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Molecular Carcinogenesis Jul 2024Baicalein has been implicated in the chemotherapy overcoming triple-negative breast cancer (TNBC). However, many unanswered questions remain regarding its role in...
Baicalein has been implicated in the chemotherapy overcoming triple-negative breast cancer (TNBC). However, many unanswered questions remain regarding its role in treating TNBC. Here, we sought to demonstrate the molecular pathway mediated by baicalein in TNBC. Lysine-specific demethylase 4E (KDM4E), reduced in TNBC cells, was identified as a target protein of baicalein, and baicalein enhanced the protein expression and stability of KDM4E in TNBC cells. Knockdown of KDM4E attenuated the inhibitory effect of baicalein on TNBC cell activity, as demonstrated by intensified mobility, viability, and apoptosis resistance in TNBC cells. KDM4E activated protein bicaudal D homolog 1 (BICD1) expression by reducing the deposition of histone H3 lysine 9 trimethylation (H3K9me3) in its promoter, whereas BICD1 promoted protease-activated receptor-1 (PAR1) endocytosis and blocked PAR1 signaling through physical interaction with PAR1. Knockdown of KDM4E strengthened the PAR1-dependent activity of TNBC cells in response to thrombin activation, whereas TNBC progression activated by PAR1 signaling was blocked by combined overexpression of BICD1. Taken together, our data indicate that baicalein-promoted KDM4E enhanced the expression of BICD1 and activated the inhibitory effect of BICD1 on PAR1 signaling, thereby inhibiting TNBC progression.
Topics: Humans; Triple Negative Breast Neoplasms; Flavanones; Female; Signal Transduction; Cell Line, Tumor; Animals; Receptor, PAR-1; Gene Expression Regulation, Neoplastic; Cell Proliferation; Apoptosis; Disease Progression; Mice
PubMed: 38607237
DOI: 10.1002/mc.23724 -
British Journal of Pharmacology Aug 2024The discovery of new bromo- and extra-terminal inhibitors presents new drugs to treat osteoarthritis (OA).
BACKGROUND AND PURPOSE
The discovery of new bromo- and extra-terminal inhibitors presents new drugs to treat osteoarthritis (OA).
EXPERIMENTAL APPROACH
The new drug, BBC0403, was identified in the DNA-encoded library screening system by searching for compounds that target BRD (bromodomain-containing) proteins. The binding force with BRD proteins was evaluated using time-resolved fluorescence energy transfer (TR-FRET) and binding kinetics assays. Subsequently, in vitro and ex vivo analyses demonstrated the effects of the BRD2 inhibitor, BBC0403, on OA. For animal experiments, medial meniscus destabilization was performed to create a 12-week-old male C57BL/6 mouse model, and intra-articular (i.a.) injections were administered. Histological and immunohistochemical analyses were then performed. The underlying mechanism was confirmed by gene set enrichment analysis (GSEA) using RNA-seq.
KEY RESULTS
TR-FRET and binding kinetics assays revealed that BBC0403 exhibited higher binding specificity for BRD2 compared to BRD3 and BRD4. The anti-OA effects of BBC0403 were tested at concentrations of 5, 10 and 20 μM (no cell toxicity in the range tested). The expression of catabolic factors, prostaglandin E2 (PGE) production and extracellular matrix (ECM) degradation was reduced. Additionally, the i.a. injection of BBC0403 prevented OA cartilage degradation in mice. Finally, BBC0403 was demonstrated to suppress NF-κB and MAPK signalling pathways.
CONCLUSION AND IMPLICATIONS
This study demonstrated that BBC0403 is a novel BRD2-specific inhibitor and a potential i.a.-injectable therapeutic agent to treat OA.
Topics: Animals; Male; Mice, Inbred C57BL; Osteoarthritis; Mice; Transcription Factors; Disease Progression; Bromodomain Containing Proteins
PubMed: 38600628
DOI: 10.1111/bph.16359 -
Scientific Reports Apr 2024The DP2 receptor is a G-protein coupled receptor involved in allergic inflammation and is the target of recently developed antagonists already being tested in clinics....
The DP2 receptor is a G-protein coupled receptor involved in allergic inflammation and is the target of recently developed antagonists already being tested in clinics. To get insights into DP2 receptor dynamics and to study its pharmacology on the level of the receptor, we constructed a fluorescence resonance energy transfer-based conformation sensor. The sensor reflects the selectivity profile of the DP2 receptor-wt and is suited for screening of agonists and antagonists due to its robust response. Furthermore, the sensor enables the direct measurement of DP2 receptor dynamics in real-time and revealed markedly distinct on- and off-rates of prostaglandin D between DP2 and DP1 receptors, suggesting a different mechanism of ligand receptor interaction.
Topics: Humans; Prostaglandin D2; Inflammation; Receptors, Prostaglandin
PubMed: 38589416
DOI: 10.1038/s41598-024-58410-2 -
Chemistry & Biodiversity Jun 2024We presented a strategy utilizing 2D NMR-based metabolomic analysis of crude extracts, categorized by different pharmacological activities, to rapidly identify the...
We presented a strategy utilizing 2D NMR-based metabolomic analysis of crude extracts, categorized by different pharmacological activities, to rapidly identify the primary bioactive components of TCM. It was applied to identify the potential bioactive components from Scutellaria crude extracts that exhibit anti-non-small cell lung cancer (anti-NSCLC) activity. Four Scutellaria species were chosen as the study subjects because of their close phylogenetic relationship, but their crude extracts exhibit significantly different anti-NSCLC activity. Cell proliferation assay was used to assess the anti-NSCLC activity of four species of Scutellaria. H-C HSQC spectra were acquired for the chemical profiling of these crude extracts. Based on the pharmacological classification (PCA, OPLS-DA and univariate hypothesis test) were performed to identify the bioactive constituents in Scutellaria associated with the anti-NSCLC activity. As a result, three compounds, baicalein, wogonin and scutellarin were identified as bioactive compounds. The anti-NSCLC activity of the three potential active compounds were further confirmed via cell proliferation assay. The mechanism of the anti-NSCLC activity by these active constituents was further explored via flow cytometry and western blot analyses. This study demonstrated 2D NMR-based metabolomic analysis of pharmacologically classified crude extracts to be an efficient approach to the identification of active components of herbal medicine.
Topics: Scutellaria; Humans; Metabolomics; Cell Proliferation; Magnetic Resonance Spectroscopy; Plant Extracts; Carcinoma, Non-Small-Cell Lung; Apigenin; Flavanones; Lung Neoplasms; Glucuronates; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Drug Screening Assays, Antitumor
PubMed: 38581076
DOI: 10.1002/cbdv.202400258 -
Genes & Diseases Jul 2024Gastric cancer is highly prevalent among digestive tract tumors. Due to the intricate nature of the gastric cancer immune microenvironment, there is currently no...
Gastric cancer is highly prevalent among digestive tract tumors. Due to the intricate nature of the gastric cancer immune microenvironment, there is currently no effective treatment available for advanced gastric cancer. However, there is promising potential for immunotherapy targeting the prostaglandin E2 receptor subtype 4 (EP4) in gastric cancer. In our previous study, we identified a novel small molecule EP4 receptor antagonist called YY001. Treatment with YY001 alone demonstrated a significant reduction in gastric cancer growth and inhibited tumor metastasis to the lungs in a mouse model. Furthermore, administration of YY001 stimulated a robust immune response within the tumor microenvironment, characterized by increased infiltration of antigen-presenting cells, T cells, and M1 macrophages. Additionally, our research revealed that YY001 exhibited remarkable synergistic effects when combined with the PD-1 antibody and the clinically targeted drug apatinib, rather than fluorouracil. These findings suggest that YY001 holds great promise as a potential therapeutic strategy for gastric cancer, whether used as a standalone treatment or in combination with other drugs.
PubMed: 38560505
DOI: 10.1016/j.gendis.2023.101164 -
Phytomedicine : International Journal... Jun 2024The experimental autoimmune myocarditis (EAM) model is valuable for investigating myocarditis pathogenesis. M1-type macrophages and CD4T cells exert key pathogenic...
BACKGROUND
The experimental autoimmune myocarditis (EAM) model is valuable for investigating myocarditis pathogenesis. M1-type macrophages and CD4T cells exert key pathogenic effects on EAM initiation and progression. Baicalein (5,6,7-trihydroxyflavone, CHO, BAI), which is derived from the Scutellaria baicalensis root, is a primary bioactive compound with potent anti-inflammatory and antioxidant properties. BAI exerts good therapeutic effects against various autoimmune diseases; however, its effect in EAM has not been thoroughly researched.
PURPOSE
This study aimed to explore the possible inhibitory effect of BAI on M1 macrophage polarisation and CD4T cell differentiation into Th1 cells via modulation of the JAK-STAT1/4 signalling pathway, which reduces the secretion of pro-inflammatory factors, namely, TNF-α and IFN-γ, and consequently inhibits TNF-α- and IFN-γ-triggered apoptosis in cardiomyocytes of the EAM model mice.
STUDY DESIGN AND METHODS
Flow cytometry, immunofluorescence, real-time quantitative polymerase chain reaction (q-PCR), and western blotting were performed to determine whether BAI alleviated M1/Th1-secreted TNF-α- and IFN-γ-induced myocyte death in the EAM model mice through the inhibition of the JAK-STAT1/4 signalling pathway.
RESULTS
These results indicate that BAI intervention in mice resulted in mild inflammatory infiltrates. BAI inhibited JAK-STAT1 signalling in macrophages both in vivo and in vitro, which attenuated macrophage polarisation to the M1 type and reduced TNF-α secretion. Additionally, BAI significantly inhibited the differentiation of CD4T cells to Th1 cells and IFN-γ secretion both in vivo and in vitro by modulating the JAK-STAT1/4 signalling pathway. This ultimately led to decreased TNF-α and IFN-γ levels in cardiac tissues and reduced myocardial cell apoptosis.
CONCLUSION
This study demonstrates that BAI alleviates M1/Th1-secreted TNF-α- and IFN-γ-induced cardiomyocyte death in EAM mice by inhibiting the JAK-STAT1/4 signalling pathway.
Topics: Animals; STAT1 Transcription Factor; Signal Transduction; Myocytes, Cardiac; Janus Kinases; Mice; Flavanones; Male; Interferon-gamma; Apoptosis; Disease Models, Animal; Tumor Necrosis Factor-alpha; Myocarditis; STAT4 Transcription Factor; Autoimmune Diseases; Mice, Inbred BALB C; Macrophages; Scutellaria baicalensis; Th1 Cells; Cell Differentiation
PubMed: 38547614
DOI: 10.1016/j.phymed.2024.155558 -
Poultry Science May 2024Cadmium (Cd) and high molybdenum (Mo) are injurious to the body. Previous research has substantiated that Cd and Mo exposure caused testicular injury of ducks, but...
Cadmium (Cd) and high molybdenum (Mo) are injurious to the body. Previous research has substantiated that Cd and Mo exposure caused testicular injury of ducks, but concrete mechanism is not fully clarified. To further survey the toxicity of co-exposure to Cd and Mo in testis, 40 healthy 8-day-old Shaoxing ducks (Anas platyrhyncha) were stochasticly distributed to 4 groups and raised with basic diet embracing Cd (4 mg/kg Cd) or Mo (100 mg/kg Mo) or both. At the 16th wk, testis tissues were gathered. The characteristic ultrastructural changes related to apoptosis and ferroptosis were observed in Mo or Cd or both groups. Besides, Mo or Cd or both repressed nuclear factor erythroid 2-related factor 2 (Nrf2) pathway via decreasing Nrf2, Heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), Glutamate-cysteine ligase catalytic subunit (GCLC) and Glutamate-cysteine ligase modifier subunit (GCLM) mRNA expression of and Nrf2 protein expression, then stimulated apoptosis by elevating Bcl-2 antagonist/killer-1 (Bak-1), Bcl-2-associated X-protein (Bax), Cytochrome complex (Cyt-C), caspase-3 mRNA expression, cleaved-caspase-3 protein expression and apoptosis rate, as well as reducing B-cell lymphoma-2 (Bcl-2) mRNA expression and ratio of Bcl-2 to Bax, and triggered ferroptosis by upregulating Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4), transferrin receptor (TFR1) and Prostaglandin-Endoperoxide Synthase 2 (PTGS2) expression levels, and downregulating ferritin heavy chain 1 (FTH1), ferritin light chain 1 (FTL1), ferroportin 1 (FPN1), solute carrier family 7 member 11 (SCL7A11) and glutathione peroxidase 4 (GPX4) expression levels. The most obvious changes of these indexes were observed in co-treated group. Altogether, the results announced that Mo or Cd or both evoked apoptosis and ferroptosis by inhibiting Nrf2 pathway in the testis of ducks, and co-exposure to Mo and Cd exacerbated these variations.
Topics: Animals; Male; Ducks; Cadmium; Testis; Apoptosis; Ferroptosis; NF-E2-Related Factor 2; Signal Transduction; Molybdenum; Avian Proteins
PubMed: 38537407
DOI: 10.1016/j.psj.2024.103653 -
Circulation. Heart Failure Apr 2024Prostaglandin E2 acts through 4 G-protein-coupled receptors (EP1-EP4). We previously reported that activation of the EP3 receptor reduces cardiac contractility, and its...
BACKGROUND
Prostaglandin E2 acts through 4 G-protein-coupled receptors (EP1-EP4). We previously reported that activation of the EP3 receptor reduces cardiac contractility, and its expression increases after a myocardial infarction (MI), mediating the reduction in cardiac function. In contrast, cardiac overexpression of the EP4 receptor in MI substantially improves cardiac function. Moreover, we recently reported that mice overexpressing EP3 have heart failure under basal conditions and worsened cardiac function after MI. Thus, the deleterious effects of the prostaglandin E2 EP receptors in the heart are mediated via its EP3 receptor. We, therefore, hypothesized that cardiomyocyte-specific knockout (CM-EP3 KO) or antagonism of the EP3 receptor protects the heart after MI.
METHODS
To test our hypothesis, we made the novel CM-EP3 KO mouse and subjected CM-EP3 KO or controls to sham or MI surgery for 2 weeks. In separate experiments, C57BL/6 mice were subjected to 2 weeks of MI and treated with either the EP3 antagonist L798 106 or vehicle starting 3 days post-MI.
RESULTS
CM-EP3 KO significantly prevented a decline in cardiac function after MI compared with WT animals and prevented an increase in hypertrophy and fibrosis. Excitingly, mice treated with L798 106 3 days after MI had significantly better cardiac function compared with vehicle-treated mice.
CONCLUSIONS
Altogether, these data suggest that EP3 may play a direct role in regulating cardiac function, and pharmaceutical targeting of the EP3 receptor may be a therapeutic option in the treatment of heart failure.
Topics: Mice; Animals; Dinoprostone; Receptors, Prostaglandin; Gene Deletion; Heart Failure; Mice, Inbred C57BL; Myocardial Infarction; Myocytes, Cardiac; Receptors, Prostaglandin E, EP4 Subtype; Receptors, Prostaglandin E, EP3 Subtype
PubMed: 38525608
DOI: 10.1161/CIRCHEARTFAILURE.123.011089 -
Phytomedicine : International Journal... Jun 2024Polycystic ovary syndrome is a metabolic and hormonal disorder that is closely linked to oxidative stress. Within individuals diagnosed with PCOS, changes occur in the...
BACKGROUND
Polycystic ovary syndrome is a metabolic and hormonal disorder that is closely linked to oxidative stress. Within individuals diagnosed with PCOS, changes occur in the ovaries, resulting in an excessive buildup of iron and peroxidation of lipids, both of which may be associated with the occurrence of ferroptosis. Baicalein, a flavonoid found in the roots of Scutellaria baicalensis and widely known as Chinese skullcap, is known for its anti-inflammatory and anti-ferroptotic properties, which protect against various diseases. Nevertheless, there has been no investigation into the impact of baicalein on polycystic ovary syndrome.
PURPOSE
This study aimed to correlate ferroptosis with polycystic ovary syndrome and to assess the effects of baicalein on ovarian dysfunction and placental development in pregnant patients.
STUDY DESIGN AND METHODS
Polycystic ovary syndrome was induced in a rat model through the administration of dehydroepiandrosterone, and these rats were treated with baicalein. Oxidative stress and inflammation levels were assessed in serum and ovaries, and tissue samples were collected for histological and protein analyses. Furthermore, different groups of female rats were mated with male rats to observe pregnancy outcomes and tissue samples were obtained for histological, protein, and RNA sequencing. Then, RNA sequencing of the placenta was performed to determine the key genes involved in ferroptosis negative regulation (FNR) signatures.
RESULTS
Baicalein was shown to reduce ovarian oxidative stress and pathology. Baicalein also ameliorated polycystic ovary syndrome by decreasing lipid peroxidation and chronic inflammation and modulating mitochondrial functions and ferroptosis in the ovaries. Specifically, glutathione peroxidase and ferritin heavy chain 1 were considerably downregulated in polycystic ovary syndrome gravid rats compared to their expression in the control group, and most of these differences were reversed after baicalein intervention.
CONCLUSIONS
Our findings, initially, indicated that baicalein could potentially enhance the prognosis of individuals suffering from polycystic ovary syndrome by reducing oxidative stress and ferroptosis, thus potentially influencing the formulation of a therapeutic approach to address this condition.
Topics: Polycystic Ovary Syndrome; Female; Flavanones; Ferroptosis; Animals; Oxidative Stress; Pregnancy; Placenta; Ovary; Rats; Rats, Sprague-Dawley; Scutellaria baicalensis; Disease Models, Animal; Lipid Peroxidation; Male
PubMed: 38518646
DOI: 10.1016/j.phymed.2024.155423 -
Respiratory Physiology & Neurobiology Jun 2024Extracellular acidification is a major component of tissue inflammation, including airway inflammation in asthmatics. However, its physiological/pathophysiological...
PURPOSE
Extracellular acidification is a major component of tissue inflammation, including airway inflammation in asthmatics. However, its physiological/pathophysiological significance in bronchial function is not fully understood. Currently, the functional role of extracellular acidification on bronchial contraction was explored.
METHODS
Left main bronchi were isolated from male BALB/c mice. Epithelium-removed tissues were exposed to acidic pH under submaximal contraction induced by 10 M acetylcholine in the presence or absence of a COX inhibitor indomethacin (10 M). Effects of AH6809 (10 M, an EP receptor antagonist), BW A868C (10 M, a DP receptor antagonist) and CAY10441 (3×10 M, an IP receptor antagonist) on the acidification-induced change in tension were determined. The release of prostaglandin E (PGE) from epithelium-denuded tissues in response to acidic pH was assessed using an ELISA.
RESULTS
In the bronchi stimulated with acetylcholine, change in the extracellular pH from 7.4 to 6.8 caused a transient augmentation of contraction followed by a sustained relaxing response. The latter inhibitory response was abolished by indomethacin and AH6809 but not by BW A868C or CAY10441. Both indomethacin and AH6809 significantly increased potency and efficacy of acetylcholine at pH 6.8. Stimulation with low pH caused an increase in PGE release from epithelium-denuded bronchi. Interestingly, the acidic pH-induced bronchial relaxation was significantly reduced in a murine asthma model that had a bronchial hyperresponsiveness to acetylcholine.
CONCLUSION
Taken together, extracellular acidification could inhibit the bronchial contraction via autocrine activation of EP receptors. The diminished acidic pH-mediated inhibition of bronchial tone may contribute to excessive bronchoconstriction in inflamed airways such as asthma.
Topics: Animals; Male; Mice; Acetylcholine; Asthma; Benzyl Compounds; Bronchi; Dinoprostone; Hydrogen-Ion Concentration; Imidazoles; Indomethacin; Inflammation; Muscle Contraction; Mice, Inbred BALB C
PubMed: 38492830
DOI: 10.1016/j.resp.2024.104251