Latest ArticlesDoxorubicin is widely used as a first-line therapeutic option in the treatment of several malignant tumors, but its clinical application is severely limited by the dose-dependent and irreversible cardiotoxicity, which has been a long-standing clinical challenge. We analyze the latest clinical guidelines on oncological cardiology and summarize the current status of doxorubicin-induced cardiotoxicity (DIC) prevention and treatment. On this basis, we have gone beyond the traditional view of direct damage to cardiomyocytes, and reviewed the research progress in recent years on the cross-talk between cardiac vascular endothelial cells and cardiomyocytes involved in DIC. The results suggest that cardiac endothelial cells play a key role in the development and maintenance of cardiac function. Doxorubicin not only directly damages these cells, but also disrupts the paracrine signals and physical barriers between them and cardiomyocytes, ultimately leading to an imbalance in cell communication and affecting cardiomyocyte survival and function, resulting in DIC.
Rheumatoid arthritis (RA) is categorized as "bi zheng" and "li-jiebing" in Chinese medicine. Liver and kidney insufficiency, marrow can not nourish the bones, feel the external evil, long-term accumulation in the body, heat into poison, damage to the qi and blood meridians and collaterals, heat and poison, phlegm, blood stasis and paralysis and the onset of the disease, mixed with the real and the imaginary, difficult to be cured. The Notch signaling pathway has a greater relevance to this disease, and it is involved in various pathological processes such as inflammatory cell infiltration, proliferation of fibroblast-like synoviocytes (FLS), microvascular formation and bone destruction. In this paper, the correlation between Notch signaling pathway and this disease is discussed from the perspective of the combination of Chinese and Western medicine, based on the theory of "XU, DU, YU" of traditional Chinese medicine, with the aim of providing a new way of thinking for the research.
To investigate the role of miRNA-633 in targeting the regulation of bone morphogenetic protein (BMP) and Smad protein pathways in promoting the proliferation and differentiation of dental pulp stem cells into dentin.
Human dental pulp stem cells were randomly divided into control, ov-miRNA-633, NC, anti-miRNA-633 and cotransfection groups. The ov-miRNA-633 and control groups were transfected with miRNA-633 overexpression vector and corresponding control blank vector, respectively. The anti-miRNA-633 and NC groups were transfected with miRNA-633 knockout vector and corresponding control blank vector, respectively. The cotransfection group was transfected with miRNA-633 overexpression vector + shRNA-N-Cadherin. Cell proliferation was detected by CCK-8 method. The expression levels of N-Cadherin were detected by real-time polymerase chain reaction. The expression levels of phosphorylated Smad 1/5/8 (p-Smad 1/5/8) were detected by Western blotting.
The optical density values on the 7th day of the control, ov-miRNA-633, NC, anti-miRNA-633 and cotransfection groups were 1.65±0.05, 1.79±0.08, 1.55±0.05, 1.19±0.08 and 1.76±0.07; the relative expression levels of N-Cadherin mRNA were 1.09±0.03, 0.63±0.03, 1.06±0.04, 1.31±0.09 and 0.46±0.06; the relative expression levels of p-Smad 1/5/8 protein were 0.79±0.05, 1.28±0.08, 0.80±0.09, 0.62±0.06 and 1.09±0.18, respectively. The differences of above indexes were statistically significant between the ov miRNA-633 group and the control group (P<0.05, P<0.01). And the differences of above indexes were statistically significant between the cotransfection group and the anti miRNA-633 group (all P<0.05).
miRNA-633 could promote the proliferation and differentiation of dental pulp stem cells into dentin by inhibiting N-cadherin expression, activating the BMPs/Smad pathway.
Sacubitril valsartan sodium tablets are a novel supramolecular co-crystal drug that combines the dual effects of angiotensin receptor blockade and neprilysin inhibitor. It has shown broad application prospects in heart failure, hypertension, maintaining water sodium balance in the body, and protecting target organs, etc. It is a major breakthrough in cardiovascular treatment drugs in recent years. It is clinically used in China for chronic heart failure in adult patients with reduced ejection fraction and primary hypertension. In recent years, pharmaceutical co-crystals has become a hot topic in the research of crystalline drugs, and sacubitril valsartan sodium tablets, as a marketed co-crystal drug, have attracted industry attention. This article summarizes the characteristics of sacubitril valsartan sodium co-crystal drug, the application and approval cases through relevant literature investigation, and discussses pharmaceutical research of the formulation, in order to provide some references for the research and development of generic drugs.
To develop a prognostic risk model for anoikis-related genes (ANRs) in bladder cancer, calculate risk scores, and analyze the relationship between bladder cancer patients with high and low risk scores and the tumor microenvironment.
Prognosis-related ANRs and clinically independent risk factors were screened by public database information and Cox regression analysis. Prognostic risk modeling was performed by least absolute shrinkage and selection operator (LASSO) analysis and column-line diagrams. Prognostic risk model accuracy was validated by kaplan-meier survival analysis and area under receiver operating characteristic curve (ROC) curve (AUC). The relationship between risk score and tumor microenvironment was explored by CIBERSORT (https://cibersortx.stanford.edu/) and single sample gene set enrichment analysis (ssGSEA).
The prognostically relevant ANRs were B-lymphoblastoma-2-associated promoter (BAD), cell cycle protein-dependent kinase inhibitor 3 (CDKN3), and proliferating cell nuclear antigen (PCNA), and the clinically independent risk factors were gender, age, clinical stage (T, N), and risk score. The prognostic risk model was expressed as risk score = (0.155 2×BAD expression) + (0.2286×CDKN3 expression) + (0.0114×PCNA expression) and column line graph. The lower the risk score the better the prognosis of bladder cancer patients, the AUC of the survival curves for 1, 3 and 5 years were 0.732, 0.620 and 0.541, respectively, and the column line graphs of the 1-, 3- and 5-year calibration curves almost corresponded diagonally, reflecting the accuracy of the model. The high and low risk groups of the prognostic risk model showed great differences in immune cell infiltration in the tumor microenvironment of bladder cancer.
The established prognostic risk model for bladder cancer loss of apoptosis-related genes is highly accurate and can better assess the prognosis of bladder cancer patients, and bladder cancer patients with high and low risk scores are closely related to the tumor microenvironment.
To analyze the application and funded projects in the field of clinical pharmacology supported by the National Natural Science Foundation of China (NSFC) from 2015 to 2024, aiming to provide a reference for the application.
Information on the application and funded projects under the "Clinical Pharmacology (H3511)" code from 2015 to 2024 was collected from the NSFC management information system, including funding year, project name, project category, funding amount, keywords, research directions, etc. A database was established based on this information for statistical analysis.
From 2015 to 2024, 2 031 applications were received for general, young scientist, and regional scientist foundation in the clinical pharmacology research field, with 320 projects funded, accumulating a direct funding of 118.48 million yuan. The number and amount of funded projects showed a fluctuating upward trend. The diseases studied in the applications were mainly concentrated in malignant tumors, cardiovascular and cerebrovascular diseases, neuropsychiatric diseases, and metabolic diseases. The research directions of the applications and funded projects were mainly focused on personalized medication, drug adverse reactions and toxicity, and clinical biomarkers, accounting for 67.6% and 70.3% of the total number of application and funded projects, respectively.
With the emergence of new methods and technologies, clinical pharmacology has developed rapidly, and basic research in this field has increasingly attracted attention. The NSFC has always emphasized support for this field. However, there are still some issues of the applications, such as the need to strengthen clinical characteristics, uneven distribution of disease types and research directions, and unbalanced development within the discipline, which require increased attention from clinical pharmacology researchers.
To evaluate the effects of fasting and high-fat diet on the pharmacokinetics of rabeprazole sodium enteric-coated tablets in healthy Chinese subjects.
A single-center, randomized, open, two-agent, two-sequence, four-cycle, fully repeated crossover, single-dose trial design was used in this study, healthy subjects were assigned to receive single dose of rabeprazole sodium enteric-coated tablets 0.1 g in either fasting or high-fat diet state, and blood samples were taken at different time points, respectively. The concentrations of rabeprazole sodium enteric-coated in plasma were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), the model method of the non-compartmental was used to calculate the pharmacokinetic parameters by Phoenix WinNonlin 8.2.
The main pharmacokinetic parameters of rabeprazole sodium enteric-coated tablets in fasting state and high-fat diet state were as follows: Cmax were (339.63±156.47) and (318.86±132.13) ng·mL-1; t1/2 were (2.34±0.68) and (3.60±2.40) h; AUC0-t were (556.62±251.65) and (528.50±201.78) ng·mL-1·h; AUC0-∞ were (563.39±255.69) and (535.15±203.24) ng·mL-1·h; tmax were 3.65 and 6.99 h. After high-fat diet, the Cmax and AUC of rapeprazole sodium after high-fat and high-calorie diet decreased, Cmax decreased by 6.12%, AUC0-t decreased by 5.05%, AUC0-∞ decreased by 5.01%, and tmax was delayed by about 3.34 h. Cmax, AUC0-t and AUC0-∞90% confidence interval were 73.13%-115.10%, 83.22%-112.28% and 83.40%-112.13%, respectively. Neither was between 85.00%-125.00%.
High-fat diet affects the absorption rate and degree of rabeprazole sodium enteric-coated, so it is suitable to be administered on an empty stomach.
To improve and refine the relevant regulations and guiding principles of warnings on drug instructions and labels in China.
This paper sorted out the drug instructions of small molecule anti-tumor drugs listed by the U.S. Food and Drug Administration (FDA) from 2005 to 2022, included the drugs mentioned in the QT interval prolongation risk, analyzed the clinical research and QT research results, and sorted out the identification and warning rules of the instructions.
A total of 35 drugs were included, 4 drugs wrote the risk of QT interval prolongation in the black box warning, 21 drugs were wrote in the warning and precautions position, 6 drugs were wrote in the adverse reaction section, and 2 drugs were only described under clinical pharmacology section. According to the severity of the QT interval prolongation caused by the drug and whether there were serious clinical consequences, they were displayed in the warnings (black box warnings), precautions (warnings and precautions) and adverse reactions in the instructions.
The aim of this article is to provide a reference for the writing of QT risk warning information of the instructions of domestic drug production enterprises and regulatory departments. It is recommended to clarify the severity of drug safety and the location of the instructions in clinical research, and continue to carry out safety monitoring and update the instructions in time after listing.
To investigate the mechanism of Achyranthoside Ⅰ inhibits pyroptosis in chondrocytes through the nuclear factor-κB (NF-κB)/NOD receptor protein structure domain related proteins 3 (NLRP3)/cystine containing aspartate specific proteins-1 (caspase-1) signaling pathway.
Primary mouse chondrocytes were divided into blank group (phosphate buffered solution with the same volume), model group [10 ng·mL-1 interleukin-1β (IL-1β)], control group (10 ng·mL-1 IL-1β+20 μmol·L-1 celecoxib) and experimental group (10 ng·mL-1 IL-1β+3 μg·mL-1 Achyranthoside Ⅰ). After 24 hours of intervention, the cell proliferation was measured by cell counting kit 8, the levels of superoxide dismutase (SOD), malondialdehyde (MDA), IL-1 and IL-6 were detected by enzyme-linked immunosorbent assay, the protein expression levels of NF-κB p65, NLRP3 and caspase-1 were detected by Western Blot.
The apoptosis rates in experimental, control, model and blank groups were (13.34±0.61)%, (15.64±1.01)%, (21.81±1.10)% and 0; the SOD levels were (147.03±16.49), (130.09±7.33), (122.03±10.71) and (164.40±22.74) nU·mL-1; the MDA levels were (6.43±0.71), (7.63±1.01), (8.89±1.84) and (5.69±0.81) nmol·L-1; the IL-1 levels were (338.69±40.95), (361.78±32.15), (391.44±30.59) and (289.23±25.19) pg·mL-1; the IL-6 levels were (89.96±8.81), (101.10±11.59), (120.39±14.71) and (60.29±6.03) pg·mL-1; the relative expression levels of NF-κB p65 were 0.68±0.05, 0.97±0.05, 1.26±0.05 and 0.57±0.05; the relative expression levels of NLRP3 were 0.71±0.08, 1.02±0.10, 1.50±0.06 and 0.31±0.05; the relative expression levels of caspase-1 were 0.70±0.07, 1.29±0.08, 1.66±0.07 and 0.51±0.07, respectively. Compared with the model group, the differences of above indexes were statistically significant in the experimental group (all P<0.05).
Achyranthoside Ⅰ can improve the oxidative stress status induced by IL-1β in chondrocytes, reduce the expression of proteins related to the NF-κB signaling pathway, and thereby decrease the occurrence of caspase-1 dependent pyroptosis, providing a protective effect on chondrocytes.
To explore the mechanism of honey-processed Hedysari Radix in the regulation of intestinal immunity in rats with spleen qi deficiency, which was based on G protein-coupled receptor 41 (GPR41)/GPR43-mediated mitogen-activated protein kinase (MAPK) signaling pathway.
The three-factor composite modeling method of eating disorder, diarrhea and fatigue was used to establish a model of spleen qi deficiency, and the rats were randomly divided into model, honey-processed Hedysari Radix, probiotics and blank groups with 15 rats per group. The honey-processed Hedysari Radix group was given by gavage 12.6 g·kg-1 aqueous extract of honey-processed Hedysari Radix. The probiotics group was given 0.625 g·kg-1 bifidobacterium triple viable solution by gavage. The blank and model groups were given the same dose of distilled water by gavage. Four groups were treated for 15 d with once a day. The expression levels of GPR41, GPR43, P38 MAPK, c-Jun N-terminal kinase (JNK) and extracellular regulatory protein kinase 1/2 (ERK1/2) in colon tissues were detected by Western blotting.
The relative expression levels of GPR41 in the blank, model, honey-processed Hedysari Radix and probiotics groups were 0.95±0.07, 0.45±0.03, 0.84±0.19 and 0.86±0.20; the relative expression levels of GPR43 were 1.17±0.11, 0.41±0.06, 0.66±0.03 and 0.57±0.01; the phosphorylated ERK1/2/ERK1/2 ratios were 0.16±0.01, 0.43±0.01, 0.39±0.01 and 0.36±0.02; the phosphorylated JNK/JNK ratios were 0.58±0.05, 1.47±0.10, 0.90±0.11 and 0.90±0.11; the phosphorylated P38 MAPK/P38 MAPK ratios were 1.77±0.33, 3.19±0.03, 2.01±0.17 and 2.23±0.59, respectively. Compared with the model group, the differences of above indexes were statistically significant in the honey-processed Hedysari Radix and probiotics groups (P<0.05, P<0.01).
The mechanism of honey-processed Hedysari Radix regulating intestinal immunity in rats with spleen qi deficiency is related to the regulation of GPR41/GPR43 mediated MAPK signaling pathway.
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