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      Vol. 28 ， Issue 7 ， 2022

        Original Article

      • Bo DENG,Li-qun JIA,Dong-gui WAN,Bao-yi WANG,Zhi-qiang CHENG,Chao DENG
        Vol. 28, Issue 7, Pages: 579-585(2022) DOI: 10.1007/s11655-022-3575-y
        Abstract：Objective:To evaluate the efficacy of Wen-Luo-Tong Granules (WLT) local administration in the treatment of patients with peripheral neuropathy (PN) induced by chemotherapy or target therapy.Methods:This study is a randomized, double-blinded, and placebo-controlled trial. Seventy-eight patients with PN induced by chemotherapy or target therapy were enrolled from China-Japan Friendship Hospital between July 2019 and January 2020. They were randomly assigned to WLT (39 cases) and control groups (39 cases) using a block randomization method. The WLT group received WLT (hand and foot bath) plus oral Mecobalamin for 1 week, while the control group received placebo plus oral Mecobalamin. The primary endpoint was PN grade evaluated by the National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE). The secondary endpoints included quantitative touch-detection threshold, neuropathy symptoms, Quality of Life Questionnaire- Chemotherapy Induced Peripheral Neuropathy (QLQ-CIPN20), and Quality of Life Questionnaire-Core30 (QLQ-C30).Results:After treatment, the PN grade in the WLT group was significantly lower than that in the control group (1.00±0.29 vs. 1.75±0.68, P<0.01). The total effective rate in the WLT group was significantly higher than that in the control group (82.05% vs. 51.28%, P<0.01). Compared with the control group, the touchdetection thresholds at fingertips, neuropathy symptom score, QLQ-CIPN 20 (sensory scale, motor scale, autonomic scale, and sum score), and QLQ-C30 (physical functioning, role functioning, emotional functioning, and global health) in the WLT group significantly improved after treatment (P<0.01 or P<0.05).Conclusion:WLT local administration was significantly effective in the treatment of patients with PN induced by chemotherapy or target therapy. (Trial registration No. ChiCTR1900023862)  
        Keywords：peripheral neuropathy;chemotherapy;target therapy;Chinese medicine;Wen-Luo-Tong;randomized controlled trial   
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        Published：2022-06-27
      • Bing JIANG,Ruo-ming WU,Hai-dong LI,Kun LI,Hui LI,Wen-zhen DANG,Gui-ze FENG,Wei-lian BAO,Guan YE,Xiao-yan SHEN
        Vol. 28, Issue 7, Pages: 586-593(2022) DOI: 10.1007/s11655-022-3570-3
        Abstract：Objective:To investigate the therapeutic effect of Yixin Ningshen Tablet (YXNS) on comorbidity of myocardial infarction (MI) and depression in rats and explore the underlying mechanism.Methods:The Sprague-Dawley rats were randomly divided into 5 groups with 7 rats in each group according to their weights, including control, model, fluoxetine (FLXT, 10 mg/kg), low-dose YXNS (LYXNS, 100 mg/kg), and high-dose YXNS (HYXNS, 300 mg/kg) groups. All rats were pretreated with corresponding drugs for 12 weeks. The rat model of MI and depression was constructed by ligation of left anterior descending coronary artery and chronic mild stress stimulation. The echocardiography, sucrose preference test, open field test, and forced swim test were performed. Myocardial infarction (MI) area and myocardial apoptosis was also detected. Serum levels of interleukin (IL)-6, IL-1β, tumor necrosis factor-α (TNF-α), 5-hydroxytryptamine (5-HT), adrenocorticotrophic hormone (ACTH), corticosterone (CORT), and norepinephrine (NE) were determined by enzyme linked immunosorbent assay. The proteins of adenosine 5'-monophosphate -activated protein kinase (AMPK), p-AMPK, peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and nuclear respiratory factor 1 (NRF1) in heart were detected by Western blot analysis. The expression levels of TNF-α, IL-6, indoleamine 2,3-dioxygenase (IDO1), kynurenine 3-monooxygenase (KMO), and kynureninase (KYNU) in hippocampus were detected by real-time quantitative polymerase chain reaction.Results:Compared with the model group, the cardiac function of rats treated with YXNS significantly improved (P<0.01). Meanwhile, YXNS effectively reduced MI size and cardiomyocytes apoptosis of rats (P<0.01 or P<0.05), promoted AMPK phosphorylation, and increased PGC-1α protein expression (P<0.01 or P<0.05). HYXNS significantly increased locomotor activity of rats, decreased the levels of TNF-α, IL-6 and IL-1β, and increased the serum levels of 5-HT, NE, ACTH, and CORT (all P<0.05). Moreover, HYXNS decreased the mRNA expressions of IDO1, KMO and KYNU (P<0.05).Conclusions:YXNS can relieve MI by enhancing myocardial energy metabolism. Meanwhile, YXNS can alleviate depression by resisting inflammation and increasing availability of monoamine neurotransmitters. It may be used as a potential drug to treat comorbidity of MI and depression.  
        Keywords：Yixin Ningshen Tablet;depression;cardiovascular disorders;inflammatory factor;monoamine neurotransmitter;kynurenine pathway;Chinese medicine   
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        Published：2022-06-27
      • Song CHEN,Yi-hang DING,Song-sheng SHI,Xian-kun TU
        Vol. 28, Issue 7, Pages: 594-602(2022) DOI: 10.1007/s11655-021-3348-z
        Abstract：Objective:To determine whether Schisandrin B (Sch B) attenuates early brain injury (EBI) in rats with subarachnoid hemorrhage (SAH).Methods:Sprague-Dawley rats were divided into sham (sham operation), SAH, SAH+vehicle, and SAH+Sch B groups using a random number table. Rats underwent SAH by endovascular perforation and received Sch B (100 mg/kg) or normal saline after 2 and 12 h of SAH. SAH grading, neurological scores, brain water content, Evan's blue extravasation, and terminal transferase-mediated dUTP nick end-labeling (TUNEL) staining were carried out 24 h after SAH. Immunofluorescent staining was performed to detect the expressions of ionized calcium binding adapter molecule 1 (Iba-1) and myeloperoxidase (MPO) in the rat brain, while the expressions of B-cell lymphoma 2 (Bcl-2), Bax, Caspase-3, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated specklike protein containing the caspase-1 activator domain (ASC), Caspase-1, interleukin (IL)-1β, and IL-18 in the rat brains were detected by Western blot.Results:Compared with the SAH group, Sch B significantly improved the neurological function, reduced brain water content, Evan's blue content, and apoptotic cells number in the brain of rats (P<0.05 or P<0.01). Moreover, Sch B decreased SAH-induced expressions of Iba-1 and MPO (P<0.01). SAH caused the elevated expressions of Bax, Caspase-3, NLRP3, ASC, Caspase-1, IL-1β, and IL-18 in the rat brain (P<0.01), all of which were inhibited by Sch B (P<0.01). In addition, Sch B increased the Bcl-2 expression (P<0.01).Conclusion:Sch B attenuated SAH-induced EBI, which might be associated with the inhibition of neuroinflammation, neuronal apoptosis, and the NLRP3 inflammatory signaling pathway.  
        Keywords：schisandrin B;subarachnoid hemorrhage;early brain injury;inflammation;neuronal apoptosis;nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3;Chinese medicine   
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        Published：2022-06-27
      • Yan YANG,Fei-lin GE,Xiao-yan ZHAN,Wen-qing MU,Zhi-yong LI,Li LIN,Zi-ying WEI,Zhao-fang BAI,SUN Qin,Xiao-he XIAO
        Vol. 28, Issue 7, Pages: 603-611(2022) DOI: 10.1007/s11655-022-3574-z
        Abstract：Objective:To investigate the protective effects of Schisandra chinensis oil (SCEO) against aristolochic acid Ⅰ (AAⅠ)-induced nephrotoxicity in vivo and in vitro and elucidate the underlying mechanism.Methods:C57BL/6 mice were randomly divided into 5 groups according to a random number table, including control group, AAⅠ group, and AAⅠ+SCEO (0.25, 0.5 and 1 g/kg) groups (n=5 per group). Pretreatment with SCEO was done for 2 days by oral administration, while the control and AAⅠ groups were treated with sodium carboxymethyl cellulose. Mice of all groups except for the control group were injected intraperitoneally with AAⅠ (5 mg/kg) from day 3 until day 7. Histopathological examination and apoptosis of kidney tissue were observed by hematoxylin and eosin and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and serum creatinine (SCr), as well as renal malondialdehyde (MDA), glutathione, r-glutamyl cysteingl+glycine (GSH), and superoxide dismutase (SOD) were analyzed using enzyme-linked immunosorbent assay (ELISA). Expressions of hepatic cytochrome P450 1A1 (CYP1A1), CYP1A2, and nad(p)hquinonedehydrogenase1 (NQO1) were analyzed using ELISA, quantitative real-time polymerase chain reaction (qPCR) and Western blot, respectively. In vitro, SCEO (40 μg/mL) was added 12 h before treatment with AAⅠ (40 μmol/mL for 48 h) in human renal proximal tubule cell line (HK-2), then apoptosis and reactive oxygen species (ROS) were analyzed by flow cytometry.Results:SCEO 0.5 and 1 g/kg ameliorated histopathological changes and TUNEL+ staining in the kidney tissues of mice with AAⅠ-induced nephrotoxicity, and reduced serum levels of ALT, AST, BUN and SCr (P<0.01 or P<0.05). SCEO 0.5 and 1 g/kg alleviated the ROS generation in kidney, containing MDA, GSH and SOD (P<0.01 or P<0.05). SCEO 1 g/kg increased the expressions of CYP1A1 and CYP1A2 and decreased NQO1 level in the liver tissues (P<0.01 or P<0.05). Besides, in vitro studies also demonstrated that SCEO 40 μg/mL inhibited apoptosis and ROS generation (P<0.05 or P<0.01).Conclusions:SCEO can alleviate AAⅠ-induced kidney damage both in vivo and in vitro. The protective mechanism may be closely related to the regulation of metabolic enzymes, thereby inhibiting apoptosis and ROS production.  
        Keywords：aristolochic acid Ⅰ;nephrotoxicity;Schisandra chinensis oil;metabolic enzymes;apoptosis;reactive oxygen species   
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        Published：2022-06-27
      • Zhi-wen ZENG,Jin-quan HUANG,Yong CHEN,Xiao YU,Wei ZHU,Dong-shu ZHANG
        Vol. 28, Issue 7, Pages: 612-619(2022) DOI: 10.1007/s11655-022-3579-7
        Abstract：Objective:To evaluate the therapeutic effects of acupoint autohemotherapy (A-AHT) on 1-chloro- 2,4-dinitrobenzene (DNCB)-induced atopic dermatitis (AD) in mice focusing on regulating T helper 1/T helper 2 (Th1/Th2) immune responses.Methods:Thirty BALB/c mice were divided into 5 groups by a random number table, including normal control (NC), AD model (AD), A-AHT, sham A-AHT (sA-AHT), and acupoint injection of normal saline (A-NS) groups, 6 mice per group. Mice were challenged by DNCB for the establishment of experimental AD model. On the 8th day, except for the NC and AD groups, the mice in the other groups received management once every other day for a total of 28 days. For the A-AHT and sA-AHT groups, 0.05 mL of autologous whole blood (AWB) was injected into bilateral Zusanli (ST 36) and Quchi (LI 11) and sham-acupoints (5 mm lateral to ST 36 and LI 11), respectively. The A-NS group was administrated with 0.05 mL of normal saline by acupoint injection into ST 36 and LI 11. Dermatitis severity for dorsal skin of mice was determined using the Severity Scoring of Atopic Dermatitis (SCORAD) every week. The total immunoglobulin E (IgE), interleukin-4 (IL-4), and interferon-gamma (IFN-γ) cytokine levels in serum were examined by enzyme-linked immunosorbent assay (ELISA). Spleen Th1/Th2 expression were analyzed via flow cytometry and immunohistochemical assay was used to detect T-box expressed in T cell (T-bet) and GATA-binding protein 3 (GATA3) expressions in skin lesions of mice.Results:Compared with the AD group, both A-AHT and sA-AHT reduced the SCORAD index and serum IgE level (P<0.05 or P<0.01); A-AHT, sA-AHT and A-NS down-regulated serum IL-4 level and upregulated IFN-γ/IL-4 ratio (P<0.05 or P<0.01); A-AHT regulated the Th1/Th2 shift specifically and increased the related transcription factors such as T-bet expression and T-bet/GATA3 ratio (P<0.05).Conclusion:A-AHT showed significant effectiveness on the AD model mice, through regulating Th1/Th2 immune responses.  
        Keywords：acupoint autohemotherapy;atopic dermatitis;Th1/Th2;immunoglobulin E   
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        Published：2022-06-27
      • Lan YIN,Si-jun FAN,Mao-nian ZHANG
        Vol. 28, Issue 7, Pages: 620-626(2022) DOI: 10.1007/s11655-021-3527-y
        Abstract：Objective:To study the protective effect of anthocyanins extracted from Vaccinium Uliginosum (VU) on retinal 661W cells against microwave radiation induced retinal injury.Methods:661W cells were divided into 6 groups, including control, model [661W cells radiated by microwave (30 mW/cm2, 1 h)] and VU groups [661W cells pretreated with anthocyanins extracted from VU (25, 50, 100 and 200 μg/mL, respectively) for 48 h, and radiated by microwave 30 mW/cm2, 1 h]. After treatment with different interventions, the cell apoptosis index (AI) was determined using Heochst staining; contents of malonaldehyde (MDA), glutataione (GSH), and activity of superoxide dismutase (SOD) were measured. mRNA expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1(HO-1) were detected by real time quantitative polymerase chain reaction, and the expression of HO-1 protein was examined by Western blot analysis. Nucleus and cytoplasm were separated and Nrf2 protein expression was further verified by Western blot analysis.Results:There was significant difference in AI among the groups (F=322.83, P<0.05). Compared with the control group, AI was significantly higher in the model group and was lower in 4 VU-pretreated groups (P<0.05). Linear regression analysis showed the decline of AI was in a dose-dependent manner with VU treatment (r=0.8419, P<0.05). The MDA and GSH contents of 661W cells in VU-treated groups were significantly lower than the model group (P<0.05). Compared with the model group, the SOD activity in the VU-treated groups (50, 100 and 200 μg/mL) was significantly higher (all P<0.05). The Nrf2 and HO-1 mRNA expressions were slightly increased after irradiation, and obviously increased in 100 μg/mL VU-treated group. After irradiation, the relative expressions of HO-1 and Nrf2 proteins in nucleus were slightly increased (P<0.05), and the changes in cytoplasm were not obvious, whereas it was significantly increased in both nucleus and cytoplasm in the VU treatment groups.Conclusions:Anthocyanins extracted from VU could reduce apoptosis, stabilize cell membrane, and alleviate oxidant injury of mouse retinal photoreceptor 661W cells. The mechanism might be through activating Nrf2/HO-1 signal pathway and inducing HO-1 transcription and translation.  
        Keywords：Vaccinium Uliginosum;anthocyaninsm;photoreceptor;microwave;apoptosis;nuclear factor erythroid 2-related factor 2/heme oxygenase 1   
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        Published：2022-06-27
      • Shan-shan WANG,Xian ZENG,Ya-li WANG,Dongzhi Zhuoma,Yu-fen ZHAO,Yu-zong CHEN
        Vol. 28, Issue 7, Pages: 627-643(2022) DOI: 10.1007/s11655-022-3573-0
        Abstract：Objective:To investigate how the National Health Commission of China (NHCC)-recommended Chinese medicines (CMs) modulate the major maladjustments of coronavirus disease 2019 (COVID-19), particularly the clinically observed complications and comorbidities.Methods:By focusing on the potent targets in common with the conventional medicines, we investigated the mechanisms of 11 NHCC-recommended CMs in the modulation of the major COVID-19 pathophysiology (hyperinflammations, viral replication), complications (pain, headache) and comorbidities (hypertension, obesity, diabetes). The constituent herbs of these CMs and their chemical ingredients were from the Traditional Chinese Medicine Information Database. The experimentally-determined targets and the activity values of the chemical ingredients of these CMs were from the Natural Product Activity and Species Source Database. The approved and clinical trial drugs against these targets were searched from the Therapeutic Target Database and DrugBank Database. Pathways of the targets was obtained from Kyoto Encyclopedia of Genes and Genomes and additional literature search.Results:Overall, 9 CMs modulated 6 targets discovered by the COVID-19 target discovery studies, 8 and 11 CMs modulated 8 and 6 targets of the approved or clinical trial drugs for the treatment of the major COVID-19 complications and comorbidities, respectively.Conclusion:The coordinated actions of each NHCC-recommended CM against a few targets of the major COVID-19 pathophysiology, complications and comorbidities, partly have common mechanisms with the conventional medicines.  
        Keywords：Covid-19;Chinese medicine;target;therapeutic mechanism;pathophysiology;comorbidity   
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        Published：2022-06-27
      • Zhen ZHANG,Jun-wei LI,Pu-hua ZENG,Wen-hui GAO,Xue-fei TIAN
        Vol. 28, Issue 7, Pages: 636-643(2022) DOI: 10.1007/s11655-021-3449-8
        Abstract：Objective:To identify specific Chinese medicines (CM) that may benefit patients with primary liver cancer (PLC), and to explore the mechanism of action of these medicines.Methods:In this retrospective, singlecenter study, prescription information from PLC patients was used in combination with Traditional Chinese Medicine Inheritance Supports System to identify the specific core drugs. A system pharmacology approach was employed to explore the mechanism of action of these medicines.Results:Taking CM more than 6 months was significantly associated with improved survival outcomes. In total, 77 putative targets and 116 bioactive ingredients of the core drugs were identified and included in the analysis (P<0.05). A total of 1,036 gene ontology terms were found to be enriched in PLC. A total of 75 pathways identified from Kyoto Encyclopedia of Genes and Genomes were also enriched in this disease, including fluid shear stress, interleukin-17 signaling, signaling between advanced glycan end products and their receptors, cellular senescence, tumor necrosis factor signaling, p53 signaling, cell cycle signaling, steroid hormone biosynthesis, T-helper 17 cell differentiation, and metabolism of xenobiotics by cytochrome. Docking studies suggested that the ingredients in the core drugs exert therapeutic effects in PLC by modulating c-Jun and interleukin-6.Conclusions:Receiving CM for 6 months or more improves survival for the patients with PLC. The core drugs that really benefit for PLC patients likely regulates the tumor microenvironment and tumor itself.  
        Keywords：Chinese medicine;primary liver cancer;system pharmacology;bioinformatics;tumor microenvironment   
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        Published：2022-06-27

        Case Report

      • Zong-jing FAN,Jin-min LIU,Xing-xing LI,Jie CUI,Bin GUO,Quan LIN,Rui ZHUANG,Zheng-bo WU,WU Yang
        Vol. 28, Issue 7, Pages: 644-649(2022) DOI: 10.1007/s11655-021-3312-y
        Abstract：甘草酸苷可引起假性醛固酮增多症 (pseudohyperaldosteronism, PsHA), 这归因于其对皮质醇代谢的影响. 在此, 我们报告了一例服用复方甘草酸苷片的病例, 重点介绍了甘草酸苷诱导PsHA的表现、病理生理学和治疗. 据我们所知, 虽然已有数起因甘草酸苷过量引起PsHA的病例报告, 但据我们所知, 这是首例发生在原发性高血压患者中的报告病例, 它是由甘草酸苷和噻嗪类利尿剂联用引起的. 本文还强调了详细病史询问的重要性.  
          
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        Published：2022-06-27

        Evidence-Based Integrative Medicine

      • Xiao-hu SUN,Shuo ZHANG,Zhen YANG,Zhen-lin CHEN,Shi-jun YUE,Sai ZHANG,Yu-ping TANG
        Vol. 28, Issue 7, Pages: 650-660(2022) DOI: 10.1007/s11655-022-3578-8
        Abstract：Background:Corona virus disease 2019 (COVID-19) has spread around the world since its outbreak, and there is no ascertained effective drug up to now. Lianhua Qingwen (LHQW) has been widely used in China and overseas Chinese, which had some advantages in the treatment of COVID-19.Objective:To evaluate the efficacy and safety of LHQW for COVID-19 by conducting a systematic review with meta-analysis.Methods:A comprehensive literature search was conducted in 12 electronic databases from their establishment to October 30, 2021. Note Express 3.2.0 was used for screening of trials, and the data was independently extracted in duplicate by 2 researchers. The risk of bias of randomized controlled trials (RCTs) and retrospective studies were assessed by using the Cochrane collaboration tool and Newcastle Ottawa Scale, respectively, followed by data analysis using RevMan 5.3. The RCTs or retrospective studies to treat COVID-19 using LHQW were included. The intervention measures in the experimental group were LHQW alone or combined with chemical drugs (LCWC), and that in the control group were chemical drugs (CDs). Outcome measures included computed tomography (CT) recovery rate, disappearance rates of primary (fever, cough, fatigue), respiratory, gastrointestinal and other symptoms, exacerbation rate and adverse reaction. Subgroup analysis was conducted according to whether LHQW was combined with CDs and the different treatment methods in the control group.Results:Nine trials with 1,152 participants with COVID-19 were included. The CT recovery rates of LHQW and LCWC were 1.36 and 1.32 times of CDs, respectively (P<0.05). Compared with CDs, LCWC remarkably increased the disappearance rates of fever, cough, fatigue, expectoration, shortness of breath, and muscle soreness (P<0.05). LHQW also obviously decreased the exacerbation rate, which was 0.45 times of CDs alone (P<0.05). There was no obvious difference between LCWC and CDs in adverse reaction (P>0.05).Conclusions:LHQW was more suitable for treating COVID-19 patients with obvious expectoration, shortness of breath and muscle soreness. LHQW had advantages in treating COVID-19 with no obvious exacerbation. (PROSPERO No. CRD42021235937)  
        Keywords：Lianhua Qingwen;Covid-19;2019-nCoV;systematic review;meta-analysis;Chinese medicine   
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        Published：2022-06-27

        Review

      • Yuan JIANG,Jin PEI,Yan ZHENG,Yu-jing MIAO,Bao-zhong DUAN,Lin-fang HUANG
        Vol. 28, Issue 7, Pages: 661-671(2022) DOI: 10.1007/s11655-021-3345-2
        Abstract：Cancer is one of the most devastating diseases worldwide and definitive therapeutics for treating cancer are not yet available despite extensive research efforts. The key challenges include limiting factors connected with traditional chemotherapeutics, primarily drug resistance, low response rates, and adverse side-effects. Therefore, there is a high demand for novel anti-cancer drugs that are both potent and safe for cancer prevention and treatment. Gallic acid (GA), a natural botanic phenolic compound, can mediate various therapeutic properties that are involved in anti-inflammation, anti-obesity, and anti-cancer activities. More recently, GA has been shown to exert anti-cancer activities via several biological pathways that include migration, metastasis, apoptosis, cell cycle arrest, angiogenesis, and oncogene expression. This review discusses two aspects, one is the anti-cancer potential of GA against different types of cancer and the underlying molecular mechanisms, the other is the bibliometric analysis of GA in cancer and tumor research. The results indicated that lung cancer, prostate cancer, stomach cancer, and colon adenocarcinoma may become a hot topic in further research. Overall, this review provides evidence that GA represents a promising novel, potent, and safe anti-cancer drug candidate for treating cancer.  
        Keywords：gallic acid;cancer;tumor;bibliometric;application   
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