteases thrombospondin type 1 domain-containing protein 4 (THSD4) and metalloproteinase with thrombospondin motifs 4 (ADAMTS4), which promote FBN1 assembly and breakdown, respectively. The decline of endothelial BMAL1 during aging prompted excessive breakdown of FBN1, leading to persistent activation of TGF-β/SMAD3 signaling and exhaustion of bone marrow mesenchymal stem cells. Meanwhile, the free TGF-β could promote osteoclast formation. Further analysis revealed that activation of ADAMTS4 in ECs lacking BMAL1 was stimulated by TGF-β/SMAD3 signaling through an ECM-positive feedback mechanism, whereas THSD4 was under direct transcriptional control by endothelial BMAL1. Our investigation has elucidated the etiology of bone aging in male mice by defining the role of ECs in upholding the equilibrium within the ECM, consequently coordinating osteogenic and osteoclastic activities and retarding skeletal aging.