Total Synthesis and Stereochemical Assignment of Callyspongiolide

Total synthesis of four callyspongiolide stereoisomers led to unambiguous assignment of relative and absolute stereochemistry of the natural product. Key features of the convergent, fully stereocontrolled route include the use of Krische allylation, Kiyooka Aldol reaction, Kociénski–Julia olefination, Still–Gennari olefination, Yamaguchi macrocyclization, and Sonogashira coupling reaction. Biological evaluation of the synthesized compounds against an array of cancer cells revealed that the stereochemistry of the macrolactone core played an important role

Ion Permeability of Polydopamine Films Revealed Using a Prussian Blue-Based Electrochemical Method

Polydopamine (PDA) is fast becoming a popular surface modification technique. Detailed understanding of the ion permeability properties of PDA films will improve their applications. Herein, we report for the first time the thickness-independent ion permeability of PDA films using a Prussian blue (PB)-based electrochemical method. In this method, PDA films are deposited via ammonium persulfate-induced dopamine polymerization onto a PB electrode. The ion permeability of the PDA films can thus be detected by observing the changes in electrochemical behaviors of the PB coated by PDA films. On the basis of this method, it was unexpectedly found that the PDA films with thickness greater than 45 nm (e.g., ∼60 and ∼113 nm) can exhibit pH-switchable but thickness-insensitive permeability to monovalent cations such as potassium and sodium ions. These observations clearly indicate the presence of a continuous network of interconnected intermolecular voids within PDA films, regardless of film thickness

Additional file 1: Figure S1. of Identification of EGF-NF-κB-FOXC1 signaling axis in basal-like breast cancer

NF-κB transcription factor mediates EGF-induced FOXC1 expression in multiple breast cancer cell lines. a MDA-MB-231 and BT-20 cell lines were transiently co-transfected with the FOXC1 promoter-luc and NF-κB (p65), IκBα S32A/S36A super-repressor (p65 + SR-IκBα), or the vector. Reporter activities were assessed by luciferase assays. *, P < 0.05; **, P < 0.001. b MDA-MB-468 cells were transiently transfected with the IKKβ or SR-IκBα constructs and immunoblotted for FOXC1 expression. c MDA-MB-231 and BT-20 cell lines were treated with 100 ng/mL EGF for 2 h after preincubation with the NF-κB inhibitor Bay 11–7082 for 1 h. FOXC1 mRNA levels were examined using qRT-PCR. **, P < 0.001. d Total protein was extracted from MDA-MB-468, MDA-MB-231 and BT-20 cell lines after no starvation or treatment (Left to right, first three lanes) or after serum-starvation overnight with or without EGF treatment for 24 h. EGFR and phosphorylated EGFR (p-EGFR) levels were examined with immunoblotting. e BT-20 cells were treated with 100 ng/mL EGF for 1 h after preincubation with the Akt inhibitor-IV or U0126 (ERK inhibitor) for 45 min. Total protein was extracted and phospho-p65 (Ser 536) was examined by immunoblotting. (TIFF 131 kb

Additional file 2: Figure S2. of Identification of EGF-NF-κB-FOXC1 signaling axis in basal-like breast cancer

Inhibition of NF-κB p65 affects FOXC1 protein levels. MDA-MB-468 cells were serum-starved overnight and treated with EGF for 24 h after pre-incubation with NF-κB inhibitors, Bay 11–7082 or BMS-345541, for 1 h. FOXC1 protein levels were examined by immunoblotting. (TIFF 56 kb

Table1_Metabolic dysfunction-associated steatotic liver disease increases hepatocellular carcinoma risk in chronic hepatitis B patients: a retrospective cohort study.DOCX

Background: The combined effect of hepatitis B virus infection and metabolic dysfunction-associated steatotic liver disease (MASLD) on hepatocellular carcinoma (HCC) risk remains unclear. The current study sought to elucidate the impact of MASLD on HCC progression in chronic hepatitis B (CHB) patients.Method: This retrospective cohort study included CHB patients who had undergone liver biopsy and abdominal imaging at the Guangdong Provincial Hospital of Chinese Medicine between 2013 and 2019. We investigated the correlation between MASLD and HCC risk, and inverse probability treatment weighting (IPTW) was used to adjust for patient characteristics.Results: A total of 1,613 patients were included, and 483 (29.9%) were diagnosed with MASLD. Over a median follow-up period of 5.02 years, 36 (2.2%) developed HCC, comprising 4.8% (23/483) of those with MASLD and 1.2% (13/1,130) of those without. Those with MASLD had a significantly higher cumulative incidence of HCC than those without (p Conclusion: The presence of MASLD is associated with a higher risk of HCC in patients with CHB. Notably, this higher risk is present in patients with MASLD, irrespective of the presence or absence of overweight or the number of CMRFs they have.</p

Discovery, Synthesis, Pharmacological Profiling, and Biological Characterization of Brintonamides A–E, Novel Dual Protease and GPCR Modulators from a Marine Cyanobacterium

Five novel modified linear peptides named brintonamides A–E (<b>1</b>–<b>5</b>) were discovered from a marine cyanobacterial sample collected from Brinton Channel, Florida Keys. The total synthesis of <b>1</b>–<b>5</b> in addition to two other structurally related analogues (<b>6</b> and <b>7</b>) was achieved, which provided more material to allow rigorous biological evaluation and SAR studies. Compounds were subjected to cancer-focused phenotypic cell viability and migration assays and orthogonal target-based pharmacological screening platforms to identify their protease and GPCR modulatory activity profiles. The cancer related serine protease kallikrein 7 (KLK7) was inhibited to similar extents with an IC₅₀ near 20 μM by both representative members <b>1</b> and <b>4</b>, which differed in the presence or lack of the N-terminal unit. In contrast to the biochemical protease profiling study, clear SAR was observed in the functional GPCR screens, where five GPCRs in antagonist mode (CCR10, OXTR, SSTR3, TACR2) and agonist mode (CXCR7) were modulated by compounds <b>1</b>–<b>7</b> to varying extents. Chemokine receptor type 10 (CCR10) was potently modulated by brintonamide D (<b>4</b>) with an IC₅₀ of 0.44 μM. We performed in silico modeling to understand the structural basis underlying the differences in the antagonistic activity among brintonamides toward CCR10. Because of the significance of KLK7 and CCR10 in cancer progression and metastasis, we demonstrated the ability of brintonamide D (<b>4</b>) at 10 μM to significantly target downstream cellular substrates of KLK7 (Dsg-2 and E-cad) in vitro and to inhibit CCL27-induced CCR10-mediated proliferation and the migration of highly invasive breast cancer cells

Discovery, Synthesis, Pharmacological Profiling, and Biological Characterization of Brintonamides A–E, Novel Dual Protease and GPCR Modulators from a Marine Cyanobacterium

Five novel modified linear peptides named brintonamides A–E (<b>1</b>–<b>5</b>) were discovered from a marine cyanobacterial sample collected from Brinton Channel, Florida Keys. The total synthesis of <b>1</b>–<b>5</b> in addition to two other structurally related analogues (<b>6</b> and <b>7</b>) was achieved, which provided more material to allow rigorous biological evaluation and SAR studies. Compounds were subjected to cancer-focused phenotypic cell viability and migration assays and orthogonal target-based pharmacological screening platforms to identify their protease and GPCR modulatory activity profiles. The cancer related serine protease kallikrein 7 (KLK7) was inhibited to similar extents with an IC₅₀ near 20 μM by both representative members <b>1</b> and <b>4</b>, which differed in the presence or lack of the N-terminal unit. In contrast to the biochemical protease profiling study, clear SAR was observed in the functional GPCR screens, where five GPCRs in antagonist mode (CCR10, OXTR, SSTR3, TACR2) and agonist mode (CXCR7) were modulated by compounds <b>1</b>–<b>7</b> to varying extents. Chemokine receptor type 10 (CCR10) was potently modulated by brintonamide D (<b>4</b>) with an IC₅₀ of 0.44 μM. We performed in silico modeling to understand the structural basis underlying the differences in the antagonistic activity among brintonamides toward CCR10. Because of the significance of KLK7 and CCR10 in cancer progression and metastasis, we demonstrated the ability of brintonamide D (<b>4</b>) at 10 μM to significantly target downstream cellular substrates of KLK7 (Dsg-2 and E-cad) in vitro and to inhibit CCL27-induced CCR10-mediated proliferation and the migration of highly invasive breast cancer cells

Discovery, Synthesis, Pharmacological Profiling, and Biological Characterization of Brintonamides A–E, Novel Dual Protease and GPCR Modulators from a Marine Cyanobacterium

Five novel modified linear peptides named brintonamides A–E (<b>1</b>–<b>5</b>) were discovered from a marine cyanobacterial sample collected from Brinton Channel, Florida Keys. The total synthesis of <b>1</b>–<b>5</b> in addition to two other structurally related analogues (<b>6</b> and <b>7</b>) was achieved, which provided more material to allow rigorous biological evaluation and SAR studies. Compounds were subjected to cancer-focused phenotypic cell viability and migration assays and orthogonal target-based pharmacological screening platforms to identify their protease and GPCR modulatory activity profiles. The cancer related serine protease kallikrein 7 (KLK7) was inhibited to similar extents with an IC₅₀ near 20 μM by both representative members <b>1</b> and <b>4</b>, which differed in the presence or lack of the N-terminal unit. In contrast to the biochemical protease profiling study, clear SAR was observed in the functional GPCR screens, where five GPCRs in antagonist mode (CCR10, OXTR, SSTR3, TACR2) and agonist mode (CXCR7) were modulated by compounds <b>1</b>–<b>7</b> to varying extents. Chemokine receptor type 10 (CCR10) was potently modulated by brintonamide D (<b>4</b>) with an IC₅₀ of 0.44 μM. We performed in silico modeling to understand the structural basis underlying the differences in the antagonistic activity among brintonamides toward CCR10. Because of the significance of KLK7 and CCR10 in cancer progression and metastasis, we demonstrated the ability of brintonamide D (<b>4</b>) at 10 μM to significantly target downstream cellular substrates of KLK7 (Dsg-2 and E-cad) in vitro and to inhibit CCL27-induced CCR10-mediated proliferation and the migration of highly invasive breast cancer cells

Discovery, Synthesis, Pharmacological Profiling, and Biological Characterization of Brintonamides A–E, Novel Dual Protease and GPCR Modulators from a Marine Cyanobacterium

Five novel modified linear peptides named brintonamides A–E (<b>1</b>–<b>5</b>) were discovered from a marine cyanobacterial sample collected from Brinton Channel, Florida Keys. The total synthesis of <b>1</b>–<b>5</b> in addition to two other structurally related analogues (<b>6</b> and <b>7</b>) was achieved, which provided more material to allow rigorous biological evaluation and SAR studies. Compounds were subjected to cancer-focused phenotypic cell viability and migration assays and orthogonal target-based pharmacological screening platforms to identify their protease and GPCR modulatory activity profiles. The cancer related serine protease kallikrein 7 (KLK7) was inhibited to similar extents with an IC₅₀ near 20 μM by both representative members <b>1</b> and <b>4</b>, which differed in the presence or lack of the N-terminal unit. In contrast to the biochemical protease profiling study, clear SAR was observed in the functional GPCR screens, where five GPCRs in antagonist mode (CCR10, OXTR, SSTR3, TACR2) and agonist mode (CXCR7) were modulated by compounds <b>1</b>–<b>7</b> to varying extents. Chemokine receptor type 10 (CCR10) was potently modulated by brintonamide D (<b>4</b>) with an IC₅₀ of 0.44 μM. We performed in silico modeling to understand the structural basis underlying the differences in the antagonistic activity among brintonamides toward CCR10. Because of the significance of KLK7 and CCR10 in cancer progression and metastasis, we demonstrated the ability of brintonamide D (<b>4</b>) at 10 μM to significantly target downstream cellular substrates of KLK7 (Dsg-2 and E-cad) in vitro and to inhibit CCL27-induced CCR10-mediated proliferation and the migration of highly invasive breast cancer cells

Additional file 11: Figure S3 of Salinity stress induces the production of 2-(2-phenylethyl)chromones and regulates novel classes of responsive genes involved in signal transduction in Aquilaria sinensis calli

Phylogenetic tree analysis of plant type III PKSs. The tree was constructed by neighbor-joining algorithm and the reliability of the tree was measured by bootstrap analysis with 1000 replicates. The indicated scale represents 0.05 amino acid substitutions per site. (PPTX 150 kb