ObjectiveTo construct and validate a clinical prediction model for Qi deficiency and blood stasis syndrome in chronic heart failure （CHF），aiming to assist clinical diagnosis and provide tools and methods for individualized treatment of CHF. MethodsThe clinical data of patients with chronic heart failure treated at Dongzhimen Hospital of Beijing University of Chinese Medicine from January 2022 to January 2024 were retrospectively collected. The patients were randomly divided into a training group and a validation group with a ratio of 7∶3. First， the least absolute shrinkage and selection operator （LASSO） regression analysis was used to preliminarily screen the predictive factors affecting the diagnosis of Qi deficiency and blood stasis syndrome in CHF. Subsequently， the Logistic regression method was applied to conduct a more in-depth and detailed analysis of these factors. Variables with P<0.05 in the results of the multi-factor Logistic regression were carefully selected and included. Based on the regression coefficients obtained from this analysis， a model was constructed， and a nomogram was accurately drawn. Using R software，the receiver operating characteristic （ROC） curve，calibration curve，and decision curve analysis （DCA） were precisely drawn. These analyses were used to comprehensively evaluate the model from three crucial aspects： discrimination，calibration，and clinical applicability. Additionally， the accuracy，specificity，sensitivity，positive predictive value，and negative predictive value of the model were meticulously calculated to conduct a more all-round and comprehensive assessment. ResultsIn total， 168 cases were successfully obtained in the training group， and 71 cases were included in the validation group. After a thorough comparison， it was found that there were no statistically significant differences in the baseline data between the two groups. After being rigorously screened by the LASSO-multivariate logistic regression method， dark red tongue，smoking history，cardiac troponin I，and N-terminal pro-B-type natriuretic peptide （NT-ProBNP） were identified as the influencing factors for diagnosing patients with the Qi deficiency and blood stasis syndrome in CHF. The constructed model demonstrated an area under the curve （AUC） of 0.812 in the training group and 0.719 in the validation group. The calibration curve showed that the predicted curve of the model was close to the actual observed curve. DCA indicated that the model could provide substantial clinical benefits for patients at the decision thresholds ranging from 0.2 to 0.9. ConclusionThe clinical prediction model for Qi deficiency and blood stasis syndrome in chronic heart failure constructed in this study shows good performance. It has certain application value in clinical practice， which may contribute to the improvement of the diagnosis and treatment of CHF patients with this syndrome.

ObjectiveTo observe the effectiveness and safety of Jiuzihuichun decoction combined with spleen- strengthening moxibustion in patients with asthenospermia infertility with spleen-kidney deficiency pattern. MethodsA total of 82 patients with asthenospermia of spleen-kidney deficiency pattern in Shanghai Seventh People's Hospital were included. The patients were randomly divided into an observation group and a control group， with 41 patients in each group. The control group received oral administration of WuziYanzong pills combined with spleen-strengthening moxibustion. The dosage of Wuzi Yanzong pills was 1 bag each time， and it was taken twice a day. The spleen-strengthening moxibustion was carried out once a week. The observation group， on the other hand， took Jiuzi Huichun decoction orally combined with spleen-strengthening moxibustion. The Jiuzi Huichun Decoction was taken 200 mL each time， twice a day， with one dose in the morning and one in the evening. The spleen-strengthening moxibustion for the observation group was also performed once a week. The treatment course for both groups was 12 weeks， and they were followed up for an additional 12 weeks. During the treatment process，12 cases were either lost to follow-up or excluded. Eventually， 70 cases were available for evaluation，with 35 cases in the control group and 35 cases in the observation group. The pregnancy status of the patients' spouse within 6 months was recorded. The traditional Chinese medicine （TCM） syndrome scores of spleen-kidney deficiency pattern before and after treatment were evaluated. The semen volume，semen routine parameters，normal sperm morphology，sperm DNA fragmentation index，seminal plasma fructose，seminal plasma acid phosphatase， and seminal plasma α-glucosidase levels of the two groups were detected before and after treatment. In addition， the safety indicators related to liver and kidney functions of the two groups were detected before and after treatment. ResultsDuring the 6-month observation period， when compared with the situation before treatment in their respective groups，the semen volume of the observation group and the control group increased. In contrast， the sperm concentration，sperm motility，proportion of a+b-grade sperm，normal sperm morphology，seminal plasma fructose，seminal plasma acid phosphatase，seminal plasma α-Glucosidase，the proportion of a-grade sperm，linear sperm motility，linear sperm concentration， and linear sperm count all increased significantly（P<0.05）. At the same time， the sperm DNA fragmentation index and the TCM syndrome scores of the spleen-kidney deficiency pattern decreased significantly（P<0.05）. When the observation group was compared with the control group after treatment， the clinical efficacy of the observation group was better（Z=-2.276，P<0.05）. The pregnancy rate of the observation group's spouses was 14.3%，which was higher than the 2.9% of the control group. The sperm motility， the proportion of a+b-grade sperm，seminal plasma fructose，the proportion of a-grade sperm，normal sperm morphology，α-glucosidase， and linear sperm motility in the observation group were higher than those in the control group （P<0.05）. Moreover， the sperm DNA fragmentation index and the TCM syndrome scores of spleen-kidney deficiency pattern in the observation group were lower than those in the control group （P<0.01）. No serious adverse reactions occurred in the two groups，and no abnormalities were found in the safety indicators after treatment. ConclusionJiuzi Huichun decoction combined with spleen-strengthening moxibustion can enhance sperm viability and sperm concentration. It can also improve the TCM-related symptoms of asthenospermia of spleen-kidney deficiency pattern and sperm morphology. Additionally， it can reduce the sperm DNA fragmentation index and regulate the level of seminal plasma bioenzyme in patients with male asthenospermia infertility of spleen-kidney deficiency pattern. Therefore， it is worthy of further promotion and application in clinical practice.

The traditional theory of "the spleen governs the dispersion of essence" refers to the spleen's pivotal role in distributing refined nutrients throughout the body. In traditional Chinese medicine （TCM）， lipids are categorized under "gaozhi （膏脂）"， and their transportation and metabolism via apolipoproteins are believed to be closely related to the spleen's dispersing function. The liver， which synthesizes apolipoproteins， is functionally linked to the spleen system in TCM. Impaired dispersion of essence by the spleen and disrupted transportation of gaozhi constitute the pathological mechanism of dyslipidemia due to spleen deficiency. Strengthening the spleen and resolving dampness is the core therapeutic principle. From the perspective of modern medicine， this may involve promoting hepatic functional recovery related to lipid metabolism， thereby enhancing lipid processing and reducing the levels of abnormally accumulated lipids in the bloodstream.

BACKGROUND: T-cell lymphoblastic lymphoma/acute lymphoblastic leukemia (T-LBL/ALL) is an aggressive form of hematological malignancy associated with poor prognosis in adult patients. Histone deacetylases (HDACs) are aberrantly expressed in T-LBL/ALL and are considered potential therapeutic targets. Here, we investigated the antitumor effect of a novel HDAC inhibitor, chidamide, on T-LBL/ALL. METHODS: HDAC1, HDAC2 and HDAC3 levels in T-LBL/ALL cell lines and patient samples were compared with those in normal controls. Flow cytometry, transmission electron microscopy, and lactate dehydrogenase release assays were conducted in Jurkat and MOLT-4 cells to assess apoptosis and pyroptosis. A specific forkhead box O1 (FOXO1) inhibitor was used to rescue pyroptosis and upregulated gasdermin E (GSDME) expression caused by chidamide treatment. The role of the FOXO1 transcription factor was evaluated by dual-luciferase reporter and chromatin immunoprecipitation assays. The efficacy of chidamide in vivo was evaluated in a xenograft mouse. RESULTS: The expression of HDAC1, HDAC2 and HDAC3 was significantly upregulated in T-LBL/ALL. Cell viability was obviously inhibited after chidamide treatment. Pyroptosis, characterized by cell swelling, pore formation on the plasma membrane and lactate dehydrogenase leakage, was identified as a new mechanism of chidamide treatment. Chidamide triggered pyroptosis through caspase 3 activation and GSDME transcriptional upregulation. Chromatin immunoprecipitation assays confirmed that chidamide led to the increased transcription of GSDME through a more relaxed chromatin structure at the promoter and the upregulation of FOXO1 expression. Moreover, we identified the therapeutic effect of chidamide in vivo . CONCLUSIONS This study suggested that chidamide exerts an antitumor effect on T-LBL/ALL and promotes a more inflammatory form of cell death via the FOXO1/GSDME axis, which provides a novel choice of targeted therapy for patients with T-LBL/ALL.
Humans ; Pyroptosis/drug effects* ; Forkhead Box Protein O1/genetics* ; Aminopyridines/pharmacology* ; Animals ; Mice ; Benzamides/pharmacology* ; Cell Line, Tumor ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Phosphate-Binding Proteins/metabolism* ; Histone Deacetylase Inhibitors/pharmacology* ; Jurkat Cells ; Histone Deacetylases/metabolism* ; Apoptosis/drug effects* ; Gasdermins

OBJECTIVES: To investigate the role of PTEN-induced putative kinase 1 (PINK1) in regulating the viability, migration, and apoptosis of colorectal cancer (CRC) cells, and to explore its potential epigenetic mechanisms. METHODS: PINK1 was overex-pressed or knocked down in HCT116 and DLD1 CRC cell lines using lentiviral vectors, with efficiency verified by qRT-PCR and Western blotting. Cell proliferation, colony formation, migration, and apoptosis were assessed using CCK-8, colony formation, wound healing, Transwell, and Hoechst 33258 staining assays, respectively. Protein levels of apoptosis-related and histone modification-related markers were analyzed by Western blotting. Genome-wide chromatin accessibility was profiled using ATAC-seq. RESULTS: PINK1 expression was significantly downregulated at both mRNA and protein levels in CRC tissues compared to normal tissues. PINK1 overexpression inhibited cell prolifera-tion, colony formation, and migration in HCT116 and DLD1 cells (all P<0.05), whereas PINK1 knockdown promoted these malignant phenotypes (all P<0.05). PINK1 overex-pression induced apoptosis, associated with decreased levels of anti-apoptotic proteins (Mcl-1, Bcl-2, Bcl-xl) and increased pro-apoptotic Bax (all P<0.05), without altering p53 expression. Mechanistically, PINK1 overexpression reduced the expression of histone H3 lysine 9 trimethylation (H3K9me3) and histone H3 lysine 27 trimethylation (H3K27me3), and increased the expression of histone H3 lysine 9 acetylation (H3K9ac) and histone H3 lysine 27 acetylation (H3K27ac). It also downregulated key histone-modifying enzymes, including EZH2, EZH1, SUZ12, and histone deacetylase 3 (HDAC3) (all P<0.01). ATAC-seq revealed that PINK1 overexpression increased chromatin accessibility, particularly around transcription start sites. CONCLUSIONS PINK1 acts as a tumor suppressor in colorectal cancer by inhibiting proliferation and migration, promoting apoptosis, and remodeling the epigenetic landscape through altering histone modifications and enhancing chromatin accessibility.

Insufficient alveolar bone thickness increases the risk of periodontal dehiscence and fenestration, especially in orthodontic tooth movement. Abaloparatide (ABL), a synthetic analog of human PTHrP (1-34) and a clinical medication for treating osteoporosis, has recently demonstrated its potential in enhancing craniofacial bone formation. Herein, we show that intraoral submucosal injection of ABL, when combined with mechanical force, promotes in situ alveolar bone thickening. The newly formed bone is primarily located outside the original compact bone, implying its origin from the periosteum. RNA sequencing of the alveolar bone tissue revealed that the focal adhesion (FA) pathway potentially mediates this bioprocess. Local injection of ABL alone enhances cell proliferation, collagen synthesis, and phosphorylation of focal adhesion kinase (FAK) in the alveolar periosteum; when ABL is combined with mechanical force, the FAK expression is upregulated, in line with the accomplishment of the ossification. In vitro, ABL enhances proliferation, migration, and FAK phosphorylation in periosteal stem cells. Furthermore, the pro-osteogenic effects of ABL on alveolar bone are entirely blocked when FAK activity is inhibited by a specific inhibitor. In summary, abaloparatide combined with mechanical force promotes alveolar bone formation via FAK-mediated periosteal osteogenesis. Thus, we have introduced a promising therapeutic approach for drug-induced in situ alveolar bone augmentation, which may prevent or repair the detrimental periodontal dehiscence, holding significant potential in dentistry.
Osteogenesis/drug effects* ; Periosteum/cytology* ; Parathyroid Hormone-Related Protein/administration & dosage* ; Animals ; Focal Adhesion Protein-Tyrosine Kinases/metabolism* ; Alveolar Process/drug effects* ; Cell Proliferation/drug effects* ; Phosphorylation ; Rats ; Male ; Humans ; Focal Adhesion Kinase 1/metabolism* ; Cell Movement/drug effects*

Lenvatinib, a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer, facing limitations due to drug resistance. Here, we applied a multidimensional, high-throughput screening platform comprising patient-derived resistant liver tumor cells (PDCs), organoids (PDOs), and xenografts (PDXs) to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings. Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment, expediting drug repurposing screens. Pharmacological screening identified romidepsin, YM155, apitolisib, NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models. Notably, romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway. A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models. Collectively, our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer, providing a feasible multidimensional platform for personalized medicine.

OBJECTIVE To screen and identify the differential substance bases of Pinellia ternate and its different concoctions,conduct network pharmacological analysis on the common and differential substance bases,and explore the relationship between the substance bases and the changes in the efficacy of Pinellia ternate before and after concoction based on the UPLC-Q-TOF-MS/MS and multivariate statistical analysis.METHODS The main substance bases of 42 batches of samples were examined by UPLC-Q-TOF-MS/MS,and the differential components were screened by orthogonal partial least squares discriminant analysis(OPLS-DA)with VIP>1.5,P<0.01 and FC>2 or<0.5 as the screening criteria.The targets were further retrieved from the TCMIP database,and their protein interactions were analysed by GO enrichment and KEGG enrichment to visualise the"herbal-component-target-pathway"map.RESULTS Compared with Pinellia ternate,Pinelliae Rhizoma Praeparatum has 14 different components,mainly glycyrrhetinic acid,glycyrrhizic acid and glycyrrhizin,etc.The components with reduced content were mainly amides.There were 18 differential constituents between raw and ginger,mainly nucleosides,flavonoids and amino acids.The content of guanosine,xanthine and tyrosine was reduced,while the content of adenosine monophosphate was increased.There were 18 differential components between raw and Pinelliae Rhizoma Praeparatum Cum Alumine,and the relative content of many components in Pinelliae Rhizoma Praeparatum Cum Alu-mine was reduced,such as sphingomyelin.Further,the TCMIP database was used to retrieve targets from the differential substance base,and protein interaction analysis was performed on the targets,resulting in 67 core targets for Pinellia ternate,45 core targets for Pinelliae Rhizoma Praeparatum,and 38 core targets for Pinelliae Rhizoma Praeparatum cum Zingibere Et Alumine.Finally,the meta-bolic pathways were analyzed by GO enrichment and KEGG enrichment.CONCLUSION The UPLC-Q-TOF-MS/MS method estab-lished in this experiment can better isolate and identify the chemical components in Pinellia ternate.Combined with multivariate statisti-cal analysis and network pharmacology,the material basis and potential mechanism of action of Pinellia ternate and its concoction prod-ucts can provide ideas for the study of the action targets and provide data support for the rational clinical application of Pinellia ternate and its concoction products.

Objective To establish a HPLC method for the simultaneous determination of artemisinin,arteannuin B,chrysosplenetin and chrysosplenol-D in the water extract of Artemisia annua L.Methods The analysis was performed on Agilent ZORBAX SB-C18(250 mm×4.6 mm,5 μm)column with a mobile phase of acetonitrile(A)-water(B)and the flow rate of 0.8 mL·min-1 in a gradient elution manner.The column temperature was 30℃.The injection volume was 10 μL,and the detection wavelength was 210 nm.Results Artemisinin,arteannuin B,chrysosplenetin and chrysosplenol-D were correlated well linearly with peak area in their respective ranges 1.608 8-16.088 μg(r=0.999 9),0.014 1-0.141 4 μg(r=1),0.185 1-1.850 9 μg(r=0.999 9),0.144 1-1.441 4 μg(r=0.999 9),the average recovery rate(n=6)were 102.44%,97.82%,95.07%,95.55%,and the RSD values were 1.12%,1.44%,1.29%,1.53%.Conclusion This method is convenient and accurate.It has good stability and repeatability,and can be used to simultaneously determine the content of artemisinin,arteannuin B,chrysosplenetin and chrysosplenol-D in the water extract of Artemisia annua L.

Fanconi anemia (FA) is an inheritable disorder that presents with bone marrow failure, developmental anomalies, and an increased susceptibility to cancer. The etiology of this condition stems from a genetic mutation that disrupts the proper repair of interstrand DNA cross-links (ICLs). The resultant dysregulation of the DNA damage response mechanism can induce genomic instability, thereby elevating the mutation rates and the likelihood of developing cancer. The FA pathway assumes a pivotal role in safeguarding genome stability through its involvement in the repair of DNA cross-links and the maintenance of overall genomic integrity. A mutation in the germ line of any of the genes responsible for encoding the FA protein results in the development of FA. The prevalence of aberrant FA gene expression in somatic cancer, coupled with the identification of a connection between FA pathway activation and resistance to chemotherapy, has solidified the correlation between the FA pathway and cancer. Consequently, targeted therapies that exploit FA pathway gene abnormalities are being progressively developed and implemented. This review critically examines the involvement of the FA protein in the repair of ICLs, the regulation of the FA signaling network, and its implications in cancer pathogenesis and prognosis. Additionally, it explores the potential utility of small-molecule inhibitors that target the FA pathway.