Clinical and Experimental Pharmacology and Physiology最新文献

Norisoboldine (NIB) displays beneficial effects on cardiovascular diseases, although its protective role and underlying mechanisms in myocardial ischemia (MI) injury remain elusive. The aim of this study is to explore the potential cardioprotective mechanism of NIB on MI injury caused by isoproterenol (ISO). We administered NIB to SD rats at 20 and 40 mg/kg daily for 7 days in this study; this was followed by an ISO injection to induce MI injury. Parameters such as electrocardiogram readings, heart rate, serum concentrations of creatine kinase (CK) and creatine kinase-MB (CK-MB), levels of inflammatory markers, some histopathological assessments and oxidative stress markers were evaluated. We conducted Western blot analyses to evaluate protein expression related to apoptosis and the TLR4–MyD88-mediated NF-κB activation pathway. The L-type Ca²⁺ current (ICa-L) and contraction of isolated ventricular cells from rats were identified using patch-clamp methods and the IonOptix detection system. The treatment with NIB resulted in improvements in heart rate and ST-segment changes, a reduction in CK and CK-MB levels, the restoration of superoxide dismutase, catalase and glutathione levels and a decrease in malondialdehyde accumulation. Furthermore, NIB reduced the expression of inflammatory markers, lowered Ca²⁺ levels and reactive oxygen species production and improved myocardial tissue morphology. It also countered ISO-induced alterations in apoptosis and the TLR4–MyD88-dependent NF-κB activation pathway. Additionally, NIB considerably attenuated ICa-L and reduced the contractile function of cardiomyocytes. These results suggest that NIB effectively mitigates ISO-induced MI injury through anti-inflammatory, antioxidative, and anti-apoptotic mechanisms, potentially involving the TLR4–MyD88-dependent NF-κB activation pathway and calcium balance.

Lung cancer is most terrible cause of cancer-related death throughout the world. This study focused on the synthesis and characterisation of novel flavokawain A ruthenium-p-cymene complex and to investigate the chemotherapeutic activity against lung carcinoma via in silico, in vitro and in vivo approaches. The complex was characterised via several spectroscopic techniques. In vitro study including cell viability, transwell migration, Western blot and flow cytometric analysis have been executed on both A549 and NCI-H460 cells. The toxicological assessment was performed and subsequently anticancer activity of complex was evaluated in benzo[α]pyrene persuaded lung carcinoma in mice. The molecular docking study demonstrated the compound has greater binding ability with β-catenin, Akt, HER2 and PARP. Followed by the complex treatment, the downregulation of β-catenin, PI3K, Akt, HER2 and PARP were investigated by Western blot analysis and cell cycle arrest was determined through flow cytometry. The outcomes of in vivo experimentation represented fruitful restoration of typical lung architecture after complex treatment. Immunohistochemical analysis demonstrated the downstream of β-catenin/m-TOR/Akt and upstream of caspase-3 and p53 expression, thereby initiating apoptosis. The complex exhibited a potent chemotherapeutic activity via the alteration of tumour microenvironment by modulating PI3K/Akt/β-catenin/HER2/PARP transduction in correlates with apoptotic events in lung carcinoma.

Rhamnetin is a naturally occurring flavonoid compound found in many wild plant species and indigenous fruits. Despite its numerous biological potentials, such as anti-inflammatory, antioxidant and antimicrobial effects, there is a lack of literature elucidating its gastroprotective action and anticipating molecular mechanism. Natural products can be a good alternative to overcome the side effects and relapses associated with anti-ulcer drugs. This study aims to elucidate rhamnetin's acute toxicity and gastroprotective effects using the indomethacin ulceration model. Animals were arbitrarily divided into five groups: a negative control group (A) and a positive control group (B), both treated with 1% carboxymethyl cellulose; a reference group (C) receiving 20 mg/kg omeprazole; and low-dose (D) and high-dose (E) rhamnetin groups receiving 30 and 60 mg/kg, respectively. After 1 h, rats in Groups B–E were subjected to indomethacin-induced ulceration. Toxicity evaluations indicated the safety of rhamnetin at doses of up to 400 mg/kg in rats, without any noticeable physiological alterations. Rhamnetin (30 and 60 mg/kg) administered orally 1 h before indomethacin-induced gastric ulcer ameliorated the stomach lesions and lowered the ulcer index area by 73.81% and 77.87%, respectively. Rhamnetin supplementation ameliorated histopathological alterations and restored gastric barriers, including gastric pH and mucin secretion. Moreover, rhamnetin-treated rats exhibited increased anti-apoptotic heat shock protein 70 and decreased Bax protein in stomach tissues. These findings were in line with lowered accumulated MDA, increased superoxide dismutase, catalase and prostaglandin E2 levels, reduced serum inflammatory mediators (TNF-α and interleukin-6) and elevated interleukin-10 cytokines. The outcomes indicate rhamnetin's cicatrising and gastroprotective effects against indomethacin-mediated ulceration, possibly due to its modulatory actions on oxidative stress, inflammation and apoptotic pathways.

Mycobacterium abscessus is a multi-drug resistant pathogen presenting significant treatment challenges. This study evaluated MRX-5, an oral prodrug of the leucyl-tRNA synthetase inhibitor MRX-6038, for its efficacy against M. abscessus both in vitro and in vivo. Stability testing of MRX-5 was conducted using liquid chromatography–tandem mass spectrometry in Middlebrook 7H9 broth at 35°C. Following this, the minimum inhibitory concentrations of MRX-5 were determined against two reference strains and 17 clinical isolates of M. abscessus. In the in vivo experiments, the pharmacokinetic properties of MRX-5 were assessed first, followed by efficacy testing conducted in a neutropenic BALB/c mouse model of M. abscessus lung infection. Remarkably, the conversion of MRX-5 to MRX-6038 in liquid broth was complete within 72 h, and MRX-5 demonstrated reduced potency compared to MRX-6038 in vitro. In vivo, MRX-5 was efficiently converted to MRX-6038, achieving an oral bioavailability of 83.95% and significant lung distribution. In the mouse model of pulmonary M. abscessus infection, MRX-5 effectively reduced bacterial load and exhibited antimicrobial activity comparable to that of linezolid. In conclusion, MRX-5 exhibited favourable lung distribution and in vivo efficacy against M. abscessus, positioning it as a promising candidate for the oral treatment of M. abscessus infections.

Polypoid lesions of the gallbladder (PLG) represent localised protrusions of the gallbladder wall, which can be either benign or malignant. Although malignant PLG is relatively rare, its prognosis is adverse. Cholecystectomy is the most efficacious treatment for malignant PLG; however, its suitability varies among PLG patients, and its indications remain controversial. To offer guidance for clinical diagnosis and treatment of PLG, 461 patients were included and classified into three subgroups based on postoperative pathological results. Logistic regression analysis was employed to identify the risk factors for PLG (the number of lesions, gallbladder wall thickness, gallbladder stones, and clinical symptoms), malignant PLG (age, polyp size, colour Doppler blood flow signal, gallbladder volume, and cholecystitis), and adenomatous PLG (CA199, the number of lesions, and gallbladder wall thickness). Multivariate logistic regression analysis was employed to construct clinical prediction models for PLG (model A, containing the number of lesions, gallbladder wall thickness, gallbladder stones, and clinical symptoms), malignant PLG (model B, containing age, polyp size, CA199, and gallbladder volume), and adenomatous PLG (model C, containing CA199, the number of lesions, and gallbladder wall thickness). Subsequently, corresponding nomograms were developed. The AUC values of all models exceeded 0.7, indicating excellent predictive efficacy. Calibration curves and DCA curves affirmed the models' reliability and validity. In conclusion, the models derived from this study demonstrate significant predictive efficacy for PLG, malignant PLG, and adenomatous PLG, respectively. They are anticipated to offer guidance for the diagnosis of PLG and provide a reliable foundation for subsequent treatment strategies.

Retinopathy of prematurity is characterised by abnormal retinal neovascularization in response to hypoxia stress. Prolyl 4-hydroxylase domain protein 3 (PHD3) is a well-known molecular oxygen sensor. However, the role that PHD3 plays in retinopathy of prematurity remains unclear. In this work, a mouse model of oxygen-induced retinopathy (OIR) was used for in vivo studies. Compared with the mice in room air, OIR mice showed sprouting of retinal neovascularization and increased level of PHD3. It was further found that PHD3 overexpression weakened OIR-induced retinal neovascularization and promoted cell apoptosis in the retina, indicating a mitigative effect on retinopathy. More importantly, OIR-induced upregulation of hypoxia inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGFA) was offset by PHD3 overexpression. In in vitro experiments, mouse retinal microvascular endothelial cells (MRMECs) were cultured under hypoxic conditions. The functions of endothelial cells including cell proliferation, cell migration, and tube formation ability were suppressed by PHD3, suggesting an anti-angiogenesis effect of PHD3. In line with in vivo experiments, the expression of HIF-1α and VEGFA levels declined in endothelial cells when PHD3 was overexpressed. Taken together, PHD3 alleviates retinopathy of prematurity through anti-angiogenesis, and the core mechanism may involve cell apoptosis of retina endothelial cell and HIF-1α–VEGFA axis. These findings provide exciting new insights into the pathogenesis of retinopathy of prematurity, and could offer new treatment directions.

Isoferulic acid (IA), a derivative of cinnamic acid, is derived from Danshen and exhibits anticancer properties by disrupting cancer cell activities. However, its role in pancreatic cancer, the “king of cancer”, was unknown. In this study, pancreatic cancer cells were subjected to treatment with IA (6.25, 12.5, 25 μM), and nude mice injected with pancreatic cancer cells were received IA at doses of 7.5 mg/kg/day or 30 mg/kg/day by oral administration. CCK8, Annexin V-FITC/propidium iodide (PI) double staining and TUNEL assay were conducted to evaluate the cell viability and apoptosis. Hoechst staining and comet assay was employed to measure DNA damage. Mitochondrial membrane potential (MMP) analysis was carried out to explain the mitochondrial damage. EdU and wound healing assay were performed for cell proliferation and migration detection. Immunofluorescence and western blot were used to explore the mechanism. We found that IA reduced cell viability and induced apoptosis, as evidenced by an increase in Annexin V-FITC⁺PI⁻ and Annexin V-FITC⁺PI⁺ cell populations, brighter TUNEL and Hoechst staining, and more percentage of tail DNA. Furthermore, IA decreased MMP and changed levels of apoptosis-related proteins. The cell proliferation and migration were inhibited by IA treatment. Mechanically, IA downregulated the phosphorylation of IĸBα and inhibited p65 nuclear translocation, consequently suppressing NF-κB pathway. In general, IA suppressed the cell proliferation and migration, and caused apoptosis of pancreatic cancer cells in a mitochondria-dependent manner through blocking NF-κB signalling pathway, indicating that IA may be a potential therapeutic strategy for pancreatic cancer.