OBJECTIVE To investigate the apoptosis-inducing effect of esculetin （Esc） on acute myeloid leukemia （AML） HL-60 cells by regulating the protein kinase B （AKT）/S-phase kinase-associated protein 2 （SKP2）/MutT homolog 1 （MTH1） pathway. METHODS AML HL-60 cells were randomly divided into control group （routine culture）， Esc low-concentration group （L-Esc group， 25 μmol/L Esc）， Esc medium-concentration group （M-Esc group， 50 μmol/L Esc）， Esc high-concentration group （H-Esc group， 100 μmol/L Esc）， and high-concentration of Esc+ SC79 （AKT agonist） group （100 μmol/L Esc+5 μmol/L SC79）. Cell proliferation in each group was detected by MTT assay and colony formation assay. The level of reactive oxygen species （ROS） in cells was measured by using the CM-H2DCFDA fluorescent probe. Cell apoptosis was analyzed by flow cytometry. Western blot assay was performed to detect the expression levels of apoptosis-related proteins [B-cell lymphoma 2 （Bcl-2）， Bcl-2-associated X protein （Bax）， cleaved caspase-3]， AKT/SKP2/MTH1 pathway-related proteins （p-AKT， AKT， SKP2， MTH1）， along with the upstream and downstream proteins of AKT phosphatidylinositol 3-kinase （PI3K）， cyclin-dependent kinase inhibitor 1 （P21） and cyclin-dependent kinase inhibitor 1B （P27）. RESULTS Compared with control group， the cell viability， colony number， and the phosphorylation levels of AKT and PI3K proteins as well as protein expressions of SKP2， MTH1 and Bcl-2 were significantly decreased （P＜0.05）， while ROS level， apoptosis rate， and the expression levels of Bax， cleaved caspase-3， P21 and P27 proteins were significantly increased （P＜0.05）. Moreover， the effects of Esc exhibited concentration-dependence （P＜0.05）. Compared with H-Esc group， above indexes of high-concentration of Esc+ SC79 group were reversed significantly （P＜0.05）. CONCLUSIONS Esc may promote massive ROS production and induce activation of apoptosis in HL-60 cells by inhibiting the AKT/SKP2/MTH1 pathway， thus inhibiting the proliferation of HL-60 cells.

ObjectiveTo investigate the effects of Anmeidan （AMD） on protein expression of the ephrin type-A receptor 4 （EphA4）/ephrinA3 signaling pathway and synaptic structural function in an aged sleep deprivation model. MethodsSeventy-two 18-month-old aged mice were randomly divided into a blank group， a model group， AMD high-， medium-， and low-dose groups （26.26， 13.13， 6.565 g·kg^-1·d^-1， respectively）， and a melatonin group （1.3 mg·kg^-1·d^-1）， with 12 mice in each group. Cognitive function was assessed using the novel object recognition test. Hematoxylin-eosin （HE） staining was used to observe cell number and morphology in hippocampal tissues， and Nissl staining was performed to examine cellular structure and quantify Nissl bodies. Transmission electron microscopy was used to observe synaptic ultrastructure， with emphasis on changes in synaptic morphology and structure. Western blot was employed to detect the expression levels of EphA4， ephrinA3， brain-derived neurotrophic factor （BDNF）， glutamate aspartate transporter （GLAST）， glutamate transporter-1 （GLT-1）， growth-associated protein 43 （GAP43）， postsynaptic density protein 95 （PSD95）， and synaptophysin （SYN） in hippocampal tissues. Immunofluorescence double labeling was performed to co-stain EphA4 and ephrinA3 with glial fibrillary acidic protein （GFAP） and neuronal nuclei antigen （NeuN）， respectively， to observe the colocalization of target proteins with neurons and astrocytes. ResultsCompared with the blank group， the model group exhibited increased exploration time of familiar objects （P<0.01）， while exploration time of novel objects and the recognition index were decreased （P<0.01）. The number of neurons in the CA1， CA3， and dentate gyrus （DG） regions of the hippocampus was reduced， Nissl bodies were decreased， and synaptic structures were damaged. Protein expression levels of BDNF， GLAST， GLT-1， GAP43， PSD95， and SYN in hippocampal tissues were decreased， whereas the expression levels of EphA4， ephrinA3， and GFAP were increased. Compared with the model group， the AMD low-， medium-， and high-dose groups and the melatonin group showed increased exploration time of novel objects and higher novel object recognition indices （P<0.01）， along with significantly reduced exploration time of familiar objects （P<0.01）. Neuronal damage in the CA1 and DG regions was ameliorated， the number of Nissl bodies in the CA1 region was increased， and organelle and synaptic structural damage was alleviated. Protein expression levels of BDNF， GLAST， GLT-1， GAP43， PSD95， and SYN were increased， and protein expression levels of EphA4， ephrinA3， and GFAP were decreased （P<0.05，P<0.01）. ConclusionAMD can regulate protein expression of the EphA4/ephrinA3 signaling pathway in an aged sleep deprivation model， enhance synaptic protein expression， and improve neuronal synaptic damage.

Compilation instruction for Expert Consensus on Clinical Application of Binghuang Fule Ointment elaborates on the formulation methods and evidence-based basis of the consensus. To address the problems of insufficient evidence on efficacy， vague indications， and a lack of uniform standard for Binghuang Fule Ointment in clinical application， 34 experts from 29 medical institutions across China participated in the compilation under the lead of the Institute of Basic Research in Clinical Medicine and Xiyuan Hospital， China Academy of Chinese Medical Sciences， as well as China-Japan Friendship Hospital. The compilation strictly adhered to the WHO Handbook for Guideline Development （GB/T 1.1—2020）， and the Guidance of Instructions for Compiling Expert Consensus on Clinical Practice of Chinese Patent Medicine. Through multidisciplinary collaboration， the compilation was completed using the Grading of Recommendations Assessment， Development and Evaluations （GRADE） evidence grading system. The detailed workflow included various key links. In clinical question construction， 15 items were screened by the nominal group method. In evidence retrieval， Chinese and English databases， along with gray literature， were covered to obtain 116 clinical and 33 pharmaceutical studies. In safety assessment， drug monitoring data and clinical research results were integrated， clarifying local adverse skin reactions and contraindications. Ultimately， 8 recommendations were formed by the GRADE grid method， while 16 consensus suggestions were reached via the majority vote rule. The results showed that the Binghuang Fule Ointment was applicable to eczema， psoriasis， neurodermatitis， tinea pedis， and other diseases. The Consensus also elucidated the syndrome differentiation points， usage and dosage for different diseases （such as adjustment of course and application frequency）， as well as the indications of combination medication. Additionally， safety assessment suggested that the Ointment should be used with caution in individuals with skin ulceration or hypersensitivity. To ensure methodological rigor， the compilation process went through three rounds of internal and external expert reviews， while a comprehensive analysis was conducted by literature analysis， the Delphi method， and other methods. This compilation instruction provided methodological support for the clinical transformation of the Consensus through key links， including project initiation， international registration， informed consent， conflict-of-interest statements， evidence evaluation， and popularization. The Consensus will be continuously improved through a dynamic revision mechanism in the future.

Compilation instruction for Expert Consensus on Clinical Application of Binghuang Fule Ointment elaborates on the formulation methods and evidence-based basis of the consensus. To address the problems of insufficient evidence on efficacy， vague indications， and a lack of uniform standard for Binghuang Fule Ointment in clinical application， 34 experts from 29 medical institutions across China participated in the compilation under the lead of the Institute of Basic Research in Clinical Medicine and Xiyuan Hospital， China Academy of Chinese Medical Sciences， as well as China-Japan Friendship Hospital. The compilation strictly adhered to the WHO Handbook for Guideline Development （GB/T 1.1—2020）， and the Guidance of Instructions for Compiling Expert Consensus on Clinical Practice of Chinese Patent Medicine. Through multidisciplinary collaboration， the compilation was completed using the Grading of Recommendations Assessment， Development and Evaluations （GRADE） evidence grading system. The detailed workflow included various key links. In clinical question construction， 15 items were screened by the nominal group method. In evidence retrieval， Chinese and English databases， along with gray literature， were covered to obtain 116 clinical and 33 pharmaceutical studies. In safety assessment， drug monitoring data and clinical research results were integrated， clarifying local adverse skin reactions and contraindications. Ultimately， 8 recommendations were formed by the GRADE grid method， while 16 consensus suggestions were reached via the majority vote rule. The results showed that the Binghuang Fule Ointment was applicable to eczema， psoriasis， neurodermatitis， tinea pedis， and other diseases. The Consensus also elucidated the syndrome differentiation points， usage and dosage for different diseases （such as adjustment of course and application frequency）， as well as the indications of combination medication. Additionally， safety assessment suggested that the Ointment should be used with caution in individuals with skin ulceration or hypersensitivity. To ensure methodological rigor， the compilation process went through three rounds of internal and external expert reviews， while a comprehensive analysis was conducted by literature analysis， the Delphi method， and other methods. This compilation instruction provided methodological support for the clinical transformation of the Consensus through key links， including project initiation， international registration， informed consent， conflict-of-interest statements， evidence evaluation， and popularization. The Consensus will be continuously improved through a dynamic revision mechanism in the future.

SkinPro Ointment is an emulsion-based preparation derived from a traditional Tibetan medical empirical formula and developed using modern pharmaceutical technology. It is an exclusive patented product of Tibet Hairong Tangguo Pharmaceutical Co. Ltd. and has been listed as a National Protected Traditional Chinese Medicine Variety， the Pharmacopoeia of the People's Republic of China， and classified as a Category B product in the National Basic Medical Insurance Catalog. The ointment possesses the functions of clearing heat and drying dampness， activating blood circulation and dispelling wind， relieving itching and reducing inflammation. Clinically， it is used for skin pruritus caused by dampness-heat accumulation or blood-heat with wind-dryness， as well as pruritic skin diseases such as neurodermatitis， eczema， tinea pedis， and psoriasis. To clarify the standards for its clinical application and promote rational drug use， a consensus working group comprising 34 national experts in dermatology， evidence-based medicine， and pharmacy was established. Through expert interviews， the nominal group technique， and questionnaire surveys， 15 clinical issues were identified. The Grading of Recommendations Assessment， Development and Evaluation （GRADE） evidence grading system was employed to assess the quality of evidence， leading to the formulation of the Expert Consensus on the Clinical Application of SkinPro Ointment. This consensus specifies that the intended users are physicians and pharmacists in medical institutions at all levels. It standardizes the clinical application of the ointment， including syndrome characteristics， dosage and course of treatment， combination therapy， precautions， and contraindications. Recommendations and consensus suggestions were formed addressing the 15 clinical issues， covering the following key areas： ①Indications and TCM syndromes： In TCM， the ointment mainly treats conditions such as "damp sores" （Shichuang）， "white scaling" （Baibi）， "collar sores" （Shelingchuang）， and "damp foot Qi" （Jiaoshiqi）， corresponding to eczema， psoriasis， neurodermatitis， and tinea pedis in Western medicine. The relevant TCM syndromes are identified as dampness-heat accumulation or blood-heat with wind-dryness. ②Usage and dosage： For external use， apply to the affected area 3 times daily. The dosage should follow the fingertip unit （FTU） principle. A treatment course of 1-2 weeks is recommended for mild to moderate cases； for serious cases， the course should be followed as prescribed by a physician. ③Combined therapy： The ointment can be used as monotherapy for mild cases. For moderate to severe cases， combination therapy is recommended， with reference to relevant clinical guidelines. ④Safety： Common adverse reactions include skin rashes， pruritus， and erythema. The ointment is contraindicated in patients with broken skin or obvious exudation at the affected area， as well as in patients with known hypersensitivity to any of its components. Contact with sensitive areas such as the eyes and oral mucosa should be avoided. Modern research shows that the ointment also has potential efficacy in other dermatological conditions， such as adult atopic dermatitis， tinea cruris， exfoliative keratolysis， acne vulgaris， and Malassezia folliculitis. This consensus provides a scientific basis for promoting the rational clinical use of SkinPro Ointment， improving its therapeutic efficacy， and reducing medication risks. Future updates will be dynamically revised according to emerging clinical issues and new evidence.

OBJECTIVE: To explore the clinical phenotypes and genetic characteristics of five children with Lamb-Shaffer syndrome (LAMSHF). METHODS: Five children with LAMSHF diagnosed at the Department of Pediatrics, the First Medical Center of Chinese PLA General Hospital from April 2021 to December 2024 were selected as study subjects. Clinical data of the children was collected. Genomic DNA was extracted from peripheral blood samples of the children and their parents. Whole exome sequencing (WES) was carried out to screen for variants. This study was approved by the Medical Ethics Committee of the Chinese PLA General Hospital (Ethics No.: S2025-411-01). RESULTS: All five children had presented with global developmental delay. Among them, two had manifestations of autism spectrum disorder, two had abnormal electroencephalogram findings, four had abnormal MRI results, and two had ocular abnormalities. WES has detected five novel variants in the SOX5 gene. Among these, c.1771G>C (p.Gly591Arg) was unreported previously. Sanger sequencing confirmed that none of the parents had carried the same variants, suggesting that they were all de novo variants. According to the guidelines from the American College of Medical Genetics and Genomics (ACMG), two nonsense variants and one missense variant were classified as pathogenic, whilst two missense variants were classified as likely pathogenic. CONCLUSION This study has clarified the correlation between the clinical phenotypes of five children with LAMSHF and variants of the SOX5 gene, which expanded the mutational spectrum of the SOX5 gene and provided a basis for the clinical diagnosis and genetic counseling.
Humans ; Male ; Female ; Phenotype ; Child, Preschool ; Child ; SOXD Transcription Factors/genetics* ; Exome Sequencing ; Mutation ; Infant

Olfactory receptors (ORs) form the largest superfamily of G protein-coupled receptors (GPCRs). Traditionally recognized for their role in the nasal olfactory epithelium, where they mediate the sense of smell, accumulating evidence has firmly established their ectopic expression in non-olfactory tissues, including the intestine, lungs, and kidneys. The intestine, as the primary site for nutrient digestion and absorption, harbors a highly complex chemical environment. To adapt to this environment, the gut employs a sophisticated network of “chemosensors” to monitor luminal contents and maintain homeostasis. Among these sensors, intestinal ORs have emerged as crucial functional components, serving as a molecular bridge that connects environmental chemical signals—such as food-derived odorants—to specific physiological responses. This discovery has significantly deepened our understanding of how dietary flavors and compounds influence intestinal physiology at the molecular level. This review systematically summarizes the expression profiles, ligand classification, and biological functions of ORs within the gastrointestinal tract. Studies indicate that intestinal ORs exhibit distinct spatial distribution patterns across different gut segments and display cell-type specificity, particularly within enterocytes and enteroendocrine cells. These receptors function as versatile sensors capable of recognizing a wide variety of ligands, including exogenous dietary components, gut microbiota metabolites such as short-chain fatty acids, and endogenous small molecules like azelaic acid. Upon activation by specific ligands, intestinal ORs trigger intracellular signaling cascades, primarily involving the AC-cAMP-PKA pathway or calcium influx channels. A major focus of this review is to elucidate the molecular mechanisms by which these receptors regulate the secretion of gut hormones. Activation of specific ORs in enteroendocrine cells has been shown to stimulate the release of hormones such as glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and serotonin (5-HT), thereby modulating systemic energy metabolism, glucose homeostasis, and gastrointestinal motility. Furthermore, the review addresses the critical roles of ORs in immune regulation and pathology. Evidence suggests that specific ORs contribute to the maintenance of intestinal immune homeostasis and may offer protection against inflammation. Beyond their involvement in inflammatory responses, ORs such as Olfr78 have been shown to regulate the differentiation and function of intestinal endocrine cells. Similarly, Olfr544 has been demonstrated to alleviate intestinal inflammation by remodeling the gut microbiome and metabolome. These findings collectively suggest that specific ORs hold promise as therapeutic targets for mitigating intestinal inflammation and maintaining gut homeostasis. Additionally, the review explores the emerging role of ORs in cancer. Although OR expression is often downregulated in tumor tissues compared to normal mucosa, activation of specific ORs by certain ligands can inhibit tumor cell proliferation and migration and induce apoptosis via pathways such as MEK/ERK and p38 MAPK. Conversely, other receptors, such as OR7C1, may serve as biomarkers for cancer-initiating cells. In conclusion, intestinal ORs represent a vital component of the gut’s sensory network. The review also discusses the translational potential of these findings. By elucidating the precise pairing relationships between dietary components and specific ORs, novel therapeutic strategies could be developed. Intestinal ORs may thus emerge as promising targets for nutritional and pharmacological interventions in metabolic diseases, inflammatory bowel diseases, and malignancies.

Objective To explore the risk factors for mineral and bone disorder in maintenance hemodialysis patients, and to construct and validate a nomogram prediction model. Methods A total of 306 patients undergoing maintenance hemodialysis at Shanghai Eighth People’s Hospital from January 2021 to May 2025 were selected as study subjects and randomly divided into a training set (n＝214) and a validation set (n＝92) in a 7∶3 ratio. In the training set, patients were divided into a normal bone mineral metabolism group and an abnormal bone mineral metabolism group, and related factors were compared between the two groups. The multivariate logistic regression analysis was used to identify the influencing factors of mineral and bone disorder in maintenance hemodialysis patients in the training set, and a nomogram prediction model was constructed. ROC curves were drawn to evaluate the ability of the nomogram model for predicting mineral and bone disorder in these patients. Calibration curves and Hosmer-Lemeshow goodness-of-fit test were used to analyze the consistency of the predictive probability of nomogram model and actual probability of mineral and bone disorder in these patients. The decision curve was used to assess the clinical benefit using nomogram prediction model. Results Among the 306 hemodialysis patients, 254 patients had mineral and bone disorder, accounting for 83.01%. Among the 214 patients in the training set, 177 had mineral and bone disorder, accounting for 82.71%. In the training set, age, gender, body mass index (BMI), hypertension rate, dialysis age, blood urea nitrogen (BUN), hemoglobin (Hb), albumin (ALB), alkaline phosphatase (ALP), serum creatinine (SCr), uric acid (UA), estimated glomerular filtration rate (eGFR), and rate of taking phosphate binders were statistically significant different between the two groups (P＜0.05). The multivariate logistic regression analysis showed higher age, female, hypertension, longer dialysis duration, decreased eGFR, and not taking phosphate binders were identified as risk factors for mineral and bone disorder in maintenance hemodialysis patients (P＜0.01). The nomogram prediction model was constructed. The area under the ROC curve of the model for mineral and bone disorder in the training set and validation set was 0.895 (95%CI 0.850-0.941) and 0.881 (95%CI 0.830-0.932), respectively, with maximum Youden indice of 0.650 and 0.600, sensitivity of 0.856 and 0.849, and specificity of 0.794 and 0.751. The Hosmer-Lemeshow test showed the nomogram prediction model had good consistency in predictive probabilities with actual probabilities in training set and validation set. The decision curve showed the nomogram model could bring clinical net benefits when the threshold probabilities in the training set and validation set were less than 0.96 and 0.91. Conclusions The nomogram prediction model constructed based on six independent risk factors including age, gender, hypertension, dialysis duration, eGFR, and using phosphate binders or not, shows good discrimination and calibration, with good clinical predictive ability, which could provide guidance for the management of maintenance hemodialysis patients.

Effective symptom management can alleviate the physical and psychological distress experienced by patients with cancer, improve quality of life, and contribute to treatment adherence and improve clinical outcomes. However, most existing guidelines are developed for healthcare professionals, and patients and the public have limited access to standardized and comprehensible guidance on symptom management. To address this gap and to facilitate effective communication and shared decision-making, this study proposes the development of a patient version of the cancer symptom management guideline. The development process will adhere to the methodological framework recommended by the Guidelines International Network and the World Health Organization. The GRADE approach will be employed to assess the certainty of evidence and to formulate recommendations. In addition, the process will be informed by the Appraisal of Guidelines for Research and Evaluation Ⅱ (AGREE Ⅱ) instrument and the Reporting Items for Practice Guidelines in Healthcare-Public or Patient Versions of Guidelines (RIGHT-PVG). This protocol outlines the establishment of the guideline working group, the identification and prioritization of key questions, evidence retrieval and appraisal, and the formulation of recommendations, with the aim of ensuring methodological rigor and transparency in the development of the patient guideline and providing methodological reference for similar guideline initiatives.

Objective:A single,center,prospective,randomized controlled study was conducted,to explore the impact of combined intervention of mindfulness based stress reduction therapy and cognitive behavioral on the psychological state and coping styles of maintenance hemodialysis(MHD)patients.Methods:This study adopted a randomized controlled trial design,120 MHD patients who were treated in our hospital from January 2021 to December 2023 were selected,the patients were divided into two groups by random number table:control group(n=60,conventional clinical interventions)and observation group(n=60,mindfulness based stress reduction therapy combined with cognitive behavioral intervention).The coping styles,psychological states,quality of life and incidence of adverse events of the two groups were compared.Result:Compared with the control group after intervention,the scores of Hamilton Depression Scale-24 items(HAMD-24),Hamilton Anxiety Scale(HAMA)score,submission and avoidance in the observation group were lower,and the scores of confrontation,physical domain,psychological domain,independence domain and social relationship domain were higher(P＜0.05).The incidence of adverse events in the observation group was lower than that in the control group(5.00％vs 16.67％,P＜0.05).Conclusion:The comprehensive psychological intervention of mindfulness based stress reduction therapy combined with cognitive behavioral intervention has significant clinical benefits for MHD patients,manifested as promoting the formation of coping styles,significantly reducing the anxiety and depression symptoms of patients,improving their quality of life,and reducing the incidence of treatment-related adverse events.