Biochemical Pharmacology

Impaired function of organic cation transporter 1 (OCT1) in hepatocellular carcinoma (HCC) has been associated with unsatisfactory response to sorafenib. However, some patients lacking OCT1 at the plasma membrane (PM) of HCC cells still responded to sorafenib, suggesting that another transporter may contribute to take up this drug. The aim of this study was to investigate whether OCT3 could contribute to the uptake of sorafenib and other tyrosine kinase inhibitors (TKIs) and whether OCT3 determination can predict HCC response to sorafenib...

This review article summarizes the role of prostaglandin E2 (PGE2 ) and its receptors (EP1-EP4) as it relates to the inflammatory cardiomyopathy, myocarditis. During the COVID-19 pandemic, the onset of myocarditis in a subset of patients prompted a debate on the use of nonsteroidal anti-inflammatory drugs (NSAIDs), like ibuprofen, which act to inhibit the actions of prostaglandins. This review aims to further understanding of the role of PGE2 in the pathogenesis or protection of the myocardium in myocarditis...

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the most aggressive solid tumours in humans. Despite its high mortality rate, effective targeted therapeutic strategies remain limited due to incomplete understanding of the underlying biological mechanisms. The NAP1L gene family has been implicated in the development and progression of various human tumours. However, the specific function and role of NAP1L5 (nucleosome assembly protein-like 5) in PDAC have not been fully elucidated. Therefore, in this study, we aimed to investigate the role of NAP1L5 in PDAC and explore the regulatory relationship between NAP1L5 and its potential downstream molecule PHLPP1 (PH domain Leucine-rich repeat Protein Phosphatase 1) in PDAC...

Although a great cure rate has been achieved for pediatric BCP-ALL, approximately 15% of patients do not respond to conventional chemotherapy and experience disease relapse. A major effort to improve the cure rates by treatment intensification would result in an undesirable increase in treatment-related toxicity and mortality, raising the need to identify novel therapeutic approaches. High-throughput (HTP) drug screening enables the profiling of patients' responses in vitro and allows the repurposing of compounds currently used for other diseases, which can be immediately available for clinical application...

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating diseases; it has a considerably poor prognosis and may become the second most lethal malignancy in the next 10 years. Chemotherapeutic resistance is common in PDAC; thus, it is necessary to exploit effective alternative drugs. In recent years, traditional folk medicines and their extracts have shown great potential in cancer treatment. The seed of Lagenaria siceraria (Molina) Standl. is a traditional medicine in Asia. Because of its analgesic effects and ability to reduce swelling, it is often used as an adjuvant treatment for abdominal tumors...

Triple-negative breast cancer (TNBC) is heterogeneous and aggressive, with high vascularity and frequent metastasis. We have already found natural flavonoid scutellarin (SC) suppressed spontaneous TNBC metastasis via normalizing tumor vasculature in vivo. In this study, supernatant from tumor necrosis factorα (TNFα)-treated human mammary microvascular endothelial cell (HMMEC) promoted cell migration and pseudopod formation in TNBC cells, but these phenomena were disappeared in SC-co-treated HMMEC...

Small cell lung cancer (SCLC) is a highly lethal subtype of lung cancer with few therapeutic options; therefore, the identification of new targets and drugs with potent combination therapy is desirable. We previously screened BH3 mimetics from a natural product library, and in this study, we validated nobiletin as a BH3 mimetic. Specifically, we observed its combination potential and mechanism with vorinostat in SCLC in vitro and in vivo. The results showed that combination treatment with nobiletin and vorinostat reduced the proliferation of SCLC H82 cells and increased the levels of apoptotic proteins such as cleaved caspase-9 and cleaved PARP...

Breast cancer is one of the most common malignancies among women worldwide. Estrogen exposure via endogenous and exogenous sources during a lifetime, together with environmental exposure to estrogenic compounds, represent the most significant risk factor for breast cancer development. As breast tumors establish, multiple pathways are deregulated. Among them is the aryl hydrocarbon receptor (AHR) signaling pathway. AHR, a ligand-activated transcription factor associated with the metabolism of polycyclic aromatic hydrocarbons and estrogens, is overexpressed in breast cancer...

The renin-angiotensin system (RAS) comprises a broad set of functional peptides and receptors that play a role in cardiovascular homeostasis and contribute to cardiovascular pathologies. Angiotensin II (Ang II) is the most potent peptide hormone produced by the RAS due to its high abundance and its strong and pleiotropic impact on the cardiovascular system. Formation of Ang II takes place in the bloodstream and additionally in tissues in the so-called local RAS. Of the two Ang II receptors (AT1 and AT2) that Ang II binds to, AT1 is the most expressed throughout the mammalian body...

Sepsis is a dysregulated systemic inflammatory response caused by infection that leads to multiple organ injury and high mortality without effective treatment. Corilagin, a natural polyphenol extracted from traditional Chinese herbs, exhibits strong anti-inflammatory properties. However, the role for Corilagin in lipopolysaccharide (LPS)-induced sepsis and the molecular mechanisms underlying this process have not been completely explored. Here we determine the effect of Corilagin on LPS-treated mice and use a screening approach integrating surface plasmon resonance with liquid chromatography-tandem mass spectrometry (SPR-LC-MS/MS) to further explore the therapeutic target of Corilagin...

Breast cancer stands as the most prevalent and heterogeneous malignancy affecting women globally, posing a substantial health concern. Enhanced comprehension of tumor pathology and the development of novel therapeutics are pivotal for advancing breast cancer treatment. Contemporary breast cancer investigation heavily leans on in vivo models and conventional cell culture techniques. Nonetheless, these approaches often encounter high failure rates in clinical trials due to species disparities and tissue structure variations...

GPR81, initially discovered in adipocytes, has been found to suppress lipolysis when activated. However, the current small molecules that target GPR81 carry the risk of off-target effects, and their impact on tumor progression remains uncertain. Here, we utilized phage display technology to screen a GPR81-targeting peptide named 7w-2 and proceeded to demonstrate its bioactivity. Although 7w-2 did not affect the proliferation of tumor cells, it effectively reduced adipocyte catabolism in vitro, consequently restraining the proliferation of co-cultured tumor cells...

Air pollution is the leading cause of lung cancer after tobacco smoking, contributing to 20% of all lung cancer deaths. Increased risk associated with living near trafficked roads, occupational exposure to diesel exhaust, indoor coal combustion and cigarette smoking, suggest that combustion components in ambient fine particulate matter (PM2.5 ), such as polycyclic aromatic hydrocarbons (PAHs), may be central drivers of lung cancer. Activation of the aryl hydrocarbon receptor (AhR) induces expression of xenobiotic-metabolizing enzymes (XMEs) and increase PAH metabolism, formation of reactive metabolites, oxidative stress, DNA damage and mutagenesis...

Both aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) belong among key regulators of xenobiotic metabolism in the intestinal tissue. AhR in particular is activated by a wide range of environmental and dietary carcinogens. The data accumulated over the last two decades suggest that both of these transcriptional regulators play a much wider role in the maintenance of gut homeostasis, and that both transcription factors may affect processes linked with intestinal tumorigenesis. Intestinal epithelium is continuously exposed to a wide range of AhR, PXR and dual AhR/PXR ligands formed by intestinal microbiota or originating from diet...

The aryl hydrocarbon receptor (AHR) signaling pathway is a complex regulatory network that plays a critical role in various biological processes, including cellular metabolism, development, and immune responses. The complexity of AHR signaling arises from multiple factors, including the diverse ligands that activate the receptor, the expression level of AHR itself, and its interaction with the AHR nuclear translocator (ARNT). Additionally, the AHR crosstalks with the AHR repressor (AHRR) or other transcription factors and signaling pathways and it can also mediate non-genomic effects...

Histone demethylation is a kind of epigenetic modification mediated by a variety of enzymes and participates in regulating multiple physiological and pathological events. Lysine-specific demethylase 7A is a kind of α-ketoglutarate- and Fe(II)-dependent demethylase belonging to the PHF2/8 subfamily of the JmjC demethylases. KDM7A is mainly localized in the nucleus and contributes to transcriptional activation via removing mono- and di-methyl groups from the lysine residues 9 and 27 of Histone H3. Mounting studies support that KDM7A is not only necessary for normal embryonic, neural, and skeletal development, and but also associated with cancer, inflammation, osteoporosis, and other diseases...

Prognosis of high-risk neuroblastoma is dismal, despite intensive induction chemotherapy, surgery, high-dose chemotherapy, radiotherapy, and maintenance. Patients who do not achieve a complete metastatic response, with clearance of bone marrow and skeletal NB infiltration, after induction have a significantly lowersurvival rate. Thus, it's necessary to further intensifytreatment during this phase. 131-I-metaiodobenzylguanidine (131-I-MIBG) is a radioactive compound highly effective against neuroblastoma, with32% response rate in relapsed/resistant cases, and only hematological toxicity...

Oral lichen planus (OLP) is a chronic T cell-mediated mucocutaneous disease characterized by T cell infiltration at the connective tissue-epithelium interface. Traditionally, topical corticosteroids are used as the first-line drugs to treat OLP. However, long-term use of corticosteroids may lead to drug tolerance, secondary candidiasis, and autoimmune adrenal insufficiency. Although topical tacrolimus has often been recommended for short-term use in corticosteroid-refractory OLP, the precise role of tacrolimus in epithelial cells remains elusive...

Prolonged vasoconstrictor signalling found in hypertension, increases arterial contraction, and alters vessel architecture by stimulating arterial smooth muscle cell (ASMC) growth, underpinning the development of re-stenosis lesions and vascular remodelling. Vasoconstrictors interact with their cognate G protein coupled receptors activating a variety of signalling pathways to promote smooth muscle proliferation. Here, angiotensin II (AngII) and endothelin 1 (ET1), but not UTP stimulates ASMC proliferation. Moreover, siRNA-mediated depletion of endogenous GRK2 expression, or GRK2 inhibitors, compound 101 or paroxetine, prevented AngII and ET1-promoted ASMC growth...

The present study evaluated the role of heme oxygenase 1 (HO-1)/carbon monoxide (CO) pathway in the cholera toxin-induced diarrhea and its possible action mechanism. The pharmacological modulation with CORM-2 (a CO donor) or Hemin (a HO-1 inducer) decreased the intestinal fluid secretion and Cl- efflux, altered by cholera toxin. In contrast, ZnPP (a HO-1 inhibitor) reversed the antisecretory effect of Hemin and potentiated cholera toxin-induced intestinal secretion. Moreover, CORM-2 also prevented the alteration of intestinal epithelial architecture and local vascular permeability promoted by cholera toxin...