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      Vol. 30 ， Issue 7 ， 2024

        Original Article

      • ZHANG Shao-yan,QIU Lei,ZHANG Shun-xian,XIAO He-ping,CHU Nai-hui,ZHANG Xia,ZHANG Hui-qiang,ZHENG Pei-yong,ZHANG Hui-yong,LU Zhen-hui
        Vol. 30, Issue 7, Pages: 579-587(2024) DOI: 10.1007/s11655-024-3812-7
        Abstract：Objective:To assess the efficacy and safety of Bufei Jiedu (BFJD) Granules as adjuvant therapy for patients with multidrug-resistant pulmonary tuberculosis (MDR-PTB).Methods:A large-scale, multi-center, double-blinded, and randomized controlled trial was conducted in 18 sentinel hospitals in China from December 2012 to December 2016. A total of 312 MDR-PTB patients were randomly assigned to BFJD Granules or placebo groups (1:1) using a stratified randomization method, which both received the long-course chemotherapy regimen for 18 months (6 Am-Lfx-P-Z-Pto, 12 Lfx-P-Z-Pto). Meanwhile, patients in both groups also received BFJD Granules or placebo twice a day for a total of 18 months, respectively. The primary outcome was cure rate. The secondary outcomes included time to sputum-culture conversion, changes in lung cavities and quality of life (QoL) of patients. Adverse reactions were monitored during and after the trial.Results:A total of 216 cases completed the trial, 111 in the BFJD Granules group and 105 in the placebo group. BFJD Granules, as adjuvant treatment, increased the cure rate by 13.6% at the end of treatment, compared with the placebo (58.4% vs. 44.8%, P=0.02), and accelerated the median time to sputum-culture conversion (5 months vs. 11 months). The cavity closure rate of the BFJD Granules group (50.6%, 43/85) was higher than that of the placebo group (32.1%, 26/81; P=0.02) in patients who completed the treatment. At the end of the intensive treatment, according to the 36-item Short Form, the BFJD Granules significantly improved physical functioning, general health, and vitality of patients relative to the placebo group (all P<0.01). Overall, the death rates in the two groups were not significantly different; 5.1% (8/156) in the BFJD Granules group and 2.6% (4/156) in the placebo group.Conclusions:Supplementing BFJD Granules with the long-course chemotherapy regimen significantly increased the cure rate and cavity closure rate, and rapidly improved QoL of patients with MDR-PTB (Registration No. ChiCTR-TRC-12002850)  
        Keywords：alternative medicine;Chinese herbal formula;Bufei Jiedu Granules;multidrug-resistant tuberculosis;long-course chemotherapy regimen;randomized controlled trial   
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        Published：2024-06-28
      • JIANG Yu-xia,ZHAO Yan-na,YU Xiao-ling,YIN Li-ming
        Vol. 30, Issue 7, Pages: 588-599(2024) DOI: 10.1007/s11655-023-3561-z
        Abstract：Objective:To investigate the role of ginsenoside Rd (GRd) in acute myeloid leukemia (AML) cell differentiation.Methods:AML cells were treated with GRd (25, 50, 100 and 200 μg/mL), retinoic acid (RA, 0.1g/L) and PD98059 (20 mg/mL) for 72 h, cell survival was detected by methylthiazolyldiphenyl-tetrazolium bromide and colony formation assays, and cell cycle was detected by flow cytometry. Cell morphology and differentiation were observed by Wright-Giemsa staining, peroxidase chemical staining and cellular immunochemistry assay, respectively. The protein expression levels of GATA binding protein 1 (GATA-1), purine rich Box-1 (PU.1), phosphorylated-extracellular signal-related kinase (p-ERK), ERK, phosphorylated-glycogen synthase kinase-3β (p-GSK3β), GSK3β and signal transducer and activator of transcription 1 (STAT1) were detected by Western blot. Thirty-six mice were randomly divided into 3 groups using a random number table: model control group (non-treated), GRd group [treated with 200 mg/(kg•d) GRd] and homoharringtonine (HTT) group [treated with 1 mg/(kg•d) HTT]. A tumor-bearing nude mouse model was established, and tumor weight and volume were recorded. Changes of subcutaneous tumor tissue were observed after hematoxylin and eosin staining. WT1 and GATA-1 expressions were detected by immunohistochemical staining.Results:The cell survival was inhibited by GRd in a dose-dependent manner and GRd caused G0/G1 cell arrest (P<0.05). GRd treatment induced leukemia cell differentiation, showing increased expressions of peroxidase and specific proteins concerning erythrogenic or granulocytic differentiation (P<0.05). GRd treatment elicited upregulation of p-ERK, p-GSK-3β and STAT1 expressions in cells, and reversed the effects of PD98059 on inhibiting the expressions of peroxidase, GATA-1 and PU.1 (P<0.05). After GRd treatment, tumor weight and volume of mice were decreased, and tumor cells underwent massive apoptosis and necrosis (P<0.05). WT1 level was decreased, and GATA-1 level was significantly increased in subcutaneous tumor tissues (P<0.05 or P<0.01).Conclusion:GRd might induce the differentiation of AML cells via regulating the ERK/GSK-3β signaling pathway.  
        Keywords：ginsenoside Rd;myeloid leukemia;survival;differentiation;extracellular signal-related kinase signaling pathway   
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        Published：2024-06-28
      • XU Ben,ZHANG Jia-en,YE Lin,YUAN Chang-wei
        Vol. 30, Issue 7, Pages: 600-607(2024) DOI: 10.1007/s11655-023-3564-9
        Abstract：Objective:To explore the molecular mechanism by which curcumin affects renal interstitial fibrosis (RIF) progression by regulating ADAM metallopeptidase with thrombospondin type 1 motif 18 (ADAMTS18) methylation.Methods:NRK-49F cells RIF model were induced with transforming growth factor β1 (TGF-β1). Effects of different concentrations of curcumin (0, 10, 20, and 30 μmol/L) on cell proliferation, cell cycle, cell apoptosis as well as cyclin D1 expression were analyzed by cell counting kit-8, flow cytometry and Western blot, respectively. ADAMTS18 methylation levels were determined by methylation-specific polymerase chain reaction. ADAMTS18, fibronectin (FN), type Ⅰ collagen (Col-Ⅰ) and alpha-smooth muscle actin (α-SMA) mRNA and protein expressions were analyzed by real-time PCR (RT-PCR) and Western blot, respectively. Meanwhile, cells were treated with 50 mmol/L 5-aza-2'-deoxycytidine (5-aza-dC, demethylation agent) for 72 h. Effect of curcumin on extracellular matrix (ECM) deposition was evaluated by immunochemical staining and Western blot. NRK-49F cells were transfected with ADAMTS18 small interfering RNA and grouped into a normal control, ADAMTS18-knock-out (KO), and ADAMTS18-KO+ 30 μmol/L curcumin groups, and whether curcumin can reverse the effect of ADAMTS18 knockdown on RIF was evaluated.Results:Compared with the control group, TGF-β1 significantly inhibited the proliferation of NRK-49F cells, blocked the G1/G0 phase, promoted cell apoptosis and inhibited cyclin D1 expression (P<0.01). Among the different concentrations of curcumin, 30 μmol/L curcumin significantly reversed these processes (P<0.01). Immunochemical staining and Western blot results showed that curcumin significantly inhibited the deposition of FN, Col-Ⅰ and α-SMA (P<0.01). Curcumin and 5-zaz-dC had synergistic effects, promoting ADAMTS18 expression, removing ADAMTS18 methylation, and reducing ECM deposition. ADAMTS18 knockdown promoted ECM accumulation, and curcumin reversed this process (P<0.01).Conclusion:TGF-β1 induced fibrosis in NRK-49F cells. Curcumin promoted ADAMTS18 expression, reduced ECM accumulation, and alleviated RIF progression by inhibiting ADAMTS18 methylation.  
        Keywords：renal fibrosis;curcumin;Chinese medicine;ADAMTS18;methylation modification   
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        Published：2024-06-28
      • WEI Ya-ru,HOU Yun-long,YIN Yu-jie,LI Zhen,LIU Yi,HAN Ning-xin,WANG Zi-xuan,LIU Lu,WANG Xiao-qi,HAO Yuan-jie,MA Kun,GU Jiao-jiao,JIA Zhen-hua
        Vol. 30, Issue 7, Pages: 608-615(2024) DOI: 10.1007/s11655-024-3652-5
        Abstract：Objective:To investigate the potential role of Tongxinluo (TXL) in attenuating myocardial fibrosis after myocardial ischemia-reperfusion injury (MIRI) in mice.Methods:A MIRI mouse model was established by left anterior descending coronary artery ligation for 45 min. According to a random number table, 66 mice were randomly divided into 6 groups (n=11 per group): the sham group, the model group, the LY-294002 group, the TXL group, the TXL+LY-294002 group and the benazepril (BNPL) group. The day after modeling, TXL and BNPL were administered by gavage. Intraperitoneal injection of LY-294002 was performed twice a week for 4 consecutive weeks. Echocardiography was used to measure cardiac function in mice. Masson staining was used to evaluate the degree of myocardial fibrosis in mice. Qualitative and quantitative analysis of endothelial mesenchymal transition (EndMT) after MIRI was performed by immunohistochemistry, immunofluorescence staining and flow cytometry, respectively. The protein expressions of platelet endothelial cell adhesion molecule-1 (CD31), α-smoth muscle actin (α-SMA), phosphatidylinositol-3-kinase (PI3K) and phospho protein kinase B (p-AKT) were assessed using Western blot.Results:TXL improved cardiac function in MIRI mice, reduced the degree of myocardial fibrosis, increased the expression of CD31 and inhibited the expression of α-SMA, thus inhibited the occurrence of EndMT (P<0.05 or P<0.01). TXL significantly increased the protein expressions of PI3K and p-AKT (P<0.05 or P<0.01). There was no significant difference between TXL and BNPL group (P>0.05). In addition, the use of the PI3K/AKT pathway-specific inhibitor LY-294002 to block this pathway and combination with TXL intervention, eliminated the protective effect of TXL, further supporting the protective effect of TXL.Conclusion:TXL activated the PI3K/AKT signaling pathway to inhibit EndMT and attenuated myocardial fibrosis after MIRI in mice.  
        Keywords：myocardial fibrosis;endothelial mesenchymal transition;myocardial ischemia-reperfusion injury;phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway   
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        Published：2024-06-28
      • Eun Jin Yang
        Vol. 30, Issue 7, Pages: 616-622(2024) DOI: 10.1007/s11655-023-3557-8
        Abstract：Objective:To examine the effect of combined treatment with Bojungikgi-tang (BJIGT, Buzhong Yiqi Decoction) and riluzole (RZ) in transactive response DNA-binding protein 43 (TDP-43) stress granule (SG) cells, a amyotrophic lateral sclerosis (ALS) cell line using transcriptomic and molecular techniques.Methods:TDP-43 SG cells were pretreated with BJIGT (100 μg/mL), RZ (50 μmol/L), and combined BJIGT (100 μg/mL)/RZ (50 μmol/L) for 6 h before treatment with lipopolysaccharide (LPS, 200 μmol/L). Cell viability assay was performed to elucidate cell toxicity in TDP-43 SC cells using a cell-counting kit-8 (CCK8) assay kit. The expression levels of cell death-related proteins, including Bax, caspase 1, cleaved caspase 3 and DJ1 in TDP-43 SG cells were examined by Western blot analysis. The autophagy-related proteins, including pmTOR/mTOR, LC3b, P62, ATG7 and Bcl-2-associated athanogene 3 (Bag3) were investigated using immunofluorescence and immunoblotting assays.Results:Cell viability assay and Western blot analysis showed that combined treatment with BJIGT and RZ suppressed LPS-induced cell death and expression of cell death-related proteins, including Bax, caspase 1, and DJ1 (P<0.05 or P<0.01). Immunofluorescence and immunoblotting assays showed that combined treatment with BJIGT and RZ reduced LPS-induced formation of TDP-43 aggregates and regulated autophagy-related protein levels, including p62, light chain 3b, Bag3, and ATG7, in TDP-43-expressing cells (P<0.05 or P<0.01).Conclusion:The combined treatment of BJIGT and RZ might reduce inflammation and regulate autophagy dysfunction in TDP-43-induced ALS.  
        Keywords：Bojungikgi-tang;Buzhong Yiqi Decoction;transactive response DNA-binding protein 43;autophagy;oxidative stress;amyotrophic lateral sclerosis   
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        Published：2024-06-28
      • YUE Yin-zi,LI Ming-xuan,WANG Xiao-hui,QIN Yuan-yuan,WANG Ya-hui,TAN Jin-hua,SU Lian-lin,YAN Shuai
        Vol. 30, Issue 7, Pages: 623-632(2024) DOI: 10.1007/s11655-023-3552-0
        Abstract：Objective:To clarify the potential mechanism of Banxia Xiexin Decoction (BXD) on colorectal cancer (CRC) from the perspective of metabolomics.Methods:Forty male C57BL/6 mice were randomly divided into normal control (NC), azoxymethane/dextran sulfate sodium (AOM/DSS) model, low-dose BXD (L-BXD), high-dose BXD (H-BXD) and mesalamine (MS) groups according to a random number table, 8 mice in each group. Colorectal cancer model was induced by AOM/DSS. BXD was administered daily at doses of 3.915 (L-BXD) and 15.66 g/kg (H-BXD) by gavage for consecutive 21 days, and 100 mg/kg MS was used as positive control. Following the entire modeling cycle, colon length of mice was measured and quantity of colorectal tumors were counted. The spleen and thymus index were determined by calculating the spleen/thymus weight to body weight. Inflammatory cytokine and changes of serum metabolites were analyzed by enzyme-linked immunosorbent assay kits and ultra performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q/TOF-MS), respectively.Results:Notably, BXD supplementation protected against weight loss, mitigated tumor formation, and diminished histologic damage in mice treated with AOM/DSS (P<0.05 or P<0.01). Moreover, BXD suppressed expression of serum inflammatory enzymes, and improved the spleen and thymus index (P<0.05). Compared with the normal group, 102 kinds of differential metabolites were screened in the AOM/DSS group, including 48 potential biomarkers, involving 18 main metabolic pathways. Totally 18 potential biomarkers related to CRC were identified, and the anti-CRC mechanism of BXD was closely related to D-glutamine and D-glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, arginine biosynthesis, nitrogen metabolism and so on.Conclusion:BXD exerts partial protective effects on AOM/DSS-induced CRC by reducing inflammation, protecting organism immunity ability, and regulating amino acid metabolism.  
        Keywords：colorectal cancer;metabolomics;ultra performance liquid chromatography-quadrupole/time-of-flight mass spectrometry;azoxymethane;dextran sulfate sodium;Banxia Xiexin Decoction;Chinese medicine   
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        Published：2024-06-28

        Acupuncture Research

      • HU Rui,PAN Jun-kang,LI Jia-hui,ZHANG Han,LI Shao-rong,ZHANG Yi
        Vol. 30, Issue 7, Pages: 633-642(2024) DOI: 10.1007/s11655-023-3553-z
        Abstract：Objective:To determine whether acupotomy ameliorates immobilization-induced muscle contracture and fibrosis via Wnt/β-catenin signaling pathway.Methods:Thirty Wistar rats were randomly divided into 5 groups (n=6) by a random number table, including control, immobilization, passive stretching, acupotomy, and acupotomy 3 weeks (3-w) groups. The rat model of gastrocnemius contracture was established by immobilizing the right hind limb in plantar flexion for 4 weeks. Rats in the passive stretching group received passive stretching at gastrocnemius, a daily series of 10 repetitions for 30 s each at 30-s intervals for 10 consecutive days. Rats in the acupotomy and acupotomy 3-w groups received acupotomy once and combined with passive stretching at gastrocnemius a daily series of 10 repetitions for 30 s each at 30-s intervals for 10 consecutive days. Additionally, rats in the acupotomy 3-w group were allowed to walk freely for 3 weeks after 10-day therapy. After treatment, range of motion (ROM), gait analysis [i.e., paw area, stance/swing and maximum ratio of paw area to paw area duration (Max dA/dT)], gastrocnemius wet weight and the ratio of muscle wet weight to body weight (MWW/BW) were tested. Gastrocnemius morphometric and muscle fiber cross-sectional area (CSA) were assessed by hematoxylin-eosin staining. Fibrosis-related mRNA expressions (i.e., Wnt 1, β-catenin, axin-2, α-smooth muscle actin, fibronectin, and types Ⅰ and Ⅲ collagen) were measured using real-time quantitative polymerase chain reactions. Wnt 1, β-catenin and fibronectin concentrations were measured by enzyme-linked immunosorbent assay. Types Ⅰ and Ⅲ collagen in the perimysium and endomysium were analyzed using immunofluorescence.Results:Compared with the control group, ROM, gait function, muscle weight, MWW/BW and CSA were significantly decreased in the immobilization group (all P<0.01), while protein levels of types Ⅰ and Ⅲ collagen, Wnt 1, β-catenin, fibronectin and mRNA levels of fibrosis-related genes were obviously increased (allP<0.01). Treatment with passive stretching or acupotomy restored ROM and gait function and increased muscle wet weight, MWW/BW and CSA (all P<0.05), while protein expression levels of Wnt 1, β-catenin, fibronectin, types Ⅰ and Ⅲ collagen and mRNA levels of fibrosis-related genes were remarkably declined compared with the immobilization group (all P<0.05). Compared with passive stretching group, ROM, gait function, MWW were remarkably restored (all P<0.05), and mRNA levels of fibrosis-related genes as well as protein expression levels of Wnt 1, β-catenin, fibronectin, types Ⅰ and Ⅲ collagen in the acupotomy group were obviously decreased (all P<0.05). Compared with the acupotomy group, ROM, paw area, Max dA/dT, and MWW were restored (all P<0.05), and mRNA levels of fibrosis-related genes along with protein levels of Wnt 1, β-catenin, fibronectin, types Ⅰ and Ⅲ collagen in the acupotomy 3-w group were decreased (P<0.05).Conclusion:Improvements in motor function, muscle contractures, and muscle fibrosis induced by acupotomy correlates with the inhibition of Wnt/β-catenin signaling pathway.  
        Keywords：acupotomy;immobilization;muscle contracture;muscle fibrosis;Wnt/β-catenin signaling   
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        Published：2024-06-28

        Evidence-Based Integrative Medicine

      • LI Rui,ZHANG Tong,YAN Shao-hua,YAN Yun-zi,DING Ya-cong,WANG Yan-song,YANG Yu-fei
        Vol. 30, Issue 7, Pages: 643-652(2024) DOI: 10.1007/s11655-023-3558-7
        Abstract：Objective:To assess the effectiveness of Chinese herbal medicine (CHM) combined with adjuvant chemotherapy on myelosuppression for colorectal cancer (CRC) patients using network meta-analysis (NMA).Methods:Literature searches in both international (PubMed, Embase, Web of Science, and Cochrane Library) and Chinese (China Science and Technology Journal Database, Wanfang Data, China National Knowledge Infrastructure) databases for relevant randomized controlled trials (RCTs) were conducted from inception until October 10, 2022. We included RCTs of patients who received CHM combined with chemotherapy, including FOLFOX, XELOX, FOLFIRI, and other relevant regimens in the CHM treatment group. The outcomes included the incidence of myelosuppression, leukopenia, hemoglobin reduction, and thrombocytopenia. Two reviewers independently screened the databases, extracted the data, and assessed the risk of bias and credibility of evidence. RevMan 5.4.1 software and STATA 14.0 were used to perform the NMA.Results:A total of 31 RCTs were included, published from 2008 to 2021 in Chinese. Among these, 2, 314 participants comparing the following 9 CHMs were identified: Shengbai Recipe (SBR), Bazhen Decoction (BZD), Jianpi Jiedu Recipe (JJR), Jianpi Recipe (JR), Compound Cantharis Capsule (CCC), Zaofan Pill (ZFP), Guilu Erxian Gel (GL), Buzhong Tiaogan Decoction (BZ), and Qiamagu Capsule (QM). The results of NMA found an indirect comparison. Based on the surface under the cumulative ranking curve (SUCRA), the ZFP+ chemotherapy group had the lowest incidence of myelosuppression, with an odds ratio (OR) of 0.08 [95% confidence interval (CI): 0.01, 0.76], whereas the GL+ chemotherapy group had the lowest incidence of leukopenia, hemoglobin reduction, and thrombocytopenia, with an OR of 5.25 (95% CI: 2.41, 11.43), 4.66 (95% CI: 2.23, 9.72), and 0.27 (95% CI: 0.13, 0.54), respectively. Moreover, BZD + chemotherapy could alleviate leukopenia, hemoglobin reduction, and thrombocytopenia (P<0.01). Pairwise comparison showed that there was no difference in the efficacy among the 8 CHMs+ chemotherapy group. The comparison and adjustment funnel plot indicated that small-study effect had no impact on these outcomes.Conclusions:This NMA provided evidence to support that patients with CRC benefit from receiving different combination of CHM chemotherapies. Among these, GL plus chemotherapy and BZD plus chemotherapy were the more effective for myelosuppression in patients; however, as the qualtiy of evidence is insufficient, further research is needed. (PROSPERO, No. CRD42022369025)  
        Keywords：Chinese herbal medicine;colorectal cancer;network meta-analysis;systematic review;myelosuppression;chemotherapy   
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        Published：2024-06-28

        Review

      • Surendra Kumar Gautam,Rakesh Kumar Paul,Devesh M. Sawant,Amita Sarwal,Kaisar Raza
        Vol. 30, Issue 7, Pages: 653-663(2024) DOI: 10.1007/s11655-023-3563-x
        Abstract：Balanites aegyptiaca Delile (BA) is an enduring xerophytic woody and spinous flowering tree and is commonly known as desert date or Ingudi (Hingot). It belongs to the family Zygophyllaceae, which is specific to be drought areas of Nigeria, Africa, South Asia and India (Rajasthan). In Ayurveda, this traditional medicinal plant is reported for the management of jaundice, syphilis, yellow fever, metabolic disorders, liver, and spleen problems. The main aim of the review is to compile its medicinal uses and further advancements to showcase the promises inherited in various parts of the plant for the benefit of mankind. As per the literature survey, various researchers have focused on the detailed investigation of BA including the phytopharmacological evidence, chemical constituents, nano-formulations, commercialized products, and clinical trials. Several remarkable scaffolds and isolated compounds like diosgenin, yamogenin, balanitin1/2, balanitin 3, bal4/5, bal6/7, rutin-3-glycosides, 3, 7-diglycosides, (3, 12, 14, 16)–(12-hydroxycholest-5-ene-3, 16-diyl-bis)-D-glucopyranoside and balanitoside have been identified. Additionally, this traditional plant has been scientifically proven by in vitro and in vivo. Based on the complete review of this plant, most of the compounds have been isolated from the fruit and kernel part. Additionally, based on the literature, a histogram was developed for pharmacological activity in which antidiabetic study was found to be more compared to other pharmacological activity. As a spinous desert dates, this plant needs to be explored more to bring out newer phytochemicals in the management of various diseases.  
        Keywords：Delile desert date;phytochemicals;nano-phytopharmaceutical;pharmacological activities;traditional medicine   
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        Published：2024-06-28
      • LIU Su-su,YU Tong,QIAO Yan-fang,GU Shu-xiao,CHAI Xin-lou
        Vol. 30, Issue 7, Pages: 664-672(2024) DOI: 10.1007/s11655-023-3545-z
        Abstract：The prevalence of hyperlipidemia has increased significantly due to genetic, dietary, nutritional and pharmacological factors, and has become one of the most common pathological conditions in humans. Hyperlipidemia can lead to a range of diseases such as atherosclerosis, stroke, coronary heart disease, myocardial infarction, diabetes, and kidney failure, etc. High circulating low-density lipoprotein cholesterol (LDL-C) is one of the causes of hyperlipidemia. LDL-C in the blood binds to LDL receptor (LDLR) and regulates cholesterol homeostasis through endocytosis. In contrast, proprotein convertase subtilisin/kexin type 9 (PCSK9) mediates LDLR degradation via the intracellular and extracellular pathways, leading to hyperlipidemia. Targeting PCSK9-synthesizing transcription factors and downstream molecules are important for development of new lipid-lowering drugs. Clinical trials regarding PCSK9 inhibitors have demonstrated a reduction in atherosclerotic cardiovascular disease events. The purpose of this review was to explore the target and mechanism of intracellular and extracellular pathways in degradation of LDLR and related drugs by PCSK9 in order to open up a new pathway for the development of new lipid-lowering drugs.  
        Keywords：hyperlipidemia;proprotein convertase subtilisin/kexin type 9;low-density lipoprotein receptor;intracellular pathway;extracellular pathway   
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        Published：2024-06-28
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