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  1. Article ; Online: Peroxisomal L-bifunctional protein (EHHADH) deficiency causes male-specific kidney hypertrophy and proximal tubular injury in mice.

    Ranea-Robles, Pablo / Portman, Kensey / Bender, Aaron / Lee, Kyung / He, John Cijiang / Mulholland, David J / Argmann, Carmen / Houten, Sander M

    Kidney360

    2021  Volume 2, Issue 9, Page(s) 1441–1454

    Abstract: Background: Proximal tubular (PT) cells are enriched in mitochondria and peroxisomes. Whereas mitochondrial fatty acid oxidation (FAO) plays an important role in kidney function by supporting the high-energy requirements of PT cells, the role of ... ...

    Abstract Background: Proximal tubular (PT) cells are enriched in mitochondria and peroxisomes. Whereas mitochondrial fatty acid oxidation (FAO) plays an important role in kidney function by supporting the high-energy requirements of PT cells, the role of peroxisomal metabolism remains largely unknown. EHHADH, also known as L-bifunctional protein, catalyzes the second and third step of peroxisomal FAO.
    Methods: We studied kidneys of WT and
    Results: We observed male-specific kidney hypertrophy and glomerular filtration rate reduction in adult
    Conclusions: Our data highlight the importance of EHHADH and peroxisomal metabolism in male kidney physiology and reveal peroxisomal FAO as a sexual dimorphic metabolic pathway in mouse kidneys.
    MeSH term(s) Animals ; Hypertrophy/metabolism ; Kidney ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Peroxisomes/metabolism
    Language English
    Publishing date 2021-09-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 2641-7650
    ISSN (online) 2641-7650
    DOI 10.34067/KID.0003772021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Dynamic plasticity of prostate cancer intermediate cells during androgen receptor-targeted therapy.

    Sandhu, Harkirat S / Portman, Kensey L / Zhou, Xianxiao / Zhao, Julia / Rialdi, Alexander / Sfakianos, John P / Guccione, Ernesto / Kyprianou, Natasha / Zhang, Bin / Mulholland, David J

    Cell reports

    2022  Volume 40, Issue 4, Page(s) 111123

    Abstract: Treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC) is associated with an epithelial lineage switch from an androgen receptor (AR)-positive to neuroendocrine (NE)-marker-positive status. Understanding the potential for reversibility of ... ...

    Abstract Treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC) is associated with an epithelial lineage switch from an androgen receptor (AR)-positive to neuroendocrine (NE)-marker-positive status. Understanding the potential for reversibility of this aggressive disease state has been hampered by the paucity of models suitable for studying rate-limiting, transitional, or intermediate tumor cell subpopulations. We define a dual reporter model that measures acute transcriptional changes in response to castration or AR targeting agents. We identify steady-state transcriptional heterogeneity in AR and NE biomarkers, including intermediate subpopulations that are coordinately high for prostate-specific antigen (PSA) and neuron-specific enoclase (NSE) promoter activity. In the presence of castration or AR inhibitors, intermediate cells were necessary and sufficient for therapy-induced conversion of human PC cells to an NSE-high transcriptional status. Using hormone add-back studies, treatment-induced PSA-NSE transcriptional plasticity was reversible in PTEN-deficient PC cells but not in the presence of secondary genetic driver genes, including MYCN.
    MeSH term(s) Androgen Receptor Antagonists/pharmacology ; Androgen Receptor Antagonists/therapeutic use ; Carcinoma, Small Cell ; Cell Line, Tumor ; Humans ; Male ; Prostate/pathology ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; Prostatic Neoplasms, Castration-Resistant/drug therapy ; Prostatic Neoplasms, Castration-Resistant/genetics ; Prostatic Neoplasms, Castration-Resistant/pathology ; Receptors, Androgen/genetics
    Chemical Substances Androgen Receptor Antagonists ; Receptors, Androgen ; Prostate-Specific Antigen (EC 3.4.21.77)
    Language English
    Publishing date 2022-07-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2022.111123
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: World Trade Center dust exposure promotes cancer in PTEN-deficient mouse prostates.

    Wang, Lin / Xu, Yitian / Zhang, Licheng / Kang, Kyeongah / Kobryn, Andriy / Portman, Kensey / Gordon, Ronald E / Pan, Ping-Ying / Taioli, Emanuela / Aaronson, Stuart A / Chen, Shu-Hsia / Mulholland, David J

    Cancer research communications

    2022  Volume 2, Issue 6, Page(s) 518–532

    Abstract: During the 9/11 attacks individuals were exposed to World Trade Center (WTC) dust which contained a complex mixture of carcinogens. Epidemiological studies have revealed the increased incidence of prostate and thyroid cancer in WTC survivors and ... ...

    Abstract During the 9/11 attacks individuals were exposed to World Trade Center (WTC) dust which contained a complex mixture of carcinogens. Epidemiological studies have revealed the increased incidence of prostate and thyroid cancer in WTC survivors and responders. While reports have shown that WTC-dust associates with the increased prevalence of inflammatory related disorders, studies to date have not determined whether this exposure impacts cancer progression. In this study, we have used genetically engineered mouse (GEM) models with prostate specific deletion of the PTEN tumor suppressor to study the impact of WTC-dust exposure on deposition of dust particles, inflammation, and cancer progression. In normal C57/BL6 mice, dust exposure increased cellular expression of inflammatory genes with highest levels in the lung and peripheral blood. In normal and tumor bearing GEM mice, increased immune cell infiltration to the lungs was observed. Pathological evaluation of mice at different time points showed that WTC-dust exposure promoted PI3K-AKT activation, increased epithelial proliferation and acinar invasion in prostates with heterozygous and homozygous
    MeSH term(s) Animals ; Humans ; Male ; Mice ; Dust ; Inflammation ; Lung Diseases ; Phosphatidylinositol 3-Kinases ; Prostate ; Prostatic Neoplasms/epidemiology ; PTEN Phosphohydrolase/genetics
    Chemical Substances Dust ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; Pten protein, mouse (EC 3.1.3.67)
    Language English
    Publishing date 2022-08-01
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ISSN 2767-9764
    ISSN (online) 2767-9764
    DOI 10.1158/2767-9764.crc-21-0111
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Mitochondrial dysfunction in skeletal muscle of fukutin-deficient mice is resistant to exercise- and 5-aminoimidazole-4-carboxamide ribonucleotide-induced rescue.

    Southern, W Michael / Nichenko, Anna S / Qualls, Anita E / Portman, Kensey / Gidon, Ariel / Beedle, Aaron M / Call, Jarrod A

    Experimental physiology

    2020  Volume 105, Issue 10, Page(s) 1767–1777

    Abstract: New findings: What is the central question of this study? Does fukutin deficiency in skeletal muscle cause mitochondrial dysfunction, and if so, can AMP-activated protein kinase (AMPK) stimulation via 5-aminoimidazole-4-carboxamide ribonucleotide ... ...

    Abstract New findings: What is the central question of this study? Does fukutin deficiency in skeletal muscle cause mitochondrial dysfunction, and if so, can AMP-activated protein kinase (AMPK) stimulation via 5-aminoimidazole-4-carboxamide ribonucleotide attenuate this through regulation of mitochondrial biogenesis and autophagy? What is the main finding and its importance? Mitochondrial dysfunction is associated with fukutin deficiency and AMPK stimulation may benefit muscle contractility to a greater extent than mitochondrial function.
    Abstract: Disruptions in the dystrophin-glycoprotein complex (DGC) are clearly the primary basis underlying various forms of muscular dystrophies and dystroglycanopathies, but the cellular consequences of DGC disruption are still being investigated. Mitochondrial abnormalities are becoming an apparent consequence and contributor to dystrophy disease pathology. Herein, we demonstrate that muscle-specific deletion of the fukutin gene (Myf5/fktn-KO mice (Fktn KO)), a model of secondary dystroglycanopathy, results in ∼30% lower muscle strength (P < 0.001) and 16% lower mitochondrial respiratory function (P = 0.002) compared to healthy littermate controls (LM). We also observed ∼80% lower expression of the gene for peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) (P = 0.004), a primary transcription factor for mitochondrial biogenesis, in Fktn KO mice that likely contributes to the mitochondrial defects. PGC-1α is post-translationally regulated via phosphorylation by AMP-activated protein kinase (AMPK). Treatment with the AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) failed to rescue mitochondrial deficits in Fktn KO mice (P = 0.458) but did have beneficial (∼30% greater) effects on recovery of muscle contractility following injury in both LM and Fktn KO mice compared to saline treatment (P = 0.006). The beneficial effects of AMPK stimulation via AICAR on muscle contractile function may be partially explained by AMPK's other role of regulating skeletal muscle autophagy, a cellular process critical for clearance of damaged and/or dysfunctional organelles. Two primary conclusions can be drawn from this data: (1) fukutin deletion produces intrinsic muscular metabolic defects that likely contribute to dystroglycanopathy disease pathology, and (2) AICAR treatment accelerates recovery of muscle contractile function following injury suggesting AMPK signalling as a possible target for therapeutic strategies.
    MeSH term(s) AMP-Activated Protein Kinases/metabolism ; Aminoimidazole Carboxamide/analogs & derivatives ; Aminoimidazole Carboxamide/pharmacology ; Animals ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/physiology ; Mice ; Mice, Knockout ; Mitochondria/drug effects ; Mitochondria/metabolism ; Mitochondria/physiology ; Mitochondrial Diseases/metabolism ; Mitochondrial Diseases/physiopathology ; Muscle Contraction/drug effects ; Muscle Contraction/physiology ; Muscle Strength/drug effects ; Muscle Strength/physiology ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/physiopathology ; Muscular Dystrophies/metabolism ; Muscular Dystrophies/physiopathology ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Physical Conditioning, Animal/physiology ; Ribonucleotides/pharmacology ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Transferases/deficiency
    Chemical Substances Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Ribonucleotides ; Aminoimidazole Carboxamide (360-97-4) ; Fcmd protein, mouse (EC 2.-) ; Transferases (EC 2.-) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; AICA ribonucleotide (F0X88YW0YK)
    Language English
    Publishing date 2020-09-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1016295-1
    ISSN 1469-445X ; 0958-0670
    ISSN (online) 1469-445X
    ISSN 0958-0670
    DOI 10.1113/EP088812
    Database MEDical Literature Analysis and Retrieval System OnLINE

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