Top read articles in the last 30 days
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Abstract
Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations of the NF1 tumor suppressor gene resulting in the loss of function of neurofibromin, a GTPase-activating protein (GAP) for Ras. While the malignant manifestations of NF1 are associated with loss of heterozygosity of the residual WT allele, the nonmalignant neurodevelopmental sequelae, including autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD) are prevalent morbidities that occur in the setting of neurofibromin haploinsufficiency. We reasoned that augmenting endogenous levels of WT neurofibromin could serve as a potential therapeutic strategy to correct the neurodevelopmental manifestations of NF1. Here, we used a combination of genetic screening and genetically engineered murine models to identify a role for the F-box protein FBXW11 as a regulator of neurofibromin degradation. Disruption of Fbxw11, through germline mutation or targeted genetic manipulation in the nucleus accumbens, increased neurofibromin levels, suppressed Ras-dependent ERK phosphorylation, and corrected social learning deficits and impulsive behaviors in male Nf1+/– mice. Our results demonstrate that preventing the degradation of neurofibromin is a feasible and effective approach to ameliorate the neurodevelopmental phenotypes in a haploinsufficient disease model.
Authors
Su Jung Park, Jodi L. Lukkes, Ka-Kui Chan, Hayley P. Drozd, Callie B. Burgin, Shaomin Qian, Morgan McKenzie Sullivan, Cesar Gabriel Guevara, Nolen Cunningham, Stephanie Arenas, Makenna A. Collins, Jacob Zucker, JinHee Won, Abbi Smith, Li Jiang, Dana K. Mitchell, Steven D. Rhodes, Steven P. Angus, D. Wade Clapp
Total views: 3144
Abstract
Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying noninvasive, blood-based immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation and identify correlates of renal parameters. Unbiased analysis identified 3 immunologically distinct groups of patients that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at 1 year. Patients with enriched circulating granzyme B+ T cells showed more active disease and increased numbers of activated CD8+ T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive but with chronic renal injuries. The major immunologic axes of variation could be distilled down to 5 simple cytometric parameters that recapitulate several clinical associations, highlighting the potential for blood immunoprofiling to translate to clinically useful noninvasive metrics to assess immune-mediated disease in LN.
Authors
Alice Horisberger, Alec Griffith, Joshua Keegan, Arnon Arazi, John Pulford, Ekaterina Murzin, Kaitlyn Howard, Brandon Hancock, Andrea Fava, Takanori Sasaki, Tusharkanti Ghosh, Jun Inamo, Rebecca Beuschel, Ye Cao, Katie Preisinger, Maria Gutierrez-Arcelus, Thomas M. Eisenhaure, Joel Guthridge, Paul J. Hoover, Maria Dall’Era, David Wofsy, Diane L. Kamen, Kenneth C. Kalunian, Richard Furie, Michael Belmont, Peter Izmirly, Robert Clancy, David Hildeman, E. Steve Woodle, William Apruzzese, Maureen A. McMahon, Jennifer Grossman, Jennifer L. Barnas, Fernanda Payan-Schober, Mariko Ishimori, Michael Weisman, Matthias Kretzler, Celine C. Berthier, Jeffrey B. Hodgin, Dawit S. Demeke, Chaim Putterman, Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network, Michael B. Brenner, Jennifer H. Anolik, Soumya Raychaudhuri, Nir Hacohen, Judith A. James, Anne Davidson, Michelle A. Petri, Jill P. Buyon, Betty Diamond, Fan Zhang, James A. Lederer, Deepak A. Rao
Total views: 2963
Abstract
Metabolic dysfunction–associated steatohepatitis (MASH) is a globally prevalent but intractable disease lacking effective pharmacotherapies. Here, we performed an integrated multilayered screening for pathogenic genes and druggable targets for MASH. We identified the subclass of metabolite-sensing G protein–coupled receptors, specifically GPR31, a critical contributor to MASH occurrence, which, to our knowledge, was previously uncharacterized. Mechanistically, Gαi3 is the essential downstream effector for the pro-MASH efficiency of GPR31 via glycosylation-dependent interaction with GPR31 and extra activation of PKCδ-MAPK signaling. Hepatocyte-specific GPR31 deficiency robustly blocked hepatic lipotoxicity and fibrosis in a mouse model of diet-induced MASH, whereas expression of the GPR31 transgene aggravated MASH development. Of translational importance, we developed a small-molecule inhibitor, named G4451, that specifically inhibits the GPR31-Gαi3 interaction by targeting the GPR31 conformational transition. Encouragingly, oral administration of G4451 effectively blocked MASH progression in preclinical models in both rodents and nonhuman primates. Collectively, the present study provides proof of concept that interference with GPR31 constitutes an attractive therapeutic strategy for MASH.
Authors
Xiao-Jing Zhang, Jiajun Fu, Xu Cheng, Hong Shen, Hailong Yang, Kun Wang, Wei Li, Han Tian, Tian Tian, Junjie Zhou, Song Tian, Zhouxiang Wang, Juan Wan, Lan Bai, Hongfei Duan, Xin Zhang, Ruifeng Tian, Haibo Xu, Rufang Liao, Toujun Zou, Jing Shi, Weiyi Qu, Liang Fang, Jingjing Cai, Peng Zhang, Zhi-Gang She, Jingwei Jiang, Yufeng Hu, Yibin Wang, Hongliang Li
Total views: 2820
Abstract
Tumor gene alterations can serve as predictive biomarkers for therapy response. The nucleotide excision repair (NER) helicase ERCC2 carries heterozygous missense mutations in approximately 10% of bladder tumors, and these may predict sensitivity to cisplatin treatment. To explore the clinical actionability of ERCC2 mutations, we assembled a multinational cohort of 2,012 individuals with bladder cancer and applied the highly quantitative CRISPR-Select assay to functionally profile recurrent ERCC2 mutations. We also developed a single-allele editing version of CRISPR-Select to assess heterozygous missense variants in their native context. From the cohort, 506 ERCC2 mutations were identified, with 93% being heterozygous missense variants. CRISPR-Select pinpointed deleterious, cisplatin-sensitizing mutations, particularly within the conserved helicase domains. Importantly, single-allele editing revealed that heterozygous helicase-domain mutations markedly increased cisplatin sensitivity. Integration with clinical data confirmed that these mutations were associated with improved response to platinum-based neoadjuvant chemotherapy. Comparison with computational algorithms showed substantial discrepancies, highlighting the importance of precision functional assays for interpreting mutation effects in clinically relevant contexts. Our results demonstrate that CRISPR-Select provides a robust platform to advance biomarker-driven therapy in bladder cancer and supports its potential integration into precision oncology workflows.
Authors
Judit Börcsök, Diyavarshini Gopaul, Daphne Devesa-Serrano, Clémence Mooser, Nicolas Jonsson, Matteo Cagiada, Dag R. Stormoen, Maya N. Ataya, Brendan J. Guercio, Hristos Z. Kaimakliotis, Gopa Iyer, Kresten Lindorff-Larsen, Lars Dyrskjøt, Kent W. Mouw, Zoltan Szallasi, Claus S. Sørensen
Total views: 2648
Abstract
SPNS1 is a lysosomal transporter that mediates the salvage of lysoglycerophospholipids, the degradative products of lysosomal phospholipid catabolism. However, an understanding of the role of lysolipid transport and salvage in regulating cellular lipid homeostasis and in disease is lacking. Here, we identified members of 2 families with biallelic SPNS1 loss-of-function variants, who presented primarily with progressive liver and striated muscle injury. Patients’ fibroblasts accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens. Notably, SPNS1 deficiency resulted in reduced biogenesis of cytosolic lipid droplets containing triglycerides and cholesteryl esters. Mechanistically, we found that lysophospholipids transported by SPNS1 into the cytosol quantitatively contributed to triglyceride synthesis, whereas lysosomal buildup of lyso-ether-phospholipid inhibited lysosomal cholesterol egress, effects that were enhanced with inhibition of mTOR. These findings support a gene-disease association and reveal connectivity between lysosomal transport of lysophospholipids and storage of reserve cellular energy as triglycerides and the regulation of cholesterol homeostasis, processes that become important under nutrient limitation.
Authors
Menglan He, Mei Ding, Michaela Chocholouskova, Cheen Fei Chin, Martin Engvall, Helena Malmgren, Matias Wagner, Marlen C. Lauffer, Jacob Heisinger, May Christine V. Malicdan, Valerie Allamand, Madeleine Durbeej, Angelica Delgado Vega, Thomas Sejersen, Ann Nordgren, Federico Torta, David L. Silver
Total views: 2405
Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disease caused by ectopic expression of the toxic protein DUX4, resulting in muscle weakness. However, the mechanism by which DUX4 exerts its toxicity remains unclear. In this study, we observed abnormal iron accumulation in muscles of patients with FSHD and in mice with muscle-specific DUX4 expression (DUX4-Tg mice). Treatment with iron chelators, an iron-deficient diet, and genetic modifications inhibiting intracellular uptake of iron did not improve but rather exacerbated FSHD pathology in DUX4-Tg mice. Unexpectedly, however, iron supplementation, from either a high-iron diet or intravenous iron administration, resulted in remarkable improvement in grip strength and running performance in DUX4-Tg mice. Iron supplementation suppressed abnormal iron accumulation and the ferroptosis-related pathway involving increased lipid peroxidation in DUX4-Tg muscle. Muscle-specific DUX4 expression led to retinal vasculopathy, a part of FSHD pathology, which was prevented by iron administration. Furthermore, high-throughput compound screening of the ferroptosis pathway identified drug candidates including ferrostatin-1 (Fer-1), a potent inhibitor of lipid peroxidation. Treatment with Fer-1 dramatically improved physical function in DUX4-Tg mice. Our findings demonstrate that DUX4-provoked toxicity is involved in the activation of the ferroptosis-related pathway and that supplementary iron could be a promising and readily available therapeutic option for FSHD.
Authors
Kodai Nakamura, Huascar Pedro Ortuste Quiroga, Naoki Horii, Shin Fujimaki, Toshiro Moroishi, Keiichi I. Nakayama, Shinjiro Hino, Yoshihiko Saito, Ichizo Nishino, Yusuke Ono
Total views: 2343
Abstract
Platelet hyperreactivity increases the risk of cardiovascular thrombosis in diabetes and failure of antiplatelet drug therapies. Elevated basal and agonist-induced calcium flux is a fundamental cause of platelet hyperreactivity in diabetes; however, the mechanisms responsible for this remain largely unknown. Using a high-sensitivity, unbiased proteomic platform, we consistently detected over 2,400 intracellular proteins and identified proteins that were differentially released by platelets in type 2 diabetes. We identified that SEC61 translocon subunit β (SEC61B) was increased in platelets from humans and mice with hyperglycemia and in megakaryocytes from mice with hyperglycemia. SEC61 is known to act as an endoplasmic reticulum (ER) calcium leak channel in nucleated cells. Using HEK293 cells, we showed that SEC61B overexpression increased calcium flux into the cytosol and decreased protein synthesis. Concordantly, platelets in hyperglycemic mice mobilized more calcium and had decreased protein synthesis. Platelets in both humans and mice with hyperglycemia had increased ER stress. ER stress induced the expression of platelet SEC61B and increased cytosolic calcium. Inhibition of SEC61 with anisomycin decreased platelet calcium flux and inhibited platelet aggregation in vitro and in vivo. These studies demonstrate the existence of a mechanism whereby ER stress–induced upregulation of platelet SEC61B leads to increased cytosolic calcium, potentially contributing to platelet hyperreactivity in diabetes.
Authors
Yvonne X. Kong, Rajan Rehan, Cesar L. Moreno, Søren Madsen, Yunwei Zhang, Huiwen Zhao, Miao Qi, Callum B. Houlahan, Siân P. Cartland, Declan Robertshaw, Vincent Trang, Frederick Jun Liang Ong, Michael Liu, Edward Cheng, Imala Alwis, Alexander Dupuy, Michelle Cielesh, Kristen C. Cooke, Meg Potter, Jacqueline Stöckli, Grant Morahan, Maggie L. Kalev-Zylinska, Matthew T. Rondina, Sol Schulman, Jean Y. H. Yang, G. Gregory Neely, Simone M. Schoenwaelder, Shaun P. Jackson, David E. James, Mary M. Kavurma, Samantha L. Hocking, Stephen M. Twigg, James C. Weaver, Mark Larance, Freda H. Passam
Total views: 2313
Abstract
Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase in the brain. Mutations in PPP2R1A, encoding the scaffolding subunit, are linked to intellectual disability, although the underlying mechanisms remain unclear. This study examined mice with heterozygous deletion of Ppp2r1a in forebrain excitatory neurons (NEX-het-conditional knockout [NEX-het-cKO]). These mice exhibited impaired spatial learning and memory, resembling Ppp2r1a-associated intellectual disability. Ppp2r1a haploinsufficiency also led to increased excitatory synaptic strength and reduced inhibitory synapse numbers on pyramidal neurons. The increased excitatory synaptic transmission was attributed to increased presynaptic release probability, likely due to reduced levels of 2-arachidonoyl glycerol (2-AG). This reduction in 2-AG was associated with increased transcription of monoacylglycerol lipase (MAGL), driven by destabilization of enhancer of zeste homolog 2 (EZH2) in NEX-het-cKO mice. Importantly, the MAGL inhibitor JZL184 effectively restored both synaptic and learning deficits. Our findings uncover an unexpected role of PPP2R1A in regulating endocannabinoid signaling, providing fresh molecular and synaptic insights into the mechanisms underlying intellectual disability.
Authors
Yirong Wang, Weicheng Duan, Hua Li, Zhiwei Tang, Ruyi Cai, Shangxuan Cai, Guanghao Deng, Liangpei Chen, Hongyan Luo, Liping Chen, Yulong Li, Jian-Zhi Wang, Bo Xiong, Man Jiang
Total views: 2270
Abstract
Late-onset Tay-Sachs (LOTS) disease is a lysosomal storage disorder most commonly caused by a point mutation (c.805G>A) in the HEXA gene encoding the α subunit of the lysosomal enzyme β-hexosaminidase A. LOTS manifests as a range of gradually worsening neurological symptoms beginning in young adulthood. Here, we explored the efficacy of an adenine base editor (ABE) programmed with an sgRNA to correct the HEXA c.805G>A mutation. Base editing in fibroblasts from a patient with LOTS successfully converted the pathogenic HEXA c.805A to G and partially restored β-hexosaminidase activity, with minimal genome-wide off-target editing. We generated a LOTS mouse model in which the mice exhibited decreased β-hexosaminidase activity, accumulation of GM2 ganglioside in the brain, progressive neurological manifestations, and reduced lifespan. Treatment of LOTS mice with the neurotropic virus AAV-PHP.eB carrying the ABE and an sgRNA targeting the LOTS point mutation partially corrected the c.805G>A mutation in the CNS, significantly increased brain β-hexosaminidase activity, and substantially reduced GM2 ganglioside accumulation in the brain. Moreover, the therapy delayed symptom onset and significantly extended median lifespan. These findings highlight the potential of base editing as an effective treatment for LOTS and its broader applicability to other lysosomal storage disorders.
Authors
Maria L. Allende, Mari Kono, Y. Terry Lee, Samantha M. Olmsted, Vienna Huso, Jenna Y. Bakir, Florencia Pratto, Cuiling Li, Colleen Byrnes, Galina Tuymetova, Hongling Zhu, Cynthia J. Tifft, Richard L. Proia
Total views: 2247
Abstract
The outflow of ‘dirty’ brain fluids from the glymphatic system drains via the meningeal lymphatic vessels to the lymph nodes in the neck, primarily the deep cervical lymph nodes (dcLN). However, it is unclear whether dcLN drainage is essential for normal cerebral homeostasis. Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and computational fluid dynamics, we studied the impact of long-term mechanical stress from compromised dcLN drainage on brain solute and fluid outflow in anesthetized rats. We found that in young, but not middle-aged, rats, impairment of dcLN drainage was linked to moderately increased intracranial pressure and the emergence of extracranial perivenous drainage, with no evidence of hydrocephalus at any age. Surprisingly, both age groups showed enhanced brain solute clearance despite reduced glymphatic influx. CSF proteomic analysis revealed cellular stress in the form of low-grade inflammation and upregulation of pathways associated with neurodegeneration and blood brain barrier leakage in the rats with impaired lymphatic drainage. Our findings highlight that dcLN drainage is indeed a prerequisite for normal cerebral homeostasis in the rat and reveal the brain’s age-dependent compensatory responses to chronic impairment of its lymphatic drainage pathways.
Authors
Zachary Gursky, Zohaib Nisar Khan, Sunil Koundal, Ankita Bhardwaj, Joaquin Caceres Melgarejo, Kaiming Xu, Xinan Chen, Hung-Mo Lin, Xianfeng Gu, Hedok Lee, Jonathan Kipnis, Yoav Dori, Allen Tannenbaum, Laura Santambrogio, Helene Benveniste
Total views: 2246
Abstract
The genetic landscape of pancreatic ductal adenocarcinoma (PDAC) is well-established and dominated by four key genetic driver mutations. Mutational activation of the KRAS oncogene is the initiating genetic event, followed by genetic loss of function of the CDKN2A, TP53, and SMAD4 tumor suppressor genes. Disappointingly, this information has not been leveraged to develop clinically effective targeted therapies for PDAC treatment, where current standards of care remain cocktails of conventional cytotoxic drugs. Nearly all (~95%) PDAC harbors KRAS mutations, and experimental studies have validated the essential role of KRAS mutation in PDAC tumorigenic and metastatic growth. Identified in 1982 as the first gene shown to be aberrantly activated in human cancer, KRAS has been the focus of intensive drug discovery efforts. Widely considered “undruggable,” KRAS has been the elephant in the room for PDAC treatment. This perception was shattered recently with the approval of two KRAS inhibitors for the treatment of KRASG12C-mutant lung and colorectal cancer, fueling hope that KRAS inhibitors will lead to a breakthrough in PDAC therapy. In this Review, we summarize the key role of aberrant KRAS signaling in the biology of pancreatic cancer; provide an overview of past, current, and emerging anti-KRAS treatment strategies; and discuss current challenges that limit the clinical efficacy of directly targeting KRAS for pancreatic cancer treatment.
Authors
Kristina Drizyte-Miller, Taiwo Talabi, Ashwin Somasundaram, Adrienne D. Cox, Channing J. Der
Total views: 3550
Abstract
Air pollution comprises a complex mixture of gaseous and particulate components. Particulate matter (PM) air pollution is associated with 4.7 million premature deaths per year. Among modifiable risk factors, air pollution exposure contributes to 8% of disability adjusted life years and ranks above factors such as high blood pressure, smoking, and high fasting plasma glucose. As the site of entry, exposure to PM air pollution causes respiratory symptoms and is a significant cause of respiratory morbidity and mortality. In this Review, we discuss the studies that link air pollution exposure with respiratory diseases. We review the epidemiological evidence linking PM exposure and lung diseases including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pneumonia, acute respiratory distress syndrome, and lung cancer. We also provide an overview of current knowledge about the mechanisms by which PM exerts its biological effects leading to adverse health effects in the respiratory system.
Authors
Robert B. Hamanaka, Gökhan M. Mutlu
Total views: 3474
Abstract
Stress has long been associated with substance misuse and substance use disorders (SUDs). The past two decades have seen a surge in research aimed at understanding the underlying mechanisms driving this association. This Review introduces a multilevel “adaptive stress response” framework, encompassing a stress baseline, acute reaction, and recovery with return-to-homeostasis phase that occurs at varying response times and across domains of analysis. It also discusses evidence showing the disruption of this adaptive stress response in the context of chronic and repeated stressors, trauma, adverse social and drug-related environments, as well as with acute and chronic drug misuse and with drug withdrawal and abstinence sequelae. Subjective, cognitive, peripheral, and neurobiological disruptions in the adaptive stress response phases and their link to inflexible, maladaptive coping; increased craving; relapse risk; and maintenance of drug intake are also presented. Finally, the prevention and treatment implications of targeting this “stress pathophysiology of addiction” are discussed, along with specific aspects that may be targeted in intervention development to rescue stress-related alterations in drug motivation and to improve SUD treatment outcomes.
Authors
Rajita Sinha
Total views: 2778
Abstract
Cannabis has been legalized for medical and recreational purposes in multiple countries. A large number of people are using cannabis and some will develop cannabis use disorder (CUD). There is a growing recognition that CUD requires specific interventions. This Review will cover this topic from a variety of perspectives, with a particular emphasis on neurobiological findings and innovative treatment approaches that are being pursued. We will first describe the epidemiology and burden of disease of CUD, including risk factors associated with CUD (both in terms of general risk and genetic risk variants). Neurobiological alterations identified in brain imaging studies will be presented. Several psychosocial interventions that are useful for the management of CUD, including motivational enhancement therapy, behavioral and cognitive therapy, and contingency management, will be covered. Although no pharmacological interventions are yet approved for CUD, we present the most promising pharmacological interventions being tested.
Authors
Bernard Le Foll, Victor M. Tang, Sergio Rueda, Leanne V. Trick, Isabelle Boileau
Total views: 2751
Abstract
Pancreatic cancer has a 5-year survival rate of approximately 13% and is projected to become the second-leading cause of cancer-related deaths by 2040. Despite advances in preclinical research, clinical translation remains challenging, and combination chemotherapy remains the standard of care. The intrinsic heterogeneity of pancreas cancer underscores the potential of precision medicine approaches to improve patient outcomes. However, clinical implementation faces substantial challenges, including patient performance status, metastatic disease at diagnosis, intrinsic drug resistance, and a highly complex tumor microenvironment. Emerging targeted therapies, such as RAS inhibitors, offer promise for personalized treatment. These developments have prompted precision medicine–focused clinical trials using molecular subtyping for patient stratification. Effective development of precision medicine therapies depends heavily on robust preclinical models capable of accurately recapitulating the complexities of the pancreatic tumor microenvironment. Two-dimensional, air-liquid interface, and patient-derived organoid cultures combined with in vivo genetically engineered mouse models and patient-derived xenografts represent valuable experimental systems. This Review critically examines the strengths and limitations of these experimental model systems. We highlight their relevance and utility for advancing precision medicine strategies in pancreas cancer.
Authors
Vasiliki Pantazopoulou, Casie S. Kubota, Satoshi Ogawa, Kevin Christian Montecillo Gulay, Xiaoxue Lin, Hyemin Song, Jonathan R. Weitz, Hervé Tiriac, Andrew M. Lowy, Dannielle D. Engle
Total views: 2479
Abstract
Trained immunity (TRIM) is a form of long-lasting functional reprogramming of innate immune cells and their progenitors that enhances responsiveness to subsequent stimuli. Although first characterized in myeloid cells, TRIM was recently extended to nonmyeloid cell types, including endothelial and glial cells, which also exhibit stimulus-driven, memory-like behavior. While initially recognized as a protective mechanism, particularly in the context of vaccines and acute infections, TRIM can also become maladaptive, promoting chronic inflammation, immune dysfunction, and disease. This Review focuses on virus-induced TRIM while also addressing microbial, metabolic, and endogenous inducers. We examine key ligands and receptors that initiate TRIM and dissect the associated signaling and epigenetic pathways. Importantly, we argue that maladaptive TRIM arises not from a specific ligand, receptor, or molecular event, but from contextual factors such as stimulus persistence, dose, tissue microenvironment, and preexisting inflammation. The nature of the secondary challenge also shapes whether a trained response is adaptive or maladaptive. We further discuss TRIM induction in the bone marrow, involvement of both myeloid and nonmyeloid cells, and the role of lipid rafts in sustaining TRIM. We review maladaptive TRIM’s potential contribution to systemic diseases, such as atherosclerosis, diabetes, sepsis, cancer, and autoimmunity, along with its influence on viral vaccine responses. Finally, we outline potential strategies to redirect maladaptive TRIM and propose key outstanding questions for future research.
Authors
Dmitri Sviridov, Mihai G. Netea, Michael I. Bukrinsky
Total views: 2449
Abstract
Testosterone (T) and 17β-estradiol (E2) are produced in male and female humans and are potent metabolic regulators in both sexes. When E2 and T production stops or decreases during aging, metabolic dysfunction develops and promotes degenerative metabolic and vascular disease. Here, we discuss the shared benefits afforded by E2 and T for metabolic function human females and males. In females, E2 is central to bone and vascular health, subcutaneous adipose tissue distribution, skeletal muscle insulin sensitivity, antiinflammatory immune function, and mitochondrial health. However, T also plays a role in female skeletal, vascular, and metabolic health. In males, T’s conversion to E2 is fundamental to bone and vascular health, as well as prevention of excess visceral adiposity and the promotion of insulin sensitivity via activation of the estrogen receptors. However, T and its metabolite dihydrotestosterone also prevent excess visceral adiposity and promote skeletal muscle growth and insulin sensitivity via activation of the androgen receptor. In conclusion, T and E2 are produced in both sexes at sex-specific concentrations and provide similar and potent metabolic benefits. Optimizing levels of both hormones may be beneficial to protect patients from cardiometabolic disease and frailty during aging, which requires further study.
Authors
Franck Mauvais-Jarvis, Sarah H. Lindsey
Total views: 2234
Abstract
Human skin acts as a physical barrier to prevent the entry of pathogenic microbes while simultaneously providing a home for commensal bacteria and fungi. Microbiome sequencing studies have demonstrated the unappreciated diversity and selectivity of these microbes. Functional studies have demonstrated the impact of specific strains to tune the immune system, sculpt the microbial community, provide colonization resistance, and promote epidermal barrier integrity. Recent studies have integrated the microbiome, immunity, and tissue integrity to understand their interplay in common disorders such as atopic dermatitis. In this Review, we explore microbiome shifts associated with cutaneous disorders with an eye toward how the microbiome can be mined to identify new therapeutic opportunities.
Authors
Tiffany C. Scharschmidt, Julia A. Segre
Total views: 2185
Abstract
A central challenge in cancer therapy is the effective delivery of anticancer treatments while minimizing adverse effects on patient health. The potential dual impact of therapy is clearly illustrated in cancer-associated cachexia, a multifactorial syndrome characterized by involuntary weight loss, systemic inflammation, metabolic dysregulation, and behavioral alterations such as anorexia and apathy. While cachexia research often focuses on tumor-driven mechanisms, the literature indicates that cancer therapies themselves, particularly chemotherapies and targeted treatments, can initiate or exacerbate the biological pathways driving this syndrome. Here, we explore how therapeutic interventions intersect with the pathophysiology of cachexia, focusing on key organ systems including muscle, adipose tissue, liver, heart, and brain. We highlight examples such as therapy-induced upregulation of IL-6 and growth-differentiation factor 15, both contributing to reduced nutrient intake and a negative energy balance via brain-specific mechanisms. At the level of nutrient release and organ atrophy, chemotherapies also converge with cancer progression, for example, activating NF-κB in muscle and PKA/CREB signaling in adipose tissue. By examining how treatment timing and modality align with the natural trajectory of cancer cachexia, we underscore the importance of incorporating physiological endpoints alongside tumor-centric metrics in clinical trials. Such integrative approaches may better capture therapeutic efficacy while preserving patient well-being.
Authors
Tuba Mansoor Thakir, Alice R. Wang, Amanda R. Decker-Farrell, Miriam Ferrer, Rohini N. Guin, Sam Kleeman, Llewelyn Levett, Xiang Zhao, Tobias Janowitz
Total views: 2164
Abstract
Autoimmune diseases are a leading cause of disability worldwide. Most autoimmune diseases occur more often in women than men, with rheumatic autoimmune diseases being among those most highly expressed in women. Several key factors, identified mainly in animal models and cell culture experiments, are important in increasing autoimmune disease in females. These include sex hormones, immune genes including those found on the X chromosome, sex-specific epigenetic effects on genes by estrogen and the environment, and regulation of genes and messenger RNA by microRNAs found in extracellular vesicles. Evidence is also emerging that viruses as well as drugs or toxins that damage mitochondria may contribute to increased levels of autoantibodies against nuclear and mitochondrial antigens, which are common in many autoimmune diseases. The purpose of this Review is to summarize our current understanding of mechanisms that may determine sex differences in autoimmune disease.
Authors
DeLisa Fairweather, Danielle J. Beetler, Elizabeth J. McCabe, Scott M. Lieberman
Total views: 2149
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)