ObjectiveTo investigate the potential mechanism of Qingguangan Ⅱ Formula （青光安Ⅱ号方， QGAⅡ） in the treatment of glaucoma from the perspectives of oxidative stress and the cyclic adenosine monophosphate/ protein kinase A （cAMP/PKA） signaling pathway. MethodsForty SD rats were randomly assigned to a medicated serum group （n=30）， which received QGAⅡby intragastric administration at 6.741 g/（kg·d）， and a blank group （n=10）， which received normal saline at 10 ml/（kg·d）. After 7 consecutive days of administration， medicated serum and blank serum were prepared. The optimal concentration of medicated serum for R28 cell intervention was determined using CCK-8 assay. An in vitro glaucoma model was established by exposing R28 cells to continuous hydrostatic pressure combined with oxygen-glucose deprivation （OGD） for 24 h to simulate the pathological microenvironment of glaucomatous optic nerve injury. The experiment set a control group （complete medium）， model group （glucose-free medium + tri-gas incubator）， medicated serum group （selected concentration of QGA-medicated serum + glucose-free medium + tri-gas incubator）， and blank serum group （blank serum + glucose-free medium + trigas incubator）. The total culture medium volume in each culture dish was 5 ml. After 24 h of culture， cell proliferation was assessed using the EdU immunofluorescence assay， and apoptosis was determined by flow cytometry. Malondialdehyde （MDA） content and superoxide dismutase （SOD） activity were measured using biochemical assays. Western Blotting was performed to detect the expression of oxidative stress-related proteins including 4-hydroxynonenal （4-HNE） and heme oxygenase-1 （HO-1）， apoptosis-related proteins including B-cell lymphoma-2 （Bcl-2）， Bcl-2-associated X protein （Bax）， and cleaved caspase-3 （C-caspase-3）， and cAMP/PKA signaling pathway-related proteins including protein kinase A （PKA）， phosphorylated PKA （p-PKA）， cAMP response element-binding protein （CREB）， and phosphorylated CREB （p-CREB）. Intracellular cyclic adenosine monophosphate （cAMP） levels were determined by ELISA. In addition， a forskolin （agonist） group， an H89 （inhibitor） group， and a 7.5% medicated serum plus inhibitor group were established to further investigate the effects of QGAⅡ-medicated serum on oxidative stress and the cAMP/PKA signaling pathway in R28 cells. ResultsA concentration of 7.5% QGAⅡ-medicated serum was identified as the optimal concentration for subsequent experiments. Compared to the control group， the model group exhibited significantly decreased cell proliferation， SOD activity， Bcl-2 protein expression， p-PKA/PKA ratio， p-CREB/CREB ratio， and cAMP content， as well as increased apoptosis rate， MDA content， and the protein expression levels of 4-HNE， HO-1， Bax， and C-caspase-3 （P＜0.01）. Compared to the model group， the 7.5% medicated serum group showed significant improvements in all of the above parameters （P＜0.01）. In the forskolin group， the apoptosis rate and the expression levels of C-caspase-3 and Bax significantly decreased， whereas Bcl-2 expression and the p-PKA/PKA and p-CREB/CREB ratios increased compared to those in the model group （P＜0.01）. Compared to the 7.5% medicated serum group， the 7.5% medicated serum plus inhibitor group exhibited significantly increased expression of C-caspase-3 and Bax， together with significantly decreased Bcl-2 expression and reduced p-PKA/PKA and p-CREB/CREB ratios （P＜0.01）. ConclusionUnder continuous hydrostatic pressure and OGD-induced injury conditions， QGAⅡ- containing serum effectively mitigates oxidative stress in R28 cells， activates the cAMP/PKA signaling pathway， and inhibits apoptosis， thereby exerting a neuroprotective effect on retinal ganglion cells

OBJECTIVE To construct and validate a prognostic prediction model for first-line immune checkpoint inhibitors （ICIs） therapy for advanced non-small cell lung cancer （NSCLC）.METHODS The clinicopathological data and peripheral blood parameters from 211 patients with advanced NSCLC who received first-line ICIs therapy at our hospital from January 2020 to December 2023 were retrospective collected. The patients were randomly divided into a training set （151 cases） and a validation set（60 cases） at a ratio of 7∶3. Using progression-free survival （PFS） as the outcome measure， LASSO regression was used to preliminarily screen predictive variables in the training set，and the preliminarily screened predictive variables were entered into a multivariable Cox regression model to construct Model 1. Meanwhile，restricted cubic splinec analysis was performed on the continuous variables preliminarily screened by LASSO regression. The variables with nonlinear relationships （ P ＜0.1） were analyzed by multivariable Cox regression in RCS form to construct Model 2. The concordance index，receiver operating characteristic curves，calibration curves，and decision curve analysis were used to compare the predictive performance of the two models； the optimal model was selected to construct a nomogram.Sensitivity analysis was performed by reconstructing the multivariable Cox regression model after excluding cases with unknown programmed death-ligand 1（PD-L1）status. Kaplan-Meier method was used to plot survival curves to analyze the survival differences among patients with different risk strata.RESULTS The variables used to construct Model 1 were sex， smoking history， PD-L1 expression status， bone metastasis， and carcinoembryonic antigen （CEA）；the variables used to construct Model 2 were sex， smoking history， PD-L1 expression status， bone metastasis， CEA， neutrophil（Neu）， and albumin（ALB）. The concordance indices of Model 2 were 0.710 in the training set and 0.672 in the validation set，both superior to those of Model 1 （0.649，0.634）. The areas under the curve （AUC） of Model 2 for 12， 18， and 24 months PFS were 0.737，0.782 and 0.788 in the training set，and 0.709，0.630 and 0.663 in the validation set，respectively，all outperforming Model 1 （0.653， 0.704， 0.697 in the training set；0.688， 0.605， 0.651 in the validation set）.The calibration curves of both models showed good consistency between the predicted probability and actual probability，and the clinical net benefit of Model 2 was higher than that of Model 1. Sensitivity analysis indicated that the prediction model was robust. The median PFS of patients in the low-risk group was significantly longer than that in the high-risk group（ P ＜0.05）.CONCLUSIONS Sex， smoking history， PD-L1 expression status， bone metastasis， Neu， ALB， and CEA were independent influencing factors for PFS in advanced NSCLC patients receiving first-line ICIs. The prediction model constructed based on the above factors has good predictive performance and can be used to predict the prognosis of advanced NSCLC patients.

OBJECTIVE To develop evidence-based clinical practice recommendations for the use of hemostatic drugs in special populations， so as to improve the efficacy and safety of medication.METHODS Led by the Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital， a working group of 79 experts covering clinical pharmacy， obstetrics and gynecology， pediatrics and other fields was established. Clinical questions regarding the efficacy and safety of hemostatic drugs in special populations were screened through literature review and two rounds of Delphi questionnaire surveys. Intervention questions were structured using the population， intervention， comparison， and outcome framework， while management questions were additionally described using the population， clinical setting, management measure， and outcome framework. Databases including Medline， Embase， Cochrane Library， CNKI， Wanfang Data， and VIP were systematically searched to collect and screen relevant evidence. Recommendations were formulated through recommendation questionnaire surveys and expert consensus meetings， and the quality of evidence and strength of recommendations were graded according to the Grading of Recommendations Assessment， Development and Evaluation system. RESULTS &CONCLUSIONS A total of 8 clinical questions were finally determined， the consensus rates of all clinical questions and recommendations were more than 90%， and 8 recommendations on the use of hemostatic drugs in special populations were formulated. These recommendations cover special populations including children， women during pregnancy/puerperium/lactation， the elderly， patients with hepatic impairment， patients in the perioperative period of liver transplantation， patients with renal impairment/on dialysis/in the perioperative period of kidney transplantation， immunocompromised patients， and patients with hematological diseases. The recommendations specify the applicable scenarios， dose adjustment principles， monitoring indicators， and safety management strategies of hemostatic drugs in different special populations， which can provide a reference for the clinical application of hemostatic drugs in special populations and help clinicians and pharmacists develop individualized medication plans.

ObjectiveTo interpret the main contents of the Expert Consensus on Clinical Application of Yifei Zhike Capsules （hereinafter referred to as the Consensus）， analyze its evidence basis， and explore future research directions， thus providing a reference for rational drug use in clinical practice. MethodsThe core contents of the Consensus are summarized. Focusing on clinical issues， this paper summarizes the recommendations and consensus suggestions in the Consensus and explains them from aspects such as indications， key advantages， usage and dosage， combined medication， contraindications， precautions， and safety. ResultsThe Consensus clearly states that Yifei Zhike capsules can be used for acute or chronic bronchitis， pulmonary tuberculosis and other respiratory system diseases. It for the first time proposes that the applicable TCM syndrome of Yifei Zhike capsules is Qi-Yin deficiency together with combined phlegm and stasis. For different diseases， the Consensus provides specific usage instructions， dosage， and treatment course recommendations， supplementing the contents not covered in the drug instructions. In terms of combined medication， the Consensus emphasizes the principle of using this drug in combination with standardized chemotherapy regimens or conventional Western medicines and the applicability for the treatment of pulmonary tuberculosis and moderate to severe acute or chronic bronchitis. In terms of safety， the Consensus proposes methods for identifying common adverse reactions， drug contraindications， and precautions based on a review of the existing data and preliminarily builds a risk management framework. However， the evidence on which the Consensus is based are mostly early studies， with small sample sizes， which result in the low evidence grades （mainly C and D） of some recommendations. ConclusionThe Consensus provides specific guidance for the clinical use of Yifei Zhike capsules. However， due to the limited quality of the existing research evidence， more high-quality clinical studies are needed in the future to further verify its efficacy， safety， and explore its broader application prospects.

The compilation instructions for the Expert Consensus on Clinical Application of Yifei Zhike Capsules systematically expound the development background， methodological framework， and core achievements of this consensus. In view of the problems existing in the clinical application of Yifei Zhike Capsules， such as insufficient efficacy evidence and lack of standardized syndrome differentiation， the Institute of Basic Research in Clinical Medicine， China Academy of Chinese Medical Sciences took the lead and collaborated with 21 tertiary grade-A hospitals and research institutions across China to form a multidisciplinary expert group （comprising 30 experts in clinical medicine， pharmacy， and methodology）. The compilation work was carried out in strict accordance with the World Health Organization （WHO） guidelines， the GB/T 1.1-2020 standard， and the writing specifications for the explanatory notes of expert consensus on clinical application of Chinese patent medicines. Through systematic literature retrieval （including 32 studies， with 24 clinical studies）， Grading of Recommendations Assessment， Development and Evaluations （GRADE）-based evidence grading， and multiple rounds of discussions using the nominal group method （25 experts voted to determine 17 clinical questions）， 5 evidence-based recommendations and 11 expert consensus suggestions were formed. It is clarified that this medicine （Yifei Zhike Capsules） is applicable to the treatment of expectoration/hemoptysis in acute and chronic bronchitis and the adjuvant treatment of pulmonary tuberculosis. It is recommended that it can be used alone or in combination with anti-tuberculosis drugs. The safety evaluation shows that this medicine mainly induces the following adverse reactions： mild gastrointestinal reactions （such as nausea and abdominal pain） and rashes. The contraindicated populations include pregnant women and women during menstruation. The compilation process of the consensus underwent three rounds of expert letter reviews， two rounds of peer reviews， and quality control assessments to ensure methodological rigor and clinical applicability. In addition， through policy alignment， academic promotion， and a dynamic revision mechanism， the standardization of clinical application was promoted， providing a demonstration for the evidence-based transformation of characteristic therapies of Miao medicine.

Glaucoma is a multifactorial degenerative optic neuropathy, and its irreversible and blinding pathological characteristics mainly come from the damage to the optic nerve, namely glaucomatous optic neuropathy(GON). The difficulty in the treatment of GON lies in the early intervention, and currently there is no optic neuroprotective drug for the treatment of all types of GON. The death of retinal ganglion cells(RGCs)is the core pathological change caused by various pathogenic mechanisms of GON. Recent studies have found that the widespread second messenger cyclic adenosine 3', 5' -monophosphate(cAMP)and its downstream effector protein kinase A(PKA)signal cascade play an important role in the pathogenesis of GON. It can also inhibit the apoptosis of RGCs and play a protective and therapeutic role in glaucoma. Therefore, this article reviews the role of cAMP/PKA pathway in the pathophysiological development of GON, focusing on its effects on glaucoma intraocular pressure regulation, oxidative stress, neuroinflammation and optic nerve degeneration, in order to find a common central regulatory target for the optic nerve damage caused by different pathological mechanisms of GON and promote the further understanding and clinical treatment of this disease.

AIM: To investigate the effects of Conbercept on various optical coherence tomography(OCT)biomarkers in patients with retinal vein occlusion-related macular edema(RVO-ME), and to analyze the correlation of these biomarker changes with visual prognosis.METHODS: Retrospective study. A total of 57 patients(57 eyes)with RVO-ME, including 25 patients(25 eyes)with central retinal vein occlusion(CRVO)and 32 patients(32 eyes)with branch retinal vein occlusion(BRVO), were enrolled in this study. All the patients received intravitreal injection of conbercept once a month, three times in total. The preoperative and postoperative best-corrected visual acuity(BCVA), and changes in OCT biomarkers, including central macular thickness(CMT), the length of disorganization of the retinal inner layers(DRIL), the number of hyperreflective dots(HRD), the area of intraretinal fluid(IRF), the area of subretinal fluid(SRF), and the length of ellipsoid zone(EZ)disruption were compared. Furthermore, the relationship of these changes with BCVA was analyzed.RESULTS:Compared with the baseline, at 3 mo post-treatment, BCVA(LogMAR)was improved, CMT was decreased, the length of DRIL was shortened, the number of HRD was reduced, the area of IRF was decreased, the area of SRF was reduced, and the length of EZ disruption was shortened(all P<0.05). Spearman correlation analysis showed that there was no correlation between the changes in CMT, the length of DRIL, the number of HRD, the area of IRF, the area of SRF and the change in BCVA before and after treatment(P>0.05). However, the change in the length of EZ disruption was positively correlated with the change in BCVA(rs=0.34, P=0.011), and the R2 value of the fitting curve between the change in the length of EZ disruption and the change in BCVA was 0.113(P=0.011). When comparing the pre- and post-treatment changes in BCVA, the length of DRIL, the number of HRD, the area of IRF, the area of SRF, and the length of EZ disruption between patients in the CRVO group and BRVO group, no significant differences were observed(all P>0.05). In contrast, a significant difference was found in the change in CMT between the two groups(P=0.002).CONCLUSION:Conbercept effectively improves multiple OCT biomarkers in patients with RVO-ME. Repair of EZ disruption is a key driver of visual recovery, and its stability may serve as a novel indicator for personalized decision-making in anti-vascular endothelial growth factor therapy.

Cardiovascular disease remains the leading cause of death in China, with its morbidity and mortality continue to rise. Ferroptosis, a unique form of iron-dependent cell death, plays a major role in many heart diseases. The classical mechanisms of ferroptosis include iron metabolism disorder, oxidative antioxidant imbalance and lipid peroxidation. Recent studies have found many additional mechanisms of ferroptosis, such as coenzyme Q10, ferritinophagy, lipid autophagy, mitochondrial metabolism disorder, and the regulation by nuclear factor erythroid 2-related factor 2 (NRF2). This article reviews recent advances in understanding the mechanisms of ferroptosis and its role in heart failure, myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, myocardial toxicity of doxorubicin, septic cardiomyopathy, and arrhythmia. Furthermore, we discuss the potential of ferroptosis inhibitors/inducers as therapeutic targets for heart diseases, suggesting that ferroptosis may be an important intervention target of heart diseases.
Ferroptosis/physiology* ; Humans ; Heart Diseases/physiopathology* ; NF-E2-Related Factor 2/physiology* ; Animals ; Myocardial Reperfusion Injury/physiopathology* ; Lipid Peroxidation ; Heart Failure/physiopathology* ; Iron/metabolism* ; Diabetic Cardiomyopathies/physiopathology* ; Ubiquinone/analogs & derivatives*

The 95% ethanol extract of Stephania hernandifolia was isolated and purified by column chromatography on silica gel and Sephadex LH-20, RP-18 medium-pressure liquid chromatography, and semi-preparative high performance liquid chromatography. The chemical structures of the compounds were identified by NMR and high-resolution mass spectrometry. Four alkaloids were isolated and identified as(-)-8-oxo-2,3,4,10,11-pentamethoxyberberine(1),(-)-8-oxo-11-hydroxy-2,3,4,10-tetramethoxyberberine(2), N-trans-feruloyl tyramine(3), and N-cis-feruloyl tyramine(4). Compounds 1 and 2 were new protoberberine alkaloids, while compounds 3 and 4 were amide alkaloids. All the four compounds were separated from this plant for the first time. The inhibitory activities of compounds 1, 3, and 4 against α-glycosidase were measured by the enzymatic reaction in vitro with 4-nitrophenyl-α-D-glucopyranoside(PNPG) as the substrate. Compounds 3 and 4 showed inhibitory activities against α-glucosidase, with median inhibition concentration(IC_(50)) values of(7.09±0.42) and(31.25±1.14) μmol·L~(-1), respectively.
Berberine Alkaloids/isolation & purification* ; Stephania/chemistry* ; Drugs, Chinese Herbal/isolation & purification* ; Molecular Structure ; alpha-Glucosidases/metabolism* ; Chromatography, High Pressure Liquid ; Alkaloids/isolation & purification*

This study aimed to investigate the correlation between changes in intestinal toxicity and compositional alterations of Euphorbiae Ebracteolatae Radix(commonly known as Langdu) before and after milk processing, and to explore the detoxification mechanism of milk processing. Mice were intragastrically administered the 95% ethanol extract of raw Euphorbiae Ebracteolatae Radix, milk-decocted(milk-processed), and water-decocted(water-processed) Euphorbiae Ebracteolatae Radix. Fecal morphology, fecal water content, and the release levels of inflammatory cytokines tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) in different intestinal segments were used as indicators to evaluate the effects of different processing methods on the cathartic effect and intestinal inflammatory toxicity of Euphorbiae Ebracteolatae Radix. LC-MS/MS was employed to analyze the small-molecule components in the raw product, the 95% ethanol extract of the milk-processed product, and the milky waste(precipitate) formed during milk processing, to assess the impact of milk processing on the chemical composition of Euphorbiae Ebracteolatae Radix. The results showed that compared with the blank group, both the raw and water-processed Euphorbiae Ebracteolatae Radix significantly increased the fecal morphology score, fecal water content, and the release levels of TNF-α and IL-1β in various intestinal segments(P<0.05). Compared with the raw group, all indicators in the milk-processed group significantly decreased(P<0.05), while no significant differences were observed in the water-processed group, indicating that milk, as an adjuvant in processing, plays a key role in reducing the intestinal toxicity of Euphorbiae Ebracteolatae Radix. Mass spectrometry results revealed that 29 components were identified in the raw product, including 28 terpenoids and 1 acetophenone. The content of these components decreased to varying extents after milk processing. A total of 28 components derived from Euphorbiae Ebracteolatae Radix were identified in the milky precipitate, of which 27 were terpenoids, suggesting that milk processing promotes the transfer of toxic components from Euphorbiae Ebracteolatae Radix into milk. To further investigate the effect of milk adjuvant processing on the toxic terpenoid components of Euphorbiae Ebracteolatae Radix, transmission electron microscopy(TEM) was used to observe the morphology of self-assembled casein micelles(the main protein in milk) in the milky precipitate. The micelles formed in casein-terpenoid solutions were characterized using particle size analysis, fluorescence spectroscopy, ultraviolet spectroscopy, and Fourier-transform infrared(FTIR) spectroscopy. TEM observations confirmed the presence of casein micelles in the milky precipitate. Characterization results showed that with increasing concentrations of toxic terpenoids, the average particle size of casein micelles increased, fluorescence intensity of the solution decreased, the maximum absorption wavelength in the UV spectrum shifted, and significant changes occurred in the infrared spectrum, indicating that interactions occurred between casein micelles and toxic terpenoid components. These findings indicate that the cathartic effect of Euphorbiae Ebracteolatae Radix becomes milder and its intestinal inflammatory toxicity is reduced after milk processing. The detoxification mechanism is that terpenoid components in Euphorbiae Ebracteolatae Radix reassemble with casein in milk to form micelles, promoting the transfer of some terpenoids into the milky precipitate.
Animals ; Mice ; Milk/chemistry* ; Drugs, Chinese Herbal/chemistry* ; Male ; Tumor Necrosis Factor-alpha/immunology* ; Intestines/drug effects* ; Interleukin-1beta/immunology* ; Tandem Mass Spectrometry ; Female