Bojungikgi-tang for Chemotherapy-induced Leukopenia: A Systematic Review and Meta-Analysis.

Chemotherapy-induced leukopenia is a common side effect of cytotoxic anticancer drugs. It can deprive patients of treatment opportunities, resulting in the delay, reduction, or discontinuation of chemotherapy or other anticancer drug administration. Two researchers searched English, Chinese, Japanese, and Korean electronic databases, without limiting the time period and language, using search terms such as "Bojungikgi," "WBC," "leuko," and "neutrop." Among the human randomized controlled studies in which Bojungikgi-tang was administered to patients who underwent chemotherapy, studies reporting leukopenia-related outcomes were selected, and data extraction, bias risk assessment, and meta-analysis were performed on the selected papers. Ten studies were selected, and a systematic review with meta-analysis was conducted. Nine papers were published in China and the total number of participants was 715. As a result of administering Bojungikgi-tang to these patients, the number of patients with chemotherapy-induced leukopenia significantly decreased (OR: 0.41, 95% CI: 0.27-0.61, P = .0001, I2 = 35%). Further, white blood cell counts were compared with that of the control group, and it showed an effect on prevention (MD: 0.64, 95% CI: 0.46-0.83, P < .00001, I2 = 90%). A pronounced effect was observed, especially when administered after a diagnosis based on the pattern identification, such as Qi deficiency. (OR: 0.32, 95% CI: 0.18-0.58, P = .0002, I2 = 0%). However, all studies had a high risk of bias due to non-blinding, and most studies had a high or uncertain risk of bias in creating random assignment orders and concealing them. Bojungikgi-tang has an effect on the prevention and treatment of chemotherapy-induced leukopenia. The effect rate can be increased when administered after proper diagnosis, and the possibility of adverse reactions and side effects is lower than that of Granulocyte-Colony Stimulating Factor (G-CSF) injection. Bojungikgi-tang appears to be useful in the treatment and prevention of leukopenia caused by cytotoxic anticancer drugs. However, it is necessary to conduct high-quality clinical studies in the future, considering the possibility of local and language bias, heterogeneity of carcinoma and intervention, and the risk of bias.Registration: PROSPERO CRD4202341054.

Qijiao Shengbai Capsule alleviated leukopenia by interfering leukotriene pathway: Integrated network study of multi-omics.

BACKGROUND: Leukopenia could be induced by chemotherapy, which leads to bone marrow suppression and even affects the therapeutic progression of cancer. Qijiao Shengbai Capsule (QSC) has been used for the treatment of leukopenia in clinic, but its bioactive components and mechanisms have not yet been elucidated clearly. PURPOSE: This study aimed to elucidate the molecular mechanisms of QSC in treating leukopenia. STUDY DESIGN: Serum pharmacochemistry, multi-omics, network pharmacology, and validation experiment were combined to study the effect of QSC in murine leukopenia model. METHODS: First, UPLC-QTOF-MS was used to clarify the absorbed components of QSC. Then, cyclophosphamide (CTX) was used to induce mice model with leukopenia, and the therapeutic efficacy of QSC was assessed by an integrative approach of multi-omics and network pharmacology strategy. Finally, molecular mechanisms and potential therapeutic targets were identified by validated experiments. RESULTS: 121 compounds absorbed in vivo were identified. QSC significantly increase the count of white blood cells (WBCs) in peripheral blood of leukopenia mice with 15 days treatment. Multi-omics and network pharmacology revealed that leukotriene pathway and MAPK signaling pathway played crucial roles during the treatment of leukopenia with QSC. Six targets (ALOX5, LTB4R, CYSLTR1, FOS, JUN, IL-1ß) and 13 prototype compounds were supposed to be the key targets and potential active components, respectively. The validation experiment further confirmed that QSC could effectively inhibit the inflammatory response induced by leukopenia. The inhibitors of ALOX5 activity can significantly increase the number of WBCs in leukopenia mice. Molecular docking of ALOX5 suggested that calycosin, daidzein, and medicarpin were the potentially active compounds of QSC. CONCLUSION: Leukotriene pathway was found for the first time to be a key role in the development of leukopenia, and ALOX5 was conformed as the potential target. QSC may inhibit the inflammatory response and interfere the leukotriene pathway, it is able to improve hematopoiesis and achieve therapeutic effects in the mice with leukopenia.

Treatment Strategy of Leukopenia After Chemotherapy with Traditional Chinese Medicine from the Generation and Transmission of Defense Qi / 中医杂志

By analysing the similarity between defense qi and leukocytes in terms of function， site of action， and circadian rhythm， it is proposed that in traditional Chinese medicine （TCM）， the pathogenesis of leukopenia is defense qi deficiency. By analyzing the relevant discussions on the generation and transmission of defense qi in TCM classics， it is believed that the original qi in lower jiao （焦） is the source of defense qi， while the water and grain qi in middle jiao enriches defense qi， and the upper jiao transmits and distributes defense qi to the whole body. Therefore， when treating leukopenia after chemotherapy with TCM， Guilu Erxian Gelatin （龟鹿二仙胶） and Yougui Pill （右归丸） are often used to tonify the kidney and supplement essence， and moxibustion at Guanyuan （CV 4） and Qihai （CV 6） is usually accompanied to replenish the original qi in lower jiao and enrich the source of defense qi. Guipi Decoction （归脾汤）， Buzhong Yiqi Decoction （补中益气汤）， Shenling Baizhu Powder （参苓白术散）， and Sijunzi Decoction （四君子汤） are often suggested to strengthen spleen and replenish qi， in combination with moxibustion at Zhongwan （CV 12） and Zusanli （ST 36） to transport the spleen and stomach in the middle jiao to enrich the defense qi. Modified Guizhi Decoction （桂枝汤） to harmonize nutrient and defensive aspects is often used， and moxibustion at Dazhui （GV 14） and Feishu （BL 13） or scraping is added to dredge the striae and interstice in the upper jiao and promote transmission and dissemination of the defense qi. Considering the whole process of generation and distribution of defense qi， it is suggested to choose the most appropriate treatment modality flexibly， and combine internal treatment with external treatment， in order to provide ideas for the treatment of leukopenia in tumour patients.

Copper Deficiency: An Overlooked Diagnosis.

Copper deficiency may often be overlooked due to physicians' poor awareness of the disease. Delayed diagnosis and therapy may lead to poor prognosis of neurological function. Here, we present a 68-year-old male with an approximately one-year history of unsteady feet who had visited several clinical departments and was finally diagnosed with copper deficiency. In the present case, it took approximately one year to diagnose the condition, and the therapy of copper supplementation led to only slight improvement in subjective symptoms. Physicians should be more aware of this condition for a good prognosis of the disease.

Exploring the effects of Qijiao Shengbai capsule on leukopenic mice from the perspective of intestinbased on metabolomics and 16S rRNA sequencing.

Qijiao Shengbai capsule (QJSB) is formulated according to the traditional Chinese medicine formula, its function is to nourish Qi and blood, improve the body's immunity. Leukopenia has been treated with it in clinical settings. However, the mechanism of leukopenia from the perspective of intestinal tract has not been reported. This study combined metabolomics and 16S rRNA sequencing technologies to investigate the mechanism of QJSB on leukopenia from the intestine. As a result of cyclophosphamide induction in mice, the results demonstrated that QJSB may greatly increase the quantity of peripheral leukocytes (including neutrophils). Meanwhile, QJSB had a restorative effect on the colon of leukopenic mice; it also increased the level of IL-2, IL-6 and G-CSF in the intestine, further enhancing the immunity and hematopoietic function of mice. Metabolic studies showed that QJSB altered 27 metabolites, most notably amino acid metabolism. In addition, QJSB had a positive regulatory effect on the intestinal microbiota, and could alter community composition by improving the diversity and abundance of the intestinal microbial, which mainly involved 6 related bacterial groups, and primarily regulates three associated SCFAs (acetic acid, butyrate acid and valeric acid). Therefore, this study suggests that QJSB can improve hematopoietic function, enhance the immune system, relieve leucopenia and improve the gut in leucopenic mice by modulating metabolic response pathways, fecal metabolites and intestinal microbiota.

Integrated transcriptomic and metabolomic profiles reveal the protective mechanism of modified Danggui Buxue decoction on radiation-induced leukopenia in mice.

Leukopenia caused by radiation hinders the continuous treatment of cancers. Danggui Buxue Decoction (DBD) has been widely used in clinical owing to low toxicity and definite therapeutic effects to increase leukocytes. Meanwhile, icaritin (ICT) has also been proved to have the effect of boosting peripheral blood cells proliferation. However, there is no study to prove the efficacy of MDBD (Modified Danggui Buxue Decoction), a derivative herbal formula composed of DBD and ICT, in the treatment of radiation-induced leukopenia. In this study, we performed a model of 3.5 Gy whole-body radiation to induce leukopenia in mice. The results of pharmacodynamic studies demonstrated that MDBD could significantly increase the white blood cells in peripheral blood by improving the activity of bone marrow nuclear cells, reducing bone marrow damage, modulating spleen index, and regulating hematopoietic factors to alleviate leukopenia. We also analyzed the integrated results of metabolomics and transcriptomics and found that MDBD could relieve leukopenia and alleviate bone marrow damage by targeting steroid biosynthesis and IL-17 signaling pathway, in which the key genes are Jun, Cxcl2 and Egr1. Therefore, our study provides a basis for the effectiveness and compatibility in the combination of traditional Chinese medicine formula and small molecule drugs.

[Effective components and mechanism of Qijiao Shengbai Capsules based on fingerprinting and network pharmacology].

Qijiao Shengbai Capsules(QJ) can invigorate Qi and replenish the blood, which is commonly used clinically for adjuvant treatment of cancer and leukopenia due to chemoradiotherapy. However, the pharmacological mechanism of QJ is still unclear. This work aims to combine the high-performance liquid chromatography(HPLC) fingerprints and network pharmacology to clarify the effective components and mechanism of QJ. The HPLC fingerprints of 20 batches of QJ were established. The similarity evaluation among 20 batches of QJ was performed by using Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine(version 2012), resulting in a similarity greater than 0.97. Eleven common peaks were identified by reference standard, including ferulic acid, calycosin 7-O-glucoside, ononin, calycosin, epimedin A, epimedin B, epimedin C, icariin, formononetin, baohuoside I, and Z-ligustilide. The "component-target-pathway" network was constructed by network pharmacy, and 10 key components in QJ were identified, such as ferulic acid, calycosin 7-O-glucoside, ononin, and calycosin. The components were involved in the phosphoinositide 3 kinase-protein kinase B(PI3K-Akt), mitogen-activated protein kinase(MAPK), and other signaling pathways by regulating potential targets, including EGFR, RAF1, PIK3R1, and RELA, to auxiliarily treat tumors, cancers, and leukopenia. The molecular docking conducted on the AutoDock Vina platform confirmed the high binding activity of 10 key effective components with core targets, with the binding energy less than-5 kcal·mol~(-1). In this study, the effective components and mechanism of QJ have been preliminary revealed based on HPLC fingerprint and network pharmacology, which provided a basis for quality control of QJ and a refe-rence for further study on its mechanism.

CT-determined sarcopenia is associated with neutropenia in patients undergoing hyperthermic intraperitoneal chemotherapy for gastrointestinal cancer.

BACKGROUND: With better patient selection and the increasing experience in patients undergoing hyperthermic intraperitoneal chemotherapy (HIPEC) combined surgery, the rate of severe postoperative complications and mortality decreased significantly. However, leukopenia and neutropenia were still a particular concern, and their relation to sarcopenia was not clarified. METHODS: Data of consecutive patients who underwent HIPEC for gastrointestinal cancer were collected and analyzed retrospectively between September 2020 and August 2022. Sarcopenia was assessed using psoas muscle index (PMI) at the L3 level on preoperative computed tomography (CT). RESULTS: Among 103 patients enrolled, 37 (35.9%) were classified as sarcopenic. Most leukopenia and neutropenia occurred during the hospital leaving period after HIPEC and surgery. Before the first time of postoperative chemotherapy, the blood tests revealed 11 (29.73%) and 6 (9.09%) patients were diagnosed with neutropenia in sarcopenia and no sarcopenia groups, respectively. Logistic regression analysis revealed sarcopenia was independently associated with the increased risk of neutropenia (OR 5.58, 95% CI 1.70-18.29, p = 0.005). An incremental albumin level was protective against the occurrence of leukopenia and neutropenia. CONCLUSIONS: Sarcopenia and low albumin level were significantly associated with an increased rate of delayed neutropenia after HIPEC in that disease setting and could be the preoperative risk predictors.

Effective components and mechanism of Qijiao Shengbai Capsules based on fingerprinting and network pharmacology / 中国中药杂志

Qijiao Shengbai Capsules(QJ) can invigorate Qi and replenish the blood, which is commonly used clinically for adjuvant treatment of cancer and leukopenia due to chemoradiotherapy. However, the pharmacological mechanism of QJ is still unclear. This work aims to combine the high-performance liquid chromatography(HPLC) fingerprints and network pharmacology to clarify the effective components and mechanism of QJ. The HPLC fingerprints of 20 batches of QJ were established. The similarity evaluation among 20 batches of QJ was performed by using Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine(version 2012), resulting in a similarity greater than 0.97. Eleven common peaks were identified by reference standard, including ferulic acid, calycosin 7-O-glucoside, ononin, calycosin, epimedin A, epimedin B, epimedin C, icariin, formononetin, baohuoside I, and Z-ligustilide. The "component-target-pathway" network was constructed by network pharmacy, and 10 key components in QJ were identified, such as ferulic acid, calycosin 7-O-glucoside, ononin, and calycosin. The components were involved in the phosphoinositide 3 kinase-protein kinase B(PI3K-Akt), mitogen-activated protein kinase(MAPK), and other signaling pathways by regulating potential targets, including EGFR, RAF1, PIK3R1, and RELA, to auxiliarily treat tumors, cancers, and leukopenia. The molecular docking conducted on the AutoDock Vina platform confirmed the high binding activity of 10 key effective components with core targets, with the binding energy less than-5 kcal·mol~(-1). In this study, the effective components and mechanism of QJ have been preliminary revealed based on HPLC fingerprint and network pharmacology, which provided a basis for quality control of QJ and a refe-rence for further study on its mechanism.

High dilution in Leukopenia treatment in five dogs

Leukopenia is associated with the consumption of peripheral leukocytes, decreasedproduction due to endotoxemia and septicemia, medullary hypoplasia, nutritional diseases orautoimmune reactions. In a case report by Narita et al, Echinacea angustifolia demonstrated theeffectiveness of treatment of leukopenia in penguins. Aims:Report the evolution of homeopathictreatment in 5 dogs' patients between 3 and 5 years old, presenting leukopenia. Methodology:The homeopathic treatment was chosen, using Echinaceaangustifolia due to its immunostimulant andimmunomodulatory actions, which evolution was analyzed by blood tests. The exposedinformation is consented by the tutors. Results:The same protocol was made for all of the patients, including 4 globules of Echinacea angustifolia 6 cH orally, every 12 hours for 30 days. The first dog attended on 07/21/2021, presented 4.000 leukocytes, which increased to 6.800 on 08/17/2021. Thesecond patient attend on 12/07/2021 presented 4.700 leukocytes, increasing to 6.800 on 01/25/2022. The third patient attended on 08/24/2021 presented 5.400 leukocytes, which increased to 6.800 on 10/15/2021. The fourth patient presented 4.300 leukocytes on 01/13/2022, increasing to 5.500 on 02/11/2022. The fifth patient presented on12/12/2021 4.600 leukocytes, increasing to 8.400 on 02/03/2022. Therefore, the average of the first collection was 3.681 leukocytes and in the second there was an increase to 6.860 leukocytes (T-test, p= 0,0167). Conclusion:The use of the homeopathic medicine Echinacea angustifolia shows great results, being a viableoption for the treatment of leukopenia, without the side effects.

A novel strategy to reveal clinical advantages and molecular mechanism of aidi injection in the treatment of pancreatic cancer based on network meta-analysis and network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Pancreatic cancer is a common malignancy worldwide due to its poor prognosis and high mortality rate. It is clinically proven that the combination of chemotherapeutic drugs and Traditional Chinese Medicine injections (TCMIs) significantly improves the therapeutic effect. AIM OF THE STUDY: To evaluate the efficacy and clinical benefits of TCMIs in combination with chemotherapy in the treatment of pancreatic cancer and to explore the mechanism of clinical advantage of Aidi injection. METHODS: Randomized controlled trials (RCTs) were searched in databases by NMA before December 29, 2020. WinBUGS 1.4, Stata 14.0, and R 4.0.4 software were used for calculations. All results were expressed as odds ratios and 95% credible intervals. Through the network pharmacology method, the chemical components and their targets, as well as the disease targets were further analyzed. And then, biological experiments were integrated to verify the results of network pharmacology analysis. (PROSPERO ID: CRD42021283559). RESULTS: A total of 33 RCTs with 8 TCMIs and 2011 patients were included. The results of NMA showed that Aidi injection can significantly improve the clinical efficacy (OR = 0.34, 95%CI: 0.16-0.74), and the clinical advantage was that it can significantly alleviate the leukopenia and thrombocytopenia caused by chemotherapy (OR = 5.65, 95%CI: 1.18-28.13). A total of 23 chemical compounds and 280 potential targets for Aidi injection were obtained from the online databases. Among them, there were 22 compounds, 50 targets and 211 signaling pathways closely related to leukopenia. Five genes were predicted to be core targets of ADI in alleviating leukopenia, and 2 of them (TP53 and VEGFA) were confirmed by biological experiments as regulatory targets of ADI in the treatment of PC. CONCLUSIONS: In conclusion, TCMIs in combination with chemotherapy, can improve clinical efficacy and safety in the treatment of pancreatic cancer. However, the overall evidence base is low, and large samples with multi-center RCTs are still needed to support further research findings. Aidi injection can alleviate leukopenia mainly by intervening in oxidative stress, regulating cell proliferation and apoptosis, and regulating the inflammatory response. The combined application of NMA, network pharmacology, and biological experiments provides a reference for clinical evaluation and mechanism of action exploration of other drugs.

A case of improvement of clozapine-induced low leukocyte counts by adenine, cepharanthin and ninjin-yoei-to in a patient with treatment-resistant schizophrenia.

BACKGROUND: Although clozapine is the optimal drug for patients with treatment-resistant schizophrenia, the drug has harmful adverse effects such as leukopenia. Adenine and cepharanthine are known to be effective for radiation- or drug-induced leukopenia. Furthermore, ninjin-yoei-to, a Chinese herbal medicine, augments the production of granulocyte-macrophage colony-stimulating factor. Thus, these drugs may be useful for clozapine-induced leukopenia. CASE PRESENTATION: A 21 years-old woman with schizophrenia was hospitalized for initiation of clozapine treatment. Despite concomitant use of adenine, cepharanthine, and lithium carbonate having activities of increasing leukocytes, a decrease in leukocyte counts occurred after the initiation of clozapine. Additional administration of ninjin-yoei-to increased leukocyte counts, which prevented the development of leukopenia. CONCLUSIONS: This is the first case that concomitant use of adenine, cepharanthin, and ninjin-yoei-to exhibited the effectiveness of reversing the decrease in leukocytes caused by clozapine. Monitoring leukocyte counts and preventing leukopenia are essential for successful treatment with clozapine for refractory schizophrenia. These medicines may be a potential option for preventing clozapine-induced leukopenia.

Effectiveness of Acupuncture in Relieving Chemotherapy-induced Leukopenia in Patients With Breast Cancer: A Systematic Review With A Meta-Analysis and Trial Sequential Analysis.

BACKGROUND: Breast cancer is one of the most common cancers and a major cause of death in women worldwide. Chemotherapy is mainly used to treat and control the progression of breast cancer. Leukopenia is the most common side effect of chemotherapy which may decrease immune function and further lead to serious fatal infections. The purpose of this study was to evaluate the effect of acupuncture on regulating hematopoietic function in chemotherapy-induced leukopenia among patients with breast cancer. METHODS: PubMed, Embase, Cochrane Library, CINAHL Plus, Web of Science, and Chinese articles in the Airiti Library and China National Knowledge Infrastructure (CNKI) databases were searched to August 2021 for papers to include in a systematic review and meta-analysis. A random-effects model was applied. The effect size was calculated by Hedges' g. Heterogeneity was determined using Cochran's Q test. Moderator analyses were performed to examine potential sources of heterogeneity. A trial sequential analysis (TSA) was conducted to determine whether the current sample size was sufficient. RESULTS: Ten randomized controlled trials involving 650 participants were eligible for inclusion. Analysis by the random-effects model showed a significant effect by acupuncture of ameliorating leukopenia during chemotherapy. Levels of white blood cells (WBCs) were increased (Hedges' g = 0.70, P < .001, I2 = 34%), neutrophil counts (Hedges' g = 0.80, P < .001, I2 = 0%) were significantly enhanced. Moreover, regardless of the manner through which acupuncture was applied, overall values of WBCs increased. CONCLUSIONS: The current meta-analysis supports acupuncture possibly ameliorating chemotherapy-induced leukopenia, as WBC and neutrophil values significantly increased after acupuncture in patients undergoing chemotherapy. Additionally, regardless of the type of acupuncture, values of WBCs increased. These findings are actionable and support both the clinical use of acupuncture to relieve chemotherapy-induced leukopenia and further research regarding the use of acupuncture in patients experiencing immunosuppression when undergoing chemotherapy.Trial Registration: PROSPERO-CRD42020215759.

Effectiveness of Herbal Medicine for Leukopenia/Neutropenia Induced by Chemotherapy in Adults with Colorectal Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the effectiveness of Chinese Herbal Medicine (CHM) on leukopenia/neutropenia induced by chemotherapy in adults with colorectal cancer (CRC). METHODS: Eight electronic databases were searched from their inception to June 2020. Randomized controlled trials with clarified sequence generation were qualified. Two reviewers independently conducted the screening and data extraction. Methodological quality was assessed using the Risk of Bias tool. RevMan 5.4 was applied to the meta-analysis. RESULTS: Twenty-seven studies involving 1867 participants were qualified, of which 26 were included in the quantitative synthesis. Meta-analysis showed that CHM significantly reduced the incidence of leukopenia induced by chemotherapy (RR = 0.69; 95% CI 0.59-0.82), as well as the grade 3/4 leukopenia (RR = 0.71; 95% CI 0.55-0.90). Meanwhile,CHM decreased the occurrence of neutropenia (RR = 0.52, 95% CI 0.35-0.77), especially for the grades 3/4 neutropenia (RR = 0.42, 95% CI 0.27-0.64). Twenty-six of the included studies focused on the adverse events related to CHM. CONCLUSION: CHM may relieve neutropenia/leukopenia induced by chemotherapy in adults with colorectal cancer.

Chinese Herbal Medicine for Chemotherapy-Induced Leukopenia: A Systematic Review and Meta-Analysis of High-Quality Randomized Controlled Trials.

Aim: We conducted a systematic review of high-quality randomized controlled trials (RCTs) to assess the efficacy and safety of Chinese herbal medicine (CHM) for the treatment of chemotherapy-induced leukopenia (CIL). Methods: Eight electronic databases were searched from the date of inception to November 4, 2020 for high-quality RCTs that met the requirements of at least four key domains of the Cochrane risk of bias (RoB) tool. RevMan 5.3 was applied for the meta-analysis. Results: Fourteen RCTs involving 1,053 patients were included. The pooled results showed that CHM + chemotherapy exerted greater beneficial effects on white blood cell (WBC), neutrophil (NEU), hemoglobin (Hb), and platelet (PLT) counts in addition to the Karnofsky performance scale (KPS) score, but showed no significant difference on granulocyte colony-stimulating factor (G-CSF) dosage compared with chemotherapy alone. Placebo (PBO) + chemotherapy and CHM + chemotherapy groups showed no significant differences in terms of reduction of the incidence of neutropenia. CHM + chemotherapy was superior to Western medicine (WM) + chemotherapy in improving the WBC count, KPS, infection amount, G-CSF use rate, and incidence of leukopenia. In addition, no severe adverse events were observed in the 14 RCTs. Conclusion: CHM in combination with chemotherapy could effectively improve the clinical symptoms of CIL when compared with chemotherapy alone or Western medicine + chemotherapy, except when comparing with PBO + chemotherapy. While CHMs were generally safe for clinical use and exerted no severe side effects in the 14 RCTs, high-quality RCTs with larger sample sizes are essential to reduce study heterogeneity.

Elucidation of the molecular mechanism of Sanguisorba Officinalis L. against leukopenia based on network pharmacology.

Leukopenia is the most common hallmark of hematopoietic diseases in clinic. Sanguisorba Officinalis L., a traditional Chinese medicine, has long been used for alleviating leukopenia. However, its associated mechanism still remains unknown. In this study, a network pharmacology approach was used to elucidate the underlying mechanisms of Sanguisorba Officinalis L. against leukopenia. Firstly, 12 active compounds of Sanguisorba Officinalis L. were identified through TCMSP database with absorption, distribution, metabolism, excretion (ADME) screening, and UHPLC-MS analysis. Then, 258 leukopenia related targets of the identified active compounds were predicted via the Swiss Target Prediction database, GeneCards database and DisGeNET database, respectively. After taking the intersection of two related targets, 72 common targets were selected. Among them, 8 core targets (VEGFA, HSP90AA1, EGFR, PTGS2, MTOR, ESR1, ERBB2, MDM2) of Sanguisorba Officinalis L. against leukopenia were obtained through the topological analysis. Meanwhile, both the GO and KEGG pathway analysis reveal that the core targets are mainly enriched in PI3K-Akt, HIF-1, VEGF and estrogen signaling pathways. In addition, molecular docking simulation was performed to explore the binding ability between the 12 active compounds of Sanguisorba Officinalis L. with 8 core targets. Furthermore, a myelosuppressive mice model was established to evaluate the protective effect of Sanguisorba Officinalis L. against leukopenia. The results showed that the ethanol extract of Sanguisorba Officinalis L. significantly raised the number of peripheral white blood cells. Overall, this study provides an insight into the underlying mechanisms of Sanguisorba Officinalis L. against leukopenia, which lays a theoretical foundation for the further experimental verification and clinical application.

A rapid and sensitive UHPLC-MS/MS method for the determination of ziyuglycoside I and its application in a preliminary pharmacokinetic study in healthy and leukopenic rats.

Ziyuglycoside I (ZgI), one of the main active ingredients in the popular Diyushengbai tablet made from Sanguisorba officinalis L., has been proven to relieve leukopenia clinically. However, to our knowledge, no studies have investigated the pharmacokinetics of either Diyushengbai tablet or ZgI in leukopenic vs. healthy individuals. In the present study, a rapid and sensitive UHPLC-MS/MS method was developed for detecting ZgI. On using this method on a novel cyclophosphamide-induced leukopenia model, we investigated differences in the pharmacokinetic characteristics of ZgI between leukopenic and normal rats. Chromatographic separation of ZgI and glycyrrhetinic acid (IS) was achieved via gradient elution in 0.5 min, and the total run time lasted for 5 min. Methodological validation results presented a good accuracy (102.6 %-110.8 %) and precision (% RSD ≤ 13.8) with a limit of quantitation of 0.5 ng/mL. Pharmacokinetic results showed a significantly shortened peak time (Tmax) (0.93 vs. 0.33 h) while a remarkably decreased maximum concentration (Cmax) (7.96 vs. 3.40 ng/L) in the 20 mg/kg leukopenia group in comparison with those in the 20 mg/kg normal group. In addition, a prolonged elimination half-life (t1/2ß) was observed in the 20 mg/kg leukopenia group (5.02 vs. 18.51 h). We observed similar trends in the 5 mg/kg oral dosing treatment and control groups, except for Cmax, which did not differ between the groups. We did not find pharmacokinetic differences in ZgI between the two leukopenia groups. Thus, the pharmacokinetic parameters of ZgI (e.g., Tmax, Cmax, and T1/2ß) changed based on the presence of a leukopenic state. This study may provide guidance for the development of ZgI as an agent for the treatment of leukopenia.

Effect of Erxian Shengbai Decoction Combined with Huangqi Huanagshan Soup on Leukopenia After Chemotherapy and Regulatory Effect on Immunity / 中国实验方剂学杂志

Objective:To observe the clinical efficacy of Erxian Shengbai decoction combined with Huangqi Huang soup for leucopenia (deficiency of spleen and kidney Qi) after chemotherapy, and to investigate the regulatory effect on immune function and cytokines. Method:One hundred and fifty patients were randomly divided into control group（75 cases） and observation group （75 cases）by random number table. Patients in group got batilol tablets by oral administration for 6 weeks, 60 mg/time, 3 times/day. And the patients at stage Ⅲ or Ⅳ additionally received recombinant human granulocyte colony stimulating factor injection (rhG-CSF) for subcutaneous injection,2-5 μg·kg-1·d-1, until the count of neutrophils recovered to 5.0×109个/L (10.0×109个/L for white blood cell). In the control group shengbaikang granules were taken orally,1 bag/time,3 times/day.Patients in observation group additionally received Erxian Shengbai decoction combined with Huangqi Huangshan soup for 6 weeks, 1 doses/day. Number of peripheral blood leukocytes (WBC) and neutrophils (NEUT), time to recovery, number of infections, duration of using antibiotics, dose and duration of rhG-CSF, red blood cell (RBC) count, hemoglobin (Hb), platelets (PLT) and rate of completed chemotherapy were recorded. Scores of traditional Chinese medicine（TCM）syndrome and karnofsky performance scale (KPS) were graded before and after treatment. Levels of T lymphocyte subsets (CD3+, CD4+, CD8+ and CD4+/CD8+) , natural killer cell (NK), interleukin-2 (IL-2), IL-6, and tumor necrosis factor-α (TNF-α) were all detected. Result:In the analysis of rank sum test, to the efficacy for leucopenia in observation group was better than that in control group (Z=2.057, P<0.05). Levels of WBC, NEUT, RBC, Hb and PLT were higher than those in control group (P<0.01). Time to recovery, number of infections and duration of using antibiotics, dose and duration of rhG-CSF were all less than those in control group (P<0.01). After treatment, the recovery rate of WBC and NEUT as well as completed chemotherapy were 76.12% (51/67), 73.13% (49/67) and 92.54% (62/67) in observation group, higher than 57.35% (39/68), 52.94% (36/68) and 79.41% (54/68) in control group (P<0.01). Levels of NK, CD3+, CD4+, CD4+/CD8+ and IL-2 were all higher than those in control group (P<0.01), while levels of CD8+ , IL-6 and TNF-α were lower than those in control group (P<0.05). Conclusion:Erxian Shengbai decoction combined with Huangqi Huangshan soup can promote the recovery of WBC and NEUT, stabilize the immune function, regulate cytokines, improve the microenvironment of bone marrow hematopoiesis, improve the completion rate of chemotherapy, reduce the number of infections and the amount of rhG-CSF, relieve clinical symptoms, and stabilize the quality of life in patients with leukopenia after chemotherapy (deficiency of spleen and kidney Qi).

[Antioxidant mechanism of diallyl sulfide in inhibiting leucopenia in peripheral blood induced by benzene in rats].

Objective: To investigate the antioxidant mechanism of diallyl sulfide (DAS) in antagonizing the reduction in peripheral blood white blood cells (WBC) induced by benzene in rats. Methods: A total of 60 specific pathogen-free adult male Sprague-Dawley rats, with a body weight of 180-220 g, were selected, and after 5 days of adaptive feeding, they were randomly divided into blank control group, DAS control group, benzene model group, benzene+low-dose DAS group, benzene+middle-dose DAS group, and benzene+high-dose DAS group, with 10 rats in each group. The rats in the benzene+low-dose DAS group, the benzene+middle-dose DAS group, the benzene+high-dose DAS group, and the DAS control group were given DAS by gavage at a dose of 40, 80, 160, and 160 mg/kg·bw, respectively, and those in the blank control group and the benzene model group were given an equal volume of corn oil; 2 hours later, the rats in the benzene model group, the benzene+low-dose DAS group, the benzene+middle-dose DAS group, and the benzene+high-dose DAS group were given a mixture of benzene (1.3 g/kg·bw) and corn oil (with a volume fraction of 50%), and those in the blank control group and the DAS control group were given an equal volume of corn oil. The above treatment was given once a day for 4 consecutive weeks. At 1 day before treatment, anticoagulated blood was collected from the jugular vein for peripheral blood cell counting. After anesthesia with intraperitoneally injected pentobarbital (50 mg/kg·bw), blood samples were collected from the abdominal aorta, serum was isolated, and the thymus, the spleen, and the femur were freed at a low temperature to measure oxidative and antioxidant indices. The femur at one side was freed for WBC counting in bone marrow. Results: Compared with the blank control group, the benzene model group had significant reductions in the volume, weight, and organ coefficient of the spleen and the thymus (P<0.05) ; compared with the benzene model group, the benzene+low-dose DAS group, the benzene+middle-dose DAS group, and the benzene+high-dose DAS group had significant increases in the volume of the spleen and the thymus and the weight and organ coefficient of the spleen (P<0.05), and the benzene+middle-dose DAS group and the benzene+high-dose DAS group had significant increases in the weight and organ coefficient of the thymus (P<0.05). Compared with the blank control group, the benzene model group had a significant reduction in WBC count in peripheral blood and bone marrow (P<0.05), and compared with the benzene model group, the benzene+middle-dose DAS group and the benzene+high-dose DAS group had a significant increase in WBC count in peripheral blood and bone marrow (P<0.05). Compared with the blank control group, the benzene model group had a significant increase in the serum level of malondialdehyde (MDA) (P<0.05) and significant reductions in total superoxide dismutase (T-SOD) activity, reduced glutathione (GSH) level, GSH/oxidized glutathione (GSSG) ratio, total antioxidant capacity (T-AOC) (P<0.05) ; compared with the benzene model group, the benzene+high-dose DAS group had a significant reduction in the serum level of MDA and significant increases in T-SOD activity, GSH level, GSH/GSSG ratio, and T-AOC (P<0.05). Compared with the blank control group, the benzene model group had a significant increase in the level of MDA (P<0.05) and significant reductions in GSH level, GSH/GSSG ratio, and T-AOC (P<0.05) in the spleen; compared with the benzene model group, the benzene+low-dose DAS group, the benzene+middle-dose DAS group, and the benzene+high-dose DAS group had a significant reduction in MDA level (P<0.05) and significant increases in GSH level and T-AOC (P<0.05), and the benzene+high-dose DAS group had significant increases in T-SOD activity and GSH/GSSG ratio (P<0.05). Compared with the blank control group, the benzene model group had a significant increase in the level of MDA in bone marrow cells (BMCs) and peripheral blood mononucleated cells (PBMCs) (P<0.05) and a significant reduction in T-AOC in PBMCs (P<0.05) ; compared with the benzene model group, the benzene+low-dose DAS group, the benzene+middle-dose DAS group, and the benzene+high-dose DAS group had a significant reduction in the level of MDA in BMCs and PBMCs (P<0.05), and the benzene+high-dose DAS group had significant increases in GSH level and GSH/GSSG ratio (P<0.05) . Conclusion: DAS can antagonize the benzene-induced reduction in peripheral blood WBC, possibly by exerting an anti-oxidative stress effect.