To investigate the regulatory mechanism of plantamajoside (PMS) on the growth and metastasis of non-small cell lung cancer (NSCLC).

A549 cells were divided into control group (normal culture), model group (40 μg·mL^-1 PMS), NC inhibitor group (40 μg·mL^-1 PMS+NC inhibitor), miR-525-5p inhibitor group (40 μg·mL^-1 PMS+miR-525-5p inhibitor), sh-NC group (40 μg·mL^-1 PMS+miR-525-5p inhibitor+sh-NC) and sh-ubiquitin conjugating enzyme E2C (UBE2C) group (40 μg·mL^-1 PMS+miR-525-5p inhibitor+sh-UBE2C). Transwell assay was used to evaluate the invasion ability of A549 cells after different treatments. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used to evaluate the apoptosis of A549 cells after different treatments. At the animal level, mice were injected with A549 cell suspension (5×10⁶/100 μL) to construct the NSCLC model. They were randomly divided into model-M group, PMS group (50 mg·kg^-1 PMS), miR-525-5p inhibitor-M group (50 mg·kg^-1 PMS+miR-525-5p inhibitor) and sh-UBE2C-M group (50 mg·kg^-1 PMS+miR-525-5p inhibitor+sh-UBE2C). All groups were treated for 5 days with once a day. The size of the transplanted tumor was measured with a ruler every 7 days, and the transplanted tumor was removed and weighed on the 28th day. The number of Transwell invasions in control group, model group, NC inhibitor group, miR-525-5p inhibitor group, sh-NC group and sh-UBE2C group were 173.62±23.46, 82.05±14.17, 84.69±13.82, 143.48±19.81, 139.57±18.24 and 105.93±16.25, respectively; the apoptosis rates were (22.65±4.01)%, (53.34±8.93)%, (51.46±8.81)%, (37.52±5.86)%, (34.83±5.27)% and (48.75±6.19)%, respectively. Compared in model group and control group, compared in miR-525-5p inhibitor group and NC inhibitor group, compared in sh-UBE2C group and sh-NC group, there were significant differences in the number of Transwell invasion and apoptosis rates (all P<0.05). At the animal level, 28 d tumor volumes of model-M group, PMS group, miR-525-5p inhibitor-M group and sh-UBE2C-M group were (966.30±176.53), (495.70±52.40), (841.10±121.25) and (623.80±105.85) mm³, respectively; the tumor weight on day 28 were (1.43±0.52), (0.75±0.21), (1.32±0.43) and (0.85±0.26) g, respectively. Differences of the tumor volume and weight between PMS group and model-M group, sh-UBE2C-M group and miR-525-5p inhibitor-M group were statistically significant at the 28th day (P<0.01, P<0.001).

PMS can significantly inhibit the growth and metastasis of NSCLC by regulating the miR-525-5p/UBE2C axis.

To explore the mechanism of long non-coding RNA prostate cancer-associated transcript 19 (LncRNA PCAT19) knockdown on oxaliplatin (OXA) sensitivity of human gastric cancer cells by regulating microRNA (miR)-200c-3p mediated ataxia-telangiectasia mutated proteins (ATM) and Rad3-related kinase-related kinase (ATR) / checkpoint kinase1(CHK1) signaling pathway.

Human gastric adenocarcinoma cells (AGS) were randomly divided into OXA group (8 μg·L^-1 OXA), OXA+si-NC+inh-NC group (si-NC and inh-NC co-transfected with +8 μg·L^-1 OXA), OXA+si-PCAT19+ inh-NC group (si-PCAT19 and inh-NC co-transfected +8 μg·L^-1 OXA), OXA+si-PCAT19+ miR-200c-3p inh group (si-PCAT19 and miR-200c-3p inh co-transfected +8 μg·L^-1 OXA). Cell proliferation in each group was detected by 5-acetylidene-2′-deoxyuridine assay; cell apoptosis was detected by in situ terminal transferase labeling technique; cell migration was detected by cell scratch assay; the expression levels of phosphorylated histone H2A.X (γH2A.X) and radiation-sensitive protein 51 (RAD51) were detected by immunofluorescence.

In OXA group, OXA+si-NC+inh-NC group, OXA+si-PCAT19+inh-NC group, OXA+si-PCAT19+miR-200c-3p group, the cell proliferation rates were (58.83±6.52)%, (59.42±6.86)%, (45.59±6.09)% and (55.71±7.69)%, respectively; the apoptosis rates were (20.06±2.44)%, (20.32±2.66)%, (31.74±4.43)% and (24.60±3.29)%, respectively; the migration rates were (54.50±6.14)%, (56.11±6.72)%, (31.51±4.13)% and (48.59±7.26)%, respectively; the relative fluorescence intensities of γH2A.X were 1.00±0.08, 0.97±0.12, 4.84±0.82 and 2.11±0.41, respectively; the relative fluorescence intensities of RAD51 were 1.00±0.06, 1.08±0.15, 0.22±0.04 and 0.55±0.08, respectively. There were no significant differences between OXA+si-NC+inh-NC group and OXA group (all P>0.05). The above indexes of OXA+si-PCAT19+inh-NC group were compared with those of OXA+si-NC+inh-NC group, the above indexes in OXA+si-PCAT19+miR-200c-3p inh group were compared with those of OXA+si-PCAT19+inh-NC group, the differences were statistically significant (all P<0.05).

Knockdown of LncRNA PCAT19 can affect the proliferation, migration, apoptosis and deoxyribonucleic acid repair of gastric cancer cells by targeting and negatively regulating miR-200c-3p, thereby enhancing the sensitivity of gastric cancer cells to OXA, which may be related to the ATR/CHK1 signaling pathway.

To explore the effects of niraparib (Nira) on ovarian cancer cell proliferation and migration by inhibiting the wingless MMTV integration site family member (Wnt)/beta-catenin (β-catenin) signaling pathway through the regulation of transcription factor 4 gene (TCF4).

SKOV3 cells were divided into control group (normal culture without any treatment), OE-NC group (10 μmol·L^-1 Nira+ transfection OE-NC treatment) and OE-TCF4 group (10 μmol·L^-1 Nira+ transfection OE-TCF4 treatment), experimental-L, M, H groups (5, 10, 15 μmol·L^-1 Nira treatment). Real-time fluorescence quantitative polymerase chain reaction and Western blotting were used to detect the protein and mRNA expression level of TCF4; cell viability was detected by cell counting kit-8 (CCK-8); and cell invasion ability was detected by Transwell. The expression levels of Wnt/β-catenin pathway-related proteins were detected by immunofluorescence.

The 48 h cell survival rates in control group, experimental-L, -M, -H groups were (98.96±3.13)%, (77.53±7.03)%, (58.31±7.52)% and (35.88±5.97)%, respectively. The relative mRNA expression levels of TCF4 in the control group and the experimental-M group were 1.00±0.16 and 0.45±0.07, respectively; while the relative protein expression levels of TCF4 were 1.00±0.12 and 0.43±0.06, respectively. The number of invasive cells in control group, experimental-M group, OE-NC group and OE-TCF4 group were 115.77±16.57, 60.81±8.80, 66.43±8.98 and 99.25±13.73, respectively; the relative fluorescence intensities of β-catenin were 1.00±0.13, 0.15±0.03, 0.17±0.04 and 0.60±0.11; the relative fluorescence intensities of cancer-Myc were 1.00±0.15, 0.07±0.01, 0.08±0.02 and 0.54±0.09, respectively; the relative fluorescence intensities of matrix metalloproteinase-9 (MMP-9) were 1.00±0.13, 0.06±0.01, 0.07±0.02 and 0.28±0.05, respectively. The control group was compared with experimental-M group, and the OE-TCF4 group was compared with OE-NC group, there were statistically significant differences in the above indexes (all P<0.05).

Nira can inhibit the activity and invasion of ovarian cancer SKOV3 cells, which may be related to the down-regulation of TCF4 to inhibit the activation of Wnt/β-catenin signaling pathway.

To investigate the effects of Cepharanthine on apoptosis, energy metabolism and angiogenesis of breast cancer cells by regulating the microRNA (miR)-378c/Golgi transport 1A protein (GOLT1A) axis.

MDA-MB-231 cells in the logarithmic growth phase were divided into the following groups: Control group (no treatment), NC inhibitor group (transfected with miR-378c inhibitor negative control), miR-378c inhibitor group (transfected with miR-378c inhibitor), si-NC group (transfected with si-NC plasmid), si-GOLT1A group (transfected with si-GOLT1A plasmid), Cepharanthine group (20 μmol·L^-1 Cepharanthine), Cepharanthine combined with miR-378c inhibitor group (Cepharanthine group with miR-378c inhibitor transfection) and miR-378c inhibitor combined with si-GOLT1A group (Cepharanthine group with co-transfection of miR-378c inhibitor and si-GOLT1A plasmid). Real-time fluorescence quantitative polymerase chain reaction was used to detect the relative expression levels of miR-378c, GOLT1A, vascular endothelial growth factor A (VEGFA) and thrombospondin-1 (THBS1); kits were used to detect energy metabolism indicators; immunofluorescence was used to detect VEGFA and THBS1 expression levels.

The relative expression levels of miR-378c in the control group and Cepharanthine group were 1.00±0.14 and 3.26±0.48, respectively; the relative expression levels of GOLT1A mRNA were 1.00±0.15 and 0.43±0.07, respectively. The glutamine concentrations in the control group, Cepharanthine group, Cepharanthine combined with miR-378c inhibitor group and miR-378c inhibitor combined with si-GOLT1A group were (22.03±3.14), (8.27±1.94), (17.25±2.86) and (13.11±2.28) nmol·10^-7 cells, respectively; the acetyl coenzyme A concentrations were (11.32±2.06), (5.71±1.19), (9.62±1.85) and (6.67±1.63) nmol·10^-6 cells, respectively; the succinate concentrations were (53.67±6.92), (21.24±3.87), (39.82±4.39) and (30.36±4.21) nmol·mg^-1·Pr^-1, respectively; the ATP production values were (2.32±0.42), (0.96±0.12), (1.91±0.33) and (1.16±0.26) mmol·mg^-1·Pr^-1, respectively; the relative expression levels of VEGFA mRNA were 1.00±0.14, 0.56±0.10, 0.84±0.13 and 0.69±0.10, respectively; the relative expression levels of THBS1 mRNA were 1.00±0.12, 3.43±0.57, 2.04±0.36 and 3.10±0.52, respectively; the relative fluorescence intensities of VEGFA were 1.00±0.11, 0.37±0.05, 0.76±0.09 and 0.48±0.06, respectively; and the relative fluorescence intensities of THBS1 were 1.00±0.09, 3.71±0.62, 1.88±0.31 and 2.55±0.37, respectively. All the above indicators showed significant differences between the control group and the Cepharanthine group, the Cepharanthine group and the Cepharanthine combined with miR-378c inhibitor group, the Cepharanthine combined with miR-378c inhibitor group and the miR-378c inhibitor combined with si-GOLT1A group (P<0.05, P<0.01, P<0.001).

Cepharanthine can promote apoptosis and inhibit energy metabolism and angiogenesis in breast cancer cells, which may be related to its regulation of the miR-378c/GOLT1A axis.

To investigate the effect of Rocaglamide (Roc-A) on paclitaxel (PTX) resistance in breast cancer MCF-7/PTX cell line and its mechanism.

With breast cancer MCF-7 cells as the research object, PTX resistant MCF-7/PTX cell line was obtained by continuous induction with low concentration of PTX. Methyl thiazolyl tetrazolium (MTT) method was used to determine the drug resistance index of MCF-7/PTX cell line, the effect of Roc-A on the proliferation activity of MCF-7/PTX cell line and the drug resistance reversal multiple. MCF-7/PTX cell lines were divided into control group (normal cultured cells), PTX group (40.8 nmol·L^-1 PTX), PTX+Roc-A-L group (40.8 nmol·L^-1 PTX+25 nmol·L^-1 Roc-A), PTX+Roc-A-M group (40.8 nmol·L^-1 PTX+50 nmol·L^-1 Roc-A) and PTX+Roc-A-H group (40.8 nmol·L^-1 PTX+100 nmol·L^-1 Roc-A). The apoptosis level of each group was detected by flow cytometry; the relative expression levels of cell autophagy related protein LC3 were detected by immunofluorescence assay; Western blotting was used to detect the relative expression levels of cell apoptosis related proteins, such as B cell lymphoma-2 associated X protein (Bax) and autophagy associated protein autophagy microtubule associated protein light chains 3 (LC3).

The PTX resistant cell line MCF-7/PTX of breast cancer was successfully constructed with a drug resistance index of 5.49; Roc-A could inhibit the proliferation activity of MCF-7/PTX cell lines in a concentration dependent manner, while the reversal multiples of PTX resistance of MCF-7/PTX cell lines to Roc-A at different concentrations (25, 50, 100 nmol·L^-1) were 1.57, 2.68 and 6.16, respectively. The apoptosis rates of the control group, PTX group, PTX+Roc-A-L group, PTX+Roc-A-M group and PTX+Roc-A-H group were (4.75±2.10)%, (21.79±3.61)%, (32.54±3.43)%, (39.82±3.26)% and (55.61±4.22)%, respectively; the relative expression levels of LC3 fluorescence were 1.00±0.08, 0.77±0.06, 0.60±0.06, 0.41±0.04 and 0.26±0.03, respectively; the relative expression levels of Bax protein were 0.12±0.04, 0.25±0.09, 0.48±0.10, 0.86±0.12 and 1.10±0.13, respectively; the LC3Ⅱ/LC3Ⅰ protein ratio were 6.52±0.27, 3.75±0.23, 1.76±0.17, 1.31±0.10 and 1.02±0.06, respectively. Compared with the control group, the PTX group, PTX+Roc-A-L group, PTX+Roc-A-M group, PTX+Roc-A-H group showed statistically significant differences in the above indicators (all P<0.05); the above indicators in the PTX+Roc-A-L group, PTX+Roc-A-M group and PTX+Roc-A-H group were compared with those in the PTX group, and the differences were statistically significant (all P<0.05), showing a dose-dependent relationship.

Roc-A can reverse the resistance of breast cancer drug resistant cell line MCF-7/PTX to PTX, and the mechanism may be related to the reduction of autophagy.

To explore the effects of Wu Wei Han bamboo slips “Yufang” on kidney injury in spontaneously hypertensive rats and its mechanism of action.

To analyze the differential genes between normal kidney tissues and hypertensive kidney tissues in GSE37460, a hypertensive kidney disease dataset in GEO database, and to explore the mechanism of hypertensive kidney injury; Spontaneously hypertensive rats (SHR) were randomly divided into model group (equal volume of distilled water), control group (7.59 mg·kg^-1 valsartan) and experimental-L, -M, -H groups (7.15, 14.29, 28.58 g·kg^-1 “Yufang” granules), with 10 rats in each group; additionally, Wistar-Kyoto (WKY) rats were taken as a normal group (equal volume of distilled water). Six groups were gavaged once a day for 8 consecutive weeks. The levels of urinary microalbumin (mAlb), N-acetyl-β-D-glucosaminidase (NAG) and serum thromboxane (TXB2), 6-keto-prostaglandin F1 α (6-keto PGF1α) were detected by enzyme linked immunosorbent assay. Western blot was used to detect the expression levels of hypoxia inducible factor-1 α (HIF-1α), vascular endothelial growth factor (VEGF) and transmembrane receptor protein 1 (Notch1) in rat kidney.

The data set GSE37460 contained 155 differential genes, 94 of which were up-regulated and 61 were down regulated and pathway enrichment involves pathways such as HIF-1α/VEGF/Notch1. The urinary mAlb levels of normal, model, control and experimental -H groups were (60.83±3.81), (159.60±20.65), (70.45±3.97) and (79.72±9.01) μg·L^-1, respectively; the urinary NAG levels were (34.37±6.92), (91.30±9.05), (44.65±10.09) and (54.79±2.87) ng·L^-1, respectively; the contents of TXB2 in serum were (78.58±3.78), (107.80±5.16), (80.92±4.02) and (85.65±2.17) pg·mL^-1, respectively; the serum 6-keto PGF1α levels were (121.50±3.45), (85.05±2.92), (108.30±2.96), (101.90±3.08) pg·mL^-1, respectively; the relative expression levels of HIF-1 α protein in rat kidney were 0.56±0.03, 1.25±0.02, 0.77±0.01 and 0.83±0.02, respectively; the relative expression levels of VEGF protein were 0.24±0.02, 1.24±0.03, 0.81±0.04 and 0.95±0.02, respectively; the relative expression levels of Notch1 protein were 0.33±0.03, 1.02±0.01, 0.50±0.04 and 0.68±0.01, respectively; there were significant differences in the above indexes between the control and experimental -H groups and the model group (all P<0.05).

The Wuwei Han bamboo slips “Yufang” can improve hypertension-related kidney damage and reduce kidney fibrosis, and its mechanism may be related to the inhibition of the HIF-1α/VEGF/Notch1 signaling pathway.

To explore the specific mechanism of the gastric protective effect of salvianolic acid B (Sal B) on precancerous lesions of the stomach (PLGC) in rats by regulating the microRNA (miR)-106b-5p/B-cell translocation gene 3 (BTG3) molecular axis.

Except for the NC group, the rat models of PLGC were established. The rats were randomly divided into the NC group (without any treatment, intragastric administration of normal saline), the model group (after successful modeling, intragastric administration of normal saline), the experimental group (intragastric administration of Sal B based on the model group), the NC mimic group (based on the experimental group, injection of NC mimic plasmid via the tail vein), the miR-106b-5p mimic group (based on the experimental group, injection of miR-106b-5p mimic plasmid via the tail vein), the pcDNA3.1-NC group (based on the miR-106b-5p mimic group, intraperitoneal injection of pcDNA3.1-NC plasmid) and the pcDNA3.1-BTG3 group (based on the miR-106b-5p mimic group, intraperitoneal injection of pcDNA3.1-BTG3 plasmid). Quantitative real-time polymerase chain reaction experiments were carried out to detect the mRNA expression levels of miR-106b-5p, BTG3 and inflammatory factors in the gastric mucosa tissues. Enzyme-linked immunosorbent assays were performed to detect the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA) and gastrin-17 (G-17) in the serum. Western blot experiments were used to detect the levels of proteins related to the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and mucin 2 (MUC2) in the gastric mucosa tissues.

The relative expression levels of miR-106b-5p in the NC group, the model group and the experimental group were 1.00±0.08, 1.76±0.35 and 1.33±0.26, respectively, and the relative expression levels of BTG3 mRNA were 1.00±0.05, 0.39±0.06 and 0.81±0.15, respectively. There were statistically significant differences in the above-mentioned indicators between the model group and the NC group, as well as between the experimental group and the model group (all P<0.05). The levels of SOD in the NC group, the model group, the experimental group, the NC mimic group, the miR-106b-5p mimic group, the pcDNA3.1-NC group and the pcDNA3.1-BTG3 group were (197.81±47.15), (118.54±20.49), (172.29±34.34), (176.78±35.57), (127.65±21.23), (119.41±20.50) and (158.28±31.07) U·mL^-1, respectively; the levels of MDA were (3.44±0.67), (8.08±1.32), (3.92±0.75), (3.84±0.70), (6.50±1.21), (6.34±1.17) and (4.22±0.79) nmol·mL^-1, respectively; the levels of G-17 were (221.57±40.26), (155.62±28.43), (201.13±37.35), (194.85±35.24), (162.72±31.65), (160.04±29.37) and (189.32±32.15) pg·mL^-1, respectively; the levels of PI3K were 1.00±0.14, 1.81±0.36, 1.23±0.21, 1.19±0.20, 1.65±0.32, 1.70±0.35 and 1.38±0.28, respectively; the ratios of phosphorylated AKT/AKT were 1.00±0.09, 1.94±0.39, 1.27±0.23, 1.21±0.18, 1.77±0.37, 1.73±0.33 and 1.42±0.26, respectively. There were statistically significant differences in the above-mentioned indicators between the miR-106b-5p mimic group and the NC mimic group, and between the pcDNA3.1-BTG3 group and the pcDNA3.1-NC group (all P<0.05).

Sal B may exert a gastric protective effect by down-regulating the targeted negative regulation of BTG3 expression by miR-106b-5p, inhibiting the activation of the PI3K/AKT signaling pathway, thereby alleviating the oxidative stress and inflammatory response in PLGC rats and improving the condition of the gastric mucosa.

To investigate the effect of curcumin on lung injury in rats with acute organophosphorus pesticide poisoning (AOPP) through the cytochrome C/apoptotic protease activating factor-1 (CytC/Apaf-1) pathway.

SD rats were divided into control group, model group, inhibitor group, experimental -L and experimental -H groups, with 10 rats in each group. Except for the control group, the rats in the other 4 groups were administrated with 20 mg·kg^-1 oxomethoate to establish the rat model of organophosphorus pesticide poisoning. After the modeling was successful, the rats in the experimental -L and experimental -H groups were given 100 and 200 mg·kg^-1 curcumin by intragastric administration, and the rats in the inhibitor group were given 67.8 mg·kg^-1 YZ-488 intramuscularily, and the model group and control group were given equal volume of normal saline in the same way by intragastric administration and intramuscularily. Five groups of rats were given the drug once a day for 28 days. Mitochondrial membrane potential detection kits were applied to detect mitochondrial membrane potential (MMP). Enzyme-linked immunosorbent assay method was applied to detect levels of serum interleukin-10 (IL-10); apoptosis in lung tissue was detected by TUNEL; Western blot was applied to detect the expression levels of CytC and Apaf-1 proteins in lung tissue.

The MMP of experimental -L and experimental -H groups, control group, model group, and inhibitor group were (0.64±0.05), (0.78±0.09), (0.93±0.06), (0.51±0.04) and (0.76±0.08) RFU·mg^-1, respectively; IL-10 levels were (67.58±6.82), (104.29±11.37), (148.62±13.54), (32.84±3.51) and (98.74±8.76) pg·mL^-1, respectively; the apoptosis rates were (29.37±3.28)%, (16.58±1.87)%, (5.72±0.64)%, (43.68±4.91)% and (17.32±2.14)%, respectively; the relative expression levels of CytC protein were 0.89±0.07, 0.63±0.05, 0.42±0.04, 1.16±0.12 and 0.65±0.06, respectively; the relative expression levels of Apaf-1 protein were 0.73±0.06, 0.48±0.04, 0.32±0.03, 0.97±0.08 and 0.49±0.05, respectively. The above indexes of the model group were statistically significant compared with those in the experimental -L and experimental -H groups, inhibitor group and control group (all P<0.05).

Curcumin may reduce inflammatory response and oxidative stress in rats by inhibiting the CytC/Apaf-1 pathway, alleviate lung tissue and mitochondrial structural damage, and thereby improve lung injury in rats with AOPP.

To investigate the pharmacokinetic characteristics, safety and tolerability of single oral administration of trifluridine/tipiracil tablet in Chinese solid tumors under fasting and fed states, to evaluate the bioequivalence of the two formulations.

A randomized, open-label, two-formulation, two-sequence, four-cycle, repeated crossover design was used, with 30 subjects enrolled in both the fasting and fed groups, receiving a single oral dose of 60 mg of the test or reference formulation in each cycle. The concentrations of trifluridine and tipiracil in plasma were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Phoenix WinNonlin 8.3 and SAS 9.4 software were used for pharmacokinetic parameter and bioequivalence analysis.

Fasting group: The pharmacokinetic parameters of trifluridine were as follows. For the test preparation, C_max was (6 711.36±1 641.92) ng·mL^-1; AUC_0-t was (14 216.19±4 420.98) h·ng·mL^-1; AUC_0-∞ was (14 432.88±4 613.02) h·ng·mL^-1. For the reference preparation, C_max was (6 332.20±1 606.03) ng·mL^-1; AUC_0-t was (14 393.26±4 070.13) h·ng·mL^-1; AUC_0-∞ was (14 636.58±4 285.74) h·ng·mL^-1. The pharmacokinetic parameters of tipiracil were as follows. For the test preparation, C_max was (140.73±44.39) ng·mL^-1; AUC_0-t was (491.99±149.66) h·ng·mL^-1; AUC_0-∞ was (499.49±150.62) h·ng·mL^-1. For the reference preparation, C_max was (142.70±42.64) ng·mL^-1; AUC_0-t was (505.43±135.58) h·ng·mL^-1; AUC_0-∞ was (513.42±137.70) h·ng·mL^-1. Fed group: The pharmacokinetic parameters of trifluridine were as follows. For the test preparation, C_max was (3 703.22±875.59) ng·mL^-1; AUC_0-t was (10 817.63±3 466.63) h·ng·mL^-1; AUC_0-∞ was (10 986.12±3 776.68) h·ng·mL^-1. For the reference preparation, C_max was (3 754.66±915.72) ng·mL^-1; AUC_0-t was (10 775.42±3 594.37) h·ng·mL^-1; AUC_0-∞ was (11 002.36±4 106.89) h·ng·mL^-1. The pharmacokinetic parameters of tipiracil were as follows. For the test preparation, C_max was (53.73±16.72) ng·mL^-1; AUC_0-t was (219.63±74.00) h·ng·mL^-1; AUC_0-∞ was (226.61±77.00) h·ng·mL^-1. For the reference preparation, C_max was (54.73±14.42) ng·mL^-1; AUC_0-t was (224.66±75.23) h·ng·mL^-1; AUC_0-∞ was (231.91±78.74) h·ng·mL^-1. The geometric mean ratios and their 90% confidence intervals for the main pharmacokinetic parameters (C_max, AUC_0-t, AUC_0-∞) of the test and reference formulations of trifluridine/tipiracil were all within the range of 80.00%-125.00%. Common adverse drug reactions in the fasting group includes sinus bradycardia and elevated alanine aminotransferase, while common adverse drug reactions in the fed group included decreased lymphocyte count and detection of urinary sediment. The incidence of adverse drug reactions in the fasting and fed conditions were 36.67% (11 cases / 30 cases) and 46.67% (14 cases / 30 cases), respectively. There were no serious adverse events occurred during the trials in the both group.

The test and reference formulations of trifluridine/tipiracil tablet are bioequivalent under both fasting and fed conditions, with good safety and tolerability.

To study the in vitro and in vivo pharmacodynamics of dirozalkib.

Prepare dirozalkib solutions with concentrations ranging from 3.81×10^-3 to 1 000.00 nmol·L^-1. The activities of dirozalkib against kinases anaplastic lymphoma kinase (ALK), ALK-L1196M, and ALK-G1202R were evaluated using the Mobility Shift Assay and Radioisotope Filter Binding methods. The inhibitory effect of dirozalkib on cell proliferation was evaluated using the CellTiter-Glo assay in multiple Ba/F3 cell lines transfected with EML4-ALK fusion genes and drug-resistant mutants, at concentrations ranging from 1.53×10^-2 to 1 000.00 nmol·L^-1. Ba/F3-EML4-ALK-L1196M (crizotinib-resistant) cells were subcutaneously inoculated in NOD SCID mice. The tumor-bearing mice were randomly divided into blank group (solvent control), experimental group (50 mg·kg^-1 dirozalkib), control group (50 mg·kg^-1 crizotinib), each group consisted of 9 mice. The mice were gavage once a day, continuous administration over a 14-day period. BALB/c nude mice were used to establish a human lung cancer tumor tissue-derived LU-01-0319R (crizotinib-resistant) patient-derived tumor xenograft (PDX) model. The tumor-bearing mice were randomly divided into blank group (solvent control), experimental group (24 mg·kg^-1 dirozalkib), control group (24 mg·kg^-1 crizotinib), each group consisted of 9 mice. The mice were gavage once a day, continuous administration over a 21-day period. Human lung cancer H228-luc cells were intracranially inoculated in BALB/c nude mice. The tumor-bearing mice were randomly divided into blank group (solvent control), experimental group (100 mg·kg^-1 dirozalkib), control group (100 mg·kg^-1 crizotinib), each group consisted of 9 mice. The mice were gavage once a day, continuous administration over a 14-day period. Assessed the anti-tumor efficacy of dirozalkib.

Dirozalkib significantly inhibited the kinase activities of ALK, ALK-L1196M, and ALK-G1202R [50% inhibiting concentration (IC₅₀) <1.0 nmol·L^-1]. In cells, dirozalkib exhibited significant proliferation inhibitory activity against NCI-H3122 cells harboring EML4-ALK fusion (IC₅₀ = 3.00 nmol·L^-1). Additionally, it demonstrated potent inhibitory activity against multiple cell lines with EML4-ALK fusion and drug-resistant mutants of crizotinib and second-generation ALK inhibitors (IC₅₀: 1.92-62.85 nmol·L^-1). In the crizotinib-resistant Ba/F3-EML4-ALK-L1196M xenograft model, dirozalkib at a dose of 50 mg·kg^-1 had a significant anti-tumor effect, with a relative tumor proliferation rate of 6.14%. In the LU-01-0319R human lung cancer xenograft model (crizotinib-resistant PDX model), the 24 mg·kg^-1 dirozalkib also had a significant tumor inhibitory effect, with a relative tumor proliferation rate of 13.19%. For the H228-luc human lung cancer intracranial inoculation model, dirozalkib at 100 mg·kg^-1 could significantly inhibit tumor growth [BLI value was (569.34±153.65) × 10⁵ photons·s^-1]and could significantly prolong the survival time of the animals.

Dirozalkib effectively inhibits ALK and various resistance mutations associated with first- and second-generation ALK-TKIs, and shows significant antitumor activity in multiple tumor models, including intracranial implantation models.