BACKGROUND: Retinal ganglion cell (RGC) death caused by acute ocular hypertension is an important characteristic of acute glaucoma. Receptor-interacting protein kinase 3 (RIPK3) that mediates necroptosis is a potential therapeutic target for RGC death. However, the current understanding of the targeting agents and mechanisms of RIPK3 in the treatment of glaucoma remains limited. Notably, artificial intelligence (AI) technologies have significantly advanced drug discovery. This study aimed to discover RIPK3 inhibitor with AI assistance. METHODS: An acute ocular hypertension model was used to simulate pathological ocular hypertension in vivo . We employed a series of AI methods, including large language and graph neural network models, to identify the target compounds of RIPK3. Subsequently, these target candidates were validated using molecular simulations (molecular docking, absorption, distribution, metabolism, excretion, and toxicity [ADMET] prediction, and molecular dynamics simulations) and biological experiments (Western blotting and fluorescence staining) in vitro and in vivo . RESULTS: AI-driven drug screening techniques have the potential to greatly accelerate drug development. A compound called HG9-91-01, identified using AI methods, exerted neuroprotective effects in acute glaucoma. Our research indicates that all five candidates recommended by AI were able to protect the morphological integrity of RGC cells when exposed to hypoxia and glucose deficiency, and HG9-91-01 showed a higher cell survival rate compared to the other candidates. Furthermore, HG9-91-01 was found to protect the retinal structure and reduce the loss of retinal layers in an acute glaucoma model. It was also observed that the neuroprotective effects of HG9-91-01 were highly correlated with the inhibition of PANoptosis (apoptosis, pyroptosis, and necroptosis). Finally, we found that HG9-91-01 can regulate key proteins related to PANoptosis, indicating that this compound exerts neuroprotective effects in the retina by inhibiting the expression of proteins related to apoptosis, pyroptosis, and necroptosis. CONCLUSION AI-enabled drug discovery revealed that HG9-91-01 could serve as a potential treatment for acute glaucoma.
Animals ; Glaucoma/metabolism* ; Neuroprotective Agents/pharmacology* ; Mice ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism* ; Artificial Intelligence ; Retinal Ganglion Cells/metabolism* ; Disease Models, Animal ; Molecular Docking Simulation ; Mice, Inbred C57BL ; Male

In recent years, recombinant human urokinase (rhPro-UK) has been widely used in the treatment of a variety of thromboembolic diseases, with significant efficacy and no obvious adverse reactions. In addition, it has a wide range of applications in many new technology fields. This article focuses on the application of rhPro-UK in the treatment of acute myocardial infarction, cerebrovascular disease, lower extremity deep vein thrombosis, arterial thrombosis and other diseases. rhPro-UK has demonstrated good thrombolytic efficacy and safety in these diseases, especially in patients with acute myocardial infarction, and adjuvant PCI therapy can significantly increase myocardial reperfusion, improve cardiac function, and do not increase the risk of bleeding. For cerebrovascular disease, rhPro-UK can significantly improve the degree of neurological deficit and has a high safety profile. In the treatment of lower extremity deep vein thrombosis, rhPro-UK has shown superior thrombolytic efficacy and safety compared with urokinase. For arterial thrombosis and biological stents, the use of rhPro-UK has also achieved some efficacy, but more research is needed to confirm its efficacy and safety. In addition, ultrasound-mediated drug-loaded thrombolysis systems also have potential applications in rhPro-UK therapy. Future research on rhPro-UK will focus more on the development of new technologies.

Objective:To observe the efficacy of self-help cognitive behavioral therapy for insomnia (CBTI), trazodone hydrochloride and their combination in the treatment of depression and insomnia comorbidity in the elderly.Methods:90 elderly patients with insomnia and depression admitted to the 901th Hospital of the Joint Logistic Support Force from October 2019 to October 2021 were selected as the study subjects. They were divided into trazodone group, CBTI group and trazodone combined with CBTI group(combination group), with 30 cases in each group. Trazodone group was treated with oral trazodone hydrochloride, CBTI group was treated with self-help CBTI, and the combination group was treated with oral trazodone hydrochloride combined with self-help CBTI. All three groups were treated for 4 weeks. The sleep latency, total sleep time and sleep efficiency of each group were compared at the time of admission and after 4 weeks of treatment. Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) were used for sleep assessment before and after treatment, and Self-Rating Depression Scale (SDS) was used for depression assessment.Results:Before treatment, there was no significant difference among the three groups in terms of sleep latency, total sleep time, sleep efficiency, PSQI, ESS and SDS (all P>0.05). After treatment, the sleep latency of the three groups was shorter than that before treatment, and the total sleep time was longer than that before treatment (all P<0.05). The sleep efficiency of the trazodone group and the combination group was higher than that before treatment, with statistically significant difference (both P<0.05). The indexes of the combined group were better than those of the trazodone group and the CBTI group (all P<0.05). The sleep latency of the trazodone group was shorter than that of the CBTI group, and the total sleep time was longer than that of the CBTI group (all P<0.05), with statistically significant difference (all P<0.05). After treatment, the PSQI, except for the SDS of CBTI group, the ESS and SDS of the three groups were lower than those before treatment (all P<0.05). The PSQI, ESS and SDS of the combined group were lower than those of the trazodone group and the CBTI group, and the ESS and SDS of the trazodone group were lower than those of the CBTI group, with statistically significant difference (all P<0.05). Conclusions:For the elderly patients with depression and insomnia, the combination of self-help CBTI and trazodone can not only improve insomnia but also relieve depression symptoms, and the effect is better than that of trazodone and self -help CBTI alone.

ObjectiveTo explore the effect and regulatory mechanism of notoginseng total saponins on apoptosis of mammary gland cells in rats with mammary gland hyperplasia. MethodSixty female non-pregnant SD rats were randomly divided into control group， model group， Notoginseng total saponins low-， medium- and high-dose （10， 20， 40 mg·kg^-1， respectively） groups and tamoxifen group （1.8 mg·kg^-1）， 10 rats per group. Rat model of mammary gland hyperplasia was established by intramuscular injection of estradiol benzoate and progesterone. Oral administration was performed according to the experimental dose of each group， once a day for 30 consecutive days. The rats in the control group and the model group were given equal volume of normal saline by gavage every day. After administration， the diameter of the second pair of nipples of the rats was measured with vernier calipers， and breast tissue samples were collected and stained with hematoxylin and eosin （HE） to observe the pathological changes. Immunohistochemistry was used to determine the expression of apoptosis regulators B-cell lymphoma-2 （Bcl-2）-associated X （Bax） and Bcl-2， and Western blot was conducted to detect the expression of phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin （PI3K/Akt/mTOR） signaling pathway-related proteins. ResultCompared with the control group， the model group had increased diameter of the second pair of nipples （P<0.05）， elevated volume of mammary lobules and number of acinus， diffuse mammary gland hyperplasia， and up-regulated expression of Bcl-2 protein， increased ratio of p-PI3K/PI3K， p-Akt/Akt， p-mTOR/mTOR （P<0.05） and decreased expression of Bax in the mammary gland （P<0.05）. Compared with the conditions in the model group， the diameter of the second pair of nipples of the rats in the notoginseng total saponins low-， medium- and high-dose groups and tamoxifen group was decreased （P<0.05）， and the number of mammary lobules and acinus and the amount of secretions were reduced. In addition， the mammary gland hyperplasia was alleviated， and a decrease was observed in the expression of Bcl-2 protein and the ratio of p-PI3K/PI3K， p-Akt/Akt， p-mTOR/mTOR （P<0.05）， and an increase in the expression of Bax （P<0.05）. ConclusionNotoginseng total saponins could improve mammary gland hyperplasia in rats， and its mechanism was related to regulating PI3K/Akt/mTOR pathway and promoting apoptosis of mammary gland cells.

Objective To predict and analyze the physicochemical properties, structural characteristics, and antigenic epitopes of viral protein (VP) VP1 of Coxsackievirus A10 (CV-A10) by bioinformatics methods. Methods The physicochemical properties and structural characteristics of CV-A10 VP1 were predicted by ProtParam, SOPMA, SWISS-MODEL, PDBsum, and ProSA-web. The antigenic epitopes of CV-A10 VP1 were predicted and analyzed by DNAstar, ABCpred, Bepipred 2.0, ElliPro, DiscoTope-2.0, NetMHCpan-4.1, NetMHCIIpan-4.0, Consurf, VaxiJen v.2.0, AllerTOP v.2.0, ToxinPred2, and IEDB immunogenicity. Results Bioinformatics analysis showed that CV-A10 VP1 was a basic, unstable, and hydrophilic protein, of which the secondary structure mainly consisted of random coil. The analysis revealed that CV-A10 VP1 had multiple potential B and T cell antigenic epitopes as well as a dominant antigenic epitope based on the potential epitope. Conclusion CV-A10 VP1 has multiple potential sites that induce specific humoral and cellular immunity, providing important support for its experimental identification, molecular epidemiological studies, and vaccine development.

Periodontitis is associated with abnormal purine metabolism, which is manifested by increased uric acid in host blood and increased expression of the purine-degrading enzyme, xanthine oxidoreductase (XOR), in periodontal tissues. Both XOR and uric acid are pro-oxidative and pro-inflammatory mediators under pathological conditions. Animal studies have found that injection of uric acid promotes the progression of periodontitis and that febuxostat (an XOR inhibitor) improves tissue destruction in periodontitis. Therefore, blocking the source of uric acid may be a therapeutic strategy to control the progression of periodontitis. In this article, the rationality of XOR inhibitors as potential therapeutic drugs for periodontitis is reviewed. The literature review results suggest that XOR inhibitors show antioxidative, anti-inflammatory, and anti-osteoclastic effects, and XOR inhibitors show clinical efficacy in the treatment of infectious, inflammatory and osteolytic diseases. Although there is no direct evidence to support the finding that XOR inhibitors can ameliorate periodontal microecological dysbiosis, these drugs can modulate intestinal microflora dysbiosis, and there is indirect evidence to support a beneficial effect of XOR inhibitors on periodontal microecological dysbiosis. In conclusion, XOR inhibitors may be used as immunomodulators for the adjuvant treatment of periodontitis by inhibiting inflammation, oxidative stress and anti-osteoclast effects.

Objective:To explore the clinical value of peripheral remnant lipoproteins (RLP), low density lipoprotein cholesterol particle (LDL-P) and sdLDL particle (sdLDL-P) measurement in the diagnosis of carotid plaque, so as to provide practical basis for the accurate diagnosis of carotid plaque and the control of carotid plaque related cardiovascular and cerebrovascular diseases.Methods:People who underwent carotid plaque ultrasound examination in Xingtai Third Hospital , from January 2020 to June 2021 were selected as the research object. According to the ultrasound results, they were divided into carotid plaque group ( n=146) and control group without carotid plaque ( n=149). The fasting RLP, LDL-P and sdLDL-P of the two groups were measured by vertical auto profile (VAP) centrifugal separation phase, and the fasting TG and LDL-C were detected by routine mixed phase method. The indexes were compared between the two groups and the true positive rate, true negative rate, false positive rate and false negative rate of the diagnosis of carotid plaque were analyzed. The receiver operating characteristic curve of each test index was drawn, and AUC was used to evaluate the clinical diagnostic value of each test index for carotid plaque. Results:The levels of RLP, LDL-P and sdLDL-P in carotid plaque group were significantly higher than those in non-carotid plaque group ([1.07±0.36] mmol/L vs [0.59±0.17] mmol/L,[1 300±370] nmol/L vs [781±215] nmol/L,[435±139] nmol/L vs [156±59] nmol/L, all P<0.01). The true positive rate (78.08% [114/146],81.51% [119/146]) and true negative rate (84.56% [126/149], 86.58%[129/149]) of serum RLP and LDL-P for the diagnosis of carotid plaque were significantly higher than TG (58.90%[86/146], 43.62%[65/149]) and LDL-C (59.59% [87/146], 46.98% [70/149]), and the false positive rate (15.44% [23/149], 13.42% [20/149]) and false negative rate (21.92% [32/146], 18.49% [27/146]) were significantly lower than TG (56.38% [84/149], 41.10% [60/146]) and LDL-C (53.02% [79/149], 40.41% [59/146], all P<0.01). The AUC of the ROC curve of RLP (0.890), LDL-P (0.902) and sdLDL-P (0.973) for the diagnosis of carotid plaque was higher than TG (0.682) and LDL-C (0.712). The AUC of ROC curve of the RLP combined with sdLDL-P (0.977) for the diagnosis of carotid plaque was higher than the RLP and sdLDL-P (all P<0.01). Conclusion:The serum RLP, LDL-P and sdLDL-P can be used as indicators of carotid plaque, and their clinical diagnostic value are superior to TG and LDL-C; the combined diagnostic effect of lipoprotein subclass is better than that of single index alone.

Objective:To explore the relationship between dietary quality and the risk of diabetes and prediabetes among urban women based on alternative healthy eating index-2010（AHEI-2010).Methods:From March to July 2016, a total of 1 061 female residents from 8 cities, Beijing, Guangzhou, Chengdu, Lanzhou, Xuchang, Jilin, Wuhu and Chenzhou in China, were selected by using the multi-stage sampling method. The basic characteristics of all participants were collected by using self-made questionnaire, and the dietary status of the subjects was collected by using 24-hour dietary recall method. AHEI-2010 scores were calculated and the diet was divided into low, medium and high dietary quality group according to the third quartile. All participants received physical examination, systolic blood pressure test, fasting blood glucose test and glycosylated hemoglobin test. Unconditional logistic regression model was used to analyze the relationship between dietary quality and the risk of diabetes and prediabetes.Results:The age of all participants was（48.0±17.5) years old. The median（ P25, P75) of AHEI-2010 score was 46.52（40.04, 54.88). The prevalence of diabetes and prediabetes were 13.3%（141 cases) and 50.0%（530 cases), respectively. Unconditional logistic regression analysis showed that after adjusting for age, city, education, diet control, physical activity, energy intake and waist circumference, compared with the low diet quality group, the OR（95% CI) values of medium, high dietary quality group and diabetes risk were 0.96（0.57-1.62) and 0.63（0.36-1.09), respectively; the OR（95% CI) values of medium, high dietary quality group and prediabetes risk were 0.93（0.64-1.35) and 1.28（0.87-1.88), respectively. Conclusion:The dietary quality of urban women based on AHEI-2010 evaluation is not related to the risk of diabetes and prediabetes.

Objective:To explore the relationship between dietary quality and the risk of diabetes and prediabetes among urban women based on alternative healthy eating index-2010（AHEI-2010).Methods:From March to July 2016, a total of 1 061 female residents from 8 cities, Beijing, Guangzhou, Chengdu, Lanzhou, Xuchang, Jilin, Wuhu and Chenzhou in China, were selected by using the multi-stage sampling method. The basic characteristics of all participants were collected by using self-made questionnaire, and the dietary status of the subjects was collected by using 24-hour dietary recall method. AHEI-2010 scores were calculated and the diet was divided into low, medium and high dietary quality group according to the third quartile. All participants received physical examination, systolic blood pressure test, fasting blood glucose test and glycosylated hemoglobin test. Unconditional logistic regression model was used to analyze the relationship between dietary quality and the risk of diabetes and prediabetes.Results:The age of all participants was（48.0±17.5) years old. The median（ P25, P75) of AHEI-2010 score was 46.52（40.04, 54.88). The prevalence of diabetes and prediabetes were 13.3%（141 cases) and 50.0%（530 cases), respectively. Unconditional logistic regression analysis showed that after adjusting for age, city, education, diet control, physical activity, energy intake and waist circumference, compared with the low diet quality group, the OR（95% CI) values of medium, high dietary quality group and diabetes risk were 0.96（0.57-1.62) and 0.63（0.36-1.09), respectively; the OR（95% CI) values of medium, high dietary quality group and prediabetes risk were 0.93（0.64-1.35) and 1.28（0.87-1.88), respectively. Conclusion:The dietary quality of urban women based on AHEI-2010 evaluation is not related to the risk of diabetes and prediabetes.

The dried root of Ranunculaceae Aconitum perennial herb of North Aconitum, is commonly used. It has the function of cardiac stimulation, anti-inflammatory and analgesic, anti-tumor and immune regulation. However, its toxicity lower the safety and applicaiton. The pharmacological and toxicological effects were discussed in this paper, in order to provide reference for the intoxication diagnosis and clinical safety.