Latest ArticlesTo investigate the efficacy of the hypoxia-inducible factor-1α (HIF-1α) inhibitor PX-478 in improving radiation-induced apoptosis in cardiomyocytes and to elucidate its molecular mechanisms.
H9c2 cells were divided into blank group, model group, experimental-L group and experimental-H group. The experimental-L, -H groups were cultured with PX-478 at concentrations of 5 and 10 mol·L-1, respectively, while the other groups were cultured in normal medium. After 24 h of culture, all groups except the blank group were irradiated with 6 Gy X-rays to establish a model of radiation-induced cardiac injury and were subsequently cultured for another 24 h. Cell viability was assessed using the cell counting kit-8 assay; relative protein expression levels were determined by Western blotting; and apoptosis was detected using Annexin V/PI flow cytometry.
The relative expression levels of HIF-1α protein in the blank group, model group, experimental-L group and experimental-H group were 0.89±0.01, 1.05±0.01, 0.64±0.02 and 0.52±0.02; the relative expression levels of aquaporin-1 (AQP1) protein were 0.79±0.02, 0.94±0.02, 0.74±0.01 and 0.59±0.01; AQP4 protein levels were 0.89±0.01, 1.03±0.01, 0.68±0.01 and 0.50±0.01; B-cell lymphoma-2 (Bcl-2) protein levels were 0.78±0.02, 0.58±0.02, 1.00±0.03 and 0.82±0.03; Bcl-2-associated X protein (Bax) levels were 0.66±0.01, 0.96±0.01, 0.77±0.01 and 0.27±0.03; Caspase-3 levels were 0.83±0.01, 1.10±0.01, 0.71±0.02 and 0.30±0.01; the apoptosis rates were (4.05±0.60)%, (17.82±0.63)%, (9.35±0.41)% and (9.07±0.57)%, respectively. The above indicators in the blank, experimental-L, experimental-H groups showed statistically significant differences compared to the model group (all P<0.05).
PX-478 can improve radiation-induced cardiomyocyte edema and reduce apoptosis by inhibiting the abnormal activation of the HIF-1α/AQPs axis in H9c2 cells after irradiation, thereby regulating fluid metabolism.
To explore effect and mechanism of microRNA 142a-3p (miR-142a-3p) on adriamycin-induced nephropathy (AN).
BALB/c mice were randomly divided into normal group and model group. The model group was injected with 10.5 mg·kg-1 doxorubicin at a time through the tail vein, and the normal group was injected with equal volume 0.9% NaCl by the same method. After 28 days of feeding, both sides of the kidney tissues were taken for experiment. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of miR-142a-3p in the renal tissues. The expression levels of autophagy related protein 16-like protein 1 (Atg16l1) and inflammatory NOD-like receptor heat protein domain associated protein 3 (NLRP3), interleukin-1β (IL-1β) and interleukin-18 (IL-18) in the renal tissues were detected by Western blotting. Human embryonic kidney 293T cells were divided into Atg16l1-WT+NC transfection group (transfected pmirGLO-Atg16l1-WT and NC mimics) and Atg16l1-WT+miRNA-142a-3p group (transfected pmirGLO-Atg16l1-WT and miR-142a-3p mimics). Dual luciferase assay was used to detect the targeted regulation of miR-142a-3p on Atg16l1.
The expression levels of miR-142a-3p in kidney tissues of normal group and model group were 1.20±0.27 and 2.02±0.14; the expression levels of Atg16l1 were 0.81±0.13 and 0.57±0.12, NLRP3 were 0.49±0.11 and 0.82±0.14; IL-1β were 0.55±0.11 and 0.84±0.08; IL-18 levels were 0.41±0.15 and 0.74±0.09, respectively, and the above indexes in the model group were significantly different from those in the normal group (all P<0.05). The relative luciferase activity in Atg16l1-WT+NC transfection group and Atg16l1-WT+miRNA-142a-3p transfection group were 1.26±0.07 and 0.92±0.10, respectively, with statistical significance (all P<0.05).
MiR-142a-3p down-regulates the expression of target protein Atg16l1 in renal tissue of adriamycin nephropathy mice, which activates NLRP3 pathway of inflammatory bodies and promotes the progressive development of adriamycin-induced nephropathy.
Temozolomide capsule is a first-line chemotherapeutic agent for the treatment of glioblastoma and anaplastic astrocytoma. Combined with radiotherapy, it can significantly improve the survival rate of patients, which is of high clinical value. Based on the public information on the websites of National Medical Products Administration, Food and Drug Administration, European Medicines Angecy and Pharmaceuticals and Medical Devices Angecy, the contents of Chineses Pharmacopoeia, United States Pharmacopeia, British Pharmacopeia, and the requirements of The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and domestic chemical generic drugs related guidelines, this paper proposed the pharmaceutical research and development concerns of this product, so as to promote the marketing of generic drugs.
Diabetic kidney disease (DKD) is one of the major complications caused by diabetes mellitus, due to its insidious onset, complex pathogenesis and not yet fully defined, it is easy to be delayed for a long period of time to progress to end-stage renal disease (ESRD) or even lead to death. DKD is characterized by the progressive aggravation of urinary protein, and is accompanied by different degrees of glomerulosclerosis, tubular dilatation, interstitial fibrosis and other renal pathologic changes. Data show that hyperglycemic state leads to decreased expression of SIRT1, and SIRT1 has been found to improve renal tissue damage and protect renal function. Therefore, SIRT1 may become a potential target for DKD prevention and treatment, inhibiting renal fibrosis and delaying DKD progression by promoting podocyte autophagy, reducing oxidative stress and inflammatory response. In this paper, we focus on the experimental studies of Chinese medicine extracts targeting the SIRT1 signaling pathway to prevent and control DKD, with a view to providing new ideas and reference basis for the clinical treatment of DKD.
To observe the effect of Tetrahydropalmatine on the epidermal growth factor receptor / phosphatidylinositol 3-kinase/protein kinase B (EGFR/PI3K/AKT) signaling pathway in endometriosis dysmenorrhoea SD rats.
The endometriosis dysmenorrhoea model was replicated by auto-transplantation in 60 female SD rats of SPF grade. After successful modelling, the rats were randomly divided into model group, control group and experimental -L, -M, -H groups according to body mass, with 12 rats in each group; and another 12 normal rats were taken as the blank group. The blank and model groups were given 10 mL·kg-1 0.9% NaCl by gavage, and the control group was given 0.25 mg·kg-1 progesterone suspension by gavage. The experimental-L, experimental-M, experimental-H groups were given 10, 20 and 40 mg·kg-1 Tetrahydropalmatine suspension by gavage, respectively. Six groups of rats were administered once daily for 4 weeks. After the last administration, 2 U of oxytocin was given to induce contractions, and the rats were observed for torsional responses. The serum levels of tumor necrosis factor -α (TNF-α), epidermal growth factor (EGF), and EGFR were measured by enzyme-linked immunosorbent assay in each group of rats, and the expression levels of EGFR, PI3K and AKT proteins in ectopic endometrial tissues were detected by Western blotting.
The number of twists in the experimental -M, -H groups and control group, model group, blank group were 9.25±1.42, 8.33±1.88, 11.17±2.41, 28.67±2.15 and 0; the inhibition rates were 67.74%, 70.95%, 61.05%, 0 and 0; serum TNF-α levels were (281.96±13.06), (278.75±10.39), (282.12±14.47), (303.59±9.09) and (274.26±15.33) ng·L-1; serum EGF levels were (313.82±13.23), (308.26±10.90), (311.39±19.52), (336.04±17.60) and (301.67±27.17) pg·mL-1; serum EGFR levels were (315.71±7.56), (311.43±11.04), (313.75±7.26), (333.56±14.22) and (307.86±17.94) ng·L-1; the relative expression levels of EGFR protein were 1.60±0.39, 1.26±0.30, 1.40±0.40, 2.08±0.41 and 1.00±0.22; the relative expression levels of PI3K protein were 1.60±0.42, 1.21±0.18, 1.27±0.24, 2.01±0.41 and 1.00±0.19; the relative expression levels of AKT protein were 1.27±0.18, 1.11±0.10, 1.27±0.16, 1.64±0.28 and 1.00±0.07, respectively. Statistically significant differences were found between the above indicators in the experimental -M, -H groups compared to the model group (P<0.01, P<0.05).
Tetrahydropalmatine may play a therapeutic role in endometriosis dysmenorrhoea by interfering with the EGFR/PI3K/AKT signaling pathway.
Tovorafenib has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma(LGGs) harboring the serine threonine kinae v-RAF murine sarcoma viral oncogene homologue B1 (BRAF) fusion or rearrangement, or BRAV600E mutation. Tovorafenib is an oral, greater brain-penetrant, selective, type Ⅱ RAF inhibitor which has potent activity against both oncogenic BRAF fusions and BRAFV600E mutations. Most tumors have been showed some degree of shrinkage. The mechanism of action, pharmacodynamics, pharmacokinetics, clinical study and safety were introduced.
As a new solid-state form of drugs, pharmaceutical co-crystals can improve the physicochemical properties of drugs (such as melting point, stability, solubility, hygroscopicity, compressibility, permeability, bioavailability, etc), thereby changing drug performance or enhancing therapeutic efficacy, providing new ideas for drug development. In recent years, pharmaceutical co-crystals has attracted much attention as a hot topic in the research of crystalline drugs, but there is currently no specialized guiding principle for pharmaceutical co-crystals research in China. This article mainly investigates the technical documents on pharmaceutical co-crystals research released by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), elaborates on the regulatory requirements for pharmaceutical co-crystals in foreign countries, compares and analyzes the regulatory requirements of FDA and EMA, in order to provide references for the research and regulation of pharmaceutical co-crystals in China.
With the deepening of molecular biology and cell biology research, the regulatory mechanism of autophagy has been gradually revealed, providing new ideas for the treatment of numerous diseases. Autophagy may be closely related to pathological changes such as apoptosis resistance of fibroblast-like synoviocytes, disturbances in bone metabolic homeostasis, and antigen presentation, the regulation of autophagy homeostasis may be an important approach for the treatment of rheumatoid arthritis (RA). In this paper, we provide a review on the pathological mechanism of autophagy in RA, with a view to providing a theoretical basis for later studies.
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 pharmacokinetic (PK) characteristics of desloratadine tablets and reference drugs in healthy subjects, and evaluate their bioequivalence and safety.
The random, open, two-period, cross-over pharmacokinetic study method was adopted, each subject received a single oral dose of desloratadine tablets test drug(T) or reference drug(R) for 5 mg. The concentrations of desloratadine and 3-hydroxy desloratadine in plasma were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS); and the PK parameters were calculated by WinNonlin 8.1 software to evaluate the bioequivalence.
The main PK parameters of T and R of desloratadine were as follows: the fasting condition Cmax were respectively (3 809.82±1 016.54) and (3 642.36±777.07) pg·mL-1; AUC0-120h were respectively (5.75×104±5.03×104) and (5.51×104±4.00×104) pg·h·mL-1; AUC0-∞ were respectively (6.85×104±1.03×104) and (6.37×104±7.92×104) pg·h·mL-1. The fed condition Cmax were respectively (4 398.98±1 191.22) and (4 744.40±1 511.97) pg·mL-1; AUC0-120 h were respectively(5.25×104±1.82×104) and (5.55×104±1.98×104) pg·h·mL-1; AUC0-∞ were respectively(5.37×104±1.86×104) and (5.68×104±2.04×104) pg·h·mL-1. The 90% confidence interval of Cmax, AUC0-t and AUC0-∞ of desloratadine were all within 80.00%~125.00%.
There was no significant difference in the main PK parameters between T and R under fasting or high-fat postprandial conditions, and desloratadine tablets were bioequivalent, safe and well tolerated.
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