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      Vol. 29 ， Issue 11 ， 2023

        Original Article

      • GAN Jing-wen,LV De-xin,FU Jin,SHI Liang-yan,YUAN Chun-yan,ZENG Xiao-qin,LI Jun,SUN Ai-jun
        Vol. 29, Issue 11, Pages: 963-970(2023) DOI: 10.1007/s11655-023-3740-y
        Abstract：Objective:To evaluate the effectiveness and safety of Zhenqi Buxue Oral Liquid (ZQ), progesterone capsules, and their combination in treating oligomenorrhea and hypomenorrhea with qi-blood and Kidney (Shen) essence deficiency.Methods:This was a prospective, randomized, multi-center controlled trial between June 2022 to December 2022. Ninety-six oligomenorrhea and hypomenorrhea patients with qi-blood and Shen essence deficiency were randomly assigned to receive ZQ (ZQ group, 29 cases), progesterone capsules (PG group, 32 cases), or the combined Chinese and Western medicine (COM group, 31 cases) at a ratio of 1:1:1. Patients in the ZQ or PG group took daily 10 mL twice a day of ZQ or 200 mg once a day of progesterone capsules for 10 consecutive days on day 15 of the menstrual cycle respectively, and patients in the COM group received the same ZQ combined with progesterone capsules. The treatment course lasted for 3 months and follow-up was performed at 1 and 3 months after the end of treatment. Primary endpoint was the menstrual Traditional Chinese Medicine Syndrome Scale (TCMSS) scores. Secondary endpoints included pictorial blood loss assessment chart (PBAC) scores, clinical efficacy rate, 36-item Short Form Health Survey (SF-36) scores, sex hormones and thickness of endometrium. Adverse events (AEs) were recorded.Results:TCMSS scores after 1- and 3-month treatment in all groups were significantly lower than those at baseline (P < 0.05). Only TCMSS scores after 3-month treatment in the ZQ and COM groups continuously decreased compared with those after 1-month treatment in the same group (P < 0.01). TCMSS scores after 3-month treatment in the ZQ and COM groups were significantly lower than those in the PG group (P < 0.05, P < 0.01). Compared with baseline, PBAC scores in the ZQ and COM groups after 3 months of treatment were also significantly higher (both P < 0.01). The total effective rates of TCM syndrome of 3-month treatment were significantly improved in all groups compared with that after 1 month of treatment (P < 0.05). The total effective rate of the COM group was the highest in the 3rd month of treatment and significantly higher than that of PG group alone (P < 0.05). Compared with baseline, only the SF-36 scores of COM group were significantly improved after 3 months of treatment (P < 0.05). No serious adverse reactions were observed after treatment.Conclusions:The combination of ZQ and PG, or ZQ only had better effects on reducing TCMSS scores compared with PG, and COM showed the higher total effective rate compared with monotherapy. Besides, COM could effectively improve menstrual blood loss and quality of life. ZQ combined with PG may be an effective and safe option for oligomenorrhea and hypomenorrhea patients with qi-blood and Shen essence deficiency.  
        Keywords：oligomenorrhea;hypomenorrhea;qi-blood and Kidney (Shen) essence deficiency;Zhenqi Buxue Oral Liquid;progesterone;integration of Chinese and Western medicine;randomized controlled trial   
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        Published：2023-11-23
      • YANG Xin-chun,LIU Yong,SUN Wei-wei,SHI Guang,WU Ying,XU Cai,MENG Qing-wei,HAO Zeng-ping,HAN Qian,ZHAO Rui-hua
        Vol. 29, Issue 11, Pages: 971-979(2023) DOI: 10.1007/s11655-023-3736-z
        Abstract：Objective:To analyze the factors related to pregnancy of endometriosis and whether Chinese herbal medicines (CHMs) can improve pregnancy outcomes in patients with endometriosis in long-term management.Methods:This multicenter cohort study retrospectively analyzed the clinical data of endometriosis patients with fertility needs from January 2019 to November 2019. A total of 252 patients with endometriosis from 5 level-Ⅲ Grade A hospitals in Beijing were included in this study. Univariate and multivariate logistic regression analysis were performed for the relevant factors. The propensity score matching (PSM) function of SPSS software was used to match the CHMs group with the non-CHMs group. The pregnancy rate and live birth rate were analyzed.Results:The results of univariate analysis showed that age, disease course, presence of infertility, presence of adenomyosis, time after surgery or use of gonadotropin-releasing hormone agonist (GnRH-a), use of CHMs and follow-up time were influencing factors of pregnancy in endometriosis patients (P < 0.05). The results of multivariate analysis showed that age, presence of adenomyosis, time after surgery or use of GnRH-a, use of CHMs and follow-up time were independent factors affecting pregnancy in endometriosis patients, among which, age 35 years old, presence of adenomyosis and follow-up time > 6 months were independent risk factors (OR=0.445, 0.348, 0.140, respectively, P < 0.05), time after surgery or use of GnRH-a 6 months and use of CHMs were independent protective factors (OR=3.839, 3.842, respectively, P < 0.05) . After PSM, 99 pairs of two groups were matched successfully. The pregnancy rate of the CHMs group was higher than that of the non-CHMs group [55.56% (55/99) vs. 36.36% (36/99), P < 0.05]. The live birth rate of the CHMs group was higher than that of the non-CHMs group [49.49% (49/99) vs. 35.35% (35/99), P < 0.05].Conclusion:CHMs can effectively improve clinical pregnancy rate and live birth rate of patients with endometriosis in the chronic disease management.  
        Keywords：endometriosis;pregnancy;Chinese herbal medicine;multivariate analysis;retrospective cohort study;long-term management   
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        Published：2023-11-23
      • Sayah Ongsricharoenbhorn,Pakanit Kupittayanant,Kanjana Thumanu,Griangsak Eumkeb,Suthida Chanlun,Pittaya Papirom,Susan Wray,Sajeera Kupittayanant
        Vol. 29, Issue 11, Pages: 980-988(2023) DOI: 10.1007/s11655-023-3742-9
        Abstract：Objective:To investigate the effect of Heliotropium indicum L. (H. indicum L.) on uterine involution and its underlying mechanisms in both in vivo and in vitro study.Methods:For in vivo studies, postpartum rats were randomly divided into 2 groups (n=24 for each): control group and treated group which were orally and daily administered with ethanolic extract of H. indicum L. (250 mg/kg body weight) until day 5 of postpartum. Uteri were collected for analysis of weight, cross-sectional area, collagen cross-sectional area, and collagen content on postpartum day 1, 3, and 5 (n=8 for each) from both groups. Blood samples were collected for hepatotoxicity and 17ß-estradiol (E2) measurement. For in vitro studies, the extract effects on uterine contraction at half maximum effective concentration of 2.50 mg/mL were studied in organ bath system for at least 20 min.Results:Uterine parameters were significantly decreased after treated with extract of H. indicum L. (P < 0.05). H. indicum L. extract significantly accelerated the reduction of those parameters and significantly decreased E2 (P < 0.05). The extract facilitated uterine involution with no hepatotoxicity. H. indicum L. extract significantly stimulated uterine contraction (P < 0.05) and synergized with oxytocin, prostaglandin and its precursor, linoleic acid. By investigating the different sequencing of the extract with the additional stimulants (added before or after), the two showed antagonistic effects, but still showed potentiated force when compared with control (without the stimulants).Conclusions:The underlying mechanisms by which H. indicum L. facilitated uterine involution might be due to reducing E2 which induces collagenase activity, leading to decreases in uterine weight and size and stimulating uterine contraction. Our study provides new findings for future drug development for facilitating uterine involution with H. indicum L.  
        Keywords：involution;contraction;postpartum hemorrhage;estradiol;collagen;Heliotropium indicum L.   
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        Published：2023-11-23
      • JIANG Qian,JIANG Wen-jun,YANG Cheng-xiu,ZHANG Rui-xue,SUN Wei,GUO Da-dong,WU Jiang-feng,GUO Bin,WANG Xing-rong,BI Hong-sheng
        Vol. 29, Issue 11, Pages: 989-997(2023) DOI: 10.1007/s11655-023-3738-x
        Abstract：Objective:To explore the underlying mechanism of inhibition by Jingui Shenqi Pills (JGSQP) on glucocorticoid-enhanced axial length elongation in experimental lens-induced myopia (LIM) guinea pigs.Methods:Sixty 2-week old male guinea pigs were randomly divided into 4 groups with 15 guinea pigs in each group, according to the random numbers generated by SPSS software: control, LIM, saline and JGSQP groups. The control group includes animals with no treatment, while the guinea pigs in the other 3 groups received lens-induced myopization on the right eyes throughout the experiment (for 8 weeks). The saline and JGSQP groups were given daily intraperitoneal injections of 10 mg/kg hydrocortisone for 2 consecutive weeks at the same time, and then orally administered either saline or JGSQP [13.5 g/(kg • d) for 6 consecutive weeks. Body weight, anal temperature and animal appearance were observed and recorded to evaluate the GC-associated symptoms. The ocular parameters, including refraction and axial length, were measured by streak retinoscopy and A-scan ultrasonography, respectively. The levels of plasma hormones associated with the hypothalamic-pituitary-adrenal axis (HPAA), including free triiodothyronine, free thyroxine, estradiol and testosterone, were measured by radioimmunoassay, and cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate were measured by enzyme-linked immunosorbent assay. In addition, the mRNA and protein expressions of retinal amphiregulin (AREG) was measured by quantitative real-time polymerase chain reaction and Western blotting, respectively.Results:JGSQP effectively increased body weight and anal temperature, improved animal appearance and suppressed axial length elongation in glucocorticoid- enhanced myopic guinea pigs with normalization of 4 HPAA-associated plasma hormones (all P < 0.05). The plasma level of cAMP was significantly increased, whereas the plasma level of cGMP and the mRNA and protein expressions of retinal AREG were decreased after treatment with JGSQP (all P < 0.05).Conclusion:JGSQP exhibited a significant inhibitory effect on axial length elongation with decreased expression of AREG in the retina, and normalized 4 HPAA-associated plasma hormones and the expression of cAMP and cGMP in GC-enhanced myopic guinea pigs.  
        Keywords：Jingui Shenqi Pills;glucocorticoid;axial length;amphiregulin;hormone   
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        Published：2023-11-23
      • ZHANG Ning,YE Tao,LU Xu,LI Zi-hui,LI Ling
        Vol. 29, Issue 11, Pages: 998-1006(2023) DOI: 10.1007/s11655-023-3744-7
        Abstract：Objective:To explore the mechanism of Radix Scrophulariae (RS) extracts in the treatment of hyperthyroidism rats by regulating proliferation, apoptosis, and autophagy of thyroid cell through the mammalian sterile 20-like kinase 1 (MST1)/Hippo pathway.Methods:Twenty-four rats were randomly divided into 4 groups according to a random number table: control, model group, RS, and RS+Hippo inhibitor (XMU-MP-1) groups (n = 6 per group). Rats were gavaged with levothyroxine sodium tablet suspension (LST, 8 μg/kg) for 21 days except for the control group. Afterwards, rats in the RS group were gavaged with RS extracts at the dose of 1, 350 mg/kg, and rats in the RS+XMU-MP-1 group were gavaged with 1, 350 mg/kg RS extracts and 1 mg/kg XMU-MP-1. After 15 days of administration, thyroid gland was taken for gross observation, and histopathological changes were observed by hematoxylin-eosin staining. The structure of Golgi secretory vesicles in thyroid tissues was observed by transmission electron microscopy. The expression of thyrotropin receptor (TSH-R) was observed by immunohistochemistry. Terminal-deoxynucleoitidyl transferase mediated nick end labeling assay was used to detect cell apoptosis in thyroid tissues. Real-time quantity primer chain reaction and Western blot were used to detect the expressions of MST1, p-large tumor suppressor gene 1 (LATS1), p-Yes1 associated transcriptional regulator (YAP), proliferating cell nuclear antigen (PCNA), G1 /S-specific cyclin-D1 (Cyclin D1), B-cell lymphoma-2 (Bcl-2), Caspase-3, microtubule-associated proeins light chain 3 Ⅱ/Ⅰ (LC3-Ⅱ/Ⅰ), and recombinant human autophagy related 5 (ATG5). Thyroxine (T4) level was detected by enzyme-linked immunosorbent assay.Results:The thyroid volume of rats in the model group was significantly increased compared to the normal control group (P < 0.01), and pathological changes such as uneven size of follicular epithelial cells, disorderly arrangement, and irregular morphology occurred. The secretion of small vesicles by Golgi apparatus was reduced, and the expressions of receptor protein TSH-R and T4 were significantly increased (P < 0.01), while the expressions of MST1, p-LATS1, p-YAP, Caspase-3, LC3-Ⅱ/Ⅰ, and ATG5 were significantly decreased (P < 0.01). The expressions of Bcl-2, PCNA, and cyclin D1 were significantly increased (P < 0.01). Compared with the model group, RS extracts reduced the volume of thyroid gland, improved pathological condition of the thyroid gland, promoted secretion of the secretory vesicles with double-layer membrane structure in thyroid Golgi, significantly inhibited the expression of TSH-R and T4 levels (P < 0.01), upregulated MST1, p-LATS1, p-YAP, Caspase-3, LC3-Ⅱ/Ⅰ, and ATG5 expressions (P < 0.01), and downregulated Bcl-2, PCNA, and Cyclin D1 expressions (P < 0.01). XMU-MP-1 inhibited the intervention effects of RS extracts (P < 0.01).Conclusion:RS extracts could inhibit proliferation and promote apoptosis and autophagy in thyroid tissues through MST1/Hippo pathway for treating hyperthyroidism.  
        Keywords：Radix Scrophulariae extracts;levothyroxine sodium tablets;hyperthyroidism;MST1/Hippo signal pathway;proliferation;apoptosis;autophagy   
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        Published：2023-11-23
      • ZHOU Qi,SUN Hui-juan,ZHANG Xi-wu
        Vol. 29, Issue 11, Pages: 1007-1017(2023) DOI: 10.1007/s11655-022-3729-y
        Abstract：Objective:To explore the mechanism of effects of total saponin fraction from Dioscorea Nipponica Makino (TSDN) on M1/M2 polarization of monocytes/macrophages and arachidonic acid (AA) pathway in rats with gouty arthritis (GA).Methods:Seventy-two Sprague Dawley rats were randomly divided into 4 groups (n =18 in each): normal, model, TSDN at 160 mg/kg, and celecoxib at 43.3 mg/kg. Monosodium urate crystal (MSU) was injected into the rats' ankle joints to induce an experimental GA model. Blood and tissue samples were collected on the 3rd, 5th, and 8th days of drug administration. Histopathological changes in the synovium of joints were observed via hematoxylin and eosin (HE) staining. The expression levels of arachidonic acid (AA) signaling pathway were assessed via real-time polymerase chain reaction (qPCR) and Western blot. Flow cytometry was used to determine the proportion of M1 and M2 macrophages in the peripheral blood. An enzyme-linked immunosorbent assay (ELISA) was used to detect interleukine (IL)-1β, tumor necrosis factor- alpha (TNF-α), IL-4, IL-10, prostaglandin E2 (PGE2), and leukotriene B4 (LTB4).Results:HE staining showed that TSDN improved the synovial tissue. qPCR and Western blot showed that on the 3rd, 5th and 8th days of drug administration, TSDN reduced the mRNA and protein expressions of cyclooxygenase (COX)2, microsomal prostaglandin E synthase-1 derived eicosanoids (mPGES-1), 5-lipoxygenase (5-LOX), recombinant human mothers against decapentaplegic homolog 3 (Smad3), nucleotide-binding oligomerization domain-like receptor protein 3 (NALP3), and inducible nitric oxide synthase (iNOS) in rats' ankle synovial tissues (P < 0.01). TSDN decreased COX1 mRNA and protein expression on 3rd and 5th day of drug administration and raised it on the 8th day (both P < 0.01). It lowered CD68 protein expression on days 3 (P < 0.01), as well as mRNA and protein expression on days 5 and 8 (P < 0.01). On the 3rd, 5th, and 8th days of drug administration, TSDN elevated the mRNA and protein expression of Arg1 and CD163 (P < 0.01). Flow cytometry results showed that TSDN decreased the percentage of M1 macrophages while increasing the percentage of M2 in peripheral blood (P < 0.05 or P < 0.01). ELISA results showed that on the 3rd, 5th, and 8th days of drug administration, TSDN decreased serum levels of IL-1β, TNF-α, and LTB4 (P < 0.01), as well as PGE2 levels on days 3rd and 8th days (P < 0.05 or P < 0.01); on day 8 of administration, TSDN increased IL-4 serum levels and enhanced IL-10 contents on days 5 and 8 (P < 0.05 or P < 0.01).Conclusion:The anti-inflammatory effect of TSDN on rats with GA may be achieved by influencing M1/M2 polarization through AA signaling pathway.  
        Keywords：gouty arthritis;Dioscorea nipponica Makino;arachidonic acid;signaling pathway;M1/M2 polarization;Chinese medicine   
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        Published：2023-11-23

        Evidence-Based Integrative Medicine

      • ZHANG Hao-ran,ZHANG Cheng,MA Pei-hong,SUN Cheng-yi,SUN Chong-yang,LIU Xiao-yu,PU Zhen-qing,LIN Yu-han,LIU Bao-yan,LIU Cun-zhi,YAN Shi-yan
        Vol. 29, Issue 11, Pages: 1021-1032(2023) DOI: 10.1007/s11655-023-3748-3
        Abstract：Background:Currently, more and more infertility couples are opting for combined acupuncture to improve success rate of in vitro fertilization (IVF). However, evidence from acupuncture for improving IVF pregnancy outcomes remains a matter of debate.Objective:To quantitatively summarized the evidence of the efficacy of acupuncture among women undergoing IVF by means of systematic review and meta-analysis.Methods:Four English (PubMed, Web of Science, EMBASE, and Cochrane Register of Controlled Clinical Trials) and Four Chinese databases (Wanfang Databases, Chinese National Knowledge Infrastructure, Chinese Science and Technology Periodical Database, and SinoMed) were searched from database inception until July 2, 2023. Randomized controlled trials (RCTs) that evaluated the acupuncture's effects for women undergoing IVF were included. The subgroup analysis was conducted with respect to the age of participants, different acupuncture types, type of control, acupuncture timing, geographical origin of the study, whether or not repeated IVF failure, and acupuncture sessions. Sensitivity analyses were predefined to explore the robustness of results. The primary outcomes were clinical pregnancy rate (CPR) and live birth rate (LBR), and the secondary outcomes were ongoing pregnancy rate and miscarriage rate. Random effects model with I2 statistics were used to quantify heterogeneity. Publication bias was estimated by funnel plots and Egger's tests.Results:A total of 58 eligible RCTs representing 10, 968 women undergoing IVF for pregnant success were identified. Pooled CPR and LBR showed a significant difference between acupuncture and control groups [69 comparisons, relative risk (RR) 1.19, 95% confidence intervals (CI) 1.12 to 1.25, I2 =0], extremely low evidence; 23 comparisons, RR 1.11, 95%CI 1.02 to 1.21, I2 =14.6, low evidence, respectively). Only transcutaneous electrical acupoint stimulation showed a positive effect on both CPR (16 comparisons, RR 1.17, 95%CI 1.06 to 1.29; I2 =0, moderate evidence) and LBR (9 comparisons, RR 1.20, 95%CI 1.04 to 1.37; I2 =8.5, extremely low evidence). Heterogeneity across studies was found and no studies were graded as high-quality evidence.Conclusion:Results showed that the convincing evidence levels on the associations between acupuncture and IVF pregnant outcomes were relatively low, and the varied methodological design and heterogeneity might influence the findings. (Registration No. PROSPERO CRD42021232430)  
        Keywords：acupuncture;in vitro fertilization;clinical pregnancy rate;live birth rate;systematic review;meta-analysis   
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        Published：2023-11-23

        Review

      • GAO Jun-wen,ZHAN Yang,WANG Yun-he,ZHAO Shu-jie,HAN Zhong-ming
        Vol. 29, Issue 11, Pages: 1033-1044(2023) DOI: 10.1007/s11655-023-3746-5
        Abstract：Saposhnikovia divaricata (Turcz.) Schischk (S. divaricata , Fangfeng) is a herb in the Apiaceae family, and its root has been used since the Western Han Dynasty (202 B.C.). Chromones and coumarins are the pharmacologically active substances in S. divaricata . Modern phytochemical and pharmacological studies have demonstrated their antipyretic, analgesic, anti-inflammatory, antioxidant, anti-tumor, and anticoagulant activities. Technological and analytical strategy theory advancements have yielded novel results; however, most investigations have been limited to the main active substances—chromones and coumarins. Hence, we reviewed studies related to the chemical composition and pharmacological activity of S. divaricata, analyzed the developing trends and challenges, and proposed that research should focus on components' synergistic effects. We also suggested that, the structure-effect relationship should be prioritized in advanced research.  
        Keywords：Saposhnikovia divaricata (Turcz.) Schischk;Chinese herbal medicine;pharmacological activity;coumarin;chromones;review   
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        Published：2023-11-23
      • XIONG Luo-jie,TIAN Yue-feng,ZHAI Chun-tao,LI Wei
        Vol. 29, Issue 11, Pages: 1045-1056(2023) DOI: 10.1007/s11655-023-3743-8
        Abstract：Immunotherapy targeting immune checkpoint molecules has emerged as a key approach in cancer treatment, representing the forefront of antitumor research. However, studies on immune checkpoint molecules have mainly focused on targeted therapies. Chinese medicine (CM) research as a complementary medicine has revealed that immune checkpoint molecules also undergo disease-specific changes in the context of autoimmune diseases. This review article presents a comprehensive analysis of CM studies on immune checkpoint molecules in the last 5 years, with a focus on their role in different diseases and treatment modalities. CM research predominantly utilizes oral administration of herbal plant extracts or acupuncture techniques, which stimulate the immune system by activating specific acupoints through temperature and needling. In this study, we analyzed the modulation and mechanisms of immune checkpoint molecules associated with different coinhibitory and costimulatory molecules, and reviewed the immune functions of related molecules and CM studies in treating autoimmune diseases and tumors. By summarizing the characteristics and research value of CM in regulating immune checkpoint molecules, this review aims to provide a useful reference for future studies in this field.  
        Keywords：acupuncture and moxibustion;Chinese materia medica;immune checkpoint;autoimmune disease;tumor   
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        Published：2023-11-23
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