Biology subjects

Zaidi, S. A.

Publications and source records attributed to Zaidi, S. A..

4 recordsLinked to original sources

bioRxiv2025

Abnormal shear stress induces ferroptosis in endothelial cells via KLF6 downregulation

Stable laminar flow maintains vascular tone regulation, while abnormal blood flow, such as disturbed flow or extreme shear stress, causes endothelial dysfunction, but the underlying mechanism is yet to be explored. We used a microfluidic device to deform flat microchannel into tunnel-like macrochannel. The cross-sectional area of this macrochannel varies with the flow rate and the thickness of the deformable layer, creating three levels of shear stress: low (0.99 dyn/cm2, LSS), medium (4.78 dyn/cm2, MSS), and high (24 dyn/cm2, HSS). Comparing different shear stress exposure to endothelial cells for 24 h, prominent ferroptosis features emerged under either LSS or HSS compared to MSS. These features included increased C11 BODIPY-labeled lipid peroxidation and 4-hydroxynonenal accumulation, CoQ10 depletion, reduced SLC7A11 protein expression, and diminished cell death with Ferrostatin-1 treatment. RNA-seq analysis (LSS/MSS) showed that LSS significantly downregulated transcription of cholesterol homeostasis and unfolded protein response (UPR). Compared to MSS, Western blot results showed that both LSS and HSS reduced the expression of two key enzymes (MVD and IDI1) in the mevalonate pathway, as well as the expression of two main UPR signaling regulators (PERK and BiP). Based on the binding prediction between transcription factors and gene promoters from differentially expressed genes identified through RNA-seq, we found KLF6 to be a key transcription factor. It regulates the PERK-mediated UPR and the mevalonate pathway, which are associated with SLC7A11 expression and CoQ10 synthesis, respectively. The overexpression of KLF6 restored SLC7A11 and CoQ10 levels under both LSS and HSS, significantly reducing foam cell formation, monocyte adhesion, and lipid peroxidation. Our findings reveal KLF6 as a crucial regulator of atherosclerosis induced by abnormal shear stress.

cell biology↗

bioRxiv2024

An opioid efficacy switch for reversible optical control of peripheral analgesia

The mu-opioid receptor (MOR) is a major target for the treatment of pain. However, opioids are prone to side effects which limit their effectiveness as analgesics and can lead to opioid use disorders or, even, lethal overdose. The systemic administration of opioid agonists makes it both very difficult to decipher their underlying circuit mechanisms of action and to limit drug action to specific receptor subpopulations to isolate therapeutic effects from adverse side effects. Here we design, synthesize, and characterize a reversibly photoswitchable morphinan agonist termed "azo-morphine-3" (AM-3) which interconverts from low to high efficacy in response to different wavelengths of light to enable optical control of MOR signaling. Cryo-EM structures of the low efficacy "trans" and high efficacy "cis" states of AM-3 bound to the MOR reveal distinct binding modes of the photoswitchable azobenzene moiety, each inducing unique structural dynamics, providing insight into the molecular basis of agonist efficacy. In mice, AM-3 drives reversible and repeatable optical control of anti-nociception with a reduced side effect profile owing to its restriction to the periphery and its ability to be locally activated at the site of pain.

pharmacology and toxicology↗

bioRxiv2021

Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Addiction States

Substance use and related mental health epidemics are causing increasing suffering and death in diverse communities.1,2 Despite extensive efforts focused on developing pharmacotherapies for treating substance use disorders, there is an urgent need for radically different therapeutic approaches.3,4 Ibogaine provides an important drug prototype in this direction, as a psychoactive iboga alkaloid suggested to have the ability to interrupt opioid use in drug-dependent humans.5 However, ibogaine and its major metabolite noribogaine present considerable safety risk associated with cardiac arrhythmias.6 We introduce a new class of iboga alkaloids - "oxa-iboga" - defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds act as potent kappa opioid receptor agonists in vitro and in vivo, but exhibit atypical behavioral features compared to standard kappa psychedelics. We show that oxa-noribogaine has greater therapeutic efficacy in rat models of opioid use, and no cardiac pro-arrhythmic potential, in contrast to noribogaine. Oxa-noribogaine induces long-lasting suppression of morphine and fentanyl intake after a single dose, persistent reduction of morphine intake and reinforcing efficacy after a short treatment regimen, and suppression of morphine and fentanyl drug seeking in relapse models. Oxa-noribogaine also induces a lasting elevation of neurotrophin proteins in the ventral tegmental area and medial prefrontal cortex, consistent with targeted neuroplasticity induction and alteration of addiction-like states. As such, oxa-iboga compounds represent candidates for a novel type of pharmacotherapy for treatment of opioid use disorder.

pharmacology and toxicology↗

bioRxiv2017

Intracellular Passage Of Na+ In An Active State G Protein Coupled Receptor

Playing a central role in cell signalling, GPCRs have evolved into the largest superfamily of membrane proteins and form the majority of drug targets in humans. How extracellular agonist binding triggers the activation of GPCRs and associated intracellular effector proteins remains, however, poorly understood. High resolution structural studies have recently revealed that inactive class-A GPCRs harbour a conserved binding site for Na+ ions in the centre of their transmembrane domain, accessible from the extracellular space. Here, we show that the opening of a conserved hydrated channel in the activated state receptors allows the Na+ ion to egress from its binding site into the cytosol. Coupled with protonation changes, this ion movement occurs without significant energy barriers, and can be driven by physiological transmembrane ion and voltage gradients. We propose that Na+ ion exchange with the cytosol is a key step in GPCR activation, which locks receptors in long-lived active-state conformations.

biophysics↗