Publications by authors named "Zhiwen Zhang"

257 Publications

M2 macrophage microvesicle-inspired nanovehicles improve accessibility to cancer cells and cancer stem cells in tumors.

J Nanobiotechnology 2021 Nov 27;19(1):397. Epub 2021 Nov 27.

State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

Cancer cells and cancer stem cells (CSCs) are the major players of cancer malignancy and metastasis, but they are extremely difficult to access. Inspired by the vital role of macrophages and microvesicle-mediated cell-cell communication in tumors, we herein designed M2 macrophage microvesicle-inspired nanovehicle of cabazitaxel (M-CFN) to promote accessibility to cancer cells and CSCs in tumors. In the 4T1 tumor model, M-CFN flexibly permeated the tumor mass, accessed cancer cells and CD90-positive cells, and significantly promoted their entry into CSC fractions in tumors. Moreover, M-CFN treatment profoundly eliminated aldehyde dehydrogenase (ALDH)-expressing CSCs in 4T1 and MCF-7 tumors, produced notable depression of tumor growth and caused 93.86% suppression of lung metastasis in 4T1 models. Therefore, the M2 macrophage microvesicle-inspired nanovehicle provides an encouraging strategy to penetrate the tumor tissues and access these insult cells in tumors for effective cancer therapy.
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http://dx.doi.org/10.1186/s12951-021-01143-5DOI Listing
November 2021

RNA mA Demethylase ALKBH5 Protects Against Pancreatic Ductal Adenocarcinoma Targeting Regulators of Iron Metabolism.

Front Cell Dev Biol 2021 18;9:724282. Epub 2021 Oct 18.

Department of Pathology, State Key Laboratory of Complex Severe and Rare Disease, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Although RNA mA regulators have been implicated in the tumorigenesis of several different types of tumors, including pancreatic cancer, their clinical relevance and intrinsic regulatory mechanism remain elusive. This study analyzed eight mA regulators (METTL3, METTL14, WTAP, FTO, ALKBH5, and YTHDF1-3) in pancreatic ductal adenocarcinoma (PDAC) and found that only RNA mA demethylase ALKBH5 serves as an independent favorable prognostic marker for this tumor. To better understand the molecular mechanism underlying the protective effect conferred by ALKBH5 against pancreatic tumorigenesis, we performed a transcriptome-wide analysis of mA methylation, gene expression, and alternative splicing (AS) using the MIA PaCa-2 stable cell line with ALKBH5 overexpression. We demonstrated that ALKBH5 overexpression induced a reduction in RNA mA levels globally. Furthermore, mRNAs encoding ubiquitin ligase FBXL5, and mitochondrial iron importers SLC25A28 and SLC25A37, were identified as substrates of ALKBH5. Mechanistically, the RNA stabilities of and , and the AS of were affected, which led to their upregulation in pancreatic cancer cell line. Particularly, we observed that downregulation of FBXL5 in tumor samples correlated with shorter survival time of patients. Owing to FBXL5-mediated degradation, ALKBH5 overexpression incurred a significant reduction in iron-regulatory protein IRP2 and the modulator of epithelial-mesenchymal transition (EMT) SNAI1. Notably, ALKBH5 overexpression led to a significant reduction in intracellular iron levels as well as cell migratory and invasive abilities, which could be rescued by knocking down . Overall, our results reveal a previously uncharacterized mechanism of ALKBH5 in protecting against PDAC through modulating regulators of iron metabolism and underscore the multifaceted role of mA in pancreatic cancer.
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http://dx.doi.org/10.3389/fcell.2021.724282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558440PMC
October 2021

miR-20a Overexpression in Adipose-Derived Mesenchymal Stem Cells Promotes Therapeutic Efficacy in Murine Lupus Nephritis by Regulating Autophagy.

Stem Cells Int 2021 21;2021:3746335. Epub 2021 Oct 21.

Department of Dermatology, Nanfang Hospital, Southern Medical University, China.

Objective: Lupus nephritis is the most common and severe complication of systemic lupus erythematosus. The aim of our study was to investigate the efficacy of miR-20a overexpressing adipose-derived stem cell (ADSC) transplantation in murine lupus nephritis (LN) and explore potential molecular mechanisms.

Methods: Mouse ADSCs were transfected with a miR-20a lentiviral vector to obtain miR-20a overexpression ADSCs (miR-20a-ADSCs). We first observed the influence of miR-20a on ADSC viability and apoptosis . B6.MRL/lpr mice were administered ADSC/miR-20a-ADSC intravenously every week from age 30 to 33 weeks, and the lupus and normal control groups received PBS on the same schedule.

Results: miR-20a expression increased in miR-20a-ADSC-derived exosomes, and miR-20a overexpression promoted ADSC proliferation and inhibited apoptosis. Compared with ADSCs, miR-20a-ADSC treatment significantly improved serologic and histologic abnormalities, as evidenced by reduced serum creatinine, anti-dsDNA antibody, 24 h urine protein levels, nephritis scores, and C3/IgG deposits. Furthermore, miR-20a-ADSC treatment resulted in downregulated Akt, mTOR, and p62 expression and upregulated miR-20a, Beclin 1, and LC3 II/I expression compared with ADSC treatment. After treatment with miR-20a-ADSC, a significant increase in the number of autophagosomes within podocytes was observed, along with upregulated expression of podocin and nephrin, compared with the ADSC group.

Conclusions: miR-20a-ADSC transplantation prevents the development of lupus nephritis and significantly ameliorates already-established disease, and its mechanism is related to autophagy by targeting the miR-20a-regulated mTOR pathway.
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http://dx.doi.org/10.1155/2021/3746335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553505PMC
October 2021

A deep learning-based method for detecting and classifying the ultrasound images of suspicious thyroid nodules.

Med Phys 2021 Oct 31. Epub 2021 Oct 31.

Department of Ultrasound, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.

Purpose: The incidence of thyroid cancer has significantly increased in the last few decades. However, diagnosis of the thyroid nodules is labor and time intensive for radiologists and strongly depends on the personal experience of the radiologists. In this pursuit, the present study envisaged to develop a deep learning-based computer-aided diagnosis (CAD) method that enabled the automatic detection and classification of suspicious thyroid nodules in order to reduce the unnecessary fine-needle aspiration biopsy.

Methods: The CAD method consisted of two main parts: detecting the location of thyroid nodules using a multiscale detection network and classifying the detected thyroid nodules by an attention-based classification network.

Results: The performance of the proposed method was evaluated and compared with that of other state-of-the-art deep learning methods and experienced radiologists. The proposed detection method outperformed three other detection architectures (average precision, 82.1% vs. 78.3%, 77.2%, and 74.8%). Moreover, the classification method showed a superior performance compared with four other state-of-the-art classification networks (accuracy, 94.8% vs. 91.2%, 85.0%, 80.8%, and 72.1%) and that by experienced radiologists (mean value of area under the curve, 0.941 vs. 0.833).

Conclusions: Our study verified the high efficiency of the proposed detection method. The findings can help improve the diagnostic performance of radiologists. However, the developed CAD system requires more training and evaluation in a large-population study.
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http://dx.doi.org/10.1002/mp.15319DOI Listing
October 2021

Nanomedicine Strategies to Circumvent Intratumor Extracellular Matrix Barriers for Cancer Therapy.

Adv Healthc Mater 2021 Oct 27:e2101428. Epub 2021 Oct 27.

State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

The dense and heterogeneous physical network of the extracellular matrix (ECM) in tumors represents a formidable barrier that limits intratumor drug delivery and the therapeutic efficacy of many anticancer therapies. Here, the two major nanomedicine strategies to circumvent intratumor ECM barriers: regulating the physiochemical properties of nanomedicines and remodeling the components and structure of the ECM are summarized. Nanomedicines can be rationally regulated by optimizing physiochemical properties or designed with biomimetic features to promote ECM permeation capability. Meanwhile, they can also be designed to remodel the ECM by modulating signaling pathways or destroying the components and architecture of the ECM via chemical, biological, or physical treatments. These efforts produce profound improvements in intratumor drug delivery and anticancer efficacy. Moreover, to aid in their anticancer efficacy, feasible approaches for improving ECM-circumventing nanomedicines are proposed.
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http://dx.doi.org/10.1002/adhm.202101428DOI Listing
October 2021

Peptide Hydrogel with Antibacterial Performance Induced by Rare Earth Metal Ions.

Langmuir 2021 Nov 27;37(44):12842-12852. Epub 2021 Oct 27.

Yantai Institute of Materia Medica, Yantai 264000, China.

Metal ion-induced peptide assembly is an interesting field. As compared to traditional antibacterial Ag, rare earth metal ions possess the advantage of antibacterial performance with photostability and low toxicity. Herein, a new peptide Fmoc-FFWDD-OH was designed and synthesized, which could form a stable hydrogel induced by rare earth metal ions, including Tb, Eu, and La. The mechanical properties were characterized by rheological measurements, and they exhibited elasticity-dominating properties. Transmission electron microscopy (TEM) images showed a large number of nanoscale fiber structures formed in the hydrogel. Circular dichroism (CD) spectra, Fourier transform infrared (FT-IR) spectra, ThT assays, and X-ray diffraction (XRD) pattern illustrated the formation mechanism of the fiber structure. The rare earth ion-induced peptide hydrogel was proved to possess good antibacterial performance on () with excellent biocompatibility. The introduction of rare earth metal ions may have some potential applications in the biological antibacterial and medical fields.
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http://dx.doi.org/10.1021/acs.langmuir.1c01815DOI Listing
November 2021

Epidemic versus economic performances of the COVID-19 lockdown in Japan: A Mobility Data Analysis.

Cities 2021 Oct 22:103502. Epub 2021 Oct 22.

School of Business, Society & Engineering, Mälardalen University, SE-72123 Västerås, Sweden.

Lockdown measures have been a "panacea" for pandemic control but also a violent "poison" for economies. Lockdown policies strongly restrict human mobility but mobility reduce does harm to economics. Governments meet a thorny problem in balancing the pros and cons of lockdown policies, but lack comprehensive and quantified guides. Based on millions of financial transaction records, and billions of mobility data, we tracked spatio-temporal business networks and human daily mobility, then proposed a high-resolution two-sided framework to assess the epidemiological performance and economic damage of different lockdown policies. We found that the pandemic duration under the strictest lockdown is less about two months than that under the lightest lockdown, which makes the strictest lockdown characterize both epidemiologically and economically efficient. Moreover, based on the two-sided model, we explored the spatial lockdown strategy. We argue that cutting off intercity commuting is significant in both epidemiological and economical aspects, and finally helped governments figure out the Pareto optimal solution set of lockdown strategy.
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http://dx.doi.org/10.1016/j.cities.2021.103502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531026PMC
October 2021

Percutaneous Mechanical Atherectomy Plus Thrombectomy Using the Rotarex®S Device Followed by a Drug-Coated Balloon for the Treatment of Femoropopliteal Artery In-stent Restenosis: A Prospective Single-Center, Single-Arm Efficacy Trial (PERMIT-ISR Trial).

Front Surg 2021 14;8:671849. Epub 2021 Sep 14.

Department of Vascular Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

Studies investigating debulking devices with drug-coated balloons (DCBs) in the treatment of femoropopliteal (FP) artery in-stent restenosis (ISR) are limited. We aimed to evaluate the safety and midterm outcome of percutaneous mechanical atherectomy plus thrombectomy (MATH) using the Rotarex®S (Straub Medical, Wangs, Switzerland) catheter followed by a DCB in the treatment of FP-ISR. This study was a single-center single-arm trial. Patients with symptomatic (Rutherford category 2-5) restenosis lesions of FP-ISR were treated with MATH and subsequent DCB. From June 2016 to May 2018, 59 patients with FP-ISR were enrolled. The primary endpoint was target lesion revascularization (TLR) and changes in the Rutherford category of the target limb at 12 months. Secondary endpoints included primary and secondary patency at 12 months, technical success rate, major adverse events, and ankle-brachial index (ABI). Risk factors for TLR were analyzed using Cox proportional hazard model. The average follow-up time was 33 ± 8 months. The rate of technical success was 88.1% (52/59). Nine patients received bailout stenting. The rate of freedom from TLR was 84.7% (50/59) at 1 year, the Rutherford category changed at 12 months were significantly improved from baseline ( < 0.01). The primary patency rates and the secondary patency at the 12-month follow-ups were 82.5 and 92.5%, respectively. The ABI changed at 12 months were significantly improved from baseline ( < 0.01). Global limb anatomic staging system (GLASS) classification III [hazard ratio (HR) 18.44, 95% CI (1.57-215.99), = 0.020] and postoperative Rutherford classification ≥4 [HR 8.28, 95% CI (1.85-37.06), = 0.006] were identified as independent predictors of TLR. Our preliminary data suggested that MATH using a Rotarex®S catheter combined with DCB angioplasty is a safe, minimally invasive, and effective treatment for FP-ISR with favorable, immediate, and midterm outcomes. http://www.chictr.org.cn, identifier [ChiCTR2000041380].
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http://dx.doi.org/10.3389/fsurg.2021.671849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477580PMC
September 2021

Gut Microbiota Disorders Promote Inflammation and Aggravate Spinal Cord Injury Through the TLR4/MyD88 Signaling Pathway.

Front Nutr 2021 13;8:702659. Epub 2021 Sep 13.

Department of Spine Surgery, The People's Hospital of Longhua, Shenzhen Longhua Clinical Medical College of Guangdong Medical University, Shenzhen, China.

In spinal cord injury (SCI), systemic inflammation and the death of nerve cells in the spinal cord are life threatening. The connection between gut microbiota and signaling pathways has been a hot research topic in recent years. The Toll-like receptor 4/Myeloid differentiation factor 88 (TLR4/MyD88) signaling pathway is closely related to the inflammatory response. This study explored whether the gut microbiota imbalance could affect the TLR4/MyD88 signaling pathway to regulate SCI to provide a new basis for SCI research and treatment. An SCI model was constructed to study the influence on the injury of gut microbiota. 16S amplicon sequencing was used to identify the diversity and abundance of gut microbes. Fecal microbiota transplantation was performed in mice with SCI. ELISA was used to detect the serum levels of pro-inflammatory and anti-inflammatory factors in mice. Hematoxylin and eosin staining was used to observe SCI in mice. Immunofluorescence was used to detect the rates of loss glial fibrillary acidic protein (GFAP), neuronal nuclear protein (NeuN), and ionized calcium-binding adapter molecule 1 (IBA1) in the spinal cord as indicators of apoptosis. The expression of the TLR4/MyD88 signaling pathway was detected by qRT-PCR and western blotting. Significant differences were observed in the gut microbiota of SCI mice and normal mice. The gut microbiota of SCI mice was imbalanced. The levels of pro-inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in SCI mice were increased, as was the level of the toxic induced nitric oxide synthase. The levels of anti-inflammatory factors IL-4, transforming growth factor-β, and IL-10 were decreased, as was the level of arginase-1. The apoptosis rates of GFAP, NeuN, and IBA1 were increased. The TLR4/MyD88 signaling pathway was activated. In the SCI group, inflammation increased after fecal transplantation, apoptosis of GFAP, NeuN, and IBA1 increased, and SCI was more serious. The TLR4/MyD88 signaling pathway promotes the death of nerve cells by inducing inflammation. Gut microbiota dysregulation can lead to aggravated SCI by activating the TLR4/MyD88 signaling pathway.
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http://dx.doi.org/10.3389/fnut.2021.702659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473614PMC
September 2021

Hub Genes and Key Pathways of Intervertebral Disc Degeneration: Bioinformatics Analysis and Validation.

Biomed Res Int 2021 10;2021:5340449. Epub 2021 Sep 10.

College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan 430061, China.

Objective: To identify significant pathways and genes in intervertebral disc degeneration (IDD) based on bioinformatics analysis.

Design: The GEO database was used to download the GSE124272 dataset. Differentially expressed genes (DEGs) were analyzed using Limma package in R language. Then, gene ontologies (GO), Kyoto encyclopedia of genes and genomes (KEGG), and protein-protein interaction (PPI) networks were used to further identify hub genes. The mRNA expression levels of top six hub genes were verified.

Results: We found 563 DEGs, of which 214 were upregulated and 349 were downregulated. The top 5 GO terms and pathways were shown including immune response, cell cycle, and p53 pathway. Based on the PPI analysis, we verified the mRNA expression levels of 6 hub genes. The mRNA levels of CHEK1, CDCA2, SKA3, and KIF20A were upregulated in degenerative NP tissue than in healthy NP tissue. However, the mRNA level of BUB1 and SPC25 was downregulated.

Conclusions: This study may provide new biomarkers for the IDD and treatments to repair IDD related to CHEK1, CDCA2, SKA3, BUB1, KIF20A, and SPC25.
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http://dx.doi.org/10.1155/2021/5340449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449732PMC
September 2021

Long non-coding RNA TUG1 knockdown prevents neurons from death to alleviate acute spinal cord injury via the microRNA-338/BIK axis.

Bioengineered 2021 12;12(1):5566-5582

Department of Orthopaedics, Huizhou City Center People's Hospital, Huizhou Guangdong, P.R. China.

Taurine up-regulated gene 1 (TUG1) is a cancer-associated long noncoding RNA (lncRNA) and engages in the development of spinal cord injury (SCI), a suffering neuropathological disorder. However, the regulatory role of TUG1 in acute SCI (ASCI) is still underdetermined. RT-qPCR and western blot analysis were applied to measure the expression of TUG1, microRNA-338 (miR-338), Bcl2-interacting killer (BIK), cleaved caspase 3 (c-caspase 3) and hypoxia-inducible factor-1 alpha (HIF-1α) in ASCI rats and hypoxic cells. Cell death was evaluated using flow cytometric analysis. The relationships among miR-338, TUG1 or BIK were confirmed by luciferase reporter assay, RNA immunoprecipitation and RNA pull-down. Accordingly, we monitored higher expression of TUG1 and BIK, but lower expression of miR-338 in ASCI rats and hypoxic cells. , hypoxia expedited cell death and c-caspase 3 levels. , ASCI rats were successfully developed as evidenced by diminished Basso-Beattie-Bresnahan (BBB) locomotor score and enhanced c-caspase 3 and HIF-1α expression. Nevertheless, TUG1 knockdown mitigated the cell death in ASCI rats and hypoxic cells. Mechanically, TUG1 interacted with miR-338 to regulate the BIK expression. Together, TUG1 silencing could alleviate the death in neurons and ASCI models via modulating the miR-338/BIK axis.
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http://dx.doi.org/10.1080/21655979.2021.1966258DOI Listing
December 2021

Nanoparticles-mediated emerging approaches for effective treatment of ischemic stroke.

Biomaterials 2021 10 31;277:121111. Epub 2021 Aug 31.

Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203, China; The Institutes of Integrative Medicine of Fudan University, 120 Urumqi Middle Road, Shanghai, 200040, China. Electronic address:

Ischemic stroke leads to high disability and mortality. The limited delivery efficiency of most therapeutic substances is a major challenge for effective treatment of ischemic stroke. Inspired by the prominent merit of nanoscale particles in brain targeting and blood-brain barrier (BBB) penetration, various functional nanoparticles have been designed as promising drug delivery platforms that are expected to improve the therapeutic effect of ischemic stroke. Based on the complex pathological mechanisms of ischemic stroke, this review outline and summarize the rationally designed nanoparticles-mediated emerging approaches for effective treatment of ischemic stroke, including recanalization therapy, neuroprotection therapy, and combination therapy. On this bases, the potentials and challenges of nanoparticles in the treatment of ischemic stroke are revealed, and new thoughts and perspectives are proposed for the design of feasible nanoparticles for effective treatment of ischemic stroke.
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http://dx.doi.org/10.1016/j.biomaterials.2021.121111DOI Listing
October 2021

More metalwork removals in patients with olecranon fracture treated by tension band wiring than plate fixation-a propensity score matching analysis.

BMC Musculoskelet Disord 2021 Aug 13;22(1):692. Epub 2021 Aug 13.

Department of Traumatology and Orthopaedic Surgery, Institute of Orthopaedics, Huizhou Municipal Central Hospital, Huizhou, Guangdong, 516001, People's Republic of China.

Background: Traditional tension band wiring and plate fixation represent the commonest methods for treating olecranon fractures. However, there is no agreement on which method provides the best outcome. The aim of this retrospective study is to compare the outcomes of tension band wiring (TBW) and plate fixation (PF) for treating displaced olecranon fractures. This is the first study to use propensity score matching analysis to compare treatment methods for olecranon fracture.

Method: A total of 107 patients aged between 18 and 85 had acute isolated and displaced olecranon fractures. The patients were divided into either TBW (n = 49) or PF (n = 58) groups. To conduct propensity score matching for the treatment method (TBW versus PF), 58 patients were analyzed by logistic regression (29 patients in each group). Various demographic and treatment-related variables were examined and analyzed to determine their correlation.

Results: Functional effects between two groups are similar (in terms of Mayo Elbow Performance Score (MEPS), the patients' range of elbow motion (ROM) and forearm rotation (RFR), the time return to work (RTW)). The total adverse events rate and metalwork removal events rate are higher in TBW than that in PF. After propensity score matching analysis, similar primary treatment efficacy (indicated by MEPS> 90) in 2 groups and more primary adverse events (indicated by metalwork removal) were perceived in TBW than that in PF. Logistic regression analysis revealed that fracture type was an independent factor that affected the efficacy of a treatment (regression coefficient = - 1.24 < 0, P = 0.03), indicating that fracture severity was inversely proportional to the efficacy of a treatment for olecranon fracture. Furthermore, logistic regression analysis demonstrated that the treatment method was an independent factor that affected metalwork removal of olecranon fracture (regression coefficient 2.38 > 0, OR = 10.77, P < 0.01), indicating that the risk of metalwork removal in the TBW Group was 10.77 times that in the PF Group.

Conclusion: When initially discussing the surgical approach with patients, physicians should fully weigh the possibility that TBW may lead to a second surgery due to the higher risk of internal fixation removal and that TBW won't yield better functional outcomes than PF .
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http://dx.doi.org/10.1186/s12891-021-04559-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364058PMC
August 2021

Circ_0025908 regulates cell vitality and proliferation via miR-137/HIPK2 axis of rheumatic arthritis.

J Orthop Surg Res 2021 Jul 30;16(1):472. Epub 2021 Jul 30.

Department of Traumatic Orthopedics, Institute of Orthopedics, Huizhou Central People's Hospital, No. 41, North E'ling Road, Huizhou, 516000, Guangdong Province, China.

Background: Rheumatic arthritis (RA) is an autoimmune disease with bad effects. Recent researches have shown that circular RNAs (circRNAs) could affect the progress of RA, but the mechanism still indistinct. In this work, we explored the roles of circ_0025908 in RA.

Methods: The levels of circ_0025908, microRNA-137 (miR-137), and mRNA of homeodomain-interacting protein kinase 2 (HIPK2) were detected by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) in RA tissues. Meanwhile, the level of HIPK2 was quantified by Western blot analysis. Besides, the cell functions were examined by CCK8 assay, EdU assay, flow cytometry assay, ELISA, and Western blot. Furthermore, the interplay between miR-137 and circ_0025908 or HIPK2 was detected by dual-luciferase reporter assay.

Results: The levels of circ_0025908 and HIPK2 were upregulated, and the miR-137 level was decreased in RA tissues in contrast to that in normal tissues. For functional analysis, circ_0025908 deficiency inhibited cell vitality, cell mitotic cycle, cell proliferation, and immunoreaction in RA cells, whereas promoted cell apoptosis. Moreover, miR-137 was confirmed to repress the progression of RA cells by suppressing HIPK2. In mechanism, circ_0025908 acted as a miR-137 sponge to regulate the level of HIPK2.

Conclusion: Circ_0025908 facilitates the development of RA through increasing HIPK2 expression by regulating miR-137, which also offered an underlying targeted therapy for RA treatment.
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http://dx.doi.org/10.1186/s13018-021-02615-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323297PMC
July 2021

MiR-206 regulates the Th17/Treg ratio during osteoarthritis.

Mol Med 2021 06 19;27(1):64. Epub 2021 Jun 19.

Department of Orthopedics, Hubei Provincial Hospital of Traditional Chinese Medicine, No.4, Hua-Yuan-Shan, Yanzhi Road, Wuchang District, Wuhan, 430061, Hubei, China.

Background: The present study aimed to determine the functional role of miR-206 in T helper 17 (Th17)/regulatory T (Treg) cell differentiation during the development of osteoarthritis (OA).

Methods: Patients with OA and healthy controls were recruited for investigating the association between miR-206 and Th17/Treg ratio. Transfection experiments were conducted in CD4 T cells to verify the mechanism of miR-206 on the balance of Treg/Th17. OA model was constructed to detect the clinical score, histopathological changes and Treg/Th17 ratio. OA model was induced in rats to verify the effect of miR-206 inhibition on Th17/Treg immunoregulation.

Results: High expression of miR-206 was positively correlated with peripheral Th17/Treg imbalance in patients with OA. The interactions between miR-206 and the 3' untranslated regions (3'-UTR) of suppressor of cytokine signaling-3 (SOCS3) and fork head transcriptional factor 3 (Foxp3) were confirmed by luciferase reporter assays. MiR-206 disturbed the Th17/Treg balance by targeting SOCS3 and Foxp3. In vivo assay demonstrated that antagomiR directed against miR-206 restored Th17/Treg balance during the development of OA.

Conclusion: MiR-206 contributed to the progression of OA by modulating Th17/Treg imbalance, suggesting that miR-206 inhibition might be a promising therapeutic strategy for the treatment of OA.
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http://dx.doi.org/10.1186/s10020-021-00315-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214293PMC
June 2021

Next-generation sequencing revealed recurrent ZFPM1 mutations in encapsulated papillary carcinoma of the breast.

NPJ Precis Oncol 2021 May 18;5(1):42. Epub 2021 May 18.

Department of Pathology, Complex Severe and Rare Disease, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Encapsulated papillary carcinoma (EPC) of the breast is a rare subtype of tumor. To date, the genetic abnormalities underlying EPC remain elusive. The purpose of this study was to gain further insight into EPC mutation profile. Forty-one EPCs diagnosed from 2015 to 2018 were included. Twenty-six EPCs were submitted to whole-exome sequencing (WES), and a 185 gene-targeted sequencing panel was designed to validate the results of the 26 EPCs that underwent WES and 15 additional cases. Recurrently mutated genes were further confirmed by Sanger sequencing. Our study revealed multiple recurrently mutated genes including PI3K-AKT-mTOR pathway genes (PIK3CA, AKT1, ULK1, MAP3K1, MAP2K4, RHOA, and PTEN) (27/41, 65.8%) and chromatin modification genes (ZFPM1, GATA3, CTCF, and KMT2C) (21/41, 51.2%) in EPC. Importantly, somatic ZFPM1 mutations existed in 9/41 (21.9%) of the EPCs. The frequency of ZFPM1 mutations in the EPCs was significantly higher than that of other tumor types. Of the nine ZFPM1 mutations, seven were frameshift mutations, and the remaining two were nonsense mutations. Moreover, a significant concurrence of ZFPM1 and PI3K-AKT-mTOR mutations were revealed in the EPCs. Of note, no TP53 mutations were detected in our EPCs, whereas it was detected in a considerable proportion of the luminal A invasive ductal carcinomas of no special type (IDC-NSTs) from TCGA. We reveal that recurrent somatic ZFPM1 mutation is characteristic of EPC and concurred with mutations in the PI3K-AKT-mTOR pathway. The distinctive genetic features of EPC might underlie its special histological structures and indolent behavior.
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http://dx.doi.org/10.1038/s41698-021-00180-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131604PMC
May 2021

MicroRNA-135b-5p Downregulation Causes Antidepressant Effects by Regulating SIRT1 Expression.

Biochem Genet 2021 Dec 17;59(6):1582-1598. Epub 2021 May 17.

Department of Psychiatry, The Seventh Hospital of Hangzhou, 305 Tianmushan Road, Hangzhou, 310013, P.R. China.

Depression is a serious and potentially life-threatening mental illness. Recently, the role of sirtuin 1 (SIRT1) in chronic unpredictable mild stress (CUMS) management has been examined. The present study explored and clarified whether microRNA (miR)-135b-5p could play a role in depression by regulating the expression of SIRT1. SIRT1 was identified as the target gene of miR-135b-5p using TargetScan and the dual luciferase reporter assay. In addition, the expression levels of SIRT1 were significantly reduced in mouse peripheral blood and hippocampal tissue samples, while the expression of miR-135b-5p exhibited the opposite effects. Subsequently, the effects of miR-135b-5p inhibition were investigated in mice with depression. The results indicated that the miR-135b-5p inhibitor significantly increased the weight loss induced by CUMS compared with the model group, while reducing the expression levels of miR-135b-5p and further alleviating the depression-like behavior induced by CUMS. Concomitantly, the results indicated that the miR-135b-5p inhibitor inhibited CUMS-induced hippocampal cell apoptosis and significantly reduced the expression levels of cleaved caspase-3 and the ratio of cleaved caspase-3/caspase-3. Moreover, the miR-135b-5p inhibitor significantly reduced the CUMS-induced increase of the inflammatory factors IL-1β, IL-6 and TNF-α in the hippocampal mouse samples, while significantly increasing the expression levels of SIRT1. Finally, the results demonstrated that all the effects of the miR-135b-5p inhibitor on CUMS-induced mice were significantly reversed by SIRT1 silencing. In conclusion, the present study indicated that the miR-135b-5p/SIRT1 pathway was a key mediator of antidepressant effects induced in depressed mice. Therefore, it could be considered a potential therapeutic target for the treatment of CUMS-induced depression.
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http://dx.doi.org/10.1007/s10528-021-10076-5DOI Listing
December 2021

Leptospirosis and Rickettsial Diseases Sero-Conversion Surveillance Among U.S. Military Personnel in Honduras.

Mil Med 2021 Apr 16. Epub 2021 Apr 16.

Viral and Rickettsial Diseases Department, Infectious Diseases Directorate, Naval Medical Research Center, Silver Spring, MD 20910, USA.

Introduction: Leptospirosis and rickettsial diseases are global zoonotic diseases. In severe infection cases, mortality can range from 10% to 30%. Currently most epidemiological data available are based on outbreak investigations and hospital-based studies from endemic countries. The U.S. soldiers at military bases in these countries are highly vulnerable due to the fact that most of them are immunologically naïve to these pathogens. No risk assessment of leptospirosis and rickettsial diseases among U.S. military personnel in Honduras is currently available. This study was aimed at determining the prevalence of leptospirosis and rickettsial diseases in U.S. military personnel deployed to Honduras using serological assays.

Materials And Methods: A cohort of pre- and post-deployment sera from the most recent 1,000 military personnel stationed in Honduras for at least 6 months between 2000 and 2016 was identified for this study. Serum specimens from these eligible subjects were retrieved. All post-deployment serum specimens were screened at a dilution of 1:100 for the presence of IgG antibodies to Leptospira and Rickettsia pathogens. The pre-deployment sera from those individuals with post-deployment IgG antibodies above cutoff (i.e., seropositive) were tested to determine seroconversion. Seroconversion was defined as conversion of an optical density value from below the cutoff (i.e., negative) in a pre-deployed specimen to above the cutoff (i.e., positive) in a post-deployed specimen at a titer of 100.

Results: The seropositive post-deployment specimens for antibodies against Leptospira (causing leptospirosis), Rickettsia typhi (causing murine typhus [MT]), spotted fever group rickettsioses (SFGR, causing SFG Rickettsia), Orientia tsutsugamushi (causing scrub typhus [ST]), and Coxiella burnetii (causing Q fever [QF]) were 11.6%, 11.3%, 6%, 5.6%, and 8.0%, respectively. The seroconverted rate in those assigned to Honduras from 2000 to 2016 was 7.3%, 1.9%, 3.9%, 4.3%, and 2.7% for leptospirosis, MT, SFGR, ST, and QF, respectively. Among the seroconverted specimens, 27 showed seroconversion of at least two antibodies. These seroconverted individuals accounted for 8.8% (3 out of 34) of the personnel who looked for medical attention during their deployment.

Conclusions: Our results suggest a leptospirosis seroconversion rate of 7.3%, which is higher than the 0.9% and 3.9% seroconversion in Korea and Japan, respectively. The higher rate of seroconversion indicates potential risk of Leptospira exposure. Additional testing of water samples in the pools and pits around the training sites to locate the infected areas is important to eliminate or reduce future exposure to Leptospira during trainings. The rates of seroconversion for ST, MT, spotted fever Rickettsia, and QF were 4.3%, 1.9%, 3.9%, and 2.7%, respectively, indicating the potential exposure to a variety of rickettsial-related pathogens. Testing of vectors for rickettsial pathogens in the areas could inform effective vector control countermeasures to prevent exposure. Proper precaution and protective measures are needed to better protect military personnel deployed to Honduras.
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http://dx.doi.org/10.1093/milmed/usab120DOI Listing
April 2021

Intracranial 131I-chTNT Brachytherapy in Patients with Deep-Seated Glioma: A Single-center Experience with 10-Year Follow-up from China.

Nuklearmedizin 2021 Aug 9;60(4):283-288. Epub 2021 Apr 9.

Department of Neurosurgery, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China.

Objective:  The intracranial brachytherapy has been applied for decades, however, no results with long-term follow-up have been reported. This study investigated the long-term efficiency of intra-tumoral injection of I-chTNT in patients with deep-seated glioma.

Method:  Thirty-five patients undergoing I-chTNT brachytherapy between December 2004 and May 2009 were enrolled. I-chTNT was injected at a dose of 1.5 mCi/cm at an interval of 1 month for consecutive 3 times. Serial ECT scan and MRI were performed during follow-up. Progression-free survival (PFS) and overall survival (OS) were analyzed. Adverse reactions were graded with WHO Toxicity Grading Scale for determining the severity of adverse events.

Results:  ECT scan showed that enhanced accumulation of radioactive agents in the tumor lasted for more than 30 days. Three months after final injection, tumor complete remission (CR) was observed in 4 patients (11.4 %), partial remission (PR) in 11 cases (31.4 %), stable disease (SD) in 10 cases (28.6 %) and progressive disease (PD) in 10 cases (28.6 %). At 6-month, CR, PR, SD and PD were 2, 6, 12 and 15 respectively. After 10 years of follow-up, median progression-free survival (PFS) and overall survival (OS) were 5.4 and 11.4 months. One-year survival was 45.7 %, two and five-year survival was 8.6 %, ten-year survival was 5.7 %. Multivariate analysis showed that pathological grade and tumor diameter were independent prognostic factors for PFS and OS. Grade I-II adverse events occurred after drug injection, including nausea, fever, headache, hairloss and fatigue.

Conclusion:  I-chTNT intracranial brachytherapy is efficient and safe for patients with deep-seated glioma. It is a reliable option for inoperable glioma patients.
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http://dx.doi.org/10.1055/a-1429-1967DOI Listing
August 2021

Gamma Knife Radiosurgery for High-Grade Gliomas: Single-Center Experience of Six Years in China.

Stereotact Funct Neurosurg 2021 23;99(3):181-186. Epub 2021 Mar 23.

Department of Neurosurgery, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China.

Objective: The aim of this study was to evaluate the efficacy of Gamma Knife radiosurgery (GKRS) as a salvage therapy for high-grade glioma in our center.

Methods: A total of 167 patients with malignant glioma were treated with GKRS in our Gamma Knife Center between January 2013 and December 2017; 140 patients (85 males and 55 females) were followed up and enrolled in our study. A single lesion was found in 110 cases, and multiple lesions were found in 30 cases; 108 cases received a single therapy, and in 32 cases, at least 2 GKRSs were performed. The median tumor volume was 13.5 cm3. The mean radiation dosage was 14.35 Gy (range, 6-18 Gy). MRI was performed regularly. The RANO criteria and Cox analysis were used to evaluate the therapeutic efficiency.

Results: Follow-up MRI showed the local control rate was 61.4% at 3 months after GKRS, 25.0% at 6 months, and 7.1% at 12 months. The mean and median progression-free survival (PFS) periods were 8.6 (95% CI, 6.3-11.0) and 4 (95% CI, 3.5-4.5) (range, 1-60) months, respectively. The overall survival (OS) after GKRS was 3-62 months, with a mean of 16.7 (95% CI, 14.6-18.9) months, and the median survival was 13 (95% CI, 12.1-13.9) months. The 1-, 2-, and 5-year survival rates were 51.4, 10.0, and 2.9%, respectively. No severe complications occurred. Cox regression showed that glioma pathology was closely related to prognosis (p < 0.05). The Karnofsky Performance Score had little influence on PFS (p > 0.05) but influenced OS significantly (p < 0.05).

Conclusion: GKRS can be used to effectively treat malignant brain glioma and can therefore be used as an alternative treatment option.
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http://dx.doi.org/10.1159/000509782DOI Listing
October 2021

Preferential Targeting Cerebral Ischemic Lesions with Cancer Cell-Inspired Nanovehicle for Ischemic Stroke Treatment.

Nano Lett 2021 04 23;21(7):3033-3043. Epub 2021 Mar 23.

Key Laboratory of Smart Drug Delivery, School of Pharmacy, Fudan University, Shanghai 201203, China.

The poor drug delivery to cerebral ischemic regions is a key challenge of ischemic stroke treatment. Inspired by the intriguing blood-brain barrier (BBB)-penetrating ability of 4T1 cancer cells upon their brain metastasis, we herein designed a promising biomimetic nanoplatform by camouflaging a succinobucol-loaded pH-sensitive polymeric nanovehicle with a 4T1 cell membrane (MPP/SCB), aiming to promote the preferential targeting of cerebral ischemic lesions to attenuate the ischemia/reperfusion injury. In transient middle cerebral artery occlusion (tMCAO) rat models, MPP/SCB could be preferentially delivered to the ischemic hemisphere with a 4.79-fold higher than that in the normal hemisphere. Moreover, MPP/SCB produced notable enhancement of microvascular reperfusion in the ischemic hemisphere, resulting in a 69.9% reduction of infarct volume and showing remarkable neuroprotective effects of tMCAO rats, which was superior to the counterpart uncamouflaged nanovehicles (PP/SCB). Therefore, this design provides a promising nanoplatform to target the cerebral ischemic lesions for ischemic stroke therapy.
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http://dx.doi.org/10.1021/acs.nanolett.1c00231DOI Listing
April 2021

Advances of peptides for antibacterial applications.

Colloids Surf B Biointerfaces 2021 Jun 8;202:111682. Epub 2021 Mar 8.

Yantai Institute of Materia Medica, Yantai, 264000, China. Electronic address:

In the past few decades, peptide antibacterial products with unique antibacterial mechanisms have attracted widespread interest. They can effectively reduce the probability of drug resistance of bacteria and are biocompatible, so they possess tremendous development prospects. This review provides recent research and analysis on the basic types of antimicrobial peptides (including poly (amino acid)s, short AMPs, and lipopeptides) and factors to optimize antimicrobial effects. It also summarizes the two most important modes of action of antimicrobial peptides and the latest developments in the application of AMPs, including antimicrobial agent, wound healing, preservative, antibacterial coating and others. Finally, we discuss the remaining challenges to improve the antibacterial peptides and propose prospects in the field.
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http://dx.doi.org/10.1016/j.colsurfb.2021.111682DOI Listing
June 2021

Oxygen-Delivering Polyfluorocarbon Nanovehicles Improve Tumor Oxygenation and Potentiate Photodynamic-Mediated Antitumor Immunity.

ACS Nano 2021 03 24;15(3):5405-5419. Epub 2021 Feb 24.

State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Hypoxia is a critical cause of tumor immunosuppression, and it significantly limits the efficacy of many anticancer modalities. Herein, we report an amphiphilic F-derivative-based oxygen-delivering polyfluorocarbon nanovehicle loading photodynamic DiIC(5) and reactive oxygen species (ROS)-sensitive prodrug of chemo-immunomodulatory gemcitabine (PFDG), aimed at relieving tumor hypoxia and boosting antitumor immunity for cancer therapy. We optimized F-based polyfluorocarbon nanovehicles with a 10-fold enhancement of tumor oxygenation. PFDG exhibited intriguing capabilities, such as oxygen-dissolving, ROS production, and responsive drug release. In tumors, PFDG exhibited flexible intratumoral permeation and boosted robust antitumor immune responses upon laser irradiation. Notably, the treatment of PFDG plus laser irradiation (PFDG+L) significantly retarded the tumor growth with an 82.96% inhibition in the 4T1 breast cancer model and a 93.6% inhibition in the PANC02 pancreatic cancer model with better therapeutic benefits than non-oxygen-delivering nanovehicles. Therefore, this study presents an encouraging polyfluorocarbon nanovehicle with deep tumor-penetrating and hypoxia-relieving capacity to boost antitumor immunity for cancer treatment.
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http://dx.doi.org/10.1021/acsnano.1c00033DOI Listing
March 2021

mTOR pathway regulates the differentiation of peripheral blood Th2/Treg cell subsets in patients with pemphigus vulgaris.

Acta Biochim Biophys Sin (Shanghai) 2021 Mar;53(4):438-445

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

Pemphigus vulgaris (PV) is a chronic and potentially life-threatening autoimmune blistering disease. Aberrant mTOR pathway activity is involved in many autoimmune diseases. This study investigated the correlation of mTOR pathway (PI3K/AKT/mTOR/p70S6K) activity with the loss of balance in T helper 2/regulatory T (Th2/Treg) cells in the peripheral blood of PV patients. CD4+ T cells were isolated from 15 PV patients and 15 healthy controls (HCs), the ratios of Th2/CD4+ T cells and Treg/CD4+ T cells, the activity of the mTOR pathway (PI3K/AKT/mTOR/p70S6K), the transcription factors and cytokines of Th2 and Treg cells were detected. Primary CD4+ T cells from PV patients were cultured under Th2- or Treg-polarizing conditions with or without rapamycin in vitro. We found that PV patients showed significantly elevated serum IL-4 when compared with HCs, and serum IL-4 level was positively correlated with the titer of anti-Dsg1/3 antibody and disease severity, while the serum TGF-β level was negatively correlated with the titer of anti-Dsg3 antibody and disease severity. Meanwhile, PV patients showed increased Th2/CD4+ T cell ratio; decreased Treg/CD4+ T cell ratio; elevated mRNA of PI3K, AKT, mTOR and protein of PI3K (P85), AKT, p-AKT (Ser473), mTOR, p-mTOR (Ser2448), p-p70S6K (Thr389), GATA3; reduced protein of forkhead box protein 3. Rapamycin inhibited Th2 cell differentiation and promoted Treg cell differentiation in vitro. These data suggest a close association between mTOR pathway activation and the loss of balance in Th2/Treg cells in peripheral blood of PV patients. Inhibiting mTORC1 can help restore the Th2/Treg balance.
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http://dx.doi.org/10.1093/abbs/gmab008DOI Listing
March 2021

Dynamics in Endolymphatic Hydrops & Symptoms in Meniere's Disease After Endolymphatic Duct Blockage, Preliminary Results.

Front Neurol 2020 21;11:622760. Epub 2021 Jan 21.

Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, China.

The purpose of the present study was to evaluate the dynamics of endolymphatic hydrops (EH) and symptoms in a group of patients who underwent endolymphatic duct blockage (EDB) for treatment of intractable Meniere's Disease (MD), and to explore a metric for verifying the effectiveness of EDB procedure. A total of 22 patients with intractable MD patients who underwent EDB participated in the present study. EH was visualized using locally enhanced inner ear magnetic resonance imaging (MRI) prior to and following surgery. The vestibular hydrops ratio (VHR) in the second MRI examination was compared with the pre-surgery recordings. Following EDB, 6 patients exhibited complete or partial reversal of EH, complete control of vertigo spells and reported improvement in hearing; 13 patients showed no changes in EH or hearing, but 5 of these patients exhibited complete control of vertigo attacks, and the other 8 patients exhibited improved control of vertigo attacks. The final 3 patients showed an increase in EH, but symptomatic worsening in 2 patients, and symptomatic improvement in 1 patient. There was a significant difference in the average VHR prior to and following EDB. Postoperative VHR was positively correlated with the frequency of vertigo spells in the latest 6 months of follow-up and improvement of postoperative average hearing threshold. The decreased EH accompanying the reduction in vertigo attacks and hearing preservation may provide a metric for verifying the effectiveness of EDB treatment in patients with MD.
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http://dx.doi.org/10.3389/fneur.2020.622760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859097PMC
January 2021

Regulation of Serum Exosomal MicroRNAs in Mice Infected with .

Microorganisms 2020 Dec 31;9(1). Epub 2020 Dec 31.

Viral and Rickettsial Diseases Department, Infectious Diseases Directorate, Naval Medical Research Center, Silver Spring, MD 20910, USA.

Exosomes are small extracellular vesicles that carry proteins, lipids, and nucleic acids. They are circulated in many body fluids and play an important role in intercellular communications. MicroRNAs (miRNAs), as major components of exosomes, are often regulated in many diseases including bacterial and viral infections. Functionally, exosome-carried miRNAs interact with various immune cells and affect their behavior. Little is known whether exosomal miRNAs are regulated during scrub typhus, a potentially lethal infection caused by intracellular bacteria, . In the present study, we utilized a scrub typhus mouse model and collected serum at various time points post infection. A custom quantitative PCR array covering 92 murine miRNAs was used to profile serum exosomal miRNAs. A total of 12 miRNAs were found to be significantly up- or down-regulated at least at one time point post infection when compared to uninfected animals. Further analysis identified multiple miRNAs in the let-7 family that were consistently down-regulated at early and late phase of infection. Functionally, serum exosomes isolated from infected mice displayed strong proinflammatory effect when incubated with bone marrow-derived macrophages. Our data revealed dynamic regulations of serum exosomal miRNA during scrub typhus infection, which could significantly influence host immune responses and disease outcome.
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http://dx.doi.org/10.3390/microorganisms9010080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823836PMC
December 2020

Implantation of regenerative complexes in traumatic brain injury canine models enhances the reconstruction of neural networks and motor function recovery.

Theranostics 2021 1;11(2):768-788. Epub 2021 Jan 1.

Tianjin Key Laboratory of Neurotrauma Repair, Institute of Traumatic Brain Injury and Neuroscience, Center for Neurology and Neurosurgery of Characteristic Medical Center of Chinese People's Armed Police Force (PAP), Chenglin Road No.220, Tianjin 300162, China.

The combination of medical and tissue engineering in neural regeneration studies is a promising field. Collagen, silk fibroin and seed cells are suitable options and have been widely used in the repair of spinal cord injury. In this study, we aimed to determine whether the implantation of a complex fabricated with collagen/silk fibroin (SF) and the human umbilical cord mesenchymal stem cells (hUCMSCs) can promote cerebral cortex repair and motor functional recovery in a canine model of traumatic brain injury (TBI). A porous scaffold was fabricated with cross-linked collagen and SF. Its physical properties and degeneration rate were measured. The scaffolds were co-cultured with hUCMSCs after which an implantable complex was formed. After complex implantation to a canine model of TBI, the motor evoked potential (MEP) and magnetic resonance imaging (MRI) were used to evaluate the integrity of the cerebral cortex. The neurologic score, motion capture, surface electromyography (sEMG), and vertical ground reaction force (vGRF) were measured in the analysis of motor functions. In vitro analysis of inflammation levels was performed by Elisa while immunohistochemistry was used in track the fate of hUCMSCs. In situ hybridization, transmission electron microscope, and immunofluorescence were used to assess neural and vascular regeneration. Favorable physical properties, suitable degradation rate, and biocompatibility were observed in the collagen/SF scaffolds. The group with complex implantation exhibited the best cerebral cortex integrity and motor functions. The implantation also led to the regeneration of more blood vessels and nerve fibers, less glial fibers, and inflammatory factors. Implantation of this complex enhanced therapy in traumatic brain injury (TBI) through structural repair and functional recovery. These effects exhibit the translational prospects for the clinical application of this complex.
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http://dx.doi.org/10.7150/thno.50540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738861PMC
August 2021

Tumor-permeated bioinspired theranostic nanovehicle remodels tumor immunosuppression for cancer therapy.

Biomaterials 2021 02 18;269:120609. Epub 2020 Dec 18.

State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address:

The robust immunosuppressive microenvironment in tumor represents a key challenge of cancer treatment, and their modulations by versatile therapeutic agents are critically hampered by the limited intratumoral delivery. Herein, we report a bioinspired tumor-responsive theranostic nanovehicle (BTN) with striking tumor-penetrating capability to relieve the profound immunosuppression in tumor for effective cancer therapy. BTN is designed by loading tumor-activated melittin pro-peptide, theranostic photochlor and reactive oxygen species (ROS)-responsive prodrug of chemo-immunomodulator gemcitabine into a bioinspired lipoprotein-based nanovehicle, which display prominent tumor accumulation and flexible intratumoral permeation. Notably, the BTN-mediated combinational treatment caused drastic elimination of multiple immunosuppressive cells and remarkable infiltration of cytotoxic lymphocytes in tumor, thereby essentially relieving the tumor immunosuppression and strikingly depressing the tumor growth. Therefore, this design provides an encouraging delivery nanoplatform with distinguished immunosuppression-relieving capacity for effective cancer therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120609DOI Listing
February 2021

Genetic aberrations in Chinese pancreatic cancer patients and their association with anatomic location and disease outcomes.

Cancer Med 2021 02 22;10(3):933-943. Epub 2020 Dec 22.

Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Objectives: Pancreatic cancer (PC) is one of the most lethal malignancies with an increasing death rate over the years. We performed targeted sequencing and survival analyses on 90 Chinese pancreatic cancer patients, hoping to identify genomic biomarkers associated with clinical outcomes and therapeutic options.

Method: Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue specimens of 90 pancreatic cancer patients and sequenced. The associations with clinicopathological factors were analyzed.

Result: High prevalence of driver mutations in KRAS, TP53, CDKN2A, SMAD4, and ARID1A genes were found. Most mutated genes in PC belonged to cell cycle and DNA damage repair pathways. Tumors that arise from the pancreas' body and tail (BT tumors) displayed a higher ratio of mutated KRAS and TP53 than those that arise from the pancreas' head and neck (HN tumors), who showed less diverse KRAS subtypes. Patients with a KRAS p.G12R mutated tumor tended to have a prolonged disease-free survival (DFS) and overall survival (OS) than other KRAS subtypes. Those with an altered ARID1A gene and more than two mutated driver genes tended to have a shorter DFS and OS.

Conclusion: HN and BT tumors of the pancreas displayed different mutational profiles, which had prognostic significances and indicated different potential therapeutic options.
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http://dx.doi.org/10.1002/cam4.3679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897942PMC
February 2021

Typical reactive carbonyl compounds in food products: Formation, influence on food quality, and detection methods.

Compr Rev Food Sci Food Saf 2020 03 11;19(2):503-529. Epub 2020 Feb 11.

NHC Key Laboratory of Food Safety Risk Assessment, Food Safety Research Unit (2019RU014) of Chinese Academy of Medical Science, China National Center for Food Safety Risk Assessment, Beijing, China.

Reactive carbonyl compounds are a large group of highly reactive electrophilic compounds containing one or more carbonyl groups, which can be created by lipid oxidation both in vivo and in food. Malondialdehyde (MDA) and 4-hydroxy-2-nonenel (HNE) are the two most important reactive carbonyl compounds in food. They can react with proteins and nucleic acids and cause biological damage to cells and lead to carbonyl stress. Therefore, they are regarded as representative products of lipid oxidation, toxic molecules, and biomarkers of oxidative stress. Apart from biological toxicity, they can also react with myoglobin and myofibrillar protein and further affect color, gel properties, hydrophobicity, or other properties of food. However, the effects of MDA and HNE on food qualities have not received as much attentions and it is noteworthy that the existing analytical methods for detecting MDA and HNE have a variety of limitations due to the complexity of food samples. To provide a comprehensive understanding of HNE and MDA, the formation mechanism, occurrence, and analytical methods for MDA and HNE in food matrix were summarized in this article. Emphasis is focused on formation mechanism including non-enzymatic pathway and enzymatic pathway, and detection methods including the extraction methods, the new development of sample pre-treatment technology and the selection of derivative reagents. Impressively, the reaction mechanism of MDA and HNE with myoglobin or myofibrillar protein is also described to explain how MDA and HNE affect food quality.
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http://dx.doi.org/10.1111/1541-4337.12535DOI Listing
March 2020
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