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Frontiers of Medicine

  • Cover Illustration

    2020, Vol.14  No.5

    Mesial temporal lobe epilepsy (mTLE), the most common type of focal epilepsy, is characterized by the paradoxical discharge in mesial temporal lobe (illustrated as the yellow flashing lightning in the brain). Combining MRI (illustrated as the stereoscopic brain) and machine learning (illustrated as the number of “0” and “1”) techniques can successfully discriminate mTLE patients from healthy controls. We get the highest accuracy of 84% in the classificatio [Detail] ...

    Table of Contents

, Volume 14 Issue 5

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EDITORIAL
Traditional Chinese medicine for combating COVID-19
Kaixian Chen, Hongzhuan Chen
Front. Med.. 2020, 14 (5): 529-532.  https://doi.org/10.1007/s11684-020-0802-9
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REVIEW
Neurological manifestations of patients with COVID-19: potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain
Zhengqian Li, Taotao Liu, Ning Yang, Dengyang Han, Xinning Mi, Yue Li, Kaixi Liu, Alain Vuylsteke, Hongbing Xiang, Xiangyang Guo
Front. Med.. 2020, 14 (5): 533-541.  https://doi.org/10.1007/s11684-020-0786-5
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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a global pandemic in only 3 months. In addition to major respiratory distress, characteristic neurological manifestations are also described, indicating that SARS-CoV-2 may be an underestimated opportunistic pathogen of the brain. Based on previous studies of neuroinvasive human respiratory coronaviruses, it is proposed that after physical contact with the nasal mucosa, laryngopharynx, trachea, lower respiratory tract, alveoli epithelium, or gastrointestinal mucosa, SARS-CoV-2 can induce intrinsic and innate immune responses in the host involving increased cytokine release, tissue damage, and high neurosusceptibility to COVID-19, especially in the hypoxic conditions caused by lung injury. In some immune-compromised individuals, the virus may invade the brain through multiple routes, such as the vasculature and peripheral nerves. Therefore, in addition to drug treatments, such as pharmaceuticals and traditional Chinese medicine, non-pharmaceutical precautions, including facemasks and hand hygiene, are critically important.

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The function and regulation of OTU deubiquitinases
Jiansen Du, Lin Fu, Yingli Sui, Lingqiang Zhang
Front. Med.. 2020, 14 (5): 542-563.  https://doi.org/10.1007/s11684-019-0734-4
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Post-translational modification of cellular proteins by ubiquitin regulates numerous cellular processes, including cell division, immune responses, and apoptosis. Ubiquitin-mediated control over these processes can be reversed by deubiquitinases (DUBs), which remove ubiquitin from target proteins and depolymerize polyubiquitin chains. Recently, much progress has been made in the DUBs. In humans, the ovarian tumor protease (OTU) subfamily of DUBs includes 16 members, most of which mediate cell signaling cascades. These OTUs show great variation in structure and function, which display a series of mechanistic features. In this review, we provide a comprehensive analysis of current progress in character, structure and function of OTUs, such as the substrate specificity and catalytic activity regulation. Then we discuss the relationship between some diseases and OTUs. Finally, we summarize the structure of viral OTUs and their function in immune escape and viral survival. Despite the challenges, OTUs might provide new therapeutic targets, due to their involvement in key regulatory processes.

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Biological properties and clinical applications of berberine
Danyang Song, Jianyu Hao, Daiming Fan
Front. Med.. 2020, 14 (5): 564-582.  https://doi.org/10.1007/s11684-019-0724-6
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Berberine, an isoquinoline alkaloid isolated from the Chinese herb Coptis chinensis and other Berberis plants, has a wide range of pharmacological properties. Berberine can be used to treat many diseases, such as cancer and digestive, metabolic, cardiovascular, and neurological diseases. Berberine has protective capacities in digestive diseases. It can inhibit toxins and bacteria, including Helicobacter pylori, protect the intestinal epithelial barrier from injury, and ameliorate liver injury. Berberine also inhibits the proliferation of various types of cancer cells and impedes invasion and metastasis. Recent evidence has confirmed that berberine improves the efficacy and safety of chemoradiotherapies. In addition, berberine regulates glycometabolism and lipid metabolism, improves energy expenditure, reduces body weight, and alleviates nonalcoholic fatty liver disease. Berberine also improves cardiovascular hemodynamics, suppresses ischemic arrhythmias, attenuates the development of atherosclerosis, and reduces hypertension. Berberine shows potent neuroprotective effects, including antioxidative, antiapoptotic, and anti-ischemic. Furthermore, berberine exerts protective effects against other diseases. The mechanisms of its functions have been extensively explored, but much remains to be clarified. This article summarizes the main pharmacological actions of berberine and its mechanisms in cancer and digestive, metabolic, cardiovascular, and neurological diseases.

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Oxidative stress and diabetes: antioxidative strategies
Pengju Zhang, Tao Li, Xingyun Wu, Edouard C. Nice, Canhua Huang, Yuanyuan Zhang
Front. Med.. 2020, 14 (5): 583-600.  https://doi.org/10.1007/s11684-019-0729-1
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Diabetes mellitus is one of the major public health problems worldwide. Considerable recent evidence suggests that the cellular reduction–oxidation (redox) imbalance leads to oxidative stress and subsequent occurrence and development of diabetes and related complications by regulating certain signaling pathways involved in β-cell dysfunction and insulin resistance. Reactive oxide species (ROS) can also directly oxidize certain proteins (defined as redox modification) involved in the diabetes process. There are a number of potential problems in the clinical application of antioxidant therapies including poor solubility, storage instability and non-selectivity of antioxidants. Novel antioxidant delivery systems may overcome pharmacokinetic and stability problem and improve the selectivity of scavenging ROS. We have therefore focused on the role of oxidative stress and antioxidative therapies in the pathogenesis of diabetes mellitus. Precise therapeutic interventions against ROS and downstream targets are now possible and provide important new insights into the treatment of diabetes.

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RESEARCH ARTICLE
Use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in context of COVID-19 outbreak: a retrospective analysis
Jiuyang Xu, Chaolin Huang, Guohui Fan, Zhibo Liu, Lianhan Shang, Fei Zhou, Yeming Wang, Jiapei Yu, Luning Yang, Ke Xie, Zhisheng Huang, Lixue Huang, Xiaoying Gu, Hui Li, Yi Zhang, Yimin Wang, Frederick G. Hayden, Peter W. Horby, Bin Cao, Chen Wang
Front. Med.. 2020, 14 (5): 601-612.  https://doi.org/10.1007/s11684-020-0800-y
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The possible effects of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) on COVID-19 disease severity have generated considerable debate. We performed a single-center, retrospective analysis of hospitalized adult COVID-19 patients in Wuhan, China, who had definite clinical outcome (dead or discharged) by February 15, 2020. Patients on anti-hypertensive treatment with or without ACEI/ARB were compared on their clinical characteristics and outcomes. The medical records from 702 patients were screened. Among the 101 patients with a history of hypertension and taking at least one anti-hypertensive medication, 40 patients were receiving ACEI/ARB as part of their regimen, and 61 patients were on anti-hypertensive medication other than ACEI/ARB. We observed no statistically significant differences in percentages of in-hospital mortality (28% vs. 34%, P=0.46), ICU admission (20% vs. 28%, P=0.37) or invasive mechanical ventilation (18% vs. 26%, P=0.31) between patients with or without ACEI/ARB treatment. Further multivariable adjustment of age and gender did not provide evidence for a significant association between ACEI/ARB treatment and severe COVID-19 outcomes. Our findings confirm the lack of an association between chronic receipt of renin-angiotensin system antagonists and severe outcomes of COVID-19. Patients should continue previous anti-hypertensive therapy until further evidence is available.

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Estimation of reproduction numbers of COVID-19 in typical countries and epidemic trends under different prevention and control scenarios
Chen Xu, Yinqiao Dong, Xiaoyue Yu, Huwen Wang, Lhakpa Tsamlag, Shuxian Zhang, Ruijie Chang, Zezhou Wang, Yuelin Yu, Rusi Long, Ying Wang, Gang Xu, Tian Shen, Suping Wang, Xinxin Zhang, Hui Wang, Yong Cai
Front. Med.. 2020, 14 (5): 613-622.  https://doi.org/10.1007/s11684-020-0787-4
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The coronavirus disease 2019 (COVID-19) has become a life-threatening pandemic. The epidemic trends in different countries vary considerably due to different policy-making and resources mobilization. We calculated basic reproduction number (R0) and the time-varying estimate of the effective reproductive number (Rt) of COVID-19 by using the maximum likelihood method and the sequential Bayesian method, respectively. European and North American countries possessed higher R0 and unsteady Rt fluctuations, whereas some heavily affected Asian countries showed relatively low R0 and declining Rt now. The numbers of patients in Africa and Latin America are still low, but the potential risk of huge outbreaks cannot be ignored. Three scenarios were then simulated, generating distinct outcomes by using SEIR (susceptible, exposed, infectious, and removed) model. First, evidence-based prompt responses yield lower transmission rate followed by decreasing Rt. Second, implementation of effective control policies at a relatively late stage, in spite of huge casualties at early phase, can still achieve containment and mitigation. Third, wisely taking advantage of the time-window for developing countries in Africa and Latin America to adopt adequate measures can save more people’s life. Our mathematical modeling provides evidence for international communities to develop sound design of containment and mitigation policies for COVID-19.

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Linking key intervention timings to rapid declining effective reproduction number to quantify lessons against COVID-19
Zhihang Peng, Wenyu Song, Zhongxing Ding, Quanquan Guan, Xu Yang, Qiaoqiao Xu, Xu Wang, Yankai Xia
Front. Med.. 2020, 14 (5): 623-629.  https://doi.org/10.1007/s11684-020-0788-3
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Coronavirus disease 2019 (COVID-19) is currently under a global pandemic trend. The efficiency of containment measures and epidemic tendency of typical countries should be assessed. In this study, the efficiency of prevention and control measures in China, Italy, Iran, South Korea, and Japan was assessed, and the COVID-19 epidemic tendency among these countries was compared. Results showed that the effective reproduction number(Re) in Wuhan, China increased almost exponentially, reaching a maximum of 3.98 before a lockdown and rapidly decreased to below 1 due to containment and mitigation strategies of the Chinese government. The Re in Italy declined at a slower pace than that in China after the implementation of prevention and control measures. The Re in Iran showed a certain decline after the establishment of a national epidemic control command, and an evident stationary phase occurred because the best window period for the prevention and control of the epidemic was missed. The epidemic in Japan and South Korea reoccurred several times with the Re fluctuating greatly. The epidemic has hardly rebounded in China due to the implementation of prevention and control strategies and the effective enforcement of policies. Other countries suffering from the epidemic could learn from the Chinese experience in containing COVID-19.

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Machine learning for detecting mesial temporal lobe epilepsy by structural and functional neuroimaging
Baiwan Zhou, Dongmei An, Fenglai Xiao, Running Niu, Wenbin Li, Wei Li, Xin Tong, Graham J Kemp, Dong Zhou, Qiyong Gong, Du Lei
Front. Med.. 2020, 14 (5): 630-641.  https://doi.org/10.1007/s11684-019-0718-4
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Mesial temporal lobe epilepsy (mTLE), the most common type of focal epilepsy, is associated with functional and structural brain alterations. Machine learning (ML) techniques have been successfully used in discriminating mTLE from healthy controls. However, either functional or structural neuroimaging data are mostly used separately as input, and the opportunity to combine both has not been exploited yet. We conducted a multimodal ML study based on functional and structural neuroimaging measures. We enrolled 37 patients with left mTLE, 37 patients with right mTLE, and 74 healthy controls and trained a support vector ML model to distinguish them by using each measure and the combinations of the measures. For each single measure, we obtained a mean accuracy of 74% and 69% for discriminating left mTLE and right mTLE from controls, respectively, and 64% when all patients were combined. We achieved an accuracy of 78% by integrating functional data and 79% by integrating structural data for left mTLE, and the highest accuracy of 84% was obtained when all functional and structural measures were combined. These findings suggest that combining multimodal measures within a single model is a promising direction for improving the classification of individual patients with mTLE.

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Correlation between serum miR-154-5p and urinary albumin excretion rates in patients with type 2 diabetes mellitus: a cross-sectional cohort study
Huiwen Ren, Can Wu, Ying Shao, Shuang Liu, Yang Zhou, Qiuyue Wang
Front. Med.. 2020, 14 (5): 642-650.  https://doi.org/10.1007/s11684-019-0719-3
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This study aimed to investigate the correlation between serum miR-154-5p and urinary albumin to creatinine ratio (UACR) in patients with type 2 diabetes mellitus (T2DM) and the association with biomarkers of inflammation and fibrosis in diabetic kidney disease (DKD). A total of 390 patients with T2DM were divided into three groups: normal albuminuria (UACR<30 mg/g, n=136, NA), microalbuminuria (UACR at 30–300 mg/g, n=132, MA), and clinical albuminuria (UACR>300 mg/g, n=122, CA). Circulating miR-154-5p, inflammatory (C-reactive protein (CRP); erythrocyte sedimentation rate (ESR); and tumor necrosis factor-α (TNF-α) and fibrotic markers (vascular endothelial growth factor (VEGF); transforming growth factor-β1 (TGF-β1); and fibronectin (FN)), and other biochemical indicators were assessed via real-time PCR, enzyme-linked immunosorbent assay, and chemiluminescence assay in patients with T2DM and 138 control subjects (NC). UACR, miR-154-5p, glycated hemoglobin (HbA1c), serum creatinine (sCr), blood urea nitrogen (BUN), ESR, CRP, VEGF, TNF-α, TGF-β1, and FN were significantly higher and the estimated glomerular filtration rate (eGFR) was significantly lower in NA, MA, and CA groups than in NC subjects (P<0.05). Elevated levels of UACR and miR-154-5p were directly correlated with HbA1c, sCr, BUN, ESR, CRP, VEGF, TNF-α, TGF-β1, and FN and negatively correlated with eGFR (P<0.05). miR-154-5p, HbA1c, sCr, BUN, eGFR, ESR, CRP, VEGF, TNF-α, TGF-β1, and FN were important factors affecting UACR. These findings indicated that elevated serum miR-154-5p is significantly correlated with high UACR in patients with T2DM and may offer a novel reference for the early diagnosis of DKD.

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High-throughput metabolomics reveals the perturbed metabolic pathways and biomarkers of Yang Huang syndrome as potential targets for evaluating the therapeutic effects and mechanism of geniposide
Heng Fang, Aihua Zhang, Xiaohang Zhou, Jingbo Yu, Qi Song, Xijun Wang
Front. Med.. 2020, 14 (5): 651-663.  https://doi.org/10.1007/s11684-019-0709-5
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High-throughput metabolomics can clarify the underlying molecular mechanism of diseases via the qualitative and quantitative analysis of metabolites. This study used the established Yang Huang syndrome (YHS) mouse model to evaluate the efficacy of geniposide (GEN). Urine metabolic data were quantified by ultra-performance liquid chromatography–tandem mass spectrometry. The non-target screening of the massive biological information dataset was performed, and a total of 33 metabolites, including tyramine glucuronide, aurine, and L-cysteine, were identified relating to YHS. These differential metabolites directly participated in the disturbance of phase I reaction and hydrophilic transformation of bilirubin. Interestingly, they were completely reversed by GEN. While, as the auxiliary technical means, we also focused on the molecular prediction and docking results in network pharmacological and integrated analysis part. We used integrated analysis to communicate the multiple results of metabolomics and network pharmacology. This study is the first to report that GEN indirectly regulates the metabolite “tyramine glucuronide” through its direct effect on the target heme oxygenase 1 in vivo. Meanwhile, heme oxygenase-1, a prediction of network pharmacology, was the confirmed metabolic enzyme of phase I reaction in hepatocytes. Our study indicated that the combination of high-throughput metabolomics and network pharmacology is a robust combination for deciphering the pathogenesis of the traditional Chinese medicine (TCM) syndrome.

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LETTER TO FRONTIERS OF MEDICINE
Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19
Lingling Tang, Yingan Jiang, Mengfei Zhu, Lijun Chen, Xiaoyang Zhou, Chenliang Zhou, Peng Ye, Xiaobei Chen, Baohong Wang, Zhenyu Xu, Qiang Zhang, Xiaowei Xu, Hainv Gao, Xiaojun Wu, Dong Li, Wanli Jiang, Jingjing Qu, Charlie Xiang, Lanjuan Li
Front. Med.. 2020, 14 (5): 664-673.  https://doi.org/10.1007/s11684-020-0810-9
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The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was identified in December 2019. The symptoms include fever, cough, dyspnea, early symptom of sputum, and acute respiratory distress syndrome (ARDS). Mesenchymal stem cell (MSC) therapy is the immediate treatment used for patients with severe cases of COVID-19. Herein, we describe two confirmed cases of COVID-19 in Wuhan to explore the role of MSC in the treatment of COVID-19. MSC transplantation increases the immune indicators (including CD4 and lymphocytes) and decreases the inflammation indicators (interleukin-6 and C-reactive protein). High-flow nasal cannula can be used as an initial support strategy for patients with ARDS. With MSC transplantation, the fraction of inspired O2 (FiO2) of the two patients gradually decreased while the oxygen saturation (SaO2) and partial pressure of oxygen (PO2) improved. Additionally, the patients’ chest computed tomography showed that bilateral lung exudate lesions were adsorbed after MSC infusion. Results indicated that MSC transplantation provides clinical data on the treatment of COVID-19 and may serve as an alternative method for treating COVID-19, particularly in patients with ARDS.

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CASE REPORT
Successful management of seven cases of critical COVID-19 with early noninvasive–invasive sequential ventilation algorithm and bundle pharmacotherapy
Mian Peng, Xueyan Liu, Jinxiu Li, Di Ren, Yongfeng Liu, Xi Meng, Yansi Lyu, Ronglin Chen, Baojun Yu, Weixiong Zhong
Front. Med.. 2020, 14 (5): 674-680.  https://doi.org/10.1007/s11684-020-0796-3
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We report the clinical and laboratory findings and successful management of seven patients with critical coronavirus disease 2019 (COVID-19) requiring mechanical ventilation (MV). The patients were diagnosed based on epidemiological history, clinical manifestations, and nucleic acid testing. Upon diagnosis with COVID-19 of critical severity, the patients were admitted to the intensive care unit, where they received early noninvasive–invasive sequential ventilation, early prone positioning, and bundle pharmacotherapy regimen, which consists of antiviral, anti-inflammation, immune-enhancing, and complication-prophylaxis medicines. The patients presented fever (n = 7, 100%), dry cough (n = 3, 42.9%), weakness (n = 2, 28.6%), chest tightness (n = 1, 14.3%), and/or muscle pain (n = 1, 14.3%). All patients had normal or lower than normal white blood cell count/lymphocyte count, and chest computed tomography scans showed bilateral patchy shadows or ground glass opacity in the lungs. Nucleic acid testing confirmed COVID-19 in all seven patients. The median MV duration and intensive care unit stay were 9.9 days (interquartile range, 6.5–14.6 days; range, 5–17 days) and 12.9 days (interquartile range, 9.7–17.6 days; range, 7–19 days), respectively. All seven patients were extubated, weaned off MV, transferred to the common ward, and discharged as of the writing of this report. Thus, we concluded that good outcomes for patients with critical COVID-19 can be achieved with early noninvasive–invasive sequential ventilation and bundle pharmacotherapy.

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COMMENTARY
The role played by traditional Chinese medicine in preventing and treating COVID-19 in China
Qingwei Li, Han Wang, Xiuyang Li, Yujiao Zheng, Yu Wei, Pei Zhang, Qiyou Ding, Jiaran Lin, Shuang Tang, Yikun Zhao, Linhua Zhao, Xiaolin Tong
Front. Med.. 2020, 14 (5): 681-688.  https://doi.org/10.1007/s11684-020-0801-x
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Traditional Chinese medicine (TCM), an ancient system of alternative medicine, played an active role in the prevention and control of COVID-19 in China. It improved the clinical symptoms of patients, reduced the mortality rate, improved the recovery rate, and effectively relieved the operating pressure on the national medical system during critical conditions. In light of the current global pandemic, TCM-related measures might open up a new channel in the control of COVID-19 in other countries and regions. Here, we summarize the TCM-related measures that were widely used in China, including TCM guidelines, the Wuchang pattern, mobile cabin hospitals, integrated treatment of TCM and modern medicine for critical patients, and non-medicine therapy for convalescent patients, and describe how TCM effectively treated patients afflicted with the COVID-19. Effective TCM therapies could, therefore, be recommended and practiced based on the existing medical evidence from increased scientific studies.

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