Injury of vascular endothelial barrier function is implicated in several pathophysiological processes. The integrity of vascular endothelium is regulated by cytoskeleton and cell-cell junctions. Small guanosine triphosphatases of the Rho family (Rho GTPases) are known to play a central role in vascular endothelial barrier function. It has been reported that RhoA, Rac1, Cdc42 and RhoB are involved and they exert both positive and negative effect on endothelial barrier integrity, depending on their subcellular location. When inflammatory factors such as thrombin attack the vascular endothelial cells, GEF of RhoA will be widely distributed throughout the cells. Thus, activated RhoA causes aggregation of F-actin fibers in a short time and disrupts the vascular endothelial barrier, a process named acute cell contraction. However, RhoA may also induce the production and maturation of intercellular junctions in new cells. Rac1 and Cdc42 help to maintain the integrity of vascular endothelial barrier at the resting state. They cause the phosphorylation of LIM kinase and inhabitation of cofilin, resulting in less remodeling of cytoskeletal in the vascular endothelial cells. On the other hand, Cdc42 can translocate to the cortex rapidly after a stimulation, where Cdc42 will activate the myosin Ⅱ and promote the reorganization of adjective junction to facilitate the recovery of vascular endothelial barrier. In this review, we overviewed how Rho GTPases regulate the vascular endothelial barrier integrity.

Chemotherapy plays an essential role in controlling tumor growth and progression. However, long-term use of chemotherapeutic drugs usually results in drug resistance in tumor cells, leading to treatment failure and disease progression. The mechanism of tumor resistance to chemotherapy and the strategy of prevention or reversal of such resistance have always been hot issues in cancer therapy research. Exosomes are small spherical vesicles secreted by cells with a diameter of 40-100 nm. They carry a variety of bioactive small molecules (including DNA, ncRNA, RNA, and proteins) and participate in regulation of cell microenvironment, thereby affecting a variety of physiological and pathological activities in the body. In recent years, studies have shown that exosomes play an important role in cancer cell resistance to chemotherapy, metastasis, and immune escape. This article reviews the role and mechanism of exosomes in the development of drug resistance in tumors, and aims to provide new ideas for the prevention or treatment of tumor resistance.

Lorlatinib (PF-06463922) is a highly selective and potent third generation anaplastic lymphoma kinase (ALK) inhibitor with dual activity against c-ros oncogene 1, a receptor tyrosine kinase (ROS1). In November 2018, the US Food and Drug Administration approved lorlatinib for treatment of disease progression in ALK-positive and late-stage NSCLC patients who receive the treatment with crizotinib and at least one of other ALK inhibitors; and those with disease progression after treatment of alectinib or ceritinib as the first ALK inhibitor. The results of Phase Ⅰ/Ⅱ clinical trials showed that it has effective initial anti-tumor activity, strong intracranial therapeutic activity, with less tolerance and safety issues. This paper systematically reviewed the chemical structure, mechanism of action, pharmacodynamics, pharmacokinetics, usage and dosage, clinical research, safety and upcoming research fields of lolatinib, to provide an update on clinical or laboratory research and clinical practice.

Adaptation to hypoxia of the plateau environment has been a focus of scientific research in decades. The geographical distributions of such living environment include the Qinghai-Tibet Plateau, Andean Plateau in South America and Ethiopian Plateau. Over the past century, the unique features of physiological adaptation to high-altitude chronic hypoxia have been documented scientifically. The genetic studies of hypoxic adaptation in the past decade have revealed genetic bases of human high-altitude adaptation, with a close relationship to the hypoxia inducible factor (HIF) pathway and hypoxia response elements (HREs). Interestingly, the genetic pattern of adaptation to hypoxia is not the same among the three plateau populations. Tibetan has developed the best high-altitude adaptation, with modification of the HIF pathway as the key genetic element. Due to the wide range of HIF pathways, HIFs could regulate hundreds of downstream genes and are closely related to various diseases such as cancer, inflammation, ischemia, acute organ damage and infection, etc. The treatment researches of these diseases through HIFs-related regulations have led to the development of stabilizers and inhibitors of HIF pathway. We review here the adaptive responses of the three plateau populations to the hypoxic environment, and the genetic mechanism of HIF and HREs in the different ethnic high-altitude populations. Classes of HIF inhibitors, such as PI3K and/or mammalian target of rapamycin (mTOR) inhibitors, DNA-binding inhibitors, histone deacetylase inhibitors, heat-shock protein 90 inhibitors, cardiac glycosides, transcription inhibitors, topoisomerase inhibitors, and HIF activators including 2-OG mimics, Fe²⁺ chelators, prolyl hydroxylase (PHD) active-site blockers and CUL2 deneddylators have been presented with the drug examples. In addition, the top 3 chemical-disease and chemical-gene (protein) co-occurrences have been presented from the Pubmed literature search. The review could serve as references for research of hypoxia adaptation and HIF-related diseases.

Protein-protein interaction (PPI) plays an important role in many steps of the human immunodeficiency virus (HIV) life cycle. Targeting these protein-protein interactions, especially the interaction between the virus with host cells, can provide new insights into the development of HIV inhibitors with novel mechanisms of action. Herein, we review the latest discoveries of PPI inhibitors based on the mechanisms of action of various protein-protein interactions with specific research examples.

The blood brain barrier can selectively block the uptake of xenobiotics from peripheral blood into the brain. Although this is important for maintaining the stability of the brain environment and normal function of the central nervous system, it presents a challenge for delivery of therapeutic drugs to the brain. Passive brain-targeting drug carrier is able to increase the drug concentration in the brain by enhancing the affinity to blood-brain barrier and/or inhibiting the efflux absorbed drug via P-glycoprotein. The active brain-targeting drug carrier can be obtained by linking specific ligands or antibodies onto passive target carriers to achieve precise delivery of drugs to the brain. Dual targeting drug carriers obtained by combining tumor cell targeting with brain targeting have shown their advantages for treatment of brain tumors. The targeted drug delivery to brain will provide a unique manner for the treatment of brain diseases such as Alzheimer's, Parkinson's, brain tumors, and stroke. Among the drug delivery systems of passive brain-targeting, active brain-targeting and dual brain-targeting, we evaluated the strategies to improve brain drug delivery efficiency, such as by reducing carrier size, opening tight junctions between cells at the blood-brain barrier, incorporating hydrophilic groups on the surface of the carrier, and alternative intranasal drug administration.

In ischemic stroke, increased level of neuronal complex of nitric oxide synthase (nNOS)-postsynaptic density protein-95 (PSD-95) plays an important role in neuronal damage. We aimed to establish a screening model to identify compounds capable of uncoupling nNOS interaction with PSD-95. In this model, human embryonic kidney-293T (HEK-293T) cells were transfected with either pCDH-Flag-nNOS or pcDNA3.1-PSD-95 plasmid to obtain the protein of Flag-nNOS or PSD-95. Incubating Flag-nNOS with PSD-95 causes formation of the nNOS-PSD-95 complex. ZL006, a known uncoupler of nNOS-PSD-95 interaction, can disturb the interaction between Flag-nNOS and PSD-95, serving as a positive control. The method coupling antibodies to magnetic beads with glutaraldehyde was used to decrease the cost and increase the efficiency. To establish that our model is suitable for selecting nNOS-PSD-95 uncouplers, we evaluated the ability of IC87201, another reported uncoupler of nNOS-PSD-95 interaction, and structural analogs of ZL006. IC87201 and one structure analog of ZL006 showed uncoupling effect, supporting that our model can be used to select different types uncoupler blocking nNOS-PSD-95 interaction.

A hyper-bilirubin cell model was established for its relevance to the pathological state of jaundice in human. This model was used to screen for the pharmacological components of Yin-Zhi-huang (YZH). Total bilirubin, indirect bilirubin in cells, and direct bilirubin in extracellular fluid were quantified after HepaRG cells were incubated with serum from rats injected with multiple components of YZH. Cellular uptake was determined by dynamic multiple reaction monitoring (DMRM) using LC-MS/MS. We found that the stable hyper-bilirubin HepaRG cell model could be established by incubating cells with 40 μg·mL^-1 bilirubin and 50 μg·mL^-1 probenecid. When the hyper-bilirubin cell model was incubated with serum from rats of YZH injection, there were 52.4% and 60.1% decrease in intercellular total bilirubin and indirect bilirubin, respectively, and 52.5% increase in extracellular direct bilirubin. Using DMRM mode, 53 components could be determined, and 8 potential bioactive candidates were identified from the serum. This method could be used to screen for bioactive metabolites of YZH. This strategy is simple, highly active, sensitive and specific, providing a new method for high throughput screening of therapeutic or toxic metabolites from traditional Chinese medicine. The regulations of Ethics Committee in the First Hospital of Lanzhou University were abided in the rat experiment of this study.

This study aimed to investigate the effect of Huangqin Tang (HQT) on oxidative stress associated with ulcerative colitis in rats, and to explore its antioxidant mechanism. After approved by Institute of Chinese Materia Medica Ethics Committees in China Academy of Chinese Medical Sciences, the rats were given 2, 4, 6-trinitrobenzenesulfonic (TNBS)/ethanol mixture to induce the ulcerative colitis (UC), and were randomly divided into normal group, model group, the salazosulfapyridine (SASP) group, and high, middle or low dose (20, 10, 5 g·kg^-1) of HQT groups. After 5 days of treatment, the activity of catalase (CAT) from micrococcus lysodeikticus, glutathione peroxidase (GSH-px), myeloperoxidase (MPO), superoxide dismutase (SOD) were detected by biochemical assays. The levels of lipid peroxide (LPO) were detected by ELISA. The positive protein expression of nuclear factor erythroid-2-related factor 2 (Nrf2) were detected by immunohistochemistry method and the downstream antioxidant enzymes of Nrf2 were determined by Western blot analyses. The levels of SOD, CAT and GSH-px activities in the normal group were significantly higher than the model group, while the serum MPO activity in the model group was obviously increased (P < 0.05 or P < 0.01). Compared with the model group, there was a significant difference in the activity of CAT in the high and middle dose groups of HQT (P < 0.05 or P < 0.01), the activity of GSH-px in the high, middle and low dose groups of HQT were apparently higher than the model group (P < 0.05); The serum levels of LPO in the model group were significantly higher than those in the normal group (P < 0.05), while the up-regulating effects on LPO were reversed by the high and middle dose groups of HQT (P < 0.05). The expression of Nrf2 in the high-dose group of HQT and SASP group was statistically significant (P < 0.05). The results of Western blot showed that compared with the model group, each of the HQT and SASP group could increase the heme oxygenase (HO-1) and NAD[P]H:quinone oxidoreductase 1 (NQO-1) expression in a dose-dependence manner. HQT has significant anti-oxidative stress and obviously improves the signs, mental status and defecation of UC rats. The mechanism of action for HQT maybe related to activate the Nrf2 pathway and increase the expression of Ⅱ phase metabolic enzymes such as HO-1 and NQO-1, reduce the content of LPO and MPO in serum and enhance the activity of SOD, CAT and GSH-px.

The combination of ginkgo ketoester tablet-donepezil (GD) is a popular combination commonly used in clinic for the treatment of Alzheimer's disease. To evaluate the learning and memory improving ability of different proportions of the two drugs. We optimized the ratio of GD for treatment of dementia using a mouse model. Dementia was induced by multiple neuronal damages in mice. The experimental protocols were approved by the Animal Experimental Ethical Committee of Nanjing University of Chinese Medicine and all the procedures were strictly conducted in accordance with ethical principle of animal use and care. Morris water maze, brain hematosylin-eosin staining and the changes of the neurotransmitters and related enzymes in the plasma or brain tissues were tested to determine the effect of GD on dementia mice. The results showed that the dementia mice were significantly different from the normal group in terms of behavior, pathological sections and related indicators. Compared to the dementia mice, partial administration groups could improve learning and memory ability as well as indexes in the blood and brain tissues. Both the principal component analysis and multi-attribute comprehensive index methods were used to comprehensively evaluate the total effect of GD on anti-dementia. The results showed that the combination of two drugs at the dose of 0.5 to 1 times was in a dose-effect relationship, and the dose of 1 (the clinical equivalent) had the best treatment effect. Then based on the optimal dose, GD 1:1 had best effect, which was consistent with the clinical use of two drugs. This provides scientific basis for more effective application of the compatibility between ketoester tablet and donepezil for modern clinic medicine.