Dual functional cholinesterase and MAO inhibitors for the treatment of Alzheimer’s disease: synthesis, pharmacological analysis and molecular modeling of homoisoflavonoid derivatives

<p>Because of the complexity of Alzheimer's disease (AD), the multi-target-directed ligand (MTDL) strategy is expected to provide superior effects for the treatment of AD, instead of the classic one-drug-one-target strategy. In this context, we focused on the design, synthesis and evaluation of homoisoflavonoid derivatives as dual acetyl cholinesterase (AChE) and monoamine oxidase (MAO-B) inhibitors. Among all the synthesized compounds, compound <b>10</b> provided a desired balance of AChE and hMAO-B inhibition activities, with IC₅₀ value of 3.94 and 3.44 μM, respectively. Further studies revealed that compound <b>10</b> was a mixed-type inhibitor of AChE and an irreversible inhibitor of hMAO-B, which was also confirmed by molecular modeling studies. Taken together, the data indicated that <b>10</b> was a promising dual functional agent for the treatment of AD.</p

Image_3_Human papillomavirus infection can alter the level of tumour stemness and T cell infiltration in patients with head and neck squamous cell carcinoma.tiff

Head and neck squamous cell carcinoma (HNSCC) usually has a poor prognosis and is associated with a high mortality rate. Its etiology is mainly the result from long-term exposure to either alcohol, tobacco or human papillomavirus (HPV) infection or a combination of these insults. However, HNSCC patients with HPV have been found to show a survival advantage over those without the virus, but the mechanism that confers this advantage is unclear. Due to the large number of HPV-independent HNSCC cases, there is a possibility that the difference in prognosis between HPV-positive (HPV+) and negative (HPV-) patients is due to different carcinogens. To clarify this, we used scRNA data and viral tracking methods in order to identify HPV+ and HPV- cells in the tumour tissues of patients infected with HPV. By comparing HPV+ and HPV- malignant cells, we found a higher level of tumour stemness in HPV- tumour cells. Using tumour stemness-related genes, we established a six-gene prognostic signature that was used to divide the patients into low- and high-risk groups. It was found that HPV patients who were at low-risk of contracting HNSCC had a higher number of CD8+ T-cells as well as a higher expression of immune checkpoint molecules. Correspondingly, we found that HPV+ tumour cells expressed higher levels of CCL4, and these were highly correlated with CD8+ T cells infiltration and immune checkpoint molecules. These data suggest that the stemness features of tumour cells are not only associated with the prognostic risk, but that it could also affect the immune cell interactions and associated signalling pathways.</p

Image_2_Human papillomavirus infection can alter the level of tumour stemness and T cell infiltration in patients with head and neck squamous cell carcinoma.tiff

Head and neck squamous cell carcinoma (HNSCC) usually has a poor prognosis and is associated with a high mortality rate. Its etiology is mainly the result from long-term exposure to either alcohol, tobacco or human papillomavirus (HPV) infection or a combination of these insults. However, HNSCC patients with HPV have been found to show a survival advantage over those without the virus, but the mechanism that confers this advantage is unclear. Due to the large number of HPV-independent HNSCC cases, there is a possibility that the difference in prognosis between HPV-positive (HPV+) and negative (HPV-) patients is due to different carcinogens. To clarify this, we used scRNA data and viral tracking methods in order to identify HPV+ and HPV- cells in the tumour tissues of patients infected with HPV. By comparing HPV+ and HPV- malignant cells, we found a higher level of tumour stemness in HPV- tumour cells. Using tumour stemness-related genes, we established a six-gene prognostic signature that was used to divide the patients into low- and high-risk groups. It was found that HPV patients who were at low-risk of contracting HNSCC had a higher number of CD8+ T-cells as well as a higher expression of immune checkpoint molecules. Correspondingly, we found that HPV+ tumour cells expressed higher levels of CCL4, and these were highly correlated with CD8+ T cells infiltration and immune checkpoint molecules. These data suggest that the stemness features of tumour cells are not only associated with the prognostic risk, but that it could also affect the immune cell interactions and associated signalling pathways.</p

Image_4_Human papillomavirus infection can alter the level of tumour stemness and T cell infiltration in patients with head and neck squamous cell carcinoma.tiff

Head and neck squamous cell carcinoma (HNSCC) usually has a poor prognosis and is associated with a high mortality rate. Its etiology is mainly the result from long-term exposure to either alcohol, tobacco or human papillomavirus (HPV) infection or a combination of these insults. However, HNSCC patients with HPV have been found to show a survival advantage over those without the virus, but the mechanism that confers this advantage is unclear. Due to the large number of HPV-independent HNSCC cases, there is a possibility that the difference in prognosis between HPV-positive (HPV+) and negative (HPV-) patients is due to different carcinogens. To clarify this, we used scRNA data and viral tracking methods in order to identify HPV+ and HPV- cells in the tumour tissues of patients infected with HPV. By comparing HPV+ and HPV- malignant cells, we found a higher level of tumour stemness in HPV- tumour cells. Using tumour stemness-related genes, we established a six-gene prognostic signature that was used to divide the patients into low- and high-risk groups. It was found that HPV patients who were at low-risk of contracting HNSCC had a higher number of CD8+ T-cells as well as a higher expression of immune checkpoint molecules. Correspondingly, we found that HPV+ tumour cells expressed higher levels of CCL4, and these were highly correlated with CD8+ T cells infiltration and immune checkpoint molecules. These data suggest that the stemness features of tumour cells are not only associated with the prognostic risk, but that it could also affect the immune cell interactions and associated signalling pathways.</p

Image_1_Human papillomavirus infection can alter the level of tumour stemness and T cell infiltration in patients with head and neck squamous cell carcinoma.tiff

Head and neck squamous cell carcinoma (HNSCC) usually has a poor prognosis and is associated with a high mortality rate. Its etiology is mainly the result from long-term exposure to either alcohol, tobacco or human papillomavirus (HPV) infection or a combination of these insults. However, HNSCC patients with HPV have been found to show a survival advantage over those without the virus, but the mechanism that confers this advantage is unclear. Due to the large number of HPV-independent HNSCC cases, there is a possibility that the difference in prognosis between HPV-positive (HPV+) and negative (HPV-) patients is due to different carcinogens. To clarify this, we used scRNA data and viral tracking methods in order to identify HPV+ and HPV- cells in the tumour tissues of patients infected with HPV. By comparing HPV+ and HPV- malignant cells, we found a higher level of tumour stemness in HPV- tumour cells. Using tumour stemness-related genes, we established a six-gene prognostic signature that was used to divide the patients into low- and high-risk groups. It was found that HPV patients who were at low-risk of contracting HNSCC had a higher number of CD8+ T-cells as well as a higher expression of immune checkpoint molecules. Correspondingly, we found that HPV+ tumour cells expressed higher levels of CCL4, and these were highly correlated with CD8+ T cells infiltration and immune checkpoint molecules. These data suggest that the stemness features of tumour cells are not only associated with the prognostic risk, but that it could also affect the immune cell interactions and associated signalling pathways.</p

Image_5_Human papillomavirus infection can alter the level of tumour stemness and T cell infiltration in patients with head and neck squamous cell carcinoma.tiff

Head and neck squamous cell carcinoma (HNSCC) usually has a poor prognosis and is associated with a high mortality rate. Its etiology is mainly the result from long-term exposure to either alcohol, tobacco or human papillomavirus (HPV) infection or a combination of these insults. However, HNSCC patients with HPV have been found to show a survival advantage over those without the virus, but the mechanism that confers this advantage is unclear. Due to the large number of HPV-independent HNSCC cases, there is a possibility that the difference in prognosis between HPV-positive (HPV+) and negative (HPV-) patients is due to different carcinogens. To clarify this, we used scRNA data and viral tracking methods in order to identify HPV+ and HPV- cells in the tumour tissues of patients infected with HPV. By comparing HPV+ and HPV- malignant cells, we found a higher level of tumour stemness in HPV- tumour cells. Using tumour stemness-related genes, we established a six-gene prognostic signature that was used to divide the patients into low- and high-risk groups. It was found that HPV patients who were at low-risk of contracting HNSCC had a higher number of CD8+ T-cells as well as a higher expression of immune checkpoint molecules. Correspondingly, we found that HPV+ tumour cells expressed higher levels of CCL4, and these were highly correlated with CD8+ T cells infiltration and immune checkpoint molecules. These data suggest that the stemness features of tumour cells are not only associated with the prognostic risk, but that it could also affect the immune cell interactions and associated signalling pathways.</p

Image2_Intestinal flora induces depression by mediating the dysregulation of cerebral cortex gene expression and regulating the metabolism of stroke patients.JPEG

Post-stroke depression (PSD) is a common cerebrovascular complication characterized by complex pathogenesis and poor treatment effects. Here, we tested the influence of differentially expressed genes (DEGs), non-targeted metabolites, and intestinal microbes on the occurrence and development of PSD. We acquired gene expression profiles for stroke patients, depression patients, and healthy controls from the Gene Expression Omnibus database. After screening for DEGs using differential expression analysis, we identified common DEGs in stroke and depression patients that were considered to form the molecular basis of PSD. Functional enrichment analysis of DEGs also revealed that the majority of biological functions were closely related to metabolism, immunity, the nervous system, and microorganisms, and we also collected blood and stool samples from healthy controls, stroke patients, and PSD patients and performed 16S rDNA sequencing and untargeted metabolomics. After evaluating the quality of the sequencing data, we compared the diversity of the metabolites and intestinal flora within and between groups. Metabolic pathway enrichment analysis was used to identify metabolic pathways that were significantly involved in stroke and PSD, and a global metabolic network was constructed to explore the pathogenesis of PSD. Additionally, we constructed a global regulatory network based on 16S rDNA sequencing, non-targeted metabolomics, and transcriptomics to explore the pathogenesis of PSD through correlation analysis. Our results suggest that intestinal flora associates the dysregulation of cerebral cortex gene expression and could potentially promote the occurrence of depression by affecting the metabolism of stroke patients. Our findings may be helpful in identifying new targets for the prevention and treatment of PSD.</p

Image6_Intestinal flora induces depression by mediating the dysregulation of cerebral cortex gene expression and regulating the metabolism of stroke patients.JPEG

Post-stroke depression (PSD) is a common cerebrovascular complication characterized by complex pathogenesis and poor treatment effects. Here, we tested the influence of differentially expressed genes (DEGs), non-targeted metabolites, and intestinal microbes on the occurrence and development of PSD. We acquired gene expression profiles for stroke patients, depression patients, and healthy controls from the Gene Expression Omnibus database. After screening for DEGs using differential expression analysis, we identified common DEGs in stroke and depression patients that were considered to form the molecular basis of PSD. Functional enrichment analysis of DEGs also revealed that the majority of biological functions were closely related to metabolism, immunity, the nervous system, and microorganisms, and we also collected blood and stool samples from healthy controls, stroke patients, and PSD patients and performed 16S rDNA sequencing and untargeted metabolomics. After evaluating the quality of the sequencing data, we compared the diversity of the metabolites and intestinal flora within and between groups. Metabolic pathway enrichment analysis was used to identify metabolic pathways that were significantly involved in stroke and PSD, and a global metabolic network was constructed to explore the pathogenesis of PSD. Additionally, we constructed a global regulatory network based on 16S rDNA sequencing, non-targeted metabolomics, and transcriptomics to explore the pathogenesis of PSD through correlation analysis. Our results suggest that intestinal flora associates the dysregulation of cerebral cortex gene expression and could potentially promote the occurrence of depression by affecting the metabolism of stroke patients. Our findings may be helpful in identifying new targets for the prevention and treatment of PSD.</p

Image9_Intestinal flora induces depression by mediating the dysregulation of cerebral cortex gene expression and regulating the metabolism of stroke patients.JPEG

Post-stroke depression (PSD) is a common cerebrovascular complication characterized by complex pathogenesis and poor treatment effects. Here, we tested the influence of differentially expressed genes (DEGs), non-targeted metabolites, and intestinal microbes on the occurrence and development of PSD. We acquired gene expression profiles for stroke patients, depression patients, and healthy controls from the Gene Expression Omnibus database. After screening for DEGs using differential expression analysis, we identified common DEGs in stroke and depression patients that were considered to form the molecular basis of PSD. Functional enrichment analysis of DEGs also revealed that the majority of biological functions were closely related to metabolism, immunity, the nervous system, and microorganisms, and we also collected blood and stool samples from healthy controls, stroke patients, and PSD patients and performed 16S rDNA sequencing and untargeted metabolomics. After evaluating the quality of the sequencing data, we compared the diversity of the metabolites and intestinal flora within and between groups. Metabolic pathway enrichment analysis was used to identify metabolic pathways that were significantly involved in stroke and PSD, and a global metabolic network was constructed to explore the pathogenesis of PSD. Additionally, we constructed a global regulatory network based on 16S rDNA sequencing, non-targeted metabolomics, and transcriptomics to explore the pathogenesis of PSD through correlation analysis. Our results suggest that intestinal flora associates the dysregulation of cerebral cortex gene expression and could potentially promote the occurrence of depression by affecting the metabolism of stroke patients. Our findings may be helpful in identifying new targets for the prevention and treatment of PSD.</p

Image7_Intestinal flora induces depression by mediating the dysregulation of cerebral cortex gene expression and regulating the metabolism of stroke patients.JPEG

Post-stroke depression (PSD) is a common cerebrovascular complication characterized by complex pathogenesis and poor treatment effects. Here, we tested the influence of differentially expressed genes (DEGs), non-targeted metabolites, and intestinal microbes on the occurrence and development of PSD. We acquired gene expression profiles for stroke patients, depression patients, and healthy controls from the Gene Expression Omnibus database. After screening for DEGs using differential expression analysis, we identified common DEGs in stroke and depression patients that were considered to form the molecular basis of PSD. Functional enrichment analysis of DEGs also revealed that the majority of biological functions were closely related to metabolism, immunity, the nervous system, and microorganisms, and we also collected blood and stool samples from healthy controls, stroke patients, and PSD patients and performed 16S rDNA sequencing and untargeted metabolomics. After evaluating the quality of the sequencing data, we compared the diversity of the metabolites and intestinal flora within and between groups. Metabolic pathway enrichment analysis was used to identify metabolic pathways that were significantly involved in stroke and PSD, and a global metabolic network was constructed to explore the pathogenesis of PSD. Additionally, we constructed a global regulatory network based on 16S rDNA sequencing, non-targeted metabolomics, and transcriptomics to explore the pathogenesis of PSD through correlation analysis. Our results suggest that intestinal flora associates the dysregulation of cerebral cortex gene expression and could potentially promote the occurrence of depression by affecting the metabolism of stroke patients. Our findings may be helpful in identifying new targets for the prevention and treatment of PSD.</p