Feasibility of an exercise-nutrition-psychology integrated rehabilitation model based on mobile health and virtual reality for cancer patients: a single-center, single-arm, prospective phase II study.

OBJECTIVE: Explore the feasibility of a mobile health(mHealth) and virtual reality (VR) based nutrition-exercise-psychology integrated rehabilitation model in Chinese cancer patients. METHODS: We recruited cancer patients in the Oncology department of the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University from October 2022 to April 2023. The rehabilitation program was provided by a team of medical oncologists, dietitians, psychotherapists, and oncology specialist nurses. Participants received standard anti-cancer therapy and integrated intervention including hospitalized group-based exercise classes, at-home physical activity prescription, behavior change education, oral nutrition supplements, and psychological counseling. An effective intervention course includes two consecutive hospitalization and two periods of home-based rehabilitation (8 weeks). Access the feasibility as well as changes in aspects of physical, nutritional, and psychological status. RESULTS: At the cutoff date of April 2023, the recruitment rate was 75% (123/165). 11.4%patients were lost to follow-up, and 3.25% withdrew halfway. Respectively, the completion rate of nutrition, exercise, and psychology were 85%,55%, and 63%. Nutrition interventions show the highest compliance. The parameters in nutrition, psychology, muscle mass, and quality of life after the rehabilitation showed significant improvements (P < .05). There was no significant statistical difference (P > .05) in handgrip strength and 6-minute walking speed. CONCLUSION: It is feasible to conduct mHealth and VR-based nutrition-exercise-psychology integrated rehabilitation model in Chinese cancer patients. A larger multi-center trial is warranted in the future. TRIAL REGISTRATION: ChiCTR2200065748 Registered 14 November 2022.

Orally administered yeast-derived ß-glucan alleviates mast cell-dependent airway hyperresponsiveness and inflammation in a murine model of asthma.

BACKGROUND: Particulate ß-glucans (WGP) are natural compounds with regulatory roles in various biological processes, including tumorigenesis and inflammatory diseases such as allergic asthma. However, their impact on mast cells (MCs), contributors to airway hyperresponsiveness (AHR) and inflammation in asthma mice, remains unknown. METHODS: C57BL/6 mice underwent repeated OVA sensitization without alum, followed by Ovalbumin (OVA) challenge. Mice received daily oral administration of WGP (OAW) at doses of 50 or 150 mg/kg before sensitization and challenge. We assessed airway function, lung histopathology, and pulmonary inflammatory cell composition in the airways, as well as proinflammatory cytokines and chemokines in the bronchoalveolar lavage fluid (BALF). RESULTS: The 150 mg/kg OAW treatment mitigated OVA-induced AHR and airway inflammation, evidenced by reduced airway reactivity to aerosolized methacholine (Mch), diminished inflammatory cell infiltration, and goblet cell hyperplasia in lung tissues. Additionally, OAW hindered the recruitment of inflammatory cells, including MCs and eosinophils, in lung tissues and BALF. OAW treatment attenuated proinflammatory tumor necrosis factor (TNF)-α and IL-6 levels in BALF. Notably, OAW significantly downregulated the expression of chemokines CCL3, CCL5, CCL20, CCL22, CXCL9, and CXCL10 in BALF. CONCLUSION: These results highlight OAW's robust anti-inflammatory properties, suggesting potential benefits in treating MC-dependent AHR and allergic inflammation by influencing inflammatory cell infiltration and regulating proinflammatory cytokines and chemokines in the airways.

ß-Glucan-A promising immunocyte-targeting drug delivery vehicle: Superiority, applications and future prospects.

Drug delivery technologies that could convert promising therapeutics into successful therapies have been under broad research for many years. Recently, ß-glucans, natural-occurring polysaccharides extracted from many organism species such as yeast, fungi and bacteria, have attracted increasing attention to serve as drug delivery carriers. With their unique structure and innate immunocompetence, ß-glucans are considered as promising carriers for targeting delivery especially when applied in the vaccine construction and oral administration of therapeutic agents. In this review, we focus on three types of ß-glucans applied in the drug delivery system including yeast ß-glucan, Schizophyllan and curdlan, highlighting the benefits of ß-glucan based delivery system. We summarize how ß-glucans as delivery vehicles have aided various therapeutics ranging from macromolecules including proteins, peptides and nucleic acids to small molecular drugs to reach desired cells or organs in terms of loading strategies. We also outline the challenges and future directions for developing the next generation of ß-glucan based delivery systems.

The engineered agonistic anti-CD40 antibody potentiates the antitumor effects of ß-glucan by resetting TAMs.

Anti-CD40 antibodies (Abs) have been shown to induce antitumor T-cell responses. We reported that the engineered agonistic anti-CD40 Ab (5C11, IgG4 isotype) recognized human CD40 antigen expressed on a human B lymphoblastoid cell line as well as on splenic cells isolated from humanized CD40 mice. Of note, a single high dosage of 5C11 was able to prohibit tumor growth in parallel with an increase in the population of infiltrated CD8+ T cells. Furthermore, the antitumor effects of 5C11 were enhanced in the presence of ß-glucan along with an increase in the population of infiltrated CD8+ T cells. In addition, the numbers of CD86+ TAMs and neutrophils were elevated in the combination of 5C11 and ß-glucan compared with either 5C11 or ß-glucan alone. Furthermore, the abundance of Faecalibaculum, one of the probiotics critical for tumor suppression, was obviously increased in the combination of 5C11 and ß-glucan-treated mice. These data reveal a novel mechanism of tumor suppression upon the combination treatment of 5C11 and ß-glucan and propose that the combination treatment of agonistic anti-human CD40 antibody 5C11 and ß-glucan could be a promising therapeutic strategy for cancer patients.

Sulforaphane Attenuates AOM/DSS-Induced Colorectal Tumorigenesis in Mice via Inhibition of Intestinal Inflammation.

Sulforaphane (SFN) is a compound derived from cruciferous plants. It has received considerable attention in recent years due to its effectiveness in cancer prevention and anti-inflammatory properties. The purpose of this study was to evaluate the antitumor potential of sulforaphane on colitis-associated carcinogenesis (CAC) through the establishment of a mouse model with AOM/DSS. First, AOM/DSS and DSS-induced model were established and administered SFN for 10 wk, and then the severity of colitis-associated colon cancer was examined macroscopically and histologically. Subsequently, immune cells and cytokines in the tumor microenvironment (TME) were quantified. Finally, the influence of sulforaphane was also investigated using different colon cell lines. We found that sulforaphane treatment decreased tumor volume, myeloid-derived suppressor cells (MDSC) expansion, the expression of the proinflammatory cytokine IL-1ß, and the level of IL-10 in serum. Also, it enhanced the antitumor activities of CD8+ T cells and significantly reduced tumorigenesis as induced by AOM/DSS. SFN also attenuated intestinal inflammation in DSS-induced chronic colitis by reshaping the inflammatory microenvironment. This work demonstrates that sulforaphane suppresses carcinogenesis-associated intestinal inflammation and prevents AOM/DSS-induced intestinal tumorigenesis and progression.

Circadian rhythm regulation in the immune system.

Circadian rhythms are a ubiquitous feature in nearly all living organisms, representing oscillatory patterns with a 24-h cycle that are widespread across various physiological processes. Circadian rhythms regulate a multitude of physiological systems, including the immune system. At the molecular level, most immune cells autonomously express clock-regulating genes, which play critical roles in regulating immune cell functions. These functions encompass migration, phagocytic activity, immune cell metabolism (such as mitochondrial structural function and metabolism), signalling pathway activation, inflammatory responses, innate immune recognition, and adaptive immune processes (including vaccine responses and pathogen clearance). The endogenous circadian clock orchestrates multifaceted rhythmicity within the immune system, optimizing immune surveillance and responsiveness; this bears significant implications for maintaining immune homeostasis and resilience against diseases. This work provides an overview of circadian rhythm regulation within the immune system.

Association of lipoprotein(a) with left ventricular hypertrophy assessed by electrocardiogram in adults: a large cross-sectional study.

Background and aims: Increasing evidence supports a causal relationship between lipoprotein(a) [Lp(a)] and atherosclerotic cardiovascular disease, yet its association with left ventricular hypertrophy (LVH) assessed by electrocardiogram (ECG) remains unknown. The aim of this study was to explore the relationship between Lp(a) and LVH assessed by ECG in general population. Methods and results: In this cross-sectional study, we screened 4,052 adults from the participants of the third National Health and Nutrition Examination Survey for analysis. Lp(a) was regarded as an exposure variable. LVH defined by the left ventricular mass index estimated from ECG was considered as an outcome variable. Multivariate logistic regression and restricted cubic spline (RCS) were used to assess the relationship between Lp(a) and LVH. Individuals with LVH had higher Lp(a) compared to individuals without LVH (P< 0.001). In the fully adjusted model, Lp(a) was strongly associated with LVH when as a continuous variable (per 1-unit increment, OR: 1.366, 95% CI: 1.043-1.789, P = 0.024), and higher Lp(a) remained independently associated with a higher risk of LVH when participants were divided into four groups according to quartiles of Lp(a) (Q4 vs Q1, OR: 1.508, 95% CI: 1.185-1.918, P = 0.001). And in subgroup analysis, this association remained significant among participants< 60 years, ≥ 60 years, male, with body mass index< 30 kg/m2, with hypertension and without diabetes (P< 0.05). In addition, we did not observe a nonlinear and threshold effect of Lp(a) with LVH in the RCS analysis (P for nonlinearity = 0.113). Conclusion: Lp(a) was closely associated with LVH assessed by ECG in general population.

RNA Sequencing and Bioinformatics Analysis to Reveal Potential Biomarkers in Patients with Combined Allergic Rhinitis and Asthma Syndrome.

Introduction: Combined allergic rhinitis and asthma syndrome (CARAS) is a concurrent clinical or subclinical allergic symptom of diseases of the upper and lower respiratory tract. This study is the first to explore the expression profiles of mRNA, lncRNA, and circRNA in CARAS using RNA sequencing, which may provide insight into the mechanisms underlying CARAS. Material and Methods: Whole blood samples from nine participants (three CARAS patients, three AR patients, and three normal control participants) were subjected to perform RNA sequencing, followed by identification of differentially expressed lncRNAs (DElncRNAs), circRNAs (DEcircRNAs) and mRNAs (DEmRNAs). Then, lncRNA/circRNA-mRNA regulatory pairs were constructed, followed by functional analysis, immune infiltration analysis, drug prediction, and expression validation with RT-qPCR and ELISA. Results: The results showed that 61 DEmRNAs, 23 DElncRNAs and 3 DEcircRNAs may be related to the occurrence and development of CARAS. KRT8 may be implicated in the development of AR into CARAS. Three immunity-related mRNAs (IDO1, CYSLTR2, and TEC) and two hypoxia-related mRNAs (TKTL1 and VLDLR) were associated with the occurrence and development of CARAS. TEC may be considered a drug target for Dasatinib in treating CARAS. Several lncRNA/circRNA-mRNA regulatory pairs were identified in CARAS, including LINC00452/MIR4280HG/hsa_circ_0007272/hsa_circ_0070934-CLC, HEATR6-DT/LINC00639/LINC01783/hsa_circ_0008903-TEC, RP11-71L14.3-IDO1/SMPD3, RP11-178F10.2-IDO1/HRH4, and hsa_circ_0008903-CYSLTR2, which may indicate potential regulatory effects of lncRNAs/circRNAs in CARAS. Dysregulated levels of immune cell infiltration may be closely related to CARAS. Conclusion: The regulating effect of lncRNA/circRNA-immunity/hypoxia-related mRNA regulatory pairs may be involved in the occurrence and development of CARAS.

[Research progress of dendritic cell-associated C-type lectin-1 (dectin-1) in anti-tumor immunology].

Dendritic cell-associated C-type lectin 1 (dectin-1) receptor is the main pattern recognition receptor for ß-glucan on the fungal cell wall. Dectin-1 is extensively expressed in myeloid cells including dendritic cells (DCs), macrophages, and neutrophils. After binding with endogenous and exogenous ligands, dectin-1 can induce intracellular signal transduction and trigger a series of cellular immune responses, and participate in anti-infection and anti-tumor processes. The interaction between dectin-1 and its different ligands triggers different signal activation pathways and cell functions. The recognition of dectin-1 with ß-glucan promotes the maturation of DCs and its ability to present antigen to T cells, which induces the proliferation of cytotoxic T lymphocytes, and activates the specific immune response in vivo, thus playing an anti-tumor role. The article summarizes the structure and signaling pathway of the dectin-1 molecule and its research progress in anti-tumor immunity.

Correlation Between Cystatin C and the Severity of Cardiac Dysfunction in Patients with Systolic Heart Failure.

Introduction: To investigate the relationship between cystatin C and cardiac dysfunction severity in patients with systolic heart failure. Methods: We recruited 100 hospitalized patients with systolic heart failure and 100 age-gender-matched controls. The clinical information of each patient was collected. Blood pressure, heart rate, height, and weight were measured, as were serum concentrations of cholesterol, renal function indices, cystatin C, and B-type natriuretic peptide (BNP). Transthoracic echocardiography was performed on each patient. Results: Cystatin C and other indices of renal function, such as urea nitrogen, creatinine, and uric acid, were significantly elevated in the serum of patients with heart failure and those with more severe cardiac dysfunction. The stepwise regression analyses showed that cystatin C was positively associated with BNP (ß = 0.18, P = 0.04, 95% CI: 21.1 ~ 1420.4) and left atrial diameter (LAD) (ß = 0.19, P = 0.04, 95% CI: 0.03 ~ 9.21) and was negatively associated with ejection fraction (ß = -0.22, P = 0.023, 95% CI: -12.4 ~ -0.93), while creatinine was only positively correlated with BNP (ß = 0.23, P = 0.03, 95% CI: 1.11 ~ 20.7). The Receiver Operating Characteristic (ROC) curves demonstrated significantly more severe cardiac dysfunction (NYHA III/IV) in patients with cystatin C ≥ 0.895mg/L (sensitivity was 83.0%, specificity was 80.9%, AUC = 0.893) and creatinine ≥ 91.5µmol/L (sensitivity was 71.7%, specificity was 70.2%, AUC = 0.764). Conclusion: Cystatin C was significantly correlated with cardiac structure and function in patients with systolic heart failure, and it was more valuable than creatinine to evaluate the severity of heart failure.

Yeast ß-glucan modulates macrophages and improves antitumor NK-cell responses in cancer.

As the largest proportion of myeloid immune cells in tumors, macrophages play an important role in tumor growth and regression according to their different phenotypes, thus reprogramming macrophages has become a new research direction for cancer immunotherapy. Yeast-derived whole ß-glucan particles (WGPs) can induce M0 macrophages to differentiate into M1 macrophages and convert M2 macrophages and tumor-associated macrophages (TAMs) into M1 macrophages. In vitro, studies have confirmed that WGP-treated macrophages increase the activating receptors in natural killer cells (NK cells) and enhance the cytotoxicity of NK cells. The extracellular regulated protein kinases (ERK) signaling pathway is involved in WGP-mediated regulation of the macrophage phenotype. Further in vivo studies show that oral WGP can significantly delay tumor growth, which is related to the increased proportion of macrophages and NK cells, the macrophage phenotype reversal, and the enhancement of NK cell immune function. NK-cell depletion reduces the therapeutic efficacy of WGP in tumor-bearing mice. These findings revealed that in addition to T cells, NK cells also participate in the antitumor process of WGP. It was confirmed that WGP regulates the macrophage phenotype to regulate NK-cell function.

Neutralizing IL-8 potentiates immune checkpoint blockade efficacy for glioma.

Malignant gliomas are largely refractory to immune checkpoint blockade (ICB) therapy. To explore the underlying immune regulators, we examine the microenvironment in glioma and find that tumor-infiltrating T cells are mainly confined to the perivascular cuffs and express high levels of CCR5, CXCR3, and programmed cell death protein 1 (PD-1). Combined analysis of T cell clustering with T cell receptor (TCR) clone expansion shows that potential tumor-killing T cells are mainly categorized into pre-exhausted/exhausted and effector CD8+ T subsets, as well as cytotoxic CD4+ T subsets. Notably, a distinct subpopulation of CD4+ T cells exhibits innate-like features with preferential interleukin-8 (IL-8) expression. With IL-8-humanized mouse strain, we demonstrate that IL-8-producing CD4+ T, myeloid, and tumor cells orchestrate myeloid-derived suppressor cell infiltration and angiogenesis, which results in enhanced tumor growth but reduced ICB efficacy. Antibody-mediated IL-8 blockade or the inhibition of its receptor, CXCR1/2, unleashes anti-PD-1-mediated antitumor immunity. Our findings thus highlight IL-8 as a combinational immunotherapy target for glioma.

Whole ß-glucan particle attenuates AOM/DSS-induced colorectal tumorigenesis in mice via inhibition of intestinal inflammation.

Yeast ß-glucan is a polysaccharide purified from the Saccharomyces cerevisiae cell wall, and its multiple biological activities are essential for immune regulation. However, the effect of ß-glucan on the intestinal immune response during colitis-associated colorectal cancer (CAC) is unclear. Here, we explore the possible role of ß-glucan in the development of CAC. Wild type (WT) mice with CAC induced by azoxmethane (AOM) and dextran sodium sulfate (DSS) had fewer tumors than untreated mice after oral ß-glucan because of increased antitumor dendritic cells (DCs) in the tumor microenvironment, resulting in more CD8+ T cells and the production of related cytokines. ß-glucan also increased resistance to DSS-induced chronic colitis by reshaping the inflammatory microenvironment. These data suggest that ß-glucan improves experimental intestinal inflammation and delays the development of CAC. Therefore, ß-glucan is feasible for treating chronic colitis and CAC in clinical practice.

NUPR1 imparts oncogenic potential in bladder cancer.

BACKGROUND: NUPR1, or p8, is a small chromatin protein that plays a central role in the resistance to treatment and progression of cancer. Nevertheless, the molecular mechanism of NUPR1 in bladder cancer (BLCA) remains unclear. METHODS: We used online databases and immunohistochemistry (IHC) to explore the expression of NUPR1 in BLCA tissues and controls. Lentivirus-mediated small interfering ribonucleic acid (siRNA) was used to knockdown the expression of NUPR1 in two human BLCA cell lines. We used an in vivo experiment to investigate the effect of NUPR1 knockdown on the growth of BLCA. Moreover, an in silico analysis was conducted to assess the differential expression profile after NUPR1 interference. The CIBERSORT algorithm was utilized to evaluate the effects of tumor-infiltrating immune cells among BLCA patients. RESULTS: The expression of NUPR1 in BLCA tissues was significantly higher than in the control. NUPR1 expression was also positively correlated with the stage of BLCA. After lentivirus-mediated interference, the expression of NUPR1 was significantly down-regulated in BLCA cell lines. The cell cycle was blocked in G1 phase and the cell proportion of S phase was decreased in both two cell lines. Moreover, in vivo experiment revealed that the tumor growth of BLCA can be delayed by inhibiting the expression of NUPR1. Both in silico analysis and functional experiments revealed that NUPR1 was correlated with epithelial-mesenchymal transition (EMT). We also revealed that macrophages were the most related immune cells associated with the expression of NUPR1 in BLCA. CONCLUSIONS: This study suggests that NUPR1 plays a carcinogenic role in BLCA. NUPR1 lentivirus-mediated interference could interfere with cycle progression of the BLCA cell, resulting in cell cycle arrest in the G1-phase. The carcinogenic effect of NUPR1 in BLCA is likely achieved through EMT. NUPR1 is correlated with the M0-type macrophage markers CD68 and CD11b-integrin.

Serum uric acid was non-linearly associated with the risk of all-cause and cardiovascular death in individuals with coronary heart disease: a large prospective cohort study.

Objective: To investigate the association of serum uric acid (SUA) with all-cause and cardiovascular death in individuals with coronary heart disease (CHD). Methods: In this prospective cohort study, 1556 individuals from the National Health and Nutrition Examination Survey (1999-2015) were included in the analysis. Multivariate COX regression analysis, restricted cubic spline plot (RCS) and threshold effect were used to investigate the association between SUA and all-cause and cardiovascular death in individuals with CHD. Results: In the fully adjusted model, when SUA was regarded as a continuous variable, it was closely associated with the risk of all-cause and cardiovascular death (P < 0.01). When all participants were divided into four groups according to the quartile of SUA, compared with Q1 group, only individuals in Q4 group had higher risk of all-cause and cardiovascular death (P = 0.002 and 0.034). The following subgroup analysis showed that the association between SUA and all-cause death risk was still statistically significant in individuals over 60 years old, male, with hypertension, without diabetes and with chronic kidney disease, while the association with cardiovascular death risk only persisted in individuals over 60 years old and male (P < 0.05). Further sensitivity analysis showed that SUA was still closely associated with all-cause and cardiovascular death, whether as a continuous variable or a classified variable (P = 0.007 and 0.044). RCS analysis revealed that SUA had a nonlinear association with all-cause and cardiovascular death risk (P for nonlinearity < 0.01). Threshold effect analysis showed that SUA below 345 umol/L was negatively associated with all-cause and cardiovascular death risk (P < 0.05), while SUA above 345 umol/L was positively associated with all-cause and cardiovascular death risk (P < 0.001), and the 2-piecewise regression model was better than the 1-line regression model (P for likelihood ratio test < 0.05). Conclusion: SUA had a nonlinear association with all-cause and cardiovascular death risk in individuals with CHD.

Inhibition of TFEB promotes tumor-educated dendritic cells activation to enhance antitumor immune responses.

Tumors can induce the generation and accumulation of immunosuppressive cells in -the tumor microenvironment (TME). Among them, tumor-educated dendritic cells (TEDCs) involved in tolerance induction contribute greatly to the progression of tumors. However, the mechanisms governing the immunosuppressive function of dendritic cells in the TME are unclear. In this study, we found that the expression of transcription factor EB (TFEB) was significantly increased in TEDCs induced by cancer cell supernatant. TFEB knockdown significantly promoted the differentiation and maturation of TEDCs, with upregulated expression of CD11c and costimulatory molecules (CD86 and MHC-II) but reduced expression of the inhibitory molecule PD-L1, and enhanced their ability to induce Th1 proliferation and differentiation. Moreover, TEDCs with TFEB knockdown significantly reduced tumor growth with increased infiltration of CD11c+MHC-II+ dendritic cells and effector T cells in tumor masses, thus leading to a delay in tumor progression. These findings demonstrate a critical role of TFEB in regulating the immunosuppression of TEDCs, with potential implications as an antitumor immune therapeutic approach.

ß-Glucan Combined With PD-1/PD-L1 Checkpoint Blockade for Immunotherapy in Patients With Advanced Cancer.

Programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) checkpoint blocking antibodies have been shown to be a powerful immune checkpoint blockade (ICB) therapy for patients with cancer. However, patients quickly develop resistance to immunotherapy. ß-glucan, an immune adjuvant, has been found to stimulate innate and adaptive immune responses. In this study, we assessed the use of whole glucan particle (WGP) ß-glucan in combination with PD-1/PD-L1-blocking antibodies to slow down the resistance to immunotherapy. Results from a tumor mouse model demonstrated that administration of WGP ß-glucan plus PD-1/PD-L1-blocking antibodies led to increased recruitment of immune-associated cells, improved regulation of the balance between T-cell activation and immune tolerance, and delayed tumor progression. This combination therapy was also found to improve progression-free survival in patients with advanced cancer who had previously discontinued anti-PD-1/PD-L1 because of disease progression. These findings suggest that ß-glucan could be used as an immune adjuvant to reverse anti-PD-1/PD-L1 resistance by regulating the immune system.

Oral administration of a whole glucan particle (WGP)-based therapeutic cancer vaccine targeting macrophages inhibits tumor growth.

Although therapeutic cancer vaccines have been gaining substantial ground, the development of cancer vaccines is impeded because of the undegradability of delivery systems, ineffective delivery of tumor antigens and weak immunogenicity of adjuvants. Here, we made use of a whole glucan particle (WGP) to encapsulate ovalbumin (OVA), thereby formulating a novel cancer vaccine. Results from in vitro experiments showed that WGP-OVA not only induced the activation of bone marrow-derived macrophages (BMDMs) including driving M0 BMDM polarization to the M1 phenotype, upregulating the costimulatory molecules and inducing the generation of cytokines, but also facilitated antigen presentation. After oral administration of the WGP-OVA formulation to mice with OVA-expressing tumors, these particles can increase tumor-infiltrating OVA-specific CD8+ CTLs and repolarize tumor-associated macrophages (TAMs) toward M1-like phenotype, which led to delayed tumor progression. These findings revealed that WGP could serve as both an antigen delivery system and an adjuvant system for promising cancer vaccines.

GnRH-a-Induced Perimenopausal Rat Modeling and Black Cohosh Preparations' Effect on Rat's Reproductive Endocrine.

Background: Endometriosis (EMS) is an estrogen-dependent disease, which easily recurs after operation. Gonadotropin-releasing hormone agonist (GnRH-a), an estrogen-inhibiting drug, can effectively inhibit the secretion of gonadotropin by pituitary gland, so as to significantly decrease the ovarian hormone level and facilitate the atrophy of ectopic endometrium, playing a positive role in preventing postoperative recurrence. The application of GnRH-a can lead to the secondary low estrogen symptoms, namely the perimenopausal symptoms, and is a main reason for patients to give up further treatment. The add-back therapy based on sex hormones can well address the perimenopausal symptoms, but long-term use of hormones may cause the recurrence of EMS, as well as liver function damage, venous embolism, breast cancer and other risks, which has long been a heated topic in the industry. Therefore, it is necessary to find effective and safe anti-additive drugs soon. Studies at home and abroad show that, as a plant extract, isopropanolic extract of cimicifuga racemosa (ICR) can well relieve the perimenopausal symptoms caused by natural menopause. Some studies have preliminarily confirmed that black cohosh preparations can antagonize perimenopausal symptoms of EMS patients treated with GnRH-a after operation. Objective: To establish a rat model of perimenopausal symptoms induced by GnRH-a injection, for the purposes of laying a foundation for further research and preliminarily exploring the effect of black cohosh preparations on reproductive endocrine of the rat model. Method: The rat model of perimenopausal symptoms was established by GnRH-a injection, and normal saline (NS injection) was used as the control. The rats were randomly divided into four groups according to different modeling methods and drug intervention schemes. GnRH-a injection + normal saline intervention group (GnRH-a + NS), normal saline injection control + normal saline intervention group (NS + NS), GnRH-a injection + estradiol intervention group (GnRH-a + E2), and GnRH-a injection + black cohosh preparations intervention group (GnRH-a + ICR). After modelling was assessed to be successful with the vaginal smear method, the corresponding drugs were given for intervention for 28d. In the process of rat modeling and drug intervention, the skin temperature and anus temperature of the rat tails were measured every other day, the body weights of the rats were measured every other day, and the dosage was adjusted according to the body weight. After the intervention was over, the serum sex hormone level, the uterine weight, the uterine index, and the endometrial histomorphology changes, as well as the ovarian weight, the ovarian index, and the morphological changes of ovarian tissues of each group were measured. Results: (1) The vaginal cell smears of the control group (NS + NS) showed estrous cycle changes, while other model rats had no estrous cycle of vaginal cells. (2) The body weight gains of the GnRH-a + NS, GnRH-a + E2 and GnRH-a + ICR groups were significantly higher than that of the NS + NS control group. The intervention with E2 and ICR could delay the weight gain trend of rats induced by GnRH-A. (3) After GnRH-a injection, the temperature of the tail and anus of rats showed an overall upward trend, and the intervention with E2 and ICR could effectively improve such temperature change. (4) The E2, FSH, and LH levels in the GnRH-a + NS, GnRH-a + E2, and GnRH-a + ICR groups were significantly lower than those in the NS + NS group (P < 0.01). The E2 level was significantly higher and the LH level was significantly lower in the GnRH-a + E2 group than those in the GnRH-a + NS and GnRH-a + ICR groups (P < 0.05). Compared with those of the GnRH-a + NS and GnRH-a + ICR groups, the FSH level of the GnRH-a + E2 group showed a slight downward trend, but the difference was not statistically significant (P > 0.05). There was no significant difference in the levels of sex hormones between the GnRH-a + NS group and GnRH-a + ICR group (P > 0.05). (5) Compared with those of the NS + NS group, the uterine weight and uterine index of the GnRH-a + NS, GnRH-a + E2 and GnRH-a + ICR groups significantly decreased (P < 0.01). In a comparison between the groups, the uterine weight and uterine index in the GnRH-a + NS and GnRH-a + ICR groups were significantly lower than those in the GnRH-a + E2 group (P < 0.01). There was a statistical difference in the uterine weight and uterine index between the GnRH-a + NS group and GnRH-a + ICR group (P > 0.05). (6) Compared with those of the NS + NS group, the ovarian weight and ovarian index of the GnRH-a + NS, GnRH-a + E2 and GnRH-a + ICR groups significantly decreased (P < 0.01). There was no statistical difference in the ovarian weight and ovarian index among the GnRH-a + E2, GnRH-a + NS and GnRH-a + ICR groups (P > 0.05). (7) Compared with those in the NS + NS group, the number of primordial follicles increased significantly, while the number of growing follicles and mature follicles decreased significantly in the GnRH-a + NS, GnRH-a + E2, and GnRH-a + ICR groups (P < 0.01), but there was a statistical difference in the total number of follicles among the four groups (P > 0.05). Conclusions: The GnRH-a injection could achieve the desired effect. The animal model successfully achieved a significant decrease in the E2, FSH, and LH levels in rats, and could cause the rats to have rising body surface temperature similar to hot flashes in the perimenopausal period. The intervention with E2 and ICR could effectively relieve such "perimenopausal symptoms", and ICR had no obvious effect on the serum sex hormone level in rats.