Publications by authors named "Huang Fang"

960 Publications

The role of alcohol dehydrogenase 1C in regulating inflammatory responses in ulcerative colitis.

Biochem Pharmacol 2021 Jul 19:114691. Epub 2021 Jul 19.

Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, Zhejiang, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou 310014, Zhejiang, China. Electronic address:

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease caused by an interaction of genetics, immune responses, and environmental factors. However, the precise pathogenesis of UC remains poorly understood. The aim of the present study was to explore the potential target genes implicated in UC and to elucidate its underlying pathogenic mechanism. Firstly, three UC-associated microarray datasets (GSE75214, GSE87466, and GSE92517) were obtained to screen the differentially expressed genes (DEGs). As a result, alcohol dehydrogenase 1C (ADH1C) was the most significantly downregulated DEG in UC. We confirmed that ADH1C was downregulated in colonic tissue taken from patients with UC and colitis mice. Moreover, ADH1C expression was also decreased in colonic cell lines (NCM460 and HT29) treated with mixed proinflammatory cytokines (TNF-α, IFN-γ, IL-1β). Interestingly, we found that overexpression of ADH1C could distinctly decrease the production of IL-6 and IL-8. To elucidate the molecular mechanism of ADH1C in UC, gene set enrichment analysis (GSEA) was performed and demonstrated that immune-related pathways were mainly enriched in the low ADH1C group. Further studies displayed that STAT1/NF-κB pathway was activated in colitis mice and inflammatory cell model. Importantly, overexpression of ADH1C could suppress the phosphorylation of STAT1 and IκB. Therefore, ADH1C might regulate inflammatory responses through STAT1/NF-κB pathway. In conclusion, ADH1C was downregulated during inflammation, and its increased expression could inhibit the activation of STAT1/NF-κB pathway, thereby alleviating the secretion of IL-6 and IL-8. These findings indicate that ADH1C may be a potential therapeutic target for UC therapy.
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http://dx.doi.org/10.1016/j.bcp.2021.114691DOI Listing
July 2021

Corydalis saxicola Bunting total alkaloids attenuate paclitaxel-induced peripheral neuropathy through PKCε/p38 MAPK/TRPV1 signaling pathway.

Chin Med 2021 Jul 19;16(1):58. Epub 2021 Jul 19.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China.

Background: Corydalis saxicola Bunting, affiliated with the Papaveraceae Juss., has been proven to work well in anti-inflammation, hemostasis, and analgesia. This study was designed to observe the effect and potential mechanism of Corydalis saxicola Bunting total alkaloids (CSBTA) on paclitaxel-induced peripheral neuropathy (PIPN).

Materials And Methods: Rats were injected 2 mg/kg paclitaxel 4 times and administrated with 30 or 120 mg/kg CSBTA. Mechanical and thermal allodynia and hyperalgesia were tested. After 40 days, serum was collected to detect PGE2, TNF-α, and IL-1β by ELISA. The L4-L6 segment spinal cord, DRG, and plantar skin were harvested, and Western-blot or RT-qPCR analyzed protein and gene levels of pro-inflammatory cytokines, p38 MAPK, PKCε, and TRPV1. The PIPN cell model was established with paclitaxel (300 nM, 5 d) in primary DRG neurons. We examined the effect of CSBTA (25 μg/ml or 50 μg/ml) by measuring the mRNA levels in PGE2, TNF-α and CGRP, and the protein expression on the PKCε/p38 MAPK/TRPV1 signaling pathway in the PIPN cell model.

Results: The results showed that CSBTA effectively ameliorated allodynia and hyperalgesia, and regulated cytokines' contents (PGE2, TNF-α, and IL-1β) and neuropeptides (CGRP and SP) in different tissues in vivo. In addition, CSBTA significantly decreased cytokine gene levels of DRG neurons (PGE2, TNF-α, and CGRP) and the protein expressions of PKCε/p38 MAPK/TRPV1 signaling pathway in vivo and in vitro.

Conclusion: Therefore, CSBTA has a perspective therapeutic effect on the treatment of paclitaxel-induced peripheral neuropathy.
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http://dx.doi.org/10.1186/s13020-021-00468-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287815PMC
July 2021

Role of nitric oxide in orthodontic tooth movement (Review).

Int J Mol Med 2021 Sep 19;48(3). Epub 2021 Jul 19.

Department of Pediatric Dentistry, Hospital of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China.

Nitric oxide (NO) is an ubiquitous signaling molecule that mediates numerous cellular processes associated with cardiovascular, nervous and immune systems. NO also plays an essential role in bone homeostasis regulation. The present review article summarized the effects of NO on bone metabolism during orthodontic tooth movement in order to provide insight into the regulatory role of NO in orthodontic tooth movement. Orthodontic tooth movement is a process in which the periodontal tissue and alveolar bone are reconstructed due to the effect of orthodontic forces. Accumulating evidence has indicated that NO and its downstream signaling molecule, cyclic guanosine monophosphate (cGMP), mediate the mechanical signals during orthodontic‑related bone remodeling, and exert complex effects on osteogenesis and osteoclastogenesis. NO has a regulatory effect on the cellular activities and functional states of osteoclasts, osteocytes and periodontal ligament fibroblasts involved in orthodontic tooth movement. Variations of NO synthase (NOS) expression levels and NO production in periodontal tissues or gingival crevicular fluid (GCF) have been found on the tension and compression sides during tooth movement in both orthodontic animal models and patients. Furthermore, NO precursor and NOS inhibitor administration increased and reduced the tooth movement in animal models, respectively. Further research is required in order to further elucidate the underlying mechanisms and the clinical application prospect of NO in orthodontic tooth movement.
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http://dx.doi.org/10.3892/ijmm.2021.5001DOI Listing
September 2021

Preparation of lignosulfonate ionic hydrogels for supercapacitors, sensors and dye adsorbent applications.

Int J Biol Macromol 2021 Jul 12. Epub 2021 Jul 12.

College of Material Engineering, Fujian Agriculture and Forestry University, Fuzhou 350108, China; Department of Chemical Engineering, University of New Brunswick, Fredericton E3B 5A3, Canada. Electronic address:

Lignin, an abundant natural polymer but presently under-utilized, has received much attention for its green/sustainable advantages. Herein, we report a facile method to fabricate lignosulfonate (LS) ionic hydrogels by simple crosslinking with poly (ethylene glycol) diglycidyl ether (PEGDGE). The as-obtained LS-PEGDGE hydrogels were comprehensively characterized by mechanical measurements, FT-IR, and SEM. The rich sulfonic and phenolic hydroxyl groups in LS hydrogels play key roles in imparting multifunctional smart properties, such as adhesiveness, conducting, sensing and dye adsorption, as well as superconductive behavior when increasing the moisture content. The hydrogels have a high adsorption capacity for cationic dyes, using methylene blue as a model, reaching 211 mg·g. As a moist-induced power generator, the maximum output voltage is 181 mV. The LS-PEGDGE hydrogel-based flexible strain sensors exhibit high sensitivity when detecting human movements. As the hydrogel electrolyte, the assembled supercapacitor shows high specific capacitance of 236.9 F·g, with the maximum energy density of 20.61 Wh·kg, power density of 2306.4 W·kg, and capacitance retention of 92.9% after 10,000 consecutive charge-discharge cycles. Therefore, this multifunctional LS hydrogels may have promising applications in various fields, providing a new platform for the value-added utilization of lignin from industrial waste.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.07.021DOI Listing
July 2021

Avidity and surface mobility in multivalent ligand-receptor binding.

Nanoscale 2021 Jul 14. Epub 2021 Jul 14.

Martin A. Fisher School of Physics, Brandeis University, Waltham, MA 02453, USA.

Targeted drug delivery relies on two physical processes: the selective binding of a therapeutic particle to receptors on a specific cell membrane, followed by transport of the particle across the membrane. In this article, we address some of the challenges in controlling the thermodynamics and dynamics of these two processes by combining a simple experimental system with a statistical mechanical model. Specifically, we characterize and model multivalent ligand-receptor binding between colloidal particles and fluid lipid bilayers, as well as the surface mobility of membrane-bound particles. We show that the mobility of the receptors within the fluid membrane is key to both the thermodynamics and dynamics of binding. First, we find that the particle-membrane binding free energy-or avidity-is a strongly nonlinear function of the ligand-receptor affinity. We attribute the nonlinearity to a combination of multivalency and recruitment of fluid receptors to the binding site. Our results also suggest that partial wrapping of the bound particles by the membrane enhances avidity further. Second, we demonstrate that the lateral mobility of membrane-bound particles is also strongly influenced by the recruitment of receptors. Specifically, we find that the lateral diffusion coefficient of a membrane-bound particle is dominated by the hydrodynamic drag against the aggregate of receptors within the membrane. These results provide one of the first direct validations of the working theoretical framework for multivalent interactions. They also highlight that the fluidity and elasticity of the membrane are as important as the ligand-receptor affinity in determining the binding and transport of small particles attached to membranes.
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http://dx.doi.org/10.1039/d1nr02083hDOI Listing
July 2021

A retrospective analysis of malaria epidemiological characteristics in Yingjiang County on the China-Myanmar border.

Sci Rep 2021 Jul 8;11(1):14129. Epub 2021 Jul 8.

National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Chinese Center for Tropical Diseases Research; NHC Key Laboratory of Parasite and Vector Biology (National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention); WHO Collaborating Centre for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai, China.

Yingjiang County, which is on the China-Myanmar border, is the main focus for malaria elimination in China. The epidemiological characteristics of malaria in Yingjiang County were analysed in a retrospective analysis. A total of 895 malaria cases were reported in Yingjiang County between 2013 and 2019. The majority of cases occurred in males (70.7%) and individuals aged 19-59 years (77.3%). Plasmodium vivax was the predominant species (96.6%). The number of indigenous cases decreased gradually and since 2017, no indigenous cases have been reported. Malaria cases were mainly distributed in the southern and southwestern areas of the county; 55.6% of the indigenous cases were reported in Nabang Township, which also had the highest risk of imported malaria. The "1-3-7" approach has been implemented effectively, with 100% of cases reported within 24 h, 88.9% cases investigated and confirmed within 3 days and 98.5% of foci responded to within 7 days. Although malaria elimination has been achieved in Yingjiang County, sustaining elimination and preventing the re-establishment of malaria require the continued strengthening of case detection, surveillance and response systems targeting the migrant population in border areas.
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http://dx.doi.org/10.1038/s41598-021-93734-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266812PMC
July 2021

Characterization, Sources and Excessive Cancer Risk of PM-Bound Polycyclic Aromatic Hydrocarbons in Different Green Spaces in Lin'an, Hangzhou, China.

Bull Environ Contam Toxicol 2021 Jul 6. Epub 2021 Jul 6.

College of Landscape Architecture, Zhejiang Agriculture and Forestry University, Hangzhou, 311300, Zhejiang, China.

PM samples were collected from residential, commercial, plaza and public green spaces in Lin'an, Hangzhou, in spring (March and April) and winter (February and December) in 2017. PAHs were detected by gas chromatography-mass spectrometry (GC-MS), and their sources were identified using the diagnostic ratio (DR) and principal component analysis-multiple linear regression (PCA-MLR). The average PAH concentration in winter was 1.3 times that in spring (p < 0.01). The PAH concentrations in the green spaces decreased as commercial > residential > plaza > public green space (p < 0.05). The sources of PAHs were vehicle emissions and coal combustion pollution transported by northern Chinese air masses. Slightly higher excessive cancer risks were determined in the commercial and residential green spaces than in the plaza and public green spaces. Green coverage, pedestrian volume, traffic flow and building density greatly influenced the decrease in the PAH concentration in the green spaces. Among the 4 types of green spaces, public green space had the most ecological benefits and should be fully utilized in urban green space planning to improve public health in urban spaces.
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http://dx.doi.org/10.1007/s00128-021-03304-6DOI Listing
July 2021

Molecular Mechanism of Xixin-Ganjiang Herb Pair Treating Chronic Obstructive Pulmonary Disease-Integrated Network Pharmacology and Molecular Docking.

Evid Based Complement Alternat Med 2021 10;2021:5532009. Epub 2021 Jun 10.

College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan 430065, China.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by high morbidity, disability, and mortality, which seriously threatens human life and health. Xixin and Ganjiang are classic herb pairs of Zhongjing Zhang, which are often used to treat COPD in China. However, the substance basis and mechanism of action of Xixin-Ganjiang herb pair (XGHP) in the treatment of COPD remain unclear.

Methods: On the website of TCMSP and the DrugBank, effective compounds and targets of XGHP were found. COPD targets were obtained from GeneCards, DisGeNET, and GEO gene chips. Intersecting these databases resulted in a library of drug targets for COPD. Then, intersection targets were used for protein-protein interaction (PPI) and pathway enrichment analysis. Finally, the binding activity between compounds and core genes was evaluated by molecular docking to verify the expression level of PTGS2 and PPARG in rats.

Results: Twelve effective compounds and 104 core genes were found in the intersection library, and kaempferol, sesamin, -sitosterol, PTGS2, and PPARG were particularly prominent in the network analysis. A total of 113 pathways were obtained and enrichment of the TNF signaling pathway, IL-17 signaling pathway, and C-type lectin receptor signaling pathway was particularly obvious. Molecular docking indicated that kaempferol, sesamin, and -sitosterol were closely related to PTGS2 and PPARG and were superior to aminophylline. Key compounds in XGHP could restrict the expression of PTGS2 in the lung tissues of COPD rats and promote the expression of PPARG.

Conclusion: Inhibition of the expression of inflammatory factor PTGS2 and promotion of the expression of PPARG may be an effective target of XGHP in the treatment of COPD.
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http://dx.doi.org/10.1155/2021/5532009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211495PMC
June 2021

Engineering the Composition of Microfibers to Enhance the Remodeling of a Cell-Free Vascular Graft.

Nanomaterials (Basel) 2021 Jun 20;11(6). Epub 2021 Jun 20.

UC Berkeley & UCSF Joint Graduate Program in Bioengineering, Berkeley & San Francisco, CA 94720 & 94143, USA.

The remodeling of vascular grafts is critical for blood vessel regeneration. However, most scaffold materials have limited cell infiltration. In this study, we designed and fabricated a scaffold that incorporates a fast-degrading polymer polydioxanone (PDO) into the microfibrous structure by means of electrospinning technology. Blending PDO with base polymer decreases the density of electrospun microfibers yet did not compromise the mechanical and structural properties of the scaffold, and effectively enhanced cell infiltration. We then used this technique to fabricate a tubular scaffold with heparin conjugated to the surface to suppress thrombosis, and the construct was implanted into the carotid artery as a vascular graft in animal studies. This graft significantly promoted cell infiltration, and the biochemical cues such as immobilized stromal cell-derived factor-1α further enhanced cell recruitment and the long-term patency of the grafts. This work provides an approach to optimize the microfeatures of vascular grafts, and will have broad applications in scaffold design and fabrication for regenerative engineering.
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http://dx.doi.org/10.3390/nano11061613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235366PMC
June 2021

The Implication of STEP in Synaptic Plasticity and Cognitive Impairments in Alzheimer's Disease and Other Neurological Disorders.

Front Cell Dev Biol 2021 14;9:680118. Epub 2021 Jun 14.

Cognitive Impairment Ward of Neurology Department, The Third Affiliated Hospital, Shenzhen University, Shenzhen, China.

STriatal-Enriched protein tyrosine Phosphatase (STEP) is a tyrosine phosphatase that has been implicated in Alzheimer's disease (AD), the most common form of dementia, and many other neurological diseases. The protein level and activity of STEP have been found to be elevated in most of these disorders, and specifically in AD as a result of dysregulation of different pathways including PP2B/DARPP32/PP1, PKA as well as impairments of both proteasomal and lysosomal systems. The upregulation in STEP leads to increased binding to, and dephosphorylation of, its substrates which are mainly found to be synaptic plasticity and thus learning and memory related proteins. These proteins include kinases like Fyn, Pyk2, ERK1/2 and both NMDA and AMPA receptor subunits GluN2B and GluA2. The dephosphorylation of these molecules results in inactivation of these kinases and internalization of NMDA and AMPA receptor complexes leading to synapse loss and cognitive impairments. In this study, we aim to review STEP regulation and its implications in AD as well as other neurological disorders and then summarize data on targeting STEP as therapeutic strategy in these diseases.
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http://dx.doi.org/10.3389/fcell.2021.680118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236946PMC
June 2021

Cultivation of the gut bacterium Prevotella copri DSM 18205 using glucose and xylose as carbon sources.

Microbiologyopen 2021 Jun;10(3):e1213

Division of Biotechnology, Department of Chemistry, Lund University, Lund, Sweden.

Prevotella copri DSM18205 is a human gut bacterium, suggested as a next-generation probiotic. To utilize it as such, it is, however, necessary to grow the species in a reproducible manner. Prevotella copri has previously been reported to be highly sensitive to oxygen, and hence difficult to isolate and cultivate. This study presents successful batch cultivation strategies for viable strain inoculations and growth in both serum bottles and a stirred tank bioreactor (STR), without the use of an anaerobic chamber, as long as the cells were kept in the exponential growth phase. A low headspace volume in the STR was important to reach high cell density. P. copri utilized xylose cultivated in Peptone Yeast Xylose medium (PYX medium), resulting in a comparable growth rate and metabolite production as in Peptone Yeast Glucose medium (PYG medium) in batch cultivations at pH 7.2.Up to 5 g/L of the carbon source was consumed, leading to the production of succinic acid, acetic acid, and formic acid, and cell densities (OD ) in the range 6-7.5. The highest yield of produced succinic acid was 0.63 ± 0.05 g/g glucose in PYG medium cultivations and 0.88 ± 0.06 g/g xylose in PYX medium cultivations.
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http://dx.doi.org/10.1002/mbo3.1213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236902PMC
June 2021

Involvement of Mast Cells in the Pathophysiology of Pain.

Front Cell Neurosci 2021 10;15:665066. Epub 2021 Jun 10.

Department of Anesthesiology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.

Mast cells (MCs) are immune cells and are widely distributed throughout the body. MCs are not only classically viewed as effector cells of some allergic diseases but also participate in host defense, innate and acquired immunity, homeostatic responses, and immunoregulation. Mounting evidence indicates that activation of MCs releasing numerous vasoactive and inflammatory mediators has effects on the nervous system and has been involved in different pain conditions. Here, we review the latest advances made about the implication of MCs in pain. Possible cellular and molecular mechanisms regarding the crosstalk between MC and the nervous system in the initiation and maintenance of pain are also discussed.
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http://dx.doi.org/10.3389/fncel.2021.665066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222580PMC
June 2021

M2a Macrophage-Secreted CHI3L1 Promotes Extracellular Matrix Metabolic Imbalances Activation of IL-13Rα2/MAPK Pathway in Rat Intervertebral Disc Degeneration.

Front Immunol 2021 8;12:666361. Epub 2021 Jun 8.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The accumulation of macrophages in degenerated discs is a common phenomenon. However, the roles and mechanisms of M2a macrophages in intervertebral disc degeneration (IDD) have not been illuminated. This study investigated the expression of the M2a macrophage marker (CD206) in human and rat intervertebral disc tissues by immunohistochemistry. To explore the roles of M2a macrophages in IDD, nucleus pulposus (NP) cells were co-cultured with M2a macrophages . To clarify whether the CHI3L1 protein mediates the effect of M2a macrophages on NP cells, siRNA was used to knock down CHI3L1 transcription. To elucidate the underlying mechanisms, NP cells were incubated with recombinant CHI3L1 proteins, then subjected to western blotting analysis of the IL-13Rα2 receptor and MAPK pathway. CD206-positive cells were detected in degenerated human and rat intervertebral disc tissues. Notably, M2a macrophages promoted the expression of catabolism genes (MMP-3 and MMP-9) and suppressed the expression of anabolism genes (aggrecan and collagen II) in NP cells. These effects were abrogated by CHI3L1 knockdown in M2a macrophages. Exposure to recombinant CHI3L1 promoted an extracellular matrix metabolic imbalance in NP cells the IL-13Rα2 receptor, along with activation of the ERK and JNK MAPK signaling pathways. This study elucidated the roles of M2a macrophages in IDD and identified potential mechanisms for these effects.
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http://dx.doi.org/10.3389/fimmu.2021.666361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217759PMC
June 2021

Long Noncoding RNA Expression Profiles of Rat Extrasynaptic and Synaptic Neurons Expressing the N-methyl-D-Aspartate Receptor Revealed by Microarray Analysis.

World Neurosurg 2021 Jun 22. Epub 2021 Jun 22.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Purpose: To study the 24-hour expression of long noncoding RNAs (lncRNAs) in synaptic and extrasynaptic neurons expressing N-methyl-D-aspartate receptor (NMDAR), and normal neuronal cultures, via microarray analysis.

Materials And Methods: Cortical neurons from embryonic (day E18) Sprague-Dawley rats were used for primary neuronal culture. NMDAR activation was blocked and the cells were then incubated for 6 hours. Total RNA was extracted, quantified, and analyzed for purity and integrity. Double-stranded cDNA was synthesized, followed by quantile normalization, quantitative polymerase chain reaction validation, and data analysis. The interactions between transcription factors and lncRNAs were analyzed by Pearson correlation.

Results: The lncRNA profiles were obtained after synaptic and extrasynaptic NMDAR activation of rat cortical neuron cultures for 24 hours. In total, 251 lncRNAs were consistently upregulated, and 335 were downregulated, after extrasynaptic NMDAR activation compared with normal neurons. After synaptic NMDAR activation, only 9 lncRNAs were upregulated and 2 were downregulated.

Conclusions: Differential expression of lncRNAs after synaptic and extrasynaptic NMDAR activation suggests that lncRNAs may be responsible for extrasynaptic NMDAR-induced neurodegeneration.
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http://dx.doi.org/10.1016/j.wneu.2021.06.070DOI Listing
June 2021

Global earth mineral inventory: A data legacy.

Geosci Data J 2021 Jun 11;8(1):74-89. Epub 2020 Nov 11.

Tetherless World Constellation, Rensselaer Polytechnic Institute, Troy, NY, USA.

Minerals contain important clues to understanding the complex geologic history of Earth and other planetary bodies. Therefore, geologists have been collecting mineral samples and compiling data about these samples for centuries. These data have been used to better understand the movement of continental plates, the oxidation of Earth's atmosphere and the water regime of ancient martian landscapes. Datasets found at 'RRUFF.info/Evolution' and 'mindat.org' have documented a wealth of mineral occurrences around the world. One of the main goals in geoinformatics has been to facilitate discovery by creating and merging datasets from various scientific fields and using statistical methods and visualization tools to inspire and test hypotheses applicable to modelling Earth's past environments. To help achieve this goal, we have compiled physical, chemical and geological properties of minerals and linked them to the above-mentioned mineral occurrence datasets. As a part of the Deep Time Data Infrastructure, funded by the W.M. Keck Foundation, with significant support from the Deep Carbon Observatory (DCO) and the A.P. Sloan Foundation, GEMI ('Global Earth Mineral Inventory') was developed from the need of researchers to have all of the required mineral data visible in a single portal, connected by a robust, yet easy to understand schema. Our data legacy integrates these resources into a digestible format for exploration and analysis and has allowed researchers to gain valuable insights from mineralogical data. GEMI can be considered a network, with every node representing some feature of the datasets, for example, a node can represent geological parameters like colour, hardness or lustre. Exploring subnetworks gives the researcher a specific view of the data required for the task at hand. GEMI is accessible through the DCO Data Portal (https://dx.deepcarbon.net/11121/6200-6954-6634-8243-CC). We describe our efforts in compiling GEMI, the Data Policies for usage and sharing, and the evaluation metrics for this data legacy.
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http://dx.doi.org/10.1002/gdj3.106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216291PMC
June 2021

Engineering circular RNA regulators to specifically promote circular RNA production.

Theranostics 2021 24;11(15):7322-7336. Epub 2021 May 24.

Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China 116044.

A large number of circular RNAs (circRNAs) have been discovered in the mammalian transcriptome with high abundance, which play vital roles in gene regulation, thereby participating in the development of multiple diseases. However, the biogenesis, regulation, and especially manipulation of circRNAs still remain largely unknown. Engineering circRNA regulators (ECRRs) were developed to promote circRNA biogenesis. Multiple circRNA mini-gene reporters were generated to evaluate the regulatory role of ECRRs. RT-PCR, qRT-PCR, northern blot, western blot, and flow cytometry assays were applied to assess the efficiency of artificial circRNA regulators on circRNA production in the presence or absence of RNase R treatment. We engineered circRNA regulators by combining sequence-specific RNA binding motifs of human Pumilio 1 with functional domains that could form dimerization. We applied these engineered regulators to promote the circRNA production of the exogenous circRNA minigene reporter circGFP, thereby stimulating the functional GFP protein generation. Crucially, such regulation is in time-course dependent and dose-dependent manners with designed specificity. Moreover, the application of ECRRs could also stimulate circRNA biogenesis of another minigene reporter circScreen, suggesting that ECRRs can be commonly used to promote circRNA generation of exogenous reporters. Most importantly, ECRRs could be utilized to specifically promote the production of the endogenous circRNAs circ10720 and circBIRC6 as well. Our approach allows the creation of engineered regulators to target virtually any pre-mRNA , offering a novel avenue to investigate circRNA biogenesis and manipulate disease-related circRNA production.
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http://dx.doi.org/10.7150/thno.56990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210604PMC
May 2021

Deep-Learning-Assisted Single-Molecule Tracking on a Live Cell Membrane.

Anal Chem 2021 Jun 16. Epub 2021 Jun 16.

State Key Laboratory of Heavy Oil Processing and Center for Bioengineering and Biotechnology, China University of Petroleum (East China), Qingdao 266580, China.

Single-molecule fluorescence imaging is a powerful tool to study protein function by tracking molecular position and distribution, but the precise and rapid identification of dynamic molecules remains challenging due to the heterogeneous distribution and interaction of proteins on the live cell membrane. We now develop a deep-learning (DL)-assisted single-molecule imaging method that can precisely distinguish the monomer and complex for rapid and real-time tracking of protein interaction. This DL-based model, which comprises convolutional layers, max pooling layers, and fully connected layers, is trained to reach an accuracy of >98% for identifying monomer and complex. We use this method to investigate the dynamic process of chemokine receptor CXCR4 on the live cell membrane during the early signaling stage. The results show that, upon ligand activation, the CXCR4 undergoes a dynamic process of forming a receptor complex. We further demonstrate that the CXCR4 complex tends to be internalized at 2.5-fold higher rate into the cell interior than the monomer via the clathrin-dependent pathway. This study is the first example to scrutinize the early signaling process of CXCR4 at the single-molecule level on the live cell membrane. We envision that this DL-assisted imaging method would be a broadly useful technique to study more protein families for elucidating their physiological and pathological functions.
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http://dx.doi.org/10.1021/acs.analchem.1c00547DOI Listing
June 2021

Underestimated humic acids release and influence on anaerobic digestion during sludge thermal hydrolysis.

Water Res 2021 May 28;201:117310. Epub 2021 May 28.

Jiangsu Key Laboratory of Anaerobic Biotechnology, School of Environment and Civil Engineering, Jiangnan University, Wuxi 214122, Jiangsu Province, PR China; Jiangsu Collaborative Innovation Center of Technology and Material of Water Treatment, Suzhou University of Science and Technology, Suzhou 215011, Jiangsu Province, PR China. Electronic address:

Humic-like acids (HAs) are abundant in sewage sludge but mainly bonded with solids. Thus, their influences are often neglected in conventional digestion processes. Currently thermal hydrolysis pretreatment (THP) has been widely adopted in sludge anaerobic digestion (AD) to enhance hydrolysis of complex matters and further to improve methane production. However, the impacts of enhanced release of HAs and the mechanisms involved are not well understood and need to be further investigated because the substantial amounts of HAs present in AD could severely threaten the sludge AD processes. Results in the present study indicated that the concentration of soluble HAs in sludge was elevated by 90 times due to the THP, from 8 mg/L in raw sludge to 727 mg/L in the pretreated sludge hydrolyzed at 180 °C. Moreover, the structural characteristics of soluble HAs, including aromatic condensation degree, elemental composition and functional group, also showed substantial differences with the increased temperature of the THP. Furthermore, the release of HAs presented significant influences on sludge digestion. Acidification rate was inhibited by over 50% with 0.4 g/L of HAs, whereas methanogenesis was improved by nearly 200% with 0.8 g/L HAs and inhibited about 50% with 2.0 g/L. The activities of proteinase and co-enzyme F were decreased by 20% and increased by 19%, respectively, under HAs stress at 0.6 g/L for 5 days. Moreover, molecular structural changes of soluble HAs also contributed to the influences. Especially, the E4/E6 value representing the degree of HAs aromatic condensation and C/N ratio of soluble HAs were closely correlated with their inhibition degree to sludge hydrolysis. The findings of this study demonstrate that the influences of HAs are evident and also vary to the different steps of anaerobic digestion processes, which shall not be negligible during the sludge digestion that is with THP. Due to the rate-limiting step was methanogenesis in the AD process of pretreated sludge by thermal hydrolysis, HAs concentration was recommended at low level, for example around 1.0 g/L, to accelerate or not limit methanogenesis.
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http://dx.doi.org/10.1016/j.watres.2021.117310DOI Listing
May 2021

Bibliometric Analysis of Global Circular RNA Research Trends from 2007 to 2018.

Cell J 2021 Jul 26;23(2):238-246. Epub 2021 May 26.

Department of Orthopaedics, Changhai Hospital, Second Military Medical University, Shanghai, China. Email:

Objective: Circular RNA (circRNA) is of significant interest in genetic research. The aim of this study was to assess global trends in circRNA research production in order to shed new light on future research frontiers.

Materials And Methods: In this retrospective study, we conducted a literature search using the Web of Science Core Collection (WoSCC) database on March 21, 2019 to retrieve publications from 2007 to 2018. Excel 2013, CiteSpace V, and VOSviewer were used to evaluate bibliometric features that included publication output, countries/regions, institutions, journals, citation frequency, H-index, and research hotspots.

Results: Global cumulative publication output on circRNA consisted of 998 papers with a total citation of 28 595 during 2007-2018. China, the US, and Germany were the most prolific countries. China ranked first in H-index (60 times) and citations (13 333 times). The most productive institution was Nanjing Medical University with 73 papers. Biochemical and Biophysical Research Communications (impact factor [IF]2017:2.559) ranked first among journals in the number of publications (64 papers). The keywords shifted from "sequence", "intron", and "splice-site" to "transcriptome", "microRNA sponge", "exon circularization", and "circRNA biogenesis" overtime. The burst keywords "transcriptome", "microRNA sponge", "exon circularization", and "circRNA biogenesis" were the latest frontiers by 2018.

Conclusion: This is a relatively novel bibliometric analysis to inspect research related to circRNA. The results show that publications have continuously increased in the past decade. China, the US, and Germany were the leading countries/regions in terms of quantity. Recent studies on topics related to circRNA biogenesis and function should be closely followed in this field.
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http://dx.doi.org/10.22074/cellj.2021.7143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181316PMC
July 2021

Role of Tim-3 in regulating tumorigenesis, inflammation, and antitumor immunity therapy.

Cancer Biomark 2021 Jun 5. Epub 2021 Jun 5.

College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang, China.

Over the past decade, cancer immunotherapy, such as immune checkpoint inhibitors (ICRs), has attained considerable progresses in clinical practice. T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) act as next ICRs, and originally function as a co-inhibitory receptor expressed on interferon (IFN)-γ producing CD4+ and CD8+ T-cells. Furthermore, Tim-3 has also been found to express on innate immune cells and several types of tumors, signifying the pivotal role that Tim-3 plays in chronic viral infections and cancer. In addition, Tim-3 and multiple ICRs are concurrently expressed and regulated on dysfunctional or exhausted T-cells, leading to improved antitumor immune responses in preclinical or clinical cancer therapy through co-blockade of Tim-3 and other ICRs such as programmed cell death-1 (PD-1). In this review, the biological characteristics of Tim-3 and the function of Tim-3 in regulating tumorigenesis and inflammation have been summarized. The usage of a single blockade of Tim-3 or in combination with multiple immunotherapy regimens have drawn attention to antitumor potential as a target for immunotherapy.
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http://dx.doi.org/10.3233/CBM-210114DOI Listing
June 2021

Detection of tyrosinase in living cells using an Enteromorpha Prolifera based fluorescent probe.

Anal Chim Acta 2021 Jul 5;1169:338605. Epub 2021 May 5.

State Key Laboratory of Heavy Oil Processing, College of Chemical Engineering, China University of Petroleum (East China), Qingdao, 266580, China. Electronic address:

Melanoma, the skin cancer with the highest mortality rate, can be diagnosed at the early stage by detecting unique biomarkers. Over-expressed tyrosinase has been confirmed by dozens of clinical studies as an independent factor to evaluate the malignancy of melanoma. Using Enteromorpha Prolifera as the raw material, herein we develop a novel fluorescent probe, ECDY, which can sensitively detect the tyrosinase activity in different types of cells. More importantly, melanoma cells can be specifically distinguished through cell lysate measurements as well as the whole-cell imaging technique. Mechanically, the tyrosine groups on the surface of ECDY can be specifically recognized by tyrosinase and further converted into dopaquinone, which consequently causes the intramolecular fluorescence quenching of the probe through photoinduced electron transfer (PET). Tyrosinase can be detected within 20 min in the solution, and the detection limit is as low as 0.067 U mL. For the in vitro demonstration, we evaluate the fluorescence decay of ECDY in response to the intracellular tyrosinase activity within the lysate of various cell lines, including non-cancerous, non-melanoma cancerous, and mouse melanoma ones. The experimental results verify that ECDY can accurately measure the apparent tyrosinase activity in different cell lines and detect melanoma cell lysate specifically. The confocal fluorescence imaging experiments further demonstrate that ECDY can distinguish melanoma cells from others significantly. We believe that ECDY provides a new strategy for the efficient detection of tyrosinase and melanoma cells, and is expected to apply as a clinical diagnosis platform.
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http://dx.doi.org/10.1016/j.aca.2021.338605DOI Listing
July 2021

ROR: Nuclear Receptor for Melatonin or Not?

Molecules 2021 May 4;26(9). Epub 2021 May 4.

Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China.

Whether the retinoic acid-related orphan receptor (ROR) is a nuclear receptor of melatonin remains controversial. ROR is inextricably linked to melatonin in terms of its expression, function, and mechanism of action. Additionally, studies have illustrated that melatonin functions analogous to ROR ligands, thereby modulating the transcriptional activity of ROR. However, studies supporting these interactions have since been withdrawn. Furthermore, recent crystallographic evidence does not support the view that ROR is a nuclear receptor of melatonin. Some other studies have proposed that melatonin indirectly regulates ROR activity rather than directly binding to ROR. This review aims to delve into the complex relationship of the ROR receptor with melatonin in terms of its structure, expression, function, and mechanism. Thus, we provide the latest evidence and views on direct binding as well as indirect regulation of ROR by melatonin, dissecting both viewpoints in-depth to provide a more comprehensive perspective on this issue.
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http://dx.doi.org/10.3390/molecules26092693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124216PMC
May 2021

Peripherally Acting Opioids in Orofacial Pain.

Front Neurosci 2021 4;15:665445. Epub 2021 May 4.

Department of Pediatric Dentistry, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.

The activation of opioid receptors by exogenous or endogenous opioids can produce significant analgesic effects in peripheral tissues. Numerous researchers have demonstrated the expression of peripheral opioid receptors (PORs) and endogenous opioid peptides (EOPs) in the orofacial region. Growing evidence has shown the involvement of PORs and immune cell-derived EOPs in the modulation of orofacial pain. In this review, we discuss the role of PORs and EOPs in orofacial pain and the possible cellular mechanisms involved. Furthermore, the potential development of therapeutic strategies for orofacial pain is also summarized.
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http://dx.doi.org/10.3389/fnins.2021.665445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129166PMC
May 2021

Ultrasensitive and ratiometric two-photon fluorescence imaging of Golgi polarity during drug-induced acute kidney injury.

Chem Commun (Camb) 2021 Jun;57(47):5838-5841

College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People's Republic of China.

We synthesized an ultrasensitive probe TP-Golgi for the two-photon ratiometric fluorescence imaging of Golgi polarity. Probe TP-Golgi possesses a large Stokes shift, excellent sensitivity and good selectivity to quantitatively detect environmental polarity. By application of TP-Golgi, we found that the Golgi polarity increased obviously in the kidneys of mice with AKI.
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http://dx.doi.org/10.1039/d1cc01411kDOI Listing
June 2021

Early risk factors for extrapulmonary organ injury in adult COVID-19 patients.

Ann Transl Med 2021 Apr;9(8):701

Department of Intensive Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.

Background: The novel 2019 coronavirus (COVID-19) has caused a global pandemic, and often leads to extrapulmonary organ injury. However, the risk factors for extrapulmonary organ injury are still unclear. We aim to explore the risk factors for extrapulmonary organ injury and the association between extrapulmonary organ injury and the prognosis in COVID-19 patients.

Methods: We implemented a single-center, retrospective, observational study, in which a total of 349 confirmed COVID-19 patients admitted to Tongji Hospital from January 25, 2020, to February 25, 2020, were enrolled. We collected demographic, clinical, laboratory, and treatment data from electronic medical records. Potential risk factors for extrapulmonary organ injury of COVID-19 patients were analyzed by a multivariable binary logistic model, and multivariable Cox proportional hazards regression model was used for survival analysis in the patients with extrapulmonary organ injury.

Results: The average age of the included patients was 61.73±14.64 years. In the final logistic model, variables including aged 60 or older [odds ratio (OR) 1.826, 95% confidence interval (CI): 1.060-3.142], acute respiratory distress syndrome (ARDS) (OR 2.748, 95% CI: 1.051-7.185), lymphocytes count lower than 1.1×10/L (OR 0.478, 95% CI: 0.240-0.949), level of interleukin-6 (IL-6) greater than 7 pg/mL (OR 1.664, 95% CI: 1.005-2.751) and D-Dimer greater than 0.5 μg/mL (OR 2.190, 95% CI: 1.176-4.084) were significantly associated with the extrapulmonary organ injury. Kaplan-Meier curve and log-rank test showed that the probabilities of survival for patients with extrapulmonary organ injury were significantly lower than those without extrapulmonary organ injury. Multivariate Cox proportional hazards model showed that only myocardial injury (P=0.000, HR: 5.068, 95% CI: 2.728-9.417) and circulatory system injury (P=0.000, HR: 4.076, 95% CI: 2.216-7.498) were the independent factors associated with COVID-19 patients' poor prognosis.

Conclusions: Older age, lymphocytopenia, high level of D-Dimer and IL-6, and the severity of lung injury were the high-risk factors of extrapulmonary organ injury in COVID-19 patients. Myocardial and circulatory system injury were the most important risk factors related to poor outcomes of COVID-19 patients. It may help clinicians to identify extrapulmonary organ injury early and initiate appropriate treatment.
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http://dx.doi.org/10.21037/atm-21-1561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106092PMC
April 2021

Clinical characteristics and outcomes of adult patients with acquired thrombotic thrombocytopenic purpura: a single center retrospective study.

Ann Palliat Med 2021 May 11;10(5):5351-5358. Epub 2021 May 11.

Department of Intensive Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare disease and a potentially life-threatening thrombotic microangiopathy. Although the diagnostic and therapeutic techniques have improved, it is still difficult for clinicians to identify early due to different initial clinical manifestations and the incidence and survival rate are reported inconsistently. This study investigated the clinical characteristics, treatment strategies, and treatment outcomes of adult patients with acquired TTP.

Methods: A retrospective analysis of 55 patients (35 females and 20 males) treated for acquired TTP from January 1, 2013 to December 31, 2017 was conducted. The analysis included clinical manifestations at onset, treatment efficacy measures, survival, cause of death, and the APACHE II (Acute Physiology and Chronic Health Evaluation II) and SOFA (sequential organ failure assessment) scores.

Results: At onset, in addition to thrombocytopenia and hemolysis, 50 patients (90.91%) presented with neurological abnormalities, but only 19 (34.55%) showed the classic TTP pentad of symptoms. The overall mortality rate was 34.55%. Plasma exchange (PEX) was performed in 49 patients. The most effective treatment was PEX with a normal dose of corticosteroid and rituximab which showed a response rate of 81.25%. The main cause of death was cerebral hemorrhage. The APACHE II and SOFA scores were higher in non-survivors compared to survivors (APACHE II: 20.12±7.83 vs. 11.50±4.49, P<0.05; SOFA: 12.06±3.27 vs. 7.74±2.10, P<0.05). Non-survivors had higher levels of lactic dehydrogenase (LDH; 1,646.94±1,269.48 vs. 942.76±740.58 IU/L, P=0.015), and higher numbers of schistocytes (6.18%±4.69% vs. 3.44%±3.13%, P=0.035) compared to survivors.

Conclusions: TTP progressed rapidly, and its clinical manifestations varied between patients. The diagnosis depended on the clinical features and laboratory tests. Combination therapy with PEX, immunosuppressive therapy, and rituximab may be useful. Higher APACHE II and SOFA scores, higher LDH levels, and a greater degree of schistocytosis were associated with the severity and outcome of TTP.
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http://dx.doi.org/10.21037/apm-21-759DOI Listing
May 2021

Response to: Mindfulness-based mobile app reduces anxiety and increases self-compassion in healthcare students: A randomised controlled trial.

Med Teach 2021 May 11. Epub 2021 May 11.

Department of dermatology, Peking University people's Hospital, Beijing, China.

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http://dx.doi.org/10.1080/0142159X.2021.1918657DOI Listing
May 2021

mTOR regulates GPVI-mediated platelet activation.

J Transl Med 2021 05 10;19(1):201. Epub 2021 May 10.

Chronic Disease Research Institute, Department of Nutrition and Food Hygiene, Zhejiang University School of Public Health, 866 Yu-Hang-Tang Road, Hangzhou, 310058, China.

Background: Due to mTOR (mammalian/mechanistic target of rapamycin) gene-loss mice die during embryonic development, the role of mTOR in platelets has not been evaluated using gene knockout technology.

Methods: A mouse model with megakaryocyte/platelet-specific deletion of mTOR was established, and be used to evaluate the role of mTOR in platelet activation and thrombus formation.

Results: mTOR platelets were deficient in thrombus formation when grown on low-concentration collagen-coated surfaces; however, no deficiency in thrombus formation was observed when mTOR platelets were perfused on higher concentration collagen-coated surfaces. In FeCl-induced mouse mesenteric arteriole thrombosis models, wild-type (WT) and mTOR mice displayed significantly different responses to low-extent injury with respect to the ratio of occluded mice, especially within the first 40 min. Additionally, mTOR platelets displayed reduced aggregation and dense granule secretion (ATP release) in response to low doses of the glycoprotein VI (GPVI) agonist collagen related peptide (CRP) and the protease-activated receptor-4 (PAR4) agonist GYPGKF-NH; these deficiencies were overcame by stimulation with higher concentration agonists, suggesting dose dependence of the response. At low doses of GPVI or PAR agonist, the activation of αβ in mTOR platelets was reduced. Moreover, stimulation of mTOR platelets with low-dose CRP attenuated the phosphorylation of S6K1, S6 and Akt Ser473, and increased the phosphorylation of PKCδ Thr505 and PKCε Ser729. Using isoform-specific inhibitors of PKCs (δ, ɛ, and α/β), we established that PKCδ/ɛ, and especially PKCδ but not PKCα/β or PKCθ, may be involved in low-dose GPVI-mediated/mTOR-dependent signaling.

Conclusion: These observations indicate that mTOR plays an important role in GPVI-dependent platelet activation and thrombus formation.
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http://dx.doi.org/10.1186/s12967-021-02756-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111939PMC
May 2021

Nonblinking carbon dots for imaging and tracking receptors on a live cell membrane.

Chem Commun (Camb) 2021 Jun 10;57(45):5554-5557. Epub 2021 May 10.

State Key Laboratory of Heavy Oil Processing and Centre for Bioengineering and Biotechnology, China University of Petroleum (East China), Qingdao, 266580, China.

Blinking occurs with nearly all fluorophores including organic dyes, fluorescent proteins, semiconductor quantum dots and carbon dots (CDs). We developed non-blinking and photoresistant fluorescent CDs by introducing multiple aromatic domains onto a single carbon dot and demonstrated their great potential for imaging and tracking of receptors on a live cell membrane.
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http://dx.doi.org/10.1039/d1cc01120kDOI Listing
June 2021

Preparation of loratadine nanocrystal tablets to improve the solubility and dissolution for enhanced oral bioavailability.

J Pharm Pharmacol 2021 Jun;73(7):937-946

State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.

Objectives: Loratadine is a selective H1 receptor inhibitor that has been widely used in the clinical treatment of allergic diseases. Here we aimed to develop a novel solid loratadine nanocrystal to increase the low and pH-dependent water solubility for bioavailability enhancement.

Methods: Loratadine solid nanocrystal was developed through high-speed shear-high pressure homogenization followed by freeze-drying, which was further prepared into tablets through direct compression. The formulation and process parameter were screened. Furthermore, the characterization and oral bioavailability of loratadine nanocrystal were studied.

Key Findings: The loratadine nanocrystal had the satisfactory particle size of 425.9 nm and great redispersibility, which was mainly attributed to the addition of Pluronic F127 and polyvinylpyrrolidone K17 as the stabilizer. The saturation solubility of the loratadine nanocrystal was increased to 3.81, 3.22 and 2.57-fold that of the crude drug in water, pH 6.8 and pH 4.5 buffer respectively. Furthermore, the pharmacokinetic studies in rats revealed that the AUC (0-∞) of the nanocrystal tablets was 2.38-fold that of raw tablets and 1.94-fold that of commercial tablets, respectively.

Conclusions: The nanocrystal tablets could significantly improve the oral bioavailability of loratadine, which would also be a promising approach to enhance the solubility of insoluble drugs.
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http://dx.doi.org/10.1093/jpp/rgab043DOI Listing
June 2021