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ACS Omega Nov 2023Hypertension has become a global threat and is one of the greatest risk factors for chronic kidney disease. Fenchyl acetate is a monoterpene that has been assessed for...
Hypertension has become a global threat and is one of the greatest risk factors for chronic kidney disease. Fenchyl acetate is a monoterpene that has been assessed for its various pharmacological activities in the past, but no study has evaluated its diuretic potential and the mechanism involved in the diuretic activity after prolonged administration in rats. Therefore, this study aimed to measure the safety and diuretic profile of fenchyl acetate in rats. For evaluating the acute toxicity, a single dose of 2000 mg/kg was administered as per the OECD guideline no. 425, and the rats were observed for 14 days. After 14 days, blood samples were assessed for biochemical, hematological, and oxidative stress parameters. For the acute diuretic study, fenchyl acetate was given in doses of 100, 200, and 400 mg/kg, and urine samples after 8 h were assessed for sodium, potassium, creatinine, uric acid excretion, and urinary output. A single dose of fenchyl acetate (F.A) was selected for prolonged diuretic activity, and furosemide was taken as the standard drug in a repeated dose administration for 7 days. Rats' urine was assessed for pH, sodium, potassium, creatinine, and uric acid excretion along with urinary volume excretion. Furthermore, blood was withdrawn by cardiac puncture, and selected organs like the heart, liver, kidney, and spleen were analyzed for oxidative stress biomarkers. Using pharmacological antagonists or inhibitors, the involvement of L-NAME, acetylcholine, or prostaglandin in F.A.-induced diuresis was determined. Mitochondrial respiratory chain enzyme complexes were also assessed in the kidney homogenates. The acute toxicity results showed F.A to be safe as its LD50 was greater than 2000 mg/kg and there were no signs of mortality or toxicity. The acute diuretic study showed that F.A resulted in a significant and dose-dependent increase in sodium, potassium, creatinine, and uric acid excretion along with urinary output, and these results were comparable to the standard drug furosemide. Prolonged administration with F.A (400 mg/kg) resulted in a comparable excretion of sodium, potassium, creatinine, uric acid, and urine output with furosemide (15 mg/kg). The oxidative stress parameters revealed that F.A (400 mg/kg) resulted in reducing the formation of free radicals. The results from the mechanism-based studies showed the involvement of NO in inducing diuresis. Furthermore, F.A (400 mg/kg) significantly increased the mitochondrial complexes I, II, III, IV, I + III, and II + III in the kidney homogenates, thus restoring the mitochondrial enzymes and improving the renal function. The current study suggests that F.A is safe with a significant diuretic potential with the involvement of NO in its mechanism of action.
PubMed: 38046311
DOI: 10.1021/acsomega.3c05638 -
Frontiers in Pharmacology 2023Prostaglandin E (PGE) is an inflammatory mediator synthesized by the brain constitutive cyclooxygenase enzyme. PGE binds to G protein-coupled EP1-4 receptors (EP1 to G,...
Prostaglandin E (PGE) is an inflammatory mediator synthesized by the brain constitutive cyclooxygenase enzyme. PGE binds to G protein-coupled EP1-4 receptors (EP1 to G, EP2,4 to G, and EP3 to G). EP2, EP3 and EP4 receptors are expressed in the locus coeruleus (LC), the main noradrenergic nucleus in the brain. EP3 receptors have been explored in the central nervous system, although its role regulating the locus coeruleus neuron activity has not been pharmacologically defined. Our aim was to characterize the function of EP3 receptors in neurons of the LC. Thus, we studied the effect of EP3 receptor agonists on the firing activity of LC cells in rat brain slices by single-unit extracellular electrophysiological techniques. The EP3 receptor agonist sulprostone (0.15 nM-1.28 µM), PGE (0.31 nM-10.2 µM) and the PGE analogue misoprostol (0.31 nM-2.56 µM) inhibited the firing rate of LC neurons in a concentration-dependent manner (EC = 15 nM, 110 nM, and 51 nM, respectively). The EP3 receptor antagonist L-798,106 (3-10 µM), but not the EP2 (PF-04418948, 3-10 µM) or EP4 (L-161,982, 3-10 µM) receptor antagonists, caused rightward shifts in the concentration-effect curves for the EP3 receptor agonists. Sulprostone-induced effect was attenuated by the G protein blocker pertussis toxin (pertussis toxin, 500 ng ml) and the inhibitors of inwardly rectifying potassium channels (GIRK) BaCl (300 µM) and SCH-23390 (15 µM). In conclusion, LC neuron firing activity is regulated by EP3 receptors, presumably by an inhibitory G protein- and GIRK-mediated mechanism.
PubMed: 38035000
DOI: 10.3389/fphar.2023.1290605 -
Frontiers in Immunology 2023Following the success of cancer immunotherapy using large molecules against immune checkpoint inhibitors, the concept of using small molecules to interfere with... (Review)
Review
Following the success of cancer immunotherapy using large molecules against immune checkpoint inhibitors, the concept of using small molecules to interfere with intracellular negative regulators of anti-tumor immune responses has emerged in recent years. The main targets for small molecule drugs currently include enzymes of negative feedback loops in signaling pathways of immune cells and proteins that promote immunosuppressive signals within the tumor microenvironment. In the adaptive immune system, negative regulators of T cell receptor signaling (MAP4K1, DGKα/ζ, CBL-B, PTPN2, PTPN22, SHP1), co-receptor signaling (CBL-B) and cytokine signaling (PTPN2) have been preclinically validated as promising targets and initial clinical trials with small molecule inhibitors are underway. To enhance innate anti-tumor immune responses, inhibitory immunomodulation of cGAS/STING has been in the focus, and inhibitors of ENPP1 and TREX1 have reached the clinic. In addition, immunosuppressive signals via adenosine can be counteracted by CD39 and CD73 inhibition, while suppression via intratumoral immunosuppressive prostaglandin E can be targeted by EP2/EP4 antagonists. Here, we present the status of the most promising small molecule drug candidates for cancer immunotherapy, all residing relatively early in development, and the potential of relevant biomarkers.
Topics: Humans; Protein Tyrosine Phosphatase, Non-Receptor Type 2; Immunotherapy; Neoplasms; Immunomodulation; Biomarkers; Tumor Microenvironment; Protein Tyrosine Phosphatase, Non-Receptor Type 22
PubMed: 38022587
DOI: 10.3389/fimmu.2023.1297175 -
Immunity, Inflammation and Disease Nov 2023The aim of this study was to elucidate the mechanism of beraprost sodium (BPS) in the intervention of myocardial fibrosis after myocardial infarction (MI) through...
OBJECTIVE
The aim of this study was to elucidate the mechanism of beraprost sodium (BPS) in the intervention of myocardial fibrosis after myocardial infarction (MI) through glycogen synthase kinase-3β (GSK-3β) and to provide new ideas for intervention in myocardial fibrosis.
MATERIALS AND METHODS
MI model rats given BPS and cardiac fibroblasts (CFs) treated with BPS and TGF-β. HE staining and Masson staining were used to detect the pathological changes of myocardial tissue. Fibrotic markers were detected by immunohistochemical staining. The expressions of GSK-3β, cAMP response element binding protein (CREB), and p-CREB were analyzed by qPCR and western blot analysis. EDU staining was used to detect the proliferation of CFs. The promoter activity of GSK-3β was detected by luciferase assay. Chromatin immunoprecipitation assay was used to detect the binding levels of GSK-3β promoter and Y-box binding protein 1 (YBX1). The levels of intracellular cyclic adenosine monophosphate (cAMP) were analyzed by enzyme-linked immunosorbent assay (ELISA).
RESULTS
After operation, BPS improved myocardial fibrosis and upregulated GSK-3β protein expression in male SD rats. BPS can down-regulate α-smooth muscle actin (α-SMA) level and up-regulate GSK-3β protein expression in CFs after TGF-β stimulation. Furthermore, GSK-3β knockdown can reverse the effect of BPS on TGF-β-activated CFs, enhance α-SMA expression, and promote the proliferation of CFs. BPS could regulate GSK-3β expression by promoting the binding of GSK-3β promoter to YBX1. BPS induced upregulation of p-CREB and cAMP, resulting in reduced fibrosis, which was reversed by the knockdown of GSK-3β or prostaglandin receptor (IPR) antagonists.
CONCLUSION
BPS treatment increased the binding of YBX1 to the GSK-3β promoter, and GSK-3β protein expression was upregulated, which further caused the upregulation of p-CREB and cAMP, and finally inhibited myocardial fibrosis.
Topics: Rats; Animals; Male; Glycogen Synthase Kinase 3 beta; Rats, Sprague-Dawley; Myocardial Infarction; Transforming Growth Factor beta; Fibrosis
PubMed: 38018586
DOI: 10.1002/iid3.1050 -
International Journal of Molecular... Nov 2023Aortic wall inflammation, abnormal oxidative stress and progressive degradation of extracellular matrix proteins are the main characteristics of abdominal aortic...
Aortic wall inflammation, abnormal oxidative stress and progressive degradation of extracellular matrix proteins are the main characteristics of abdominal aortic aneurysms (AAAs). The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome dysregulation plays a crucial role in aortic damage and disease progression. The first aim of this study was to examine the effect of baicalein (5,6,7-trihydroxy-2-phenyl-4H-1-benzopyran-4-one) on AAA formation in apolipoprotein E-deficient (ApoE) mice. The second aim was to define whether baicalein attenuates aberrant vascular smooth muscle cell (VSMC) proliferation and inflammation in VSMC culture. For male ApoE mice, a clinically relevant AAA model was randomly divided into four groups: saline infusion, baicalein intraperitoneal injection, Angiotensin II (Ang II) infusion and Ang II + baicalein. Twenty-seven days of treatment with baicalein markedly decreased Ang II-infused AAA incidence and aortic diameter, reduced collagen-fiber formation, preserved elastic structure and density and prevented smooth muscle cell contractile protein degradation. Baicalein inhibited rat VSMC proliferation and migration following the stimulation of VSMC cultures with Ang II while blocking the Ang II-inducible cell cycle progression from G/G to the S phase in the synchronized cells. Cal-520 AM staining showed that baicalein decreased cellular calcium in Ang II-induced VSMCs; furthermore, a Western blot assay indicated that baicalein inhibited the expression of PCNA and significantly lowered levels of phospho-Akt and phospho-ERK, along with an increase in baicalein concentration in Ang II-induced VSMCs. Immunofluorescence staining showed that baicalein pretreatment reduced NF-κB nuclear translocation in Ang II-induced VSMCs and furthered the protein expressions of NLRP3 while ASC and caspase-1 were suppressed in a dose-dependent manner. Baicalein pretreatment upregulated Nrf2/HO-1 signaling in Ang II-induced VSMCs. Thus, 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining showed that its reactive oxygen species (ROS) production decreased, along with the baicalein pretreatment. Our overall results indicate that baicalein could have therapeutic potential in preventing aneurysm development.
Topics: Male; Mice; Rats; Animals; Angiotensin II; NLR Family, Pyrin Domain-Containing 3 Protein; Aortic Aneurysm, Abdominal; Oxidative Stress; Inflammation; Apolipoproteins E; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 37958985
DOI: 10.3390/ijms242116004 -
Antiviral Research Dec 2023With approximately 3.8 billion people at risk of infection in tropical and sub-tropical regions, Dengue ranks among the top ten threats worldwide. Despite the potential...
With approximately 3.8 billion people at risk of infection in tropical and sub-tropical regions, Dengue ranks among the top ten threats worldwide. Despite the potential for severe disease manifestation and the economic burden it places on endemic countries, there is a lack of approved antiviral agents to effectively treat the infection. Flavonoids, including baicalein, have garnered attention for their antimicrobial properties. In this study, we took a rational and iterative approach to develop a series of baicalein derivatives with improved antiviral activity against Dengue virus (DENV). Compound 11064 emerged as a promising lead candidate, exhibiting antiviral activity against the four DENV serotypes and representative strains of Zika virus (ZIKV) in vitro, with attractive selectivity indices. Mechanistic studies revealed that Compound 11064 did not prevent DENV attachment at the cell surface, nor viral RNA synthesis and viral protein translation. Instead, the drug was found to impair the post-receptor binding entry steps (endocytosis and/or uncoating), as well as the late stage of DENV infection cycle, including virus assembly/maturation and/or exocytosis. The inability to raise DENV resistant mutants, combined with significant antiviral activity against an unrelated RNA virus (Enterovirus-A71) suggested that Compound 11064 targets the host rather than a viral protein, further supporting its broad-spectrum antiviral potential. Overall, Compound 11064 represents a promising antiviral candidate for the treatment of Dengue and Zika.
Topics: Humans; Zika Virus; Zika Virus Infection; Flavivirus; Dengue Virus; Antiviral Agents; Dengue
PubMed: 37944824
DOI: 10.1016/j.antiviral.2023.105739 -
Journal of Ovarian Research Nov 2023The present study aimed to investigate whether baicalein improves the sensitivity of resistant ovarian cancer cells to cisplatin.
PURPOSE
The present study aimed to investigate whether baicalein improves the sensitivity of resistant ovarian cancer cells to cisplatin.
METHODS
Transcriptomic sequencing and bioinformatics analysis were used to screen differentially expressed CirSLC7A6 in A2780 and A2780/CDDP cells. RT-qPCR was performed to examine the expression levels of CirSLC7A6, miR-2682-5p, and SLC7A6. Cell proliferation and apoptosis were examined using a Cell Counting Kit-8 assay and flow cytometry, and cell migration and invasion were analyzed using wound healing and Transwell assays. Cell suspensions were inoculated into the subcutaneous tissues of the bilateral interscapular region of nude mice. Saline, cisplatin, baicalein and cisplatin plus baicalein were intraperitoneally injected to observe the effects on tumor growth. Toxicity analyses in the liver and kidney were performed using H&E staining. RT-qPCR and immunohistochemistry were used to detect the expression of CirSLC7A6, miR-2682-5p, and SLC7A6 in tumor tissues, and western blot analysis was carried out to measure protein expression levels.
RESULTS
CirSLC7A6 was markedly upregulated in A2780/CDDP cells compared with the A2780 cells. CirSLC7A6 knockdown notably increased the expression of miR-2682-5p and decreased SLC7A6 expression. The rates of inhibition and apoptosis in the group treated with a combination of cisplatin and baicalein were significantly higher than those of the cisplatin and baicalein groups of A2780/CDDP shCirSLC7A6 cells. In A2780/CDDP shCirSLC7A6 cells, migration and invasion were significantly higher in the cisplatin and baicalein groups, compared with the combined treatment group. In the A2780/CDDP shCirSLC7A6 cell xenograft, the tumor weight of the combined treatment group was significantly lower than that of the cisplatin and baicalein groups. In addition, the combination of cisplatin and baicalein did not induce higher levels of toxicity in the liver or kidney. Baicalein alone and in combination with cisplatin notably reduced the expression of CirSLC7A6 and SLC7A6, and increased the expression of miR-2682-5p in the A2780/CDDP shCirSLC7A6 cell xenograft. In A2780/CDDP shCirSLC7A6 cells, the expression levels of P-Akt, P-mTOR, P-Erk, Bcl-2 and MMP2 were lower in the combined treatment group than in the control group.
CONCLUSIONS
Treatment with baicalein improved the sensitivity of ovarian cancer cells to cisplatin and inhibited cell proliferation, metastasis and tumor growth.
Topics: Animals; Mice; Humans; Female; Cisplatin; Ovarian Neoplasms; Antineoplastic Agents; Drug Resistance, Neoplasm; Mice, Nude; Cell Line, Tumor; Apoptosis; Cell Proliferation; MicroRNAs; Amino Acid Transport Systems, Basic
PubMed: 37940982
DOI: 10.1186/s13048-023-01285-0 -
Scientific Reports Nov 2023Exposure to particulate matter (PM) causes mitochondrial dysfunction and lung inflammation. The cyclooxygenase-2 (COX-2) pathway is important for inflammation and...
Exposure to particulate matter (PM) causes mitochondrial dysfunction and lung inflammation. The cyclooxygenase-2 (COX-2) pathway is important for inflammation and mitochondrial function. However, the mechanisms by which glucocorticoid receptors (GRs) suppress COX-2 expression during PM exposure have not been elucidated yet. Hence, we examined the mechanisms underlying the dexamethasone-mediated suppression of the PM-induced COX-2/prostaglandin E2 (PGE2) pathway in A549 cells. The PM-induced increase in COX-2 protein, mRNA, and promoter activity was suppressed by glucocorticoids; this effect of glucocorticoids was antagonized by the GR antagonist RU486. COX-2 induction was correlated with the ability of PM to increase reactive oxygen species (ROS) levels. Consistent with this, antioxidant treatment significantly abolished COX-2 induction, suggesting that ROS is involved in PM-mediated COX-2 induction. We also observed a low mitochondrial membrane potential in PM-treated A549 cells, which was reversed by dexamethasone. Moreover, glucocorticoids significantly enhanced Bcl-2/GR complex formation in PM-treated A549 cells. Glucocorticoids regulate the PM-exposed induction of COX-2 expression and mitochondrial dysfunction and increase the interaction between GR and Bcl-2. These findings suggest that the COX-2/PGE2 pathway and the interaction between GR and Bcl-2 are potential key therapeutic targets for the suppression of inflammation under PM exposure.
Topics: Humans; Glucocorticoids; Cyclooxygenase 2; Dexamethasone; A549 Cells; Particulate Matter; Dinoprostone; Reactive Oxygen Species; Inflammation
PubMed: 37919369
DOI: 10.1038/s41598-023-46257-y -
Respiratory Research Nov 2023Pulmonary arterial hypertension (PAH), Group 1 pulmonary hypertension (PH), is a type of pulmonary vascular disease characterized by abnormal contraction and remodeling... (Review)
Review
BACKGROUND
Pulmonary arterial hypertension (PAH), Group 1 pulmonary hypertension (PH), is a type of pulmonary vascular disease characterized by abnormal contraction and remodeling of the pulmonary arterioles, manifested by pulmonary vascular resistance (PVR) and increased pulmonary arterial pressure, eventually leading to right heart failure or even death. The mechanisms involved in this process include inflammation, vascular matrix remodeling, endothelial cell apoptosis and proliferation, vasoconstriction, vascular smooth muscle cell proliferation and hypertrophy. In this study, we review the mechanisms of action of prostaglandins and their receptors in PAH.
MAIN BODY
PAH-targeted therapies, such as endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, activators of soluble guanylate cyclase, prostacyclin, and prostacyclin analogs, improve PVR, mean pulmonary arterial pressure, and the six-minute walk distance, cardiac output and exercise capacity and are licensed for patients with PAH; however, they have not been shown to reduce mortality. Current treatments for PAH primarily focus on inhibiting excessive pulmonary vasoconstriction, however, vascular remodeling is recalcitrant to currently available therapies. Lung transplantation remains the definitive treatment for patients with PAH. Therefore, it is imperative to identify novel targets for improving pulmonary vascular remodeling in PAH. Studies have confirmed that prostaglandins and their receptors play important roles in the occurrence and development of PAH through vasoconstriction, vascular smooth muscle cell proliferation and migration, inflammation, and extracellular matrix remodeling.
CONCLUSION
Prostacyclin and related drugs have been used in the clinical treatment of PAH. Other prostaglandins also have the potential to treat PAH. This review provides ideas for the treatment of PAH and the discovery of new drug targets.
Topics: Humans; Prostaglandins; Pulmonary Arterial Hypertension; Receptors, Prostaglandin; Vascular Remodeling; Familial Primary Pulmonary Hypertension; Epoprostenol; Prostaglandins I; Inflammation; Pulmonary Artery
PubMed: 37915044
DOI: 10.1186/s12931-023-02559-3 -
Pharmaceuticals (Basel, Switzerland) Oct 2023Recently, a G-protein coupled receptor 44 (GPR44) was discovered to play a significant role in the process of inflammation-related diseases, including cancer and...
Recently, a G-protein coupled receptor 44 (GPR44) was discovered to play a significant role in the process of inflammation-related diseases, including cancer and diabetes. However, the precise role of GPR44 has yet to be fully elucidated. Currently, there is a strong and urgent need for the development of GPR44 radiotracers as a non-invasive methodology to explore the exact mechanism of GPR44 on inflammation-related diseases and monitor the progress of therapy. TM-30089 is a potent GPR44 antagonist that exhibits a high specificity and selectivity for GPR44. Its structure contains a fluorine nuclide, which could potentially be replaced with F. In the present study, we successfully took a highly effective synthesis strategy that pretreated the unprotected carboxylic acid group of the precursor and developed a feasible one-step automatic radiosynthesis strategy for [F]TM-30089 with a high radiochemical purity and a good radiochemical yield. We further evaluated this radiotracer using mice models implanted with 1.1 B4 cell lines (GPR44-enriched cell lines) and human islets (high GPR44 expression), respectively. The results revealed the persistent and specific uptake of [F]TM-30089 in GPR44 region, indicating that [F]TM-30089 is a promising candidate for targeting GPR44. Further evaluation is ongoing.
PubMed: 37895951
DOI: 10.3390/ph16101480