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Scientific Reports Jun 2024Sphaeropsidins are iso-pimarane diterpenes produced by phytopathogenic fungi that display promising anticancer activities. Sphaeropsidin A, in particular, has been shown...
Sphaeropsidins are iso-pimarane diterpenes produced by phytopathogenic fungi that display promising anticancer activities. Sphaeropsidin A, in particular, has been shown to counteract regulatory volume increase, a process used by cancer cells to avoid apoptosis. This study reports the hemi-synthesis of new lipophilic derivatives obtained by modifications of the C15,C16-alkene moiety. Several of these compounds triggered severe ER swelling associated with strong proteasomal inhibition and consequently cell death, a feature that was not observed with respect to mode of action of the natural product. Significantly, an analysis from the National Cancer Institute sixty cell line testing did not reveal any correlations between the most potent derivative and any other compound in the database, except at high concentrations (LC). This study led to the discovery of a new set of sphaeropsidin derivatives that may be exploited as potential anti-cancer agents, notably due to their maintained activity towards multidrug resistant models.
Topics: Humans; Endoplasmic Reticulum; Cell Line, Tumor; Apoptosis; Antineoplastic Agents; Diterpenes; Abietanes
PubMed: 38918539
DOI: 10.1038/s41598-024-65335-3 -
Frontiers in Chemistry 2024Numerous local herbal extract species have been investigated as potential medicinal ingredients due to their promising anti-cancer properties. However, the primary...
Numerous local herbal extract species have been investigated as potential medicinal ingredients due to their promising anti-cancer properties. However, the primary constraint of the class of plant flavonoids lies in their low solubility and limited membrane permeability, leading to chemical instability and restricted bioavailability that impede biomedical applications. In this study, we have developed an ideal nanozyme-Galazyme, comprising galangin-loaded copper Nanozyme coated by DSPE-PEG, which amplifies oxidative stress to induce apoptosis via the regulation of reactive oxygen species (ROS) generation and mitogen-activated protein kinase (MAPK) activation. Galazyme exhibited significant peroxidase mimetic activity, demonstrating its potential to generate ROS and elevate oxidative stress. Upon uptake by HepG-2 cells, Galazyme efficiently converts excess hydrogen peroxide (H2O2) into highly reactive •OH radicals and upregulates MAPK expression, leading to the activation of Bax and Caspase 3, thereby promoting irreversible tumor cell apoptosis. Both and results demonstrate that Galazyme inhibits tumor cell growth and induces apoptosis by generating ample ROS and activating the MAPK pathway. Our study offers novel evidence supporting the enhancement of Galazyme-induced apoptosis through the upregulation of Bax and Caspase 3, along with the elucidation of the interaction between MAPK and apoptosis.
PubMed: 38915904
DOI: 10.3389/fchem.2024.1426634 -
Scientific Reports Jun 2024Cryptosporidiosis is a worldwide zoonotic disease. Oxymatrine, an alkaloid extracted and isolated from the plant bitter ginseng, has been reported to have therapeutic...
Cryptosporidiosis is a worldwide zoonotic disease. Oxymatrine, an alkaloid extracted and isolated from the plant bitter ginseng, has been reported to have therapeutic effects on cryptosporidiosis. However, the underlying mechanism of its action remains unclear. In this study, we utilized network pharmacology and experimental validation to investigate the mechanism of oxymatrine in the treatment of cryptosporidiosis. First, the potential targets of drugs and diseases were predicted by TCMSP, Gene Cards, and other databases. Following the intersection of drug-disease targets, the DAVID database was used to implement the enrichment analysis of GO functions and KEGG pathways, and then the network diagram of "intersected target-KEGG" relationship was constructed. Autodock 4.2.6 software was used to carry out the molecular docking of core targets to drug components. Based on the establishment of a mouse model of cryptosporidiosis, the validity of the targets in the TNF/NF-κB signaling pathway was confirmed using Western blot analysis and Quantitative Rea-ltime-PCR. A total of 41 intersectional targets of oxymatrine and Cryptosporidium were generated from the results, and five core targets were screened out by network analysis, including RELA, AKT1, ESR1, TNF, and CASP3. The enrichment analysis showed that oxymatrine could regulate multiple gene targets, mediate TNF, Apoptpsis, IL-17, NF-κB and other signaling pathways. Molecular docking experiments revealed that oxymatrine was tightly bound to core targets with stable conformation. Furthermore, we found through animal experiments that oxymatrine could regulate the mRNA and protein expression of IL-6, NF-κB, and TNF-α in the intestinal tissues of post-infected mice through the TNF/NF-κB signaling pathway. Therefore, it can be concluded that oxymatrine can regulate the inflammatory factors TNF-α, NF-κB, and IL-6 through the TNF/NF-κB signaling pathway for the treatment of cryptosporidiosis. This prediction has also been validated by network pharmacology and animal experiments.
Topics: Quinolizines; Cryptosporidiosis; Animals; Signal Transduction; Alkaloids; Mice; NF-kappa B; Network Pharmacology; Molecular Docking Simulation; Tumor Necrosis Factor-alpha; Disease Models, Animal; Humans; Matrines
PubMed: 38914662
DOI: 10.1038/s41598-024-65362-0 -
Fitoterapia Jun 2024Hemp (Cannabis sativa L.), an annual dioecious plant, has shown extensive application in the fields of fibers, food, oil, medicine, etc. Currently, most attention has...
Hemp (Cannabis sativa L.), an annual dioecious plant, has shown extensive application in the fields of fibers, food, oil, medicine, etc. Currently, most attention has been paid to the therapeutic properties of phytocannabinoids. However, the pharmaceutical research on essential oil from hemp is still lacking. In this study, hemp essential oil (HEO) was extracted from hemp flowers and leaves, and the components were analyzed by GC-MS. Quatitative analysis of three main compounds β-caryophyllene, β-caryophyllene oxide, α -humulene were determined by GC-FID. The anti-tumor and anti-neuropathic pain effects of HEO were evaluated. In the paclitaxel induced neuropathic mice model, HEO reduced the serum level of inflammatory cytokines TNF-α to achieve the analgesic effect, which was tested by evaluating mechanical and thermal hyperalgesia. Further investigation with cannabinoid receptor 2 (CB2 R) antagonist AM630 revealed the mechanism of reversing mechanical hyperalgesia may be related to CB2 R. In Lewis lung cancer grafted mice model, the tumor growth was significantly inhibited, the levels of tumor inflammatory cytokines TNF-α and IL-6 were downregulated, immune organ index was modified and immune-related CD4+, CD8+ T lymphocytes level, CD4+/CD8+ ratio were increased when administered with HEO. These results reveal that HEO plays a role not only in tumor chemotherapy induced peripheral neuropathy treatment, but also in anti-tumor treatment which offers key information for new strategies in cancer treatment and provides reference for the medicinal development of hemp.
PubMed: 38914272
DOI: 10.1016/j.fitote.2024.106092 -
RSC Medicinal Chemistry Jun 2024Inflammation is the body's response to defence against infection or injury, and is associated with the progression of many diseases, such as inflammatory bowel disease...
Inflammation is the body's response to defence against infection or injury, and is associated with the progression of many diseases, such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). LCA, a dibenzylbutane lignan extracted from the roots of traditional medicinal plant (Lour.) Pers., has demonstrated promising anti-inflammatory activity. In this study, a series of novel LCA derivatives were designed, synthesized, and evaluated for anti-inflammatory activity. Lipopolysaccharide (LPS)-induced RAW 264.7 cell model experiments showed that compound 10h (at 20 μM of concentration) had the strongest inhibitory effect on NO release, and inhibited the secretion and gene expression levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α In addition, western blot, immunofluorescence, and molecular docking showed that the anti-inflammatory mechanism of compound 10h may be related to the nuclear factor (NF)-κB signalling pathway. studies based on a carrageenan-induced mouse paw edema model have shown significant anti-inflammatory activity of compound 10h at 20 mg kg. Preliminary and studies indicate that compound 10h has the potential to be developed as a novel anti-inflammatory agent.
PubMed: 38911165
DOI: 10.1039/d4md00053f -
Frontiers in Pharmacology 2024Lung cancer is the most commonly diagnosed and the main cause of cancer death, usually related to cigarette smoking. Furthermore, the microbiota of people exposed to...
INTRODUCTION
Lung cancer is the most commonly diagnosed and the main cause of cancer death, usually related to cigarette smoking. Furthermore, the microbiota of people exposed to cigarette smoke can be modified, making it difficult to eliminate opportunistic microorganisms. The leaves of are a by-product of fruit production and, to date, there have been no studies addressing the antiproliferative, anti-inflammatory, and antimicrobial activities.
OBJECTIVE
Investigate the antimicrobial, Nitric Oxide (NO)-production inhibition, and antiproliferative activities of the essential oil from leaves and its possible effect on the treatment and prevention of damage caused by tobacco.
METHODS
The essential oil (EO) was obtained by hydrodistillation (3 h). Its chemical composition was investigated by GC-MS. It was proposed to investigate antiproliferative activity against human tumor cell lines, namely, breast adenocarcinoma (MCF-7), lung (NCI-H460), cervical (HeLa), and hepatocellular (HepG2) carcinomas. A non-tumor primary culture from pig liver (PLP2) was also tested. The EO capacity to inhibit nitric oxide (NO) production was evaluated by a lipopolysaccharide stimulated murine macrophage cell line. Antibacterial and antifungal activities against opportunistic pathogens were investigated against seven strains of bacteria and eight fungi.
RESULTS
The results indicated the presence of 23 compounds in the essential oil, the majority were spathulenol (45.63%) and β-caryophyllene oxide (12.72%). Leaf EO provided 50% inhibition of nitric oxide production at a concentration of 92.04 µg mL. The EO also demonstrated antiproliferative activity against all human tumor cell lines studied, with GI50 values comprised between 270.86 and 337.25 µg mL. The essential oil showed antimicrobial potential against the bacteria monocytogenes (Murray et al.) Pirie (NCTC 7973) and ATCC 13311 (MIC 1870 µg mL) and fungi ATCC 11730, ATCC 12066, ATCC 90288, var. cyclopium (Westling) Samson, Stolk & Hadlok (food isolate) (MIC 1870 µg mL) and Pers. IAM 5061 (1,400 µg mL).
CONCLUSION
The demonstrated anti-inflammatory, antiproliferative, and antimicrobial activities in the leaves of can add value to the production chain of this plant, being a possible option for preventing and combating cancer, including lung cancer.
PubMed: 38910894
DOI: 10.3389/fphar.2024.1415659 -
Journal of Ethnopharmacology Jun 2024Phytolacca acinosa Roxb. (PAR) is a Traditional Chinese Medicinal (TCM) plant with a broad global distribution encompassing 35 species, four of which are found in the...
Mechanistic insights into xanthomicrol as the active anti-HCC ingredient of Phytolacca acinosa Roxb.: A network pharmacology analysis and transcriptomics integrated experimental verification.
ETHNOPHARMACOLOGICAL RELEVANCE
Phytolacca acinosa Roxb. (PAR) is a Traditional Chinese Medicinal (TCM) plant with a broad global distribution encompassing 35 species, four of which are found in the People's Republic of China. It occupies a significant role in both Oriental and American traditional medicine, employed in treating a range of conditions such as edema, inflammation, dermatitis, and rheumatism. PAR is also used as a molluscicide and for addressing tumors and bronchitis. The plant is documented in the Chinese Pharmacopoeia and has a longstanding history in TCM, particularly for its diuretic properties and in treating ailments such as edema, swelling, and ulcers. Notably, PAR has demonstrated potent inhibitory effects against the A549 human lung cancer cell line, underscoring its potential in contributing to the development of novel cancer therapeutics.
AIM OF THE STUDY
The research aims to elucidate the active components of PAR and their mechanisms in treating hepatocellular carcinoma (HCC).
MATERIALS AND METHODS
Employing network pharmacology, this study predicted the principal active compounds and key targets of PAR. A holistic methodology incorporating biological network analysis, transcriptomics sequencing, molecular docking, and molecular dynamics (MD) simulations was utilized to forecast the effects of PAR on HCC, with empirical evidence supporting these findings.
RESULTS
Network pharmacology identified xanthomicrol as the foremost active compound in PAR. The tumor-suppressive functions of PAR, as indicated by KEGG pathway analysis and transcriptomics sequencing, predominantly occur via the PI3K/AKT pathway. Molecular docking and dynamics simulations demonstrated the high affinity of xanthomicrol towards TNF, MMP9, PPARG, KDR, and MMP2. In vivo experiments verified the efficacy of xanthomicrol in curtailing HCC tumor growth, while in vitro assessments revealed its substantial impact on the proliferation and apoptosis of HepG2 and HCCLM3 cells. Moreover, the study indicates that xanthomicrol may modulate the expression of TNF, MMP9, PPARG, KDR, and MMP2 in HCC cells and inhibit the activation of the PI3K/AKT pathway.
CONCLUSIONS
Xanthomicrol, a principal active component of PAR, has been identified to impede the growth of HCC by targeting the PI3K/Akt/MMP9 pathway. This insight could enhance therapeutic approaches for HCC.
PubMed: 38909826
DOI: 10.1016/j.jep.2024.118467 -
European Journal of Medicinal Chemistry Jun 2024Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to the development and progression of multiple types of cancer. Although many FGFR...
Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to the development and progression of multiple types of cancer. Although many FGFR inhibitors have been approved by the FDA, their long-term therapeutic efficacy is hampered by acquired resistance to gatekeeper mutations and low subtype selectivity. FGFR2 has been found to be frequently amplified or mutated in many tumors. In this study, we designed several PROTACs with different E3 ligands based on LY2874455. By screening the length of the linker and the binding site in various degraders, we obtained a novel and highly efficient FGFR2-selective degrader 28e (DC = 0.645 nM, DC = 86 %). Compound 28e selectively degraded FGFR2 and essentially avoided degradation of FGFR1,3,4 isoforms (DC > 300 nM). Compound 28e significantly inhibited the proliferation of FGFR2-overexpressing cell lines, including KATOIII, SNU16, and AN3CA (IC = 0.794 nM/0.207 nM/4.626 nM), comparable to parental inhibitors. At the same time, the preferred compound showed superiority over the parental inhibitor in kinase inhibitory activity against the gatekeeper mutant isoform FGFR2 (IC = 0.121 nM). In summary, we identified 28e as a novel selective degrader of FGFR2 with high potency and high potential to overcome resistance to gatekeeper mutation. The discovery of 28e provides new evidence for the strategy of pan-inhibitor-based development of selective degrading agents.
PubMed: 38908103
DOI: 10.1016/j.ejmech.2024.116612 -
Methods in Molecular Biology (Clifton,... 2024Mutation-containing immunogenic peptides from tumor cells, also named as neoantigens, have various amino acid descriptors and physical-chemical properties characterized...
Mutation-containing immunogenic peptides from tumor cells, also named as neoantigens, have various amino acid descriptors and physical-chemical properties characterized intrinsic features, which are useful in prioritizing the immunogenicity potentials of neoantigens and predicting patients' survival. Here, we describe a glioma neoantigen intrinsic feature database, GNIFdb, that hosts computationally predicted HLA-I restricted neoantigens of gliomas, their intrinsic features, and the tools for calculating intrinsic features and predicting overall survival of gliomas. We illustrate the application of GNIFdb in searching for possible neoantigen candidates from ATF6 that plays important roles in tumor growth and resistance to radiotherapy in glioblastoma. We also demonstrate the application of intrinsic feature associated tools in GNIFdb to predict the overall survival of primary IDH wild-type glioblastoma.
Topics: Humans; Histocompatibility Antigens Class I; Antigens, Neoplasm; Computer Simulation; Glioma; Computational Biology; Glioblastoma; Brain Neoplasms; Mutation
PubMed: 38907902
DOI: 10.1007/978-1-0716-3874-3_16 -
Scientific Reports Jun 2024Breast cancer (BC) remains a significant health concern for women globally, prompting the relentless pursuit of novel therapeutic modalities. As a traditional Chinese...
Breast cancer (BC) remains a significant health concern for women globally, prompting the relentless pursuit of novel therapeutic modalities. As a traditional Chinese medicine, Boswellia carterii has been extensively used to treat various cancers, such as BC. However, the anti-BC effect and underlying mechanism of Boswellia carterii remain largely unclear. The aim of this study is to explore the therapeutic effect of Boswellia carterii n-hexane extract (BCHE) against BC as well as its underlying mechanism. The present study showed that BCHE significantly suppressed the viability of human BC cells. Moreover, BCHE exhibited potent anti-BC activity in vivo with no significant toxic effects. Additionally, BCHE induced ferroptosis via increased Transferrin expression and the intracellular accumulation of Fe, as well as decreased glutathione peroxidase 4 (GPX4) expression and the upregulation of reactive oxygen species (ROS)-induced lipid peroxidation in BC cells. In vivo experimental results also demonstrated that BCHE effectively induced ferroptosis through GPX4 downregulation and Transferrin upregulation in tumor-bearing mice. Overall, BCHE inhibited the growth of BC cells by inducing ferroptosis mediated by modulating the iron accumulation pathway and the lipid peroxidation pathway. Therefore, BCHE could serve as a potential ferroptosis-targeting drug for treating BC.
Topics: Ferroptosis; Phospholipid Hydroperoxide Glutathione Peroxidase; Humans; Breast Neoplasms; Female; Animals; Transferrin; Mice; Plant Extracts; Cell Line, Tumor; Boswellia; Reactive Oxygen Species; Xenograft Model Antitumor Assays; Cell Proliferation; Hexanes; Down-Regulation; Lipid Peroxidation; Up-Regulation; Gene Expression Regulation, Neoplastic; Mice, Nude; Mice, Inbred BALB C
PubMed: 38906931
DOI: 10.1038/s41598-024-65170-6