Exploring the mechanism of Xihuang Pill's anti-hyperplasia of mammary glands effect based on UPLC-Q-orbitrap-MS technology / 药学学报

Based on UPLC-Q-orbitrap-MS and biological network analysis tools, the mechanism of Xihuang Pill in improving hyperplasia of mammary glands was systematically analyzed. The rat model of hyperplasia of mammary glands was established by intramuscular injection of estradiol benzoate and progesterone. LC-MS tissue metabolomics was used to explore the key metabolites and metabolic pathways of Xihuang Pill in improving hyperplasia of mammary glands in rat. The network analysis of the key metabolites regulated by Xihuang Pill was carried out by integrating biological network analysis tools, focusing on the key metabolic pathways, and exploring the potential targets of Xihuang Pill to improve hyperplasia of mammary glands. Compared with the control group, there were significant differences in the content of 49 differential metabolites in the tissues of the model group (P < 0.05). Xihuang Pills could significantly call back 17 metabolites such as L-alanine, threonine, indole-3-carboxylic aldehyde, lysine, arginine, alanylleucine, glycyltyrosine, γ-glutamyl leucine, vitamin B3, serine leucine, threonine leucine, isoleucine glutamic acid, γ-glutamyl tyrosine, decanoyl-L-carnitine, uric acid, leucylleucine, S-adenosyl-methionine. Further network analysis and literature research on the key metabolites regulated by Xihuang Pills showed that the AGE-RAGE signaling pathway may be one of the important pathways for Xihuang Pills to improve hyperplasia of mammary glands. STAT3, MAPK1, EGFR, CASP3, CASP8, PRKCA and JUN in the AGE-RAGE signaling pathway may be potential targets for Xihuang Pills to improve hyperplasia of mammary glands. The animal experiment operations involved in this paper follow the provisions of the Animal Ethics Committee of Gansu University of Traditional Chinese Medicine and pass the ethical review of animal experiments (approval number: 2022-705).

Five New Diarylbutyrolactones and Sesquilignans from Saussurea medusa and Their Inhibitory Effects on LPS-induced NO Production.

Five new diarylbutyrolactones and sesquilignans (1A/1B:  - 4: ), including one pair of enantiomers (1A/1B: ), together with 10 known analogues (5:  - 14: ), were isolated from the whole plants of Saussurea medusa. Compound 1: was found to possess an unusual 7,8'-diarylbutyrolactone lignan structure. Separation by chiral HPLC analysis led to the isolation of one pair of enantiomers, (+)-1A: and (-)-1B: . The structures of the new compounds were elucidated by extensive spectroscopic data. All compounds, except compounds 5, 7: and 9: , were isolated from S. medusa for the first time. Moreover, compounds 1:  -  4, 8: and 10:  - 14: had never been obtained from the genus Saussurea previously. Compounds (+)- 1A, 2, 5, 7: , and 9:  - 11: were found to inhibit the lipopolysaccharide (LPS)-induced release of NO by RAW264.7 cells with IC50 values ranging from 10.1 ± 1.8 to 41.7 ± 2.1 µM. Molecular docking and iNOS expression experiments were performed to examine the interactions between the active compounds and the iNOS enzyme.

Mechanism of blood-activating and mass-dissipating Chinese patent medicine against hyperplasia of mammary glands and use with other medicine: a review / 中国中药杂志

Caused by endocrine disorder, hyperplasia of mammary glands(HMG) tends to occur in the young with increasing incidence, putting patients at the risk of cancer and threatening the health of women. Therefore, the prevention and treatment of HMG is attracting more and more attention. Amid the modernization of traditional Chinese medicine(TCM), many scholars have found that Chinese patent medicine has unique advantages and huge potential in treatment of endocrine disorder. Particularly, Chinese patent medicine with the function of blood-activating and mass-dissipating, such as Xiaojin Pills and Xiaozheng Pills, has been commonly used in clinical treatment of HMG, which features multiple targets, obvious efficacy, small side effect, and ease of taking and carrying around. Clinical studies have found that the combination of Chinese patent medicine with other medicine can not only improve the efficacy and relieve symptoms such as hyperplasia and pain but also reduce the toxic and side effects of western medicine. Therefore, based on precious pharmacological research and clinical research, this study reviewed the mechanisms of blood-activating mass-dissipating Chinese patent medicine alone and in combination with other medicine, such as regulating levels of in vivo hormones and receptors, promoting apoptosis, inhibiting angiogenesis, improving hemorheology indexes, enhancing immunity, and boosting antioxidant ability. In addition, limitations and problems were summarized. Thereby, this study is expected to lay a theoretical basis for the further study and clinical application of blood-activating mass-dissipating Chinese patent medicine alone or in combination with other medicine against HMG.

Neobavaisoflavone inhibits antitumor immunosuppression via myeloid-derived suppressor cells.

Neobavaisoflavone (Neo), as a traditional Chinese medicine, is the active ingredient in the herb Psoralea corylifolial and has antitumor activity. Myeloid-derived suppressor cells (MDSCs), which are a heterogeneous population of haematopoietic cells of the myeloid lineage, have been reported to be closely related to the pathogenesis of tumour progression, but whether Neo can regulate MDSC expansion and function remains unclear. Here, we found that Neo could inhibit the expansion and suppressive function of MDSCs by targeting STAT3. Importantly, Neo inhibited the growth of 4T1 and LLC tumours in vivo, as well as lung metastasis of 4T1 tumours in vivo. Furthermore, we identified MDSCs as the direct targets by which Neo attenuated tumour progression. In addition, Neo notably enhanced anti-PD-1 efficacy in anti-PD-1-insensitive 4T1 tumours. Therefore, our study sheds light on the development of Neobased therapeutic strategies against cancer.

Oxymatrine improves blood-brain barrier integrity after cerebral ischemia-reperfusion injury by downregulating CAV1 and MMP9 expression.

BACKGROUND: Ischemic stroke (IS) is a major neurological condition associated with extremely high morbidity and mortality worldwide. Oxymatrine (OMT), a quinolizidine alkaloid extracted from the root of Sophora flavescens, has neuroprotective properties and protects against IS. However, whether its protective effect involves alterations in the integrity of the blood-brain barrier (BBB) is unknown. PURPOSE: Here, we used in vivo and in vitro models of IS to evaluate the protective effects of OMT and to establish whether its effects are mediated via the modulation of the BBB function. METHODS: We assessed the effects of OMT by using neurological function scores, triphenyltetrazolium chloride staining, Nissl staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling. RESULTS: OMT significantly prevented cellular damage, improved neurological function, and reduced BBB permeability in a mouse model of cerebral ischemia-reperfusion. Additionally, OMT protected the function of the tight junctions of bEend.3 cells against the consequences of oxygen-glucose deprivation. Furthermore, intracranial lentivirus injection of short hairpin RNA targeting Cav1 decreased caveolin-1 expression and inhibited the neuroprotective effects of OMT. CONCLUSIONS: OMT attenuated ischemia-reperfusion injury-induced damage to the BBB, and this neuroprotective action was at least partially dependent on the expression levels of CAV1 and MMP9 proteins. Therefore, OMT may offer effective protection against BBB injury induced by ischemia-reperfusion episodes.

Identifying Novel ATX Inhibitors via Combinatory Virtual Screening Using Crystallography-Derived Pharmacophore Modelling, Docking Study, and QSAR Analysis.

Autotaxin (ATX) is considered as an interesting drug target for the therapy of several diseases. The goal of the research was to detect new ATX inhibitors which have novel scaffolds by using virtual screening. First, based on two diverse receptor-ligand complexes, 14 pharmacophore models were developed, and the 14 models were verified through a big test database. Those pharmacophore models were utilized to accomplish virtual screening. Next, for the purpose of predicting the probable binding poses of compounds and then carrying out further virtual screening, docking-based virtual screening was performed. Moreover, an excellent 3D QSAR model was established, and 3D QSAR-based virtual screening was applied for predicting the activity values of compounds which got through the above two-round screenings. A correlation coefficient r2, which equals 0.988, was supplied by the 3D QSAR model for the training set, and the correlation coefficient r2 equaling 0.808 for the test set means that the developed 3D QSAR model is an excellent model. After the filtering was done by the combinatory virtual screening, which is based on the pharmacophore modelling, docking study, and 3D QSAR modelling, we chose nine potent inhibitors with novel scaffolds finally. Furthermore, two potent compounds have been particularly discussed.

Concomitant memantine and Lactobacillus plantarum treatment attenuates cognitive impairments in APP/PS1 mice.

Trimethylamine-N-oxide (TMAO) is a gut microbial metabolite that promotes Alzheimer's disease (AD) progression. Given that probiotics can alleviate AD symptoms by inhibiting the synthesis of TMAO, here we investigated the correlation between TMAO and cognitive deterioration by measuring TMAO levels in the plasma of choline-treated APP/PS1 mice (an AD mouse model) with and without probiotic treatments. We found that declines in L.plantarum in the gut were associated with cognitive impairment. Moreover, 12-weeks of treatment with memantine plus L. plantarum ameliorated cognitive deterioration, decreased Αß levels in the hippocampus, and protected neuronal integrity and plasticity. These effects were accompanied by reductions in TMAO synthesis and neuroinflammation. These experiments demonstrate that L. plantarum augments the beneficial therapeutic effects of memantine treatment in APP/PS1 mice by remodeling the intestinal microbiota, inhibiting the synthesis of TMAO, and reducing clusterin levels. Our results thus highlight intestinal microbiota as a potential therapeutic target to decrease the risk of AD.

Ire1α in Pomc Neurons Is Required for Thermogenesis and Glycemia.

Whether neuronal inositol-requiring enzyme 1 (Ire1) is required for the proper regulation of energy balance and glucose homeostasis is unclear. We found that pro-opiomelanocortin (Pomc)-specific deficiency of Ire1α accelerated diet-induced obesity concomitant with a decrease in energy expenditure. This hypometabolic phenotype included deficits in thermogenic responses to diet and cold exposure as well as "beiging" of white adipose tissue. We also demonstrate that loss of Ire1α in Pomc neurons impaired whole-body glucose and insulin tolerance as well as hepatic insulin sensitivity. At the cellular level, deletion of Ire1α in Pomc neurons elevated hypothalamic endoplasmic reticulum (ER) stress and predisposed Pomc neurons to leptin and insulin resistance. Together, the current studies extend and confirm conclusions that Ire1α-Xbp1s and associated molecular targets link ER stress in arcuate Pomc neurons to aspects of normal energy and glucose homeostasis.

Study on the Extraction Technology for Active Constituents of Tibetan Medicine Pedicularis kansuensis / 中国药房

OBJECTIVE:To optimize the extraction technology of Tibetan medicine Pedicularis kansuensis and compare con-tent of verbascoside and isoverbascoside differences in P. kansuensis from various habitats. METHODS:Using verbascoside and iso-verbascoside and dry paste yield as comprehensive evaluation indexes,single factor test and orthogonal test were used to investigate the extraction solvent,solvent dosage,extraction time and times to optimize extraction technology,and the verification test was conducted. Contents of the 2 constituents verbascoside and isoverbascoside in P. kansuensis from Gansu,Qinghai and Sichuan were compared. RESULTS:The optimal extraction technology was as follows as 8-fold 50% ethanol,extraction for 3 times,90 min each time. The verification results showed that the average contents of verbascoside and isoverbascoside were 3.49%(RSD=1.28%,n=3),1.26%(RSD=1.32%,n=3),and average dry paste yields were 37.99%(RSD=1.97%,n=3). The contents of verbascoside and isoverbascoside in P. kansuensis from Qinghai were relatively higher. CONCLUSIONS:Optimized extraction tech-nology is reasonable,stable,feasible;the contents of index constituents in P. kansuensis from different habitats have certain differ-ences. The study can provide scientific evidence for the development and utilization of extraction,and the in-depth study of quality evaluation for medicinal material.

A Miniaturized On-Chip Colorimeter for Detecting NPK Elements.

Recently, precision agriculture has become a globally attractive topic. As one of the most important factors, the soil nutrients play an important role in estimating the development of precision agriculture. Detecting the content of nitrogen, phosphorus and potassium (NPK) elements more efficiently is one of the key issues. In this paper, a novel chip-level colorimeter was fabricated to detect the NPK elements for the first time. A light source-microchannel photodetector in a sandwich structure was designed to realize on-chip detection. Compared with a commercial colorimeter, all key parts are based on MEMS (Micro-Electro-Mechanical System) technology so that the volume of this on-chip colorimeter can be minimized. Besides, less error and high precision are achieved. The cost of this colorimeter is two orders of magnitude less than that of a commercial one. All these advantages enable a low-cost and high-precision sensing operation in a monitoring network. The colorimeter developed herein has bright prospects for environmental and biological applications.

A clinical study of Mahuang-Fuzi-Xixin decoction and Wuling powder combined with routine western medicine therapy for chronic renal disease stage 3 / 国际中医中药杂志

Objective To evaluate the efficacy of Mahuang-Fuzi-Xixin decoction and Wuling powder combined with routine western medicine therapy for chronic kidney disease (CKD) stage 3.Methods A total of 65 patients with CKD stage 3 were recruited and randomized into a treatment group (32 cases) and a control group (33 cases).On the basis of the same routine western medicine therapy,the patients in the treatment group was treated with Mahuang-Fuzi-Xixin decoction and Wuling powder,while those in the control group was treated with ketosteril.All patients were treated for one month.Renal function was evaluated by serum creatinine,urea nitrogen and uric acid before and after treatment.The therapeutic effect was compared between the two group.Results The serum ereatinine after treatment in the treatment group was significantly decreased than that in the control group (387.52 ± 92.13 mol/L vs.502.78 ± 117.35 mol/L;t=4.395,P＜0.01).The total effective rate in the treatment group was significantly higher than that in the control group (87.5％ vs.42.4％;X2=12.533,P＜0.01).In respects of syndrome improvements,tiredness/weakness (90.6％ vs.48.5％,x2=11.637),waist soreness/leg weakness (90.0％ vs.35.5％;x2=17.040,P＜0.01),anorexia and tympanites (93.3％ vs.37.9％;x2=17.802,P＜0.01),loose stool (93.1％ vs.25.8％;x2=25.219,P＜0.01),anasarca (84.6％ vs.41.7％;x2=8.214,P＜0.01),pale and teeth-printed tongue (76.7％ vs.26.7％;x2=13.081,P＜0.01) in the treatment group were significantly better than those in the control group.Conclusions Mahuang-Fuzi-Xixin decoction and Wuling powder combined with routine western medicine therapy can improve the renal function and syndromes in patients with CKD stage 3.

[Research progress of emodin anti-gallbladder carcinoma].

Emodin is an effective active ingredient extracted from Chinese herbal medicine, which has the function of antimicrobial, anti-inflammatory, antioxidant and scavenging oxygen free radicals, inhibiting platelet aggregation, improving microcirculation, protecting various organs and tissues as well as a wide range of anti-tumor effect. Primary biliary gallbladder is a common malignant tumor resection rate and lack of effective adjuvant treatment. It has been confirmed that emodin has broad spectrum antitumor effect, whereas, whether it has curative effect in the treatment of gallbladder carcinoma there is no reliable clinical trials confirmed that its resistance to gallbladder carcinoma function needs further experimental research. In this review, we report the research progress of emodin anti-gallbladder carcinoma.

Research progress of emodin anti-gallbladder carcinoma / 中国中药杂志

Emodin is an effective active ingredient extracted from Chinese herbal medicine, which has the function of antimicrobial, anti-inflammatory, antioxidant and scavenging oxygen free radicals, inhibiting platelet aggregation, improving microcirculation, protecting various organs and tissues as well as a wide range of anti-tumor effect. Primary biliary gallbladder is a common malignant tumor resection rate and lack of effective adjuvant treatment. It has been confirmed that emodin has broad spectrum antitumor effect, whereas, whether it has curative effect in the treatment of gallbladder carcinoma there is no reliable clinical trials confirmed that its resistance to gallbladder carcinoma function needs further experimental research. In this review, we report the research progress of emodin anti-gallbladder carcinoma.

TroVax(®) vaccine therapy for renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common primary malignancy affecting the kidney. In the past decade, several well-designed clinical trials have shifted the treatment paradigm for RCC to favor targeted therapies as first-line agents. Recognition of the immunogenic nature of RCC has also resulted in the development of immunotherapy approaches with high-dose IL-2 treatment being the best established and associated with durable disease control. The lack of defined antigens in RCC has hindered more specific vaccine development. TroVax(®) is a novel vaccine based on a modified vaccinia virus Ankara vector engineered to express the 5T4 tumor-associated antigen, found on over 95% of clear cell and papillary RCC tumors. The safety and efficacy of TroVax has been evaluated in several Phase I/II clinical trials and in a multicenter Phase III trial. This article will discuss the clinical background of RCC, the rationale for TroVax development, results of several TroVax clinical trials and future directions for optimizing TroVax therapy in patients with RCC and other cancers.

The effect of erythropoietin on microcirculation perfusion and tissue bioenergetics of the small intestine in a hemorrhagic shock and resuscitation rat model.

BACKGROUND: Erythropoietin (EPO) can exert acute hemodynamic and anti-inflammatory effects in addition to erythropoiesis. We tested the hypothesis that EPO given at resuscitation with saline will improve capillary perfusion and tissue oxygenation in the gut using a hemorrhagic shock model. METHODS: Sprague-Dawley rats were bled 30 mL/kg to maintain a mean arterial blood pressure of 40 mm Hg for 50 minutes and then randomized to one of four resuscitation groups (n = 6 per group): blood, blood + recombinant human EPO (rHuEPO), saline, and saline + rHuEPO. Intravenous rHuEPO (1,000 U/kg) was given at the start of resuscitation. Intravital microscopy was used to measure perfused capillary density, flow motion of red blood cell (RBC), and tissue NADH fluorescence 60 minutes after resuscitation. Venous oxygenation saturation (Svo2) was also measured in a second experiment. RESULTS: In the blood +/- rHuEPO resuscitation group, the perfused capillary density, RBC flow motion scores, and NADH fluorescence returned to near normal values. The saline + rHuEPO group compared with the saline group demonstrated an increased RBC flow motion score (2.32 vs. 1.60; p < 0.01); however, the perfused capillary density was not significantly increased (23.03 Cap/mm vs. 21.61 Cap/mm; p = 0.40). The saline + rHuEPO group also demonstrated statistically significant lower NADH fluorescence than the saline group after shock following resuscitation (110% +/- 3.64% vs. 122% +/- 4.26%; p < 0.05) suggesting decreased tissue dysoxia. The Svo2 in the saline + rHuEPO group was higher when compared with the saline group (45% vs. 38% by continuous oximetry; 38% vs. 29% by co-oximetry; p < 0.05). CONCLUSION: Our results suggest that the addition of rHuEPO at the time of saline resuscitation may have beneficial effects in hemorrhagic shock by improving tissue perfusion and decreasing dysoxia in the gut.

Erythropoietin improves skeletal muscle microcirculation and tissue bioenergetics in a mouse sepsis model.

INTRODUCTION: The relationship between oxygen delivery and consumption in sepsis is impaired, suggesting a microcirculatory perfusion defect. Recombinant human erythropoietin (rHuEPO) regulates erythropoiesis and also exerts complex actions promoting the maintenance of homeostasis of the organism under stress. The objective of this study was to test the hypothesis that rHuEPO could improve skeletal muscle capillary perfusion and tissue oxygenation in sepsis. METHODS: Septic mice in three experiments received rHu-EPO 400 U/kg subcutaneously 18 hours after cecal ligation and perforation (CLP). The first experiment measured the acute effects of rHuEPO on hemodynamics, blood counts, and arterial lactate level. The next two sets of experiments used intravital microscopy to observe capillary perfusion and nicotinamide adenine dinucleotide (NADH) fluorescence post-CLP after treatment with rHuEPO every 10 minutes for 40 minutes and at 6 hours. Perfused capillary density during a three-minute observation period and NADH fluorescence were measured. RESULTS: rHuEPO did not have any effects on blood pressure, lactate level, or blood cell numbers. CLP mice demonstrated a 22% decrease in perfused capillary density compared to the sham group (28.5 versus 36.6 capillaries per millimeter; p < 0.001). Treatment of CLP mice with rHuEPO resulted in an immediate and significant increase in perfused capillaries in the CLP group at all time points compared to baseline from 28.5 to 33.6 capillaries per millimeter at 40 minutes; p < 0.001. A significant increase in baseline NADH, suggesting tissue hypoxia, was noted in the CLP mice compared to the sham group (48.3 versus 43.9 fluorescence units [FU]; p = 0.03) and improved with rHuEPO from 48.3 to 44.4 FU at 40 minutes (p = 0.02). Six hours after treatment with rHuEPO, CLP mice demonstrated a higher mean perfused capillary density (39.4 versus 31.7 capillaries per millimeter; p < 0.001) and a lower mean NADH fluorescence as compared to CLP+normal saline mice (49.4 versus 52.7 FU; p = 0.03). CONCLUSION: rHuEPO produced an immediate increase in capillary perfusion and decrease in NADH fluorescence in skeletal muscle. Thus, it appears that rHuEPO improves tissue bioenergetics, which is sustained for at least six hours in this murine sepsis model.