AIM：To explore the potential mechanism of arecoline in promoting oral submucous fibrosis based on key factors of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. METHODS: SD rats were randomly divided into arecoline low-dose group, arecoline medium-dose group, and arecoline high-dose group (5, 10, and 15 mg/mL). The oral buccal mucosa was injected with the corresponding concentration of arecoline (ANE) solution to induce the establishment of oral submucous fibrosis (OSF) models, with 8 rats in each group. Another 8 unmodeled rats were selected as the blank group, and the changes in mouth opening of the rats were detected after 8 weeks of grouping and intervention. HE and Masson staining were used to observe the pathological changes of oral buccal mucosa, measure the length of epithelial staple process and calculate collagen volume fraction. Western blot and qRT-PCR were used to detect the expression of collagen-Ⅰ (COL-I), E-cadherin, fibronectin (FN) and PI3K/Akt/mTOR signaling pathway-related proteins and mRNA in rat oral buccal mucosa.The levels of tumor necrosis factor (TNF) -α, interleukin (IL) -1β and transforming growth factor (TGF) -β1 in rat serum were detected by ELISA. Human immortalized keratinocytes (HaCaT cell line) were cultured in vitro, and the effects of different concentrations of arecoline, PI3K activator, and PI3K inhibitor on the survival rate of HaCaT cells were investigated by CCK-8 method. According to the results of CCK-8, the concentration of arecoline 75 μg/mL, the concentration of PI3K activator 10 μmol/L, and the concentration of PI3K inhibitor 2 μmol/L were selected as the subsequent experimental concentrations. The cells were set as blank group, arecoline group, PI3K activator group, PI3K inhibitor group, and arecoline + PI3K inhibitor group. The mRNA expression levels of COL-I, E-cadherin, FN, PI3K, Akt, and mTOR in each group of cells were detected by qRT-PCR. The levels of TNF-α, IL-1β and TGF-β1 in each group of cells were detected by ELISA. RESULTS: Compared with the blank group, the arecoline low-dose group, the arecoline medium-dose group, and the arecoline high-dose group significantly reduced the mouth opening, significantly shortened the length of the epithelial staple process, significantly increased the collagen volume fraction, inflammatory cell infiltration, and severe pathological damage. The protein expression levels of COL-I, FN, p-PI3K, p-Akt, and p-mTOR were up-regulated, and the protein expression levels of E-cadherin were down-regulated. The mRNA expressions of COL-I, FN, PI3K, Akt, and mTOR were significantly increased. The mRNA expression of E-cadherin was significantly reduced, and the levels of TNF-α, IL-1β, and TGF-β1 were significantly increased (all P<0.05 or P<0.01). Compared with the blank group, the mRNA expression levels of COL-I, FN, PI3K, Akt, and mTOR in the cells of the arecoline group and the PI3K activator group were up-regulated, and the mRNA expression levels of E-cadherin were down-regulated. Compared with the blank group, the mRNA expression levels of COL-I, FN, PI3K, Akt, and mTOR in the cells of the PI3K inhibitor group were down-regulated, and the mRNA expression levels of E-cadherin were up-regulated. Compared with the PI3K inhibitor group, the mRNA expression levels of COL-I, FN, PI3K, Akt, and mTOR in the cells of the arecoline + PI3K inhibitor group were up-regulated, the mRNA expression levels of E-cadherin were down-regulated, and the levels of TNF-α, IL-1β, and TGF-β1 were significantly increased (all P<0.05 or P<0.01). CONCLUSION: Arecoline can significantly promote oral submucous fibrosis, which may play a pro-fibrotic role by upregulating the PI3K/Akt/mTOR signaling pathway.

AIM: To investigate the preventive and therapeutic effects of sesamin (SES) on fatty liver disease in rats with hypertension combined with dyslipidemia, and to explore the potential mechanisms based on mRNA-seq. METHODS: Spontaneously hypertensive rats (SHRs) were fed a high-fat, high-cholesterol diet to establish a rat model of hypertension combined with dyslipidemia, and then treated with SES for 16 weeks continuously. The experiment was divided into four groups: WKY, SHR, Model, and Model+SES (160 mg·kg-1·d-1). Blood pressure was measured using the tail-cuff method. Body weight was monitored, and body mass index was calculated. Liver morphology was detected by ultrasound, and liver thickness was measured. Liver wet weight was weighed, and liver index was calculated. Liver volume was detected by the water displacement method. Serum triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bile acids (TBA) were detected by ELISA. Liver sequencing analysis was performed using mRNA-seq. Liver histomorphological changes were observed by HE staining. The degree of hepatic steatosis was observed by Oil Red O staining, and the degree of hepatic fibrosis was observed by MASSON staining. The mRNA expression of Aldh1a7, Nnmt, Irs2, Pltp, and Scd was detected by q-PCR. The protein expression of Scd, Nnmt, AMPK, p-AMPK, PPARα, and PPARγ was detected by Western blotting. RESULTS: After 16 weeks of continuous SES administration to rats with hypertension combined with dyslipidemia, blood pressure was significantly reduced (P<0.01), and body weight was decreased. Serum TG, TC, and LDL-C levels were decreased, while HDL-C levels were increased. Serum ALT and AST levels were decreased. Liver weight, organ index, liver thickness, and liver volume were decreased. The degree of hepatic steatosis and hepatic fibrosis was improved. A total of 545 differentially expressed mRNAs were identified in the livers of rats in each group, of which 278 were upregulated and 267 were downregulated. Among the 27 commonly differentially expressed mRNAs, five mRNAs related to lipid metabolism were screened, namely Aldh1a7, Nnmt, Irs2, Pltp, and Scd. KEGG enrichment analysis showed that the enriched pathways were AMPK and PPAR. Further validation revealed that in the SES-treated group, the mRNA expression of Scd in the liver was decreased, while the mRNA expression of Nnmt was increased. The protein expression of Scd was decreased, while the protein expression of Nnmt, AMPK, p-AMPK, PPARα, and PPARγ was increased. CONCLUSION: SES has preventive and therapeutic effects on fatty liver disease in rats with hypertension combined with dyslipidemia, and its mechanism of action may be related to the reduction of Scd expression levels in the liver and the increase in the expression of Nnmt, AMPK, p-AMPK, PPARα, and PPARγ.

AIM: To investigate the protective effect of osthole (Ost) on APAP-induced liver injury in mice and its molecular mechanism. METHODS: We established the APAP-induced liver injury model in mice, and Ost was used to intervene. The expression of AST, ALT, SOD, ROS, MDA, LDH, GSH-PX in mice plasma were detected by biochemical method. HE staining was used to observe the changes of liver tissue structure. Immunofluorescence assay was used to detect the expression of Tif1γ and Smad4 in liver tissue. The mRNA expression of IL-1β, IL-6, TNF-α, Smad4, and Tif1γ were detected by qRT-PCR. Western blot was applied to assess the protein expression of Smad2/3 and pSmad2/3 in liver tissue. RESULTS: Compared with the control group, the liver structure destruction and hepatocyte death was increased, ALT, AST, ROS, MDA and LDH were increased, while SOD and GSH-PX were decreased, and the mRNA expressions of IL-1β, IL-6 and TNF-α were increased in the model group. Compared with the model group, the Ost intervention group had improved liver structure and decreased liver cell death; decreased ALT, AST, ROS, MDA and LDH, increased SOD and GSH-PX, and decreased expression of IL-1β, IL-6 and TNF-α mRNA. Compared with the control group, liver tissues of model mice showed increased expression of pSmad2/3, Smad4 protein and Smad4 mRNA, and decreased Tif1γ protein and mRNA. Compared with the model group, the liver tissues of the Ost intervention group showed decreased expression of pSmad2/3, Smad4 protein and Smad4 mRNA, and increased expression of Tif1γ protein and mRNA. CONCLUSION: Ost can improve liver function, reduce oxidative stress and inflammatory reaction, and protect hepatocyte damage induced by APAP in mice, which may be related to the up-regulation of Tif1γ and inhibition of TGF-β1/Smad signaling pathway.

AIM: To investigate the therapeutic effect of crocetin on diabetic lower limb ischemia and explore its underlying mechanism. METHODS: Male C57BL/6J mice aged 8 weeks were used to establish a diabetic mouse model through intraperitoneal injection of streptozotocin (STZ). Following successful induction of diabetes, femoral artery ligation (FAL) surgery was performed to create a model of diabetic lower limb ischemia. Fourteen days after STZ injection, the mice were treated with crocetin (3 mg/kg and 6 mg/kg) by gavage for 21 consecutive days. Post-FAL surgery, Doppler flowmetry was employed to assess blood flow in the mice of each group. Immunofluorescence staining techniques were utilized to observe the expression levels of platelet-endothelial cell adhesion molecule (CD31), α-smooth muscle actin (α-SMA), and inflammatory-related factors including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and transforming growth factor-β (TGF-β) in the gastrocnemius muscle of diabetic mice with lower limb ischemia. RESULTS: Compared to the normal group, the model group exhibited significantly elevated blood glucose levels and significantly reduced lower limb blood flow (P<0.05). While CD31 and α-SMA expression showed no significant change, the expression levels of TNF-α, IL-1β, IL-6, and TGF-β were significantly increased (P<0.05, P<0.01, P<0.05, P<0.05). Compared to the model group, crocetin-treated groups showed no significant change in blood glucose levels but demonstrated significantly increased lower limb blood flow (P<0.05). The high-dose crocetin group (6 mg/kg) significantly enhanced CD31 and α-SMA expression (P<0.0001, P<0.05) and significantly reduced the expression levels of IL-1β, IL-6, and TGF-β (P<0.001, P<0.05, P<0.05). CONCLUSION: Crocetin may exert its beneficial effects on diabetic lower limb ischemia through anti-inflammatory and angiogenic mechanisms.

AIM: To investigate the mechanism of action of Tamarix chinensis Lour. on streptozotocin-induced type 2 diabetes mellitus (T2DM) through network pharmacology, molecular docking and experimental validation. METHODS: Using the TCSMP database and Swiss Target Prediction tools screen the active components and predict potential targets in Tamarix chinensis Lour.. Retrieving potential disease targets associated with T2DM from databases such as GeneCards, OMIM, and DisGeNET. The intersection targets of Tamarix chinensis Lour. and T2DM disease was obtained through Venny platform. The STRING database was used to constructed PPI network, and Cytoscape 3.8.0 software was use to visualized. GO function enrichment and KEGG pathway enrichment analysis were performed through the Metascape database. Docking of important target proteins and compounds was carried out by AutoDock software. SPF grade male rats were randomly divided into normal group, model group, MET group (88.5 mg/kg), TE high-dose (800 mg/kg) group, TE medium-dose (400 mg/kg) group and TE low-dose (200 mg/kg) group (n=10). High-fat and high sugar feed combined with low dose STZ (45 mg/kg) was used to induce T2DM rat model, and the rats were administered orally for 5 weeks. Fasting blood glucose( FBG),insulin（FINS）level and HOMA-IR index, biochemical indicators ［superoxide dismutase (SOD), malondialdehyde (MDA), glycosylated hemoglobin A1c (HbA1c) and inflammatory factor ［interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), vascular cell adhesion molecular (VCAM-1) levels of the rats were also observed; morphological changes of renal tissue was observe by HE staining. RESULTS: Based on the screening conditions of oral bioavailability (OB) ≥ 30% and drug like properties (DL) ≥ 0.18, a total of 19 main active ingredients with potential therapeutic effects on T2DM were screened from Tamarix chinensis Lour., including ergosta-5,24(28)-dien-3,7,16-triol, quercetin-3,3'-dimethyl ether, kaempferol, quercetin, and others. By analyzing the potential targets of Tamarix chinensis Lour. for treating T2DM, a total of 185 potential target genes were screened, including SRC, EGFR, HSP90AA1, AKT1, ESR1, H1F1A, TNF, PIK3R1, etc, involving cancer signaling pathways, insulin resistance, MAPK signaling pathways, PI3K Akt signaling pathways, etc. Molecular docking results showed that the binding energies were all less than -5.0 kcal/mol, indicating that a strong binding ability between the active ingredients screened by Tamarix chinensis Lour. and the potential targets for the treatment of T2DM. The animal experiment results showed that compared with the model group, the weight loss of rats in the MET and TE groups was slowed down, and the levels of FBG, FINS, MDA, HbA1c, IL-1β, TNF-α, VCAM-1, HOMA-IR index were reduced，the SOD level was increased，and the differences were statistically significant (P<0.05，P<0.01),Renal tissue cellular morphology also showed notable improvement. Most importantly, all these results demonstrating dose-dependent effects. CONCLUSION: Tamarix chinensis Lour. displays a significant therapeutic effect on T2DM through multi-component, multi-target, and multi-pathway synergistic actions to improve blood glucose levels. The findings of this study provide a theoretical basis for the clinical application of Tamarix chinensis Lour. in the treatment of T2DM.

AIM: To observe the effect of dexmedetomidine (DEX) on cerebral ischemia and reperfusion (I/R) injury and investigate the possible mechanism of nuclear factor erythroid derived 2-like 2 (Nrf2) mediated ferroptosis on hippocampal neurons. METHODS: The oxygen glucose deprivation/reoxygenation (OGD/R) model in rat primary cultured hippocampal neurons was simulated, DEX (50 μmol/L) and Nrf inhibitor BRU (100 nmol/L) were used to observe the changes of ROS levels by DHE fluorescence probe. The middle cerebral artery occlusion model in male SD rats were established, the degree of neurological impairment was detected by Longa score, and cerebral infarct size was detected by TTC staining. The Fe2+ concentration and levels of oxidative stress related factors were detected, oxidative stress and ferroptosis related protein expressions were detected by Western blot. RESULTS: The fluorescence intensity of DHE in OGD/R+Dex Group was lower than that in CON group, and the fluorescence intensity of DHE in OGD/R+DEX + BRU group was higher than that in OGD/R+Dex group. Compared with Sham group, the Longa score and cerebral infarct size in I/R group were significantly increased (P<0.01), the levels of SOD, CAT, GSH and GSH-PX were significantly decreased. MDA and Fe2+ concentrations were increased, the protein expressions of Nrf2, HO-1, GPX4, FTH1 and FPN1 were decreased, and TFR1 protein expression was increased. Compared with I/R group, in DEX+I/R group, the Longa score and cerebral infarct size were decreased (P<0.01), the levels of SOD, CAT, GSH and GSH-PX were increased. MDA and Fe2+ concentrations were decreased, the protein expressions of Nrf2, HO-1, GPX4, FTH1 and FPN1 were increased, and TFR1 protein expression was decreased. The Nrf2 inhibitor Bru reversed the role of DEX. CONCLUSION: DEX protects against cerebral I/R injury through activating Nrf2 signaling pathway and inhibiting ferroptosis in hippocampal neurons.

AIM: To explore the role of miR-195-5p in mediating trastuzumab resistance in gastric cancer and to validate its potential as a therapeutic target along with its target gene GPRC5A. METHODS: Trastuzumab-resistant gastric cancer cell lines (NCI-N87 and MKN45) were established. Cell viability under trastuzumab treatment was assessed using CCK-8 assays. Expression levels of miR-195-5p were determined by RT-qPCR. Transfection with miR-195-5p mimics was performed to evaluate changes in trastuzumab sensitivity and proliferation. GPRC5A expression was also measured by RT-qPCR, and the targeting relationship between miR-195-5p and GPRC5A was confirmed using a dual-luciferase reporter assay. RESULTS: Parental cells showed higher sensitivity to trastuzumab than resistant cells, with miR-195-5p expression significantly lower in the latter. Overexpression of miR-195-5p in resistant cells enhanced trastuzumab sensitivity and reduced proliferation. GPRC5A was found to be upregulated in resistant cells, and miR-195-5p directly targeted GPRC5A, affecting cell proliferation under trastuzumab treatment. CONCLUSION: miR-195-5p may regulate trastuzumab sensitivity in gastric cancer by targeting GPRC5A, suggesting potential as a molecular marker for trastuzumab therapy guidance.

AIM: To study the efficacy and molecular mechanism of PX-478 in enhancing radiotherapy effect of lung cancer. METHODS: H460, A549 cells were divided into blank group, radiation group and radiation combined PX-478 group. In addition to the blank group, the radiation group and the PX-478 group were given 2Gy X-ray irradiation to establish the radiation model, and the radiation combined with the PX-478 group was given 20 μmol/L PX-478 intervention after modeling, and cultured for 24 h. Inverted microscope was used to observe cell growth and cell number, CCK-8 method was used to detect cell viability, cloning was used to observe cell proliferation, flow cytometry was used to detect cell apoptosis, and Western blot was used to detect HIF-1α, GLUT1, HK2, PFK1, PKM2, LDHA protein expression. RESULTS: Compared with blank group, the number of H460,A549 cells in radiation group decreased, cell viability and proliferation ability decreased, cell apoptosis rate increased, HIF-1α, GLUT1, HK2, PFK1, PKM2, LDHA protein expression increased (P<0.01). Compared with the radiation group, the number of H460, A549 cells in the radiation combined PX-478 group was significantly decreased, the cell viability and proliferation ability were significantly weakened, the apoptosis rate was significantly increased, and the protein expressions of HIF-1α, GLUT1, HK2, PFK1, PKM2 and LDHA were significantly decreased (P<0.01).CONCLUSION: PX-478 can regulate the HIF-1α-mediated glycolysis in A549,H460 cells after radiation, regulate the energy metabolism, increase the apoptosis of tumor cells, and improve the effect of radiotherapy.

AIM: To evaluate the application effectiveness of a Bayesian mixture model based on the principal stratum strategy for estimating the complier average causal effect (CACE) in clinical trials with non-compliance. METHODS: Using a non-inferiority randomized controlled trial investigating a novel drug for primary type 2 diabetes mellitus (non-inferiority margin: -0.4) as a case study, the primary analysis applied a Bayesian mixture model under the monotonicity assumption to estimate CACE of between-group differences in glycated hemoglobin (HbA1c) changes within the compliant stratum, followed by non-inferiority testing. Sensitivity analyses included a Bayesian mixture model relaxing the monotonicity assumption and comparing results with per-protocol set (PPS) analysis. RESULTS: In the primary analysis, the posterior mean of CACE for HbA1c change in the compliant stratum was 0.081%, with a one-sided 97.5% credible interval lower bound of -0.124, exceeding the non-inferiority margin (-0.4%), supporting the non-inferiority efficacy of the novel drug in the compliant stratum (P(H1|Data) = 1). Consistent findings were observed in PPS analyses (estimated effect: 0.136%; one-sided 97.5% credible interval lower bound: -0.069%), further validating methodological robustness. CONCLUSION: In clinical trials with noncompliance as an intercurrent event, the Bayesian mixture model under the principal stratum strategy effectively adjusts for compliance-related bias and yields conservative, robust estimates of causal effects, supporting its value in efficacy evaluation under complex compliance scenarios.

AIM: To investigate the effect of Toll-like receptor 9 (TLR-9) gene rs5743836 (1237 T/C) single nucleotide polymorphism on recurrent infection in patients with diabetic foot (DF). MEHTODS: A total of 128 DF patients admitted to our hospital from June 2020 to June 2022 were collected and divided into an infected group (n=53) and a non-infected group (n=75) according to the presence or absence of recurrent infection. The general data and TLR-9 gene polymorphism were compared between the two groups. The genotypes and allele frequencies of TLR-9 (1237 T/C) gene polymorphism were detected and compared between the two groups. Logistic regression was used to analyze the correlation between TLR-9 gene 1237 T/C polymorphism and recurrence of DF patients. RESULTS: There were significant differences between the two groups in invasive operation, course of antibiotic use and peripheral vascular disease of both lower limbs (P<0.05). The wild type TT homozygote produced two fragments of 108 bp and 27 bp in length, the variant CC homozygote produced three fragments of 60 bp, 48 bp and 27 bp in length, and the heterozygous TC produced four fragments of 108 bp, 60 bp, 48 bp and 27 bp in length. The TLR-9 (1237 T/C) gene identity was 100%. The genotype frequencies met the Hardy-Weinberg genetic equilibrium (P>0.05). There were significant differences in CC gene frequency, TC gene frequency, TT gene frequency, C gene distribution and T gene distribution between the two groups (P<0.05). Logistic regression analysis showed that TLR-9 CC genotype increased the risk of recurrent infection in DF patients in the co-dominant model (OR=5.357, 95%CI: 1.901-15.100). After adjusting for sex, age and smoking (OR=5.341, 95%CI: 1.874-15.015, P<0.01), the C allele significantly increased the risk of recurrent infection in DF patients (OR=2.328, 95%CI: 1.874-15.015, P<0.01). 1.078-5.936), and the difference was statistically significant (P<0.01). The TT genotype and CC+TC genotype of TLR-9 were not significantly associated with smoking history, Wagner grade, peripheral neuropathy, retinopathy, hypertension, osteoporosis and lower extremity arteriosclerosis obliterans in DF patients (P>0.05). There were significant differences in the course of DM, DF, levels of HbAlc, LDL-C, CRP and PCT between patients with CC genotype and patients with TT+TC genotype (P<0.05). CC genotype, DM duration ≥9 years, DF duration ≥5 months, HbAlc<5.00%, LDL-C≥3.03 mmol/L, CRP≥23.25 mg/mL, PCT≥0.87 ng/mL were risk factors for recurrent infection in DF patients (P<0.05). HbAlc, LDL-C, CRP and PCT all showed interaction with TLR-9 (1237 T/C) gene. The risk of recurrent infection in DF patients with abnormal HbAlc, LDL-C, CRP and PCT levels and TLR-9 (1237 T/C) gene polymorphism interaction combination was 2.659 times higher than that in DF patients without the above combination, and the difference was statistically significant (P<0.05). CONCLUSION: CC genotype and C allele of TLR-9　gene 1237 T/C are independent risk factors for recurrent infection in DF patients.

Polycythemia vera (PV) is a type of BCR::ABL1 negative myeloproliferative neoplasms (MPN), which is a chronic myeloid tumor caused by gene mutations in hematopoietic stem cells. PV has a certain risk of progressing to myelofibrosis or acute myeloid leukemia. At present, the goal of PV treatment is still to prevent thrombosis. With the deepening of PV research, it is possible to transform the lifelong treatment to prevent the progression of the disease from alleviating the symptoms of patients. This article reviews the mechanism of traditional cytoreductive therapy drugs and the latest clinical trial results, as well as the early clinical trial data and their mechanism of action of new PV drugs and combination of drugs, in order to provide help for researchers who pay attention to PV treatment.

Lung cancer is the most common malignant tumors in clinical practice, posing a significant threat to human health. In recent years, with the advancement of high-throughput sequencing technologies, a large number of non-coding RNAs (ncRNAs) have been found to play crucial roles in the regulation of apoptosis in lung cancer cells. This article reviews the research progress of ncRNA (miRNA, lncRNA, circRNA, piRNA) mediated apoptosis in lung cancer, aiming to provide new theoretical basis for ncRNA therapy of lung cancer.

Breast cancer is a common clinical gynecological tumor. According to the 2022 global cancer data statistics, breast cancer ranks second in terms of incidence among newly diagnosed cancer cases worldwide. Modern medicine often adopts surgical operation, chemotherapy, and other methods, which have certain efficacy but also many problems such as high drug resistance rates and significant adverse reactions. Chinese patent medicines exhibit extensive anticancer effects. The study found that Shenyi Capsule, Pingxiao Capsule, and Zhenqi Fuzheng Granules were widely used in the treatment of breast cancer, exerting therapeutic effects on breast cancer by inhibiting cell proliferation, invasion, and metastasis, suppressing angiogenesis, reversing cellular drug resistance, and inhibiting precancerous lesions. Meanwhile, the oral administration of Chinese patent medicines in combination with other traditional Chinese medicine (TCM) compounds, TCM decoctions, or modern medical treatments can improve patients' quality of life and reduce adverse reactions. Currently, there are numerous studies on the treatment of breast cancer with Chinese patent medicines, but a systematic summary is lacking. Therefore, this study conducted a systematic review of the mechanisms of action and clinical applications of Chinese patent medicines as adjuvant therapy for breast cancer, aiming to provide guidance for clinical medication.

Cardiovascular disease (CVD), as one of the diseases with the highest morbidity and mortality rates globally, has always been a focus of medical research. In recent years, with a deeper understanding of the pathogenesis of CVD, novel metabolic drugs have demonstrated great potential in its treatment. These novel drugs regulate multiple aspects of cardiovascular metabolism, including reducing blood glucose and lipid levels, inhibiting inflammatory responses, and protecting vascular endothelial cells, thereby providing new strategies for the prevention and treatment of CVD. In terms of lowering blood glucose levels, SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and Metformin, as clinically commonly used drugs, have been proven to be beneficial for the prevention and treatment of CVD, regardless of the presence or absence of diabetes. For lipid regulation, PCSK9 inhibitors and Ezetimibe, as newly developed lipid-lowering drugs, not only reduce serum low-density lipoprotein cholesterol levels but also directly protect the cardiovascular system from damage. The development and application of these drugs have not only improved the treatment outcomes of CVD but also provided patients with more therapeutic options.

The treatment of multidrug-resistant gram-negative bacterial infections has become a challenge in today's healthcare field, and time-to-event data analysis has shown significant value in clinical prognostic studies of critically ill patients. This study comprehensively reviewed the results of the application of time-to-event analysis in clinical studies of anti- multidrug-resistant gram-negative bacterial drugs, aiming to provide a scientific basis for the optimization of therapeutic strategies and prognostic assessment of multidrug-resistant gram-negative bacterial infections, and to promote the widespread application of time-to-event analysis methods in similar studies.