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MultiTarget Pharmaceuticals network pharmacology
Network Pharmacology, supplied by MultiTarget Pharmaceuticals, used in various techniques. Bioz Stars score: 90/100, based on 1 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
https://www.bioz.com/product/multitarget/network+pharmacology/pm40659692-39-0-16
Average 90 stars, based on 1 article reviews

network pharmacology - by Bioz Stars, 2026-11

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Article Title: In vitro and in silico evaluation of phytocompounds from Leucaena leucocephala and Entada phaseoloides targeting DNA gyrase, topoisomerase II, AKT1.
Article Snippet: Network pharmacology is an advanced approach that integrates diverse databases to study pharmacological effects through a multicomponent-multitarget-multi-pathway lens.

Article Title: Elucidation of mechanisms of action of Wei-Sheng-Fang-Yi-Bao-Dan in the treatment of COVID-19 and depression using network pharmacology and molecular docking
Article Snippet: Network pharmacology is widely used to predict the mechanisms of action of Chinese medicine formulations in line with the "multigene, multitarget and multi-disease" principle [3].

Protein-Protein interactions:

Article Title: Synergistic Network Pharmacology: Preclinical Validation and Clinical Safety in Acute Ischemic Stroke
Article Snippet: .. Indeed, we addressed 2 roadblocks in translational stroke research by, first, building on validated risk genes, the resulting PPI module followed by a multitarget network pharmacology approach ; and second, by including 1 of the most relevant stroke comorbidities, diabetes. ..

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Screening potential candidates of TET-family inhibitors in infected hiPSC-CMs via computational molecular docking simulation. (A) The flowchart of the drug screening platform for molecular docking analysis of TET2 in complex with its DNA substrate and representative inhibitors. (B) Schematic representation of the molecular docking of representative TET2 inhibitors—Bobcat339, TFMB-2HG, and TETi76—into the catalytic pocket of TET2. The figure illustrates the catalytic core of TET2 binding to methylated DNA, followed by computational screening and docking of small-molecule inhibitors into the active site. (C) TET2 in complex with DNA substrate (Protein Data Bank [PDB] ID: 7NE3). Left: Overall structure showing TET2 (ribbon representation) bound to DNA (sticks in orange and magenta). Middle: Close-up view of the catalytic pocket highlighting the interaction surface. Right: 2-dimensional (2D) interaction diagram illustrating contacts between TET2 and the DNA substrate. (D) TET2 in complex with TETi76. Left: Chemical structure of TETi76. Middle: Docked pose of TETi76 in the TET2 catalytic site. Right: 2D interaction diagram showing hydrogen bonding and hydrophobic contacts. (E) TET2 in complex with Bobcat339. Left: Chemical structure of Bobcat339. Middle: Docked binding mode of Bobcat339 in the catalytic site. Right: 2D interaction map illustrating hydrogen bonds, hydrophobic interactions, and halogen bonding. (F) TET2 in complex with TFMB-2HG. Left: Chemical structure of TFMB-2HG. Middle: Docked pose within the TET2 active site. Right: 2D interaction map showing hydrogen bonding and minimal hydrophobic interactions.

Journal: Biomaterials Research

Article Title: Epitranscriptomic Modulation of TET2 Inhibition Suppressed SARS-CoV-2 Infection and Blocked Viral Nucleocapsid Protein in Induced-Pluripotent-Stem-Cell-Derived Cardiomyocyte Screening Models

doi: 10.34133/bmr.0229

Figure Lengend Snippet: Screening potential candidates of TET-family inhibitors in infected hiPSC-CMs via computational molecular docking simulation. (A) The flowchart of the drug screening platform for molecular docking analysis of TET2 in complex with its DNA substrate and representative inhibitors. (B) Schematic representation of the molecular docking of representative TET2 inhibitors—Bobcat339, TFMB-2HG, and TETi76—into the catalytic pocket of TET2. The figure illustrates the catalytic core of TET2 binding to methylated DNA, followed by computational screening and docking of small-molecule inhibitors into the active site. (C) TET2 in complex with DNA substrate (Protein Data Bank [PDB] ID: 7NE3). Left: Overall structure showing TET2 (ribbon representation) bound to DNA (sticks in orange and magenta). Middle: Close-up view of the catalytic pocket highlighting the interaction surface. Right: 2-dimensional (2D) interaction diagram illustrating contacts between TET2 and the DNA substrate. (D) TET2 in complex with TETi76. Left: Chemical structure of TETi76. Middle: Docked pose of TETi76 in the TET2 catalytic site. Right: 2D interaction diagram showing hydrogen bonding and hydrophobic contacts. (E) TET2 in complex with Bobcat339. Left: Chemical structure of Bobcat339. Middle: Docked binding mode of Bobcat339 in the catalytic site. Right: 2D interaction map illustrating hydrogen bonds, hydrophobic interactions, and halogen bonding. (F) TET2 in complex with TFMB-2HG. Left: Chemical structure of TFMB-2HG. Middle: Docked pose within the TET2 active site. Right: 2D interaction map showing hydrogen bonding and minimal hydrophobic interactions.

Article Snippet: Molecular docking analysis revealed that Bobcat339 exhibited a high binding affinity for multiple viral targets, including nsp16, RdRp, and N protein, indicating a multitarget mechanism of action.

Techniques: Infection, Drug discovery, Binding Assay, Methylation

Treatment with Bobcat339 suppressed the viral replication and N-protein expression in infected hiPSC-CMs during SARS-CoV-2 infection. (A) Experimental workflow for assessing virus-mediated regulation of TET2 and its functional role using the selective TET2 inhibitor Bobcat339. (B) qRT-PCR analysis of TET2 mRNA expression in SARS-CoV-2-infected hiPSC-CMs treated with Bobcat339 (80 μM) or dimethyl sulfoxide (DMSO) for 24 h. (C) qRT-PCR analysis of N-protein mRNA expression in SARS-CoV-2-infected hiPSC-CMs treated with Bobcat339 (80 μM) or DMSO for 24 h. (D) Western blot analysis showing the protein expression levels of TET2 and SARS-CoV-2 N protein in hiPSC-CMs treated with Bobcat339 or DMSO for 24 h postinfection. (E) qRT-PCR analysis of TET2 mRNA expression in hiPSC-CMs treated with Bobcat339 or DMSO for 48 h postinfection. (F) qRT-PCR analysis of N-protein mRNA expression in hiPSC-CMs treated with Bobcat339 or DMSO for 48 h postinfection. (G) Western blot analysis showing the protein expression levels of TET2 and SARS-CoV-2 N protein in hiPSC-CMs treated with Bobcat339 or DMSO for 48 h postinfection. (H) Dot blot analysis of total RNA extracted from hiPSC-CMs showing hm5C levels after treatment with different concentrations of Bobcat339 (0 to 80 μM) or DMSO. Methylene blue (MB) was used as a loading control. (I) Dot blot analysis of total RNA extracted from hiPSC-CMs showing hm5C levels after treatment with Bobcat339 (80 μM) or DMSO, with or without SARS-CoV-2 infection. MB was used as a loading control. (J) Schematic diagram illustrating the proposed mechanism: SARS-CoV-2 infects hiPSC-CMs and induces TET2-mediated RNA demethylation (conversion of m5C to hm5C), which is inhibited by Bobcat339. Data in panels (B), (C), (E), and (F) are presented as mean ± SEM from 3 independent experiments. Statistical significance: ** P < 0.01 and **** P < 0.0001.

Journal: Biomaterials Research

doi: 10.34133/bmr.0229

Figure Lengend Snippet: Treatment with Bobcat339 suppressed the viral replication and N-protein expression in infected hiPSC-CMs during SARS-CoV-2 infection. (A) Experimental workflow for assessing virus-mediated regulation of TET2 and its functional role using the selective TET2 inhibitor Bobcat339. (B) qRT-PCR analysis of TET2 mRNA expression in SARS-CoV-2-infected hiPSC-CMs treated with Bobcat339 (80 μM) or dimethyl sulfoxide (DMSO) for 24 h. (C) qRT-PCR analysis of N-protein mRNA expression in SARS-CoV-2-infected hiPSC-CMs treated with Bobcat339 (80 μM) or DMSO for 24 h. (D) Western blot analysis showing the protein expression levels of TET2 and SARS-CoV-2 N protein in hiPSC-CMs treated with Bobcat339 or DMSO for 24 h postinfection. (E) qRT-PCR analysis of TET2 mRNA expression in hiPSC-CMs treated with Bobcat339 or DMSO for 48 h postinfection. (F) qRT-PCR analysis of N-protein mRNA expression in hiPSC-CMs treated with Bobcat339 or DMSO for 48 h postinfection. (G) Western blot analysis showing the protein expression levels of TET2 and SARS-CoV-2 N protein in hiPSC-CMs treated with Bobcat339 or DMSO for 48 h postinfection. (H) Dot blot analysis of total RNA extracted from hiPSC-CMs showing hm5C levels after treatment with different concentrations of Bobcat339 (0 to 80 μM) or DMSO. Methylene blue (MB) was used as a loading control. (I) Dot blot analysis of total RNA extracted from hiPSC-CMs showing hm5C levels after treatment with Bobcat339 (80 μM) or DMSO, with or without SARS-CoV-2 infection. MB was used as a loading control. (J) Schematic diagram illustrating the proposed mechanism: SARS-CoV-2 infects hiPSC-CMs and induces TET2-mediated RNA demethylation (conversion of m5C to hm5C), which is inhibited by Bobcat339. Data in panels (B), (C), (E), and (F) are presented as mean ± SEM from 3 independent experiments. Statistical significance: ** P < 0.01 and **** P < 0.0001.

Techniques: Expressing, Infection, Virus, Functional Assay, Quantitative RT-PCR, Western Blot, Dot Blot, Control

Computational protein–ligand binding prediction of Bobcat339 with molecular docking modeling of SARS-CoV-2 proteins in N protein, RNA-dependent RNA polymerase (RdRp), and nonstructural protein 16 (nsp16). (A) Illustration of the docking process. The diagram shows the process of target molecule docking by first defining the active center within the protein, then docking the ligand (Bobcat339) into the binding pocket, and finally observing the key interactions formed after docking, such as hydrogen bonds and hydrophobic contacts. (B) The docking of Bobcat339 into the RNA binding site of the SARS-CoV-2 N protein. The left panel depicts Bobcat339 positioned inside the binding pocket, while the middle panel highlights the hydrophobicity and detailed docking interactions. The right panel presents the specific molecular interactions between Bobcat339 and N-protein amino acid residues, including π–π stacking and hydrogen bonds. (C) The docking of Bobcat339 within the RNA binding domain of the SARS-CoV-2 nsp16 protein. The left panel presents the docking site; the middle panel, the binding pocket environment; and the right panel, interactions such as hydrogen bonds and hydrophobic contacts between Bobcat339 and surrounding amino acids. (D) Bobcat339 is docked into the RNA binding site of the SARS-CoV-2 RdRp. The left panel shows the overall docking location, the middle panel zooms into the binding pocket illustrating the hydrophobic interactions, and the right panel details the hydrogen bonding and hydrophobic interactions between Bobcat339 and specific RdRp residues.

Journal: Biomaterials Research

doi: 10.34133/bmr.0229

Figure Lengend Snippet: Computational protein–ligand binding prediction of Bobcat339 with molecular docking modeling of SARS-CoV-2 proteins in N protein, RNA-dependent RNA polymerase (RdRp), and nonstructural protein 16 (nsp16). (A) Illustration of the docking process. The diagram shows the process of target molecule docking by first defining the active center within the protein, then docking the ligand (Bobcat339) into the binding pocket, and finally observing the key interactions formed after docking, such as hydrogen bonds and hydrophobic contacts. (B) The docking of Bobcat339 into the RNA binding site of the SARS-CoV-2 N protein. The left panel depicts Bobcat339 positioned inside the binding pocket, while the middle panel highlights the hydrophobicity and detailed docking interactions. The right panel presents the specific molecular interactions between Bobcat339 and N-protein amino acid residues, including π–π stacking and hydrogen bonds. (C) The docking of Bobcat339 within the RNA binding domain of the SARS-CoV-2 nsp16 protein. The left panel presents the docking site; the middle panel, the binding pocket environment; and the right panel, interactions such as hydrogen bonds and hydrophobic contacts between Bobcat339 and surrounding amino acids. (D) Bobcat339 is docked into the RNA binding site of the SARS-CoV-2 RdRp. The left panel shows the overall docking location, the middle panel zooms into the binding pocket illustrating the hydrophobic interactions, and the right panel details the hydrogen bonding and hydrophobic interactions between Bobcat339 and specific RdRp residues.

Techniques: Ligand Binding Assay, Binding Assay, RNA Binding Assay

Development of epitranscriptomic-based drug screening and TET2-targeting pathways/TET inhibitors as a novel strategy for anti-SARS-CoV-2 infection via an in vitro model of hiPSC-derived cardiomyocytes. This schematic depicts the development of epigenetic therapies for SARS-CoV-2. hiPSCs are differentiated into cardiomyocytes, infected with SARS-CoV-2, and analyzed using NGS for molecular insights. Drug screening, computational evaluation, and validation with compounds like Bobcat339 aid in the advancement of antiviral therapy. This approach may significantly impact the future of antiviral drug development and personalized medicine, offering a sophisticated tool for understanding and combating systemic SARS-CoV-2 infections.

Journal: Biomaterials Research

doi: 10.34133/bmr.0229

Figure Lengend Snippet: Development of epitranscriptomic-based drug screening and TET2-targeting pathways/TET inhibitors as a novel strategy for anti-SARS-CoV-2 infection via an in vitro model of hiPSC-derived cardiomyocytes. This schematic depicts the development of epigenetic therapies for SARS-CoV-2. hiPSCs are differentiated into cardiomyocytes, infected with SARS-CoV-2, and analyzed using NGS for molecular insights. Drug screening, computational evaluation, and validation with compounds like Bobcat339 aid in the advancement of antiviral therapy. This approach may significantly impact the future of antiviral drug development and personalized medicine, offering a sophisticated tool for understanding and combating systemic SARS-CoV-2 infections.

Techniques: Drug discovery, Infection, In Vitro, Derivative Assay, Biomarker Discovery

Dose-response curves and IC₅₀ determination of CB2R compounds across gastric cancer cell lines. MTT assays were performed at 48 and 72 h to calculate IC₅₀ values. The graphs represented the results expressed as % of vitality at 48 h and displayed five coloured sigmoid curves, each corresponding to a different CB2R compound: blue for the antagonist AM630 , red for CC48 , green for Fi9 , purple for ASF151 and yellow for the reference compound 1 . The corresponding IC₅₀ values with their standard error of the mean (SEM), are shown alongside. Data are from one of three independent experiments; each performed in triplicate

Journal: Journal of Experimental & Clinical Cancer Research : CR

Article Title: CC48 a new CB2R agonist/FAAH inhibitor dual drug blocks gastric cancer progression and overcomes paclitaxel resistance

doi: 10.1186/s13046-025-03476-7

Figure Lengend Snippet: Dose-response curves and IC₅₀ determination of CB2R compounds across gastric cancer cell lines. MTT assays were performed at 48 and 72 h to calculate IC₅₀ values. The graphs represented the results expressed as % of vitality at 48 h and displayed five coloured sigmoid curves, each corresponding to a different CB2R compound: blue for the antagonist AM630 , red for CC48 , green for Fi9 , purple for ASF151 and yellow for the reference compound 1 . The corresponding IC₅₀ values with their standard error of the mean (SEM), are shown alongside. Data are from one of three independent experiments; each performed in triplicate

Article Snippet: In conclusion, the activity exhibited by CC48 across all investigated pathways supports a multitarget approach.

Techniques:

CB2R-binding compounds counter PTX resistance and promote PTX-mediated inhibition of cell proliferation.The Ki67 cytofluorimetric assay was performed after treatment of PTX-sensitive HGC27 cells and their resistant counterparts and NCI-N87 cells with a combination of 10µM CC48 or Fi9 or ASF151 or 1 or 6 µM AM630 with 4 µM PTX. A ) Representative flow cytometry charts after exposure to CC48 and reporting the percentage of Ki67 negative (blue) and positive (red) cells; the Ki67 + population of the control is shown in grey. B ) Statistical charts reporting the results obtained in HGC27-S, HGC27-R and NCI-N87, from three independent experiments and expressed as means ± SD. Statistical analysis was assessed by comparing the values obtained using single drug treatment to those of corresponding untreated cells and the combined treatments to those with PTX alone, * p < 0.05; ** p < 0.01

Journal: Journal of Experimental & Clinical Cancer Research : CR

Article Title: CC48 a new CB2R agonist/FAAH inhibitor dual drug blocks gastric cancer progression and overcomes paclitaxel resistance

doi: 10.1186/s13046-025-03476-7

Figure Lengend Snippet: CB2R-binding compounds counter PTX resistance and promote PTX-mediated inhibition of cell proliferation.The Ki67 cytofluorimetric assay was performed after treatment of PTX-sensitive HGC27 cells and their resistant counterparts and NCI-N87 cells with a combination of 10µM CC48 or Fi9 or ASF151 or 1 or 6 µM AM630 with 4 µM PTX. A ) Representative flow cytometry charts after exposure to CC48 and reporting the percentage of Ki67 negative (blue) and positive (red) cells; the Ki67 + population of the control is shown in grey. B ) Statistical charts reporting the results obtained in HGC27-S, HGC27-R and NCI-N87, from three independent experiments and expressed as means ± SD. Statistical analysis was assessed by comparing the values obtained using single drug treatment to those of corresponding untreated cells and the combined treatments to those with PTX alone, * p < 0.05; ** p < 0.01

Article Snippet: In conclusion, the activity exhibited by CC48 across all investigated pathways supports a multitarget approach.

Techniques: Binding Assay, Inhibition, Cytofluorimetric Assay, Flow Cytometry, Control

Western blot analysis of the expression and activation levels of key proteins involved in cell proliferation. Representative western blotting analyses performed in HGC27-S/R and statistical charts reporting the results from three independent experiments expressed as means ± SD. The expression of the phosphorylated and/or total forms of TSC2, AKT, p70, S6, 4EBP1, PI3K, and ERK1/2 after 48 h of treatment with the compounds AM630 , CC48 , Fi9 , ASF151 and 1 . The expression levels of each of the investigated proteins were normalized to the actin level, * p < 0.05; ** p < 0.01; *** p < 0.001

Journal: Journal of Experimental & Clinical Cancer Research : CR

Article Title: CC48 a new CB2R agonist/FAAH inhibitor dual drug blocks gastric cancer progression and overcomes paclitaxel resistance

doi: 10.1186/s13046-025-03476-7

Figure Lengend Snippet: Western blot analysis of the expression and activation levels of key proteins involved in cell proliferation. Representative western blotting analyses performed in HGC27-S/R and statistical charts reporting the results from three independent experiments expressed as means ± SD. The expression of the phosphorylated and/or total forms of TSC2, AKT, p70, S6, 4EBP1, PI3K, and ERK1/2 after 48 h of treatment with the compounds AM630 , CC48 , Fi9 , ASF151 and 1 . The expression levels of each of the investigated proteins were normalized to the actin level, * p < 0.05; ** p < 0.01; *** p < 0.001

Article Snippet: In conclusion, the activity exhibited by CC48 across all investigated pathways supports a multitarget approach.

Techniques: Western Blot, Expressing, Activation Assay

Western blot analysis of expression levels of key proteins involved in autophagy. A) Representative WB experiments showing the expression levels of autophagy-involved proteins ATG5, ATG7, ATG12, Beclin-1, LC3-II in PTX-sensitive and resistant HGC27 cell lines and AGS after 48 h of treatment with the compounds AM630 , CC48 , Fi9 , ASF151 and 1 . B ) Statistical charts reporting the results from three independent experiments and expressed as means ± SD. Expression levels of each of the investigated proteins were normalized to the Tubulin level, * p < 0.05; ** p < 0.01; *** p < 0.001;**** p < 0.0001

Journal: Journal of Experimental & Clinical Cancer Research : CR

Article Title: CC48 a new CB2R agonist/FAAH inhibitor dual drug blocks gastric cancer progression and overcomes paclitaxel resistance

doi: 10.1186/s13046-025-03476-7

Figure Lengend Snippet: Western blot analysis of expression levels of key proteins involved in autophagy. A) Representative WB experiments showing the expression levels of autophagy-involved proteins ATG5, ATG7, ATG12, Beclin-1, LC3-II in PTX-sensitive and resistant HGC27 cell lines and AGS after 48 h of treatment with the compounds AM630 , CC48 , Fi9 , ASF151 and 1 . B ) Statistical charts reporting the results from three independent experiments and expressed as means ± SD. Expression levels of each of the investigated proteins were normalized to the Tubulin level, * p < 0.05; ** p < 0.01; *** p < 0.001;**** p < 0.0001

Article Snippet: In conclusion, the activity exhibited by CC48 across all investigated pathways supports a multitarget approach.

Techniques: Western Blot, Expressing

Apoptotic effects of CB2R ligands in GC cell lines. A ) Muse Annexin V Cell Assay for HGC27-S/R and AGS cell lines evaluated after 48 h of treatment with 1 µM or 6 µM of AM630 and 1 µM or 10 µM of CC48 , Fi9 , ASF151 and compound 1 . Results expressed as relative apoptosis rate compared to control cells and derived from three independent experiments were expressed as mean ± SD and plotted in the corresponding graphs. * p < 0.05; ** p < 0.01; B ) Representative western blotting analyses performed in HGC27-S/R and AGS cells regarding the expression of PPRγ, P-JUN/JUN, P-JNK/JNK and cleaved caspase 3/7. Actin was used as a normalizer of the protein extracts. C ) Statistical charts reporting the results from three independent western blotting experiments performed in HGC27-S/R and AGS cells and expressed as means ± SD, * p < 0.05; ** p < 0.01; *** p < 0.001

Journal: Journal of Experimental & Clinical Cancer Research : CR

Article Title: CC48 a new CB2R agonist/FAAH inhibitor dual drug blocks gastric cancer progression and overcomes paclitaxel resistance

doi: 10.1186/s13046-025-03476-7

Figure Lengend Snippet: Apoptotic effects of CB2R ligands in GC cell lines. A ) Muse Annexin V Cell Assay for HGC27-S/R and AGS cell lines evaluated after 48 h of treatment with 1 µM or 6 µM of AM630 and 1 µM or 10 µM of CC48 , Fi9 , ASF151 and compound 1 . Results expressed as relative apoptosis rate compared to control cells and derived from three independent experiments were expressed as mean ± SD and plotted in the corresponding graphs. * p < 0.05; ** p < 0.01; B ) Representative western blotting analyses performed in HGC27-S/R and AGS cells regarding the expression of PPRγ, P-JUN/JUN, P-JNK/JNK and cleaved caspase 3/7. Actin was used as a normalizer of the protein extracts. C ) Statistical charts reporting the results from three independent western blotting experiments performed in HGC27-S/R and AGS cells and expressed as means ± SD, * p < 0.05; ** p < 0.01; *** p < 0.001

Article Snippet: In conclusion, the activity exhibited by CC48 across all investigated pathways supports a multitarget approach.

Techniques: Control, Derivative Assay, Western Blot, Expressing

Journal: Journal of Experimental & Clinical Cancer Research : CR

Article Title: CC48 a new CB2R agonist/FAAH inhibitor dual drug blocks gastric cancer progression and overcomes paclitaxel resistance

doi: 10.1186/s13046-025-03476-7

Figure Lengend Snippet: Apoptotic profile of CB2R ligands and PTX in HGC27-S/R and NCI-N87 cells. The Muse caspase 3/7 activation Cell Assay was assessed after 48 h of both single drug treatments with 4 nM PTX, 6 µM AM630 , 10 µM CC48 , Fi9 , ASF151 and compound 1 , and after combined treatment of PTX with CB2R target compounds. A ) Representative flow cytometry charts of HGC27-S/R are shown. Four cell populations can be distinguished, namely the percentage of live cells (bottom left quadrant), cells in early apoptosis (bottom right quadrant), in late apoptosis (top right quadrant) and dead cells (top left quadrant). B ) The results derived from three independent experiments on HGC27-S, HGC27-R and NCI-N87 cell lines are expressed as means ± SD and reported in the relative graphs. Statistical analysis was conducted, comparing the values obtained using single drug treatment to those of corresponding untreated cells and the combined treatments to those of the single treatments, * p < 0.05; ** p < 0.01; *** p < 0.001

Article Snippet: In conclusion, the activity exhibited by CC48 across all investigated pathways supports a multitarget approach.

Techniques: Activation Assay, Flow Cytometry, Derivative Assay

Effects of CB2R ligands on inhibition of cell migration and VEGFA secretion. A ) Scratch assay evaluated on HGC27-S/R and AGS treated with 1 and 6 µM AM630 and 1 and 10 µM CC48 , Fi9 , ASF151 and 1 . Cells were microscopically analyzed at the time of scratching (T0) and after 24 h (T1). The relative migration rate was calculated by placing the percentage migration of control cells at time T1 equal to 1 and comparing the percentage migration of cells after each drug treatment with this value. The experiments were performed in triples and the average SD values were plotted in the relative graph. * p < 0,05; ** p < 0,01; B ) Representative western blotting analyses performed in HGC27- S/R and AGS cells regarding the expression of P-βcatenin/βcatenin, vimentin and P-cofillin/cofillin. Actin was used as a normalization of the protein extracts; C ) Effects of CB2R ligands on VEGFA/VEGFC secretion. The ELISA assay was assessed on HGC27-S/R and AGS treated with 1 and 6 µM AM630 and 1 and 10 µM CC48 , Fi9 , ASF151 and 1 . The concentration of VEGFA was determined in the medium and normalized for the cell number. The values ± SD, obtained from three independent experiments expressed as pg/mL were shown in the relative graphs.** p < 0,01; *** p < 0,001

Journal: Journal of Experimental & Clinical Cancer Research : CR

Article Title: CC48 a new CB2R agonist/FAAH inhibitor dual drug blocks gastric cancer progression and overcomes paclitaxel resistance

doi: 10.1186/s13046-025-03476-7

Figure Lengend Snippet: Effects of CB2R ligands on inhibition of cell migration and VEGFA secretion. A ) Scratch assay evaluated on HGC27-S/R and AGS treated with 1 and 6 µM AM630 and 1 and 10 µM CC48 , Fi9 , ASF151 and 1 . Cells were microscopically analyzed at the time of scratching (T0) and after 24 h (T1). The relative migration rate was calculated by placing the percentage migration of control cells at time T1 equal to 1 and comparing the percentage migration of cells after each drug treatment with this value. The experiments were performed in triples and the average SD values were plotted in the relative graph. * p < 0,05; ** p < 0,01; B ) Representative western blotting analyses performed in HGC27- S/R and AGS cells regarding the expression of P-βcatenin/βcatenin, vimentin and P-cofillin/cofillin. Actin was used as a normalization of the protein extracts; C ) Effects of CB2R ligands on VEGFA/VEGFC secretion. The ELISA assay was assessed on HGC27-S/R and AGS treated with 1 and 6 µM AM630 and 1 and 10 µM CC48 , Fi9 , ASF151 and 1 . The concentration of VEGFA was determined in the medium and normalized for the cell number. The values ± SD, obtained from three independent experiments expressed as pg/mL were shown in the relative graphs.** p < 0,01; *** p < 0,001

Article Snippet: In conclusion, the activity exhibited by CC48 across all investigated pathways supports a multitarget approach.

Techniques: Inhibition, Migration, Wound Healing Assay, Control, Western Blot, Expressing, Enzyme-linked Immunosorbent Assay, Concentration Assay

CB2R agonist CC48 reduces tumor masses in mice. (A) Tumor growth was evaluated weekly using an IVIS spectrum PerkinElmer. Tumor masses measurements were started on the fifth day after intraperitoneal inoculation of GC cell line NCl-N87_LUC and were performed twice a week until day 41; (B) From the statistical analysis performed on the data obtained throughout the study (up to day 41), a substantial and significant decrease in tumor volume was observed at day 41 in mice treated with both CC48 concentrations (GP2, 10 mg/kg and GP3, 20 mg/kg), compared to the control group (vehicle) (** p < 0.01 for GP2 and *** p < 0.001 for GP3).Dunnett’s multiple comparison statistical test was applied; (C) No statistically significant differences were observed between the control group (vehicle) and the two treated groups (GP2 and GP3) in relation to body weight, suggesting that the drug did not negatively affect the growth or energy balance of the animals. D-E) Similarly, the biochemical (D , E) and urinary (E) parameters analysed did not show any significant alterations in the treated groups (GP2 and GP3), as compared to the control group. Abbreviations BW: Body Weight; AST: Aspartate Transferase; ALT: Alanine Aminotransferase; Cre: Creatinine; GFR Glomerular Filtration Rate

Journal: Journal of Experimental & Clinical Cancer Research : CR

Article Title: CC48 a new CB2R agonist/FAAH inhibitor dual drug blocks gastric cancer progression and overcomes paclitaxel resistance

doi: 10.1186/s13046-025-03476-7

Figure Lengend Snippet: CB2R agonist CC48 reduces tumor masses in mice. (A) Tumor growth was evaluated weekly using an IVIS spectrum PerkinElmer. Tumor masses measurements were started on the fifth day after intraperitoneal inoculation of GC cell line NCl-N87_LUC and were performed twice a week until day 41; (B) From the statistical analysis performed on the data obtained throughout the study (up to day 41), a substantial and significant decrease in tumor volume was observed at day 41 in mice treated with both CC48 concentrations (GP2, 10 mg/kg and GP3, 20 mg/kg), compared to the control group (vehicle) (** p < 0.01 for GP2 and *** p < 0.001 for GP3).Dunnett’s multiple comparison statistical test was applied; (C) No statistically significant differences were observed between the control group (vehicle) and the two treated groups (GP2 and GP3) in relation to body weight, suggesting that the drug did not negatively affect the growth or energy balance of the animals. D-E) Similarly, the biochemical (D , E) and urinary (E) parameters analysed did not show any significant alterations in the treated groups (GP2 and GP3), as compared to the control group. Abbreviations BW: Body Weight; AST: Aspartate Transferase; ALT: Alanine Aminotransferase; Cre: Creatinine; GFR Glomerular Filtration Rate

Article Snippet: In conclusion, the activity exhibited by CC48 across all investigated pathways supports a multitarget approach.

Techniques: Control, Comparison, Filtration

CC48 reduces tumor cells proliferation in treated mice (A) Histological sections stained with hematoxylin & eosin, representative of the tumor masses from each of the three experimental groups, vehicle-treated control group (GP1), group treated with 10 mg/Kg CC48 (GP2) and group treated with 20 mg/Kg CC48 (GP3) Lens: 10X. Bar: 100 μm. Circled areas enclose details of each histologic section taken at 40X magnification. In GP1 there are viable neoplastic cells, in GP2 the red arrow on the left indicates the necrotic area, and the two red arrows on the right indicate the lymphocytic infiltrate. In the GP3 group of mice, where the malignancy infiltrates the striated muscle of the murine diaphragm, the left arrow indicates a foamy histiocyte with fragmented nucleus, the right arrow indicates another foamy histiocyte with pyknotic nucleus (hydropic degeneration of tumor tissue) Lens: 40X. Bar: 25 μm. (B) At Immunohistochemical analysis of the intra-tumoral Ki67 marker as an index of cell proliferation, we calculated a mean of 35% of Ki67 stained nuclei in GP1 and a mean of 15–20% in GP2/GP3 (* p < 0.05 GP3 vs. GP1). Red arrows indicate some Ki67 positive nuclei. Lens: 10X. Bar: 100 μm. (C) The sampled tumor masses were photographed on graph paper. Images are representative of each treatment group

Journal: Journal of Experimental & Clinical Cancer Research : CR

Article Title: CC48 a new CB2R agonist/FAAH inhibitor dual drug blocks gastric cancer progression and overcomes paclitaxel resistance

doi: 10.1186/s13046-025-03476-7

Figure Lengend Snippet: CC48 reduces tumor cells proliferation in treated mice (A) Histological sections stained with hematoxylin & eosin, representative of the tumor masses from each of the three experimental groups, vehicle-treated control group (GP1), group treated with 10 mg/Kg CC48 (GP2) and group treated with 20 mg/Kg CC48 (GP3) Lens: 10X. Bar: 100 μm. Circled areas enclose details of each histologic section taken at 40X magnification. In GP1 there are viable neoplastic cells, in GP2 the red arrow on the left indicates the necrotic area, and the two red arrows on the right indicate the lymphocytic infiltrate. In the GP3 group of mice, where the malignancy infiltrates the striated muscle of the murine diaphragm, the left arrow indicates a foamy histiocyte with fragmented nucleus, the right arrow indicates another foamy histiocyte with pyknotic nucleus (hydropic degeneration of tumor tissue) Lens: 40X. Bar: 25 μm. (B) At Immunohistochemical analysis of the intra-tumoral Ki67 marker as an index of cell proliferation, we calculated a mean of 35% of Ki67 stained nuclei in GP1 and a mean of 15–20% in GP2/GP3 (* p < 0.05 GP3 vs. GP1). Red arrows indicate some Ki67 positive nuclei. Lens: 10X. Bar: 100 μm. (C) The sampled tumor masses were photographed on graph paper. Images are representative of each treatment group

Article Snippet: In conclusion, the activity exhibited by CC48 across all investigated pathways supports a multitarget approach.

Techniques: Staining, Control, Immunohistochemical staining, Marker

CB2R agonist CC48 reduces circulating levels of specific inflammatory cytokine. Serum levels of eotaxin, G-CSF, IFN-γ, IL-1α, IL-12 (p70), IL-17 A, GRO/KC (CXCL1), MCP-1 (CCL2), MIP-1β and RANTES were measured in serum samples and compared within the three experimental groups (GP1: vehicle; GP2: 10 mg/Kg CC48; GP3: 20 mg/Kg CC48). For each analyte, the value is the average of the six mice in each group ± SD ed expressed as pg/mL.* p < 0.05; ** p < 0.01

Journal: Journal of Experimental & Clinical Cancer Research : CR

Article Title: CC48 a new CB2R agonist/FAAH inhibitor dual drug blocks gastric cancer progression and overcomes paclitaxel resistance

doi: 10.1186/s13046-025-03476-7

Figure Lengend Snippet: CB2R agonist CC48 reduces circulating levels of specific inflammatory cytokine. Serum levels of eotaxin, G-CSF, IFN-γ, IL-1α, IL-12 (p70), IL-17 A, GRO/KC (CXCL1), MCP-1 (CCL2), MIP-1β and RANTES were measured in serum samples and compared within the three experimental groups (GP1: vehicle; GP2: 10 mg/Kg CC48; GP3: 20 mg/Kg CC48). For each analyte, the value is the average of the six mice in each group ± SD ed expressed as pg/mL.* p < 0.05; ** p < 0.01

Article Snippet: In conclusion, the activity exhibited by CC48 across all investigated pathways supports a multitarget approach.

Techniques:

Effects of CC48 on tumour growth, selected as a first-in-class cannabinoid receptor type 2 (CB2R) multi-target agent. The agonist CC48 exerts its antitumour activity in gastric cancer cell models by (i) binding to CB2R; (ii) inhibiting the FAAH enzyme; (iii) interacting with the P-gp protein responsible for the efflux of the chemotherapeutic drug PTX from the tumor cell. The main molecular pathways regulated by CC48 and involved in proliferation, autophagy and apoptosis were depicted. Previous studies have shown that the same pathways are involved in the anti-tumor activity of PTX. CC48 enhances PTX-induced cell growth inhibition, even in chemotherapy-resistant cell models. Image created in https://BioRender.com

Journal: Journal of Experimental & Clinical Cancer Research : CR

Article Title: CC48 a new CB2R agonist/FAAH inhibitor dual drug blocks gastric cancer progression and overcomes paclitaxel resistance

doi: 10.1186/s13046-025-03476-7

Figure Lengend Snippet: Effects of CC48 on tumour growth, selected as a first-in-class cannabinoid receptor type 2 (CB2R) multi-target agent. The agonist CC48 exerts its antitumour activity in gastric cancer cell models by (i) binding to CB2R; (ii) inhibiting the FAAH enzyme; (iii) interacting with the P-gp protein responsible for the efflux of the chemotherapeutic drug PTX from the tumor cell. The main molecular pathways regulated by CC48 and involved in proliferation, autophagy and apoptosis were depicted. Previous studies have shown that the same pathways are involved in the anti-tumor activity of PTX. CC48 enhances PTX-induced cell growth inhibition, even in chemotherapy-resistant cell models. Image created in https://BioRender.com

Article Snippet: In conclusion, the activity exhibited by CC48 across all investigated pathways supports a multitarget approach.

Techniques: Activity Assay, Binding Assay, Inhibition

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