PIEZO1 is a distal nephron mechanosensor and is required for flow-induced K+ secretion
We examined whether PIEZO1, a mechanosensitive Ca2+-permeable channel expressed in the basolateral membranes of ICs, is required for FIKS. In isolated cortical collecting ducts (CCDs), the mechanosensitive cation-selective channel inhibitor GsMTx4 dampened flow-induced increases in intracellular Ca2+ concentration ([Ca2+]i), whereas the PIEZO1 activator Yoda1 increased [Ca2+]i and BK channel activity. CCDs from mice fed a high-K+ (HK) diet exhibited a greater Yoda1-dependent increase in [Ca2+]i than CCDs from mice fed a control K+ diet. ICs in CCDs isolated from mice with a targeted gene deletion of Piezo1 in ICs (IC-Piezo...
Source: Journal of Clinical Investigation - March 1, 2024 Category: Biomedical Science Authors: Rolando Carrisoza-Gaytan, Stephanie M. Mutchler, Francisco Carattino, Joanne Soong, Marianela G. Dalghi, Peng Wu, WenHui Wang, Gerard Apodaca, Lisa M. Satlin, Thomas R. Kleyman Source Type: research
The multivisceral landscape of colorectal cancer metastasis: implications for targeted therapies
Colorectal cancer (CRC) is among the most common cancer types and the second deadliest malignancy for both sexes. Metastatic disease poses substantial therapeutic challenges, and peritoneal spread, in particular, reduces quality of life and has a dismal outcome. In this issue of the JCI, Berlin and authors have made considerable advancements in understanding the cellular and molecular composition of multivisceral CRC metastasis in a sophisticated murine orthotopic organoid model and in humans. The study provides unprecedented insights into the complex biology of the disease and points toward the development of compartmenta...
Source: Journal of Clinical Investigation - March 1, 2024 Category: Biomedical Science Authors: Dominik Wolf, Stefan Salcher, Andreas Pircher Source Type: research
Increased LL37 in psoriasis and other inflammatory disorders promotes LDL uptake and atherosclerosis
Patients with chronic inflammatory disorders such as psoriasis have an increased risk of cardiovascular disease and elevated levels of LL37, a cathelicidin host defense peptide that has both antimicrobial and proinflammatory properties. To explore whether LL37 could contribute to the risk of heart disease, we examined its effects on lipoprotein metabolism and show that LL37 enhanced LDL uptake in macrophages through the LDL receptor (LDLR), scavenger receptor class B member 1 (SR-B1), and CD36. This interaction led to increased cytosolic cholesterol in macrophages and changes in expression of lipid metabolism genes consist...
Source: Journal of Clinical Investigation - March 1, 2024 Category: Biomedical Science Authors: Yoshiyuki Nakamura, Nikhil N. Kulkarni, Toshiya Takahashi, Haleh Alimohamadi, Tatsuya Dokoshi, Edward Liu, Michael Shia, Tomofumi Numata, Elizabeth W.C. Luo, Adrian F. Gombart, Xiaohong Yang, Patrick Secrest, Philip L.S.M. Gordts, Sotirios Tsimikas, Gerar Source Type: research
Glucocorticoid receptor-dependent therapeutic efficacy of tauroursodeoxycholic acid in preclinical models of spinocerebellar ataxia type 3
Spinocerebellar ataxia type 3 (SCA3) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the ataxin-3 (ATXN3) gene. No effective treatment is available for this disorder, other than symptom-directed approaches. Bile acids have shown therapeutic efficacy in neurodegenerative disease models. Here, we pinpointed tauroursodeoxycholic acid (TUDCA) as an efficient therapeutic, improving the motor and neuropathological phenotype of SCA3 nematode and mouse models. Surprisingly, transcriptomic and functional in vivo data showed that TUDCA acts in neuronal tissue through the glucocorticoid receptor (GR...
Source: Journal of Clinical Investigation - March 1, 2024 Category: Biomedical Science Authors: Sara Duarte-Silva, Jorge Diogo Da Silva, Daniela Monteiro-Fernandes, Marta Daniela Costa, Andreia Neves-Carvalho, Mafalda Raposo, Carina Soares-Cunha, Joana S. Correia, Gonçalo Nogueira-Goncalves, Henrique S. Fernandes, Stephanie Oliveira, Ana Rita Ferre Source Type: research
Serum amyloid A expression in liver promotes synovial macrophage activation and chronic arthritis via NFAT5
Nuclear factor of activated T-cells 5 (NFAT5), an osmo-sensitive transcription factor, can be activated by isotonic stimuli, such as infection. It remains unclear, however, whether NFAT5 is required for damage-associated molecular pattern–triggered (DAMP-triggered) inflammation and immunity. Here, we found that several DAMPs increased NFAT5 expression in macrophages. In particular, serum amyloid A (SAA), primarily generated by the liver, substantially upregulated NFAT5 expression and activity through TLR2/4-JNK signalling pathway. Moreover, the SAA-TLR2/4-NFAT5 axis promoted migration and chemotaxis of macrophages in an ...
Source: Journal of Clinical Investigation - March 1, 2024 Category: Biomedical Science Authors: Meiling Li, Yu-Mi Kim, Jung Hee Koh, Jihyun Park, H. Moo Kwon, Jong-Hwan Park, Jingchun Jin, Youngjae Park, Donghyun Kim, Wan-Uk Kim Source Type: research
Stromal Pbrm1 mediates chromatin remodeling necessary for embryo implantation in the mouse uterus
We report that the switch/sucrose nonfermentable (SWI/SNF) remodeling complex containing polybromo-1 (PBRM1) and Brahma-related gene 1 (BRG1) is essential for implantation of the embryonic blastocyst on the wall of the uterus in mice. Although preimplantation development is unaffected, conditional ablation of Pbrm1 in uterine stromal cells disrupts progesterone pathways and uterine receptivity. Heart and neural crest derivatives expressed 2 (Hand2) encodes a basic helix-loop-helix (bHLH) transcription factor required for embryo implantation. We identify an enhancer of the Hand2 gene in stromal cells that requires PBRM1 for...
Source: Journal of Clinical Investigation - March 1, 2024 Category: Biomedical Science Authors: Qiliang Xin, Iris Feng, Guoyun Yu, Jurrien Dean Source Type: research
Neutrophil extracellular traps induced by chemotherapy inhibit tumor growth in murine models of colorectal cancer
Neutrophil extracellular traps (NETs), a web-like structure of cytosolic and granule proteins assembled on decondensed chromatin, kill pathogens and cause tissue damage in diseases. Whether NETs can kill cancer cells is unexplored. Here, we report that a combination of glutaminase inhibitor CB-839 and 5-FU inhibited the growth of PIK3CA-mutant colorectal cancers (CRCs) in xenograft, syngeneic, and genetically engineered mouse models in part through NETs. Disruption of NETs by either DNase I treatment or depletion of neutrophils in CRCs attenuated the efficacy of the drug combination. Moreover, NETs were present in tumor bi...
Source: Journal of Clinical Investigation - March 1, 2024 Category: Biomedical Science Authors: Yamu Li, Sulin Wu, Yiqing Zhao, Trang Dinh, Dongxu Jiang, J. Eva Selfridge, George Myers, Yuxiang Wang, Xuan Zhao, Suzanne Tomchuck, George Dubyak, Richard T. Lee, Bassam Estfan, Marc Shapiro, Suneel Kamath, Amr Mohamed, Stanley Ching-Cheng Huang, Alex Y. Source Type: research
A humanized IL-2 mutein expands Tregs and prolongs transplant survival in preclinical models
Long-term organ transplant survival remains suboptimal, and life-long immunosuppression predisposes transplant recipients to an increased risk of infection, malignancy, and kidney toxicity. Promoting the regulatory arm of the immune system by expanding Tregs may allow immunosuppression minimization and improve long-term graft outcomes. While low-dose IL-2 treatment can expand Tregs, it has a short half-life and off-target expansion of NK and effector T cells, limiting its clinical applicability. Here, we designed a humanized mutein IL-2 with high Treg selectivity and a prolonged half-life due to the fusion of an Fc domain,...
Source: Journal of Clinical Investigation - March 1, 2024 Category: Biomedical Science Authors: Orhan Efe, Rodrigo B. Gassen, Leela Morena, Yoshikazu Ganchiku, Ayman Al Jurdi, Isadora T. Lape, Pedro Ventura-Aguiar, Christian LeGuern, Joren C. Madsen, Zachary Shriver, Gregory J. Babcock, Thiago J. Borges, Leonardo V. Riella Source Type: research
Challenges in developing therapies in fragile X syndrome: how the FXLEARN trial can guide research
Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and the single-gene cause of autism, is caused by decreased expression of the fragile X messenger ribonucleoprotein protein (FMRP), a ribosomal-associated RNA-binding protein involved in translational repression. Extensive preclinical work in several FXS animal models supported the therapeutic potential of decreasing metabotropic glutamate receptor (mGluR) signaling to correct translation of proteins related to synaptic plasticity; however, multiple clinical trials failed to show conclusive evidence of efficacy. In this issue of the JCI, B...
Source: Journal of Clinical Investigation - March 1, 2024 Category: Biomedical Science Authors: Jeffrey L. Neul Source Type: research
Reversible synaptic adaptations in a subpopulation of murine hippocampal neurons following early-life seizures
Early-life seizures (ELSs) can cause permanent cognitive deficits and network hyperexcitability, but it is unclear whether ELSs induce persistent changes in specific neuronal populations and whether these changes can be targeted to mitigate network dysfunction. We used the targeted recombination of activated populations (TRAP) approach to genetically label neurons activated by kainate-induced ELSs in immature mice. The ELS-TRAPed neurons were mainly found in hippocampal CA1, remained uniquely susceptible to reactivation by later-life seizures, and displayed sustained enhancement in α-amino-3-hydroxy-5-methyl-4-isoxazolepr...
Source: Journal of Clinical Investigation - March 1, 2024 Category: Biomedical Science Authors: Bo Xing, Aaron J. Barbour, Joseph Vithayathil, Xiaofan Li, Sierra Dutko, Jessica Fawcett-Patel, Eunjoo Lancaster, Delia M. Talos, Frances E. Jensen Source Type: research
Effects of AFQ056 on language learning in fragile X syndrome
CONCLUSION Despite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATION ClincalTrials.gov NCT02920892.FUNDING SOURCES NeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205...
Source: Journal of Clinical Investigation - March 1, 2024 Category: Biomedical Science Authors: Elizabeth Berry-Kravis, Leonard Abbeduto, Randi Hagerman, Christopher S. Coffey, Merit Cudkowicz, Craig A. Erickson, Andrea McDuffie, David Hessl, Lauren Ethridge, Flora Tassone, Walter E. Kaufmann, Katherine Friedmann, Lauren Bullard, Anne Hoffmann, Jere Source Type: research
A membrane-associated phosphoswitch in Rad controls adrenergic regulation of cardiac calcium channels
The ability to fight or flee from a threat relies on an acute adrenergic surge that augments cardiac output, which is dependent on increased cardiac contractility and heart rate. This cardiac response depends on β-adrenergic–initiated reversal of the small RGK G protein Rad–mediated inhibition of voltage-gated calcium channels (CaV) acting through the Cavβ subunit. Here, we investigate how Rad couples phosphorylation to augmented Ca2+ influx and increased cardiac contraction. We show that reversal required phosphorylation of Ser272 and Ser300 within Rad’s polybasic, hydrophobic C-terminal domain (CTD). Phosphorylat...
Source: Journal of Clinical Investigation - March 1, 2024 Category: Biomedical Science Authors: Arianne Papa, Pedro J. del Rivero Morfin, Bi-Xing Chen, Lin Yang, Alexander N. Katchman, Sergey I. Zakharov, Guoxia Liu, Michael S. Bohnen, Vivian Zheng, Moshe Katz, Suraj Subramaniam, Joel A. Hirsch, Sharon Weiss, Nathan Dascal, Arthur Karlin, Geoffrey S Source Type: research
G protein–coupled receptors: from radioligand binding to cellular signaling
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - March 1, 2024 Category: Biomedical Science Authors: Howard A. Rockman, Robert J. Lefkowitz Source Type: research
Mechanosensitive channels TMEM63A and TMEM63B mediate lung inflation–induced surfactant secretion
Pulmonary surfactant is a lipoprotein complex lining the alveolar surface to decrease the surface tension and facilitate inspiration. Surfactant deficiency is often seen in premature infants and in children and adults with respiratory distress syndrome. Mechanical stretch of alveolar type 2 epithelial (AT2) cells during lung expansion is the primary physiological factor that stimulates surfactant secretion; however, it is unclear whether there is a mechanosensor dedicated to this process. Here, we show that loss of the mechanosensitive channels TMEM63A and TMEM63B (TMEM63A/B) resulted in atelectasis and respiratory failure...
Source: Journal of Clinical Investigation - March 1, 2024 Category: Biomedical Science Authors: Gui-Lan Chen, Jing-Yi Li, Xin Chen, Jia-Wei Liu, Qian Zhang, Jie-Yu Liu, Jing Wen, Na Wang, Ming Lei, Jun-Peng Wei, Li Yi, Jia-Jia Li, Yu-Peng Ling, He-Qiang Yi, Zhenying Hu, Jingjing Duan, Jin Zhang, Bo Zeng Source Type: research
A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder
Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway — KYNU, HAAO, and NADSYN1 — have been identified in humans with congenital malformations defined as congenital NAD deficiency disorder (CNDD). Here, we identified 13 further individuals with biallelic NADSYN1 variants predicted to be damaging, and phenotypes ranging from multiple severe malformations to the complete absence of malformation. Enzymatic assessment of variant deleteriousness in vitro revealed protein domain...
Source: Journal of Clinical Investigation - February 15, 2024 Category: Biomedical Science Authors: Justin O. Szot, Hartmut Cuny, Ella M.M.A. Martin, Delicia Z. Sheng, Kavitha Iyer, Stephanie Portelli, Vivien Nguyen, Jessica M. Gereis, Dimuthu Alankarage, David Chitayat, Karen Chong, Ingrid M. Wentzensen, Catherine Vincent-Delormé, Alban Lermine, Emma Source Type: research
