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1.
Acta Pharmaceutica Sinica B ; (6): 801-820, 2022.
Article in English | WPRIM | ID: wpr-929328

ABSTRACT

Pharmacological activation of the xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) is well-known to increase drug metabolism and reduce inflammation. Little is known regarding their physiological functions on the gut microbiome. In this study, we discovered bivalent hormetic functions of PXR/CAR modulating the richness of the gut microbiome using genetically engineered mice. The absence of PXR or CAR increased microbial richness, and absence of both receptors synergistically increased microbial richness. PXR and CAR deficiency increased the pro-inflammatory bacteria Helicobacteraceae and Helicobacter. Deficiency in both PXR and CAR increased the relative abundance of Lactobacillus, which has bile salt hydrolase activity, corresponding to decreased primary taurine-conjugated bile acids (BAs) in feces, which may lead to higher internal burden of taurine and unconjugated BAs, both of which are linked to inflammation, oxidative stress, and cytotoxicity. The basal effect of PXR/CAR on the gut microbiome was distinct from pharmacological and toxicological activation of these receptors. Common PXR/CAR-targeted bacteria were identified, the majority of which were suppressed by these receptors. hPXR-TG mice had a distinct microbial profile as compared to wild-type mice. This study is the first to unveil the basal functions of PXR and CAR on the gut microbiome.

2.
Acta Pharmaceutica Sinica B ; (6): 2798-2818, 2021.
Article in English | WPRIM | ID: wpr-888888

ABSTRACT

Inflammatory bowel disease (IBD) is a chronic intestinal disease with painful clinical manifestations and high risks of cancerization. With no curative therapy for IBD at present, the development of effective therapeutics is highly advocated. Drug delivery systems have been extensively studied to transmit therapeutics to inflamed colon sites through the enhanced permeability and retention (EPR) effect caused by the inflammation. However, the drug still could not achieve effective concentration value that merely utilized on EPR effect and display better therapeutic efficacy in the inflamed region because of nontargeted drug release. Substantial researches have shown that some specific receptors and cell adhesion molecules highly expresses on the surface of colonic endothelial and/or immune cells when IBD occurs, ligand-modified drug delivery systems targeting such receptors and cell adhesion molecules can specifically deliver drug into inflamed sites and obtain great curative effects. This review introduces the overexpressed receptors and cell adhesion molecules in inflamed colon sites and retrospects the drug delivery systems functionalized by related ligands. Finally, challenges and future directions in this field are presented to advance the development of the receptor-mediated targeted drug delivery systems for the therapy of IBD.

4.
Acta Pharmaceutica Sinica B ; (6): 961-977, 2021.
Article in English | WPRIM | ID: wpr-881178

ABSTRACT

As one of the most important components of caveolae, caveolin-1 is involved in caveolae-mediated endocytosis and transcytosis pathways, and also plays a role in regulating the cell membrane cholesterol homeostasis and mediating signal transduction. In recent years, the relationship between the expression level of caveolin-1 in the tumor microenvironment and the prognostic effect of tumor treatment and drug treatment resistance has also been widely explored. In addition, the interplay between caveolin-1 and nano-drugs is bidirectional. Caveolin-1 could determine the intracellular biofate of specific nano-drugs, preventing from lysosomal degradation, and facilitate them penetrate into deeper site of tumors by transcytosis; while some nanocarriers could also affect caveolin-1 levels in tumor cells, thereby changing certain biophysical function of cells. This article reviews the role of caveolin-1 in tumor prognosis, chemotherapeutic drug resistance, antibody drug sensitivity, and nano-drug delivery, providing a reference for the further application of caveolin-1 in nano-drug delivery systems.

5.
Acta Pharmaceutica Sinica B ; (6): 609-620, 2021.
Article in English | WPRIM | ID: wpr-881159

ABSTRACT

The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon-

6.
Acta Pharmaceutica Sinica B ; (6): 287-296, 2016.
Article in English | WPRIM | ID: wpr-309956

ABSTRACT

Exosomes are small intracellular membrane-based vesicles with different compositions that are involved in several biological and pathological processes. The exploitation of exosomes as drug delivery vehicles offers important advantages compared to other nanoparticulate drug delivery systems such as liposomes and polymeric nanoparticles; exosomes are non-immunogenic in nature due to similar composition as body׳s own cells. In this article, the origin and structure of exosomes as well as their biological functions are outlined. We will then focus on specific applications of exosomes as drug delivery systems in pharmaceutical drug development. An overview of the advantages and challenges faced when using exosomes as a pharmaceutical drug delivery vehicles will also be discussed.

7.
Acta Pharmaceutica Sinica B ; (6): 378-389, 2015.
Article in English | WPRIM | ID: wpr-310013

ABSTRACT

Hypoxia-inducible factor-1 (HIF-1) has been recognized as an important cancer drug target. Many recent studies have provided convincing evidences of strong correlation between elevated levels of HIF-1 and tumor metastasis, angiogenesis, poor patient prognosis as well as tumor resistance therapy. It was found that hypoxia (low O2 levels) is a common character in many types of solid tumors. As an adaptive response to hypoxic stress, hypoxic tumor cells activate several survival pathways to carry out their essential biological processes in different ways compared with normal cells. Recent advances in cancer biology at the cellular and molecular levels highlighted the HIF-1α pathway as a crucial survival pathway for which novel strategies of cancer therapy could be developed. However, targeting the HIF-1α pathway has been a challenging but promising progresses have been made in the past twenty years. This review summarizes the role and regulation of the HIF-1α in cancer, and recent therapeutic approaches targeting this important pathway.

8.
Acta Pharmaceutica Sinica B ; (6): 402-418, 2015.
Article in English | WPRIM | ID: wpr-310011

ABSTRACT

Cancer metastasis is the major cause of cancer morbidity and mortality, and accounts for about 90% of cancer deaths. Although cancer survival rate has been significantly improved over the years, the improvement is primarily due to early diagnosis and cancer growth inhibition. Limited progress has been made in the treatment of cancer metastasis due to various factors. Current treatments for cancer metastasis are mainly chemotherapy and radiotherapy, though the new generation anti-cancer drugs (predominantly neutralizing antibodies for growth factors and small molecule kinase inhibitors) do have the effects on cancer metastasis in addition to their effects on cancer growth. Cancer metastasis begins with detachment of metastatic cells from the primary tumor, travel of the cells to different sites through blood/lymphatic vessels, settlement and growth of the cells at a distal site. During the process, metastatic cells go through detachment, migration, invasion and adhesion. These four essential, metastatic steps are inter-related and affected by multi-biochemical events and parameters. Additionally, it is known that tumor microenvironment (such as extracellular matrix structure, growth factors, chemokines, matrix metalloproteinases) plays a significant role in cancer metastasis. The biochemical events and parameters involved in the metastatic process and tumor microenvironment have been targeted or can be potential targets for metastasis prevention and inhibition. This review provides an overview of these metastasis essential steps, related biochemical factors, and targets for intervention.

9.
Article in Korean | WPRIM | ID: wpr-120708

ABSTRACT

OBJECTIVE: This study was performed to investigate the expression of EGF mRNA and protein in eutopic and ectopic endometrial tissues of the patients with endometriosis and in eutopic endometrial tissues of the patients without endometriosis. METHODS: Study group was composed of 34 women with endometriosis taking surgical treatment at the Department of Obstetrics and Gynecology, Asan Medical Center, from October 2004 to December 2005. Control group consisted of 14 women who had undergone surgical treatment for cervical intraepithelial neoplasia or benign gynecologic conditions other than endometriosis during the same period. Eutopic endometrial tissues of both groups and ectopic endometrial tissues of study group were collected during the operations. Real time reverse transcriptase-polymerase chain reaction (RT-PCR) was used to quantify EGF mRNA of these tissues. Western blot analysis was performed to ascertain the expression of EGF protein. RESULTS: The expressions of EGF mRNA were significantly lower in both eutopic (P<0.01) and ectopic (P<0.01) endometrial tissues of the women with endometriosis than in eutopic endometrial tissues of control group. The expressions of EGF protein were shown to be lower in both eutopic and ectopic endometrial tissues of the women with endometriosis than in eutopic endometrial tissues of control group. CONCLUSION: We found some correlations between the lower expression of EGF in endometrial tissues and the development of endometriosis. In addition, the change or defect of some factors in the eutopic endometrium might play an important role in the development of endometriosis.


Subject(s)
Blotting, Western , Cervical Intraepithelial Neoplasia , Endometriosis , Endometrium , Epidermal Growth Factor , Female , Gynecology , Humans , Obstetrics , RNA, Messenger
10.
Article in English | WPRIM | ID: wpr-153771

ABSTRACT

BACKGROUND: Hypersecretion of mucin due to goblet cell hyperplasia is frequently encountered in many chronic airway diseases, such as chronic bronchitis, bronchiectasis, bronchial asthma and cystic fibrosis. Even in normal individuals, viral infection or bacterial pneumonia frequently provoke huge amounts of bronchial secretions which may cause airway obstruction. The production of mucin was regulated by epidermal growth factor (EGF) in vitro. To know whether this EGF system regulates mucin secretion in vivo and Pseudomonas also stimulates the mucin secretion by the same pathway, we studied these relationships in the cultured rat tracheal epithelial cells. METHODS: Rat tracheal epithelial cells were obtained by pronase dissociation from the male Fisher 344 rats. When cells became confluent, they were divided into 6 groups and stimulated with either EGF for 24 hours or Pseudomonas extracts for 12 hours with or without selective EGF-R tyrosine kinase inhibitor tyrphostin AG1478. RESULTS: We found that both EGF and Pseudomonas extracts phosphorylated the tyrosine residue in the EGF receptor from the rat tracheal epithelial cells and this tyrosine phosphorylation was nearly completely blocked by selective EGF-R tyrosine kinase inhibitor tyrphostin AG1478. The mucin secretion was also stimulated by either EGF or Pseudomonas extracts but more strong secretion of mucin and MUC5AC gene expression in the rat tracheal epithelial cell was done by Pseudomonas extracts. CONCLUSION: These data suggest that Pseudomonas secretes the mucin by way of the EGF receptor and MUC5AC gene expression and the inhibitors of EGF receptor tyrosine phosphorylation would be useful to prevent the huge production of mucin due to Pseudomonas aeruginosa lung infection.


Subject(s)
Animals , Blotting, Western , Cells, Cultured , Comparative Study , Epidermal Growth Factor/metabolism , Epithelial Cells/drug effects , Gene Expression , Male , Models, Animal , Mucins/drug effects , Pseudomonas aeruginosa , RNA, Messenger/analysis , Rats , Rats, Inbred F344 , Reverse Transcriptase Polymerase Chain Reaction , Sensitivity and Specificity , Trachea/cytology
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