OBJECTIVE: To evaluate the efficacy and safety of Shexiang Tongxin Dropping Pill (STDP) in treating stable angina patients with phlegm-heat and blood-stasis syndrome by exercise duration and metabolic equivalents. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled stable angina patients with phlegm-heat and blood-stasis syndrome from 22 hospitals. They were randomized 1:1 to STDP (35 mg/pill, 6 pills per day) or placebo for 56 days. The primary outcome was the exercise duration and metabolic equivalents (METs) assessed by the standard Bruce exercise treadmill test after 56 days of treatment. The secondary outcomes included the total angina symptom score, Chinese medicine (CM) symptom scores, Seattle Angina Questionnaire (SAQ) scores, changes in ST-T on electrocardiogram and adverse events (AEs). RESULTS: This trial enrolled 309 patients, including 155 and 154 in the STDP and placebo groups, respectively. STDP significantly prolonged exercise duration with an increase of 51.0 s, compared to a decrease of 12.0 s with placebo (change rate: -11.1% vs. 3.2%, P<0.01). The increase in METs was significantly greater in the STDP group than in the placebo group (change: -0.4 vs. 0.0, change rate: -5.0% vs. 0.0%, P<0.01). The improvement of total angina symptom scores (25.0% vs. 0.0%), CM symptom scores (38.7% vs. 11.8%), reduction of nitroglycerin consumption (100.0% vs. 11.3%), and all domains of SAQ, were significantly greater with STDP than placebo (all P<0.01). The changes in Q-T intervals at 28 and 56 days from baseline were similar between the two groups (both P>0.05). Twenty-five participants (16.3%) with STDP and 16 (10.5%) with placebo experienced AEs (P=0.131), with no serious AEs observed. CONCLUSION STDP could improve exercise tolerance in patients with stable angina and phlegm-heat and blood stasis syndrome, with a favorable safety profile. (Registration No. ChiCTR-IPR-15006020).
Humans ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Middle Aged ; Angina, Stable/physiopathology* ; Aged ; Syndrome ; Treatment Outcome ; Placebos ; Tablets

Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C₀), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug‍-‍drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

ObjectiveAs the central hub of the classical visual pathway, the primary visual cortex not only encodes and processes visual information but also establishes dense neural circuit connections with higher-order cognitive brain regions. Numerous studies have shown that 40 Hz flicker stimulation can induce γ oscillations in the brain and significantly improve learning and cognitive impairments in patients with neurodegenerative diseases. Moreover, flickering light phenomena naturally occur in daily environments. Given that the primary visual cortex serves as the brain’s first cortical hub for receiving visual input, it is essential to comprehensively understand how non-invasive light flicker stimulation modulates its information processing mechanisms. This study systematically investigates the effects of non-invasive light flicker stimulation at different frequencies on the functional properties of neurons in the primary visual cortex of adult mice, aiming to uncover how such stimulation modulates this region and, consequently, affects overall brain function. MethodsThree groups of adult mice (approximately 12 weeks old) were exposed to light flicker stimulation at frequencies of 20 Hz, 40 Hz, and 60 Hz, respectively, for a duration of two months. A control group was exposed to the same light intensity without flickering. Following the stimulation period, in vivo multi-channel electrophysiological recordings were conducted. During these recordings, anesthetized mice were presented with various types of moving sinusoidal light gratings to assess the effects of different flicker frequencies on the functional properties of neurons in the primary visual cortex. ResultsThe experimental results demonstrate that two months of light flicker stimulation at 20 Hz, 40 Hz, and 60 Hz enhances the orientation tuning capabilities of neurons in the primary visual cortex. Specifically, 40 Hz and 60 Hz stimulation improved contrast sensitivity, whereas 20 Hz had no significant effect. Further analysis revealed that all three frequencies reduced neuronal response variability (as measured by the Fano factor), increased the signal-to-noise ratio, and decreased noise correlation (r_sc) between neurons. ConclusionNon-invasive light flicker stimulation enhances orientation tuning (e.g., orientation bias index) and contrast sensitivity (e.g., contrast threshold and C₅₀) in neurons of the primary visual cortex. This enhancement is likely due to improved information processing efficiency, characterized by reduced neuronal variability and increased signal-to-noise ratio. These findings suggest that the primary visual cortex can achieve precise and efficient information encoding in complex lighting environments by selectively adapting to different flicker frequencies and optimizing receptive field properties. This study provides new experimental evidence on how various types of light flicker influence visual perception and offers insights into the mechanisms through which specific frequencies enhance brain function.

Objective To assess the effectiveness of the evaluation of military physical function(EMPF)system in predicting the occurrence of military training injuries among new recruits to provide scientific guidance and methodological choice for military training.Methods A total of 527 new recruits from 5 grassroots units from July 2016 to February 2018 were selected for the study.The recruits underwent EMPF testing,and their military training injuries were monitored over a 2-year follow-up period.Those who sustained injuries during training were divided into injury group(n=163),while the remaining recruits were placed in healthy group(n=364).The predictive ability of the total EMPF score for training injuries was assessed using the receiver operating characteristic curve(ROC),and the correlation between the total EMPF score,individual test scores,and military training injuries were analyzed using binary logistic regression.Results The total EMPF score of new recruits in injury group(19.52±1.97)was significantly lower than that of healthy group(24.31±1.54)(P<0.001),which also demonstrated a high diagnostic value in predicting the risk of military training injuries,with an area under the curve(AUC)of ROC of 0.971(P<0.001).A cut-off value of 22 scores was found to have the highest accuracy in predicting future training injuries,with an odds ratio(OR)of 25.63,sensitivity of 0.939,specificity of 0.879,positive likelihood ratio of 7.76,and a post-test probability of 0.67.Binary logistic regression analysis revealed that 6 EMPF tests,including holding the ball over and leaning back,bending forward and touching the ground with the ball,lunge squat and twist,swallow balance with holding the ball afterward,vertical jump,and respiratory pattern assessment,were negatively associated with the risk of military training injuries(P<0.0001).Conclusion The EMPF system can effectively predict the risk of military training injuries,with military personnel whose total EMPF score is less than 22 being at higher risk of sustaining such injuries.

Military training represents one of the most essential activities for troops during peacetime,of which the prevention and treatment of training-induced injuries are a very important part.Recent findings of research suggest that cold atmospheric plasma(CAP)exhibits a distinctive and multifaceted superiority in terms of broad-spectrum sterilization,rapid blood coagulation and healing promotion for wounds.Consequently,CAP has good prospects of applications in diverse fields such as clinical medicine,emergency rescue and military medicine.Based on a review of the research progress in plasma medicine,the applicability of CAP in the prevention and treatment of military training injuries was discussed in this paper by focusing on the urgent issues related to military training injury,including the typical application scenarios and methods for CAP,the safety and effectiveness of plasma trauma prevention and treatment,and the key issues facing the prevention and treatment of military training injuries.

Objective:To explore the role of lactate in Superoxide dismutase 2 (SOD2) lactylation in cerebral ischemia-reperfusion injury in mice.Methods:Male C57BL/6 mice were randomLy (random number) divided into 4 groups: sham operation group (Sham group), Middle Cerebral Artery Occlusion/Reperfusion group (MCAO/R group), Middle Cerebral Artery Occlusion/Reperfusion+2-Deoxy-D-glucose group (MCAO/R+2-DG group), Middle Cerebral Artery Occlusion/Reperfusion+sodium lactate group (MCAO/R+Nala group). Cerebral ischemia reperfusion injury model was established in the mice of MCAO/R group using the thread occlusion. In the MCAO/R+2-DG group, mice received an intraperitoneal injection of 250 mg/kg of 2-DG 90 min before ischemia. Mice in the MCAO/R+ Nala group was given an intraventricular injection of 2 μL of 100 mmol/L Nala 24 h before ischemia. Commercial kits was used to detect lactate levels, Hematoxylin & Eosin Staining (HE) was employed to observe cell morphology, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was performed to assess cell apoptosis, and immunofluorescence was utilized to detect reactive oxygen species (ROS). Western blot was conducted to measure SOD2, Superoxide Dismutase 2 Lysine 114 Lactylation(SOD2-K114la), Iron regulatory protein 2(IRP2) and transferrin receptor protein 1(TFR1) levels. The above indicators were analyzed and compared by one-way variance.Results:Compared with the Sham group, the MCAO/R group showed increased levels of lactate, SOD2-K114la, TUNEL positive rate, ROS, IRP2 and TFR1[lactate: (0.608±0.064) vs. (0.376±0.030), P<0.005; SOD2-K114la: (2.311±0.146) vs. (1.009±0.073), P<0.0005; TUNEL positive rate: (35.420±2.832) vs. (0.294±0.147), P<0.0001; ROS: (3.415±0.229) vs. (1.166±0.155), P<0.0001; IRP2: (1.735±0.125) vs. (1.000±0.000), P<0.0001; TFR1: (1.611±0.058) vs. (1.000±0.000), P<0.0001], while SOD2 decreased[(0.545±0.062) vs. (1.082±0.088), P<0.0001]. HE staining indicated brain damage. Compared with the MCAO/R group, the MCAO/R+2-DG group showed reduced levels of lactate, SOD2-K114la, TUNEL positive rate, ROS, IRP2, and TFR1[lactate: (0.453±0.047) vs. (0.608±0.064), P<0.05; SOD2-K114la: (1.764±0.188) vs. (2.311±0.146), P<0.05; TUNEL positive rate: (23.800±3.168) vs. (35.420±2.832), P<0.005; ROS: (2.640±0.213) vs. (3.415±0.229), P<0.005; IRP2: (1.463±0.055) vs. (1.735±0.125), P<0.05; TFR1: (1.252±0.081) vs. (1.611±0.058), P<0.005], with higher level of SOD2 [(0.727±0.026) vs. (0.545±0.062), P<0.05]. Meanwhile, HE staining indicated reduced damage. Compared with the MCAO/R group, the MCAO/R+Nala group showed increased levels of lactate, SOD2-K114la, TUNEL positive rate, ROS, IRP2 and TFR1[lactate: (1.021±0.051) vs. (0.608±0.064), P<0.0001; SOD2-K114la: (3.479±0.275) vs. (2.311±0.146), P<0.0005; TUNEL positive rate: (53.430±3.551) vs. (35.420±2.832), P<0.0001; ROS: (4.687±0.253) vs. (3.415±0.229), P<0.0001; IRP2: (2.463±0.117) vs. (1.735±0.125), P<0.0001; TFR1: (2.209±0.094) vs. (1.611±0.058), P<0.0001], with decreased levels of SOD2 [(0.286±0.040) vs. (0.545±0.062), P<0.0001]. And HE staining revealed worsened braindamage. Conclusions:Increased lactate levels can enhance the lactylation of SOD2, exacerbating brain damage after Cerebral ischemia reperfusion injury(CIRI). Inhibiting lactate production may alleviate brain injury by regulating iron Metabolism.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been included in various neoadjuvant therapy (NAT) regimens for non-small cell lung cancer (NSCLC). However, due to the relatively short period for the use of ICIs in NAT, patients' clinical outcomes with different regimens are uncertain. Our study aims to examine the efficacy of neoadjuvant immunotherapy (NAIT) for NSCLC patients and compare the overall survival (OS) and event-free survival (EFS) of patients receiving different NAT regimens. METHODS: This study retrospectively included 308 NSCLC patients treated with different NAT regimens and subsequent surgery in National Cancer Center between August 1, 2016 and July 31, 2022. Kaplan-Meier survival analysis and Cox proportional hazards regression analysis were conducted to evaluate the prognosis of patients. RESULTS: With a median follow-up of 27.5 months, the 1-year OS rates were 98.8% and 96.2%, and the 2-year OS rates were 96.6% and 85.8% in patients of the NAIT and neoadjuvant chemotherapy (NACT) group, respectively (hazard ratio [HR], 0.339; 95% confidence interval [CI], 0.160-0.720; P = 0.003). The 1-year EFS rates were 96.0% and 88.0%, and the 2-year EFS rates were 92.0% and 77.7% for patients in the NAIT and NACT groups, respectively (HR, 0.438; 95% CI, 0.276-0.846; P = 0.010). For patients who did not achieve pathological complete response (pCR), significantly longer OS ( P = 0.012) and EFS ( P = 0.019) were observed in patients receiving NAIT than those receiving NACT. Different NAT regimens had little effect on surgery and the postoperative length of stay (6 [4, 7] days vs . 6 [4, 7] days, Z = -0.227, P = 0.820). CONCLUSIONS NAIT exhibited superior efficacy to NACT for NSCLC, resulting in longer OS and EFS. The OS and EFS benefits were also observed among patients in the NAIT group who did not achieve pCR.
Humans ; Carcinoma, Non-Small-Cell Lung/mortality* ; Male ; Female ; Lung Neoplasms/mortality* ; Middle Aged ; Immune Checkpoint Inhibitors/therapeutic use* ; Neoadjuvant Therapy/methods* ; Retrospective Studies ; Aged ; Adult ; Kaplan-Meier Estimate ; Treatment Outcome ; Immunotherapy/methods*

This study aims to explore the mechanism of lung and gut protection by Tanreqing Capsules on the mice infected with influenza virus based on "the lung-gut axis". A total of 110 C57BL/6J mice were randomized into control group, model group, oseltamivir group, and low-and high-dose Tanreqing Capsules groups. Ten mice in each group underwent body weight protection experiments, and the remaining 12 mice underwent experiments for mechanism exploration. Mice were infected with influenza virus A/Puerto Rico/08/1934(PR8) via nasal inhalation for the modeling. The lung tissue was collected on day 3 after gavage, and the lung tissue, colon tissue, and feces were collected on day 7 after gavage for subsequent testing. The results showed that Tanreqing Capsules alleviated the body weight reduction and increased the survival rate caused by PR8 infection. Compared with model group, Tanreqing Capsules can alleviate the lung injury by reducing the lung index, alleviating inflammation and edema in the lung tissue, down-regulating viral gene expression at the late stage of infection, reducing the percentage of neutrophils, and increasing the percentage of T cells. Tanreqing Capsules relieved the gut injury by restoring the colon length, increasing intestinal lumen mucin secretion, alleviating intestinal inflammation, and reducing goblet cell destruction. The gut microbiota analysis showed that Tanreqing Capsules increased species diversity compared with model group. At the phylum level, Tanreqing Capsules significantly increased the abundance of Firmicutes and Actinobacteria, while reducing the abundance of Bacteroidota and Proteobacteria to maintain gut microbiota balance. At the genus level, Tanreqing Capsules significantly increased the abundance of unclassified＿f＿Lachnospiraceae while reducing the abundance of Bacteroides, Eubacterium, and Phocaeicola to maintain gut microbiota balance. In conclusion, Tanreqing Capsules can alleviate mouse lung and gut injury caused by influenza virus infection and restore the balance of gut microbiota. Treating influenza from the lung and gut can provide new ideas for clinical practice.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Mice ; Lung/metabolism* ; Mice, Inbred C57BL ; Capsules ; Orthomyxoviridae Infections/virology* ; Gastrointestinal Microbiome/drug effects* ; Male ; Humans ; Female ; Influenza A virus/physiology* ; Influenza, Human/virology*

In the present study, a mouse model of coronary artery ligation was employed to evaluate the effects of Jiming Powder on mitophagy in the mouse model of myocardial infarction and elucidate its underlying mechanisms. A mouse model of myocardial infarction post heart failure was constructed by ligating the left anterior descending branch of the coronary artery. The therapeutic efficacy of Jiming Powder was assessed from multiple perspectives, including ultrasonographic imaging, hematoxylin-eosin(HE) staining, Masson staining, and serum cardiac enzyme profiling. Dihydroethidium(DHE) staining was employed to evaluate the oxidative stress levels in the hearts of mice from each group. Mitophagy levels were assessed by scanning electron microscopy and immunofluorescence co-localization. Western blot was employed to determine the levels of key proteins involved in mitophagy, including Bcl-2-interacting protein beclin 1(BECN1), sequestosome 1(SQSTM1), microtubule-associated protein 1 light chain 3 beta(LC3B), PTEN-induced putative kinase 1(PINK1), phospho-Parkinson disease protein(p-Parkin), and Parkinson disease protein(Parkin). The results demonstrated that compared with the model group, high and low doses of Jiming Powder significantly reduced the left ventricular internal diameter in systole(LVIDs) and left ventricular internal diameter in diastole(LVIDd) and markedly improved the left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS), effectively improving the cardiac function in post-myocardial infarction mice. Jiming Powder effectively reduced the levels of myocardial injury markers such as creatine kinase(CK), creatine kinase isoenzyme(CK-MB), and lactate dehydrogenase(LDH), thereby protecting ischemic myocardium. HE staining revealed that Jiming Powder attenuated inflammatory cell infiltration after myocardial infarction. Masson staining indicated that Jiming Powder effectively inhibited ventricular remodeling. Western blot results showed that Jiming Powder activated the PINK1-Parkin pathway, up-regulated the protein level of BECN1, down-regulated the protein level of SQSTM1, and increased the LC3Ⅱ/LC3Ⅰ ratio to promote mitophagy. In conclusion, Jiming Powder exerts therapeutic effects on myocardial infarction by inhibiting ventricular remodeling. The findings pave the way for subsequent pharmacological studies on the active components of Jiming Powder.
Animals ; Myocardial Infarction/physiopathology* ; Mitophagy/drug effects* ; Mice ; Drugs, Chinese Herbal/administration & dosage* ; Protein Kinases/genetics* ; Male ; Ubiquitin-Protein Ligases/genetics* ; Humans ; Disease Models, Animal ; Mice, Inbred C57BL ; Signal Transduction/drug effects*

This study employed a mouse model of coronary artery ligation to assess the effect and mechanism of Jiming Powder on mitochondrial autophagy in mice with myocardial infarction. The mouse model of heart failure post-myocardial infarction was established by ligating the left anterior descending coronary artery. The pharmacological efficacy of Jiming Powder was evaluated through echocardiographic imaging, hematoxylin-eosin(HE) staining, and Masson staining. The levels of malondialdehyde(MDA), Fe~(2+), reduced glutathione(GSH), and superoxide dismutase(SOD) in heart tissues, as well as MDA immunofluorescence of heart tissues, were measured to assess lipid peroxidation and Fe~(2+) levels in the hearts of mice in different groups. Ferroptosis levels in the groups were evaluated using scanning electron microscopy and Prussian blue staining. Western blot analysis was conducted to detect the levels of key ferroptosis-related proteins, including nuclear factor erythroid 2-related factor 2(NRF2), ferritin heavy chain(FTH), glutathione peroxidase 4(GPX4), solute carrier family 7 member 11(SLC7A11), heme oxygenase 1(HO-1), and Kelch-like ECH-associated protein 1(KEAP1). The results showed that compared with the model group, both the high-and low-dose Jiming Powder groups exhibited significantly reduced left ventricular internal diameter in systole(LVIDs) and left ventricular internal diameter in diastole(LVIDd), while the left ventricular ejection fraction(EF) and left ventricular fractional shortening(FS) were significantly improved, effectively enhancing cardiac function in mice post-myocardial infarction. HE staining revealed that Jiming Powder attenuated myocardial inflammatory cell infiltration post-infarction, and Masson staining indicated that Jiming Powder effectively reduced fibrosis in the infarct margin area. Treatment with Jiming Powder reduced the levels of MDA and Fe~(2+), indicators of lipid peroxidation post-myocardial infarction, while increasing GSH and SOD levels, thus protecting ischemic myocardium. Western blot results demonstrated that Jiming Powder reduced KEAP1 protein accumulation, activated the NRF2/HO-1/GPX4 pathway, and up-regulated the protein expression of FTH and SLC7A11, exerting an inhibitory effect on ferroptosis. This study reveals that Jiming Powder exerts a therapeutic effect on myocardial infarction by inhibiting ferroptosis through the NRF2/HO-1/GPX4 pathway, providing a foundation for subsequent research on the pharmacological effects of Jiming Powder.
Animals ; Ferroptosis/drug effects* ; Myocardial Infarction/physiopathology* ; NF-E2-Related Factor 2/genetics* ; Mice ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Heme Oxygenase-1/genetics* ; Phospholipid Hydroperoxide Glutathione Peroxidase/genetics* ; Humans ; Mice, Inbred C57BL ; Signal Transduction/drug effects* ; Disease Models, Animal