OBJECTIVE To investigate the effects of ertugliflozin on pharmacokinetic of sorafenib and donafenib in rats and explore the mechanism. METHODS Twenty-four male SD rats were randomly divided into four groups， with 6 rats in each group. Groups A and B were respectively gavaged with 0.5% sodium carboxymethyl cellulose solution and ertugliflozin （1.5 mg/kg） for 7 consecutive days， and both were given sorafenib （100 mg/kg） on the 7th day. Groups C and D were administered intragastrically in the same way as those in Groups A and B， respectively， for the first 7 days； after the drug administration on the 7th day， all rats in Groups C and D were further gavaged with donafenib （40 mg/kg）. Blood samples were collected at different time points before and after administration of sorafenib or donafenib， the concentrations of sorafenib in plasma of rats in groups A and B and donafenib in groups C and D were determined by UPLC-MS/MS method. The pharmacokinetic parameters were calculated by DAS 2.1.1 software. Six additional rats were randomly divided into blank control group and ertugliflozin group， with three rats in each group. Blank control group was given 0.5% sodium carboxymethyl cellulose intragastrically， while rats in ertugliflozin group were given ertugliflozin （1.5 mg/kg） once a day for 7 consecutive days. After the last administration， the mRNA expression levels of uridine diphosphate glucuronosyl transferase 1A7 （UGT1A7）， breast cancer resistance protein （BCRP）， and P-glycoprotein （P-gp） in the liver and small intestine tissues of the rats were detected. RESULTS Compared with group A， the AUC0-t， AUC0-∞， cmax， tmax， MRT0-t and MRT0-∞ of sorafenib in group B were decreased significantly， while CL and V were increased significantly. Compared with group C， the AUC0-t， AUC0-∞ ， tmax， cmax and MRT0-t of Δ donafenib in group D were decreased significantly， while V and CL were increased significantly （P＜0.05）. mRNA expression of UGT1A7， P-gp and BCRP in the liver tissue and small intestine of rats were not significantly affected after intragastric administration of ertugliflozin for 7 consecutive days. CONCLUSIONS Ertugliflozin can affect the pharmacokinetics of sorafenib and donafenib in rats and decrease the plasma exposure of them significantly. However， its mechanism of action may not be through the regulation of related metabolic enzymes and transporters. When using drugs in combination clinically， one should be vigilant about the potential for disease progression due to poor therapeutic effects.

ObjectiveTo investigate the effects of Congrong Zonggan capsules （CRZG） on cognitive impairment in the Alzheimer's disease （AD） model of mice and its related mechanisms. MethodsSPF grade 4-week-old 5×FAD mice were divided into a model group， low-dose CRZG （0.819 g·kg^-1） and high-dose CRZG （1.638 g·kg^-1） groups， and Donepezilepezil hydrochloride group （2 mg·kg^-1）， with eight mice in each group. Eight C57 mice with the same background were set as the normal group. After one week of adaptive feeding， mice were orally administered continuously for six months. On the 5th month of drug administration， Y maze， new object recognition， and Morris water maze tests were conducted separately. After administration， mouse brain tissue was taken， and the levels of tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） in brain tissue were detected by enzyme-linked immunosorbent assay （ELISA）. Immunofluorescence （IF） was used to detect the expression of small glial cell markers Iba1， astrocyte markers GFAP， and amyloid protein 1-42 （Aβ_1-42） in the hippocampus of the brain tissue. The hematoxylin-eosin （HE） staining was used to detect pathological changes in the hippocampus of brain tissue. Western blot was used to detect the expression of nuclear factor-κB （NF-κB） p65， NOD-like receptor protein 3 （NLRP3）， cleaved Caspase-1， apoptosis-associated speck-like protein containing a CARD （ASC）， and other proteins in the brain tissue. ResultsCompared with those in the normal group， the mice in the model group had obvious cognitive impairment. The spontaneous alternation rate of the Y maze was decreased， and the discrimination index of novel object recognition was decreased significantly （P<0.01）. The escape latency in the water maze was shortened significantly （P<0.01）. The contents of IL-6 and TNF-α in brain tissue were increased. The fluorescence levels of Iba1 and Aβ_1-42 in the hippocampus were significantly increased （P<0.01）. There was a significant increase in neuronal lesions， neuronal atrophy， loose arrangement of tissue structure， and abnormal erythrocyte aggregation in the hippocampus. The protein expressions of p-NF-κB p65/NF-κB p65， cleaved Caspase-1， ASC， IL-6， and IL-1β were significantly increased （P<0.05， P<0.01）. Compared with the model group， the spontaneous alternation rate and discrimination index of the high-dose CRZG group were increased significantly （P<0.01）， and the escape latency was shortened significantly （P<0.05， P<0.01）. The content of IL-6 decreased in the brain， and that of TNF-α dropped significantly （P<0.01）. The expression of Iba1 protein and Aβ_1-42 in the hippocampus decreased significantly （P<0.05， P<0.01）. The hippocampal neurons were densely arranged， and the pyramidal nuclei were clear and centered. The abnormal aggregation of red blood cells was alleviated. The value of p-NF-κB/NF-κB proteins and the expression of ASC， cleaved Caspase-1， IL-6， and IL-1β were significantly decreased （P<0.05， P<0.01）. ConclusionCRZG can effectively improve cognitive impairment in 5×FAD mice with Alzheimer's disease， and its mechanism may be related to the regulation of the NF-κB/NLRP3 pathway to reduce the abnormal activation of microglia and inhibit neuroinflammation.

Chronic atrophic gastritis （CAG）， a common digestive system disease， has an unclear pathogenesis. Currently， it is mostly believed to be related to Helicobacter pylori （Hp） infection， immune factors， dietary factors， bile reflux， long-term use of antibiotics and anti-inflammatory drugs， and other factors. Ferroptosis is a regulated cell death mechanism that is iron-dependent and characterized by disruption of iron metabolism and accumulation of lipid peroxides. More and more studies have found that ferroptosis is closely related to the onset of CAG. Professor LI Diangui， a master of traditional Chinese medicine， first proposed the turbid toxin theory， which holds that spleen deficiency and turbid toxin is the main pathogenic mechanism of CAG. Abnormal iron metabolism regulation is a prerequisite for the accumulation of turbid toxin in CAG， and ferroptosis is in accordance with the pathogenic mechanism （spleen deficiency and turbid toxin） of CAG. This article explores the pathological mechanism of spleen deficiency and turbid toxin in CAG from the perspectives of iron metabolism， oxidative stress， and lipid peroxidation， providing theoretical support of traditional Chinese medicine for the modern research on CAG. It enriches the modern scientific connotation of the turbid toxicity theory and provides new ideas and breakthrough points for the clinical treatment of CAG.

Chronic atrophic gastritis （CAG）， a common digestive system disease， has an unclear pathogenesis. Currently， it is mostly believed to be related to Helicobacter pylori （Hp） infection， immune factors， dietary factors， bile reflux， long-term use of antibiotics and anti-inflammatory drugs， and other factors. Ferroptosis is a regulated cell death mechanism that is iron-dependent and characterized by disruption of iron metabolism and accumulation of lipid peroxides. More and more studies have found that ferroptosis is closely related to the onset of CAG. Professor LI Diangui， a master of traditional Chinese medicine， first proposed the turbid toxin theory， which holds that spleen deficiency and turbid toxin is the main pathogenic mechanism of CAG. Abnormal iron metabolism regulation is a prerequisite for the accumulation of turbid toxin in CAG， and ferroptosis is in accordance with the pathogenic mechanism （spleen deficiency and turbid toxin） of CAG. This article explores the pathological mechanism of spleen deficiency and turbid toxin in CAG from the perspectives of iron metabolism， oxidative stress， and lipid peroxidation， providing theoretical support of traditional Chinese medicine for the modern research on CAG. It enriches the modern scientific connotation of the turbid toxicity theory and provides new ideas and breakthrough points for the clinical treatment of CAG.

AIM: To explore the factors affecting the whole-eye astigmatism after pterygium excision combined with autologous limbal stem cell transplantation.METHODS: A retrospective analysis was conducted on the medical records of 42 patients(42 eyes)with primary pterygium admitted in the ophthalmology department of Xijing Hospital from January 2023 to October 2023. They underwent pterygium excision combined with autologous limbal stem cell transplantation. The maximum invasion depth of pterygium into the cornea was measured with anterior segment optical coherence tomography(AS-OCT)before operation, the length of the pterygium invading cornea, the width of the limbus and the area of the invading cornea were measured during the operation, and three-dimensional values of corneal astigmatism of anterior segment, index of surface variance(ISV), index of vertical asymmetry(IVA), best corrected visual acuity(BCVA)and whole-eye astigmatism were collected before and at 1 mo after surgery. Patients with astigmatism ≤0.50 D or >0.50 D of the whole eye at 1 mo after surgery were assigned to group A and B, respectively. The differences of clinical data before and at 1 mo after surgery between the two groups, and the correlation between pre-operative clinical indicators and whole-eye astigmatism were analyzed. The decision tree algorithm was performed to explore the influencing factors of whole-eye astigmatism at 1 mo postoperatively.RESULTS: The maximum invasion depth of pterygium in the group A was significantly less than that in the group B [80.00(40.00, 180.00)μm vs 175.00(123.00, 190.00)μm, P=0.002]. Preoperative BCVA(LogMAR), whole-eye astigmatism, cornea astigmatism, ISV, IVA and maximum invasion depth of pterygium were positively correlated with whole-eye astigmatism at 1 mo after surgery(rs=0.317, P=0.041; rs=0.545, P<0.001; rs=0.448, P=0.003; rs=0.389, P=0.011; rs=0.382, P=0.013; rs=0.391, P=0.010). The decision tree algorithm screened out two influential factors: the maximum invasion depth of pterygium into the cornea and preoperative whole-eye astigmatism. The risk of whole-eye astigmatism >0.50 D at 1 mo after operation was higher with maximum invasion depth of pterygium into the cornea >95 μm than that with ≤95 μm. Among the patients with whole-eye astigmatism >2.63 D before operation, the probability of residual whole-eye astigmatism >0.50 D was 88.9%, and the predictive model AUC was 0.804.CONCLUSION: The whole-eye astigmatism after pterygium resection is mainly affected by the maximum invasion depth of pterygium into the cornea and preoperative whole-eye astigmatism. When the maximum invasion depth of pterygium into the corneal is >95 μm and the whole-eye stigmatism is >2.63 D before surgery, the patient should receive surgical treatment as soon as possible in order to obtain good clinical benefits.

ObjectiveTo explore the therapeutic effect and mechanism of Xianglian Huazhuo prescription on chronic atrophic gastritis （CAG） in rats based on the Hedgehog signaling pathway. MethodsThe CAG rat model was established by sodium salicylate， N-methyl-N′-nitro-N-nitroguanidine （MNNG）， and irregular feeding. The successfully modeled rats were randomly divided into a model group （180 mg·L^-1）， a moradan group （1.4 g·kg^-1）， and Xianglian Huazhuo Prescription groups with high， medium， and low doses （36， 9， 18 g·kg^-1）， followed by drug intervention. Hematoxylin-eosin （HE） staining was used to observe morphological changes in the gastric mucosa. Transmission electron microscopy was used to observe the ultrastructure of gastric mucosa cells. Real-time quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of Sonic Hedgehog （Shh）， Patched 1 （Ptch1）， and Glioma-associated oncogene homolog 1 （Gli1）. Western blot was used to detect the protein expression levels of Shh， Ptch1， and Gli1 in the gastric mucosa. Immunohistochemistry was used to observe the protein expression of the epithelial marker E-cadherin. ResultsCompared with the normal group， the CAG model group showed a reduction in gastric mucosal intrinsic glands and infiltration of inflammatory cells. The ultrastructure of gastric mucosal cells showed nuclear pyknosis， fewer mitochondria， and abnormal mitochondrial structure. The mRNA and protein expression of Shh， Ptch1， and Gli1 in the gastric mucosa were significantly decreased （P<0.05）， and E-cadherin protein expression was decreased. Compared with the model group， the intervention groups showed varying degrees of improvement in histopathological morphology and cellular ultrastructure. The mRNA and protein expression of Shh， Ptch1， Gli1， and E-cadherin increased to varying degrees. Xianglian Huazhuo Prescription upregulated the expression of key Hedgehog pathway factors and E-cadherin at both the mRNA and protein levels （P<0.05）. ConclusionXianglian Huazhuo prescription has a therapeutic effect on CAG in rats， and its mechanism may be related to activation of the Hedgehog signaling pathway and inhibition of epithelial-mesenchymal transition （EMT）.

Objective To compare the differences in alkaloids between Nelumbinis Semen and Nelumbinis Plumula and their inhibitory effects on the proliferation of HepG2 cells, and investigate the material basis for their anti-cancer activity differences. Methods Simultaneous Thermal Analysis was used to preliminarily compare the component differences between Nelumbinis Semen and Nelumbinis Plumula. Alkaloids were extracted from them by both using reflux extraction, and their contents were measured by UV and HPLC methods. The CCK-8 method was used to assess the in vitro inhibitory effects of the alkaloids on the HepG2 cells, and to verify pharmacological differences. Results Simultaneous thermal analysis revealed distinct peak shapes, positions, and sizes in the thermal analysis curves of Nelumbinis Semen and Nelumbinis Plumula at respective temperature stages. The contents of total alkaloids showed as follows: the total alkaloids in Nelumbinis Plumula > total extract of Nelumbinis Plumula > the total alkaloids in Nelumbinis Semen. The total alkaloids in Nelumbinis Plumula effectively inhibited HepG2 cell proliferation, while the total alkaloids in Nelumbinis Semen showed no impact. Conclusion Differences in the composition and content of alkaloids may be key factors underlying the biological activities differences between Nelumbinis Semen and Nelumbinis Plumula. This study provided a basis for exploring the material foundation of the differential efficacy and properties of Nelumbinis Semen and Nelumbinis Plumula, which could support their rational clinical application.

Objective:To analyze long-term prognosis and influencing factors of recurrence in vocal fold leukoplakia treated by endoscopic cordectomy with CO 2 laser. Methods:A retrospective review was conducted on 599 patients with vocal fold leukoplakia [566 males and 33 females, aged 17-84 years (median age 55 years)], undergoing endoscopic cordectomy by CO 2 laser under general anesthesia at the Department of Otorhinolaryngology Head and Neck Surgery of Beijing Tongren Hospital, Capital Medical University, from January 2000 to December 2023. The study analyzed the clinical features, pathological grade, surgical methods, postoperative voice function, recurrence, malignant changes and analyzed the long-term efficacy and and its influencing factors. The patients were followed up for a duration of 6-249 months postoperatively, with a median follow-up time of 48 months. SPSS 20.0 software was used for statistical analysis. Results:Among the 599 patients, the histopathological grades included simple squamous cell hyperplasia in ( n=264, 44.08%), mild dysplasia ( n=96, 16.03%), moderate dysplasia ( n=74, 12.35%), severe dysplasia( n=43, 7.81%), carcinoma in situ( n=35, 5.84%), and carcinoma in situ with microinvasion( n=87, 14.52%). The 3-year and 5-year overall recurrence rates were 12.91% and 16.00%, respectively. In patients with precancerous lesion, 3.91% of recurrences presented with an upgraded pathologic grade and 2.34% evolved into carcinoma. The risk of recurrence was higher in lesions involving the anterior commissure, larger lesions, significant reduction/absence of mucosal waves, neovascularization/suspected neovascularization, and pathology of dysplasia/carcinoma in situ/carcinoma in situ with microinvasion( F=44.76,21.54,11.55,8.78,23.20,respectively, P<0.05). Additionally, patients with recurrent disease exhibited higher reflux symptom index scores compared to those without recurrence. Exophytic lesion characteristics and the inability to cease smoking postoperatively were identified as independent risk factors for recurrence with an upgraded pathological grade, with odds ratios of 8.675 and 11.380 times greater than those with non-exophytic lesions and successful smoking cessation, respectively. At the 6-months postoperative assessment, patients who underwent subepithelial cordectomy (typeⅠ) demonstrated a statistically significant increase in fundamental frequency ( t=-3.38, P<0.05), and while other voice acoustic parameters were not significantly different.Conversely, those who underwent transmuscular cordectomy (TypeⅢ) exhibited significant alterations in multiple voice acoustic parameters when compared to preoperative values ( P<0.05). Furthermore, postoperative vocal fold adhesions developed in 84 patients with 13 of these individuals requiring surgical intervention for adhesion release. Conclusions:Lesions involving the anterior commissure, larger lesions, pathology of dysplasia/carcinoma in situ/carcinoma in situ with microinfiltration, significant reduction/absence of vocal fold mucosal waves, and neovascularization visible under NBI are indicative of an increased risk of recurrence, whereas exophytic lesions and the inability to cease smoking postoperatively significantly increase the risk of recurrence with elevated pathologic grade. Recovery of postoperative voice quality is procedure-dependent, underscoring the importance of surgical approach selection in the management of vocal fold leukoplakia.

ObjectiveTo construct traditional Chinese medicine （TCM） diagnostic scale of turbid toxin syndrome in order to provide corresponding reference for the standardization of TCM syndromes and studies. MethodsWe systematically searched the Chinese Medical Dictionary （CMD）， China Knowledge Network （CNKI）， Wanfang Data Knowledge Service Platform （WF） and VIP database for TCM classics and modern literature on turbid toxin syndrome， and initially screened the four diagnosis information of turbid toxin syndrome， established a pool of information entries， and conducted a cross-sectional clinical survey. Discrete trend method， correlation coefficient method， Cronbach's coefficient method， and factor analysis method were applied to objectively screen the entries. The diagnostic scale of turbid toxin syndrome were constructed through three rounds of Delphi method expert survey to determine the scale entries， using hierarchical analysis to get the judgement matrix scores and relative weight of each entry， after passing consistency test and then isometric expansion of the relative weight of the entries to get the weight of each entry and assign the value. ResultsA total of 35 articles were included， 45 entries were obtained after the initial screening. After the clinical investigation， 12 entries were not suitable by the discrete trend method， 23 entries not suitable by correlation coefficient method， 13 entries by the internal consistency screening were removed with the Cronbach's alpha coefficient rising， and 10 entries not suitable by the factor analysis method. Twenty-two entries were retained after objective screening by the combined use of the four statistical methods. The positive coefficients of experts in the three rounds of Delphi method of expert consultation were 96.67%， the coefficients of expert authority were 0.834， 0.856， and 0.867， and the coefficients of co-ordination were 0.126， 0.326， and 0.312， respectively. After consulting with clinical experts， and three rounds of Delphi method survey and hierarchical analysis method weight assignment， the diagnostic scale entries of turbid toxin syndrome were finally established. Primary symptoms： dark red or purple and dusky tongue， yellowish greasy or dry coating （10 points）； sticky and unpleasant stools （8 points）； disharmony of tastes including halitosis， sticky and greasy taste in the mouth， dry mouth and bitter taste in the mouth （6 points）； unfavourable or yellowish or red urination （5 points）； and dark complexion （4 points）. Secondary symptoms： heavy body （3 points）； dizziness （3 points）； profuse， sticky， foul-smelling secretions （2 points）； wiry and slippery， or slippery， or slippery and rapid pulse （2 points）； feeling of hardness in the abdomen （1 point）. ConclusionUsing Delphi method combined with the hierarchical analysis method， combining qualitative and quantitative study， a diagnostic scale of turbid toxin syndrome was initially developed.

Objective Preliminary exploration of the effects of modified electroconvulsive therapy(MECT)on cognitive function and gender differences in middle-aged and young patients with depressive episodes.Methods A group of middle-aged and young patients with depressive episodes,who were admitted to Beijing Anding Hospital affiliated to Capital Medical University,completed 6 rounds of MECT.The 17-item Hamilton depression scale(HAMD-17),Hamilton anxiety scale(HAMA),and repetitive battery for the assessment of neuropsychological status(RBANS)were used to score depressive symptoms,anxiety symptoms,and cognitive function at baseline,after the 3rd MECT,and after the 6th MECT,respectively.Gender differences were compared between the young and middle-aged groups.Results A total of 122 patients with depressive episodes were included,with 83 cases in the youth group and 39 cases in the middle-aged group.There was no gender difference in baseline HAMD and HAMA scores,as well as the HAMD reduction rates after MECT between the two groups(P>0.05).Repeated measures ANOVA showed that in the youth group,the time effects of RBANS total score,visual breadth factor score,and attention factor score were significant(P<0.05),and increased after treatment compared to baseline.There was no significance in gender group effects or interaction effects(P>0.05).In the middle-aged group,the time and gender interaction effect of RBANS total score and visual breadth factor score was significant(P<0.05).Female patients showed an increase in RBANS total score,visual breadth factor score,and attention factor score after the 6th MECT compared to baseline(P<0.05),while there was no significance in time effect and gender group effect(P>0.05).Conclusion Middle-aged and young depressed patients showed overall improvement in cognitive function after MECT,while there were gender differences in cognitive function changes among middle-aged patients.It is necessary to optimize the MECT program based on the patient's gender and age characteristics to reduce cognitive impairment.