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3.
Am J Transl Res ; 13(3): 1337-1351, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841660

RESUMO

Random skin flaps have been widely applied in reconstructive and plastic surgery; however, necrosis usually happens due to insufficient blood supply in the ischemic area of flaps. Curcumin (CUR) is a primary bioactive compound of turmeric (Curcuma longa, L.), which has been proven to be effective on anticancer, decreasing oxidative stress and apoptosis through activating autophagy, and promoting angiogenesis in ischemic tissue. Therefore, the potential therapeutic effect of CUR on promoting survival of ischemic random skin flaps and its underlying mechanism associated with autophagy were investigated. After establishment of dorsal random skin flaps, sixty mice were randomly divided into three groups: Control, CUR or CUR+3-methyladenine (3-MA, an autophagy inhibitor). The results showed that CUR increased the viability area and blood flow as well as relieved the edema of skin flaps through promoting angiogenesis, decreasing oxidative stress, and inhibiting apoptosis of the ischemic area. Further study confirmed that CUR activated autophagy in the random skin flaps, and 3-MA effectively reversed the effect on viability, neovascularization, oxidative stress and apoptosis, suggesting autophagy played a vital role in these CUR's protective effect on random skin flaps. Moreover, this CUR-induced autophagy should be mediated through downregulating the PI3K/AKT/mTOR signaling pathway. Together with secondary response of increased angiogenesis, reduced oxidative stress and apoptosis, CUR effectively improved survival of random skin flaps in vivo. To sum up, our research showed the great potential of CUR using as a promising flap protective therapy for random skin flap survival and regeneration.

4.
Zhongguo Gu Shang ; 34(4): 363-7, 2021 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-33896138

RESUMO

OBJECTIVE: To investigate the expression and clinical significance of receptor interacting protein serine-threonine kinases 1 (RIPK1) in the nucleus pulposus of patients with lumbar disc herniation (LDH). METHODS: Nucleus pulposus tissue specimens of 40 patients with LDH patients underwent surgical treatment from January 2016 to January 2018 as the case group, and nucleus pulposus tissue specimens of 30 patients with lumbar spine fracture underwent surgical treatment at the same time as the control group. The expression of RIPK1 mRNA and protein of receptor interaction were detected by polymerase chain reaction (PCR) and Western blot, respectively. The expression of RIPK1 protein in the nucleus pulposus were detected by immunohistochemical staining. The concentrations of RIPK1 and tumor necrosis factor-α (TNF-α) in nucleus pulposus were detected by ELISA method. The relationship between the concentrations of RIPK1, TNF-α in nucleus pulposus and the Pearce grade of LDH patients was analyzed by one-way ANOVA. The correlation between RIPK1 and TNF-α was analyzed by Pearson. RESULTS: RIPK1 was weakly positively expressed in nucleus pulposus of control group, and RIPK1 protein was positively or strongly positively expressed in case group. The expression of RIPK1 mRNA in nucleus pulposus of case group was higher than that of control group (P<0.05). The expression of RIPK1 protein in nucleus pulposus of case group was higher than that of control group(P<0.05). The RIPK1 concentration in nucleus pulposus of case group was higher than that of control group (P=0.012). The concentration of TNF-α in nucleus pulposus of case group was significantly higher than that of control group (P=0.009). There were significantdifferences in concentrations of RIPK1 and TNF-α in nucleus pulposus of LDH patients with different Pearce classification (P>0.05). The concentration of RIPK1 and TNF-α in nucleus pulposus increased significantly with the increase of Pearce grade. Pearson correlation analysis showed that there was a significant positive correlation between RIPK1 and TNF-α in nucleus pulposus of LDH patients (r=0.781, P<0.001). CONCLUSION: The expression levels of RIPK1 mRNA and protein in the intervertebral disc tissues of LDH patients are higher than those of normal intervertebral disc tissues, and increased with the increase of Pearce grade, which may be an important factor involved in LDH inflammatory disease.


Assuntos
Degeneração do Disco Intervertebral , Deslocamento do Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Humanos , Disco Intervertebral/metabolismo , Deslocamento do Disco Intervertebral/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
5.
ACS Nano ; 14(10): 13681-13690, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-32926626

RESUMO

Pharmaceutical evaluations of nanomedicines are of great significance for their further launch into industry and clinic. Near-infrared (NIR) fluorescence imaging plays essential roles in preclinical drug development by providing important insights into the biodistributions of drugs in vivo with deep tissue penetration and high spatiotemporal resolution. However, NIR-II fluorescence imaging has rarely been exploited for in vivo real-time pharmaceutical evaluations of nanomedicine. Herein, we developed a highly emissive NIR-II luminophore to establish a versatile nanoplatform to noninvasively monitor the in vivo metabolism of nanomedicines bound various polyethylene glycol (PEG) ligands in a real-time manner. An alternative D-A-D conjugated oligomer (DTTB) was synthesized to achieve NIR-II emission peaked at ∼1050 nm with high fluorescence QYs of 13.4% and a large absorption coefficient. By anchoring with the DTTB molecule, intrinsically fluorescent micelles were fabricated and bound with PEG ligands at various chain lengths. In vivo NIR-II fluorescence and photoacoustic imaging results revealed that an appropriate PEG chain length could effectively contribute to the longer blood circulation and better tumor targeting. In vivo therapeutic experiments also confirmed the optimized nanomedicines have efficient photothermal elimination of tumors and good biosafety. This work offered an alternative highly fluorescent NIR-II material and demonstrated a promising approach for real-time pharmaceutical evaluation of nanomedicine in vivo.


Assuntos
Hipertermia Induzida , Neoplasias , Técnicas Fotoacústicas , Humanos , Ligantes , Nanomedicina , Neoplasias/terapia , Fototerapia , Polietilenoglicóis , Nanomedicina Teranóstica
6.
EMBO Rep ; 21(10): e49863, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-32783360

RESUMO

RNA modifications represent a novel layer of regulation of gene expression. Functional experiments revealed that N6 -methyladenosine (m6 A) on messenger RNA (mRNA) plays critical roles in cell fate determination and development. m6 A mark also resides in the decoding center of 18S ribosomal RNA (rRNA); however, the biological function of m6 A on 18S rRNA is still poorly understood. Here, we report that methyltransferase-like 5 (METTL5) methylates 18S rRNA both in vivo and in vitro, which is consistent with previous reports. Deletion of Mettl5 causes a dramatic differentiation defect in mouse embryonic stem cells (mESCs). Mechanistically, the m6 A deposited by METTL5 is involved in regulating the efficient translation of F-box and WD repeat domain-containing 7 (FBXW7), a key regulator of cell differentiation. Deficiency of METTL5 reduces FBXW7 levels and leads to the accumulation of its substrate c-MYC, thereby delaying the onset of mESC differentiation. Our study uncovers an important role of METTL5-mediated 18S m6 A in mESC differentiation through translation regulation and provides new insight into the functional significance of rRNA m6 A.


Assuntos
Metiltransferases , Células-Tronco Embrionárias Murinas , Animais , Diferenciação Celular/genética , Metiltransferases/genética , Camundongos , RNA Mensageiro , RNA Ribossômico 18S/genética
7.
Small ; 16(34): e2002672, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32697430

RESUMO

Multi-modality imaging-guided cancer therapy is considered as a powerful theranostic platform enabling simultaneous precise diagnosis and treatment of cancer. However, recently reported multifunctional systems with multiple components and sophisticate structures remain major obstacles for further clinical translation. In this work, a single-photomolecular theranostic nanoplatform is fabricated via a facile nanoprecipitation strategy. By encapsulating a semiconductor oligomer (IT-S) into an amphiphilic lipid, water-dispersible IT-S nanoparticles (IT-S NPs) are prepared. The obtained IT-S NPs have a very simple construction and possess ultra-stable near-infrared (NIR) fluorescence (FL)/photoacoustic (PA) dual-modal imaging and high photothermal conversion efficiency of 72.3%. Accurate spatiotemporal distribution profiles of IT-S NPs are successfully visualized by NIR FL/PA dual-modal imaging. With the comprehensive in vivo imaging information provided by IT-S NPs, tumor photothermal ablation is readily realized under precise manipulation of laser irradiation, which greatly improves the therapeutic efficacy without any obvious side effects. Therefore, the IT-S NPs allow high tumor therapeutic efficacy under the precise guidance of FL/PA imaging techniques and thus hold great potential as an effective theranostic platform for future clinical applications.


Assuntos
Hipertermia Induzida , Nanopartículas , Neoplasias , Técnicas Fotoacústicas , Linhagem Celular Tumoral , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Imagem Óptica , Fototerapia , Nanomedicina Teranóstica
8.
J Cell Physiol ; 235(12): 9933-9945, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32542807

RESUMO

The treatment of wounds remains a clinical challenge because of poor angiogenesis under the wound bed, and increasingly, the patients' need for functional and aesthetically pleasing scars. For the wound healing process, new blood vessels which can deliver nutrients and oxygen to the wound area are necessary. In this study, we investigated the pro-angiogenesis ability and mechanism in wound healing of paeoniflorin (PF), which is a traditional Chinese medicine. In our in vitro results, the ability for proliferation, migration and in vitro angiogenesis in human umbilical vein endothelial cells was promoted by coculturing with PF (1.25-5 µM). Meanwhile, molecular docking studies revealed that PF has excellent binding abilities to phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT), and consistent with our western blot results, that PF suppressed PI3K and AKT phosphorylation. Furthermore, to investigate the healing effect of PF in vivo, we constructed a full-thickness cutaneous wound model in rats. PF stimulated the cellular proliferation status, collagen matrix deposition and remodeling processes in vitro and new blood vessel formation at the wound bed resulting in efficient wound healing after intragastric administration of 10 mg·kg-1 ·day-1 in vivo. Overall, PF performed the pro-angiogenetic effect in vitro and accelerating wound healing in vivo. In summary, the capacity for angiogenesis in endothelial cells could be enhanced by PF treatment via the PI3K/AKT pathway in vitro and could accelerate the wound healing process in vivo through collagen deposition and angiogenesis in regenerated tissue. This study provides evidence that application of PF represents a novel therapeutic approach for the treatment of cutaneous wounds.


Assuntos
Glucosídeos/farmacologia , Monoterpenos/farmacologia , Neovascularização Fisiológica/genética , Pele/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Humanos , Neovascularização Fisiológica/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Regeneração/efeitos dos fármacos , Regeneração/genética , Transdução de Sinais/efeitos dos fármacos , Pele/lesões , Pele/patologia
9.
Theranostics ; 10(11): 4929-4943, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308759

RESUMO

Diabetic wound repair and skin regeneration remains a worldwide challenge due to the impaired functionality of re-vascularization. Methods: This study reports a bioactive self-healing antibacterial injectable dual-network silica-based nanocomposite hydrogel scaffolds that can significantly enhance the diabetic wound healing/skin tissue formation through promoting early angiogenesis without adding any bioactive factors. The nanocomposite scaffold comprises a main network of polyethylene glycol diacrylate (PEGDA) forming scaffolds, with an auxiliary dynamic network formed between bioactive glass nanoparticles containing copper (BGNC) and sodium alginate (ALG) (PABC scaffolds). Results: PABC scaffolds exhibit the biomimetic elastomeric mechanical properties, excellent injectabilities, self-healing behavior, as well as the robust broad-spectrum antibacterial activity. Importantly, PABC hydrogel significantly promoted the viability, proliferation and angiogenic ability of endothelial progenitor cells (EPCs) in vitro. In vivo, PABC hydrogel could efficiently restore blood vessels networks through enhancing HIF-1α/VEGF expression and collagen matrix deposition in the full-thickness diabetic wound, and significantly accelerate wound healing and skin tissue regeneration. Conclusion: The prominent multifunctional properties and angiogenic capacity of PABC hydrogel scaffolds enable their promising applications in angiogenesis-related regenerative medicine.


Assuntos
Antibacterianos/farmacologia , Diabetes Mellitus/patologia , Nanogéis/uso terapêutico , Neovascularização Fisiológica/efeitos dos fármacos , Tecidos Suporte , Cicatrização/efeitos dos fármacos , Alginatos/farmacologia , Animais , Materiais Biocompatíveis/uso terapêutico , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos ICR , Polietilenoglicóis/farmacologia , Ratos , Ratos Sprague-Dawley , Medicina Regenerativa , Dióxido de Silício/farmacologia
10.
Colloids Surf B Biointerfaces ; 190: 110951, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32172167

RESUMO

Human hair is a readily available source for hair protein-based biomaterial and is increasingly explored as an alternative to existing hemostatic materials. The hair protein is a complex mixture of multiple proteins, which are preferably extracted at relatively high temperatures (50-90 °C) for increasing protein yields. However, the effect of processing temperature on the hemostatic property of the hair derived proteins are not yet well-understood. The objective of the current study was to characterize the influence of thermal treatments (37 °C, 50 °C, 75 °C, 80 °C, and 90 °C) on the (i) secondary structure of different fractions of hair proteins including keratin (40-65 kDa) and keratin-associated proteins (KAPs, 6-30 kDa), and (ii) their capability to precipitate the soluble fibrinogen in an in vitro fibrin clotting assay. Our results indicated that the thermal treatments induced changes to the helical contents of hair-derived protein extracts and also increased the precipitation amount and rate of soluble fibrinogen. While further studies are required to better understand the exact role of hair protein fractions on the coagulation process, the current research suggests that the hair proteins extracted under relatively high temperatures is a prerequisite approach for improving the hemostatic property of human hair-derived proteins.


Assuntos
Fibrinogênio/química , Cabelo/química , Queratinas/química , Temperatura , Hemostasia , Humanos
11.
ACS Nano ; 13(9): 10279-10293, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31483606

RESUMO

Diabetic wound healing and angiogenesis remain a worldwide challenge for both clinic and research. The use of adipose stromal cell derived exosomes delivered by bioactive dressing provides a potential strategy for repairing diabetic wounds with less scar formation and fast healing. In this study, we fabricated an injectable adhesive thermosensitive multifunctional polysaccharide-based dressing (FEP) with sustained pH-responsive exosome release for promoting angiogenesis and diabetic wound healing. The FEP dressing possessed multifunctional properties including efficient antibacterial activity/multidrug-resistant bacteria, fast hemostatic ability, self-healing behavior, and tissue-adhesive and good UV-shielding performance. FEP@exosomes (FEP@exo) can significantly enhance the proliferation, migration, and tube formation of endothelial cells in vitro. In vivo results from a diabetic full-thickness cutaneous wound model showed that FEP@exo dressing accelerated the wound healing by stimulating the angiogenesis process of the wound tissue. The enhanced cell proliferation, granulation tissue formation, collagen deposition, remodeling, and re-epithelialization probably lead to the fast healing with less scar tissue formation and skin appendage regeneration. This study showed that combining bioactive molecules into multifunctional dressing should have great potential in achieving satisfactory healing in diabetic and other vascular-impaired related wounds.


Assuntos
Antibacterianos/farmacologia , Diabetes Mellitus Experimental/patologia , Exossomos/metabolismo , Nanopartículas/química , Neovascularização Fisiológica , Pele/patologia , Raios Ultravioleta , Cicatrização/efeitos dos fármacos , Adesivos/farmacologia , Animais , Bactérias/efeitos dos fármacos , Bandagens , Colágeno/metabolismo , Hemostasia/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Queratinas/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Neovascularização Fisiológica/efeitos dos fármacos , Pele/efeitos dos fármacos , Tecidos Suporte/química
12.
Med Sci Monit ; 25: 2377-2385, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30936416

RESUMO

BACKGROUND In this study we prepared liposome microbubbles loading resveratrol (LMLR) and evaluated its therapeutic effect on injury of gastrocnemius muscle in rats. MATERIAL AND METHODS LMLR was prepared and characterized by particle size, potential, and microscopy, and a rat model of acute blunt injury of gastrocnemius muscle was established. After treatments with resveratrol or LMLR, the therapeutic effects were evaluated by hematoxylin-eosin (HE) staining. The expression of MHCIIB and vimentin in mRNA level was measured by real-time PCR. The expression of desmin and collagen I protein was assessed by immunohistochemistry. RESULTS LMLR showed regular cycle shape in a size of ~1000 nm. LMLR was negatively charged (-30 mV). The in vitro release of LMLR was close to 80% at 10 h and 90% at 48 h. Acute gastrocnemius muscle injury was established in rats and tissue recovery was observed after LMLR treatment as evidenced by HE staining, decreased expression of MHCIIB, and increased expression of vimentin. Moreover, LMLR treatment obviously facilitated desmin expression and reduced collagen I expression. CONCLUSIONS LMLR is effective in treating acute blunt injury of gastrocnemius muscle in rats.


Assuntos
Músculo Esquelético/efeitos dos fármacos , Resveratrol/administração & dosagem , Resveratrol/farmacologia , Animais , Colágeno/análise , Desmina/análise , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/farmacologia , Masculino , Microbolhas/uso terapêutico , Modelos Animais , Ratos , Ratos Sprague-Dawley , Resveratrol/metabolismo
14.
Theranostics ; 9(1): 65-76, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30662554

RESUMO

Rationale: Chronic nonhealing diabetic wound therapy and complete skin regeneration remains a critical clinical challenge. The controlled release of bioactive factors from a multifunctional hydrogel was a promising strategy to repair chronic wounds. Methods: Herein, for the first time, we developed an injectable, self-healing and antibacterial polypeptide-based FHE hydrogel (F127/OHA-EPL) with stimuli-responsive adipose-derived mesenchymal stem cells exosomes (AMSCs-exo) release for synergistically enhancing chronic wound healing and complete skin regeneration. The materials characterization, antibacterial activity, stimulated cellular behavior and in vivo full-thickness diabetic wound healing ability of the hydrogels were performed and analyzed. Results: The FHE hydrogel possessed multifunctional properties including fast self-healing process, shear-thinning injectable ability, efficient antibacterial activity, and long term pH-responsive bioactive exosomes release behavior. In vitro, the FHE@exosomes (FHE@exo) hydrogel significantly promoted the proliferation, migration and tube formation ability of human umbilical vein endothelial cells (HUVECs). In vivo, the FHE@exo hydrogel significantly enhanced the healing efficiency of diabetic full-thickness cutaneous wounds, characterized with enhanced wound closure rates, fast angiogenesis, re-epithelization and collagen deposition within the wound site. Moreover, the FHE@exo hydrogel displayed better healing outcomes than those of exosomes or FHE hydrogel alone, suggesting that the sustained release of exosomes and FHE hydrogel can synergistically facilitate diabetic wound healing. Skin appendages and less scar tissue also appeared in FHE@exo hydrogel treated wounds, indicating its potent ability to achieve complete skin regeneration. Conclusion: This work offers a new approach for repairing chronic wounds completely through a multifunctional hydrogel with controlled exosomes release.


Assuntos
Antibacterianos/administração & dosagem , Produtos Biológicos/administração & dosagem , Pé Diabético/tratamento farmacológico , Exossomos/metabolismo , Hidrogel de Polietilenoglicol-Dimetacrilato/administração & dosagem , Ferimentos e Lesões/tratamento farmacológico , Animais , Produtos Biológicos/isolamento & purificação , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Regeneração/efeitos dos fármacos , Pele/patologia , Cicatrização
15.
Exp Mol Med ; 50(11): 1-15, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30459300

RESUMO

Wound healing is delayed in diabetic patients. Increased apoptosis and endothelial progenitor cell (EPC) dysfunction are implicated in delayed diabetic wound healing. Melatonin, a major secretory product of the pineal gland, promotes diabetic wound healing; however, its mechanism of action remains unclear. Here, EPCs were isolated from the bone marrow of mice. Treatment of EPCs with melatonin alleviated advanced glycation end product (AGE)-induced apoptosis and cellular dysfunction. We further examined autophagy flux after melatonin treatment and found increased light chain 3 (LC3) and p62 protein levels in AGE-treated EPCs. However, lysosome-associated membrane protein 2 expression was decreased, indicating that autophagy flux was impaired in EPCs treated with AGEs. We then evaluated autophagy flux after melatonin treatment and found that melatonin increased the LC3 levels, but attenuated the accumulation of p62, suggesting a stimulatory effect of melatonin on autophagy flux. Blockage of autophagy flux by chloroquine partially abolished the protective effects of melatonin, indicating that autophagy flux is involved in the protective effects of melatonin. Furthermore, we found that the AMPK/mTOR signaling pathway is involved in autophagy flux stimulation by melatonin. An in vivo study also illustrated that melatonin treatment ameliorated impaired wound healing in a streptozotocin-induced diabetic wound healing model. Thus, our study shows that melatonin protects EPCs against apoptosis and dysfunction via autophagy flux stimulation and ameliorates impaired wound healing in vivo, providing insight into its mechanism of action in diabetic wound healing.


Assuntos
Apoptose , Autofagia , Diabetes Mellitus Experimental/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Células Progenitoras Endoteliais/metabolismo , Melatonina/uso terapêutico , Cicatrização , Animais , Células Cultivadas , Células Progenitoras Endoteliais/efeitos dos fármacos , Produtos Finais de Glicação Avançada/metabolismo , Masculino , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Proteínas Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo
16.
Food Funct ; 9(4): 2374-2385, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29589609

RESUMO

Wound therapy remains a clinical challenge due to the poor vascularization during the healing process and the high demand to achieve functional and aesthetically satisfactory scars. Newly-formed blood vessels are necessary for wound healing since they can deliver nutrients and oxygen to the wound area. In this study, the role of leonurine (LN), a traditional Chinese medicine isolated from Herba leonuri, in promoting angiogenesis and its function in wound healing have been investigated. The results of co-culture with human umbilical vein endothelial cells (HUVECs) demonstrated that LN treatment (5-20 µM) could promote the proliferation and migration and enhance the ability of in vitro angiogenesis through up-regulating the mTOR/ERK signaling pathway. Furthermore, a full-thickness cutaneous wound model was used to investigate the healing effect of LN in vivo. Intragastric administration of 20 mg per kg per day LN stimulated the regeneration of more blood vessels at the wound sites, which confirmed the in vitro results of promoting angiogenesis. Due to fast vascularization, the collagen matrix deposition and remodeling processes were also accelerated in LN treated wounds, resulting in efficient wound healing. In summary, LN promoted angiogenesis of endothelial cells in vitro by activating the mTOR/ERK pathway, and could efficiently enhance the angiogenesis and collagen deposition of the regenerated tissue, together with facilitating the wound healing process in vivo. This study provides evidence for LN-stimulated angiogenesis and tissue regeneration in skin wounds, especially in ischemic wounds.


Assuntos
Indutores da Angiogênese/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ácido Gálico/análogos & derivados , Regeneração/efeitos dos fármacos , Pele/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Ferimentos e Lesões/tratamento farmacológico , Animais , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/genética , Ácido Gálico/administração & dosagem , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Neovascularização Patológica , Ratos , Transdução de Sinais/efeitos dos fármacos , Pele/irrigação sanguínea , Pele/metabolismo , Pele/fisiopatologia , Serina-Treonina Quinases TOR/genética , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/genética , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/fisiopatologia
17.
Acta Biomater ; 69: 156-169, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29397318

RESUMO

Wound therapy with a rapid healing performance remains a critical clinical challenge. Cellular delivery is considered to be a promising approach to improve the efficiency of healing, yet problems such as compromised cell viability and functionality arise due to the inefficient delivery. Here, we report the efficient delivery of endothelial progenitor cells (EPCs) with a bioactive nanofibrous scaffold (composed of collagen and polycaprolactone and bioactive glass nanoparticles, CPB) for enhancing wound healing. Under the stimulation of CPB nanofibrous system, the viability and angiogenic ability of EPCs were significantly enhanced through the activation of Hif-1α/VEGF/SDF-1α signaling. In vivo, CPB/EPC constructs significantly enhanced the formation of high-density blood vessels by greatly upregulating the expressions of Hif-1α, VEGF, and SDF-1α. Moreover, owing to the increased local delivery of cells and fast neovascularization within the wound site, cell proliferative activity, granulation tissue formation, and collagen synthesis and deposition were greatly promoted by CPB/EPC constructs resulting in rapid re-epithelialization and regeneration of skin appendages. As a result, the synergistic enhancement of wound healing was observed from CPB/EPC constructs, which suggests the highly efficient delivery of EPCs. CPB/EPC constructs may become highly competitive cell-based therapeutic products for efficient impaired wound healing application. This study may also provide a novel strategy to develop bioactive cell therapy constructs for angiogenesis-related regenerative medicine. STATEMENT OF SIGNIFICANCE: This paper reported a highly efficient local delivery of EPCs using bioactive glass-based CPB nanofibrous scaffold for enhancing angiogenesis and wound regeneration. In vitro study showed that CPB can promote the proliferation, migration, and tube formation of EPCs through upregulation of the Hif-1α/VEGF/SDF-1α signaling pathway, indicating that the bioactivity and angiogenic ability of EPCs can be highly maintained and promoted by the CPB scaffold. Moreover, CPB/EPC constructs effectively stimulated the regeneration of diabetic wounds with satisfactory vascularization and better healing outcomes in a full-thickness wound model, suggesting that the highly efficient delivery of EPCs to wound site facilitates angiogenesis and further leads to wound healing. The high angiogenic capacity and excellent healing ability make CPB/EPC constructs highly competitive in cell-based therapeutic products for efficient wound repair application.


Assuntos
Células Imobilizadas , Células Progenitoras Endoteliais , Nanofibras/química , Neovascularização Fisiológica , Tecidos Suporte/química , Cicatrização , Animais , Células Imobilizadas/citologia , Células Imobilizadas/metabolismo , Células Imobilizadas/transplante , Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/transplante , Masculino , Ratos , Ratos Sprague-Dawley
18.
J Cell Mol Med ; 22(3): 1583-1600, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29278309

RESUMO

Attenuating oxidative stress-induced damage and promoting endothelial progenitor cell (EPC) differentiation are critical for ischaemic injuries. We suggested monotropein (Mtp), a bioactive constituent used in traditional Chinese medicine, can inhibit oxidative stress-induced mitochondrial dysfunction and stimulate bone marrow-derived EPC (BM-EPC) differentiation. Results showed Mtp significantly elevated migration and tube formation of BM-EPCs and prevented tert-butyl hydroperoxide (TBHP)-induced programmed cell death through apoptosis and autophagy by reducing intracellular reactive oxygen species release and restoring mitochondrial membrane potential, which may be mediated viamTOR/p70S6K/4EBP1 and AMPK phosphorylation. Moreover, Mtp accelerated wound healing in rats, as indicated by reduced healing times, decreased macrophage infiltration and increased blood vessel formation. In summary, Mtp promoted mobilization and differentiation of BM-EPCs and protected against apoptosis and autophagy by suppressing the AMPK/mTOR pathway, improving wound healing in vivo. This study revealed that Mtp is a potential therapeutic for endothelial injury-related wounds.


Assuntos
Indutores da Angiogênese/farmacologia , Antioxidantes/farmacologia , Células Progenitoras Endoteliais/efeitos dos fármacos , Iridoides/farmacologia , Ferida Cirúrgica/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/efeitos dos fármacos , Autofagia/genética , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Ferida Cirúrgica/genética , Ferida Cirúrgica/metabolismo , Ferida Cirúrgica/patologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , terc-Butil Hidroperóxido/antagonistas & inibidores , terc-Butil Hidroperóxido/farmacologia
19.
Acta Pharmacol Sin ; 39(3): 393-404, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29219948

RESUMO

Wound therapy remains a clinical challenge due to the complexity of healing pathology and high demand of achieving functional and aesthetically satisfactory scars. Newly formed blood vessels are essential for tissue repair since they can support cells at the wound site with nutrition and oxygen. In this study, we investigated the effects of Asperosaponin VI (ASA VI) isolated from a traditional Chinese medicine, the root of Dipsacus asper Wall, in promoting angiogenesis, as well as its function in wound therapeutics. Treatment of human umbilical vein endothelial cells (HUVECs) with ASA VI (20-80 µg/mL) dose-dependently promoted the proliferation, migration and enhanced their angiogenic ability in vitro, which were associated with the up-regulated HIF-1α/VEGF signaling. Full-thickness cutaneous wound model rats were injected with ASA VI (20 mg·kg-1·d-1, iv) for 21 d. Administration of ASA VI significantly promoted the cutaneous wound healing, and more blood vessels were observed in the regenerated tissue. Due to rapid vascularization, the cellular proliferation status, granulation tissue formation, collagen matrix deposition and remodeling processes were all accelerated, resulting in efficient wound healing. In summary, ASA VI promotes angiogenesis of HUVECs in vitro via up-regulating the HIF-1α/VEGF pathway, and efficiently enhances the vascularization in regenerated tissue and facilitates wound healing in vivo. The results reveal that ASA VI is a potential therapeutic for vessel injury-related wounds.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Neovascularização Fisiológica/fisiologia , Saponinas/farmacologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Cicatrização/efeitos dos fármacos , Animais , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Ratos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
20.
ACS Appl Mater Interfaces ; 9(10): 8460-8470, 2017 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-28240539

RESUMO

The lack of safe and efficient drug and gene delivery vectors has become a major obstacle for the clinical applications of drug and nonviral gene therapy. To date, for nonviral gene vectors, most studies are focused on cationic polymers, liposomes, and modified inorganic nanoparticles which have shown high cellular toxicity, low transfection efficiency, or nondegradation. Additionally, few biodegradable biomaterials demonstrate intrinsic high binding abilities to both drug and gene. Bioactive glasses (BGs) have achieved successful applications in bone regeneration due to their high biocompatibility and biodegradation. Here, for the first time, we demonstrate the intrinsic ultrahigh drug and miRNA binding ability of bioactive glass nanoparticles (BGNs) without any cationic polymer modification. BGNs demonstrate an over 45-fold improvement in hydrophilic drug loading (diclofenac sodium) and 7-fold enhancement in miRNA binding over their corresponding silica nanoparticles. The hydrophilic drug loading ability of BGNs (>45 wt % loading) is also higher than that of most other reported inorganic nanoparticles, including mesoporous silica nanoparticles. BGNs show significantly lower cytotoxicity and higher cellular uptake and miRNA transfection efficiency compared to those of commercial transfection reagents polyethylenimine and lipofectamine 3000. Our results demonstrate that BGNs may become a new competitive vehicle for drug and gene delivery applications. This study may also provide a new strategy to develop novel biomaterials with intrinsic drug and gene binding ability for disease therapy.


Assuntos
Nanopartículas , Técnicas de Transferência de Genes , Vidro , MicroRNAs , Transfecção
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