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  • MDPI AG  (55)
  • Pharmacy  (55)
  • 11
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    GO-Y078, a Curcumin Analog, Induces Both Apoptotic Pathways in Human Osteosarcoma Cells via Activation of JNK and p38 Signaling
    MDPI AG ; 2021
    In:  Pharmaceuticals Vol. 14, No. 6 ( 2021-05-24), p. 497-
    Details
    In: Pharmaceuticals, MDPI AG, Vol. 14, No. 6 ( 2021-05-24), p. 497-
    Abstract: Osteosarcoma is the most common primary bone malignancy in teenagers and continues to confer a generally poor prognosis due to its highly metastatic potential. Poor solubility in water and instability of curcumin limits its bioavailability for use in the adjuvant situation to improve the prognosis and the long-term survival of patients with osteosarcoma. To further obtain information regarding the apoptosis induced by a new curcumin analog, GO-Y078, in human osteosarcoma cells, flow cytometric analysis, annexin V-FITC/PI apoptosis staining assay, human apoptosis array, and Western blotting were employed. GO-Y078 dose-dependently decreased viabilities of human osteosarcoma U2OS, MG-63, 143B, and Saos-2 cells and induced sub-G1 fraction arrest and apoptosis in U2OS and 143B cells. In addition to the effector caspase 3 and poly adenosine diphosphate-ribose polymerase, GO-Y078 significantly activated both initiators of extrinsic caspase 8 and intrinsic caspase 9, whereas cellular inhibitors of apoptosis 1 (cIAP-1) and X-chromosome-linked IAP (XIAP) in U2OS and 143B cells were significantly repressed. Moreover, GO-Y078 increased phosphorylation of extracellular signal-regulated protein kinases (ERK)1/2, c-Jun N-terminal kinases (JNK)1/2, and p38 in U2OS and 143B cells. Using inhibitors of JNK (JNK-in-8) and p38 (SB203580), GO-Y078′s increases in cleaved caspases 8, 9, and 3 could be expectedly suppressed, but they could not be affected by co-treatment with the ERK inhibitor (U0126). Altogether, GO-Y078 simultaneously induces both apoptotic pathways and cell arrest in U2OS and 143B cells through activating JNK and p38 signaling and repressing IAPs. These findings contribute to a better understanding of the mechanisms responsible for GO-Y078′s apoptotic effects on human osteosarcoma cells.
    Type of Medium: Online Resource
    ISSN: 1424-8247
    URL: Article
    DOI: 10.3390/ph14060497
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 12
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    Fabrication of Injectable Chitosan-Chondroitin Sulfate Hydrogel Embedding Kartogenin-Loaded Microspheres as an Ultrasound-Triggered Drug Delivery System for Cartilage Tissue Engineering
    MDPI AG ; 2021
    In:  Pharmaceutics Vol. 13, No. 9 ( 2021-09-16), p. 1487-
    Details
    In: Pharmaceutics, MDPI AG, Vol. 13, No. 9 ( 2021-09-16), p. 1487-
    Abstract: Ultrasound-responsive microspheres (MPs) derived from natural polysaccharides and injectable hydrogels have been widely investigated as a biocompatible, biodegradable, and controllable drug delivery system and cell scaffolds for tissue engineering. In this study, kartogenin (KGN) loaded poly (lactide-co-glycolic acid) (PLGA) MPs (MPs@KGN) were fabricated by premix membrane emulsification (PME) method which were sonicated by an ultrasound transducer. Furthermore, carboxymethyl chitosan-oxidized chondroitin sulfate (CMC-OCS) hydrogel were prepared via the Schiff’ base reaction-embedded MPs to produce a CMC-OCS/MPs scaffold. In the current work, morphology, mechanical property, porosity determination, swelling property, in vitro degradation, KGN release from scaffolds, cytotoxicity, and cell bioactivity were investigated. The results showed that MPs presented an obvious collapse after ultrasound treatment. The embedded PLGA MPs could enhance the compressive elastic modulus of soft CMC-OCS hydrogel. The cumulative release KGN from MPs exhibited a slow rate which would display an appropriate collapse after ultrasound, allowing KGN to maintain a continuous concentration for at least 28 days. Moreover, the composite CMC-OCS@MPs scaffolds exhibited faster gelation, lower swelling ratio, and lower in vitro degradation. CCK-8 and LIVE/DEAD staining showed these scaffolds did not influence rabbit bone marrow mesenchymal stem cells (rBMMSCs) proliferation. Then these scaffolds were cultured with rBMMSCs for 2 weeks, and the immunofluorescent staining of collagen II (COL-2) showed that CMC-OCS hydrogel embedded with MPs@KGN (CMC-OCS@MPs@KGN) with ultrasound had the ability to increase the COL-2 synthesis. Overall, due to the improved mechanical property and the ability of sustained KGN release, this injectable hydrogel with ultrasound-responsive property is a promising system for cartilage tissue engineering.
    Type of Medium: Online Resource
    ISSN: 1999-4923
    URL: Article
    DOI: 10.3390/pharmaceutics13091487
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527217-2
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  • 13
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    Engineered Exosomes-Based Photothermal Therapy with MRI/CT Imaging Guidance Enhances Anticancer Efficacy through Deep Tumor Nucleus Penetration
    MDPI AG ; 2021
    In:  Pharmaceutics Vol. 13, No. 10 ( 2021-09-30), p. 1593-
    Details
    In: Pharmaceutics, MDPI AG, Vol. 13, No. 10 ( 2021-09-30), p. 1593-
    Abstract: Exosomes, as natural nanovesicles, have become a spotlight in the field of cancer therapy due to their reduced immunogenicity and ability to overcome physiological barriers. However, the tumor targeting ability of exosomes needs to be improved before its actual application. Herein, a multiple targeted engineered exosomes nanoplatform was constructed through rare earth element Gd and Dy-doped and TAT peptide-modified carbon dots (CDs:Gd,Dy-TAT) encapsulated into RGD peptide engineered exosomes (Exo-RGD), which were used to enhance the effect of cancer imaging diagnosis and photothermal therapy. In vitro and in vivo experiments showed that the resulting CDs:Gd,Dy-TAT@Exo-RGD could effectively accumulate at cancer site with an increased concentration owing to the targeting peptides modification and exosomes encapsulation. The tumor therapy effects of mice treated with CDs:Gd,Dy-TAT@Exo-RGD were heightened compared with mice from the CDs:Gd,Dy control group. After intravenous injection of CDs:Gd,Dy-TAT@Exo-RGD into tumor-bearing mice, the temperature of tumors rose to above 50 °C under NIR irradiation and the localized hyperpyrexia induced by CDs could remarkably ablate tumors. The survival rate of the mice was 100% after 60 days. In addition, the CDs:Gd,Dy-TAT@Exo-RGD exhibited higher MRI/CT imaging contrast enhancement of tumor sites than that of CDs:Gd,Dy. Our study identified that engineered exosomes are a powerful tool for encapsulating multiple agents to enhance cancer theranostic efficiency and provide insight into precise personalized nanomedicine.
    Type of Medium: Online Resource
    ISSN: 1999-4923
    URL: Article
    DOI: 10.3390/pharmaceutics13101593
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 14
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    The Experimental Study of Periodontal Ligament Stem Cells Derived Exosomes with Hydrogel Accelerating Bone Regeneration on Alveolar Bone Defect
    MDPI AG ; 2022
    In:  Pharmaceutics Vol. 14, No. 10 ( 2022-10-14), p. 2189-
    Details
    In: Pharmaceutics, MDPI AG, Vol. 14, No. 10 ( 2022-10-14), p. 2189-
    Abstract: Introduction: this study was conducted to investigate the osteogenic ability of periodontal ligament stem cells (PDLSCs) derived exosomes (PDLSCs-Exos) and the effect of PDLSCs-Exos with hydrogel on alveolar bone defect repairment in the rat. Methods: the PDLSCs were obtained through primary cell culture, and PDLSCs-Exos were purified by the ultracentrifugation method. The CCK-8 kit and ALP staining were used to explore the effect of PDLSCs-Exos on promoting the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). In vivo, the alveolar bone defect models were made mesial to the bilateral maxillary first molars of rats. MicroCT, HE staining, and Masson staining were used to analyze the new bone at the bone defect of rats. Results: the periodontal ligament stem cells and the periodontal ligament stem cells derived exosomes were successfully extracted. The results of the CCK-8 kit and ALP staining showed PDLSCs-Exos significantly promoted the proliferation osteogenic differentiation of BMSCs. In vivo experiment results revealed that compared with the control group and the hydrogel group, the rats in the hydrogel with exosomes group showed more new bone formation in alveolar bone defects. Conclusion: Periodontal ligament stem cells and exosomes derived from periodontal ligament stem cells were successfully extracted. The results demonstrated that the hydrogel successfully delivered periodontal ligament stem cells derived exosomes for repairing alveolar bone defects in rats in vivo at the initial stage.
    Type of Medium: Online Resource
    ISSN: 1999-4923
    URL: Article
    DOI: 10.3390/pharmaceutics14102189
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
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  • 15
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    Eriodictyol Suppresses Gastric Cancer Cells via Inhibition of PI3K/AKT Pathway
    MDPI AG ; 2022
    In:  Pharmaceuticals Vol. 15, No. 12 ( 2022-11-27), p. 1477-
    Details
    In: Pharmaceuticals, MDPI AG, Vol. 15, No. 12 ( 2022-11-27), p. 1477-
    Abstract: Gastric cancer (GC) is among the five most common malignancies worldwide. Traditional chemotherapy cannot efficiently treat the disease and faces the problems of side effects and chemoresistance. Polygoni orientalis Fructus (POF), with flavonoids as the main bioactive compounds, exerts anti-cancer potential. In this study, we compared the anti-GC effects of the main flavonoids from POF and investigated the anti-cancer effects of eriodictyol towards GC both in vitro and in vivo. CCK-8 assays were performed to examine the inhibitory effects of common flavonoids from POF on GC cell viability. Colony formation assays were used to determine cell proliferation after eriodictyol treatment. Cell cycle distribution was analyzed using flow cytometry. Induction of apoptosis was assessed with Annexin V/PI staining and measurement of related proteins. Anti-cancer effects in vivo were investigated using a xenograft mouse model. Potential targets of eriodictyol were clarified by network pharmacological analysis, evaluated by molecular docking, and validated with Western blotting. We found that eriodictyol exhibited the most effective inhibitory effect on cell viability of GC cells among the common flavonoids from POF including quercetin, taxifolin, and kaempferol. Eriodictyol suppressed colony formation of GC cells and induced cell apoptosis. The inhibitory effects of eriodictyol on tumor growth were also validated using a xenograft mouse model. Moreover, no obvious toxicity was identified with eriodictyol treatment. Network pharmacology analysis revealed that PI3K/AKT signaling ranked first among the anti-GC targets. The molecular docking model of eriodictyol and PI3K was constructed, and the binding energy was evaluated. Furthermore, efficient inhibition of phosphorylation and activation of PI3K/AKT by eriodictyol was validated in GC cells. Taken together, our results identify eriodictyol as the most effective anti-GC flavonoids from POF and the potential targets of eriodictyol in GC. These findings suggest that eriodictyol has the potential to be a natural source of anti-GC agents.
    Type of Medium: Online Resource
    ISSN: 1424-8247
    URL: Article
    DOI: 10.3390/ph15121477
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
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  • 16
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    Macrosphelide A Exhibits a Specific Anti-Cancer Effect by Simultaneously Inactivating ENO1, ALDOA, and FH
    MDPI AG ; 2021
    In:  Pharmaceuticals Vol. 14, No. 10 ( 2021-10-19), p. 1060-
    Details
    In: Pharmaceuticals, MDPI AG, Vol. 14, No. 10 ( 2021-10-19), p. 1060-
    Abstract: Aerobic glycolysis in cancer cells, also known as the Warburg effect, is an indispensable hallmark of cancer. This metabolic adaptation of cancer cells makes them remarkably different from normal cells; thus, inhibiting aerobic glycolysis is an attractive strategy to specifically target tumor cells while sparing normal cells. Macrosphelide A (MSPA), an organic small molecule, is a potential lead compound for the design of anti-cancer drugs. However, its role in modulating cancer metabolism remains poorly understood. MSPA target proteins were screened using mass spectrometry proteomics combined with affinity chromatography. Direct and specific interactions of MSPA with its candidate target proteins were confirmed by in vitro binding assays, competition assays, and simulation modeling. The siRNA-based knockdown of MSPA target proteins indirectly confirmed the cytotoxic effect of MSPA in HepG2 and MCF-7 cancer cells. In addition, we showed that MSPA treatment in the HEPG2 cell line significantly reduced glucose consumption and lactate release. MSPA also inhibited cancer cell proliferation and induced apoptosis by inhibiting critical enzymes involved in the Warburg effect: aldolase A (ALDOA), enolase 1 (ENO1), and fumarate hydratase (FH). Among these enzymes, the purified ENO1 inhibitory potency of MSPA was further confirmed to demonstrate the direct inhibition of enzyme activity to exclude indirect/secondary factors. In summary, MSPA exhibits anti-cancer effects by simultaneously targeting ENO1, ALDOA, and FH.
    Type of Medium: Online Resource
    ISSN: 1424-8247
    URL: Article
    DOI: 10.3390/ph14101060
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 17
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    Insulin-Mimic Components in Acer truncatum Leaves: Bio-Guided Isolation, Annual Variance Profiling and Regulating Pathway Investigated by Omics
    MDPI AG ; 2021
    In:  Pharmaceuticals Vol. 14, No. 7 ( 2021-07-11), p. 662-
    Details
    In: Pharmaceuticals, MDPI AG, Vol. 14, No. 7 ( 2021-07-11), p. 662-
    Abstract: Insulin mimic can promote transporting glucose to muscle tissue and accelerate glucose consumption. It is commonly occurring in many functional foods or traditional medicines. Anti-diabetes molecules from food sources are highly safe and suitable for long-term use to prevent early diabetes. The leaves of Acer truncatum was found glucose uptake promotion in our phenotypic screening. However, its bioactive components and mechanism are still unclear. We collected leaves from trees of different ages (2, 3, 4, 7 and 11 years old) and profiled the ingredients by LC-MS/MS. The essential active component (myricitrin) was acquired following bio-guide on a whole organism Zebrafish (Danio rerio). Its content in the leaves was not affected by tree ages. Therefore, myricitrin can serve as a quality mark for functional foods derived from A. truncatum leaves. The transcriptomic and metabolomic analysis in Zebrafish explored the differentially expressed genes and metabolites. Based on joint-pathway enrichment and qRT-PCR verification, the critical bioactive component myricitrin was found to affect toll-like receptors signaling pathways to regulate glucose uptake. Our findings disclosed a bioactive marker (myricitrin) in A. truncatum leaves and explored its regulation mechanism, which rationalized the anti-diabetes function of the herbal food.
    Type of Medium: Online Resource
    ISSN: 1424-8247
    URL: Article
    DOI: 10.3390/ph14070662
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 18
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    Antimicrobial and Immunomodulating Activities of Two Endemic Nepeta Species and Their Major Iridoids Isolated from Natural Sources
    MDPI AG ; 2021
    In:  Pharmaceuticals Vol. 14, No. 5 ( 2021-04-28), p. 414-
    Details
    In: Pharmaceuticals, MDPI AG, Vol. 14, No. 5 ( 2021-04-28), p. 414-
    Abstract: Two Balkan Peninsula endemics, Nepeta rtanjensis and N. argolica subsp. argolica, both characterized by specialized metabolite profiles predominated by iridoids and phenolics, are differentiated according to the stereochemistry of major iridoid aglycone nepetalactone (NL). For the first time, the present study provides a comparative analysis of antimicrobial and immunomodulating activities of the two Nepeta species and their major iridoids isolated from natural sources—cis,trans-NL, trans,cis-NL, and 1,5,9-epideoxyloganic acid (1,5,9-eDLA), as well as of phenolic acid rosmarinic acid (RA). Methanol extracts and pure iridoids displayed excellent antimicrobial activity against eight strains of bacteria and seven strains of fungi. They were especially potent against food-borne pathogens such as L. monocytogenes, E. coli, S. aureus, Penicillium sp., and Aspergillus sp. Targeted iridoids were efficient agents in preventing biofilm formation of resistant P. aeruginosa strain, and they displayed additive antimicrobial interaction. Iridoids are, to a great extent, responsible for the prominent antimicrobial activities of the two Nepeta species, although are probably minor contributors to the moderate immunomodulatory effects. The analyzed iridoids and RA, individually or in mixtures, have the potential to be used in the pharmaceutical industry as potent antimicrobials, and in the food industry to increase the shelf life and safety of food products.
    Type of Medium: Online Resource
    ISSN: 1424-8247
    URL: Article
    DOI: 10.3390/ph14050414
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 19
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    Efficacies of Colistin–Carbapenem versus Colistin–Tigecycline in Critically Ill Patients with CR-GNB-Associated Pneumonia: A Multicenter Observational Study
    MDPI AG ; 2021
    In:  Antibiotics Vol. 10, No. 9 ( 2021-09-07), p. 1081-
    Details
    In: Antibiotics, MDPI AG, Vol. 10, No. 9 ( 2021-09-07), p. 1081-
    Abstract: Background: Evaluating the options for antibiotic treatment for carbapenem-resistant Gram-negative bacteria (CR-GNB)-associated pneumonia remains crucial. We compared the therapeutic efficacy and nephrotoxicity of two combination therapies, namely, colistin + carbapenem (CC) versus colistin + tigecycline (CT), for treating CR-GNB-related nosocomial pneumonia in critically ill patients. Methods: In this multicenter, retrospective, and cohort study, we recruited patients admitted to intensive care units and diagnosed with CR-GNB-associated nosocomial pneumonia. We divided the enrolled patients into CC (n = 62) and CT (n = 59) groups. After propensity score matching (n = 39), we compared the therapeutic efficacy by mortality, favorable outcome, and microbiological eradication and compared nephrotoxicity by acute kidney injury between groups. Results: There was no significant difference between the CC and CT groups regarding demographic characteristics and disease severities as assessed using the Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, and other organ dysfunction variables. Therapeutic efficacy was non-significantly different between groups in all-cause mortality, favorable outcomes, and microbiological eradication at days 7, 14, and 28; as was the Kaplan-Meier analysis of 28-day survival. For nephrotoxicity, both groups had similar risks of developing acute kidney injury, evaluated using the Kidney Disease Improving Global Outcomes criteria (p = 1.000). Conclusions: Combination therapy with CC or CT had similar therapeutic efficacy and risk of developing acute kidney injury for treating CR-GNB-associated nosocomial pneumonia in critically ill patients.
    Type of Medium: Online Resource
    ISSN: 2079-6382
    URL: Article
    DOI: 10.3390/antibiotics10091081
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2681345-2
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  • 20
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    Isolation and Characterization of Antibacterial Carotane Sesquiterpenes from Artemisia argyi Associated Endophytic Trichoderma virens QA-8
    MDPI AG ; 2021
    In:  Antibiotics Vol. 10, No. 2 ( 2021-02-20), p. 213-
    Details
    In: Antibiotics, MDPI AG, Vol. 10, No. 2 ( 2021-02-20), p. 213-
    Abstract: Carotane sesquiterpenes are commonly found in plants but are infrequently reported in the fungal kingdom. Chemical investigation of Trichoderma virens QA-8, an endophytic fungus associated with the inner root tissue of the grown medicinal herb Artemisia argyi H. Lév. and Vaniot, resulted in the isolation and characterization of five new carotane sesquiterpenes trichocarotins I–M (1–5), which have diverse substitution patterns, and seven known related analogues (6–12). The structures of these compounds were established on the basis of a detailed interpretation of their NMR and mass spectroscopic data, and the structures including the relative and absolute configurations of compounds 1–3, 5, 9, and 10 were confirmed by X-ray crystallographic analysis. In the antibacterial assays, all isolates exhibited potent activity against Escherichia coli EMBLC-1, with MIC values ranging from 0.5 to 32 µg/mL, while 7β-hydroxy CAF-603 (7) strongly inhibited Micrococcus luteus QDIO-3 (MIC = 0.5 µg/mL). Structure-activity relationships of these compounds were discussed. The results from this study demonstrate that the endophytic fungus T. virens QA-8 from the planted medicinal herb A. argyi is a rich source of antibacterial carotane sesquiterpenes, and some of them might be interesting for further study to be developed as novel antibacterial agents.
    Type of Medium: Online Resource
    ISSN: 2079-6382
    URL: Article
    DOI: 10.3390/antibiotics10020213
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2681345-2
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