ObjectiveTo observe the clinical efficacy and safety of Tangning Tongluo tablets in the treatment of nonproliferative diabetic retinopathy （DR）. MethodsFourteen research centers participated in this study， which spanned a time interval from September 2021 to May 2023. A total of 240 patients with nonproliferative DR were included and randomly assigned into an observation group （120 cases） and a control group （120 cases）. The observation group was treated with Tangning Tongluo tablets， and the control group with calcium dobesilate capsules. Both groups were treated for 24 consecutive weeks. The vision， DR progression rate， retinal microhemangioma， hemorrhage area， exudation area， glycosylated hemoglobin （HbA1c） level， and TCM syndrome score were assessed before and after treatment， and the safety was observed. ResultsThe vision changed in both groups after treatment （P<0.05）， and the observation group showed higher best corrected visual acuity （BCVA） than the control group （P<0.05）. The DR progression was slow with similar rates in the two groups. The fundus hemorrhage area and exudation area did not change significantly after treatment in both groups， while the observation group outperformed the control group in reducing the fundus hemorrhage area and exudation area. There was no significant difference in the number of microhemangiomas between the two groups before treatment. After treatment， the number of microhemangiomas decreased in both the observation group （Z=-1.437， P<0.05） and the control group （Z=-2.238， P<0.05）， and it showed no significant difference between the two groups. As the treatment time prolonged， the number of microhemangiomas gradually decreased in both groups. There was no significant difference in the HbA1c level between the two groups before treatment. After treatment， the decline in the HbA1c level showed no significant difference between the two groups. The TCM syndrome score did not have a statistically significant difference between the two groups before treatment. After treatment， neither the TCM syndrome score nor the response rate had significant difference between the two groups. With the extension of the treatment time， both groups showed amelioration of TCM syndrome compared with the baseline. ConclusionTangning Tongluo tablets are safe and effective in the treatment of nonproliferative DR， being capable of improving vision and reducing hemorrhage and exudation in the fundus.

With the rapid development of sequencing technologies, the detection of alternative polyadenylation (APA) in mammals has become more precise. APA precisely regulates gene expression by altering the length and position of the poly(A) tail, and is involved in various biological processes such as disease occurrence and embryonic development. The research on APA in mammals mainly focuses on the following aspects:(1) identifying APA based on transcriptome data and elucidating their characteristics; (2) investigating the relationship between APA and gene expression regulation to reveal its important role in life regulation;(3) exploring the intrinsic connections between APA and disease occurrence, embryonic development, differentiation, and other life processes to provide new perspectives and methods for disease diagnosis and treatment, as well as uncovering embryonic development regulatory mechanisms. In this review, the classification, mechanisms and functions of APA were elaborated in detail and the methods for APA identifying and APA data resources based on various transcriptome data were systematically summarized. Moreover, we epitomized and provided an outlook on research on APA, emphasizing the role of sequencing technologies in driving studies on APA in mammals. In the future, with the further development of sequencing technology, the regulatory mechanisms of APA in mammals will become clearer.

OBJECTIVE: To explore the efficacy and apoptosis of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of acute myeloid leukemia (AML) with ASXL1 mutation. METHODS: The clinical data of 80 AML patients with ASXL1 mutation treated in our hospital from January 2019 to December 2021 were retrospectively analyzed. The clinical characteristics of the patients were summarized, and the therapeutic effect and prognostic factors of allo-HSCT for the patients were analyzed. RESULTS: Among the 80 patients, 38 were males and 42 were females, and the median age was 39(14-65) years. There were 17 patients in low-risk group, 25 patients in medium-risk group and 38 patients in high-risk group. ASXL1 mutation co-occurred with many other gene mutations, and the frequent mutated genes were TET2 (71.25%), NRAS (18.75%), DNMT3A (16.25%), NPM1 (15.00%), CEBPA (13.75%). Among medium and high-risk patients, 29 underwent allo-HSCT, while 34 received chemotherapy. The 2-year overall survival (OS) rate and disease-free survival (DFS) rate of the allo-HSCT group were 72.4% and 70.2%, while those of the chemotherapy group were 44.1% and 34.0%, respectively. The statistical analysis showed significant differences between the two groups (both P < 0.01). Multivariate analysis showed that age at transplantation >50- years and occurrence of acute graft-versus-host disease after transplantation were poor prognostic factors for OS and DFS in transplantation patients. CONCLUSION Allo-HSCT can improve the prognosis of AML patients with ASXL1 mutation.
Humans ; Leukemia, Myeloid, Acute/therapy* ; Hematopoietic Stem Cell Transplantation ; Female ; Male ; Middle Aged ; Mutation ; Adult ; Repressor Proteins/genetics* ; Adolescent ; Retrospective Studies ; Aged ; Nucleophosmin ; Young Adult ; Transplantation, Homologous ; Prognosis ; Survival Rate

OBJECTIVE: To investigate the antidepressant effects of Xiaoyao Pill (XYP) by exploring its interactions with gut microbiota and tryptophan metabolism. METHODS: Utilizing network pharmacology, the functional substance groups, key targets, and pathways of XYP in the treatment of depression were identified. The chronic unpredictable mild stress (CUMS) protocol was implemented in male Sprague-Dawley rats to establish depression model. Thirty rats were randomly divided into 3 groups according to their body weight (10 for each): control, CUMS and XYP groups (1.8 g/kg). After 28-day interventions, behavioral phenotyping including sucrose preference test (SPT) and open field test (OFT) were performed. Biochemical validation encompassed enzyme-linked immunosorbent assay for serum cortisol, hematoxylin-eosin histopathology, and immunohistochemistry. Liquid chromatography-mass spectrometry was utilized to profile serum metabolites, while fecal samples underwent metagenomic sequencing for gut microbiota characterization. RESULTS: Network pharmacology studies predicted that key components can protect the nervous system by regulating inflammatory pathways through the blood-brain barrier. SPT and OFT showed that XYP treatment significantly ameliorated depressive-like behaviors (all P<0.05). XYP treatment also restored hippocampal neuronal density, increased serum neurotransmitter levels of neurotransmitters such as 5-hydroxytryptamine and vasoactive intestinal peptide, and while suppressing inflammatory markers such as tumor necrosis factor-alpha, interleukin-1 beta (IL-1 β), and IL-6 (all P<0.05). Metagenomics revealed significant restructuring of gut microbiota, notably the regulation of Parabacteroides distasonis (P<0.05). Non-targeted metabolomics analysis showed that the level of metabolites in the tryptophan and kynurenine pathway significantly changed (variable importance in the projection >1, P<0.05), and the change of metabolic flux was significantly correlated with behavioral improvement (P<0.05). CONCLUSIONS XYP exerts antidepressant effects by increasing neurotransmitter levels, reducing inflammatory makers and modulating Parabacteroides distasonis. Through further exploration of metabolomics, we found that XYP may play a protective role in depression by regulating tryptophan metabolism.
Animals ; Tryptophan/metabolism* ; Drugs, Chinese Herbal/therapeutic use* ; Gastrointestinal Microbiome/drug effects* ; Rats, Sprague-Dawley ; Depression/blood* ; Male ; Stress, Psychological/drug therapy* ; Behavior, Animal/drug effects* ; Rats ; Chronic Disease ; Hippocampus/drug effects*

Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca²⁺ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
Animals ; Laminin/genetics* ; Hippocampus/metabolism* ; Neuralgia/metabolism* ; Cognitive Dysfunction/etiology* ; Male ; Peripheral Nerve Injuries/metabolism* ; Extracellular Matrix/metabolism* ; Integrin beta1/metabolism* ; Pyramidal Cells/metabolism* ; Signal Transduction

Kirsten rat sarcoma viral oncogene homolog (KRAS) protein inhibitors are a promising class of therapeutics, but research on molecules that effectively penetrate the blood-brain barrier (BBB) remains limited, which is crucial for treating central nervous system (CNS) malignancies. Although molecular generation models have recently advanced drug discovery, they often overlook the complexity of biological and chemical factors, leaving room for improvement. In this study, we present a structure-constrained molecular generation workflow designed to optimize lead compounds for both drug efficacy and drug absorption properties. Our approach utilizes a variational autoencoder (VAE) generative model integrated with reinforcement learning for multi-objective optimization. This method specifically aims to enhance BBB permeability (BBBp) while maintaining high-affinity substructures of KRAS inhibitors. To support this, we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models. Additionally, we introduce two novel metrics, the knowledge-integrated reproduction score (KIRS) and the composite diversity score (CDS), to assess structural performance and biological relevance. Retrospective validation with KRAS inhibitors, AMG510 and MRTX849, demonstrates the framework's effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications. This study provides a robust framework for accelerating the structural enhancement of lead compounds, advancing the drug development process across diverse targets.

Dental treatments for children and adolescents have unique clinical characteristics that differ from dental care for adults in terms of children's physiology, psychology, and behavior. These differences impose specific requirements on the application of local anesthesia in pediatric dental procedures. This article presents expert consensus on the principles of local anesthesia techniques in pediatric dental therapies, including the use of common anesthetic drugs and dosage control, safety and efficacy evaluation, and prevention and management of complications. The aim is to improve the safety and quality of pediatric dental treatments and offer guidance for clinical application by dentists.
Humans ; Child ; Anesthesia, Local/methods* ; Consensus ; Anesthesia, Dental/methods* ; Adolescent ; Anesthetics, Local/administration & dosage* ; Dental Care for Children

Objective To observe the effects of pegylated losenatide injection combined with metformin tablets on serum metabolism,lipid levels and intestinal flora in obese type 2 diabetes mellitus(T2DM)patients after axial gastrectomy.Methods Obese T2DM patients who underwent axial gastrectomy were divided into treatment group and control group by cohort methods.The control group was treated with metformin hydrochloride tablet 0.5 g orally,tid.The treatment group was treated by subcutaneous injection of pegylated losenatide injection 0.2 mg once a week on the basis of control group.Both groups were treated continuously for 3 months.Body mass index(BMI),serum metabolic indexes,blood lipid levels,blood glucose levels,intestinal flora and adverse drug reactions were compared between the two groups.Results In this study,a total of 70 subjects were included in the treatment group,and 50 subjects were included in the control group.After three months of treatment,the BMI indices of the treatment and control groups were(26.35±2.36)and(29.34±3.59)kg·m-2,respectively;the glutathione peroxidase levels were(192.42±13.18)and(134.27±12.86)U;interleukin-6 levels were(6.14±1.78)and(7.65±2.09)μg·L-1;fasting blood glucose levels were(5.36±0.41)and(7.43±0.78)mmol·L-1;total cholesterol levels were(2.55±0.67)and(3.47±0.79)mmol·L-1 for the treatment and control groups,respectively.The levels of Bifidobacteria,Bacteroides,Lactobacilli,Enterobacteria,and Enterococci in the treatment group were(8.79±1.36),(9.62±1.37),(6.74±2.15),(7.98±0.61),and(7.23±1.29)logN·g-1,respectively;in the control group,these levels were(7.98±1.79),(8.13±1.45),(5.71±2.41),(9.21±0.88),and(8.15±1.54)logN·g-1.The differences in the above indicators between the treatment and control groups were statistically significant(all P＜0.05).The main adverse drug reactions in the treatment group included nausea,headache,dizziness,elevated blood pressure,and indigestion.In the control group,the main adverse drug reactions were nausea,headache,and indigestion.The total incidence of adverse drug reactions in the treatment and control groups was 8.57％and 6.00％,respectively,with no statistically significant difference(P＞0.05).Conclusion Pegylated losenatide injection combined with metformin tablets has a significant effect on axial gastrectomy in obese type 2 diabetes patients.

Objective To investigate the effect and mechanism of hypericin on osteoporosis(OP)in rats with chronic obstructive pulmonary disease(COPD).Methods COPD combined with OP rat model was established by cigarette combined with bacteria.The rats were randomly divided into control group,model group(COPD combined with OP model was constructed),experimental-L group(50 mg·kg-1 hypericin was given by intragastric administration after constructing COPD combined with OP model),experimental-H group(100 mg·kg-1 hypericin was given intragastric administration after constructing COPD combined with OP model),positive group(subcutaneous injection of 16 U·kg-1 salmon calcitonin after constructing COPD combined with OP model);each group was given 12 rats for 90 days.The lung function of rats was detected by pulmonary function apparatus;bone mineral density(BMD)was detected by micro-computed tomography(CT);serum bone metabolism and inflammatory factors were detected by enzyme-linked immunosorbent assay(ELISA);Western blot assay was used to detect the relevant indicators of the pathway.Results The levels of forced vital capacity(FVC)in control group,model group,experimental-H group and positive group were(10.42±1.40),(4.10±0.60),(6.75±0.37),(4.18±0.33)mL,respectively;BMD levels were(0.31±0.04),(0.12±0.02),(0.28±0.03),(0.29±0.04)g·mm-3,respectively;bone alkaline phosphatase(BALP)levels were(200.04±20.03),(80.80±6.00),(148.16±14.23),(173.97±23.55)U·L1,respectively;interleukin-1β(IL-1β)levels were(122.60±8.70),(695.59±74.84),(422.41±44.86),(527.90±39.36)pg·mL-1,respectively;phosphorylated p38 mitogen-activated protein kinase(p-P38)protein expression levels were 0.99±0.11,0.36±0.05,0.79±0.08,0.36±0.04,respectively.Compared with the control group,the above indexes in the model group had statistical significance(all P＜0.05);the above indexes in experimental-H group were significantly different from those in model group(all P＜0.05).Conclusion Hypericin can inhibit inflammatory response,improve bone metabolism and biomechanics.

Macroautophagy (referred to as autophagy hereafter) is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and organelles. Previous studies showed that autophagy protects against acetaminophen (APAP)-induced injury (AILI) via selective removal of damaged mitochondria and APAP protein adducts. The lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with autophagosomes. In the present study, we showed that transcription factor EB (TFEB), a master transcription factor for lysosomal biogenesis, was impaired by APAP resulting in decreased lysosomal biogenesis in mouse livers. Genetic loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI, respectively. Mechanistically, overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2 (NRF2) activation to protect against AILI. We also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB agonists. Among these agonists, salinomycin, an anticoccidial and antibacterial agent, activated TFEB and protected against AILI in mice. In conclusion, genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.