scholarly journals Platycodin D enhances LDLR expression and LDL uptake via down-regulation of IDOL mRNA in hepatic cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yu-Jeong Choi ◽  
Sol Ji Lee ◽  
Hyo In Kim ◽  
Hee Jung Lee ◽  
So Jung Kang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Synergistic Effects ◽  
Biological Activities ◽  
Therapeutic Option ◽  
Molecular Evidence ◽  
Triterpenoid Saponin ◽  
Atherosclerotic Cardiovascular Disease ◽  
Down Regulation ◽  
Hepatic Cells

AbstractThe root of Platycodon grandiflorum (PG) has long been used as a traditional herbal medicine in Asian country. Platycondin D (PD), triterpenoid saponin that is a main constituent of PG, exhibits various biological activities such as anti-inflammatory, anti-oxidant, anti-diabetic, and anti-cancer effects. A previous study showed that PD had cholesterol-lowering effects in mice that develop hypercholesterolemia, but the underlying molecular mechanisms have not been elucidated during the last decade. Here, we demonstrated that both PG and PD markedly increased levels of cell surface low-density lipoprotein receptor (LDLR) by down-regulation of the E3 ubiquitin ligase named inducible degrader of the LDLR (IDOL) mRNA, leading to the enhanced uptake of LDL-derived cholesterol (LDL-C) in hepatic cells. Furthermore, cycloheximide chase analysis and in vivo ubiquitination assay revealed that PD increased the half-life of LDLR protein by reducing IDOL-mediated LDLR ubiquitination. Finally, we demonstrated that treatment of HepG2 cells with simvastatin in combination with PG and PD had synergistic effects on the improvement of LDLR expression and LDL-C uptake. Together, these results provide the first molecular evidence for anti-hypercholesterolemic activity of PD and suggest that PD alone or together with statin could be a potential therapeutic option in the treatment of atherosclerotic cardiovascular disease.

scholarly journals In Vivo Effect of Resveratrol-Loaded Solid Lipid Nanoparticles to Relieve Physical Fatigue for Sports Nutrition Supplements

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5302
Author(s):  
Lili Qin ◽  
Tianfeng Lu ◽  
Yao Qin ◽  
Yiwei He ◽  
Ningxin Cui ◽  
...  
Keyword(s):  
Solid Lipid Nanoparticles ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Lipid Nanoparticles ◽  
Correlation Spectroscopy ◽  
Physical Fatigue ◽  
Scanning Calorimetry ◽  
Solid Lipid ◽  
Sequestosome 1

Resveratrol (RSV) is a natural flavonoid polyphenol compound extracted from the plants which shows various biological activities. However, the clinical application of RSV is limited by its poor aqueous solubility, rapid metabolism and poor bioavailability. In this study, resveratrol-loaded solid lipid nanoparticles (RSV- SLNs) was design as a nano-antioxidant against the physical fatigue. The resultant RSV-SLNs were characterized by photon correlation spectroscopy (PCS), transmission electron micrographs (TEM), zeta potential, differential scanning calorimetry (DSC) and Raman spectroscopy pattern. Furthermore, the in vivo anti-fatigue effect assays showed that RSV-SLNs prolonged the mice exhausted time and running distance. The biochemical parameters of blood related to fatigue suggested that RSV-SLNs have potential applications to improve the antioxidant defense of the mice after extensive exercise and confer anti-fatigue capability. Furthermore, the molecular mechanisms of antioxidant by RSV-SLNs supplementation was investigated through the analysis of silent information regulator 2 homolog 1 (SIRT1) protein expression, which demonstrated that it could downregulate the expression of SIRT1 and increase autophagy markers, microtubule-associated protein 1 light chain 3-II (LC3-II) and sequestosome-1 (SQSTM1/p62). These results reveal that the RSV-SLNs may have great potential used as a novel anti-fatigue sports nutritional supplement.

scholarly journals Angiostatin regulates the expression of antiangiogenic and proapoptotic pathways via targeted inhibition of mitochondrial proteins

Blood ◽  
2009 ◽  
Vol 114 (9) ◽  
pp. 1987-1998 ◽  
Author(s):  
Tong-Young Lee ◽  
Stefan Muschal ◽  
Elke A. Pravda ◽  
Judah Folkman ◽  
Amir Abdollahi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Antiangiogenic Therapy ◽  
Krebs Cycle ◽  
In Vivo Studies ◽  
Antitumor Effects ◽  
Down Regulation ◽  
Proteolytic Fragment ◽  
Induced Apoptosis

Angiostatin, a proteolytic fragment of plasminogen, is a potent endogenous antiangiogenic agent. The molecular mechanisms governing angiostatin's antiangiogenic and antitumor effects are not well understood. Here, we report the identification of mitochondrial compartment as the ultimate target of angiostatin. After internalization of angiostatin into the cell, at least 2 proteins within the mitochondria bind this molecule: malate dehydrogenase, a member of Krebs cycle, and adenosine triphosphate synthase. In vitro and in vivo studies revealed differential regulation of key prosurvival and angiogenesis-related proteins in angiostatin-treated tumors and tumor-endothelium. Angiostatin induced apoptosis via down-regulation of mitochondrial BCL-2. Angiostatin treatment led to down-regulation of c-Myc and elevated levels of another key antiangiogenic protein, thrombospondin-1, reinforcing its antitumor and antiangiogenic effects. Further evidence is provided for reduced recruitment and infiltration of bone marrow–derived macrophages in angiostatin-treated tumors. The observed effects of angiostatin were restricted to the tumor site and were not observed in other major organs of the mice, indicating unique tumor specific bioavailability. Together, our data suggest mitochondria as a novel target for antiangiogenic therapy and provide mechanistic insights to the antiangiogenic and antitumor effects of angiostatin.

scholarly journals Bee Venom: From Venom to Drug

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4941
Author(s):  
Abdelwahab Khalil ◽  
Basem H. Elesawy ◽  
Tarek M. Ali ◽  
Osama M. Ahmed
Keyword(s):  
Molecular Mechanisms ◽  
Biological Activities ◽  
Biologically Active ◽  
Bee Venom ◽  
Bee Sting ◽  
Anti Cancer ◽  
Defensive Substance ◽  
Injectable Form

Insects of the order Hymenoptera have a defensive substance that contains many biologically active compounds. Specifically, venom from honeybees (Apis mellifera) contains many enzymes and peptides that are effective against various diseases. Different research papers stated the possibility of using bee venom (a direct bee sting or in an injectable form) in treating several complications; either in vivo or in vitro. Other reports used the active fractions of bee venom clinically or at labratory scale. Many reports and publications have stated that bee venom and its constituents have multiple biological activities including anti-microbial, anti-protozoan, anti-cancer, anti-inflammatory, and anti-arthritic properties. The present review aims to refer to the use of bee venom itself or its fractions in treating several diseases and counteracting drug toxicities as an alternative protocol of therapy. The updated molecular mechanisms of actions of bee venom and its components are discussed in light of the previous updated publications. The review also summarizes the potential of venom loaded on nanoparticles as a drug delivery vehicle and its molecular mechanisms. Finally, the products of bee venom available in markets are also demonstrated.

scholarly journals Histone methyltransferase SET8 is regulated by miR-192/215 and induces oncogene-induced senescence via p53-dependent DNA damage in human gastric carcinoma cells

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Xiaojing Zhang ◽  
Yin Peng ◽  
Yuan Yuan ◽  
Yuli Gao ◽  
Fan Hu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Expression Profiles ◽  
Carcinoma Cells ◽  
Negative Regulator ◽  
Expression Change ◽  
Human Gastric Carcinoma Cells

Abstract Gastric cancer (GC) is the most common cancer throughout the world. Despite advances of the treatments, detailed oncogenic mechanisms are largely unknown. In our previous study, we investigated microRNA (miR) expression profiles in human GC using miR microarrays. We found miR-192/215 were upregulated in GC tissues. Then gene microarray was implemented to discover the targets of miR-192/215. We compared the expression profile of BGC823 cells transfected with miR-192/215 inhibitors, and HFE145 cells transfected with miR-192/-215 mimics, respectively. SET8 was identified as a proposed target based on the expression change of more than twofold. SET8 belongs to the SET domain-containing methyltransferase family and specifically catalyzes monomethylation of H4K20me. It is involved in diverse functions in tumorigenesis and metastasis. Therefore, we focused on the contributions of miR-192/215/SET8 axis to the development of GC. In this study, we observe that functionally, SET8 regulated by miR-192/215 is involved in GC-related biological activities. SET8 is also found to trigger oncogene-induced senescence (OIS) in GC in vivo and in vitro, which is dependent on the DDR (DNA damage response) and p53. Our findings reveal that SET8 functions as a negative regulator of metastasis via the OIS-signaling pathway. Taken together, we investigated the functional significance, molecular mechanisms, and clinical impact of miR-192/215/SET8/p53 in GC.

scholarly journals Induction of ferroptosis in human nasopharyngeal cancer cells by cucurbitacin B: molecular mechanism and therapeutic potential

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Shuai Huang ◽  
Bihui Cao ◽  
Jinling Zhang ◽  
Yunfei Feng ◽  
Lu Wang ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Tumour Progression ◽  
Biological Activities ◽  
Nasopharyngeal Cancer ◽  
Migration And Invasion ◽  
Cucurbitacin B

AbstractCucurbitacin B (CuB) is a widely available triterpenoid molecule that exhibits various biological activities. Previous studies on the anti-tumour mechanism of CuB have mostly focused on cell apoptosis, and research on the ferroptosis-inducing effect has rarely been reported. Herein, we first discovered the excellent cytotoxicity of CuB towards human nasopharyngeal carcinoma cells and elucidated its potential ferroptosis-inducing mechanisms. Morphology alterations of mitochondrial ultrastructure, as observed via transmission electron microscopy, showed that CuB-treated cells undergo ferroptosis. CuB caused intracellular accumulation of iron ions and depletion of glutathione. Detailed molecular mechanism investigation confirmed that CuB both induced widespread lipid peroxidation and downregulated the expression of GPX4, ultimately initiating a multipronged mechanism of ferroptosis. Furthermore, CuB exhibited anti-tumour effects in vitro by inhibiting cellular microtubule polymerization, arresting cell cycle and suppressing migration and invasion. Finally, CuB significantly inhibited tumour progression without causing obvious side effects in vivo. Altogether, our study highlighted the therapeutic potential of CuB as a ferroptosis-inducing agent for nasopharyngeal cancer, and it provided valuable insights for developing effective anti-tumour agents with novel molecular mechanisms derived from natural products.

scholarly journals Recent Updates on Marine Cancer-Preventive Compounds

Marine Drugs ◽  
2021 ◽  
Vol 19 (10) ◽  
pp. 558
Author(s):  
Sergey A. Dyshlovoy
Keyword(s):  
Molecular Mechanisms ◽  
Biological Activities ◽  
Relevant Literature ◽  
Tumor Development ◽  
Chemical Structures ◽  
Preventive Activity ◽  
Marine Compounds ◽  
Current Article ◽  
Unique Chemical

The natural compounds derived from marine organisms often exhibit unique chemical structures and potent biological activities. Cancer-preventive activity is one of the rather new activities that has emerged and been extensively studied over the last decades. This review summarizes the recent updates on the marine chemopreventive compounds covering the relevant literature published in 2013–2021 and following the previous comprehensive review by Stonik and Fedorov (Marine Drugs 2014, 12, 636–671). In the current article, only the molecules having an effect on malignant transformation (or related pathway and molecules), cancer stem cells, or carcinogen-induced in vivo tumor development were considered to be “true” cancer-preventive compounds and were, therefore, reviewed. Additionally, particular attention has been given to the molecular mechanisms of chemoprevention, executed by the reported marine compounds.

scholarly journals Cellular Basis of Organotin(IV) Derivatives as Anticancer Metallodrugs: A Review

2021 ◽  
Vol 9 ◽  
Author(s):  
Sharifah Nadhira Syed Annuar ◽  
Nurul Farahana Kamaludin ◽  
Normah Awang ◽  
Kok Meng Chan
Keyword(s):  
Molecular Mechanisms ◽  
Antimicrobial Agents ◽  
Human Cancer ◽  
Synergistic Effects ◽  
Biological Activities ◽  
Human Cancer Cell Lines ◽  
Cycle Arrest ◽  
Ability To Act ◽  
Potential Applications ◽  
Anticancer Metallodrugs

Organotin(IV) compounds have wide applications in industrial and agricultural fields owing to their ability to act as poly(vinyl chloride) stabilizers and catalytic agents as well as their medicinal properties. Moreover, organotin(IV) compounds may have applications as antitumor, anti-inflammatory, antifungal, or antimicrobial agents based on the observation of synergistic effects following the binding of their respective ligands, resulting in the enhancement of their biological activities. In this review, we describe the antiproliferative activities of organotin(IV) compounds in various human cancer cell lines based on different types of ligands. We also discuss the molecular mechanisms through which organotin(IV) compounds induce cell death via apoptosis through the mitochondrial intrinsic pathway. Finally, we present the mechanisms of cell cycle arrest induced by organotin(IV) compounds. Our report provides a basis for studies of the antitumor activities of organotin(IV) compounds and highlights the potential applications of these compounds as anticancer metallodrugs with low toxicity and few side effects.

scholarly journals The variations of Endophilin A2-FoxO3a-autophagy signal in AngⅡ-induced dopaminergic neuron injury mouse model and By Biochanin A

2021 ◽  
Author(s):  
Yi-Gui Yu ◽  
Jun-Hui Han ◽  
Hai-Xia Xue ◽  
Weizu Li ◽  
Wen-Ning Wu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Beclin 1 ◽  
Biochanin A ◽  
Protective Effects ◽  
Behavioral Dysfunction ◽  
Related Proteins ◽  
Neuron Injury

Biochanin A is a natural plant estrogen, with various biological activities such as anti-apoptosis, anti-oxidation and suppression of inflammatory. In this study, we investigated the protective effects of biochanin A on AngⅡ-induced dopaminergic neurons damage in vivo and molecular mechanisms. Spontaneous activity and motor ability of mice among groups was detected by open-field test and swim-test. The expression of TH, LC3BⅡ/LC3BⅠ, Beclin-1, P62, p-FoxO3a / FoxO3a, FoxO3 and Endophilin A2 were determined by western blot and immunohistochemistry or immunofluorescence staining. Our results showed that AngⅡ treatment significantly increased the behavioral dysfunction of mice and DA neurons damage. Meanwhile, AngⅡ treatment increased the expression of LC3BⅡ/LC3BⅠ, Beclin-1, P62 and FoxO3a and decreased the expression of Endophilin A2 and p-FoxO3a / FoxO3a, however, biochanin A treatment alleviate these changes. In summary, these results suggest that biochanin A exerts protective effects on AngⅡ-induced mouse model may be related to regulating Endophilin A2, FoxO3a and autophagy-related proteins. However, the specific mechanism is not yet clear and needs further study.

scholarly journals Molecular Mechanisms of Anticancer Activity of N-Glycosides of Indolocarbazoles LCS-1208 and LCS-1269

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7329
Author(s):  
Roman G. Zenkov ◽  
Olga A. Vlasova ◽  
Varvara P. Maksimova ◽  
Timur I. Fetisov ◽  
Natalia Y. Karpechenko ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Chromatin Remodeling ◽  
Anticancer Agents ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Biological Activities ◽  
Binding Constants ◽  
Histone H1 ◽  
Immortalized Cells

Novel indolocarbazole derivatives named LCS were synthesized by our research group. Two of them were selected as the most active anticancer agents in vivo. We studied the mechanisms of anticancer activity in accordance with the previously described effects of indolocarbazoles. Cytotoxicity was estimated by MTT assay. We analyzed LCS-DNA interactions by circular dichroism in cholesteric liquid crystals and fluorescent indicator displacement assay. The effect on the activity of topoisomerases I and II was studied by DNA relaxation assay. Expression of interferon signaling target genes was estimated by RT-PCR. Chromatin remodeling was analyzed–the effect on histone H1 localization and reactivation of epigenetically silenced genes. LCS-induced change in the expression of a wide gene set was counted by means of PCR array. Our study revealed the cytotoxic activity of the compounds against 11 cancer cell lines and it was higher than in immortalized cells. Both compounds bind DNA; binding constants were estimated—LCS-1208 demonstrated higher affinity than LCS-1269; it was shown that LCS-1208 intercalates into DNA that is typical for rebeccamycin derivatives. LCS-1208 also inhibits topoisomerases I and IIα. Being a strong intercalator and topoisomerase inhibitor, LCS-1208 upregulates the expression of interferon-induced genes. In view of LCSs binding to DNA we analyzed their influence on chromatin stability and revealed that LCS-1269 displaces histone H1. Our analysis of chromatin remodeling also included a wide set of epigenetic experiments in which LCS-1269 demonstrated complex epigenetic activity. Finally, we revealed that the antitumor effect of the compounds is based not only on binding to DNA and chromatin remodeling but also on alternative mechanisms. Both compounds induce expression changes in genes involved in neoplastic transformation and target genes of the signaling pathways in cancer cells. Despite of being structurally similar, each compound has unique biological activities. The effects of LCS-1208 are associated with intercalation. The mechanisms of LCS-1269 include influence on higher levels such as chromatin remodeling and epigenetic effects.

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