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Scientific Reports Jun 2024Cancer remains a formidable global health challenge, with metastasis being a key contributor to its lethality. Abundant high molecular mass hyaluronic acid, a major...
Cancer remains a formidable global health challenge, with metastasis being a key contributor to its lethality. Abundant high molecular mass hyaluronic acid, a major non-protein component of extracellular matrix, protects naked mole rats from cancer and reduces cancer incidence in mice. Hyaluronidase plays a critical role in degrading hyaluronic acid and is frequently overexpressed in metastatic cancer. Here we investigated the potential of targeting hyaluronidases to reduce metastasis. A high throughput screen identified delphinidin, a natural plant compound found in fruits and vegetables, as a potent hyaluronidase inhibitor. Delphinidin-mediated inhibition of hyaluronidase activity led to an increase in high molecular weight hyaluronic acid in cell culture and in mouse tissues, and reduced migration and invasion behavior of breast, prostate, and melanoma cancer cells. Moreover, delphinidin treatment suppressed melanoma metastasis in mice. Our study provides a proof of principle that inhibition of hyaluronidase activity suppresses cancer cell migration, invasion and metastasis. Furthermore, we identified a natural compound delphinidin as a potential anticancer therapeutic. Thus, we have identified a path for clinical translation of the cancer resistance mechanism identified in the naked mole rat.
Topics: Hyaluronoglucosaminidase; Animals; Mice; Humans; Anthocyanins; Cell Movement; Cell Line, Tumor; Neoplasm Metastasis; Female; Hyaluronic Acid; Male; Enzyme Inhibitors
PubMed: 38942920
DOI: 10.1038/s41598-024-64924-6 -
Progress in Molecular Biology and... 2024Cardiovascular diseases (CVDs) are characterized by abnormalities in the heart, blood vessels, and blood flow. CVDs comprise a diverse set of health issues. There are... (Review)
Review
Cardiovascular diseases (CVDs) are characterized by abnormalities in the heart, blood vessels, and blood flow. CVDs comprise a diverse set of health issues. There are several types of CVDs like stroke, endothelial dysfunction, thrombosis, atherosclerosis, plaque instability and heart failure. Identification of a new drug for heart disease takes longer duration and its safety efficacy test takes even longer duration of research and approval. This chapter explores drug repurposing, nano-therapy, and plant-based treatments for managing CVDs from existing drugs which saves time and safety issues with testing new drugs. Existing drugs like statins, ACE inhibitor, warfarin, beta blockers, aspirin and metformin have been found to be useful in treating cardiac disease. For better drug delivery, nano therapy is opening new avenues for cardiac research by targeting interleukin (IL), TNF and other proteins by proteome interactome analysis. Nanoparticles enable precise delivery to atherosclerotic plaques, inflammation areas, and damaged cardiac tissues. Advancements in nano therapeutic agents, such as drug-eluting stents and drug-loaded nanoparticles are transforming CVDs management. Plant-based treatments, containing phytochemicals from Botanical sources, have potential cardiovascular benefits. These phytochemicals can mitigate risk factors associated with CVDs. The integration of these strategies opens new avenues for personalized, effective, and minimally invasive cardiovascular care. Altogether, traditional drugs, phytochemicals along with nanoparticles can revolutionize the future cardiac health care by identifying their signaling pathway, mechanism and interactome analysis.
Topics: Humans; Drug Repositioning; Drug Discovery; Animals; Heart Diseases
PubMed: 38942536
DOI: 10.1016/bs.pmbts.2024.02.001 -
Planta Medica Jun 2024Hyaluronic acid is composed of repeating sugar units, glucuronic acid and N-acetylglucosamine, which are often associated with increased tumor progression. agglutinin...
Hyaluronic acid is composed of repeating sugar units, glucuronic acid and N-acetylglucosamine, which are often associated with increased tumor progression. agglutinin is a potential component that exhibits a high affinity for binding to N-acetylglucosamine. This study aimed to investigate Agglutinin's potential to inhibit the proliferation and migration of prostate cancer cells with high expression of hyaluronic acid through molecular docking and studies. The expression of hyaluronan synthase genes in prostate tissue and cell lines was checked by an study, and the interaction between hyaluronic acid with both CD44 transmembrane glycoprotein and agglutinin was analyzed through molecular docking. Agglutinin's effect on cell viability (neutral red uptake assay), migration (scratch wound healing assays), and both and expression (quantitative real-time polymerase chain reaction) were assessed . The results showed that in prostate cancer cell lines, the PC3 cell line has the highest expression of hyaluronan synthase genes. agglutinin exhibits an interaction of six specific residues on CD44 compared to hyaluronic acid's singular residue. While agglutinin alone effectively reduced cell viability and wound closer (≥ 150 µg/mL), combining it with hyaluronic acid significantly shifted the effective concentration to a higher dose (≥ 350 µg/mL). These results, together with low and high gene expression, suggest that agglutinin may impair the CD44-HA pathway in PC3 cells. This possibility is supported by Agglutinin's ability to compete with hyaluronic acid for binding to CD44. Based on this, agglutinin as a plant lectin shows promise in inhibiting cancer proliferation and migration by targeting its dependence on hyaluronic acid.
PubMed: 38942031
DOI: 10.1055/a-2324-2250 -
Medicine Jun 2024Ferroptosis was reported to possess the therapeutic potentials in various human cancers. In the present study, we explored the expression, clinical significance and the...
BACKGROUND
Ferroptosis was reported to possess the therapeutic potentials in various human cancers. In the present study, we explored the expression, clinical significance and the molecular mechanism of FK506 binding protein 3 (FKBP3) in the progression of lung adenocarcinoma (LUAD).
MATERIAL AND METHOD
Cox regression was performed to obtain the prognosis related to differentially expressed genes (DEGs) in LUAD datasets from TCGA. We also downloaded the ferroptosis-related gene datasets from GeneCards. Venn diagram was performed to find the intersecting genes and FKBP3 was selected as the targeted gene by analyzing the diagnostic and prognostic values of Top10 intersecting genes. Moreover, univariate and multivariate analyses were performed to evaluate the association between clinicopathological factors and survival rates. GO/KEGG and GSEA analysis was performed to explore the function of FKBP3 in LUAD progression. Protein-protein interaction (PPI) network was performed via STRING database and the top10 hub genes were selected. Finally, the relationship between FKBP3 and immune infiltration was explored by ssGSEA analysis.
RESULTS
Firstly, 184 genes associated with the prognosis of LUAD and ferroptosis were obtained. FKBP3 was found to be significantly associated with a poor overall survival rate of LUAD patients. Immunohistochemical staining results showed that FKBP3 was highly located in cytoplasm and membrane of cells in LUAD tissues. PPI network analysis results showed that HDAC1, YY1, HDAC2, MTOR, PSMA3, PIN1, NCL, C14orf166, PIN4, and LARP6 were the top10 hub genes. Furthermore, spearman analysis results showed that the expression of FKBP3 was positively correlated with the abundance of Th2 cells and T helper cells.
CONCLUSION
High level of FKBP3 was associated with poor prognostic outcomes of LUAD patients, which also inhibited immune infiltration in LUAD tissues. Additionally, FKBP3 was involved in regulating the ferroptosis process in LUAD patients. Thus, FKBP3 possessed the tumor promotion role might be involving in regulating ferroptosis and immune infiltration in LUAD progression.
Topics: Humans; Ferroptosis; Prognosis; Female; Disease Progression; Male; Adenocarcinoma of Lung; Lung Neoplasms; Middle Aged; Tacrolimus Binding Proteins; Biomarkers, Tumor; Aged; Gene Expression Regulation, Neoplastic; Protein Interaction Maps
PubMed: 38941396
DOI: 10.1097/MD.0000000000038606 -
Plant Foods For Human Nutrition... Jun 2024Jack bean (JB), Canavalia ensiformis (L.) DC, is a commonly cultivated legume in Indonesia. It is rich in protein, which can be hydrolyzed, making it potentially a good...
Jack bean (JB), Canavalia ensiformis (L.) DC, is a commonly cultivated legume in Indonesia. It is rich in protein, which can be hydrolyzed, making it potentially a good source of bioactive peptides. Intestinal inflammation is associated with several diseases, and the production of interleukin-8 (IL-8) in intestinal epithelial cells induced by tumor necrosis factor (TNF)-α has an important role in inflammatory reaction. The present study investigated the anti-inflammatory effects of peptides generated from enzymatic hydrolysis of JB protein on human intestinal Caco-2BBe cells. Additionally, in silico approaches were used to identify potential bioactive peptides. JB protein hydrolysate (JBPH) prepared using pepsin and pancreatin reduced the IL-8 expression at protein and mRNA levels in Caco-2BBe cells stimulated with TNF-α. Immunoblot analysis showed that the JBPH reduced the TNF-α-induced phosphorylation of c-Jun-NH(2)-terminal kinase, nuclear factor kappa B (NF-κB), and p38 proteins. Anti-inflammatory activity was observed in the 30% acetonitrile fraction of JBPH separated on a Sep-Pak C18 column. An ultrafiltration method revealed that relatively small peptides (< 3 kDa) had a potent inhibitory effect on the IL-8 production. Purification of the peptides by reversed-phase and anion-exchange high performance chromatography produced three peptide fractions with anti-inflammatory activities. A combination of mass spectrometry analysis and in silico approaches identified the potential anti-inflammatory peptides. Peptides derived from JB protein reduces the TNF-α-induced inflammatory response in Caco-2BBe cells via NF-κB and mitogen-activated protein kinase signaling pathways. Our results may lead to a novel therapeutic approach to promote intestinal health.
PubMed: 38940894
DOI: 10.1007/s11130-024-01201-x -
Journal of Integrative Neuroscience Jun 2024root, cataloged as "" in the Korean Pharmacopeia, is rich in various anthraquinones known for their anti-inflammatory and antioxidant properties. Formulations...
BACKGROUND
root, cataloged as "" in the Korean Pharmacopeia, is rich in various anthraquinones known for their anti-inflammatory and antioxidant properties. Formulations containing are traditionally employed for treating neurological conditions. This study aimed to substantiate the antiepileptic and neuroprotective efficacy of root extract (RTE) against trimethyltin (TMT)-induced epileptic seizures and hippocampal neurodegeneration.
METHODS
The constituents of RTE were identified by ultra-performance liquid chromatography (UPLC). Experimental animals were grouped into the following five categories: control, TMT, and three TMT+RTE groups with dosages of 10, 30, and 100 mg/kg. Seizure severity was assessed daily for comparison between the groups. Brain tissue samples were examined to determine the extent of neurodegeneration and neuroinflammation using histological and molecular biology techniques. Network pharmacology analysis involved extracting herbal targets for and disease targets for epilepsy from multiple databases. A protein-protein interaction network was built using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and pivotal targets were determined by topological analysis. Enrichment analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool to elucidate the underlying mechanisms.
RESULTS
The RTE formulation was found to contain sennoside A, sennoside B, chrysophanol, emodin, physcion, (+)-catechin, and quercetin-3-O-glucuronoid. RTE effectively inhibited TMT-induced seizures at 10, 30, and 100 mg/kg dosages and attenuated hippocampal neuronal decay and neuroinflammation at 30 and 100 mg/kg dosages. Furthermore, RTE significantly reduced mRNA levels of tumor necrosis factor (), glial fibrillary acidic protein (), and in hippocampal tissues. Network analysis revealed TNF, Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Protein c-fos (FOS), RAC-alpha serine/threonine-protein kinase (AKT1), and Mammalian target of rapamycin (mTOR) as the core targets. Enrichment analysis demonstrated significant involvement of components in neurodegeneration ( = 4.35 × 10-5) and TNF signaling pathway ( = 9.94 × 10-5).
CONCLUSIONS
The and analyses performed in this study suggests that RTE can potentially modulate TMT-induced epileptic seizures and neurodegeneration. Therefore, root is a promising herbal treatment option for antiepileptic and neuroprotective applications.
Topics: Animals; Neuroprotective Agents; Trimethyltin Compounds; Plant Extracts; Rheum; Plant Roots; Male; Anticonvulsants; Epilepsy; Hippocampus; Disease Models, Animal; Neurodegenerative Diseases; Computer Simulation; Network Pharmacology; Protein Interaction Maps; Rats
PubMed: 38940090
DOI: 10.31083/j.jin2306122 -
Open Veterinary Journal May 2024Diabetes mellitus (DM) is a long-term condition marked by high blood glucose levels caused by insulin resistance which will lead to complications of other diseases such...
BACKGROUND
Diabetes mellitus (DM) is a long-term condition marked by high blood glucose levels caused by insulin resistance which will lead to complications of other diseases such as dyslipidemia, which also affects the health of the liver and kidneys. Butterfly pea flower ( L.) has phenolic and flavonoid compounds which have the potential as herbal medicines for antidiabetics.
AIM
The purpose of this study is to examine the potential of butterfly pea flower extract (BPE) as an antidiabetic, anti-dyslipidemia, and renoprotection.
METHODS
test was performed on Sprague Dawley rats ( L.) induced by Streptozotocin-Nicotinamide and High Fat Diet-Propylthiouracil as models of DM and dyslipidemia, and BPE was administered orally (200, 400, and 800 mg/kg BW) for 28 days. glutathione peroxidase (GSH-Px), glutathione S-transferase (GST), tumor necrosis factor-α (TNF-α), nuclear factor-kappa beta (NF-kB), alkaline phosphatase (ALP), liver albumin levels, serum blood urea nitrogen (BUN), serum creatinine, and serum uric acid (UA), were measured by ELISA and colorimetry methods.
RESULTS
Treatment of BPE 800 mg/kg BW increased levels of GSH-Px, GST, albumin, and serum protein. BPE decreased TNF-α, NF-kB, and ALP. BPE also decreased BUN, serum CR, and serum UA.
CONCLUSION
BPE has the potential to be used as a drug alternative for the treatment of DM and dyslipidemia as well as a hepatoprotective and renoprotective agent.
Topics: Animals; Plant Extracts; Rats, Sprague-Dawley; Rats; Dyslipidemias; Male; Hypoglycemic Agents; Hypolipidemic Agents; Diabetes Mellitus, Experimental; Flowers
PubMed: 38938424
DOI: 10.5455/OVJ.2024.v14.i5.7 -
MedComm Jul 2024Targeting the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway has been identified as a successful approach for tumor immunotherapy. Here, we...
Targeting the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway has been identified as a successful approach for tumor immunotherapy. Here, we identified that the small molecule 5,7,4'-trimethoxyflavone (TF) from Wall reduces PD-L1 expression in colorectal cancer cells and enhances the killing of tumor cells by T cells. Mechanistically, TF targets and stabilizes the ubiquitin ligase HMG-CoA reductase degradation protein 1 (HRD1), thereby increasing the ubiquitination of PD-L1 and promoting its degradation through the proteasome pathway. In mouse MC38 xenograft tumors, TF can activate tumor-infiltrating T-cell immunity and reduce the immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells, thus exerting antitumor effects. Moreover, TF synergistically exerts antitumor immunity with CTLA-4 antibody. This study provides new insights into the antitumor mechanism of TF and suggests that it may be a promising small molecule immune checkpoint modulator for cancer therapy.
PubMed: 38938284
DOI: 10.1002/mco2.611 -
Molecular Plant Jun 2024Steroidal glycoalkaloids (SGAs) are specialized metabolites produced by hundreds of Solanum species, including important vegetable crops such as tomato, potato and...
Steroidal glycoalkaloids (SGAs) are specialized metabolites produced by hundreds of Solanum species, including important vegetable crops such as tomato, potato and eggplant. Though SGAs are better known for their role in defence in plants and 'anti-nutritional' effects (e.g., toxicity and bitterness) to humans, many of these molecules have documented anti-cancer, anti-microbial, anti-inflammatory, anti-viral and anti-pyretic activities. Among these, α-solasonine and α-solamargine isolated from black nightshade (Solanum nigrum), are reported to have potent anti-tumor, anti-proliferative and anti-inflammatory activities. Notably, α-solasonine and α-solamargine, along with the core steroidal aglycone solasodine are the most widespread SGAs produced among the Solanum plants. However, it is still unknown how plants synthesize these bioactive steroidal molecules. Through comparative metabolomic-transcriptome guided approach, biosynthetic logic, combinatorial expression in Nicotiana benthamiana and functional recombinant enzyme assays, here we report the discovery of 12 enzymes from S. nigrum that converts the staring cholesterol precursor to solasodine aglycone, and the downstream α-solasonine, α-solamargine and malonyl-solamargine SGA products. We further identified 6 enzymes from cultivated eggplant that catalyse the production of α-solasonine, α-solamargine and malonyl-solamargine SGAs from solasodine aglycone, via glycosylation and atypical malonylation decorations. Our work provides the gene tool box and platform for engineering the production of high value, steroidal bioactive molecules in heterologous hosts using synthetic biology.
PubMed: 38937971
DOI: 10.1016/j.molp.2024.06.013 -
Advanced Materials (Deerfield Beach,... Jun 2024Cuproptosis is a novel copper-dependent programmed cell death. The efficacy of cuproptosis is highly dependent on intracellular copper accumulation and counteracted by a...
Cuproptosis is a novel copper-dependent programmed cell death. The efficacy of cuproptosis is highly dependent on intracellular copper accumulation and counteracted by a high level of glutathione (GSH) in tumor cells. Here, we developed a self-amplified cuproptosis nanoplatform (Cel-Cu NP) using celastrol (Cel), a natural product isolated from medical plant. In Cel-Cu NP, Cel serves as a versatile copper ionophore, exhibiting an ideal coordination capacity towards copper ions without compromising the cuproptosis induction. Notably, Cel can simultaneously scavenge GSH content to amplify cuproptosis. Moreover, this self-amplified cuproptosis further activates immunogenic cell death (ICD) to elicit robust immune response. Combining with immune checkpoint blockade, Cel-Cu NP effectively eradicates metastatic tumors in a mouse lung metastasis model. This study provides an efficient nanomedicine by inducing self-amplified cuproptosis for robust immunotherapy. This article is protected by copyright. All rights reserved.
PubMed: 38935977
DOI: 10.1002/adma.202404971