Cancer represents a significant disease that profoundly impacts human health and longevity. Projections indicate a 47% increase in the global cancer burden by 2040 compared to 2020, accompanied by a further rise in the associated economic burden. Consequently, there is an urgent need to discover and develop new alternative drugs to mitigate the global impact of cancer. Natural products (NPs) play a crucial role in the identification and development of anticancer therapeutics. This study identified ustusolate E (UE) and its analog 11α-hydroxy-ustusolate E (HUE) from strain Aspergilluscalidoustus TJ403-EL05, and examined their antitumor activities and mechanisms of action. The findings demonstrate that both compounds significantly inhibited the proliferation and colony formation of AGS (human gastric cancer cells) and 786-O (human renal clear cell carcinoma cells), induced irreversible DNA damage, blocked the cell cycle at the G₂/M phase, and further induced apoptosis in tumor cells. To the best of the authors' knowledge, this is the first report on the anticancer effects of UE and HUE and their underlying mechanisms. The present study suggests that HUE and UE could serve as lead compounds for the development of novel anticancer drugs.
Humans ; Apoptosis/drug effects* ; TOR Serine-Threonine Kinases/genetics* ; Proto-Oncogene Proteins c-akt/genetics* ; Cell Line, Tumor ; Phosphatidylinositol 3-Kinases/genetics* ; Signal Transduction/drug effects* ; Tumor Suppressor Protein p53/genetics* ; Cell Proliferation/drug effects* ; Antineoplastic Agents/pharmacology* ; Sesquiterpenes/pharmacology* ; Aspergillus/chemistry*

Through in vitro and in vivo experiments, combined with network pharmacology and molecular docking techniques, this study investigated the mechanism of action of osthole in the treatment of colorectal cancer(CRC). The relevant targets of osthole and CRC were retrieved from the SwissTargetPrediction and SuperPred in drug databases, as well as GeneCards and OMIM in disease databases. Protein-protein interaction(PPI) networks were constructed using the STRING database and Cytoscape 3.8.0 software, and core targets were screened. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were performed on common targets. Molecular docking validation of core targets with osthole was conducted using AutoDock Vina software. HCT116 cells were treated with different concentrations of osthole, and cell proliferation was detected using the CCK-8 assay and the clonogenic assay. Cell migration ability was assessed using Transwell assay. Western blot and RT-qPCR were performed to detect the expression of caspase-3(CASP3), hypoxia-inducible factor 1 alpha(HIF1A), nuclear factor kappa B subunit 1(NFKB1), glycogen synthase kinase-3 beta(GSK3B), phosphorylated-GSK3B(p-GSK3B), protein kinase B(Akt), phosphorylated-Akt(p-Akt), mammalian target of rapamycin(mTOR), and phosphorylated-mTOR(p-mTOR). A subcutaneous tumor model of HCT116 cells in nude mice was established, and the mice were randomly divided into the model group, low-dose osthole group(20 mg·kg~(-1)), medium-dose osthole group(40 mg·kg~(-1)), and high-dose osthole group(60 mg·kg~(-1)). After 18 days of administration, the growth of tumor xenografts was observed, and the size and weight of tumors were measured after excision. Hematoxylin-eosin(HE) staining was performed to observe the histological changes in tumors in each group. Network pharmacology analysis revealed that osthole treatment of CRC mainly involved 106 treatment targets and 113 treatment pathways, with key pathways including the PI3K/Akt signaling pathway and MAPK signaling pathway. Molecular docking results showed a strong correlation between osthole and core targets. In vitro studies demonstrated that osthole significantly inhibited the proliferation and migration ability of HCT116 cells. Western blot and RT-qPCR experiments showed that compared to those in the model group, the expression of NFKB1, HIF1A, p-Akt, p-mTOR, and GSK3B in the osthole-treated group was significantly decreased, while the expression of CASP3 and p-GSK3B(Ser9) was significantly increased. In vivo studies showed that compared to the model group, osthole-fed animals significantly reduced tumor weight and volume, inhibited tumor growth, and promoted tumor apoptosis, and the results showed a dose-dependent trend. The study suggested that osthole could inhibit the proliferation and migration of HCT116 cells in CRC, and its mechanism may be related to the regulation of the PI3K/Akt signaling pathway and the expression of core targets.
Coumarins/chemistry* ; Humans ; Molecular Docking Simulation ; Colorectal Neoplasms/pathology* ; Animals ; Network Pharmacology ; Mice ; Cell Proliferation/drug effects* ; HCT116 Cells ; Mice, Nude ; Mice, Inbred BALB C ; Proto-Oncogene Proteins c-akt/genetics* ; TOR Serine-Threonine Kinases/genetics* ; Cell Movement/drug effects* ; Apoptosis/drug effects* ; Signal Transduction/drug effects* ; Protein Interaction Maps/drug effects*

Arabidopsis ; chemistry ; genetics ; metabolism ; Arabidopsis Proteins ; chemistry ; genetics ; metabolism ; Crystallography, X-Ray ; Intercellular Signaling Peptides and Proteins ; chemistry ; genetics ; metabolism ; Protein Conformation ; Protein-Serine-Threonine Kinases ; chemistry ; genetics ; metabolism

The innate immune response against viral infection is mainly relies on type I interferon, the production of which is mediated by TANK-binding kinase 1 (TBK1). It is revealed that the downstream TBK1 is activated by viral nucleic acid sensors RIG-I, cGAS and TLR3. The activity of TBK1 is complexly and precisely regulated by different type of protein modifications, including phosphorylation, ubiquitination and Sumolylation. This article focuses on the role of TBK1 in anti-viral innate immunity and the regulatory mechanism for the TBK1 activation.
Humans ; Immunity, Innate ; genetics ; physiology ; Interferon Type I ; Phosphorylation ; Protein Processing, Post-Translational ; immunology ; Protein-Serine-Threonine Kinases ; chemistry ; physiology ; Signal Transduction ; Ubiquitination ; Virus Diseases ; physiopathology

OBJECTIVETo investigate the role of interleukin-17 (IL-17) in alveolar fluid clearance in mice with acute lung injury (ALI) and explore the possible mechanism.

METHODSSixteen IL-17-knockout mice and 16 wild-type mice were both randomized for intratracheal instillation of PBS (control) on lipopolysaccharide (LPS) to induce ALI. Forty-eight hours after the treatments, the wet-dry ratio (W/D) of the lungs, IL-8 in the bronchoalveolar lavage fluid (BALF) and histopathological changes of the lung tissues were examined. The expressions of epithelial sodium channel α subunit (α-ENaC) was detected with Western blotting and liver kinase B1 (LKB1) was detected with immunohistochemistry.

RESULTSCompared with wild-type mice treated with LPS, IL-17 knockout mice showed significantly decreased W/D of the lungs (9.739∓3.3 vs 5.351∓0.56) and IL-8 level in the BALF (67.50∓7.33 vs 41.00∓3.16 pg/mL) following LPS challenge. Pathological examination revealed reduced alveolar edema fluid aggregations and lower lung injury score in IL-17 knockout mice with also higher expression levels of ENaC and LKB1 compared with the wild-type mice.

CONCLUSIONKnocking out IL-17 in mice not only alleviates inflammation of the lung tissue following ALI but also reduces the loss of ENaC protein and promotes alveolar fluid clearance, mechanism of which is probably associated with LKB1.

Acute Lung Injury ; metabolism ; Animals ; Bronchoalveolar Lavage Fluid ; chemistry ; Epithelial Sodium Channels ; metabolism ; Gene Knockout Techniques ; Interleukin-17 ; genetics ; metabolism ; Interleukin-8 ; metabolism ; Lipopolysaccharides ; Lung ; pathology ; Mice ; Protein-Serine-Threonine Kinases ; metabolism

Pentraxin 3 (PTX3) was identified as a marker of the inflammatory response and overexpressed in various tissues and cells related to cardiovascular disease. Honokiol, an active component isolated from the Chinese medicinal herb Magnolia officinalis, was shown to have a variety of pharmacological activities. In the present study, we aimed to investigate the effects of honokiol on palmitic acid (PA)-induced dysfunction of human umbilical vein endothelial cells (HUVECs) and to elucidate potential regulatory mechanisms in this atherosclerotic cell model. Our results showed that PA significantly accelerated the expression of PTX3 in HUVECs through the IkappaB kinase (IKK)/IkappaB/nuclear factor-kappaB (NF-kappaB) pathway, reduced cell viability, induced cell apoptosis and triggered the inflammatory response. Knockdown of PTX3 supported cell growth and prevented apoptosis by blocking PA-inducted nitric oxide (NO) overproduction. Honokiol significantly suppressed the overexpression of PTX3 in PA-inducted HUVECs by inhibiting IkappaB phosphorylation and the expression of two NF-kappaB subunits (p50 and p65) in the IKK/IkappaB/NF-kappaB signaling pathway. Furthermore, honokiol reduced endothelial cell injury and apoptosis by regulating the expression of inducible NO synthase and endothelial NO synthase, as well as the generation of NO. Honokiol showed an anti-inflammatory effect in PA-inducted HUVECs by significantly inhibiting the generation of interleukin-6 (IL-6), IL-8 and monocyte chemoattractant protein-1. In summary, honokiol repaired endothelial dysfunction by suppressing PTX3 overexpression in an atherosclerotic cell model. PTX3 may be a potential therapeutic target for atherosclerosis.
Apoptosis/drug effects ; Atherosclerosis/chemically induced/*drug therapy/immunology/pathology ; Biphenyl Compounds/chemistry/isolation & purification/*pharmacology ; C-Reactive Protein/*genetics/immunology ; Down-Regulation/drug effects ; Drugs, Chinese Herbal/chemistry/isolation & purification/*pharmacology ; Human Umbilical Vein Endothelial Cells ; Humans ; I-kappa B Kinase/*immunology ; Lignans/chemistry/isolation & purification/*pharmacology ; Magnolia/chemistry ; Palmitic Acid ; Protein-Serine-Threonine Kinases/*immunology ; Serum Amyloid P-Component/*genetics/immunology ; Signal Transduction/drug effects

Peutz-Jeghers syndrome (PJS) is a very rare genetic disorder. PJS carries a high risk of developing gastrointestinal (GI) cancer or non-GI cancer with advancing years. However, major symptoms of PJS in childhood are obstruction, intussusception, and bleeding from hamartomatous intestinal polyps which in majority of cases are not related to cancer. Generally, first GI symptom develops by 20 years in one half of children diagnosed with PJS. Children under two years of age who had PJS polyp-related intestinal symptoms are rare, and there have been no published report on intestinal carcinoma development, adenomatous change or dysplasia of polyps in Korean children with PJS. Recently, the authors have experienced a case PJS with adenomatous polyp change in a 15-month-old boy who had STK11 gene mutation. Therefore, early evaluation could be necessary and considered in children with PJS.
Adenoma/*diagnosis/pathology ; Base Sequence ; Colonoscopy ; Heterozygote ; Humans ; Infant ; Male ; Peutz-Jeghers Syndrome/*diagnosis/genetics/pathology ; Polymorphism, Single Nucleotide ; Polyps/pathology ; Protein-Serine-Threonine Kinases/chemistry/genetics

To explore the antagonistic effect of gingerols against the inflammation induced by lectin from Pinellia ternata. In this study, ELISA method was used to determine the effect of different extracts from gingerols on the release of inflammatory factor TNF-α from macrophages induced by lectin from P. ternata. The fluorescence probe was used to determine the effect of gingerols on the changes in ROS of macrophages induced by lectin from P. ternata. The western-blot method was applied to study the effect of gingerols on the increase in expression of cell receptor interacting protein RIP3 in macrophages induced by lectin from P. ternata. The scanning electron microscope (SEM) was used to study the effect of gingerols on morphological changes in macrophages induced by lectin from P. ternata. According to the results, gingerols can significantly inhibit the release of inflammatory factor from macrophages induced by lectin from P. ternata, ROS overproduction and increase in RIP3 expression. SEM results showed that gingerols can inhibit the cytomorphosis and necrocytosis induced by lectin from P. ternata. Fresh ginger's detoxication may be related to gingerols' effects in inhibiing release of inflammatory factor, ROS overproduction and increase in RIP3 expression caused by macrophages induced by lectin from P. ternata, which are mainly inflammatory development.
Animals ; Catechols ; pharmacology ; Cells, Cultured ; Drug Antagonism ; Fatty Alcohols ; pharmacology ; Ginger ; chemistry ; Lectins ; toxicity ; Macrophages ; drug effects ; metabolism ; Male ; Mice ; Mice, Inbred ICR ; Pinellia ; chemistry ; toxicity ; Reactive Oxygen Species ; metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases ; genetics ; metabolism ; Tumor Necrosis Factor-alpha ; genetics ; metabolism

To observe the effects of Danshen-containing serum on SuFu and DYRK2 expression in the HSCs stimulated by leptin. SD rats (n = 60) were used to make danshen-containing serum by gastric perfusion for ten days with Danshen water decoction, normal saline and colchicine. The HSCs that were cultured in vitro would be stimulated for 24 hours by leptin (100 μg x L(-1)) except blank control group, after being intervened, the drug serum in each group would be cultured at 37 degrees C in 5% incubator. The cells would be collected after 24 hours, then the effects of danshen-containing serum on the proliferation of HSCs were detected by MTT, the expression of SuFu mRNA and DYRK2 mRNA were detected by RT-PCR, the expression of SuFu and DYRK2 proteins were tested by Western blot. Compared with blank control group, the expression of DYRK2 mRNA and DYRK2 proteins were enhanced obviously after stimulated the HSCs of rats by leptin (P < 0.01), but the expression of SuFu mRNA and SuFu proteins were decreased significantly (P < 0.01). Compared with the model group, after cyclopamine group (Hh pathway inhibitor), Danshen-containing serum and colchicine were interfered, the expression of DYRK2 mRNA and DYRK2 proteins were decreased clearly (P < 0.01), but the expression of SuFu mRNA and SuFu proteins were increased significantly (P < 0.01 or P < 0.05). Compared with model group, adding purmorphamine (Hh pathway agonist) to model group and making it activate could increase the expression of DYRK2 mRNA and DYRK2 proteins, but the expression of SuFu mRNA and SuFu proteins were decreased significantly (P < 0.01). Compared with the model group, using the Danshen-containing serum to interfere the purmorphamine group could make the expression of DYRK2 mRNA and DYRK2 proteins decrease and the expression of SuFu mRNA and SuFu proteins increase significantly (P < 0.01). Danshen-containing serum would inhibition the activation and increment of HSCs by interfering the expression of SuFu and DYRK2 which were induced by leptin.
Animals ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Hepatic Stellate Cells ; drug effects ; metabolism ; Humans ; Liver Cirrhosis ; drug therapy ; genetics ; metabolism ; Male ; Protein-Serine-Threonine Kinases ; genetics ; metabolism ; Protein-Tyrosine Kinases ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Repressor Proteins ; genetics ; metabolism ; Salvia miltiorrhiza ; chemistry

In recent years, human cancer genome projects provide unprecedented opportunities for the discovery of cancer genes and signaling pathways that contribute to tumor development. While numerous gene mutations can be identified from each cancer genome, what these mutations mean for cancer is a challenging question to address, especially for those from less understood putative new cancer genes. As a powerful approach, in silico bioinformatics analysis could efficiently sort out mutations that are predicted to damage gene function. Such an analysis of human large tumor suppressor genes, LATS1 and LATS2, has been carried out and the results support a role of hLATS1//2 as negative growth regulators and tumor suppressors.
Adaptor Proteins, Signal Transducing ; chemistry ; metabolism ; Animals ; Carrier Proteins ; chemistry ; metabolism ; Computational Biology ; Genes, Neoplasm ; Humans ; LIM Domain Proteins ; chemistry ; metabolism ; Mice ; Mutation ; Neoplasms ; genetics ; pathology ; Phosphoproteins ; chemistry ; metabolism ; Phosphorylation ; Protein Binding ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases ; chemistry ; genetics ; metabolism ; Transferases (Other Substituted Phosphate Groups) ; chemistry ; metabolism ; Tumor Suppressor Proteins ; chemistry ; genetics ; metabolism