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  1. Article ; Online: Scaffold protein SH3BP2 signalosome is pivotal for immune activation in nephrotic syndrome.

    Srivastava, Tarak / Garola, Robert E / Zhou, Jianping / Boinpelly, Varun C / Rezaiekhaligh, Mohammad H / Joshi, Trupti / Jiang, Yuexu / Ebadi, Diba / Sharma, Siddarth / Sethna, Christine / Staggs, Vincent S / Sharma, Ram / Gipson, Debbie S / Hao, Wei / Wang, Yujie / Mariani, Laura H / Hodgin, Jeffrey B / Rottapel, Robert / Yoshitaka, Teruhito /
    Ueki, Yasuyoshi / Sharma, Mukut

    JCI insight

    2024  Volume 9, Issue 3

    Abstract: Despite clinical use of immunosuppressive agents, the immunopathogenesis of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remains unclear. Src homology 3-binding protein 2 (SH3BP2), a scaffold protein, forms an immune ... ...

    Abstract Despite clinical use of immunosuppressive agents, the immunopathogenesis of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remains unclear. Src homology 3-binding protein 2 (SH3BP2), a scaffold protein, forms an immune signaling complex (signalosome) with 17 other proteins, including phospholipase Cγ2 (PLCγ2) and Rho-guanine nucleotide exchange factor VAV2 (VAV2). Bioinformatic analysis of human glomerular transcriptome (Nephrotic Syndrome Study Network cohort) revealed upregulated SH3BP2 in MCD and FSGS. The SH3BP2 signalosome score and downstream MyD88, TRIF, and NFATc1 were significantly upregulated in MCD and FSGS. Immune pathway activation scores for Toll-like receptors, cytokine-cytokine receptor, and NOD-like receptors were increased in FSGS. Lower SH3BP2 signalosome score was associated with MCD, higher estimated glomerular filtration rate, and remission. Further work using Sh3bp2KI/KI transgenic mice with a gain-in-function mutation showed ~6-fold and ~25-fold increases in albuminuria at 4 and 12 weeks, respectively. Decreased serum albumin and unchanged serum creatinine were observed at 12 weeks. Sh3bp2KI/KI kidney morphology appeared normal except for increased mesangial cellularity and patchy foot process fusion without electron-dense deposits. SH3BP2 co-immunoprecipitated with PLCγ2 and VAV2 in human podocytes, underscoring the importance of SH3BP2 in immune activation. SH3BP2 and its binding partners may determine the immune activation pathways resulting in podocyte injury leading to loss of the glomerular filtration barrier.
    MeSH term(s) Animals ; Humans ; Mice ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Glomerulosclerosis, Focal Segmental/genetics ; Glomerulosclerosis, Focal Segmental/metabolism ; Kidney/pathology ; Kidney Glomerulus/pathology ; Mice, Transgenic ; Nephrosis, Lipoid/pathology ; Nephrotic Syndrome/metabolism ; Phospholipase C gamma/genetics ; Phospholipase C gamma/metabolism
    Chemical Substances Adaptor Proteins, Signal Transducing ; Phospholipase C gamma (EC 3.1.4.3) ; SH3BP2 protein, human ; Sh3bp2 protein, mouse
    Language English
    Publishing date 2024-02-08
    Publishing country United States
    Document type Journal Article
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.170055
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Chalcone: A potential scaffold for NLRP3 inflammasome inhibitors.

    Thapa, Pritam / Upadhyay, Sunil P / Singh, Vikas / Boinpelly, Varun C / Zhou, Jianping / Johnson, David K / Gurung, Prajwal / Lee, Eung Seok / Sharma, Ram / Sharma, Mukut

    European journal of medicinal chemistry reports

    2022  Volume 7

    Abstract: Overactivated NLRP3 inflammasome has been shown to associate with an increasing number of disease conditions. Activation of the NLRP3 inflammasome results in caspase-1-catalyzed formation of active pro-inflammatory cytokines (IL-1β and IL-18) resulting ... ...

    Abstract Overactivated NLRP3 inflammasome has been shown to associate with an increasing number of disease conditions. Activation of the NLRP3 inflammasome results in caspase-1-catalyzed formation of active pro-inflammatory cytokines (IL-1β and IL-18) resulting in pyroptosis. The multi-protein composition of the NLRP3 inflammasome and its sensitivity to several damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) make this extensively studied inflammasome an attractive target to treat chronic conditions. However, none of the known NLRP3 inhibitors has been approved for clinical use. Sulfonylurea and covalent inhibitors with electrophilic warhead (Michael acceptor) are among the prominent classes of compounds explored for their NLRP3 inhibitory effects. Chalcone, a small molecule with α, β unsaturated carbonyl group (Michael acceptor), has also been studied as a promising scaffold for the development of NLRP3 inhibitors. Low molecular weight, easy to manipulate lipophilicity and cost-effectiveness have attracted many to use chalcone scaffold for drug development. In this review, we highlight chalcone derivatives with NLRP3 inflammasome inhibitory activities. Recent developments and potential new directions summarized here will, hopefully, serve as valuable perspectives for investigators including medicinal chemists and drug discovery researchers to utilize chalcone as a scaffold for developing novel NLRP3 inflammasome inhibitors.
    Language English
    Publishing date 2022-12-31
    Publishing country France
    Document type Journal Article
    ISSN 2772-4174
    ISSN (online) 2772-4174
    DOI 10.1016/j.ejmcr.2022.100100
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Prostanoid receptors in hyperfiltration-mediated glomerular injury: Novel agonists and antagonists reveal opposing roles for EP2 and EP4 receptors.

    Srivastava, Tarak / Garola, Robert E / Zhou, Jianping / Boinpelly, Varun C / Priya, Lakshmi / Ali, Mohammed Farhan / Rezaiekhaligh, Mohammad H / Heruth, Daniel P / Novak, Jan / Alon, Uri S / Joshi, Trupti / Jiang, Yuexu / McCarthy, Ellen T / Savin, Virginia J / Johnson, Mark L / Sharma, Ram / Sharma, Mukut

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    2022  Volume 36, Issue 10, Page(s) e22559

    Abstract: Increased fluid-flow shear stress (FFSS) contributes to hyperfiltration-induced podocyte and glomerular injury resulting in progression of chronic kidney disease (CKD). We reported that increased FFSS in vitro and in vivo upregulates PGE2 receptor EP2 ( ... ...

    Abstract Increased fluid-flow shear stress (FFSS) contributes to hyperfiltration-induced podocyte and glomerular injury resulting in progression of chronic kidney disease (CKD). We reported that increased FFSS in vitro and in vivo upregulates PGE2 receptor EP2 (but not EP4 expression), COX2-PGE
    MeSH term(s) Albumins ; Albuminuria ; Animals ; Creatinine ; Cyclooxygenase 2 ; Dinoprostone/metabolism ; Glycogen Synthase Kinase 3 beta ; Gonadal Steroid Hormones ; Mice ; Proto-Oncogene Proteins c-akt ; Receptors, Prostaglandin E, EP2 Subtype/metabolism ; Receptors, Prostaglandin E, EP4 Subtype ; Renal Insufficiency, Chronic ; beta Catenin
    Chemical Substances Albumins ; Gonadal Steroid Hormones ; Receptors, Prostaglandin E, EP2 Subtype ; Receptors, Prostaglandin E, EP4 Subtype ; beta Catenin ; Creatinine (AYI8EX34EU) ; Cyclooxygenase 2 (EC 1.14.99.1) ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Dinoprostone (K7Q1JQR04M)
    Language English
    Publishing date 2022-09-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    DOI 10.1096/fj.202200875R
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2266: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 296: Show issues

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  4. Article ; Online: The serotonin-2C agonist Lorcaserin delays intravenous choice and modifies the subjective and cardiovascular effects of cocaine: A randomized, controlled human laboratory study.

    Pirtle, Jimmie L / Hickman, Melissa D / Boinpelly, Varun C / Surineni, Kamalakar / Thakur, Hemant K / Grasing, Kenneth W

    Pharmacology, biochemistry, and behavior

    2019  Volume 180, Page(s) 52–59

    Abstract: Background: Lorcaserin is a modestly selective agonist for 2C serotonin receptors (5-HT: Methods and participants: We evaluated effects of single 10 mg doses of lorcaserin on the subjective and reinforcing effects of cocaine, using a randomized, ... ...

    Abstract Background: Lorcaserin is a modestly selective agonist for 2C serotonin receptors (5-HT
    Methods and participants: We evaluated effects of single 10 mg doses of lorcaserin on the subjective and reinforcing effects of cocaine, using a randomized, double-blind, within-subject, cross-over design. Male, non-treatment-seeking, regular cocaine users received either single doses of oral placebo (n = 9) or lorcaserin (n = 9), followed by low- or high- doses of intravenous cocaine (0.23 or 0.46 mg/kg-injection). They were then allowed to self-administer the lower dose of cocaine.
    Results: Cocaine was well tolerated after lorcaserin pretreatment. Oral lorcaserin did not modify the number of cocaine injections self-administered. However, it prolonged the time over which participants made intravenous choices relative to the duration of monetary (cash) decisions. Lorcaserin increased ratings of 'high' and 'stimulated' after low-dose cocaine or vehicle, but decreased craving for cocaine after intravenous vehicle. It also caused small but significant increases in heart rate following noncontingent injections of intravenous placebo or cocaine. When active cocaine was self-administered, lorcaserin decreased heart rate after selection of a monetary choice, but increased it following an intravenous choice.
    Conclusions: Combined treatment with cocaine and lorcaserin was safe in a limited number of subjects, but did not diminish cocaine-motivated behavior or drug-induced 'high'. Some positive subjective effects of cocaine were enhanced by lorcaserin, and it delayed intravenous choices and decreased craving under some conditions. Effects on heart rate depended on the type of reinforcer being self-administered.
    Trial registration: clinicaltrials.gov Identifier, NCT02680288.
    MeSH term(s) Administration, Intravenous ; Administration, Oral ; Adult ; Benzazepines/administration & dosage ; Benzazepines/adverse effects ; Benzazepines/pharmacology ; Blood Pressure/drug effects ; Cocaine/administration & dosage ; Cocaine/adverse effects ; Cocaine/pharmacology ; Cocaine-Related Disorders/drug therapy ; Craving/drug effects ; Cross-Over Studies ; Depression, Chemical ; Double-Blind Method ; Drug Therapy, Combination ; Heart Rate/drug effects ; Humans ; Male ; Middle Aged ; Self Administration ; Serotonin 5-HT2 Receptor Agonists/administration & dosage ; Serotonin 5-HT2 Receptor Agonists/adverse effects ; Serotonin 5-HT2 Receptor Agonists/pharmacology ; Stimulation, Chemical ; Treatment Outcome ; Vasoconstrictor Agents/administration & dosage ; Vasoconstrictor Agents/adverse effects ; Vasoconstrictor Agents/pharmacology
    Chemical Substances Benzazepines ; Serotonin 5-HT2 Receptor Agonists ; Vasoconstrictor Agents ; lorcaserin (637E494O0Z) ; Cocaine (I5Y540LHVR)
    Language English
    Publishing date 2019-02-24
    Publishing country United States
    Document type Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 191042-5
    ISSN 1873-5177 ; 0091-3057
    ISSN (online) 1873-5177
    ISSN 0091-3057
    DOI 10.1016/j.pbb.2019.02.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1060: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Upregulated proteoglycan-related signaling pathways in fluid flow shear stress-treated podocytes.

    Srivastava, Tarak / Joshi, Trupti / Jiang, Yuexu / Heruth, Daniel P / Rezaiekhaligh, Mohamed H / Novak, Jan / Staggs, Vincent S / Alon, Uri S / Garola, Robert E / El-Meanawy, Ashraf / McCarthy, Ellen T / Zhou, Jianping / Boinpelly, Varun C / Sharma, Ram / Savin, Virginia J / Sharma, Mukut

    American journal of physiology. Renal physiology

    2020  Volume 319, Issue 2, Page(s) F312–F322

    Abstract: The ultrafiltrate flow over the major processes and cell body generates fluid flow shear stress (FFSS) on podocytes. Hyperfiltration-associated increase in FFSS can lead to podocyte injury and detachment. Previously, we showed that FFSS-induced ... ...

    Abstract The ultrafiltrate flow over the major processes and cell body generates fluid flow shear stress (FFSS) on podocytes. Hyperfiltration-associated increase in FFSS can lead to podocyte injury and detachment. Previously, we showed that FFSS-induced upregulation of the cyclooxygenase 2 (COX2)-PGE
    MeSH term(s) Cyclooxygenase 2/metabolism ; Kidney Glomerulus/metabolism ; Mechanotransduction, Cellular/physiology ; Podocytes/metabolism ; Proteoglycans/metabolism ; Receptors, Prostaglandin E, EP2 Subtype/metabolism ; Stress, Mechanical ; TOR Serine-Threonine Kinases/metabolism ; Transcriptional Activation/physiology ; Up-Regulation
    Chemical Substances Proteoglycans ; Receptors, Prostaglandin E, EP2 Subtype ; Cyclooxygenase 2 (EC 1.14.99.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2020-07-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 603837-2
    ISSN 1522-1466 ; 0363-6127
    ISSN (online) 1522-1466
    ISSN 0363-6127
    DOI 10.1152/ajprenal.00183.2020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uc I Zs.89: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  6. Article ; Online: Transcription Factor β-Catenin Plays a Key Role in Fluid Flow Shear Stress-Mediated Glomerular Injury in Solitary Kidney.

    Srivastava, Tarak / Heruth, Daniel P / Duncan, R Scott / Rezaiekhaligh, Mohammad H / Garola, Robert E / Priya, Lakshmi / Zhou, Jianping / Boinpelly, Varun C / Novak, Jan / Ali, Mohammed Farhan / Joshi, Trupti / Alon, Uri S / Jiang, Yuexu / McCarthy, Ellen T / Savin, Virginia J / Sharma, Ram / Johnson, Mark L / Sharma, Mukut

    Cells

    2021  Volume 10, Issue 5

    Abstract: Increased fluid flow shear stress (FFSS) in solitary kidney alters podocyte ... ...

    Abstract Increased fluid flow shear stress (FFSS) in solitary kidney alters podocyte function
    MeSH term(s) Animals ; Cell Line ; Databases, Genetic ; Disease Models, Animal ; Genes, fos ; Glomerular Filtration Rate ; Lac Operon ; Lymphoid Enhancer-Binding Factor 1/genetics ; Mechanotransduction, Cellular ; Mice, Transgenic ; Podocytes/metabolism ; Podocytes/pathology ; Promoter Regions, Genetic ; Solitary Kidney/genetics ; Solitary Kidney/metabolism ; Solitary Kidney/pathology ; Solitary Kidney/physiopathology ; Stress, Mechanical ; Transcription Factor 3/genetics ; beta Catenin/genetics ; beta Catenin/metabolism
    Chemical Substances CTNNB1 protein, mouse ; Lymphoid Enhancer-Binding Factor 1 ; Transcription Factor 3 ; beta Catenin
    Language English
    Publishing date 2021-05-19
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells10051253
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: A mouse model of prenatal exposure to Interleukin-6 to study the developmental origin of health and disease.

    Srivastava, Tarak / Joshi, Trupti / Heruth, Daniel P / Rezaiekhaligh, Mohammad H / Garola, Robert E / Zhou, Jianping / Boinpelly, Varun C / Ali, Mohammed Farhan / Alon, Uri S / Sharma, Madhulika / Vanden Heuvel, Gregory B / Mahajan, Pramod / Priya, Lakshmi / Jiang, Yuexu / McCarthy, Ellen T / Savin, Virginia J / Sharma, Ram / Sharma, Mukut

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 13260

    Abstract: Systemic inflammation in pregnant obese women is associated with 1.5- to 2-fold increase in serum Interleukin-6 (IL-6) and newborns with lower kidney/body weight ratio but the role of IL-6 in increased susceptibility to chronic kidney (CKD) in adult ... ...

    Abstract Systemic inflammation in pregnant obese women is associated with 1.5- to 2-fold increase in serum Interleukin-6 (IL-6) and newborns with lower kidney/body weight ratio but the role of IL-6 in increased susceptibility to chronic kidney (CKD) in adult progeny is not known. Since IL-6 crosses the placental barrier, we administered recombinant IL-6 (10 pg/g) to pregnant mice starting at mid-gestation yielded newborns with lower body (p < 0.001) and kidney (p < 0.001) weights. Histomorphometry indicated decreased nephrogenic zone width (p = 0.039) with increased numbers of mature glomeruli (p = 0.002) and pre-tubular aggregates (p = 0.041). Accelerated maturation in IL-6 newborns was suggested by early expression of podocyte-specific protein podocin in glomeruli, increased 5-methyl-cytosine (LC-MS analysis for CpG DNA methylation) and altered expression of certain genes of cell-cycle and apoptosis (RT-qPCR array-analysis). Western blotting showed upregulated pJAK2/pSTAT3. Thus, treating dams with IL-6 as a surrogate provides newborns to study effects of maternal systemic inflammation on future susceptibility to CKD in adulthood.
    MeSH term(s) Animals ; Animals, Newborn/growth & development ; Apoptosis/drug effects ; Birth Weight/drug effects ; Cell Cycle/drug effects ; Female ; Interleukin-6/adverse effects ; Kidney/growth & development ; Kidney/metabolism ; Kidney/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Organ Size/drug effects ; Pregnancy ; Prenatal Exposure Delayed Effects/chemically induced ; Prenatal Exposure Delayed Effects/pathology
    Chemical Substances Interleukin-6
    Language English
    Publishing date 2021-06-24
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-92751-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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