Publications by authors named "Guojun Chen"

157 Publications

Salicylic acid-based nanomedicine with self-immunomodulatory activity facilitates microRNA therapy for metabolic skeletal disorders.

Acta Biomater 2021 Jun 3. Epub 2021 Jun 3.

National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Department of Oral Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China. Electronic address:

Metabolic skeletal disorders remain a major clinical challenge. The complexity of this disease requires a strategy to address the net effects of both inflammation and impaired bone formation. microRNA-based gene therapy provides several therapeutic advantages to tackle these issues. Herein, we describe a microRNA-21 (miR-21) delivery system with an additional therapeutic effect from that of the delivery carrier itself. Poly (salicylic acid) (PSA) is, for the first time, synthesized via polycondensation of salicylic acid (SA), a bioactive ingredient widely used for anti-inflammation in medicine. PSA can self-assemble into nanoparticles (PSA-NPs) and can effectively deliver genes both in vitro and in vivo. The carrier was then attached to repetitive sequences of aspartate, serine, serine (DSS) for delivering miRNAs specifically to bone-formation surfaces. In vitro studies showed that [email protected] could effectively realize the intracellular delivery of miR-21 with low toxicity, while in vivo results indicated that the [email protected] prolonged blood circulation time, enhanced bone accumulation, and significantly improved the efficacy of miR-21-based bone anabolic therapy in osteoporotic mice. The constructed delivery system ([email protected]) inherited the advantages of both SA and miR-21, which could ameliorate bone-inflamed niche and rescued the impaired bone formation ability. The synergy of anti-inflammatory and pro-osteogenic effects significantly improved trabecular bone microstructure in osteoporotic mice. STATEMENT OF SIGNIFICANCE: The complexity of metabolic skeletal disorders requires a strategy to address the net effects of both inflammation and impaired bone formation. microRNA-based gene therapy provides several therapeutic advantages to tackle these issues. We develop a novel microRNA-21 delivery system with additional therapeutic effect from that of the gene carrier itself. Poly (salicylic acid) (PSA) nanoparticles, for the first time, synthesized via polycondensation of salicylic acid and can effectively deliver genes both in vitro and in vivo. The constructed delivery system ([email protected]) inherited the advantages of both SA (commonly used anti-inflammation drug in medicine) and miR-21 (a pro-osteogenic molecule), which could ameliorate bone-inflamed niche, rescued impaired bone formation ability and significantly improved trabecular bone microstructure in osteoporotic mice.
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http://dx.doi.org/10.1016/j.actbio.2021.05.024DOI Listing
June 2021

Adipocyte-Derived Anticancer Lipid Droplets.

Adv Mater 2021 May 13: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
May 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 May 10. 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
May 2021

Inhibition of SENP2-mediated Akt deSUMOylation promotes cardiac regeneration via activating Akt pathway.

Clin Sci (Lond) 2021 Mar;135(6):811-828

Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

Post-translational modification (PTM) by small ubiquitin-like modifier (SUMO) is a key regulator of cell proliferation and can be readily reversed by a family of SUMO-specific proteases (SENPs), making SUMOylation an ideal regulatory mechanism for developing novel therapeutic strategies for promoting a cardiac regenerative response. However, the role of SUMOylation in cardiac regeneration remains unknown. In the present study, we assessed whether targeting protein kinase B (Akt) SUMOylation can promote cardiac regeneration. Quantitative PCR and Western blotting results showed that small ubiquitin-like modifier-specific protease 2 (SENP2) is up-regulated during postnatal heart development. SENP2 deficiency promoted P7 and adult cardiomyocyte (CM) dedifferentiation and proliferation both in vitro and in vivo. Mice with SENP2 deficiency exhibited improved cardiac function after MI due to CM proliferation and angiogenesis. Mechanistically, the loss of SENP2 up-regulated Akt SUMOylation levels and increased Akt kinase activity, leading to a decrease in GSK3β levels and subsequently promoting CM proliferation and angiogenesis. In summary, inhibition of SENP2-mediated Akt deSUMOylation promotes CM differentiation and proliferation by activating the Akt pathway. Our results provide new insights into the role of SUMOylation in cardiac regeneration.
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http://dx.doi.org/10.1042/CS20201408DOI Listing
March 2021

Injectable Biodegradable Polymeric Complex for Glucose-Responsive Insulin Delivery.

ACS Nano 2021 03 8;15(3):4294-4304. Epub 2021 Mar 8.

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

Insulin therapy is the central component of treatment for type 1 and advanced type 2 diabetes; however, its narrow therapeutic window is associated with a risk of severe hypoglycemia. A glucose-responsive carrier that demonstrates consistent and slow basal insulin release under a normoglycemic condition and accelerated insulin release in response to hyperglycemia in real-time could offer effective blood glucose regulation with reduced risk of hypoglycemia. Here, we describe a poly(l-lysine)-derived biodegradable glucose-responsive cationic polymer for constructing polymer-insulin complexes for glucose-stimulated insulin delivery. The effects of the modification degree of arylboronic acid in the synthesized cationic polymer and polymer-to-insulin ratio on the glucose-dependent equilibrated free insulin level and the associated insulin release kinetics have been studied. In addition, the blood glucose regulation ability of these complexes and the associated glucose challenge-triggered insulin release are evaluated in type 1 diabetic mice.
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http://dx.doi.org/10.1021/acsnano.0c07291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210813PMC
March 2021

The Effect of Lecithins Coupled Decorin Nanoliposomes on Treatment of Carbon Tetrachloride-Induced Liver Fibrosis.

Biomed Res Int 2020 13;2020:8815904. Epub 2020 Dec 13.

Department of Surgery, Zhejiang University Hospital, Zhejiang University, Hangzhou, Zhejiang 310027, China.

This study aimed to investigate the effect of bile duct-targeting lecithins- (PC-) coupled decorin (DCN) (PC-DCN) nanoliposomes against liver fibrosis in vitro and in vivo. We prepared PC-DCN nanoliposomes by using rat astrocytes, HSC-T6, to verify the antifibrosis effect of PC-DCN in vitro. First, we established a rat model of carbon tetrachloride-induced fibrosis. PC-DCN nanoliposomes were then injected into fibrotic rats via the portal vein or bile duct. The EdU assay was performed to analyze cell proliferation. Immunofluorescence staining was used to detect -smooth muscle actin (-SMA) expression. Western blot was performed to examine the expression of -SMA, collagen type I alpha 1 (COL1A1), and transforming growth factor- (TGF-) protein. The levels of aspartate transaminase (AST), alanine transaminase (ALT), and total bilirubin (TBIL) were examined by enzyme-linked immunosorbent assay (ELISA) analysis. Hematoxylin and eosin (H&E) staining and Masson trichrome staining were used to determine liver tissue lesions and liver fibrosis. Compared with TGF- group, PC-DCN treatment could significantly reduce cell proliferation. Western blot analysis indicated that the expression of -SMA, COL1A1, and TGF- was downregulated after treatment with PC-DCN in vitro and in vivo. Immunofluorescence staining confirmed that -SMA expression was reduced by PC-DCN. Furthermore, H&E staining and Masson trichrome staining showed that the administration of PC-DCN nanoliposomes via the bile duct could reduce the extent of liver fibrosis. PCR analysis showed that PC-DCN administration could reduce proinflammatory cytokines IL-6, TNF-, and IL-1 expression via the bile duct. The administration of PC-DCN nanoliposomes also significantly downregulated liver function indicators ALT, AST, and TBIL. The results of our study indicated that PC-DCN could effectively reduce the extent of liver fibrosis.
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http://dx.doi.org/10.1155/2020/8815904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752282PMC
December 2020

Cryo-shocked cancer cells for targeted drug delivery and vaccination.

Sci Adv 2020 Dec 9;6(50). Epub 2020 Dec 9.

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

Live cells have been vastly engineered into drug delivery vehicles to leverage their targeting capability and cargo release behavior. Here, we describe a simple method to obtain therapeutics-containing "dead cells" by shocking live cancer cells in liquid nitrogen to eliminate pathogenicity while preserving their major structure and chemotaxis toward the lesion site. In an acute myeloid leukemia (AML) mouse model, we demonstrated that the liquid nitrogen-treated AML cells (LNT cells) can augment targeted delivery of doxorubicin (DOX) toward the bone marrow. Moreover, LNT cells serve as a cancer vaccine and promote antitumor immune responses that prolong the survival of tumor-bearing mice. Preimmunization with LNT cells along with an adjuvant also protected healthy mice from AML cell challenge.
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http://dx.doi.org/10.1126/sciadv.abc3013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725453PMC
December 2020

Dual self-regulated delivery of insulin and glucagon by a hybrid patch.

Proc Natl Acad Sci U S A 2020 11 11;117(47):29512-29517. Epub 2020 Nov 11.

Department of Bioengineering, University of California, Los Angeles, CA 90095;

Reduced β-cell function and insulin deficiency are hallmarks of diabetes mellitus, which is often accompanied by the malfunction of glucagon-secreting α-cells. While insulin therapy has been developed to treat insulin deficiency, the on-demand supplementation of glucagon for acute hypoglycemia treatment remains inadequate. Here, we describe a transdermal patch that mimics the inherent counterregulatory effects of β-cells and α-cells for blood glucose management by dynamically releasing insulin or glucagon. The two modules share a copolymerized matrix but comprise different ratios of the key monomers to be "dually responsive" to both hyper- and hypoglycemic conditions. In a type 1 diabetic mouse model, the hybrid patch effectively controls hyperglycemia while minimizing the occurrence of hypoglycemia in the setting of insulin therapy with simulated delayed meal or insulin overdose.
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http://dx.doi.org/10.1073/pnas.2011099117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703584PMC
November 2020

A Systematic Review and Meta- Analysis of Green-Light Laser Vaporization for Superficial Bladder.

Urol J 2020 Sep 30;17(6):578-586. Epub 2020 Sep 30.

Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin 13125, Germany.

Purpose: The related research of green-light laser vaporization in the treatment of non-muscle invasive bladder cancer (NMIBC) is limited. This study focused on analyzing the effectiveness and safety of it from the perspective of an extensive literature review.

Methods: A comprehensive search of CNKI, WanFang, VIP, PubMed, Embase, and CENTRAL databases for photoselective vaporization of bladder tumor and transurethral resection of bladder tumor treatment of non-muscle invasive bladder cancer (NMIBC). The search included studies from January 1996 to December 2019. Two reviewers independently screened literature, extracted data, assessed the risk of bias of included studies. RevMan 5.3 software was used for Meta-analysis.

Results: A total of 18 RCTs involving 1648 patients met the predefined criteria. Meta-analysis data demonstrated that the PVBT group exhibited a significant advantage over the TURBT group in intraoperative obturator nerve reflex (RR = 0.09, 95% CI [0.04, 0.18], P< 0.001)and bladder perforation (RR = 0.14, 95% CI [0.07, 0.28], P< 0.001) and postoperative 1-year recurrence (RR = 0.52, 95% CI [0.40, 0.67], P< 0.001). The PVBT procedure has advantages over TURBT in the amount of surgical bleeding (MD = -17.27, 95% CI [-24.73, -9.81], P< 0.001) and the length of hospital stay (MD = -2.80, 95% CI [-3.82, -1.87], P< 0.001), bladder irrigation time (MD = -0.95, 95% CI [-1.49, -0.42], P< 0.001), and catheter indwelling time (MD = -2.60, 95% CI [-3.30, -1.90], P< 0.001). There was no difference between the two types of surgery in the incidence of postoperative urethral stricture (RR = 0.53, 95% CI [0.15, 1.83], P = 0.32) and the length of surgery (MD = -2.46, 95% CI [-5.37, 0.46], P = 0.10).

Conclusion: Our systematic review and meta-analysis suggests that PVBT is better than TURBT as an alternative treatment for patients with NMIBC in safe aspect. However, whether it is equally effective in terms of oncological control remains to be elucidated, and additional high quality RCTs are needed to confirm our findings.
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http://dx.doi.org/10.22037/uj.v16i7.5854DOI Listing
September 2020

[The triglyceride-lowering effects of PCSK9 inhibitor differ in patients with different baseline triglyceride levels].

Nan Fang Yi Ke Da Xue Xue Bao 2020 Aug;40(8):1141-1147

Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

Objective: To investigate the triglyceride (TG)-lowering effects of PCSK9 inhibitor in patients with in different baseline triglyceride levels.

Methods: Between February, 2019 and March, 2020, a total of 59 patients were treated with PCSK9 inhibitor (Evolocumab) in 5 hospitals, including Nanfang Hospital, Guangdong Provincial People's Hospital, First Affiliated Hospital of Sun Yat-sen University, Foshan Nanhai District People's Hospital and Yulin First People's Hospital. According to baseline triglyceride levels, the patients were divided into normal TG group (< 1.70 mmol/L, =24), mild hypertriglyceridemia group (1.70-2.29 mmol/L, =11), moderate hypertriglyceridemia group (2.30-5.63 mmol/L, =13), and severe hypertriglyceridemia group (≥5.64 mmol/L, =11), and the changes in TG level after the treatment were compared among the 4 groups.

Results: In the groups with normal and mildly elevated baseline TG level, the patients did not show significant changes in TG levels after the treatment. In patients with moderately and severely elevated baseline TG levels, treatment with PCSK9 inhibitor significantly reduced their TG levels ( < 0.005).

Conclusions: PCSK9 inhibitor has a significant TG-lowering effect in patients with moderate to severe hypertriglyceridemia but not in patients with only mildly elevated baseline TG level.
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http://dx.doi.org/10.12122/j.issn.1673-4254.2020.08.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429163PMC
August 2020

METTL3 Induces AAA Development and Progression by Modulating N6-Methyladenosine-Dependent Primary miR34a Processing.

Mol Ther Nucleic Acids 2020 Sep 10;21:394-411. Epub 2020 Jun 10.

Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address:

Identifying effective drugs to delay the progression of aortic aneurysms is a formidable challenge in vascular medicine. Methyltransferase-like 3 (METTL3) plays a key role in catalyzing the formation of N6-methyladenosine (mA), but despite the functional importance of METTL3 and mA in various fundamental biological processes, their roles in abdominal aortic aneurysm (AAA) are unknown. Here, we found that METTL3 knockdown in apolipoprotein E-deficient (ApoE) mice treated with angiotensin II suppressed the formation of AAAs, while METTL3 overexpression exerted the opposite effects. Similar results were obtained in a calcium chloride (CaCl)-induced mouse AAA model. Mechanistically, METTL3-dependent mA methylation promoted primary microRNA-34a (miR-34a, pri-miR34a) maturation through DGCR8. Moreover, miR-34a overexpression significantly decreased SIRT1 expression and aggravated AAA formation, while miR-34a deficiency produced the opposite effects. In a rescue experiment, miR-34a knockdown or forced expression of SIRT1 partially attenuated the protective effects of METTL3 deficiency against AAA formation. Our studies reveal an important role for METTL3/mA-mediated miR-34a maturation in AAA formation and provide a novel therapeutic target and diagnostic biomarker for AAA treatment.
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http://dx.doi.org/10.1016/j.omtn.2020.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347714PMC
September 2020

Advances in Antimicrobial Microneedle Patches for Combating Infections.

Adv Mater 2020 Aug 29;32(33):e2002129. Epub 2020 Jun 29.

Institute for Polymers, Composites, and Biomaterials (IPCB), National Research Council (CNR), Naples, 80125, Italy.

Skin infections caused by bacteria, viruses and fungi are difficult to treat by conventional topical administration because of poor drug penetration across the stratum corneum. This results in low bioavailability of drugs to the infection site, as well as the lack of prolonged release. Emerging antimicrobial transdermal and ocular microneedle patches have become promising medical devices for the delivery of various antibacterial, antifungal, and antiviral therapeutics. In the present review, skin anatomy and its barriers along with skin infection are discussed. Potential strategies for designing antimicrobial microneedles and their targeted therapy are outlined. Finally, biosensing microneedle patches associated with personalized drug therapy and selective toxicity toward specific microbial species are discussed.
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http://dx.doi.org/10.1002/adma.202002129DOI Listing
August 2020

Efficacy and safety outcomes in novel oral anticoagulants versus vitamin-K antagonist on post-TAVI patients: a meta-analysis.

BMC Cardiovasc Disord 2020 06 26;20(1):307. Epub 2020 Jun 26.

Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Background: Transcatheter aortic valve implantation (TAVI) has been a favored option for the patient who suffered from symptomatic aortic stenosis. However, the efficacy and safety outcomes in novel oral anticoagulants (NOACs) versus Vitamin-K antagonist (VKA) for post-TAVI patients are still controversial. This meta-analysis aims at comparing the clinical outcome and safety of NOACs and VKA in the patients after receiving TAVI.

Method: We searched literature articles in all reachable databases, and observational study as well as randomized controlled trial would be included in order to perform a comprehensive analysis. All-cause mortality, major or life-threatening bleeding, disabling or nondisabling stroke were main pooled outcome measures. Subgroup analysis and meta-regression were adopted to explore heterogeneity. Assessment of bias was performed under the suggestion of Cochrane's Collaboration Tool.

Results: We collected 3841 non-duplicate citations from PubMed, Embase, Cochrane and ClinicalTrials.gov, and eventually 7 studies were included for this meta-analysis. As a result, VKA showed priority against NOACs in the field of anti-thromboembolism (4435 participants, RR:1.44, 95% CI: 1.05 to 1.99, I = 0%, P = 0.02).

Conclusion: With corroborative analysis of severe complications, VKA is shown to be more protective on post-TAVI patients in disabling or nondisabling stroke scenario but not in mortality or bleeding event.
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http://dx.doi.org/10.1186/s12872-020-01582-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318737PMC
June 2020

Iliac vein stenting guided by intravascular ultrasound without iodinated contrast medium.

Vasa 2021 Jan 19;50(1):68-73. Epub 2020 Jun 19.

Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, Lewisburg, West Virginia, United States.

Iliac vein compression syndrome, also known as May-Thurner Syndrome, is a type of vein reflux disorders which is often ignored due to lack of efficient diagnostic methods. The traditional gold standard of diagnosis is venography, but this has been challenged and largely replaced by intravascular ultrasound (IVUS). Here we report a case that a patient suffered with iodine anaphylaxis was successfully performed iliac vein stenting guided by using IVUS alone. This case provides the evidence that IVUS can offer necessary information for physicians in the diagnosis and treatment of iliac vein compression. We also find that balloon dilatation notch cannot precisely reflect the whole lesion, indicating it may be unreliable for diagnosis. Differ from the commonly accepted opinion, we find that comparing to IVUS, the notch of balloon dilatation cannot completely reflect the extent of lesion narrowness. Thus, we think the notch should not be used as a reference for seriousness of the lesion, and the diagnosis of stenosis cannot be ruled out even if there is no presence of notch.
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http://dx.doi.org/10.1024/0301-1526/a000873DOI Listing
January 2021

Transdermal Drug Delivery for Hair Regrowth.

Mol Pharm 2021 02 20;18(2):483-490. Epub 2020 May 20.

Department of Bioengineering, University of California, Los Angeles, Los Angeles, California 90095, United States.

Today, about 50% of men and 15-30% of women suffer from hair loss as well as the associated psychological impact. Drug therapy, especially through topical administration, is the main treatment strategy for stimulating hair regrowth. However, challenges exist due to the skin barrier that hinders drug penetration. To this end, many efforts have been made to enhance drug penetration efficiency. This review focuses on the advancement of the transdermal drug delivery strategies for hair loss therapy reported in the last five years, especially those via nanoformulations for topical administration and microneedles for transdermal delivery. In addition, physical or chemical penetration enhancers are also introduced, which are often applied with the drug delivery systems to achieve a synergy effect.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00041DOI Listing
February 2021

Source identification of chromium in the sediments of the Xiaoqing River and Laizhou Bay: A chromium stable isotope perspective.

Environ Pollut 2020 Sep 29;264:114686. Epub 2020 Apr 29.

CAS Key Laboratory of Crust-Mantle Materials and Environments, University of Science and Technology of China, Hefei, 230026, PR China; CAS Center for Excellence in Comparative Planetology, Hefei, 230026, PR China. Electronic address:

Hexavalent chromium, Cr(VI), is a heavy metal contaminant and the reduction of Cr(VI) is accompanied by large isotopic fractionation. In this study, the sources of Cr were explored using the Cr isotopic composition of sediments from the Xiaoqing River, a heavily polluted river located in the Shandong Province of China, which flows into Laizhou Bay. The results show that δCr values of the sediments are the highest upstream near the pollution source, and gradually decrease along the river toward the range for igneous reservoirs observed near the estuary. Based on the calculation of authigenic Cr isotopic composition (δCr) using the detrital index and leaching experiments, we suggest that the authigenic Cr in the sample near the pollution source with the highest δCr value mainly comes from the reduction of Cr(VI) discharged by anthropogenic activity, and authigenic Cr in other samples in the midstream with δCr values slightly higher than the range of igneous reservoirs may come from natural oxidative Cr weathering products. By introducing a Rayleigh model, we calculate that at least 31%-55% of Cr(VI) in the river water had been reduced to Cr(III) near the pollution source. Due to the self-purification ability of the river, Cr(VI) was reduced; thus, there is no record of high δCr values in the downstream of the Xiaoqing River and Laizhou Bay, indicating no obvious Cr pollution in these locations. The limited variation of δCr values for samples from a sediment core in Laizhou Bay is also indicative of no obvious Cr pollution in the history. The Cr isotopic compositions of the river sediments are useful for the identification of Cr sources and can be used to advise environmental remediation on Cr pollution.
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http://dx.doi.org/10.1016/j.envpol.2020.114686DOI Listing
September 2020

PERK Inhibition Mitigates Restenosis and Thrombosis: A Potential Low-Thrombogenic Antirestenotic Paradigm.

JACC Basic Transl Sci 2020 Mar 19;5(3):245-263. Epub 2020 Feb 19.

Department of Surgery, College of Medicine, The Ohio State University, Columbus, Ohio.

Developing endothelial-protective, nonthrombogenic antirestenotic treatments has been a challenge. A major hurdle to this has been the identification of a common molecular target in both smooth muscle cells and endothelial cells, inhibition of which blocks dysfunction of both cell types. The authors' findings suggest that the PERK kinase could be such a target. Importantly, PERK inhibition mitigated both restenosis and thrombosis in preclinical models, implicating a low-thrombogenic antirestenotic paradigm.
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http://dx.doi.org/10.1016/j.jacbts.2019.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7091514PMC
March 2020

Transdermal colorimetric patch for hyperglycemia sensing in diabetic mice.

Biomaterials 2020 04 13;237:119782. Epub 2020 Jan 13.

Department of Bioengineering, University of California, Los Angeles, CA, 90095, United States; California NanoSystems Institute, University of California, Los Angeles, CA, 90095, United States; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, 90095, United States; Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA, 90095, United States. Electronic address:

The integration of sampling and instant metabolite readout can fundamentally elevate patient compliance. To circumvent the need for complex in-lab apparatus, here, an all-in-one sampling and display transdermal colorimetric microneedle patch was developed for sensing hyperglycemia in mice. The coloration of 3,3',5,5'-tetramethylbenzidine (TMB) is triggered by the cascade enzymatic reactions of glucose oxidase (GOx) and horseradish peroxidase (HRP) at abnormally high glucose levels. The HRP in the upper layer is biomineralized with calcium phosphate (CaP) shell to add a pH responsive feature for increased sensitivity as well as protection from nonspecific reactions. This colorimetric sensor achieved minimally invasive extraction of the interstitial fluid from mice and converted glucose level to a visible color change promptly. Quantitative red green and blue (RGB) information could be obtained through a scanned image of the microneedle. This costless, portable colorimetric sensor could potentially detect daily glucose levels without blood drawing procedures.
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http://dx.doi.org/10.1016/j.biomaterials.2020.119782DOI Listing
April 2020

Transdermal cold atmospheric plasma-mediated immune checkpoint blockade therapy.

Proc Natl Acad Sci U S A 2020 02 6;117(7):3687-3692. Epub 2020 Feb 6.

Department of Bioengineering, University of California, Los Angeles, CA 90095;

Despite the promise of immune checkpoint blockade (ICB) therapy against cancer, challenges associated with low objective response rates and severe systemic side effects still remain and limit its clinical applications. Here, we described a cold atmospheric plasma (CAP)-mediated ICB therapy integrated with microneedles (MN) for the transdermal delivery of ICB. We found that a hollow-structured MN (hMN) patch facilitates the transportation of CAP through the skin, causing tumor cell death. The release of tumor-associated antigens then promotes the maturation of dendritic cells in the tumor-draining lymph nodes, subsequently initiating T cell-mediated immune response. Anti-programmed death-ligand 1 antibody (aPDL1), an immune checkpoint inhibitor, released from the MN patch further augments the antitumor immunity. Our findings indicate that the proposed transdermal combined CAP and ICB therapy can inhibit the tumor growth of both primary tumors and distant tumors, prolonging the survival of tumor-bearing mice.
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http://dx.doi.org/10.1073/pnas.1917891117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035610PMC
February 2020

Glucose-responsive insulin patch for the regulation of blood glucose in mice and minipigs.

Nat Biomed Eng 2020 05 3;4(5):499-506. Epub 2020 Feb 3.

Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA.

Glucose-responsive insulin delivery systems that mimic pancreatic endocrine function could enhance health and improve quality of life for people with type 1 and type 2 diabetes with reduced β-cell function. However, insulin delivery systems with rapid in vivo glucose-responsive behaviour typically have limited insulin-loading capacities and cannot be manufactured easily. Here, we show that a single removable transdermal patch, bearing microneedles loaded with insulin and a non-degradable glucose-responsive polymeric matrix, and fabricated via in situ photopolymerization, regulated blood glucose in insulin-deficient diabetic mice and minipigs (for minipigs >25 kg, glucose regulation lasted >20 h with patches of ~5 cm). Under hyperglycaemic conditions, phenylboronic acid units within the polymeric matrix reversibly form glucose-boronate complexes that-owing to their increased negative charge-induce the swelling of the polymeric matrix and weaken the electrostatic interactions between the negatively charged insulin and polymers, promoting the rapid release of insulin. This proof-of-concept demonstration may aid the development of other translational stimuli-responsive microneedle patches for drug delivery.
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http://dx.doi.org/10.1038/s41551-019-0508-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231631PMC
May 2020

A prophylactic and a therapeutic against AML.

Authors:
Guojun Chen Zhen Gu

Nat Biomed Eng 2020 01;4(1):4-5

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

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http://dx.doi.org/10.1038/s41551-019-0509-xDOI Listing
January 2020

Red blood cell-derived nanoerythrosome for antigen delivery with enhanced cancer immunotherapy.

Sci Adv 2019 10 23;5(10):eaaw6870. Epub 2019 Oct 23.

Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, China.

Erythrocytes or red blood cells (RBCs) represent a promising cell-mediated drug delivery platform due to their inherent biocompatibility. Here, we developed an antigen delivery system based on the nanoerythrosomes derived from RBCs, inspired by the splenic antigen-presenting cell targeting capacity of senescent RBCs. Tumor antigens were loaded onto the nanoerythrosomes by fusing tumor cell membrane-associated antigens with nanoerythrosomes. This tumor antigen-loaded nanoerythrosomes ([email protected]) elicited antigen responses in vivo and, in combination with the anti-programmed death ligand 1 (PD-L1) blockade, inhibited the tumor growth in B16F10 and 4T1 tumor models. We also generated a tumor model showing that "personalized [email protected]" could be achieved by fusing RBCs and surgically removed tumors, which effectively reduced tumor recurrence and metastasis after surgery.
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http://dx.doi.org/10.1126/sciadv.aaw6870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810293PMC
October 2019

Radical Hydroboration and Hydrosilylation of -Difluoroalkenes: Synthesis of α-Difluorinated Alkylborons and Alkylsilanes.

Org Lett 2019 10 10;21(20):8454-8458. Epub 2019 Oct 10.

School of Pharmaceutical Sciences , Sun Yat-sen University , Guangzhou 510006 , P.R. China.

A first example of radical hydroboration and hydrosilylation of -difluoroalkenes using ABIN as the radical initiator is described. This protocol features good functional group tolerance, operational simplicity, high atom economy, and easy scale-up, enabling efficient assembly of a wide range of α-difluorinated alkylborons and alkylsilanes in moderate to excellent yields. The synthetic utility of these products is demonstrated by further transformation of the C-B bond and C-Si bond into valuable CF-containing molecules.
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http://dx.doi.org/10.1021/acs.orglett.9b03218DOI Listing
October 2019

Silver-promoted decarboxylative radical addition/annulation of oxamic acids with gem-difluoroolefins: concise access to CF-containing 3,4-dihydroquinolin-2-ones.

Org Biomol Chem 2019 09;17(37):8527-8532

Key Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, Generic Drug Research Center of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi 563006, P. R. China.

Described is a silver-promoted decarboxylative radical addition/annulation of oxamic acids with gem-difluoroalkenes. This reaction proceeded under mild reaction conditions with broad functional group compatibility, enabling the convenient synthesis of various structurally diverse CF2-containing 3,4-dihydroquinolin-2-ones that might find applications in medical chemistry.
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http://dx.doi.org/10.1039/c9ob01236bDOI Listing
September 2019

A biodegradable nanocapsule delivers a Cas9 ribonucleoprotein complex for in vivo genome editing.

Nat Nanotechnol 2019 10 9;14(10):974-980. Epub 2019 Sep 9.

Department of Materials Science and Engineering, University of Wisconsin-Madison, Madison, WI, USA.

Delivery technologies for the CRISPR-Cas9 (CRISPR, clustered regularly interspaced short palindromic repeats) gene editing system often require viral vectors, which pose safety concerns for therapeutic genome editing. Alternatively, cationic liposomal components or polymers can be used to encapsulate multiple CRISPR components into large particles (typically >100 nm diameter); however, such systems are limited by variability in the loading of the cargo. Here, we report the design of customizable synthetic nanoparticles for the delivery of Cas9 nuclease and a single-guide RNA (sgRNA) that enables the controlled stoichiometry of CRISPR components and limits the possible safety concerns in vivo. We describe the synthesis of a thin glutathione (GSH)-cleavable covalently crosslinked polymer coating, called a nanocapsule (NC), around a preassembled ribonucleoprotein (RNP) complex between a Cas9 nuclease and an sgRNA. The NC is synthesized by in situ polymerization, has a hydrodynamic diameter of 25 nm and can be customized via facile surface modification. NCs efficiently generate targeted gene edits in vitro without any apparent cytotoxicity. Furthermore, NCs produce robust gene editing in vivo in murine retinal pigment epithelium (RPE) tissue and skeletal muscle after local administration. This customizable NC nanoplatform efficiently delivers CRISPR RNP complexes for in vitro and in vivo somatic gene editing.
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http://dx.doi.org/10.1038/s41565-019-0539-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778035PMC
October 2019

Expression profile of tRNA‑derived fragments and their potential roles in human varicose veins.

Mol Med Rep 2019 Oct 1;20(4):3191-3201. Epub 2019 Aug 1.

Department of Vascular Surgery, Shanghai East Hospital Affiliated to Tongji University School of Medicine, Shanghai 200120, P.R. China.

Varicose veins (VVs) is a common disease presenting with chronic venous insufficiency. tRNA‑derived fragments (tRFs) are associated with a variety of pathological conditions. However, the functions of tRFs in VVs have not been elucidated to date. The present study aimed to identify the key tRFs and investigate their potential roles in VVs. Small RNA sequencing (RNA‑seq) was performed to investigate the expression of tRFs in tissues of patients with VVs and their matched adjacent normal veins tissues (ANVs). Reverse transcription‑quantitative PCR (RT‑qPCR) was used to confirm the differential expression of tRFs. A total of 13,789 tRFs were identified by small RNA‑seq, including 45 differentially expressed tRFs (DETs), which comprised 14 upregulated and 31 downregulated tRFs in VV tissues compared with ANVs. In addition, DETs were mainly involved in the function of epidermal growth factor receptor and vascular endothelial growth factor receptor signaling pathways in VVs. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the target genes of DETs were predominantly involved in Wnt and mitogen‑activated protein kinase (MAPK) signaling pathways, as well as calcium signaling. Additionally, two upregulated tRFs (tRF‑36‑F900BY4D84KRIME and tRF‑23‑87R8WP9IY) and one downregulated tRF (tRF‑40‑86J8WPMN1E8Y7Z2R) were further validated by RT‑qPCR, and a signaling pathway regulation network of their target genes confirmed their involvement in the calcium, Wnt and MAPK signaling pathways. The results of the present study identified three DETs (tRF‑36‑F900BY4D84KRIME, tRF‑23‑87R8WP9IY and tRF‑40‑86J8WPMN1E8Y7Z2R), which may have crucial roles in the occurrence and progression of VVs by regulating Wnt and MAPK signaling, as well as calcium signaling. The present results may provide a basis for further investigation of the functional roles of tRFs in VVs.
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http://dx.doi.org/10.3892/mmr.2019.10544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755252PMC
October 2019

Charge-switchable polymeric complex for glucose-responsive insulin delivery in mice and pigs.

Sci Adv 2019 07 10;5(7):eaaw4357. Epub 2019 Jul 10.

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

Glucose-responsive insulin delivery systems with robust responsiveness that has been validated in animal models, especially in large animal models, remain elusive. Here, we exploit a new strategy to form a micro-sized complex between a charge-switchable polymer with a glucose-sensing moiety and insulin driven by electrostatic interaction. Both high insulin loading efficiency (95%) and loading capacity (49%) can be achieved. In the presence of a hyperglycemic state, the glucose-responsive phenylboronic acid (PBA) binds glucose instantly and converts the charge of the polymeric moiety from positive to negative, thereby enabling the release of insulin from the complex. Adjusting the ratio of the positively charged group to PBA achieves inhibited insulin release from the complex under normoglycemic conditions and promoted release under hyperglycemic conditions. Through chemically induced type 1 diabetic mouse and swine models, in vivo hyperglycemia-triggered insulin release with fast response is demonstrated after the complex is administrated by either subcutaneous injection or transdermal microneedle array patch.
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http://dx.doi.org/10.1126/sciadv.aaw4357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620100PMC
July 2019

Eradication of unresectable liver metastasis through induction of tumour specific energy depletion.

Nat Commun 2019 07 11;10(1):3051. Epub 2019 Jul 11.

Collaborative Innovation Center of Chemistry for Life Sciences, College of Engineering and Applied Sciences, Nanjing University, Nanjing, Jiangsu, China.

Treatment of liver metastasis experiences slow progress owing to the severe side effects. In this study, we demonstrate a strategy capable of eliminating metastatic cancer cells in a selective manner. Nucleus-targeting WO nanoparticles (WONPs) are conjugated to mitochondria-selective mesoporous silica nanoparticles (MSNs) containing photosensitizer (Ce6) through a Cathepsin B-cleavable peptide. In hepatocytes, upon the laser irradiation, the generated singlet oxygen species are consumed by WONPs, in turn leading to the loss of their photothermally heating capacity, thereby sparing hepatocyte from thermal damage induced by the laser illumination. By contrast, in cancer cells, the cleaved peptide linker allows WONPs and MSNs to respectively target nucleus and mitochondria, where the therapeutic powers could be unleashed, both photodynamically and photothermally. This ensures the energy production of cancer cells can be abolished. We further assess the underlying molecular mechanism at both gene and protein levels to better understand the therapeutic outcome.
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http://dx.doi.org/10.1038/s41467-019-11082-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624273PMC
July 2019

Bioresponsive Protein Complex of aPD1 and aCD47 Antibodies for Enhanced Immunotherapy.

Nano Lett 2019 08 11;19(8):4879-4889. Epub 2019 Jul 11.

Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States.

Despite the promising efficacy of immune checkpoint blockade (ICB) in treating many types of cancers, the clinical benefits have often been restricted by the low objective response rates and systemic immune-related adverse events. Here, a bioresponsive ICB treatment is developed based on the reactive oxygen species (ROS)-sensitive protein complex for controlled sequential release of anti- "don't eat me" signal antibody (aCD47) and antiprogrammed cell death protein 1 (aPD1), by leveraging the abundant ROS in the tumor microenvironment (TME). These protein complexes can also act as scavengers of ROS in the TME to reverse the immunosuppressive responses, thereby enhancing antitumor efficacy in vivo. In a melanoma cancer model, the synergistic antitumor efficacy was achieved, which was accompanied by enhanced T cell immune responses together with reduced immunosuppressive responses.
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http://dx.doi.org/10.1021/acs.nanolett.9b00584DOI Listing
August 2019