Microbiota-dependent indole production stimulates the development of collagen-induced arthritis in mice
Altered tryptophan catabolism has been identified in inflammatory diseases like rheumatoid arthritis (RA) and spondyloarthritis (SpA), but the causal mechanisms linking tryptophan metabolites to disease are unknown. Using the collagen-induced arthritis (CIA) model, we identified alterations in tryptophan metabolism, and specifically indole, that correlated with disease. We demonstrated that both bacteria and dietary tryptophan were required for disease and that indole supplementation was sufficient to induce disease in their absence. When mice with CIA on a low-tryptophan diet were supplemented with indole, we observed sig...
Source: Journal of Clinical Investigation - February 15, 2024 Category: Biomedical Science Authors: Brenda J. Seymour, Brandon Trent, Brendan E. Allen, Adam J. Berlinberg, Jimmy Tangchittsumran, Widian K. Jubair, Meagan E. Chriswell, Sucai Liu, Alfredo Ornelas, Andrew Stahly, Erica E. Alexeev, Alexander S. Dowdell, Sunny L. Sneed, Sabrina Fechtner, Jenn Source Type: research
Controlled human infection study underpins efficacy of the tetravalent live-attenuated dengue vaccine TV005
Dengue fever, caused by four distinct serotypes of the dengue virus (DENV1–4), poses a public health concern for much of the world. The NIH’s Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases (NIAID) has developed a series of single-dose, live-attenuated tetravalent DENV vaccines, including TV005. However, phase III trials require a lengthy three-to-five year follow-up. In contrast, controlled human infection models (CHIMs) offer a faster means to assess vaccine efficacy for any of the four serotypes. In this issue of the JCI, Pierce, Durbin, and colleagues conducted a CHIM ...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Annelies Wilder-Smith Source Type: research
Clinical investigation of hypoxia-inducible factors: getting there
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Gregg L. Semenza Source Type: research
KBTBD13 is an actin-binding protein that modulates muscle kinetics
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Josine M. de Winter, Joery P. Molenaar, Michaela Yuen, Robbert van der Pijl, Shengyi Shen, Stefan Conijn, Martijn van de Locht, Menne Willigenburg, Sylvia J.P. Bogaards, Esmee S.B. van Kleef, Saskia Lassche, Malin Persson, Dilson E. Rassier, Tamar E. Szta Source Type: research
Should I stay or should I go? Transsulfuration influences invasion and growth in glioblastoma
A major challenge in treating patients with glioblastoma is the inability to eliminate highly invasive cells with chemotherapy, radiation, or surgical resection. As cancer cells face the issue of replicating or invading neighboring tissue, they rewire their metabolism in a concerted effort to support necessary cellular processes and account for altered nutrient abundance. In this issue of the JCI, Garcia et al. compared an innovative 3D hydrogel–based invasion device to regional patient biopsies through a comprehensive multiomics-based approach paired with a CRISPR knockout screen. Their findings elucidate a role for cys...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: András K. Ponti, Daniel J. Silver, Christopher Hine, Justin D. Lathia Source Type: research
Circadian immunity from bench to bedside: a practical guide
The immune system is built to counteract unpredictable threats, yet it relies on predictable cycles of activity to function properly. Daily rhythms in immune function are an expanding area of study, and many originate from a genetically based timekeeping mechanism known as the circadian clock. The challenge is how to harness these biological rhythms to improve medical interventions. Here, we review recent literature documenting how circadian clocks organize fundamental innate and adaptive immune activities, the immunologic consequences of circadian rhythm and sleep disruption, and persisting knowledge gaps in the field. We...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Huram Mok, Elaine Ostendorf, Alex Ganninger, Avi J. Adler, Guy Hazan, Jeffrey A. Haspel Source Type: research
Molecular and cellular mechanisms underlying the failure of mitochondrial metabolism drugs in cancer clinical trials
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Karthik Vasan, Navdeep S. Chandel Source Type: research
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 cli...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Bryan Mackowiak, Yaojie Fu, Luca Maccioni, Bin Gao Source Type: research
Mitochondria- and NOX4-dependent antioxidant defense mitigates progression to nonalcoholic steatohepatitis in obesity
Nonalcoholic fatty liver disease (NAFLD) is prevalent in the majority of individuals with obesity, but in a subset of these individuals, it progresses to nonalcoholic steatohepatitis (0NASH) and fibrosis. The mechanisms that prevent NASH and fibrosis in the majority of patients with NAFLD remain unclear. Here, we report that NAD(P)H oxidase 4 (NOX4) and nuclear factor erythroid 2–related factor 2 (NFE2L2) were elevated in hepatocytes early in disease progression to prevent NASH and fibrosis. Mitochondria-derived ROS activated NFE2L2 to induce the expression of NOX4, which in turn generated H2O2 to exacerbate the NFE2L2 a...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Spencer Greatorex, Supreet Kaur, Chrysovalantou E. Xirouchaki, Pei K. Goh, Florian Wiede, Amanda J. Genders, Melanie Tran, YaoYao Jia, Arthe Raajendiran, Wendy A. Brown, Catriona A. McLean, Junichi Sadoshima, Matthew J. Watt, Tony Tiganis Source Type: research
Biofilm-derived oxylipin 10-HOME mediated immune response in women with breast implants
Breast implant illness (BII) is a poorly understood disease in which patients develop symptoms typical of autoimmune conditions following breast implantation. There is no known underlying cause, and patients often resort to breast implant removal and capsulectomy to alleviate symptoms. In this issue of the JCI, Khan and colleagues examined 86 breast explants from patients that reported BII symptoms and 55 control explants. The BII group showed a disproportionally high degree of biofilm, which was associated with oxylipin (10-HOME) on the implant surfaces. Injections of 10-HOME in the mammary fat pad of a murine model recap...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Tyler M. Bauer, Katherine A. Gallagher Source Type: research
Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion
Pancreatic β cells are specialized for coupling glucose metabolism to insulin peptide production and secretion. Acute glucose exposure robustly and coordinately increases translation of proinsulin and proteins required for secretion of mature insulin peptide. By contrast, chronically elevated glucose levels that occur during diabetes impair β cell insulin secretion and have been shown experimentally to suppress insulin translation. Whether translation of other genes critical for insulin secretion is similarly downregulated by chronic high glucose is unknown. Here, we used high-throughput ribosome profiling and nascent pr...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Abigael Cheruiyot, Jennifer Hollister-Lock, Brooke Sullivan, Hui Pan, Jonathan M. Dreyfuss, Susan Bonner-Weir, Jean E. Schaffer Source Type: research
PD-1H/VISTA mediates immune evasion in acute myeloid leukemia
Acute myeloid leukemia (AML) presents a pressing medical need in that it is largely resistant to standard chemotherapy as well as modern therapeutics, such as targeted therapy and immunotherapy, including anti–programmed cell death protein (anti-PD) therapy. We demonstrate that programmed death-1 homolog (PD-1H), an immune coinhibitory molecule, is highly expressed in blasts from the bone marrow of AML patients, while normal myeloid cell subsets and T cells express PD-1H. In studies employing syngeneic and humanized AML mouse models, overexpression of PD-1H promoted the growth of AML cells, mainly by evading T cell–med...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Tae Kon Kim, Xue Han, Qianni Hu, Esten N. Vandsemb, Carly M. Fielder, Junshik Hong, Kwang Woon Kim, Emily F. Mason, R. Skipper Plowman, Jun Wang, Qi Wang, Jian-Ping Zhang, Ti Badri, Miguel F. Sanmamed, Linghua Zheng, Tianxiang Zhang, Jude Alawa, Sang Won Source Type: research
Pancreatic β cell function versus insulin resistance: application of the hyperbolic law of glucose tolerance
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Richard N. Bergman Source Type: research
TIMP2 ameliorates blood-brain barrier disruption in traumatic brain injury by inhibiting Src-dependent VE-cadherin internalization
Blood-brain barrier (BBB) disruption is a serious pathological consequence of traumatic brain injury (TBI), for which there are limited therapeutic strategies. Tissue inhibitor of metalloproteinase-2 (TIMP2), a molecule with dual functions of inhibiting MMP activity and displaying cytokine-like activity through receptor binding, has been reported to inhibit VEGF-induced vascular hyperpermeability. Here, we investigate the ability of TIMP2 to ameliorate BBB disruption in TBI and the underlying molecular mechanisms. Both TIMP2 and AlaTIMP2, a TIMP2 mutant without MMP-inhibiting activity, attenuated neurological deficits and ...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Jingshu Tang, Yuying Kang, Yujun Zhou, Nianying Shang, Xinnan Li, Hongyue Wang, Jiaqi Lan, Shuai Wang, Lei Wu, Ying Peng Source Type: research
AEP-cleaved DDX3X induces alternative RNA splicing events to mediate cancer cell adaptation in harsh microenvironments
Oxygen and nutrient deprivation are common features of solid tumors. Although abnormal alternative splicing (AS) has been found to be an important driving force in tumor pathogenesis and progression, the regulatory mechanisms of AS that underly the adaptation of cancer cells to harsh microenvironments remain unclear. Here, we found that hypoxia- and nutrient deprivation–induced asparagine endopeptidase (AEP) specifically cleaved DDX3X in a HIF1A-dependent manner. This cleavage yields truncated carboxyl-terminal DDX3X (tDDX3X-C), which translocates and aggregates in the nucleus. Unlike intact DDX3X, nuclear tDDX3X-C compl...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Wenrui Zhang, Lu Cao, Jian Yang, Shuai Zhang, Jianyi Zhao, Zhonggang Shi, Keman Liao, Haiwei Wang, Binghong Chen, Zhongrun Qian, Haoping Xu, Linshi Wu, Hua Liu, Hongxiang Wang, Chunhui Ma, Yongming Qiu, Jianwei Ge, Jiayi Chen, Yingying Lin Source Type: research
