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  • 1
    Online Resource
    Online Resource
    DataSheet_4.pdf
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 13 ( 2022-12-21)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2022-12-21)
    Abstract: Drug repurposing is a fast and effective way to develop drugs for an emerging disease such as COVID-19. The main challenges of effective drug repurposing are the discoveries of the right therapeutic targets and the right drugs for combating the disease. Methods Here, we present a systematic repurposing approach, combining Homopharma and hierarchal systems biology networks (HiSBiN), to predict 327 therapeutic targets and 21,233 drug-target interactions of 1,592 FDA drugs for COVID-19. Among these multi-target drugs, eight candidates (along with pimozide and valsartan) were tested and methotrexate was identified to affect 14 therapeutic targets suppressing SARS-CoV-2 entry, viral replication, and COVID-19 pathologies. Through the use of in vitro (EC 50 = 0.4 μM) and in vivo models, we show that methotrexate is able to inhibit COVID-19 via multiple mechanisms. Results Our in vitro studies illustrate that methotrexate can suppress SARS-CoV-2 entry and replication by targeting furin and DHFR of the host, respectively. Additionally, methotrexate inhibits all four SARS-CoV-2 variants of concern. In a Syrian hamster model for COVID-19, methotrexate reduced virus replication, inflammation in the infected lungs. By analysis of transcriptomic analysis of collected samples from hamster lung, we uncovered that neutrophil infiltration and the pathways of innate immune response, adaptive immune response and thrombosis are modulated in the treated animals. Conclusions We demonstrate that this systematic repurposing approach is potentially useful to identify pharmaceutical targets, multi-target drugs and regulated pathways for a complex disease. Our findings indicate that methotrexate is established as a promising drug against SARS-CoV-2 variants and can be used to treat lung damage and inflammation in COVID-19, warranting future evaluation in clinical trials.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
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    DOI: 10.3389/fimmu.2022.1080897
    DOI: 10.3389/fimmu.2022.1080897.s001
    DOI: 10.3389/fimmu.2022.1080897.s002
    DOI: 10.3389/fimmu.2022.1080897.s003
    DOI: 10.3389/fimmu.2022.1080897.s004
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    Publisher: Frontiers Media SA
    Publication Date: 2022
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  • 2
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    Data_Sheet_1.docx
    Frontiers Media SA ; 2021
    In:  Frontiers in Cell and Developmental Biology Vol. 9 ( 2021-4-15)
    Details
    In: Frontiers in Cell and Developmental Biology, Frontiers Media SA, Vol. 9 ( 2021-4-15)
    Abstract: Nasal inverted papilloma (NIP) is a common benign tumor. Yes-associated protein (YAP) is the core effector molecule of the Hippo pathway, which regulates the proliferation and differentiation of airway epithelium. While its role in proliferation may be connected to NIP formation, no definitive association has been made between them. Methods We compared the difference of YAP expression and proliferation level between the control inferior turbinate, NP (nasal polyps), and NIP groups. In addition, we further used PCR, immunofluorescence, and immunohistochemistry to investigate YAP’s role in the proliferation and differentiation of the nasal epithelium and inflammatory cell infiltration, correlating them with different grades of epithelial remodeling. We further used an IL-13 remodeling condition to investigate YAP’s role in differentiation in an in vitro air-liquid interface (ALI) human nasal epithelial cell (hNECs) model. Finally, we also explored the correlation between YAP expression and clinical indicators of NIP. Results The expression of YAP/active YAP in the NIP group was significantly higher than that in the NP group and control group. Moreover, within the NIP group, the higher grade of epithelial remodeling was associated with higher YAP induced proliferation, leading to reduced ciliated cells and goblet cells. The finding was further verified using an IL-13 remodeling condition in differentiating ALI hNECs. Furthermore, YAP expression was positively correlated with proliferation and neutrophil infiltration in NIP. YAP expression was also significantly increased in NIP patients with adverse outcomes. Conclusion Abnormal expression of YAP/active YAP is associated with proliferation, differentiation, neutrophil infiltration, and adverse outcome in NIP and may present a novel target for diagnosis and intervention in NIP.
    Type of Medium: Online Resource
    ISSN: 2296-634X
    URL: Article
    URL: Article
    DOI: 10.3389/fcell.2021.625251
    DOI: 10.3389/fcell.2021.625251.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
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  • 3
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    Human Umbilical Cord Mesenchymal Stem Cells to Treat Neuromyelitis Optica Spectrum Disorder (hUC–MSC–NMOSD): A Study Protocol for a Prospective, Multicenter, Randomized, Placebo-Controlled Clinical Trial
    Frontiers Media SA ; 2022
    In:  Frontiers in Neurology Vol. 13 ( 2022-4-25)
    Details
    In: Frontiers in Neurology, Frontiers Media SA, Vol. 13 ( 2022-4-25)
    Abstract: Neuromyelitis Optica spectrum disorder (NMOSD) is severe relapsing and disabling autoimmune disease of the central nervous system. Its optimal first-line treatment to reduce relapse rate and ameliorate neurological disability remains unclear. We will conduct a prospective, multicenter, randomized, placebo-controlled clinical trial to study the safety and effectiveness of human umbilical cord mesenchymal stem cells (hUC–MSCs) in treating NMOSD. Methods The trial is planned to recruit 430 AQP4-IgG seropositive NMOSD patients. It consists of three consecutive stages. The first stage will be carried out in the leading center only and aims to evaluate the safety of hUC—MSCs. Patients will be treated with three different doses of hUC–MSCs: 1, 2, or 5 × 10 6 MSC/kg·weight for the low-, medium-, and high-dose group, respectively. The second and third stages will be carried out in six centers. The second stage aims to find the optimal dosage. Patients will be 1:1:1:1 randomized into the low-, medium-, high-dose group and the controlled group. The third stage aims to evaluate the effectiveness. Patients will be 1:1 randomized into the optimal dose and the controlled group. The primary endpoint is the first recurrent time and secondary endpoints are the recurrent times, EDSS scores, MRI lesion numbers, OSIS scores, Hauser walking index, and SF-36 scores. Endpoint events and side effects will be evaluated every 3 months for 2 years. Discussion Although hUC–MSC has shown promising treatment effects of NMOSD in preclinical studies, there is still a lack of well-designed clinical trials to evaluate the safety and effectiveness of hUC–MSC among NMOSD patients. As far as we know, this trial will be the first one to systematically demonstrate the clinical safety and efficacy of hUC–MSC in treating NMOSD and might be able to determine the optimal dose of hUC–MSC for NMOSD patients. Trial registration The study was registered with the Chinese Clinical Trial Registry ( CHICTR.org.cn ) on 2 March 2016 (registration No. ChiCTR-INR-16008037), and the revised trial protocol (Protocol version 1.2.1) was released on 16 March 2020.
    Type of Medium: Online Resource
    ISSN: 1664-2295
    URL: Article
    DOI: 10.3389/fneur.2022.860083
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
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  • 4
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    Long-Term Motor Cortical Electrical Stimulation Ameliorates 6-Hydroxydopamine-Induced Motor Dysfunctions and Exerts Neuroprotective Effects in a Rat Model of Parkinson’s Disease
    Frontiers Media SA ; 2022
    In:  Frontiers in Aging Neuroscience Vol. 14 ( 2022-2-16)
    Details
    In: Frontiers in Aging Neuroscience, Frontiers Media SA, Vol. 14 ( 2022-2-16)
    Abstract: Cortical electrical stimulation (CES) can modulate cortical excitability through a plasticity-like mechanism and is considered to have therapeutic potentials in Parkinson’s disease (PD). However, the precise therapeutic value of such approach for PD remains unclear. Accordingly, we adopted a PD rat model to determine the therapeutic effects of CES. The current study was thus designed to identify the therapeutic potential of CES in PD rats. Methods A hemiparkinsonian rat model, in which lesions were induced using unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, was applied to identify the therapeutic effects of long-term (4-week) CES with intermittent theta-burst stimulation (iTBS) protocol (starting 24 h after PD lesion observation, 1 session/day, 5 days/week) on motor function and neuroprotection. After the CES intervention, detailed functional behavioral tests including gait analysis, akinesia, open-field locomotor activity, apomorphine-induced rotation as well as degeneration level of dopaminergic neurons were performed weekly up to postlesion week 4. Results After the CES treatment, we found that the 4-week CES intervention ameliorated the motor deficits in gait pattern, akinesia, locomotor activity, and apomorphine-induced rotation. Immunohistochemistry and tyrosine hydroxylase staining analysis demonstrated that the number of dopamine neurons was significantly greater in the CES intervention group than in the sham treatment group. Conclusion This study suggests that early and long-term CES intervention could reduce the aggravation of motor dysfunction and exert neuroprotective effects in a rat model of PD. Further, this preclinical model of CES may increase the scope for the potential use of CES and serve as a link between animal and PD human studies to further identify the therapeutic mechanism of CES for PD or other neurological disorders.
    Type of Medium: Online Resource
    ISSN: 1663-4365
    URL: Article
    DOI: 10.3389/fnagi.2022.848380
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2558898-9
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  • 5
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    Image_9.TIFF
    Frontiers Media SA ; 2020
    In:  Frontiers in Immunology Vol. 11 ( 2020-2-20)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 11 ( 2020-2-20)
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
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    DOI: 10.3389/fimmu.2020.00062
    DOI: 10.3389/fimmu.2020.00062.s001
    DOI: 10.3389/fimmu.2020.00062.s002
    DOI: 10.3389/fimmu.2020.00062.s003
    DOI: 10.3389/fimmu.2020.00062.s004
    DOI: 10.3389/fimmu.2020.00062.s005
    DOI: 10.3389/fimmu.2020.00062.s006
    DOI: 10.3389/fimmu.2020.00062.s007
    DOI: 10.3389/fimmu.2020.00062.s008
    DOI: 10.3389/fimmu.2020.00062.s009
    DOI: 10.3389/fimmu.2020.00062.s010
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2020
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  • 6
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    Maternal Cigarette Smoke Exposure Exaggerates the Behavioral Defects and Neuronal Loss Caused by Hypoxic-Ischemic Brain Injury in Female Offspring
    Frontiers Media SA ; 2022
    In:  Frontiers in Cellular Neuroscience Vol. 16 ( 2022-2-18)
    Details
    In: Frontiers in Cellular Neuroscience, Frontiers Media SA, Vol. 16 ( 2022-2-18)
    Abstract: Hypoxic-ischemic encephalopathy affects ∼6 in 1,000 preterm neonates, leading to significant neurological sequela (e.g., cognitive deficits and cerebral palsy). Maternal smoke exposure (SE) is one of the common causes of neurological disorders; however, female offspring seems to be less affected than males in our previous study. We also showed that maternal SE exaggerated neurological disorders caused by neonatal hypoxic-ischemic brain injury in adolescent male offspring. Here, we aimed to examine whether female littermates of these males are protected from such insult. Methods BALB/c dams were exposed to cigarette smoke generated from 2 cigarettes twice daily for 6 weeks before mating, during gestation and lactation. To induce hypoxic-ischemic brain injury, half of the pups from each litter underwent left carotid artery occlusion, followed by exposure to 8% oxygen (92% nitrogen) at postnatal day (P) 10. Behavioral tests were performed at P40–44, and brain tissues were collected at P45. Results Maternal SE worsened the defects in short-term memory and motor function in females with hypoxic-ischemic injury; however, reduced anxiety due to injury was observed in the control offspring, but not the SE offspring. Both hypoxic-ischemic injury and maternal SE caused significant loss of neuronal cells and synaptic proteins, along with increased oxidative stress and inflammatory responses. Conclusion Oxidative stress and inflammatory response due to maternal SE may be the mechanism of worsened neurological outcomes by hypoxic-ischemic brain injury in females, which was similar to their male littermates shown in our previous study.
    Type of Medium: Online Resource
    ISSN: 1662-5102
    URL: Article
    DOI: 10.3389/fncel.2022.818536
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
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  • 7
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    Table_9.xlsx
    Frontiers Media SA ; 2022
    In:  Frontiers in Plant Science Vol. 12 ( 2022-1-21)
    Details
    In: Frontiers in Plant Science, Frontiers Media SA, Vol. 12 ( 2022-1-21)
    Abstract: The mechanisms associated with the regulation of iron (Fe) homeostasis have been extensively examined, however, epigenetic regulation of these processes remains largely unknown. Here, we report that a naturally occurring epigenetic mutant, Colorless non-ripening ( Cnr ), displayed increased Fe-deficiency responses compared to its wild-type Ailsa Craig (AC). RNA-sequencing revealed that a total of 947 and 1,432 genes were up-regulated by Fe deficiency in AC and Cnr roots, respectively, while 923 and 1,432 genes were, respectively, down-regulated. Gene ontology analysis of differentially expressed genes showed that genes encoding enzymes, transporters, and transcription factors were preferentially affected by Fe deficiency. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed differential metabolic responses to Fe deficiency between AC and Cnr . Based on comparative transcriptomic analyses, 24 genes were identified as potential targets of Cnr epimutation, and many of them were found to be implicated in Fe homeostasis. By developing CRISPR/Cas9 genome editing SlSPL-CNR knockout (KO) lines, we found that some Cnr -mediated Fe-deficiency responsive genes showed similar expression patterns between SlSPL-CNR KO plants and the Cnr epimutant. Moreover, both two KO lines displayed Fe-deficiency-induced chlorosis more severe than AC plants. Additionally, the Cnr mutant displayed hypermethylation in the 286-bp epi-mutated region on the SlSPL-CNR promoter, which contributes to repressed expression of SlSPL-CNR when compared with AC plants. However, Fe-deficiency induced no change in DNA methylation both at the 286-bp epi-allele region and the entire region of SlSPL-CNR gene. Taken together, using RNA-sequencing and genetic approaches, we identified Fe-deficiency responsive genes in tomato roots, and demonstrated that SlSPL-CNR is a novel regulator of Fe-deficiency responses in tomato, thereby, paving the way for further functional characterization and regulatory network dissection.
    Type of Medium: Online Resource
    ISSN: 1664-462X
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    DOI: 10.3389/fpls.2021.796893
    DOI: 10.3389/fpls.2021.796893.s001
    DOI: 10.3389/fpls.2021.796893.s002
    DOI: 10.3389/fpls.2021.796893.s003
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    DOI: 10.3389/fpls.2021.796893.s007
    DOI: 10.3389/fpls.2021.796893.s008
    DOI: 10.3389/fpls.2021.796893.s009
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    DOI: 10.3389/fpls.2021.796893.s011
    DOI: 10.3389/fpls.2021.796893.s012
    DOI: 10.3389/fpls.2021.796893.s013
    DOI: 10.3389/fpls.2021.796893.s014
    DOI: 10.3389/fpls.2021.796893.s015
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
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  • 8
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    Table_2.docx
    Frontiers Media SA ; 2021
    In:  Frontiers in Genetics Vol. 11 ( 2021-2-1)
    Details
    In: Frontiers in Genetics, Frontiers Media SA, Vol. 11 ( 2021-2-1)
    Abstract: Acute myeloid leukemia (AML) is a threatening hematological malignant disease in which new successful approaches in therapy are needed. Cyclin-dependent kinase 6 ( CDK6 ), a regulatory enzyme of the cell cycle that plays an important role in leukemogenesis and the maintenance of leukemia stem cells (LSC), has the potential to predict the prognosis of AML. By analyzing public databases, we observed that the messenger RNA (mRNA) levels of CDK6 were significantly overexpressed in AML cell lines and non-acute promyelocytic leukemia (non-APL) AML patients when compared to healthy donors. Furthermore, CDK6 expression was significantly reduced in AML patients who achieved complete remission (CR) compared to that at the time of diagnosis in our validated cohort. The expression of CDK6 was tightly correlated with peripheral blood blasts, French–American–British (FAB) subtypes, CCAAT-enhancer-binding protein α (CEBPA) mutation, and chromosomal abnormalities of t(8;21). However, the clinical significance and effects of CDK6 expression on the prognosis of non-APL AML patients remain uncertain. We found that CDK6 expression was inversely correlated with overall survival (OS) among non-APL AML patients using the Kaplan–Meier analysis. CDK6 was also found to be positively associated with genes identified to contribute to the development of leukemia, including CCND2 , DNMT3B , SOX4 , and IKZF2 , as well as being negatively associated with anticancer microRNAs, including miR-187, miR-9, miR-582, miR708, and miR-362. In summary, our study revealed that CDK6 might be a potential diagnostic and prognostic biomarker in non-APL AML patients.
    Type of Medium: Online Resource
    ISSN: 1664-8021
    URL: Article
    URL: Article
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    DOI: 10.3389/fgene.2020.600227
    DOI: 10.3389/fgene.2020.600227.s001
    DOI: 10.3389/fgene.2020.600227.s002
    DOI: 10.3389/fgene.2020.600227.s003
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
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  • 9
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    DataSheet_1.docx
    Frontiers Media SA ; 2021
    In:  Frontiers in Oncology Vol. 11 ( 2021-12-9)
    Details
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 11 ( 2021-12-9)
    Abstract: Hepatoid adenocarcinoma of the stomach (HAS) is a highly malignant and aggressive tumor. The purpose of this study was to describe the clinical, computed tomography (CT), and prognostic features of HAS to increase the awareness of this entity and determine its distinguishing features from non-HAS tumors. Methods The CT features and clinical data of 47 patients in our hospital with pathologically documented HAS were retrospectively analyzed, and the relevant differences between pure HAS (pHAS) and mixed HAS (mHAS) were determined. In addition, 141 patients with non-HAS tumors in the same T stage in the same period were selected as the control group. The data were compared between the two groups, and factors affecting the prognosis of HAS were analyzed. In addition, we included 9 patients with HAS and 27 patients with non-HAS tumors from another center for external validation. Results The patients in the HAS group were predominantly men (n = 33), and the tumor location was mostly the cardia or fundus (n = 27). Between the HAS and non-HAS groups, there were observed differences in terms of: sex, serum alpha-fetoprotein (AFP), carbohydrate antigen (CA)-125, and CA-724 levels; longest tumor diameter; degree of differentiation; vascular invasion; N stage, M stage, and tumor-node-metastasis (TNM) stage; thickest tumor diameter; plain CT attenuation; arterial-phase CT attenuation; CT attenuation between the venous and arterial phases; enhancement modes; and degrees of enhancement (all P & lt; 0.05). In the data from another center for external validation, there were observed differences in terms of: age, degree of differentiation, vascular invasion, thickest tumor diameter, the ratio of arterial CT attenuation to CT attenuation of the abdominal aorta at the same level (R A ), CT attenuation difference between the venous phase and arterial phase (HUv-a) (all P & lt; 0.05). The results of the multivariate analysis revealed that the independent factors for differentiation were serum AFP level ( P = 0.001), M stage ( P = 0.038), and tumor enhancement on CT ( P = 0.014). Among patients in the HAS group, 72.34% had pHAS and 27.66% had mHAS. The thickest tumor diameter and the longest short diameter of the metastatic lymph nodes of the mHAS group were on average 6.39 cm and 1.45 cm, respectively, which were larger than those in the pHAS group. The median progression-free survival time was 18.25 months in the HAS group, which was shorter than that in the non-HAS group (72.96 months; P = 0.001). The median overall survival time in the HAS group was 24.80 months, which was shorter than that in the non-HAS group (67.96 months; P = 0.001). The factors affecting the prognosis of HAS were M stage ( P = 0.001), overall TNM stage ( P = 0.048), presence of vascular cancer emboli ( P = 0.040), and pHAS type ( P = 0.046). Multifactorial analysis revealed that M stage ( P = 0.027) and pHAS type ( P = 0.009) were independent risk factors affecting the prognosis of HAS. Conclusion Although HAS is a rare clinical entity, it should be considered in the differential diagnosis of gastric tumors. Patients with HAS often have advanced-stage disease at presentation and a worse prognosis than patients with non-HAS tumors. CT findings, combined with laboratory results, can support the diagnosis of HAS. However, the final diagnosis needs to be confirmed with a histopathologic examination. If the postoperative pathologic findings reveal the mHAS type, a rapid clinical intervention and a detailed follow-up with CT are essential.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    URL: Article
    URL: Article
    DOI: 10.3389/fonc.2021.772636
    DOI: 10.3389/fonc.2021.772636.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
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  • 10
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    Data_Sheet_1.pdf
    Frontiers Media SA ; 2023
    In:  Frontiers in Stroke Vol. 2 ( 2023-1-26)
    Details
    In: Frontiers in Stroke, Frontiers Media SA, Vol. 2 ( 2023-1-26)
    Abstract: The optimal mechanical thrombectomy technique for acute ischaemic stroke (AIS) caused by distal, medium vessel occlusion (DMVO) is uncertain. We performed a systematic review and meta-analysis evaluating the efficacy and safety of first-line thrombectomy with combined techniques, which entail simultaneous use of a stent retriever and aspiration catheter, vs. single-device techniques, whether stent retriever or direct aspiration alone, for DMVO-AIS patients. Methods We systematically searched the PubMed, Embase and Cochrane CENTRAL databases from inception until 2 September 2022 for studies comparing combined and single-device techniques in DMVO-AIS patients. We adopted the Distal Thrombectomy Summit Group's definition of DMVO. Our outcomes were the modified first-pass effect [mFPE; modified Thrombolysis in Cerebral Infarction (mTICI) 2b-3 at first-pass], first-pass effect (FPE; mTICI 2c-3 at first-pass), successful and complete final reperfusion (mTICI 2b-3 and 2c-3 at end of all procedures, respectively), 90-day functional independence (modified Rankin scale 0-2), 90-day mortality, and symptomatic intracranial hemorrhage (sICH). Results Nine studies were included, with 477 patients receiving combined techniques, and 670 patients receiving single-device thrombectomy. Combined techniques achieved significantly higher odds of mFPE [odds ratio (OR), 2.12; 95% confidence interval (CI), 1.12–4.02; p = 0.021] and FPE (OR, 3.55; 95% CI, 1.97–6.38; p & lt; 0.001), with lower odds of sICH (OR, 0.23; 95% CI 0.06–0.93; p = 0.040). There were no significant differences in final reperfusion, functional independence (OR, 1.19; 95% CI 0.87–1.63; p = 0.658), or mortality (OR, 0.94; 95% CI, 0.50–1.76; p = 0.850). Conclusions In DMVO-AIS patients, mechanical thrombectomy combining stent retrievers and aspiration catheters achieved higher odds of FPE and lower odds of sICH over single-device techniques. There were no differences in functional independence and mortality. Further trials are warranted to establish these findings. Systematic review registration https://www.crd.york.ac.uk/prospero/display_recor d.php?ID=CRD42022370160 , identifier: CRD42022370160.
    Type of Medium: Online Resource
    ISSN: 2813-3056
    URL: Article
    URL: Article
    DOI: 10.3389/fstro.2023.1126130
    DOI: 10.3389/fstro.2023.1126130.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 3139161-8
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