Publications by authors named "Aiping Lu"

338 Publications

An aged immune system drives senescence and ageing of solid organs.

Nature 2021 May 12. Epub 2021 May 12.

Department of Orthopedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence in the immune system only. We show that Vav-iCre;Ercc1 mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre;Ercc1 or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre;Ercc1 mice with rapamycin reduced markers of senescence in immune cells and improved immune function. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
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http://dx.doi.org/10.1038/s41586-021-03547-7DOI Listing
May 2021

Improved Bone Quality and Bone Healing of Dystrophic Mice by Parabiosis.

Metabolites 2021 Apr 16;11(4). Epub 2021 Apr 16.

Steadman Philippon Research Institute, Vail, CO 81657, USA.

Duchenne muscular dystrophy (DMD) is a degenerative muscle disorder characterized by a lack of dystrophin expression in the sarcolemma of muscle fibers. DMD patients acquire bone abnormalities including osteopenia, fragility fractures, and scoliosis indicating a deficiency in skeletal homeostasis. The dKO (dystrophin/Utrophin double knockout) is a more severe mouse model of DMD than the mdx mouse (dystrophin deficient), and display numerous clinically-relevant manifestations, including a spectrum of degenerative changes outside skeletal muscle including bone, articular cartilage, and intervertebral discs. To examine the influence of systemic factors on the bone abnormalities and healing in DMD, parabiotic pairing between dKO mice and mdx mice was established. Notably, heterochronic parabiosis with young mdx mice significantly increased bone mass and improved bone micro-structure in old dKO-hetero mice, which showed progressive bone deterioration. Furthermore, heterochronic parabiosis with WT C56/10J mice significantly improved tibia bone defect healing in dKO-homo mice. These results suggest that systemic blood-borne factor(s) and/or progenitors from WT and young mdx mice can influence the bone deficiencies in dKO mice. Understanding these circulating factors or progenitor cells that are responsible to alleviate the bone abnormalities in dKO mice after heterochronic parabiosis might be useful for the management of poor bone health in DMD.
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http://dx.doi.org/10.3390/metabo11040247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073674PMC
April 2021

Structural Biology for the Molecular Insight between Aptamers and Target Proteins.

Int J Mol Sci 2021 Apr 15;22(8). Epub 2021 Apr 15.

Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China.

Aptamers are promising therapeutic and diagnostic agents for various diseases due to their high affinity and specificity against target proteins. Structural determination in combination with multiple biochemical and biophysical methods could help to explore the interacting mechanism between aptamers and their targets. Regrettably, structural studies for aptamer-target interactions are still the bottleneck in this field, which are facing various difficulties. In this review, we first reviewed the methods for resolving structures of aptamer-protein complexes and for analyzing the interactions between aptamers and target proteins. We summarized the general features of the interacting nucleotides and residues involved in the interactions between aptamers and proteins. Challenges and perspectives in current methodologies were discussed. Approaches for determining the binding affinity between aptamers and target proteins as well as modification strategies for stabilizing the binding affinity of aptamers to target proteins were also reviewed. The review could help to understand how aptamers interact with their targets and how alterations such as chemical modifications in the structures affect the affinity and function of aptamers, which could facilitate the optimization and translation of aptamers-based theranostics.
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http://dx.doi.org/10.3390/ijms22084093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071422PMC
April 2021

ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties.

Nucleic Acids Res 2021 Apr 24. Epub 2021 Apr 24.

Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, China.

Because undesirable pharmacokinetics and toxicity of candidate compounds are the main reasons for the failure of drug development, it has been widely recognized that absorption, distribution, metabolism, excretion and toxicity (ADMET) should be evaluated as early as possible. In silico ADMET evaluation models have been developed as an additional tool to assist medicinal chemists in the design and optimization of leads. Here, we announced the release of ADMETlab 2.0, a completely redesigned version of the widely used AMDETlab web server for the predictions of pharmacokinetics and toxicity properties of chemicals, of which the supported ADMET-related endpoints are approximately twice the number of the endpoints in the previous version, including 17 physicochemical properties, 13 medicinal chemistry properties, 23 ADME properties, 27 toxicity endpoints and 8 toxicophore rules (751 substructures). A multi-task graph attention framework was employed to develop the robust and accurate models in ADMETlab 2.0. The batch computation module was provided in response to numerous requests from users, and the representation of the results was further optimized. The ADMETlab 2.0 server is freely available, without registration, at https://admetmesh.scbdd.com/.
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http://dx.doi.org/10.1093/nar/gkab255DOI Listing
April 2021

Targeting long noncoding RNA PMIF facilitates osteoprogenitor cells migrating to bone formation surface to promote bone formation during aging.

Theranostics 2021 20;11(11):5585-5604. Epub 2021 Mar 20.

Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.

The migration of mesenchymal osteoprogenitor cells (OPCs) to bone formation surface is the initial step of osteoblastogenesis before they undergo osteoblast differentiation and maturation for governing bone formation. However, whether the migration capacity of OPCs is compromised during aging and how it contributes to the aging-related bone formation reduction remain unexplored. In the present study, we identified a migration inhibitory factor (, long noncoding RNA PMIF) and examined whether targeting lnc-PMIF could facilitate osteoprogenitor cells migrating to bone formation surface to promote bone formation during aging. Primary OPCs from young (6-momth-old) and aged (18-momth-old) C57BL/6 mice and stable lnc-PMIF knockdown/overexpression cell lines were used for and cell migration assay (, wound healing assay, transwell assay and cell intratibial injection assay). RNA pulldown-MS/WB and RIP-qPCR were performed to identify the RNA binding proteins (RBPs) of lnc-PMIF. Truncations of lnc-PMIF and the identified RBP were engaged to determine the interaction motif between them by RNA pulldown-WB and EMSA. By cell-based therapy approach and by pharmacological approach, small interfering RNA (siRNA)-mediated lnc-PMIF knockdown were used in aged mice. The cell migration ability was evaluated by transwell assay and cell intratibial injection assay. The bone formation was evaluated by microCT analysis and bone morphometry analysis. We reported that the decreased bone formation was accompanied by the reduced migration capacity of the bone marrow mesenchymal stem cells (BMSCs, the unique source of OPCs in bone marrow) in aged mice. We further identified that the long non-coding RNA PMIF (postulated migration inhibitory factor) (, lnc-PMIF) was highly expressed in BMSCs from aged mice and responsible for the reduced migration capacity of aged OPCs to bone formation surface. Mechanistically, we found that lnc-PMIF could bind to human antigen R (HuR) for interrupting the HuR-β-actin mRNA interaction, therefore inhibit the expression of β-actin for suppressing the migration of aged OPCs. We also authenticated a functionally conserved human lncRNA ortholog of the murine lnc-PMIF. By cell-based therapy approach, we demonstrated that replenishing the aged BMSCs with small interfering RNA (siRNA)-mediated lnc-PMIF knockdown could promote bone formation in aged mice. By pharmacological approach, we showed that targeted delivery of lnc-PMIF siRNA approaching the OPCs around the bone formation surface could also promote bone formation in aged mice. Toward translational medicine, this study hints that targeting lnc-PMIF to facilitate aged OPCs migrating to bone formation surface could be a brand-new anabolic strategy for aging-related osteoporosis.
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http://dx.doi.org/10.7150/thno.54477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039942PMC
March 2021

Targeting Strategies for Enhancing Paclitaxel Specificity in Chemotherapy.

Front Cell Dev Biol 2021 29;9:626910. Epub 2021 Mar 29.

Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong.

Paclitaxel (PTX) has been used for cancer treatment for decades and has become one of the most successful chemotherapeutics in the clinic and financially. However, serious problems with its use still exist, owing to its poor solubility and non-selective toxicity. With respect to these issues, recent advances have addressed the water solubility and tumor specificity related to PTX application. Many measures have been proposed to remedy these limitations by enhancing tumor recognition via ligand-receptor-mediated targeting as well as other associated strategies. In this review, we investigated various kinds of ligands that have emerged as PTX tumor-targeting tools. In particular, this article highlights small molecule-, protein-, and aptamer-functionalized conjugates and nanoparticles (NPs), providing a promising approach for PTX-based individualized treatment prospects.
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http://dx.doi.org/10.3389/fcell.2021.626910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039396PMC
March 2021

Transcriptomics-based analysis of the mechanism by which Wang-Bi capsule alleviates joint destruction in rats with collagen-induced arthritis.

Chin Med 2021 Apr 12;16(1):31. Epub 2021 Apr 12.

Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease accompanied with joint destruction that often leads to disability. Wang-Bi capsule (WB), a traditional Chinese medicine-based herbs formula, has exhibited inhibition effect on joint destruction of collagen-induced arthritis (CIA) animal model in our previous study. But its molecular mechanisms are still obscure.

Methods: CIA rats were treated intragastrical with WB for eight weeks, and the effect of joints protection were evaluated by hematoxylin and eosin (H&E) staining, safranin O fast green staining, tartrate-resistant acid phosphatase (TRAP) staining and micro‑CT scanning analysis. The transcriptomic of tarsal joints were used to investigate how WB alleviated joint destruction.

Results: The histological examination of ankle joints showed WB alleviated both cartilage damage and bone destruction of CIA rats. This protective effect on joints were further evidenced by micro-CT analysis. The transcriptomic analysis showed that WB prominently changed 12 KEGG signaling pathways ("calcium signaling pathway", "cAMP signaling pathway", "cell adhesion molecules", "chemokine signaling pathway", "complement and coagulation cascades", "MAPK signaling pathway", "NF-kappa B signaling pathway", "osteoclast differentiation", "PI3K-Akt signaling pathway", "focal adhesion", "Gap junction" and "Rap1 signaling pathway") associated with bone or cartilage. Several genes (including Il6, Tnfsf11, Ffar2, Plg, Tnfrsf11b, Fgf4, Fpr1, Siglec1, Vegfd, Cldn1, Cxcl13, Chad, Arrb2, Fgf9, Egfr) regulating bone resorption, bone formation and cartilage development were identified by further analysis. Meanwhile, these differentially expressed genes were validated by real-time quantitative PCR.

Conclusions: Overall, the protective effect of WB treatment on joint were confirmed in CIA rats, and its basic molecular mechanisms may be associated with regulating some genes (including Il6, Tnfsf11, Ffar2 and Plg etc.) involved in bone resorption, bone formation and cartilage development.
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http://dx.doi.org/10.1186/s13020-021-00439-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042720PMC
April 2021

Artificial Intelligence in Aptamer-Target Binding Prediction.

Int J Mol Sci 2021 Mar 30;22(7). Epub 2021 Mar 30.

Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.

Aptamers are short single-stranded DNA, RNA, or synthetic Xeno nucleic acids (XNA) molecules that can interact with corresponding targets with high affinity. Owing to their unique features, including low cost of production, easy chemical modification, high thermal stability, reproducibility, as well as low levels of immunogenicity and toxicity, aptamers can be used as an alternative to antibodies in diagnostics and therapeutics. Systematic evolution of ligands by exponential enrichment (SELEX), an experimental approach for aptamer screening, allows the selection and identification of in vitro aptamers with high affinity and specificity. However, the SELEX process is time consuming and characterization of the representative aptamer candidates from SELEX is rather laborious. Artificial intelligence (AI) could help to rapidly identify the potential aptamer candidates from a vast number of sequences. This review discusses the advancements of AI pipelines/methods, including structure-based and machine/deep learning-based methods, for predicting the binding ability of aptamers to targets. Structure-based methods are the most used in computer-aided drug design. For this part, we review the secondary and tertiary structure prediction methods for aptamers, molecular docking, as well as molecular dynamic simulation methods for aptamer-target binding. We also performed analysis to compare the accuracy of different secondary and tertiary structure prediction methods for aptamers. On the other hand, advanced machine-/deep-learning models have witnessed successes in predicting the binding abilities between targets and ligands in drug discovery and thus potentially offer a robust and accurate approach to predict the binding between aptamers and targets. The research utilizing machine-/deep-learning techniques for prediction of aptamer-target binding is limited currently. Therefore, perspectives for models, algorithms, and implementation strategies of machine/deep learning-based methods are discussed. This review could facilitate the development and application of high-throughput and less laborious in silico methods in aptamer selection and characterization.
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http://dx.doi.org/10.3390/ijms22073605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038094PMC
March 2021

Mesenchymal stem cell-derived extracellular vesicles reduce senescence and extend health span in mouse models of aging.

Aging Cell 2021 04 16;20(4):e13337. Epub 2021 Mar 16.

Center on Aging and Departments of Molecular Medicine, Scripps Research, Jupiter, Florida, USA.

Aging drives progressive loss of the ability of tissues to recover from stress, partly through loss of somatic stem cell function and increased senescent burden. We demonstrate that bone marrow-derived mesenchymal stem cells (BM-MSCs) rapidly senescence and become dysfunctional in culture. Injection of BM-MSCs from young mice prolonged life span and health span, and conditioned media (CM) from young BM-MSCs rescued the function of aged stem cells and senescent fibroblasts. Extracellular vesicles (EVs) from young BM-MSC CM extended life span of Ercc1 mice similarly to injection of young BM-MSCs. Finally, treatment with EVs from MSCs generated from human ES cells reduced senescence in culture and in vivo, and improved health span. Thus, MSC EVs represent an effective and safe approach for conferring the therapeutic effects of adult stem cells, avoiding the risks of tumor development and donor cell rejection. These results demonstrate that MSC-derived EVs are highly effective senotherapeutics, slowing the progression of aging, and diseases driven by cellular senescence.
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http://dx.doi.org/10.1111/acel.13337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045949PMC
April 2021

The Roles of Sclerostin in Immune System and the Applications of Aptamers in Immune-Related Research.

Front Immunol 2021 25;12:602330. Epub 2021 Feb 25.

Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.

Wnt signaling is one of the fundamental pathways that play a major role in almost every aspect of biological systems. In addition to the well-known influence of Wnt signaling on bone formation, its essential role in the immune system also attracted increasing attention. Sclerostin, a confirmed Wnt antagonist, is also proven to modulate the development and differentiation of normal immune cells, particularly B cells. Aptamers, single-stranded (ss) oligonucleotides, are capable of specifically binding to a variety of target molecules by virtue of their unique three-dimensional structures. With in-depth study of those functional nucleic acids, they have been gradually applied to diagnostic and therapeutic area in immune diseases due to their various advantages over antibodies. In this review, we focus on several issues including the roles of Wnt signaling and Wnt antagonist sclerostin in the immune system. For the sake of understanding, current examples of aptamers applications for the immune diseases are also discussed. At the end of this review, we propose our ideas for the future research directions.
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http://dx.doi.org/10.3389/fimmu.2021.602330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946814PMC
February 2021

Hyocholic acid species as novel biomarkers for metabolic disorders.

Nat Commun 2021 03 5;12(1):1487. Epub 2021 Mar 5.

Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Hyocholic acid (HCA) is a major bile acid (BA) species in the BA pool of pigs, a species known for its exceptional resistance to spontaneous development of diabetic phenotypes. HCA and its derivatives are also present in human blood and urine. We investigate whether human HCA profiles can predict the development of metabolic disorders. We find in the first cohort (n = 1107) that both obesity and diabetes are associated with lower serum concentrations of HCA species. A separate cohort study (n = 91) validates this finding and further reveals that individuals with pre-diabetes are associated with lower levels of HCA species in feces. Serum HCA levels increase in the patients after gastric bypass surgery (n = 38) and can predict the remission of diabetes two years after surgery. The results are replicated in two independent, prospective cohorts (n = 132 and n = 207), where serum HCA species are found to be strong predictors for metabolic disorders in 5 and 10 years, respectively. These findings underscore the association of HCA species with diabetes, and demonstrate the feasibility of using HCA profiles to assess the future risk of developing metabolic abnormalities.
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http://dx.doi.org/10.1038/s41467-021-21744-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935989PMC
March 2021

Therapeutic Effects of (5R)-5-Hydroxytriptolide on Fibroblast-Like Synoviocytes in Rheumatoid Arthritis lncRNA WAKMAR2/miR-4478/E2F1/p53 Axis.

Front Immunol 2021 16;12:605616. Epub 2021 Feb 16.

Department of Rheumatology, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai, China.

Rheumatoid arthritis (RA) is an autoimmune disease. Fibroblast-like synoviocytes (FLS) serve a major role in synovial hyperplasia and inflammation in RA. (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, shows promising therapeutic effects for RA and is now in phase II clinical trials in China. However, the underlying mechanism of LLDT-8 is still not fully understood. Here, we found that LLDT-8 inhibited proliferation and invasion of RA FLS, as well as the production of cytokines. Microarray data demonstrated that LLDT-8 upregulated the expression of long non-coding RNA (lncRNA) WAKMAR2, which was negatively associated with proliferation and invasion of RA FLS, as well as the production of pro-inflammatory cytokines. Knockdown of WAKMAR2 abolished the inhibitory effects of LLDT-8 on RA FLS. Mechanistically, WAKMAR2 sponged miR-4478, which targeted E2F1 and downstreamed p53 signaling. Rescue experiments indicated that the inhibitory effects of LLDT-8 on RA FLS were dependent on WAKMAR2/miR-4478/E2F1/p53 axis.
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http://dx.doi.org/10.3389/fimmu.2021.605616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921149PMC
February 2021

Systems Pharmacology-Based Strategy to Explore the Pharmacological Mechanisms of Peel (Chenpi) for Treating Complicated Diseases.

Am J Chin Med 2021 20;49(2):391-411. Epub 2021 Feb 20.

Department of Respirology & Allergy, Third Affiliated Hospital of Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen University, Shenzhen, P. R. China.

Citri Reticulatae Pericarpium (CRP), also known as Chenpi in Chinese, is the dry mature peel of Blanco or its cultivated varieties. CRP as the health-care food and dietary supplement has been widely used in various diseases. However, the potential pharmacological mechanisms of CRP to predict and treat various diseases have not yet been fully elucidated. A systems pharmacology-based approach is developed by integrating absorption, distribution, metabolism, and excretion screening, multiple target fishing, network pharmacology, as well as pathway analysis to comprehensively dissect the potential mechanism of CRP for therapy of various diseases. The results showed that 39 bioactive components and 121 potential protein targets were identified from CRP. The 121 targets are closely related to various diseases of the cardiovascular system, respiratory system, gastrointestinal system, etc. These targets are further mapped to compound-target, target-disease, and target-pathway networks to clarify the therapeutic mechanism of CRP at the system level. The current study sheds light on a promising way for promoting the discovery of new botanical drugs.
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http://dx.doi.org/10.1142/S0192415X2150018XDOI Listing
February 2021

Enhancement of myogenic potential of muscle progenitor cells and muscle healing during pregnancy.

FASEB J 2021 Mar;35(3):e21378

Department of Orthopaedic Surgery, The University of Texas Health Science Center at Houston, Houston, TX, USA.

The decline of muscle regenerative potential with age has been attributed to a diminished responsiveness of muscle progenitor cells (MPCs). Heterochronic parabiosis has been used as a model to study the effects of aging on stem cells and their niches. These studies have demonstrated that, by exposing old mice to a young systemic environment, aged progenitor cells can be rejuvenated. One interesting idea is that pregnancy represents a unique biological model of a naturally shared circulatory system between developing and mature organisms. To test this hypothesis, we evaluated the muscle regeneration potential of pregnant mice using a cardiotoxin (CTX) injury mouse model. Our results indicate that the pregnant mice demonstrate accelerated muscle healing compared to nonpregnant control mice following muscle injury based on improved muscle histology, superior muscle regeneration, and a reduction in inflammation and necrosis. Additionally, we found that MPCs isolated from pregnant mice display a significant improvement of myogenic differentiation capacity in vitro and muscle regeneration in vivo when compared to the MPCs from nonpregnant mice. Furthermore, MPCs from nonpregnant mice display enhanced myogenic capacity when cultured in the presence of serum obtained from pregnant mice. Our proteomics data from these studies provides potential therapeutic targets to enhance the myogenic potential of progenitor cells and muscle repair.
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http://dx.doi.org/10.1096/fj.202001914RDOI Listing
March 2021

Triptolide delivery: Nanotechnology-based carrier systems to enhance efficacy and limit toxicity.

Pharmacol Res 2021 Mar 20;165:105377. Epub 2021 Jan 20.

State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Institute of Integrated Bioinformedicine & Translational Science, Hong Kong Baptist University Shenzhen Research Institute and Continuing Education, Shenzhen, 518000, China; Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China. Electronic address:

Triptolide (TP) possesses a wide range of biological and pharmacological activities involved in the treatment of various diseases. However, widespread usages of TP raise the urgent issues of the severe toxicity, which hugely limits its further clinical application. The novel functional nanostructured delivery system, which is of great significance in enhancing the efficacy, reducing side effects and improving bioavailability, could improve the enrichment, penetration and controlled release of drugs in the lesion location. Over the past decades, considerable efforts have been dedicated to designing and developing a variety of TP delivery systems with the intention of alleviating the adverse toxicity effects and enhancing the bioavailability. In this review, we briefly summarized and discussed the recent functionalized nano-TP delivery systems for the momentous purpose of guiding further development of novel TP delivery systems and providing perspectives for future clinical applications.
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http://dx.doi.org/10.1016/j.phrs.2020.105377DOI Listing
March 2021

Interaction of nobiletin with methotrexate ameliorates 7-OH methotrexate-induced nephrotoxicity through endoplasmic reticulum stress-dependent PERK/CHOP signaling pathway.

Pharmacol Res 2021 Mar 15;165:105371. Epub 2021 Jan 15.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China. Electronic address:

Drug-induced nephrotoxicity is a frequent adverse event that contributes to acute kidney injury with tubular and/or glomerular lesions. Methotrexate (MTX) is a folate analog used against a myriad of malignancies and autoimmune diseases. Unfortunately, ambiguous renal toxicology limits its safe clinical usage. Based on our previous studies, 7-OH MTX as an overlooked oxidative metabolite of MTX was proposed to be the main culprit responsible for nephrotoxicity, while nobiletin, a naturally occurring polymethoxylated flavonoid screened from our prepared total phenolic extracts of Citrus aurantium L. (TPE-CA), was employed as a therapeutic agent for drug-drug interactions. According to the present study, nobiletin can ameliorate the renal accumulation of 7-OH MTX through the interaction with aldehyde oxidase. RNA-seq analysis revealed that 7-OH MTX was mainly related to protein processing in endoplasmic reticulum (ER) stress, with the PERK/CHOP pathway selected as the most significant for metabolic nephrotoxicity. Meanwhile, the cross-linked proteins and conducted signals were investigated by western blotting and further verified by GSK inhibition analyses. These results indicated that nobiletin protected renal function from MTX-induced nephrotoxicity by modulating metabolism and ameliorated the metabolic toxicity of 7-OH MTX on ER stress-induced PERK/CHOP conduction by maintaining Ca homeostasis and reducing the production of reactive oxygen species.
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http://dx.doi.org/10.1016/j.phrs.2020.105371DOI Listing
March 2021

Unbiased RNA-Seq-driven identification and validation of reference genes for quantitative RT-PCR analyses of pooled cancer exosomes.

BMC Genomics 2021 Jan 6;22(1):27. Epub 2021 Jan 6.

Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.

Background: Exosomes are extracellular vesicles (EVs) derived from endocytic compartments of eukaryotic cells which contain various biomolecules like mRNAs or miRNAs. Exosomes influence the biologic behaviour and progression of malignancies and are promising candidates as non-invasive diagnostic biomarkers or as targets for therapeutic interventions. Usually, quantitative real-time polymerase chain reaction (qRT-PCR) is used to assess gene expression in cancer exosomes, however, the ideal reference genes for normalization yet remain to be identified.

Results: In this study, we performed an unbiased analysis of high-throughput mRNA and miRNA-sequencing data from exosomes of patients with various cancer types and identify candidate reference genes and miRNAs in cancer exosomes. The expression stability of these candidate reference genes was evaluated by the coefficient of variation "CV" and the average expression stability value "M". We subsequently validated these candidate reference genes in exosomes from an independent cohort of ovarian cancer patients and healthy control individuals by qRT-PCR.

Conclusions: Our study identifies OAZ1 and hsa-miR-6835-3p as the most reliable individual reference genes for mRNA and miRNA quantification, respectively. For superior accuracy, we recommend the use of a combination of reference genes - OAZ1/SERF2/MPP1 for mRNA and hsa-miR-6835-3p/hsa-miR-4468-3p for miRNA analyses.
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http://dx.doi.org/10.1186/s12864-020-07318-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789813PMC
January 2021

Aberrant RhoA activation in macrophages increases senescence-associated secretory phenotypes and ectopic calcification in muscular dystrophic mice.

Aging (Albany NY) 2020 12 23;12(24):24853-24871. Epub 2020 Dec 23.

Steadman Philippon Research Institute, Center for Regenerative Sports Medicine, Vail, CO 81657, USA.

Duchenne Muscular Dystrophy (DMD) patients often suffer from both muscle wasting and osteoporosis. Our previous studies have revealed reduced regeneration potential in skeletal muscle and bone, concomitant with ectopic calcification of soft tissues in double knockout (, ; utrophin-/-) mice, a severe murine model for DMD. We found significant involvement of RhoA/ROCK (Rho-Associated Protein Kinase) signaling in mediating ectopic calcification of muscles in mice. However, the cellular identity of these RhoA+ cells, and the role that RhoA plays in the chronic inflammation-associated pathologies has not been elucidated. Here, we report that CD68+ macrophages are highly prevalent at the sites of ectopic calcification of mice, and that these macrophages highly express RhoA. Macrophages from mice feature a shift towards a more pro-inflammatory M1 polarization and an increased expression of various senescence-associated secretory phenotype (SASP) factors that was reduced with the RhoA/ROCK inhibitor Y-27632. Further, systemic inhibition of RhoA activity in mice led to reduced number of RhoA+/CD68+ cells, as well as a reduction in fibrosis and ectopic calcification. Together, these data revealed that RhoA signaling may be a key regulator of imbalanced mineralization in the dystrophic musculoskeletal system and consequently a therapeutic target for the treatment of DMD or other related muscle dystrophies.
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http://dx.doi.org/10.18632/aging.202413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803538PMC
December 2020

Deciphering Antitumor Mechanism of Pien Tze Huang in Mice of Hepatocellular Carcinoma Based on Proteomics.

J Immunol Res 2020 3;2020:4876251. Epub 2020 Dec 3.

Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.

The Chinese formula Pien Tze Huang (PZH) has been used to treat hepatocellular carcinoma (HCC) and showed positive clinical effects. However, the antitumor mechanism of PZH in HCC remains unclear. In this study, HCC xenograft Balb/c mice were treated with PZH; then, proteomics detection and Ingenuity Pathway Analysis (IPA) were used to analyze the differentiated phosphorylated proteins in tumor tissues. The results indicated that PZH could inhibit tumor weight by 50.76%. Eighty-four upregulated and 11 downregulated phosphorylated proteins were identified in PZH-treated mice. Twenty signaling pathways were associated with inflammation (including the IL-6 and TNFR1/2 pathways), cancer growth (including the p53 and FAK pathways), and the cell cycle (including the G2/M and G1/S checkpoint regulation pathways). Moreover, TNF-, IL-6, and several typical differentially expressed phosphorylated proteins (such as p-CCNB1, p-FOXO3, and p-STAT3) in tumor tissues, tumor cell viability, and cell cycle arrest assay further verify the results of IPA. These results revealed that PZH achieved antitumor activity in HCC; the underlying mechanisms of which were mainly through regulating the inflammation-associated cytokine secretion, cancer growth pathways, and induction of G2/M arrest. These data provided the potential molecular basis for PZH to act as a therapeutic drug or a supplement to chemotherapy drugs for human HCC in the future.
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http://dx.doi.org/10.1155/2020/4876251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728492PMC
December 2020

Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism.

Cell Metab 2021 Apr 17;33(4):791-803.e7. Epub 2020 Dec 17.

Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; University of Hawaii Cancer Center, Honolulu, HI 96813, USA; School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. Electronic address:

Hyocholic acid (HCA) and its derivatives are found in trace amounts in human blood but constitute approximately 76% of the bile acid (BA) pool in pigs, a species known for its exceptional resistance to type 2 diabetes. Here, we show that BA depletion in pigs suppressed secretion of glucagon-like peptide-1 (GLP-1) and increased blood glucose levels. HCA administration in diabetic mouse models improved serum fasting GLP-1 secretion and glucose homeostasis to a greater extent than tauroursodeoxycholic acid. HCA upregulated GLP-1 production and secretion in enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor (FXR), a unique mechanism that is not found in other BA species. We verified the findings in TGR5 knockout, intestinal FXR activation, and GLP-1 receptor inhibition mouse models. Finally, we confirmed in a clinical cohort, that lower serum concentrations of HCA species were associated with diabetes and closely related to glycemic markers.
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http://dx.doi.org/10.1016/j.cmet.2020.11.017DOI Listing
April 2021

Roles of MicroRNAs in Bone Destruction of Rheumatoid Arthritis.

Front Cell Dev Biol 2020 19;8:600867. Epub 2020 Nov 19.

Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.

As an important pathological result of rheumatoid arthritis (RA), bone destruction will lead to joint injury and dysfunction. The imbalance of bone metabolism caused by increased osteoclast activities and decreased osteoblast activities is the main cause of bone destruction in RA. MicroRNAs (MiRNAs) play an important role in regulating bone metabolic network. Recent studies have shown that miRNAs play indispensable roles in the occurrence and development of bone-related diseases including RA. In this paper, the role of miRNAs in regulating bone destruction of RA in recent years, especially the differentiation and activities of osteoclast and osteoblast, is reviewed. Our results will not only help provide ideas for further studies on miRNAs' roles in regulating bone destruction, but give candidate targets for miRNAs-based drugs research in bone destruction therapy of RA as well.
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http://dx.doi.org/10.3389/fcell.2020.600867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710907PMC
November 2020

Evidence-based Chinese Medicine Clinical Practice Guideline for Stroke in Hong Kong.

Chin Med 2020 Nov 3;15(1):116. Epub 2020 Nov 3.

Hong Kong Chinese Medicine Clinical Study Centre, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China.

Background: Stroke in Chinese Medicine (CM) includes the concepts of ischemic and hemorrhagic strokes from Western Medicine and is a common disease in Hong Kong. This clinical practice guideline (CPG) aims to evaluate and demonstrate CM treatment options for stroke, provide guideline for local CM practice, and act as a reference for decision makers on drafting CM related health policies.

Methods: Based on the principle of multidisciplinary integration and evidence-based medicine, a steering committee oversaw the CPG development process in accordance with a published protocol. Clinical questions and evidences were identified, appraised, and synthesised through systematic literature reviews, text mining, and two rounds of Delphi surveys with a multidisciplinary panel of experts.

Results: In this CPG, we defined stroke from the perspectives of both CM and Western Medicine, reported corresponding CM treatment options, and carried out evaluation based on levels of evidence and grade of recommendation. Suggested CM interventions include herbal medicine treatment based on pattern differentiation, acupuncture treatment, and nursing care.

Conclusion: The target population is Hong Kong stroke patients with prodrome or sequela stage. This CPG is intended to help standardizing CM clinical practice and enhancing efficiency of clinical service in Hong Kong.
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http://dx.doi.org/10.1186/s13020-020-00397-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607854PMC
November 2020

pH-Responsive Fluorescence Enhanced Nanogel for Targeted Delivery of AUR and CDDP Against Breast Cancer.

Int J Nanomedicine 2020 29;15:8369-8382. Epub 2020 Oct 29.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China.

Introduction: Auraptene (AUR), a natural bioactive prenyloxy coumarin, is a highly pleiotropic molecule that can bind to the MT1 receptor and can effectively reduce the proliferation and migration of breast cancer cells. Cisplatin (CDDP), as the first synthetic platinum-based anticancer drug, is widely used in the clinic due to its definite mechanism and therapeutic effect on diverse tumors. However, both of AUR and CDDP exhibit some disadvantages when used alone, including poor solubility, low bioavailability, lack of selectivity and systemic toxicity when they are used singly.

Methods: Therefore, the biodegradable materials hyaluronic acid (HA) and β-cyclodextrin derivative (mono-(6-amino-mono-6-deoxy)-β-CD, CD) were employed as carriers to load AUR and CDDP to form nanogel (HA-CD@AUR) capable of dual-targeted delivery and synergistic therapy for breast cancer and cell imaging.

Results: With the help of the CDDP-crosslinked CD-loaded structure, the newly synthesized nanogel exhibited excellent physiological stability and fluorescence effects. The release of AUR and CDDP was affected by the pH value, which was beneficial to the selective release in the tumor microenvironment. Cell experiments in vitro demonstrated that the nanogel could be selectively internalized by MCF-7 cells and exhibited low cytotoxicity to HK-2 cells. Antitumor experiments in vivo showed that the nanogel have better antitumor effects and lower systemic toxicity.

Conclusion: Based on these, the nanogel loaded with AUR and CDDP have the potential for targeted delivery against breast cancer.
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http://dx.doi.org/10.2147/IJN.S274842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605673PMC
November 2020

Potential Advantages of Bioactive Compounds Extracted From Traditional Chinese Medicine to Inhibit Bone Destructions in Rheumatoid Arthritis.

Front Pharmacol 2020 7;11:561962. Epub 2020 Oct 7.

Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.

Bone destruction is an important pathological feature of rheumatoid arthritis (RA), which finally leads to the serious decline of life quality in RA patients. Bone metabolism imbalance is the principal factor of bone destruction in RA, which is manifested by excessive osteoclast-mediated bone resorption and inadequate osteoblast-mediated bone formation. Although current drugs alleviate the process of bone destruction to a certain extent, there are still many deficiencies. Recent studies have shown that traditional Chinese medicine (TCM) could effectively suppress bone destruction of RA. Some bioactive compounds from TCM have shown good effect on inhibiting osteoclast differentiation and promoting osteoblast proliferation. This article reviews the research progress of bioactive compounds exacted from TCM in inhibiting bone destruction of RA, so as to provide references for further clinical and scientific research.
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http://dx.doi.org/10.3389/fphar.2020.561962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577042PMC
October 2020

Disorders of Calcium and Phosphorus Metabolism and the Proteomics/Metabolomics-Based Research.

Front Cell Dev Biol 2020 10;8:576110. Epub 2020 Sep 10.

Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tsai, Hong Kong.

Since calcium and phosphorus play vital roles in a multitude of physiologic systems, disorders of calcium and phosphorus metabolism always lead to severe consequences such as skeletal-related and cardiovascular morbidity, or even life-threatening. Physiologically, the maintenance of calcium and phosphorus homeostasis is achieved via a variety of concerted actions of hormones such as parathyroid hormone (PTH), vitamin D, and fibroblast growth factor (FGF23), which could be regulated mainly at three organs, the intestine, kidney, and bone. Disruption of any organ or factor might lead to disorders of calcium and phosphorus metabolism. Currently, lacking of accurate diagnostic approaches and unknown molecular basis of pathophysiology will result in patients being unable to receive a precise diagnosis and personalized treatment timely. Therefore, it is urgent to identify early diagnostic biomarkers and develop therapeutic strategies. Fortunately, proteomics and metabolomics offer promising tools to discover novel indicators and further understanding of pathological mechanisms. Therefore, in this review, we will give a systematic introduction on PTH-1,25(OH)D-FGF23 axis in the disorders of calcium and phosphorus metabolism, diagnostic biomarkers identified, and potential altered metabolic pathways involved.
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http://dx.doi.org/10.3389/fcell.2020.576110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511772PMC
September 2020

Identifying Transcription Factor Combinations to Modulate Circadian Rhythms by Leveraging Virtual Knockouts on Transcription Networks.

iScience 2020 Aug 22;23(9):101490. Epub 2020 Aug 22.

HKBU Institute for Research and Continuing Education, Shenzhen 518057, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 999077, China. Electronic address:

The mammalian circadian systems consist of indigenous, self-sustained 24-h rhythm generators. They comprise many genes, molecules, and regulators. To decode their systematic controls, a robust computational approach was employed. It integrates transcription-factor-occupancy and time-series gene-expression data as input. The model equations were constructed and solved to determine the transcriptional regulatory logics in the mouse transcriptome network. This hypothesizes to explore the underlying mechanisms of combinatorial transcriptional regulations for circadian rhythms in mouse. We reconstructed the quantitative transcriptional-regulatory networks for circadian gene regulation at a dynamic scale. Transcriptional-simulations with virtually knocked-out mutants were performed to estimate their influence on networks. The potential transcriptional-regulators-combinations modulating the circadian rhythms were identified. Of them, CLOCK/CRY1 double knockout preserves the highest modulating capacity. Our quantitative framework offers a quick, robust, and physiologically relevant way to characterize the druggable targets to modulate the circadian rhythms at a dynamic scale effectively.
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http://dx.doi.org/10.1016/j.isci.2020.101490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492989PMC
August 2020

Natural Ingredient-Based Polymeric Nanoparticles for Cancer Treatment.

Molecules 2020 Aug 9;25(16). Epub 2020 Aug 9.

School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 999077, China.

Cancer is a global health challenge. There are drawbacks to conventional chemotherapy such as poor bioavailability, development of drug resistance and severe side effects. Novel drug delivery system may be an alternative to optimize therapeutic effects. When such systems consist of natural materials, they offer important advantages: they are usually highly biocompatible, biodegradable, nontoxic and nonimmunogenic. Furthermore, natural materials can be easily modified for conjugation with a wide range of therapeutic agents and targeting ligands, according to the therapeutic purpose. This article reviews different natural ingredients and their applications in drug delivery systems for cancer therapy. Firstly, an overview of the polysaccharides and protein-based polymers that have been extensively investigated for drug delivery are described. Secondly, recent advances in using various natural ingredient-based polymeric nanoparticles for cancer therapy are reviewed. The characteristics of these delivery systems are summarized, followed by a discussion of future development and clinical potential. This review aims to summarize current knowledge and provide a basis for developing effective tailor-made formulations for cancer therapy in the future.
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http://dx.doi.org/10.3390/molecules25163620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463484PMC
August 2020

A Loop-Based and AGO-Incorporated Virtual Screening Model Targeting AGO-Mediated miRNA-mRNA Interactions for Drug Discovery to Rescue Bone Phenotype in Genetically Modified Mice.

Adv Sci (Weinh) 2020 Jul 28;7(13):1903451. Epub 2020 May 28.

School of Chinese Medicine Faculty of Medicine The Chinese University of Hong Kong Hong Kong SAR China.

Several virtual screening models are proposed to screen small molecules only targeting primary miRNAs without selectivity. Few attempts have been made to develop virtual screening strategies for discovering small molecules targeting mature miRNAs. Mature miRNAs and their specific target mRNA can form unique functional loops during argonaute (AGO)-mediated miRNA-mRNA interactions, which may serve as potential targets for small-molecule drug discovery. Thus, a loop-based and AGO-incorporated virtual screening model is constructed for targeting the loops. The previously published studies have found that miR-214 can target ATF4 to inhibit osteoblastic bone formation, whereas miR-214 can target TRAF3 to promote osteoclast activity. By using the virtual model, the top ten candidate small molecules targeting miR-214-ATF4 mRNA interactions and top ten candidate small molecules targeting miR-214-TRAF3 mRNA interactions are selected, respectively. Based on both in vitro and in vivo data, one small molecule can target miR-214-ATF4 mRNA to promote ATF4 protein expression and enhance osteogenic potential, whereas one small molecule can target miR-214-TRAF3 mRNA to promote TRAF3 protein expression and inhibit osteoclast activity. These data indicate that the loop-based and AGO-incorporated virtual screening model can help to obtain small molecules specifically targeting miRNA-mRNA interactions to rescue bone phenotype in genetically modified mice.
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http://dx.doi.org/10.1002/advs.201903451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341099PMC
July 2020

Recent Progress in Aptamer Discoveries and Modifications for Therapeutic Applications.

ACS Appl Mater Interfaces 2021 Mar 30;13(8):9500-9519. Epub 2020 Jun 30.

Institute of Precision Medicine and Innovative Drug Discovery, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.

Aptamers are oligonucleotide sequences with a length of about 25-80 bases which have abilities to bind to specific target molecules that rival those of monoclonal antibodies. They are attracting great attention in diverse clinical translations on account of their various advantages, including prolonged storage life, little batch-to-batch differences, very low immunogenicity, and feasibility of chemical modifications for enhancing stability, prolonging the half-life in serum, and targeted delivery. In this Review, we demonstrate the emerging aptamer discovery technologies in developing advanced techniques for producing aptamers with high performance consistently and efficiently as well as requiring less cost and resources but offering a great chance of success. Further, the diverse modifications of aptamers for therapeutic applications including therapeutic agents, aptamer-drug conjugates, and targeted delivery materials are comprehensively summarized.
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http://dx.doi.org/10.1021/acsami.0c05750DOI Listing
March 2021

A PD-L1 Aptamer Selected by Loss-Gain Cell-SELEX Conjugated with Paclitaxel for Treating Triple-Negative Breast Cancer.

Med Sci Monit 2020 Jun 23;26:e925583. Epub 2020 Jun 23.

School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China (mainland).

BACKGROUND The clinical challenges of triple-negative breast cancer (TNBC) includes the lack of targeted therapy and chemoresistance. TNBC has relatively high PD-L1 expression, and PD-L1 antibody in combination with nab-paclitaxel has been approved by FDA for TNBC treatment. Aptamers, also termed chemical antibody, are widely used in targeted drug delivery. The present study aimed to select a DNA aptamer that could specifically bind and deliver drugs to TNBC cells. MATERIAL AND METHODS An innovative loss-gain cell-SELEX strategy was used to select DNA aptamer for PD-L1 protein. Construction of PD-L1 knock-out and over-expression MDA-MB-231 cell lines were conducted through transfection and confirmed by western blot and flow cytometry. Confocal microscopy and flow cytometry were used to analyze the binding ability of aptamer with TNBC cells. The cytotoxicity of aptamer-paclitaxel complex against TNBC cells was evaluated by Cell Counting Kit-8 assay. The reactivation of the T cell function by aptamer was measured by IL-2 enzyme-linked immunosorbent assay after T cells co-cultured with tumor cells. RESULTS In this work, using an innovative loss-gain cell-SELEX strategy, we screened a PD-L1-targeting aptamer. PD-L1 aptamer selectively bound to PD-L1 over-expressed TNBC cells with a dissociation constant in the nanomolar range. PD-L1 aptamer could also inhibit PD-1/PD-L1 interaction and restore the function of T cells. Moreover, we developed a PD-L1 aptamer-paclitaxel conjugate which showed improved cellular uptake and anti-proliferation efficacy in PD-L1 over-expressed TNBC cells. CONCLUSIONS In summary, these findings suggest that the selected PD-L1 aptamer might have potential implication in immune modulation and targeted therapy against TNBC.
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http://dx.doi.org/10.12659/MSM.925583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331476PMC
June 2020