Top read articles in the last 30 days
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Abstract
Stroke remains a leading cause of morbidity and mortality worldwide, with few effective interventions to promote recovery. Targeting circadian timing and glymphatic function may represent viable therapeutic strategies. Here, we show that the small-molecule clock modulator, KL001; high-dose melatonin; acute light pulses; and active-phase time-restricted feeding were each sufficient to enhance glymphatic function in mice. Moreover, initiating treatment with either KL001 or active-phase time-restricted feeding 3 days after preclinical models of stroke improved motor outcomes, reduced lesion volume, increased glymphatic flow, and lowered poststroke brain cytokine burden. These findings suggest that reinforcing normal daily rhythmicity after stroke can markedly enhance neurological recovery, even when interventions are initiated several days after stroke onset.
Authors
Emma Waight, Yuxi Zhu, Ashley Caudell, Velia S. Vizcarra, Evan Newbold, Michael J. Giannetto, Evalien Duyvestyn, Estephanie Balbuena, Wei Song, Tanzil M. Arefin, Yuki Mori, Maiken Nedergaard, Lauren M. Hablitz
Total views: 2705
Abstract
Interrupting glucagon signaling decreases gluconeogenesis and the fractional extraction of amino acids by liver from blood, resulting in lower glycemia. The resulting hyperaminoacidemia stimulates α cell proliferation and glucagon secretion via a liver/α cell axis. We hypothesized that α cells detect and respond to circulating amino acids’ levels via a unique amino acid transporter repertoire. We found that Slc7a2/SLC7A2 is the most highly expressed cationic amino acid transporter in α cells, with its expression being 3-fold greater in α than β cells in both mouse and human. Employing cell culture, zebrafish, and knockout mouse models, we found that the cationic amino acid arginine and SLC7A2 are required for α cell proliferation in response to interrupted glucagon signaling. Ex vivo and in vivo assessment of islet function in Slc7a2–/– mice showed decreased arginine-stimulated glucagon and insulin secretion. We found that arginine activation of mTOR signaling and induction of the glutamine transporter SLC38A5 was dependent on SLC7A2, showing that the role of both in α cell proliferation is dependent on arginine transport and SLC7A2. Finally, we identified single nucleotide polymorphisms in SLC7A2 associated with HbA1c. Together, these data indicate a central role for SLC7A2 in amino acid–stimulated α cell proliferation and islet hormone secretion.
Authors
Erick Spears, Jade E. Stanley, Matthew Shou, Linlin Yin, Xuan Li, Chunhua Dai, Amber Bradley, Katelyn Sellick, Greg Poffenberger, Katie C. Coate, Shristi Shrestha, Anna Marie R. Schornack, Taverlyn Shepard, Madushika Wimalarathne, Regina Jenkins, Kyle W. Sloop, Keith T. Wilson, Alan D. Attie, Mark P. Keller, Wenbiao Chen, Alvin C. Powers, E. Danielle Dean
Total views: 2562
Abstract
Vitiligo is an autoimmune skin disease characterized by depigmentation, mainly due to CD8+ T cell–mediated destruction of melanocytes. Hyperglycemia exacerbates autoimmune responses and is associated with vitiligo; however, the underlying immunometabolic mechanisms are poorly understood. Here, we demonstrated the correlation between hyperglycemia and vitiligo in a case-control study and demonstrated that hyperglycemia aggravated vitiligo based on a mouse model. Targeted metabolomics identified succinate as the potential metabolite mediating hyperglycemia-aggravated vitiligo. Mechanistically, succinate promotes the activation of CD8+ T cells through succinate receptor 1 (SUCNR1) and promotes keratinocytes to secrete CXCL9 and CXCL10 by enhancing the stability and nuclear translocation of hypoxia-inducible factor-1α, facilitating the skin-homing of CD8+ T cells. Thus, hyperglycemia aggravates vitiligo through succinate/SUCNR1 axis–regulated CD8+ T cell hyperactivation. Our study provides insights into the long-observed yet previously unclear mechanism by which hyperglycemia accelerates vitiligo progression and highlights SUCNR1 as a potential therapeutic target.
Authors
Pan Kang, Yuqian Chang, Tingting Wang, Xiuli Yi, Yinghan Wang, Pengran Du, Jiaxi Chen, Baizhang Li, Shuli Li, Zhongjun Shao, Jianru Chen, Chunying Li
Total views: 2460
Abstract
Alveolar type 2 cells (AT2s) are critical to lung regeneration, and the absence of large-scale methods to expand AT2s has hindered regenerative medicine efforts. We report a microcarrier-based, large-scale expansion method that was used to generate hundreds of billions of human AT2s. Through our process, expanded AT2s largely retained their phenotype. Furthermore, we showed that culture medium, substrate composition, and stiffness are all critical to the maintenance of AT2s. Finally, we showed that expanded AT2s can differentiate into alveolar type 1–like cells, both in vitro and in a decellularized porcine lung, demonstrating the utility of these cells for lung tissue engineering.
Authors
Lauren K. Rochelle, Rachael S. Van, Richard J. Ottman, Daren F. Robinson, Ashley R. Dockham, Amy K. Smith, Daniel P. Keeley, Jia C. Wang, Darell W. McCoy, Tyler R. Zimmerman, Bryan A. Fioret, Ryan W. Bonvillain, Thomas H. Petersen, Sarah S. Hogan, Laila C. Roudsari
Total views: 2439
Abstract
BACKGROUND Liquid biopsy has emerged as a minimally invasive method for tumor diagnosis, monitoring, and therapeutic guidance. For CNS tumors, cerebrospinal fluid (CSF) provides a reliable and accessible source of tumor-derived cell-free DNA (ctDNA).METHODS This study evaluates the clinical utility of CSF liquid biopsy in a real-world prospective setting. A total of 148 CSF samples from 120 patients underwent molecular analysis using droplet digital PCR (ddPCR) and/or next-generation sequencing to detect mutations, fusions, copy number alterations, and mismatch-repair deficient signatures (MMRDness). Samples were collected via lumbar puncture (n = 82; 45% ctDNA positive) or from ventricle sources at the time of surgery or through shunts (n = 66; 65% ct DNA positive).RESULTS Overall, ctDNA was detected in 54% of samples with higher detection in high-grade gliomas at diagnosis (100%, 1 sample equivocal) compared with low-grade gliomas (50%). Among low-grade gliomas, ctDNA detection was higher in disseminated cases (80% versus 43%) and from ventricular versus lumbar samples (56% versus 38%).CONCLUSION Liquid biopsy distinguished relapse from second malignancy and serial sampling demonstrated the potential for ctDNA levels to track treatment response and disease progression. In patients with MMRD tumors, high MMRDness score from ctDNA supported active disease. These findings demonstrate that combined liquid biopsy assays facilitate diagnosis, monitoring, and personalized treatment decisions, offering a viable alternative to invasive surgical biopsies in pediatric CNS tumors.TRIAL REGISTRATION None.FUNDING Proof of Principle Grant from The Hospital for Sick Children; The Canadian Institutes of Health Research; The Canadian Cancer Society; The We Love You Connie Foundation; Garron Family Cancer Center at SickKids; SickKids Clinician Training Program; Ben Stelter Foundation through the Women and Children’s Health Research Institute; Jeffrey Brock Cancer Genetics Research Fellowship; Garron Family Cancer Center Research Fellowship/Scotiabank Clinician Scientist Fellowship; Atrium/CMCC and Hold’em for Life Oncology Fellowship; Tokyo Children’s Cancer Study Group Scholarship of the Gold Ribbons Network.
Authors
Liana Nobre, Yoshiko Nakano, Ian Burns, Robert Siddaway, Michal Zápotocky, Monique Johnson, Mansuba Rana, Cyril Li, Rodney K. Lyn, Richard Yuditskiy, Michelle Ku, Javal Sheth, Adrian B. Levine, Cody L. Nesvick, Anirban Das, Chantel Cacciotti, Shayna Zelcer, Seth A. Climans, Maria MacDonald, Logine Negm, Jiil Chung, Julie Bennett, Andrew Bondoc, Jim Loukides, Lucie Stengs, Melissa Edwards, Eric Bouffet, Vijay Ramaswamy, Anthony P.Y. Liu, Annie Huang, Ute Bartels, Peter B. Dirks, Uri Tabori, Cynthia Hawkins
Total views: 2388
Abstract
The blood and lymphatic vascular systems are regulated by angiopoietin (ANGPT) growth factors, which signal via endothelial TIE receptor tyrosine kinases and integrins. However, mechanistic understanding of how these receptors crosstalk is limited. Here, we show how β1-integrin inactivation regulates endothelial ANGPT/TIE2 signaling. By integrating biophysical analyses, X-ray crystallography, size-exclusion chromatography–small-angle X-ray scattering and atomistic molecular dynamics simulations, we show that ANGPT2 binds through its asymmetrically positioned C-terminal fibrinogen-like domains to both TIE2 and α5β1-integrin, forming a trimeric complex compatible with the inactive α5β1-integrin conformation. Inactive β1-integrin colocalizes with ANGPT-induced TIE2 in cell-cell junctions and stabilizing β1-integrin in its inactive state enhances junctional TIE2 accumulation and promotes nuclear exclusion of the TIE2 transcriptional effector FOXO1 in cultured endothelial cells. Endothelial-specific β1-integrin deletion in adult mice reduces venous TIE2 phosphorylation, whereas endotoxemia diminishes junctional β1-integrin along with decreased phosphorylated TIE2. In contrast, without TIE2, ANGPT2 uniquely engages active β1-integrin, via its N-terminal superclustering domain. Altogether, our results provide structural and mechanistic evidence of ANGPT signaling via α5β1-integrin and support a model in which inactive α5β1-integrin acts as a junctional scaffold for ANGPT/TIE2/FOXO1 signaling, explaining how integrin conformational switching spatially organizes growth factor signaling in the endothelium.
Authors
Tuomas Sipilä, Srinivas Kumar Ponna, Abhinandan Venkatesha Murthy, Anne Pink, Giray Enkavi, Shraman Kumar Bohra, Klaudia Lewna, Keerthana Ganesh, Qina Liu, Mirka Korhonen, Tommi Kajander, Michael Potente, Johanna Ivaska, Ilpo Vattulainen, Veli-Matti Leppänen, Pipsa Saharinen
Total views: 2355
Abstract
Metabolic signals critically shape innate immune responses. Through pharmacological screening of metabolic pathways, we identified aspartate metabolism as a key regulator of cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling. Genetically or aminooxyacetic acid–mediated (AOA-mediated) pharmacologically reducing aspartate levels markedly potentiated the cGAS-STING pathway, leading to stronger upregulation of type I interferons and interferon-stimulated genes. Mechanistically, disruption of de novo pyrimidine synthesis, a major downstream pathway of aspartate, induced mtDNA replication stress and increased mtDNA double-strand breaks, promoting mtDNA release into the cytosol. Cytosolic mtDNA synergized with cGAS-STING agonists to upregulate Z-DNA binding protein 1 (ZBP1), which recruits RIPK1/3 to sustain IRF3 phosphorylation, forming a positive feedback loop that amplifies innate immune signaling. In immunocompetent mouse models, AOA enhanced the antitumor efficacy of STING agonists, chemotherapy, or radiotherapy, whereas aspartate supplementation abrogated these effects. Consistently, aspartate levels negatively correlated with antitumor immunity in colorectal cancer patient samples. Together, our study identifies aspartate–pyrimidine metabolism as a critical metabolic checkpoint that licenses STING signaling by enabling mtDNA stress to cooperate with agonist stimulation, driving type I interferon–dependent ZBP1 induction and feed-forward amplification of STING signaling, thus offering a promising strategy to enhance antitumor immunity.
Authors
Yuheng Liao, Hanze Wang, Hengxin Liu, Xi Chen, Renqiang Sun, Xie Li, Zhen Yang, Chenying Liu, Wei Wu, Ziqian He, Yuzheng Zhao, Ying Mao, Dan Ye, Hui Yang
Total views: 2330
Abstract
Neuropathic pain affects over 20 million people in the United States, and painful diabetic neuropathy (PDN), a common complication of diabetes, is among its most prevalent and treatment-resistant forms. Although PDN is characterized by nociceptor dysfunction, the upstream peripheral mechanisms remain incompletely understood. While dorsal root ganglion (DRG) nociceptor hyperexcitability is a hallmark of PDN, emerging evidence suggests that nonneuronal skin cells may modulate nociceptor function. Here, we investigated whether epidermal Langerhans cells (LCs) contribute to neuropathic pain in PDN through neuroimmune signaling. Using a clinically relevant high-fat diet (HFD) mouse model, transgenic LC ablation, behavioral assays, human skin biopsies, and single-cell RNA seq of epidermis and DRG, we found that LC density increased in male diabetic mice in parallel with mechanical allodynia. In skin samples of people with PDN, LCs exhibited increased volume and dendritic complexity correlating with diabetes duration. Genetic depletion of LCs prevented mechanical allodynia and spontaneous pain-like behavior in male, but not female, HFD mice, revealing a sex-dependent contribution. Single-cell and interactome analyses identified male-specific inflammatory LC programs, including upregulation of chemokine signaling pathways. Consistently, LC secretome profiling showed increased CCL2 release, and local CCR2 blockade reversed allodynia. These findings identify epidermal LCs as peripheral regulators of PDN pain and highlight sex-dependent chemokine-mediated neuron-immune communication at the skin-nerve interface.
Authors
Paola Pacifico, Dale George, Nirupa D. Jayaraj, Dongjun Ren, James S. Coy-Dibley, Abdelhak A. Belmadani, Sofia Veronesi, Mirna Andelic, Daniele Cartelli, Grazia Devigili, Raffaella Lombardi, Giuseppe Lauria Pinter, Amy S. Paller, Richard J. Miller, Daniela M. Menichella
Total views: 2186
Abstract
Androgen deprivation therapy (ADT), a cornerstone of advanced prostate cancer treatment, effectively suppresses androgen signaling but frequently induces systemic metabolic dysregulation. Here, we delineate an unrecognized intestinal steroid/bile acid regulatory axis that mechanistically links androgen suppression to extratumoral metabolic aberrations. HSD3B1 is the most common inherited link to prostate cancer mortality and mediates its effects by regulating steroid metabolism. Integrated metabolomic profiling of patients undergoing ADT revealed a rapid genotype-associated reduction in circulating bile acids, most pronounced in carriers of the adrenal-permissive HSD3B1 (1245C) allele. Surprisingly, analyses in human intestinal tissue and mechanistic investigations in in vitro models identified the terminal ileum as a unique site of HSD3B1 and SLC10A2 (ASBT) coexpression, where catalytically active 3βHSD1 is transcriptionally governed by liver receptor homolog-1 (LRH-1). Pharmacologic or genetic LRH-1 inhibition coordinately suppressed HSD3B1 and SLC10A2 expression and function, while inducing adaptive HSD11B2 upregulation and enhanced glucocorticoid inactivation. This LRH-1–dependent regulatory program persisted independently of androgen and glucocorticoid receptor signaling under in vitro conditions modeling androgen deprivation. These findings establish LRH-1 as a central integrator of intestinal steroidogenesis and bile acid transport and implicate the LRH-1/HSD3B1/SLC10A2 network as a mechanistic driver of ADT-associated metabolic disturbances and a potential target for therapeutic intervention.
Authors
Nikou Fotouhi, Robert Diaz, Mohammad Alyamani, Yoon-Mi Chung, Gail West, Pranab K. Mukherjee, Alireza Abdshah, Robert A. Burgess, Samreen Jatana, Rana R. McKay, Florian Rieder, Mary-Ellen Taplin, Nima Sharifi
Total views: 2108
Abstract
Lineage plasticity underscores the resilience of cancer cells in the context of drug treatment. However, lineage fates can also be therapeutically directed. We demonstrate that the eukaryotic initiation factor 4E (eIF4E) cap-binding domain is a critical regulator of lineage plasticity in prostate cancer. Using a first-in-class cap-binding domain inhibitor, we found that plasticity is driven by translational repression of basal keratins through a shared cis-regulatory element enciphered in their 5’ untranslated regions (UTRs). Simultaneously, this stabilized the androgen receptor (AR) through translational upregulation of the deubiquitinases BAP1 and OTUD3. This lineage program is essential for cell survival and drives a druggable vulnerability. Notably, tumors resistant to AR blockade regained sensitivity upon eIF4E cap-binding domain inhibition, which reprogrammed them toward a luminal state. In patients with castration-resistant prostate cancer (CRPC), elevated eIF4E expression was associated with a basal phenotype, reduced luminal differentiation, and accelerated resistance to AR pathway inhibitors (ARPIs). These discoveries uncover a role for the eIF4E cap-binding domain in lineage plasticity and highlight that targeting this domain offers a promising strategy to overcome treatment resistance in prostate cancer.
Authors
Rashmi Mishra, Sihyeon Song, Dhruv Choradia, Dmytro Rudoy, Cynthia L. Wladyka, Patrick Hoang, Jin Yeong Kim, Ilsa M. Coleman, Sonali Arora, Stephanie Dobersch, Alexander E. Orellana, Chenwei Lin, Philip R. Gafken, Eva Corey, Peter S. Nelson, Sita Kugel, Haolong Li, Arnab Sengupta, Andrew C. Hsieh
Total views: 2102
Abstract
The reality of an aging population demands a deeper understanding of aging as a biological process, rather than as a chronological descriptor. Chronological age poorly captures interindividual heterogeneity in physiological and functional decline, disease susceptibility, and mortality risk. In contrast, biological age encompasses deterioration at the molecular, cellular, tissue, organ, functional, and organismal levels and provides insight into why two individuals with the same chronological age exhibit differences in physiological function, disease susceptibility, and mortality risk. While early models of biological age relied on functional markers or composite scores derived largely from longitudinal cohort studies, more recent models integrate molecular profiling with machine learning to ascertain biological aging trajectories. In parallel, new artificial intelligence tools have been applied to various imaging modalities and other forms of complex data to elucidate latent patterns and estimate biological age. In this state-of-the-art Review, we explore historical and modern approaches to estimating biological age and highlight key conceptual, technical, and translational challenges that remain unresolved. As geroscience-guided interventions are incorporated into clinical evaluations, robust and accurate interpretable measures of biological aging are crucial to ascertain treatment effects in clinical trials.
Authors
Baljash S. Cheema, Bedirhan Boztepe, Moses O. Awofolaju, Mallory S. Hubbard, William B. Marcus, Frank J. Palella, Mohamed Abdel-Mohsen, David M. Liebovitz, Manjot K. Gill, R. James Cotton, John T. Wilkins, Douglas E. Vaughan
Total views: 7379
Abstract
Polycystic ovary syndrome (PCOS), also known as polyendocrine metabolic ovarian syndrome (PMOS), is the most common endocrinologic disorder to affect women. Despite this, the pathophysiology of the disease is not entirely known. This has hindered the diagnosis of the disease and appropriate treatment for millions of individuals. In this Review, we discuss the proposed pathophysiology of PCOS from a translational perspective. We review the existing diagnostic criteria of PCOS and current management strategies. Finally, we discuss the long-term health sequelae associated with PCOS, future directions, and areas of needed research in this often-overlooked disease.
Authors
Jessica L. Chan, Irene Masini, Margareta D. Pisarska
Total views: 6345
Abstract
GLP-1 receptor agonist (GLP-1RA) medications have transformed the treatment of type 2 diabetes (T2D) and obesity, with robust evidence for cardiovascular and renal benefits. Nevertheless, GLP-1RA therapy is associated with a pattern of adverse events affecting their safety and tolerability. Here, we delineate mechanisms potentially leading to adverse responses to GLP-1RAs, describe the impact of side effects on treatment persistence, discuss potential mitigation strategies, and identify areas requiring further studies. Concerns that GLP-1RAs raise the risk for acute pancreatitis and pancreatic cancer have been dispelled by long-term clinical trials. However, GLP-1RAs may confer an increased risk for thyroid cancer. Sight-threatening eye complications resulting from rapid reductions in glycemia may be avoided by retinal screening and ophthalmologic treatment before GLP-1RA initiation. The slowing of gastric emptying with GLP-1RA treatment increases the propensity for retained gastric contents, which could increase the risk of aspiration during upper gastrointestinal endoscopy or general anesthesia. These risks may, however, be elevated in individuals with long-standing T2D even in the absence of GLP-1RA treatment. Improved pharmacovigilance and a more standardized, quantitative assessment of adverse events in clinical trials, particularly in the assessment of gastrointestinal symptoms, would facilitate definition of the benefit-risk relationship for individual medications and indications.
Authors
Ryan J. Jalleh, Nicholas J. Talley, Michael Horowitz, Michael A. Nauck
Total views: 5562
Abstract
As a widely distributed network of cells, tissues, and organs, the human immune system is profoundly vulnerable to the effects of aging. Intrinsic and extrinsic stressors progressively erode its structural integrity and functional resilience, weakening core protective responses and increasing susceptibility to infection, malignancy, and tissue degeneration. At the same time, aging heightens the risk of chronic inflammation and autoimmune disease. Hematopoietic stem cells become uniquely compromised as aging intensifies metabolic and replicative stress. Their continuous high-volume turnover results in diminished self-renewal capacity, skewed lineage output, and dominance of expanded clones. These changes undermine innate immune competence and amplify inflammatory activity. Adaptive immune function declines with age through coordinated cellular and molecular programs. T and B lymphocytes exhibit a decline in naive cells, progressive loss of stemness, shortened lifespan, and constrained clonal diversity. Aging lymphocytes reconfigure transcriptional networks, undergo widespread organelle dysfunction, develop maladaptive stress responses, and redistribute into noncanonical tissue niches. Collectively, these alterations reduce antigen specificity and precision, promote innate-like immune behavior, and confer resistance to tolerance. These mechanisms result in concurrent immunodeficiency and autoimmunity, exemplified by two autoimmune diseases disproportionately affecting older adults: rheumatoid arthritis and giant cell arteritis.
Authors
Cornelia M. Weyand, Jörg J. Goronzy
Total views: 4301
Abstract
Therapies based on glucagon-like peptide-1 (GLP-1) reduce rates of cardiovascular and chronic kidney disease in people with type 2 diabetes and/or obesity, with ongoing clinical trials investigating their effects in people with metabolic liver disease, arthritis, and both substance use and neurodegenerative disorders. Acute and chronic activation of GLP-1 receptor signaling also reduces systemic and tissue inflammation in mice and humans, through weight loss–dependent and –independent mechanisms, actions that may contribute to the expanding spectrum of clinical benefits ascribed to GLP-1 medicines. In this Review, we highlight current understanding of the direct and indirect antiinflammatory effects and mechanisms of GLP-1 medicines in both preclinical and clinical studies, covering emerging concepts, clinical relevance, and areas of uncertainty that require further investigation.
Authors
Chi Kin Wong, Daniel J. Drucker
Total views: 2699
Abstract
Cancer diagnoses are prevalent in people with obesity and type 2 diabetes, and abundant clinical evidence supports the protective effects of weight loss for cancer prevention. Glucagon-like peptide-1 (GLP-1) receptor agonists have revolutionized obesity and type 2 diabetes medicine and alleviate many comorbidities of these metabolic diseases. In this Review, we summarize the current clinical evidence for GLP-1 receptor agonists and cancer risk, including thyroid, pancreatic, gastrointestinal, and hormone-dependent malignancies. With few exceptions, recent meta-analyses report that GLP-1 receptor therapies do not increase cancer incidence and may lower risk in some cases. Preclinical studies reinforce the anticancer effects of GLP-1 receptor therapies, even in non-obese models. However, there are still many opportunities for translational insight as the field grows. Immune-modulating effects of GLP-1 receptor agonists are reported in several preclinical cancer studies, which may reflect direct action on immune cells or result from improved metabolic function. We highlight ongoing clinical trials for GLP-1 receptor therapies in cancer patients, and offer considerations for preclinical studies, including perspectives on the timing and duration of GLP-1 receptor agonist treatment, concurrent use of standard anticancer therapies, and interpretation of models of cancer risk versus progression.
Authors
Estefania Valencia-Rincón, Rajani Rai, Vishal Chandra, Elizabeth A. Wellberg
Total views: 2449
Abstract
Historically, antiobesity medications have been modestly effective at best, with side-effect profiles that limit compliance and often preclude the long-term therapy required to maintain weight loss. Recently developed therapies based on analogs of the gut hormone glucagon-like peptide-1 (GLP-1) have transformed the medical management of obesity, leading both to a degree of weight loss that rivals bariatric surgery and a reduction in morbidity and mortality associated with obesity-related complications. GLP-1 receptor agonist (GLP-1RA) therapies were developed to mimic the peripheral effects of GLP-1, but it is now well established that their efficacy in the treatment of obesity depends on reducing energy intake through their action in the central nervous system (CNS). Recent data indicate that the aversive gastrointestinal side effects of GLP-1RAs are also CNS mediated. Although a complete understanding of the neural circuits underlying GLP-1RA–induced weight loss remains elusive, a great deal has been learned in recent years. This Review summarizes proposed gut-brain and central mechanisms through which GLP-1 and its synthetic analogs regulate food intake and bodyweight.
Authors
Lisa R. Beutler
Total views: 2349
Abstract
Each year, sepsis claims more lives in the United States than many major cancers and HIV/AIDS combined, yet therapeutic progress has been modest. Adding to this crisis is the alarming rise of multidrug-resistant “superbugs,” which increasingly render conventional antibiotics ineffective. Pathogen-targeted antibiotics will always remain a cornerstone of sepsis treatment, and research into novel antibiotics must continue unabated. However, the consistent mortality in sepsis tells us this approach is insufficient. Most deaths in sepsis do not occur during the early cytokine storm–driven hyper-inflammatory phase but rather days or weeks after the initial insult, during a protracted phase of immune suppression. Here, we make the case that a crucial way to reduce sepsis mortality lies in restoration of the patient’s immune competence, enabling the patient to contain and kill the invading microbes. Adjuvant immune therapies will not only enable killing of the initial, invading pathogens but also prevent secondary, hospital-acquired infections. Immunotherapy revolutionized oncology by challenging the assumption that cancer was best treated through cytotoxic or targeted tumor-directed approaches, and sepsis now stands at a similar inflection point. We argue that embracing immune restoration as a core therapeutic objective offers the most promising means to improve survival in this lethal disorder.
Authors
Richard S. Hotchkiss, Guillaume Monneret
Total views: 2272
Abstract
Half of adults in the United States have hypertension as defined by clinical practice guidelines. Interestingly, women are generally more likely to be aware of their hypertension and have their blood pressure controlled with treatment compared with men, yet hypertension-related mortality is greater in women. This may reflect the fact that the female sex remains underrepresented in clinical and basic science studies investigating the effectiveness of therapies and the mechanisms controlling blood pressure. This Review provides an overview of the impact of the way hypertension research has explored sex as a biological variable (SABV). Emphasis is placed on epidemiological studies, hypertension clinical trials, the genetics of hypertension, sex differences in immunology and gut microbiota in hypertension, and the effect of sex on the central control of blood pressure. The goal is to offer historical perspective on SABV in hypertension, highlight recent studies that include SABV, and identify key gaps in SABV inclusion and questions that remain in the field. Through continued awareness campaigns and engagement/education at the level of funding agencies, individual investigators, and in the editorial peer review system, investigation of SABV in the field of hypertension research will ultimately lead to improved clinical outcomes.
Authors
Michael J. Ryan, John S. Clemmer, Roy O. Mathew, Jessica L. Faulkner, Erin B. Taylor, Justine M. Abais-Battad, Fiona Hollis, Jennifer C. Sullivan
Total views: 2169
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: 1886
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ISSN: 0021-9738 (print), 1558-8238 (online)