Life Science Alliance最新文献_第5页

Helicobacter pylori induces the expression of Lgr5 and stem cell properties in gastric target cells. 幽门螺杆菌诱导胃靶细胞表达 Lgr5 和干细胞特性。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-08-27 Print Date: 2024-11-01 DOI: 10.26508/lsa.202402783

Zuzana Nascakova, Jiazhuo He, Giovanni Papa, Biel Francas, Flora Azizi, Anne Müller

{"title":"Helicobacter pylori induces the expression of Lgr5 and stem cell properties in gastric target cells.","authors":"Zuzana Nascakova, Jiazhuo He, Giovanni Papa, Biel Francas, Flora Azizi, Anne Müller","doi":"10.26508/lsa.202402783","DOIUrl":"10.26508/lsa.202402783","url":null,"abstract":"Helicobacter pylori infection predisposes carriers to a high risk of developing gastric cancer. The cell-of-origin of antral gastric cancer is the Lgr5+ stem cell. Here, we show that infection of antrum-derived gastric organoid cells with H. pylori increases the expression of the stem cell marker Lgr5 as determined by immunofluorescence microscopy, qRT-PCR, and Western blotting, both when cells are grown and infected as monolayers and when cells are exposed to H. pylori in 3D structures. H. pylori exposure increases stemness properties as determined by spheroid formation assay. Lgr5 expression and the acquisition of stemness depend on a functional type IV secretion system (T4SS) and at least partly on the T4SS effector CagA. The pharmacological inhibition or genetic ablation of NF-κB reverses the increase in Lgr5 and spheroid formation. Constitutively active Wnt/β-catenin signaling because of Apc inactivation exacerbates H. pylori-induced Lgr5 expression and stemness, both of which persist even after eradication of the infection. The combined data indicate that H. pylori has stemness-inducing properties that depend on its ability to activate NF-κB signaling.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11350067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism. 通过调节精氨酸代谢对乳腺肿瘤相关巨噬细胞进行重编程。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-08-27 Print Date: 2024-11-01 DOI: 10.26508/lsa.202302339

Veani Fernando, Xunzhen Zheng, Vandana Sharma, Osama Sweef, Eun-Seok Choi, Saori Furuta

{"title":"Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism.","authors":"Veani Fernando, Xunzhen Zheng, Vandana Sharma, Osama Sweef, Eun-Seok Choi, Saori Furuta","doi":"10.26508/lsa.202302339","DOIUrl":"10.26508/lsa.202302339","url":null,"abstract":"HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor-associated macrophages (TAMs). Although TAMs consist of the immune-stimulatory M1 type and immune-suppressive M2 type, the M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1- versus M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2-TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- versus M2-TAMs is attributed to different availability of BH4 (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH4 precursor, elevates the expression of M1-TAM markers within HER2+ tumors. Here, we show that SEP restores BH4 levels in M2-like macrophages, which then redirects arginine metabolism to NO synthesis and converts M2 type to M1 type. The reprogrammed macrophages exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in the metabolic shift of the HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11350068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of single-cell blasts in pediatric acute myeloid leukemia using an autoencoder. 利用自动编码器识别小儿急性髓性白血病中的单细胞突变。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-08-27 Print Date: 2024-11-01 DOI: 10.26508/lsa.202402674

Alice Driessen, Susanne Unger, An-Phi Nguyen, Rhonda E Ries, Soheil Meshinchi, Stefanie Kreutmair, Chiara Alberti, Pavel Sumazin, Richard Aplenc, Michele S Redell, Burkhard Becher, María Rodríguez Martínez

{"title":"Identification of single-cell blasts in pediatric acute myeloid leukemia using an autoencoder.","authors":"Alice Driessen, Susanne Unger, An-Phi Nguyen, Rhonda E Ries, Soheil Meshinchi, Stefanie Kreutmair, Chiara Alberti, Pavel Sumazin, Richard Aplenc, Michele S Redell, Burkhard Becher, María Rodríguez Martínez","doi":"10.26508/lsa.202402674","DOIUrl":"10.26508/lsa.202402674","url":null,"abstract":"Pediatric acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis and high relapse rate. Current challenges in the identification of immunotherapy targets arise from patient-specific blast immunophenotypes and their change during disease progression. To overcome this, we present a new computational research tool to rapidly identify malignant cells. We generated single-cell flow cytometry profiles of 21 pediatric AML patients with matched samples at diagnosis, remission, and relapse. We coupled a classifier to an autoencoder for anomaly detection and classified malignant blasts with 90% accuracy. Moreover, our method assigns a developmental stage to blasts at the single-cell level, improving current classification approaches based on differentiation of the dominant phenotype. We observed major immunophenotype and developmental stage alterations between diagnosis and relapse. Patients with KMT2A rearrangement had more profound changes in their blast immunophenotypes at relapse compared to patients with other molecular features. Our method provides new insights into the immunophenotypic composition of AML blasts in an unbiased fashion and can help to define immunotherapy targets that might improve personalized AML treatment.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11358707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

mTORC1 hampers Hedgehog signaling in Tsc2 deficient cells. 在缺乏 Tsc2 的细胞中，mTORC1 阻碍了刺猬信号的传递。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-08-26 Print Date: 2024-11-01 DOI: 10.26508/lsa.202302419

Lasse Jonsgaard Larsen, Elsebet Østergaard, Lisbeth Birk Møller

{"title":"mTORC1 hampers Hedgehog signaling in Tsc2 deficient cells.","authors":"Lasse Jonsgaard Larsen, Elsebet Østergaard, Lisbeth Birk Møller","doi":"10.26508/lsa.202302419","DOIUrl":"10.26508/lsa.202302419","url":null,"abstract":"The mTORC1-complex is negatively regulated by TSC1 and TSC2. Activation of Hedgehog signaling is strictly dependent on communication between Smoothened and the Hedgehog-signaling effector and transcription factor, GLI2, in the primary cilium. Details about this communication are not known, and we wanted to explore this further. Here we report that in Tsc2 -/- MEFs constitutively activated mTORC1 led to mis-localization of Smoothened to the plasma membrane, combined with increased concentration of GLI2 in the cilia and reduced Hedgehog signaling, measured by reduced expression of the Hedgehog target gene, Gli1 Inhibition of mTORC1 rescued the cellular localization of Smoothened to the cilia, reduced the cilia concentration of GLI2, and restored Hedgehog signaling. Our results reveal evidence for a two-step activation process of GLI2. The first step includes GLI2 stabilization and cilium localization, whereas the second step includes communication with cilia-localized Smoothened. We found that mTORC1 inhibits the second step. This is the first demonstration that mTORC1 is involved in the regulation of Hedgehog signaling.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11349048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CC2D1A causes ciliopathy, intellectual disability, heterotaxy, renal dysplasia, and abnormal CSF flow. CC2D1A会导致纤毛症、智力障碍、异位发育、肾发育不良和脑脊液流动异常。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-08-21 Print Date: 2024-10-01 DOI: 10.26508/lsa.202402708

Angelina Haesoo Kim, Irmak Sakin, Stephen Viviano, Gulten Tuncel, Stephanie Marie Aguilera, Gizem Goles, Lauren Jeffries, Weizhen Ji, Saquib A Lakhani, Canan Ceylan Kose, Fatma Silan, Sukru Sadik Oner, Oktay I Kaplan, Mahmut Cerkez Ergoren, Ketu Mishra-Gorur, Murat Gunel, Sebnem Ozemri Sag, Sehime G Temel, Engin Deniz

{"title":"CC2D1A causes ciliopathy, intellectual disability, heterotaxy, renal dysplasia, and abnormal CSF flow.","authors":"Angelina Haesoo Kim, Irmak Sakin, Stephen Viviano, Gulten Tuncel, Stephanie Marie Aguilera, Gizem Goles, Lauren Jeffries, Weizhen Ji, Saquib A Lakhani, Canan Ceylan Kose, Fatma Silan, Sukru Sadik Oner, Oktay I Kaplan, Mahmut Cerkez Ergoren, Ketu Mishra-Gorur, Murat Gunel, Sebnem Ozemri Sag, Sehime G Temel, Engin Deniz","doi":"10.26508/lsa.202402708","DOIUrl":"10.26508/lsa.202402708","url":null,"abstract":"Intellectual and developmental disabilities result from abnormal nervous system development. Over a 1,000 genes have been associated with intellectual and developmental disabilities, driving continued efforts toward dissecting variant functionality to enhance our understanding of the disease mechanism. This report identified two novel variants in CC2D1A in a cohort of four patients from two unrelated families. We used multiple model systems for functional analysis, including Xenopus, Drosophila, and patient-derived fibroblasts. Our experiments revealed that cc2d1a is expressed explicitly in a spectrum of ciliated tissues, including the left-right organizer, epidermis, pronephric duct, nephrostomes, and ventricular zone of the brain. In line with this expression pattern, loss of cc2d1a led to cardiac heterotaxy, cystic kidneys, and abnormal CSF circulation via defective ciliogenesis. Interestingly, when we analyzed brain development, mutant tadpoles showed abnormal CSF circulation only in the midbrain region, suggesting abnormal local CSF flow. Furthermore, our analysis of the patient-derived fibroblasts confirmed defective ciliogenesis, further supporting our observations. In summary, we revealed novel insight into the role of CC2D1A by establishing its new critical role in ciliogenesis and CSF circulation.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11339347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Examining the liver-pancreas crosstalk reveals a role for the molybdenum cofactor in β-cell regeneration. 通过研究肝脏与胰腺之间的相互关系，可以发现钼辅助因子在β细胞再生中的作用。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-08-19 Print Date: 2024-11-01 DOI: 10.26508/lsa.202402771

Christos Karampelias, Bianca Băloiu, Birgit Rathkolb, Patricia da Silva-Buttkus, Etty Bachar-Wikström, Susan Marschall, Helmut Fuchs, Valerie Gailus-Durner, Lianhe Chu, Martin Hrabě de Angelis, Olov Andersson

{"title":"Examining the liver-pancreas crosstalk reveals a role for the molybdenum cofactor in β-cell regeneration.","authors":"Christos Karampelias, Bianca Băloiu, Birgit Rathkolb, Patricia da Silva-Buttkus, Etty Bachar-Wikström, Susan Marschall, Helmut Fuchs, Valerie Gailus-Durner, Lianhe Chu, Martin Hrabě de Angelis, Olov Andersson","doi":"10.26508/lsa.202402771","DOIUrl":"10.26508/lsa.202402771","url":null,"abstract":"Regeneration of insulin-producing β-cells is an alternative avenue to manage diabetes, and it is crucial to unravel this process in vivo during physiological responses to the lack of β-cells. Here, we aimed to characterize how hepatocytes can contribute to β-cell regeneration, either directly or indirectly via secreted proteins or metabolites, in a zebrafish model of β-cell loss. Using lineage tracing, we show that hepatocytes do not directly convert into β-cells even under extreme β-cell ablation conditions. A transcriptomic analysis of isolated hepatocytes after β-cell ablation displayed altered lipid- and glucose-related processes. Based on the transcriptomics, we performed a genetic screen that uncovers a potential role of the molybdenum cofactor (Moco) biosynthetic pathway in β-cell regeneration and glucose metabolism in zebrafish. Consistently, molybdenum cofactor synthesis 2 (Mocs2) haploinsufficiency in mice indicated dysregulated glucose metabolism and liver function. Together, our study sheds light on the liver-pancreas crosstalk and suggests that the molybdenum cofactor biosynthesis pathway should be further studied in relation to glucose metabolism and diabetes.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11333758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhancing uterine receptivity for embryo implantation through controlled collagenase intervention. 通过受控胶原酶干预提高子宫对胚胎植入的接受能力。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-08-16 Print Date: 2024-10-01 DOI: 10.26508/lsa.202402656

Eldar Zehorai, Tamar Gross Lev, Elee Shimshoni, Ron Hadas, Idan Adir, Ofra Golani, Guillaume Molodij, Ram Eitan, Karl E Kadler, Orit Kollet, Michal Neeman, Nava Dekel, Inna Solomonov, Irit Sagi

{"title":"Enhancing uterine receptivity for embryo implantation through controlled collagenase intervention.","authors":"Eldar Zehorai, Tamar Gross Lev, Elee Shimshoni, Ron Hadas, Idan Adir, Ofra Golani, Guillaume Molodij, Ram Eitan, Karl E Kadler, Orit Kollet, Michal Neeman, Nava Dekel, Inna Solomonov, Irit Sagi","doi":"10.26508/lsa.202402656","DOIUrl":"10.26508/lsa.202402656","url":null,"abstract":"Ineffective endometrial matrix remodeling, a key factor in infertility, impedes embryo implantation in the uterine wall. Our study reveals the cellular and molecular impact of human collagenase-1 administration in mouse uteri, demonstrating enhanced embryo implantation rates. Collagenase-1 promotes remodeling of the endometrial ECM, degrading collagen fibers and proteoglycans. This process releases matrix-bound bioactive factors (e.g., VEGF, decorin), facilitating vascular permeability and angiogenesis. Collagenase-1 elevates embryo implantation regulators, including NK cell infiltration and the key cytokine LIF. Remarkably, uterine tissue maintains structural integrity despite reduced endometrial collagen fiber tension. In-utero collagenase-1 application rescues implantation in heat stress and embryo transfer models, known for low implantation rates. Importantly, ex vivo exposure of human uterine tissue to collagenase-1 induces collagen de-tensioning and VEGF release, mirroring remodeling observed in mice. Our research highlights the potential of collagenases to induce and orchestrate cellular and molecular processes enhancing uterine receptivity for effective embryo implantation. This innovative approach underscores ECM remodeling mechanisms critical for embryo implantation.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11329778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neutrophil-avid nanocarrier uptake by STAT3 dominant-negative hyper-IgE syndrome patient neutrophils. STAT3显性阴性高IgE综合征患者中性粒细胞对纳米载体的吸收。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-08-12 Print Date: 2024-11-01 DOI: 10.26508/lsa.202402618

Kathryn M Rubey, Alexandra Freeman, Alexander R Mukhitov, Andrew J Paris, Susan M Lin, Ryan Rue, Hossein Fazelinia, Lynn A Spruce, Jennifer Roof, Jacob S Brenner, Jennifer Heimall, Vera P Krymskaya

{"title":"Neutrophil-avid nanocarrier uptake by STAT3 dominant-negative hyper-IgE syndrome patient neutrophils.","authors":"Kathryn M Rubey, Alexandra Freeman, Alexander R Mukhitov, Andrew J Paris, Susan M Lin, Ryan Rue, Hossein Fazelinia, Lynn A Spruce, Jennifer Roof, Jacob S Brenner, Jennifer Heimall, Vera P Krymskaya","doi":"10.26508/lsa.202402618","DOIUrl":"10.26508/lsa.202402618","url":null,"abstract":"Recurrent infections are a hallmark of STAT3 dominant-negative hyper-IgE syndrome (STAT3 HIES), a rare immunodeficiency syndrome previously known as Jobs syndrome, along with elevated IgE levels and impaired neutrophil function. We have been developing nanoparticles with neutrophil trophism that home to the sites of infection via these first-responder leukocytes, named neutrophil-avid nanocarriers (NANs). Here, we demonstrate that human neutrophils can phagocytose nanogels (NGs), a type of NAN, with enhanced uptake after particle serum opsonization, comparing neutrophils from healthy individuals to those with STAT3 HIES, where both groups exhibit NG uptake; however, the patient group showed reduced phagocytosis efficiency with serum-opsonized NANs. Proteomic analysis of NG protein corona revealed complement components, particularly C3, as predominant in both groups. Difference between groups includes STAT3 HIES samples with higher neutrophil protein and lower acute-phase protein expression. The study suggests that despite neutrophil dysfunction in STAT3 HIES, NANs have potential for directed delivery of cargo therapeutics to improve neutrophil infection clearance.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11321353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

JAK inhibition with tofacitinib rapidly increases contractile force in human skeletal muscle. 用托法替尼抑制 JAK 可迅速增加人体骨骼肌的收缩力。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-08-09 Print Date: 2024-11-01 DOI: 10.26508/lsa.202402885

Joseph B Shrager, Ryan Randle, Myung Lee, Syed Saadan Ahmed, Winston Trope, Natalie Lui, George Poultsides, Doug Liou, Brendan Visser, Jeffrey A Norton, Shannon M Nesbit, Hao He, Ntemena Kapula, Bailey Wallen, Emmanuel Fatodu, Cheyenne A Sadeghi, Harrison B Konsker, Irmina Elliott, Brandon Guenthart, Leah Backhus, Roger Cooke, Mark Berry, Huibin Tang

{"title":"JAK inhibition with tofacitinib rapidly increases contractile force in human skeletal muscle.","authors":"Joseph B Shrager, Ryan Randle, Myung Lee, Syed Saadan Ahmed, Winston Trope, Natalie Lui, George Poultsides, Doug Liou, Brendan Visser, Jeffrey A Norton, Shannon M Nesbit, Hao He, Ntemena Kapula, Bailey Wallen, Emmanuel Fatodu, Cheyenne A Sadeghi, Harrison B Konsker, Irmina Elliott, Brandon Guenthart, Leah Backhus, Roger Cooke, Mark Berry, Huibin Tang","doi":"10.26508/lsa.202402885","DOIUrl":"10.26508/lsa.202402885","url":null,"abstract":"Reduction in muscle contractile force associated with many clinical conditions incurs serious morbidity and increased mortality. Here, we report the first evidence that JAK inhibition impacts contractile force in normal human muscle. Muscle biopsies were taken from patients who were randomized to receive tofacitinib (n = 16) or placebo (n = 17) for 48 h. Single-fiber contractile force and molecular studies were carried out. The contractile force of individual diaphragm myofibers pooled from the tofacitinib group (n = 248 fibers) was significantly higher than those from the placebo group (n = 238 fibers), with a 15.7% greater mean maximum specific force (P = 0.0016). Tofacitinib treatment similarly increased fiber force in the serratus anterior muscle. The increased force was associated with reduced muscle protein oxidation and FoxO-ubiquitination-proteasome signaling, and increased levels of smooth muscle MYLK. Inhibition of MYLK attenuated the tofacitinib-dependent increase in fiber force. These data demonstrate that tofacitinib increases the contractile force of skeletal muscle and offers several underlying mechanisms. Inhibition of the JAK-STAT pathway is thus a potential new therapy for the muscle dysfunction that occurs in many clinical conditions.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11316201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Distribution of lipid droplets in hippocampal neurons and microglia: impact of diabetes and exercise. 海马神经元和小胶质细胞中脂滴的分布：糖尿病和运动的影响。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-08-08 Print Date: 2024-10-01 DOI: 10.26508/lsa.202302239

Gezime Seferi, Harald S Mjønes, Mona Havik, Herman Reiersen, Knut Tomas Dalen, Kaja Nordengen, Cecilie Morland

{"title":"Distribution of lipid droplets in hippocampal neurons and microglia: impact of diabetes and exercise.","authors":"Gezime Seferi, Harald S Mjønes, Mona Havik, Herman Reiersen, Knut Tomas Dalen, Kaja Nordengen, Cecilie Morland","doi":"10.26508/lsa.202302239","DOIUrl":"10.26508/lsa.202302239","url":null,"abstract":"Neuroinflammation, aging, and neurodegenerative disorders are associated with excessive accumulation of neutral lipids in lipid droplets (LDs) in microglia. Type 2 diabetes mellitus (T2DM) may cause neuroinflammation and is a risk factor for neurodegenerative disorders. Here, we show that hippocampal pyramidal neurons contain smaller, more abundant LDs than their neighboring microglia. The density of LDs varied between pyramidal cells in adjacent subregions, with CA3 neurons containing more LDs than CA1 neurons. Within the CA3 region, a gradual increase in the LD content along the pyramidal layer from the hilus toward CA2 was observed. Interestingly, the high neuronal LD content correlated with less ramified microglial morphotypes. Using the db/db model of T2DM, we demonstrated that diabetes increased the number of LDs per microglial cell without affecting the neuronal LD density. High-intensity interval exercise induced smaller changes in the number of LDs in microglia but was not sufficient to counteract the diabetes-induced changes in LD accumulation. The changes observed in response to T2DM may contribute to the cerebral effects of T2DM and provide a mechanistic link between T2DM and neurodegenerative disorders.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11310565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0