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  • MDPI AG  (24)
  • Pharmacy  (24)
  • 1
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    Online Resource
    Combined Treatment of Heteronemin and Tetrac Induces Antiproliferation in Oral Cancer Cells
    MDPI AG ; 2020
    In:  Marine Drugs Vol. 18, No. 7 ( 2020-07-02), p. 348-
    Details
    In: Marine Drugs, MDPI AG, Vol. 18, No. 7 ( 2020-07-02), p. 348-
    Abstract: Background: Heteronemin, a marine sesterterpenoid-type natural product, possesses an antiproliferative effect in cancer cells. In addition, heteronemin has been shown to inhibit p53 expression. Our laboratory has demonstrated that the thyroid hormone deaminated analogue, tetrac, activates p53 and induces antiproliferation in colorectal cancer. However, such drug mechanisms are still to be studied in oral cancer cells. Methods: We investigated the antiproliferative effects by Cell Counting Kit-8 and flow cytometry. The signal transduction pathway was measured by Western blotting analyses. Quantitative PCR was used to evaluate gene expression regulated by heteronemin, 3,3’,5,5’-tetraiodothyroacetic acid (tetrac), or their combined treatment in oral cancer cells. Results: Heteronemin inhibited not only expression of proliferative genes and Homo Sapiens Thrombospondin 1 (THBS-1) but also cell proliferation in both OEC-M1 and SCC-25 cells. Remarkably, heteronemin increased TGF-β1 expression in SCC-25 cells. Tetrac suppressed expression of THBS-1 but not p53 expression in both cancer cell lines. Furthermore, the synergistic effect of tetrac and heteronemin inhibited ERK1/2 activation and heteronemin also blocked STAT3 signaling. Combined treatment increased p53 protein and p53 activation accumulation although heteronemin inhibited p53 expression in both cancer cell lines. The combined treatment induced antiproliferation synergistically more than a single agent. Conclusions: Both heteronemin and tetrac inhibited ERK1/2 activation and increased p53 phosphorylation. They also inhibited THBS-1 expression. Moreover, tetrac suppressed TGF-β expression combined with heteronemin to further enhance antiproliferation and anti-metastasis in oral cancer cells.
    Type of Medium: Online Resource
    ISSN: 1660-3397
    URL: Article
    DOI: 10.3390/md18070348
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2175190-0
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  • 2
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    Administration of mRNA-Nanomedicine-Augmented Calvarial Defect Healing via Endochondral Ossification
    MDPI AG ; 2023
    In:  Pharmaceutics Vol. 15, No. 7 ( 2023-07-17), p. 1965-
    Details
    In: Pharmaceutics, MDPI AG, Vol. 15, No. 7 ( 2023-07-17), p. 1965-
    Abstract: Large-area craniofacial defects remain a challenge for orthopaedists, hastening the need to develop a facile and safe tissue engineering strategy; osteoconductive material and a combination of optimal growth factors and microenvironment should be considered. Faced with the unmet need, we propose that abundant cytokines and chemokines can be secreted from the bone defect, provoking the infiltration of endogenous stem cells to assist bone regeneration. We can provide a potent mRNA medicine cocktail to promptly initiate the formation of bone templates, osteogenesis, and subsequent bone matrix deposition via endochondral ossification, which may retard rapid fibroblast infiltration and prevent the formation of atrophic non-union. We explored the mutual interaction of BMP2 and TGFβ3 mRNA, both potent chondrogenic factors, on inducing endochondral ossification; examined the influence of in vitro the transcribed polyA tail length on mRNA stability; prepared mRNA nanomedicine using a PEGylated polyaspartamide block copolymer loaded in a gelatin sponge and grafted in a critical-sized calvarial defect; and evaluated bone regeneration using histological and μCT examination. The BMP2 and TGFβ3 composite mRNA nanomedicine resulted in over 10-fold new bone volume (BV) regeneration in 8 weeks than the BMP2 mRNA nanomedicine administration alone, demonstrating that the TGFβ3 mRNA nanomedicine synergistically enhances the bone’s formation capability, which is induced by BMP2 mRNA nanomedicine. Our data demonstrated that mRNA-medicine-mediated endochondral ossification provides an alternative cell-free tissue engineering methodology for guiding craniofacial defect healing.
    Type of Medium: Online Resource
    ISSN: 1999-4923
    URL: Article
    DOI: 10.3390/pharmaceutics15071965
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2527217-2
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  • 3
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    The Potential Application of Spring Sargassum glaucescens Extracts in the Moisture-Retention of Keratinocytes and Dermal Fibroblast Regeneration after UVA-Irradiation
    MDPI AG ; 2019
    In:  Cosmetics Vol. 6, No. 1 ( 2019-03-04), p. 17-
    Details
    In: Cosmetics, MDPI AG, Vol. 6, No. 1 ( 2019-03-04), p. 17-
    Abstract: Sargassum glaucescens is a marine brown alga with high antioxidant activity. To evaluate the potential application of Sargassum glaucescens extracts (SGE) in skincare, we performed in vitro assays in dermal fibroblasts and epidermal keratinocytes. The antioxidant activity of SGE was confirmed by the suppression of H2O2-induced reactive oxygen species (ROS) production in dermal fibroblasts and in vitro 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity. In the wound healing assay, application of 2 mg/ml SGE stimulated the wound closure of CCD-966SK fibroblasts by a 2.95-fold in comparison to the control. Furthermore, treatment with SGE of concentrations ranging from 0.25 to 1 mg/ml promoted CCD-966SK cell regeneration after UVA irradiation. At the molecular level, 1 mg/ml SGE induced expressions of anti-oxidative genes SOD1 (Superoxide dismutase 1) and GPX1 (Glutathione peroxidase 1), and DNA repair regulatory genes XRCC1 (X-ray repair cross-complementing protein 1) and ERCC6 (Excision repair cross-complementation Group 6) in CCD-966SK cells after UVA irradiation. Therefore, SGE displayed beneficial effects on cell regeneration and the protection of dermal cells against UVA irradiation. In epidermal cells, SGE stimulated the cell proliferation of human primary epidermal keratinocytes. Application of 0.03125 mg/ml SGE induced the expressions of skin barrier-related genes TGM1 (Transglutaminase 1), KRT10 (Keratin 10) and KRT14 in keratinocytes. Meanwhile, SGE induced the gene expression of FLG (Filaggrin), which promoted the production of natural moisturizing factor (NMF) for maintaining the moisture and barrier functions of skin.
    Type of Medium: Online Resource
    ISSN: 2079-9284
    URL: Article
    DOI: 10.3390/cosmetics6010017
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2720868-0
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  • 4
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    New 8-Hydroxybriaranes from the Gorgonian Coral Junceella fragilis (Ellisellidae)
    MDPI AG ; 2019
    In:  Marine Drugs Vol. 17, No. 9 ( 2019-09-14), p. 534-
    Details
    In: Marine Drugs, MDPI AG, Vol. 17, No. 9 ( 2019-09-14), p. 534-
    Abstract: Three new 8-hydroxybriaranes—fragilides R–T (1–3) were obtained from a sea whip gorgonian coral Junceella fragilis. The structures of briaranes 1–3 were elucidated by using spectroscopic methods, including 1D (1H and 13C NMR), 2D (COSY, HSQC, HMBC, and NOESY experiments) NMR studies, and (+)-HRESIMS. Fragilides S and T (2 and 3) are the only briaranes known to possess 8α-hydroxy and 17β-methyl groups, respectively. Briarane 2 exerted an inhibition effect on iNOS release from RAW264.7; a macrophage cell line that originated from a mouse monocyte macrophage, stimulated with lipopolysaccharides.
    Type of Medium: Online Resource
    ISSN: 1660-3397
    URL: Article
    DOI: 10.3390/md17090534
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2175190-0
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  • 5
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    Online Resource
    Real-World Comparative Effectiveness of Nivolumab versus Pembrolizumab in Patients with Unresectable Hepatocellular Carcinoma
    MDPI AG ; 2022
    In:  Pharmaceutics Vol. 14, No. 11 ( 2022-10-23), p. 2263-
    Details
    In: Pharmaceutics, MDPI AG, Vol. 14, No. 11 ( 2022-10-23), p. 2263-
    Abstract: Purpose: Immune checkpoint inhibitors are effective therapies for advanced hepatocellular carcinoma (HCC); however, comparisons of the clinical efficacy and safety profile for these drugs are still scarce. Thus, the aims of this study were to investigate the differences in efficacy and safety between nivolumab and pembrolizumab in unresectable HCC patients in a real-world setting. Patients and methods: A total of 115 patients who received treatment with nivolumab (n = 73) or pembrolizumab (n = 42) in combination with or without tyrosine kinase inhibitors was enrolled. Therapeutic response, survival outcomes, and safety profiles were compared among these groups. Multivariate analysis of survival response was performed using Cox proportional hazards regression. Results: Patients treated with pembrolizumab demonstrated a significantly higher objective response rate than those with nivolumab (38.1% vs. 15.1%; odds ratio 4.18, p = 0.005) regardless of the combination strategies. In addition, pembrolizumab performed a better overall survival (OS) than nivolumab, (34.9 vs. 9.5 months; hazard ratio (HR) = 0.39, p = 0.004). In subgroup analysis, pembrolizumab exhibited favorable OS than nivolumab for monotherapy (HR = 0.16, p = 0.001) or combination therapy (HR = 0.33, p = 0.006) as second-line or later-line (HR = 0.19, p = 0.001) therapy and those with (HR = 0.31, p = 0.006) or without (HR = 0.15, p = 0.004) well-compensated liver disease. The incidence of adverse events was comparable for both treatments. Conclusion: Both pembrolizumab and nivolumab had significant effects for HCC therapy, and pembrolizumab had a significant survival benefit as compared with nivolumab.
    Type of Medium: Online Resource
    ISSN: 1999-4923
    URL: Article
    DOI: 10.3390/pharmaceutics14112263
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527217-2
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  • 6
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    A Novel ALDH2 Activator AD-9308 Improves Diastolic and Systolic Myocardial Functions in Streptozotocin-Induced Diabetic Mice
    MDPI AG ; 2021
    In:  Antioxidants Vol. 10, No. 3 ( 2021-03-13), p. 450-
    Details
    In: Antioxidants, MDPI AG, Vol. 10, No. 3 ( 2021-03-13), p. 450-
    Abstract: Diabetes mellitus has reached epidemic proportion worldwide. One of the diabetic complications is cardiomyopathy, characterized by early left ventricular (LV) diastolic dysfunction, followed by development of systolic dysfunction and ventricular dilation at a late stage. The pathogenesis is multifactorial, and there is no effective treatment yet. In recent years, 4-hydroxy-2-nonenal (4-HNE), a toxic aldehyde generated from lipid peroxidation, is implicated in the pathogenesis of cardiovascular diseases. Its high bioreactivity toward proteins results in cellular damage. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is the major enzyme that detoxifies 4-HNE. The development of small-molecule ALDH2 activator provides an opportunity for treating diabetic cardiomyopathy. This study found that AD-9308, a water-soluble andhighly selective ALDH2 activator, can improve LV diastolic and systolic functions, and wall remodeling in streptozotocin-induced diabetic mice. AD-9308 treatment dose-dependently lowered serum 4-HNE levels and 4-HNE protein adducts in cardiac tissue from diabetic mice, accompanied with ameliorated myocardial fibrosis, inflammation, and apoptosis. Improvements of mitochondrial functions, sarco/endoplasmic reticulumcalcium handling and autophagy regulation were also observed in diabetic mice with AD-9308 treatment. In conclusion, ADLH2 activation effectively ameliorated diabetic cardiomyopathy, which may be mediated through detoxification of 4-HNE. Our findings highlighted the therapeutic potential of ALDH2 activation for treating diabetic cardiomyopathy.
    Type of Medium: Online Resource
    ISSN: 2076-3921
    URL: Article
    DOI: 10.3390/antiox10030450
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2704216-9
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  • 7
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    New 1,4-Dienonesteroids from the Octocoral Dendronephthya sp.
    MDPI AG ; 2019
    In:  Marine Drugs Vol. 17, No. 9 ( 2019-09-11), p. 530-
    Details
    In: Marine Drugs, MDPI AG, Vol. 17, No. 9 ( 2019-09-11), p. 530-
    Abstract: Two new steroids, dendronesterones D (1) and E (2), featuring with 1,4-dienone moiety, along with three known steroids, methyl 3-oxochola-4,22-diene-24-oate (3), 5α,8α-epidioxy-24(S)- methylcholesta-6,22-dien-3β-ol (4), and 5α,8α-epidioxy-24(S)-methylcholesta-6,9(11),22-trien-3β-ol (5), were isolated from an octocoral Dendronephthya sp. The structures of steroids 1 and 2 were elucidated by using spectroscopic methods and steroid 1 was found to exhibit significant in vitro anti-inflammatory activity in lipopolysaccharides (LPS)-induced RAW264.7 macrophage cells by inhibiting the expression of the iNOS protein.
    Type of Medium: Online Resource
    ISSN: 1660-3397
    URL: Article
    DOI: 10.3390/md17090530
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
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  • 8
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    Predicting Anticancer Drug Resistance Mediated by Mutations
    MDPI AG ; 2022
    In:  Pharmaceuticals Vol. 15, No. 2 ( 2022-01-24), p. 136-
    Details
    In: Pharmaceuticals, MDPI AG, Vol. 15, No. 2 ( 2022-01-24), p. 136-
    Abstract: Cancer drug resistance presents a challenge for precision medicine. Drug-resistant mutations are always emerging. In this study, we explored the relationship between drug-resistant mutations and drug resistance from the perspective of protein structure. By combining data from previously identified drug-resistant mutations and information of protein structure and function, we used machine learning-based methods to build models to predict cancer drug resistance mutations. The performance of our combined model achieved an accuracy of 86%, a Matthews correlation coefficient score of 0.57, and an F1 score of 0.66. We have constructed a fast, reliable method that predicts and investigates cancer drug resistance in a protein structure. Nonetheless, more information is needed concerning drug resistance and, in particular, clarification is needed about the relationships between the drug and the drug resistance mutations in proteins. Highly accurate predictions regarding drug resistance mutations can be helpful for developing new strategies with personalized cancer treatments. Our novel concept, which combines protein structure information, has the potential to elucidate physiological mechanisms of cancer drug resistance.
    Type of Medium: Online Resource
    ISSN: 1424-8247
    URL: Article
    DOI: 10.3390/ph15020136
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2193542-7
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  • 9
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    Resveratrol Protects against Cerebral Ischemic Injury via Restraining Lipid Peroxidation, Transition Elements, and Toxic Metal Levels, but Enhancing Anti-Oxidant Activity
    MDPI AG ; 2021
    In:  Antioxidants Vol. 10, No. 10 ( 2021-09-24), p. 1515-
    Details
    In: Antioxidants, MDPI AG, Vol. 10, No. 10 ( 2021-09-24), p. 1515-
    Abstract: Cerebral ischemia is related to increased oxidative stress. Resveratrol displays anti-oxidant and anti-inflammatory properties. The transition elements iron (Fe) and copper (Cu) are indispensable for the brain but overload is deleterious to brain function. Aluminum (Al) and arsenic (As) are toxic metals that seriously threaten brain health. This study was conducted to elucidate the correlation of the neuroprotective mechanism of resveratrol to protect cerebral ischemic damage with modulation of the levels of lipid peroxidation, anti-oxidants, transition elements, and toxic metals. Experimentally, 20 mg/kg of resveratrol was given once daily for 10 days. The cerebral ischemic operation was performed via occlusion of the right common carotid artery together with the right middle cerebral artery for 60 min followed by homogenization of the brain cortex and collection of supernatants for biochemical analysis. In the ligation group, levels of malondialdehyde, Fe, Cu, Al, and As increased but those of the anti-oxidants superoxide dismutase and catalase decreased. Pretreating rats with resveratrol before ischemia significantly reversed these effects. Our findings highlight the association of overload of Fe, Cu, As, and Al with the pathophysiology of cerebral ischemia. In conclusion, resveratrol protects against cerebral ischemic injury via restraining lipid peroxidation, transition elements, and toxic metals, but increasing anti-oxidant activity.
    Type of Medium: Online Resource
    ISSN: 2076-3921
    URL: Article
    DOI: 10.3390/antiox10101515
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2704216-9
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  • 10
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    13-Acetoxysarcocrassolide Exhibits Cytotoxic Activity against Oral Cancer Cells through the Interruption of the Keap1/Nrf2/p62/SQSTM1 Pathway: The Need to Move Beyond Classical Concepts
    MDPI AG ; 2020
    In:  Marine Drugs Vol. 18, No. 8 ( 2020-07-23), p. 382-
    Details
    In: Marine Drugs, MDPI AG, Vol. 18, No. 8 ( 2020-07-23), p. 382-
    Abstract: 13-Acetoxysarcocrassolide (13-AC), a marine cytotoxic product isolated from the alcyonacean coral Lobophytum crassum, exhibited potent antitumor and immunostimulant effects as reported in previous studies. However, the 13-AC antitumor mechanism of action against oral cancer cells remains unclear. The activity of 13-AC against Ca9-22 cancer cells was determined using MTT assay, flow cytometric analysis, immunofluorescence, immunoprecipitation, Western blotting, and siRNA. 13-AC induced apoptosis in oral cancer cells Ca9-22 through the disruption of mitochondrial membrane potential (MMP) and the stimulation of reactive oxygen species (ROS) generation. It increased the expression of apoptosis- and DNA damage-related proteins in a concentration- and time-dependent manner. It exerted potent antitumor effect against oral cancer cells, as demonstrated by the in vivo xenograft animal model. It significantly reduced the tumor volume (55.29%) and tumor weight (90.33%). The pretreatment of Ca9-22 cells with N-acetylcysteine (NAC) inhibited ROS production resulting in the attenuation of the cytotoxic activity of 13-AC. The induction of the Keap1-Nrf2 pathway and the promotion of p62/SQSTM1 were observed in Ca9-22 cells treated with 13-AC. The knockdown of p62 expression by siRNA transfection significantly attenuated the effect of 13-AC on the inhibition of cell viability. Our results indicate that 13-AC exerted its cytotoxic activity through the promotion of ROS generation and the suppression of the antioxidant enzyme activity. The apoptotic effect of 13-AC was found to be mediated through the interruption of the Keap1/Nrf2/p62/SQSTM1 pathway, suggesting its potential future application as an anticancer agent.
    Type of Medium: Online Resource
    ISSN: 1660-3397
    URL: Article
    DOI: 10.3390/md18080382
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2175190-0
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