Publications by authors named "Shan Feng"

142 Publications

Catalpol improves impaired neurovascular unit in ischemic stroke rats via enhancing VEGF-PI3K/AKT and VEGF-MEK1/2/ERK1/2 signaling.

Acta Pharmacol Sin 2021 Nov 18. Epub 2021 Nov 18.

College of Pharmaceutical Sciences & Chinese Medicine, Southwest University, Chongqing, 400715, China.

Neurovascular unit (NVU) is organized multi-cellular and multi-component networks that are essential for brain health and brain homeostasis maintaining. Neurovascular unit dysfunction is the central pathogenesis process of ischemic stroke. Thus integrated protection of NVU holds great therapeutic potential for ischemic stroke. Catalpol, classified into the iridoid monosaccharide glycoside, is the main active ingredient of the radix from traditional Chinese medicine, Rehmannia glutinosa Libosch, that exhibits protective effects in several brain-related diseases. In the present study, we investigated whether catalpol exerted protective effects for NVU in ischemic stroke and the underlying mechanisms. MCAO rats were administered catalpol (2.5, 5.0, 10.0 mg·kg·d, i.v.) for 14 days. We showed that catalpol treatment dose-dependently reduced the infarction volume and significantly attenuated neurological deficits score in MCAO rats. Furthermore, catalpol treatment significantly ameliorated impaired NVU in ischemic region by protecting vessel-neuron-astrocyte structures and morphology, and promoting angiogenesis and neurogenesis to replenish lost vessels and neurons. Moreover, catalpol treatment significantly increased the expression of vascular endothelial growth factor (VEGF) through up-regulating PI3K/AKT signaling, followed by increasing FAK and Paxillin and activating PI3K/AKT and MEK1/2/ERK1/2 pathways. The protective mechanisms of catalpol were confirmed in an in vitro three-dimensional NVU model subjected to oxygen-glucose deprivation. In conclusion, catalpol protects NVU in ischemic region via activation of PI3K/AKT signaling and increased VEGF production; VEGF further enhances PI3K/AKT and MEK1/2/ERK1/2 signaling, which may trigger a partly feed-forward loop to protect NVU from ischemic stroke.
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http://dx.doi.org/10.1038/s41401-021-00803-4DOI Listing
November 2021

Chorionic villus-derived mesenchymal stem cells induce E3 ligase TRIM72 expression and regulate cell behaviors through ubiquitination of p53 in trophoblasts.

FASEB J 2021 12;35(12):e22005

Department of Pain Management, Qingdao Municipal Hospital, Qingdao, China.

Preeclampsia is a significant contributor for maternal or fetal morbidity and mortality, which is characterized by reduced invasion capacity of trophoblasts and is regulated by extracellular matrix (ECM). It is still under investigation whether chorionic villus-derived mesenchymal stem cells (CVMSC) could affect the functionality of trophoblasts. In this study, CVMSC-derived exosomes were isolated; their effect on trophoblasts was investigated based on the CCK8 assay, migration assay, and apoptosis detection. And the underlying mechanism of this effect was investigated using mRNA sequencing, western blot, co-immunoprecipitation, luciferase report assay, and ubiquitination assay. The results show that CVMSC-derived exosomes promote migration and proliferation of trophoblasts, and also reduce cell apoptosis. mRNA sequencing confirmed that after treatment of CVMSC-derived exosomes, Tripartite Motif Containing 72 (TRIM72) expression was upregulated and Tumor Protein P53 (P53) expression was downregulated, both significantly in trophoblasts. Subsequent study confirms that TRM72 can directly interact with P53 and promote P53 ubiquitination and proteasomal degradation, reducing apoptosis rate and elevating proliferation and migration in trophoblasts. Our study confirms that CVMSC-derived exosomes promote trophoblast migration and proliferation by upregulating TRIM72 expression, and subsequently advance P53 ubiquitination and proteasomal degradation.
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http://dx.doi.org/10.1096/fj.202100801RDOI Listing
December 2021

L-Carnitine and Acetyl-L-Carnitine: Potential Novel Biomarkers for Major Depressive Disorder.

Front Psychiatry 2021 30;12:671151. Epub 2021 Sep 30.

Affiliated Psychological Hospital of Anhui Medical University, Hefei, China.

The lack of biomarkers greatly limits the diagnosis and treatment of major depressive disorder (MDD). Endogenous L-carnitine (LC) and its derivative acetyl-L-carnitine (ALC) play antidepressant roles by improving brain energy metabolism, regulating neurotransmitters and neural plasticity. The levels of ALC in people and rodents with depression are significantly reduced. It is necessary to determine whether serum LC and ALC might be used as novel biomarkers for the diagnosis of MDD. Here, ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to determine the concentration of LC and ALC in the serum of healthy controls and patients with MDD; among the latter, in patients who were responsive (effective group) and non-responsive (ineffective group) after 2 weeks of treatment. The diagnostic value of serum LC and ALC for MDD was assessed. Compared with healthy controls, the serum LC and ALC concentrations in patients with MDD were significantly decreased ( < 0.001). Pearson correlation analysis shows that the HDRS-24 score was negatively associated with serum ALC ( = -0.325, = 0.007). Receiver operating characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.801 with 83.1% sensitivity and 66.3% specificity for LC, and an AUC of 0.898 with 88.8% sensitivity and 76.4% specificity for ALC, differentiating patients with MDD from healthy controls. Furthermore, the concentration of LC and ALC in patients with depression was significantly increased in the effective treatment group, and no significant change was observed in the ineffective treatment group. These results suggest that serum LC and ALC may be novel biomarkers for the diagnosis of MDD.
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http://dx.doi.org/10.3389/fpsyt.2021.671151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514700PMC
September 2021

How Self-tracking and the Quantified Self Promote Health and Well-being: Systematic Review.

J Med Internet Res 2021 09 21;23(9):e25171. Epub 2021 Sep 21.

Department of Management and Entrepreneurship, Turku School of Economics, University of Turku, Turku, Finland.

Background: Self-tracking technologies are widely used in people's daily lives and health care. Academic research on self-tracking and the quantified self has also accumulated rapidly in recent years. Surprisingly, there is a paucity of research that reviews, classifies, and synthesizes the state of the art with respect to self-tracking and the quantified self.

Objective: Our objective was to identify the state of the art of self-tracking and the quantified self in terms of health and well-being.

Methods: We have undertaken a systematic literature review on self-tracking and the quantified self in promoting health and well-being. After a rigorous literature search, followed by inclusions, exclusions, and the application of article quality assessment protocols, 67 empirical studies qualified for the review.

Results: Our results demonstrate that prior research has focused on 3 stakeholders with respect to self-tracking and the quantified self, namely end users, patients and people with illnesses, and health care professionals and caregivers. We used these stakeholder groups to cluster the research themes of the reviewed studies. We identified 11 research themes. There are 6 themes under the end-user cluster: user motivation and goal setting, usage and effects of self-tracking, continuance intention and long-term usage, management of personal data, rejection and discontinuance, and user characteristics. The patient and people with illnesses cluster contains three themes: usage experience of patients and people with illnesses, management of patient-generated data, and advantages and disadvantages in the clinical context. The health care professional and caregiver cluster contains two themes: collaboration among patients, health care professionals, and caregivers, and changes in the roles of patients and professionals. Moreover, we classified the future research suggestions given in the literature into 5 directions in terms of research designs and research topics. Finally, based on our reflections on the observations from the review, we suggest four future research directions: (1) users' cognitions and emotions related to processing and interpreting the information produced by tracking devices and apps; (2) the dark side of self-tracking (eg, its adverse psychosocial consequences); (3) self-tracking as a societal phenomenon; and (4) systemic impacts of self-tracking on health care and the actors involved.

Conclusions: This systematic literature review contributes to research and practice by assisting future research activities and providing practitioners with a concise overview of the state of the art of self-tracking and the quantified self.
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http://dx.doi.org/10.2196/25171DOI Listing
September 2021

Neutralisation titres against SARS-CoV-2 are sustained 6 months after onset of symptoms in individuals with mild COVID-19.

EBioMedicine 2021 Sep 19;71:103519. Epub 2021 Aug 19.

Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background: Given the importance of neutralising antibodies in protection against SARS-CoV-2 infection, it is critical to assess neutralisation persistence long-term following recovery. This study investigated neutralisation titres against SARS-CoV-2 up to 6 months post-symptom onset in individuals with mild COVID-19.

Methods: Plasma neutralisation titres in convalescent COVID-19 individuals were determined at baseline and 6 months post-symptom onset using a cell culture infectious SARS-CoV-2 assay. Total SARS-CoV-2 spike-specific IgG and IgA binding was measured using a lectin capture ELISA and compared between timepoints and correlated to neutralising titres.

Findings: All 48 convalescent COVID-19 individuals were found to have detectable SARS-CoV-2 50% inhibitory dilution neutralisation titres (ID) at baseline and 6 months post-symptom onset with mean ID of 1/943 and 1/411, respectively. SARS-CoV-2 neutralisation titres peaked within 1-2 months post-symptom onset. However, 50% of individuals showed comparable ID at baseline and 6 months post-symptom onset. Both SARS-CoV-2 spike-specific IgG and IgA levels correlated well with neutralising titres. IgG binding was found to be sustained up to 6 months post-symptom onset, whereas IgA levels declined.

Interpretation: This study demonstrates durability of SARS-CoV-2 spike-specific IgG and neutralisation responses following recovery from mild COVID-19. Thus, all subjects included in this study might potentially have protective levels of neutralising antibodies 6 months post-symptom onset. This study also demonstrates a relationship between spike-specific IgA and neutralisation decline, with implications for long-term protection against SARS-CoV-2 infection.

Funding: Novo Nordisk Foundation, Independent Research Fund Denmark and Danish Agency for Science and Higher Education.
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http://dx.doi.org/10.1016/j.ebiom.2021.103519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375401PMC
September 2021

An Amphiphilic Carbonaceous/Nanosilver Composite-Incorporated Urinary Catheter for Long-Term Combating Bacteria and Biofilms.

ACS Appl Mater Interfaces 2021 Aug 6;13(32):38029-38039. Epub 2021 Aug 6.

College of Pharmacy, Institutes of Environment and Medicine, Henan University, Kaifeng 475004, China.

Biofilms formed on urinary catheters remain a major headache in the modern healthcare system. Among the various kinds of biocide-releasing urinary catheters that have been developed to prevent biofilm formation, Ag nanoparticles (AgNPs)-coated catheters are of great promising potential. However, the deposition of AgNPs on the surface of catheters suffers from several inherent shortcomings, such as damage to the urethral mucosa, uncontrollable Ag ion kinetics, and unexpected systematic toxicity. Here, AgNPs-decorated amphiphilic carbonaceous particles ([email protected]) with commendable dispersity in solvents of different polarities and broad-spectrum antibacterial activity are first prepared. The resulting [email protected] exert good compatibility with silicone rubber, which enables the easy fabrication of urinary catheters using a laboratory-made mold. Therefore, [email protected] not only endow the urinary catheter with forceful biocidal activity but also improve its mechanical properties and surface wettability. Hence, the designed urinary catheter possesses excellent capacity to resist bacterial adhesion and biofilm formation both and in an rabbit model. Specifically, a long-term antibacterial study highlights its sustainable antibacterial activity. Of note, no obvious toxicity or inflammation in rabbits was triggered by the designed urinary catheter . Overall, the hybrid urinary catheter may serve as a promising biocide-releasing urinary catheter for antibacterial and antibiofilm applications.
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http://dx.doi.org/10.1021/acsami.1c07399DOI Listing
August 2021

Mechanism of LolCDE as a molecular extruder of bacterial triacylated lipoproteins.

Nat Commun 2021 08 3;12(1):4687. Epub 2021 Aug 3.

Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.

Lipoproteins are important for bacterial growth and antibiotic resistance. These proteins use lipid acyl chains attached to the N-terminal cysteine residue to anchor on the outer surface of cytoplasmic membrane. In Gram-negative bacteria, many lipoproteins are transported to the outer membrane (OM), a process dependent on the ATP-binding cassette (ABC) transporter LolCDE which extracts the OM-targeted lipoproteins from the cytoplasmic membrane. Lipid-anchored proteins pose a unique challenge for transport machinery as they have both hydrophobic lipid moieties and soluble protein component, and the underlying mechanism is poorly understood. Here we determined the cryo-EM structures of nanodisc-embedded LolCDE in the nucleotide-free and nucleotide-bound states at 3.8-Å and 3.5-Å resolution, respectively. The structural analyses, together with biochemical and mutagenesis studies, uncover how LolCDE recognizes its substrate by interacting with the lipid and N-terminal peptide moieties of the lipoprotein, and identify the amide-linked acyl chain as the key element for LolCDE interaction. Upon nucleotide binding, the transmembrane helices and the periplasmic domains of LolCDE undergo large-scale, asymmetric movements, resulting in extrusion of the captured lipoprotein. Comparison of LolCDE and MacB reveals the conserved mechanism of type VII ABC transporters and emphasizes the unique properties of LolCDE as a molecule extruder of triacylated lipoproteins.
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http://dx.doi.org/10.1038/s41467-021-24965-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333309PMC
August 2021

Cryo-EM structure of human Wntless in complex with Wnt3a.

Nat Commun 2021 07 27;12(1):4541. Epub 2021 Jul 27.

Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.

Wntless (WLS), an evolutionarily conserved multi-pass transmembrane protein, is essential for secretion of Wnt proteins. Wnt-triggered signaling pathways control many crucial life events, whereas aberrant Wnt signaling is tightly associated with many human diseases including cancers. Here, we report the cryo-EM structure of human WLS in complex with Wnt3a, the most widely studied Wnt, at 2.2 Å resolution. The transmembrane domain of WLS bears a GPCR fold, with a conserved core cavity and a lateral opening. Wnt3a interacts with WLS at multiple interfaces, with the lipid moiety on Wnt3a traversing a hydrophobic tunnel of WLS transmembrane domain and inserting into membrane. A β-hairpin of Wnt3a containing the conserved palmitoleoylation site interacts with WLS extensively, which is crucial for WLS-mediated Wnt secretion. The flexibility of the Wnt3a loop/hairpin regions involved in the multiple binding sites indicates induced fit might happen when Wnts are bound to different binding partners. Our findings provide important insights into the molecular mechanism of Wnt palmitoleoylation, secretion and signaling.
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http://dx.doi.org/10.1038/s41467-021-24731-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316347PMC
July 2021

In vitro efficacy of artemisinin-based treatments against SARS-CoV-2.

Sci Rep 2021 07 16;11(1):14571. Epub 2021 Jul 16.

Max Planck Institute for Colloids and Interfaces, Am Mühlenberg 1, 14476, Potsdam, Germany.

Effective and affordable treatments for patients suffering from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are needed. We report in vitro efficacy of Artemisia annua extracts as well as artemisinin, artesunate, and artemether against SARS-CoV-2. The latter two are approved active pharmaceutical ingredients of anti-malarial drugs. Concentration-response antiviral treatment assays, based on immunostaining of SARS-CoV-2 spike glycoprotein, revealed that treatment with all studied extracts and compounds inhibited SARS-CoV-2 infection of VeroE6 cells, human hepatoma Huh7.5 cells and human lung cancer A549-hACE2 cells, without obvious influence of the cell type on antiviral efficacy. In treatment assays, artesunate proved most potent (range of 50% effective concentrations (EC) in different cell types: 7-12 µg/mL), followed by artemether (53-98 µg/mL), A. annua extracts (83-260 µg/mL) and artemisinin (151 to at least 208 µg/mL). The selectivity indices (SI), calculated based on treatment and cell viability assays, were mostly below 10 (range 2 to 54), suggesting a small therapeutic window. Time-of-addition experiments in A549-hACE2 cells revealed that artesunate targeted SARS-CoV-2 at the post-entry level. Peak plasma concentrations of artesunate exceeding EC values can be achieved. Clinical studies are required to further evaluate the utility of these compounds as COVID-19 treatment.
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http://dx.doi.org/10.1038/s41598-021-93361-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285423PMC
July 2021

SARS-CoV-2 Production in a Scalable High Cell Density Bioreactor.

Vaccines (Basel) 2021 Jun 29;9(7). Epub 2021 Jun 29.

Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital-Hvidovre, 2650 Hvidovre, Denmark.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has demonstrated the value of pursuing different vaccine strategies. Vaccines based on whole viruses, a widely used vaccine technology, depend on efficient virus production. This study aimed to establish SARS-CoV-2 production in the scalable packed-bed CelCradle 500-AP bioreactor. CelCradle 500-AP bottles with 0.5 L working volume and 5.5 g BioNOC™ II carriers were seeded with 1.5 × 10 Vero (WHO) cells, approved for vaccine production, in animal component-free medium and infected at a multiplicity of infection of 0.006 at a total cell number of 2.2-2.5 × 10 cells/bottle seven days post cell seeding. Among several tested conditions, two harvests per day and a virus production temperature of 33 °C resulted in the highest virus yield with a peak SARS-CoV-2 infectivity titer of 7.3 log 50% tissue culture infectious dose (TCID)/mL at 72 h post-infection. Six harvests had titers of ≥6.5 log TCID/mL, and a total of 10.5 log TCID were produced in ~5 L. While trypsin was reported to enhance virus spread in cell culture, addition of 0.5% recombinant trypsin after infection did not improve virus yields. Overall, we demonstrated successful animal component-free production of SARS-CoV-2 in well-characterized Vero (WHO) cells in a scalable packed-bed bioreactor.
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http://dx.doi.org/10.3390/vaccines9070706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310283PMC
June 2021

Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 .

Antimicrob Agents Chemother 2021 08 17;65(9):e0268020. Epub 2021 Aug 17.

Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital-Hvidovregrid.5254.6, Hvidovre, Denmark.

Antivirals targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could improve treatment of COVID-19. We evaluated the efficacy of clinically relevant hepatitis C virus (HCV) NS3 protease inhibitors (PIs) against SARS-CoV-2 and their interactions with remdesivir, the only direct-acting antiviral approved for COVID-19 treatment. HCV PIs showed differential potency in short-term treatment assays based on the detection of SARS-CoV-2 spike protein in Vero E6 cells. Linear PIs boceprevir, telaprevir, and narlaprevir had 50% effective concentrations (EC) of ∼40 μM. Among the macrocyclic PIs, simeprevir had the highest (EC, 15 μM) and glecaprevir the lowest (EC, >178 μM) potency, with paritaprevir, grazoprevir, voxilaprevir, vaniprevir, danoprevir, and deldeprevir in between. Acyclic PIs asunaprevir and faldaprevir had ECs of 72 and 23 μM, respectively. ACH-806, inhibiting the HCV NS4A protease cofactor, had an EC of 46 μM. Similar and slightly increased PI potencies were found in human hepatoma Huh7.5 cells and human lung carcinoma A549-hACE2 cells, respectively. Selectivity indexes based on antiviral and cell viability assays were highest for linear PIs. In short-term treatments, combination of macrocyclic but not linear PIs with remdesivir showed synergism in Vero E6 and A549-hACE2 cells. Longer-term treatment of infected Vero E6 and A549-hACE2 cells with 1-fold EC PI revealed minor differences in the barrier to SARS-CoV-2 escape. Viral suppression was achieved with 3- to 8-fold EC boceprevir or 1-fold EC simeprevir or grazoprevir, but not boceprevir, in combination with 0.4- to 0.8-fold EC remdesivir; these concentrations did not lead to viral suppression in single treatments. This study could inform the development and application of protease inhibitors for optimized antiviral treatments of COVID-19.
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http://dx.doi.org/10.1128/AAC.02680-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370243PMC
August 2021

Transcriptome and proteome analysis of walnut (Juglans regia L.) fruit in response to infection by Colletotrichum gloeosporioides.

BMC Plant Biol 2021 May 31;21(1):249. Epub 2021 May 31.

College of Forestry, Shandong Agricultural University, Tai'an, Shandong Province, China.

Background: Walnut anthracnose induced by Colletotrichum gloeosporioides is a disastrous disease affecting walnut production. The resistance of walnut fruit to C. gloeosporioides is a highly complicated and genetically programmed process. However, the underlying mechanisms have not yet been elucidated.

Results: To understand the molecular mechanism underlying the defense of walnut to C. gloeosporioides, we used RNA sequencing and label-free quantitation technologies to generate transcriptomic and proteomic profiles of tissues at various lifestyle transitions of C. gloeosporioides, including 0 hpi, pathological tissues at 24 hpi, 48 hpi, and 72 hpi, and distal uninoculated tissues at 120 hpi, in anthracnose-resistant F26 fruit bracts and anthracnose-susceptible F423 fruit bracts, which were defined through scanning electron microscopy. A total of 21,798 differentially expressed genes (DEGs) and 1929 differentially expressed proteins (DEPs) were identified in F26 vs. F423 at five time points, and the numbers of DEGs and DEPs were significantly higher in the early infection stage. Using pairwise comparisons and weighted gene co-expression network analysis of the transcriptome, we identified two modules significantly related to disease resistance and nine hub genes in the transcription expression gene networks. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of the DEGs and DEPs revealed that many genes were mainly related to immune response, plant hormone signal transduction, and secondary metabolites, and many DEPs were involved in carbon metabolism and photosynthesis. Correlation analysis between the transcriptome data and proteome data also showed that the consistency of the differential expression of the mRNA and corresponding proteins was relatively higher in the early stage of infection.

Conclusions: Collectively, these results help elucidate the molecular response of walnut fruit to C. gloeosporioides and provide a basis for the genetic improvement of walnut disease resistance.
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http://dx.doi.org/10.1186/s12870-021-03042-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166054PMC
May 2021

[Analysis of blood components of Yougui Yin in normal rats and rats with kidney deficiency caused by adenine based on UPLC-MS technology].

Zhongguo Zhong Yao Za Zhi 2021 May;46(9):2287-2297

Chongqing Key Laboratory of New Drug Screening from Traditional Chinese Medicine, Pharmacology of Chinese Materia Medica-the Key Discipline Constructed by the State Administration of Traditional Chinese Medicine, College of Pharmaceutical Sciences & Chinese Medicine, Southwest University Chongqing 400715, China Southwest University Hospital Chongqing 400715, China.

Based on the serum medicinal method, this study aims to investigate the migrating components of Yougui Yin in the blood after intragastric administration, and to provide reference for the basic research of its pharmacodynamics. The kidney deficiency rat model was replicated by adenine method. Normal rats and model rats were administered orally for a single gavage of Yougui Yin. The components in blood were rapidly analyzed and identified by ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) and multiple reaction monitoring(MRM), and the migrating components in blood of Yougui Yin were explored by multivariate statistical analysis. The results showed that there were 42 characteristic peaks in the plasma of normal rats by UPLC-Q-TOF-MS technology and 13 chemical components were identified, including 6 alkaloids, 2 flavonoids, 2 triterpenoid saponins, 1 iridoid, 1 phenylpropanoid and 1 monoterpenoid. There were 22 characteristic peaks in the plasma of kidney-deficiency rats, and 12 chemical components were identified, including 2 iridoids, 6 alkaloids, 2 flavonoids, 1 monoterpenoid and 1 triterpenoid saponin. Verbascoside, isoacteoside, acteoside, pinoresinoldiglucoside, loganin and morroniside were identified by MRM both in the plasma of normal rats and kidney-deficiency rats. Compared with 85 monomer components in Yougui Yin, 17 common prototype components were found by UPLC-MS in the plasma of normal rats and kidney deficiency rats, including verbascoside, isoacteoside, acteoside, rehmapicrogenin derived from Rehmanniae Radix Praeparata, pinoresinol diglucoside and geniposidic acid from Eucommiea Cortex, loganin and morroniside derived from Corni Fructus, mesaconine, benzoylmesaconine, benzoylaconitine, benzoylhypacoitine, mesaconitine, aconitine derived from Aconiti Lateralis Radix Praeparata, liquiritin, isoliquiritin and glycyrrhizic acid derived from Glycyrrhizae Radix et Rhizoma. Thirty-one metabolites of medicinal ingredients not found in the plasma of adenine-induced kidney deficiency rats were also detected in the plasma of normal rats. Twelve metabolites of medicinal materials not found in the plasma of normal rats were detected in the plasma of kidney deficiency rats. The results of the study provide reference for explaining the material basis and mechanism of Yougui Yin in the treatment of kidney deficiency.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20201015.201DOI Listing
May 2021

Infection is associated with elevated serum concentrations of antipsychotic drugs.

Int Clin Psychopharmacol 2021 09;36(5):264-267

Department of Pharmacy, Hefei Fourth People's Hospital.

We aimed to investigate the effects of infection on serum concentrations of different antipsychotics in inpatients with respiratory tract infections treated with psychiatric drugs, including risperidone, clozapine, quetiapine, and aripiprazole. All patients underwent therapeutic drug monitoring (TDM) and routine blood tests during infection and noninfection periods. The Wilcoxon signed-rank test was used to analyze intra-individual differences in dose-corrected serum concentrations (C/D) levels in infection and noninfection periods. To study the effects of infection intensity on drug concentrations, white blood cells (WBCs) parameters and C/D levels were analyzed by Spearman's correlation analysis using all samples. The median C/D levels of risperidone (risperidone + 9-OH, n = 36) and clozapine (n = 42) were significantly higher (P < 0.001), whereas the median C/D levels of quetiapine (n = 21) and aripiprazole (n = 13) were slightly significantly higher (P < 0.01) in infection than in noninfection period. A significant positive association between C/D levels and WBC parameters was observed for risperidone, clozapine, and quetiapine. These results indicated reduced clearance of all drugs evaluated, especially clozapine and risperidone, due to infection. Therefore, during infection in patients receiving risperidone, clozapine, quetiapine, or aripiprazole, TDM should be performed to minimize the possible adverse effects associated with elevated drug concentrations.
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http://dx.doi.org/10.1097/YIC.0000000000000366DOI Listing
September 2021

Identifying the primary meteorological factors affecting the growth and development of Tartary buckwheat and a comprehensive landrace evaluation using a multi-environment phenotypic investigation.

J Sci Food Agric 2021 Nov 10;101(14):6104-6116. Epub 2021 May 10.

State Key Laboratory of Crop Stress Biology for Arid Areas/College of Agronomy, Northwest A & F University, Yangling, China.

Background: Tartary buckwheat (Fagopyrum tataricum) is a traditional edible and medicinal crop and has been praised as one of the green foods for humans in the 21st century. However, its production and promotion are restricted by the low yields of current varieties. The interaction of genotype and environment could lead to inconsistent phenotypic performance of genotypes across different environments. Climate change has intensified these effects and poses a substantial threat to crop production.

Results: In the present study, the effects of meteorological factors on the phenotypic traits of 200 Tartary buckwheat landraces across four macro-environments were investigated. Overall, the phenotypic performance of these Tartary buckwheat landraces was markedly varied across the different environments. Also, the average daily temperature and precipitation had relatively higher impacts on phenotypic performance. The results also revealed the negative impacts of relative humidity on the yield-related traits. Twenty-five Tartary buckwheat landraces were ultimately identified as having good overall phenotypic performance and high yield stability.

Conclusion: Understanding the impacts of meteorological factors on the phenotypic performance of crops can guide appropriate measures and facilitate germplasm selection for yield enhancement in the context of climate change. The landraces selected comprehensively in this study could be used as parents or intermediate materials for breeding high-quality Tartary buckwheat varieties in the future. The methods used could also be extended to other crops for breeding and germplasm innovation. © 2021 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.11267DOI Listing
November 2021

Overcoming Culture Restriction for SARS-CoV-2 in Human Cells Facilitates the Screening of Compounds Inhibiting Viral Replication.

Antimicrob Agents Chemother 2021 06 17;65(7):e0009721. Epub 2021 Jun 17.

Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark.

Efforts to mitigate the coronavirus disease 2019 (COVID-19) pandemic include the screening of existing antiviral molecules that could be repurposed to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Although SARS-CoV-2 replicates and propagates efficiently in African green monkey kidney (Vero) cells, antivirals such as nucleos(t)ide analogs (NUCs) often show decreased activity in these cells due to inefficient metabolization. SARS-CoV-2 exhibits low viability in human cells in culture. Here, serial passages of a SARS-CoV-2 isolate (original-SARS2) in the human hepatoma cell clone Huh7.5 led to the selection of a variant (adapted-SARS2) with significantly improved infectivity in human liver (Huh7 and Huh7.5) and lung cancer (unmodified Calu-1 and A549) cells. The adapted virus exhibited mutations in the spike protein, including a 9-amino-acid deletion and 3 amino acid changes (E484D, P812R, and Q954H). E484D also emerged in Vero E6-cultured viruses that became viable in A549 cells. Original and adapted viruses were susceptible to scavenger receptor class B type 1 (SR-B1) receptor blocking, and adapted-SARS2 exhibited significantly less dependence on ACE2. Both variants were similarly neutralized by COVID-19 convalescent-phase plasma, but adapted-SARS2 exhibited increased susceptibility to exogenous type I interferon. Remdesivir inhibited original- and adapted-SARS2 similarly, demonstrating the utility of the system for the screening of NUCs. Among the tested NUCs, only remdesivir, molnupiravir, and, to a limited extent, galidesivir showed antiviral effects across human cell lines, whereas sofosbuvir, ribavirin, and favipiravir had no apparent activity. Analogously to the emergence of spike mutations , the spike protein is under intense adaptive selection pressure in cell culture. Our results indicate that the emergence of spike mutations will most likely not affect the activity of remdesivir.
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http://dx.doi.org/10.1128/AAC.00097-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406809PMC
June 2021

[Study on chemical constituents of Wedelia trilobata].

Zhongguo Zhong Yao Za Zhi 2021 Feb;46(3):630-634

Institute of Immune Therapy, Faculty of Pharmacy, Fujian Medical University Fuzhou 350122, China.

A new taraxer-based triterpenoid ester, taraxer-14-en-30-al-3β-O-palmitate(1), was isolated from the whole plant of Wedelia trilobata, along with six known compounds, ent-kaur-16-en-19-oic acid(2), 16α-hydroxy-ent-kauran-19-oic acid(3), tara-xerol(4), β-amyrin(5), 1β-acetoxy-4α, 9α-dihydroxy-6β-isobutyroxyprostatolide(6), and stigmasterol(7). Their structures were elucidated with use of a combination of spectroscopic techniques(IR, HR-ESI-MS, 1 D, 2 D NMR data) and chemical methods.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20200628.203DOI Listing
February 2021

Bifurcated monocyte states are predictive of mortality in severe COVID-19.

bioRxiv 2021 Feb 10. Epub 2021 Feb 10.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection presents with varied clinical manifestations , ranging from mild symptoms to acute respiratory distress syndrome (ARDS) with high mortality . Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in severe COVID-19. We performed high-dimensional cellular and molecular profiling of blood and respiratory samples from critically ill COVID-19 patients to define immune cell genomic states that are predictive of outcome in severe COVID-19 disease. Critically ill patients admitted to the intensive care unit (ICU) manifested increased frequencies of inflammatory monocytes and plasmablasts that were also associated with ARDS not due to COVID-19. Single-cell RNAseq (scRNAseq)-based deconvolution of genomic states of peripheral immune cells revealed distinct gene modules that were associated with COVID-19 outcome. Notably, monocytes exhibited bifurcated genomic states, with expression of a cytokine gene module exemplified by (MIP-1β) associated with survival and an interferon signaling module associated with death. These gene modules were correlated with higher levels of MIP-1β and CXCL10 levels in plasma, respectively. Monocytes expressing genes reflective of these divergent modules were also detectable in endotracheal aspirates. Machine learning algorithms identified the distinctive monocyte modules as part of a multivariate peripheral immune system state that was predictive of COVID-19 mortality. Follow-up analysis of the monocyte modules on ICU day 5 was consistent with bifurcated states that correlated with distinct inflammatory cytokines. Our data suggests a pivotal role for monocytes and their specific inflammatory genomic states in contributing to mortality in life-threatening COVID-19 disease and may facilitate discovery of new diagnostics and therapeutics.
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http://dx.doi.org/10.1101/2021.02.10.430499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885916PMC
February 2021

COVID-19 versus Non-COVID-19 Acute Respiratory Distress Syndrome: Comparison of Demographics, Physiologic Parameters, Inflammatory Biomarkers, and Clinical Outcomes.

Ann Am Thorac Soc 2021 07;18(7):1202-1210

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

There is an urgent need for improved understanding of the mechanisms and clinical characteristics of acute respiratory distress syndrome (ARDS) due to coronavirus disease (COVID-19). To compare key demographic and physiologic parameters, biomarkers, and clinical outcomes of COVID-19 ARDS and ARDS secondary to direct lung injury from other etiologies of pneumonia. We enrolled 27 patients with COVID-19 ARDS in a prospective, observational cohort study and compared them with a historical, pre-COVID-19 cohort of patients with viral ARDS ( = 14), bacterial ARDS ( = 21), and ARDS due to culture-negative pneumonia ( = 30). We recorded clinical demographics; measured respiratory mechanical parameters; collected serial peripheral blood specimens for measurement of plasma interleukin (IL)-6, IL-8, and IL-10; and followed patients prospectively for patient-centered outcomes. We conducted between-group comparisons with nonparametric tests and analyzed time-to-event outcomes with Kaplan-Meier and Cox proportional hazards models. Patients with COVID-19 ARDS had higher body mass index and were more likely to be Black, or residents of skilled nursing facilities, compared with those with non-COVID-19 ARDS ( < 0.05). Patients with COVID-19 had lower delivered minute ventilation compared with bacterial and culture-negative ARDS ( < 0.01) but not compared with viral ARDS. We found no differences in static compliance, hypoxemic indices, or carbon dioxide clearance between groups. Patients with COVID-19 had lower IL-6 levels compared with bacterial and culture-negative ARDS at early time points after intubation but no differences in IL-6 levels compared with viral ARDS. Patients with COVID-19 had longer duration of mechanical ventilation but similar 60-day mortality in both unadjusted and adjusted analyses. COVID-19 ARDS bears several similarities to viral ARDS but demonstrates lower minute ventilation and lower systemic levels of IL-6 compared with bacterial and culture-negative ARDS. COVID-19 ARDS was associated with longer dependence on mechanical ventilation compared with non-COVID-19 ARDS. Such detectable differences of COVID-19 do not merit deviation from evidence-based management of ARDS but suggest priorities for clinical research to better characterize and treat this new clinical entity.
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http://dx.doi.org/10.1513/AnnalsATS.202008-1026OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328355PMC
July 2021

Unravelling the Role of LncRNA WT1-AS/miR-206/NAMPT Axis as Prognostic Biomarkers in Lung Adenocarcinoma.

Biomolecules 2021 02 2;11(2). Epub 2021 Feb 2.

College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China.

Lung cancer is the world's highest morbidity and mortality of malignant tumors, with lung adenocarcinoma (LUAD) as a major subtype. The competitive endogenous RNA (ceRNA) regulative network provides opportunities to understand the relationships among different molecules, as well as the regulative mechanisms among them in order to investigate the whole transcriptome landscape in cancer pathology. We designed this work to explore the role of a key oncogene, MYC, in the pathogenesis of LUAD, and this study aims to identify important long noncoding RNA (lncRNA)-microRNA (miRNA)- transcription factor (TF) interactions in non-small cell lung cancer (NSCLC) using a bioinformatics analysis. The Cancer Genome Atlas (TCGA) database, containing mRNA expression data of NSCLC, was used to determine the deferentially expressed genes (DEGs), and the ceRNA network was composed of WT1-AS, miR-206, and nicotinamide phosphoribosyltransferase (NAMPT) bashing on the MYC expression level. The Kaplan-Meier univariate survival analysis showed that these components may be closely related prognostic biomarkers and will become new ideas for NSCLC treatment. Moreover, the high expression of WT1-AS and NAMPT and low expression of miR-206 were associated with a shortened survival in NSCLC patients, which provided a survival advantage. In summary, the current study constructing a ceRNA-based WT1-AS/miR-206/NAMPT axis might be a novel important prognostic factor associated with the diagnosis and prognosis of LUAD.
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http://dx.doi.org/10.3390/biom11020203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912827PMC
February 2021

Intractable Coronavirus Disease 2019 (COVID-19) and Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Replication in a Chimeric Antigen Receptor-Modified T-Cell Therapy Recipient: A Case Study.

Clin Infect Dis 2021 08;73(3):e815-e821

Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

A chimeric antigen receptor-modified T-cell therapy recipient developed severe coronavirus disease 2019, intractable RNAemia, and viral replication lasting >2 months. Premortem endotracheal aspirate contained >2 × 1010 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA copies/mL and infectious virus. Deep sequencing revealed multiple sequence variants consistent with intrahost virus evolution. SARS-CoV-2 humoral and cell-mediated immunity were minimal. Prolonged transmission from immunosuppressed patients is possible.
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http://dx.doi.org/10.1093/cid/ciab072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929077PMC
August 2021

Network Pharmacology-Based Prediction of Catalpol and Mechanisms against Stroke.

Evid Based Complement Alternat Med 2021 7;2021:2541316. Epub 2021 Jan 7.

College of Pharmaceutical Sciences &; College of Chinese Medicine, Southwest University, Chongqing 400715, China.

Aim: To apply the network pharmacology method to screen the target of catalpol prevention and treatment of stroke, and explore the pharmacological mechanism of Catalpol prevention and treatment of stroke.

Methods: PharmMapper, GeneCards, DAVID, and other databases were used to find key targets. We selected hub protein and catalpol which were screened for molecular docking verification. Based on the results of molecular docking, the ITC was used to determine the binding coefficient between the highest scoring protein and catalpol. The GEO database and ROC curve were used to evaluate the correlation between key targets.

Results: 27 key targets were obtained by mapping the predicted catalpol-related targets to the disease. Hub genes (ALB, CASP3, MAPK1 (14), MMP9, ACE, KDR, etc.) were obtained in the key target PPI network. The results of KEGG enrichment analysis showed that its signal pathway was involved in angiogenic remodeling such as VEGF, neurotrophic factors, and inflammation. The results of molecular docking showed that ACE had the highest docking score. Therefore, the ITC was used for the titration of ACE and catalpol. The results showed that catalpol had a strong binding force with ACE.

Conclusion: Network pharmacology combined with molecular docking predicts key genes, proteins, and signaling pathways for catalpol in treating stroke. The strong binding force between catalpol and ACE was obtained by using ITC, and the results of molecular docking were verified to lay the foundation for further research on the effect of catalpol on ACE. ROC results showed that the AUC values of the key targets are all >0.5. This article uses network pharmacology to provide a reference for a more in-depth study of catalpol's mechanism and experimental design.
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http://dx.doi.org/10.1155/2021/2541316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810528PMC
January 2021

Genome-wide identification and characterization of long non-coding RNAs conferring resistance to Colletotrichum gloeosporioides in walnut (Juglans regia).

BMC Genomics 2021 Jan 6;22(1):15. Epub 2021 Jan 6.

College of Forestry, Shandong Agricultural University, Tai'an, 271018, Shandong Province, China.

Background: Walnut anthracnose caused by Colletotrichum gloeosporioides (Penz.) Penz. and Sacc. is an important walnut production problem in China. Although the long non-coding RNAs (lncRNAs) are important for plant disease resistance, the molecular mechanisms underlying resistance to C. gloeosporioides in walnut remain poorly understood.

Results: The anthracnose-resistant F26 fruits from the B26 clone and the anthracnose-susceptible F423 fruits from the 4-23 clone of walnut were used as the test materials. Specifically, we performed a comparative transcriptome analysis of F26 and F423 fruit bracts to identify differentially expressed LncRNAs (DELs) at five time-points (tissues at 0 hpi, pathological tissues at 24 hpi, 48 hpi, 72 hpi, and distal uninoculated tissues at 120 hpi). Compared with F423, a total of 14,525 DELs were identified, including 10,645 upregulated lncRNAs and 3846 downregulated lncRNAs in F26. The number of upregulated lncRNAs in F26 compared to in F423 was significantly higher at the early stages of C. gloeosporioides infection. A total of 5 modules related to disease resistance were screened by WGCNA and the target genes of lncRNAs were obtained. Bioinformatic analysis showed that the target genes of upregulated lncRNAs were enriched in immune-related processes during the infection of C. gloeosporioides, such as activation of innate immune response, defense response to bacterium, incompatible interaction and immune system process, and enriched in plant hormone signal transduction, phenylpropanoid biosynthesis and other pathways. And 124 known target genes for 96 hub lncRNAs were predicted, including 10 known resistance genes. The expression of 5 lncRNAs and 5 target genes was confirmed by qPCR, which was consistent with the RNA-seq data.

Conclusions: The results of this study provide the basis for future functional characterizations of lncRNAs regarding the C. gloeosporioides resistance of walnut fruit bracts.
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http://dx.doi.org/10.1186/s12864-020-07310-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789297PMC
January 2021

Ethanol-soluble proteins from the royal jelly of Xinjiang black bees.

Protein Sci 2021 02 10;30(2):291-296. Epub 2020 Nov 10.

Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China.

Royal jelly is a nutritious food that has beneficial effects to human health. However, the functional substances remain unclear. Herein, we fractioned the royal jelly proteins of Xinjing black bees according to the Osboren method. Two main proteins from the ethanol-soluble fraction were purified and identified. RJG-1 was determined as glucosylceramidase, and RJG-2 was major royal jelly protein 1 (MRJP1). RJG-1 showed potent cytotoxicity toward various mammalian cells, and caused quick disruption of cell membranes. With glucosylceramidase activity, RJG-1 may degrade the glucosylceramide of the cell membranes and disrupt the membrane structure, thereby resulting in cell necrosis. This study extends our knowledge about the composition and function of royal jelly, and is significant for the application of royal jelly.
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http://dx.doi.org/10.1002/pro.3985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784752PMC
February 2021

A UPLC-MS/MS method for determination of endogenous l-carnitine and acetyl-l-carnitine in serum of patients with depression.

Biomed Chromatogr 2021 Mar 13;35(3):e4991. Epub 2020 Dec 13.

Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, China.

A simple, rapid, and selective ultra-performance liquid chromatography-tandem mass spectrometry method for determination of l-carnitine (LC) and acetyl-l-carnitine (ALC) in human serum was developed. Acetyl-l-carnitine-d (ALC-d ) was selected as internal standard (IS). After protein precipitation with acetonitrile-water (1 mL, 2:1, v/v), the analytes and IS were separated on a 2.5-μm XSelect HSS T3 C column by gradient elution with methanol-water (containing 0.01% ammonia water) as the mobile phase at a flow rate of 0.2 mL/min. Analytes were detected with multiple reaction monitoring using a positive scan mode with electrospray ionization. Good linearity (R  > 0.999) was observed in the concentration range for LC and ALC. The inter- and intra-day values of relative error were -10.4% to 10.0% with CVs less than 9.84%. The average recoveries of the two analytes were 91.29%-98.23%. Blood samples containing LC and ALC were stable under various storage conditions. Normal, haemolytic, and hyperlipidaemic serum had no significant effect on the quantification of LC and ALC. This method was successfully applied to study the concentrations of endogenous LC and ALC in the serum of patients with first-episode depression.
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http://dx.doi.org/10.1002/bmc.4991DOI Listing
March 2021

Antagonism of interleukin 17 protects chronic obstructive pulmonary disease rat lungs from adverse effects of environmental PM.

Am J Transl Res 2020 15;12(9):5808-5817. Epub 2020 Sep 15.

Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University No. 215, Heping West Road, Shijiazhuang 050000, Hebei, China.

Severe air pollution has raised concerns about the adverse effects of particulate matters 2.5 μm in size (PM) on human health. However, the mechanisms elucidating how PM affects lungs, especially in COPD, remain unclear. In this study, we examined the concentration changes of environmental PM from 2013 to 2019 in Shijiazhuang city. PM was collected to study its effects on a COPD lung. Inflammatory factors present in bronchoalveolar lavage fluid (BLF) were examined after exposure. An antagonist of IL-17 was used to reverse PM-induced pathological and functional impairments in COPD rat lungs. Our results show that the degree of air pollution changed significantly (55.873, < 0.001) during the study period in accordance with PM tendency. PM and PM was present in higher concentrations from December 2013 to January 2014 and December 2016 to January 2017, respectively. After COPD rats were exposed to PM for 2 or 4 weeks, all indicators of lung function (FEV0.3, FVC, FEV0.3/FVC, PEF, Rrs) decreased continuously and significantly. The levels of TGF-β1, IL-6, IL-17, and IL-21 in BLF, as well as the expression of IL-17 in lung tissues, were significantly increased after exposure for 2 or 4 weeks. When an IL-17 antagonist was introduced following PM exposure, inflammatory factor levels in BLF and pathological scores of lung tissues decreased significantly. Moreover, lung functions were partially rescued. Collectively, our data demonstrate that IL-17 is a potential therapeutic target for COPD lungs after PM exposure.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540087PMC
September 2020

Characterization of the Fc-III-4C-based recombinant protein expression system by using carbonic anhydrase as the model protein.

Protein Expr Purif 2021 01 19;177:105761. Epub 2020 Sep 19.

MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China; Tsinghua University-Peking University Joint Center for Life Sciences, Beijing, 100084, China. Electronic address:

Development of new affinity tags is important for recombinant protein expression and purification. Based on our earlier work, we devised an affinity tag by addition of two cysteine residues onto the N- and C-termini of the Fc-III peptide and designated as the Fc-III-4C tag, in which four cysteine residues form two disulfide linkages. The binding affinity of Fc-III-4C tag to human IgG is measured as 2.28 nM (K) and is 100 times higher than that of the Fc-III tag to IgG. Fc-III-4C tagged carbonic anhydrase (CA) can be effectively purified with IgG-immobilized beads, and Fc-III-4C tag does not possess adverse effects on the structure and stability of CA. Furthermore, the Fc-III-4C tagged protein binds to multiple transition metal ions, which enhances activities of enzymes that use metal ions as co-factors. These results suggest that Fc-III-4C tag is a useful tool for expression and purification of recombinant proteins and enhances the activities of some fusion proteins that use Zn or Cu as cofactors.
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http://dx.doi.org/10.1016/j.pep.2020.105761DOI Listing
January 2021

Effective combinatorial immunotherapy for penile squamous cell carcinoma.

Nat Commun 2020 05 1;11(1):2124. Epub 2020 May 1.

Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, 46556, USA.

Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.
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http://dx.doi.org/10.1038/s41467-020-15980-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195486PMC
May 2020

G-5555 synergized miR-485-5p to alleviate cisplatin resistance in ovarian cancer cells via Pi3k/Akt signaling pathway.

J Reprod Immunol 2020 08 14;140:103129. Epub 2020 Apr 14.

Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, 226001, China. Electronic address:

The present study was meant for the discovery of the underlying functions of miR-485-5p in ovarian cancer concerning cisplatin resistance in vitro. RT-qPCR assessed the miR-485-5p expression in ovarian cancer cell lines, normal cells and cisplatin-resistant Cell line OVCA433-CR. After OVCA433-CR treated with 0,3,5umol/L cisplatin, miR-485-5p expressions were determined. MTT observed the cell cytotoxicity in OVCA433-CR after regulation of miR-485-5p. Targets can predicted the putative binding between miR-485-5p and PAK1 and Luciferase Assay verified this. RT-qPCR decided the inhibitory effect in between. MTT tested the cytotoxicity in different combinations of miR-485-5p and PAK1. Western Blot tested the phosphorylation of Pi3k and Akt in response to miR-485-5p and PAK1 interplay. We evaluated the role of Pi3k/Akt signaling in regulation of miR-485-5p and cisplatin resistance with Wortmannin. miR-485-5p was lower expressed in ovarian cancer cells than normal ones and even lower in OVCA433-CR than OVCA433. As the cisplatin concerntration increased, miR-485-5p decreased. miR-485-5p mimics induced lower cisplatin resistance while miR-485-5p inhibitor caused higher resistance. PAK1 targeted miR-485-5p and inhibited miR-485-5p. PAK1 inhibitor helped to lower the resistance to cisplatin caused by miR-485-5p upregulation. miR-485-5p mimics silenced Pi3k/Akt signaling and PAK1 inhibitor aggravated the silencing. Inhibition of Pi3k/Akt signaling increased miR-485-5p, thereby decreasing the cisplatin-resistance in OVCA433-CR. miR-485-5p decreased cisplatin resistance in ovarian cancer cells via Pi3k/Akt signaling, suggesting that miR-485-5p upregulation might alleviate the cisplatin resistance in ovarian patients.
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http://dx.doi.org/10.1016/j.jri.2020.103129DOI Listing
August 2020

Evidence of a Relationship Between Plasma Leptin, Not Nesfatin-1, and Craving in Male Alcohol-Dependent Patients After Abstinence.

Front Endocrinol (Lausanne) 2020 24;11:159. Epub 2020 Mar 24.

Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China.

The goal of this study was to determine whether the plasma leptin, nesfatin-1, cortisol, brain-derived neurotrophic factor (BDNF), and inflammatory cytokines could be used as potential biomarkers for the degree of craving in the alcohol-dependent patients after 1 month of abstinence. A total of 83 patients with alcohol use disorder (AUD) and 61 healthy subjects were assessed. Patients with AUD were selected from Department of Material Dependence, Anhui Mental Health Center, and subjects in the control group were selected from healthy volunteers. The Alcohol Urge questionnaire Scale (AUQ) was used to evaluate the extent of craving for alcohol, and the Michigan Alcoholism Screening Test (MAST), the Fagerstrom Test for Nicotine Dependence (FTND), the Self-Rating Anxiety Scale (SAS), and the Self-Rating Depression Scale (SDS) were also assessed in patients with AUD. Enzyme-Linked Immunosorbent Assay (ELISA) was used for the measurement of plasma leptin, nesfatin-1, cortisol, BDNF, Interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) levels. Compare with healthy controls, the average leptin, leptin/BMI, IL-6, CRP, and TNF-α levels in patients with AUD were significantly increased, while the BDNF levels were significantly decreased. Moreover, the partial correlational analysis showed that the AUQ scores of the alcohol-dependent patients were positively correlated with the plasma leptin levels ( = 0.613, < 0.001), rather than nesfatin-1 ( = 0.066, = 0.569) after controlling for age as covariate. Furthermore, plasma nesfatin-1 levels were found to be correlated with the SDS scores ( = 0.366, = 0.001) in the AUD group. In addition, plasma leptin levels were positively associated with the plasma IL-6 ( = 0.257, = 0.033), CRP ( = 0.305, = 0.011), and TNF-α ( = 0.311, = 0.009) levels, and negatively associated with the BDNF levels ( = -0.245, = 0.042) in patients with AUD. These results suggest that plasma leptin, but not nesfatin-1, might be a potential biomarker for the degree of craving in alcohol-dependent patients after 1 month of abstinence, the mechanism of which might be related to the dysfunction of the inflammatory cytokines and BDNF levels.
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http://dx.doi.org/10.3389/fendo.2020.00159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105814PMC
February 2021
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