Publications by authors named "Guanhua Du"

236 Publications

Differences in the Prevention and Control of Cardiovascular and Cerebrovascular Diseases.

Pharmacol Res 2021 Jun 17:105737. Epub 2021 Jun 17.

Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.

At present, the prevention and control of cardiovascular diseases (CAVDs) has made initial advancements, although the prevention and control of cerebrovascular diseases (CEVDs) has not yet achieved the desired progress. In this paper, we review the prevention and control of CEVDs and CAVDs, and analyze the differences in prevention effects, and the pathological and physiological structures pertaining to CEVDs and CAVDs. Combined with the different effects of low-dose aspirin in the primary prevention of CEVDs and CAVDs by meta-analysis, aspirin plays a more important role in the primary prevention of CAVDs than CEVDs. We recognize the misunderstandings and blind spots concerning prevention and control of CEVDs, which can be summarized as follows: (1) CEVDs and CAVDs can be controlled by the same methods and drugs; (2) considering the same pathological factors for cardiovascular disease; (3) a lack of understanding of the particularity of CEVDs; (4) a focus on platelets and neglect of cerebrovascular protection. In summary, our research clarifies the differences in the prevention measures and drugs used for CEVDs and CAVDs. Of particular concern is the serious lack of preventive drugs for CEVDs in clinical use. An ideal drug for the prevention of CEVDs should have protective effects on the blood, the vascular endothelium, the blood-brain barrier (BBB), and other related factors. Our review aims to highlight several issues in the current prevention of CEVDs and CAVDs, and to provide an optimized plan for preventive drug discovery.
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http://dx.doi.org/10.1016/j.phrs.2021.105737DOI Listing
June 2021

Venlafaxine Caffeic Acid Salt: Synthesis, Structural Characterization, and Hypoglycemic Effect Analysis.

ACS Omega 2021 Jun 17;6(21):13895-13903. Epub 2021 May 17.

Beijing City Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College. Beijing 100050, China.

Depression is a recurrent and chronic mental disorder requiring long-term treatment. Major depressive disorder is present in 15-20% of patients with type 1 or type 2 diabetes. Large-scale evidence revealed that depression and depressive symptoms are independent risk factors for the development of type 2 diabetes, and they may contribute to hyperglycemia and even accelerate the premature onset of diabetes complications. Venlafaxine is a clinical first-line antidepressant used for more than 30 years. Recently, clinical reports showed that venlafaxine overdose might cause hypoglycemia. Venlafaxine is insoluble and salt formation technology is the most appropriate method to improve the physicochemical properties and the pharmacokinetic profile of the drug. In the present work, the use of the solvent evaporation method, slurry, and the liquid-assisted grinding method resulted in the crystalline salt venlafaxine-caffeic acid (1:1). The compounds were characterized using a series of solid-state techniques, viz., powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared spectroscopy, and solid-state nuclear magnetic resonance, and the crystal structure was determined by single-crystal X-ray diffraction. Besides, a comparative study of solubility, dissolution, and hypoglycemic activity of the parent drug and the new salt has been carried out. The tested venlafaxine-caffeic acid salt showed about 16-fold higher solubility than the pure drug. Moreover, the glucose consumption assay results showed that the novel salt possesses potent hypoglycemic activity , suggesting that it is a promising candidate effective for major depressive disorder patients with type 2 diabetes.
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http://dx.doi.org/10.1021/acsomega.1c01581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173613PMC
June 2021

Baicalein alleviates depression-like behavior in rotenone- induced Parkinson's disease model in mice through activating the BDNF/TrkB/CREB pathway.

Biomed Pharmacother 2021 Jun 1;140:111556. Epub 2021 Jun 1.

Beijing Key Laboratory of Drug Targets Research and New Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nongtan Street, Beijing, 100050, China. Electronic address:

Background: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the world. In addition to motor symptoms, a variety of non-motor symptoms seriously affect the life quality of PD patients. Baicalein, a flavonoid extracted from the herb Scutellaria baicalensis Georgi, exhibits anti-PD activity through alleviation of its motor symptoms. However, its effects on non-motor symptoms were barely reported. This study aimed to investigate the therapeutic effects of baicalein on PD-related depression.

Methods: After a 2-week injection of rotenone, mice with PD-related depression behavior were selected, divided into three groups, and administrated saline, baicalein, or madopar orally for four weeks. Behavior, neuroinflammation, neurotransmitters, and synaptic plasticity were evaluated.

Results: Our results showed that 4-week baicalein treatment significantly alleviated the depression-like behavior in the rotenone-induced mice model. Repeated baicalein treatment reduced α-synuclein aggregation, inhibited neuroinflammation, and maintained neurotransmitters homeostasis. Moreover, we found that baicalein treatment could remarkably protect the synaptic plasticity and activate the BDNF/TrkB/CREB pathway in the PD-related depression mice model. As traditional dopamine replacement therapy unleashed few effects on depression-like symptom amelioration and synaptic function protection, baicalein might be a more appropriate choice for PD-related depression.

Conclusions: The current results suggested that baicalein could act as a treatment for PD-related depression.
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http://dx.doi.org/10.1016/j.biopha.2021.111556DOI Listing
June 2021

Cocrystal of Apixaban-Quercetin: Improving Solubility and Bioavailability of Drug Combination of Two Poorly Soluble Drugs.

Molecules 2021 May 3;26(9). Epub 2021 May 3.

Beijing City Key Laboratory of Polymorphic Drugs, Center of Pharmaceutical Polymorphs, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Drug combinations have been the hotspot of the pharmaceutical industry, but the promising applications are limited by the unmet solubility and low bioavailability. In this work, novel cocrystals, consisting of two antithrombotic drugs with poor solubility and low bioavailability in vivo, namely, apixaban (Apx) and quercetin (Que), were developed to discover a potential method to improve the poor solubility and internal absorption of the drug combination. Compared with Apx, the dissolution behavior of Apx-Que (1:1) and Apx-Que-2ACN (1:1:2) was enhanced significantly, while the physical mixture of the chemicals failed to exhibit the advantages. The dissolution improvements of Apx-Que-2ACN could be explained by the fact that the solid dispersion-like structure and column-shaped cage of Que accelerated the access of the solvent to the inner layer of Apx. The fracture of the hydrogen bonds of Apx, which was the joint of the adjacent Que chains, facilitated the break-up of the structures. Besides, the bioavailability of Apx-Que was increased compared with the physical mixture and Apx, and Apx-Que remained stable in high temperature and illumination conditions. Therefore, a drug-drug cocrystal of two antithrombotic agents with poor solubility was developed, which exhibited greatly improved solubility, bioavailability and superior stability, indicating a novel method to overcome the shortages of drug combination.
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http://dx.doi.org/10.3390/molecules26092677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124247PMC
May 2021

Xiao-Xu-Ming decoction prevented hemorrhagic transformation induced by acute hyperglycemia through inhibiting AGE-RAGE-mediated neuroinflammation.

Pharmacol Res 2021 Jul 5;169:105650. Epub 2021 May 5.

College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, 280 Waihuan East Road, Panyu District, Guangdong 510006, PR China; Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China. Electronic address:

Stroke is one of the leading causes of death worldwide. Hemorrhagic transformation (HT) is a common serious complication of ischemic stroke (IS) and is related to poor prognosis. Hyperglycemia after stroke is associated with the occurrence of HT and seriously affects the clinical treatment of stroke. Our previous experiments demonstrated that the Xiao-Xu-Ming decoction effective components group (XXMD), which is a Chinese medicine formula reconstituted by active ingredients, has multiple pharmacological effects in the treatment of IS. However, the effects of XXMD on HT after IS remain unclear. Thus, we investigated the preventive effects of XXMD on hyperglycemia-induced HT and further explored the underlying mechanism. Acute hyperglycemia combined with the electrocoagulation cerebral ischemia model was used to establish the HT model. XXMD (37.5, 75, 150 mg/kg/d) was given by gavage for 5 days. Network pharmacology was used to predict potential targets and pathways of XXMD in HT occurrence, and further studies confirmed the related targets. The results showed that hyperglycemia aggravated neurological deficits and blood-brain barrier (BBB) disruption, leading to intracerebral hemorrhage. Pretreatment with XXMD improved neurological function and BBB integrity and inhibited HT occurrence. Network pharmacology revealed that AGE-RAGE-mediated neuroinflammation may be associated with hyperglycemia-induced HT. Further studies confirmed that hyperglycemia activated the AGE-RAGE signaling pathway, increased the expression of HMGB1, TLR4 and p-p65, and induced the release of inflammatory factors and neutrophil infiltration, leading to HT. XXMD could inhibit AGE-RAGE-mediated neuroinflammation. These findings indicated that pretreatment with XXMD alleviated hyperglycemia-induced HT, which may be associated with the inhibition of AGE-RAGE-mediated neuroinflammation. Therefore, XXMD may be a potential therapeutic drug for HT.
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http://dx.doi.org/10.1016/j.phrs.2021.105650DOI Listing
July 2021

Study on antidepressant mechanism of Radix Bupleuri-Radix Paeoniae Alba herb pair by metabonomics combined with 1H nuclear magnetic resonance and ultra-high-performance liquid chromatography-tandem mass spectrometry detection technology.

J Pharm Pharmacol 2021 Apr 22. Epub 2021 Apr 22.

Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.

Objectives: Radix Bupleuri-Radix Paeoniae Alba (BP), a traditional Chinese medicine herb pair, has treated depression by coordinating the liver in Chinese classical medicine books and modern research. This study aims to verify the antidepressant effect of BP by behavioural examination, and reveal the underlying antidepressant mechanisms of BP.

Methods: The antidepressant effects in chronic unpredictable mild stress (CUMS) of BP were observed by behavioural indicators and 1H nuclear magnetic resonance (1H-NMR) and ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) metabonomics techniques combined with the related analysis platforms.

Key Findings: BP could significantly improve the depressive behaviour of CUMS rats. Compared with the model group, body weight (P < 0.05), the number of crossing (P < 0.001) and rearing (P < 0.01) and sucrose preference rate (P < 0.01) were significantly enhanced, and the immobility time was shortened in the forced swimming test (P < 0.001) of the BP group. In metabonomics study, 35 depression-related metabolites were identified by 1H NMR and UHPLC-MS/MS metabonomics by comparing model and control groups. BP could significantly retrieve 17 depression-related metabolites. Thirteen depression-related metabolic pathways were found through Met-PA and BP could regulate seven metabolic pathways.

Conclusions: BP herb pair had significantly antidepressant effect, which provides a basis for further finding drug targets.
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http://dx.doi.org/10.1093/jpp/rgab061DOI Listing
April 2021

Studies on the Changes of Pharmacokinetics Behaviors of Phytochemicals and the Influence on Endogenous Metabolites After the Combination of Radix Bupleuri and Radix Paeoniae Alba Based on Multi-Component Pharmacokinetics and Metabolomics.

Front Pharmacol 2021 8;12:630970. Epub 2021 Mar 8.

Modern Research Center for Traditional Chinese Medicine of Shanxi University, Taiyuan, China.

Radix Bupleuri-Radix Paeoniae Alba (RB-RPA) is a classic herb pair, which is commonly used to treat depression by soothing "liver qi stagnation" in the clinic. However, little is yet known concerning the combination mechanism of Radix Bupleuri (RB) and Radix Paeoniae Alba (RPA), their bioactive forms and the regulatory effects on the organism. The present study aimed to elucidate the changes in multi-component pharmacokinetics (PK) behavior after the combination of RB and RPA by a high-resolution full-scan mode of UPLC-HRMS method (a total of 38 components PK profiles were obtained, of which 23 components come from RB and 15 components come from RPA). Moreover, the metabolomics approach was used to analyze the dynamic response of endogenous metabolites intervened by RB-RPA, and the correlation between concentration-time curves of 38 components from RB-RPA and the dynamic response profiles of endogenous metabolites was characterized by Pearson correlation analysis. The results demonstrated that the combination of RB and RPA could significantly improve the bioavailability of five components in RB, and six components in RPA. Besides, metabolomics results indicated that a total of 21 endogenous metabolites exhibited time-dependent changes in response to the RB-RPA administration, of which 12 endogenous metabolites were significantly increased, and nine endogenous metabolites were significantly decreased. Furthermore, correlation analysis results indicated that the components with significantly improved bioavailability after combination such as saikogenin F, saikogenin G, albiflorin, methyl gallate, paeonimetabolin II were significantly positively correlated with picolinic acid, a metabolite with neuroprotective effect; saikogenin F, saikogenin G were significantly positively correlated with itaconic acid, a endogenous metabolite with anti-inflammatory activity; and albiflorin, paeonimetabolin II were significantly positively correlated with α-linolenic acid, a metabolite with strong protective actions on brain functions. These results indicated that the combination of RB and RPA can enhance each other's neuroprotective and anti-inflammatory activities. In this study, A novel and efficient strategy has been developed to analyze the influence of the combination of RB and RPA behaviors by combining multi-component pharmacokinetics with metabolomics, which was contributed to clarifying the scientific connotation of herb-herb compatibility.
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http://dx.doi.org/10.3389/fphar.2021.630970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982521PMC
March 2021

Inhibition of hypoxia inducible factor 1 by YC-1 attenuates tissue plasminogen activator induced hemorrhagic transformation by suppressing HMGB1/TLR4/NF-κB mediated neutrophil infiltration in thromboembolic stroke rats.

Int Immunopharmacol 2021 May 28;94:107507. Epub 2021 Feb 28.

Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Centre for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address:

Hemorrhagic transformation (HT) is a frequent complication of ischemic stroke after thrombolytic therapy and seriously affects the prognosis of stroke. Due to the limited therapeutic window and hemorrhagic complications, tissue plasminogen activator (t-PA) is underutilized in acute ischemic stroke. Currently, there are no clinically effective drugs to decrease the incidence of t-PA-induced HT. Hypoxia-inducible factor 1 (HIF-1) is an important transcription factor that maintains oxygen homeostasis and mediates neuroinflammation under hypoxia. However, the effect of HIF-1 on t-PA-induced HT is not clear. The aim of this study was to investigate the role of HIF-1 in t-PA-induced HT by applying YC-1, an inhibitor of HIF-1. In the present study, we found that HIF-1 expression was significantly increased in ischemic brain tissue after delayed t-PA treatment and was mainly localized in neurons and endothelial cells. Inhibition of HIF-1 by YC-1 improved infarct volume and neurological deficits. YC-1 inhibited matrix metalloproteinase protein expression, increased tight junction protein expression, and ameliorated BBB disruption and the occurrence of HT. Furthermore, YC-1 suppressed the release of inflammatory factors, neutrophil infiltration and the activation of the HMGB1/TLR4/NF-κB signaling pathway. These results demonstrated that inhibition of HIF-1 could protect BBB integrity by suppressing HMGB1/TLR4/NF-κB-mediated neutrophil infiltration, thereby reducing the risk of t-PA-induced HT. Thus, HIF-1 may be a potential therapeutic target for t-PA-induced HT.
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http://dx.doi.org/10.1016/j.intimp.2021.107507DOI Listing
May 2021

Network Pharmacology-Based Analysis of Xiao-Xu-Ming Decoction on the Treatment of Alzheimer's Disease.

Front Pharmacol 2020 4;11:595254. Epub 2020 Dec 4.

Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Alzheimer's disease (AD) has become a worldwide disease that is harmful to human health and brings a heavy economic burden to healthcare system. Xiao-Xu-Ming Decoction (XXMD) has been widely used to treat stroke and other neurological diseases for more than 1000 years in China. However, the synergistic mechanism of the constituents in XXMD for the potential treatment of AD is still unclear. Therefore, the present study aimed to predict the potential targets and uncover the material basis of XXMD for the potential treatment of AD. A network pharmacology-based method, which combined data collection, drug-likeness filtering and absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties filtering, target prediction and network analysis, was used to decipher the effect and potential targets of XXMD for the treatment of AD. Then, the acetylcholinesterase (AChE) inhibitory assay was used to screen the potential active constituents in XXMD for the treatment of AD, and the molecular docking was furtherly used to identify the binding ability of active constituents with AD-related target of AChE. Finally, three cell models were applied to evaluate the neuroprotective effects of potential lead compounds in XXMD. Through the China Natural Products Database, Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database, Traditional Chinese Medicine (TCM)-Database @Taiwan and literature, a total of 1481 compounds in XXMD were finally collected. After ADME/T properties filtering, 908 compounds were used for the further study. Based on the prediction data, the constituents in XXMD formula could interact with 41 AD-related targets. Among them, cyclooxygenase-2 (COX-2), estrogen receptor α (ERα) and AChE were the major targets. The constituents in XXMD were found to have the potential to treat AD through multiple AD-related targets. 62 constituents in it were found to interact with more than or equal to 10 AD-related targets. The prediction results were further validated by biology experiment, resulting in several potential anti-AD multitarget-directed ligands (MTDLs), including two AChE inhibitors with the IC values ranging from 4.83 to 10.22 μM. Moreover, fanchinoline was furtherly found to prevent SH-SY5Y cells from the cytotoxicities induced by sodium nitroprusside, sodium dithionate and potassium chloride. In conclusion, XXMD was found to have the potential to treat AD by targeting multiple AD-related targets and canonical pathways. Fangchinoline and dauricine might be the potential lead compounds in XXMD for the treatment of AD.
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http://dx.doi.org/10.3389/fphar.2020.595254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774966PMC
December 2020

Evidence-based Guideline for Therapeutic Drug Monitoring of Vancomycin: 2020 Update by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society.

Clin Infect Dis 2020 12;71(Suppl 4):S363-S371

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Background: Clinical practice guidelines or recommendations often require timely and regular updating as new evidence emerges, because this can alter the risk-benefit trade-off. The scientific process of developing and updating guidelines accompanied by adequate implementation can improve outcomes. To promote better management of patients receiving vancomycin therapy, we updated the guideline for the therapeutic drug monitoring (TDM) of vancomycin published in 2015.

Methods: Our updated recommendations complied with standards for developing trustworthy guidelines, including timeliness and rigor of the updating process, as well as the use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. We also followed the methodology handbook published by the National Institute for Health and Clinical Excellence and the Spanish National Health System.

Results: We partially updated the 2015 guideline. Apart from adults, the updated guideline also focuses on pediatric patients and neonates requiring intravenous vancomycin therapy. The guideline recommendations involve a broadened range of patients requiring TDM, modified index of TDM (both 24-hour area under the curve and trough concentration), addition regarding the necessity and timing of repeated TDM, and initial dose for specific subpopulations. Overall, 1 recommendation was deleted and 3 recommendations were modified. Eleven new recommendations were added, and no recommendation was made for 2 clinical questions.

Conclusions: We updated an evidence-based guideline regarding the TDM of vancomycin using a rigorous and multidisciplinary approach. The updated guideline provides more comprehensive recommendations to inform rational and optimized vancomycin use and is thus of greater applicability.
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http://dx.doi.org/10.1093/cid/ciaa1536DOI Listing
December 2020

Neuroinflammation in hemorrhagic transformation after tissue plasminogen activator thrombolysis: Potential mechanisms, targets, therapeutic drugs and biomarkers.

Int Immunopharmacol 2021 Jan 6;90:107216. Epub 2020 Dec 6.

Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Centre for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address:

Hemorrhagic transformation (HT) is a common and serious complication following ischemic stroke, especially after tissue plasminogen activator (t-PA) thrombolysis, which is associated with increased mortality and disability. Due to the unknown mechanisms and targets of HT, there are no effective therapeutic drugs to decrease the incidence of HT. In recent years, many studies have found that neuroinflammation is closely related to the occurrence and development of HT after t-PA thrombolysis, including glial cell activation in the brain, peripheral inflammatory cell infiltration and the release of inflammatory factors, involving inflammation-related targets such as NF-κB, MAPK, HMGB1, TLR4 and NLRP3. Some drugs with anti-inflammatory activity have been shown to protect the BBB and reduce the risk of HT in preclinical experiments and clinical trials, including minocycline, fingolimod, tacrolimus, statins and some natural products. In addition, the changes in MMP-9, VAP-1, NLR, sICAM-1 and other inflammatory factors are closely related to the occurrence of HT, which may be potential biomarkers for the diagnosis and prognosis of HT. In this review, we summarize the potential inflammation-related mechanisms, targets, therapeutic drugs, and biomarkers associated with HT after t-PA thrombolysis and discuss the relationship between neuroinflammation and HT, which provides a reference for research on the mechanisms, prevention and treatment drugs, diagnosis and prognosis of HT.
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http://dx.doi.org/10.1016/j.intimp.2020.107216DOI Listing
January 2021

MELK is an oncogenic kinase essential for metastasis, mitotic progression, and programmed death in lung carcinoma.

Signal Transduct Target Ther 2020 12 2;5(1):279. Epub 2020 Dec 2.

The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, China.

Lung cancer is the fastest growth rate of morbidity and mortality in nearly a decade, and remains difficult to treat. Furthermore, the molecular mechanisms underlying its development are still unclear. In this study, bioinformatics analysis showed that MELK was highly expressed in lung cancer and negatively correlated to the survival of lung adenocarcinoma (LUAD). Immunohistochemistry analysis of LUAD patient tissues revealed there were a high level of MELK expression in LUAD. Knockdown of MELK expression inhibits the migration and invasion of LUAD cells, which may be mediated by Twist1, Slug, MMP7, and N-catenin. Overexpression of MELK promoted the growth of LUAD cells in medium, 3D Matrigel, and nude mice. Inhibition of MELK by OTSSP167 arrested cycle of LUAD cells at G2/M phase via PLK1-CDC25C-CDK1 pathway, and triggered apoptosis-mediated pyroptosis. Together, these data indicate that MELK is critical for metastasis, mitotic progression, and programmed death of LUAD and may be a promising therapeutic target for LUAD.
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http://dx.doi.org/10.1038/s41392-020-00288-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708490PMC
December 2020

Puerarin ameliorates skeletal muscle wasting and fiber type transformation in STZ-induced type 1 diabetic rats.

Biomed Pharmacother 2021 Jan 26;133:110977. Epub 2020 Nov 26.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines and Beijing Key Laboratory of Drug Target and Screening Research, Institute of Materia Medica of Peking Union Medical College, Beijing, 100050, PR China. Electronic address:

Puerarin is an isoflavonoid extracted from Pueraria lobate with extensive pharmacological effects in traditional Chinese medicine. The evidence implicates that puerarin mitigates hyperglycemia and various relevant complications. Here, the effect of puerarin on skeletal muscle wasting induced by type 1 diabetes (T1D) was explored. Streptozotocin (STZ)-induced T1D male Sprague Dawley (SD) rats were used in this study. Muscle strength, weight and size were measured. L6 rat skeletal muscle cells were applied for in vitro study. Our results showed that eight-week oral puerarin administration (100 mg/kg) increased muscle strengths and weights accompanied by enhanced skeletal muscle cross-sectional areas in diabetic rats. Simultaneously, puerarin also reduced expressions of several muscle wasting marker genes including F-box only protein 32 (Atrogin-1) and muscle-specific RING-finger 1 (Murf-1) in diabetic group both in vitro and in vivo. Transformation from type I fibers (slow muscle) to type II fibers (fast muscle) were also observed under puerarin administration in diabetic rats. Puerarin promoted Akt/mTOR while inhibited LC3/p62 signaling pathway in skeletal muscle cells. In conclusion, our study showed that puerarin mitigated skeletal muscle wasting in T1D rats and closely related with Akt/mTOR activation and autophagy inhibition. Whether this effect in murine applies to humans remains to be determined.
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http://dx.doi.org/10.1016/j.biopha.2020.110977DOI Listing
January 2021

Integrating hippocampal metabolomics and network pharmacology deciphers the antidepressant mechanisms of Xiaoyaosan.

J Ethnopharmacol 2021 Mar 3;268:113549. Epub 2020 Nov 3.

Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, Shanxi, China; Shanxi Key Laboratory of Active Constituents Research and Utilization of TCM, Taiyuan, 030006, Shanxi, China. Electronic address:

Ethnopharmacological Relevance: Xiaoyaosan (XYS), a classic description, has a history of thousands of years for treating depression through invigorating the liver and strengthening the spleen, which have been verified both clinically and experimentally. However, explanation of its underlying mechanisms remains a great challenge.

Aim Of The Study: The mechanisms of XYS in treating depression were investigated, with emphasis on the important biomarkers, targets and pathways.

Materials And Methods: In this study, taking the targeted organ of depression, hippocampus, as the object, a combination of GC-MS based metabolomics and network pharmacology was established to illustrate the abnormality of metabolic characteristics of hippocampus of depression rats and to demonstrate the antidepressant mechanisms of XYS. Hippocampal metabolomics demonstrated potential metabolites involving in the antidepressant effects of XYS, as well as the corresponding metabolic pathways. Network pharmacology screened the potential ingredients and the targets of XYS against depression.

Results: Metabolomics revealed that XYS significantly regulated the abnormal levels of lactic acid, glycerol, glutamine, glutamic acid, hypoxanthine, myo-inositol and cholesterol, which involved in the D-glutamine and D-glutamate metabolism, arginine biosynthesis and alanine, aspartate and glutamate metabolism. Network pharmacology showed that XYS exhibited anti-depression effects through paeoniflorin, quercetin, licochalcone a, naringenin, β-sitosterol, formononetin and kaempferol acting on interleukin-6 (IL6), mitogen-activated protein kinase 1 (MAPK1), signal transducer and activator of transcription 3 (STAT3) and transcription factor AP-1 (JUN).

Conclusion: Based on hippocampal metabolomics and network pharmacology, this study proved that the actions of XYS in treating depression depend on multi-components, multi-targets and multi-pathways, the unique characteristics of TCMs.
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http://dx.doi.org/10.1016/j.jep.2020.113549DOI Listing
March 2021

Anti-inflammatory Effects and Mechanisms of Rhein, an Anthraquinone Compound, and Its Applications in Treating Arthritis: A Review.

Nat Prod Bioprospect 2020 Dec 30;10(6):445-452. Epub 2020 Oct 30.

Beijing Key Laboratory of Polymorphic Drugs, Center of Pharmaceutical Polymorphs, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.

Inflammation is a defensive response of living tissues to damaging agents, which exists in two forms, acute inflammation and chronic inflammation, and chronic inflammation is closely related to arthritis. Currently, the commonly prescribed anti-inflammatory medications are greatly limited by high incidence of gastrointestinal erosions in the clinical applications. Rhein, a bioactive constituent of anthraquinone, exhibits excellent anti-inflammatory activities and therapeutic effects on arthritis with less gastrointestinal damages. Although there are numbers of studies on anti-inflammatory effects and mechanisms of rhein in the last few decades, to the best of our knowledge, only a few review articles pay attention to the interactive relationships of rhein on multiple inflammatory signaling pathways and cellular processes from a comprehensive perspective. Herein, we summarized anti-inflammatory effects and mechanisms of rhein and its practical applications in the treatment of arthritis, thereby providing a reference for its basic researches and clinical applications.
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http://dx.doi.org/10.1007/s13659-020-00272-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648819PMC
December 2020

The comprehensive study on the therapeutic effects of baicalein for the treatment of COVID-19 in vivo and in vitro.

Biochem Pharmacol 2021 01 27;183:114302. Epub 2020 Oct 27.

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Drug Target Identification and Drug Screening, National Center for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. Electronic address:

Baicalein is the main active compound of Scutellaria baicalensis Georgi, a medicinal herb with multiple pharmacological activities, including the broad anti-virus effects. In this paper, the preclinical study of baicalein on the treatment of COVID-19 was performed. Results showed that baicalein inhibited cell damage induced by SARS-CoV-2 and improved the morphology of Vero E6 cells at a concentration of 0.1 μM and above. The effective concentration could be reached after oral administration of 200 mg/kg crystal form β of baicalein in rats. Furthermore, baicalein significantly inhibited the body weight loss, the replication of the virus, and relieved the lesions of lung tissue in hACE2 transgenic mice infected with SARS-CoV-2. In LPS-induced acute lung injury of mice, baicalein improved the respiratory function, inhibited inflammatory cell infiltration in the lung, and decreased the levels of IL-1β and TNF-α in serum. In conclusion, oral administration of crystal form β of baicalein could reach its effective concentration against SARS-CoV-2. Baicalein could inhibit SARS-CoV-2-induced injury both in vitro and in vivo. Therefore, baicalein might be a promising therapeutic drug for the treatment of COVID-19.
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http://dx.doi.org/10.1016/j.bcp.2020.114302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588320PMC
January 2021

The cardioprotective effects of the new crystal form of puerarin in isoproterenol-induced myocardial ischemia rats based on metabolomics.

Sci Rep 2020 10 20;10(1):17787. Epub 2020 Oct 20.

Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2A Nan Wei Road, Beijing, 100050, China.

Puerarin has shown unique pharmacological effects on myocardial ischemia (MI). Changing the crystal form is an effective approach to improve the cardioprotective effects of puerarin. However, the mechanisms of the new crystal form of puerarin are unclear. In this study, an electrocardiogram, echocardiography, cardiac marker enzymatic activity, oxidative stress indices, and myocardial histology analysis of cardiac tissues were performed to evaluate the cardioprotective effects of the new crystal form of puerarin. Moreover, serum and cardiac tissue metabolomics based on nuclear magnetic resonance (NMR) were used to investigate the potential mechanism of the new crystal form. The results indicated that the new crystal form of puerarin (30 mg/kg) could improve oxidative stress indices, and these improvements were similar to those of the original crystal form of puerarin (120 mg/kg). The new crystal form of puerarin (30 mg/kg) could effectively improve the activities of cardiac marker enzymes, and the improvement effects were better than those of the original crystal form (120 mg/kg). Moreover, metabolomics analysis showed that amino acid metabolism, oxidative stress and energy metabolism were disturbed after MI and could be improved by puerarin. These results demonstrated that the new crystal form of puerarin was effective in treating MI.
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http://dx.doi.org/10.1038/s41598-020-74246-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575583PMC
October 2020

Target RNA modification for epigenetic drug repositioning in neuroblastoma: computational omics proximity between repurposing drug and disease.

Aging (Albany NY) 2020 Oct 12;12(19):19022-19044. Epub 2020 Oct 12.

Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China.

RNA modifications modulate most steps of gene expression. However, little is known about its role in neuroblastoma (NBL) and the inhibitors targeting it. We analyzed the RNA-seq (n=122) and CNV data (n=78) from NBL patients in Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. The NBL sub-clusters (cluster1/2) were identified via consensus clustering for expression of RNA modification regulators (RNA-MRs). Cox regression, principle component analysis and chi-square analysis were used to compare differences of survival, transcriptome, and clinicopathology between clusters. Cluster1 showed significantly poor prognosis, of which RNA-MRs' expression and CNV alteration were closely related to pathologic stage. RNA-MRs and functional related prognostic genes were obtained using spearman correlation analysis, and queried in CMap and L1000 FWD database to obtain 88 inhibitors. The effects of 5 inhibitors on RNA-MRs were confirmed in SH-SY5Y cells. The RNA-MRs exhibited two complementary regulation functions: one conducted by TET2 and related to translation and glycolysis; another conducted by ALYREF, NSUN2 and ADARB1 and related to cell cycle and DNA repair. The perturbed proteomic profile of HDAC inhibitors was different from that of others, thus drug combination overcame drug resistance and was potential for NBL therapy with RNA-MRs as therapeutic targets.
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http://dx.doi.org/10.18632/aging.103671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732279PMC
October 2020

Characterization of a New Solvatomorph of Drospirenone by Thermogravimetry-Mass Spectrometry Combined with Other Solid-State Analysis Methods.

ACS Omega 2020 Oct 24;5(39):25289-25296. Epub 2020 Sep 24.

Beijing City Key Laboratory of Drug Target and Screening Research, National Center for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Drospirenone (DE) is a fourth-generation progesterone that has been widely used in oral contraceptives for women because of its safety and few side effects in terms of pharmacological activity. A new solvatomorph (crystal form C) of DE with dimethyl sulfoxide was identified and characterized for the first time through a thermogravimetry-mass spectrometry (TG-MS) coupling system. The thermodynamic property of the new solvatomorph of DE was different from those of most pharmaceutical solvatomorphs, and it was revealed via the skimmer-type interfaced TG-MS system and differential scanning calorimetry. This new solvatomorph and a polymorph of DE obtained without solvent (crystal form A) were well characterized by X-ray crystallography and vibrational spectroscopic analysis. Computational studies based on their single-crystal structures, such as Hirshfeld surface analyses, were used to determine the intermolecular interactions in the crystal network. The single-crystal structure of crystal form C of DE was determined and reported for the first time.
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http://dx.doi.org/10.1021/acsomega.0c03531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542801PMC
October 2020

Liquiritin protects PC12 cells from corticosterone-induced neurotoxicity via regulation of metabolic disorders, attenuation ERK1/2-NF-κB pathway, activation Nrf2-Keap1 pathway, and inhibition mitochondrial apoptosis pathway.

Food Chem Toxicol 2020 Dec 6;146:111801. Epub 2020 Oct 6.

Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China; Shanxi Key Laboratory of Active Constituents Research and Utilization of TCM, Shanxi University, Taiyuan, China. Electronic address:

Liquiritin, a flavone derived from the medicine food homology plant liquorice, possesses neuroprotective. However, the neuroprotective mechanism is not clear. In this study, metabolomics based LC-MS was performed to discover the metabolite changes in PC12 cells treated with corticosterone-induced neurotoxicity after liquiritin treatment. A total of 30 metabolites were identified as differential metabolites. Among them, 11 metabolites were regulated by liquiritin, and involved in the D-glutamine and D-glutamate metabolism, and glutathione metabolism, etc. Based on the results of metabolomics, three cell signaling pathways related to these metabolic pathways were verified. The results showed that the ERK1/2-NF-κB pathway related to the D-glutamine and D-glutamate metabolism was attenuated by liquiritin via down-regulation phospho-ERK1/2, phospho-IκBα, phospho-NF-κB protein expression levels. Furthermore, the Nrf2-Keap1 pathway related to glutathione metabolism was activated by liquiritin via up-regulation Nrf2, Keap1, HO-1, NQO1 protein expression levels, and increased SOD, CAT, GSH-PX enzyme activity, thus exerting antioxidant activity. Additionally, liquiritin inhibited the mitochondrial apoptosis by decreasing the Ca concentration, improving MMP, up-regulating Bcl-2, and down-regulating Bax, cytochrome C, cleaved-Caspase-3 expression levels. These results suggest that the neuroprotective mechanisms of liquiritin are connected to the regulation of metabolic disorders, activation Nrf2/Keap1 pathway, attenuation ERK1/2/NF-κB pathway, and inhibition mitochondrial apoptosis pathway.
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http://dx.doi.org/10.1016/j.fct.2020.111801DOI Listing
December 2020

A Novel Co-Crystal of Bexarotene and Ligustrazine Improves Pharmacokinetics and Tissue Distribution of Bexarotene in SD Rats.

Pharmaceutics 2020 Sep 23;12(10). Epub 2020 Sep 23.

Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China.

Bexarotene (BEX), a specific retinoic acid X receptor (RXR) agonist granted by Food and Drug Administration (FDA) approval for the clinical treatment of T cell lymphoma, has now been found to exert pharmacological effects in the nervous system, with low bioavailability and poor cerebral distribution limiting its application in treatment on neurological disorders. Pharmaceutical co-crystal was a helpful method to improve the bioavailability and tissue distribution of active pharmaceutical ingredients (APIs). Here, 2bexarotene-ligustrazine (2BEX-LIG), a novel co-crystal system of BEX and ligustrazine (LIG) of which with BEX is an API, was constructed with satisfactory stability and enhanced solubility. The pharmacokinetics characteristics of BEX were detected, and the results showed that the absolute bioavailability and the cerebral concentration of BEX in rats administrated with 2BEX-LIG were enhanced from 22.89% to 42.86% and increased by 3.4-fold, respectively, compared with those in rats administrated an equivalent of BEX. Hence, our present study indicated that the novel co-crystal of 2BEX-LIG contributed to improving BEX oral bioavailability and cerebral distribution, thereby providing significant advantages for clinical application of brain tumors and other neurological diseases.
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http://dx.doi.org/10.3390/pharmaceutics12100906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598278PMC
September 2020

The strategies and techniques of drug discovery from natural products.

Pharmacol Ther 2020 12 19;216:107686. Epub 2020 Sep 19.

Beijing Key Laboratory of Drug Target Research and Drug Screening, State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address:

Natural products have been the main sources of new drugs. The different strategies have been developed to find the new drugs based on natural products. The traditional and ethic medicines have provided information on the therapeutic effects and resulted in some notable drug discovery of natural products. The special activities of the medicine plants such as the side effects have inspired scientists to develop the novel small molecular. The microorganisms and the endogenous active substances from human or animal also become the important approaches to the drug discovery. The tremendous progress in technology led to the new strategies in drug discovery from natural products. The bioinformation and artificial intelligence have facilitated the research and development of natural products. We will provide a scene of strategies and technologies for drug discovery from natural products in this review.
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http://dx.doi.org/10.1016/j.pharmthera.2020.107686DOI Listing
December 2020

Research Progress of the Antiviral Bioactivities of Natural Flavonoids.

Nat Prod Bioprospect 2020 Oct 18;10(5):271-283. Epub 2020 Sep 18.

Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China.

Flavonoids are now considered as an indispensable component in a variety of nutraceutical and pharmaceutical applications. Most recent researches have focused on the health aspects of flavonoids for humans. Especially, different flavonoids have been investigated for their potential antiviral activities, and several natural flavonoids exhibited significant antiviral properties both in vitro and in vivo. This review provides a survey of the literature regarding the evidence for antiviral bioactivities of natural flavonoids, highlights the cellular and molecular mechanisms of natural flavonoids on viruses, and presents the details of most reported flavonoids. Meanwhile, future perspectives on therapeutic applications of flavonoids against viral infections were discussed.
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http://dx.doi.org/10.1007/s13659-020-00257-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500501PMC
October 2020

Using Flammulina velutipes derived chitin-glucan nanofibrils to stabilize palm oil emulsion:A novel food grade Pickering emulsifier.

Int J Biol Macromol 2020 Dec 15;164:4628-4637. Epub 2020 Sep 15.

College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China. Electronic address:

We herein report chitin-glucan nanofibrils from edible mushroom Flammulina velutipes (CGNFs) as a novel stabilizer for palm oil Pickering emulsion (o/w, 30:70, v:v). Generally, these CGNFs being composed of glucose and glucosamine, are threadlike with 4.9 ± 1.2 nm wide and 222.6 ± 91.9 nm long. They were easily absorbed on the oil-water interface to form a compact layer around the oil droplets referring to Pickering emulsion. This emulsion presented shear-thinning and gel-like behaviors, wherein CGNFs concentration had a profound influence on the emulsion volume, droplet size, and stabilization index. Moreover, CGNFs showed an ability to stabilize the emulsion with a minimum of surface coverage approximately 30%. It indicated that moderate concentration of NaCl improved the emulsification effect, and the emulsion were stable in a large range of pH. These CGNFs are easy to prepare, eco-friendly and sustainable, which provides a potential for large-scale application of Pickering emulsion in food and nutraceuticals fields.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.09.073DOI Listing
December 2020

Bexarotene combined with lapatinib for the treatment of Cushing's disease: evidence based on drug repositioning and experimental confirmation.

Signal Transduct Target Ther 2020 08 29;5(1):175. Epub 2020 Aug 29.

Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, 1 Xian Nong Tan Street, 100050, Beijing, China.

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http://dx.doi.org/10.1038/s41392-020-00284-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456421PMC
August 2020

Puerarin attenuates the endothelial-mesenchymal transition induced by oxidative stress in human coronary artery endothelial cells through PI3K/AKT pathway.

Eur J Pharmacol 2020 Nov 27;886:173472. Epub 2020 Aug 27.

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address:

Endothelial-mesenchymal transition (EndMT) is a process in which endothelial cells lose their specific morphology/markers and undergo a dramatic remodeling of the cytoskeleton. It has been implicated in the progression of cardiovascular diseases such as cardiac fibrosis and cardiac dysfunction. Recent study indicated that puerarin could inhibit EndMT against cardiac fibrosis. However, the precise role of puerarin in EndMT and the underlying molecular mechanisms remain unclear. EndMT was induced by HO (150 μM) in human coronary artery endothelial cells (HCAECs). HCAECs were exposed to HO for six days with or without puerarin pretreated 2 h. The protein changes of EndMT markers (CD31, VE-cadherin, FSP1 and α-SMA) in HCAECs were detected. The levels of phosphoinositide-3-kinase (PI3K) and protein kinase B (AKT) proteins were analyzed by Western Blot. Wound healing and transwell assay were carried out to examine cell chemotaxis. Puerarin mitigated HO-induced EndMT as indicated by alleviating the reduced expression of CD31 and VE-cadherin and inhibiting the upregulation of α-SMA and FSP1. Furthermore, the mechanisms study showed that puerarin activated the PI3K/AKT pathway by inhibiting reactive oxygen species and further attenuated EndMT. On the other hand, PI3K inhibitor LY294002 reversed this effect imposed by puerarin. Puerarin alleviated the migration of mesenchymal-like cells through reducing MMPs protein expression. These results implicated that puerarin exhibited cytoprotective effects against HO-induced EndMT in HCAECs through alleviating oxidative stress, activating the PI3K/AKT pathway and limiting cell migration.
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http://dx.doi.org/10.1016/j.ejphar.2020.173472DOI Listing
November 2020

Control over Polymorph Formation of Polydatin in Binary Solvent System and Structural Characterization.

J Pharm Biomed Anal 2020 Oct 17;190:113260. Epub 2020 Mar 17.

Beijing City Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College. Beijing, 100050, China. Electronic address:

Polydatin is a natural product used for anti-oxidant, anti-inflammatory and anti-tumor purposes, and often added in medicine, nutraceutical, cosmetics, and dietary supplement. Polymorphism is a key feature of solid-state pharmaceutical products. Polymorphic modifications may exhibit different physical and chemical properties. Here we report two different polymorphs, and the amorphous form of Polydatin. Polymorphs were prepared in binary solvent system. The crystal structures of the two forms were revealed for the first time. The structure and 3D packing were determined with single crystal X-ray diffraction analysis. The batch consistency and stability were identified with Powder X-ray diffraction analysis. Various functional groups present in the polymorphs were analyzed with fourier transform infrared spectroscopic method. The thermal properties were investigated with DSC and TGA. HPLC-MS was used for the pharmacokinetic study. Results show that form B has the faster absorption, and can be maintained in animal bodies for a longer time than form A.
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http://dx.doi.org/10.1016/j.jpba.2020.113260DOI Listing
October 2020

Systematic analysis of molecular mechanism of resveratrol for treating pulmonary hypertension based on network pharmacology technology.

Eur J Pharmacol 2020 Dec 14;888:173466. Epub 2020 Aug 14.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address:

Resveratrol is a polyphenolic antioxidant derived from plant products such as grapes. Previous studies explored the effects of resveratrol on pulmonary hypertension (PH). However, systematic research on the exact mechanism of action of resveratrol is still lacking; in particular, our knowledge on the molecule-gene interaction is limited. In this study, systematic pharmacology and bioinformatic approaches were employed to identify the potential targets of resveratrol for treating PH. Furthermore, core genes were identified by constructing a protein-protein interaction network and by conducting topology analyses. The results showed that the effect of resveratrol may be closely associated with targets such as AKT serine/threonine kinase 1 (AKT1), mitogen-activated protein kinase 3 (MAPK3), Sirtuin-1 (SIRT1) and proto-oncogene tyrosine-protein kinase Src (SRC), as well as biological processes such as cell proliferation, inflammatory response, and redox balance. The present study systematically elucidates the mechanisms by which resveratrol alleviates PH and provides a new perspective on drug research for this disease.
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http://dx.doi.org/10.1016/j.ejphar.2020.173466DOI Listing
December 2020

Comprehensive Lipidome Profiling of the Kidney in Early-Stage Diabetic Nephropathy.

Front Endocrinol (Lausanne) 2020 19;11:359. Epub 2020 Jun 19.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College, Beijing Key Laboratory of Drug Target, Screening Research, Chinese Academy of Medical Sciences, Beijing, China.

Metabolic changes associated with diabetes are reported to lead to the onset of early-stage diabetic nephropathy (DN). Furthermore, lipotoxicity is implicated in renal dysfunction. Most studies of DN have focused on a single or limited number of lipids, and the lipidome of the kidney during early-stage DN remains to be elucidated. In the present study, we aimed to comprehensively identify lipid abnormalities during early-stage DN; to this end, we established an early-stage DN rat model by feeding a high-sucrose and high-fat diet combined with administration of low-dose streptozotocin. Using a high-coverage, targeted lipidomic approach, we established the lipid profile, comprising 437 lipid species and 25 lipid classes, of the kidney cortex in normal rats and the DN rat model. Our findings additionally confirmed that the DN rat model had been successfully established. We observed distinct lipidomic signatures in the DN kidney, with characteristic alterations in side chain composition and degree of unsaturation. Glyceride lipids, especially cholesteryl esters, showed a significant increase in the DN kidney cortex. The levels of most phospholipids exhibited a decline, except those of phospholipids with side chain of 36:1. Furthermore, the levels of lyso-phospholipids and sphingolipids, including ceramide and its derivatives, were dramatically elevated in the present DN rat model. Our findings, which provide a comprehensive lipidome of the kidney cortex in rats with DN, are expected to be useful for the identification of pathologically relevant lipid species in DN. Furthermore, the results represent novel insights into the mechanistic basis of DN.
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http://dx.doi.org/10.3389/fendo.2020.00359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325916PMC
May 2021

DL0410 attenuates oxidative stress and neuroinflammation via BDNF/TrkB/ERK/CREB and Nrf2/HO-1 activation.

Int Immunopharmacol 2020 Sep 6;86:106729. Epub 2020 Jul 6.

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address:

Oxidative stress and neuroinflammation have been deeply associated with Alzheimer's disease. DL0410 is a novel acetylcholinesterase inhibitor with potential anti-oxidative effects in AD-related animal models, while the specific mechanism has not been fully clarified. In this study, DL0410 was predicted to be related to the modification of cell apoptosis, oxidation-reduction process, inflammatory response and ERK1/ERK2 cascade by in silico target fishing and GO enrichment analysis. Then the possible protective effects of DL0410 were evaluated by hydrogen peroxide (HO)-induced oxidative stress model and lipopolysaccharides (LPS)-induced neuroinflammation model HO decreased the viability of SH-SY5Y cells, induced malondialdehyde (MDA) accumulation, mitochondrial membrane potential (Δψm) loss and cell apoptosis, which could be reversed by DL0410 dose-dependently, indicating that DL0410 protected SH-SY5Y cells against HO-mediated oxidative stress. Western blot analysis showed that DL0410 increased the HO-triggered down-regulated TrkB, ERK and CREB phosphorylation and the expression of BDNF. In addition, TrkB inhibitor ANA-12, ERK inhibitor SCH772984 and CREB inhibitor 666-15 eliminated the inhibition of DL0410 on MDA accumulation and Δψm loss. Furthermore, DL0410 attenuates inflammatory responses and ROS production in LPS-treated BV2 cells, which is responsible for Nrf2 and HO-1 up-regulation. The present study demonstrates that DL0410 is a potential activator of the BDNF/TrkB/ERK/CREB and Nrf2/HO-1 pathway and may be a potential candidate for regulating oxidative stress and neuroinflammatory response in the brain. Together, the results showed that DL0410 is a promising drug candidate for treating AD and possibly other nervous system diseases associated with oxidative stress and neuroinflammation.
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http://dx.doi.org/10.1016/j.intimp.2020.106729DOI Listing
September 2020