Publications by authors named "Mei Zhou"

413 Publications

Genome-wide detection of genetic structure and runs of homozygosity analysis in Anhui indigenous and Western commercial pig breeds using PorcineSNP80k data.

BMC Genomics 2022 May 17;23(1):373. Epub 2022 May 17.

Key Laboratory of Pig Molecular Quantitative Genetics of Anhui Academy of Agricultural Sciences, Anhui Provincial Key Laboratory of Livestock and Poultry Product Safety Engineering, Institute of Animal Husbandry and Veterinary Medicine, Anhui Academy of Agricultural Sciences, Hefei, 230031, China.

Background: Runs of homozygosity (ROH) are continuous homozygous regions typically located in the DNA sequence of diploid organisms. Identifications of ROH that lead to reduced performance can provide valuable insight into the genetic architecture of complex traits. Here, we systematically investigated the population genetic structure of five Anhui indigenous pig breeds (AHIPs), and compared them to those of five Western commercial pig breeds (WECPs). Furthermore, we examined the occurrence and distribution of ROHs in the five AHIPs and estimated the inbreeding coefficients based on the ROHs (F) and homozygosity (F). Finally, we identified genomic regions with high frequencies of ROHs and annotated candidate genes contained therein.

Results: The WECPs and AHIPs were clearly differentiated into two separate clades consistent with their geographical origins, as revealed by the population structure and principal component analysis. We identified 13,530 ROHs across all individuals, of which 4,555 and 8,975 ROHs were unique to AHIPs and WECPs, respectively. Most ROHs identified in our study were short (< 10 Mb) or medium (10-20 Mb) in length. WECPs had significantly higher numbers of short ROHs, and AHIPs generally had longer ROHs. F values were significantly lower in AHIPs than in WECPs, indicating that breed improvement and conservation programmes were successful in AHIPs. On average, F and F values were highly correlated (0.952-0.991) in AHIPs and WECPs. A total of 27 regions had a high frequency of ROHs and contained 17 key candidate genes associated with economically important traits in pigs. Among these, nine candidate genes (CCNT2, EGR2, MYL3, CDH13, PROX1, FLVCR1, SETD2, FGF18, and FGF20) found in WECPs were related to muscular and skeletal development, whereas eight candidate genes (CSN1S1, SULT1E1, TJP1, ZNF366, LIPC, MCEE, STAP1, and DUSP) found in AHIPs were associated with health, reproduction, and fatness traits.

Conclusion: Our findings provide a useful reference for the selection and assortative mating of pig breeds, laying the groundwork for future research on the population genetic structures of AHIPs, ultimately helping protect these local varieties.
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http://dx.doi.org/10.1186/s12864-022-08583-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9115978PMC
May 2022

Size-changeable nanoprobes for the combined radiotherapy and photodynamic therapy of tumor.

Eur J Nucl Med Mol Imaging 2022 May 10. Epub 2022 May 10.

Jiangsu Key Laboratory of Molecular Imaging and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, People's Republic of China.

Purpose: Radiation therapy (RT) and photodynamic therapy (PDT) are promising while challenging in treating tumors. The potential radiation resistance of tumor cells and side effects to healthy tissues restrict their clinical treatment efficacy. Effective delivery of therapeutic agents to the deep tumor tissues would be available for tumor-accurate therapy and promising for the tumor therapy. Thus, developing nanoprobes with effectively delivering radiotherapy sensitizers and photosensitizers to the interior of tumors is needed for the accurate combined RT and PDT of tumor.

Methods: The size-changeable nanoprobes of [email protected] (BGBC) were synthesized with a crosslinking method. Magnetic resonance imaging (MRI) and in vivo near-infrared (NIR) imaging were measured to evaluate the nanoprobes' tumor accumulation and intratumor penetration effect. The tumor suppression effect of combined RT and PDT with these nanoprobes was also studied for the 4T1 bearing Balb/c mice.

Results: The nanoprobes BGBC showed high tumor accumulation and disintegrated into small particles responding to the photo-irradiation-produced reactive oxygen species (ROS), allowing for tumor penetration. Abundant radiotherapy sensitizers and photosensitizers were delivered to the deep tumor tissues, which is available for the accurate therapy of tumor. In addition, the BGBC displayed outstanding MRI and fluorescence imaging effects for evaluating the biodistribution and tumor suppression effect of nanoprobes. Consequently, significant tumor suppression effect was obtained based on the accurate tumor treatment with the combined RT and PDT.

Conclusion: The designed size-changeable nanoprobes BGBC showed excellent tumor accumulation and deep tumor penetration, resulting in a significant tumor suppression effect based on the combined RT and PDT. This study provides a novel strategy for dual delivery of radiotherapy sensitizers and photosensitizers into the deep tumor tissues and is promising for the accurate theranostics of tumor.
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http://dx.doi.org/10.1007/s00259-022-05830-9DOI Listing
May 2022

Mild-Temperature Photothermal Effect Enhanced by Functional Conjugated Polymer Nanoparticles through Enzyme-Mediated Starvation.

ACS Appl Bio Mater 2022 May 10. Epub 2022 May 10.

Key Laboratory of Hebei Province for Molecular Biophysics, Institute of Biophysics, Hebei University of Technology, Tianjin 300401, P.R. China.

Mild-temperature photothermal therapy (PTT) is being extensively explored because it causes less injury to normal cells. However, the effect of mild-temperature PTT is decreased because of heat shock protein (HSP) overexpression. To solve this problem, we designed functional conjugated polymer nanoparticles (CPNs-G) that enhance the mild-temperature photothermal effect. Upon near-infrared (NIR) light irradiation, CPNs-G generate local heat to realize the photothermal effect. Meanwhile, the increased temperature enhances the catalytic activity of GOx, thus impeding the generation of adenosine triphosphate (ATP) and inhibiting HSP expression. Therefore, this work provides a strategy for overcoming thermoresistance through an enzyme-mediated starvation effect regulated by NIR light.
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http://dx.doi.org/10.1021/acsabm.2c00288DOI Listing
May 2022

POU6F1 cooperates with RORA to suppress the proliferation of lung adenocarcinoma by downregulation HIF1A signaling pathway.

Cell Death Dis 2022 May 3;13(5):427. Epub 2022 May 3.

Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China.

Lung adenocarcinoma (LUAD) represents the most frequently diagnosed histological subtype of non-small cell lung cancer with the highest mortality worldwide. Transcriptional dysregulation is a hallmark of nearly all kinds of cancers. In the study, we identified that the POU domain, class 6, transcription factor 1 (POU6F1), a member of the POU family of transcription factors, was closely associated with tumor stage and death in LUAD. We revealed that POU6F1 was downregulated in LUAD tissues and downregulated POU6F1 was predictive of an unfavorable prognosis in LUAD patients. In vitro assays, including CCK8, soft agar, transwell, clone formation, wound-healing assay, and nude mouse xenograft model all revealed that POU6F1 inhibited the growth and invasion of LUAD cells. Mechanistically, POU6F1 bound and stabilized retinoid-related orphan receptor alpha (RORA) to exert the transcriptional inhibition of hypoxia-inducible factor 1-alpha (HIF1A) and alter the expression of HIF1A signaling pathway-associated genes, including ENO1, PDK1, and PRKCB, thereby leading to the suppression of LUAD cells. Collectively, these results demonstrated the suppressive role of POU6F1/RORA in the progression of LUAD and may potentially be used as a target for the treatment of LUAD.
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http://dx.doi.org/10.1038/s41419-022-04857-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065044PMC
May 2022

Locomotor Pattern and Force Generation Modulated by Ionic Channels: A Computational Study of Spinal Networks Underlying Locomotion.

Front Comput Neurosci 2022 14;16:809599. Epub 2022 Apr 14.

Shanghai Key Laboratory of Multidimensional Information Processing, School of Communication and Electronic Engineering, East China Normal University, Shanghai, China.

Locomotion is a fundamental movement in vertebrates produced by spinal networks known as central pattern generators (CPG). During fictive locomotion cat lumbar motoneurons (MNs) exhibit changes in membrane properties, including hyperpolarization of voltage threshold, reduction of afterhyperpolarization and input resistance, and amplification of nonlinear membrane properties. Both modeling and electrophysiological studies suggest that these changes can be produced by upregulating voltage-gated sodium channel (VGSC), persistent sodium (NaP), or L-type calcium channel (LTCC) or downregulating delayed-rectifier potassium (K(DR)) or calcium-dependent potassium channel (KCa) in spinal MNs. Further studies implicate that these channel modulations increase motor output and facilitate MN recruitment. However, it remains unknown how the channel modulation of CPG networks or MN pools affects the rhythmic generation of locomotion and force production of skeletal muscle during locomotion. In order to investigate this issue, we built a two-level CPG model composed of excitatory interneuron pools (Exc-INs), coupled reciprocally with inhibitory interneuron pools (Inh-INs), and projected to the flexor-extensor MN pools innervating skeletal muscles. Each pool consisted of 100 neurons with membrane properties based on cat spinal neurons. VGSC, K(DR), NaP, KCa, LTCC, and H-current channels were included in the model. Simulation results showed that (1) upregulating VGSC, NaP, or LTCC or downregulating KCa in MNs increased discharge rate and recruitment of MNs, thus facilitating locomotor pattern formation, increased amplitude of electroneurogram (ENG) bursting, and enhanced force generation of skeletal muscles. (2) The same channel modulation in Exc-INs increased the firing frequency of the Exc-INs, facilitated rhythmic generation, and increased flexor-extensor durations of step cycles. (3) Contrarily, downregulation of NaP or LTCC in MNs or Exc-INs or both CPG (Exc-INs and Inh-INs) and MNs disrupted locomotor pattern and reduced or even blocked the ENG bursting of MNs and force generation of skeletal muscles. (4) Pharmacological experiments showed that bath application of 25 μM nimodipine or 2 μM riluzole completely blocked fictive locomotion in isolated rat spinal cord, consistent with simulation results. We concluded that upregulation of VGSC, NaP, or LTCC or downregulation of KCa facilitated rhythmic generation and force production during walking, with NaP and LTCC playing an essential role.
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http://dx.doi.org/10.3389/fncom.2022.809599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9050146PMC
April 2022

Transcriptomic Changes of Photoperiodic Response in the Hypothalamus Were Identified in Ovariectomized and Estradiol-Treated Sheep.

Front Mol Biosci 2022 11;9:848144. Epub 2022 Apr 11.

Key Laboratory of Animal Genetics and Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China.

Accurate timing of seasonal changes is an essential ability for an animal's survival, and the change in the photoperiod is the key factor affecting reproductive seasonality in mammals. Emerging evidence has suggested that multiple hypothalamic genes participate in the photoperiod-induced regulation of reproductive activities in sheep, but the mechanism is still unclear. In this study, we initially examined the plasma level of two major reproductive hormones, namely, follicle-stimulating hormone (FSH) and prolactin (PRL), under different photoperiods in ovariectomized and estradiol-treated (OVX + E) sheep using radioimmunoassay (RIA). Of the two hormones, the concentration of PRL significantly increased with the extension of the photoperiod, while FSH showed the opposite trend. Subsequently, an examination of the transcriptomic variation between the short photoperiod (SP) and long photoperiod (LP) was conducted. Differential expression analyses and functional annotation showed that several key genes in the insulin secretion (, , , and ), GnRH (, , , , and ) pathways, and circadian entrainment (, , , , and ), as well as numerous lncRNAs, including XR_173257.3, XR_173415.3, XR_001435315.1, XR_001024596.2, and XR_001023464.2, were shown potentially vital for the hypothalamic photoperiodic response. Four of the differentially expressed mRNAs and lncRNAs were validated by qPCR. The constructed mRNA-mRNA interaction networks further revealed that transcripts potentially participated in hypothalamic thyroid hormone synthesis, endocrine resistance, and neuroactive ligand-receptor interactions. The interactome analysis of lncRNAs and their targets implied that XR_173257.3 and its target arylalkylamine N-acetyltransferase () and XR_173415.3 and its target might participate in the regulation of seasonal reproduction. Together, the changes in reproductive hormones and transcriptome will help to determine the important photoperiod-induced lncRNAs and mRNAs and provide a valuable resource for further research on reproductive seasonality in sheep.
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http://dx.doi.org/10.3389/fmolb.2022.848144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9036065PMC
April 2022

Artificial Intelligence Uncovers Natural MMP Inhibitor Crocin as a Potential Treatment of Thoracic Aortic Aneurysm and Dissection.

Front Cardiovasc Med 2022 6;9:871486. Epub 2022 Apr 6.

Beijing Anzhen Hospital, Capital Medical University, Beijing, China.

Thoracic aortic aneurysm and dissection (TAAD) is a lethal cardiovascular condition without effective pharmaceutical therapy. Identifying novel drugs that target the key pathogenetic components is an urgent need. Bioinformatics analysis of pathological studies indicated "extracellular matrix organization" as the most significant functional pathway related to TAAD, in which matrix metallopeptidase (MMP) 2 and MMP9 ranked above other proteases. MMP1-14 were designated as the prototype molecules for docking against PubChem Compound Database using Surflex-Dock, and nine natural compounds were identified. Using a generic MMP activity assay and an aminopropionitrile (BAPN)-induced TAAD mouse model, we identified crocin as an effective MMP inhibitor, suppressing the occurrence and rupture of TAAD. Biolayer interferometry and AI/bioinformatics analyses indicated that crocin may inhibit MMP2 activity by direct binding. Possible binding sites were investigated. Overall, the integration of artificial intelligence and functional experiments identified crocin as an MMP inhibitor with strong therapeutic potential.
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http://dx.doi.org/10.3389/fcvm.2022.871486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9019136PMC
April 2022

Machine learning to predict no reflow and in-hospital mortality in patients with ST-segment elevation myocardial infarction that underwent primary percutaneous coronary intervention.

BMC Med Inform Decis Mak 2022 Apr 24;22(1):109. Epub 2022 Apr 24.

Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, 530021, Guangxi, China.

Background: The machine learning algorithm (MLA) was implemented to establish an optimal model to predict the no reflow (NR) process and in-hospital death that occurred in ST-elevation myocardial infarction (STEMI) patients who underwent primary percutaneous coronary intervention (pPCI).

Methods: The data were obtained retrospectively from 854 STEMI patients who underwent pPCI. MLA was applied to predict the potential NR phenomenon and confirm the in-hospital mortality. A random sampling method was used to split the data into the training (66.7%) and testing (33.3%) sets. The final results were an average of 10 repeated procedures. The area under the curve (AUC) and the associated 95% confidence intervals (CIs) of the receiver operator characteristic were measured.

Results: A random forest algorithm (RAN) had optimal discrimination for the NR phenomenon with an AUC of 0.7891 (95% CI: 0.7093-0.8688) compared with 0.6437 (95% CI: 0.5506-0.7368) for the decision tree (CTREE), 0.7488 (95% CI: 0.6613-0.8363) for the support vector machine (SVM), and 0.681 (95% CI: 0.5767-0.7854) for the neural network algorithm (NNET). The optimal RAN AUC for in-hospital mortality was 0.9273 (95% CI: 0.8819-0.9728), for SVM, 0.8935 (95% CI: 0.826-0.9611); NNET, 0.7756 (95% CI: 0.6559-0.8952); and CTREE, 0.7885 (95% CI: 0.6738-0.9033).

Conclusions: The MLA had a relatively higher performance when evaluating the NR risk and in-hospital mortality in patients with STEMI who underwent pPCI and could be utilized in clinical decision making.
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http://dx.doi.org/10.1186/s12911-022-01853-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9036765PMC
April 2022

Engineering and Structural Insights of a Novel BBI-like Protease Inhibitor Livisin from the Frog Skin Secretion.

Toxins (Basel) 2022 Apr 12;14(4). Epub 2022 Apr 12.

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325015, China.

The Bowman-Birk protease inhibitor (BBI) family is a prototype group found mainly in plants, particularly grasses and legumes, which have been subjected to decades of study. Recently, the discovery of attenuated peptides containing the canonical Bowman-Birk protease inhibitory motif has been detected in the skin secretions of amphibians, mainly from Ranidae family members. The roles of these peptides in amphibian defense have been proposed to work cooperatively with antimicrobial peptides and reduce peptide degradation. A novel trypsin inhibitory peptide, named livisin, was found in the skin secretion of the green cascade frog, . The cDNA encoding the precursor of livisin was cloned, and the predicted mature peptide was characterized. The mature peptide was found to act as a potent inhibitor against several serine proteases. A comparative activity study among the native peptide and its engineered analogs was performed, and the influence of the P and P positions, as well as the C-terminal amidation on the structure-activity relationship for livisin, was illustrated. The findings demonstrated that livisin might serve as a potential drug discovery/development tool.
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http://dx.doi.org/10.3390/toxins14040273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9030697PMC
April 2022

Fibroblast-Secreted Phosphoprotein 1 Mediates Extracellular Matrix Deposition and Inhibits Smooth Muscle Cell Contractility in Marfan Syndrome Aortic Aneurysm.

J Cardiovasc Transl Res 2022 Apr 12. Epub 2022 Apr 12.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.

Fibrillin 1 (Fbn1) mutation causes Marfan syndrome (MFS) with thoracic aortic aneurysm (TAA) as the main complication. The mechanisms for extracellular matrix (ECM) homeostasis disruption in MFS TAA are unclear. Here, we found ECM-related gene secreted phosphoprotein 1 (Spp1) increased in Fbn1 mice using transcriptome sequencing and a distinct fibroblast subcluster with Spp1 as the strongest marker was identified with analysis of the MFS mouse aortic single-cell sequencing dataset. Immunostaining confirmed elevated Spp1 in adventitial fibroblasts, and Spp1 might regulate fibroblast and smooth muscle cell (SMC) communication primarily through Itga8/Itgb1. Then, we observed Spp1 reduced contractile genes Acta2 and Tagln expression in SMCs and increased collagen expression in fibroblasts, which might contribute to TAA development. Finally, we also found elevated SPP1 plasma level was associated with an increased risk of TAA in patients. Therefore, SPP1 may serve as a biomarker and therapeutic target for TAA.
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http://dx.doi.org/10.1007/s12265-022-10239-8DOI Listing
April 2022

Targeting Cancer Cell Ferroptosis to Reverse Immune Checkpoint Inhibitor Therapy Resistance.

Front Cell Dev Biol 2022 24;10:818453. Epub 2022 Mar 24.

Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Hubei Clinical Research Center for Respiratory Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

In recent years, cancer therapies using immune checkpoint inhibitors (ICIs) have achieved meaningful success, with patients with advanced tumors presenting longer survival times and better quality of life. However, several patients still do not exhibit good clinical outcomes for ICI therapy due to low sensitivity. To solve this, researchers have focused on identifying the cellular and molecular mechanisms underlying resistance to ICI therapy. ICI therapy induces apoptosis, which is the most frequent regulated cell death (RCD) but lacks immunogenicity and is regarded as an "immune silent" cell death. Ferroptosis, a unique type of non-apoptotic-RCD, has been preliminarily identified as an immunogenic cell death (ICD), stimulating tumor-antigen-specific immune responses and augmenting anti-tumor immune effects. However, ferroptosis has rarely been used in clinical practice. Present evidence strongly supports that the interferon-γ signaling pathway is at the crossroads of ICI therapy and ferroptosis. TYRO3, a receptor tyrosine kinase, is highly expressed in tumors and can induce anti-programmed cell death (PD)-ligand 1/PD-1 therapy resistance by limiting tumoral ferroptosis. Therefore, in this review, we summarize the clinical practice and effects of ICI therapy in various cancers. We also provide an overview of ferroptosis and report the molecular connections between cancer cell ferroptosis and ICI therapy, and discuss the possibility to reverse ICI therapy resistance by inducing cancer cell ferroptosis.
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http://dx.doi.org/10.3389/fcell.2022.818453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8988234PMC
March 2022

Terminalia chebula extracts ameliorate methamphetamine-induced memory deficits via activating the ERK and Nrf2 pathway.

Brain Res Bull 2022 Jun 8;184:76-87. Epub 2022 Apr 8.

Wuhan Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China. Electronic address:

As a psychoactive substance abused worldwide, methamphetamine (METH) abuse leads to multiple neurodegenerative symptoms including memory deficits. Terminalia chebula retzius extracts (TREs) isolated by our lab have great antioxidant activity and its effect on METH-induced memory deficits has not been investigated yet. The present study was designed to investigate the protective effect of TREs on METH induced cell apoptosis in vitro and memory deficits in vivo. The results showed that TREs treatment attenuated free radical release and improved cell survival of primary hippocampal neurons after METH injury. In the Morris water maze task, TREs treatment reversed METH-induced learning and memory deficits in acquisition and retention. Moreover, TREs reduced oxidative stress in the serum and hippocampus of mice. Additionally, extracellular regulated protein kinases (ERK1/2) pathway and the nuclear factor E2-related factor 2 (Nrf2) pathway were inactivated after METH treatment, and were significantly activated after TREs pretreatment. These findings suggest that TREs may exert potent neuroprotective effect via activation of both ERK and Nrf2 pathways, thus providing a basis for its potential use for ameliorating memory deficits induced by METH.
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http://dx.doi.org/10.1016/j.brainresbull.2022.04.002DOI Listing
June 2022

Emerging nanotherapeutics alleviating rheumatoid arthritis by readjusting the seeds and soils.

J Control Release 2022 May 6;345:851-879. Epub 2022 Apr 6.

College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China; Institute of Pharmaceutics, Anhui Academy of Chinese Medicine, Hefei 230012, China; Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Hefei 230012, China; Engineering Technology Research Center of Modern Pharmaceutical Preparation, Anhui Province, Hefei 230012, China. Electronic address:

Rheumatoid arthritis (RA) is a complicated autoimmune disease that results in severe joint inflammation, synovial hyperplasia, pannus formation, cartilage and bone destruction, and other RA-associated complications. Although the pathogenesis of RA remains unclear, increasing reports have shown that inflammation-relevant cells and the microenvironment of inflamed joints play a critical role in the formation and aggravation of RA. Recently, numerous nanotherapeutics have been engineered to overcome these intractable challenges by readjusting inflammation-related seeds (endothelial cells, macrophages, neutrophils, antigen-presenting cells, fibroblasts, osteoclasts, T cells, B cells, and chondrocytes) and inflamed soils (NO, cell-free DNA, hypoxia, ROS, and pro-inflammatory cytokines). In this review, we first present a detailed pathogenesis of RA, with an emphasis on the emerging advances in regulating seeds or remodeling soils for RA treatment. We then outline these intelligent therapeutics via synergistic seed-soil adjustment, particularly for spatiotemporally cascade-responsive or all-in-one integrational nanosystems. Finally, we briefly discuss the ongoing challenges and prospects for the clinical development and translation of seed soil-based therapies.
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http://dx.doi.org/10.1016/j.jconrel.2022.04.001DOI Listing
May 2022

Application of multi-wavelength dual-position absorption spectrum to improve the accuracy of leukocyte spectral quantitative analysis based on "M + N" theory.

Spectrochim Acta A Mol Biomol Spectrosc 2022 Aug 26;276:121199. Epub 2022 Mar 26.

State Key Laboratory of Precision Measurement Technology and Instrument, Tianjin University, Tianjin 300072, China; China and Tianjin Key Laboratory of Biomedical Detecting Techniques and Instruments, Tianjin University, Tianjin 300072, China. Electronic address:

Leukocytes are the most important immune cells in human body, which are very important to maintain the immune function of human body. They can phagocytose foreign bodies and produce antibodies to resist the invasion of pathogens. Nowadays, the abuse of antibiotics is widespread, and the detection and analysis of leukocytes is very important for clinical diagnosis. It is of great medical significance to use chemical quantitative analysis method based on spectrum to realize the rapid and trace detection of leukocytes in clinic. It is the development direction of clinical detection in the future and provides a new way to improve the abuse of antibiotics. However, due to the influence of nonlinearity introduced by the measurement, the relationship between absorbance and concentration deviates from Lambert-Beer law, which leads to low measurement accuracy and restricts its development in clinical application. In order to improve the accuracy of spectral analysis, this paper with the guidance of "M + N" theory measured the transmission spectra of 392 whole blood samples under two different optical path lengths, and subtracts them to obtain the multi-band differential absorption spectra for modeling and prediction of leukocyte concentration. The following experiments were designed: using the transmission spectra measured at one position and the absorption spectra obtained by subtracting the transmission spectra measured at position 1 and position 2 as the input of modeling. Partial least squares (PLS) method was proposed in this paper for modeling and predicting the concentration of leukocyte. The experimental results show that the modeling results of dual-position absorption spectrum have been significantly improved and promoted compared with the modeling results of transmission spectrum in one position, and the calibration set correlation coefficient (R) values has increased by 57.92% to 0.864904, where the prediction set correlation coefficient (R) increased by 106.81% to 0.8502. The root mean square error of the calibration set (RMSEC) decreased by 40.01% from 3.1149 to 1.8686. The results suggest that modelling and analysing leukocytes with a multi-band dual-position absorption spectrum may reduce the influence of nonlinearity to a certain amount, significantly increase the model's prediction precision and accuracy, and obtain satisfactory results. This paper provides the possibility for rapid clinical micro-detection of leukocytes, as well as the ideas and directions for improving the accuracy of spectral quantitative analysis of components in complex solutions.
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http://dx.doi.org/10.1016/j.saa.2022.121199DOI Listing
August 2022

SARS-CoV-2: Mechanism of infection and emerging technologies for future prospects.

Rev Med Virol 2021 03 16;31(2):e2168. Epub 2020 Sep 16.

Department of Cell Biology, School of Life Sciences, Central South University, Changsha, China.

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally to over 200 countries with more than 23 million confirmed cases and at least 800,000 fatalities as of 23 August 2020. Declared a pandemic on March 11 by World Health Organization, the disease caused by SARS-CoV-2 infection, called coronavirus disease 2019 (COVID-19), has become a global public health crisis that challenged all national healthcare systems. This review summarized the current knowledge about virologic and pathogenic characteristics of SARS-CoV-2 with emphasis on potential immunomodulatory mechanism and drug development. With multiple emerging technologies and cross-disciplinary approaches proving to be crucial in our global response against COVID-19, the application of PROteolysis TArgeting Chimeras strategy, CRISPR-Cas9 gene editing technology, and Single-Nucleotide-Specific Programmable Riboregulators technology in developing antiviral drugs and detecting infectious diseases are proposed here. We also discussed the available but still limited epidemiology of COVID-19 as well as the ongoing efforts on vaccine development. In brief, we conducted an in-depth analysis of the pathogenesis of SARS-CoV-2 and reviewed the therapeutic options for COVID-19. We also proposed key research directions in the future that may help uncover more underlying molecular mechanisms governing the pathology of COVID-19.
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http://dx.doi.org/10.1002/rmv.2168DOI Listing
March 2021

In Vitro & In Vivo Studies on Identifying and Designing Temporin-1CEh from the Skin Secretion of as the Optimised Antibacterial Prototype Drug.

Pharmaceutics 2022 Mar 10;14(3). Epub 2022 Mar 10.

Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR 999078, China.

Amphibian skin secretion is an ideal source of antimicrobial peptides that are difficult to induce drug resistance to due to their membrane-targeting mechanism as a new treatment scheme. In this study, a natural antimicrobial peptide Temporin-1CEh was identified by molecular cloning and mass spectrometry from the skin secretions of the Chinese forest frog (). Through the study of the structure and biological activity, it was found that Temporin-1CEh was a helical peptide from the Temporin family, and possessed good anti-Gram-positive bacteria activity through the mechanism of membrane destruction. Seven analogues were further designed to obtain broad-spectrum antimicrobial activity and higher stability in different physiological conditions. The results showed that T1CEh-KKPWW showed potent antibacterial activity with significantly increasing the activity against Gram-negative bacteria in vitro and in vivo with low haemolysis. In addition, T1CEh-KKPWW2 showed high sensitivity to the pH, serum or salts conditions, which applied a branched structure to allow the active units of the peptide to accumulate. Even though the haemolytic activity was increased, the stable antibacterial activity made this novel analogue meet the conditions to become a potential candidate in future antimicrobial and antibiofilm applications.
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http://dx.doi.org/10.3390/pharmaceutics14030604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8949600PMC
March 2022

Hypoxia-induced interstitial transformation of microvascular endothelial cells by mediating HIF-1α/VEGF signaling in systemic sclerosis.

PLoS One 2022 1;17(3):e0263369. Epub 2022 Mar 1.

Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, P.R. China.

Objective: The aim of this research was to systematically investigate the effects of endothelial mesenchymal transition (EndMT) induced by hypoxia on the skin microvascular remodeling of systemic sclerosis (SSc) and the underlying mechanism.

Methods: Skin tissues from SSc patients and controls were collected for isobaric tags for the relative and absolute quantification (iTRAQ)-based proteomics and immunohistochemical test. Human microvascular endothelial cell line-1 (HMEC-1) cultured in hypoxic or normal conditions was treated by tamoxifen or bevacizumab.

Results: The iTRAQ-based proteomics indicated a significantly upregulated hypoxia-inducible factor-1 (HIF-1) signal in SSc samples. The immunohistochemical results demonstrated the significant downregulation of CD31, the positive staining of α-smooth muscle actin (α-SMA), HIF-1α, and vascular endothelial growth factor (VEGF-a) in SSc skin tissues, compared with control samples. Consistent with these observations, HMEC-1 cells cultured under hypoxic conditions exhibited a significant decrease in CD31 and VE-cadherin expression, alongside a marked increase in the expression of α-SMA and fibronectin, as well as a distinct upregulation of HIF-1α and VEGF-a, when compared with those under normal conditions. It is noteworthy that the inhibition of HIF-1α by tamoxifen effectively downregulated the hypoxic induction of VEGF-a and α-SMA while rescuing the hypoxic suppression of CD31. In addition, the VEGF-a inhibitor bevacizumab treatment had the same effect on the hypoxic expression of α-SMA and CD31, as a tamoxifen intervention, but did not reduce HIF-1α.

Conclusion: These results suggest that the HIF-1α/VEGF signaling pathway can have a critical role in mediating the effect of hypoxia-induced EndMT on the skin microvascular remodeling of SSc.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0263369PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8887755PMC
March 2022

Kassporin-KS1: A Novel Pentadecapeptide from the Skin Secretion of : Studies on the Structure-Activity Relationships of Site-Specific "Glycine-Lysine" Motif Insertions.

Antibiotics (Basel) 2022 Feb 13;11(2). Epub 2022 Feb 13.

School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.

Due to the abuse of traditional antibiotics and the continuous mutation of microbial resistance genes, microbial infections have become serious problems for human health. Therefore, novel antibacterial agents are urgently required, and amphibian antimicrobial peptides (AMP) are among the most interesting potential antibacterial leads. In this research, a novel peptide, named kassporin-KS1 (generically QUB-1641), with moderate antibacterial activity against Gram-positive bacteria, was discovered in the skin secretion of the Senegal running frog, . Using site-specific sequence enrichment with a motif "glycine-lysine" that frequently occurs in ranid frog temporin peptides, a series of QUB-1641 analogues were synthesized, and effects on selected bioactivities were studied. The greatest activity enhancement was obtained when the "glycine-lysine" motif was located at the eighth and ninth position as in QUB-1570.QUB-1570 had a broader antibacterial spectrum than QUB-1641, and was eight-fold more potent. Moreover, QUB-1570 inhibited biofilm most effectively, and significantly enhanced the viability of insect larvae infected with . When the "glycine-lysine" motif of QUB-1570 was substituted to reduce the helix ratio and positive charge, the antibacterial activities of these synthetic analogues decreased. These data revealed that the "glycine-lysine" motif at positions 8 and 9 had the greatest enhancing effect on the antibacterial properties of QUB-1570 through increasing positive charge and helix content. This research may provide strategies for the site's selective amino acid modification of some natural peptides to achieve the desired enhancement of activity.
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http://dx.doi.org/10.3390/antibiotics11020243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8868508PMC
February 2022

Immune-Related lncRNA Pairs as Prognostic Signature and Immune-Landscape Predictor in Lung Adenocarcinoma.

Front Oncol 2021 10;11:673567. Epub 2022 Jan 10.

Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Suppressive tumor microenvironment is closely related to the progression and poor prognosis of lung adenocarcinoma (LUAD). Novel individual and universal immune-related biomarkers to predict the prognosis and immune landscape of LUAD patients are urgently needed. Two-gene pairing patterns could integrate and utilize various gene expression data.

Methods: The RNA-seq and relevant clinicopathological data of the LUAD project from the TCGA and well-known immune-related genes list from the ImmPort database were obtained. Co-expression analysis followed by an analysis of variance was performed to identify differentially expressed immune-related lncRNA (irlncRNA) (DEirlncRNA) between tumor and normal tissues. Two arbitrary DEirlncRNAs (DEirlncRNAs pair) in a tumor sample underwent pairwise comparison to generate a score (0 or 1). Next, Univariate analysis, Lasso regression and Multivariate analysis were used to screen survival-related DEirlncRNAs pairs and construct a prognostic model. The Acak information standard (AIC) values of the receiver operating characteristic (ROC) curve for 3 years are calculated to determine the cut-off point for high- or low-risk score. Finally, we evaluated the relationship between the risk score and overall survival, clinicopathological features, immune landscape, and chemotherapy efficacy.

Results: Data of 54 normal and 497 tumor samples of LUAD were enrolled. After a strict screening process, 15 survival-independent-related DEirlncRNA pairs were integrated to construct a prognostic model. The AUC value of the 3-year ROC curve was 0.828. Kaplan-Meier analysis showed that patients with low risk lived longer than patients with high risk (p <0.001). Univariate and Multivariate Cox analysis suggested that the risk score was an independent factor of survival. The risk score was negatively associated with most tumor-infiltrating immune cells, immune score, and microenvironment scores. The low-risk group was correlated with increased expression of ICOS. The high-risk group had a connection with lower half inhibitory centration (IC50) of most chemotherapy drugs (e.g., etoposide, paclitaxel, vinorelbine, gemcitabine, and docetaxel) and targeted medicine-erlotinib, but with higher IC50 of methotrexate.

Conclusion: The established irlncRNA pairs-based model is a promising prognostic signature for LUAD patients. Furthermore, the prognostic signature has great potential in the evaluation of tumor immune landscape and guiding individualized treatment regimens.
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http://dx.doi.org/10.3389/fonc.2021.673567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8784752PMC
January 2022

Clinicopathological analysis and prognostic significance of NF-κB p65 and IKKβ protein and mRNA expression in nasopharyngeal carcinoma.

J Int Med Res 2022 Jan;50(1):3000605211069195

Department of Pathology, Traditional Chinese Medical Hospital, Zhongshan, Guangdong, China.

Objective: To investigate the clinicopathological significance of NF-κB p65 and IKKβ protein and mRNA expression in nasopharyngeal carcinoma (NPC) patients from Guangdong Province, China.

Methods: Data and tissues from patients with NPC were retrospectively studied. Immunohistochemical staining and quantitative reverse transcription polymerase chain reaction were used to evaluate and compare NF-κB p65 and IKKβ protein and mRNA levels, respectively, in 60 NPC and 30 nasopharyngitis tissue samples. Statistical analysis was conducted to determine correlations between NF-κB p65 and IKKβ protein and mRNA levels with clinicopathological characteristics and prognoses of NPC patients.

Results: NF-κB p65 and IKKβ protein and mRNA expression in NPC were significantly correlated with tumor size, lymph node metastasis, and TNM stage. NF-κB p65 and IKKβ protein and mRNA levels were significantly increased in NPC patients with deep tumor invasion (T3-4), lymph node metastasis, and stage III/IV disease; high NF-κB p65 and IKKβ mRNA expression were associated with significantly shorter disease-free survival rates compared with cases showing low NF-κB p65 and IKKβ mRNA expression.

Conclusions: NF-κB p65 and IKKβ may affect the prognosis of NPC patients and could be potential therapeutic targets for this disease.
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http://dx.doi.org/10.1177/03000605211069195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743962PMC
January 2022

Exploration of the Structure-Function Relationships of a Novel Frog Skin Secretion-Derived Bioactive Peptide, t-DPH1, through Use of Rational Design, Cationicity Enhancement and In Vitro Studies.

Antibiotics (Basel) 2021 Dec 14;10(12). Epub 2021 Dec 14.

School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.

Amphibian skin-derived antimicrobial peptides (AMPs) have attracted increasing attention from scientists because of their excellent bioactivity and low drug resistance. In addition to being the alternative choice of antibiotics or anticancer agents, natural AMPs can also be modified as templates to optimise their bioactivities further. Here, a novel dermaseptin peptide, t-DPH1, with extensive antimicrobial activity and antiproliferative activity, was isolated from the skin secretion of through 'shotgun' cloning. A series of cationicity-enhanced analogues of t-DPH1 were designed to further improve its bioactivities and explore the charge threshold of enhancing the bioactivity of t-DPH1. The present data suggest that improving the net charge can enhance the bioactivities to some extent. However, when the charge exceeds a specific limit, the bioactivities decrease or remain the same. When the net charge achieves the limit, improving the hydrophobicity makes no sense to enhance bioactivity. For t-DPH1, the upper limit of the net charge was +7. All the designed cationicity-enhanced analogues produced no drug resistance in the Gram-negative bacterium, . These findings provide creative insights into the role of natural drug discovery in providing templates for structural modification for activity enhancement.
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http://dx.doi.org/10.3390/antibiotics10121529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8698721PMC
December 2021

Photothermal Conjugated Polymer Nanoparticles for Suppressing Breast Tumor Growth by Regulating TRPA1 Ion Channels.

Adv Healthc Mater 2022 04 7;11(8):e2102506. Epub 2022 Jan 7.

School of Materials Science and Engineering, Hebei University of Technology, Tianjin, 300401, P. R. China.

Cancer cells survive by relying on oxidative stress defense against the accumulation of reactive oxygen species (ROS) during tumor formation. ROS-sensitive TRPA1 ion channels are overexpressed in breast cancer cells and induce a large influx of Ca which upregulates the anti-apoptotic pathway to lead breast cancer cells to produce oxidative stress defense and enhance the resistance to ROS related chemotherapy. Targeting and inhibiting the TRPA1 ion channels are critical for breaking down the oxidative stress defense system and overcoming cellular resistance. Here, near-infrared (NIR) light-responsive conjugated polymer nanoparticles are designed and prepared to promote apoptosis of breast cancer cells, reduce cell drug resistance and suppress tumor growth through the remote and precise regulation of TRPA1 ion channels. Upon 808 nm laser irradiation, the nanoparticles block the formation of Ca /CaM complex and regulate the content of MCL-1 protein. Especially, the nanoparticles overcome drug resistance of cancer cells, therefore accelerating apoptosis of cancer cells and suppressing tumor growth in mice. Compared with carboplatin, the volume of tumor induced by NPs-H decreases by 54.1%. This work provides a strategy to disrupt the oxidative stress defense system and downregulate the antiapoptotic signaling pathway in cancer cells.
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http://dx.doi.org/10.1002/adhm.202102506DOI Listing
April 2022

and Studies on the Antibacterial Activity and Safety of a New Antimicrobial Peptide Dermaseptin-AC.

Microbiol Spectr 2021 12 15;9(3):e0131821. Epub 2021 Dec 15.

School of Chinese Materia Medica, Beijing University of Chinese Medicinegrid.24695.3c, Beijing, China.

Antimicrobial resistance has been an increasing public health threat in recent years. Antimicrobial peptides are considered as potential drugs against drug-resistant bacteria because they are mainly broad-spectrum and are unlikely to cause resistance. In this study, a novel peptide was obtained from the skin secretion of Agalychnis callidryas using the "shotgun" cloning method. The amino acid sequence, molecular weight, and secondary structure of Dermaseptin-AC were determined. The antimicrobial activity, hemolysis, and cytotoxicity of Dermaseptin-AC were evaluated. MICs and minimum bactericidal concentrations (MBCs) of Dermaseptin-AC against seven different bacterial strains ranged between 2 ∼ 4 μM and 2 ∼ 8 μM. The HC (50% maximum hemolysis concentration) of Dermaseptin-AC against horse erythrocytes was 76.55 μM. The anti-MRSA effect was tested on immune-suppressed MRSA pneumonia in mice. Dermaseptin-AC showed anti-MRSA effects similar to the same dose of vancomycin (10 mg/kg body weight). Short-term (7 days of intraperitoneal injection, 10 mg/kg body weight) safety evaluation of Dermaseptin-AC was tested on mice. The survival rate during the 7-day injection was 80%. Dermaseptin-AC showed no obvious effect on the liver, heart, spleen, kidney, and blood, but did induce slight pulmonary congestion. The skin safety of Dermaseptin-AC was evaluated on wounds on the back skin of a rat, and no irritation was observed. In this study, we discovered a new antimicrobial peptide, Dermaseptin-AC, and studied its and antimicrobial activity. These studies provide some data for finding new antimicrobial peptides for overcoming antimicrobial resistance. Dermaseptin-AC showed strong broad-spectrum antibacterial activity and relatively low hemolysis, and was more cytotoxic to cancer cells than to normal cells. Dermaseptin-AC was active , and its anti-MRSA effect was similar to that of vancomycin when administered by intraperitoneal injection. Safety studies found that continuous injection of Dermaseptin-AC may cause mild pulmonary congestion, while there was no obvious irritation when it was applied to skin wounds. Chronic wounds are often accompanied by high bacterial burdens and, at the same time, antimicrobial resistance is more likely to occur during repeated infections and treatments. Therefore, developing Dermaseptin-AC to treat chronic wound infection may be an attractive choice.
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http://dx.doi.org/10.1128/Spectrum.01318-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672897PMC
December 2021

Modulating donor of dicyanoisophorone-based fluorophores to detect human serum albumin with NIR fluorescence.

Spectrochim Acta A Mol Biomol Spectrosc 2022 Mar 27;268:120666. Epub 2021 Nov 27.

Guangdong Research Center for Interfacial Engineering of Functional Materials, College of Materials Science and Engineering, Shenzhen University, Shenzhen 518060, PR China. Electronic address:

It is urgently needed to develop NIR-fluorescent probe for detection of human serum albumin (HSA) since the interference of short-wavelength-fluorescence from endogenous species in real serum and urine. However, most previous reports were located in the short-wavelength region (<600 nm). In this work, a series of dicyanoisophorone (DCO)-based fluorophores 1-4 with different donor groups have been designed and investigated. A systematic study of their photophysical properties has been carried out. Among these probes, 4 exhibited NIR emission with the highest fluorescence brightness and the most sensitive signal response to HSA. Further studies demonstrated that 4 could strongly bind into the DS1 pocket of HSA with a 1:1 ratio. Importantly, the method based on 4 has been proven to be capable of sensing HSA in real serum and urine samples.
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http://dx.doi.org/10.1016/j.saa.2021.120666DOI Listing
March 2022

Thermogravimetric analysis of the pyrolysis and combustion kinetics of surface dead combustibles in the Daxing'an Mountains.

PLoS One 2021 2;16(12):e0260790. Epub 2021 Dec 2.

Forestry College of Inner Mongolia Agricultural University, Hohhot, China.

In boreal regions, the frequency of forest fires is increasing. In this study, thermogravimetric analysis was used to analyze the pyrolysis kinetics of dead surface combustibles in different forest types within the Daxing'an Mountains, China. The results show that the combustible material load of forest types, the Larix forest (LG) is relatively high. Base on the E of kinetic parameters, the LG, and Quercus forest (QM) forest types had relatively high combustibility values and comprehensive combustibility values for 1-, 10-, and 100-h time lags. According to the obtained P values, the pyrolysis of dead surface fuels with 1-, 10-, and 100-h time lags is relatively difficult in the Larix / Betula mixed forest (L-B) and QM forest types. Therefore, mixed forests of the LG, L-B, and QM tree species can be established as fire-resistant forests to establish a fire barrier, reduce the combustibility of forest stands, and reduce the possibility of forest fires.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0260790PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8638970PMC
January 2022

Quantitative analysis of urea in serum by synchronous modulation and demodulation fluorescence spectroscopy.

Spectrochim Acta A Mol Biomol Spectrosc 2022 Mar 18;268:120645. Epub 2021 Nov 18.

State Key Laboratory of Precision Measurement Technology and Instruments, Tianjin University, China. Electronic address:

High-precision spectral data is a necessary prerequisite for quantitative analysis of complex solution components. In order to improve the accuracy of spectral data, this paper proposes a method of synchronous modulation and demodulation. This article also combines the "M + N" theory, cleverly uses the excitation fluorescence of the components in the serum and its self-absorption phenomenon, collects the fluorescence spectrum of the serum sample, and then uses the partial least squares (PLS) method and the cubic optimization model method to establish a model to analyze the urea concentration of serum. At the same time, in order to verify the effectiveness of synchronous modulation and demodulation method, the unmodulated fluorescence spectrum is used to establish the regression model of urea concentration. Compared with the unmodulated fluorescence spectrum modeling results, the fluorescence spectrum modeling results after modulation and demodulation have been significantly improved. In the modeling results of fluorescence spectrum after synchronous modulation and demodulation, the Rc is 0.916753, the RMSEC is 2.05848 mmol/L, the Rp is 0.79663, and the RMSEP is 3.16812 mmol/L, the Rp-all is 0.88879, and the RMSEP-all is 2.32114 mmol/L. The results show that the method of synchronous modulation and demodulation proposed in this paper not only reduces the influence of dark current, ambient light and background noise on the signal-to-noise ratio of the spectral data, but also effectively avoids the error caused by the non-synchronization of the chopper and the spectrometer. Therefore, the method used in this paper not only improves the signal-to-noise ratio and accuracy of spectral data, but also improves the accuracy of spectral quantitative analysis of complex solutions.
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http://dx.doi.org/10.1016/j.saa.2021.120645DOI Listing
March 2022

Effects of aging on the histology and biochemistry of rat tendon healing.

BMC Musculoskelet Disord 2021 Nov 15;22(1):949. Epub 2021 Nov 15.

Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China.

Introduction: Tendon diseases and injuries are a serious problem for the aged population, often leading to pain, disability and a significant decline in quality of life. The purpose of this study was to determine the influence of aging on biochemistry and histology during tendon healing and to provide a new strategy for improving tendon healing.

Method: A total of 24 Sprague-Dawley rats were equally divided into a young and an aged group. A rat patellar tendon defect model was used in this study. Tendon samples were collected at weeks 2 and 4, and hematoxylin-eosin, alcian blue and immunofluorescence staining were performed for histological analysis. Meanwhile, reverse transcription-polymerase chain reaction (RT-PCR) and western blot were performed to evaluate the biochemical changes.

Results: The histological scores in aged rats were significantly lower than those in young rats. At the protein level, collagen synthesis-related markers Col-3, Matrix metalloproteinase-1 and Metallopeptidase Inhibitor 1(TIMP-1) were decreased at week 4 in aged rats compared with those of young rats. Though there was a decrease in the expression of the chondrogenic marker aggrecan at the protein level in aged tendon, the Micro-CT results from weeks 4 samples showed no significant difference(p>0.05) on the ectopic ossification between groups. Moreover, we found more adipocytes accumulated in the aged tendon defect with the Oil Red O staining and at the gene and protein levels the markers related to adipogenic differentiation.

Conclusions: Our findings indicate that tendon healing is impaired in aged rats and is characterized by a significantly lower histological score, decreased collagen synthesis and more adipocyte accumulation in patellar tendon after repair.
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http://dx.doi.org/10.1186/s12891-021-04838-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594129PMC
November 2021

Excessive DNA damage mediates ECM degradation via the RBBP8/NOTCH1 pathway in sporadic aortic dissection.

Biochim Biophys Acta Mol Basis Dis 2022 02 12;1868(2):166303. Epub 2021 Nov 12.

Department of Thoracic and Cardiovascular Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Institute of Cardiothoracic Vascular Disease, Nanjing University, Nanjing 210008, China. Electronic address:

Stanford type A aortic dissection (TA-AD) is a life-threatening disease. Most cases of aortic dissection (AD) are sporadic rather than inherited. Unlike that of inherited AD, the pathogenesis of sporadic AD is still unclear. In the current study, we aimed to explore the pathogenesis of sporadic AD through transcriptome sequencing data analyses. We downloaded sporadic TA-AD transcriptome profiles from Gene Expression Omnibus (GEO) and found response to DNA damage stimulus was activated in AD. Furthermore, by conducting mouse AD tissue single cell RNA sequencing and immunostaining, we found that DNA damage mainly occurred in smooth muscle cells (SMCs) and fibroblasts. Next, we examined the repair patterns in response to DNA damage and found the linker molecules RBBP8/NOTCH1 between DNA damage/repair and extracellular matrix (ECM) organization through protein-protein interaction analysis. Thus, we proposed that DNA damage could contribute to AD by regulating ECM changes. To explore the underlying mechanism, we knocked down the DNA repair-related gene RBBP8 in aortic SMCs, which could exacerbate DNA damage, and observed decreased expression level of NOTCH1. Inhibition of NOTCH1 with crenigacestat in vivo accelerated β-aminopropionitrile-induced formation of AD and increased mortality. Meanwhile, phenotype switching of SMCs was induced by Notch1 knockdown or inhibition; this switching occurred via a pathway involving downregulation of contractile marker gene expression and upregulation of MMP2 expression, which might aggravate ECM degradation. In conclusion, excessive DNA damage is a characteristic pathological change of sporadic aortic dissection, which might contribute to ECM changes and AD development via action on the NOTCH1 pathway.
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http://dx.doi.org/10.1016/j.bbadis.2021.166303DOI Listing
February 2022

Histologic and biomechanical evaluation of the thoracolumbar fascia graft for massive rotator cuff tears in a rat model.

J Shoulder Elbow Surg 2022 Apr 11;31(4):699-710. Epub 2021 Nov 11.

Department of Orthopedic Surgery, Southwest Hospital, Army Military Medical University, Chongqing, China. Electronic address:

Background: Fascial autografts, which are easily available grafts, have provided a promising option in patients with massive rotator cuff tears. However, no fascial autografts other than the fascia lata have been reported, and the exact healing process of the fascia-to-bone interface is not well understood. The objective of this study is to histologically and biomechanically evaluate the effect of the thoracolumbar fascia (TLF) on fascia-to-bone healing.

Methods: A total of 88 rats were used in this study. Eight rats were killed at the beginning to form an intact control group, and the other rats were divided randomly into 2 groups (40 rats per group): the TLF augmentation group (TLF group) and the repair group (R group). The right supraspinatus was detached, and a 3 × 5 mm defect of the supraspinatus was created. The TLF was used to augment the torn supraspinatus in the TLF group, whereas in the R group, the torn supraspinatus was repaired in only a transosseous manner. Histology and biomechanics were assessed at 1, 2, 4, 8, and 16 weeks postoperatively.

Results: The modified tendon maturation score of the TLF group was higher than that of the R group at 8 weeks (23.00 ± 0.71 vs. 24.40 ± 0.89, P = .025) and 16 weeks (24.60 ± 0.55 vs. 26.40 ± 0.55, P ≤ .001). The TLF group showed a rapid vascular reaction, and the peak value appeared at 1 week. Later, the capillary density decreased, and almost no angiogenesis was observed at 8 weeks postoperatively. Immunohistochemistry results demonstrated a significantly higher percentage of collagen I in the TLF group at 4, 8, and 16 weeks (24.78% ± 2.76% vs. 20.67% ± 2.11% at 4 weeks, P = .046; 25.46% ± 1.77% vs. 21.49% ± 2.33% at 8 weeks, P = .026; 34.77% ± 2.25% vs. 30.01% ± 3.17% at 16 weeks, P = .040) postoperatively. Biomechanical tests revealed that the ultimate failure force in the TLF group was significantly higher than that in the R group at the final evaluation (29.13 ± 2.49 N vs. 23.10 ± 3.47 N, P = .022).

Conclusions: The TLF autograft can promote a faster biological healing process and a better fixation strength. It could be used as an alternative reinforcement or bridging patch when the fascia lata is not appropriate or available for superior capsule reconstruction (SCR).
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http://dx.doi.org/10.1016/j.jse.2021.10.019DOI Listing
April 2022

MiR-6924-5p-rich exosomes derived from genetically modified Scleraxis-overexpressing PDGFRα(+) BMMSCs as novel nanotherapeutics for treating osteolysis during tendon-bone healing and improving healing strength.

Biomaterials 2021 12 5;279:121242. Epub 2021 Nov 5.

Department of Orthopedics/Sports Medicine Center, State Key Laboratory of Trauma, Burn and Combined Injury, First Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, 400000, China. Electronic address:

Osteolysis at the tendon-bone interface can impair pullout strength during tendon-bone healing and lead to surgery failure, but the effects of clinical treatments are not satisfactory. Mesenchymal stem cell (MSC)-derived exosomes have been used as potent and feasible natural nanocarriers for drug delivery and have been proven to enhance tendon-bone healing strength, indicating that MSC-derived exosomes could be a promising therapeutic strategy. In this study, we explored Scleraxis (Scx) dynamically expressed in PDGFRα(+) bone marrow-derived mesenchymal stem cells (BMMSCs) during natural tendon-bone healing. Then, we investigated the role of PDGFRα(+) BMMSCs in tendon-bone healing after Scx overexpression as well as the underlying mechanisms. Our data demonstrated that Scx-overexpressing PDGFRα(+) BMMSCs (BMMSC) could efficiently inhibit peritunnel osteolysis and enhance tendon-bone healing strength by preventing osteoclastogenesis in an exosomes-dependent manner. Exosomal RNA-seq revealed that the abundance of a novel miRNA, miR-6924-5p, was highest among miRNAs. miR-6924-5p could directly inhibit osteoclast formation by binding to the 3'-untranslated regions (3'UTRs) of OCSTAMP and CXCL12. Inhibition of miR-6924-5p expression reversed the prevention of osteoclastogenic differentiation by BMMSC derived exosomes (BMMSC-exos). Local injection of BMMSC-exos or miR-6924-5p dramatically reduced osteoclast formation and improved tendon-bone healing strength. Furthermore, delivery of miR-6924-5p efficiently inhibited the osteoclastogenesis of human monocytes. In brief, our study demonstrates that BMMSC-exos or miR-6924-5p could serve as a potential therapy for the treatment of osteolysis during tendon-bone healing and improve the outcome.
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http://dx.doi.org/10.1016/j.biomaterials.2021.121242DOI Listing
December 2021
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