Latest ArticlesSmall interference RNA (siRNA) drugs have unique characteristics in molecular structure, mechanism of action and pharmacokinetic characteristics, presenting numerous challenges during the clinical research phase. This paper mainly presents the clinical pharmacology study of six siRNA drugs, that have been approved by the U.S. Food and Drug Administration, from the pharmacokinetic characteristics, drug-drug interactions, the special population with liver or kidney dysfunction, immunogenicity and cardiac safety etc. By the comprehensive overview of the early clinical pharmacology evaluation method of siRNA drugs, we hope to provide references for the design of early clinical trials and the translation of clinical research of siRNA drugs.
Neuroinflammation, neuronal damage, and signal fragmentation between neurons make cognitive dysfunction is the main pathological basis of Alzheimer’s disease (AD). It is characterized by significant cognitive and sensory impairment caused by irreversible progressive neurological dysfunction. It is unclear how molecular changes associated with AD affect information processing in neuronal circuits and translate into cognitive dysfunction. c-Jun N-terminal kinase (JNK) plays a key regulatory role in the AD process. In this paper, we review the pathological process of AD research progress of JNK-targeted inhibitory drugs to provide a basis for the treatment of AD diseases and the development and application of targeted drugs.
Bone is the main target organ for malignant tumor metastasis, but there is still a lack of effective early diagnosis and treatment methods in clinical practice. Therefore, bone metastasis has become an important cause of death in patients with malignant tumors. Bone metastasis often causes a series of bone related events (SREs) such as pathological fractures, spinal cord compression, bone pain, and bone radiation therapy, seriously affecting the quality of life of patients. Based on previous researches and combined with domestic and foreign literatures. This review aims to elucidate the mechanism of bone microenvironment formation and escape, colonization, dormancy, reactivation, and proliferation in six stages. And summarize the latest research progress on the intervention of traditional Chinese medicine monomers and formulas in the process of tumor bone metastasis, clarify whether there is a synergistic effect of integrated traditional Chinese and Western medicine treatment on bone metastasis, in order to provide new ideas and medication basis for the in-depth study of the pathogenesis and drug treatment of tumor bone metastasis, aiming to further illustrate the advantages of multi-target treatment of traditional Chinese medicine and its important role in the treatment of tumor bone metastasis, and improve the efficacy of bone metastasis.
Citrus aurantium L. belongs to the homologous resource of medicine and food, and has a wide application prospect in the field of modern functional food and Chinese herbal pieces. At present, the research is mainly carried out on the immature fruits of Citrus aurantium L., but the development of mature fruits is limited. Citrus aurantium L. mainly contains secondary metabolic components such as flavonoids, alkaloids, limonoids, and volatile oils, which are used for unique biological activities and pharmacological effects. With a comprehensive overview of the anti-obesity, anti-tumor and anti-anxiety mechanisms of Citrus aurantium L. and its active components, the gastrointestinal regulation, antioxidant, antibacterial and insecticide-related activities of Citrus aurantium L. extract, and the clinical application of Citrus aurantium L. essential oil in anti-anxiety, reveals its potential medicinal and edible value, and points out the shortcomings of its research and future research directions, in order to provide theoretical basis for further development and utilization of ripe fruit resources of Citrus aurantium L.
To observe the clinical efficacy and safety of evolocumab injection combined with rosuvastatin tablets in the treatment of patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI).
The AMI patients were randomly divided into control group and treatment group. The control group was given oral rosuvastatin at an initial dose of 10 mg daily, if the level of low-density lipoprotein cholesterol (LDL-C) >1.4 mmol·L-1, the dose was increased to 20 mg daily. On the basis of control group, the treatment group received evolocumab 140 mg, subcutaneous injection of the abdomen, once every 2 weeks. Two groups were treated for 6 months. The clinical efficacy, myocardial injury markers, lipid metabolism parameters, overall incidence of cardiovascular events and safety were compared between two groups.
Treatment group were enrolled 55 cases, 2 cases dropped out, and 53 cases were finally included in the statistical analysis. Control group were enrolled 53 cases, 1 case dropped out, and 52 cases were finally included in the statistical analysis. After treatment, the total effective rates of treatment and control groups were 92.45% (49 cases/53 cases) and 78.85% (41 cases / 52 cases), with statistically significant difference (P<0.05). After treatment, the levels of high-sensitivity cardiac troponin were (2.02±0.61) and (2.78±0.73) ng·L-1, the levels of creatine kinase-MB were (38.90±6.47) and (50.05±6.15) U·L-1, the levels of total cholesterol were (2.27±0.15) and (3.15±0.19) mmol·L-1, the levels of triglycerides were (1.61±0.12) and (1.77±0.17) mmol·L-1, the levels of LDL-C were (1.25±0.15) and (2.08±0.13) mmol·L-1, the overall incidences of cardiovascular events were 5.77% and 16.98%, respectively. The differences of above indexes were statistically significant (all P<0.05). The adverse drug reactions of treatment group were skin rash, elevated creatine kinase and liver injury, while those in the control group were nausea and vomiting, skin rash and liver injury. The total incidences of adverse drug reactions in treatment and control groups were 9.43% and 5.77%, without statistically significant difference (P>0.05).
Evolocumab injection combined with rosuvastatin tablets has a definitive clinical efficacy in the treatment of patients with AMI after PCI, which can significantly improve cardiac function, reduce the risk of myocardial injury and cardiovascular events, with good safety.
To observe the clinical efficacy and safety of omalizumab injection combined with salmeterol ticasone inhalation powder in the treatment of patients with chest tightness variant asthma (CTVA).
Patients with CTVA were randomly divided into treatment group and control group. Patients in the control group were given salmeterol ticasone inhalation powder one puff each time, twice a day. Treatment group was given subcutaneous injection of omalizumab injection on the basis of control group, 150-600 mg per time according to symptoms, once every 4 weeks, continuous treatment for 12 weeks. Clinical efficacy, improvement of symptoms, airway resistance and lung function and safety were compared between the two groups.
A total of 10 cases dropped out during the trial, and 49 cases and 48 cases were included in the final control group and treatment group, respectively. After treatment, the total effective rates of the control group and treatment group were 79.59% (39 cases/49 cases) and 93.75% (45 cases/48 cases), respectively, with statistical significance (P<0.05). After treatment, the daytime cough scores of the control group and the treatment group were (0.51±0.17) and (0.42±0.13) score, the nighttime cough scores were (0.72±0.20) and (0.54±0.18) score, and the chest tightness scores were (0.44±0.12) and (0.37±0.09) score, forced expiratory volume in one second was (2.44±0.33) and (2.60±0.37) L, peak expiratory flow rates were (4.72±0.45) and (4.95±0.39) L·s-1, total airway resistance measured value/predicted values were 126.34±10.77 and 121.94±9.28, central airway resistance measured value/predicted values were 86.47±6.20 and 82.16±7.33, and the differences were statistically significant (all P<0.05). The adverse drug reactions in the treatment group mainly included mild oropharyngeal edema, headache, swelling at the injection site, and epigastric pain, while those in the control group mainly included mild oropharyngeal edema, subjective palpitation, and headache. The total incidences of adverse drug reactions in the treatment group and the control group were 10.42% (5 cases/48 cases) and 8.16% (4 cases/49 cases), respectively. There was no statistically significant difference (P>0.05).
Omalizumab injection combined with salmeterol ticasone inhalation powder is more effective than monotherapy in the treatment of patients with CTVA, without increasing the incidences of adverse drug reactions.
To observe the clinical efficacy and safety of ropivacaine for erector spinae plane block (ESPB) combined with total intravenous anesthesia (TIVA) in patients undergoing colorectal cancer surgery.
Patients with colorectal cancer were randomly divided into treatment and control groups. Before the general anesthesia induction, treatment group received deep injection of 0.375% ropivacaine solution (25 mL) for local anesthesia in the erector spinae plane. Two groups received anesthesia induction with 0.05 mg·kg-1 midazolam + 0.4 μg·kg-1 sufentanil + 1.5 mg·kg-1 propofol + 0.15 mg·kg-1 cisatracurium, and anesthesia maintenance with 3-4 mg·L-1 propofol + 0.5-1.0 μg·kg-1 sufentanil + 0.05-0.10 mg·kg-1 cisatracurium. The sufentanil dosage, hemodynamics, visual analogue scale (VAS) and Ramsay sedation scores, interleukin (IL)-6 and cortisol levels and safety were compared between two groups.
Treatment group were enrolled 57 cases, 5 cases dropped out, and 52 cases were finally included in the statistical analysis. Control group were enrolled 55 cases, 3 cases dropped out, and 52 cases were finally included in the statistical analysis. At extubation, heart rates of treatment and control groups were (89.54±5.41) and (101.98±8.58) beat·min-1, mean arterial pressures were (83.60±7.48) and (93.12±7.35) mmHg, and the differences were statistically significant (all P<0.05). Intraoperative sufentanil dosages of treatment and control groups were (16.35±2.54) and (23.77±3.02) μg, VAS scores at 24 h after operation were (2.98±0.42) and (3.67±0.58) points, IL-6 levels at 24 h after operation were (17.92±2.41) and (28.12±3.81) ng·L-1, cortisol levels at 24 h after operation were (154.88±24.06) and (187.46±27.51) ng·mL-1, respectively; the differences were statistically significant (all P<0.05). Ramsay scores at 1 and 24 h postoperatively showed no statistically significant differences between and within groups (all P>0.05). The adverse drug reactions of treatment group were block site hematoma, nausea and vomiting, while those in control group were nausea and vomiting, hypotension and delirium. The incidences of total adverse drug reactions in the treatment and control groups were 11.54% and 21.15%, without significant difference (P>0.05).
Ropivacaine ESPB combined with TIVA can help the patients undergoing colorectal cancer surgery to maintain stable intraoperative hemodynamics, reduce sufentanil consumption and pain, decrease postoperative inflammatory and stress responses, without increasing the incidence of adverse drug reactions.
To explore the mechanism of regulating reactive oxygen species (ROS)/Nod-like receptor family pyrin domain-contain-ning protein 3 (NLRP3) by Tilianin liposomes improved macrophage pyroptosis.
Macrophage pyroptosis model using lipopolysaccharide (LPS) combined with adenosine triphosphate (ATP) was established. They were divided into control group, model group, and experimental group (RAW 264.7 macrophages). The experimental group was treated with 5 μg·mL-1 Tilianin liposomes for 12 hours, while the control group and model group were cultured normally in complete culture medium without medication for 12 hours. Microplate method was used to detect the release of lactate dehydrogenase (LDH). Enzyme linked immunosorbent assay was used to detect the contents of interleukin (IL)-1β and IL-18. Detection of ROS content in cells was done by flow cytometry. Western blotting was used to detect the relative expression levels of NLRP3.
The LDH release levels in the experimental, control and model groups were (568.54±68.04), (556.05±83.31) and (984.41±138.82) U·L-1; the IL-1β contents were (8.99±2.17), (5.51±0.49) and (38.78±3.33) pg·mL-1; the IL-18 contents were (35.95±5.24), (20.95±2.36) and (64.14±9.73) pg·mL-1; the ROS release levels were 4.00±0.48, 0.68±0.50 and 9.58±0.42; the relative expression levels of NLRP3 protein were 2.44±0.46, 1.00±0.10 and 4.76±0.61, respectively. The above indicators in the experimental and control groups were compared with those in the model group, and there were statistically significant differences (all P<0.01).
Tilianin liposomes can reduce endogenous ROS production and improve LPS/ATP induced RAW 264.7 macrophage pyroptosis, which may be related to the regulation of ROS/NLRP3 inflammasome signaling pathway.
To investigate the effects of long non-coding RNA (lncRNA) MAGI1-IT1 on the proliferation, invasion, migration and epithelial mesenchymal transformation (EMT) of breast cancer cells by regulating the miR-485-5p/actin gamma 1 (ACTG1) axis.
HCC1937 cells were cultured in vitro and randomly divided into control, si-MAGI1-IT1, miR-485-5p mimics, negative cotransfection and positive cotransfection groups. Control group was cultured normally without transfection; si-MAGI1-IT1 group was transfected with si-MAGI1-IT1; miR-485-5p mimics group was transfected with miR-485-5p mimics; negative cotransfection group was transfected with si-NC and NC-miR-485-5p; positive cotransfection group was given si-MAGI1-IT1 and miR-485-5p inhibitor combined transfection. Cell proliferation was detected by cell counting kit-8 method, cell migration was detected by cell scratch assay, cell invasion was detected by Transwell assay, and expression levels of lncRNA MAGI1-IT1, miR-485-5p and ACTG1 were detected by real-time fluorescence quantitative polymerase chain reaction method. The expression of proliferation and EMT-related proteins were detected by immunohistochemical staining.
The cell activities (optical density) of the control, si-MAGI1-IT1, miR-485-5p mimics, negative cotransfection and positive cotransfection groups were 0.89±0.12, 0.36±0.05, 0.32±0.03, 0.89±0.10 and 0.85±0.11; the migration rates were (91.82±11.13)%, (38.40±7.64)%, (33.17±6.03)%, (92.43±10.87)% and (86.10±10.76)%; the number of invasions was 296.50±23.48, 93.00±17.36, 76.50±15.01, 302.50±25.32 and 269.00±24.92; the relative expression levels of lncRNA MAGI1-IT1 were 0.98±0.11, 0.29±0.06, 0.96±0.10, 1.00±0.12 and 0.30±0.07; the relative expression levels of miR-485-5p were 0.99±0.13, 2.12±0.16, 2.20±0.18, 0.98±0.15 and 1.04±0.16; the relative expression levels of ACTG1 were 1.01±0.12, 0.34±0.05, 0.31±0.07, 1.02±0.14 and 0.97±0.11; the positive expression levels of proliferating cell nuclear antigen (optical density) were 1.65±0.16, 0.53±0.12, 0.45±0.08, 1.64±0.14 and 1.60±0.17; the positive expression levels of Cyclin D1 (optical density) were 1.53±0.15, 0.46±0.11, 0.40±0.06, 1.52±0.14 and 1.48±0.13; the positive expression levels of Vimentin (optical density) were 1.49±0.14, 0.45±0.07, 0.39±0.06, 1.50±0.12 and 1.45±0.13, respectively. The above indexes in the si-MAGI1-IT1 group were compared with the control group, the above indexes in the miR-485-5p mimics group (except lncRNA MAGI1-IT1) were compared with the control group, the above indexes in the positive cotransfection group (except lncRNA MAGI1-IT1) were compared with the si-MAGI1-IT1 group, the differences were statistically significant (all P<0.05).
Knockdown of lncRNA MAGI1-IT1 can reduce the expression of ACTG1 by up-regulating miR-485-5p, thereby inhibiting the proliferation, migration, invasion and EMT of breast cancer cells.
To investigate the effect of pyrotinib on ferroptosis in gastric cancer cells through the regulation of the tumor protein 53 (p53)/solute carrier family 7 member 11 (SLC7A11) axis by the long noncoding RNA small nucleolar RNA host gene 16 (LncRNA SNHG16).
Human gastric cancer cells (NCI-N87) were selected and divided into NCI-N87 group (NCI-N87 cells were cultured normally without treatment), experimental group (NCI-N87 cells treated with 0.5 μmol·L-1 pyrotinib for 72 h), and oe-NC group (based on the transfection of oe-NC in experimental group), LncRNA SNHG16 group (based on experimental group transfected with oe-LncRNA SNHG16). Real-time fluorescence quantitative polymerase chain reaction and fluorescence in situ hybridisation were used to determine the expression level of LncRNA SNHG16, cell viability was detected by cell counting kit-8; invasive ability was detected by Transwell assay; reactive oxygen species (ROS) fluorescence level was detected by fluorescent probe staining of dihydroethidium (DHE); malondialdehyde (MDA) level and glutathione (GSH) activity were detected by kits; and the expression level of p53 and SLC7A11 protein was detected by Western blot.
The relative expression levels of LncRNA SNHG16 in the NCI-N87 group, the experimental group, the oe-NC group and the LncRNA SNHG16 group were 1.00±0.18, 0.39±0.06, 0.41±0.07 and 0.80±0.15, respectively; the relative fluorescence intensities of LncRNA SNHG16 were 1.00±0.16, 0.27±0.05, 0.23±0.04 and 0.81±0.17, respectively; the number of cell invasion was (82.16±14.67), (29.03±4.75), (31.82±5.69) and (74.98±11.34) pieces, respectively; the relative fluorescence levels of ROS were 1.00±0.15, 4.57±0.86, 3.95±0.61 and 1.54±0.33, respectively; MDA levels were (5.49±1.08), (11.27±1.93), (10.85±1.64) and (6.73±0.95) μmol·mg-1, respectively; GSH relative activities were 1.00±0.00, 0.54±0.09, 0.56±0.07 and 0.83±0.14, respectively; the relative expression levels of p53 protein were 1.00±0.17, 2.26±0.38, 1.98±0.32 and 1.24±0.19, respectively; the relative expression levels of SLC7A11 protein were 1.00±0.13, 0.34±0.05, 0.41±0.09 and 0.79±0.11, respectively. The differences in the above indicators between the NCI-N87 group and the experimental group, as well as between the oe-NC group and the LncRNA SNHG16 group, were all statistically significant (P<0.001).
Pyrotinib can regulate the p53/SLC7A11 signaling pathway by inhibiting the expression of LncRNA SNHG16 to induce ferroptosis of gastric cancer cells and inhibit the proliferation and invasion of gastric cancer cells.