Breast cancer (BC) is one of the most prevalent malignant tumors affecting women worldwide, with its incidence rate continuously increasing. As a result, treatment strategies for this disease have received considerable attention. Research has highlighted the crucial role of the Hedgehog (Hh) signaling pathway in the initiation and progression of BC, particularly in promoting tumor growth and metastasis. Therefore, molecular targets within this pathway represent promising opportunities for the development of novel BC therapies. This study aims to elucidate the therapeutic mechanisms by which natural compounds modulate the Hh signaling pathway in BC. By conducting a comprehensive review of various natural compounds, including polyphenols, terpenes, and alkaloids, we reveal both common and unique regulatory mechanisms that influence this pathway. This investigation represents the first comprehensive analysis of five distinct mechanisms through which natural compounds modulate key molecules within the Hh pathway and their impact on the aggressive behaviors of BC. Furthermore, by exploring the structure-activity relationships between these compounds and their molecular targets, we shed light on the specific structural features that enable natural compounds to interact with various components of the Hh pathway. These novel insights contribute to advancing the development and clinical application of natural compound-based therapeutics. Our thorough review not only lays the groundwork for exploring innovative BC treatments but also opens new avenues for leveraging natural compounds in cancer therapy.

Objective To explore the mechanism of Shengmai Decoction in improving heart failure by regulating mitochondrial apoptosis based on network pharmacology and experimental verification;To provide a basis for its clinical application.Methods The active components and targets of Shengmai Decoction were obtained through TCMSP and TCMID databases.Heart failure and mitochondrial apoptosis related targets were retrieved from GeneCards,OMIM,DrugBank,PharmGKB and TTD databases.A protein-protein interaction(PPI)network at the intersection of drugs and diseases was constructed using the STRING database,and a component-target network was constructed using Cytoscape 3.8.2 software.GO and KEGG pathway enrichment analysis was performed on intersecting targets using the DAVID database.Molecular docking was conducted to assess the binding affinity of key components to core target proteins.A rat model of heart failure was established,and the cardiac function of rats were detected by echocardiogram,ELISA was used to detect serum contents of BNP and NT-proBNP,mitochondrial ultrastructure was observed by transmission electron microscope,and Western blot was used to detect protein expressions of Bcl-2/Bax/Caspase-3 signaling pathway.Results A total of 66 active components and 146 targets of Shengmai Decoction were identified,and 22 intersecting targets with heart failure and mitochondrial apoptosis,including key proteins such as TNF,Bcl-2,Bax and Caspase-3.GO enrichment analysis revealed that the intersecting targets were closely associated with inflammation and cell signaling,while KEGG pathway analysis showed that the targets were primarily involved in the TNF signaling pathway,IL-17 signaling pathway,and mitochondrial function regulation.Molecular docking results indicated that Ginsenoside rh2,Beta-sitosterol and other components of Shengmai Decoction exhibited strong binding affinities with Bcl-2,Bax and Caspase-3.Animal experiments demonstrated that Shengmai Decoction significantly improved cardiac function(P<0.05,P<0.01),reduced serum BNP and NT-proBNP contents(P<0.01),alleviated mitochondrial damage,and inhibited mitochondrial apoptosis by upregulating Bcl-2 and downregulating Bax and Caspase-3 protein expression(P<0.01),thereby protecting cardiomyocytes.Conclusion Shengmai Decoction can target and regulate the Bcl-2/Bax/Caspase-3 signaling pathway,improving pathological processes associated with heart failure,which can provide a foundation for clinical optimization of Shengmai Decoction.

Breast cancer(BC)is one of the most prevalent malignant tumors affecting women worldwide,with its incidence rate continuously increasing.As a result,treatment strategies for this disease have received considerable attention.Research has highlighted the crucial role of the Hedgehog(Hh)signaling pathway in the initiation and progression of BC,particularly in promoting tumor growth and metastasis.There-fore,molecular targets within this pathway represent promising opportunities for the development of novel BC therapies.This study aims to elucidate the therapeutic mechanisms by which natural com-pounds modulate the Hh signaling pathway in BC.By conducting a comprehensive review of various natural compounds,including polyphenols,terpenes,and alkaloids,we reveal both common and unique regulatory mechanisms that influence this pathway.This investigation represents the first comprehen-sive analysis of five distinct mechanisms through which natural compounds modulate key molecules within the Hh pathway and their impact on the aggressive behaviors of BC.Furthermore,by exploring the structure-activity relationships between these compounds and their molecular targets,we shed light on the specific structural features that enable natural compounds to interact with various components of the Hh pathway.These novel insights contribute to advancing the development and clinical application of natural compound-based therapeutics.Our thorough review not only lays the groundwork for exploring innovative BC treatments but also opens new avenues for leveraging natural compounds in cancer therapy.

ObjectiveTo explore effect of Xianlian Jiedu prescription on the recurrence of colorectal cancer （CRC） and investigate the related mechanisms. MethodsA postoperative recurrence model was established in 25 Balb/c mice by injecting CT26 cells subcutaneously into the armpit， followed by surgical removal of 99% of the subcutaneous tumor. The mice were randomly divided into model group， low-dose Xianlian Jiedu prescription （XLJDP-L） group （6.45 g·kg^-1·d^-1）， medium-dose Xianlian Jiedu prescription （XLJDP-M） group （12.9 g·kg^-1·d^-1）， high-dose Xianlian Jiedu prescription （XLJDP-H） group （25.8 g·kg^-1·d^-1）， and 5-fluorouracil （5-FU） group （1×10^-3 g·kg^-1·d^-1）. The mice were euthanized after 14 days of continuous intervention， and recurrent tumor tissue was harvested. Hematoxylin and eosin （HE） staining was used to observe pathological and morphological changes in the recurrent tumor tissue. Immunohistochemistry （IHC） was employed to assess the expression of proliferating cell nuclear antigen （Ki67）， vascular endothelial growth factor （VEGF）， and platelet-endothelial cell adhesion molecule （CD31） in recurrent tumor tissue. The Western blot was used to detect the protein expression levels of angiopoietin-2 （ANG-2）， VEGF， phosphorylated-protein kinase B （p-Akt）， protein kinase B （Akt）， phosphorylated-phosphatidylinositol 3-kinase （p-PI3K）， and phosphatidylinositol 3-kinase （PI3K） in recurrent tumor tissue. ResultsBefore treatment， there were no statistical differences in tumor volume， tumor weight， and body mass among the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group compared to the model group， indicating model stability. After treatment， compared with those in the model group， the tumor volume and tumor weight in the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group were significantly reduced （P<0.01）， showing dose dependency. Meanwhile， there were no significant differences in body weight among the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group compared to the model group. HE staining showed that compared with that in the model group， tumor tissue in the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group had loosely arranged cells， increased intercellular spaces， small and shriveled nuclei， light staining， fewer mitotic figures and atypical nuclei， and increased necrotic areas. IHC showed that compared with those of the model group， the positive rates of Ki67， VEGF， and CD31 in the recurrent tumor tissue of the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group were significantly reduced （P<0.01） in a dose-dependent manner. Western blot results showed that compared with those of the model group， the protein expression levels of ANG-2 and VEGF in the recurrent tumor tissue of the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group were significantly downregulated （P<0.05， P<0.01）， and the p-Akt/Akt and p-PI3K/PI3K ratios were significantly decreased in a dose-dependent manner （P<0.05， P<0.01）. ConclusionXianlian Jiedu prescription significantly inhibits the recurrence of CRC in mice after subcutaneous tumor surgery. The mechanism may involve regulating the PI3K/Akt pathway and downregulating key angiogenic proteins such as ANG-2， VEGF， and CD31.

Objective To investigate the binding interaction between the calmodulin(CaM)mutant D130V and the IQ motif of the car-diac Cav1.2 channel.Methods The binding of mutant CaM-D130V to the IQ motif was predicted by fold recognition modeling,homology modeling,and protein docking.The plasmid was transformed into Escherichia coli BL-21 sensory cells via heat shock at 42 ℃ to induce the expression of glutathione S-transferase(GST)fusion protein.The protein was extracted by ultrasonic fragmentation and purified using GS-4B beads.PreScission protease was applied to remove the GST.SDS-PAGE was performed to detect the purity of protein.A GST pull-down assay was conducted to detect the interaction between CaM-D130V and IQ motif.Results Protein docking results showed that both CaM-WT and CaM-D130V could bind to the IQ motif of the cardiac Cav1.2 channel,but the binding sites of the mutant CaM-D130V to the IQ motif were reduced,and its binding conformation was changed compared with the CaM-WT,with decreased binding energy(|S|reduced from 48.086 6 kcal/mol to 47.309 5 kcal/mol).The GST pull-down assay indicated that the binding of CaM-D130V to IQ motif significantly decreased(P＜0.01),and the affinity was significantly reduced at 2 mmol/L Ca2+concentration compared with CaM-WT.Conclusion The reduced binding ability of CaM-D130V to the IQ motif of the cardiac Cav1.2 channel may contribute to functional alterations in the channel.These findings provide a theoretical basis for understanding the pathogenesis of CaM mutant-associated cardio-vascular diseases as well as targeted therapies.

Objective To explore the mechanism of Shengmai Decoction in improving heart failure by regulating mitochondrial apoptosis based on network pharmacology and experimental verification;To provide a basis for its clinical application.Methods The active components and targets of Shengmai Decoction were obtained through TCMSP and TCMID databases.Heart failure and mitochondrial apoptosis related targets were retrieved from GeneCards,OMIM,DrugBank,PharmGKB and TTD databases.A protein-protein interaction(PPI)network at the intersection of drugs and diseases was constructed using the STRING database,and a component-target network was constructed using Cytoscape 3.8.2 software.GO and KEGG pathway enrichment analysis was performed on intersecting targets using the DAVID database.Molecular docking was conducted to assess the binding affinity of key components to core target proteins.A rat model of heart failure was established,and the cardiac function of rats were detected by echocardiogram,ELISA was used to detect serum contents of BNP and NT-proBNP,mitochondrial ultrastructure was observed by transmission electron microscope,and Western blot was used to detect protein expressions of Bcl-2/Bax/Caspase-3 signaling pathway.Results A total of 66 active components and 146 targets of Shengmai Decoction were identified,and 22 intersecting targets with heart failure and mitochondrial apoptosis,including key proteins such as TNF,Bcl-2,Bax and Caspase-3.GO enrichment analysis revealed that the intersecting targets were closely associated with inflammation and cell signaling,while KEGG pathway analysis showed that the targets were primarily involved in the TNF signaling pathway,IL-17 signaling pathway,and mitochondrial function regulation.Molecular docking results indicated that Ginsenoside rh2,Beta-sitosterol and other components of Shengmai Decoction exhibited strong binding affinities with Bcl-2,Bax and Caspase-3.Animal experiments demonstrated that Shengmai Decoction significantly improved cardiac function(P<0.05,P<0.01),reduced serum BNP and NT-proBNP contents(P<0.01),alleviated mitochondrial damage,and inhibited mitochondrial apoptosis by upregulating Bcl-2 and downregulating Bax and Caspase-3 protein expression(P<0.01),thereby protecting cardiomyocytes.Conclusion Shengmai Decoction can target and regulate the Bcl-2/Bax/Caspase-3 signaling pathway,improving pathological processes associated with heart failure,which can provide a foundation for clinical optimization of Shengmai Decoction.

Objective To investigate the binding interaction between the calmodulin(CaM)mutant D130V and the IQ motif of the car-diac Cav1.2 channel.Methods The binding of mutant CaM-D130V to the IQ motif was predicted by fold recognition modeling,homology modeling,and protein docking.The plasmid was transformed into Escherichia coli BL-21 sensory cells via heat shock at 42 ℃ to induce the expression of glutathione S-transferase(GST)fusion protein.The protein was extracted by ultrasonic fragmentation and purified using GS-4B beads.PreScission protease was applied to remove the GST.SDS-PAGE was performed to detect the purity of protein.A GST pull-down assay was conducted to detect the interaction between CaM-D130V and IQ motif.Results Protein docking results showed that both CaM-WT and CaM-D130V could bind to the IQ motif of the cardiac Cav1.2 channel,but the binding sites of the mutant CaM-D130V to the IQ motif were reduced,and its binding conformation was changed compared with the CaM-WT,with decreased binding energy(|S|reduced from 48.086 6 kcal/mol to 47.309 5 kcal/mol).The GST pull-down assay indicated that the binding of CaM-D130V to IQ motif significantly decreased(P＜0.01),and the affinity was significantly reduced at 2 mmol/L Ca2+concentration compared with CaM-WT.Conclusion The reduced binding ability of CaM-D130V to the IQ motif of the cardiac Cav1.2 channel may contribute to functional alterations in the channel.These findings provide a theoretical basis for understanding the pathogenesis of CaM mutant-associated cardio-vascular diseases as well as targeted therapies.

Objective:To explore the effects of aerobic exercise therapy and anaerobic exercise therapy on improving depressive symptoms, sleep quality, and cognitive function in patients with mild and moderate depression.Methods:A prospective study was conducted to collect clinical data from 148 inpatients with mild to moderate depression treated at the Second Affiliated Hospital of Xinxiang Medical College from February 2019 to May 2023 including 74 males and 74 females aged 18 to 60 (40.08±11.03) years. They were randomly assigned the conventional treatment group (group A, 49 cases), the conventional treatment+moderate-intensity aerobic exercise therapy intervention group (group B, 51 cases), and the conventional treatment+moderate intensity anaerobic exercise therapy intervention group (group C, 48 cases). Patients in each group were treated the corresponding intervention for 4 weeks. The 24-item Hamilton Depression Scale (HAMD 24), Pittsburgh Sleep Quality Index (PSQI), and the Montreal Cognitive Assessment (MOCA) were used to score depressive symptoms, sleep quality, and cognitive function, respectively, before and after intervention. Paired sample t-tests were used to compare the changes in scores before and after the intervention. One-way ANOVA was used to analyze and compare the score differences on each scale among the groups. Results:After the intervention, HAMD 24 and PSQI scores in all groups decreased compared with those before the intervention (Group A: HAMD 24 (15.08±4.15) vs (29.33±4.75), PSQI (12.76±2.52) vs (14.88±3.64); Group B: HAMD 24 (12.82±3.83) vs (28.61±5.08), PSQI (11.59±2.26) vs (14.55±4.14); Group C: HAMD 24 (14.44±3.60) vs (29.44±4.98), PSQI (11.40±2.30) vs (15.13±4.62)) (all P<0.001). After the intervention, the MOCA scores in all groups were higher than those before the intervention (Group A: (26.04±2.21) vs (25.92±2.34), t=-2.20, P=0.032; Group B: (26.22±1.59) vs (25.35±1.95), t=-4.45, P<0.001; Group C: (26.10±2.15) vs (25.21±2.13), t=-3.15, P=0.003). After the intervention, the HAMD 24 scores of Group B were lower than those of Group A and Group C ((12.82±3.83) vs (15.08±4.15) vs (14.44±3.60)) (all P<0.05), and the PSQI scores of groups B and C were lower than those of group A ((11.59±2.26) and (11.40±2.30) vs (12.76±2.52)) (all P<0.05). No statistically significant differences in MOCA scores among Group A, Group B, and Group C after the intervention ( P=0.906). Conclusion:Exercise therapy is helpful in improving depressive symptoms and sleep quality in patients with mild to moderate depression, but it does not have a significant advantages in improving cognitive function.

Objective:To use pan-genomics and subtractive proteomics techniques to screen the new antibacterial targets from the Staphylococcus aureus genome,and to lay the foundation for the development of anti-Staphylococcus aureus drugs.Methods:The genome sequencing data of 50 strains with sequencing level Complete were collected by searching the whole genome sequencing data in the National Center for Biotechnology Information(NCBI)Database with Staphylococcus aureus as the keyword;BPGA tool was used to conduct the pan-genomics analysis on the genomic data to obtain the core genes of Staphylococcus aureus;subtractive proteomics technique was used to screen the potential antibacterial targets from the core genes.These potential antibacterial targets were used as the receptors;LibDock software was used to screen the potential anti-Staphylococcus aureus drugs from the US Food and Drug Administration(FDA)-approved drug library;molecular docking technology was used to analyze the binding abilities of the drugs and targets.Results:There were 14 379 gene families in the 50 Staphylococcus aureus genomes,of which 1 620 were the core genes.The subtractive proteomics analysis results showed that tyrosine autokinase 1335 was the potential anti-Staphylococcus aureus target.LibDock software screened out nine compounds,including balofloxacin,tenofovir disoproxil fumarate,and adefovir,that may exert anti-Staphylococcus aureus effects on this target protein.The molecular docking results showed there was good binding abilities between the targets and the compounds.Conclusion:Tyrosine autokinase may be the potential target for antii-Staphylococcus aureus.