ABSTRACT
The voltage-dependent anion channel 1 (VDAC1) forms an oligomeric structure on the mitochondrial outer membrane, which plays critical roles in many physiological processes. Research studies have demonstrated that the knockout of VDAC1 increases pigment content and up-regulates the expression of melanogenic genes. Due to its involvement in various physiological processes, the depletion of VDAC1 has significant detrimental effects on cellular functions and the inhibition of VDAC1 oligomerization has recently emerged as a promising strategy for the treatment of several diseases. In this study, we found that VDAC1 oligomerization inhibitors, VBIT-12 and NSC-15364, promote melanogenesis, dendrite formation and melanosome transport in human epidermal melanocytes (HEMCs). Mechanistically, treatment of HEMCs with an oligomerization inhibitor increased the level of cytoplasmic calcium ions, which activated calcium-calmodulin dependent protein kinase (CaMK) and led to the phosphorylation of CREB and the nuclear translocation of CREB-regulated transcription coactivators (CRTCs). Subsequently, CRTCs, p-CREB and CREB-binding protein (CBP) in the nucleus cooperatively recruit the transcription machinery to initiate the transcription of MITF thus promoting pigmentation. Importantly, our study also demonstrates that VDAC1 oligomerization inhibitors increase pigmentation in zebrafish and in human skin explants, highlighting their potential as a therapeutic strategy for skin pigmentation disorders.
Subject(s)
Pigmentation Disorders , Animals , Humans , Pigmentation Disorders/metabolism , Voltage-Dependent Anion Channel 1/genetics , Voltage-Dependent Anion Channel 1/metabolism , Calcium/metabolism , Zebrafish/metabolism , Melanocytes , Melanins/metabolism , Pigmentation , Microphthalmia-Associated Transcription Factor/genetics , Microphthalmia-Associated Transcription Factor/metabolism , Microphthalmia-Associated Transcription Factor/pharmacologyABSTRACT
Epimedin B (EB), a predominant compound found in Herba Epimedii, has been shown to be effective in the treatment of osteoporosis and peripheral neuropathy. However, the anti-inflammatory effect of EB has not yet been reported. The anti-inflammatory activity of EB was evaluated in a zebrafish inflammation model induced by copper sulfate (CuSO4) and tail cutting. Our findings demonstrated that EB effectively inhibited acute inflammation, mitigated the accumulation of reactive oxygen species (ROS), and ameliorated the neuroinflammation-associated impairment of locomotion in zebrafish. Moreover, EB regulates several genes related to the mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB)/Nod-like receptor signalling pathways (mapk8b, src, mmp9, akt1, mapk14a, mapk14b, mapk1, egfra, map3k4, nfκb2, iκbαa, pycard, nlrp3 and caspase1) and inflammatory cytokine (stat6, arg1, irfÉ, stat1É, il-1ß, il-4, il-6, il-8, cox-2, ptges, tnf-α and tgf-ß). Therefore, our findings indicate that EB could serve as a promising therapeutic candidate for treating inflammation.
Subject(s)
Anti-Inflammatory Agents , NF-kappa B , Signal Transduction , Zebrafish , Animals , Zebrafish/immunology , NF-kappa B/metabolism , NF-kappa B/genetics , NF-kappa B/immunology , Anti-Inflammatory Agents/pharmacology , Signal Transduction/drug effects , Inflammation/drug therapy , Inflammation/immunology , Fish Diseases/immunology , Mitogen-Activated Protein Kinases/metabolism , Mitogen-Activated Protein Kinases/genetics , Mitogen-Activated Protein Kinases/immunology , Flavonoids/pharmacology , Flavonoids/administration & dosageABSTRACT
The damage behavior and defect evolution in Si-doped and Fe-doped ß-Ga2O3 crystals were investigated using an electron irradiation of 1 MeV at a dose of 1 × 1016 cm-2 in conjunction with structural and optoelectronic characterizations. Distinct decline in electron spin resonance (ESR) signal with g = 1.96 and a UV luminesce of 375 nm were observed in Si-doped ß-Ga2O3 due to the capture of free carriers by irradiation defects. As for the Fe-doped sample, both defect-related blue emission and Cr3+ impurity-related red luminescence underwent prominent suppression after electron irradiation, which can be correlated to the creation of VO and VGa defects and the formation of non-radiative recombination. Noticeably, neither VO- nor VGa-related ESR signals were detected in Fe-doped and Si-doped ß-Ga2O3 irrespective of irradiation; g = 2.003 resonance was observed in Mg-doped ß-Ga2O3 and it experienced remarkable augmentation after electron irradiation. We assigned the g = 2.003 peak to the VGa acceptor. Besides, although the Raman mode of 258 cm-1 in Si-doped ß-Ga2O3 has been suggested to be electron concentration dependent, no obvious change in peak intensity was observed before and after electron irradiation.
ABSTRACT
BACKGROUND: Deer antlers are the only known mammalian structure that undergoes full regeneration. In addition, it is peculiar because when growing, it contains vascularized cartilage. The differentiation of antler stem cells (ASCs) into chondrocytes while inducing endochondral extension of blood vessels is necessary to form antler vascularized cartilage. Therefore, antlers provide an unparalleled opportunity to investigate chondrogenesis, angiogenesis, and regenerative medicine. A study found that Galectin-1 (GAL-1), which can be used as a marker in some tumors, is highly expressed in ASCs. This intrigued us to investigate what role GAL-1 could play in antler regeneration. METHODS: We measured the expression level of GAL-1 in antler tissues and cells by immunohistochemistry, WB and QPCR. We constructed antlerogenic periosteal cells (APCs, one cell type of ASCs) with the GAL-1 gene knocked out (APCGAL-1-/-) using CRISPR-CAS9 gene editing system. The effect of GAL-1 on angiogenesis was determined by stimulating human umbilical vein endothelial cells (HUVECs) using APCGAL-1-/- conditioned medium or adding exogenous deer GAL-1 protein. The effect of APCGAL-1-/- on chondrogenic differentiation was evaluated compared with the APCs under micro-mass culture. The gene expression pattern of APCGAL-1-/- was analyzed by transcriptome sequencing. RESULTS: Immunohistochemistry revealed that GAL-1 was widely expressed in the antlerogenic periosteum (AP), pedicle periosteum (PP) and antler growth center. Western blot and qRT-PCR analysis using deer cell lines further supports this result. The proliferation, migration, and tube formation assays of human umbilical vein endothelial cells (HUVECs) showed that the proangiogenic activity of APCGAL-1-/- medium was significantly decreased (P < 0.05) compared with the APCs medium. The proangiogenic activity of deer GAL-1 protein was further confirmed by adding exogenous deer GAL-1 protein (P < 0.05). The chondrogenic differentiation ability of APCGAL-1-/- was impeded under micro-mass culture. The terms of GO and KEGG enrichment of the differentially expressed genes (DEGs) of APCGAL-1-/- showed that down-regulated expression of pathways associated with deer antler angiogenesis, osteogenesis and stem cell pluripotency, such as the PI3K-AKT signaling pathway, signaling pathways regulating pluripotency of stem cells and TGF-ß signaling pathway. CONCLUSIONS: Deer GAL-1, has strong angiogenic activity, is widely and highly expressed in deer antler. The APCs can induce angiogenesis by secreting GAL-1. The knockout of GAL-1 gene of APCs damaged its ability to induce angiogenesis and differentiate into chondrocytes. This ability is crucial to the formation of deer antler vascularized cartilage. Moreover, Deer antlers offer a unique model to explore explore how angiogenesis at high levels of GAL-1 expression can be elegantly regulated without becoming cancerous.
Subject(s)
Antlers , Deer , Animals , Humans , Chondrogenesis/genetics , Deer/genetics , Galectin 1/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Endothelial CellsABSTRACT
Isoliquiritigenin (ISL), a flavonoid component from the hydrolysis products of licorice root. It has been reported that ISL inhibited melanogenesis by suppressing the tyrosinase activity in human melanocytes. Recently, ISL was found to induce melanin degradation in human epidermal keratinocytes. However, the role of ISL in pigmentation is not fully understood. In the current study, we aimed to investigate the effects of ISL on pigmentation, and further explored the underlying mechanism. Our results suggested that ISL suppressed basal and α-MSH-, ACTH- and UV-induced melanin synthesis, in addition to inhibiting melanocyte dendricity and melanosome transport. ISL played these roles mainly by activating the extracellular signal-regulated protein kinase pathway. Once activated, it induced microphthalmia-associated transcription factor degradation and decreased the expression of tyrosinase, TRP-1, DCT, Rab27a and Cdc42, finally inhibited melanogenesis, melanocyte dendricity and melanosome transport. Our findings suggested that ISL exhibited no cytotoxicity in our research, it may prove quite useful as a safer natural skin-whitening agent.
Subject(s)
Chalcones/pharmacology , Enzyme Inhibitors/pharmacology , Melanins/biosynthesis , Microphthalmia-Associated Transcription Factor/metabolism , Skin Pigmentation/drug effects , Skin/drug effects , Adrenocorticotropic Hormone/pharmacology , Cell Line, Tumor , Humans , Intramolecular Oxidoreductases/metabolism , Keratinocytes/metabolism , MAP Kinase Signaling System/drug effects , Male , Melanocytes/drug effects , Melanocytes/metabolism , Monophenol Monooxygenase/metabolism , Protein Biosynthesis/drug effects , Protein Transport/drug effects , Skin/metabolism , Tissue Culture Techniques , Trypsin/metabolism , alpha-MSH/pharmacologyABSTRACT
Aß aggregation is one of the pathological biomarkers of Alzheimer's disease (AD). However, the possible mechanism related to Aß-induced pathological signaling pathway is still unknown. In the present study, Aß1-42-induced time-dependent memory impairment and its possible relationship to hypothalamic-pituitary-adrenal (HPA) axis hyperactivity were examined. Aß1-42-treated mice significantly impaired acquisition activity in the learning curve at 10 days, 1 and 4 months in the Morris water-maze (MWM) task. This learning activity was back to normal at 8 months after Aß1-42 treatment. In the probe trial test, Aß1-42-treated mice needed longer latencies to touch the precious platform location and fewer numbers of crossing from 10 days to 4 months after microinjection. This Aß1-42 induced memory loss was consistent with the results of the step-down passive avoidance test. The HPA axis related parameters, such as corticosterone (CORT) level in the serum, glucocorticoid receptor (GR) and corticotropin-releasing factor receptor (CRF-R) expression in the frontal cortex and hippocampus increased in Aß1-42-treated mice from 10 days to 4 months. While the downstream molecules phosphorylation of cyclic AMP response element binding (pCREB) and brain-derived neurotrophic factor (BDNF) expression decreased during this time. These effects were back to normal 8 months after treatment with Aß1-42. Altogether, our results suggested that Aß1-42 induced significant learning and memory impairment, which is involved in HPA axis dysfunction.
Subject(s)
Amyloid beta-Peptides/toxicity , Hypothalamo-Hypophyseal System/metabolism , Maze Learning/physiology , Memory Disorders/chemically induced , Memory Disorders/metabolism , Peptide Fragments/toxicity , Pituitary-Adrenal System/metabolism , Amyloid beta-Peptides/administration & dosage , Animals , Avoidance Learning/drug effects , Avoidance Learning/physiology , Hypothalamo-Hypophyseal System/drug effects , Injections, Intraventricular , Male , Maze Learning/drug effects , Mice , Mice, Inbred ICR , Peptide Fragments/administration & dosage , Pituitary-Adrenal System/drug effects , Time FactorsABSTRACT
The origin of ZnO radiation resistance is fascinating but still unclear. Herein, we found that radiation tolerance of ZnO can be tuned by engineering intrinsic defects into the ZnO. The role played by native defects in the radiation tolerance of ZnO was systematically explored by carrying out N+ implantation on a set of home-grown ZnO nanocrystals with various lattice defect types and concentrations. Interestingly, decreasing the VO and Zni concentration significantly aggravated N+ radiation damage, indicating the presence of O-deficient defects to be the potential cause of the radiation hardness of ZnO. A similar phenomenon was also observed for H+-implanted ZnO. This work offers a new way to manipulate ZnO and endow it with desired physicochemical properties, and is expected to pave the way for its application in radiative environments.
ABSTRACT
Growing bodies of data show that psychological stress can be associated with hair loss and vitiligo. Researchers have revealed that stress could indeed inhibit hair growth in vivo, but the relationship between chronic stress and melanogenesis remains unknown. In this study, we established two types of stress models, chronic restraint stress (CRS) and chronic unpredicted mild stress (CUMS) mice models, and explored the possible role of stress in mice hair follicle melanogenesis. We found that stress changed hippocampal morphology, decreased 5-HT level in brain and skin and down-regulated 5-HT1A receptor expression in hippocampal CA1 region and skin. The alterations of 5-HT and 5-HT1A receptor might be a threshold of central stress to associate with the behaviour changes. Both two stresses caused cellular damage of melanocytes and inhibition of keratinocytes proliferation in HF, which made the synthetic pigment loss. CRS which was considered primarily as a "psychological" stressor had the lower melanin production in HF, as well as the level of 5-HT in skin was down-regulated more than those in CUMS group.
Subject(s)
Hair Color , Hair Follicle/physiopathology , Hippocampus/metabolism , Melanins/biosynthesis , Serotonin/metabolism , Stress, Psychological/physiopathology , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Animals , Behavior, Animal , Cell Line, Tumor , Cell Proliferation , Chronic Disease , Cyclohexanes/pharmacology , Disease Models, Animal , Hair Follicle/metabolism , Hair Follicle/pathology , Hippocampus/pathology , Intramolecular Oxidoreductases/metabolism , Keratinocytes/physiology , Male , Melanins/blood , Melanocytes/pathology , Membrane Glycoproteins/agonists , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred C57BL , Monophenol Monooxygenase/metabolism , Oxidoreductases/antagonists & inhibitors , Oxidoreductases/metabolism , Piperazines/pharmacology , Protein Biosynthesis/drug effects , Pyramidal Cells/pathology , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , Skin/metabolismABSTRACT
The simultaneous introduction of shallow acceptors and elimination of donor compensation is the key issue toward achieving p-type ZnO. Herein, through accurate control of the Li dopant configuration and systematic spectroscopy characterization, we obtain direct evidence that Li doping creates isolated VZn in ZnO with a luminescence peak around 414 nm (â¼3.0 eV), and at the same time, removes donors. Interestingly, the same defect emission is also created by simple H2O2 treatment and appeared in a ZnO single crystal with abundant metal vacancies, unambiguously demonstrating its shallow acceptor characteristic.
ABSTRACT
A class of flavanone was found to improve melanogenesis in B16F10 mouse melanoma cell line, but little is known about its target. Herein we described the synthesis and bioevaluation of sixteen 3',4',7-trihydroxyflavanone analogues and further synthesized a novel fluorescent flavanone-BODIPY, which could improve melanogenesis in B16F10 cell line by selectively binding to its endoplasmic reticulum. The fluorescent flavanone-BODIPY was proved to be a valuable probe for studying the localization of intracellular flavanone on living cells.
Subject(s)
Boron Compounds/chemistry , Flavanones/pharmacology , Melanoma/metabolism , Porphobilinogen/analogs & derivatives , Animals , Cell Line, Tumor , Endoplasmic Reticulum/metabolism , Flavanones/chemical synthesis , Flavanones/chemistry , Fluorescent Dyes/chemistry , Mice , Mice, Inbred C57BL , Porphobilinogen/chemistryABSTRACT
BACKGROUND: Circular RNAs (circRNAs) play an important role in osteoarthritis (OA). However, the role of circRNA in OA is still unclear. Here, we explored the role and mechanism of circ_0044235 in OA. METHODS: CHON-001 cells were treated with IL-1ß to establish OA model in vitro. The levels of circ_0044235, miR-375 and phosphoinositide 3-kinase (PI3K) regulatory subunit 3 (PIK3R3) were detected by quantitative real-time PCR. Cell count kit-8 assay and flow cytometry assay were used to detect cell viability and apoptosis. The concentrations of inflammation factors were determined by enzyme-linked immunosorbent assay. Western blot was used to detect protein levels. The interaction between miR-375 and circ_0044235 or PIK3R3 was analyzed by dual-luciferase reporter assay and RNA immunoprecipitation assay. RESULTS: Circ_0044235 was significantly decreased in OA cartilage tissue and IL-1ß-treated CHON-001 cells. Overexpression of circ_0044235 promoted IL-1ß-stimulated CHON-001 cell viability and inhibited apoptosis, inflammation, and extracellular matrix (ECM) degradation. In mechanism analysis, circ_0044235 could act as a sponge for miR-375 and positively regulate PIK3R3 expression. In addition, miR-375 ameliorated the effect of circ_0044235 overexpression on IL-1ß-mediated CHON-001 cells injury. In addition, miR-375 inhibition mitigated IL-1ß-induced CHON-001 cell injury, while PIK3R3 silencing restored the effect. CONCLUSION: Circ_0044235 knockdown alleviated IL-1ß-induced chondrocytes injury by regulating miR-375/PIK3R3 axis, confirming that circ_0044235 might be a potential target for OA treatment.
Subject(s)
MicroRNAs , Osteoarthritis , Humans , Phosphatidylinositol 3-Kinases/genetics , Osteoarthritis/genetics , Inflammation , Apoptosis/genetics , Chondrocytes , Interleukin-1beta/genetics , MicroRNAs/geneticsABSTRACT
BACKGROUND: Articular cartilage has limited self-repair capacity, and current clinical treatment options for cartilage defects are inadequate. However, deer antler cartilage possesses unique regenerative properties, with the ability to rapidly repair itself. This rapid self-repair process is closely linked to the paracrine factors released by deer antler stem cells. These findings present potential for the development of cell-free therapies for cartilage defects in clinical settings. The aim of this study was to investigate a novel method for repairing cartilage. METHODS: A rat model with articular cartilage defects was established through surgery. Hydrogels loaded with exosomes (Exos) derived from antler stem cells (ASC-Exos) were implanted into the rat cartilage defects. The extent of cartilage damage repair was assessed using histological methods. The effects of ASC-Exos on chondrocytes and rat bone marrow mesenchymal stem cells (BMSCs) were evaluated using cell viability assays, proliferation assays, and scratch assays. Additionally, the maintenance of the chondrocyte phenotype by ASC-Exos was assessed using real-time fluorescence quantitative PCR (qPCR) and western blot analysis. The protein components contained of the Exos were identified using data-independent acquisition (DIA) mass spectrometry. RESULTS: ASC-Exos significantly promoted the repair of cartilage tissue damage. The level of cartilage repair in the experimental group (ASC-Exos) was higher than that in the positive control (human adipose-derived stem cells, hADSC-Exos) and negative control (dulbecco's modified eagle medium) groups (p < 0.05). In vitro experiments demonstrated that ASC-Exos significantly enhanced the proliferation abilities of chondrocytes and the proliferation abilities and the migration abilities of BMSCs (p < 0.05). ASC-Exos up-regulated the expression levels of Aggrecan, Collagen II (COLII), and Sox9 mRNA and proteins in chondrocytes. Analysis of ASC-Exos protein components revealed the presence of active components such as Serotransferrin (TF), S100A4, and Insulin-like growth factor-binding protein 1 (IGF1). CONCLUSIONS: ASC-Exos have a significant effect on cartilage damage repair, which may be attributed to their promotion of chondrocyte and BMSCs proliferation and migration, as well as the maintenance of chondrocyte phenotype. This effect may be mediated by the presence of TF, S100A4, and IGF1.
Subject(s)
Antlers , Cartilage, Articular , Chondrocytes , Deer , Exosomes , Mesenchymal Stem Cells , Stem Cells , Animals , Antlers/metabolism , Antlers/chemistry , Exosomes/metabolism , Exosomes/transplantation , Chondrocytes/metabolism , Cartilage, Articular/metabolism , Cartilage, Articular/pathology , Cartilage, Articular/injuries , Stem Cells/metabolism , Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/cytology , Rats , Cell Proliferation , Male , Rats, Sprague-Dawley , Cell SurvivalABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Tribuloside, a natural flavonoid extracted from Chinese medicine Tribulus terrestris L., has shown potent efficacy in treating various diseases. In China, the fruits of Tribulus terrestris L. have long been utilized for relieving headache, dizziness, itchiness, and vitiligo. Water-based extract derived from Tribulus terrestris L. can enhance melanogenesis in mouse hair follicle melanocytes by elevating the expression of α-melanocyte stimulating hormone (α-MSH) and melanocortin-1 recepter (MC-1R). Nevertheless, there is a lack of information regarding the impact of tribuloside on pigmentation in both laboratory settings and living organisms. AIM OF THE STUDY: The present research aimed to examine the impact of tribuloside on pigmentation, and delve into the underlying mechanism. MATERIALS AND METHODS: Following the administration of tribuloside in human epidermal melanocytes (HEMCs), we utilized microplate reader, Masson-Fontana ammoniacal silver stain, transmission electron microscopy (TEM) and scanning electron microscopy (SEM) to measure melanin contents, dendrite lengths, melanosome counts; L-DOPA oxidation assay to indicate tyrosinase activity, Western blotting to evaluate the expression of melanogenic and associated phosphodiesterase (PDE)/cyclic adenosine monophosphate (cAMP)/cyclic-AMP dependent protein kinase A (PKA) pathway proteins. A PDE-Glo assay to verify the inhibitory effect of tribuloside on PDE was also conducted. Additionally, we examined the impact of tribuloside on the pigmentation in both zebrafish model and human skin samples. RESULTS: Tribuloside had a notable impact on the production of melanin in melanocytes, zebrafish, and human skin samples. These functions might be attributed to the inhibitory effect of tribuloside on PDE, which could increase the intracellular level of cAMP to stimulate the phosphorylation of cAMP-response element binding (CREB). Once activated, it induced microphthalmia-associated transcription factor (MITF) expression and increased the expression of tyrosinase, Rab27a and cell division cycle protein 42 (Cdc42), ultimately facilitating melanogenesis, melanocyte dendricity, and melanin transport. CONCLUSION: Tribuloside acts on the PDE/cAMP/PKA pathway to enhance melanogenesis, melanocyte dendricity, and melanosome transport; meanwhile, tribuloside does not have any toxic effects on cells and may be introduced into clinical prescriptions to promote pigmentation.
Subject(s)
Melanins , Melanosomes , Animals , Mice , Humans , Melanins/metabolism , Melanosomes/metabolism , Zebrafish , Monophenol Monooxygenase/metabolism , Melanogenesis , Phosphoric Diester Hydrolases/metabolism , Phosphoric Diester Hydrolases/pharmacology , Cyclic AMP-Dependent Protein Kinases/metabolism , Melanocytes , Cyclic AMP/metabolism , Microphthalmia-Associated Transcription Factor/metabolism , Cell Line, TumorABSTRACT
Cutaneous pigmentation was recently shown to be an event regulated by clock proteins. Cryptochrome (CRY) is a key protein composing the feedback loop of circadian clock, however, the function of CRY in melanocytes remains unclear. Here, we found that KL001, a synthetic small molecule modulator of CRY1, inhibited melanin synthesis, as well as reduced melanocyte dendrite elongation and melanosome transport. In addition, the dominant role of CRY1 in KL001-induced anti-melanogenesis was revealed by small interfering RNA transfection. Cellular tyrosinase activity and expression level of melanogenic proteins, including tyrosinase, TRP-1, TRP-2, and transport proteins like Rab27a, Cdc42 and Myosin Va induced by α-MSH were remarkably reversed after KL001 treatment. Mechanistically, CRY1 activation inhibited melanogenesis through CREB-dependent downregulation of MITF and CREB phosphorylation was mediated by classical cAMP/PKA pathway. In addition, the other CRY1 activator, KL044 also suppressed cAMP/PKA/CREB pathway and inhibited melanogenesis. Finally, anti-melanogenic efficacy of KL001 was confirmed by determination of melanin contents in UVB-tanning model of brown guinea pigs, which indicated that targeting CRY1 activity, via topical application of small molecule activator, can be utilized therapeutically to manage human pigmentary disorders.
ABSTRACT
Objective: To investigate the clinical efficacy of PHILOS plates in the treatment of Vancouver B1 periprosthetic femoral fracture (PFF) and to validate its biomechanical reliability via finite element analysis and mechanical testing on the Synbone femoral models. Methods: Ten males and eight females with Vancouver B1 PFF who underwent PHILOS plate fixation between September 2017 and January 2022 were selected. The average age was 72.61 ± 8.19 years, with a range of 57-86 years old. X-ray films were taken to assess the fracture healing situation around the femoral prosthesis as well as the position of the PHILOS plates and femoral prosthesis. Two different plates (the PHILOS plate and the Cable GTR plate) were used for fixation, and the differences in biomechanical stability of the two fixation methods were compared using finite element analysis and mechanical testing on the Synbone femoral models to validate the biomechanical dependability of the PHILOS plate. Results: All 18 cases were followed for at least 1 year, as a result. The average period of follow-up was 17 months, ranging from 12 to 36 months. At the most recent follow-up, Harris scores for the hip joints of patients ranged from 82 to 89, with an average score of 86. The X-rays revealed that all fractures surrounding the femoral prosthesis had healed and that there was no looseness in the femoral prosthesis. None of the PHILOS license plates had expired. All patients were able to perform full-load walking, and pain and claudication in affected limbs were significantly reduced. Finite element analysis and mechanical testing of the Synbone femoral model revealed that the fixation effect of the PHILOS group was superior to that of the Cable group; consequently, PHILOS plates can be used to effectively fix fractures around the proximal femoral prosthesis. Conclusion: PHILOS plates are initially used in the treatment of Vancouver B1 PFF, which may be a good choice due to their simpler operation, lower medical costs, and satisfactory clinical efficacy.
ABSTRACT
Pterostilbene is a trans stilbene compound, which is an effective component of herbaceous plants such as Dalbergia woods and Vaccinium. Although pterostilbene has many uses in anti-inflammatory, anti-oxidant and anti-tumor, its whitening effect is drawing more and more attention, the mechanism of melanogenesis and melanosome transport still needs further study. In this research, we tried to further investigate how melanocyte melanogenesis is affected by pterostilbene and whether pterostilbene play a part in melanin transport. Our results showed that pterostilbene has a potent inhibitory effect on melanogenesis in B16F10 cells (3 µM, p < 0.001), in-vitro human skin (10 µM, p < 0.05) and zebrafish embryos (3 µM, p < 0.01). Besides, pterostilbene not only inhibited melanogenesis, but also inhibited melanocyte dendritic development and melanosome transport. Pterostilbene mainly plays a role by inhibiting cAMP/PKA/CREB signal pathway. After the cAMP/PKA/CREB signaling pathway was inhibited, tyrosinase activity and the expression of MITF, TYR, Rab27A, Rab17 and gp100 were decreased, which in turn suppressed melanogenesis, melanocyte dendritic development and melanosome transport. Our findings showed that pterostilbene can potently inhibit melanogenesis and melanosome transport, suggesting the applicability of pterostilbene in skin lightning. Therefore, a novel pharmacologic way to treat hyperpigmentation has been proposed.
Subject(s)
Melanins , Stilbenes , Animals , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Cell Line, Tumor , Humans , Melanocytes , Melanosomes/metabolism , Microphthalmia-Associated Transcription Factor/metabolism , Monophenol Monooxygenase/metabolism , Monophenol Monooxygenase/pharmacology , Stilbenes/pharmacology , Zebrafish/metabolismABSTRACT
Three novel 14-membered cyclopeptide alkaloids, justicianenes B-D (1-3), were isolated from the EtOH extract of the whole plant of Justicia procumbens L., and their structures were determined on the basis of detailed NMR spectroscopic data and the absolute stereochemistry of the ring-bonded α-amino acids in the cyclopeptide alkaloids were determined by ECD spectra. The isolated compounds were evaluated for their in vitro cytotoxicity against human cancer cell lines, including brest cancer MCF-7, cervix carcinoma HeLa, lung cancer A549 and H460, and diphyllin (14) showed moderate cytotoxicity against the HeLa, A549 and H460 cells with IC50 of 9.13, 23.12, 42.34 µM, respectively, justicianene D showed weak cytotoxicity against the MCF-7 cell with inhibition rate of 50% at the concentration of 90 µM.
Subject(s)
Alkaloids , Antineoplastic Agents, Phytogenic/pharmacology , Justicia , Peptides, Cyclic , Alkaloids/pharmacology , Humans , Justicia/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Peptides, Cyclic/pharmacologyABSTRACT
The therapeutic use of curcumin and chemically modified curcumin (CMC) for suppressing melanogenesis and tyrosinase activity have been recognized. J147 is a modified version of curcumin with superior bioavailability and stability. However, there is no report about the effects of J147 on pigmentation in vitro and in vivo. In our studies, we investigated the hypopigmentary effects of J147 treatment on melanocytes and explored the underlying mechanism. The present studies suggested that J147 suppressed both basal and α-MSH-induced melanogenesis, as well as decreased melanocyte dendricity extension and melanosome transport. J147 played these roles mainly by activating the extracellular signal-regulated protein kinase (ERK) pathway. Once activated, it resulted in MITF degradation and further down-regulated the expression of tyrosinase, TRP-1, TRP-2, Myosin Va, Rab27a and Cdc42, ultimately inhibited melanin synthesis and melanosome transport. Furthermore, the hypopigmentary effects of J147 were demonstrated in vivo in a zebrafish model and UVB-induced hyperpigmentation model in brown guinea pigs. Our findings also suggested that J147 exhibited no cytotoxicity in vitro and in vivo. Taken together, these data confirmed that J147 may prove quite useful as a safer natural skin-whitening agent.
ABSTRACT
Phosphodiesterase 4 (PDE4)-dependent cAMP signaling plays a crucial role in cognitive impairment associated with Alzheimer's disease (AD). However, whether inhibition of PDE4 subtypes or their splice variants in the prefrontal cortex positively regulates synaptic plasticity and antioxidative stress, and reverses ß-amyloid 1-42 (Aß1-42, Aß42)-induced cognitive impairment still need to be clarified. The present study determined whether and how PDE4D knockdown by microinjection of lenti-PDE4D-miRNA into the prefrontal cortex reversed Aß1-42-induced cognitive impairment in behavioral, neurochemical, and molecular biology assays. The results suggested that PDE4D knockdown increased time to explore the novel object and decreased latency to leave the platform in novel object recognition and step-down passive avoidance tests. Further study suggested that PDE4D knockdown decreased the number of working memory errors in the eight-arm maze test. These effects were prevented by PKA inhibitor H89. The subsequent experiment suggested that inhibition of PDE4D in the prefrontal cortex rescued the long-term potentiation (LTP) and synaptic proteins' expression; it also increased antioxidant response by increasing superoxide dismutase (SOD) and decreasing malondialdehyde (MDA) levels. PDE4D knockdown also increased phosphorylated cAMP response element-binding protein (pCREB), brain-derived neurotrophic factor (BNDF), and anti-apoptotic proteins' expression, i.e., the ratio of Bcl-2/Bax, and decreased caspase-3 level in the prefrontal cortex. These findings extend the previous findings and support the hypothesis that RNA interference-mediated PDE4D knockdown in the prefrontal cortex ameliorated memory loss associated with synaptic failure in an AD mouse model by its antioxidant, anti-apoptotic, and neuroprotective properties.
ABSTRACT
Fructus Gardeniae (FG) is medicine food widely used for the treatment and prevention of various diseases. However, in recent years, research has suggested that high doses of FG can cause hepatotoxicity and nephrotoxicity. To assess this potential toxicity in more depth, this study investigated the effects of decocted FG and two of its bioactive constituents (geniposide and genipin) on liver and kidney function in rats. Rats were intragastrically administered FG (330 mg/kg body weight), geniposide (50 mg/kg body weight), or genipin (50 mg/kg body weight) for 12 weeks. Changes in body weight, liver and kidney indices, biochemical indices, and inflammatory factors were monitored. In addition, pathological sections were assessed and the expression of caspase-3, NF-κBp65, COX-2, and iNOS was detected by immunohistochemistry and Western blot. It was found that the levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine, and urea nitrogen increased following administration of FG, geniposide, and genipin. Furthermore, the activities of superoxide dismutase and reduced glutathione decreased following treatment, while malondialdehyde levels increased. Pathological and immunohistochemical evaluations further confirmed that FG and its constituents may cause damage to the liver and kidneys. The mechanism study revealed that the protein level of inflammatory pathway increased and further promoted apoptosis, suggesting that it should not be taken orally for extended periods of time. PRACTICAL APPLICATIONS: Chinese medicine and food safety have always been public health concerns. Fructus Gardeniae (FG) is a plant with a dual-purpose as it is used as both a medicine and food. Medicinally, it has the effects of heat-clearing and detoxification. However, its adverse effects and related mechanisms are not clear, and this has potential safety implications. In this study, rats were treated with FG for 12 weeks and found that the long-term administration of FG or high dosing can lead to damage to liver and kidney function. Therefore, close attention must be paid to the dosage of FG in order to achieve a therapeutic effect and avoid adverse reactions. Thus, this study lays a foundation for the safety evaluation and clinical application of FG.