Naunyn-Schmiedeberg's archives of pharmacology最新文献

The most prevalent disease in the world and the main reason for women mortality from cancer is breast cancer. The recommended treatment for hormone receptor-positive metastatic breast cancer (MBC) is cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), Abemaciclib. Radiotherapy (RT) is one of the main options to control breast cancer. This work intended to examine the impact of CDK 4/6i and palliative radiation on human breast cancer cell lines. Breast cancer cell lines (MCF7, MDA-MD-468, and MDA-MD-231) were treated with varying doses of Abemaciclib and left to incubate for 48 h. Different radiation doses were applied to the lines that had the best IC50. The intrinsic treatment objectives for MBC are presented in this study, along with the PI3K/AKT/mTOR pathway; CDK4, CDK6, and the NF-κβ/TGF-β pathway; BAX/BcL2, P53; caspase-3, caspase-6, caspase-7, caspase-8, and caspase-9; cytokeratin 18 (CK18); cycloxygenase-2 (COX2); IL-6; IL1β; matrix metalloproteinases (MMP2 and MMP9); and oxidative stress markers. The biochemical assays revealed that abemaciclib hindered the progression of breast cancer cells MDA-MB-231 and MCF-7 and enhanced RT (10 Gy) by provoking cell cycle arrest throughout the restraint of CDK4 and CDK6 expression and increasing apoptosis, in addition to decreasing the PI3K/AKT/mTOR and NF-κβ/TGF-β pathway expression; inhibiting CK18 and COX2 activity; boosting the protein concentration of BAX and P53; and decreasing Bcl-2, IL-6, IL-1β, MMP2, and MMP9, modulating oxidative stress markers. These results implied potential effects of radiation and CDK4/6i abemaciclib on breast cancer cell lines.

Diabetic nephropathy (DN) represents the primary cause of chronic kidney disease (CKD) worldwide. Orientin is a natural bioactive flavonoid with profound immunomodulatory, anti-inflammatory, and antioxidative effects. This study aimed to investigate the nephroprotective effect of orientin on rat prototypes of high-fat diet (HFD) and streptozotocin (STZ)-induced DN. 75 male rats were divided into 5 groups of 15 rats each. Rats were fed a HFD for 4 weeks, injected with a single dose of STZ 30 mg/kg, and continued on HFD for 15 weeks. Orientin was administered daily at 40 mg/kg for 15 weeks. The diabetic group reported substantially greater fasting blood glucose, HbA1c, and renal function measures than normal controls, as well as notable kidney histological abnormalities such as interstitial inflammation, glomerular shrinkage, and tubular necrosis. Additionally, the diabetic group showed dramatically greater amounts of IL-1β, IL-6, TNF-α, TGF-β1, MDA, and a much lower level of GSH than the control group. However, orientin had no effect on the glycaemic parameters, but it dramatically reduced blood creatinine levels, prevented the development of histopathological irregularities, and minimized the renal concentrations of inflammatory and oxidative markers. Orientin may be a promising natural medication for improving diabetic nephropathy thanks to its robust anti-inflammatory and anti-proliferative properties.

Chronic obstructive pulmonary disease (COPD) is a global health problem due to its high death and morbidity worldwide, which is characterized by an incompletely reversible limitation in airflow that is not fully reversible. Unfortunately, Western medical treatments are unable to reverse the progressive decline in lung function. Importantly, polyphenolic compounds isolated from Chinese herbal medicine exhibited therapeutic/interventional effects on COPD in preclinical studies. This review systematically analyzed the pathogenesis of COPD, such as inflammation, oxidative stress, protease/antiprotease imbalance, aging, cell death, and dysbiosis of gut microbiota. Moreover, this review summarized the regulatory mechanisms of natural polyphenolic compounds for the treatment of COPD. Several studies have demonstrated that natural polyphenolic compounds have therapeutic effects on COPD by regulating various biological processes, such as anti-inflammatory, reduction of oxidative damage, anti-cell death, and inhibition of airway hyperglycemia. Mechanistically, this review found that the promising effects of natural polyphenolic compounds on COPD were mainly achieved through modulating the NF-κB and MAPK inflammatory pathways, the Nrf2 oxidative stress pathway, and the SIRT1/PGC-1α lung injury pathway. Furthermore, this review analyzed the efficacy and safety of natural polyphenolic compounds for the treatment of COPD in clinical trials, and discussed their challenges and future development directions. In conclusion, this review combined the latest literature to illustrate the various pathogenesis and interrelationships of COPD in the form of graphs, texts, and tables, and sorted out the functional role and mechanisms of natural polyphenols in treating COPD, with a view to providing new ideas and plans for the in-depth research on COPD and the systemic treatment of COPD with Chinese herbal medicine.

The widespread presence of contaminants in various zones of the environment raises an alarming signal for the need of assessing their ability in causing deleterious health effects in humans and degradation of environment. This investigation mainly aims at evaluation of the genotoxicity and oxidative damage induced by the pharmaceutical industry wastes in Hyderabad, India. Pollution load in effluents was determined by water quality assessment and heavy metal analysis. Wistar rats were orally administered low, medium, and high doses of effluents for a 28-day period, collected from two private and one government pharmaceuticals' manufacturing units. DNA damage quantification in peripheral blood lymphocytes and liver was done using comet assay and micronucleus test in bone marrow cells. Oxidative stress assessment was done by estimation of reduced glutathione, catalase, and malondialdehyde levels. Effluent-induced histopathological changes were reported in the liver and kidney tissues of rats treated that received a high dose of effluent. Significant induction of genotoxicity and alterations in antioxidant enzymes and serum biochemistry parameters were documented. Results of this study reveal altered levels of various physicochemical parameters, above permissible limits in pharmaceutical industry treated effluent indicating their potential role as a disastrous contaminant. The study innovatively evaluates the chronic effects of pharmaceutical effluents on rat health, providing critical insights into systemic toxicity, biochemical alterations, and potential health risks after 28-day repeated oral exposure.

Colorectal cancer (CRC) ranks third globally in cancer diagnoses. The dysregulation of the NLRP3 inflammasome is prominently linked to several types of cancers. Oridonin, a principal component of Rabdosia rubescens, exhibits inhibitory activity against NLRP3 and is well-recognized for its diverse pharmacological benefits. However, its role in an animal model of colitis-associated colorectal cancer (CACC) remains unexplored. In the present study, the effectiveness of oridonin was investigated against CACC, developed using azoxymethane (AOM), a tumour initiator, and dextran sulphate sodium (DSS), a tumour promoter, in male BALB/c mice. The two-stage murine model of inflammation-associated cancer was established by administering AOM (10 mg/kg b.w.; i.p., once) followed by DSS (2% w/v) in drinking water (3 cycles, 7 days/cycle). Over a span of 10 weeks, the dose-dependent (2.5, 5, and 10 mg/kg, b.w.; i.p.) effects of oridonin were investigated in BALB/c mice. Oridonin significantly alleviated CACC severity, as evidenced by reduced DAI scores and restored body weight. Moreover, it attenuated surrogate markers of inflammation, including myeloperoxidase, nitrite, plasma LPS, TNF-α, IL-1β, and DNA damage. Histopathological examination revealed diminished tumorigenesis and apoptotic cells, corroborated by reduced Ki-67 and TNF-α, along with increased p53 expression in the colon. Following oridonin treatment, IHC/immunofluorescence analyses demonstrated a significantly reduced expression of the components of NLRP3 inflammasome including NLRP3, ASC-1, and caspase-1. Notably, the high dose of oridonin (10 mg/kg) consistently exhibited significant protective effects against CACC by modulating various molecular targets. Present findings confirmed the potential of oridonin in the protection of colitis-associated colorectal cancer, providing valuable insights into its mechanism of action and clinical significance.

Owing to anti-cancer potency of the benzodiazepinone derivatives, the study aims to synthesize a library of thiourea-tethered benzodiazepinone derivatives targeting JAK-3 kinase for anti-breast cancer potency. Test compounds showed favourable in silico interactions with the active site of JAK-3 kinase. Compound 5i demonstrated a significant JAK-3 kinase inhibitory potential of 68.28% and appreciable growth inhibition (72.9%) of MDA-MB-468 (breast cancer cells) as per the anti-proliferative screening done by NCI-USA. In addition, 5i was also found to induce apoptosis moderately by 12.4% in the late apoptosis quadrant and arrested cell cycle at the G2/M phase. The wound healing assay demonstrated the anti-metastatic impact of drug 5i by reducing the migratory potential of MDA-MB-468 cells and was found to be stable within the target protein in the molecular dynamic simulation. All the synthesized compounds exhibited drug-appropriate pharmacokinetic profiles as corroborated by computational ADMET analysis. The study indicates that the synthesized library of benzodiazepinone derivatives is efficacious and compound 5i has emerged as a promising hit candidate, and can be explored further for development of potent JAK-3 kinase inhibitors targeting breast cancer.

We aimed to explore tacrolimus population pharmacokinetic (PPK) characteristics in adult liver transplantation patients and develop individualized dosing software for precision dosing. Data were retrospectively extracted from adult liver transplantation patients receiving tacrolimus at Chinese PLA General Hospital and Beijing Friendship Hospital. The PPK model was established using Phoenix, with the final model developed through forward inclusion-backward elimination. Bootstrap and visual predictive check (VPC) were used to validate the final model. External validation was conducted, and the mean error (ME), mean absolute error (MAE), and root mean square error (RMSE) were calculated. The software, developed in C# language, predicted drug concentrations three times for each of the 10 patients, calculating the predictive error (PE) and the absolute predictive error (APE). The application of this software for dosing regimen recommendations was also elucidated. Fifty-seven patients were included, with 633 blood drug concentrations collected. Data from 41 patients (Chinese PLA General Hospital) were used for modeling, and a one-compartment model with first-order absorption was built. Postoperative days and γ-glutamyl transferase affected clearance. The final model parameters were within Bootstrap's prediction range, and VPC prediction results aligned with the observations. Data from 16 patients (Beijing Friendship Hospital) were used for external validation, ME, MAE, and RMSE were - 0.32, 2.07, and 2.76 ng/mL, respectively, indicating robust predictive capability. PE and APE decreased with an increase in the number of blood drug concentrations. The developed software accurately predicts drug concentrations and the accuracy of these predictions increases with the number of drug concentrations used. A robust PPK model was established for liver transplant adults. The individualized dosing software not only predicts drug concentrations with increasing precision but also facilitates the practical application of model-informed precision dosing, offering customized dosing regimens that are poised to optimize therapeutic outcomes in liver transplant patients.

Thyroid hormones are among the most prescribed medicines. In many countries, there are shortages combined with evidence of overuse and irrational prescribing. An analysis was conducted for ATC class H with a focus on thyroid hormones for OECD countries. This study aims to evaluate prescribing behaviours, forecast long-term developments and promote rational prescribing behaviour. The ARIMA(2,1,2) (autoregressive integrated moving average) model successfully predicted the future for 30 OECD countries and the non-OECD country Croatia until 2040. An upward trend is forecast for 18 countries, including Austria (+ 5.7%), Chile (+ 220.0%), Czechia (+ 52.8%), Denmark (+ 15.6%), Estonia (+ 87.8%), Greece (+ 238.7%), Hungary (+ 5.7%), Iceland (+ 18.6%), Italy (+ 42.9%), Latvia (+ 83.7%), Lithuania (+ 131.2%), Portugal (+ 106.7%), Slovakia (+ 182.1%), Slovenia (+ 57.4%), Spain (+ 162.8%), Turkey (+ 168.7%), the United Kingdom (+ 138.1%) and Croatia (+ 190.6%). A downward trend is forecast for 13 countries, including Australia (-3.4%), Belgium (-38.8%), Canada (-95.1%), Costa Rica (-79.5%), Finland (-14.7%), France (-100.0%), Germany (-16.4%), Israel (-21.6%), Korea (-100.0%), Luxembourg (-100.0%), the Netherlands (-35.9%), Norway (-23.6%) and Sweden (-43.6%). The reliability and accuracy of the forecasts varies, being influenced by data quality. While a downward trend is favoured, an upward trend is seen as problematic. Increasing trends predominate in Southern and Eastern Europe and Latin America, while decreasing trends predominate in Northern and Western Europe and the Asia-Pacific Region. Some external factors affect all countries, like an increasing prevalence of thyroid disease. There is evidence of cultural influences on prescribing behaviour. While there is evidence of inappropriate use in countries where prescriptions are predicted to increase, measures to restrict the use of thyroid hormones are more common in countries with a recently reported and predicted declining trend.