ArchiveTo investigate the association between CAPN10 rs3792269 and SLC47A2 rs12943590 gene polymorphisms and the efficacy of metformin in type 2 diabetes mellitus (T2DM) patients receiving metformin monotherapy in Xinjiang, providing references for individualized drug therapy in local patients.
A total of 450 T2DM patients who had been regularly taking metformin monotherapy for ≥3 months from July 2024 to July 2025 in a tertiary hospital in Xinjiang were selected. Clinical data were collected and target locus genotypes were detected. Using glycated hemoglobin (HbA1c%) as the efficacy indicator, patients were divided into wild-type homozygous and mutant genotype groups. Propensity score matching (PSM) was employed to analyze the association between gene polymorphisms and efficacy, followed by post hoc power analysis.
The PSM analysis revealed that the CAPN10 rs3792269 A>G variant was an independent protective factor for good glycemic control (PSM-adjusted OR=0.478, 95%CI 0.266-0.862, P<0.05). In contrast, the SLC47A2 rs12943590 polymorphism showed no significant association with treatment efficacy. For the CAPN10 rs3792269 locus, the absolute difference in glycemic control rates between the two groups was 17.3%, with OR=2.10 and statistical power of approximately 90%. For the SLC47A2 rs12943590 locus, the absolute difference was 2.5%, with OR=0.91 and statistical power of only 7%.
This study clarifies that the CAPN10 rs3792269 A>G variant is significantly associated with improved efficacy of metformin in the Xinjiang population of China, while the SLC47A2 rs12943590 locus shows no association in this sample. The influence of genetic factors on metformin efficacy exhibits population heterogeneity. The sample size in this study provids sufficient power for detecting moderate to large effects, which may serve as a reference for individualized medication and blood glucose management in local patients.
To explore changes in serum diamine oxidase (DAO) levels and their clinical significance in patients with gastrointestinal toxicity induced by fluorouracil antineoplastic drugs.
Patients with gastrointestinal tumors receiving fluorouracil-based antineoplastic therapy were divided into treatment group and control group according to whether gastrointestinal toxicity occurred during chemotherapy. The treatment group was further subdivided into ≤grade Ⅱ group and grade Ⅲ group based on the severity of gastrointestinal toxicity. General clinical data were collected, and serum DAO levels before chemotherapy and 7 days after chemotherapy were compared between treatment and control groups, as well as among patients with different grades of gastrointestinal toxicity. Logistic regression model was used to analyze the relationship between DAO levels and gastrointestinal toxicity, and receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive value of serum DAO levels 7 days after chemotherapy for the occurrence of gastrointestinal toxicity.
A total of 50 patients were ultimately included as study subjects, with 26 in treatment group and 24 in control group. The serum DAO levels 7 days after chemotherapy were (14.71±3.44) and (10.89±3.67) U·L-1 in treatment and control groups, respectively. The serum DAO level in treatment group was significantly higher than that in control group 7 days after chemotherapy (P<0.05). The serum DAO levels 7 days after chemotherapy in ≤grade Ⅱ subgroup and grade Ⅲ subgroup were (13.38±3.06) and (16.37±3.25) U·L-1, respectively. The serum DAO level in the ≤grade Ⅱ subgroup was significantly lower than that in the grade Ⅲ subgroup (P<0.05). Multivariate logistic regression analysis indicated that the serum DAO level 7 days after chemotherapy was an influencing factor for the occurrence of gastrointestinal toxicity in patients (P<0.001). ROC curve analysis showed that the optimal threshold for serum DAO in predicting gastrointestinal toxicity after chemotherapy was 11.92 U·L-1, with an area under the curve (AUC) of 0.79 (P<0.05). The sensitivity and specificity were 77.78% and 86.96%, respectively.
Chemotherapy with fluorouracil-based antineoplastic drugs can lead to elevated serum DAO levels in patients with gastrointestinal tumors. The serum DAO level is associated with the severity of gastrointestinal toxicity and the grade of adverse drug reactions, and may serve as a predictive indicator for the occurrence of gastrointestinal toxicity following chemotherapy.
To observe the clinical efficacy and safety of trifluridine-tipiracil hydrochloride tablets combined with tislelizumab injection and fruquintinib capsules in advanced colorectal cancer patients after progression in second-line treatment.
Advanced colorectal cancer patients who had progression after second-line treatment were divided into the control group and the treatment group according to the treatment methods. The control group received tislelizumab injection 200 mg combined with fruquintinib capsules 5 mg, and the treatment group received 25 mg·m2 trifluridine-tipiracil hydrochloride tablets combined with tislelizumab injection and fruquintinib capsules. A 21-day period was considered as one cycle, and both groups were treated continuously for 3 cycles. Clinical efficacy, tumor marker levels, angiogenesis factor levels, safety evaluation and survival were compared between the two groups.
This study enrolled 86 patients in total. The control group consisted of 45 patients, while the treatment group had 41 patients. After treatment, the disease control rates of the control group and the treatment group were 48.89% (22 cases/45 cases) and 73.17% (30 cases/41 cases), respectively; the levels of carbohydrate antigen 125 were (51.97±6.49) and (48.17±4.55) U·mL-1, respectively; the levels of cytokeratin 19 fragment antigen 21-1 were (24.41±4.54) and (21.53±3.56) μg·L-1, respectively; the levels of carcinoembryonic antigen were (30.84±6.42) and (27.76±4.44) ng·mL-1, respectively; the levels of vascular endothelial growth factor (VEGF) were (97.82±16.74) and (90.29±16.74) pg·mL-1, respectively; the levels of angiopoietin (Ang)-1 were (11 829.14±1 367.27) and (12 612.20±1 889.47) pg·mL-1, respectively; the levels of Ang-2 were (486.90±113.66) and (430.59±76.93) pg·mL-1, respectively; the levels of interleukin (IL)-8 were (10.54±2.39) and (9.05±1.85) pg·mL-1, respectively; and the median progression free survival periods were 11 and 16 months, respectively. The above indicators of the treatment group were statistically significant different compared with the control group (all P<0.05). The main adverse drug reactions in the treatment group and the control group were nausea and vomiting, leukopenia, anemia, thrombocytopenia, hematochezia, elevated alanine aminotransferase, hand-foot syndrome, hypothyroidism, oral mucositis, hypertension and proteinuria. There was no statistically significant difference in the incidence of adverse drug reactions between the treatment group and the control group (P>0.05).
Trifluridine-tipiracil hydrochloride tablets combined with tislelizumab injection and fruquintinib capsules can significantly improve the clinical efficacy in patients with advanced colorectal cancer who progressed after second-line treatment, prolong progression-free survival, reduce angiogenesis factor levels, and have a certain degree of safety.
To observe the clinical efficacy and safety of anlotinib hydrochloride capsules combined with standard chemotherapy (cisplatin for injection+paclitaxel injection) in the treatment of patients with recurrent and metastatic cervical cancer.
The patients with recurrent and metastatic cervical cancer were divided into treatment group and control group according to the treatment methods. In control group, paclitaxel injection (175 mg·m-2, infused within 3 hours) and cisplatin for injection (infusion time≥1 h) were intravenously infused. In treatment group, based on the treatment in control group, anlotinib hydrochloride capsules (12 mg qd) were orally administered. Both groups were continuously treated for 4 courses. The clinical efficacy, tumor marker levels, tumor angiogenesis-related indicators, quality of life, short-term prognosis of the two groups were compared, and the safety was evaluated.
The patients (n=125) were divided into control group (n=64) and treatment group (n=61). After treatment, the disease control rate (DCR) was 67.19% (43 cases/64 cases) in control group and 83.61% (51 cases /61 cases) in treatment group; the objective response rate (ORR) were 23.44% (15 cases /64 cases) and 40.98% (25 cases /61 cases), respectively; the median progression-free survival (PFS) were 6.40 and 11.31 months, respectively; and the median overall survival (OS) were 10.22 and 16.13 months, respectively. All the aforementioned indicators in treatment group were statistically significantly different from those in control group (all P<0.05). After treatment, the squamous cell carcinoma antigen levels in control group and treatment group were (2.80±0.53) and (2.56±0.47) ng·mL-1, respectively; the carcinoembryonic antigen levels were (3.09±0.62) and (2.85±0.45) μg·L-1, respectively; the carbohydrate antigen 19-9 levels were (21.08±3.04) and (19.59±2.72) U·mL-1, respectively; the cytokeratin 19 fragment antigen 21-1 levels were (26.09±3.44) and (24.63±3.01) μg·L-1, respectively; the vascular endothelial growth factor receptor levels were (461.93±97.86) and (415.74±101.87) pg·mL-1, respectively; the platelet-derived growth factor receptor levels were (69.68±12.15) and (64.87±11.39) pg·mL-1, respectively; the physiological condition scores were (18.66±4.04) and (21.49±4.15) points, respectively; the social/family situation scores were (17.16±4.03) and (19.57 ± 4.15) points, respectively; the functional status scores were (14.64±2.99) and (16.36±3.81) points, respectively; and the emotional state scores were (16.89±3.32) and (18.46±5.19) points, respectively. All the above-mentioned indicators in treatment group had statistically significant differences from those in control group (all P<0.05). No statistical significant difference in adverse drug reactions was observed between the two groups (P>0.05).
Anlotinib combined with the standard chemotherapy regimen has a remarkable efficacy in treating patients with recurrent and metastatic cervical cancer. It can reduce the levels of tumor markers in patients, inhibit tumor angiogenesis, improve their quality of life and short-term prognosis, and is highly safe.
To observe the clinical efficacy and safety of quilu tablets combined with lithium carbonate tablets and modified electroconvulsive therapy (MECT) in the treatment of bipolar disorder.
Patients with bipolar disorder were divided into control group and treatment group, both receiving routine treatment. The control group received MECT in addition to conventional treatment, with 3 sessions per week, administered every other day, totaling 12 treatments. During the treatment period, the patient was prescribed sustained-release lithium carbonate tablets with an initial dose of 0.25 g·d-1, administered in 1-2 divided doses. Serum lithium levels were monitored weekly, maintained within the therapeutic range of 0.8-1.2 mmol·L-1, and the medication was continued for a total of 6 weeks. The treatment group took quetiapine fumarate tablets orally after meals based on control group. The total doses for the first 4 days were 50, 100, 20 and 300 mg, respectively, taken in 2 doses. After the 4th day, the dose gradually increased to 300-450 mg·d-1, and the dose was adjusted according to the patient’s clinical response and tolerance. The intake was controlled at 150-750 mg·d-1, and the medication was shared for 6 weeks. Clinical efficacy, serological testing, depression and mania severity, cognitive ability, social function and occurrence of adverse drug reactions were compared between the two groups.
A total of 136 cases were screened in this study. Among them, 22 did not meet the inclusion and exclusion criteria, leaving 114 eligible for the study. They were divided into treatment group and control group, each comprising 57 cases. Six cases in control group were excluded due to personal reasons and loss to follow-up, while two cases in treatment group were excluded due to adverse drug reactions and loss to follow-up. Ultimately, 51 and 55 cases were included in control and treatment groups, respectively. After 6 weeks of treatment, the overall response rates were 72.55% (37 cases/51 cases) and 89.09% (49 cases /55 cases) in control and treatment groups; thyroid-stimulating hormone (TSH) levels were (2.72±0.42) and (2.90±0.44) μIU·mL-1, respectively; prolactin (PR) levels were (13.58±2.40) and (15.27±2.56) ng·mL-1, respectively; Hamilton depression scale -17 (HAMD-17) scores were (9.53±1.79) and (8.76±1.67) score, respectively; Bech - Rafaelsen mania rating scale (BRMS) scores were (7.04±1.39) and (6.47±1.35) score, respectively; Hopkins verbal learning test-revised (HVLT-R) scores were (26.94±4.85) and (29.76±3.81) score, respectively; continuous performance test (CPT) scores were (0.79±0.12) and (0.84±0.10) score, respectively; and social dysfunction screening scale (SDSS) scores were (6.92±1.18) and (6.38±0.99) score, respectively. All these indicators in treatment group showed statistically significant differences compared to control group (all P<0.05). During treatment, the main adverse drug reactions in treatment group were drowsiness, dry mouth, dizziness and orthostatic hypotension; while those in control group were nausea, drowsiness, dry mouth and constipation. The overall incidence of adverse drug reactions were 11.76% (6 cases/51 cases) and 7.27% (4 cases /55 cases) in control and treatment groups, respectively, with no statistically significant difference (P>0.05).
Quetiapine tablets combined with lithium carbonate tablets and MECT are more effective than using only lithium carbonate tablets and MECT in treating bipolar disorder, and the safety is good.
To explore the effects of apple polyphenols (AP) on lung function and immune imbalance in rats with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) by adjusting the miR-21-5p/SKP2 pathway.
The stable stage of COPD was established by cigarette smoking and endotoxin infusion, and then AECOPD rats were established by nasal infusion of Staphylococcus aureus bacterial solution. They were randomly assigned into the AECOPD group, the AP-25 group, the AP-100 group, the dexamethasone group, the AP-100+NC agomir group, and the AP-100+miR-21-5p agomir group. And rats intervened with normal saline were as the control group. Subsequently, tracheal intubation was performed to measure the peak expiratory and inspiratory flow rates (PEF, PIF), and the ratio of forced expiratory volume to forced vital capacity in 0.3 seconds (FEV0.3/FVC). Serum was collected to measure the levels of tumor necrosis factor -α (TNF-α) and interleukin-6 (IL-6). Bronchoalveolar lavage fluid (BALF) was recovered, and the numbers of neutrophils, lymphocytes and macrophages were determined. Left lung lobe sections were prepared, and lung tissue lesions and scores were observed. The right lung tissue of rats was taken. The proportions of Th17 and Treg cells, the mRNA expression of miR-21-5p and SKP2, and the protein expression of retinoic acid-related orphan receptor γt (RORγt), IL-17A, forkhead box protein P3 (Foxp3), IL-10 and SKP2 in the lung tissue were detected.
The AECOPD group had higher RORγt, IL-17A, miR-21-5p, TNF-α, IL-6, macrophages, neutrophils, lymphocytes, Th17 cell proportion, and Th17/Treg than the control group, and had lower Foxp3, IL-10, SKP2 mRNA and protein expression, Treg cell proportion, PEF, PIF, and FEV0.3/FVC than the control group (P<0.05). The AP-25 group, AP-100 group and dexamethasone group had lower RORγt, IL-17A, miR-21-5p, TNF-α, IL-6, macrophages, neutrophils, lymphocytes, Th17 cell proportion, and Th17/Treg than the AECOPD group, and had higher Foxp3, IL-10, SKP2 mRNA and protein expression, Treg cell proportion, PEF, PIF, and FEV0.3/FVC than the AECOPD group (P<0.05). In addition, miR-21-5p agomir reversed the protective effect of AP on AECOPD rats.
AP improves lung function and immune imbalance in AECOPD rats by inhibiting the miR-21-5p/SKP2 pathway.
To investigate the promoting effect and mechanism of hyperoside (Hyp) on wound healing in diabetic foot ulcer (DFU) rats by inhibiting the nuclear factor-kappa B (NF-κB) pathway and the Nod-like receptor family Pyrin domain-containing 3 (NLRP3) inflammasome.
A total of 50 SD rats were randomly divided into blank group, model group, metformin group, low-dose experimental group and high-dose experimental group, with 10 rats in each group. Fasting blood glucose (FBG), wound healing rate and transcutaneous oxygen partial pressure (TcpO2) in the tissues surrounding the wounds were measured using a blood glucose meter. Pathological changes in the wound tissues were observed using hematoxylin-eosin (HE) staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum levels of interleukin (IL)-8, IL-1β, tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP). Western blotting was employed to assess the relative expression levels of matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1), NF-κB p65, phosphorylated (p)-NF-κB p65 and NLRP3 proteins.
The FBG levels in blank, model, metformin, low-dose experimental and high-dose experimental groups were (5.31±0.91), (22.52±3.18), (11.27±2.35), (13.11±2.67) and (8.76±1.15) mmol·L-1, respectively; the wound healing rates were (76.91±12.30)%, (9.53±1.01)%, (45.26±6.15)%, (39.94±5.47)% and (57.10±9.26)%, respectively; the TcpO2 values were (41.09±8.51), (24.35±4.97), (33.27±5.68), (30.84±3.26), and (37.92±4.14) mmHg, respectively; the serum levels of IL-8 were (15.34±0.39), (41.92±3.12), (26.68±2.28), (30.55±3.27) and (17.95±2.70) ng·L-1, respectively; IL-1β levels were (31.05±4.62), (64.39±7.14), (46.62±5.07), (50.21±3.92) and (39.54±4.25) ng·L-1, respectively; TNF-α levels were (26.95±4.15), (69.74±7.43), (39.85±4.29), (45.08±4.36) and (35.52±2.95) ng·L-1, respectively; and CRP levels were (0.69±0.08), (5.11±0.60), (3.23±0.58), (3.68±0.71) and (1.95±0.30) ng·L-1, respectively; the protein relative expression levels of MMP-9 were 0.23±0.03, 0.99±0.11, 0.62±0.05, 0.74±0.06 and 0.39±0.04, respectively; the MMP-9/TIMP-1 ratios were (22.56±1.23)%, (97.07±5.67)%, (60.18±5.01)%, (70.49±5.98)% and (38.39±4.15)%, respectively; the p-NF-κB p65/NF-κB p65 protein relative expression levels were 0.21±0.02, 1.23±0.10, 0.51±0.04, 0.57±0.06 and 0.33±0.04, respectively; and the NLRP3 protein relative expression levels were 0.25±0.01, 0.93±0.07, 0.72±0.08, 0.80±0.06 and 0.35±0.04, respectively. Statistically significant differences were observed when comparing the model group with the blank group and the low- and high-dose experimental groups with the model group (all P<0.05).
Hyp promotes wound healing in DFU rats by inhibiting NF-κB and NLRP3 pathways, reducing inflammation and reducing MMP-9 expression.
To investigate the effect and underlying mechanism of Sijunzi Decoction in ameliorating insulin resistance (IR) within the pancreatic islets of rats with type 2 diabetes mellitus (T2DM).
A total of 40 Sprague-Dawley (SD) rats were randomly divided into control group (n=10, fed with normal diet) and high-sugar and high-fat group [n=30, fed with high-sugar and high-fat diet coupled with intraperitoneal injection of streptozotocin (STZ) to create a type 2 diabetes mellitus (T2DM) model]. The smoothly modeled SD rats were further randomly assigned into model group, positive control group (0.003 g·mL-1) and experimental group (0.848 g·mL-1). The normal group and model group were given distilled water by gavage, while the other two groups were administered the corresponding drugs by gavage for 4 consecutive weeks. Fasting blood glucose (FBG) was measured using a blood glucose meter. Serum levels of fasting insulin (FINS), total cholesterol (TC), total triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) in rats of each group were detected with commercial assay kits. The pancreatic index (PI) was calculated based on the detection of pancreatic tissue. Reverse transcription-polymerase chain reaction (RT-PCR) was employed to determine the mRNA expression levels of related proteins, and Western blotting was performed to ascertain the formulation standards of correlated total proteins.
The FBG, FINS, TC, TG, HDL-C, LDL-C and PI in the model group and experimental group were (13.60±0.61) mmol·L-1 vs. (9.73±0.43) mmol·L-1, (15.24±0.76) mIU·L-1 vs. (12.39±1.13) mIU·L-1, (5.42±0.41) mmol·L-1 vs. (3.76±0.26) mmol·L-1, (1.49±0.26) mmol·L-1 vs. (0.65±0.05) mmol·L-1, (0.82±0.06) mmol·L-1 vs. (1.12±0.08) mmol·L-1, (4.82±0.43) mmol·L-1 vs. (3.02±0.42) mmol·L-1, and (0.27±0.09)% vs. (0.34±0.02)%, respectively. The mRNA expression levels of INSR, IRS-1, PI3K, AKT, GLUT4, GSK-3β, and FOXO1 were 0.44±0.16 vs. 0.61±0.16, 0.48±0.13 vs. 0.72±0.16, 0.62±0.30 vs. 0.84±0.12, 0.74±0.20 vs. 0.92±0.02, 0.48±0.22 vs. 0.78±0.24, 1.90±0.16 vs. 1.56±0.25, and 1.83±0.16 vs. 1.60±0.21, respectively. The total protein expression levels of INSR, IRS-1, PI3K, AKT, GLUT4, GSK-3β, and FOXO1 were 0.59±0.29 vs. 0.82±0.18, 0.65±0.28 vs. 0.72±0.16, 0.49±0.14 vs. 0.74±0.15, 0.50±0.17 vs. 0.68±0.12, 0.65±0.28 vs. 0.86±0.14, 2.73±0.19 vs. 2.50±0.22, and 1.61±0.49 vs. 1.21±0.35, respectively. Compared with the model group, all the above indicators in the experimental group showed statistically significant differences (P<0.001, P<0.01, P<0.05).
Sijunzi Decoction can improve pancreatic insulin resistance (IR) in rats with type 2 diabetes mellitus (T2DM) by regulating the expression of 7 signaling factors in the upstream, middle and downstream of the PI3K/AKT signaling pathway.
To investigate the effect of sestrin 2 (SESN2) on JS-1 cell activation through unc-51-like kinase 1 (ULK1) and its mechanism.
The JS-1 cells were divided into seven groups: the control group (cultured under normal conditions), si-NC group (transfected with si-NC), the si-SESN2 group (transfected with si-SESN2), model group (cultured in medium containing 5 μg·L-1 transforming growth factor-β1 for 24 h), model + oe-SESN2 group (transfected with oe-SESN2 on the basis of the model group), model + si-SESN2 group (transfected with si-SESN2 on the basis of the model group), and model+si-SESN2 + oe-ULK1 group (co-transfected with si-SESN2 and oe-ULK1 on the basis of the model group). The levels of fibrous actin (F-actin) was detected by immunofluorescence. Quantitative real time polymerase chain reaction was used to detect the ULK1 mRNA level. The relevtive expression levels of SESN2, light chain 3 Ⅱ/Ⅰ (LC3Ⅱ/Ⅰ), connective tissue growth factor (CTGF), collagen type I α1 (Col1a1), phospho-c-Jun N-terminal kinase (p-JNK), c-Jun N-terminal kinase (JNK), c-Jun and activating transcription factor 2 (ATF2) were detected by Western Blot. Cell proliferation rate was detected by cell counting kit-8. Transwell assesses the ability of cells to invade.
The relative expression levels of SESN2 protein in the control group, model group, model+oe-SESN2 group, and model+si-SESN2 group were 1.00±0.19, 2.57±0.49, 3.61±0.68, and 1.66±0.31, respectively; the relative fluorescence intensity of F-actin was 1.00±0.18, 4.57±0.92, 6.33±1.19, and 2.81±0.57, respectively; the relative expression levels of ULK1 mRNA were 1.00±0.15, 2.67±0.48, 3.52±0.66, and 1.95±0.37, respectively. The relative expression levels of LC3Ⅱ/Ⅰ protein in the control group, model group, model+oe-SESN2 group, model+si-SESN2 group, and model+si-SESN2+oe-ULK1 group were 1.00±0.20, 2.79±0.53, 3.57±0.68, 1.88±0.35, and 2.51±0.48, respectively; the cell proliferation rates were (100.00±2.23)%, (141.31±4.17)%, (156.52±8.84)%, (109.49±7.35)%, and (127.08±8.16)%, respectively; the number of cell invasions was 66.04±11.45, 137.84±21.73, 215.19±35.28, 75.46±13.51, and 124.27±19.50, respectively; the relative expression levels of CTGF protein were 1.00±0.17, 2.65±0.51, 3.77±0.72, 1.51±0.29, and 2.53±0.51, respectively; the relative expression levels of Col1a1 protein were 1.00±0.15, 2.93±0.57, 3.88±0.75, 1.61±0.31, and 2.72±0.52, respectively; the relative phosphorylation levels of JNK protein were 1.00±0.16, 2.21±0.42, 3.08±0.59, 1.46±0.29, and 2.04±0.37, respectively. Compared with the control group, the above indicators of the model group showed statistically significant differences; compared with the model group, the above indicators of the model+oe-SESN2 group or model+si-SESN2 group showed statistically significant differences; compared with the model+si-SESN2 group, the above indicators of the model+si-SESN2+oe-ULK1 group all showed statistically significant differences (P<0.05, P<0.01, P<0.001).
SESN2 activates ULK1, promotes JS-1 cell activation, promotes cell proliferation and invasion, and regulates cell homeostasis, possibly through the activation of JNK signaling pathway.
To evaluate the uncertainty for the determination of 10,11-dihydro-10-hydroxycarbazepine (MHD) in human plasma by ultra performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS).
An isotope-labeled internal standard was employed. Chromatographic separation was achieved within 3 min on a BEH C18 column (2.1 mm×50.0 mm, 1.7 μm) using a gradient elution at a flow rate of 0.4 mL·min-1, with a mobile phase consisting of methanol containing 0.1% formic acid and water containing 5% methanol plus 0.1% formic acid. Plasma sample concentrations were determined by UHPLC-MS/MS with electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. The method was validated for selectivity, calibration curve, lower limit of quantification, precision, recovery, matrix effect, and stability. The influencing factors in the quantification of MHD were analyzed and evaluated to calculate the individual uncertainties, combined uncertainty, and finally the expanded uncertainty.
MHD demonstrated good linearity within the range of 0.03 to 6.00 mg·L-1. The accuracy (bias from the theoretical concentration) for within-run and between-run analyses was within ±15%, and the precision (coefficient of variation) was within 13.32%. Plasma samples showed good stability under the following conditions: 9 hours at 25 ℃, 5 hours at 4 ℃, three freeze-thaw cycles, and storage at -80 ℃ for 18 days. Based on the calculated uncertainty values for each contributing factor, repeatability, matrix effect, and recovery represented the major sources of uncertainty for the low-concentration quality control (QC) sample, with values of 1.96×10-2, 5.49×10-2, and 7.25×10-2, respectively. For the high-concentration QC sample, matrix effect and recovery contributed substantially to the overall uncertainty, with values of 4.92×10-2 and 2.01×10-2, respectively. The expanded uncertainties (P=95%, k=2) for MHD at low (0.09 mg·L-1) and high (4.50 mg·L-1) concentrations in human plasma were 1.62×102 mg·L-1 and 0.48 mg·L-1, respectively.
The measurement uncertainty of MHD concentration in human plasma determined by UHPLC-MS/MS is primarily contributed by repeatability, matrix effect and recovery at low concentration levels, while dominated by matrix effect and recovery at high concentrations
The ICH S1B(R1) guideline addendum, adopted by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) in August 2022, introduces a comprehensive Weight of Evidence (WoE)-based approach into the traditional framework for drug carcinogenicity risk assessment. This method aims to conduct an integrated analysis by incorporating multiple key factors to evaluate whether the two-year rat carcinogenicity study can provide additional valuable information for human carcinogenicity risk assessment. Consequently, under certain circumstances, the two-year rat carcinogenicity study may be waived, allowing resources to be focused on more scientific, mechanism-based carcinogenicity assessments. This transformation is grounded in scientific advances since the release of ICH S1B in 1997, retrospective analyses of drug databases, and an international prospective study, confirming that the WoE approach can adequately assess risks in specific contexts and aligns with the 3R principles (Replacement, Reduction, Refinement) aimed at reducing animal use. The addendum emphasizes a systematic evaluation of factors such as target biology, secondary pharmacology, histopathology from long-term toxicity studies, hormonal effects, genotoxicity, and immunomodulation, encouraging a mechanism-driven risk assessment strategy. However, its implementation faces scientific and procedural challenges, and there may be disagreements between regulatory authorities and applicants regarding WoE conclusions. Promoting practical application requires early communication, standardized documentation submission, and international experience sharing. Although current implementation experience is limited and both regulators and industry remain cautious, coordinated efforts by the ICH Implementation Working Group (IWG) and accumulating case studies are expected to advance WoE-based carcinogenicity assessment, optimize drug development processes, reduce unnecessary animal testing, and foster the safe and ethical development of innovative drugs.
The global prevalence and incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) are steadily increasing, with the situation being particularly pronounced in China. Currently, MASLD has become the most common form of chronic liver disease in the country, posing a serious threat to public health. The pathogenesis of MASLD is highly complex, involving multiple contributing factors, which presents significant challenges for researchers exploring treatment strategies. This article provides a comprehensive review of MASLD, with a focus on elucidating its pathogenesis and current advances in therapeutic research, aiming to offer valuable insights for future studies and contribute to addressing this serious health challenge.
Myocardial injury is frequently associated with an exacerbated cardiac-specific inflammatory response, leading to an imbalance in immune micro environment homeostasis. T cells and macrophages recruited to the site of injury constitute the primary components of inflammatory infiltration. Both the polarization status of macrophages and the differentiation levels of inflammatory T cells exhibit plasticity, transitioning from pro-inflammatory to anti-inflammatory phenotypes during the disease course. However, under conditions of intensified inflammation and immune dysregulation, a persistent pro-inflammatory state is maintained, characterized by M1 macrophages and helper T cell 1 (Th1)/Th17/Th22 cells, along with group 3 innate lymphoid cells (ILC3s). Salidroside (SAL) exerts antioxidant, anti-inflammatory, immunomodulatory, and anti-apoptotic effects on cardiomyocytes. This review aims to analyze the mechanism by which the single molecule SAL simultaneously reprograms the crosstalk balance between the three key cellular components (macrophages-T cells-cardiomyocytes) within the inflammatory microenvironment. Furthermore, it summarizes SAL’s mechanism of alleviating myocardial immune imbalance and associated inflammatory injury. This is achieved through blockade of the signal transducer and activator of transcription 3 (STAT3)/Th17/Interleukin-22 through type 2 cytokine receptor complex(IL-22-IL-22R) pro-inflammatory axis, promotion of macrophage polarization towards an anti-inflammatory phenotype, and modulation of T cell differentiation.
Hyperuricemia (HUA) is a metabolic disorder characterized by abnormally elevated serum uric acid levels, with a rising prevalence worldwide. The potential hazards of HUA and its precise intervention strategies have emerged as a central focus in clinical medicine research. Current research indicates that HUA is closely associated with various systemic diseases, such as cardiovascular and renal diseases. Its pathogenic mechanisms involve multiple pathways, such as oxidative stress, inflammatory factor activation, and urate crystal deposition. However, the treatment of HUA patients with comorbid cardiovascular or renal diseases—particularly those with asymptomatic hyperuricemia (AH)—remains highly controversial. Existing clinical guidelines show significant regional variations, European and American guidelines favor a conservative monitoring approach, while Asian guidelines advocate for earlier intervention. Therefore, to establish the long-term clinical benefits for HUA patients, there is an urgent need for evidence-based medical support through large-scale prospective cohort studies and randomized controlled trials (RCTs). These studies will provide a more reliable foundation for standardized clinical management.
To investigate the mechanism of professor Fu Deyu’s core prescription, Danyu Hemai Granules (DYHMG), in treating hypertension using network pharmacology, and to conduct preliminary validation through molecular docking technology.
Active components and targets of Danyu Hemai Granules were screened with traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP), traditional Chinese medicine integrated database (TCMID), and HERB database. Hypertension-related targets were retrieved from GeneCards and OMIM. Intersection targets were identified, and protein-protein interaction (PPI) networks were constructed via STRING. The "Herb-Active Component-Target-Disease" network was visualized using Cytoscape to identify core targets. GO and KEGG pathway enrichment analyses were performed with Metascape. Finally, molecular docking validation was performed between key active components and core targets.
A total of 127 active ingredients and 312 targets of DYHMG, and 5 251 hypertension-related targets were identified, resulting in 229 common targets. Analysis suggested DYHMG exerts its antihypertensive effects primarily through active ingredients such as quercetin, kaempferol, luteolin, beta-sitosterol, stigmasterol, and wogonin. These ingredients acted on core targets including signal transducer and activator of transcription 3 (STAT3), RAC-alpha serine/threonine-protein kinase (AKT1), and estrogen receptor alpha (ESR1). Key pathways involved were lipid and atherosclerosis, the HIF-1 signaling pathway, insulin resistance, calcium signaling pathway, cAMP signaling pathway, MAPK signaling pathway, necroptosis, the renin-angiotensin system (RAS), and efferocytosis pathways.
Danyu Hemai Granules exhibits the characteristics of multi-component, multi-target, and multi-pathway in the treatment of hypertension. This study can provide ideas for the in-depth research on Danyu Hemai Granules in the treatment of hypertension and offer a scientific basis for its rational clinical application.
To systematically analyze the linear plasmid-related studies published from 1994 to 2023 by using bibliometric methods, and to sort out the research pattern, core forces and development context of this field.
A total of 989 linear plasmid-related literatures indexed in the Web of Science Core Collection were selected as research objects. Bibliometric analysis was carried out from the dimensions of country, institution, journal, author and keyword by using CiteSpace (a literature analysis software) and GraphPad Prism (a graphing software).
Linear plasmids were taken as the core research object. The United States and Germany together contributed 53% of the relevant literature, with the USA National Institutes of Health (NIH) ranking first in the number of publications (50 papers). Journal of Bacteriology has published 80 papers on this topic, and German scholar Meinhardt Friedhelm (16 papers) is the core author in this field. Among them,Borrelia burgdorferi is the classic research microorganism, and the research hotspots include comparative genomics, replication and horizontal transfer mechanisms, and gene regulation. In addition, the dissemination of antibacterial drug resistance genes mediated by linear plasmids and the evolution of resistant plasmids have also attracted great attention.
Over the past 30 years, research on linear plasmids has evolved from sequence analysis to functional mechanism exploration, and has continuously integrated new technologies. However, the current research still has limitations such as insufficient breadth and depth. In the future, international cooperation should be strengthened to conduct in-depth research on linear plasmids, which can provide theoretical support for the formulation of drug resistance prevention and control strategies and the development of new antibacterial drugs.
Lidocaine and Prilocaine Cream is a topical cream preparation made by a eutectic mixture of lidocaine and prilocaine in a ratio of 1∶1 by weight. Lidocaine and prilocaine are amide-type local anesthetic agents. Both lidocaine and prilocaine stabilize neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action. It is clinically used mainly for local anesthesia of the skin for punctures and superficial surgical procedures. Considering this product is a topical preparation, when evaluating its quality and efficacy consistency with the reference preparation, a stepwise comparative study be conducted based on the drug's characteristics, including pharmaceutical, nonclinical, and/or necessary clinical comparative studies, to support the equivalence evaluation of the generic drug the reference preparation. Clinical comparative studies of this product can be human bioequivalence (BE) studies with the reference preparation. In BE studies, the study type, dose and method of administration, application time, PK blood sampling, skin reaction observation, bioequivalence evaluation, and reactivity evaluation should be fully considered and reasonably designed. This article, based on the characteristics of Lidocaine and Prilocaine Cream and the BE study examples before the domestic launch of the same variety of generic drugs, systematically explores the general design requirements and related considerations for the bioequivalence study of this product.
Acetylcysteine is a commonly used clinical drug, and its free thiol group can break the disulfide bond (S-S) in the glycoprotein peptide chain in sputum, thereby reducing sputum viscosity and promoting sputum excretion. It is an endogenous substance. When conducting bioequivalence studies, it is necessary to fully consider and design aspects such as the research type, dosage, blood collection point design, bioequivalence evaluation, etc., and fully evaluate the impact of endogenous acetylcysteine on bioequivalence evaluation. This article integrates the pharmacokinetic (PK) characteristics of acetylcysteine granules along with the bioequivalence research conducted on its generic version prior to domestic marketing. Through this approach, it comprehensively explores the general design requirements and key considerations for conducting bioequivalence studies on this product.
Efgartigimod, as a novel FcRn inhibitor, can improve neuromuscular transmission in patients with generalized myasthenia gravis (gMG) by accelerating the degradation of pathogenic IgG antibodies. Although clinical trials have confirmed its efficacy and good tolerability, its safety profile in the real-world setting requires comprehensive evaluation. This study utilized data from the U.S. FDA Adverse Event Reporting System (FAERS) to investigate and assess potential adverse event (AE) signals associated with Efgartigimod. The aim was to evaluate its real-world safety characteristics and provide evidence for clinical safe medication use and risk monitoring.
Reports listing Efgartigimod as the primary suspected drug were extracted from Q1 2020 to Q4 2023. After deduplication and terminology standardization, disproportionality analysis was conducted using three methods: Reporting Odds Ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayes Geometric Mean (EBGM), to identify significant signals at both the System Organ Class (SOC) and Preferred Term (PT) levels. Important Medical Events (IMEs) were also screened.
A total of 788 individual case safety reports involving 13 551 AEs were included. At the SOC level, the strongest signals were for nervous system disorders (ROR=5.12) and neoplasms (ROR=4.78). At the PT level, multiple strong signals were identified, including myasthenic crisis (ROR=2 269.29), bulbar paralysis (ROR=275.64), and thymoma (ROR=170.02). IME analysis further confirmed these events as high-priority safety concerns.
This study identified several potential new safety signals for Efgartigimod in the neurological, oncological, and immunological domains, suggesting that clinicians should remain vigilant about adverse reactions related to these organ systems and providing a basis for further targeted safety research.
Gene therapy drugs based on adeno-associated virus (AAV) have become the most widely used viral vectors for in vivo gene therapy in clinical applications. Until July 2025, nine AAV-based gene therapy drugs have been approved globally, with many more in research or clinical trials. This article analyzes the basic characteristics, adverse reactions, and risk management strategies of AAV gene therapy drugs, aiming to provide valuable insights for risk assessment and mitigation in this field.
Decentralized clinical trials (DCT) have shown a rapid growth trend in recent years due to their advantages such as being geographically unrestricted, enhancing research efficiency, and reducing research costs. The United States has a significant development advantage in this field, with a clear concentration trend. China is still in its infancy in this area, lacking practical experience and summaries. This study takes the "Multicenter Prospective Open Randomized Controlled Clinical Study on the Early Intervention of Lianhua Qingwen Granules in Acute Pharyngitis Patients" as an example, and through the implementation of DCT digital management based on the internet platform, it sorts out and summarizes the key links in conducting DCT, explores the technical aspects and applicable fields of DCT in China, and provides practical references for accelerating the resolution of the bottlenecks in promoting DCT.
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