STZ-induced diabetes exacerbates neurons ferroptosis after ischemic stroke by upregulating LCN2 in neutrophils.

Diabetic is a major contributor to the unfavorable prognosis of ischemic stroke. However, intensive hypoglycemic strategies do not improve stroke outcomes, implying that diabetes may affect stroke outcomes through other ways. Ferroptosis is a novel programmed cell death pathway associated with the development of diabetes and ischemic stroke. This study aimed to investigate the effect of streptozotocin (STZ)-induced diabetes on ferroptosis after stroke from the immune cell perspective, and to provide a theoretical foundation for the clinical management of ischemic stroke in patients with diabetes. The results revealed that STZ-induced diabetes not only facilitates the infiltration of neutrophils into the brain after stroke, but also upregulates the expression of lipocalin 2 (LCN2) in neutrophils. LCN2 promotes lipid peroxide accumulation by increasing intracellular ferrous ions, which intensify ferroptosis in major brain cell populations, especially neurons. Our findings suggest that STZ-induced diabetes aggravates ischemic stroke partially by mediating ferroptosis through neutrophil-derived LCN2. These data contribute to improved understanding of post-stroke immune regulation in diabetes, and offer a potentially novel therapeutic target for the management of acute-stage ischemic stroke complicated with diabetes.

High-speed and large-scale intrinsically stretchable integrated circuits.

Intrinsically stretchable electronics with skin-like mechanical properties have been identified as a promising platform for emerging applications ranging from continuous physiological monitoring to real-time analysis of health conditions, to closed-loop delivery of autonomous medical treatment1-7. However, current technologies could only reach electrical performance at amorphous-silicon level (that is, charge-carrier mobility of about 1 cm2 V-1 s-1), low integration scale (for example, 54 transistors per circuit) and limited functionalities8-11. Here we report high-density, intrinsically stretchable transistors and integrated circuits with high driving ability, high operation speed and large-scale integration. They were enabled by a combination of innovations in materials, fabrication process design, device engineering and circuit design. Our intrinsically stretchable transistors exhibit an average field-effect mobility of more than 20 cm2 V-1 s-1 under 100% strain, a device density of 100,000 transistors per cm2, including interconnects and a high drive current of around 2 µA µm-1 at a supply voltage of 5 V. Notably, these achieved parameters are on par with state-of-the-art flexible transistors based on metal-oxide, carbon nanotube and polycrystalline silicon materials on plastic substrates12-14. Furthermore, we realize a large-scale integrated circuit with more than 1,000 transistors and a stage-switching frequency greater than 1 MHz, for the first time, to our knowledge, in intrinsically stretchable electronics. Moreover, we demonstrate a high-throughput braille recognition system that surpasses human skin sensing ability, enabled by an active-matrix tactile sensor array with a record-high density of 2,500 units per cm2, and a light-emitting diode display with a high refreshing speed of 60 Hz and excellent mechanical robustness. The above advancements in device performance have substantially enhanced the abilities of skin-like electronics.

Th17 Cells and IL-17A in Ischemic Stroke.

The neurological injury and repair mechanisms after ischemic stroke are complex. The inflammatory response is present throughout stroke onset and functional recovery, in which CD4 + T helper(Th) cells play a non-negligible role. Th17 cells, differentiated from CD4 + Th cells, are regulated by various extracellular signals, transcription factors, RNA, and post-translational modifications. Th17 cells specifically produce interleukin-17A(IL-17A), which has been reported to have pro-inflammatory effects in many studies. Recently, experimental researches showed that Th17 cells and IL-17A play an important role in promoting stroke pathogenesis (atherosclerosis), inducing secondary damage after stroke, and regulating post-stroke repair. This makes Th17 and IL-17A a possible target for the treatment of stroke. In this paper, we review the mechanism of action of Th17 cells and IL-17A in ischemic stroke and the progress of research on targeted therapy.

Real-time continuous image guidance for endoscopic retrograde cholangiopancreatography based on 3D/2D registration and respiratory compensation.

BACKGROUND: It has been confirmed that three-dimensional (3D) imaging allows easier identification of bile duct anatomy and intraoperative guidance of endoscopic retrograde cholangiopancreatography (ERCP), which reduces the radiation dose and procedure time with improved safety. However, current 3D biliary imaging does not have good real-time fusion with intraoperative imaging, a process meant to overcome the influence of intraoperative respiratory motion and guide navigation. The present study explored the feasibility of real-time continuous image-guided ERCP. AIM: To explore the feasibility of real-time continuous image-guided ERCP. METHODS: We selected 2 3D-printed abdominal biliary tract models with different structures to simulate different patients. The ERCP environment was simulated for the biliary phantom experiment to create a navigation system, which was further tested in patients. In addition, based on the estimation of the patient's respiratory motion, preoperative 3D biliary imaging from computed tomography of 18 patients with cholelithiasis was registered and fused in real-time with 2D fluoroscopic sequence generated by the C-arm unit during ERCP. RESULTS: Continuous image-guided ERCP was applied in the biliary phantom with a registration error of 0.46 mm ± 0.13 mm and a tracking error of 0.64 mm ± 0.24 mm. After estimating the respiratory motion, 3D/2D registration accurately transformed preoperative 3D biliary images to each image in the X-ray image sequence in real-time in 18 patients, with an average fusion rate of 88%. CONCLUSION: Continuous image-guided ERCP may be an effective approach to assist the operator and reduce the use of X-ray and contrast agents.

S-sulfhydration of SIRT3 combats BMSC senescence and ameliorates osteoporosis via stabilizing heterochromatic and mitochondrial homeostasis.

Senescence of bone marrow mesenchymal stem cells (BMSCs) is one of the leading causes of osteoporosis. SIRT3, an essential NAD-dependent histone deacetylase, is highly correlated with BMSC senescence-mediated bone degradation and mitochondrial/heterochromatic disturbance. S-sulfhydration of cysteine residues favorably enhances SIRT3 activity by forming persulfides. Nevertheless, the underlying molecular mechanism of SIRT3 S-sulfhydration on mitochondrial/heterochromatic homeostasis involved in BMSC senescence remains unknown. Here, we demonstrated that CBS and CSE, endogenous hydrogen sulfide synthases, are downregulated with BMSC senescence. Exogenous H2S donor NaHS-mediated SIRT3 augmentation rescued the senescent phenotypes of BMSCs. Conversely, SIRT3 deletion accelerated oxidative stress-induced BMSC senescence through mitochondrial dysfunction and the detachment of the heterochromatic protein H3K9me3 from the nuclear envelope protein Lamin B1. H2S-mediated SIRT3 S-sulfhydration modification rescued the disorganized heterochromatin and fragmented mitochondria induced by the S-sulfhydration inhibitor dithiothreitol, thus leading to elevated osteogenic capacity and preventing BMSC senescence. The antisenescence effect of S-sulfhydration modification on BMSCs was abolished when the CXXC sites of the SIRT3 zinc finger motif were mutated. In vivo, aged mice-derived BMSCs pretreated with NaHS were orthotopically transplanted to the ovariectomy-induced osteoporotic mice, and we proved that SIRT3 ameliorates bone loss by inhibiting BMSC senescence. Overall, our study for the first time indicates a novel role of SIRT3 S-sulfhydration in stabilizing heterochromatin and mitochondrial homeostasis in counteracting BMSC senescence, providing a potential target for the treatment of degenerative bone diseases.

Oleic acid improves hepatic lipotoxicity injury by alleviating autophagy dysfunction.

Lipotoxicity caused by excess free fatty acids, particularly saturated fatty acids (SFAs) such as palmitic acid (PA), is one of the most important pathogenesis of nonalcoholic fatty liver disease (NAFLD). However, unsaturated fatty acids (UFAs), such as oleic acid (OA), are nontoxic and can combat SFA-induced toxicity through alleviation of cell apoptosis, endoplasmic reticulum stress (ER stress) and lipids metabolism disorder. However, whether OA is able to regulate autophagy is largely unknown. So, this study aims to investigate the mechanism underlying OA mediated modulation of autophagy in hepatocytes and mice with NAFLD. In vitro, human hepatoma cell line HepG2 cells, human normal liver cells L-02 and mouse normal liver cells AML12 were treated with palmitic acid (PA)/tunicamycin (TM) or/and OA for 48 h. In vivo, C57/BL6 mice were fed with high fat diet (HFD) to induce NAFLD. And the HFD was partial replaced by olive oil to observe the protective effects of olive oil. We demonstrated that PA/TM impaired cell viability and induced cellular apoptosis in HepG2 cells and L-02 cells. Moreover, PA/TM induced autophagy impairment by reducing the nuclear translocation of transcription factor EB (TFEB) and inhibiting the activity of CTSB. However, OA substantially alleviated PA/TM induced cellular apoptosis and autophagy dysfunction in hepatocytes. Additionally, restoring autophagy function is able to reduce ER stress. Similarly, HFD for 20 weeks successfully established NAFLD model in C57/BL6 mice, and significant autophagy impairment were observed in liver tissues. Noteworthily, 30% replacement of HFD with olive oil had profoundly reversed NAFLD. It significantly impoved steatosis, and reduced autophagy dysfunction, ER stress and apoptosis in liver tissue. Conclusively, these data demonstrated that OA is able to effectively impove autophagy dysfunction under the context of both PA and ER stress inducer induced lipotoxicity, and OA mediated regulation of lysosome dysfunction through TFEB plays an important role, suggesting that the regulation of ER stress-autophagy axis is a critical mechanism in OA driven protection in NAFLD.

Macrophage-derived exosomal miR-195a-5p impairs tubular epithelial cells mitochondria in acute kidney injury mice.

Macrophages (Mφ) infiltration is a common characteristic of acute kidney injury (AKI). Exosomes-mediated cell communication between tubular epithelial cells (TECs) and Mφ has been suggested to be involved in AKI. Exosomes-derived from injured TECs could regulate Mφ polarization during AKI. However, little is known regarding how activated Mφ regulates kidney injury. To explore the role of activated Mφ in the AKI process, we revealed that Mφ-derived exosomes from AKI mice (ExosAKI ) caused mitochondria damage and induced TECs injury. Then, we detected the global miRNA expression profiles of MφNC and MφAKI and found that among the upregulated miRNAs, miR-195a-5p, which regulates mitochondria metabolism in cancer, was significantly increased in MφAKI . Due to the enrichment of miR-195a-5p in ExosAKI , the miR-195a-5p level in the kidney was elevated in AKI mice. More interestingly, based on the high expression of pri-miR-195a-5p in kidney-infiltrated Mφ, and the reduction of miR-195a-5p in kidney after depletion of Mφ in AKI mice, we confirmed that miR-195a-5p may be produced in infiltrated Mφ, and shuttled into TECs via ExosMφ . Furthermore, in vitro inhibition of miR-195a-5p alleviated the effect of ExosAKI induced mitochondrial dysfunction and cell injury. Consistently, antagonizing miR-195a-5p with a miR-195a-5p antagomir attenuated cisplatin-induced kidney injury and mitochondrial dysfunction in mice. These findings revealed that the Mφ exosomal miR-195a-5p derived from AKI mice played a critical pathologic role in AKI progression, representing a new therapeutic target for AKI.

Molecular mechanisms and physiological functions of autophagy in kidney diseases.

Autophagy is a highly conserved cellular progress for the degradation of cytoplasmic contents including micromolecules, misfolded proteins, and damaged organelles that has recently captured attention in kidney diseases. Basal autophagy plays a pivotal role in maintaining cell survival and kidney homeostasis. Accordingly, dysregulation of autophagy has implicated in the pathologies of kidney diseases. In this review, we summarize the multifaceted role of autophagy in kidney aging, maladaptive repair, tubulointerstitial fibrosis and discuss autophagy-related drugs in kidney diseases. However, uncertainty still remains as to the precise mechanisms of autophagy in kidney diseases. Further research is needed to clarify the accurate molecular mechanism of autophagy in kidney diseases, which will facilitate the discovery of a promising strategy for the prevention and treatment of kidney diseases.

Peritoneal M2 macrophage-derived extracellular vesicles as natural multitarget nanotherapeutics to attenuate cytokine storms after severe infections.

Cytokine storms are a primary cause of multiple organ damage and death after severe infections, such as SARS-CoV-2. However, current single cytokine-targeted strategies display limited therapeutic efficacy. Here, we report that peritoneal M2 macrophage-derived extracellular vesicles (M2-EVs) are multitarget nanotherapeutics that can be used to resolve cytokine storms. In detail, primary peritoneal M2 macrophages exhibited superior anti-inflammatory potential than immobilized cell lines. Systemically administered M2-EVs entered major organs and were taken up by phagocytes (e.g., macrophages). M2-EV treatment effectively reduced excessive cytokine (e.g., TNF-α and IL-6) release in vitro and in vivo, thereby attenuating oxidative stress and multiple organ (lung, liver, spleen and kidney) damage in endotoxin-induced cytokine storms. Moreover, M2-EVs simultaneously inhibited multiple key proinflammatory pathways (e.g., NF-κB, JAK-STAT and p38 MAPK) by regulating complex miRNA-gene and gene-gene networks, and this effect was collectively mediated by many functional cargos (miRNAs and proteins) in EVs. In addition to the direct anti-inflammatory role, human peritoneal M2-EVs expressed angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2 spike protein, and thus could serve as nanodecoys to prevent SARS-CoV-2 pseudovirus infection in vitro. As cell-derived nanomaterials, the therapeutic index of M2-EVs can be further improved by genetic/chemical modification or loading with specific drugs. This study highlights that peritoneal M2-EVs are promising multifunctional nanotherapeutics to attenuate infectious disease-related cytokine storms.

Matrine alleviates cisplatin-induced acute kidney injury by inhibiting mitochondrial dysfunction and inflammation via SIRT3/OPA1 pathway.

Cisplatin is extensively used to treat malignancies. However, its clinical use is always limited due to the serious side effects, especially the nephrotoxicity. Matrine (MAT), a tetracyclic quinolizine alkaloid found in sophora genus, exerts multiple pharmacological roles, including anti-oxidative stress, anti-inflammation and anti-apoptosis, but the role of MAT on acute kidney injury (AKI) has not been evaluated. Here, we found that MAT potently inhibited cell injury induced by cisplatin in HK2 cells in vitro, which was associated with the inhibition of oxidative injury and NF-κB-mediated inflammation. Moreover, MAT treatment could activate the SIRT3/OPA1 axis and subsequently suppress the mitochondrial fragmentation and improve mitochondrial function. More importantly, SIRT3 knockdown suppressed the deacetylation of OPA1, which blocked the protective role of MAT on cisplatin-induced cell injury. In vivo, MAT treatment alleviated renal dysfunction, histological damage and inflammation induced by cisplatin in mice. Furthermore, consistent with the founding in vitro, MAT also activated SIRT3-mediated deacetylation of OPA1 and alleviated mitochondrial dysfunction in AKI mice. Our study proved that MAT protected against cisplatin-induced AKI by synergic anti-oxidative stress and anti-inflammation actions via SIRT3/OPA1-mediated improvement of mitochondrial function, suggesting that MAT may be a novel and effective strategy for AKI.

Using anatomical traits to understand root functions across root orders of herbaceous species in a temperate steppe.

Root anatomical traits play crucial roles in understanding root functions and root form-function linkages. However, the root anatomy and form-function linkages of monocotyledonous and dicotyledonous herbs remain largely unknown. We measured order-based anatomical traits and mycorrhizal colonization rates of 32 perennial herbs of monocotyledons and dicotyledons in a temperate steppe. For monocots, relative constant proportion of cortex and mycorrhizal colonization rates, but increased cell-wall thickening of the endodermis and proportion of stele were observed across root orders, indicating a slight reduction in absorption capacity and improvement in transportation capacity across orders. For dicots, the cortex and mycorrhizal colonization disappeared in the fourth-order and/or fifth-order roots, whereas the secondary vascular tissue increased markedly, suggesting significant transition of root functions from absorption to transportation across root orders. The allometric relationships between stele and cortex differed across root orders and plant groups, suggesting different strategies to coordinate the absorption and transportation functions among plant groups. In summary, our results revealed different functional transition patterns across root orders and distinct strategies for coordinating the absorption and transportation of root system between monocots and dicots. These findings will contribute to our understanding of the root form and functions in herbaceous species.

Regulatory T cells in COVID-19.

The outbreak of coronavirus disease 2019 (COVID-19) is caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which leads to the disruption of immune system, exacerbated inflammation, and even multiple organ dysfunction syndrome. Regulatory T cells (Tregs) are an important subpopulation of T cells that exert immunosuppressive effects. Recent studies have demonstrated that the number of Tregs is significantly reduced in COVID-19 patients, and this reduction may affect COVID-19 patients on several aspects, such as weakening the effect of inflammatory inhibition, causing an imbalance in Treg/Th17 ratio, and increasing the risk of respiratory failure. Treg-targeted therapy may alleviate the symptoms and retard disease progression in COVID-19 patients. This study highlights the recent findings on the involvement of Tregs in the regulation of immune responses to COVID-19, and we hope to provide novel perspectives on the alternative immunotherapeutic strategies for this disease that is currently prevalent worldwide.

Value of shear wave elastography in predicting hepatorenal syndrome in patients with liver cirrhosis and ascites.

BACKGROUND: Early detection of renal damage in cirrhosis is critical to prevent hepatorenal syndrome (HRS). Although shear wave elastography (SWE) is useful for the assessment of kidney stiffness, no study has yet investigated the clinical feasibility of SWE for predicting HRS. OBJECTIVE: The aim of this study was to evaluate the value of SWE in predicting HRS in patients with cirrhosis and ascites. METHODS: A total of 131 patients with liver cirrhosis and ascites were recruited and followed them for 30 days for the development of AKI. Ultrasonographic examination was performed on all patients at hospital admission. The baseline clinical characteristics, renal biomarkers, renal resistive index (RI) and Young's modulus (YM) were recorded, and their relationship with development HRS was investigated. RESULTS: Sixty-eight patients developed AKI, 23 of them were HRS. Compared with patients in the non-AKI group and non-HRS group, the values of serum cystatin C (CystC), urine neutrophil gelatinase-associated lipocalin (NGAL) and renal RI were significantly increased, while the YM value was significantly decreased in the AKI group and HRS group. Correlation analysis showed that YM was significantly and negatively associated with serum creatinine, serum CystC, urinary NGAL and renal RI in addition to the significant association with the AKI stage. Logistic regression and ROC analysis showed that urine NGAL, renal RI and YM were closely related to the development of HRS. Among them, YM had a good predictive ability in predicting the occurrence of HRS, and the predictive value (AUC = 0.894) was improved when combined with renal RI. CONCLUSION: SWE can indicate renal injury in patients with cirrhosis and ascites. The combination of YM and RI has a good predictive value for the occurrence of HRS.

Elevated branched-chain α-keto acids exacerbate macrophage oxidative stress and chronic inflammatory damage in type 2 diabetes mellitus.

AIMS: Chronic inflammation is a primary reason for type 2 diabetes mellitus (T2DM) and its complications, while disordered branched-chain amino acids (BCAA) metabolism is found in T2DM, but the link between BCAA catabolic defects and inflammation in T2DM remains elusive and needs to be investigated. METHODS: The changes in BCAA catabolism, inflammation, organ damage, redox status, and mitochondrial function in db/db mice with treatments of BCAA-overload or BCAA catabolism activator were analyzed in vivo. The changes in BCAA catabolic metabolism, as well as the direct effects of BCAAs/branched-chain alpha-keto acids (BCKAs) on cytokine release and redox status were also analyzed in primary macrophages in vitro. RESULTS: Inactivation of branched-chain ɑ-ketoacid dehydrogenase (BCKDH) complex was found in multiple organs (liver, muscle and kidney) of db/db mice. Long-term high BCAA supplementation further increased BCKA levels, inflammation, tissue fibrosis (liver and kidney), and macrophage hyper-activation in db/db mice, while enhancing BCAA catabolism with pharmacological activator reduced these adverse effects in db/db mice. In vitro, the BCAA catabolism was unchanged in primary macrophages of db/db mice, and elevated BCKAs but not BCAAs promoted the cytokine production in primary macrophages. Moreover, BCKA stimulation was associated with increased mitochondrial oxidative stress and redox imbalance in macrophages and diabetic organs. CONCLUSION: Impaired BCAA catabolism is strongly associated with chronic inflammation and tissue damage in T2DM, and this effect is at least partly due to the BCKAs-induced macrophage oxidative stress. This study highlights that targeting BCAA catabolism is a potential strategy to attenuate T2DM and its complications.

Mesenchymal stem cells transplantation attenuates hyperuricemic nephropathy in rats.

Mesenchymal stem cells (MSCs), due to their multi-directional differentiation, paracrine and immunomodulation potentials, and the capacity of homing to target organ, have been reported to facilitate regeneration and repair of kidney and improve kidney function in acute or chronic kidney injury. The present study was aimed to evaluate whether MSCs could have a protective effect in hyperuricemic nephropathy (HN) and the underlying mechanisms. A rat HN model was established by oral administration of a mixture of potassium oxonate (PO, 1.5 g/kg) and adenine (Ad, 50 mg/kg) daily for 4 weeks. For MSCs treatment, MSCs (3 × 106 cells/kg per week) were injected via tail vein from the 2nd week for 3 times. The results showed that along with the elevated uric acid (UA) in HN rats, creatinine (CREA), blood urea nitrogen (BUN), microalbuminuria (MAU) and 24-hour urinary protein levels were significantly increased comparing with the normal control rats, while decreased after MSCs treatment. Moreover, the mRNA levels of inflammation and fibrosis-related gene were reduced in UA + MSCs group. Consistently, hematoxylin-eosin (HE) staining results showed the destruction of kidney structure and fibrosis were significantly alleviated after MSCs administration. Similarly, in vitro, NRK-52Es cells were treated with high concentration UA (10 mg/dL) in the presence of MSCs, and we found that MSCs co-culture could inhibited UA-induced cell injury, characterized as improvement of cell viability and proliferation, inhibition of apoptosis, inflammation, and fibrosis. Collectively, MSCs treatment could effectively attenuate UA-induced renal injury, and thus it might be a potential therapy to hyperuricemia-related renal diseases.

Injectable self-assembling peptide nanofiber hydrogel as a bioactive 3D platform to promote chronic wound tissue regeneration.

Chronic wounds remain a worldwide clinical challenge, and bioactive materials that can promote skin regeneration are required. Self-assembling peptide (SAP) hydrogels have shown great potential in tissue repair, but their regenerative efficacy and possible mechanism in chronic wound healing are unclear. Here, we report an SAP (KGH) that enhances extracellular matrix (ECM) remodeling and angiogenesis, thereby promoting chronic wound healing in diabetic mice. In vivo, the KGH hydrogel was retained in wounds up to 7 days after injection, and it was effective in speeding up wound closure by ∼20% compared to the control groups and enhancing angiogenesis (e.g., VEGFA, CD31+ capillaries), cell proliferation (e.g., PCNA+ cells), formation of granulation tissue (e.g., α-SMA), and ECM deposition/remodeling (e.g., collagen I, fibronectin). In vitro, the KGH hydrogel created a 3D microenvironment for skin cells, maintained the sustained growth of cell spheroids, and increased the secretion of ECM proteins (e.g., laminin) and growth factors (e.g., PDGFB, VEGFA, and TGF-ß) in skin keratinocytes compared to the conventional 2D culture. Mechanistically, the KGH hydrogel might promote wound tissue regeneration by activating the Rho/ROCK and TGF-ß/MEK/MAPK pathways. As a type of designed material, SAP can be further re-engineered with biological motifs, therapeutic reagents, or stem cells to enhance skin regeneration. This study highlights that SAP hydrogels are a promising material platform for advanced chronic wound healing and might have translational potential in future clinical applications. STATEMENT OF SIGNIFICANCE: Chronic wounds are a common and serious health issue worldwide, and bioactive dressing materials are required to address this issue. SAP hydrogels have shown certain tissue repair potential, but their regenerative efficacy and underlying mechanism in chronic wound healing remain elusive. Herein, we report that SAP hydrogels create a native 3D microenvironment that can remarkably stimulate angiogenesis and ECM remodeling in diabetic wounds. Mechanistically, the SAP hydrogel promoted ECM proteins and GFs secretion in skin cells through the activation of the Rho/ROCK and TGF-ß/MEK/MAPK pathways. Additionally, SAP can be readily engineered with various bioactive motifs or therapeutic drugs/cells. This work highlights SAP hydrogels as a promising biomaterial platform for chronic wound healing and the regeneration of many other tissues.

Ischemic Stroke: An Underestimated Complication of COVID-19.

The coronavirus disease 2019 (COVID-19) has spread rapidly as a pandemic around the world. In addition to severe acute respiratory syndrome, more and more studies have focused on the complication of COVID-19, especially ischemic stroke. Here, we propose several pathophysiological processes and possible mechanisms underlying ischemic stroke after COVID-19 for early prevention and better treatment of COVID-19-related stroke.