Search

Your search keyword '"Siddiqui, M. Rizwan"' showing total 23 results
Start Over Author "Siddiqui, M. Rizwan"
23 results on '"Siddiqui, M. Rizwan"'

6. Metformin alleviates lung-endothelial hyperpermeability by regulating cofilin-1/PP2AC pathway.

Author

Siddiqui, M. Rizwan, Reddy, Narsa M., Faridi, Hafeez M., Shahid, Mohd, and Shanley, Thomas P.

Subjects
ENDOTHELIAL cells, LUNGS, METFORMIN, ADULT respiratory distress syndrome, ELECTRIC impedance, ADHERENS junctions
Abstract

Background: Microvascular endothelial hyperpermeability is an earliest pathological hallmark in Acute Lung Injury (ALI), which progressively leads to Acute Respiratory Distress Syndrome (ARDS). Recently, vascular protective and anti-inflammatory effect of metformin, irrespective of glycemic control, has garnered significant interest. However, the underlying molecular mechanism(s) of metformin's barrier protective benefits in lung-endothelial cells (ECs) has not been clearly elucidated. Many vascular permeability-increasing agents weakened adherens junctions (AJ) integrity by inducing the reorganization of the actin cytoskeleton and stress fibers formation. Here, we hypothesized that metformin abrogated endothelial hyperpermeability and strengthen AJ integrity via inhibiting stress fibers formation through cofilin-1-PP2AC pathway. Methods: We pretreated human lung microvascular ECs (human-lung-ECs) with metformin and then challenged with thrombin. To investigate the vascular protective effects of metformin, we studied changes in ECs barrier function using electric cell-substrate impedance sensing, levels of actin stress fibers formation and inflammatory cytokines IL-1β and IL-6 expression. To explore the downstream mechanism, we studied the Ser3-phosphorylation-cofilin-1 levels in scramble and PP2AC-siRNA depleted ECs in response to thrombin with and without metformin pretreatment. Results: In-vitro analyses showed that metformin pretreatment attenuated thrombin-induced hyperpermeability, stress fibers formation, and the levels of inflammatory cytokines IL-6 and IL-β in human-lung-ECs. We found that metformin mitigated Ser3-phosphorylation mediated inhibition of cofilin-1 in response to thrombin. Furthermore, genetic deletion of PP2AC subunit significantly inhibited metformin efficacy to mitigate thrombin-induced Ser3-phosphorylation cofilin-1, AJ disruption and stress fibers formation. We further demonstrated that metformin increases PP2AC activity by upregulating PP2AC-Leu309 methylation in human-lung-ECs. We also found that the ectopic expression of PP2AC dampened thrombin-induced Ser3-phosphorylation-mediated inhibition of cofilin-1, stress fibers formation and endothelial hyperpermeability. Conclusion: Together, these data reveal the unprecedented endothelial cofilin-1/ PP2AC signaling axis downstream of metformin in protecting against lung vascular endothelial injury and inflammation. Therefore, pharmacologically enhancing endothelial PP2AC activity may lead to the development of novel therapeutic approaches for prevention of deleterious effects of ALI on vascular ECs. [ABSTRACT FROM AUTHOR]

Published
2023
Full Text
View/download PDF

7. Contributors

Author

Ahmad, Aamir, primary, Alemdehy, Mir Farshid, additional, Anderson, Tyler, additional, Awad, Hamdy, additional, Balakrishnan, Asha, additional, Balkhi, Mumtaz Yaseen, additional, Bally-Cuif, Laure, additional, Banerjee, Jaideep, additional, Bao, Bin, additional, Barry, Christopher Taylor, additional, Beclin, Christophe, additional, Boison, Detlev, additional, Bosio, Andreas, additional, Brandi, Maria Luisa, additional, Brown, Melissa, additional, Calin, George A., additional, Cao, Yang, additional, Capogrossi, Maurizio C., additional, Caporali, Andrea, additional, Carulli, Christian, additional, Chan, Yuk Cheung, additional, Chavali, Pavithra L., additional, Chavali, Sreenivas, additional, Chen, Alex F., additional, Chen, Xiaona, additional, Cook, Charles, additional, Coolen, Marion, additional, Cremer, Harold, additional, Czeisler, Catherine, additional, Dakhlallah, Duaa, additional, Das, Amitava, additional, Delany, Anne M., additional, Dolezalova, Dasa, additional, Domínguez-Bendala, Juan, additional, Emanueli, Costanza, additional, Erkeland, Stefan J., additional, Ezzie, Michael, additional, Fasanaro, Pasquale, additional, Foinquinos, Ariana, additional, Franceschetti, Tiziana, additional, Gambari, Roberto, additional, Ahmad, Shazia, additional, Ghatak, Subhadip, additional, Guan, Le Luo, additional, Guttridge, Denis C., additional, Gygli, Patrick Edwin, additional, Haider, Khawaja H., additional, Hampl, Aleš, additional, Harmsen, Martin C., additional, Hasegawa, Yoshinori, additional, Hindges, Robert, additional, Hinsdale, Myron, additional, Houlé, John D., additional, Howard, Lynsey, additional, Hui Chan, Derryn Xin, additional, Ichi, Shunsuke, additional, Innocenti, Massimo, additional, Jagdeo, Jared, additional, Kagele, Dominique A., additional, Khan, Mahmood, additional, Klein, Dagmar, additional, Kobayashi, Tatsuya, additional, Kong, Dejuan, additional, Krenning, Guido, additional, Li, Yiwei, additional, Liechty, Kenneth W., additional, Lisse, Thomas, additional, Liu, Lin, additional, Lloyd, Pamela, additional, Lu, Leina, additional, Lusardi, Theresa A., additional, Luzi, Ettore, additional, Macera, Armando, additional, Magenta, Alessandra, additional, Maiorano, Nicola Antonio, additional, Malik, Obaid, additional, Mamalis, Andrew, additional, Mania-Farnell, Barbara, additional, Marsh, Clay B., additional, Mayanil, C. Shekhar, additional, McLone, David, additional, Möbus, Selina, additional, Mohler, Peter J., additional, Moldovan, Leni, additional, Monroig, Paloma del C., additional, Mraz, Marek, additional, Nana-Sinkam, S. Patrick, additional, Nguyen, Laurent, additional, O’Connell, Ryan M., additional, Otero, José Javier, additional, Pal, Durba, additional, Papaioannou, Garyfallia, additional, Pastori, Ricardo L., additional, Piper, Melissa G., additional, Pirotte, Sophie, additional, Pompilio, Giulio, additional, Ramsamy, Srinivas, additional, Romao, Josue Moura, additional, Rossini, Alessandra, additional, Roy, Sashwati, additional, Sampath, Prabha, additional, Sarkar, Fazlul H., additional, Sato, Mitsuo, additional, Sen, Chandan K., additional, Shames, David S., additional, Shantikumar, Saran, additional, Sharma, Amar Deep, additional, Siddiqui, M. Rizwan, additional, Sinha, Mithun, additional, Sun, Hao, additional, Sun, Yeqing, additional, Tahara, Hidetoshi, additional, Thum, Thomas, additional, Tili, Esmerina, additional, Tomita, Tadanori, additional, Trgovich, Joanne, additional, Viereck, Janika, additional, Volvert, Marie-Laure, additional, Wang, Jie-Mei, additional, Wang, Lijun, additional, Wang, Huating, additional, Wang, Yijie, additional, Xu, Dan, additional, Xu, Junwang, additional, Yang, Dakai, additional, Zambrotta, Marina E., additional, Zgheib, Carlos, additional, Zhao, Yu, additional, and Zhou, Liang, additional

Published
2015
Full Text
View/download PDF

8. MicroRNAs in Neural Crest Development

Author

Mayanil, C. Shekhar, primary, Siddiqui, M. Rizwan, additional, Ichi, Shunsuke, additional, Mania-Farnell, Barbara, additional, Tomita, Tadanori, additional, and McLone, David, additional

Published
2015
Full Text
View/download PDF

9. Metformin Attenuates High Glucose‐Induced Coronary Vascular Endothelial Hyper Permeability Via Inhibition of Orai‐1 Mediated Store‐Operated Calcium Entry

Author

Ali, Shamsideen, primary, Doan, Do, additional, Ojong, Terrence, additional, Solomon, Helawi, additional, Corpuz, Ersever, additional, Huynh, Thai, additional, Haziq, Muhammad, additional, Shahid, Mohd, additional, Siddiqui, M. Rizwan, additional, Newaz, Mohammad, additional, Akhtar, Suhail, additional, Ahmad, Zulfiqar, additional, and Tauseef, Mohammad, additional

Published
2020
Full Text
View/download PDF

21. Folate Receptor Alpha Upregulates Oct4, Sox2and Klf4and Downregulates miR‐138 and miR‐let‐7 in Cranial Neural Crest Cells

Author

Mohanty, Vineet, Shah, Amar, Allender, Elise, Siddiqui, M. Rizwan, Monick, Sarah, Ichi, Shunsuke, Mania‐Farnell, Barbara, G. McLone, David, Tomita, Tadanori, and Mayanil, Chandra Shekhar

Abstract

Prenatal folic acid (FA) supplementation prevents neural tube defects. Folate receptor alpha (FRα) is critical for embryonic development, including neural crest (NC) development. Previously we showed that FRα translocates to the nucleus in response to FA, where it acts as a transcription factor. In this study, we examined if FA through interaction with FRα regulates stem cell characteristics of cranial neural crest cells (CNCCs)‐critical for normal development. We hypothesized that FRα upregulates coding genes and simultaneously downregulates non‐coding miRNA which targets coding genes in CNCCs. Quantitative RT‐PCR and chromatin immunoprecipitation showed that FRα upregulates Oct4, Sox2,and Klf4by binding to their cis‐regulator elements‐5′ enhancer/promoters defined by H3K27Ac and p300 occupancy. FA via FRα downregulates miRNAs, miR‐138 and miR‐let‐7, which target Oct4and Trim71(an Oct4 downstream effector), respectively. Co‐immunoprecipitation data suggests that FRα interacts with the Drosha‐DGCR8 complex to affect pre‐miRNA processing. Transfecting anti‐miR‐138 or anti‐miR‐let‐7 into non‐proliferating neural crest cells (NCCs) derived from Splotch(Sp−/−), restored their proliferation potential. In summary, these results suggest a novel pleiotropic role of FRα: (a) direct activation of Oct4, Sox2,and Klf4genes; and (b) repression of biogenesis of miRNAs that target these genes or their effector molecules. StemCells2016;34:2721–2732 Hypothetical model of FRα function in NCCs. In response to FA, FRα translocates to the nucleus where it binds the cis‐regulatory elements of Oct4, Sox2,and Klf4, activating transcription; this in turn activates downstream targets such as Trim71 and downregulates levels of miR‐138 and miR‐let‐7, which target Oct4and Trim71respectively thus removing the inhibitory effects on Oct4and Trim71expression.

Published
2016
Full Text
View/download PDF

22. Evidence of a common mechanism of disassembly of adherens junctions through Gα13 targeting of VE-cadherin

Author

Gong, Haixia, Gao, Xiaopei, Feng, Shaoting, Siddiqui, M. Rizwan, Garcia, Alexander, Bonini, Marcelo G., Komarova, Yulia, Vogel, Stephen M., Mehta, Dolly, and Malik, Asrar B.

Abstract

The heterotrimeric G protein Gα13 transduces signals from G protein–coupled receptors (GPCRs) to induce cell spreading, differentiation, migration, and cell polarity. Here, we describe a novel GPCR-independent function of Gα13 in regulating the stability of endothelial cell adherens junctions (AJs). We observed that the oxidant H2O2, which is released in response to multiple proinflammatory mediators, induced the interaction of Gα13 with VE-cadherin. Gα13 binding to VE-cadherin in turn induced Src activation and VE-cadherin phosphorylation at Tyr 658, the p120-catenin binding site thought to be responsible for VE-cadherin internalization. Inhibition of Gα13–VE-cadherin interaction using an interfering peptide derived from the Gα13 binding motif on VE-cadherin abrogated the disruption of AJs in response to inflammatory mediators. These studies identify a unique role of Gα13 binding to VE-cadherin in mediating VE-cadherin internalization and endothelial barrier disruption and inflammation.

Published
2014
Full Text
View/download PDF

23. Caveolin-1-eNOS signaling promotes p190RhoGAP-A nitration and endothelial permeability.

Author

Siddiqui MR, Komarova YA, Vogel SM, Gao X, Bonini MG, Rajasingh J, Zhao YY, Brovkovych V, and Malik AB

Subjects
Animals, Caveolin 1 deficiency, Cells, Cultured, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide metabolism, Permeability, Peroxynitrous Acid metabolism, Caveolin 1 metabolism, Endothelial Cells metabolism, Nitric Oxide Synthase Type III metabolism, Signal Transduction, rhoA GTP-Binding Protein metabolism
Abstract

Endothelial barrier function is regulated by adherens junctions (AJs) and caveolae-mediated transcellular pathways. The opening of AJs that is observed in caveolin-1(-/-) (Cav-1(-/-)) endothelium suggests that Cav-1 is necessary for AJ assembly or maintenance. Here, using endothelial cells isolated from Cav-1(-/-) mice, we show that Cav-1 deficiency induced the activation of endothelial nitric oxide synthase (eNOS) and the generation of nitric oxide (NO) and peroxynitrite. We assessed S-nitrosylation and nitration of AJ-associated proteins to identify downstream NO redox signaling targets. We found that the GTPase-activating protein (GAP) p190RhoGAP-A was selectively nitrated at Tyr1105, resulting in impaired GAP activity and RhoA activation. Inhibition of eNOS or RhoA restored AJ integrity and diminished endothelial hyperpermeability in Cav-1(-/-) mice. Thrombin, a mediator of increased endothelial permeability, also induced nitration of p120-catenin-associated p190RhoGAP-A. Thus, eNOS-dependent nitration of p190RhoGAP-A represents a crucial mechanism for AJ disassembly and resultant increased endothelial permeability.

Published
2011
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results