Publications by authors named "Zhaowei Chen"

109 Publications

Alteration in Rab11-mediated endocytic trafficking of LDL receptor contributes to angiotensin II-induced cholesterol accumulation and injury in podocytes.

Cell Prolif 2022 May 14:e13229. Epub 2022 May 14.

Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.

Objectives: Exposure of podocytes to angiotensin II (Ang II) enhances the abundance of the cell surface glycoprotein, low-density lipoprotein receptor (LDLR) and promotes significant changes in the cellular cholesterol content. Recent investigation provides evidence that the small GTPase Rab11 is involved in the regulation of LDLR, but the exact mechanisms remain unknown. In this study, the role of Rab11 in post-transcriptional regulation of LDLR was evaluated to investigate potential mechanisms of podocyte cholesterol dysregulation in chronic kidney disease.

Materials And Methods: Cholesterol content, LDLR and Rab11 expression were assessed in podocytes from Ang II-infused mice. In vitro, the intracellular localization of LDLR was detected under different conditions. Rab11 expression was modulated and we then explored the effect of anti-lipid cytotoxicity by detecting LDLR expression and trafficking, cholesterol content and apoptosis in podocytes.

Results: Cholesterol accumulation, upregulated expression of LDLR and Rab11 were discovered in podocytes from Ang II-infused mice. Ang II enhanced the co-precipitation of LDLR with Rab11 and accelerated the endocytic recycling of LDLR to the plasma membrane. Additionally, silencing Rab11 promoted lysosomal degradation of LDLR and alleviated Ang II-induced cholesterol accumulation and apoptosis in podocytes. Conversely, overexpression of Rab11 or inhibition of lysosomal degradation up-regulated the abundance of LDLR and aggravated podocyte cholesterol deposition.

Conclusions: Rab11 triggers the endocytic trafficking and recycling of LDLR; overactivation of this pathway contributes to Ang II-induced podocyte cholesterol accumulation and injury.
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http://dx.doi.org/10.1111/cpr.13229DOI Listing
May 2022

Flexible patch with printable and antibacterial conductive hydrogel electrodes for accelerated wound healing.

Biomaterials 2022 Apr 14;285:121479. Epub 2022 Apr 14.

Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA; Center for Minimally Invasive Therapeutics (C-MIT), California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA; Terasaki Institute for Biomedical Innovation, Los Angeles, CA, 90064, USA; Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA; Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA. Electronic address:

Electrical stimulation can facilitate wound healing with high efficiency and limited side effects. However, current electrical stimulation devices have poor conformability with wounds due to their bulky nature and the rigidity of electrodes utilized. Here, a flexible electrical patch (ePatch) made with conductive hydrogel as electrodes to improve wound management was reported. The conductive hydrogel was synthesized using silver nanowire (AgNW) and methacrylated alginate (MAA), with the former chosen as the electrode material considering its antibacterial properties, and the latter used due to its clinical suitability in wound healing. The composition of the hydrogel was optimized to enable printing on medical-grade patches for personalized wound treatment. The ePatch was shown to promote re-epithelization, enhance angiogenesis, mediate immune response, and prevent infection development in the wound microenvironment. In vitro studies indicated an elevated secretion of growth factors with enhanced cell proliferation and migration ability in response to electrical stimulation. An in vivo study in the Sprague-Dawley rat model revealed a rapid wound closure within 7 days compared to 20 days of usual healing process in rodents.
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http://dx.doi.org/10.1016/j.biomaterials.2022.121479DOI Listing
April 2022

Transition of acute kidney injury to chronic kidney disease: role of metabolic reprogramming.

Metabolism 2022 Jun 26;131:155194. Epub 2022 Mar 26.

Division of Nephrology, Renmin Hospital of Wuhan University, 430060 Wuhan, China; Nephrology and Urology Research Institute of Wuhan University, 430060 Wuhan, China. Electronic address:

Acute kidney injury (AKI) is a global public health concern associated with high morbidity and mortality. Although advances in medical management have improved the in-hospital mortality of severe AKI patients, the renal prognosis for AKI patients in the later period is not encouraging. Recent epidemiological investigations have indicated that AKI significantly increases the risk for the development of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the future, further contributing to the economic burden on health care systems. The transition of AKI to CKD is complex and often involves multiple mechanisms. Recent studies have suggested that renal tubular epithelial cells (TECs) are more prone to metabolic reprogramming during AKI, in which the metabolic process in the TECs shifts from fatty acid β-oxidation (FAO) to glycolysis due to hypoxia, mitochondrial dysfunction, and disordered nutrient-sensing pathways. This change is a double-edged role. On the one hand, enhanced glycolysis acts as a compensation pathway for ATP production; on the other hand, long-term shut down of FAO and enhanced glycolysis lead to inflammation, lipid accumulation, and fibrosis, contributing to the transition of AKI to CKD. This review discusses developments and therapies focused on the metabolic reprogramming of TECs during AKI, and the emerging questions in this evolving field.
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http://dx.doi.org/10.1016/j.metabol.2022.155194DOI Listing
June 2022

Scattered seeding of CAR T cells in solid tumors augments anticancer efficacy.

Natl Sci Rev 2022 Mar 21;9(3):nwab172. Epub 2021 Sep 21.

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

Chimeric antigen receptor T cell (CAR T) therapy was a milestone in the treatment of relapsed and refractory B cell malignancies. However, beneficial effects of CAR T cells have not been obtained in solid tumors yet. Herein, we implement a porous microneedle patch that accommodates CAR T cells and allows penetration-mediated seeding of CAR T cells when implanted in the tumor bed or in the post-surgical resection cavity. CAR T cells loaded in the pores of the microneedle tips were readily escorted to the tumor in an evenly scattered manner without losing their activity. Such microneedle-mediated local delivery enhanced infiltration and immunostimulation of CAR T cells as compared to direct intratumoral injection. This tailorable patch offers a transformative platform for scattered seeding of living cells for treating a variety of tumors.
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http://dx.doi.org/10.1093/nsr/nwab172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8900686PMC
March 2022

Ultrasensitive Label-Free DNA Detection Based on Solution-Gated Graphene Transistors Functionalized with Carbon Quantum Dots.

Anal Chem 2022 02 11;94(7):3320-3327. Epub 2022 Feb 11.

Hubei Collaborative Innovation Center for Advanced Organic Chemical Materials, Key Laboratory for the Green Preparation and Application of Functional Materials, Ministry of Education, Hubei Key Laboratory of Polymer Materials, School of Materials Science and Engineering, Hubei University, Wuhan 430062, P. R. China.

Developing highly sensitive, reliable, cost-effective label-free DNA biosensors is challenging with traditional fluorescence, electrochemical, and other techniques. Most conventional methods require labeling fluorescence, enzymes, or other complex modification. Herein, we fabricate carbon quantum dot (CQD)-functionalized solution-gated graphene transistors for highly sensitive label-free DNA detection. The CQDs are immobilized on the surface of the gate electrode through mercaptoacetic acid with the thiol group. A single-stranded DNA (ssDNA) probe is immobilized on CQDs by strong π-π interactions. The ssDNA probe can hybridize with the ssDNA target and form double-stranded DNA, which led to a shift of Dirac voltage and the channel current response. The limit of detection can reach 1 aM which is 2-5 orders of magnitude lower than those of other methods reported previously. The sensor also exhibits a good linear range from 1 aM to 0.1 nM and has good specificity. It can effectively distinguish one-base mismatched target DNA. The response time is about 326 s for the 1 aM target DNA molecules. This work provides good perspectives on the applications in biosensors.
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http://dx.doi.org/10.1021/acs.analchem.1c05309DOI Listing
February 2022

PFKP Activation Ameliorates Foot Process Fusion in Podocytes in Diabetic Kidney Disease.

Front Endocrinol (Lausanne) 2021 14;12:797025. Epub 2022 Jan 14.

Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.

Background: Glycolysis dysfunction is an important pathogenesis of podocyte injury in diabetic kidney disease (DKD). Foot process fusion of podocytes and increased albuminuria are markers of early DKD. Moreover, cytoskeletal remodeling has been found to be involved in the foot process fusion of podocytes. However, the connections between cytoskeletal remodeling and alterations of glycolysis in podocytes in DKD have not been clarified.

Methods: mRNA sequencing of glomeruli obtained from db/db and db/m mice with albuminuria was performed to analyze the expression profiling of genes in glucose metabolism. Expressions of phosphofructokinase platelet type (PFKP) in the glomeruli of DKD patients were detected. Clotrimazole (CTZ) was used to explore the renal effects of PFKP inhibition in diabetic mice. Using siRNA or recombinant plasmid to manipulate PFKP expression, the effects of PFKP on high glucose (HG) induced podocyte damage were assessed . The levels of fructose-1,6-bisphosphate (FBP) were measured. Targeted metabolomics was performed to observe the alterations of the metabolites in glucose metabolism after HG stimulation. Furthermore, aldolase type b siRNA or recombinant plasmid were applied to evaluate the influence of FBP level alteration on podocytes. FBP was directly added to podocyte culture media. Db/db mice were treated with FBP to investigate its effects on their kidney.

Results: mRNA sequencing showed that glycolysis enzyme genes were altered, characterized by upregulation of upstream genes () and down-regulation of downstream genes of glycolysis (). Moreover, the expression of PFKP was increased in glomeruli of DKD patients. The CTZ group presented more severe renal damage. , the siRNA group and ALDOB overexpression group showed much more induced cytoskeletal remodeling in podocytes, while overexpression of PFKP and suppression of ALDOB rescued podocytes from cytoskeletal remodeling through regulation of FBP levels and inhibition of the RhoA/ROCK1 pathway. Furthermore, targeted metabolomics showed FBP level was significantly increased in HG group compared with the control group. Exogenous FBP addition reduced podocyte cytoskeletal remodeling and renal damage of db/db mice.

Conclusions: These findings provide evidence that PFKP may be a potential target for podocyte injury in DN and provide a rationale for applying podocyte glycolysis enhancing agents in patients with DKD.
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http://dx.doi.org/10.3389/fendo.2021.797025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8794994PMC
March 2022

A multifunctional platinum(IV) and cyanine dye-based polyprodrug for trimodal imaging-guided chemo-phototherapy.

J Mater Chem B 2022 02 16;10(7):1031-1041. Epub 2022 Feb 16.

Institute of Food Safety and Environment Monitoring, College of Chemistry, Fuzhou University, Fuzhou 350108, P. R. China.

Imaging-guided chemo-phototherapy based on a single nanoplatform has a great significance to improve the efficiency of cancer therapy and diagnosis. However, high drug content, no burst release and real-time tracking of nanodrugs are the three main challenges for this kind of multifunctional nanotheranostics. In this work, we developed an innovative theranostic nanoplatform based on a Pt(IV) prodrug and a near-infrared (NIR) photosensitizer. A Pt(IV) prodrug and a cyanine dye (HOCyOH, Cy) were copolymerized and incorporated into the main chain of a polyprodrug (PCPP), which self-assembled into nanoparticles (NPs) with ∼27.61% Cy loading and ∼9.37% Pt loading, respectively. PCPP NPs enabled reduction-triggered backbone cleavage of polyprodrugs and bioactive Pt(II) release; Cy could be activated under 808 nm laser irradiation to produce local hyperthermia and reactive oxygen species (ROS) for phototherapy. Moreover, PCPP NPs with extremely high Cy and Pt heavy metal contents in the backbone of the polyprodrug could directly track the nanodrugs themselves near-infrared fluorescence (NIRF) imaging, photothermal imaging, and computed tomography (CT) imaging and . As revealed by trimodal imaging, PCPP NPs were found to exhibit excellent tumor accumulation and antitumor efficiency after intravenous injection into H22-tumor-bearing mice. The dual-drug backboned polyprodrug nanoplatform exhibited great potential for bioimaging and combined chemo-phototherapy.
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http://dx.doi.org/10.1039/d1tb02682hDOI Listing
February 2022

Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes PERK Pathway.

Front Cell Dev Biol 2021 20;9:769213. Epub 2021 Dec 20.

Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.

The endoplasmic reticulum (ER) stress and mitochondrial dysfunction in high glucose (HG)-induced podocyte injury have been demonstrated to the progression of diabetic kidney disease (DKD). However, the pathological mechanisms remain equivocal. Mitofusin2 (Mfn2) was initially identified as a dynamin-like protein involved in fusing the outer mitochondrial membrane (OMM). More recently, Mfn2 has been reported to be located at the ER membranes that contact OMM. Mitochondria-associated ER membranes (MAMs) is the intercellular membrane subdomain, which connects the mitochondria and ER through a proteinaceous tether. Here, we observed the suppression of Mfn2 expression in the glomeruli and glomerular podocytes of patients with DKD. Streptozotocin (STZ)-induced diabetic rats exhibited abnormal mitochondrial morphology and MAMs reduction in podocytes, accompanied by decreased expression of Mfn2 and activation of all three unfolded protein response (UPR) pathways (IRE1, ATF6, and PERK). The HG-induced mitochondrial dysfunction, MAMs reduction, and increased apoptosis were accompanied by the downregulation of Mfn2 and activation of the PERK pathway. Mfn2 physically interacts with PERK, and HG promotes a decrease in Mfn2-PERK interaction. In addition, Mfn2-silenced podocytes showed mitochondrial dysfunction, MAMs reduction, activation of PERK pathway, and increased apoptosis. Conversely, all these effects of HG stimulation were alleviated significantly by Mfn2 overexpression. Furthermore, the inhibition of PERK phosphorylation protected mitochondrial functions but did not affect the expression of Mfn2 in HG-treated podocytes. Therefore, this study confirmed that Mfn2 regulates the morphology and functions of MAMs and mitochondria, and exerts anti-apoptotic effects on podocytes by inhibiting the PERK pathway. Hence, the Mfn2-PERK signaling pathway may be a new therapeutic target for preventing podocyte injury in DKD
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http://dx.doi.org/10.3389/fcell.2021.769213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721005PMC
December 2021

Roles of SIRT6 in kidney disease: a novel therapeutic target.

Cell Mol Life Sci 2021 Dec 24;79(1):53. Epub 2021 Dec 24.

Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.

SIRT6 is an NAD dependent deacetylase that belongs to the mammalian sirtuin family. SIRT6 is mainly located in the nucleus and regulates chromatin remodeling, genome stability, and gene transcription. SIRT6 extensively participates in various physiological activities such as DNA repair, energy metabolism, oxidative stress, inflammation, and fibrosis. In recent years, the role of epigenetics such as acetylation modification in renal disease has gradually received widespread attention. SIRT6 reduces oxidative stress, inflammation, and renal fibrosis, which is of great importance in maintaining cellular homeostasis and delaying the chronic progression of kidney disease. Here, we review the structure and biological function of SIRT6 and summarize the regulatory mechanisms of SIRT6 in kidney disease. Moreover, the role of SIRT6 as a potential therapeutic target for the progression of kidney disease will be discussed. SIRT6 plays an important role in kidney disease. SIRT6 regulates mitochondrial dynamics and mitochondrial biogenesis, induces G2/M cycle arrest, and plays an antioxidant role in nephrotoxicity, IR, obstructive nephropathy, and sepsis-induced AKI. SIRT6 prevents and delays progressive CKD induced by hyperglycemia, kidney senescence, hypertension, and lipid accumulation by regulating mitochondrial biogenesis, and has antioxidant, anti-inflammatory, and antifibrosis effects. Additionally, hypoxia, inflammation, and fibrosis are the main mechanisms of the AKI-to-CKD transition. SIRT6 plays a critical role in the AKI-to-CKD transition and kidney repair through anti-inflammatory, antifibrotic, and mitochondrial quality control mechanisms. AKI Acute kidney injury, CKD Chronic kidney disease.
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http://dx.doi.org/10.1007/s00018-021-04061-9DOI Listing
December 2021

The circular RNA hsa_circ_000780 as a potential molecular diagnostic target for gastric cancer.

BMC Med Genomics 2021 11 27;14(1):282. Epub 2021 Nov 27.

Department of Gastroenterology, The Affiliated Cancer Hospital of Hainan Medical University, Haikou, 570123, China.

Background: The present study aimed to identify a specific circular RNA (circRNA) for early diagnosis of gastric cancer (GC).

Methods: Totally 82 patients with GC, 30 with chronic nonatrophic gastritis and 30 with chronic atrophic gastritis were included in this study. Four of the 82 GC patients were selected for screening. Total RNA from malignant and adjacent tissue samples was extracted, and circRNAs in four patients were screened. According to the screening results, the eight most upregulated and downregulated circRNAs with a statistically significant association with GC were identified by real-time fluorescent quantitative polymerase chain reaction (PCR). Then, the most regulated circRNA was selected for further sensitivity and specificity assessments. CircRNA expression was examined by quantitative reverse transcriptase PCR in 78 GC (21 and 57 early and advanced GC, respectively) and adjacent tissue samples, as well as in gastric fluid samples from 30 patients with chronic nonatrophic gastritis, 30 with chronic atrophic gastritis, and 78 GC.

Results: A total of 445 circRNAs, including 69 upregulated and 376 downregulated circRNAs, showed significantly altered expression in GC tissue samples. Hsa_circ_000780 was significantly downregulated in 80.77% of GC tissue samples, with levels in GC tissue samples correlating with tumor size, tumor stage, T stage, venous invasion, carcinoembryonic antigen amounts, and carbohydrate antigen 19-9 levels. Strikingly, this circRNA was found in the gastric fluid of patients with early and advanced GC.

Conclusions: The present study uncovered a new circRNA expression profile in human GC, with hsa_circ_000780 significantly downregulated in GC tissue and gastric fluid specimens. These findings indicate that hsa_circ_000780 should be considered a novel biomarker for early GC screening.
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http://dx.doi.org/10.1186/s12920-021-01096-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627072PMC
November 2021

Cellular transformers for targeted therapy.

Adv Drug Deliv Rev 2021 12 1;179:114032. Epub 2021 Nov 1.

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China; Zhejiang Laboratory of Systems and Precision Medicine, Zhejiang University Medical Center, Hangzhou 310058, PR China; Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, PR China; MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310058, PR China. Electronic address:

Employing natural cells as drug carriers has been a hotspot in recent years, attributing to their biocompatibility and inherent dynamic properties. In the earlier stage, cells were mainly used as vehicles by virtue of their lipid-delimited compartmentalized structures and native membrane proteins. The scope emphasis was 'what cell displays' instead of 'how cell changes'. More recently, the dynamic behaviours, such as changes in surface protein patterns, morphologies, polarities and in-situ generation of therapeutics, of natural cells have drawn more attention for developing advanced drug delivery systems by fully taking advantage of these processes. In this review, we revolve around the dynamic cellular transformation behaviours which facilitate targeted therapy. Cellular deformation in geometry shape, spitting smaller vesicles, activation of antigen present cells, polarization between distinct phenotypes, local production of therapeutics, and hybridization with synthetic materials are involved. Other than focusing on the traditional delivery of concrete cargoes, more functional 'handles' that are derived from the cells themselves are introduced, such as information exchange, cellular communication and interactions between cell and extracellular environment.
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http://dx.doi.org/10.1016/j.addr.2021.114032DOI Listing
December 2021

Cd and Pb immobilisation with iron oxide/lignin composite and the bacterial community response in soil.

Sci Total Environ 2022 Jan 26;802:149922. Epub 2021 Aug 26.

School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China. Electronic address:

Iron oxide is a natural mineral that generally exists in the form of iron oxide-organic complexes (Fe-OM) in soil. Lignin is a naturally occurring polymer that is considered to be an important part of soil carbon cycling. In this study we prepared a composite material (MGE) with iron oxide and lignin based on the Fe-OM present in the soil. MGE was then applied to remediate Cd and Pb in contaminated soil. The results show that DTPA-Cd and DTPA-Pb levels were reduced by 58.87% and 78.09%, respectively. The bacterial community diversity index decreased in the iron oxide (GE) group, but a slight increase was observed in the MGE group. In terms of species composition in the MGE group, the abundance of Proteobacteria, Gemmatimonadota and Acidobacteriota increased, while the abundance of Bacteroidota, Actinobacteriota and Firmicutes decreased. The outcome in the GE group was the opposite. In the MGE group, HCl-Fe, HCl-Fe, and pH were significantly higher than in the other groups, indicating that MGE stimulated the growth of iron-reducing bacteria (FeRB) and promoted iron redox reactions. Iron oxide could be reduced to Fe due to the activity of FeRB, and then Fe would be oxidised and hydrolysed, which led to an increase in soil pH. Secondary minerals were formed during this process. With the oxidation of Fe and the formation of secondary minerals, Cd and Pb could be stabilised in the oxides and were not easily released through a co-precipitation mechanism.
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http://dx.doi.org/10.1016/j.scitotenv.2021.149922DOI Listing
January 2022

Mitoquinone Protects Podocytes from Angiotensin II-Induced Mitochondrial Dysfunction and Injury via the Keap1-Nrf2 Signaling Pathway.

Oxid Med Cell Longev 2021 13;2021:1394486. Epub 2021 Aug 13.

Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, China.

Podocyte mitochondrial dysfunction plays a critical role in the pathogenesis of chronic kidney disease (CKD). Previous studies demonstrated that excessive mitochondrial fission could lead to the overproduction of reactive oxygen species (ROS) and promote podocyte apoptosis. Therefore, the maintenance of stable mitochondrial function is a newly identified way to protect podocytes and prevent the progression of CKD. As a mitochondria-targeted antioxidant, mitoquinone (MitoQ) has been proven to be a promising agent for the prevention of mitochondrial injury in cardiovascular disease and Parkinson's disease. The present study examined the effects of MitoQ on angiotensin II- (Ang II-) induced podocyte injury both and . Podocyte mitochondria in Ang II-infused mice exhibited morphological and functional alterations. The observed mitochondrial fragmentation and ROS production were alleviated with MitoQ treatment. , alterations in mitochondrial morphology and function in Ang II-stimulated podocytes, including mitochondrial membrane potential reduction, ROS overproduction, and adenosine triphosphate (ATP) deficiency, were significantly reversed by MitoQ. Moreover, MitoQ rescued the expression and translocation of Nrf2 (nuclear factor E2-related factor 2) and decreased the expression of Keap1 (Kelch-like ECH-associated protein 1) in Ang II-stimulated podocytes. Nrf2 knockdown partially blocked the protective effects of MitoQ on Ang II-induced mitochondrial fission and oxidative stress in podocytes. These results demonstrate that MitoQ exerts a protective effect in Ang II-induced mitochondrial injury in podocytes via the Keap1-Nrf2 signaling pathway.
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http://dx.doi.org/10.1155/2021/1394486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380182PMC
January 2022

Nanotechnology lights up the antitumor potency by combining chemotherapy with siRNA.

J Mater Chem B 2021 09 22;9(36):7302-7317. Epub 2021 Sep 22.

Institute of Food Safety and Environment Monitoring, College of Chemistry, Fuzhou University, Fuzhou, P. R. China.

Nanotechnology-based combination anticancer therapy offers novel approaches to overcome the limitations of single-agent administration. The emerging siRNA technology combined with chemotherapy has shown considerable promise in anticancer therapy. There are three main challenges in the fabrication of siRNA/chemotherapeutic drug co-loaded nanovectors: adequate cargo protection, precise targeted delivery, and site-specific cargo release. This review presents a summary of the nanosystems that have recently been developed for co-delivering siRNA and chemotherapeutic drugs. Their combined therapeutic effects are also discussed.
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http://dx.doi.org/10.1039/d1tb01379cDOI Listing
September 2021

Multistage Cooperative Nanodrug Combined with PD-L1 for Enhancing Antitumor Chemoimmunotherapy.

Adv Healthc Mater 2021 11 12;10(21):e2101199. Epub 2021 Aug 12.

MOE Key Laboratory for Analytical Science of Food Safety and Biology, Fuzhou University, Fuzhou, Fujian, 350116, P. R. China.

Combinatorial CpG oligonucleotide (CPG) and chemotherapy drug represent a promising approach to reactivate immune system. However, these two agents possess different physicochemical properties, hindering the application of direct self-assembly of these two cargos into a single nanostructure. Here, a multistage cooperative nanodrug is developed by the direct self-assembly of cis-platinum (CDDP, Pt), l-arginine (l-Arg, R), and CPG (defined as PtR/CPG) for antitumor chemoimmunotherapy. First, the CDDP can induce cell apoptosis. Meanwhile, CDDP also promotes the production of H O , catalyzing the conversion of l-Arg into nitric oxide (NO). The generated NO decreases the multidrug resistance of cells toward CDDP. Thus, the synergistic effects of CDDP and NO can trigger immunogenic cell death to produce tumor-associated antigens (TAAs). The TAAs and CPG will induce the maturation of dendritic cells (DCs) and enhance antigen presentation ability of DCs. In this way, the PtR/CPG can reverse the immunosuppressive microenvironment, sensitizing tumors to immune checkpoint inhibitors mediated by the programmed death-ligand 1 (PD-L1) antibody. Furthermore, the PtR/CPG combined with the PD-L1 antibody decreases the exhaustion and dysfunction of cytotoxic T lymphocytes to elicit durable systemic immune response. As a result, the prepared PtR/CPG nanodrug in combination with PD-L1 may be highly significant for cancer immunotherapy.
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http://dx.doi.org/10.1002/adhm.202101199DOI Listing
November 2021

An Amphiphilic Carbonaceous/Nanosilver Composite-Incorporated Urinary Catheter for Long-Term Combating Bacteria and Biofilms.

ACS Appl Mater Interfaces 2021 Aug 6;13(32):38029-38039. Epub 2021 Aug 6.

College of Pharmacy, Institutes of Environment and Medicine, Henan University, Kaifeng 475004, China.

Biofilms formed on urinary catheters remain a major headache in the modern healthcare system. Among the various kinds of biocide-releasing urinary catheters that have been developed to prevent biofilm formation, Ag nanoparticles (AgNPs)-coated catheters are of great promising potential. However, the deposition of AgNPs on the surface of catheters suffers from several inherent shortcomings, such as damage to the urethral mucosa, uncontrollable Ag ion kinetics, and unexpected systematic toxicity. Here, AgNPs-decorated amphiphilic carbonaceous particles ([email protected]) with commendable dispersity in solvents of different polarities and broad-spectrum antibacterial activity are first prepared. The resulting [email protected] exert good compatibility with silicone rubber, which enables the easy fabrication of urinary catheters using a laboratory-made mold. Therefore, [email protected] not only endow the urinary catheter with forceful biocidal activity but also improve its mechanical properties and surface wettability. Hence, the designed urinary catheter possesses excellent capacity to resist bacterial adhesion and biofilm formation both and in an rabbit model. Specifically, a long-term antibacterial study highlights its sustainable antibacterial activity. Of note, no obvious toxicity or inflammation in rabbits was triggered by the designed urinary catheter . Overall, the hybrid urinary catheter may serve as a promising biocide-releasing urinary catheter for antibacterial and antibiofilm applications.
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http://dx.doi.org/10.1021/acsami.1c07399DOI Listing
August 2021

Compressive Buckling Fabrication of 3D Cell-Laden Microstructures.

Adv Sci (Weinh) 2021 09 15;8(17):e2101027. Epub 2021 Jul 15.

Department of Biomedical Engineering, State University of New York at Buffalo, Buffalo, NY, 14260, USA.

Tissue architecture is a prerequisite for its biological functions. Recapitulating the three-dimensional (3D) tissue structure represents one of the biggest challenges in tissue engineering. Two-dimensional (2D) tissue fabrication methods are currently in the main stage for tissue engineering and disease modeling. However, due to their planar nature, the created models only represent very limited out-of-plane tissue structure. Here compressive buckling principle is harnessed to create 3D biomimetic cell-laden microstructures from microfabricated planar patterns. This method allows out-of-plane delivery of cells and extracellular matrix patterns with high spatial precision. As a proof of principle, a variety of polymeric 3D miniature structures including a box, an octopus, a pyramid, and continuous waves are fabricated. A mineralized bone tissue model with spatially distributed cell-laden lacunae structures is fabricated to demonstrate the fabrication power of the method. It is expected that this novel approach will help to significantly expand the utility of the established 2D fabrication techniques for 3D tissue fabrication. Given the widespread of 2D fabrication methods in biomedical research and the high demand for biomimetic 3D structures, this method is expected to bridge the gap between 2D and 3D tissue fabrication and open up new possibilities in tissue engineering and regenerative medicine.
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http://dx.doi.org/10.1002/advs.202101027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425919PMC
September 2021

pH and Reduction Dual-Responsive Bi-Drugs Conjugated Dextran Assemblies for Combination Chemotherapy and In Vitro Evaluation.

Polymers (Basel) 2021 May 8;13(9). Epub 2021 May 8.

Shandong Provincial Key Laboratory of Molecular Engineering, School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Science), Jinan 250353, China.

Polymeric prodrugs, synthesized by conjugating chemotherapeutic agents to functional polymers, have been extensively investigated and employed for safer and more efficacious cancer therapy. By rational design, a pH and reduction dual-sensitive dextran-di-drugs conjugate (oDex-g-Pt+DOX) was synthesized by the covalent conjugation of Pt (IV) prodrug and doxorubicin (DOX) to an oxidized dextran (oDex). Pt (IV) prodrug and DOX were linked by the versatile efficient esterification reactions and Schiff base reaction, respectively. oDex-g-Pt+DOX could self-assemble into nanoparticles with an average diameter at around 180 nm. The acidic and reductive (GSH) environment induced degradation and drug release behavior of the resulting nanoparticles (oDex-g-Pt+DOX NPs) were systematically investigated by optical experiment, DLS analysis, TEM measurement, and in vitro drugs release experiment. Effective cellular uptake of the oDex-g-Pt+DOX NPs was identified by the human cervical carcinoma HeLa cells via confocal laser scanning microscopy. Furthermore, oDex-g-Pt+DOX NPs displayed a comparable antiproliferative activity than the simple combination of free cisplatin and DOX (Cis+DOX) as the extension of time. More importantly, oDex-g-Pt+DOX NPs exhibited remarkable reversal ability of tumor resistance compared to the cisplatin in cisplatin-resistant lung carcinoma A549 cells. Take advantage of the acidic and reductive microenvironment of tumors, this smart polymer-dual-drugs conjugate could serve as a promising and effective nanomedicine for combination chemotherapy.
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http://dx.doi.org/10.3390/polym13091515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125917PMC
May 2021

Adipocyte-Derived Anticancer Lipid Droplets.

Adv Mater 2021 Jul 13;33(26):e2100629. Epub 2021 May 13.

Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA.

Engineering of efficient and safe materials remains a challenge for cancer therapy. Here, the lipid droplet, an organelle in adipocytes, is demonstrated to be a controllable and biocompatible vehicle to deliver anticancer drugs. It is validated that isolated lipid droplets maintain their key physiological functions to interact with other organelles and augment the therapeutic effect of cancer photodynamic therapy by encapsulation with a lipid-conjugated photosensitizer (Pyrolipid) through a variety of pathways, including generation of reactive oxygen species (ROS); lipid peroxidation; and endoplasmic reticulum (ER) stress. As such, the IC value of Pyrolipid is reduced by 6.0-fold when loaded into the lipid droplet. Of note, in vivo results demonstrate that engineered lipid droplets induce significant inhibition of tumor growth with minimal side effects.
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http://dx.doi.org/10.1002/adma.202100629DOI Listing
July 2021

Disrupting tumour vasculature and recruitment of aPDL1-loaded platelets control tumour metastasis.

Nat Commun 2021 05 13;12(1):2773. Epub 2021 May 13.

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.

Although therapies of cancer are advancing, it remains challenging for therapeutics to reach the sites of metastasis, which accounts for majority of cancer associated death. In this study, we have developed a strategy that guides an anti-programmed cell death-ligand 1 (aPDL1) antibody to accumulate in metastatic lesions to promote anti-tumour immune responses. Briefly, we have developed a combination in which Vadimezan disrupts tumour blood vessels of tumour metastases and facilitates the recruitment and activation of adoptively transferred aPDL1-conjugated platelets. In situ activated platelets generate aPDL1-decorated platelet-derived microparticles (PMP) that diffuse within the tumour and elicit immune responses. The proposed combination increases 10-fold aPDL1 antibody accumulation in lung metastases as compared to the intravenous administration of the antibody and enhances the magnitude of immune responses leading to improved antitumour effects.
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http://dx.doi.org/10.1038/s41467-021-22674-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119987PMC
May 2021

Bioorthogonal catalytic patch.

Nat Nanotechnol 2021 08 10;16(8):933-941. Epub 2021 May 10.

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China.

Bioorthogonal catalysis mediated by transition metals has inspired a new subfield of artificial chemistry complementary to enzymatic reactions, enabling the selective labelling of biomolecules or in situ synthesis of bioactive agents via non-natural processes. However, the effective deployment of bioorthogonal catalysis in vivo remains challenging, mired by the safety concerns of metal toxicity or complicated procedures to administer catalysts. Here, we describe a bioorthogonal catalytic device comprising a microneedle array patch integrated with Pd nanoparticles deposited on TiO nanosheets. This device is robust and removable, and can mediate the local conversion of caged substrates into their active states in high-level living systems. In particular, we show that such a patch can promote the activation of a prodrug at subcutaneous tumour sites, restoring its parent drug's therapeutic anticancer properties. This in situ applied device potentiates local treatment efficacy and eliminates off-target prodrug activation and dose-dependent side effects in healthy organs or distant tissues.
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http://dx.doi.org/10.1038/s41565-021-00910-7DOI Listing
August 2021

Gaseous Plastron on Natural and Biomimetic Surfaces for Resisting Marine Biofouling.

Molecules 2021 Apr 29;26(9). Epub 2021 Apr 29.

Institute of Food Safety and Environment Monitoring, College of Chemistry, Fuzhou University, Fuzhou 350108, China.

In recent years, various biomimetic materials capable of forming gaseous plastron on their surfaces have been fabricated and widely used in various disciplines and fields. In particular, on submerged surfaces, gaseous plastron has been widely studied for antifouling applications due to its ecological and economic advantages. Gaseous plastron can be formed on the surfaces of various natural living things, including plants, insects, and animals. Gaseous plastron has shown inherent anti-biofouling properties, which has inspired the development of novel theories and strategies toward resisting biofouling formation on different surfaces. In this review, we focused on the research progress of gaseous plastron and its antifouling applications.
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http://dx.doi.org/10.3390/molecules26092592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125344PMC
April 2021

Cytosolic Delivery of Thiolated Mn-cGAMP Nanovaccine to Enhance the Antitumor Immune Responses.

Small 2021 04 14;17(17):e2006970. Epub 2021 Mar 14.

MOE Key Laboratory for Analytical Science of Food Safety and Biology, State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, 350116, P. R. China.

As a stimulator of interferon gene (STING), cyclic dinucleotide activates a broad cellular immune response for anti-cancer immunotherapy (CIT). However, the inherent of instability of 2' 3'-cyclic-GMP-AMP (cGAMP) with poor cellular targeting, rapid clearance, and inefficient transport to the cytoplasm seriously hinders cGAMP potency. Here, a thiolated and Mn coordinated cyclic dinucleotide nanovaccine (termed as Mn-cGAMP NVs) to enable direct cytosolic co-delivery of cGAMP and Mn to potentiate the antitumor immune response is presented. In the NVs, the fixation cGAMP with Mn ions not only improve its stability, but also potentiate the activation of STING. Meanwhile, the presence of polysulfides on the NVs surface allowed direct cytosolic delivery while avoiding degradation. In this way, the production of cytokines for activating T cells immunity is greatly elevated, which in turn suppressed the primary and distal tumors growth through long-term immune memory and led to long-term survival of poorly immunogenic B16F10 melanoma mice. Moreover, by further combining with anti-PD-L1 monoclonal antibody, synergistic T cells antitumor immune response is elicited. This work offers a promising strategy to enhance the potency of cGAMP, holding a considerable potential for CIT applications.
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http://dx.doi.org/10.1002/smll.202006970DOI Listing
April 2021

Loss of sarcomeric proteins via upregulation of JAK/STAT signaling underlies interferon-γ-induced contractile deficit in engineered human myocardium.

Acta Biomater 2021 05 8;126:144-153. Epub 2021 Mar 8.

Department of Biomedical Engineering, Duke University, 101 Science Drive, Durham, NC 27708, USA. Electronic address:

The level of circulating interferon-γ (IFNγ) is elevated in various clinical conditions including autoimmune and inflammatory diseases, sepsis, acute coronary syndrome, and viral infections. As these conditions are associated with high risk of myocardial dysfunction, we investigated the effects of IFNγ on 3D fibrin-based engineered human cardiac tissues ("cardiobundles"). Cardiobundles were fabricated from human pluripotent stem cell-derived cardiomyocytes, exposed to 0-20 ng/ml of IFNγ on culture days 7-14, and assessed for changes in tissue structure, viability, contractile force and calcium transient generation, action potential propagation, cytokine secretion, and expression of select genes and proteins. We found that application of IFNγ induced a dose-dependent reduction in contractile force generation, deterioration of sarcomeric organization, and cardiomyocyte disarray, without significantly altering cell viability, action potential propagation, or calcium transient amplitude. At molecular level, the IFNγ-induced structural and functional deficits could be attributed to altered balance of pro- and anti-inflammatory cytokines, upregulation of JAK/STAT signaling pathway (JAK1, JAK2, and STAT1), and reduced expression of myosin heavy chain, myosin light chain-2v, and sarcomeric α-actinin. Application of clinically used JAK/STAT inhibitors, tofacitinib and baricitinib, fully prevented IFNγ-induced cardiomyopathy, confirming the critical roles of this signaling pathway in inflammatory cardiac disease. Taken together, our in vitro studies in engineered myocardial tissues reveal direct adverse effects of pro-inflammatory cytokine IFNγ on human cardiomyocytes and establish the foundation for a potential use of cardiobundle platform in modeling of inflammatory myocardial disease and therapy. STATEMENT OF SIGNIFICANCE: Various inflammatory and autoimmune diseases including rheumatoid arthritis, sepsis, lupus erythematosus, Chagas disease, and others, as well as viral infections including H1N1 influenza and COVID-19 show increased systemic levels of a pro-inflammatory cytokine interferon-γ (IFNγ) and are associated with high risk of heart disease. Here we explored for the first time if chronically elevated levels of IFNγ can negatively affect structure and function of engineered human heart tissues in vitro. Our studies revealed IFNγ-induced deterioration of myofibrillar organization and contractile force production in human cardiomyocytes, attributed to decreased expression of multiple sarcomeric proteins and upregulation of JAK/STAT signaling pathway. FDA-approved JAK inhibitors fully blocked the adverse effects of IFNγ, suggesting a potentially effective strategy against human inflammatory cardiomyopathy.
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http://dx.doi.org/10.1016/j.actbio.2021.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096718PMC
May 2021

Wireless Optogenetic Modulation of Cortical Neurons Enabled by Radioluminescent Nanoparticles.

ACS Nano 2021 03 24;15(3):5201-5208. Epub 2021 Feb 24.

Center for Nanoscale Materials, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, United States.

While offering high-precision control of neural circuits, optogenetics is hampered by the necessity to implant fiber-optic waveguides in order to deliver photons to genetically engineered light-gated neurons in the brain. Unlike laser light, X-rays freely pass biological barriers. Here we show that radioluminescent Gd(WO):Eu nanoparticles, which absorb external X-rays energy and then downconvert it into optical photons with wavelengths of ∼610 nm, can be used for the transcranial stimulation of cortical neurons expressing red-shifted, ∼590-630 nm, channelrhodopsin ReaChR, thereby promoting optogenetic neural control to the practical implementation of minimally invasive wireless deep brain stimulation.
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http://dx.doi.org/10.1021/acsnano.0c10436DOI Listing
March 2021

Fast Stereolithography Printing of Large-Scale Biocompatible Hydrogel Models.

Adv Healthc Mater 2021 05 15;10(10):e2002103. Epub 2021 Feb 15.

Department of Biomedical Engineering, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA.

Large size cell-laden hydrogel models hold great promise for tissue repair and organ transplantation, but their fabrication using 3D bioprinting is limited by the slow printing speed that can affect the part quality and the biological activity of the encapsulated cells. Here a fast hydrogel stereolithography printing (FLOAT) method is presented that allows the creation of a centimeter-sized, multiscale solid hydrogel model within minutes. Through precisely controlling the photopolymerization condition, low suction force-driven, high-velocity flow of the hydrogel prepolymer is established that supports the continuous replenishment of the prepolymer solution below the curing part and the nonstop part growth. The rapid printing of centimeter-sized hydrogel models using FLOAT is shown to significantly reduce the part deformation and cellular injury caused by the prolonged exposure to the environmental stresses in conventional 3D printing methods. Embedded vessel networks fabricated through multiscale printing allows media perfusion needed to maintain the high cellular viability and metabolic functions in the deep core of the large-sized models. The endothelialization of this vessel network allows the establishment of barrier functions. Together, these studies demonstrate a rapid 3D hydrogel printing method and represent a first step toward the fabrication of large-sized engineered tissue models.
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http://dx.doi.org/10.1002/adhm.202002103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212355PMC
May 2021

Topographical nanostructures for physical sterilization.

Drug Deliv Transl Res 2021 08 4;11(4):1376-1389. Epub 2021 Feb 4.

College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, People's Republic of China.

The development in nanobiotechnology provides an in-depth understanding of cell-surface interactions at the nanoscale level. Particularly, several surface features have shown the ability to interrogate the bacterial behavior and fate. In the past decade, the mechanical and physical sterilization has attracted considerable attention, as paradigms of such do not rely on chemical substances to damage or kill bacteria, whereas it is associated with natural living organisms or synthetic materials. Of note, such antibacterial scenario does not cause bacterial resistance, as the morphology of nanometer can directly cause bacterial death through physical and mechanical interactions. In this review, we provide an overview of recently developed technologies of leveraging topographical nanofeatures for physical sterilization. We mainly discuss the development of various morphologic nanostructures, and colloidal nanostructures show casing the capacity of "mechanical sterilization." Mechanically sterilized nanostructures can penetrate or cut through bacterial membranes. In addition, surface morphology, such as mechanical bactericidal nanoparticles and nanoneedles, can cause damage to the membrane of microorganisms, leading to cell lysis and death. Although the research in the field of mechanical sterilization is still in infancy, the effect of these nanostructure morphologies on sterilization has shown remarkable antibacterial potential, which could provide a new toolkit for anti-infection and antifouling applications. The mechanical and physical sterilization has attracted considerable attention, as paradigms of such do not rely on chemical substances to damage or kill bacteria. Moreover, such antibacterial scenario does not cause bacterial resistance, as the morphology of nanometer can directly cause bacterial death through physical and mechanical interactions. In this review, we focus on the advanced development of various morphologic nanostructures and colloidal nanostructures that show the capacity of "mechanical sterilization."
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http://dx.doi.org/10.1007/s13346-021-00906-9DOI Listing
August 2021

Exercise mimetics and JAK inhibition attenuate IFN-γ-induced wasting in engineered human skeletal muscle.

Sci Adv 2021 01 22;7(4). Epub 2021 Jan 22.

Department of Biomedical Engineering, Duke University, Durham, NC, USA.

Chronic inflammatory diseases often lead to muscle wasting and contractile deficit. While exercise can have anti-inflammatory effects, the underlying mechanisms remain unclear. Here, we used an in vitro tissue-engineered model of human skeletal muscle ("myobundle") to study effects of exercise-mimetic electrical stimulation (E-stim) on interferon-γ (IFN-γ)-induced muscle weakness. Chronic IFN-γ treatment of myobundles derived from multiple donors induced myofiber atrophy and contractile loss. E-stim altered the myobundle secretome, induced myofiber hypertrophy, and attenuated the IFN-γ-induced myobundle wasting and weakness, in part by down-regulating JAK (Janus kinase)/STAT1 (signal transducer and activator of transcription 1) signaling pathway amplified by IFN-γ. JAK/STAT inhibitors fully prevented IFN-γ-induced myopathy, confirming the critical roles of STAT1 activation in proinflammatory action of IFN-γ. Our results reveal a previously unknown mechanism of the cell-autonomous anti-inflammatory effects of muscle exercise and establish the utility of human myobundle platform for studies of inflammatory muscle disease and therapy.
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http://dx.doi.org/10.1126/sciadv.abd9502DOI Listing
January 2021
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