OBJECTIVES: Primary tumor treatment through surgical resection and adjuvant therapy has been extensively studied, but there is a lack of effective strategies and drugs for the treatment of tumor metastases. Here, we describe a functional product based on a combination of compounds, which can be used as an adjuvant therapy and has well-known mechanisms for inhibiting cancer metastases, improving anti-cancer treatment, and enhancing immunity and antioxidant capacity. Our designed combination, named MVBL, consists of four inexpensive compounds: L-selenium-methylselenocysteine (MSC), D-‍α‍-tocopheryl succinic acid (VES), β‍-carotene (β‍-Ca), and L-lysine (Lys). METHODS: The effects of MVBL on cell viability, cell cycle, cell apoptosis, cell migration, cell invasion, reactive oxygen species (ROS), and paclitaxel (PTX)-combined treatment were studied in vitro. The inhibition of tumor metastasis, antioxidation, and immune enhancement capacity of MVBL were determined in vivo. RESULTS: MVBL exhibited higher toxicity to tumor cells than to normal cells. It did not significantly affect the cell cycle of cancer cells, but increased their apoptosis. Wound healing, adhesion, and transwell assays showed that MVBL significantly inhibited tumor cell migration, adhesion, and invasion. MVBL sensitized MDA-MB-231 breast cancer cells to PTX, indicating that it can be used as an adjuvant to enhance the therapeutic effect of chemotherapy drugs. In mice, experimental data showed that MVBL inhibited tumor metastasis, prolonged their survival time, and enhanced their antioxidant capacity and immune function. CONCLUSIONS This study revealed the roles of MVBL in improving immunity and antioxidation, preventing tumor growth, and inhibiting metastasis in vitro and in vivo. MVBL may be used as an adjuvant drug in cancer therapy for improving the survival and quality of life of cancer patients.
Mice ; Animals ; beta Carotene ; Lysine/pharmacology* ; Antioxidants/pharmacology* ; Quality of Life ; Paclitaxel/pharmacology* ; Apoptosis ; alpha-Tocopherol ; Succinates/pharmacology* ; Cell Line, Tumor ; Cell Proliferation ; Neoplasms

Blakeslea trispora is a natural source of carotenoids, including β-carotene and lycopene, which have industrial applications. Therefore, classical selective breeding techniques have been applied to generate strains with increased productivity, and microencapsulated β-carotene preparation has been used in food industry (Li et al., 2019). In B. trispora, lycopene is synthesized via the mevalonate pathway (Venkateshwaran et al., 2015). Lycopene cyclase, which is one of the key enzymes in this pathway, is a bifunctional enzyme that can catalyze the cyclization of lycopene to produce β-carotene and exhibit phytoene synthase activity (He et al., 2017).
Citric Acid Cycle ; Fermentation ; Gas Chromatography-Mass Spectrometry/methods* ; Lycopene/metabolism* ; Mucorales/metabolism* ; Nicotine/pharmacology* ; beta Carotene/biosynthesis*

We investigated whether β-carotene (β-CA) or ellagic acid (EA), originating from various fruits and vegetables, has a preventive effect against male infertility induced by exogenous scrotal hyperthermia. ICR adult mice were intraperitoneally treated with 10 mg/kg of β-CA or EA daily for 13 days consecutively. During this time, mice were subjected to transient scrotal heat stress in a water bath at 43℃ for 20 min on day 7, and their testes and blood were obtained on day 14 for histopathologic and biochemical analyses. Heat stress induced significant testicular weight reduction, germ cell loss and degeneration, as well as abnormal localization of phospholipid hydroperoxide glutathione peroxidase (PHGPx) and manganese superoxide dismutase (MnSOD) in spermatogenic and Leydig cells. Heat stress also altered the levels of oxidative stress (lipid peroxidation, SOD activity, and PHGPx, MnSOD, and HIF-1α mRNAs), apoptosis (Bax, Bcl-xL, caspase 3, NF-κB, and TGF-β1 mRNAs), and androgen biosynthesis (serological testosterone concentration and 3β-hydroxysteroid dehydrogenase mRNA) in testes. These changes were all improved significantly by β-CA treatment, but only slightly improved by EA treatment. These findings indicate that β-CA, through modulations of oxidative stress, apoptosis, and androgen biosynthesis, is a potent preventive agent against testicular injuries induced by scrotal hyperthermia.
Adult ; Animals ; Apoptosis ; Baths ; beta Carotene ; Caspase 3 ; Ellagic Acid ; Fever ; Fruit ; Germ Cells ; Glutathione Peroxidase ; Hot Temperature ; Humans ; Hydrogen Peroxide ; Infertility, Male ; Leydig Cells ; Male ; Mice ; Oxidative Stress ; Oxidoreductases ; Superoxide Dismutase ; Testis ; Testosterone ; Vegetables ; Water ; Weight Loss

BACKGROUND: Helicobacter pylori infection is a major risk factor in the development of gastric cancer. H. pylori infection of gastric epithelial cells increases the levels of reactive oxygen species (ROS), activates oncogenes, and leads to β-catenin-mediated hyper-proliferation. β-Carotene reduces ROS levels, inhibits oxidant-mediated activation of inflammatory signaling and exhibits anticancer properties. The present study was carried out to determine if β-carotene inhibits H. pylori-induced cell proliferation and the expression of oncogenes c-myc and cyclin E by reducing the levels of β-catenin and phosphorylated glycogen synthase kinase 3β (p-GSK3β). METHODS: Gastric epithelial AGS cells were pre-treated with β-carotene (5 and 10 μM) for 2 hours prior to H. pylori infection and cultured for 6 hours (for determination of the levels of p-GSK3β, GSK3β, and β-catenin) and 24 hours (for determination of cell viability and protein levels of c-myc and cyclin E). Cell viability was determined by the MTT assay and protein levels were determined via western blot-based analysis. RESULTS: β-Carotene inhibited H. pylori-induced increases in the percentage of viable cells, phosphorylated GSK3β (p-GSK3β), and the levels of β-catenin, c-myc and cyclin E. CONCLUSIONS: β-Carotene inhibits H. pylori-induced hyper-proliferation of gastric epithelial cells by suppressing β-catenin signaling and oncogene expression.
beta Carotene ; beta Catenin ; Cell Proliferation ; Cell Survival ; Cyclin E ; Cyclins ; Epithelial Cells ; Glycogen Synthase Kinases ; Helicobacter pylori ; Helicobacter ; Oncogenes ; Reactive Oxygen Species ; Risk Factors ; Stomach Neoplasms

BACKGROUND: Beta-carotene (BC) is a carotenoid which exerts anti-cancer effects in several types of cancer, including colorectal cancer. Epigenetic modifications of genes, such as histone deacetylation and DNA hypermethylation, have also been detected in various types of cancer. To understand the molecular mechanism underlying cancer preventive and therapeutic effects of BC, microRNAs (miRNAs), histone acetylation, and global DNA methylation in colon cancer stem cells (CSCs) were investigated.METHODS: HCT116 colon cancer cells positive for expression of CD44 and CD133 were sorted by flow cytometry and used in subsequent experiments. Cell proliferation was examined by the MTT assay and self-renewal capacity was analyzed by the sphere formation assay. The miRNA sequencing array was used to detect miRNAs regulated by BC. Histone acetylation levels were measured by the Western blot analysis. mRNA expression of DNA methyltransferases (DNMTs) was examined by qPCR and global DNA methylation levels were determined by enzyme-linked immunosorbent assay.RESULTS: Treatment of CD44⁺CD133⁺ colon CSCs with BC caused a reduction in both cell proliferation and sphere formation. Analysis of the miRNA sequencing array showed that BC regulated expression of miRNAs associated with histone acetylation. Histone H3 and H4 acetylation levels were elevated by BC treatment. In addition, BC treatment down-regulated DNMT3A mRNA expression and global DNA methylation in colon CSCs.CONCLUSIONS: These results suggest that BC regulates epigenetic modifications for its anti-cancer effects in colon CSCs.
Acetylation ; beta Carotene ; Blotting, Western ; Cell Proliferation ; Colon ; Colonic Neoplasms ; Colorectal Neoplasms ; DNA Methylation ; DNA ; Enzyme-Linked Immunosorbent Assay ; Epigenomics ; Flow Cytometry ; Histones ; Methyltransferases ; MicroRNAs ; RNA, Messenger ; Stem Cells ; Therapeutic Uses

Isoprenoids are all derived from two five-carbon building blocks called isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), which are synthesized either by the mevalonate (MVA) pathway or 2-C-methyld-D-erythritol-4-phosphate (MEP) pathway. In this study, the MVA pathway genes were integrated into the chromosome of LYC101, in which the expression of key genes in the MEP synthesis pathway and lycopene synthesis pathway were optimized by artificial regulatory parts, to further improve the production of isoprenoids in Escherichia coli. The plasmids pALV23 and pALV145 were screened from a plasmid library that constructed by using the RBS library to link the genes of the MVA pathway, which greatly increased the production of β-carotene. The effects of plasmids pALV23 and pALV145 on the lycopene production in low and high lycopene production strain, LYC001 and LYC101, were compared, respectively. The production of lycopene was increased by plasmids pALV23 and pALV145 in both strains. In high lycopene production strain LYC101, pALV23 produced more lycopene than pALV145. Then, the MVA gene together of promoter of pALV23 was integrated into the chromosome of LYC101 at poxB site using method of homologous recombination helped by CRISPR-Cas9 system, resulted in genetically stable strain, LYC102. The yield of lycopene of LYC102 was 40.9 mg/g DCW, 1.19-folds higher than that of LYC101, and 20% more than that of LYC101 with pALV23. Simultaneous expression of MVA pathway and MEP pathway in recombinant E. coli can effectively increase the yield of terpenoids. In this study, a plasmid-free, genetically stable, high-yielding lycopene strain was constructed, which could be used for industrialization. Also, the platform strain can be used for the synthesis of other terpenoids.
Chromosomes, Bacterial ; Escherichia coli ; Lycopene ; Mevalonic Acid ; beta Carotene

β-Carotene is one of the most abundant natural pigments in foods; however, usage of β-carotene is limited because of its instability. Microencapsulation techniques are usually applied to protect microencapsulated β-carotene from oxidization. In this study, β-carotene was microencapsulated using different drying processes: spray-drying, spray freeze-drying, coating, and spray granulation. The properties of morphology, particle size, water content, thermal characteristic, and chemical stability have been explored and compared. Scanning electron microscopy measurements showed that the coated powder had a dense surface surrounded by starch and suggested that the coating process gave a microencapsulated powder with the smallest bulk density and the best compressibility among the prepared powders. The chemical stabilities of microcapsules were evaluated during six months of storage at different temperatures. The coated powder had the highest mass fraction of β-carotene, which indicated that the coating process was superior to the three other drying processes.
Drug Compounding/methods* ; Drug Stability ; Freeze Drying ; Microscopy, Electron, Scanning ; Technology, Pharmaceutical ; beta Carotene/chemistry*

BACKGROUND: Oxidative stress occurs in white adipose tissue and dysregulates the expression of adipokines secreted from adipocytes. Since adipokines influence inflammation, supplementation with antioxidants might be beneficial for preventing oxidative stress-mediated inflammation in adipocytes and inflammation-associated complications. β-Carotene is the most prominent antioxidant carotenoid and scavenges reactive oxygen species in various tissues. The purpose of this study was to determine whether β-carotene regulates the expression of adipokines, such as adiponectin, monocyte chemoattractant protein-1 (MCP-1), and regulated on activation, normal T cell expressed and secreted (RANTES) in 3T3-L1 adipocytes treated with glucose/glucose oxidase (G/GO). METHODS: 3T3-L1 adipocytes were cultured with or without β-carotene and treated with G/GO, which produces H2O2. mRNA and protein levels in the medium were determined by a real-time PCR and an ELISA. DNA binding activities of transcription factors were assessed using an electrophoretic mobility shift assay. RESULTS: G/GO treatment increased DNA binding affinities of redox-sensitive transcription factors, such as NF-κB, activator protein-1 (AP-1), and STAT3. G/GO treatment reduced the expression of adiponectin and increased the expression of MCP-1 and RANTES. G/GO-induced activations of NF-κB, AP-1, and STAT3 were inhibited by β-carotene. G/GO-induced dysregulation of adiponectin, MCP-1, and RANTES were significantly recovered by treatment with β-carotene. CONCLUSIONS: β-Carotene inhibits oxidative stress-induced inflammation by suppressing pro-inflammatory adipokines MCP-1 and RANTES, and by enhancing adiponectin in adipocytes. β-Carotene may be beneficial for preventing oxidative stress-mediated inflammation, which is related to adipokine dysfunction.
Adipocytes ; Adipokines ; Adiponectin ; Adipose Tissue, White ; Antioxidants ; beta Carotene ; Chemokine CCL2 ; Chemokine CCL5 ; DNA ; Electrophoretic Mobility Shift Assay ; Enzyme-Linked Immunosorbent Assay ; Inflammation ; Oxidative Stress ; Oxidoreductases ; Reactive Oxygen Species ; Real-Time Polymerase Chain Reaction ; RNA, Messenger ; Transcription Factor AP-1 ; Transcription Factors

Helicobacter pylori is a dominant bacterium living in the human gastric tissues. In H. pylori-infected tissues, the infiltrated inflammatory cells produce reactive oxygen species (ROS), leading to gastric inflammation with production of various mediators. According to numerous epidemiological studies, dietary carotenoids may prevent gastric inflammation due to their antioxidant properties. Recent studies showed that antioxidant and anti-inflammatory effects of astaxanthin and β-carotene may contribute to inhibition of H. pylori-induced gastric inflammation. Astaxanthin changes H. pylori-induced activation of T helper cell type 1 response towards T helper cell type 2 response in the infected tissues. Astaxanthin inhibits the growth of H. pylori. Even though astaxanthin reduces H. pylori-induced gastric inflammation, it does not reduce cytokine levels in the infected tissues. β-Carotene suppresses ROS-mediated inflammatory signaling, including mitogen-activated protein kinases and redox-sensitive transcription factors, and reduces expression of inflammatory mediators, including interleukin-8, inducible nitric oxide synthase, and cyclooxygenase-2 in the infected tissues. Therefore, consumption of astaxanthin- and β-carotene-rich foods may be beneficial to prevent H. pylori-induced gastric inflammation. This review will summarize anti-inflammatory mechanisms of astaxanthin and β-carotene in H. pylori-mediated gastric inflammation.
beta Carotene ; Carotenoids ; Cyclooxygenase 2 ; Epidemiologic Studies ; Helicobacter pylori ; Helicobacter* ; Humans ; Inflammation* ; Interleukin-8 ; Mitogen-Activated Protein Kinases ; Nitric Oxide Synthase Type II ; Reactive Oxygen Species ; T-Lymphocytes, Helper-Inducer ; Transcription Factors

1,3,5-Trimethylbenzene (1,3,5-TMB) was used as the pore-enlarging modifier to expand the pore size of MCM-41 (mobil company of matter) mesoporous silica nanoparticles. The solvent impregnation method was adopted to assemble non-water-soluble β-carotene into the pore channel of MCM-41. The MCM-41 and drug assemblies were characterized by TEM, FT-IR, elemental analysis and N2 adsorption-desorption. The results showed that MCM-41 has good sphericity and regular pore structure. The research also investigated the optimal loading time, the drug loading and the vitro stability of the β-carotene. As a drug carrier, the modified MCM-41 showing a shorter drug loading time, the drug loading as high as 85.58% and the stability of β-carotene in drug assemblies has improved. The study of this new formulation provides a new way for β-carotene application.
Drug Carriers ; chemistry ; Drug Delivery Systems ; Drug Stability ; Nanoparticles ; chemistry ; Silicon Dioxide ; chemistry ; beta Carotene ; chemistry ; pharmacology