The Journal of Clinical Investigation最新文献_第10页

Metabolic dysfunction-associated steatotic liver disease and pregnancy. 代谢功能障碍相关的脂肪变性肝病与妊娠。

The Journal of Clinical Investigation Pub Date : 2025-05-15 DOI: 10.1172/jci186426

Monika Sarkar,Tatyana Kushner

{"title":"Metabolic dysfunction-associated steatotic liver disease and pregnancy.","authors":"Monika Sarkar,Tatyana Kushner","doi":"10.1172/jci186426","DOIUrl":"https://doi.org/10.1172/jci186426","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is rising among reproductive-aged individuals and in pregnancy. MASLD in pregnancy does increase such risks as gestational diabetes, preeclampsia, and preterm birth. Although routine screening for MASLD has not been established in pregnancy, individuals with metabolic comorbidities, such as type 2 diabetes mellitus, should be evaluated by liver imaging and liver panel. Preconception counseling should address potential risks as well as need for optimized metabolic health before and during pregnancy. Fibrosis assessment should ideally be completed before pregnancy, to identify cases of cirrhosis that may warrant additional preconception management, such as variceal screening, as well as comanagement with maternal-fetal medicine specialists. In patients with MASLD, aspirin is advised at 12 weeks of gestational age to lower preeclampsia risk. In the absence of cirrhosis, no additional blood test monitoring is needed. In the general population, breastfeeding has beneficial effects on metabolic health in birthing parents and offspring and thus should be encouraged in the setting of MASLD, including access to enhanced lactation support. Research needs include evaluation of the long-term risks of MASLD in pregnancy on metabolic health in birthing parents and infants, as well as safety data for MASLD-directed therapies during pregnancy and lactation.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AgRP neuron hyperactivity drives hyperglycemia in a mouse model of type 2 diabetes. 在2型糖尿病小鼠模型中，AgRP神经元亢进驱动高血糖。

The Journal of Clinical Investigation Pub Date : 2025-05-15 DOI: 10.1172/jci189842

Yang Gou,Micaela Glat,Vincent Damian,Caeley L Bryan,Bao Anh Phan,Chelsea L Faber,Arikta Trivedi,Matthew K Hwang,Jarrad M Scarlett,Gregory J Morton,Michael W Schwartz

{"title":"AgRP neuron hyperactivity drives hyperglycemia in a mouse model of type 2 diabetes.","authors":"Yang Gou,Micaela Glat,Vincent Damian,Caeley L Bryan,Bao Anh Phan,Chelsea L Faber,Arikta Trivedi,Matthew K Hwang,Jarrad M Scarlett,Gregory J Morton,Michael W Schwartz","doi":"10.1172/jci189842","DOIUrl":"https://doi.org/10.1172/jci189842","url":null,"abstract":"Growing evidence suggests that the pathogenesis of type 2 diabetes (T2D) involves dysfunctional central mechanisms, and, hence, the brain can be targeted to treat this disease. As an example, a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) can normalize hyperglycemia for weeks or months in rodent models of T2D. Convergent evidence implicates inhibition of a particular subset of neurons as a mediator of this FGF1 effect. Specifically, AgRP neurons, which are located in the hypothalamic arcuate nucleus (ARC) and are hyperactive in Lepob/ob mice and other rodent models of T2D. To investigate whether chronic AgRP neuron inactivation mimics the antidiabetic action of FGF1, we directed an adeno-associated virus (AAV) containing a cre-inducible tetanus toxin-GFP (TeTx-GFP) cassette (or cre-inducible AAV GFP control) to the ARC of obese, diabetic male Lepob/ob mice in which cre recombinase is expressed solely by AgRP neurons (Lepob/ob AgRP-Cre mice). We report that over a 10-wk period of observation, hyperglycemia was fully normalized by AgRP neuron inactivation. In contrast, changes in energy homeostasis parameters (food intake, energy expenditure, body weight, and fat mass) were not observed. We conclude that in diabetic male Lepob/ob mice, AgRP neuron hyperactivity is required for hyperglycemia but is dispensable for obesity.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IL-32-producing CD8+ memory T cells define immunoregulatory niches in human cutaneous leishmaniasis. 产生il -32的CD8+记忆T细胞定义了人皮肤利什曼病的免疫调节壁龛。

The Journal of Clinical Investigation Pub Date : 2025-05-15 DOI: 10.1172/jci182040

Nidhi S Dey,Shoumit Dey,Naj Brown,Sujai Senarathne,Luiza Campos Reis,Ritika Sengupta,Jose Al Lindoso,Sally R James,Lesley Gilbert,Dave Boucher,Mitali Chatterjee,Hiro Goto,Shalindra Ranasinghe,Paul M Kaye

{"title":"IL-32-producing CD8+ memory T cells define immunoregulatory niches in human cutaneous leishmaniasis.","authors":"Nidhi S Dey,Shoumit Dey,Naj Brown,Sujai Senarathne,Luiza Campos Reis,Ritika Sengupta,Jose Al Lindoso,Sally R James,Lesley Gilbert,Dave Boucher,Mitali Chatterjee,Hiro Goto,Shalindra Ranasinghe,Paul M Kaye","doi":"10.1172/jci182040","DOIUrl":"https://doi.org/10.1172/jci182040","url":null,"abstract":"Human cutaneous leishmaniasis (CL) is characterized by chronic skin pathology. Experimental and clinical data suggest that immune checkpoints (ICs) play a crucial role in disease outcome, but the cellular and molecular niches that facilitate IC molecule expression during leishmaniasis are ill defined. In Sri Lankan patients with CL, indoleamine 2,3-dioxygenase 1 (IDO1) and programmed death-ligand 1 (PD-L1) were enriched in skin lesions, and reduced PD-L1 expression early after treatment initiation was predictive of a cure rate following antimonial therapy. Here, we used spatial cell interaction mapping to identify IL-32-expressing CD8+ memory T cells and Tregs as key components of the IDO1/PD-L1 niche in Sri Lankan patients with CL and in patients with distinct forms of dermal leishmaniasis in Brazil and India. Furthermore, the abundance of IL-32+ cells and IL-32+CD8+ T cells at treatment initiation was negatively correlated with the rate of cure in Sri Lankan patients. This study provides insights into the spatial mechanisms underpinning IC expression during CL and offers a strategy for identifying additional biomarkers of treatment response.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Aldehyde metabolism governs resilience of mucociliary clearance to air pollution exposure. 醛代谢控制毛粘清除对空气污染暴露的恢复力。

The Journal of Clinical Investigation Pub Date : 2025-05-15 DOI: 10.1172/jci191276

Noriko Shinjyo,Haruna Kimura,Tomomi Yoshihara,Jun Suzuki,Masaya Yamaguchi,Shigetada Kawabata,Yasutaka Okabe

{"title":"Aldehyde metabolism governs resilience of mucociliary clearance to air pollution exposure.","authors":"Noriko Shinjyo,Haruna Kimura,Tomomi Yoshihara,Jun Suzuki,Masaya Yamaguchi,Shigetada Kawabata,Yasutaka Okabe","doi":"10.1172/jci191276","DOIUrl":"https://doi.org/10.1172/jci191276","url":null,"abstract":"Air pollution is a serious environmental threat to public health; however, the molecular basis underlying its detrimental effects on respiratory fitness remains poorly understood. Here, we show that exposure to particulate matter ≤2.5 µm (PM2.5), a significant fraction of air pollutants, induces the generation of reactive aldehyde species in the airway. We identified aldehyde dehydrogenase 1A1 (ALDH1A1), which is selectively expressed in airway epithelium, as an enzyme responsible for detoxifying these reactive aldehyde species. Loss of ALDH1A1 function results in the accumulation of aldehyde adducts in the airway, which selectively impairs mucociliary clearance (MCC), a critical defense mechanism against respiratory pathogens. Thus, ALDH1A1-deficient mice pre-exposed to PM2.5 exhibited increased susceptibility to pneumonia. Conversely, pharmacological enhancement of ALDH1A1 activity promoted the restoration of MCC function. These findings elucidate the critical role of aldehyde metabolism in protecting against PM2.5 exposure, offering a potential target to mitigate the negative health consequences of air pollution.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144130743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Activation of intestinal endogenous retroviruses by alcohol exacerbates liver disease. 酒精激活肠道内源性逆转录病毒可加重肝脏疾病。

The Journal of Clinical Investigation Pub Date : 2025-05-13 DOI: 10.1172/jci188541

Noemí Cabré,Marcos F Fondevila,Wenchao Wei,Tomoo Yamazaki,Fernanda Raya Tonetti,Alvaro Eguileor,Ricard Garcia-Carbonell,Abraham S Meijnikman,Yukiko Miyamoto,Susan Mayo,Yanhan Wang,Xinlian Zhang,Thorsten Trimbuch,Seija Lehnardt,Lars Eckmann,Derrick E Fouts,Cristina Llorente,Hidekazu Tsukamoto,Peter Stärkel,Bernd Schnabl

{"title":"Activation of intestinal endogenous retroviruses by alcohol exacerbates liver disease.","authors":"Noemí Cabré,Marcos F Fondevila,Wenchao Wei,Tomoo Yamazaki,Fernanda Raya Tonetti,Alvaro Eguileor,Ricard Garcia-Carbonell,Abraham S Meijnikman,Yukiko Miyamoto,Susan Mayo,Yanhan Wang,Xinlian Zhang,Thorsten Trimbuch,Seija Lehnardt,Lars Eckmann,Derrick E Fouts,Cristina Llorente,Hidekazu Tsukamoto,Peter Stärkel,Bernd Schnabl","doi":"10.1172/jci188541","DOIUrl":"https://doi.org/10.1172/jci188541","url":null,"abstract":"Alcohol-associated liver disease represents a significant global health challenge, with gut microbial dysbiosis and bacterial translocation playing a critical role in its pathogenesis. Patients with alcohol-associated hepatitis had increased fecal abundance of mammalian viruses including retroviruses. This study investigated the role of endogenous retroviruses (ERVs) in the development of alcohol-associated liver disease. Transcriptomic analysis of duodenal and liver biopsies revealed increased expression of several human ERVs, including HERV-K and HERV-H, in patients with alcohol-associated liver disease compared with controls. Chronic-binge ethanol feeding markedly induced ERV abundance in intestinal epithelial cells, but not the liver of mice. Ethanol increased ERV expression and activated the Z-DNA binding protein 1 (Zbp1)-mixed lineage kinase domain-like pseudokinase (Mlkl) signaling pathways to induce necroptosis in intestinal epithelial cells. Antiretroviral treatment reduced ethanol-induced intestinal ERV expression, stabilized the gut barrier, and decreased liver disease in microbiota-humanized mice. Furthermore, mice with an intestine-specific deletion of Zbp1 were protected against bacterial translocation and ethanol-induced steatohepatitis. These findings indicate that ethanol exploits this pathway by inducing ERVs and promoting innate immune responses, which results in the death of intestinal epithelial cells, gut barrier dysfunction and liver disease. Targeting the ERV-Zbp1 pathway may offer new therapies for patients with alcohol-associated liver disease.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"96 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The gut microbiome controls reactive astrocytosis during Aβ amyloidosis via propionate-mediated regulation of IL-17. 肠道微生物组通过丙酸介导的IL-17调控β淀粉样变性过程中的星形细胞反应。

The Journal of Clinical Investigation Pub Date : 2025-05-13 DOI: 10.1172/jci180826

Sidhanth Chandra,Jelena Popovic,Naveen K Singhal,Elyse A Watkins,Hemraj B Dodiya,Ian Q Weigle,Miranda A Salvo,Abhirami Ramakrishnan,Zhangying Chen,James T Watson,Aashutosh Shetti,Natalie Piehl,Xiaoqiong Zhang,Leah K Cuddy,Katherine R Sadleir,Steven J Schwulst,Murali Prakriya,David Gate,Sangram S Sisodia,Robert Vassar

{"title":"The gut microbiome controls reactive astrocytosis during Aβ amyloidosis via propionate-mediated regulation of IL-17.","authors":"Sidhanth Chandra,Jelena Popovic,Naveen K Singhal,Elyse A Watkins,Hemraj B Dodiya,Ian Q Weigle,Miranda A Salvo,Abhirami Ramakrishnan,Zhangying Chen,James T Watson,Aashutosh Shetti,Natalie Piehl,Xiaoqiong Zhang,Leah K Cuddy,Katherine R Sadleir,Steven J Schwulst,Murali Prakriya,David Gate,Sangram S Sisodia,Robert Vassar","doi":"10.1172/jci180826","DOIUrl":"https://doi.org/10.1172/jci180826","url":null,"abstract":"Accumulating evidence implicates the gut microbiome (GMB) in the pathogenesis and progression of Alzheimer's disease (AD). We recently showed that the GMB regulates reactive astrocytosis and Aβ plaque accumulation in male APPPS1-21 AD model mice. Yet, the mechanism(s) by which GMB perturbation alters reactive astrocytosis in a manner that reduces Aβ deposition remain unknown. Here, we performed metabolomics on plasma from mice treated with antibiotics (abx) and identified a significant increase in plasma propionate, a gut-derived short chain fatty acid, only in male mice. Administration of sodium propionate reduced reactive astrocytosis and Aβ plaques in APPPS1-21 mice, phenocopying the abx-induced phenotype. Astrocyte-specific RNA sequencing on abx and propionate treated mice showed reduced expression of pro-inflammatory and increased expression of neurotrophic genes. Next, we performed flow cytometry experiments where we found abx and propionate decreased peripheral RAR-related orphan receptor-γ (Rorγt)+ CD4+ (Th17) cells and IL-17 secretion, which positively correlated with reactive astrocytosis. Lastly, using an IL-17 monoclonal antibody to deplete IL-17, we found that propionate reduces reactive astrocytosis and Aβ plaques in an IL-17-dependent manner. Together, these results suggest that gut-derived propionate regulates reactive astrocytosis and Aβ amyloidosis by decreasing peripheral Th17 cells and IL-17 release. Thus, propionate treatment or strategies boosting propionate production may represent novel therapeutic strategies for AD.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"2020 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SARM1 loss protects retinal ganglion cells in a mouse model of Autosomal Dominant Optic Atrophy. SARM1缺失在常染色体显性视神经萎缩小鼠模型中保护视网膜神经节细胞。

The Journal of Clinical Investigation Pub Date : 2025-05-09 DOI: 10.1172/jci191315

Chen Ding,Papa S Ndiaye,Sydney R Campbell,Michelle Y Fry,Jincheng Gong,Sophia R Wienbar,Whitney Gibbs,Philippe Morquette,Luke H Chao,Michael Tri H Do,Thomas Schwarz

{"title":"SARM1 loss protects retinal ganglion cells in a mouse model of Autosomal Dominant Optic Atrophy.","authors":"Chen Ding,Papa S Ndiaye,Sydney R Campbell,Michelle Y Fry,Jincheng Gong,Sophia R Wienbar,Whitney Gibbs,Philippe Morquette,Luke H Chao,Michael Tri H Do,Thomas Schwarz","doi":"10.1172/jci191315","DOIUrl":"https://doi.org/10.1172/jci191315","url":null,"abstract":"Autosomal Dominant Optic Atrophy (ADOA), the most prevalent hereditary optic neuropathy, leads to retinal ganglion cell (RGC) degeneration and vision loss. ADOA is primarily caused by mutations in the OPA1 gene, which encodes a conserved GTPase important for mitochondrial inner membrane dynamics. To date, the disease mechanism remains unclear, and no therapies are available. We generated a mouse model carrying the pathogenic Opa1R290Q/+ allele that recapitulated key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC functions. We identified SARM1, a neurodegeneration switch, as a key driver of RGC degeneration in these mice. Sarm1 knockout nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation. Additionally, we showed that a portion of SARM1 localized within the mitochondrial intermembrane space (IMS). These findings indicated that SARM1 was activated downstream of mitochondrial dysfunction in ADOA, highlighting it as a promising therapeutic target.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The tumor suppressor HNRNPK induces p53-dependent nucleolar stress to drive ribosomopathies. 肿瘤抑制因子HNRNPK诱导p53依赖性核仁应激驱动核糖体病变。

The Journal of Clinical Investigation Pub Date : 2025-05-08 DOI: 10.1172/jci183697

Pedro Aguilar-Garrido,María Velasco-Estévez,Miguel Ángel Navarro-Aguadero,Alvaro Otero-Sobrino,Marta Ibañez-Navarro,Miguel Ángel Marugal,María Hernández-Sánchez,Prerna Malaney,Ashley Rodriguez,Oscar Benitez,Xiaorui Zhang,Marisa Jl Aitken,Alejandra Ortiz-Ruiz,Diego Megias,Manuel Pérez-Martínez,Gadea Mata,Jesús Gomez,Miguel Lafarga,Orlando Dominguez,Osvaldo Graña-Castro,Eduardo Caleiras,Pilar Ximenez-Embun,Marta Isasa,Paloma J de Andrés,Sandra Rodriguez-Perales,Raul Torres-Ruiz,Enrique Revilla,Rosa María García-Martín,Daniel Azorín,Josune Zubicaray,Julian Sevilla,Oleksandra Sirozh,Vanesa Lafarga,Joaquín Martinez-Lopez,Sean M Post,Miguel Gallardo

{"title":"The tumor suppressor HNRNPK induces p53-dependent nucleolar stress to drive ribosomopathies.","authors":"Pedro Aguilar-Garrido,María Velasco-Estévez,Miguel Ángel Navarro-Aguadero,Alvaro Otero-Sobrino,Marta Ibañez-Navarro,Miguel Ángel Marugal,María Hernández-Sánchez,Prerna Malaney,Ashley Rodriguez,Oscar Benitez,Xiaorui Zhang,Marisa Jl Aitken,Alejandra Ortiz-Ruiz,Diego Megias,Manuel Pérez-Martínez,Gadea Mata,Jesús Gomez,Miguel Lafarga,Orlando Dominguez,Osvaldo Graña-Castro,Eduardo Caleiras,Pilar Ximenez-Embun,Marta Isasa,Paloma J de Andrés,Sandra Rodriguez-Perales,Raul Torres-Ruiz,Enrique Revilla,Rosa María García-Martín,Daniel Azorín,Josune Zubicaray,Julian Sevilla,Oleksandra Sirozh,Vanesa Lafarga,Joaquín Martinez-Lopez,Sean M Post,Miguel Gallardo","doi":"10.1172/jci183697","DOIUrl":"https://doi.org/10.1172/jci183697","url":null,"abstract":"The nucleolus is a membraneless organelle and an excellent stress sensor. Any changes in its architecture or composition lead to nucleolar stress, resulting in cell cycle arrest and interruption of ribosomal activity, critical factors in aging and cancer. In this study, we identified and described the pivotal role of the RNA-binding protein (RBP) HNRNPK in ribosome and nucleolar dynamics. We developed an in vitro model of endogenous HNRNPK overexpression and an in vivo mouse model of ubiquitous HNRNPK overexpression. These models showed disruptions in translation and caused alterations in the nucleolar structure, resulting in p53-dependent nucleolar stress, cell cycle arrest, senescence, and bone marrow failure phenotype, similar to what is observed in patients with ribosomopathies. Together, our findings identify HNRNPK as a master regulator of ribosome biogenesis (RiBi) and nucleolar homeostasis through p53, providing a new perspective on the orchestration of nucleolar integrity, ribosome function and cellular senescence.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PPIL2 is a target of the JAK2/STAT5 pathway and promotes myeloproliferation via p53-mediated degradation. PPIL2是JAK2/STAT5通路的靶标，并通过p53介导的降解促进骨髓增殖。

The Journal of Clinical Investigation Pub Date : 2025-05-08 DOI: 10.1172/jci181394

Pan Wang,Xu Han,Kehan Ren,Ermin Li,Honghao Bi,Inci Aydemir,Madina Sukhanova,Yijie Liu,Jing Yang,Peng Ji

{"title":"PPIL2 is a target of the JAK2/STAT5 pathway and promotes myeloproliferation via p53-mediated degradation.","authors":"Pan Wang,Xu Han,Kehan Ren,Ermin Li,Honghao Bi,Inci Aydemir,Madina Sukhanova,Yijie Liu,Jing Yang,Peng Ji","doi":"10.1172/jci181394","DOIUrl":"https://doi.org/10.1172/jci181394","url":null,"abstract":"The activated JAK2/STAT pathway is characteristic of myeloproliferative neoplasms (MPNs). Pleckstrin-2 (PLEK2) signalosome is downstream of the JAK2/STAT5 pathway and plays an important role in MPN development. The detailed molecular composition of this signalosome is unclear. Here, we revealed peptidylprolyl isomerase-like 2 (PPIL2) as a critical component of the complex in regulating human and murine erythropoiesis. PPIL2 was a direct target of STAT5 and was upregulated in MPN patients and a Jak2V617F MPN mouse model. Mechanistically, PPIL2 interacted with and catalyzed p53 polyubiquitination and proteasome-mediated degradation to promote cell growth. Ppil2 deficiency, or inhibition by cyclosporin A, led to a marked upregulation of p53 in vivo and ameliorated myeloproliferative phenotypes in Jak2V617F mice. Cyclosporin A also markedly reduced JAK2 mutated erythroid and myeloid proliferation in an induced pluripotent stem cell-derived human bone marrow organoid model. Our findings revealed PPIL2 as a critical component of the PLEK2 signalosome in driving MPN pathogenesis through negatively regulating p53, thus providing a target and an opportunity for drug repurposing by using cyclosporin A to treat MPNs.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GluN2B suppression restores phenylalanine-induced neuroplasticity and cognition impairments in a mouse model of phenylketonuria. 在苯丙酮尿小鼠模型中，GluN2B抑制可恢复苯丙氨酸诱导的神经可塑性和认知障碍。

The Journal of Clinical Investigation Pub Date : 2025-05-08 DOI: 10.1172/jci184299

Woo Seok Song,Young Sook Kim,Young-Soo Bae,Sang Ho Yoon,Jae Min Lim,Myoung-Hwan Kim

{"title":"GluN2B suppression restores phenylalanine-induced neuroplasticity and cognition impairments in a mouse model of phenylketonuria.","authors":"Woo Seok Song,Young Sook Kim,Young-Soo Bae,Sang Ho Yoon,Jae Min Lim,Myoung-Hwan Kim","doi":"10.1172/jci184299","DOIUrl":"https://doi.org/10.1172/jci184299","url":null,"abstract":"Phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, is a common cause of intellectual disability. However, the mechanisms by which elevated phenylalanine (Phe) levels cause cognitive impairment remain unclear. Here, we show that submillimolar Phe perturbs synaptic plasticity through the hyperactivation of GluN2B-containing NMDARs. PahEnu2 PKU model mice exhibited submillimolar and supramillimolar concentrations of Phe in the cerebrospinal fluid (CSF) and serum, respectively. L-Phe produced concentration-dependent bidirectional effects on NMDA-induced currents, without affecting synaptic NMDARs in hippocampal CA1 neurons. L-Phe-induced hyperactivation of extrasynaptic GluN2B resulted in activity-dependent downregulation of AMPARs during burst or sustained synaptic activity. Administration of L-Phe in mice decreased neural activity and impaired memory, which were blocked by pretreatment with GluN2B inhibitors. Furthermore, pharmacological and virus-mediated suppression of GluN2B reversed the impaired learning in PahEnu2 mice. Collectively, these results suggest that the concentration of Phe in the CSF of patients with PKU perturbs extrasynaptic NMDARs and synaptic plasticity, and that suppression of GluN2B may have the potential to improve cognitive function in patients with PKU.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"69 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0