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1.
Toxicol Res ; 39(4): 669-679, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37779588

ABSTRACT

Glioblastoma (GBM) is the most aggressive type of central nervous system tumor. Molecular targeting may be important when developing efficient GBM treatment strategies. Sequencing of GBMs revealed that the receptor tyrosine kinase (RTK)/RAS/phosphatidylinositol-3-kinase pathway was altered in 88% of samples. Interestingly, AXL, a member of RTK, was proposed as a promising target in glioma therapy. However, the molecular mechanism of AXL modulation of GBM genesis and proliferation is still unclear. In this study, we investigated the expression and localization of hypoxia-inducible factor-1 alpha (HIF-1α) by AXL in GBM. Both AXL mRNA and protein are overexpressed in GBM. Short-interfering RNA knockdown of AXL in U251-MG cells reduced viability and migration. However, serum withdrawal reduced AXL expression, abolishing the effect on viability. AXL is also involved in hypoxia regulation. In hypoxic conditions, the reduction of AXL decreased the level and nuclear localization of HIF-1α. The co-expression of HIF-1α and AXL was found in human GBM samples but not normal tissue. This finding suggests a mechanism for GBM proliferation and indicates that targeting AXL may be a potential GBM therapeutic. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00195-z.

2.
Mol Ther ; 30(8): 2800-2816, 2022 08 03.
Article in English | MEDLINE | ID: mdl-35526096

ABSTRACT

Several preclinical studies demonstrate that antitumor efficacy of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade can be improved by combination with other checkpoint inhibitors. Lymphocyte-activation gene 3 (LAG-3) is an inhibitory checkpoint receptor involved in T cell exhaustion and tumor immune escape. Here, we describe ABL501, a bispecific antibody targeting LAG-3 and PD-L1 in modulating immune cell responses against tumors. ABL501 that efficiently inhibits both LAG-3 and PD-L1 pathways enhances the activation of effector CD4+ and CD8+ T cells with a higher degree than a combination of single anti-LAG-3 and anti-PD-L1. The augmented effector T cell responses by ABL501 resulted in mitigating regulatory-T-cell-mediated immunosuppression. Mechanistically, the simultaneous binding of ABL501 to LAG-3 and PD-L1 promotes dendritic cell (DC) activation and tumor cell conjugation with T cells that subsequently mounts effective CD8+ T cell responses. ABL501 demonstrates its potent in vivo antitumor efficacy in a humanized xenograft model and with knockin mice expressing human orthologs. The immune profiling analysis of peripheral blood reveals an increased abundance of LAG-3hiPD-1hi memory CD4+ T cell subset in relapsed cholangiocarcinoma patients after gemcitabine plus cisplatin therapy, which are more responsive to ABL501. This study supports the clinical evaluation of ABL501 as a novel cancer immunotherapeutic, and a first-in-human trial has started (NCT05101109).


Subject(s)
Antibodies, Bispecific , Antigens, CD , B7-H1 Antigen , Neoplasms , Animals , Antibodies, Bispecific/pharmacology , Antibodies, Bispecific/therapeutic use , B7-H1 Antigen/metabolism , CD8-Positive T-Lymphocytes , Dendritic Cells , Mice , Neoplasms/drug therapy , Programmed Cell Death 1 Receptor , Tumor Escape , Lymphocyte Activation Gene 3 Protein
3.
J Immunother Cancer ; 9(7)2021 07.
Article in English | MEDLINE | ID: mdl-34230109

ABSTRACT

BACKGROUND: Stimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or for overcoming resistance to ICIs. However, dose-dependent hepatotoxicity was observed in clinical trials with monoclonal anti-4-1BB agonistic antibodies due to the activation of 4-1BB signaling in liver resident Kupffer cells. METHODS: To avoid this on-target liver toxicity, we developed a novel bispecific antibody (4-1BB×PD-L1 bispecific antibody, termed "ABL503") uniquely designed to activate 4-1BB signaling only in the context of PD-L1, while also blocking PD-1/PD-L1 signaling. RESULTS: Functional evaluation using effector cells expressing both 4-1BB and PD-1 revealed superior biological activity of ABL503 compared with the combination of each monoclonal antibody. ABL503 also augmented T-cell activation in in vitro assays and further enhanced the anti-PD-L1-mediated reinvigoration of tumor-infiltrating CD8+ T cells from patients with cancer. Furthermore, in humanized PD-L1/4-1BB transgenic mice challenged with huPD-L1-expressing tumor cells, ABL503 induced superior anti-tumor activity and maintained an anti-tumor response against tumor rechallenge. ABL503 was well tolerated, with normal liver function in monkeys. CONCLUSION: The novel anti-4-1BB×PD-L1 bispecific antibody may exert a strong anti-tumor therapeutic efficacy with a low risk of liver toxicity through the restriction of 4-1BB stimulation in tumors.


Subject(s)
Antibodies, Bispecific/therapeutic use , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy/methods , Neoplasms/drug therapy , Animals , Antibodies, Bispecific/pharmacology , Humans , Immune Checkpoint Inhibitors/pharmacology , Male , Mice
4.
Toxicol Res ; 37(1): 71-83, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33489859

ABSTRACT

The purpose of this study is to explore the effects of Diplectria barbata (Wall. Ex C.B. Clarke) Franken & Roons (DFR) on wound healing, antioxidant and aging in Normal Human Dermal Fibroblast cell (NHDF) cells and mouse skin models. We investigated the effects of the aging process in vitro and in vivo. DFRtreated NHDF cells showed a concentration-dependent increase in the expression of extracellular matrix (ECM) proteins (Collagen-2.5-fold increase at 50 µg/ml, Elastin-1.5-fold increase at 1µg/ml) as well as an increase in proteins related to cell survival, differentiation, and development, while expression of aging proteins such as matrix metalloproteinase 3 (MMP-3) was decreased (5-fold decrease at 50 µg/ml). DFR treatment also led to enhanced expression of antioxidant proteins such as nuclear factor erythroid 2-related factor 2 (10-fold increase at 50 µg/ml) and heme oxygenase 1 (1.5-fold increase at 25 µg/ml). To further investigate the antioxidative effects of DFR extracts, the 2,2-diphenyl-1-picrylhydrazyl radical scavenging activities were also evaluated. DFR extracts improved wound healing and resulted in increased expression of ECM proteins, while enzymes involved in collagen degradation, including MMP-3, were decreased in NHDF cells as well as in a mouse model. This study demonstrates the anti-aging, antioxidant, and wound healing properties of DFR extracts. Therefore, DFR extracts present may facilitate skin protection and care.

5.
Biochem Biophys Res Commun ; 528(3): 478-484, 2020 07 30.
Article in English | MEDLINE | ID: mdl-32507602

ABSTRACT

BACKGROUND: Cell division is regulated by protein kinase B (PKB)-mediated FCH domain only 1 (FCHO1) phosphorylation. METHODS: FCHO1560-571, a synthetic water-soluble peptide, was generated from the PKB substrate motif 560PPRRLRSRKVSC571 found in the human FCHO1 protein. RESULTS: In this study, we found that in vitro FCHO1560-571 inhibits cell proliferation via PKB/ERK/SMAD4 pathways in KRAS-mutated A549 lung cancer cells. In addition, FCHO1560-571, at effective doses of 15 and 30 mg/kg, significantly suppressed tumor growth and decreased the size and weight of tumors in A549-xenograft mice. CONCLUSION: These results suggest that the FCHO1560-571 peptide could be a potential therapy for lung cancer.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Membrane Proteins/pharmacology , A549 Cells , Amino Acid Motifs , Amino Acid Sequence , Animals , CDC2 Protein Kinase/antagonists & inhibitors , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Proliferation/drug effects , Disease Progression , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Male , Membrane Proteins/chemistry , Membrane Proteins/genetics , Mice , Mice, Inbred BALB C , Mice, Nude , Peptide Fragments/chemistry , Peptide Fragments/genetics , Peptide Fragments/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , Smad4 Protein/metabolism , Substrate Specificity , Xenograft Model Antitumor Assays
6.
Cell Death Differ ; 27(12): 3321-3336, 2020 12.
Article in English | MEDLINE | ID: mdl-32555448

ABSTRACT

The development of skeletal muscle requires progression of a highly ordered cascade of events comprising myogenic lineage commitment, myoblast proliferation, and terminal differentiation. The process of myogenesis is controlled by several myogenic transcription factors that act as terminal effectors of signaling cascades and produce appropriate developmental stage-specific transcripts. PHD finger protein 20 (PHF20) is a multidomain protein and subunit of a lysine acetyltransferase complex that acetylates histone H4 and p53, but its function is unclear. Notably, it has been reported that PHF20 knockout mice die shortly after birth and display a wide variety of phenotypes within the skeletal and hematopoietic systems. Therefore, the putative role of PHF20 in myogenic differentiation was further investigated. In the present study, we found that protein and mRNA expression levels of PHF20 were decreased during myogenic differentiation in C2C12 cells. At the same time, Yin Yang 1 (YY1) was also decreased during myogenic differentiation. PHF20 overexpression increased YY1 expression during myogenic differentiation, together with a delay in MyoD expression. PHF20 expression enhanced the transcriptional activity of YY1 while shRNA-mediated depletion of PHF20 resulted in the reduction of YY1 promoter activity in C2C12 cells. In addition, PHF20 directly bounds to the YY1 promoter in C2C12 cells. In a similar manner, YY1 expression was elevated while myosin heavy chain expression was decreased in PHF20 transgenic (TG) mice. Histological analysis revealed abnormalities in the shape and length of muscles in PHF20-TG mice. Furthermore, PHF20-TG muscles slowly regenerated after cardiotoxin injection, indicating that PHF20 affected muscle differentiation and regeneration after injury in vivo. Taken together, these results suggested that PHF20 plays an important role in myogenic differentiation by regulating YY1.


Subject(s)
Cell Differentiation/genetics , DNA-Binding Proteins/metabolism , Muscle Development/genetics , Transcription Factors/metabolism , YY1 Transcription Factor/metabolism , Animals , Cell Line , DNA-Binding Proteins/genetics , Histones/metabolism , Male , Mice , Mice, Inbred C57BL , Promoter Regions, Genetic , Regeneration , Transcription Factors/genetics , YY1 Transcription Factor/genetics
7.
Toxicol Res ; 36(2): 123-130, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32257924

ABSTRACT

Lung cancer is the most common cause of cancer-associated death worldwide. Most patients with non-small cell lung cancer die within several years of the initial diagnosis, and new therapies are desperately needed. Transmembrane protein (TMEM) 39AS41, a synthetic peptide, was generated from the protein kinase B substrate motif 34GLRNRNGSAIGLPVP48 found in the human TMEM39A protein. Myristic acid was conjugated to the N-terminus of the peptide to confer cell permeability. In this study, we found that in vitro TMEM39AS41 peptide led to cell death via inhibition of inflammation/autophagy pathways in KRAS-mutated cell and tissues. In addition, TMEM39A, at a dose of 30 mg/kg, significantly suppressed tumor growth in KRASLA1 non-small cell lung cancer mice. These results suggest that the TMEM39AS41 peptide could have therapeutic potential for lung cancer.

8.
Toxicol Res ; 35(4): 361-369, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31636847

ABSTRACT

1,2-Dichloropropane (1,2-DCP) has been used as an industrial solvent and a chemical intermediate, as well as in soil fumigants. Human exposure may occur during its production and industrial use. The target organs of 1,2-DCP are the eyes, respiratory system, liver, kidneys, central nervous system, and skin. Repeated or prolonged contact may cause skin sensitization. In this study, 1,2-DCP was dissolved in corn oil at 0, 2.73, 5.75, and 8.75 mL/kg. The skin of mice treated with 1,2-DCP was investigated using western blotting, hematoxylin and eosin staining, and immunohistochemistry. 1,2-DCP was applied to the dorsal skin and both ears of C57BL/6J mice. The thickness of ears and the epidermis increased significantly following treatment, and the appearance of blood vessels was observed in the dorsal skin. Additionally, the expression of vascular endothelial growth factor, which is tightly associated with neovascularization, increased significantly. The levels of protein kinase-B (PKB), phosphorylated PKB, mammalian target of rapamycin (mTOR), and phosphorylated mTOR, all of which are key components of the phosphoinositide 3-kinase/PKB/mTOR signaling pathway, were also enhanced. Taken together, 1,2-DCP induced angiogenesis in dermatitis through the PI3K/PKB/mTOR pathway in the skin.

9.
J Ginseng Res ; 43(3): 431-441, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31308815

ABSTRACT

BACKGROUND: The efficacy of ginseng, the representative product of Korea, and its chemical effects have been well investigated. The ginsenoside RG3 has been reported to exhibit apoptotic, anticancer, and antidepressant-like effects. METHODS: In this report, the putative effect of RG3 on several cellular function including cell survival, differentiation, development and aging process were evaluated by monitoring each specific marker. Also, mitochondrial morphology and function were investigated in ultraviolet (UV)-irradiated normal human dermal fibroblast cells. RESULTS: RG3 treatment increased the expression of extracellular matrix proteins, growth-associated immediate-early genes, and cell proliferation genes in UV-irradiated normal human dermal fibroblast cells. And, RG3 also resulted in enhanced expression of antioxidant proteins such as nuclear factor erythroid 2-related factor-2 and heme oxygenase-1. In addition, RG3 affects the morphology of UV-induced mitochondria and plays a role in protecting mitochondrial dysfunction. CONCLUSIOIN: RG3 restores mitochondrial adenosine triphosphate (ATP) and membrane potential via its antioxidant effects in skin cells damaged by UV irradiation, leading to an increase in proteins linked with the extracellular matrix, cell proliferation, and antioxidant activity.

10.
Cell Signal ; 48: 13-24, 2018 Aug.
Article in English | MEDLINE | ID: mdl-29673648

ABSTRACT

Mitochondrial morphology, which is associated with changes in metabolism, cell cycle, cell development and cell death, is tightly regulated by the balance between fusion and fission. In this study, we found that S6 kinase 1 (S6K1) contributes to mitochondrial dynamics, homeostasis and function. Mouse embryo fibroblasts lacking S6K1 (S6K1-KO MEFs) exhibited more fragmented mitochondria and a higher level of Dynamin related protein 1 (Drp1) and active Drp1 (pS616) in both whole cell extracts and mitochondrial fraction. In addition, there was no evidence for autophagy and mitophagy induction in S6K1 depleted cells. Glycolysis and mitochondrial respiratory activity was higher in S6K1-KO MEFs, whereas OxPhos ATP production was not altered. However, inhibition of Drp1 by Mdivi1 (Drp1 inhibitor) resulted in higher OxPhos ATP production and lower mitochondrial membrane potential. Taken together the depletion of S6K1 increased Drp1-mediated fission, leading to the enhancement of glycolysis. The fission form of mitochondria resulted in lower yield for OxPhos ATP production as well as in higher mitochondrial membrane potential. Thus, these results have suggested a potential role of S6K1 in energy metabolism by modulating mitochondrial respiratory capacity and mitochondrial morphology.


Subject(s)
Energy Metabolism/physiology , Mitochondria/metabolism , Mitochondrial Dynamics/physiology , Mitophagy/physiology , Ribosomal Protein S6 Kinases, 90-kDa/physiology , Animals , Autophagy , Dynamins/antagonists & inhibitors , Dynamins/metabolism , Embryo, Mammalian , Fibroblasts , Gene Knockout Techniques , Glycolysis , Homeostasis , Membrane Potential, Mitochondrial , Mice , Ribosomal Protein S6 Kinases, 90-kDa/genetics
11.
Mol Med Rep ; 17(3): 4540-4546, 2018 03.
Article in English | MEDLINE | ID: mdl-29363730

ABSTRACT

TRIO and F-actin-binding protein (TrioBP), which was initially discovered as a binding partner of Trio and F­actin, is a critical factor associated with hearing loss in humans. However, the function of TrioBP in cancer has not been investigated. In the present study, TrioBP expression was indicated to be highly elevated in U87­MG and U343­MG cells. Furthermore, the TrioBP mRNA expression level was markedly increased in U87­MG and U251­MG cells compared with that in cerebral cortex cells, as determined by deep sequencing. Comprehensive analysis of a public TCGA dataset confirmed that TrioBP expression is elevated in patients with glioblastoma. In summary, the present data indicate that TrioBP expression is increased in glioblastoma cell lines and in patients with glioma, suggesting that TrioBP has potential as a diagnostic marker or therapeutic agent for glioma.


Subject(s)
Brain Neoplasms/pathology , Carrier Proteins/metabolism , Glioblastoma/pathology , Guanine Nucleotide Exchange Factors/metabolism , Microfilament Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Brain Neoplasms/metabolism , Carrier Proteins/genetics , Cell Line, Tumor , Cell Movement , Cell Proliferation , Glioblastoma/metabolism , Guanine Nucleotide Exchange Factors/antagonists & inhibitors , Guanine Nucleotide Exchange Factors/genetics , High-Throughput Nucleotide Sequencing , Humans , Immunohistochemistry , Microfilament Proteins/genetics , Microscopy, Confocal , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , RNA Interference , RNA, Small Interfering/metabolism , Sequence Analysis, RNA , Up-Regulation
12.
Biochem Biophys Res Commun ; 495(1): 594-600, 2018 01 01.
Article in English | MEDLINE | ID: mdl-29128360

ABSTRACT

Autophagy is a biological recycling process via the self-digestion of organelles, proteins, and lipids for energy-consuming differentiation and homeostasis. The Golgi serves as a donor of the double-membraned phagophore for autophagosome assembly. In addition, recent studies have demonstrated that pulmonary and hepatic fibrosis is accompanied by autophagy. However, the relationships among Golgi function, autophagy, and fibrosis are unclear. Here, we show that the deletion of GOLGA2, encoding a cis-Golgi protein, induces autophagy with Golgi disruption. The induction of autophagy leads to fibrosis along with the reduction of subcellular lipid storage (lipid droplets and lamellar bodies) by autophagy in the lung and liver. GOLGA2 knockout mice clearly demonstrated fibrosis features such as autophagy-activated cells, densely packed hepatocytes, increase of alveolar macrophages, and decrease of alveolar surfactant lipids (dipalmitoylphosphatidylcholine). Therefore, we confirmed the associations among Golgi function, fibrosis, and autophagy. Moreover, GOLGA2 knockout mice may be a potentially valuable animal model for studying autophagy-induced fibrosis.


Subject(s)
Autoantigens/metabolism , Autophagy , Liver Cirrhosis/metabolism , Liver/metabolism , Lung/metabolism , Membrane Proteins/metabolism , Pulmonary Fibrosis/metabolism , Animals , Lipid Droplets/metabolism , Liver/pathology , Liver Cirrhosis/pathology , Lung/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pulmonary Fibrosis/pathology
13.
Toxicol Res ; 33(3): 205-209, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28744351

ABSTRACT

Transmembrane Protein 39A (TMEM39A) is a member of TMEM family. The understanding about this protein is still limited. The earlier studies indicated that TMEM39A was a key mediator of autoimmune disease. TMEM39A seems to be involved in systemic lupus erythematosus and multiple sclerosis in numerous of populations. All of these works stop at insufficient information by using gene functioning methods such as: Genome-wide association studies (GWASs) and/or follow-up study. It is the fact that the less understood of TMEM39A actually is the attraction to the scientist in near future. In this review the current knowledge about TMEM39A and its possible roles in cell biology, physiology and pathology will be described.

14.
Mol Med Rep ; 15(6): 3781-3786, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28440425

ABSTRACT

Mitochondrial transcription factor A (TFAM), which was initially discovered as a transcription factor for mitochondrial DNA, has known to be critical for the regulation of mitochondrial DNA. However the possible involvement of TFAM in cancer is largely unknown. In this study, we have provided some evidence that TFAM may have a potential role in brain tumor. Western blot analysis with anti­TFAM antibody indicated that TFAM is overexpressed in glioblastoma cell lines including U87MG and U251MG. Transcriptome profiling of U87MG and U251MG cells by using deep­sequencing revealed that TFAM transcripts were upregulated in these cells compared to its of cerebral cortex. Confocal microscopic analysis of U251MG cells with anti­TFAM antibody showed that TFAM is located to the dot­like structure close to nucleus, probably mitochondria and endosome. Immunohistochemical analysis of glioma tissue specimens indicated that TFAM is highly upregulated. Bioinformatical analysis with Rembrandt knowledgebase also supported that TFAM mRNA is upregulated in glioma patients. Taken together, the results presented in this study obviously provided the evidence that TFAM was upregulated in glioma cell line and glioma tissue specimens. Therefore TFAM may be a novel diagnostic marker and therapeutic target for glioma and other cancer.


Subject(s)
DNA-Binding Proteins/genetics , Gene Expression Regulation, Neoplastic , Glioma/genetics , Mitochondrial Proteins/genetics , Transcription Factors/genetics , Cell Line, Tumor , DNA-Binding Proteins/metabolism , Glioma/diagnosis , Glioma/metabolism , Humans , Mitochondrial Proteins/metabolism , Prognosis , Protein Transport , RNA, Messenger/genetics , Transcription Factors/metabolism , Up-Regulation
15.
Toxicol Res ; 33(1): 63-69, 2017 Jan.
Article in English | MEDLINE | ID: mdl-28133515

ABSTRACT

Transmembrane protein 39A (TMEM39A) belongs to the TMEM39 family. TMEM39A gene is a susceptibility locus for multiple sclerosis. In addition, TMEM39A seems to be implicated in systemic lupus erythematosus. However, any possible involvement of TMEM39A in cancer remains largely unknown. In the present report, we provide evidence that TMEM39A may play a role in brain tumors. Western blotting using an anti-TMEM39A antibody indicated that TMEM39A was overexpressed in glioblastoma cell lines, including U87-MG and U251-MG. Deep-sequencing transcriptomic profiling of U87-MG and U251-MG cells revealed that TMEM39A transcripts were upregulated in such cells compared with those of the cerebral cortex. Confocal microscopic analysis of U251-MG cells stained with anti-TMEM39A antibody showed that TMEM39A was located in dot-like structures lying close to the nucleus. TMEM39A probably located to mitochondria or to endosomes. Immunohistochemical analysis of glioma tissue specimens indicated that TMEM39A was markedly upregulated in such samples. Bioinformatic analysis of the Rembrandt knowledge base also supported upregulation of TMEM39A mRNA levels in glioma patients. Together, the results afford strong evidence that TMEM39A is upregulated in glioma cell lines and glioma tissue specimens. Therefore, TMEM39A may serve as a novel diagnostic marker of, and a therapeutic target for, gliomas and other cancers.

16.
Clin Interv Aging ; 11: 1017-26, 2016.
Article in English | MEDLINE | ID: mdl-27536082

ABSTRACT

BACKGROUND: Aging of skin is associated with environmental factors such as ultraviolet rays, air pollution, gravity, and genetic factors, all of which can lead to wrinkling of skin. Previous reports suggest that the wound repair is impaired by the aging process and strategies to manipulate the age-related wound healing are necessary in order to stimulate repair. OBJECTIVE: Several traditional plant extracts are well-known for their properties of skin protection and care. Piper cambodianum P. Fourn. (PPF), a member of Piperacecae, is a plant found in Vietnam that might have therapeutic properties. Therefore, the effects of PPF stem and leaf extract on aging process were investigated in vitro and in vivo. METHODS: PPF extract dissolved in methanol was investigated using Western blotting, real-time quantitative reverse transcription-polymerase chain reaction, flow cytometry, and cell wound-healing assays. We assessed the anti-aging effect of PPF in mouse using the wound-healing assay. The results were analyzed by Student's unpaired t-test; *P<0.05 and **P<0.01 were considered to indicate significant and highly significant values, respectively, compared with corresponding controls. RESULTS: PPF treatment demonstrated in vitro and in vivo anti-aging activity. Western blot analysis of PPF-treated normal human dermal fibroblast cells showed a dose-dependent increase in the expression of extracellular matrix genes such as collagen and elastin, but decreased expression of the aging gene matrix metalloproteinase-3. Quantitative polymerase chain reaction showed that PPF-treated cells displayed dose-dependent increase in messenger RNA expression levels of collagen, elastin, and hyaluronan synthase-2 and decreased expression levels of matrix metalloproteinase-1 aging gene. PPF treatment led to decreased production of reactive oxygen species in cells subjected to ultraviolet irradiation. Furthermore, PPF extract showed positive wound-healing effects in mice. CONCLUSION: This study demonstrated the anti-aging and wound-healing effects of PPF extract. Therefore, PPF extract represents a promising new therapeutic agent for anti-aging and wound-healing treatments.


Subject(s)
Antioxidants/pharmacology , Fibroblasts/drug effects , Piper/chemistry , Plant Extracts/pharmacology , Skin Aging/drug effects , Wound Healing/drug effects , Animals , Cell Proliferation/drug effects , Cells, Cultured , Collagen/genetics , Elastin/genetics , Extracellular Matrix/drug effects , Humans , Matrix Metalloproteinase 1/genetics , Matrix Metalloproteinase 3/genetics , Mice , Reactive Oxygen Species/metabolism
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