Latest Issue
      Vol. 30 ， Issue 4 ， 2024

        Original Article

      • LAI Yuan-yuan,LIU Li-ying,WU Yong-na,HUANG Lei,ZHENG Xiao-yan,GAN Di,YU Si-yi,ZHONG Ying,LIANG Fan-rong,ZHOU Ying,YANG Jie
        Vol. 30, Issue 4, Pages: 291-298(2024) DOI: 10.1007/s11655-024-3758-9
        Abstract：Objective:To investigate the immediate effects of electro-acupuncture (EA) on endometrial blood flow among recurrent implantation failure (RIF) patients.Methods:Eighty RIF patients, enrolled from March 2022 to December 2022, were randomly allocated into either the EA group (40 cases) or the waiting-list (WL) group (40 cases) by using a random number table. The EA group underwent acupuncture at points of Shenting (GV 24), Baihui (GV 4), Benshen (GB 13), bilateral Zigong (EX-CA 1), Huangshu (KI 16), Sanyinjiao (SP 6) and Xuehai (SP10), and electric acupuncture apparatus was connected to EX-CA 1, KI 16, SP 6, and SP 10 with disperse-dense waves at 4/20 Hz frequencies for 30 min after transvaginal ultrasound, while the WL group received no intervention. The primary outcome measured was the endometrial volume blood flow. The secondary outcomes included the bilateral uterine artery index, endometrial volume, endometrial blood flow type, vascular distribution index (VIMV) for endometrial and ovary, clinical pregnancy rate, and embryo implantation rate.Results:In the EA group, there was a notable decrease in the bilateral pulsatility index and a significant improvement in the endometrial blood flow type post-EA (P <0.05). Both the endometrial blood flow type and VIMV for the endometrium and right ovary were markedly higher in the EA group compared to the WL group post-treatment (P <0.05). Conversely, no significant disparities were observed in vascular index, flow index, vascular blood flow index, uterine arterial blood flow indices, endometrial volume, clinical pregnancy rate and embryo implantation rate between the two groups after treatment (P >0.05). Besides, no adverse events related to EA were observed.Conclusions:EA can promptly ameliorate VIMV for the endometrial and right ovary, and endometrial blood flow type. Future randomized controlled trials are warranted to investigate the long-term effects of EA on blood flow of RIF patients and its implications for pregnancy outcomes. (Trial registration No. ChiCTR2200057377)  
        Keywords：electro-acupuncture;recurrent implantation failure;transvaginal ultrasound;endometrial receptivity analysis;randomized controlled trial   
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        Published：2024-03-22
      • LIU Xiao-rong,LI Shuo-fu,MEI Wen-ya,LIU Xiang-dan,ZHOU Ri-bao
        Vol. 30, Issue 4, Pages: 299-310(2024) DOI: 10.1007/s11655-023-3753-6
        Abstract：Objective:To investigate the effect of isorhamnetin on the pathology of rheumatoid arthritis (RA).Methods:Tumor necrosis factor (TNF)-α-induced fibroblast-like synoviocytes (FLS) was exposed to additional isorhamnetin (10, 20 and 40 μmol/L). Overexpression vectors for matrix metalloproteinase-2 (MMP2) or MMP9 or SRC were transfected to explore their roles in isorhamnetin-mediated RA-FLS function. RA-FLS viability, migration, and invasion were evaluated. Moreover, a collagen-induced arthritis (CIA) rat model was established. Rats were randomly divided to sham, CIA, low-, medium-, and high-dosage groups using a random number table (n=5 in each group) and administed with normal saline or additional isorhamnetin [2, 10, and 20 mg/(kg•day)] for 4 weeks, respectively. Arthritis index was calculated and synovial tissue inflammation was determined in CIA rats. The levels of MMP2, MMP9, TNF-α, interleukin-6 (IL-6), and IL-1β, as well as the phosphorylation levels of SRC, extracellular regulated kinase (ERK), and cyclic adenosine monophosphate response element-binding (CREB), were detected in RA-FLS and synovial tissue. Molecular docking was also used to analyze the binding of isorhamnetin to SRC.Results:In in vitro studies, isorhamnetin inhibited RA-FLS viability, migration and invasion (P <0.05). Isorhamnetin downregulated the levels of MMP2, MMP9, TNF-α, IL-6, and IL-1β in RA-FLS (P <0.05). The overexpression of either MMP2 or MMP9 reversed isorhamnetin-inhibited RA-FLS migration and invasion, as well as the levels of TNF-α, IL-6, and IL-1β (P <0.05). Furthermore, isorhamnetin bound to SRC and reduced the phosphorylation of SRC, ERK, and CREB (P <0.05). SRC overexpression reversed the inhibitory effect of isorhamnetin on RA-FLS viability, migration and invasion, as well as the negative regulation of MMP2 and MMP9 (P <0.05). In in vivo studies, isorhamnetin decreased arthritis index scores (P <0.05) and alleviated synovial inflammation. Isorhamnetin reduced the levels of MMP2, MMP9, TNF-α, IL-6, and IL-1β, as well as the phosphorylation of SRC, ERK, and CREB in synovial tissue (P <0.05). Notably, the inhibitory effect of isorhamnetin was more pronounced at higher concentrations (P <0.05).Conclusion:Isorhamnetin exhibited anti-RA effects through modulating SRC/ERK/CREB and MMP2/MMP9 signaling pathways, suggesting that isorhamnetin may be a potential therapeutic agent for RA.  
        Keywords：rheumatoid arthritis;isorhamnetin;SRC/ERK/CREB;matrix metalloproteinase   
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        Published：2024-03-22
      • Lea Ling-Yu Kan,Ben Chung-Lap Chan,Grace Gar-Lee Yue,LI Pei-ting,Sharon Sze-Man Hon,HUANG Dan-qi,Miranda Sin-Man Tsang,Clara Bik-San Lau,Ping-Chung Leung,Chun-Kwok Wong
        Vol. 30, Issue 4, Pages: 311-321(2024) DOI: 10.1007/s11655-023-3745-6
        Abstract：Objective:To investigate the in vivo immunomodulatory and anti-tumor mechanisms of the combined treatment of novel Four-Herb formula (4HF) and doxorubicin in triple-negative breast cancer (TNBC).Methods:Murine-derived triple-negative mammary carcinoma cell line, 4T1 cells, was cultured and inoculated into mouse mammary glands. Sixty-six mice were randomly assigned into 6 groups (n=11 in ench): naïve, control, LD 4HF (low dose 4HF), HD 4HF (high dose 4HF), LD 4HF + D (low dose and doxorubicin), and D (doxorubicin). Apart from the naïve group, each mouse received subcutaneous inoculation with 5×105 4T1 cells resuspended in 100 μL of normal saline in the mammary fat pads. Starting from the day of tumor cell inoculation, tumors were grown for 6 days. The LD and HD groups received daily oral gavage of 658 and 2,630 mg/kg 4HF, respectively. The LD 4HF+D group received daily oral gavage of 658 mg/kg 4HF and weekly intraperitoneal injection of doxorubicin (5 mg/kg). The D group received weekly intraperitoneal injections of doxorubicin (5 mg/kg). The treatment naïve mice received daily oral gavage of 0.2 mL double distilled water and 0.1 mL normal saline via intraperitoneal injection once a week. The control group received daily oral gavage of 0.2 mL double-distilled water. The treatment period was 30 days. At the end of treatment, mice organs were harvested to analyze immunological activities via immunophenotyping, gene and multiplex analysis, histological staining, and gut microbiota analysis.Results:Mice treated with the combination of 4HF and doxorubicin resulted in significantly reduced tumor and spleen burdens (P <0.05), altered the hypoxia and overall immune lymphocyte landscape, and manipulated gut microbiota to favor the anti-tumor immunological activities. Moreover, immunosuppressive genes, cytokines, and chemokines such as C-C motif chemokine 2 and interleukin-10 of tumors were significantly downregulated (P <0.05). 4HF-doxorubicin combination treatment demonstrated synergetic activities and was most effective in activating the anti-tumor immune response (P <0.05).Conclusion:The above results provide evidence for evaluating the immune regulating mechanisms of 4HF in breast cancer and support its clinical significance in its potential as an adjunctive therapeutic agent or immune supplement.  
        Keywords：adjunctive therapy;breast cancer;cytokines;Chinese medicine;tumor microenvironment   
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        Published：2024-03-22
      • QIN Jing-jing,NIU Meng-da,CHA Zhe,GENG Qing-hua,LI Yu-lin,REN Chun-guang,David P. Molloy,YU Hua-rong
        Vol. 30, Issue 4, Pages: 322-329(2024) DOI: 10.1007/s11655-023-3752-7
        Abstract：Objective:To investigate the mechanistic basis for the anti-proliferation and anti-invasion effect of tumor necrosis factor-related apoptosis-induced ligand (TRAIL) and celastrol combination treatment (TCCT) in glioblastoma cells.Methods:Cell counting kit-8 was used to detect the effects of different concentrations of celastrol (0–16 μmol/L) and TRAIL (0–500 ng/mL) on the cell viability of glioblastoma cells. U87 cells were randomly divided into 4 groups, namely control, TRAIL (TRAIL 100 ng/mL), Cel (celastrol 0.5 μmol/L) and TCCT (TRAIL 100 ng/mL + celastrol 0.5 μmol/L). Cell proliferation, migration, and invasion were detected by colony formation, wound healing, and Transwell assays, respectively. Quantitative reverse transcription polymerase chain reaction and Western blotting were performed to assess the levels of epithelial-mesenchymal transition (EMT) markers (zona occludens, N-cadherin, vimentin, zinc finger E-box-binding homeobox, Slug, and β-catenin). Wnt pathway was activated by lithium chloride (LiCl, 20 mol/L) and the mechanism for action of TCCT was explored.Results:Celastrol and TRAIL synergistically inhibited the proliferation, migration, invasion, and EMT of U87 cells (P <0.01). TCCT up-regulated the expression of GSK-3β and down-regulated the expression of β-catenin and its associated proteins (P <0.05 or P <0.01), including c-Myc, Cyclin-D1, and matrix metalloproteinase (MMP)-2. In addition, LiCl, an activator of the Wnt signaling pathway, restored the inhibitory effects of TCCT on the expression of β-catenin and its downstream genes, as well as the migration and invasion of glioblastoma cells (P <0.05 or P <0.01).Conclusions:Celastrol and TRAIL can synergistically suppress glioblastoma cell migration, invasion, and EMT, potentially through inhibition of Wnt/β-catenin pathway. This underlies a novel mechanism of action for TCCT as an effective therapy for glioblastoma.  
        Keywords：celastrol;Chinese medicine;tumor necrosis factor-related apoptosis-induced ligand;glioblastoma;β-catenin;Tripterygium wilfordii   
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        Published：2024-03-22
      • MA Jing,SUN Bo,TE Li-ger,HUANG Xin,ZUO Xin,HAN Xiao-ke,WANG Shu-song
        Vol. 30, Issue 4, Pages: 330-338(2024) DOI: 10.1007/s11655-023-3750-9
        Abstract：Objective:To determine the possible protective effects of Jinghuosu, a dietary supplement (DS), on tripterygium glycosides (TG)-induced reproductive system injury in rats and its underlying mechanisms.Methods:A reproductive damage model was established in rats by feeding of TGs. Twenty-eight male Sprague Dawley rats were randomly divided into 4 groups using a random number table (n=7 in each): control (C) group, model (M) group, DS group and L-carnitine (LC) group. Rats in M, DS and LC groups received 40 mg/kg TGs orally. Starting from the 5th week, after administration of TGs for 4 h every day, rats in DS and LC groups were administered with 2.7 g/kg DS and 0.21 g/kg LC, respectively, for protective treatment over the next 4 weeks. Rats in Group C continued to receive the control treatment. Hematoxylin-eosin staining was used for histopathological analysis of rat testicular tissues. Enzyme-linked immunosorbent assay was performed to measure alkaline phosphatase (ALP), lactate dehydrogenase, alcohol dehydrogenase, total antioxidant capacity (T-AOC), superoxide dismutase, glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) concentrations. Chemiluminescence assay was used to determine the serum testosterone content. Quantitative real-time PCR and Western blotting were conducted to analyze the expression of genes and proteins related to the testosterone synthesis pathway and the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 antioxidant pathway.Results:Oral administration of TGs induced significant increases in the testicular levels of zinc transporter 1 and MDA (P <0.05). On the other hand, sperm concentration, sperm motility, and serum testosterone, serum zinc, testicular zinc, Zrt-, Irt-like protein 1, ALP, luteinizing hormone (LH) receptor, steroidogenic acute regulatory protein, Cytochrome P450 family 11 subfamily A member 1, 3β-hydroxysteroid dehydrogenase1, T-AOC, GSH-Px, nuclear factor erythroid 2-related factor 2, heme oxygenase-1 and NAD (P)H: quinone oxidoreductase 1 levels decreased following TGs exposure (P <0.05). All of these phenotypes were evidently reversed by DS (P <0.05).Conclusion:DS Jinghuosu protects against TG-induced reproductive system injury in rats, probably by improving zinc homeostasis, enhancing the testosterone synthesis and attenuating oxidative stress.  
        Keywords：dietary supplement;Jinghuosu;tripterygium glycosides;reproductive damage;infertility   
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        Published：2024-03-22
      • JI Hua-feng,YANG Zi-qiang,HAN Jun-jun,LI He-fang,JIN Zhao-qing,CHEN Wei-qing,CHEN Fei-hua,GONG Mou-chun
        Vol. 30, Issue 4, Pages: 339-347(2024) DOI: 10.1007/s11655-023-3705-1
        Abstract：Objective:To explore the anti-tumor effect of safflower yellow (SY) against hepatocellular carcinoma (HCC) and the underlying potential mechanism.Methods:An in vitro model was established by mixing Luc-Hepa1-6 cells and CD3+CD8+ T cells, followed by adding programmed cell death protein 1 (PD-1) antibody (Anti-mPD-1) with or without SY. The apoptosis was detected by flow cytometry and the level of inflammatory cytokines was determined by enzyme-linked immunosorbent assay. The protein levels of programmed cell death 1 ligand 1 (PD-L1), chemokine ligand (CCL5), C-X-C motif chemokine ligand 10 (CXCL10) were measured by Western blot. An in situ animal model was established in mice followed by treatment with anti-mPD-1 with or without SY. Bioluminescence imaging was monitored with an AniView 100 imaging system. To establish the FAK-overexpressed Luc-Hepa1-6 cells, cells were transfected with adenovirus containing pcDNA3.1-FAK for 48 h.Results:The fluorescence intensity, apoptotic rate, release of inflammatory cytokines, and CCL5/CXCL10 secretion were dramatically facilitated by anti-mPD-1 (P <0.01), accompanied by an inactivation of PD-1/PD-L1 axis, which were extremely further enhanced by SY (P <0.05 or P <0.01). Increased fluorescence intensity, elevated percentage of CD3+CD8+ T cells, facilitated release of inflammatory cytokines, inactivated PD-1/PD-L1 axis, and increased CCL5/CXCL10 secretion were observed in Anti-mPD-1 treated mice (P <0.01), which were markedly enhanced by SY (P <0.05 or P <0.01). Furthermore, the enhanced effects of SY on inhibiting tumor cell growth, facilitating apoptosis and inflammatory cytokine releasing, suppressing the PD-1/PD-L1 axis, and inducing the CCL5/CXCL10 secretion in Anti-mPD-1 treated mixture of Luc-Hepa1-6 cells and CD3+CD8+ T cells were abolished by FAK overexpression (P <0.01).Conclusion:SY inhibited the progression of HCC by mediating immunological tolerance through inhibiting FAK.  
        Keywords：hepatocellular carcinoma;safflower yellow;Chinese medicine;tumor microenvironment;programmed cell death protein 1;focal adhesion kinase   
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        Published：2024-03-22
      • FU Yu-bing,LIU Chen-feng,WANG Jin-jia,JI Xiao-lin,TANG Rong-han,LIAO Kun-yu,CHEN Ling-yue,HONG Ya-zhen,FAN Bin-bin,WANG Shi-cong,LIU Wen-Hsien
        Vol. 30, Issue 4, Pages: 348-358(2024) DOI: 10.1007/s11655-023-3749-2
        Abstract：Objective:To investigate the anti-tumor effects of Pien Tze Huang (PZH) in mouse models of B16-F10 melanoma, MC38 colorectal cancer, Hep1-6 hepatocellular carcinoma and chemically induced hepatocellular carcinoma model.Methods:Various tumor models, including B16-F10, MC38 and Hep1-6 tumor hypodermic inoculation models, B16-F10 and Hep1-6 pulmonary metastasis models, Hep1-6 orthotopic implantation model, and chemically induced hepatocellular carcinoma model, were utilized to evaluate the anti-tumor function of PZH. Tumor growth was assessed by measuring tumor size and weight of solid tumors isolated from C57BL/6 mice. For cell proliferation and death of tumor cells in vitro, as well as T cell activation markers, cytokine production and immune checkpoints analysis, single-cell suspensions were prepared from mouse spleen, lymph nodes, and tumors after PZH treatment.Results:PZH demonstrated significant therapeutic efficacy in inhibiting tumor growth (P <0.01). Treatment with PZH resulted in a reduction in tumor size in subcutaneous MC38 colon adenocarcinoma and B16-F10 melanoma models, and decreased pulmonary metastasis of B16-F10 melanoma and Hep1-6 hepatoma (P <0.01). However, in vitro experiments showed that PZH only had slight impact on the cell proliferation and survival of tumor cells (P >0.05). Nevertheless, PZH exhibited a remarkable ability to enhance T cell activation and the production of interferon gamma, tumor necrosis factor alpha, and interleukin 2 in CD4+ T cells in vitro (P <0.01 or P <0.05). Importantly, PZH substantially inhibited T cell exhaustion and boosted cytokine production by tumor-infiltrating CD8+ T cells (P <0.01 or P <0.05).Conclusion:This study has confirmed a novel immunomodulatory function of PZH in T cell-mediated anti-tumor immunity, indicating that PZH holds promise as a potential therapeutic agent for cancer treatment.  
        Keywords：Pien Tze Huang;metastasis;anti-tumor immunity;T cell activation;T cell exhaustion;immune checkpoints;Chinese medicine   
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        Published：2024-03-22

        Academic Exploration

      • XIE Ying-lan,HAN Fei,JIN Ying-hui,DING Yan-bing,GUO Jing,JI Dong-xiao,ZHANG Teng,CHEN Xiao-min,SHANG Hong-cai
        Vol. 30, Issue 4, Pages: 359-365(2024) DOI: 10.1007/s11655-023-3739-9
        Abstract：The transformation and implementation of clinical practice guidelines for integrated traditional Chinese medicine (TCM) and Western medicine (WM) is crucial to the adoption of medical science and technological findings and is an important way for TCM to be made available to the world. First, clinical practice guidelines (CPGs) of TCM and WM integration in recent years was analyzed to clarify the current situation and problems in the existing guidelines according to the following four perspectives: (1) perspective of TCM and WM integration in guidelines, (2) diagnosis Using integrated TCM and WM, (3) integration of TCM and WM treatment, (4) promoting TCM and WM integration. Secondly, the information and quality evaluation of CPGs for integrated Chinese and Western medicine in 2020–2022 were analyzed to explore the degree and methods of integration of Chinese and Western medicine guidelines. And last this study aimed to lay a foundation for the further establishment of Chinese characteristic, repeatable, and calculable clinical practice guidelines of TCM and WM integration.  
        Keywords：clinical practice guidelines;integrated traditional Chinese and Western medicine;organic integration   
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        Published：2024-03-22

        Herbal and Botanical Review

      • ZUO Qian,XU Ding-qiao,YUE Shi-jun,FU Rui-jia,TANG Yu-ping
        Vol. 30, Issue 4, Pages: 366-378(2024) DOI: 10.1007/s11655-024-3708-6
        Abstract：Chinese medicine cinobufacini is an extract from the dried skin of Bufo bufo gargarizans Cantor, with active ingredients of bufadienolides and indole alkaloids. With further research and clinical applications, it is found that cinobufacini alone or in combination with other therapeutic methods can play an anti-tumor role by controlling proliferation of tumor cells, promoting apoptosis, inhibiting formation of tumor neovascularization, reversing multidrug resistance, and regulating immune response; it also has the functions of relieving cancer pain and regulating immune function. In this paper, the chemical composition, pharmacological effects, clinical applications, and adverse reactions of cinobufacini are summarized. However, the extraction of monomer components of cinobufacini, the relationship between different mechanisms, and the causes of adverse reactions need to be further studied. Also, high-quality clinical studies should be conducted.  
        Keywords：cinobufacini;chemical composition;Chinese medicine;pharmacological effect;clinical application;adverse effect   
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        Published：2024-03-22

        Review

      • XIN Li,TAN Guo-yao,ZHANG Qiang,ZHANG Qun
        Vol. 30, Issue 4, Pages: 379-384(2024) DOI: 10.1007/s11655-023-3751-8
        Abstract：Phellodendron (PN) species, traditionally used in Chinese medicine for centuries, hold promise as a potential treatment for osteoporosis (OP) and osteoarthritis (OA) due to their bioactive compounds. The bioactive compounds, including berberine and palmatine, exhibit anti-inflammatory, antioxidant, and bone-protective properties, contributing to their potential therapeutic benefits in promoting bone health and preventing bone loss. However, challenges such as the need for standardized preparation and dosing, limited clinical studies, and potential interactions with other medications hinder their clinical use. Nonetheless, the rich history of PN species in Chinese medicine provides a promising foundation for future investigation into their potential as alternative treatments for OP and OA. Further research is needed to fully understand the underlying mechanisms of action and explore the clinical implications of PN for bone health.  
        Keywords：Phellodendron species;bone health;osteoporosis;osteoarthritis;review   
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        Published：2024-03-22
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