Advances in research of heart organoid and its application in drug discovery / 药学学报

Cardiovascular diseases are fatal threats to human health and also important fields in drug discovery. Organoid is a miniature with the structure and function similar to the organ, which is formed by the self-updating and specific differentiation of stem cells during the in vitro culture. Considering its characteristics of human origin, physical features, self-assembling and genetic stability, heart organoid has attracted much attention in the study of cardiogenesis, cardiovascular diseases modeling and related drug research. Hence, this article will review the development of heart organoids and its construction strategies, highlighting its application and prospects in drug discovery.

The preventive effect and mechanism of Dayuanyin in hypoxic pulmonary hypertension through NF-κB signaling pathway / 药学学报

Dayuanyin (DYY) has been shown to reduce lung inflammation in both coronavirus disease 2019 (COVID-19) and lung injury. This experiment was designed to investigate the efficacy and mechanism of action of DYY against hypoxic pulmonary hypertension (HPH) and to evaluate the effect of DYY on the protection of lung function. Animal welfare and experimental procedures are approved and in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Science. Male C57/BL6J mice were randomly divided into 4 groups: control group, model group, DYY group (800 mg·kg-1), and positive control sildenafil group (100 mg·kg-1). The animals were given control solvents or drugs by gavage three days in advance. On day 4, the animals in the model group, DYY group and sildenafil group were kept in a hypoxic chamber containing 10% ± 0.5% oxygen, and the animals in the control group were kept in a normal environment, and the control solvent or drugs continued to be given continuously for 14 days. The right ventricular systolic pressure, right ventricular hypertrophy index, organ indices and other metrics were measured in the experimental endpoints. Meantime, the expression levels of the inflammatory factors in mice lung tissues were measured. The potential therapeutic targets of DYY on pulmonary hypertension were predicted using network pharmacology, the expression of nuclear factor kappa B (NF-κB) signaling pathway-related proteins were measured by Western blot assay. It was found that DYY significantly reduced the right ventricular systolic pressure, attenuated lung injury and decreased the expression of inflammatory factors in mice. It can also inhibit hypoxia-induced activation of NF-κB signaling pathway. DYY has a protective effect on lung function, as demonstrated by DYY has good efficacy in HPH, and preventive administration can slow down the disease progression, and its mechanism may be related to inhibit the activation of NF-κB and signal transducer and activator of transcription 3 (STAT3) by DYY.

Study on the differences in chemical composition of Scutellaria baicalensis leaves from different origins in Shanxi Province based on plant metabolomics and targeted quantitative analysis / 药学学报

By integrating plant metabonomics and target quantitative analysis methods, this study systematically analyzed the differences of chemical constituents in Scutellaria baicalensis leaves from different producing areas in Shanxi, so as to provide theoretical basis for rational and effective utilization of Scutellaria baicalensis leaves. Based on the idea of plant metabonomics, the liquid quality of 53 batches of Scutellaria baicalensis leaves from 8 different producing areas in Shanxi was analyzed by UPLC-QTOF-MS, and the collected data were imported into SIMCA 14.1 software for multivariate statistical analysis to screen the different chemical constituents among different habitats in Shanxi. Meanwhile, a method for simultaneous determination of 7 flavonoids and 3 organic acids in Scutellaria baicalensis leaves was optimized and established to quantitatively analyze the differences of chemical components in Scutellaria baicalensis leaves from different producing areas in Shanxi. The results of plant metabonomics showed that there were differences in the chemical composition of Scutellaria baicalensis leaves in northern Shanxi (Datong, Xinzhou), Jinzhong (Yangquan, Luliang) and southern Shanxi (Changzhi, Yuncheng, Jincheng, Linfen): there were 14 significant differences in chemical composition between northern Shanxi and Jinzhong; there were 18 significant differences in chemical constituents between southern Shanxi and central Shanxi. There were 15 significant differences in chemical constituents between northern Shanxi and southern Shanxi. Among them, scutellarin and isocarthamidin-7-O-glucuronide were the common differences among the three regions, and the content of scutellarin was the highest in southern Shanxi and the lowest in northern Shanxi. The content of isocarthamidin-7-O-glucuronide was the highest in Jinzhong area and the lowest in northern Shanxi area. Quantitative analysis further confirmed that the average contents of apigenin, naringenin and citric acid were the highest in northern Shanxi, scutellarin, caffeic acid, apigenin-7-O-glucuronide, malic acid and wogonoside were the highest in southern Shanxi, and wogonoside and baicalin were the highest in central Shanxi. This study is of great significance to the quality control of Scutellaria baicalensis leaf resources, and provides theoretical basis for rational and effective utilization of Scutellaria baicalensis leaf resources.

Research progress on experimental animal models of hyperuricemia / 中国药理学通报

Hyperuricemia is a chronic metabolic disease caused by purine metabolism disorder or uric acid excretion disorder. The experimental animal model of hyperuricemia is the basis for studying the pathological mechanism and drug treatment of hyperuricemia. This paper reviews the experimental animal models of hyperuricemia commonly used in drug research, and introduces the modeling principle, preparation methods, species selection and related detection techniques of the models, so as to provide reference for the application of such models in research.

Exploring the mechanism of anti-hereditary Parkinson's disease of baicalein based on PINK1 RNAi Drosophila model / 药学学报

The aim of this study was to investigate the effect of baicalein on a Drosophila model of hereditary Parkinson's disease caused by gene mutations and to preliminarily elucidate the mechanism of baicalein in delaying hereditary Parkinson's disease. In this paper, PTEN-induced putative kinase 1 (PINK1)-RNAi Parkinson's Drosophila were used as the model group and wild-type Drosophila w1118 were used as the control group. Different doses of baicalein and Madopa were administered to the model group to observe their effects on the life span, motor ability, the abnormal rate of wings, dopamine content and dopaminergic neurons of PINK1-RNAi Parkinson's Drosophila and their effects on mitochondrial dysfunction including adenosine triphosphate (ATP), mitochondrial DNA (mtDNA) and reactive oxygen species (ROS) content. The results showed that the effective administration doses of baicalein were 0.8 mg·mL-1 for low concentration, 1.6 mg·mL-1 for medium concentration and 3.2 mg·mL-1 for high concentration, and the optimal administration dose of the positive drug Madopa was 0.1 μg·mL-1. Baicalein and Madopa could significantly improve the life span, exercise ability and reduce the abnormal rate of wings of PINK1-RNAi male Drosophila (P < 0.05), and low dose baicalein showed the best effect; baicalein could improve the loss of dopaminergic neurons, and the effects of low dose and high dose were the best, but Madopa showed no significant effect; baicalein and Madopa had no significant effect on dopamine content (P > 0.05). Baicalein and Madopa could increase the ATP content of PINK1-RNAi male Drosophila (P < 0.05), and low dose baicalein showed the best effect; middle dose baicalein could significantly increase the mtDNA content of PINK1-RNAi male Drosophila (P < 0.05), but Madopa had no significant effect; baicalein and Madopa had no significant effect on ROS content (P > 0.05).

Progress on targets and therapeutic drugs for pancreatic cancer / 药学学报

Pancreatic cancer is a highly malignant tumor with a poor prognosis. It is very hard to treat pancreatic cancers for their high heterogeneity, complex tumor microenvironment, and drug resistance. Currently, gemcitabine plus nab-paclitaxel, capecitabine and FOLFIRINOX are standard chemotherapy for resectable or advanced metastatic pancreatic cancer. Considering the limited efficacy and toxic side effects of chemotherapy, targeted and immune drugs have gradually attracted attention and made some progress. In this article, we systematically reviewed the chemotherapeutic drugs, targets and related targeted drugs, and immunotherapy drugs for pancreatic cancer.

Research progress in drugs targeting tumor associated macrophage / 药学学报

Tumor brings great threat to human public health. In recent years, incidence rate and mortality of tumor were rapidly increased in the world. Anti-tumor therapies have undergone the development of cytotoxic therapy, targeted therapy, and immunotherapy. Among them, tumor immunotherapy is rapidly developed and becomes an important anti-tumor therapy in recent years, although it also brings some related side effects. Tumor microenvironment (TME) is composed of immune cells, vascular vessels, fibroblasts, the extracellular matrix, etc. TME significantly affects the efficacy of immunotherapy. Macrophages in the TME are named as tumor associated macrophages (TAMs). Recently, increasing studies have shown that TAMs play an important role in the regulation of tumor immunity, especially in tumor immune surveillance and immune escape. Currently, more and more anti-tumor immunotherapy strategies targeting TAMs are at the development stage. Based on the important role of TAMs in the TME and their potential as therapeutic targets in tumor immunotherapy, we first reviewed the subtypes and functions of TAMs, as well as the roles of TAMs in tumors. Furthermore, we summarized the research progress on anti-tumor strategies targeting TAMs and the current status of drug targeting TAMs. The current review will provide new ideas and novel insights for tumor immunotherapy.

Research progress of cystine/glutamate antiporter as drug targets / 药学学报

Cystine/glutamate antiporter [system Xc(-)] is a sodium independent amino acid transporter, which is a heterodimer composed of light chain subunit xCT and heavy chain subunit 4F2hc (CD98) through covalent disulfide bond. System Xc(-) typically mediates cystine uptake and glutamate output, helps to maintain the balance of glutamate, cystine and cysteine inside and outside the cell, regulates the level of glutamate inside and outside the membrane and the synthesis of intracellular glutathione, thus affecting oxidative stress and glutamate neurotoxicity. This review expounds the structure and function of system Xc(-), analyzes the role of the transporter in physiology and pathology, discusses the role and mechanism in different diseases, and discusses the specific research progress of system Xc(-) as a drug target. This review summarizes the research status of system Xc(-) and provides theoretical guidance for further research on system Xc(-) and drug discovery.

Identification of multi-target anti-cancer agents from TCM formula by in silico prediction and in vitro validation / 中国天然药物

Cancer is a complex disease associated with multiple gene mutations and malignant phenotypes, and multi-target drugs provide a promising therapy idea for the treatment of cancer. Natural products with abundant chemical structure types and rich pharmacological characteristics could be ideal sources for screening multi-target antineoplastic drugs. In this paper, 50 tumor-related targets were collected by searching the Therapeutic Target Database and Thomson Reuters Integrity database, and a multi-target anti-cancer prediction system based on mt-QSAR models was constructed by using naïve Bayesian and recursive partitioning algorithm for the first time. Through the multi-target anti-cancer prediction system, some dominant fragments that act on multiple tumor-related targets were analyzed, which could be helpful in designing multi-target anti-cancer drugs. Anti-cancer traditional Chinese medicine (TCM) and its natural products were collected to form a TCM formula-based natural products library, and the potential targets of the natural products in the library were predicted by multi-target anti-cancer prediction system. As a result, alkaloids, flavonoids and terpenoids were predicted to act on multiple tumor-related targets. The predicted targets of some representative compounds were verified according to literature review and most of the selected natural compounds were found to exert certain anti-cancer activity in vitro biological experiments. In conclusion, the multi-target anti-cancer prediction system is very effective and reliable, and it could be further used for elucidating the functional mechanism of anti-cancer TCM formula and screening for multi-target anti-cancer drugs. The anti-cancer natural compounds found in this paper will lay important information for further study.

The research advance on subtypes and relevant therapy of Parkinson's disease / 药学学报

Parkinson's disease (PD) is a progressive neurodegenerative disease with a high clinical heterogeneity. According to its motor symptoms, PD patients are divided into predominant tremor-dominant, postural instability and gait difficulty-dominant/akinetic-rigid and mixed subtypes. Different subtypes show different prognostic characteristics and different sensitivities to drugs. Therefore, the early classification of PD is of great significance for the treatment and prognosis of the disease. This paper reviews the clinical classification methods of different subtypes of PD, summarizes the latest biochemical markers and imaging features, and analyzed the differences in incidence, prognosis and pathological mechanism. The current clinical treatment drugs and methods have been preliminarily targeted for treatment based on PD classification, and there are many animal models of PD subtypes have been studied, providing new methods and strategies for mechanism research and preclinical pharmacodynamics evaluation of PD subtypes.

Based on plasma metabonomics and network analysis to research the mechanisms of Chaigui granules for treating depression / 药学学报

The purpose of this study was to systematically analyze the antidepressant mechanism of Chaigui granules from the perspective of biological metabolic network by using integrated metabolomics and biological network analysis tools. The model of chronic unpredictable mild stress (CUMS) depression rat was established, and LC-MS-based plasma metabolomics was used to identify the key metabolites and analyze metabolic pathways underlying the antidepressant effects of Chaigui Granules. The key metabolites regulated by Chaigui granules was integrated with biological network analysis tools to further focus on the key metabolic pathways and explore the potential targets of the antidepressant effect of Chaigui granules. The results showed that there were significant differences in the plasma levels of 20 metabolites in the model group compared with the control group (P < 0.05), Chaigui granules significantly regulated 12 metabolites including docosatrienoic acid, 3-hydroxybutyric acid, 4-hydroxybenzaldehyde, chenodeoxycholic acid, cholic acid, L-glutamine, glycocholic acid, linoleyl carnitine, L-tyrosine, N-acetylvaline, palmitoylcarnitine, arachidonic acid. Further network analysis of the key metabolites regulated by Chaigui granules indicated that plasma arachidonic acid metabolism might be the core pathway for the antidepressant effect of Chaigui granules, with 10 proteins were potential targets for the antidepressant effect of Chaigui granules, including CYP2B6, CYP2E1, CYP2C9, CYP2C8, PLA2G6, PTGS2, ALOX15B, PTGS1, ALOX12 and ALOX5. The animal experimental operations involved in this paper was followed the regulations of the Animal Ethics Committee of Shanxi University and passed the animal experimental ethical review (Approval No. SXULL2020028).

Puerarin reduces oxidative damage to vascular endothelial cells by improving mitochondrial respiratory function / 药学学报

This study investigated the effect of puerarin on human umbilical vein endothelial cells (HUVEC) injured with hydrogen peroxide (H2O2). HUVEC were divided into three groups: a control group, a model group (H2O2 400 μmol·L-1) and a puerarin-treated group (3, 10, 30 and 100 μmol·L-1). HUVEC were cultured with varied concentration of puerarin for 2 h and treated with H2O2 for another 24 h. Cell proliferation was detected by a CCK-8 assay. The mitochondrial membrane potential was measured by a JC-1 fluorescent probe. A transwell chamber assay was adopted to observe cell migration ability. Mitochondrial respiratory function was measured in a two-chamber titration injection respirometer (Oxygraph-2k). The expression of interleukin-1β (IL-1β), interleukin-18 (IL-18) and tumor necrosis factor-α (TNF-α) was detected by quantitative real-time PCR. The expression of pyroptosis-mediated proteins, including cleaved-cysteinyl aspartate-specific proteinase-1 (caspase-1), N-gasdermin D (N-GSDMD), NOD-like receptor protein 3 (NLRP3) and purinergic ligand-gated ion channel 7 receptor (P2X7R) was detected by Western blot. The results show that 400 μmol·L-1 H2O2 treatment for 24 h causes obvious damage to HUVEC. Compared with the model group, puerarin protected against cellular injury in a dose-dependent manner, with the greatest effect at a dose of 30 and 100 μmol·L-1. Puerarin significantly decreased the mitochondrial membrane potential and improved mitochondrial function. Puerarin inhibited cell migration induced by H2O2, suppressed the expression of IL-1β, IL-18 and TNF-α, and down-regulated the pyroptosis-mediated protein. These changes are statistically significant (P < 0.05). These findings demonstrate that puerarin has a protective effect against H2O2-induced oxidative damage of HUVEC by inhibiting the migration of HUVEC cells. The mechanism may be related to improved mitochondrial respiratory function and inhibition of pyroptosis.

The mechanisms of type 2 diabetic skeletal muscle atrophy and the effects of commonly used hypoglycemic drugs: a review / 药学学报

Type 2 diabetes is a hypermetabolic disease characterized with disorders of glucose/lipid metabolism, absolute or relative lack of insulin, and can induce skeletal muscle atrophy. Hyperglycemia, hyperlipidemia, insulin resistance, and abnormal release of inflammatory factors can lead to abnormal signal transduction in skeletal muscle, thus make protein synthesis and degradation imbalance and eventually causing muscle atrophy. Under normal conditions, insulin-like growth factor 1 (IGF-1)/insulin can activate phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT). AKT not only increases protein synthesis through mammalian target protein of rapamycin (mTOR), but also phosphorylates forkhead box O (FoxO) transcription factor and then inhibits the transcription of several ubiquitin ligases (such as MAFbx/atrogin-1 and MuRF1), or autophagy related genes. The weakened IGF-1/PI3K/AKT pathway in type 2 diabetes is an important factor leading to skeletal muscle atrophy. Studies have shown that the commonly used anti-type 2 diabetic drugs have different effects in regulating the synthesis and degradation of skeletal muscle protein. Studies reported that drugs with effect of anti-diabetic muscle atrophy include thiazolidinediones, glucagon-like peptide analogs, glucose-sodium cotransporter 2 inhibitors, etc.; drugs that are still in controversial or even promote skeletal muscle atrophy include metformin, and some sulfonylurea or non-sulfonylurea insulin secretagogues. This article overviewed and analyzed the currently commonly used drugs for type 2 diabetes and summarized the related mechanisms, with the aim to provide references for the rational applications of drugs for type 2 diabetes.

Progress in RIPK3-mediated necroptosis involved in myocardial ischemia-reperfusion injury / 中国药理学通报

Aim Timely re establishment of coronary blood How in patients with myocardial infarction is the cornerstone of their treatment; however, substantial amount of damage can oecur as a consequence of reperfusion.In recent years it has been found that receptor interacting protein kinase 3 ( RIPK3 ) contributes remarkably to myocardial ischemia-reperfusion injury (MIRI).RIPK3 can regulate necroptosis through RIPK1/RIPK3/MLKL and CaMKII, respectively, and participate in the MIRI process.This artiele reviews the researeh progress of RIPK3-mediated ne¬ croptosis involved in MIRI from endoplasmic reticulum stress, mitochondrial fragmentation disturbanee, cardiac microvascular dysfunction and inflammation, and focuses on whether RIPK3 can be used as a new target for anti-MIRI, so as to provide a new strategy and choice for improving the clinical treatment effect and prognosis of ischemic heart disease.

Research progress and application of animal models for drug development in multiple sclerosis / 中国药理学通报

Multiple sclerosis ( MS) is an immune-mediated chro¬nic inflammatory disease of the central nervous system (CNS) , which is regulated by multiple pathophysiological mechanisms.There are four clinical phenotypes of MS, including relapsing-re- mitting MS ( RRMS) , primary progressive MS ( PPMS) , sec- ondary-pmgressive MS ( SPMS) , and progressive relapsing MS ( PRMS) , among which RRMS is the main type.'Hie pathogen¬esis of MS is not clear and it could not he cured, so long-term drug treatment is needed for the MS patients.Nowadays, animal models play an important role in the preclinical research of MS drugs.'Hie MS animal models are mainly divided into experi¬mental autoimmune encephalomyelitis (EAE) model, toxin in¬ duced demyelination model, and vims induced demyelination model, among which EAE model is most widely used.'Hie three types of MS animal models demonstrate specific characteristics due to the different induction methods and animal species, and they correspond to specific clinical types of MS.According to the different clinical types of MS, the use of appropriate animal models for drug research and development will help us develop more targeted and potential therapeutic dnrgs, making it possible to cure MS.

Preparation and evaluation of experimental animal models of ischemic brain injury / 中国药理学通报

Aim Ischemic brain injury ( IBI) is one of the main causes of death and disability worldwide.Faced with this serious disease, human beings still laek effective treatment methods.With the advancement of science and the improvement of medi¬cal standards, the basic and clinieal research of cerebrovaseular diseases continues to develop to a higher and more in-depth lev¬el.Due to the limitations of clinical researeh, animal models of eerebral ischemia have beeome an indispensable tool for studying the mechanism of cerebrovascular disease damage and prevention and treatment measures.It is necessary to construct scientific, standard and standardized experimental methods and proee- dures..Methods This artiele combines our laboratory s long-tenn praetieal experienee in preparing animal models of cerebral is¬chemia.comprehensive literature data, comparison and evalua¬tion of the characteristics of commonly used animal models.Re¬sults Standardized preparation methods and discusses the com¬mon criteria for preparing experimental animal models of cerebral Ischemia, which is the occurrence of cerebral ischemia injury.Conclusions 'Hie researeh of mechanism and the researeh and de¬velopment of prevention and treatment drugs provide reliable ex¬perimental animal models.

Research progress on mechanisms and therapeutic drugs of hypoxic pulmonary hypertension / 中国药理学通报

Hypoxic pulmonary hypertension ( HPH) is a complex mechanism of HPH is complex, and it has a high mortality rate cardiopulmonary disease eaused by hypoxia.The pathological of disability.Clinically the diug of treatment for HPH is unspe-cialized, mainly relying on traditional vasomotor dnrgs, inclu¬ding prostaglandin 12 receptor agonists, endothelin receptor an¬tagonists and phosphodiesterase-5 inhibitors, but their efficacy cannot be achieved.To meet the clinical need, it is of great sig¬nificance to develop targeted anti-HPH dnigs.To provide ideas for the discovery of HPH treatment drugs, the pathophysiological mechanism of HPH and the current status of dmg development are reviewed in the paper.

Mitochondrial retrograde signaling: a new option for the treatment of mitochondrially related diseases / 药学学报

Mitochondria play a key role in cell metabolism. In addition to synthesizing ATP, they also participate in many physiological and pathological processes, including apoptosis, inflammation, oxidative stress, neuronal disease, tumor development, and aging. Most gene transcription of mitochondrial proteins occurs in the nucleus, so the biogenesis of mitochondria and the maintenance of mitochondrial homeostasis mainly depend on the expression of nuclear genes (nDNA) and mitochondria-nucleus interactions. Conversely, mitochondria can affect the expression of nuclear genes through nuclear transcription factors, a process called mitochondrial retrograde signaling. This review summarizes the research progress on mitochondria-nucleus retrograde signaling and its regulation, including the ways by which mitochondria regulate nuclear genes and affect biological processes, and discusses new strategies for the treatment of diseases that involve mitochondrial retrograde signaling in disease pathology.

Research advances on the protective effects and mechanism of salvianolic acids against ischemic heart disease / 药学学报

Salvianolic acids are the main water-soluble active compounds of Salvia miltiorrhiza and have been widely used for the treatment of cardiovascular diseases. Based on the latest studies in China and abroad, we summarize the pharmacological effects and mechanism of salvianolic acids on ischemic heart disease by describing how salvianolic acid A and salvianolic acid B protect the vascular endothelium, relax coronary arteries, promote angiogenesis and anti-platelet aggregation, inhibit the inflammatory response, anti-cell apoptosis, and scavenge free radicals. This review provides a theoretical basis for further research on the effects of salvianolic acids on ischemic heart disease and their potential for drug development.

Evaluation of the preventive effect of DL0805-2 against monocrotaline induced rat pulmonary arterial hypertension / 药学学报

In the treatment of hypertensive crisis, the novel Rho kinase inhibitor DL0805-2 can rapidly lower systematic blood pressure, reduce pulmonary artery pressure, and has a significant protective effect on lung injury. This experiment intends to evaluate the efficacy of DL0805-2 against pulmonary arterial hypertension (PAH) and preliminarily reveals its underlying mechanism. Animal welfare and experimental procedures are in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. Sprague Dawley (SD) rats were randomly divided into DL0805-2 low, medium, and high dose groups (1, 3, and 10 mg·kg-1), bosentan positive control group, model group, and blank control group. The drug was administered daily on the 7th day after model establishment by monocrotaline injection. On the 25th day of the experiment, relevant indicators were examined to observe the therapeutic effect of DL0805-2 on pulmonary hypertension. DL0805-2 significantly relieved the abnormal changes in the physiological parameters related to PAH induced by monocrotaline, including reducing right ventricular systolic pressure, alleviating cardiac damage caused by pressure overload, and reducing the levels of endothelin-1 and inflammatory factors in lung tissues. DL0805-2 also attenuated pulmonary arteries remodeling. It was preliminarily discovered that DL0805-2 exerts preventive and therapeutic effect on PAH through Rho-kinase pathway. Our results suggested that DL0805-2 had good therapeutic effects on monocrotaline-induced PAH rat model. It intervened early in the disease process, effectively prevented the development of the disease, and reduced the mortality of the diseased animals. The mechanism is related to Rho-kinase pathway.