AIM: To identify the primary active components and underlying mechanisms of Yijing Decoction(YJD)in treating early diabetic retinopathy(DR)based on liquid chromatography-mass spectrometry and network pharmacology.METHODS: Active components of YJD were characterized through LC-MS. Components with optimal ADME(absorption, distribution, metabolism, excretion)properties were selected as key bioactive candidates. Network pharmacology approaches were employed to predict YJD-DR therapeutic targets. Protein-protein interaction(PPI)networks, gene ontology(GO)enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis were subsequently conducted to predict core targets and networks. Critical targets and pathways were experimentally validated through Western blot.RESULTS: Ten core therapeutic targets were identified, including TNF, Alb, EGFR, STAT3, PTGS2, ESR1, PPAR, MMP9, TLR4, and MAPK. YJD was related to cancer-related signaling, fluid shear stress and atherosclerosis, and neurodegenerative diseases, encompassing key biological processes such as inflammatory response regulation, programmed cell death activation, and enhanced cell migration. Furthermore, Western blot analysis confirmed that YJD significantly inhibited high glucose-induced phosphorylation of STAT3(P-STAT3/STAT3)and ERK(P-ERK/ERK)in rat retinal microvascular endothelial cells.CONCLUSION: This study revealed YJD's pharmacodynamical basis and its multi-component, multi-target, and multi-paths pharmacology. YJD exerts therapeutic effects on DR by coordinately regulating critical signaling pathways and alleviating intraocular inflammation, thus preserving retinal vascular endothelial cells, maintaining blood-retinal barrier integrity, and facilitating retinal neurovascular repair.

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

Obesity usually exacerbates the immunosuppressive tumor microenvironment (ITME), hindering CD8⁺ T cell infiltration and function, which further represents a significant barrier to the efficacy of immunotherapy. Herein, a multifunctional liposomal system (CR-Lip) for encapsulating celastrol (CEL) was utilized to remodel obesity-related ITME and improve cancer immunotherapy, wherein Ginsenoside Rg3 (Rg3) was detected interspersed in the phospholipid bilayer and its glycosyl exposed on the surface of the liposome. CR-Lip had a relatively uniform size (116.5 nm), facilitating favorable tumor tissue accumulation through the interaction between Rg3 and glucose transporter 1 overexpressed in obese tumor cells. Upon reaching the tumor region, CR-Lip was found to induce the immunogenic cell death (ICD) of HFD tumor cells. Notably, the level of PHD3 in HFD tumor cells was effectively boosted by CR-Lip to effectively block metabolic reprogramming and increase the availability of major free fatty acids fuel sources. In vivo, experiments studies revealed that the easy-obtained nano platform stimulated enhanced the production of various cytokines in tumor tissues, DC maturation, CD8⁺ T-cell infiltration, and synergistic anticancer therapeutic potency with aPD-1 (tumor inhibition rate = 82.1%) towards obesity-related melanoma. Consequently, this study presented an efficacious approach to tumor immunotherapy in obese mice by encompassing tumor eradication, inducing ICD, and reprogramming metabolism. Furthermore, it offered a unique insight into a valuable attempt at the immunotherapy of obesity-associated related tumors.

Colorectal tumorigenesis generally progresses from adenoma to adenocarcinoma, accompanied by dynamic changes in the tumor microenvironment (TME). A randomized controlled trial has confirmed the efficacy and safety of Shen-Bai-Jie-Du decoction (SBJDD) in preventing colorectal tumorigenesis. However, the mechanism remains unclear. In this study, we employed single-cell RNA sequencing (scRNA-seq) to investigate the dynamic evolution of the TME and validated cell infiltration with multiplex immunohistochemistry and flow cytometry. Bulk RNA sequencing was utilized to assess the underlying mechanisms. Our results constructed the mutually verifiable single-cell transcriptomic atlases in Apc ^Min/+ mice and clinical patients. There was a marked accumulation of CCL22⁺ dendritic cells (DCs) and an enhanced immunosuppressive action, which SBJDD and berberine reversed. Combined treatment with cholesterol and lipopolysaccharide induced characteristic gene expression of CCL22⁺ DCs, which may represent "exhausted DCs". Intraperitoneal injection of these DCs after SBJDD treatment eliminated its therapeutic effects. TMEM131 derived CCL22⁺ DCs generation by TNF signaling pathway and may be a potential target of berberine in retarding colorectal tumorigenesis. These findings emphasize the role of exhausted DCs and the regulatory mechanisms of SBJDD and berberine in colorectal cancer (CRC), suggesting that the multi-component properties of SBJDD may help restore TME homeostasis and offer novel cancer therapy.

Background::A phase II trial on recombinant human tenecteplase tissue-type plasminogen activator (rhTNK-tPA) has previously shown its preliminary efficacy in ST elevation myocardial infarction (STEMI) patients. This study was designed as a pivotal postmarketing trial to compare its efficacy and safety with rrecombinant human tissue-type plasminogen activator alteplase (rt-PA) in Chinese patients with STEMI.Methods::In this multicenter, randomized, open-label, non-inferiority trial, patients with acute STEMI were randomly assigned (1:1) to receive an intravenous bolus of 16 mg rhTNK-tPA or an intravenous bolus of 8 mg rt-PA followed by an infusion of 42 mg in 90 min. The primary endpoint was recanalization defined by thrombolysis in myocardial infarction (TIMI) flow grade 2 or 3. The secondary endpoint was clinically justified recanalization. Other endpoints included 30-day major adverse cardiovascular and cerebrovascular events (MACCEs) and safety endpoints.Results::From July 2016 to September 2019, 767 eligible patients were randomly assigned to receive rhTNK-tPA ( n = 384) or rt-PA ( n = 383). Among them, 369 patients had coronary angiography data on TIMI flow, and 711 patients had data on clinically justified recanalization. Both used a –15% difference as the non-inferiority efficacy margin. In comparison to rt-PA, both the proportion of patients with TIMI grade 2 or 3 flow (78.3% [148/189] vs. 81.7% [147/180]; differences: –3.4%; 95% confidence interval [CI]: –11.5%, 4.8%) and clinically justified recanalization (85.4% [305/357] vs. 85.9% [304/354]; difference: –0.5%; 95% CI: –5.6%, 4.7%) in the rhTNK-tPA group were non-inferior. The occurrence of 30-day MACCEs (10.2% [39/384] vs. 11.0% [42/383]; hazard ratio: 0.96; 95% CI: 0.61, 1.50) did not differ significantly between groups. No safety outcomes significantly differed between groups. Conclusion::rhTNK-tPA was non-inferior to rt-PA in the effect of improving recanalization of the infarct-related artery, a validated surrogate of clinical outcomes, among Chinese patients with acute STEMI.Trial registration::www.ClinicalTrials.gov (No. NCT02835534).

Objective:To explore the potential application of two-dimensional speckle tracking echocardiography (2D-STE) in terms of quantification and evaluating left and right atrial function in normal fetuses, and to investigate the relevant factors affecting left and right atrial function in normal fetuses as well as differences between both atrial function.Methods:A total of 100 single fetuses underwent fetal echocardiography in the Department of Diagnostic Ultrasound & Echocardiography, Sir Run Run Shaw Hospital, Zhejiang University College of Medicine from January 2019 to October 2022 were retrospectively enrolled. The standard basal or apical four-chamber view clips were obtained, and the left and right atrial function were quantitatively analyzed using TomTec-ARENA off-line cardiac analysis software for quantitative assessment of both atrial strain measurements including left atrial reservoir phase longitudinal strain (LASr), left atrial ductal phase longitudinal strain (LAScd), left atrial systolic phase longitudinal strain (LASct), right atrial reservoir phase longitudinal strain (RASr), right atrial ductal phase longitudinal strain (RAScd), right atrial systolic phase longitudinal strain (RASct), and the ratio of systolic longitudinal strain to conduit longitudinal strain in left and right atrial systolic display groups were calculated which was denoted as Sct/Scd.Routine fetal obstetric ultrasound measurements and fetal echocardiographic parameters in the two groups were obtained including fetal heart rate (FHR), left atrial end-systolic length (LAESL), left atrial end-systolic diameter (LAESD), left atrial end-systolic area (LAESA), left ventricular end-diastolic transverse diameter (LVEDD), right atrial end-systolic length (RAESL), right atrial end-systolic diameter (RAESD), right atrial end-systolic area (RAESA), right ventricular end-diastolic transverse diameter (RVEDD), peak blood flow velocity of mitral valve and tricuspid valve in early and late diastolic period (E, A), peak ratio of E and A: E/A (MV), E/A (TV), and the difference between the left and right atrial strain indices and the routine fetal obstetric ultrasound and fetal echocardiographic parameters, as well as the correlation between the above parameters and gestational age were analyzed. The repeatability tests were performed using the intra-class correlation coefficientt (ICC).Results:Significant differences were found in LASr and RASr, LAScd and RAScd, LASct and LAScd, Sct/Scd between the left atrium and right atrium, E/A (MV) and E/A (TV), LAESD and RAESD, LAESL and RAESL (all P<0.05), there was significant difference in FHR between the left atrial contraction display group and the no atrial contraction display group ( P=0.011), no significant difference in other parameters (all P>0.05). Correlation analysis showed that, LASr, LASct, RASr, and RASct showed moderate negative correlation with gestational age ( rs=-0.570, -0.601, -0.469, -0.568; all P<0.001). While LAScd, RAScd, E/A (MV), E/A (TV) were moderately positively related with gestational age ( rs=0.310, 0.350, 0.330, 0.343; all P<0.05). LAESL, LAESD, LAESA, RAESL, RAESD, RAESA, LVEDD and RVEDD were significantly positively related with gestational age ( rs=0.662, 0.768, 0.792, 0.728, 0.828, 0.822, 0.838, 0.802, all P<0.001). The inter-examiner ICC of fetal LASr and RASr were 0.89 and 0.84 (both P<0.05) and the intra-examiner ICC of fetal RASr and LASr both were 0.80 (both P<0.05), with good consistency. Conclusions:2D-STE is highly feasible and reproducible in assessing fetal atrial function. The corresponding variation values of fetal atria at different gestational weeks were obtained in this study, which provides a new reference index for us to further study normal fetal atria as well as comparative analysis of fetal cardiac function under prenatal pathological conditions.

AIM: To observe the changes of corneal densitometry(CD)in patients with keratoconus after corneal cross-linking(CXL).METHODS: Retrospective study. A total of 32 patients(43 eyes)with keratoconus in Ningxia Eye Hospital from April 2020 to April 2022 were selected. Pentacam analysis system divided the cornea into three layers: anterior 120 μm, middle layer and posterior 60 μm, and divides it into five regions with diameters of 0-2, 2-6, 6-10, 10-12 mm and full diameter according to the diameter, and measures the CD in different ranges. The changes of CD were compared before operation and at 1, 3 and 6 mo after operation.RESULTS: There were differences in uncorrected visual acuity, best corrected visual acuity and intraocular pressure before and 6 mo after operation(all P<0.05), and there was no difference in corneal endothelial cells(P=0.477). CD reached its peak at 1 mo after operation, and decreased at 3 mo and 6 mo after operation, but it was still higher than that before operation. There is a significant positive correlation between CD and Kmax in the anterior layer and the whole layer(r=0.164, P=0.016; r=0.152, P=0.023).CONCLUSION: The values of CD peaked at 1 mo after CXL, then it gradually decreased, tending to become stable at 6 mo postoperatively.

Objective To investigate the etiology of chronic renal failure (CRF) in middle-aged and elderly people, and to analyze related factors influencing the prognosis. Methods The clinical data of 456 middle-aged and elderly CRF patients treated in our hospital from January 2018 to January 2021 were collected. The etiology and related factors affecting prognosis were analyzed. Results The etiology of 456 middle-aged and elderly patients with CRF was as follows: 220 cases of primary glomerulonephritis (48.24%), 78 cases of diabetic nephropathy (17.14%), 65 cases of hypertensive nephropathy (14.25%), and 37 cases of pyelonephritis (8.11%), 19 cases of drug-induced renal injury (4.16%), 18 cases of obstructive nephropathy (3.95%), 12 cases of lupus nephritis (2.63%), and 7 cases of polycystic kidney disease (1.54%). The age of onset in patients with primary glomerulonephritis and lupus nephritis was lower than that in patients with other causes (P<0.05). The results showed that 94 of the 456 patients died in the hospital, and the mortality rate was 20.6%. Multivariate logistic regression analysis showed that age, severe infection, cerebrovascular disease, arrhythmia, hypertension stage III, left ventricular hypertrophy, and myocardial infarction were high-risk factors leading to poor prognosis (P<0.05). Conclusion The main causes of CRF in middle-aged and elderly patients are primary glomerulonephritis, diabetic nephropathy, and hypertensive nephropathy. Heart disease is the main factor leading to the poor prognosis of such patients. Efforts shall be put into disease prevention and control work for high-risk groups, so as to reduce the incidence and mortality of CRF.

Zn²⁺ is required for the activity of many mitochondrial proteins, which regulate mitochondrial dynamics, apoptosis and mitophagy. However, it is not understood how the proper mitochondrial Zn²⁺ level is achieved to maintain mitochondrial homeostasis. Using Caenorhabditis elegans, we reveal here that a pair of mitochondrion-localized transporters controls the mitochondrial level of Zn²⁺. We demonstrate that SLC-30A9/ZnT9 is a mitochondrial Zn²⁺ exporter. Loss of SLC-30A9 leads to mitochondrial Zn²⁺ accumulation, which damages mitochondria, impairs animal development and shortens the life span. We further identify SLC-25A25/SCaMC-2 as an important regulator of mitochondrial Zn²⁺ import. Loss of SLC-25A25 suppresses the abnormal mitochondrial Zn²⁺ accumulation and defective mitochondrial structure and functions caused by loss of SLC-30A9. Moreover, we reveal that the endoplasmic reticulum contains the Zn²⁺ pool from which mitochondrial Zn²⁺ is imported. These findings establish the molecular basis for controlling the correct mitochondrial Zn²⁺ levels for normal mitochondrial structure and functions.
Animals ; Caenorhabditis elegans/metabolism* ; Cation Transport Proteins/genetics* ; Homeostasis ; Mitochondria/metabolism* ; Zinc/metabolism*

Objective:To carry out prenatal screening and diagnosis for a woman with advanced maternal age.Methods:Non-invasive prenatal testing (NIPT) was carried out to determine the risk of fetal chromosome aneuploidy. Aminiocentesis was proceeded for fetal chromosomal karyotyping and copy number variation sequencing (CNV-seq). The fetus was subjected to systematic ultrasound screening in the second trimester.Results:NIPT has indicated there was a loss of fetal sex chromosome. Karotyping of the amniocyte showed a mosaic sex chromosome abnormality 45, X[53]/46, X, + mar[7]. The result of fetal DNA CNV-seq was seq[GRCh37]del(Yq11.1q12) chrY: g. 13 104 553-28 819 361del, seq[GRCh37]del(Yp11.32p11.2) chrY: g. 10 001-9 873 915del (mosaic ratio: 30%). Ultrasonography discovered that the fetus had renal dysplasia and male external genitalia. The karyotypes of the couple were both normal.Conclusion:Multiple genetic tests should be carried out for fetus with a high risk for chromosome aneuploidies signaled by NIPT. It is difficult to predict the post-natal phenotype for fetuses with mosaic sex chromosomal aneuploidies. The couple should be carefully counseled upon genetic counseling.