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Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality; however, few mechanistic biomarkers are available for high-risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from the Chronic Renal Insufficiency Cohort (CRIC) study, the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D), and the American Indian Study determined whether urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in the CRIC study and SMART2D. ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in the CRIC study, SMART2D, and the American Indian study. Empagliflozin lowered UAdCR in nonmacroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology, and single-cell transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mTOR. Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.
Kumar Sharma, Guanshi Zhang, Jens Hansen, Petter Bjornstad, Hak Joo Lee, Rajasree Menon, Leila Hejazi, Jian-Jun Liu, Anthony Franzone, Helen C. Looker, Byeong Yeob Choi, Roman Fernandez, Manjeri A. Venkatachalam, Luxcia Kugathasan, Vikas S. Sridhar, Loki Natarajan, Jing Zhang, Varun S. Sharma, Brian Kwan, Sushrut S. Waikar, Jonathan Himmelfarb, Katherine R. Tuttle, Bryan Kestenbaum, Tobias Fuhrer, Harold I. Feldman, Ian H. de Boer, Fabio C. Tucci, John Sedor, Hiddo Lambers Heerspink, Jennifer Schaub, Edgar A. Otto, Jeffrey B. Hodgin, Matthias Kretzler, Christopher R. Anderton, Theodore Alexandrov, David Cherney, Su Chi Lim, Robert G. Nelson, Jonathan Gelfond, Ravi Iyengar, for the Kidney Precision Medicine Project
Total views: 16367
Healthy adipose tissue is essential for normal physiology. There are 2 broad types of adipose tissue depots: brown adipose tissue (BAT), which contains adipocytes poised to burn energy through thermogenesis, and white adipose tissue (WAT), which contains adipocytes that store lipids. However, within those types of adipose, adipocytes possess depot and cell-specific properties that have important implications. For example, the subcutaneous and visceral WAT confers divergent risk for metabolic disease. Further, within a depot, different adipocytes can have distinct properties; subcutaneous WAT can contain adipocytes with either white or brown-like (beige) adipocyte properties. However, the pathways that regulate and maintain this cell and depot-specificity are incompletely understood. Here, we found that the transcription factor KLF15 is required for maintaining white adipocyte properties selectively within the subcutaneous WAT. We revealed that deletion of Klf15 is sufficient to induce beige adipocyte properties and that KLF15’s direct regulation of Adrb1 is a critical molecular mechanism for this process. We uncovered that this activity is cell autonomous but has systemic implications in mouse models and is conserved in primary human adipose cells. Our results elucidate a pathway for depot-specific maintenance of white adipocyte properties that could enable the development of therapies for obesity and associated diseases.
Liang Li, Brian J. Feldman
Total views: 10653
The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein (AgRP) nerve terminals and thus tonically suppresses multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of the MC3R and the melanocortin system in regulating the response to various anorexigenic agents. The genetic deletion or pharmacological inhibition of the MC3R, or subthreshold doses of an MC4R agonist, improved the dose responsiveness to glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor leptin demonstrated that increased sensitivity to anorectic agents was a generalized result of MC3R antagonism. We observed enhanced neuronal activation in multiple hypothalamic nuclei using Fos IHC following low-dose liraglutide in MC3R-KO mice (Mc3r–/–), supporting the hypothesis that the MC3R is a negative regulator of circuits that control multiple aspects of feeding behavior. The enhanced anorectic response in Mc3r–/– mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1 receptor (GLP1R) analogs, suggesting that MC3R antagonists or MC4R agonists may have value in enhancing the dose-response range of obesity therapeutics.
Naima S. Dahir, Yijun Gui, Yanan Wu, Patrick R. Sweeney, Alix A.J. Rouault, Savannah Y. Williams, Luis E. Gimenez, Tomi K. Sawyer, Stephen T. Joy, Anna K. Mapp, Roger D. Cone
Total views: 3181
Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske iron-sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, the hearts underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA sequencing revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in α-ketoglutarate (required for TET-mediated demethylation) and an increase in S-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways. We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes, resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation.
Gregory B. Waypa, Kimberly A. Smith, Paul T. Mungai, Vincent J. Dudley, Kathryn A. Helmin, Benjamin D. Singer, Clara Bien Peek, Joseph Bass, Lauren Nelson, Sanjiv J. Shah, Gaston Ofman, J. Andrew Wasserstrom, William A. Muller, Alexander V. Misharin, G.R. Scott Budinger, Hiam Abdala-Valencia, Navdeep S. Chandel, Danijela Dokic, Elizabeth Bartom, Shuang Zhang, Yuki Tatekoshi, Amir Mahmoodzadeh, Hossein Ardehali, Edward B. Thorp, Paul T. Schumacker
Total views: 2420
Given the global surge in autoimmune diseases, it is critical to evaluate emerging therapeutic interventions. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leveraged advances in programmable-phage immunoprecipitation methodology to explore the modulation, or lack thereof, of autoantibody profiles, proteome-wide, in both health and disease. Using a custom set of over 730,000 human-derived peptides, we demonstrated that each individual, regardless of disease state, possesses a distinct and complex constellation of autoreactive antibodies. For each individual, the set of resulting autoreactivites constituted a unique immunological fingerprint, or “autoreactome,” that was remarkably stable over years. Using the autoreactome as a primary output, we evaluated the relative effectiveness of various immunomodulatory therapies in altering autoantibody repertoires. We found that therapies targeting B cell maturation antigen (BCMA) profoundly altered an individual’s autoreactome, while anti-CD19 and anti-CD20 therapies had minimal effects. These data both confirm that the autoreactome comprises autoantibodies secreted by plasma cells and strongly suggest that BCMA or other plasma cell–targeting therapies may be highly effective in treating currently refractory autoantibody-mediated diseases.
Aaron Bodansky, David J.L. Yu, Alysa Rallistan, Muge Kalaycioglu, Jim Boonyaratanakornkit, Damian J. Green, Jordan Gauthier, Cameron J. Turtle, Kelsey Zorn, Brian O’Donovan, Caleigh Mandel-Brehm, James Asaki, Hannah Kortbawi, Andrew F. Kung, Elze Rackaityte, Chung-Yu Wang, Aditi Saxena, Kimberly de Dios, Gianvito Masi, Richard J. Nowak, Kevin C. O’Connor, Hao Li, Valentina E. Diaz, Rowan Saloner, Kaitlin B. Casaletto, Eva Q. Gontrum, Brandon Chan, Joel H. Kramer, Michael R. Wilson, Paul J. Utz, Joshua A. Hill, Shaun W. Jackson, Mark S. Anderson, Joseph L. DeRisi
Total views: 2198
Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.
Chien-Hui Lo, Zhiquan Liu, Siyu Chen, Frank Lin, Andrew R. Berneshawi, Charles Q. Yu, Euna B. Koo, Tia J. Kowal, Ke Ning, Yang Hu, Won-Jing Wang, Y. Joyce Liao, Yang Sun
Total views: 1975
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a multiorgan disease that is characterized by diverse metabolic defects. However, other than specific CFTR mutations, the factors that influence disease progression and severity remain poorly understood. Aberrant metabolite levels have been reported, but whether CFTR loss itself or secondary abnormalities (infection, inflammation, malnutrition, and various treatments) drive metabolic defects is uncertain. Here, we implemented comprehensive arteriovenous metabolomics in newborn CF pigs, and the results revealed CFTR as a bona fide regulator of metabolism. CFTR loss impaired metabolite exchange across organs, including disruption of lung uptake of fatty acids, yet enhancement of uptake of arachidonic acid, a precursor of proinflammatory cytokines. CFTR loss also impaired kidney reabsorption of amino acids and lactate and abolished renal glucose homeostasis. These and additional unexpected metabolic defects prior to disease manifestations reveal a fundamental role for CFTR in controlling multiorgan metabolism. Such discovery informs a basic understanding of CF, provides a foundation for future investigation, and has implications for developing therapies targeting only a single tissue.
Hosung Bae, Bo Ram Kim, Sunhee Jung, Johnny Le, Dana van der Heide, Wenjie Yu, Sang Hee Park, Brieanna M. Hilkin, Nicholas D. Gansemer, Linda S. Powers, Taekyung Kang, David K. Meyerholz, Victor L. Schuster, Cholsoon Jang, Michael J. Welsh
Total views: 1895
Group 3 innate lymphoid cells (ILC3s) are key players in intestinal homeostasis. ER stress is linked to inflammatory bowel disease (IBD). Here, we used cell culture, mouse models, and human specimens to determine whether ER stress in ILC3s affects IBD pathophysiology. We show that mouse intestinal ILC3s exhibited a 24-hour rhythmic expression pattern of the master ER stress response regulator inositol-requiring kinase 1α/X-box–binding protein 1 (IRE1α/XBP1). Proinflammatory cytokine IL-23 selectively stimulated IRE1α/XBP1 in mouse ILC3s through mitochondrial ROS (mtROS). IRE1α/XBP1 was activated in ILC3s from mice exposed to experimental colitis and in inflamed human IBD specimens. Mice with Ire1α deletion in ILC3s (Ire1αΔRorc) showed reduced expression of the ER stress response and cytokine genes including Il22 in ILC3s and were highly vulnerable to infections and colitis. Administration of IL-22 counteracted their colitis susceptibility. In human ILC3s, IRE1 inhibitors suppressed cytokine production, which was upregulated by an IRE1 activator. Moreover, the frequencies of intestinal XBP1s+ ILC3s in patients with Crohn’s disease before administration of ustekinumab, an anti-IL-12/IL-23 antibody, positively correlated with the response to treatment. We demonstrate that a noncanonical mtROS-IRE1α/XBP1 pathway augmented cytokine production by ILC3s and identify XBP1s+ ILC3s as a potential biomarker for predicting the response to anti–IL-23 therapies in IBD.
Siyan Cao, Jose L. Fachi, Kaiming Ma, Alina Ulezko Antonova, Qianli Wang, Zhangying Cai, Randal J. Kaufman, Matthew A. Ciorba, Parakkal Deepak, Marco Colonna
Total views: 1858
Endothelial cells (ECs) in the descending aorta are exposed to high laminar shear stress, and this supports an antiinflammatory phenotype. High laminar shear stress also induces flow-aligned cell elongation and front-rear polarity, but whether these are required for the antiinflammatory phenotype is unclear. Here, we showed that caveolin-1–rich microdomains polarize to the downstream end of ECs that are exposed to continuous high laminar flow. These microdomains were characterized by high membrane rigidity, filamentous actin (F-actin), and raft-associated lipids. Transient receptor potential vanilloid (TRPV4) ion channels were ubiquitously expressed on the plasma membrane but mediated localized Ca2+ entry only at these microdomains where they physically interacted with clustered caveolin-1. These focal Ca2+ bursts activated endothelial nitric oxide synthase within the confines of these domains. Importantly, we found that signaling at these domains required both cell body elongation and sustained flow. Finally, TRPV4 signaling at these domains was necessary and sufficient to suppress inflammatory gene expression and exogenous activation of TRPV4 channels ameliorated the inflammatory response to stimuli both in vitro and in vivo. Our work revealed a polarized mechanosensitive signaling hub in arterial ECs that dampened inflammatory gene expression and promoted cell resilience.
Soon-Gook Hong, Julianne W. Ashby, John P. Kennelly, Meigan Wu, Michelle Steel, Eesha Chattopadhyay, Rob Foreman, Peter Tontonoz, Elizabeth J. Tarling, Patric Turowski, Marcus Gallagher-Jones, Julia J. Mack
Total views: 1851
BACKGROUND Predicting immune effector cell–associated neurotoxicity syndrome (ICANS) in patients infused with CAR T cells is still a conundrum. This complication, thought to be consequent to CAR T cell activation, arises a few days after infusion, when circulating CAR T cells are scarce and specific CAR T cell–derived biomarkers are lacking.METHODS CAR+ extracellular vesicle (CAR+EV) release was assessed in human CD19.CAR T cells cocultured with CD19+ target cells. A prospective cohort of 100 patients with B cell lymphoma infused with approved CD19.CAR T cell products was assessed for plasma CAR+EVs as biomarkers of in vivo CD19.CAR T cell activation. Human induced pluripotent stem cell–derived (iPSC-derived) neural cells were used as a model for CAR+EV-induced neurotoxicity.RESULTS In vitro release of CAR+EVs occurs within 1 hour after target engagement. Plasma CAR+EVs are detectable 1 hour after infusion. A concentration greater than 132.8 CAR+EVs/μL at hour +1 or greater than 224.5 CAR+EVs/μL at day +1 predicted ICANS in advance of 4 days, with a sensitivity and a specificity outperforming other ICANS predictors. ENO2+ nanoparticles were released by iPSC-derived neural cells upon CAR+EV exposure and were increased in plasma of patients with ICANS.CONCLUSION Plasma CAR+EVs are an immediate signal of CD19.CAR T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis.TRIAL REGISTRATION NCT04892433, NCT05807789.FUNDING Life Science Hub–Advanced Therapies (financed by Health Ministry as part of the National Plan for Complementary Investments to the National Recovery and Resilience Plan [NRRP]: E.3 Innovative health ecosystem for APC fees and immunomonitoring).
Gianluca Storci, Francesco De Felice, Francesca Ricci, Spartaco Santi, Daria Messelodi, Salvatore Nicola Bertuccio, Noemi Laprovitera, Michele Dicataldo, Lucrezia Rossini, Serena De Matteis, Beatrice Casadei, Francesca Vaglio, Margherita Ursi, Francesco Barbato, Marcello Roberto, Maria Guarino, Gian Maria Asioli, Mario Arpinati, Pietro Cortelli, Enrico Maffini, Enrica Tomassini, Marta Tassoni, Carola Cavallo, Francesco Iannotta, Maria Naddeo, Pier Luigi Tazzari, Elisa Dan, Cinzia Pellegrini, Serafina Guadagnuolo, Matteo Carella, Barbara Sinigaglia, Chiara Pirazzini, Caterina Severi, Paolo Garagnani, Katarzyna Malgorzata Kwiatkowska, Manuela Ferracin, Pier Luigi Zinzani, Massimiliano Bonafè, Francesca Bonifazi
Total views: 1764
Cancer risk is modulated by hereditary and somatic mutations, exposures, age, sex, and gender. The mechanisms by which sex and gender work alone and in combination with other cancer risk factors remain underexplored. In general, cancers that occur in both the male and female sexes occur more commonly in XY compared with XX individuals, regardless of genetic ancestry, geographic location, and age. Moreover, XY individuals are less frequently cured of their cancers, highlighting the need for a greater understanding of sex and gender effects in oncology. This will be necessary for optimal laboratory and clinical cancer investigations. To that end, we review the epigenetics of sexual differentiation and its effect on cancer hallmark pathways throughout life. Specifically, we will touch on how sex differences in metabolism, immunity, pluripotency, and tumor suppressor functions are patterned through the epigenetic effects of imprinting, sex chromosome complement, X inactivation, genes escaping X inactivation, sex hormones, and life history.
Joshua B. Rubin, Tamara Abou-Antoun, Joseph E. Ippolito, Lorida Llaci, Camryn T. Marquez, Jason P. Wong, Lihua Yang
Total views: 7665
A growing body of research has identified circadian-rhythm disruption as a risk factor for metabolic health. However, the underlying biological basis remains complex, and complete molecular mechanisms are unknown. There is emerging evidence from animal and human research to suggest that the expression of core circadian genes, such as circadian locomotor output cycles kaput gene (CLOCK), brain and muscle ARNT-Like 1 gene (BMAL1), period (PER), and cryptochrome (CRY), and the consequent expression of hundreds of circadian output genes are integral to the regulation of cellular metabolism. These circadian mechanisms represent potential pathophysiological pathways linking circadian disruption to adverse metabolic health outcomes, including obesity, metabolic syndrome, and type 2 diabetes. Here, we aim to summarize select evidence from in vivo animal models and compare these results with epidemiologic research findings to advance understanding of existing foundational evidence and potential mechanistic links between circadian disruption and altered clock gene expression contributions to metabolic health–related pathologies. Findings have important implications for the treatment, prevention, and control of metabolic pathologies underlying leading causes of death and disability, including diabetes, cardiovascular disease, and cancer.
Lauren A. Schrader, Sean M. Ronnekleiv-Kelly, John B. Hogenesch, Christopher A. Bradfield, Kristen M.C. Malecki
Total views: 4716
Apoptosis is a form of programmed cell death that is mediated by intrinsic and extrinsic pathways. Dysregulation of and resistance to cell death are hallmarks of cancer. For over three decades, the development of therapies to promote treatment of cancer by inducing various cell death modalities, including apoptosis, has been a main goal of clinical oncology. Apoptosis pathways also interact with other signaling mechanisms, such as the p53 signaling pathway and the integrated stress response (ISR) pathway. In addition to agents directly targeting the intrinsic and extrinsic pathway components, anticancer drugs that target the p53 and ISR signaling pathways are actively being developed. In this Review, we discuss selected and promising anticancer therapies in various stages of development, including drug targets, mechanisms, and resistance to related treatments, focusing especially on B cell lymphoma 2 (BCL-2) inhibitors, TRAIL analogues, DR5 antibodies, and strategies that target p53, mutant p53, and the ISR.
Xiaobing Tian, Praveen R. Srinivasan, Vida Tajiknia, Ashley F. Sanchez Sevilla Uruchurtu, Attila A. Seyhan, Benedito A. Carneiro, Arielle De La Cruz, Maximilian Pinho-Schwermann, Andrew George, Shuai Zhao, Jillian Strandberg, Francesca Di Cristofano, Shengliang Zhang, Lanlan Zhou, Alexander G. Raufi, Arunasalam Navaraj, Yiqun Zhang, Nataliia Verovkina, Maryam Ghandali, Dinara Ryspayeva, Wafik S. El-Deiry
Total views: 2154
Biological sex is an important modifier of physiology and influences pathobiology in many diseases. While heart disease is the number one cause of death worldwide in both men and women, sex differences exist at the organ and cellular scales, affecting clinical presentation, diagnosis, and treatment. In this Review, we highlight baseline sex differences in cardiac structure, function, and cellular signaling and discuss the contribution of sex hormones and chromosomes to these characteristics. The heart is a remarkably plastic organ and rapidly responds to physiological and pathological cues by modifying form and function. The nature and extent of cardiac remodeling in response to these stimuli are often dependent on biological sex. We discuss organ- and molecular-level sex differences in adaptive physiological remodeling and pathological cardiac remodeling from pressure and volume overload, ischemia, and genetic heart disease. Finally, we offer a perspective on key future directions for research into cardiac sex differences.
Thomas G. Martin, Leslie A. Leinwand
Total views: 2094
Mutations in the tumor-suppressor genes BRCA1 and BRCA2 resulting in BRCA1/2 deficiency are frequently identified in breast, ovarian, prostate, pancreatic, and other cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cancer cells by inducing synthetic lethality, providing an effective biomarker-guided strategy for targeted cancer therapy. However, a substantial fraction of cancer patients carrying BRCA1/2 mutations do not respond to PARPis, and most patients develop resistance to PARPis over time, highlighting a major obstacle to PARPi therapy in the clinic. Recent studies have revealed that changes of specific functional defects of BRCA1/2-deficient cells, particularly their defects in suppressing and protecting single-stranded DNA gaps, contribute to the gain or loss of PARPi-induced synthetic lethality. These findings not only shed light on the mechanism of action of PARPis, but also lead to revised models that explain how PARPis selectively kill BRCA-deficient cancer cells. Furthermore, new mechanistic principles of PARPi sensitivity and resistance have emerged from these studies, generating potentially useful guidelines for predicting the PARPi response and design therapies for overcoming PARPi resistance. In this Review, we will discuss these recent studies and put them in context with the classic views of PARPi-induced synthetic lethality, aiming to stimulate the development of new therapeutic strategies to overcome PARPi resistance and improve PARPi therapy.
Xin Li, Lee Zou
Total views: 1787
Cellular senescence is a hallmark of aging defined by stable exit from the cell cycle in response to cellular damage and stress. Senescent cells (SnCs) can develop a characteristic pathogenic senescence-associated secretory phenotype (SASP) that drives secondary senescence and disrupts tissue homeostasis, resulting in loss of tissue repair and regeneration. The use of transgenic mouse models in which SnCs can be genetically ablated has established a key role for SnCs in driving aging and age-related disease. Importantly, senotherapeutics have been developed to pharmacologically eliminate SnCs, termed senolytics, or suppress the SASP and other markers of senescence, termed senomorphics. Based on extensive preclinical studies as well as small clinical trials demonstrating the benefits of senotherapeutics, multiple clinical trials are under way. This Review discusses the role of SnCs in aging and age-related diseases, strategies to target SnCs, approaches to discover and develop senotherapeutics, and preclinical and clinical advances of senolytics.
Lei Zhang, Louise E. Pitcher, Matthew J. Yousefzadeh, Laura J. Niedernhofer, Paul D. Robbins, Yi Zhu
Total views: 1051
Mitochondrial dysfunction and cell senescence are hallmarks of aging and are closely interconnected. Mitochondrial dysfunction, operationally defined as a decreased respiratory capacity per mitochondrion together with a decreased mitochondrial membrane potential, typically accompanied by increased production of oxygen free radicals, is a cause and a consequence of cellular senescence and figures prominently in multiple feedback loops that induce and maintain the senescent phenotype. Here, we summarize pathways that cause mitochondrial dysfunction in senescence and aging and discuss the major consequences of mitochondrial dysfunction and how these consequences contribute to senescence and aging. We also highlight the potential of senescence-associated mitochondrial dysfunction as an antiaging and antisenescence intervention target, proposing the combination of multiple interventions converging onto mitochondrial dysfunction as novel, potent senolytics.
Satomi Miwa, Sonu Kashyap, Eduardo Chini, Thomas von Zglinicki
Total views: 943
Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, and comprises a spectrum of several different disorders, including simple steatosis, steatohepatitis, cirrhosis, and superimposed hepatocellular carcinoma. Although tremendous progress has been made in the field of ALD over the last 20 years, the pathogenesis of ALD remains obscure, and there are currently no FDA-approved drugs for the treatment of ALD. In this Review, we discuss new insights into the pathogenesis and therapeutic targets of ALD, utilizing the study of multiomics and other cutting-edge approaches. The potential translation of these studies into clinical practice and therapy is deliberated. We also discuss preclinical models of ALD, interplay of ALD and metabolic dysfunction, alcohol-associated liver cancer, the heterogeneity of ALD, and some potential translational research prospects for ALD.
Bryan Mackowiak, Yaojie Fu, Luca Maccioni, Bin Gao
Total views: 799
Over the last decade, several organoid models have evolved to acquire increasing cellular, structural, and functional complexity. Advanced lung organoid platforms derived from various sources, including adult, fetal, and induced pluripotent stem cells, have now been generated, which more closely mimic the cellular architecture found within the airways and alveoli. In this regard, the establishment of novel protocols with optimized stem cell isolation and culture conditions has given rise to an array of models able to study key cellular and molecular players involved in lung injury and repair. In addition, introduction of other nonepithelial cellular components, such as immune, mesenchymal, and endothelial cells, and employment of novel precision gene editing tools have further broadened the range of applications for these systems by providing a microenvironment and/or phenotype closer to the desired in vivo scenario. Thus, these developments in organoid technology have enhanced our ability to model various aspects of lung biology, including pathogenesis of diseases such as chronic obstructive pulmonary disease, pulmonary fibrosis, cystic fibrosis, and infectious disease and host-microbe interactions, in ways that are often difficult to undertake using only in vivo models. In this Review, we summarize the latest developments in lung organoid technology and their applicability for disease modeling and outline their strengths, drawbacks, and potential avenues for future development.
Ana I. Vazquez-Armendariz, Purushothama Rao Tata
Total views: 787
Myasthenia gravis (MG) stands as a prototypical antibody-mediated autoimmune disease: it is dependent on T cells and characterized by the presence of autoantibodies targeting proteins located on the postsynaptic surface of skeletal muscle, known as the neuromuscular junction. Patients with MG exhibit a spectrum of weakness, ranging from limited ocular muscle involvement to life-threatening respiratory failure. Recent decades have witnessed substantial progress in understanding the underlying pathophysiology, leading to the delineation of distinct subcategories within MG, including MG linked to AChR or MuSK antibodies as well as age-based distinction, thymoma-associated, and immune checkpoint inhibitor–induced MG. This heightened understanding has paved the way for the development of more precise and targeted therapeutic interventions. Notably, the FDA has recently approved therapeutic inhibitors of complement and the IgG receptor FcRn, a testament to our improved comprehension of autoantibody effector mechanisms in MG. In this Review, we delve into the various subgroups of MG, stratified by age, autoantibody type, and histology of the thymus with neoplasms. Furthermore, we explore both current and potential emerging therapeutic strategies, shedding light on the evolving landscape of MG treatment.
Henry J. Kaminski, Patricia Sikorski, S. Isabel Coronel, Linda L. Kusner
Total views: 744