Effect of Quercetin-Loaded Mesoporous Silica Nanoparticles on Myocardial Ischemia-Reperfusion Injury in Rats and Its Mechanism
Authors: Li Yao
Bo-Tao Zhao
Chen-Jie Liu
Ya-Min Hu
Journal: International Journal of Nanomedicine (2021)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: JAK2/STAT3 pathway; cardiovascular diseases; myocardial ischemia-reperfusion injury; quercetin-loaded mesoporous silica nanoparticles.
Affiliations: ECG Room of Physical Examination Center of Cangzhou Central Hospital, Cangzhou, Hebei, 061001, People's Republic of China., Six Cardiovascular Departments of Cangzhou Central Hospital, Cangzhou, Hebei, 061001, People's Republic of China.

Abstract:  Background: Quercetin has potential value in treating cardiovascular diseases, but it is not suitable for clinical application due to its own water solubility. The limitation of quercetin can be distinctly ameliorated by delivering it with nanocarriers. Objective: To determine the effect of quercetin-loaded mesoporous silica nanoparticles (Q-MSNs) on myocardial ischemia-reperfusion injury in rats and its mechanism. Methods: Q-MSNs were synthesized, and the morphology of Q-MSNs and MSNs was characterized by transmission electron microscopy and dynamic light scattering technique, respectively. Healthy rats were enrolled and randomly divided into a sham operation control group, an ischemia-reperfusion (IR) group, an IR+Q group, an IR+Q-MSNs group, and an MSNs group (each n = 10). Rats in the sham operation group were not treated with ischemia reperfusion, but given normal perfusion meantime. Rats in the sham operation control group, IR group, and MSNs group were given normal saline for 10 days before ischemia reperfusion, and rats in the IR+Q group and IR+Q-MSNs group were given drugs by gavage for 10 days before ischemia reperfusion. Primary myocardial cells were sampled from SD neonatal rats to construct hypoxia/reoxygenation myocardial cell models. The myocardial cells were assigned to a control group, IR group, quercetin (Q) group, Q-MSNs group, and MSNs group. Except for the control group, all the other groups were treated with hypoxia/reoxygenation. Cells in the Q group were treated with quercetin (10 μM, 20 μM, 40 μM) for 24 h in advance and then treated with measures to cause hypoxia-reoxygenation injury. Cells in the Q-MSNs group were treated with the same concentration of loaded quercetin and the same method used for the Q group. The myocardial apoptosis, myocardial infarction, ventricular remodeling, hemodynamic indexes, physiological and biochemical indexes, and JAK2/STAT3 pathway expression of each group were detected, and the apoptosis, viability, oxidative stress, and JAK2/STAT3 pathway expression of primary myocardial cells in each group were also detected. Results: Quercetin significantly activated the JAK2/STAT3 pathway in vivo and in vitro, and MSNs intensified the activation. Compared with quercetin, Q-MSNs were more effective in inhibiting cell apoptosis and oxidative stress, reducing myocardial infarction size, improving ventricular remodeling and cardiac function-related biochemical indexes, and promoting the recovery of cardiac blood flow. Conclusion: Q-MSNs can significantly enhance the activation effect of quercetin on JAK2/STAT3 pathway, thus enhancing its protection on the heart of MIRI rats. 

Retracted: No

PubPeer comments:
 Some questions about the references here:  Loading quercetin with MSNs may help to improve the absorption and release of quercetin in organisms.36 Ref [36] is  Quantification and evaluations of **catechin hydrate polymeric nanoparticles** used in brain targeting for the treatment of epilepsy ([Ahmad et al 2020] ). Alert readers will notice that it does not address quercetin in any way; nor mesoporous silica NPs. --------------------------------------------------------------------  Nanocarriers are a powerful tool to improve the bioavailability and pharmacokinetics of compounds at this point,26u201328 ... Refs 26 to 28 are -  Quantification and evaluation of thymoquinone loaded mucoadhesive nanoemulsion for treatment of cerebral ischemia ([Ahmad et al 2016] ); -  Improvement of oral efficacy of irinotecan through biodegradable polymeric nanoparticles through invitro and invivo investigations ([Ahmad et al 2018] ); -  Poloxamer-Chitosan-based Naringenin nanoformulation used in brain targeting for the treatment of Cerebral Ischemia ([Ahmad et al 2020] ). Of these, [27] was retracted for manipulation and re-use of images. The same fate befall [seven other papers from Ahmad s group] , while many others have attracted criticism in PubPeer threads, including [26] and [28]. I am not sure how much trust can be put in their work. -------------------------------------------- [Nanocarriers]  can effectively overcome the above defects of quercetin, and thus improve the efficacy of quercetin in disease treatment.29u201334 Here [32] is  Quercetin exerts anti-melanoma activities and inhibits STAT3 signaling (Cao et al 2014), which (as readers will have guessed if they are paying attention) does not mention nanocarriers. --------------------------------------------  Previous studies have confirmed that nanoparticles are helpful to promote myocardial tissue repair, 37,38 . [38] is  The development of a trimodal contrast agent for acoustic and magnetic particle imaging of stem cells (Lemaster et al 2018), and I struggle to see its relevance in this context. The references also include [12]  Effect of propofol on myocardial ischemia reperfusion injury in rats through JAK STAT signaling pathway ([Chen et al 2019)] ) and [22]  Quercetin attenuates myocardial ischemia-reperfusion injury via downregulation of the HMGB1-TLR4-NF-kappaB signaling pathway ([Dong et al 2018)] ), where I have linked to the corresponding PubPeer threads. , 
 Fig 2A.  Cell apoptosis in each group determined by annexin V PI staining. There was inhibition on cell apoptosis in both Q group and Q-MSNs group. At the same concentration, the inhibitory effect in the 40Q-MSNs group was better, and silica nanoparticles alone had no effect on apoptosis. ![file] Each panel contains a halo of regularly-spaced dots, surrounding a central clump with a curious tapestry texture, almost woven in appearance (see e.g. [Wang, Zhao Wang 2020] for similar results). Perhaps these are instrumentation artefacts of some kind. Is it possible for the authors to upload the raw data files to a data repository somewhere? Here is a spreadsheet containing similar examples of these crocheted beetroot scatterplots (currently 11 retractions): https: docs.google.com spreadsheets d 1NKBplrpW1txuL9PjhYb3bbvtQbk-TcsnqyqI8Uj-5Q8 edit?usp=sharing ,