Although teniposide(VM26)is widely used in the treatment of lymphoma,its poor water sol-ubility,low bioavailability and systemic toxicities still limit its clinical application.Nano-delivery systems are effective in increasing the bioavailability and reducing the toxicity of VM26,but there is an urgent need to overcome the problem of its non-specific targeting.Therefore,in this paper,we designed and constructed a hyaluronic acid-modified teniposide-targeted nano-delivery system(VM26-TNDS),and characterised its drug encapsulation rate,particle size and zeta potential.We also investigated the effects of VM26-TNDS on B-cell lymphoma cells with different expression of CD44 receptor,in terms of cellular targeting,inhibitory effect of proliferation,and induction of apoptosis and necrosis.The results showed that the drug encapsulation efficiency of VM26-TNDS exceeded 85％,and its liquid formulation could be stably stored at 4 ℃ for more than 6 months without precipitation.Based on CD44 receptor expression,Granta-519(high expression),Raji(medium-low expression)and SU-DHL-4(almost no expression)were screened for cellular experiments.Compared with VM26-NDS,the targeted modification could effec-tively reduce the uptake of VM26-TNDS by RAW264.7 and increase the uptake of VM26-TNDS by CD44 receptor-expressing lymphoma cells.The inhibitory proliferative effect and apoptotic necrosis-inducing a-bility of VM26-TNDS were stronger than those of VM26-NDS for Granta-519 and Raji cells,whereas there was no significant difference in the inhibitory effect on proliferation and ability to induce apoptosis and necrosis between VM26-NDS and VM26-TNDS in SU-DHL-4 cells,reflecting the targeting advantage for VM26-TNDS,as expected.However,its toxic effect on B-cell lymphoma cells only reflected the targeting advantage at some concentrations(0.25 μmol/L and 0.5 μmol/L),which met the expectation.The a-bove results indicate that a teniposide-targeted nano-delivery system,VM26-TNDS,has been successfully prepared in this study.VM26-TNDS improves the delivery efficiency of VM26 by targeting human B-cell lymphoma cells expressing the CD44 receptor,thus killing human B-cell lymphoma cells more effectively and overcoming the problem of non-specific targeting in drug delivery to improve the therapeutic effect.Its biological therapeutic effects and mechanisms still need to be proved by more in vitro and in vivo ex-perimental evidence.

Although teniposide(VM26)is widely used in the treatment of lymphoma,its poor water sol-ubility,low bioavailability and systemic toxicities still limit its clinical application.Nano-delivery systems are effective in increasing the bioavailability and reducing the toxicity of VM26,but there is an urgent need to overcome the problem of its non-specific targeting.Therefore,in this paper,we designed and constructed a hyaluronic acid-modified teniposide-targeted nano-delivery system(VM26-TNDS),and characterised its drug encapsulation rate,particle size and zeta potential.We also investigated the effects of VM26-TNDS on B-cell lymphoma cells with different expression of CD44 receptor,in terms of cellular targeting,inhibitory effect of proliferation,and induction of apoptosis and necrosis.The results showed that the drug encapsulation efficiency of VM26-TNDS exceeded 85％,and its liquid formulation could be stably stored at 4 ℃ for more than 6 months without precipitation.Based on CD44 receptor expression,Granta-519(high expression),Raji(medium-low expression)and SU-DHL-4(almost no expression)were screened for cellular experiments.Compared with VM26-NDS,the targeted modification could effec-tively reduce the uptake of VM26-TNDS by RAW264.7 and increase the uptake of VM26-TNDS by CD44 receptor-expressing lymphoma cells.The inhibitory proliferative effect and apoptotic necrosis-inducing a-bility of VM26-TNDS were stronger than those of VM26-NDS for Granta-519 and Raji cells,whereas there was no significant difference in the inhibitory effect on proliferation and ability to induce apoptosis and necrosis between VM26-NDS and VM26-TNDS in SU-DHL-4 cells,reflecting the targeting advantage for VM26-TNDS,as expected.However,its toxic effect on B-cell lymphoma cells only reflected the targeting advantage at some concentrations(0.25 μmol/L and 0.5 μmol/L),which met the expectation.The a-bove results indicate that a teniposide-targeted nano-delivery system,VM26-TNDS,has been successfully prepared in this study.VM26-TNDS improves the delivery efficiency of VM26 by targeting human B-cell lymphoma cells expressing the CD44 receptor,thus killing human B-cell lymphoma cells more effectively and overcoming the problem of non-specific targeting in drug delivery to improve the therapeutic effect.Its biological therapeutic effects and mechanisms still need to be proved by more in vitro and in vivo ex-perimental evidence.

Emodin is a hydroxyanthraquinone compound that is widely distributed and has multiple pharmacological activities, including anti-diarrheal, anti-inflammatory, and liver-protective effects. Research indicates that emodin may be one of the main components responsible for inducing hepatotoxicity. However, studies on the mechanisms of liver injury are relatively limited, particularly those related to bile acids(BAs) metabolism. This study aims to systematically investigate the effects of different dosages of emodin on BAs metabolism, providing a basis for the safe clinical use of traditional Chinese medicine(TCM)containing emodin. First, this study evaluated the safety of repeated administration of different dosages of emodin over a 5-week period, with a particular focus on its impact on the liver. Next, the composition and content of BAs in serum and liver were analyzed. Subsequently, qRT-PCR was used to detect the mRNA expression of nuclear receptors and transporters related to BAs metabolism. The results showed that 1 g·kg~(-1) emodin induced hepatic damage, with bile duct hyperplasia as the primary pathological manifestation. It significantly increased the levels of various BAs in the serum and primary BAs(including taurine-conjugated and free BAs) in the liver. Additionally, it downregulated the mRNA expression of farnesoid X receptor(FXR), retinoid X receptor(RXR), and sodium taurocholate cotransporting polypeptide(NTCP), and upregulated the mRNA expression of cholesterol 7α-hydroxylase(CYP7A1) in the liver. Although 0.01 g·kg~(-1) and 0.03 g·kg~(-1) emodin did not induce obvious liver injury, they significantly increased the level of taurine-conjugated BAs in the liver, suggesting a potential interference with BAs homeostasis. In conclusion, 1 g·kg~(-1) emodin may promote the production of primary BAs in the liver by affecting the FXR-RXR-CYP7A1 pathway, inhibit NTCP expression, and reduce BA reabsorption in the liver, resulting in BA accumulation in the peripheral blood. This disruption of BA homeostasis leads to liver injury. Even doses of emodin close to the clinical dose can also have a certain effect on the homeostasis of BAs. Therefore, when using traditional Chinese medicine or formulas containing emodin in clinical practice, it is necessary to regularly monitor liver function indicators and closely monitor the risk of drug-induced liver injury.
Emodin/administration & dosage* ; Bile Acids and Salts/metabolism* ; Animals ; Male ; Liver/injuries* ; Chemical and Drug Induced Liver Injury/genetics* ; Drugs, Chinese Herbal/adverse effects* ; Humans ; Rats, Sprague-Dawley ; Mice ; Rats

Objective:To investigate the genetic mutation characteristics of patients with bilateral macronodular adrenocortical disease（BmacAD）and to analyze the clinical phenotypes and adrenal nodule transcriptomic profiles associated with different genotypes.Methods:This retrospective study analyzed the clinical data of 37 patients diagnosed with BmacAD by clinical and pathological assessment who underwent surgery at Peking Union Medical College Hospital from January 2001 to December 2024. Data included symptoms and signs related to hypercortisolism，24-hour urinary free cortisol，plasma adrenocorticotropic hormone（ACTH），and overnight low-dose dexamethasone suppression test results. Whole-exome sequencing（WES）was performed on frozen adrenal hyperplasia tissue samples from surgical specimens and matched frozen residual blood samples for all patients to screen for germline and somatic mutations. Sanger sequencing was used to validate some of the identified mutations. The relation between genetic mutations and clinical features was analyzed. Transcriptome sequencing of the hyperplastic tissues was conducted，and unsupervised clustering，differential gene expression analysis，and pathway enrichment analysis were used to compare the transcriptomic profiles of patients with different genotypes.Results:A total of 37 cases were included（23 males and 14 females），aged between 31?68 years old. Among the patients with available clinical data，most exhibited signs of hypercortisolism，including hypertension（100.0%，36/36），diabetes（50.0%，18/36），and centripetal obesity（55.9%，19/34），accompanied by relevant endocrine abnormalities such as elevated 24-hour urinary free cortisol（79.4%，27/34），suppressed ACTH（77.8%，28/36），and a positive overnight low-dose dexamethasone suppression test（45.2%，14/31）. WES and Sanger sequencing revealed that ARMC5 gene mutations were the most common. Among the 37 patients，33（89.2%）had ARMC5 germline mutations，and 31（83.8%）concurrently harbored ARMC5 somatic mutations，including 3 cases of loss of heterozygosity. Two patients without detectable ARMC5 mutations both carried a somatic p.S45P mutation in the CTNNB1 gene and neither had typical manifestations of hypercortisolism. Transcriptome sequencing results suggested that patients with ARMC5 mutations had an upregulation of pathways related to steroid secretion.Conclusions:The majority of BmacAD patients present with typical manifestations of hypercortisolism，while a minority exhibit only mild autonomous cortisol secretion without obvious symptoms. Biallelic inactivation of the ARMC5 gene is the primary genetic driver of this disease，leading to more severe hypercortisolism by upregulating steroid hormone secretion. CTNNB1 mutations may be involved in the pathogenesis of some patients without ARMC5 mutations.

OBJECTIVES: To investigate the impact of high expression of transmembrane and coiled helix structural domain 1 (TMCO1) on prognosis of gastric cancer and the possible mechanisms. METHODS: TMCO1 expression in gastric cancer and its effect on gastric cancer progression and prognosis were analyzed using publicly available databases and clinical data of patients undergoing radical surgery in our hospital, and its possible biological functions were explored using KEGG and GO analyses. In gastric cancer HGC-27 cells, the effects of lentivirus-mediated TMCO1 overexpression and TMCO1 silencing on cell apoptosis, proliferation, invasion and migration were examined. RESULTS: TMCO1 expression was significantly elevated in gastric cancer tissues (P<0.05), and its high expression was positively correlated with cancer progression (P<0.001) and a lowered postoperative 5-year survival rate of the patients (P<0.05). Bioinformatic analyses suggested that TMCO1 may affect gastric cancer cell apoptosis via Wnt signaling. In HGC-27 cells, TMCO1 overexpression significantly promoted tumor cell proliferation, inhibited cell apoptosis, and enhanced cell migration and invasion, whereas TMCO1 silencing produced the opposite effects. Western blotting showed that β-catenin levels were significantly upregulated in TMCO1-overexpressing cells and downregulated in cells with TMCO1 silencing. CONCLUSIONS TMCO1 is overexpressed in gastric cancer tissues, and its high expression promotes gastric cancer progression and affects long-term prognosis of the patients possibly by activating the Wnt/ β-catenin signaling pathway to inhibit apoptosis of gastric cancer cells.
Humans ; Stomach Neoplasms/metabolism* ; Apoptosis ; Prognosis ; Cell Line, Tumor ; Cell Proliferation ; Cell Movement ; Wnt Signaling Pathway ; beta Catenin/metabolism* ; Gene Expression Regulation, Neoplastic

Objective To utilize single-cell and peripheral blood transcriptomic data from 3D brain organoids,combined with machine learning,to analyze the role of mitochondrial autophagy genes in schizophrenia(SCZ).Methods By integrating two machine learning algorithms,we identified differentially expressed mitochondrial autophagy-related genes between schizophrenia patients and healthy controls using peripheral blood RNA sequencing data.The relationship between mitophagy gene,immune cells and inflammatory factors was further explored.Comprehensive single-cell analysis was used to explore the signaling pathways and specific transcription factors based on mitophagy genes.Results Using machine learning,seven key mitophagy genes expressed in schizophrenia patients were identified.Based on Mitoscore analysis,at the single-cell level,neurons with high mitochondrial autophagy activity(Mitohigh_Neuron)formed new interactions with endothelial cells via the SPP1 signaling pathway.Conclusion This study identified two subtypes of mitophagy and seven key mitophagy genes in schizophrenia,providing new insights into the pathogenesis of the disease.

Objective:To investigate the genetic mutation characteristics of patients with bilateral macronodular adrenocortical disease（BmacAD）and to analyze the clinical phenotypes and adrenal nodule transcriptomic profiles associated with different genotypes.Methods:This retrospective study analyzed the clinical data of 37 patients diagnosed with BmacAD by clinical and pathological assessment who underwent surgery at Peking Union Medical College Hospital from January 2001 to December 2024. Data included symptoms and signs related to hypercortisolism，24-hour urinary free cortisol，plasma adrenocorticotropic hormone（ACTH），and overnight low-dose dexamethasone suppression test results. Whole-exome sequencing（WES）was performed on frozen adrenal hyperplasia tissue samples from surgical specimens and matched frozen residual blood samples for all patients to screen for germline and somatic mutations. Sanger sequencing was used to validate some of the identified mutations. The relation between genetic mutations and clinical features was analyzed. Transcriptome sequencing of the hyperplastic tissues was conducted，and unsupervised clustering，differential gene expression analysis，and pathway enrichment analysis were used to compare the transcriptomic profiles of patients with different genotypes.Results:A total of 37 cases were included（23 males and 14 females），aged between 31?68 years old. Among the patients with available clinical data，most exhibited signs of hypercortisolism，including hypertension（100.0%，36/36），diabetes（50.0%，18/36），and centripetal obesity（55.9%，19/34），accompanied by relevant endocrine abnormalities such as elevated 24-hour urinary free cortisol（79.4%，27/34），suppressed ACTH（77.8%，28/36），and a positive overnight low-dose dexamethasone suppression test（45.2%，14/31）. WES and Sanger sequencing revealed that ARMC5 gene mutations were the most common. Among the 37 patients，33（89.2%）had ARMC5 germline mutations，and 31（83.8%）concurrently harbored ARMC5 somatic mutations，including 3 cases of loss of heterozygosity. Two patients without detectable ARMC5 mutations both carried a somatic p.S45P mutation in the CTNNB1 gene and neither had typical manifestations of hypercortisolism. Transcriptome sequencing results suggested that patients with ARMC5 mutations had an upregulation of pathways related to steroid secretion.Conclusions:The majority of BmacAD patients present with typical manifestations of hypercortisolism，while a minority exhibit only mild autonomous cortisol secretion without obvious symptoms. Biallelic inactivation of the ARMC5 gene is the primary genetic driver of this disease，leading to more severe hypercortisolism by upregulating steroid hormone secretion. CTNNB1 mutations may be involved in the pathogenesis of some patients without ARMC5 mutations.

Aim To explore the effect and mechanism of the artesunate(ART)on hepatocellular carcinoma(HCC).Methods The cell lines MHCC-97H and HCC-LM3 were used to be detected.MTT and clone formation were used to determine the cell proliferation;Wound healing was used to detect the cell migration;Transwell was used to test the cell invasion.Flow-cy-tometry was used to detect cell apoptosis and cell cy-cle.RNA-seq and qRT-PCR was used to detect the genes expression.Results The proliferation,migra-tion and invasion of treated cells were obviously inhibi-ted(P＜0.01).Moreover,the apoptosis rate in-creased significantly,so did the proportion of G2/M cells.Transcriptomic analysis identified GADD45A as a potential target of ART through RNA-sequencing da-ta,and suggested that ART might induce apoptosis and cell cycle arrest through regulating the expression of GADD45A.In addition,the results of mechanism studies and signaling analysis suggested that GADD45A had interaction with its upstream gene NACC1(nucle-us accumbens associated 1).Moreover,after ART treatment,the expressions of GADD45A and NACC1 were changed significantly.Conclusion ART may be a potential drug to resist HCC by affecting the expres-sion of GADD45A and its upstream gene NACC1,which provides a new drug,a new direction and a new method for the clinical treatment of HCC.

AIM To investigate the effects of stir-frying,processing with butter and carbonizing by stir-frying on oil components in Gleditsiae sinensis Fructus and Gleditsiae Fructus Abnormalis.METHODS The volatile oils and fatty oils were extracted by steam distillation method and Soxhlet extraction method,respectively,after which the extraction rates were determined.GC-MS was applied to analyzing the kinds and relative contents of oil components,after which cluster analysis was performed.RESULTS After the processing,the two medicinal materials demonstrated increased extraction rates of fatty oils and decreased extraction rates of volatile oils(except for processing with butter),the extraction rates of oil components in Gleditsiae sinensis Fructus were higher than those in Gleditsiae Fructus Abnormalis,and the reduced relative contents of toxic olefin benzene components were observable.CONCLUSION The kinds and relative contents of oil components in Gleditsiae sinensis Fructus and Gleditsiae Fructus Abnormalis exist obvious differences,the former displays better medicinal quality,whose processing mechanism in alleviating dryness and strength may contribute to the reduction of relative contents of toxic olefin benzene components.

Objective To investigate the risk factors for pulmonary infection in patients with acute-on-chronic liver failure(ACLF),and to establish a predictive model.Methods A retrospective analysis was performed for 585 ACLF patients who were admitted to Department of Infectious Diseases,The Second Affiliated Hospital of Air Force Medical University,from January 2009 to September 2022,and according to the condition of pulmonary infection after admission,they were divided into infection group with 213 patients and non-infection group with 372 patients.The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups,and the chi-square test was used for comparison of categorical data between groups.The clinical data of these patients were collected.Univariate and multivariate Logistic regression analyses were used to investigate the risk factors for pulmonary infection in ACLF patients and establish a predictive model,and the receiver operating characteristic(ROC)curve was plotted to assess the predictive value of the model.The Hosmer-Lemeshow test was used to evaluate the degree of fitting of the model,and the ROC curve and the area under the ROC curve(AUC)were used to assess the predictive performance of the model.Results Among the 585 patients with ACLF,213 experienced pulmonary infection,with an infection rate of 36.41%.The multivariate logistic analysis showed that upper gastrointestinal bleeding(odds ratio[OR]=2.463,P=0.047),infection at other sites(OR=2.218,P=0.004),femoral vein catheterization(OR=2.520,P＜0.001),and combined use of two or more antibiotics(OR=2.969,P＜0.001)were risk factors for pulmonary infection in ACLF patients.These factors were included in the risk factor predictive model of Logit(P)=-1.869+0.901×upper gastrointestinal bleeding+0.755×infection at other sites+0.924×femoral vein catheterization+1.088×combined use of two or more antibiotics.The ROC curve analysis showed that the model had a good predictive value(Hosmer-Lemeshow χ2=3.839,P=0.698),with an AUC of 0.753(95%confidence interval:0.700-0.772).Conclusion There is a relatively high incidence rate of pulmonary infection in patients with ACLF,and upper gastrointestinal bleeding,spontaneous peritonitis,femoral vein catheterization,and combined use of two or more antibiotics are related risk factors.The model established based on these factors can effectively predict the onset of pulmonary infection in ACLF patients.