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

Objective To investigate the effect of Shanzha Xiaozhi capslue on intima-media thickness(IMT) and plaques score of carotid artery in patients with non-acute phase coronary heart disease and traditional Chinese medicine(TCM)syndrome of phlegm and blood stasis. Methods A prospective study was conducted to carry out a research on 102 patients with non-acute phase coronary heart disease and TCM syndrome of phlegm and blood stasis. They were randomly divided into two groups:a control group(50 cases)treated with conventional western medicine alone and a observation group(52 cases)which was treated by both conventional western medicine and Shanzha Xiaozhi capslue(the main TCM ingredients:Shanzha,Dahuang)0.7 g,3 times a day,the therapeutic course being 6 months in both groups. The cardiocerebral vascular incidences of the two groups were observed,in the mean time,the carotid artery IMT and plagues score were registered,the scores of phlegm stagnation syndrome and blood-stasis syndrome were measured,adverse reaction was observed and compared in both groups before and after treatment. Results After treatment,the occurrence of major adverse acute cardiovascular and cerebrovascular events in observation group were reduced significantly compared with those in the control group(5.77%vs. 20.00%,P<0.05). The IMT and plaques score of carotid artery and the scores of phlegm stagnation syndrome and blood-stasis syndrome were all decreased obviously compared to those before treatment,and the effect was more remarkable in the treatment group〔IMT of carotid artery(mm):0.80±0.13 vs. 0.95±0.12,the plaques score:1.35±0.65 vs. 1.75±0.88, phlegm syndrome score:20.98±6.42 vs. 35.55±9.22,blood-stasis syndrome score:23.23±5.12 vs. 28.95±6.38, P<0.05 or P<0.01〕. Abdominal pain appeared in 2 patients of observation group without other adverse reactions. Conclusion Shanzha Xiaozhi capsule can stabilize atherosclerotic plaque and reduce the occurrence of acute adverse cardiocerebral vascular events in patients with non-acute phase coronary heart disease and phlegm and blood stasis syndrome possibly by removing phlegm and blood stasis to decrease the IMT and plaques score of carotid artery.

OBJECTIVE:The effects of Astragulus injection on cardiac function in myocardial infarction convalescents were observed.METHODS:42 cases were randomly divided into two groups(therapeutic group and control group).21 cases in therapeutic group were treated with routine treatment and 21 cases in control group were treated with Astragulus injection on the basis of routine treatment for three weeks.The ejection fraction(EF),early diastolic peak velocity of blood flow(E),late diastolic peak velocity of blood flow(A) and A/E of all patients were measured with pulse ultrasonic Doppler cardiography before and after the treatment.RESULTS:After the treatment,the EF,E and A/E were improved (P