-
Brain Research Bulletin Mar 2024Neuroinflammation induced by chronic cerebral hypoperfusion (CCH) plays a crucial role in the pathophysiologic mechanisms of vascular dementia (VD). A growing body of...
Neuroinflammation induced by chronic cerebral hypoperfusion (CCH) plays a crucial role in the pathophysiologic mechanisms of vascular dementia (VD). A growing body of research has found that intestinal microbiota is associated with a variety of central nervous system disorders and that there is a relationship between intestinal microbiota dysbiosis and cognitive dysfunction and inflammatory responses. Baicalein belongs to the class of flavonoids and has a variety of biological functions, including anti-inflammatory, antioxidant and anti-apoptotic. Baicalein has a significant improvement in memory and learning, and can be used as a potential drug for the protection and treatment of central nervous system disorders. Whether baicalein has an ameliorative effect on cognitive impairment in VD, and whether its mechanism is related to the inhibition of inflammatory response and regulation of intestinal microbiota has not been reported. We used bilateral common carotid artery occlusion (BCCAO) to establish a VD rat model. Morris water maze (MWM) test showed that baicalein improved cognitive dysfunction in VD rats. We applied HE staining, immunofluorescence and ELISA to observe that baicalein treatment significantly improved CCH-induced neuronal damage in the CA1 region of the hippocampus, and reduced glial cell activation and release of pro-inflammatory factors. Western blot showed that baicalein inhibited the activation of the TLR4/MyD88/NF-κB signaling pathway in VD rats. We applied 16 S rDNA sequencing to analyze the composition of the intestinal microbiota. The results showed that baicalein modulated the diversity and composition of the intestinal microbiota, and suppressed the relative abundance of inflammation-associated microbiota in VD rats. In conclusion, this study found that baicalein ameliorated cognitive impairment, attenuated hippocampal inflammatory responses, inhibited the TLR4/MyD88/NF-κB signaling pathway, and modulated intestinal microbiota in VD rats.
Topics: Rats; Animals; Dementia, Vascular; NF-kappa B; Neuroinflammatory Diseases; Gastrointestinal Microbiome; Toll-Like Receptor 4; Myeloid Differentiation Factor 88; Cognitive Dysfunction; Brain Ischemia; Flavanones
PubMed: 38295883
DOI: 10.1016/j.brainresbull.2024.110888 -
Allergology International : Official... Jul 2024Nasal congestion in allergic rhinitis (AR) is caused by vascular hyperpermeability and vascular relaxation of the nasal mucosa. We previously detected high levels of a...
BACKGROUND
Nasal congestion in allergic rhinitis (AR) is caused by vascular hyperpermeability and vascular relaxation of the nasal mucosa. We previously detected high levels of a lipoxygenation metabolite of dihomogammalinolenic acid, 15-hydroxy-8Z,11Z,13E-eicosatrienoic acid (15-HETrE) in the nasal lavage fluid of AR model mice. Here, we investigated the effects of 15-HETrE on vascular functions associated with nasal congestion.
METHODS
We measured 15-HETrE levels in the nasal lavage fluid of ovalbumin-induced AR model mice and nasal discharge of patients with AR. We also assessed nasal congestion and vascular relaxation in mice. Vascular contractility was investigated using isolated mouse aortas.
RESULTS
Five ovalbumin challenges increased 15-HETrE levels in AR model mice. 15-HETrE was also detected in patients who exhibiting AR-related symptoms. Intranasal administration of 15-HETrE elicited dyspnea-related behavior and decreased the nasal cavity volume in mice. Miles assay and whole-mount immunostaining revealed that 15-HETrE administration caused vascular hyperpermeability and relaxation of the nasal mucosa. Intravital imaging demonstrated that 15-HETrE relaxed the ear vessels that were precontracted via thromboxane receptor stimulation. Moreover, 15-HETrE dilated the isolated mouse aortas, and this effect was attenuated by K channel inhibitors and prostaglandin D (DP) and prostacyclin (IP) receptor antagonists. Additionally, vasodilatory effects of 15-HETrE were accompanied by an increase in intracellular cAMP levels.
CONCLUSIONS
Our results indicate that 15-HETrE, whose levels are elevated in the nasal cavity upon AR, can be a novel lipid mediator that exacerbates nasal congestion. Moreover, it can stimulate DP and IP receptors and downstream K channels to dilate the nasal mucosal vasculature.
Topics: Animals; Mice; Rhinitis, Allergic; Disease Models, Animal; Humans; Male; Nasal Mucosa; Hydroxyeicosatetraenoic Acids; Female; Nasal Obstruction; Capillary Permeability; Ovalbumin; Vasodilation; Nasal Lavage Fluid
PubMed: 38286715
DOI: 10.1016/j.alit.2023.12.007 -
Molecular Vision 2023To investigate the therapeutic effects of eye drops, namely, timolol maleate, a β-adrenergic receptor antagonist, and latanoprost, a prostaglandin F2α analog, on...
PURPOSE
To investigate the therapeutic effects of eye drops, namely, timolol maleate, a β-adrenergic receptor antagonist, and latanoprost, a prostaglandin F2α analog, on retinal edema in a murine retinal vein occlusion (RVO) model.
METHODS
An RVO model was established using laser-induced RVO in mice, which were administered timolol maleate and latanoprost eye drops several times after venous occlusion. Subsequently, the thickness of the inner nuclear layer (INL) and the expression levels of such genes as and , which are stress markers of the endoplasmic reticulum, were examined. Primary human cultured retinal microvascular endothelial cells (HRMECs) were treated with timolol under hypoxic conditions, after which the gene expression pattern was investigated. Importantly, an integrated stress response inhibitor (ISRIB) was used in the RVO model, he known , which suppresses the expression of in retinal edema.
RESULTS
Increased INL thickness was suppressed by timolol eye drops, as were the expressions of and , in the RVO model. However, latanoprost eye drops did not induce any change in INL thickness. In HRMECs, hypoxic stress and serum deprivation increased the and expressions; in response, treatment with timolol suppressed the expression. Furthermore, the ISRIB decreased the expression pattern and edema formation, which are associated with RVO.
CONCLUSIONS
These results indicate that timolol eye drops may be a potential option for RVO treatment.
Topics: Male; Humans; Mice; Animals; Timolol; Retinal Vein Occlusion; Ophthalmic Solutions; Latanoprost; Papilledema; Endothelial Cells; Vascular Endothelial Growth Factor A; Edema
PubMed: 38222457
DOI: No ID Found -
International Journal of Molecular... Jan 2024The aim of this study was to evaluate the possible relationships between polymorphisms in the interleukin-1 () , , and genes and concentrations of the inflammatory...
The Influence of Genetic Polymorphisms on the Expression of Interleukin-1beta, Prostaglandin E2 and Tumor Necrosis Factor Alpha in Peri-Implant Crevicular Fluid: A Cross-Sectional Study.
The aim of this study was to evaluate the possible relationships between polymorphisms in the interleukin-1 () , , and genes and concentrations of the inflammatory mediators IL-1β, tumor necrosis factor-alpha (TNF-α), and prostaglandin E2 (PGE2) in peri-implant crevicular fluid (PICF). A cross-sectional analytical study was conducted on 51 patients with dental implants. Samples from the buccal mucosa were obtained, and genetic analysis was performed using the real-time polymerase chain reaction (PCR) technique for and and PCR and restriction fragment length polymorphism analysis for . For the biochemical analysis, the concentrations of IL-1β and TNF-α were analyzed using multiplexed fluorescent sphere immunoassays, and PGE2 by enzyme-linked immunosorbent assay. In patients with detected polymorphism, there was an increase in the concentration of the three mediators with statistically significant differences in the mean values of TNF-α and PGE2, regardless of peri-implant health status ( = 0.002 and = 0.049, respectively). The concentrations of all three mediators were positively and significantly correlated (IL-1β vs. TNF-α Rho = 0.480, < 0.001; IL-1β vs. PGE2 Rho = 0.382, = 0.006; and TNF-α vs. PGE2 Rho = 0.528, < 0.001). We can conclude that the polymorphism exerts an influence on the PICF immune response, which may explain the influence of this genetic polymorphism on the occurrence of peri-implantitis.
Topics: Humans; Cross-Sectional Studies; Dinoprostone; Interleukin-1beta; Polymorphism, Genetic; Tumor Necrosis Factor-alpha; Interleukin 1 Receptor Antagonist Protein; Gingival Crevicular Fluid; Dental Implants
PubMed: 38203822
DOI: 10.3390/ijms25010651 -
Respiratory Research Jan 2024Although Traditional Chinese Medicine (TCM) has been used for treating asthma for centuries, the understanding of its mechanism of action is still limited. Thus, the...
BACKGROUND
Although Traditional Chinese Medicine (TCM) has been used for treating asthma for centuries, the understanding of its mechanism of action is still limited. Thus, the purpose of this study was to explore the possible therapeutic effects, and underlying mechanism of baicalein in the treatment of asthma.
METHODS
Freely availabled atabases (e.g. OMIM, TTD, Genecards, BATMAN-TCM, STITCH 5.0, SEA, SwissTargetPrediction) and software (e.g. Ligplot 2.2.5 and PyMoL) were used for disease drug target prediction and molecular docking by network pharmacology. The efficacy and mechanism of action of baicalein in the treatment of asthma were validated using an ovalbumin (OVA)-induced asthma mouse model and molecular biology techniques.
RESULTS
A total of 1655 asthma-related genes and 161 baicalein-related targets were identified from public databases. Utilizing common databases and software for network pharmacology and molecular docking analysis, seven potential target proteins for the therapeutic effects of baicalein on asthma were selected, including v-akt murine thymoma viral oncogene homolog 1 (AKT1), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR), proto-oncogene tyrosine-protein kinase Src (SRC), mitogen-activated protein kinase 3 (MAPK3), matrix metallopeptidase 9 (MMP9), and MAPK1. In vivo, baicalein treatment via intraperitoneal injection at a dose of 50 mg/kg significantly reduced airway inflammation, collagen deposition, smooth muscle thickness, lung interleukin (IL)-4 and IL-13 levels, peripheral blood immunoglobulin (Ig)E levels, as well as the count and ratio of eosinophils in bronchoalveolar lavage fluid (BALF) in an OVA-induced asthma mouse model. Further validation by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting analysis revealed that the VEGF and EGFR signaling pathways involving VEGFA, MAPK1, MAPK3, and EGFR were inhibited by baicalein in the asthma mouse model.
CONCLUSION
Baicalein attenuates airway inflammation and airway remodeling through inhibition of VEGF and EGFR signaling pathways in an OVA-induced asthma mouse model. This will provide a new basis for the development of baicalein as a treatment for asthma and highlights the potential of network pharmacology and molecular docking in drug discovery and development.
Topics: Animals; Mice; Ovalbumin; Vascular Endothelial Growth Factor A; Airway Remodeling; Molecular Docking Simulation; Asthma; Inflammation; Signal Transduction; Bronchoalveolar Lavage Fluid; ErbB Receptors; Mice, Inbred BALB C; Disease Models, Animal
PubMed: 38178132
DOI: 10.1186/s12931-023-02637-6 -
Frontiers in Pharmacology 2023Preterm birth is the leading cause of infant morbidity and mortality. There has been an interest in developing prostaglandin F (PGF) antagonists as a new treatment for...
Preterm birth is the leading cause of infant morbidity and mortality. There has been an interest in developing prostaglandin F (PGF) antagonists as a new treatment for preterm birth, although much of the rationale for their use is based on studies in rodents where PGF initiates labour by regressing the corpus luteum and reducing systemic progesterone concentrations. How PGF antagonism would act in humans who do not have a fall in systemic progesterone remains unclear. One possibility, in addition to an acute stimulation of contractions, is a direct alteration of the myometrial smooth muscle cell state towards a pro-labour phenotype. In this study, we developed an immortalised myometrial cell line, MYLA, derived from myometrial tissue obtained from a pregnant, non-labouring patient, as well as a novel class of PGF receptor (FP) antagonist. We verified the functionality of the cell line by stimulation with PGF, resulting in Gα-specific coupling and Ca release, which were inhibited by FP antagonism. Compared to four published FP receptor antagonists, the novel FP antagonist N582707 was the most potent compound [F 7.67 ± 0.63 (IC 21.26 nM), AUC 7.30 ± 0.32 (IC 50.43 nM), and frequency of Ca oscillations 7.66 ± 0.41 (IC 22.15 nM)]. RNA-sequencing of the MYLA cell line at 1, 3, 6, 12, 24, and 48 h post PGF treatment revealed a transforming phenotype from a fibroblastic to smooth muscle mRNA profile. PGF treatment increased the expression of , , and as well as the pro-labour genes , , and , which were inhibited by FP antagonism. Concomitant with the inhibition of a smooth muscle, pro-labour transition, FP antagonism increased the expression of the fibroblast marker genes , , and . Our findings suggest that in addition to the well-described acute contractile effect, PGF transforms myometrial smooth muscle cells from a myofibroblast to a smooth muscle, pro-labour-like state and that the novel compound N582707 has the potential for prophylactic use in preterm labour management beyond its use as an acute tocolytic drug.
PubMed: 38155905
DOI: 10.3389/fphar.2023.1285779 -
Cells Nov 2023Abnormal sexual maturity exhibits significant detrimental effects on adult health outcomes, and previous studies have indicated that targeting histone acetylation might...
Abnormal sexual maturity exhibits significant detrimental effects on adult health outcomes, and previous studies have indicated that targeting histone acetylation might serve as a potential therapeutic approach to regulate sexual maturity. However, the mechanisms that account for it remain to be further elucidated. Using the mouse model, we showed that Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, downregulated the protein level of Hdac1 in ovaries to promote the apoptosis of granulosa cells (GCs), and thus arrested follicular development and delayed sexual maturity. Using porcine GCs as a cell model, a novel sexual maturity-associated lncRNA, which was named as the stimulatory factor of follicular development (), transcribed from mitochondrion and mediated by , was identified using RNA sequencing. Mechanistically, knockdown significantly reduced the H3K27ac level at the -953/-661 region of to epigenetically inhibit its transcription. knockdown released miR-202-3p to reduce the expression of cyclooxygenase 1 (), an essential rate-limited enzyme involved in prostaglandin synthesis. This reduction inhibited the proliferation and secretion of 17β-estradiol (E2) while promoting the apoptosis of GCs. Consequently, follicular development was arrested and sexual maturity was delayed. Taken together, knockdown-mediated downregulation promoted the apoptosis of GCs through the miR-202-3p- axis and lead to delayed sexual maturity. Our findings reveal a novel regulatory network modulated by , and -mediated may be a promising new therapeutic target to treat delayed sexual maturity.
Topics: Animals; Female; Mice; Apoptosis; Cell Proliferation; Cyclooxygenase 1; Granulosa Cells; MicroRNAs; RNA, Long Noncoding; Sexual Maturation; Swine; Histone Deacetylase 1; Hydroxamic Acids
PubMed: 38067162
DOI: 10.3390/cells12232734 -
Pharmacological Research Jan 2024Cancer is a leading cause of death worldwide. The burden of cancer incidence and mortality is increasing rapidly. New approaches to cancer prevention and treatment are... (Review)
Review
Cancer is a leading cause of death worldwide. The burden of cancer incidence and mortality is increasing rapidly. New approaches to cancer prevention and treatment are urgently needed. Natural products are reliable and powerful sources for anticancer drug discovery. Baicalin and baicalein, two major flavones isolated from Scutellaria baicalensis Georgi, a multi-purpose traditional medicinal plant in China, exhibit anticancer activities against multiple cancers. Of note, these phytochemicals exhibit extremely low toxicity to normal cells. Besides their cytotoxic and cytostatic activities toward diverse tumor cells, recent studies demonstrated that baicalin and baicalein modulate a variety of tumor stromal cells and extracellular matrix (ECM) in the tumor microenvironment (TME), which is essential for tumorigenesis, cancer progression and metastasis. In this review, we summarize the therapeutic potential and the mechanism of action of baicalin and baicalein in the regulation of tumor microenvironmental immune cells, endothelial cells, fibroblasts, and ECM that reshape the TME and cancer signaling, leading to inhibition of tumor angiogenesis, progression, and metastasis. In addition, we discuss the biotransformation pathways of baicalin and baicalein, related therapeutic challenges and the future research directions to improve their bioavailability and clinical anticancer applications. Recent advances of baicalin and baicalein warrant their continued study as important natural ways for cancer interception and therapy.
Topics: Humans; Tumor Microenvironment; Endothelial Cells; Flavonoids; Flavanones; Neoplasms
PubMed: 38061594
DOI: 10.1016/j.phrs.2023.107032 -
BioMed Research International 2023The tumor microenvironment (TME) is thought to influence the antitumor efficacy of immuno-oncology agents through various products of both tumor and stromal cells. One...
The tumor microenvironment (TME) is thought to influence the antitumor efficacy of immuno-oncology agents through various products of both tumor and stromal cells. One immune-suppressive factor is prostaglandin E (PGE), a lipid mediator whose biosynthesis is regulated by ubiquitously expressed cyclooxygenase- (COX-) 1 and inducible COX-2. By activating its receptors, PGE induces immune suppression to modulate differentiation of myeloid cells into myeloid-derived suppressor cells (MDSCs) rather than dendritic cells (DCs). Pharmacological blockade of prostaglandin E receptor 4 (EP4) causes a decrease in MDSCs, reprogramming of macrophage polarization, and increase in tumor-infiltrated T cells, leading to enhancement of antitumor immunity in preclinical models. Here, we report the effects of the highly potent EP4 antagonist ASP7657 on the DC population in tumor and antitumor immune activation in an immunocompetent mouse tumor model. Oral administration of ASP7657 inhibited tumor growth, which was accompanied by an increase in intratumor DC and CD8 T cell populations and a decrease in the M-MDSC population in a CT26 immunocompetent mouse model. The antitumor activity of ASP7657 was dependent on CD8 T cells and enhanced when combined with an antiprogrammed cell death-1 (PD-1) antibody. Notably, ASP7657 also significantly enhanced the antitumor efficacy of radiotherapy in an anti-PD-1 antibody refractory model. These results indicate that the therapeutic potential of ASP7657 arises via upregulation of DCs and subsequent CD8 T cell activation in addition to suppression of MDSCs in mouse models and that combining EP4 antagonists with radiotherapy or an anti-PD-1 antibody can improve antitumor efficacy.
Topics: Animals; Mice; CD8-Positive T-Lymphocytes; Cell Differentiation; Cyclooxygenase 2; Indoles; Neoplasms; Tumor Microenvironment
PubMed: 38058393
DOI: 10.1155/2023/7133726 -
Nature Communications Dec 2023The lipid prostaglandin E (PGE) mediates inflammatory pain by activating G protein-coupled receptors, including the prostaglandin E2 receptor 4 (EP4R). Nonsteroidal...
The lipid prostaglandin E (PGE) mediates inflammatory pain by activating G protein-coupled receptors, including the prostaglandin E2 receptor 4 (EP4R). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce nociception by inhibiting prostaglandin synthesis, however, the disruption of upstream prostanoid biosynthesis can lead to pleiotropic effects including gastrointestinal bleeding and cardiac complications. In contrast, by acting downstream, EP4R antagonists may act specifically as anti-inflammatory agents and, to date, no selective EP4R antagonists have been approved for human use. In this work, seeking to diversify EP4R antagonist scaffolds, we computationally dock over 400 million compounds against an EP4R crystal structure and experimentally validate 71 highly ranked, de novo synthesized molecules. Further, we show how structure-based optimization of initial docking hits identifies a potent and selective antagonist with 16 nanomolar potency. Finally, we demonstrate favorable pharmacokinetics for the discovered compound as well as anti-allodynic and anti-inflammatory activity in several preclinical pain models in mice.
Topics: Humans; Mice; Animals; Dinoprostone; Receptors, Prostaglandin; Phagocytosis; Anti-Inflammatory Agents; Pain; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 38057319
DOI: 10.1038/s41467-023-43506-6