Rhein alleviates MPTP-induced Parkinson's disease by suppressing neuroinflammation via MAPK/IκB pathway.

Background: Parkinson's disease (PD) is a common neurodegenerative disease with a rapid increase in incidence in recent years. Existing treatments cannot slow or stop the progression of PD. It was proposed that neuroinflammation leads to neuronal death, making targeting neuroinflammation a promising therapeutic strategy. Our previous studies have demonstrated that rhein protects neurons in vitro by inhibiting neuroinflammation, and it has been found to exhibit neuroprotective effects in Alzheimer's disease and epilepsy, but its neuroprotective mechanisms and effects on PD are still unclear. Methods: PD animal model was induced by 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP). ELISA, RT-qPCR, western blot and Immunofluorescence were used to detect the levels of inflammatory cytokines and M1 polarization markers. The protein expression levels of signaling pathways were measured by western blot. Hematoxylin-eosin (HE) staining showed that rhein did not damage the liver and kidney. Two behavioral tests, pole test and rotarod test, were used to evaluate the improvement effect of rhein on movement disorders. The number of neurons in the substantia nigra was evaluated by Nissl staining. Immunohistochemistry and western blot were used to detect tyrosine hydroxylase (TH) and α-synuclein. Results: Rhein inhibited the activation of MAPK/IκB signaling pathway and reduced the levels of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and M1 polarization markers of microglia in vivo. In a mouse model of PD, rhein ameliorated movement disorders, reduced dopaminergic neuron damage and α-synuclein deposition. Conclusion: Rhein inhibits neuroinflammation through MAPK/IκB signaling pathway, thereby reducing neurodegeneration, α-synuclein deposition, and improving movement disorders in Parkinson's disease.

Synthesis of Co@CoO/C by micro-tube method and their electrochemical performances.

Lithium-ion batteries (LIBs) are promising secondary batteries that are widely used in portable electronic devices, electric vehicles and smart grids. The design and synthesis of high-performance electrode materials play a crucial role in achieving lithium-ion batteries with high energy density, prolonged cycle life, and superior safety. CoO has attracted significant attention as a negative electrode material for lithium-ion batteries due to its high theoretical capacity and abundant resources. However, its limited conductivity and suboptimal cycling performance impede its potential applications. The study proposes a novel micro-tube reaction method for the synthesis of Co@CoO/C, utilizing Kapok fiber as a template with a special hollow structure. The microstructure and composition of the samples were characterized using X-ray powder diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). After conducting electrochemical performance tests, it was discovered that at a current density of 100 mA/g and within the range of 0.01-3.0 V for 50 charge and discharge cycles. Co@CoO/C composite negative electrode exhibits a reversible lithium insertion specific capacity of 499.8 mAh/g and keep a discharge capacity retention rate of 97.6 %. The greatly improved lithium storage and stability performance of Co@CoO/C composite anode is mainly attributed to the synergistic effect between Co@CoO nanoparticles and the kapok carbon microtubule structure.

Tissue engineering RPE sheet derived from hiPSC-RPE cell spheroids supplemented with Y-27632 and RepSox.

BACKGROUND: Retinal pigment epithelium (RPE) cell therapy is a promising way to treat many retinal diseases. However, obtaining transplantable RPE cells is time-consuming and less effective. This study aimed to develop novel strategies for generating engineered RPE patches with physiological characteristics. RESULTS: Our findings revealed that RPE cells derived from human induced pluripotent stem cells (hiPSCs) successfully self-assembled into spheroids. The RPE spheroids treated with Y27632 and Repsox had increased expression of epithelial markers and RPE-specific genes, along with improved cell viability and barrier function. Transcriptome analysis indicated enhanced cell adhesion and extracellular matrix (ECM) organization in RPE spheroids. These RPE spheroids could be seeded and bioprinted on collagen vitrigel (CV) membranes to construct engineered RPE sheets. Circular RPE patches, obtained by trephining a specific section of the RPE sheet, exhibited abundant microvilli and pigment particles, as well as reduced proliferative capacity and enhanced maturation. CONCLUSIONS: Our study suggests that the supplementation of small molecules and 3D spheroid culture, as well as the bioprinting technique, can be effective methods to promote RPE cultivation and construct engineered RPE sheets, which may support future clinical RPE cell therapy and the development of RPE models for research applications.

Hydrodynamic Groundwater Modeling and Hydrochemical Conceptualization of the Closure Mining Area of the WuMa River Watershed of China.

The WuMa River (WMR) watershed is located in Renhuai City, Guizhou Province of China, which is a first-class tributary of the Chishui River. The geochemical investigation mainly included the determination of groundwater pH, total hardness, total dissolution solid, major cationic and anionic, and the geochemical groundwater modeling. The principal component analysis (PCA) and Gibbs model were used to analyze the pollution type and geochemical composition. The geochemical investigation results show that the cations of groundwater are dominated by Ca2+ and the anions are dominated by HCO3-; therefore, two main hydrochemical types in the study area are identified as Ca2+-Mg2+-HCO3- and Ca2+-Mg2+-SO42-. The chemical composition of groundwater in this area is mainly controlled by weathering of the carbonate rocks. The ion concentration of groundwater in the study area exhibited significant spatial variability between dry and wet seasons, while temporal changes of cationic and anionic concentrations exhibited irregularities. In PCA and FA analysis, PC1, PC2, and PC3 were extracted, which could explain 51.92, 26.98, and 12.61% of the total information, respectively. F1 explained 67.44% of the total variance, among which Ca2+, Mg2+, K+, SO42-, and Cl- contributed the most among the factors and were the main factors controlling the chemical composition of groundwater. The relative error between the measured water level and the simulated water level is less than 2%, which meets the requirements of simulation accuracy. During the simulation period of the model, a total recharge of 339.05 × 104 m3 was observed in the simulated area, primarily attributed to infiltration from rainfall. The total excretion amounted to 330.78 × 104 m3, primarily through evaporation, with a minor amount of lateral outflow. The migration pathway of pollutants in groundwater primarily follows the direction of groundwater flow while diffusing vertically. The migration range of the pollutant is in accordance with the direction of groundwater flow and extends along the larger hydraulic gradient, demonstrating consistency. The findings of this study serve as a reminder that the closure of coal mines can constitute a significant source of water pollution. Simultaneously, they offer empirical data and theoretical references for the simulation and prediction of groundwater contamination in enclosed coal mines.

Self-endowed magnetic photocatalysts derived from iron-rich sludge and its recycling in photocatalytic process for tetracycline degradation.

The disposal of iron-rich sludge by landfill or incineration poses environmental risks and wastes resources. The utilization of iron-rich sludge for magnetic material preparation offers a sustainable and resource-efficient solution for its disposal. Herein, self-endowed magnetic photocatalysts were initially prepared by pyrolysis using iron-rich sludge without any additives. The photocatalysts performance were evaluated for tetracycline degradation, with the highest degradation rate of 95.3 % at a concentration of 10 mg·L-1 (pH = 7) within 5 h being achieved for the photocatalyst prepared at 800 °C. The reactive radical species in the photocatalysis process were confirmed to be •OH and O2•- activated by ferrous oxygen species under light irradiation. Furthermore, quinone-like structures induced bound persistent free radicals, which emerged as the predominant factors influencing 1O2 formation. The employed photocatalyst can be efficiently separated and recovered owing to its magnetism. This work presents an economic solution for antibiotic removal using waste iron-rich sludge.

SARS-CoV-2 N protein induced acute kidney injury in diabetic db/db mice is associated with a Mincle-dependent M1 macrophage activation.

"Cytokine storm" is common in critically ill COVID-19 patients, however, mechanisms remain largely unknown. Here, we reported that overexpression of SARS-CoV-2 N protein in diabetic db/db mice significantly increased tubular death and the release of HMGB1, one of the damage-associated molecular patterns (DAMPs), to trigger M1 proinflammatory macrophage activation and production of IL-6, TNF-α, and MCP-1 via a Mincle-Syk/NF-κB-dependent mechanism. This was further confirmed in vitro that overexpression of SARS-CoV-2 N protein caused the release of HMGB1 from injured tubular cells under high AGE conditions, which resulted in M1 macrophage activation and production of proinflammatory cytokines via a Mincle-Syk/NF-κB-dependent mechanism. This was further evidenced by specifically silencing macrophage Mincle to block HMGB1-induced M1 macrophage activation and production of IL-6, TNF-α, and MCP-1 in vitro. Importantly, we also uncovered that treatment with quercetin largely improved SARS-CoV-2 N protein-induced AKI in db/db mice. Mechanistically, we found that quercetin treatment significantly inhibited the release of a DAMP molecule HMGB1 and inactivated M1 pro-inflammatory macrophage while promoting reparative M2 macrophage responses by suppressing Mincle-Syk/NF-κB signaling in vivo and in vitro. In conclusion, SARS-CoV-2 N protein-induced AKI in db/db mice is associated with Mincle-dependent M1 macrophage activation. Inhibition of this pathway may be a mechanism through which quercetin inhibits COVID-19-associated AKI.

Capturing Cu2+ and recycling spent Cu-adsorbents as catalyst for eliminating Rhodamine B: reactivity and mechanism.

The thorny problem of adsorption is the disposing of spent adsorbent. In this manuscript, the exhaust adsorbent of efficient capture Cu(II) over ZSM-5 that supported zero-valent iron (nZVI) was reused as a catalyst for eliminating Rhodamine B (RhB). Batch experiments were used to evaluate the removal performance of Cu2+ and RhB. The results demonstrated that the Cu2+ adsorption process obeyed pseudo-second-order kinetics, and the adsorption performance was dependent on solution pH. The maximum adsorption capacity at the optimal pH 4.0 was 375.9 mg/g; equilibrium was reached rapidly within 35 min. From XPS, the reduction-oxidation between Fe0 and Cu2+ was occurred in the adsorption process, and Fe2+, Fe3+, and Cu0 was formed. In the recycling experiments, RhB was removed by the spent Cu adsorbent, with the removal performance being dependent on the initial Cu concentration, in the order of 5 mg/L > 20 mg/L > 0 mg/L > 100 mg/L > 500 mg/L. RhB removal also improved with increasing H2O2 concentration. More than 99.9% of the RhB was degraded within 8 min using 1.75 mM H2O2, which was a large improvement over the previously used catalyst. The hydroxyl radical was found to be the main free radical responsible for RhB degradation.

Redox Homeostasis Disruptors Based on Metal-Phenolic Network Nanoparticles for Chemo/Chemodynamic Synergistic Tumor Therapy through Activating Apoptosis and Cuproptosis.

The combination of chemo/chemodynamic therapy is a promising strategy for improving antitumor efficacy. Herein, metal-phenolic network nanoparticles (NPs) self-assembled from copper ions and gallic acid (Cu-GA) are developed to evoke apoptosis and cuproptosis for synergistic chemo/chemodynamic therapy. The Cu-GA NPs are biodegraded in response to the highly expressed glutathione (GSH) in tumor cells, resulting in the simultaneous release of Cu+ and GA. The intracellular GSH content is dramatically reduced by the released GA, rendering the tumor cells incapable of scavenging reactive oxygen species (ROS) and more susceptible to cuproptosis. Meanwhile, ROS levels within the tumor cells are significantly increased by the Fenton-like reaction of released Cu+ , which disrupts redox homeostasis and achieves apoptosis-related chemodynamic therapy. Moreover, massive accumulation of Cu+ in the tumor cells further induces aggregation of lipoylated dihydrolipoamide S-acetyltransferase and downregulation of iron-sulfur cluster protein, activating cuproptosis to enhance the antitumor efficacy of Cu-GA NPs. The experiments in vivo further demonstrate that Cu-GA NPs exhibited the excellent biosafety and superior antitumor capacity, which can efficiently inhibit the growth of tumors due to the activation by the tumor specific GSH and hydrogen peroxide. These Cu-based metal-phenolic network NPs provide a potential strategy to build up efficient and safe cancer therapy.

JMJD6 protects against isoproterenol-induced cardiac hypertrophy via inhibition of NF-κB activation by demethylating R149 of the p65 subunit.

Histone modification plays an important role in pathological cardiac hypertrophy and heart failure. In this study we investigated the role of a histone arginine demethylase, Jumonji C domain-containing protein 6 (JMJD6) in pathological cardiac hypertrophy. Cardiac hypertrophy was induced in rats by subcutaneous injection of isoproterenol (ISO, 1.2 mg·kg-1·d-1) for a week. At the end of the experiment, the rats underwent echocardiography, followed by euthanasia and heart collection. We found that JMJD6 levels were compensatorily increased in ISO-induced hypertrophic cardiac tissues, but reduced in patients with heart failure with reduced ejection fraction (HFrEF). Furthermore, we demonstrated that JMJD6 overexpression significantly attenuated ISO-induced hypertrophy in neonatal rat cardiomyocytes (NRCMs) evidenced by the decreased cardiomyocyte surface area and hypertrophic genes expression. Cardiac-specific JMJD6 overexpression in rats protected the hearts against ISO-induced cardiac hypertrophy and fibrosis, and rescued cardiac function. Conversely, depletion of JMJD6 by single-guide RNA (sgRNA) exacerbated ISO-induced hypertrophic responses in NRCMs. We revealed that JMJD6 interacted with NF-κB p65 in cytoplasm and reduced nuclear levels of p65 under hypertrophic stimulation in vivo and in vitro. Mechanistically, JMJD6 bound to p65 and demethylated p65 at the R149 residue to inhibit the nuclear translocation of p65, thus inactivating NF-κB signaling and protecting against pathological cardiac hypertrophy. In addition, we found that JMJD6 demethylated histone H3R8, which might be a new histone substrate of JMJD6. These results suggest that JMJD6 may be a potential target for therapeutic interventions in cardiac hypertrophy and heart failure.

Plumbagin Exhibits Genotoxicity and Induces G2/M Cell Cycle Arrest via ROS-Mediated Oxidative Stress and Activation of ATM-p53 Signaling Pathway in Hepatocellular Cells.

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone, PLB), a naturally occurring naphthoquinone mainly isolated from the plant Plumbago zeylanica L., has been proven to possess anticancer activities towards multiple types of cancer. Although there has been an increasing amount of research regarding its anticancer effects, the association between oxidative stress, genotoxicity and the cell cycle arrest induced by PLB still remains unclear. Therefore, it is important to investigate their potential connections and the involvement of DNA damage and the ataxia telangiectasia mutated protein (ATM)-p53 signaling pathway in PLB's anticancer mechanism. The present study showed that PLB exposure significantly reduced HCC cell viability and colony formation. In addition, PLB-induced G2/M cell cycle arrest, oxidative stress, and DNA damage was detected, which could be almost blocked by NAC pretreatment. PLB could trigger a DNA damage response by activating cell cycle checkpoints such as ATM, checkpoint kinase 1 (Chk1), checkpoint kinase 2 (Chk2) and p53. Meanwhile, the key modulator of the G2/M transition factor, Cell Division Cycle 25C (cdc25C), was significantly downregulated in an ROS-dependent manner. Furthermore, pretreatment with ATM and p53 inhibitors (KU55933 and Pifithrin-α) could reduce the occurrence of G2/M cell cycle arrest by inhibiting the activation of the ATM-p53 pathway. Taken together, these results indicate that ROS-mediated oxidative stress plays a key role in PLB-induced G2/M cell cycle arrest mediated by the ATM-p53 pathway.

Effective degradation of tetracycline via recyclable free-standing three-dimensional copper-based graphene as a persulfate catalyst.

Water pollution by antibiotics is a serious and growing problem. Given this challenge, a free-standing three-dimensional (3D) reduced graphene oxide foam supported copper oxide nanoparticles (3D-rGO-CuxO) was synthesized using GO as a precursor and applied as an efficient persulfate activator for tetracycline (TC) degradation. The influences of CuxO mass, solution pH, persulfate dosage, and common anions on the TC degradation were investigated in detail. Analytical techniques indicated that the 3D-rGO-CuxO showed a cross-linking three-dimensional network structure, and CuxO particles with irregular shapes were uniformly loaded on graphene pore walls. The XPS and Auger spectra of Cu confirmed that Cu2O was the main component in solid copper compounds. The addition of CuxO was vitally important for the activation of the oxidation system, and the removal rate reached 98% with a CuxO load of 7:1. The pH showed little influence on the activation effect on TC degradation. For common anions, Cl- and CO32- had little influence on the system, while humic acid had a great inhibitory effect. The EPR test and quenching experiment revealed that the active substances in the oxidative degradation process mainly include SO4-·, ·OH, 1O2, and reactive Cu(III). Additionally, the 3D-rGO-CuxO material proved highly stable according to the replicated test results and was promising for the remediation of antibiotic-contaminated water.

Regulation of the Keratocyte Phenotype and Cell Behavior Derived from Human Induced Pluripotent Stem Cells by Substrate Stiffness.

Substrate stiffness has been indicated as an important factor to control stem cell fate, including proliferation and differentiation. To optimize the stiffness for the differentiation process from h-iPSCs (human induced pluripotent stem cells) into h-iCSCs (human corneal stromal cells derived from h-iPSCs) and the phenotypic maintenance of h-iCSCs in vitro, h-iPSCs were cultured on matrigel-coated tissue culture plate (TCP) (106 kPa), matrigel-coated polydimethylsiloxane (PDMS) 184 (1250 kPa), and matrigel-coated PDMS 527 (4 kPa) before they were differentiated to h-iCSCs. Immunofluorescence staining, quantitative real-time polymerase chain reaction (RT-qPCR), and western blot demonstrated that the stiffer substrate TCP promoted the h-iCSCs' differentiation from h-iPSCs. On the contrary, softer PDMS 527 was more effective to maintain the phenotype of h-iCSCs cultured in vitro. Finally, we cultured h-iCSCs on PDMS 527 until P3 and seeded them on a biomimetic collagen membrane to form the single-layer and multiple-layer bioengineered corneal stroma with high transparency properties and cell survival rate. In conclusion, the study is helpful for differentiating h-iPSCs to h-iCSCs and corneal tissue engineering by manipulating stiffness mechanobiology.

Treatment with quercetin inhibits SARS-CoV-2 N protein-induced acute kidney injury by blocking Smad3-dependent G1 cell-cycle arrest.

Increasing evidence shows that SARS-CoV-2 can infect kidneys and cause acute kidney injury (AKI) in critically ill COVID-19 patients. However, mechanisms through which COVID-19 induces AKI are largely unknown, and treatment remains ineffective. Here, we report that kidney-specific overexpressing SARS-CoV-2 N gene can cause AKI, including tubular necrosis and elevated levels of serum creatinine and BUN in 8-week-old diabetic db/db mice, which become worse in those with older age (16 weeks) and underlying diabetic kidney disease (DKD). Treatment with quercetin, a purified product from traditional Chinese medicine (TCM) that shows effective treatment of COVID-19 patients, can significantly inhibit SARS-CoV-2 N protein-induced AKI in diabetic mice with or without underlying DKD. Mechanistically, quercetin can block the binding of SARS-CoV-2 N protein to Smad3, thereby inhibiting Smad3 signaling and Smad3-mediated cell death via the p16-dependent G1 cell-cycle arrest mechanism in vivo and in vitro. In conclusion, SARS-CoV-2 N protein is pathogenic and can cause severe AKI in diabetic mice, particularly in those with older age and pre-existing DKD, via the Smad3-dependent G1 cell-cycle arrest mechanism. Importantly, we identify that quercetin may be an effective TCM compound capable of inhibiting COVID-19 AKI by blocking SARS-CoV-2 N-Smad3-mediated cell death pathway.

Ascorbic acid enhanced ferrous/persulfate system for degradation of tetracycline contaminated groundwater.

Persulfate (PS) activated by Fe(ii) has been widely investigated for degradation of contaminants. However, the Fe(ii)/PS systems used for actual contaminated groundwater remediation have been restricted by circulation of Fe(iii)/Fe(ii). Herein, an ascorbic acid (AA) enhanced Fe(ii)/PS system was developed for degradation of tetracycline (TC) contaminated groundwater. The influence of Fe(ii), AA, PS dosage and pH on degradation of TC was investigated, the free radicals produced in the reaction were identified and the reusability of Fe(ii) in the Fe(ii)/PS/AA system for degradation of TC was also evaluated. The results showed that AA significantly promoted the degradation of TC in the Fe(ii)/PS system, and a degradation rate of 86% for TC was achieved at 60 min. The dominant oxidant species for contaminant degradation in the Fe(ii)/PS/AA system is ˙OH. Appropriate Fe(ii), AA and PS dosage can improve the degradation rate of TC. Moreover, the degradation rate of TC in the Fe(ii)/PS/AA system under acidic conditions is higher than that under alkaline conditions. With the increase of reaction time, TC can also be completely degraded even with a little Fe(ii) or under alkaline conditions in the Fe(ii)/PS/AA system, and Fe(ii) showed a good reusability for the degradation of TC. Thus, the AA-enhanced Fe(ii)/PS system for the degradation of contaminants displays the advantages of less Fe(ii) consumption and a wide range of pH. This method provides a new strategy for in situ remediation of contaminated groundwater.

Retinal organoids and microfluidic chip-based approaches to explore the retinitis pigmentosa with USH2A mutations.

Retinitis pigmentosa (RP) is a leading cause of vision impairment and blindness worldwide, with limited medical treatment options. USH2A mutations are one of the most common causes of non-syndromic RP. In this study, we developed retinal organoids (ROs) and retinal pigment epithelium (RPE) cells from induced pluripotent stem cells (iPSCs) of RP patient to establish a sustainable in vitro RP disease model. RT-qPCR, western blot, and immunofluorescent staining assessments showed that USH2A mutations induced apoptosis of iPSCs and ROs, and deficiency of the extracellular matrix (ECM) components. Transcriptomics and proteomics findings suggested that abnormal ECM-receptor interactions could result in apoptosis of ROs with USH2A mutations via the PI3K-Akt pathway. To optimize the culture conditions of ROs, we fabricated a microfluidic chip to co-culture the ROs with RPE cells. Our results showed that this perfusion system could efficiently improve the survival rate of ROs. Further, ECM components such as laminin and collagen IV of ROs in the RP group were upregulated compared with those maintained in static culture. These findings illustrate the potential of microfluidic chip combined with ROs technology in disease modelling for RP.

Ablation of cardiomyocyte-derived BDNF during development causes myocardial degeneration and heart failure in the adult mouse heart.

Objective: Brain-derived neurotrophic factor (BDNF) and its receptor TrkB-T1 were recently found to be expressed in cardiomyocytes. However, the functional role of cardiomyocyte-derived BDNF in heart pathophysiology is not yet fully known. Recent studies revealed that BDNF-TrkB pathway plays a critical role to maintain integrity of cardiac structure and function, cardiac pathology and regeneration of myocardial infarction (MI). Therefore, the BDNF-TrkB pathway may be a novel target for myocardial pathophysiology in the adult heart. Approach and results: In the present study, we established a cardiomyocyte-derived BDNF conditional knockout mouse in which BDNF expression in developing cardiomyocytes is ablated under the control of the Myosin heavy chain 6 (MYH6) promoter. The results of the present study show that ablation of cardiomyocyte-derived BDNF during development does not impair survival, growth or reproduction; however, in the young adult heart, it causes cardiomyocyte death, degeneration of the myocardium, cardiomyocyte hypertrophy, left atrial appendage thrombosis, decreased cardiac function, increased cardiac inflammation and ROS activity, and metabolic disorders, leading to heart failure (HF) in the adult heart and eventually resulting in a decrease in the one-year survival rate. In addition, ablation of cardiomyocyte-derived BDNF during the developmental stage leads to exacerbation of cardiac dysfunction and poor regeneration after MI in adult hearts. Conclusion: Cardiomyocyte-derived BDNF is irreplaceable for maintaining the integrity of cardiac structure and function in the adult heart and regeneration after MI. Therefore, the BDNF-TrkB pathway will be a novel target for myocardial pathophysiology in the adult heart.

Establishment of iPS cell line (KLRMMEi002-A) by reprogramming peripheral blood mononuclear cells from a patient with USH2A-associated Usher syndrome.

USH type 2 (USH2) is an autosomal recessive disorder that is characterized by inherited retinopathies and sensorineural hearing loss. USH type 2 (USH2) is frequently caused by USH2A mutations, which account for 74-90% of USH2 cases. We used peripheral blood mononuclear cells (PBMCs) from a USH2 patient with a USH2A gene mutation (c.8559-2A > G) to create an induced pluripotent stem (iPS) cell line. The patient-specific iPS cell line with the specific point mutation exhibited typical iPS cell characteristics, and it can be used as a model to investigate the pathogenic mechanisms underlying USH2A-associated retinal degeneration and sensorineural hearing loss.

SARS-CoV-2 N Protein Induces Acute Kidney Injury via Smad3-Dependent G1 Cell Cycle Arrest Mechanism.

COVID-19 is infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and can cause severe multiple organ injury and death. Kidney is one of major target organs of COVID-19 and acute kidney injury (AKI) is common in critically ill COVID-19 patients. However, mechanisms through which COVID-19 causes AKI remain largely unknown and treatment remains unspecific and ineffective. Here, the authors report that normal kidney-specifically overexpressing SARS-CoV-2 N develops AKI, which worsens in mice under ischemic condition. Mechanistically, it is uncovered that SARS-CoV-2 N-induced AKI is Smad3-dependent as SARS-CoV-2 N protein can interact with Smad3 and enhance TGF-ß/Smad3 signaling to cause tubular epithelial cell death and AKI via the G1 cell cycle arrest mechanism. This is further confirmed in Smad3 knockout mice and cells in which deletion of Smad3 protects against SARS-CoV-2 N protein-induced cell death and AKI in vivo and in vitro. Most significantly, it is also found that targeting Smad3 with a Smad3 pharmacological inhibitor is able to inhibit SARS-CoV-2 N-induced AKI. In conclusion, the authors identify that SARS-CoV-2 N protein is a key mediator for AKI and induces AKI via the Smad3-dependent G1 cell cycle arrest mechanism. Targeting Smad3 may represent as a novel therapy for COVID-19-asscoaited AKI.