Publications by authors named "Yuqi Yang"

119 Publications

Overexpression of ABCG2 Confers Resistance to MLN7243, a Ubiquitin-Activating Enzyme (UAE) Inhibitor.

Front Cell Dev Biol 2021 14;9:697927. Epub 2021 Jul 14.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

Overexpression of ATP-binding cassette transporter superfamily G member 2 (ABCG2), is known as a major mechanism mediating multidrug resistance (MDR) in cancer cells. MLN7243 is a small-molecule ubiquitin activating enzyme inhibitor currently under clinical investigation. The aim of the current study is to determine if MLN7243 is a substrate of MDR-related ABCG2 transporter. Our results showed that cancer cells overexpressing ABCG2 transporter were resistant to MLN7243 compared to the parental cells, while knockout of ABCG2 gene or pharmacological inhibition of ABCG2 efflux function completely reversed the drug resistance. Unexpectedly, the endogenous low expression of ABCG2 is sufficient to confer cancer cells resistance to MLN7243. The ABCG2 ATPase assay and HPLC assay suggested that MLN7243 can significantly stimulate ABCG2 ATPase activity and be pumped out from ABCG2-overexpressing cells by ABCG2. The docking analysis also implied that MLN7243 binds to ABCG2 drug-binding pocket with optimal binding affinity. However, MLN7243 did not competitively inhibit the efflux of other ABCG2 substrate drugs, indicating it may not serve as an MDR reversal agent. In conclusion, our study provides direct evidence to show that MLN7243 is a potent ABCG2 substrate. If our results can be translated to humans, it suggests that combining MLN7243 with ABCG2 inhibitors may enhance the anticancer efficacy for patients with high tumor ABCG2 level.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2021.697927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316815PMC
July 2021

Coloring ultrasensitive MRI with tunable metal-organic frameworks.

Chem Sci 2021 Feb 9;12(12):4300-4308. Epub 2021 Feb 9.

Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics Wuhan 430071 China

As one of the most important imaging modalities, magnetic resonance imaging (MRI) still faces relatively low sensitivity to monitor low-abundance molecules. A newly developed technology, hyperpolarized Xe magnetic resonance imaging (MRI), can boost the signal sensitivity to over 10 000-fold compared with that under conventional MRI conditions, and this technique is referred to as ultrasensitive MRI. However, there are few methods to visualize complex mixtures in this field due to the difficulty in achieving favorable "cages" to capture the signal source, namely, Xe atoms. Here, we proposed metal-organic frameworks (MOFs) as tunable nanoporous hosts to provide suitable cavities for xenon. Due to the widely dispersed spectroscopic signals, Xe in different MOFs was easily visualized by assigning each chemical shift to a specific color. The results illustrated that the pore size determined the exchange rate, and the geometric structure and elemental composition influenced the local charge experienced by xenon. We confirmed that a complex mixture was first differentiated by specific colors in ultrasensitive MRI. The introduction of MOFs helps to overcome long-standing obstacles in ultrasensitive, multiplexed MRI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0sc06969hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179523PMC
February 2021

RIP1-Mediated Necroptosis Facilitates Oxidative Stress‒Induced Melanocyte Death, Offering Insight into Vitiligo.

J Invest Dermatol 2021 Jun 5. Epub 2021 Jun 5.

Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi'an, China. Electronic address:

Vitiligo is a common depigmentation disease characterized by melanocyte death, which is attributed to various mechanisms such as apoptosis and autoimmune destruction. However, whether necroptosis, a newly discovered way of cell death, plays a key role in the pathogenesis of vitiligo is still elusive and has not been well-studied. In this study, we found that necroptosis markers, including phosphorylated RIP3 and phosphorylated-MLKL, were positive in melanocytes from vitiligo perilesional skins, which supported the existence of necroptosis in vitiligo. Furthermore, the expression of RIP1 was remarkably upregulated in melanocytes treated with hydrogen peroxide. Then, RIP1 intervention suppression and MLKL deficiency could significantly enhance the resistance of melanocytes to hydrogen peroxide‒induced necroptosis. Mechanistically, we confirmed that RIP1 and RIP3 could form necrosomes under oxidative stress and further trigger phosphorylated MLKL translocation to the cell membrane, which led to the destruction of melanocytes. Finally, we showed that RIP1-mediated generation of mitochondrial ROS contributed to necrosome formation in melanocytes. Collectively, our study confirms that necroptosis significantly facilitates oxidative stress‒induced melanocyte death through the RIP1 signaling pathway, offering insight into vitiligo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2020.06.042DOI Listing
June 2021

Plasmonic-doped melanin-mimic for CXCR4-targeted NIR-II photoacoustic computed tomography-guided photothermal ablation of orthotopic hepatocellular carcinoma.

Acta Biomater 2021 07 31;129:245-257. Epub 2021 May 31.

Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China; Institute of Digital Intelligence of Zhujiang Hospital of Southern Medical University, Guangzhou, 510280, China; Guangdong Provincial Clinical and Engineering Technology Center of Digital Medicine, Guangzhou, 510280, China. Electronic address:

Effective and noninvasive diagnosis and prompt treatment of early-stage hepatocellular carcinoma (HCC) are urgently needed to reduce its mortality rate. Herein, the integration of high-resolution diagnostic second near-infrared (NIR-II) photoacoustic computed tomography (PACT) and imaging-guided targeted photothermal ablation of orthotopic small HCC (SHCC) is presented for the first time, which was enabled by a plasmonic platinum (Pt)-doped polydopamine melanin-mimic nanoagent. As designed, an antibody-modified nanoagent (designated [email protected]) with a plasmonic blackbody-like NIR absorption and superior photothermal conversion efficiency (71.3%) selectively targeted and killed CXCR4-overexpressing HCC (HepG2) cells, which was validated in in vitro experiments. The targeted accumulation properties of [email protected] in vivo were previously recognized by demonstrating effective NIR-II PA imaging and photothermal ablation in a subcutaneous HCC mouse model. Subsequently, with real-time quantitative guidance by PACT for the accurate diagnosis of intraabdominal SHCC (approximately 4 mm depth), the effective and noninvasive photothermal ablation of SHCCs was successfully demonstrated in an orthotopic tumor-bearing mouse model without damaging adjacent liver tissues. These results show a great potential of NIR-II PACT-guided noninvasive photothermal therapy as an innovative phototheranostic approach and expand the biomedical applications of melanin-mimic materials. STATEMENT OF SIGNIFICANCE: In this paper, we report the first diagnostic NIR-II photoacoustic computed tomography (PACT)-guided noninvasive photothermal ablation of small hepatocellular carcinoma (SHCC) located in deep tissues in orthotopic tumor-bearing mice; this process is empowered by a polydopamine-based melanin-mimic tumor-targeting nanoagent doped with plasmonic platinum that provides superior NIR-II (1064 nm) absorption and photothermal conversion efficiency of 71.3%. Following surface modification with anti-CXCR4 antibodies, the nanoagent (namely [email protected]) can selectively target CXCR4-overexpressed HepG2 carcinoma cells and tumor lesions, and serve as the theranostic agent for both NIR-II PACT-based diagnosis of orthotopic SHCC (diameter less than 5 mm) and efficient NIR-II PTT in vivo. This study may also extend the potential of melanin-derived blackbody materials for optical-biomedical and water distillation applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.actbio.2021.05.034DOI Listing
July 2021

Transcriptomic Profiling of Human Placenta in Gestational Diabetes Mellitus at the Single-Cell Level.

Front Endocrinol (Lausanne) 2021 7;12:679582. Epub 2021 May 7.

Womens Hospital of Nanjing Medical University, Nanjing, China.

Gestational diabetes mellitus (GDM) is associated with an increased risk of adverse pregnancy outcomes. Increasing evidence shows that placentation defects may play important roles in GDM. However, our understanding of the human placenta remains limited. In this study, we generated a comprehensive transcriptomic profile of cellular signatures and transcriptomes in the human placenta in GDM using single-cell RNA sequencing (scRNA-seq), constructed a comprehensive cell atlas, and identified cell subtypes and subtype-specific marker genes. In addition, we investigated the placental cellular function and intercellular interactions in GDM. These findings help to elucidate the molecular mechanisms of GDM, and may facilitate the development of new approaches to GDM treatment and prevention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2021.679582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139321PMC
May 2021

Development of a novel starch-based dietary fiber using glucanotransferase.

Food Funct 2021 Jul;12(13):5745-5754

State Key Laboratory of Food Science & Technology, Jiangnan University, 1800 Lihu Avenue, Wuxi, Jiangsu 214122, P. R. China.

In this study, a glucanotransferase from prokaryotic Azotobacter chroococcum NCIMB 8003 was recombinantly expressed and its biochemical characteristics and bioconversion ability for starch were investigated. The purified enzyme has the optimum activity at 55 °C and pH 6.5-7.0, as well as a melting temperature of 62 °C. The double-charged ion Ca2+ stimulated the activity of the enzyme by approximately 2.4 times. The kinetic parameters and specificity analysis revealed that this glucanotransferase had a higher affinity for high-amylose starch. During the transglycosylation reaction, the starch molecule was converted into a relatively small polymer with a narrow size distribution. For the enzyme modification of high-amylose starch for 72 h, the amount of α-1,6 linkages increased from 1.9% to 22.7% and the content of resistant starch (RS) increased from 3.18% to 17.83%. In addition, the fine structure displayed the reuteran-like highly branched glucan linked by single linear α-1,6 linkages and α-1,4/6 branching points. These results revealed that a promising prebiotic dietary fiber was synthesized from starch with glucanotransferase modification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d1fo00287bDOI Listing
July 2021

Anti-Angiogenic Efficacy of PSORI-CM02 and the Associated Mechanism in Psoriasis and .

Front Immunol 2021 30;12:649591. Epub 2021 Apr 30.

The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China.

Psoriasis is a chronic proliferative autoimmune dermatologic disease characterised by abnormal angiogenesis. Thus, regulating angiogenesis in the skin is an important treatment strategy for psoriasis. PSORI-CM02, an empirical Chinese medicine formula optimised from Yin Xie Ling, was created by the Chinese medicine specialist, Guo-Wei Xuan. Clinical studies have shown that PSORI-CM02 is safe and effective for the treatment of psoriasis. However, its anti-psoriatic mechanisms remain to be further explored. In this study, we investigated the effects of PSORI-CM02 on angiogenesis in the skin and the underlying mechanisms in IL-17A-stimulated human umbilical vein endothelial cells (HUVECs) and a murine model of imiquimod (IMQ)-induced psoriasis. , PSORI-CM02 significantly inhibited the proliferation and migration of IL-17A-stimulated HUVECs in a dose-dependent manner. Further, it markedly regulated the antioxidative/oxidative status and inflammation; suppressed the expression of VEGF, VEGFR1, VEGFR2, ANG1, and HIF-1α; and reduced the phosphorylation of MAPK signalling pathway components in IL-17A-stimulated HUVECs. studies showed that PSORI-CM02 markedly reduced angiogenesis in the skin of mice with IMQ-induced psoriasis, while significantly rebalancing antioxidant/oxidant levels; inhibiting the production of IL-6, TNF-α, IL-17A, and IL-17F; and repressing the synthesis of angiogenic mediators. In addition, PSORI-CM02 markedly reduced the activation of the MAPK signalling pathway in psoriatic skin tissue. Taken together, our results demonstrated that PSORI-CM02 inhibited psoriatic angiogenesis by reducing the oxidative status and inflammation, suppressing the expression of angiogenesis-related molecules, and inhibiting the activation of the MAPK signalling pathway and .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.649591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119787PMC
April 2021

Using an artificial neural network to predict the residual stress induced by laser shock processing.

Appl Opt 2021 Apr;60(11):3114-3121

With the purpose of using the artificial neural network (ANN) method to predict the residual stresses induced by laser shock processing (LSP), the Ni-Cr-Fe-based precipitation-hardening superalloy GH4169 was selected as the experimental material in this work, and the experimental samples were treated by LSP with laser power densities of 4.24/, 7.07/, and 9.90/ and overlap rates of 10%, 30%, and 50%. The depth-wise residual stresses of experimental samples prior to and after LSP were taken according to the x-ray diffraction method and electrolytic-polished layer by layer. The ANN model for residual stress prediction was established, and the laser power density, overlap rate, and depth were set as input parameters, while residual stress was set as the output parameter. The residual stresses of untreated samples and those treated with laser power densities of 4.24/ and 9.90/ were selected as the training sets, and the data of experimental samples treated with a laser power density of 7.07/ were reserved as testing sets for validating the trained network. After LSP, beneficial stable compressive residual stresses were introduced in the material's near surface, and the overall maximum compressive residual stresses were formed on the top surface (surface residual stress). Depending on the LSP process parameters, the surface residual stresses ranged from -236 to -799, and the compressive residual stress depths of all treated samples were over 0.50 mm. According to the results obtained by ANN, the coefficient of determination of the training sets is 0.9948, which shows a good fitness for the training network. The of the testing sets is 0.9931, which is less than that of the training sets but still shows high accuracy. This work proves that the ANN method can be applied to predict the residual stress of metallic materials by LSP treatment with high accuracy and provides a guiding value for the optimization of the LSP process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/AO.421431DOI Listing
April 2021

Preparation and characterization of metal-tea polysaccharide complexes and their inhibition on α-glucosidase.

J Food Biochem 2021 05 4;45(5):e13689. Epub 2021 Apr 4.

College of Food Science and Engineering, Ocean University of China, Qingdao, People's Republic of China.

The preparation method and the sources of metal elements may affect the activity of the metal-polysaccharide complex. In this study, four Fe-tea polysaccharide complexes were prepared and three tea polysaccharides (TPSs) from different seasons were extracted. Moreover, the binding mode of TPSs with internal and external metallic elements as well as their inhibitory effect on α-glucosidase was explored. The results revealed that the binding mode (-C-O-Fe and -C-Fe) of the Fe-TPS complex prepared at pH 5.0 was closer to TPS with internal metallic elements. The TPS with the least amount of internal metallic elements (61.72 mg/g) exhibited a high inhibitory activity on α-glucosidase (37.90%). The inhibitory activity of Fe-TPS on α-glucosidase was lower than that without Fe. But the quenching effect and the inhibition type of TPSs on α-glucosidase were not affected by metallic elements. Therefore, the metallic elements have the potential to reduce the hypoglycemic activity of TPS. PRACTICAL APPLICATIONS: In this paper, TPS was extracted from crude tea in different seasons, and the effects of metallic elements in TPS on hypoglycemic activity, physicochemical properties, and structure of TPS were discussed. TPS metal complexes were prepared by adding Fe or removing metallic elements, and the differences of internal metallic elements in TPS were discussed. It is of great academic significance to use tea pruned leaves and crude tea as potential resources to develop polysaccharide hypoglycemic products and to reveal the relationship between TPS metal ions and their structure and activity. In addition, it has guiding value for consumers to choose tea-producing regions and growers to choose chemical fertilizer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jfbc.13689DOI Listing
May 2021

Operando Cooperated Catalytic Mechanism of Atomically Dispersed Cu-N and Zn-N for Promoting Oxygen Reduction Reaction.

Angew Chem Int Ed Engl 2021 Jun 13;60(25):14005-14012. Epub 2021 May 13.

Key Laboratory of Functional Inorganic Materials Chemistry, Ministry of Education of the People's Republic of China, Heilongjiang University, Harbin, 150080, China.

Dual-metal single-atom catalysts exhibit superior performance for oxygen reduction reaction (ORR), however, the synergistic catalytic mechanism is not deeply understood. Herein, we report a dual-metal single-atom catalyst consisted of Cu-N and Zn-N on the N-doped carbon support (Cu/Zn-NC). It exhibits high-efficiency ORR activity with an E of 0.98 V and an E of 0.83 V, excellent stability (no degradation after 10 000 cycles), surpassing state-of-the-art Pt/C and great mass of Pt-free single atom catalysts. Operando XANES demonstrates that the Cu-N as active center experiences the change from atomic dispersion to cluster with the cooperation of Zn-N during ORR process, and then turns to single atom state again after reaction. DFT calculation further indicates that the adjustment effect of Zn on the d-orbital electron distribution of Cu could benefit to the stretch and cleavage of O-O on Cu active center, speeding up the process of rate determining step of OOH*.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.202102053DOI Listing
June 2021

Overexpression of ABCC1 Confers Drug Resistance to Betulin.

Front Oncol 2021 25;11:640656. Epub 2021 Feb 25.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, United States.

Betulin is a lupane-type pentacyclic triterpene, which is isolated from birch bark. It has a broad spectrum of biological and pharmacological properties, such as anti-inflammatory, anti-tumor, anti-viral, and anti-bacterial activity. Herein, we explored the factors that may result in betulin resistance, especially with respect to its interaction with ATP-binding cassette subfamily C member 1 (ABCC1). ABCC1 is an important member of the ATP-binding cassette (ABC) transporter family, which is central to mediating multidrug resistance (MDR) in naturally derived anticancer agents. An MTT-based cell viability assay showed that ABCC1 overexpression has the ability to desensitize both cancer cell line and gene-transfected cell line to betulin and that this betulin-induced resistance can be antagonized by a known ABCC1 inhibitor MK571 at 25 μM. Additionally, betulin upregulates the ABCC1 protein expression level in both concentration-dependent and time-dependent manners, also blocks the transport function mediated by ABCC1. Subsequently, a high affinity score of betulin was achieved in a computational docking analysis, demonstrating a strong interaction of betulin with ABCC1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.640656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951056PMC
February 2021

A genetic screen for temperature-sensitive morphogenesis-defective Caenorhabditis elegans mutants.

G3 (Bethesda) 2021 04;11(4)

Institute of Molecular Biology, University of Oregon, Eugene, OR, 97402, USA.

Morphogenesis involves coordinated cell migrations and cell shape changes that generate tissues and organs, and organize the body plan. Cell adhesion and the cytoskeleton are important for executing morphogenesis, but their regulation remains poorly understood. As genes required for embryonic morphogenesis may have earlier roles in development, temperature-sensitive embryonic-lethal mutations are useful tools for investigating this process. From a collection of ∼200 such Caenorhabditis elegans mutants, we have identified 17 that have highly penetrant embryonic morphogenesis defects after upshifts from the permissive to the restrictive temperature, just prior to the cell shape changes that mediate elongation of the ovoid embryo into a vermiform larva. Using whole genome sequencing, we identified the causal mutations in seven affected genes. These include three genes that have roles in producing the extracellular matrix, which is known to affect the morphogenesis of epithelial tissues in multicellular organisms: the rib-1 and rib-2 genes encode glycosyltransferases, and the emb-9 gene encodes a collagen subunit. We also used live imaging to characterize epidermal cell shape dynamics in one mutant, or1219ts, and observed cell elongation defects during dorsal intercalation and ventral enclosure that may be responsible for the body elongation defects. These results indicate that our screen has identified factors that influence morphogenesis and provides a platform for advancing our understanding of this fundamental biological process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/g3journal/jkab026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133775PMC
April 2021

Establishment and Characterization of an Irinotecan-Resistant Human Colon Cancer Cell Line.

Front Oncol 2020 22;10:624954. Epub 2021 Feb 22.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, United States.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Irinotecan is widely used as a chemotherapeutic drug to treat CRC. However, the mechanisms of acquired resistance to irinotecan in CRC remain inconclusive. In the present study, we established a novel irinotecan-resistant human colon cell line to investigate the underlying mechanism(s) of irinotecan resistance, particularly the overexpression of ABC transporters. The irinotecan-resistant S1-IR20 cell line was established by exposing irinotecan to human S1 colon cancer cells. MTT cytotoxicity assay was carried out to determine the drug resistance profile of S1-IR20 cells. The drug-resistant cells showed about 47-fold resistance to irinotecan and cross-resistance to ABCG2 substrates in comparison with S1 cells. By Western blot analysis, S1-IR20 cells showed significant increase of ABCG2, but not ABCB1 or ABCC1 in protein expression level as compared to that of parental S1 cells. The immunofluorescence assay showed that the overexpressed ABCG2 transporter is localized on the cell membrane of S1-IR20 cells, suggesting an active efflux function of the ABCG2 transporter. This finding was further confirmed by reversal studies that inhibiting efflux function of ABCG2 was able to completely abolish drug resistance to irinotecan as well as other ABCG2 substrates in S1-IR20 cells. In conclusion, our work established an model of irinotecan resistance in CRC and suggested ABCG2 overexpression as one of the underlying mechanisms of acquired resistance to irinotecan. This novel resistant cell line may enable future studies to overcome drug resistance and improve CRC treatment .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.624954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937870PMC
February 2021

OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance.

Front Pharmacol 2021 15;12:620874. Epub 2021 Feb 15.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

OTS964 is a potent T-LAK cell-originated protein kinase (TOPK) inhibitor. Herein, we investigated the interaction of OTS964 and multidrug resistance (MDR)-associated ATP-binding cassette sub-family G member 2 (ABCG2). The cell viability assay indicated that the effect of OTS964 is limited in cancer drug-resistant and transfected cells overexpressing ABCG2. We found that the known ABCG2 transporter inhibitor has the ability to sensitize ABCG2-overexpressing cells to OTS964. In mechanism-based studies, OTS964 shows inhibitory effect on the efflux function mediated by ABCG2, and in turn, affects the pharmacokinetic profile of other ABCG2 substrate-drugs. Furthermore, OTS964 upregulates ABCG2 protein expression, resulting in enhanced resistance to ABCG2 substrate-drugs. The ATPase assay demonstrated that OTS964 stimulates ATPase activity of ABCG2 in a concentration-dependent manner. The computational molecular docking analysis combined with results from ATPase assay suggested that OTS964 interacts with drug-binding pocket of ABCG2 and has substrate-like behaviors. Thus, OTS964 is an MDR-susceptible agent due to its interactions with ABCG2, and overexpression of ABCG2 transporter may attenuate its therapeutic effect in cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.620874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917255PMC
February 2021

Covalent conjugation of extracellular vesicles with peptides and nanobodies for targeted therapeutic delivery.

J Extracell Vesicles 2021 Feb 16;10(4):e12057. Epub 2021 Feb 16.

Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Singapore.

Natural extracellular vesicles (EVs) are ideal drug carriers due to their remarkable biocompatibility. Their delivery specificity can be achieved by the conjugation of targeting ligands. However, existing methods to engineer target-specific EVs are tedious or inefficient, having to compromise between harsh chemical treatments and transient interactions. Here, we describe a novel method for the covalent conjugation of EVs with high copy numbers of targeting moieties using protein ligases. Conjugation of EVs with either an epidermal growth factor receptor (EGFR)-targeting peptide or anti-EGFR nanobody facilitates their accumulation in EGFR-positive cancer cells, both and . Systemic delivery of paclitaxel by EGFR-targeting EVs at a low dose significantly increases drug efficacy in a xenografted mouse model of EGFR-positive lung cancer. The method is also applicable to the conjugation of EVs with peptides and nanobodies targeting other receptors, such as HER2 and SIRP alpha, and the conjugated EVs can deliver RNA in addition to small molecules, supporting the versatile application of EVs in cancer therapies. This simple, yet efficient and versatile method for the stable surface modification of EVs bypasses the need for genetic and chemical modifications, thus facilitating safe and specific delivery of therapeutic payloads to target cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jev2.12057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886705PMC
February 2021

New approaches in extracellular vesicle engineering for improving the efficacy of anti-cancer therapies.

Semin Cancer Biol 2021 Feb 17. Epub 2021 Feb 17.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute for Digital Medicine, Immunology Programme and Cancer Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; N.1 Institute for Health, National University of Singapore, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Cancer is a disease that evolves continuously with unpredictable outcomes. Although conventional chemotherapy can display significant antitumor effects, the lack of specificity and poor bioavailability remain major concerns in cancer therapy. Moreover, with the advent of novel anti-cancer gene therapies, there is an urgent need for drug delivery vectors capable of bypassing cellular barriers and efficiently transferring therapeutic cargo to recipient cells. A number of drug delivery systems have been proposed to overcome these limitations, but their successful clinical translation has been hampered by the onset of unexpected side effects and associated toxicities. The application of extracellular vesicles (EVs), a class of naturally released, cell-derived particles, as drug delivery vectors presents a breakthrough in nanomedicine, taking into account their biocompatibility and natural role in intercellular communication. Combining the advantageous intrinsic properties of EVs with surface functionalization and the encapsulation of drugs allows for a new class of engineered EVs that serve as effective therapeutic carriers. Here, we describe the various successful approaches involving the application of engineered EVs as bio-derived drug delivery vectors in cancer therapy. The latest and most effective strategies of engineering EVs to improve drug loading, stealth properties and tumour targeting capabilities of EVs are debated. Finally, current obstacles and future perspectives of smart engineered EVs are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semcancer.2021.02.010DOI Listing
February 2021

Natural Product as Substrates of ABC Transporters: A Review.

Recent Pat Anticancer Drug Discov 2021 Feb 18. Epub 2021 Feb 18.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York 11439, . United States.

Background: To date, many compounds extracting from natural products have anti-tumor activity, such as citronellol, ellagitannin-containing pomegranate extract, etc. Evidence from clinical context shows that multidrug resistance is an obstacle that impedes the effectiveness of natural products, such as chemotherapeutic agents paclitaxel and vincristine. Overexpression of ATP-Binding Cassette (ABC) transporters is the leading cause of MDR. Therefore, it is crucial to investigate whether these natural products are substrates of MDR-associated ABC transporters, which may benefit the development of their clinical usage.

Objective: This review summarizes the latest insight on natural products possessing substrate profile and analyzed some possible regularity to provide direction for future drug discovery.

Conclusion: The anti-tumor effects of natural products are constantly being explored, but the drug resistance issues cannot be ignored, which limits their prospects as anti-tumor drugs to a certain extent. At the same time, some natural products are taken as a daily diet, and their possible role in increasing the drug resistance of the substrate should arouse the attention of clinical cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1574892816666210218220943DOI Listing
February 2021

Elevated ABCB1 Expression Confers Acquired Resistance to Aurora Kinase Inhibitor GSK-1070916 in Cancer Cells.

Front Pharmacol 2020 14;11:615824. Epub 2021 Jan 14.

Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.

The emergence of multidrug resistance (MDR) has been a major issue for effective cancer chemotherapy as well as targeted therapy. One prominent factor that causes MDR is the overexpression of ABCB1 transporter. In the present study, we revealed that the Aurora kinase inhibitor GSK-1070916 is a substrate of ABCB1. GSK-1070916 is a newly developed inhibitor that is currently under clinical investigation. The cytotoxicity assay showed that overexpression of ABCB1 significantly hindered the anticancer effect of GSK-1070916 and the drug resistance can be abolished by the addition of an ABCB1 inhibitor. GSK-1070916 concentration-dependently stimulated ABCB1 ATPase activity. The HPLC drug accumulation assay suggested that the ABCB1-overexpressing cells had lower levels of intracellular GSK-1070916 compared with the parental cells. GSK-1070916 also showed high binding affinity to ABCB1 substrate-binding site in the computational docking analysis. In conclusion, our study provides strong evidence that ABCB1 can confer resistance to GSK-1070916, which should be taken into consideration in clinical setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.615824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841342PMC
January 2021

Low serum parathyroid hormone is a risk factor for peritonitis episodes in incident peritoneal dialysis patients: a retrospective study.

BMC Nephrol 2021 01 29;22(1):44. Epub 2021 Jan 29.

Renal Division, Department of Medicine, Guizhou Provincial People's Hospital, Guiyang, China.

Background: Serum parathyroid hormone (PTH) levels have been reported to be associated with infectious mortality in peritoneal dialysis (PD) patients. Peritonitis is the most common and fatal infectious complication, resulting in technique failure, hospital admission and mortality. Whether PTH is associated with peritonitis episodes remains unclear.

Methods: We examined the association of PTH levels and peritonitis incidence in a 7-year cohort of 270 incident PD patients who were maintained on dialysis between January 2012 and December 2018 using Cox proportional hazard regression analyses. Patients were categorized into three groups by serum PTH levels as follows: low-PTH group, PTH < 150 pg/mL; middle-PTH group, PTH 150-300 pg/mL; high-PTH group, PTH > 300 pg/mL.

Results: During a median follow-up of 29.5 (interquartile range 16-49) months, the incidence rate of peritonitis was 0.10 episodes per patient-year. Gram-positive organisms were the most common causative microorganisms (36.2%), and higher percentage of Gram-negative organisms was noted in patients with low PTH levels. Low PTH levels were associated with older age, higher eGFR, higher hemoglobin, calcium levels and lower phosphate, alkaline phosphatase levels. After multivariate adjustment, lower PTH levels were identified as an independent risk factor for peritonitis episodes [hazard ratio 1.643, 95% confidence interval 1.014-2.663, P = 0.044].

Conclusions: Low PTH levels are independently associated with peritonitis in incident PD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-021-02241-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847059PMC
January 2021

Multidrug resistance proteins (MRPs): Structure, function and the overcoming of cancer multidrug resistance.

Drug Resist Updat 2021 Jan 13;54:100743. Epub 2021 Jan 13.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. Electronic address:

ATP-binding cassette (ABC) transporters mediate the ATP-driven translocation of structurally and mechanistically distinct substrates against steep concentration gradients. Among the seven human ABC subfamilies namely ABCA-ABCG, ABCC is the largest subfamily with 13 members. In this respect, 9 of the ABCC members are termed "multidrug resistance proteins" (MRPs1-9) due to their ability to mediate cancer multidrug resistance (MDR) by extruding various chemotherapeutic agents or their metabolites from tumor cells. Furthermore, MRPs are also responsible for the ATP-driven efflux of physiologically important organic anions such as leukotriene C, folic acid, bile acids and cAMP. Thus, MRPs are involved in important regulatory pathways. Blocking the anticancer drug efflux function of MRPs has shown promising results in overcoming cancer MDR. As a result, many novel MRP modulators have been developed in the past decade. In the current review, we summarize the structure, tissue distribution, biological and pharmacological functions as well as clinical insights of MRPs. Furthermore, recent updates in MRP modulators and their therapeutic applications in clinical trials are also discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.drup.2021.100743DOI Listing
January 2021

Overexpression of human ATP-binding cassette transporter ABCG2 contributes to reducing the cytotoxicity of GSK1070916 in cancer cells.

Biomed Pharmacother 2021 Apr 12;136:111223. Epub 2021 Jan 12.

Precision Medicine Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, PR China. Electronic address:

The emergence of multidrug resistance (MDR) is one of the main factors that impair therapeutic outcome in cancer therapy. Among all the factors that contribute to MDR, overexpression of ABCG2 transporter has been described as a key factor. GSK1070916 is a potent Aurora kinase inhibitor with broad anticancer effects. The robust efficacy shown in preclinical studies allowed the drug progress to clinical investigation. However, the potential mechanisms of acquired resistance to GSK1070916 remain inconclusive. Since several Aurora kinase inhibitors were reported to be transported substrates of ABCG2, we aimed to identify the potential interaction of GSK1070916 with ABCG2. Our data showed that ABCG2-overexpressing cells demonstrated high resistance-fold to GSK1070916 compared to the parental cells. In addition, combination of GSK1070916 with an ABCG2 inhibitor was able to restore its sensitivity. The multicellular tumor spheroid assay supported this finding by demonstrating attenuated growth inhibition in ABCG2-overexpressing tumor spheroids. In addition, the ABCG2 ATPase assay and computational modeling suggested that GSK1070916 could bind to ABCG2 substrate-binding site. The HPLC assay provided another direct evidence that ABCG2-overexpressing cells showed attenuated intracellular accumulation of GSK1070916, and such phenomenon was abolished by Ko143, a known ABCG2 inhibitor. Furthermore, GSK1070916 was able to hinder the efflux activity of ABCG2, indicating possible drug-drug interactions with other ABCG2 substrate drugs. In summary, we revealed that overexpression of ABCG2 can cause GSK1070916 resistance in cancer cells. The combination of an ABCG2 inhibitor with GSK1070916 may be a rational strategy to overcome the drug resistance and should be considered for clinical investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2021.111223DOI Listing
April 2021

Pharmacokinetics and pharmacodynamics integration of danofloxacin against Eschrichia coli in piglet ileum ultrafiltration probe model.

Sci Rep 2021 01 12;11(1):681. Epub 2021 Jan 12.

Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, 150030, Heilongjiang, People's Republic of China.

Improper use of antibiotics results in poor treatment and severe bacterial resistance. In this study, ultrafiltration probes were successfully placed in the ileum of piglets with the aid of anesthetic. After the fluoroquinolone antimicrobial drug danofloxacin (DAN) was intramuscularly administered, blood and ileum ultrafiltrate were collected at different time points and then determined by High Performance Liquid Chromatography (HPLC). Pharmacokinetics (PK) parameters for plasma and ileum ultrafiltrate were calculated by WinNonlin software. The DAN concentration in ileum ultrafiltrate was much higher than that in plasma during the period 1.2-48 h. The DAN concentration in plasma reached its maximum at 1.10 ± 0.03 h, but reached at 6.00 ± 0.00 h in the ileum ultrafiltrate. The mean C of the ileum is 13.59 times that of plasma. The elimination half-life (T) in the ileum ultrafiltrate (6.84 ± 1.49 h) was shorter than those in plasma (7.58 ± 3.20 h). The MIC, MBC and MPC of DAN in MH broth against Escherichia coli (O) were 0.5 µg/mL, 0.5 µg/mL and 4 µg/mL, respectively. Both in vitro and ex vivo kill curves indicated that the killing mechanism of DAN against E. coli is concentration-dependent. The AUC/MPC ratio is 21.33 ± 2.14. Mean PK/PD index (AUC/MIC) for ileum ultrafiltrate that achieved bacteriostatic, bactericidal, and eradication were 99.85, 155.57, and 218.02 h, respectively. Three different dosages (1.49 mg/kg, 2.42 mg/kg, and 3.24 mg/kg) were calculated respectively based on AUC/MIC ratio above, which might provide a novel approach to the rational design of dosage schedules.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-80272-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804201PMC
January 2021

Effect of core-based exercise in people with scoliosis: A systematic review and meta-analysis.

Clin Rehabil 2021 May 27;35(5):669-680. Epub 2020 Dec 27.

Department of Rehabilitation, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.

Objective: To systematically assess the effectiveness of core-based exercise for correcting a spinal deformity and improving quality of life in people with scoliosis.

Data Sources: The PubMed, Embase, Cochrane Library, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Web of Science databases were searched from inception up to September 30, 2020.

Methods: Clinical controlled trials were eligible if they compared the effectiveness of core-based exercise to other nonsurgical interventions in people with scoliosis. The revised Cochrane risk of bias assessment tool for randomized trials and the methodological index for non-randomized studies scale were used to assess the risk of bias. The outcomes included the Cobb angle, the angle of trunk rotation and quality of life. RevMan 5.3 was used, and intergroup differences were determined by calculating mean differences (MD) and 95% confidence intervals (CIs).

Results: After screening 1348 studies, nine studies with 325 participants met the inclusion criteria. The exercise group had significantly lower Cobb angles (MD = -2.08, 95% CI: -3.89 to -0.28,  = 0.02) and significantly better quality of life as measured by the Scoliosis Research Society-22 questionnaire (MD = 0.25, 95% CI: 0.02 to 0.49,  = 0.03) than the control groups. However, no significant difference was observed regarding the angle of trunk rotation between groups (MD = -0.69, 95% CI: -2.61 to 1.22,  = 0.48). Furthermore, no serious adverse events were reported. The overall quality of evidence ranged from low to very low.

Conclusion: Core-based exercise may have a beneficial role in reducing the Cobb angle and improving quality of life in people with scoliosis in the short term.

Prospero Registration Number: CRD42020160509 (Available at http://www.crd.york.ac.uk/prospero/).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0269215520975105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076838PMC
May 2021

ROS-Scavenging Nanomaterials to Treat Periodontitis.

Front Chem 2020 4;8:595530. Epub 2020 Nov 4.

Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.

The incidence of periodontitis is very high, and up to 45-50% of people are suffering from periodontitis. Periodontitis is caused by pathogens that invade teeth-supporting tissues such as gingiva, periodontal ligament, and alveolar bone. Pathogens trigger host immune responses characterized by the overproduction of reactive oxygen species (ROS). The development of effective ROS scavengers through nanotechnology has been emerging as a promising strategy for the treatment of periodontitis. Nanomaterial-based antioxidants can effectively scavenge ROS, prevent ROS-mediated tissue damage, and relieve inflammation in periodontitis. This mini-review focuses on the generation of ROS in periodontitis and its molecular mechanism of destroying periodontal tissue. Meanwhile, we summarize the research progress of ROS-scavenging nanomaterials in the treatment of periodontitis and discuss the challenges and prospects of its application.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fchem.2020.595530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672210PMC
November 2020

A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma.

J Immunother Cancer 2020 12;8(2)

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China

Background: The therapeutic effect of immune checkpoint blockers, especially the neutralizing antibodies of programmed cell death (PD-1) and its ligand programmed death ligand 1 (PD-L1), has been well verified in melanoma. Nevertheless, the dissatisfactory response rate and the occurrence of resistance significantly hinder the treatment effect. Inflammation-related molecules like A20 are greatly implicated in cancer immune response, but the role of tumorous A20 in antitumor immunity and immunotherapy efficacy remains elusive.

Methods: The association between tumorous A20 expression and the effect of anti-PD-1 immunotherapy was determined by immunoblotting, immunofluorescence staining and flow cytometry analysis of primary tumor specimens from melanoma patients. Preclinical mouse model, in vitro coculture system, immunohistochemical staining and flow cytometry analysis were employed to investigate the role of A20 in regulating the effect of anti-PD-1 immunotherapy. Bioinformatics, mass spectrum analysis and a set of biochemical analyzes were used to figure out the underlying mechanism.

Results: We first discovered that upregulated A20 was associated with impaired antitumor capacity of CD8T cells and poor response to anti-PD-1 immunotherapy in melanoma patients. Subsequent functional studies in preclinical mouse model and in vitro coculture system proved that targeting tumorous A20 prominently improved the effect of immunotherapy through the invigoration of infiltrating CD8T cells via the regulation of PD-L1. Mechanistically, A20 facilitated the ubiquitination and degradation of prohibitin to potentiate STAT3 activation and PD-L1 expression. Moreover, tumorous A20 expression was highly associated with the ratio of Ki-67 percentage in circulating PD-1CD8T cells to tumor burden.

Conclusions: Together, our findings uncover a novel crosstalk between inflammatory molecules and antitumor immunity in melanoma, and highlight that A20 can be exploited as a promising target to bring clinical benefit to melanomas refractory to immune checkpoint blockade.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-001866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733187PMC
December 2020

Curcumin ameliorates duodenal toxicity of AFB1 in chicken through inducing P-glycoprotein and downregulating cytochrome P450 enzymes.

Poult Sci 2020 Dec 7;99(12):7035-7045. Epub 2020 Oct 7.

Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, P R China. Electronic address:

It has been reported that oral intake of aflatoxin B1 (AFB1)-contaminated feed could cause acute, sub-chronic, or chronic toxicity in livestock and poultry. However, the harmful effect of AFB1 on the small intestine is still controversial. Therefore, blocking the entry of AFB1 into the body through the digestive tract is one of the important methods to prevent its toxicity. In the present study, 1-day-old Arbor Acres broilers were randomly divided into 6 groups including control group, curcumin control group (450 mg curcumin/kg feed), curcumin low-, medium-, and high-dose group (150, 300, and 450 mg curcumin/kg feed + 5 mg AFB1/kg feed), and AFB1 group (5 mg AFB1/kg feed). After 28 d, the samples of chickens' duodenums were collected for further analyses. AFB1 caused abnormal functional and morphological changes in the duodenum, including histological lesions, increased the length of the duodenum and depth of crypt, decreased the unit weight of the duodenum, height of villus, and the value of villus height/crypt depth. Meanwhile, AFB1 administration enhanced malonaldehyde activity, 8-HOdG level, and the mRNA expression of cytochrome P450 (CYP450) enzymes, and reduced superoxide dismutase, catalase, adenosine triphosphatase (ATPase) activity and the mRNA expression of Abcb1. Importantly, curcumin supplementation partially ameliorated AFB1-induced abnormal functional and morphological signs of the duodenum, alleviated AFB1-induced oxidative stress, and decreased the mRNA expression of CYP450 enzymes. Furthermore, curcumin ameliorated AFB1-induced decrease in the Abcb1 mRNA expression, P-glycoprotein (P-gp) level, and ATPase activities. It has been suggested from these results that curcumin supplementation in the feed could ameliorate AFB1-induced duodenal toxicity and damage through downregulating CYP450 enzymes, promoting ATPase activities, and inducing P-gp in chickens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.psj.2020.09.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705060PMC
December 2020

Delicately Designed Cancer Cell Membrane-Camouflaged Nanoparticles for Targeted F MR/PA/FL Imaging-Guided Photothermal Therapy.

ACS Appl Mater Interfaces 2020 Dec 24;12(51):57290-57301. Epub 2020 Nov 24.

Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences - Wuhan National Laboratory for Optoelectronics, Wuhan 430071, P. R. China.

Our exploration of multimodal nanoprobes aims to combine photoacoustic (PA) imaging, F magnetic resonance (MR), and fluorescence (FL) imaging, which offers complementary advantages such as high spatial resolution, unlimited penetration, and high sensitivity to enable more refined images for accurate tumor diagnoses. In this research, perfluorocarbons (PFCs) and indocyanine green (ICG) are encapsulated by poly(lactic--glycolic acid) (PLGA) for intravital F MR/FL/PA tri-modal imaging-guided photothermal therapy. Then, it is coated with an A549 cancer cell membrane (AM) to fabricate versatile theranostic nanoprobes ([email protected]). After systemic administration, FLI reveals time-dependent tumor homing of NPs with high sensitivity, F MRI provides tumor localization of NPs without background signal interference, and PAI illustrates the detailed distribution of NPs inside the tumor with high spatial resolution. What is more, [email protected] accumulated in the tumor area exhibit a prominent photothermal effect (48.4 °C) under near infrared (NIR) laser irradiation and realize an enhanced antitumor response in vivo. These benefits, in combination with the excellent biocompatibility, make [email protected] a potential theranostic nanoagent for accurate tumor localization and ultimately achieve superior cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.0c13865DOI Listing
December 2020

Artesunate alleviates myocardial ischemia/reperfusion-induced myocardial necrosis in rats and hypoxia/reoxygenation-induced apoptosis in H9C2 cells via regulating the FAK/PI3K/Akt pathway.

Ann Transl Med 2020 Oct;8(20):1291

Department of Heart Center, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Background: The various anti-inflammatory, anti-apoptotic, and antioxidant effects of Artesunate (Art) have been explored in numerous studies. This study aimed to evaluate the function of Art on myocardial necrosis in apoptotic cardiomyocytes and .

Methods: Sprague Dawley (SD) rats were randomly divided into groups: a control group, a myocardial ischemia reperfusion (MI/R) group, and MI/R+ Art groups. To establish a MI/R model, rats were subjected to left anterior descending artery ischemia for 45 minutes, and then reperfusion for 2 hours. Hypoxia was induced in H9C2 cells by subjecting them to hypoxic conditions at 37 °C for 4 hours, before placing them in a normoxic chamber for 2 hours. The test methods were used in this test, such as echocardiography, enzyme-linked immunosorbent assay (ELISA), HE staining, TUNEL staining, immunohistochemistry, flow cytometry, western blot, and CCK-8 assay.

Results: Art improved myocardial systolic function caused by MI/R injury . Simultaneously, Art reduced the levels of cardiac troponin I (cTnl), creatine kinase-MB (CK-MB) and myohemoglobin (Mb) and . Moreover, Art inhibited cardiomyocyte apoptosis and . The focal adhesion kinase (FAK)/phosphatidylinositide-3 kinases (PI3K)/AKT signaling pathway was also activated by Art and . Furthermore, after inhibitor PF573228 was added, Art inhibited apoptosis in H9C2 cells via activation of the FAK/PI3K/AKT signaling pathway

Conclusions: This study confirms that Art alleviated MI/R injury and inhibited cardiomyocyte apoptosis and . Art exerted an inhibitory effect on cardiomyocyte apoptosis by activating the FAK/PI3K/AKT signaling pathway. Therefore, Art may serve as an alternative treatment for MI/R injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm-20-5182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661874PMC
October 2020

Impact on Mechanical Properties and Microstructural Response of Nickel-Based Superalloy GH4169 Subjected to Warm Laser Shock Peening.

Materials (Basel) 2020 Nov 16;13(22). Epub 2020 Nov 16.

Shenyang Institute of Automation, Chinese Academy of Science, Shenyang 110016, China.

Laser shock peening (LSP), as an innovative surface treatment technology, can effectively improve fatigue life, surface hardness, corrosion resistance, and residual compressive stress. Compared with laser shock peening, warm laser shock peening (WLSP) is a newer surface treatment technology used to improve materials' surface performances, which takes advantage of thermal mechanical effects on stress strengthening and microstructure strengthening, resulting in a more stable distribution of residual compressive stress under the heating and cyclic loading process. In this paper, the microstructure of the GH4169 nickel superalloy processed by WLSP technology with different laser parameters was investigated. The proliferation and tangling of dislocations in GH4169 were observed, and the dislocation density increased after WLSP treatment. The influences of different treatments by LSP and WLSP on the microhardness distribution of the surface and along the cross-sectional depth were investigated. The microstructure evolution of the GH4169 alloy being shocked with WLSP was studied by TEM. The effect of temperature on the stability of the high-temperature microstructure and properties of the GH4169 alloy shocked by WLSP was investigated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ma13225172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698307PMC
November 2020

Poziotinib Inhibits the Efflux Activity of the ABCB1 and ABCG2 Transporters and the Expression of the ABCG2 Transporter Protein in Multidrug Resistant Colon Cancer Cells.

Cancers (Basel) 2020 Nov 4;12(11). Epub 2020 Nov 4.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.

Colorectal cancer (CRC) is a leading cause of cancer deaths in the United States. Currently, chemotherapy is a first-line treatment for CRC. However, one major drawback of chemotherapy is the emergence of multidrug resistance (MDR). It has been well-established that the overexpression of the ABCB1 and/or ABCG2 transporters can produce MDR in cancer cells. In this study, we report that in vitro, poziotinib can antagonize both ABCB1- and ABCG2-mediated MDR at 0.1-0.6 μM in the human colon cancer cell lines, SW620/Ad300 and S1-M1-80. Mechanistic studies indicated that poziotinib increases the intracellular accumulation of the ABCB1 transporter substrates, paclitaxel and doxorubicin, and the ABCG2 transporter substrates, mitoxantrone and SN-38, by inhibiting their substrate efflux function. Accumulation assay results suggested that poziotinib binds reversibly to the ABCG2 and ABCB1 transporter. Furthermore, western blot experiments indicated that poziotinib, at 0.6 μM, significantly downregulates the expression of the ABCG2 but not the ABCB1 transporter protein, suggesting that the ABCG2 reversal effect produced by poziotinib is due to transporter downregulation and inhibition of substrate efflux. Poziotinib concentration-dependently stimulated the ATPase activity of both ABCB1 and ABCG2, with EC values of 0.02 μM and 0.21 μM, respectively, suggesting that it interacts with the drug-substrate binding site. Molecular docking analysis indicated that poziotinib binds to the ABCB1 (-6.6 kcal/mol) and ABCG2 (-10.1 kcal/mol) drug-substrate binding site. In summary, our novel results show that poziotinib interacts with the ABCB1 and ABCG2 transporter, suggesting that poziotinib may increase the efficacy of certain chemotherapeutic drugs used in treating MDR CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12113249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694178PMC
November 2020
-->