Browsing by Author "Ali, Yusuf"

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    Clinical proof of concept for anti-FGF2 therapy in exudative age-related macular degeneration (nAMD): phase 2 trials in treatment-naïve and anti-VEGF pretreated patients
    (Springer Nature, 2024) Pereira, Daniel S.; Maturi, Raj K.; Akita, Kazumasa; Mahesh, Vinaya; Bhisitkul, Robert B.; Nishihata, Toshiaki; Sakota, Eri; Ali, Yusuf; Nakamura, Emiko; Bezwada, Padma; Nakamura, Yoshikazu; Ophthalmology, School of Medicine
    Background/objective: Intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents are the first-line treatment for exudative age-related macular degeneration (nAMD). Due to the limitations of these standard therapies, targeting alternative mechanisms of action may be helpful for treatment of this very common disease. Here, we investigated an anti-fibroblast growth factor-2 (FGF2) aptamer, umedaptanib pegol, a next generation therapeutic for the treatment of nAMD. Methods: Three phase 2 studies were designed. First, a multicentre, randomized, double-masked TOFU study assessed the efficacy of intravitreal injections of umedaptanib pegol monotherapy or in combination with aflibercept, compared to aflibercept monotherapy in 86 subjects with anti-VEGF pretreated nAMD. Second, 22 subjects who had exited the TOFU study received 4 monthly intravitreal injections of umedaptanib pegol (extension, RAMEN study). Third, as an investigator-sponsored trial (TEMPURA study), a single-center, open-label, 4-month study was designed to evaluate the safety and treatment efficacy of umedaptanib pegol in five naïve nAMD patients who had not received any prior anti-VEGF treatment. Results: The TOFU study demonstrated that umedaptanib pegol alone or in combination with aflibercept did not improve best-corrected visual acuity (BCVA) and central subfield thickness (CST) over aflibercept alone. However, the change in BCVA and CST at primary endpoint was marginal in all the three treatment groups, suggesting that umedaptanib pegol is effective to prevent the disease progression. The RAMEN study confirmed the cessation of disease progression. In the TEMPURA study, naïve nAMD patients showed improvement and no further macular degeneration, with striking improvement of visual acuity and central subfield thickness in some of the patients. Conclusions: These results demonstrate, for the first time, clinical proof of concept for aptamer based anti-FGF2 therapy of nAMD.
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    Mitofusins Mfn1 and Mfn2 Are Required to Preserve Glucose- but Not Incretin-Stimulated β-Cell Connectivity and Insulin Secretion
    (American Diabetes Association, 2022) Georgiadou, Eleni; Muralidharan, Charanya; Martinez, Michelle; Chabosseau, Pauline; Akalestou, Elina; Tomas, Alejandra; Wern, Fiona Yong Su; Stylianides, Theodoros; Wretlind, Asger; Legido-Quigley, Cristina; Jones, Ben; Lopez-Noriega, Livia; Xu, Yanwen; Gu, Guoqiang; Alsabeeh, Nour; Cruciani-Guglielmacci, Céline; Magnan, Christophe; Ibberson, Mark; Leclerc, Isabelle; Ali, Yusuf; Soleimanpour, Scott A.; Linnemann, Amelia K.; Rodriguez, Tristan A.; Rutter, Guy A.; Biochemistry and Molecular Biology, School of Medicine
    Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic β-cells. Whether mitofusin gene expression, and hence, mitochondrial network integrity, is important for glucose or incretin signaling has not previously been explored. Here, we generated mice with β-cell-selective, adult-restricted deletion knock-out (dKO) of the mitofusin genes Mfn1 and Mfn2 (βMfn1/2 dKO). βMfn1/2-dKO mice displayed elevated fed and fasted glycemia and a more than fivefold decrease in plasma insulin. Mitochondrial length, glucose-induced polarization, ATP synthesis, and cytosolic and mitochondrial Ca2+ increases were all reduced in dKO islets. In contrast, oral glucose tolerance was more modestly affected in βMfn1/2-dKO mice, and glucagon-like peptide 1 or glucose-dependent insulinotropic peptide receptor agonists largely corrected defective glucose-stimulated insulin secretion through enhanced EPAC-dependent signaling. Correspondingly, cAMP increases in the cytosol, as measured with an Epac-camps-based sensor, were exaggerated in dKO mice. Mitochondrial fusion and fission cycles are thus essential in the β-cell to maintain normal glucose, but not incretin, sensing. These findings broaden our understanding of the roles of mitofusins in β-cells, the potential contributions of altered mitochondrial dynamics to diabetes development, and the impact of incretins on this process.
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    Neutrophil NADPH oxidase promotes bacterial eradication and regulates NF-κB-Mediated inflammation via NRF2 signaling during urinary tract infections
    (Elsevier, 2025) Cotzomi-Ortega, Israel; Rosowski, Emily E.; Wang, Xin; Sanchez-Zamora, Yuriko I.; Lopez-Torres, Jeimy M.; Sanchez-Orellana, Gamaliel; Han, Rachel; Vásquez-Martínez, Gabriela; Andrade, Gabriel Mayoral; Ballash, Gregory; Cortado, Hanna; Li, Birong; Ali, Yusuf; Rascon, Raul; Robledo-Avila, Frank; Partida-Sanchez, Santiago; Pérez-Campos, Eduardo; Olofsson-Sahl, Peter; Zepeda-Orozco, Diana; Spencer, John David; Becknell, Brian; Ruiz-Rosado, Juan de Dios; Pediatrics, School of Medicine
    The precise role of neutrophil-derived reactive oxygen species (ROS) in combating bacterial uropathogens during urinary tract infections (UTI) remains largely unexplored. In this study, we elucidate the antimicrobial significance of NADPH oxidase 2 (NOX2)-derived ROS, as opposed to mitochondrial ROS, in facilitating neutrophil-mediated eradication of uropathogenic Escherichia coli (UPEC), the primary causative agent of UTI. Furthermore, NOX2-derived ROS regulate NF-κB-mediated inflammatory responses in neutrophils against UPEC by inducing the release of nuclear factor erythroid 2-related factor 2 (Nrf2) from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1). Consistently, the absence of NOX2 (Cybb-/-) in mice led to uncontrolled bacterial infection associated with increased NF-κB signaling, heightened neutrophilic inflammation, and increased bladder pathology during cystitis. These findings underscore a dual role for neutrophil NOX2 in both eradicating UPEC and mitigating neutrophil-mediated inflammation in the urinary tract, revealing a previously unrecognized effector and regulatory mechanism in the control of UTI.