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1.
Polymers (Basel) ; 16(10)2024 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-38794576

RESUMO

Acute pneumonia (AP), triggered primarily by pathogens like bacteria and viruses, is a leading cause of human mortality. Ribavirin, a broad-spectrum antiviral agent, plays a pivotal role in the treatment of AP. However, its therapeutic use is hindered by the need for high dosages and the associated cardiac and hepatic toxicities. In this study, we synthesized polyethylene glycol-modified cationic liposomes to encapsulate ribavirin (RBV-PCL) and formulated it into a spray, aiming to enhance the effectiveness of RBV through respiratory administration. Lipopolysaccharide (LPS), a compound known to induce AP models in animals, was utilized in our research. Successfully, we established an acute pneumonia model in mice using aerosol inhalation. Through animal experiments, we investigated the therapeutic effects of RBV-PCL on mice with AP. In vivo studies revealed promising results. RBV-PCL effectively prolonged the survival of mice with AP, significantly reduced the levels of inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and inhibited the infiltration of neutrophils in the lungs and spleens of mice. These findings suggest that RBV-PCL can effectively suppress the inflammatory response in mice with AP, thus holding significant potential as a novel therapeutic approach for the treatment of acute pneumonia.

2.
J Biomater Appl ; : 8853282241258311, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38820587

RESUMO

BACKGROUND: Diclofenac sodium (DS) and celecoxib (CEL) are primary anti-inflammatory agents used in the treatment of osteoarthritis (OA). Formulating these drugs into extended-release versions can effectively address the issue of multiple daily doses. In this study, we designed and synthesized a novel poly(lactic-co-glycolic acid) (PLGA) nanoliposome as a dual-drug delivery sustained-release formulation (PPLs-DS-CEL) to achieve long-lasting synergistic treatment of OA with both DS and CEL. METHODS: PPLs-DS-CEL was synthesized by the reverse evaporation method and evaluated for its physicochemical properties, encapsulation efficiency, drug release kinetics and biological properties. A rat OA model was established to assess the therapeutic efficacy and biosafety of PPLs-DS-CEL. RESULTS: The particle size of PPLs-DS-CEL was 218.36 ± 6.27 nm, with a potential of 32.56 ± 3.28 mv, indicating a homogeneous vesicle size. The encapsulation of DS and CEL by PPLs-DS-CEL was 95.18 ± 4.43% and 93.63 ± 5.11%, with drug loading of 9.56 ± 0.32% and 9.68 ± 0.34%, respectively. PPLs-DS-CEL exhibited low cytotoxicity and hemolysis, and was able to achieve long-lasting synergistic analgesic and anti-inflammatory therapeutic effects in OA through slow release of DS and CEL, demonstrating good biosafety properties. CONCLUSION: This study developed a novel sustained-release nanoliposomes formulation capable of co-loading two drugs for the long-acting synergistic treatment of OA. It offers a new and effective therapeutic strategy for OA treatment in the clinic settings and presents a promising approach for drug delivery systems.

3.
Front Biosci (Landmark Ed) ; 29(3): 120, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38538251

RESUMO

BACKGROUND: Osteosarcoma cells are prone to metastasis, and the mechanism of N6-methyladenosine (m6A) methylation modification in this process is still unclear. Methylation modification of m6A plays an important role in the development of osteosarcoma, which is mainly due to abnormal expression of enzymes related to methylation modification of m6A, which in turn leads to changes in the methylation level of downstream target genes messenger RNA (mRNA) leading to tumor development. METHODS: We analyzed the expression levels of m6A methylation modification-related enzyme genes in GSE12865 whole-genome sequencing data. And we used shRNA (short hairpin RNA) lentiviral interference to interfere with METTL3 (Methyltransferase 3) expression in osteosarcoma cells. We studied the cytological function of METTL3 by Cell Counting Kit-8 (CCK8), flow cytometry, migration and other experiments, and the molecular mechanism of METTL3 by RIP (RNA binding protein immunoprecipitation), Western blot and other experiments. RESULTS: We found that METTL3 is abnormally highly expressed in osteosarcoma and interferes with METTL3 expression in osteosarcoma cells to inhibit metastasis, proliferation, and apoptosis of osteosarcoma cells. We subsequently found that METTL3 binds to the mRNA of CBX4 (chromobox homolog 4), a very important regulatory protein in osteosarcoma metastasis, and METTL3 regulates the mRNA and protein expression of CBX4. Further studies revealed that METTL3 inhibited metastasis of osteosarcoma cells by regulating CBX4. METTL3 has been found to be involved in osteosarcoma cells metastasis by CBX4 affecting the protein expression of matrix metalloproteinase 2 (MMP2), MMP9, E-Cadherin and N-Cadherin associated with osteosarcoma cells metastasis. CONCLUSIONS: These results suggest that the combined action of METTL3 and CBX4 plays an important role in the regulation of metastasis of osteosarcoma, and therefore, the METTL3-CBX4 axis pathway may be a new potential therapeutic target for osteosarcoma.


Assuntos
Adenina , Neoplasias Ósseas , Metaloproteinase 2 da Matriz , Osteossarcoma , Humanos , Adenina/análogos & derivados , Epigênese Genética , Ligases/genética , Metaloproteinase 2 da Matriz/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , Osteossarcoma/genética , Osteossarcoma/secundário , Proteínas do Grupo Polycomb/genética , RNA Mensageiro/genética , RNA Interferente Pequeno , Neoplasias Ósseas/patologia
4.
J Control Release ; 367: 620-636, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38311244

RESUMO

Chemotherapeutic efficacy for pancreatic cancer is severely compromised by limited drug availability to tumor cells. Herein, we constructed a cancer cell membrane-fused liposome containing a siATG5-loaded calcium phosphate (CaP) core, termed CLip@siATG5. Through cancer cell membrane camouflage, the liposomes evaded immune clearance, actively infiltrated tumor tissues, and were preferentially taken up by homotypic tumor cells. Then, siATG5 escaped from the endosomes and was liberated in the cytoplasm, mainly benefiting from CaP dissolution-induced endosome rupture and liposome disassembly in acidic endosomes. The released siATG5 silenced autophagy protein 5 (ATG5) to inhibit autophagy, starving tumor cells. An alternative nutrient procurement pathway, macropinocytosis, was then upregulated in the cells, leading to increased uptake of the albumin-bound chemotherapeutic agent (nanoparticle albumin-bound paclitaxel (Nab-PTX)). Finally, in a murine pancreatic cancer model, CLip@siATG5 combined with Nab-PTX exerted superior efficacy to a twofold dose of Nab-PTX while avoiding its toxicity. Overall, we justified enhancing chemotherapeutic delivery by modulating the pancreatic cancer cell metabolism, which will enlighten the development of more effective chemotherapeutic adjuvants for pancreatic cancer in the future.


Assuntos
Nanopartículas , Neoplasias Pancreáticas , Humanos , Animais , Camundongos , Lipossomos/uso terapêutico , Paclitaxel/uso terapêutico , Paclitaxel/farmacologia , Neoplasias Pancreáticas/patologia , Albuminas , Pâncreas/metabolismo , Membrana Celular/metabolismo , Linhagem Celular Tumoral , Paclitaxel Ligado a Albumina/farmacologia
5.
J Cell Biochem ; 125(1): 100-114, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38031891

RESUMO

Osteoporosis (OP) is a bone remodeling disease characterized by an imbalance between bone resorption and formation. Osteoclasts are the primary therapeutic targets for treating bone destruction. Koumine (KM), the most bioactive component in Gelsemium alkaloids, exhibits antitumor, immunosuppressive, anti-inflammatory, and analgesic properties. However, the effects of bone loss have not been well studied. This study conducted in vitro and in vivo verification experiments on KM. The results showed that KM inhibited bone resorption and tartrate-resistant acid phosphatase positive (TRAP+) osteoclasts development by mature osteoclasts in a dose-dependent manner. Moreover, KM prevented OVX-induced OP in vivo and potentially inhibited ubiquitination, a process closely related to various biological activities, including protein interaction, transcription, and transmembrane signal transduction regulation, especially within the nuclear factor-κB (NF-κB) pathway. Previous studies have demonstrated that several proteins ubiquitination promotes osteoclastogenesis, our study indicated that KM inhibits early NF-κB activation and receptor activator of NF-κB ligand induced ubiquitination, a critical factor in osteoclast differentiation. In conclusion, our research suggests that KM holds potential as an effective therapeutic agent for OP.


Assuntos
Reabsorção Óssea , Alcaloides Indólicos , Osteoporose , Feminino , Humanos , NF-kappa B/metabolismo , Osteoclastos/metabolismo , Osteogênese , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/prevenção & controle , Reabsorção Óssea/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Osteoporose/prevenção & controle , Ovariectomia/efeitos adversos , Ligante RANK/metabolismo , Diferenciação Celular
6.
Front Immunol ; 14: 1164278, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37063929

RESUMO

Stroke, especially ischemic stroke, is an important cause of neurological morbidity and mortality worldwide. Growing evidence suggests that the immune system plays an intricate function in the pathophysiology of stroke. Gelsevirine (Gs), an alkaloid from Gelsemium elegans, has been proven to decrease inflammation and neuralgia in osteoarthritis previously, but its role in stroke is unknown. In this study, the middle cerebral artery occlusion (MCAO) mice model was used to evaluate the protective effect of Gs on stroke, and the administration of Gs significantly improved infarct volume, Bederson score, neurobiological function, apoptosis of neurons, and inflammation state in vivo. According to the data in vivo and the conditioned medium (CM) stimulated model in vitro, the beneficial effect of Gs came from the downregulation of the over-activity of microglia, such as the generation of inflammatory factors, dysfunction of mitochondria, production of ROS and so on. By RNA-seq analysis and Western-blot analysis, the JAK-STAT signal pathway plays a critical role in the anti-inflammatory effect of Gs. According to the results of molecular docking, inhibition assay, and thermal shift assay, the binding of Gs on JAK2 inhibited the activity of JAK2 which inhibited the over-activity of JAK2 and downregulated the phosphorylation of STAT3. Over-expression of a gain-of-function STAT3 mutation (K392R) abolished the beneficial effects of Gs. So, the downregulation of JAK2-STAT3 signaling pathway by Gs contributed to its anti-inflammatory effect on microglia in stroke. Our study revealed that Gs was benefit to stroke treatment by decreasing neuroinflammation in stroke as a potential drug candidate regulating the JAK2-STAT3 signal pathway.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Camundongos , Animais , Isquemia Encefálica/metabolismo , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/metabolismo , Microglia/metabolismo , Doenças Neuroinflamatórias , Simulação de Acoplamento Molecular , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Inflamação/metabolismo , Anti-Inflamatórios/uso terapêutico
7.
J Mater Chem B ; 11(11): 2455-2465, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36810638

RESUMO

Nanomedicines have been widely used for cancer therapy, while controlling their activity for effective and safe treatment remains a big challenge. Herein, we report the development of a second near-infrared (NIR-II) photoactivatable enzyme-loaded nanomedicine for enhanced cancer therapy. Such a hybrid nanomedicine contains a thermoresponsive liposome shell loaded with copper sulfide nanoparticles (CuS NPs) and glucose oxidase (GOx). The CuS nanoparticles mediate the generation of local heat under 1064 nm laser irradiation, which not only can be used for NIR-II photothermal therapy (PTT), but also leads to the destruction of the thermal-responsive liposome shell to achieve the on-demand release of CuS nanoparticles and GOx. In a tumor microenvironment, GOx oxidizes glucose to produce hydrogen peroxide (H2O2) that acts as a medium to promote the efficacy of chemodynamic therapy (CDT) by CuS nanoparticles. This hybrid nanomedicine enables the synergetic action of NIR-II PTT and CDT to obviously improve efficacy without remarkable side effects via NIR-II photoactivatable release of therapeutic agents. Such a hybrid nanomedicine-mediated treatment can achieve complete ablation of tumors in mouse models. This study provides a promising nanomedicine with photoactivatable activity for effective and safe cancer therapy.


Assuntos
Neoplasias , Terapia Fototérmica , Animais , Camundongos , Nanomedicina , Lipossomos/uso terapêutico , Peróxido de Hidrogênio/uso terapêutico , Neoplasias/tratamento farmacológico , Microambiente Tumoral
8.
Tissue Cell ; 81: 102032, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36701898

RESUMO

Ellagic acid (EA), found in fruits and foods, has been shown to be effective in the treatment of breast, colon and bladder cancer. However, due to the complexity of colon cancer, the therapeutic mechanism of EA for colon cancer is still unclear. Cell Counting Kit-8 (CCK-8) assay were employed to investigate the cell proliferation. Western blotting and flow cytometry assays were utilized to investigate apoptosis and autophagy in CRC cells (HCT116), respectively. Moreover, western blotting and luciferase reporter assays were evaluated the effect of EA on AMPK/mTOR pathway. Through flow cytometry analysis, EA could promote the apoptosis of HCT116 cells. In addition, EA can reduce the phosphorylation of mTOR, promoted phosphorylation of AMPK, and induced autophagy in HCT116 cells. Also, Dorsomorphin pretreatment can reduce the expression of autophagy protein, which indicates that EA induces autophagy through AMPK/mTOR pathway. These results suggest that EA inhibits the growth of colon cancer through AMPK/mTOR pathway and induces apoptosis and protective autophagy.


Assuntos
Proteínas Quinases Ativadas por AMP , Neoplasias do Colo , Humanos , Proteínas Quinases Ativadas por AMP/metabolismo , Ácido Elágico/farmacologia , Ácido Elágico/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Neoplasias do Colo/tratamento farmacológico , Apoptose , Autofagia
9.
Curr Pharm Des ; 28(34): 2825-2834, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36056848

RESUMO

BACKGROUND: Acute kidney injury (AKI) is closely linked to the pathogenesis of sepsis. Oxidative stress can affect the development of AKI by increasing damage to renal tubular epithelial cells. Astragaloside IV (AS-IV) is a natural saponin widly verified beneficial for ameliorating sepsis-induced kidney injury. However, the underlying mechanisms of AS-IV on relieving oxidative stress in renal tubular epithelial cells are yet to be established. PURPOSE: We aimed to investigate whether AS-IV could attenuate mitochondrialdysfunction and apoptosis in renal tubular epithelial cells and reveal its underlying mechanisms. METHODS: For the in vivo study, mice were divided into four groups (n=6): sham+saline, CLP+saline, CLP+ASIV- low dosage (5 mg/kg), CLP+AS-IV-high dosage (10 mg/kg), After 6 h or 24 h of treatment, the renal injuries were assessed based on related parameters of blood, protein and histopathological examination. Immunohistochemistry and ELISA were used to examine renal function. The molecular mechanism of AS-IV inhibited apoptosis and mitochondrial damage were monitored by flow cytometry and western blot analysis in HK-2 cells. RESULTS: We found that AS-IV ameliorates renal vacuolization, brush border loss, mitochondrial ultrastructure changes in sepsis-induced AKI, and the apoptosis and oxidative damage were greatly mitigated by AS-IV (10 mg/kg)-treated group. Abnormal changes in mitochondrial morphology and mitochondrial membrane potential were alleviated, and the expression of mitochondrial complex protein I (NDUFB8) and mitochondrial complex protein II (SDHB8) increased with (10 mg/kg)-treated group. Tubular epithelial cell apoptosis in AS-IV (20 µM)-treated cells was reduced by the Bax and cleaved caspase3 pathway. CONCLUSION: These studies demonstrated that AS-IV protects against sepsis-induced kidney tubular injury by alleviating oxidative stress, mitochondrial dysfunction possibly associated with the restored cleaved caspase3 pathway.


Assuntos
Injúria Renal Aguda , Saponinas , Sepse , Camundongos , Animais , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/etiologia , Saponinas/farmacologia , Saponinas/uso terapêutico , Saponinas/metabolismo , Sepse/complicações , Sepse/tratamento farmacológico , Apoptose , Mitocôndrias/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Células Epiteliais/metabolismo
10.
J Funct Biomater ; 13(3)2022 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-35893459

RESUMO

The purpose of this study is to fabricate different anti-cancer drug-eluted chitosan microspheres for combination therapy of osteosarcoma. In this study, electrospray in combination with ground liquid nitrogen was utilized to manufacture the microspheres. The size of obtained chitosan microspheres was uniform, and the average diameter was 532 µm. The model drug release rate and biodegradation rate of chitosan microspheres could be controlled by the glutaraldehyde vapor crosslinking time. Then the 5-fluorouracil (5-FU), paclitaxel (PTX), and Cis-dichlorodiammine-platinum (CDDP) eluted chitosan microspheres were prepared, and two osteosarcoma cell lines, namely, HOS and MG-63, were selected as cell models for in vitro demonstration. We found the 5-FU microspheres, PTX microspheres, and CDDP microspheres could significantly inhibit the growth and migration of both HOS and MG-63 cells. The apoptosis of both cells treated with 5-FU microspheres, PTX microspheres, and CDDP microspheres was significantly increased compared to the counterparts of control and blank groups. The anti-cancer drug-eluted chitosan microspheres show great potential for the treatment of osteosarcoma.

11.
Front Immunol ; 13: 856327, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35296098

RESUMO

Coronavirus Disease 2019 (COVID-19) infected by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been declared a public health emergency of international concerns. Cytokine storm syndrome (CSS) is a critical clinical symptom of severe COVID-19 patients, and the macrophage is recognized as the direct host cell of SARS-CoV-2 and potential drivers of CSS. In the present study, peramivir was identified to reduce TNF-α by partly intervention of NF-κB activity in LPS-induced macrophage model. In vivo, peramivir reduced the multi-cytokines in serum and bronchoalveolar lavage fluid (BALF), alleviated the acute lung injury and prolonged the survival time in mice. In human peripheral blood mononuclear cells (hPBMCs), peramivir could also inhibit the release of TNF-α. Collectively, we proposed that peramivir might be a candidate for the treatment of COVID-19 and other infections related CSS.


Assuntos
Tratamento Farmacológico da COVID-19 , Síndrome da Liberação de Citocina , Ácidos Carbocíclicos , Animais , Síndrome da Liberação de Citocina/tratamento farmacológico , Guanidinas , Humanos , Leucócitos Mononucleares , Camundongos , SARS-CoV-2 , Fator de Necrose Tumoral alfa
12.
Biochem Pharmacol ; 198: 114975, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35202579

RESUMO

Low-grade and chronic inflammation is recognized as an important mediator of the pathogenesis of osteoarthritis (OA). The aim of current work was to test the therapeutic effects of gelsevirine on age-related and surgically induced OA in mice and elucidate the underlying mechanism. The in vitro studies revealed that gelsevirine treatment mitigated IL-1ß-induced inflammatory response and degeneration in cultured chondrocytes, evidenced by reduced apoptosis and expression of MMP3, MMP9, MMP13, IFNß, TNFɑ, and Il6, and increased expression of Col2A and Il10. Furthermore, gelsevirine treatment in IL-1ß-stimulated chondrocytes reduced the protein expression of stimulator of IFN genes (STING, also referred to Tmem173) and p-TBK1. Importantly, gelsevirine treatment did not provide further protection in STING-deficient chondrocytes against IL-1ß stimulation. The in vivo studies revealed that gelsevirine treatment mitigated articular cartilage destruction in age-related and destabilization of the medial meniscus (DMM)-induced OA. Similarly, gelsevirine treatment did not provide further beneficial effects against OA in STING deficient mice. Mechanistically, gelsevirine promoted STING K48-linked poly-ubiquitination and MG-132 (a proteasome inhibitor) reversed the inhibitive effects of gelsevirine on IL-1ß-induced activation of STING/TBK1 pathway in chondrocytes. Collectively, we identify that gelsevirine targets STING for K48 ubiquitination and degradation and improves age-related and surgically induced OA in mice.


Assuntos
Cartilagem Articular , Proteínas de Membrana , Osteoartrite , Animais , Cartilagem Articular/metabolismo , Células Cultivadas , Condrócitos , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo
13.
J Mater Chem B ; 10(12): 1960-1968, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-35195150

RESUMO

Effective treatment of colorectal cancer is important to improve the quality of life for patients, which however remains a great challenge in the clinic. Herein, we report the construction of a composite hydrogel that can modulate the tumor redox microenvironment for enhanced sonodynamic therapy (SDT) of colorectal cancer. Such composite hydrogels consist of sonosensitizer protoporphyrin IX (PpIX)-conjugated manganese oxide (MnO2) nanoparticles and a glutathione (GSH) inhibitor after Ca2+ induced in situ gelation in the tumor site. In the acidic tumor microenvironment, MnO2 nanoparticles can produce oxygen to relieve hypoxia and thus amplify the generation of reactive oxygen species (ROS) via the SDT effect. Meanwhile, the GSH inhibitor blocks the intracellular synthesis of GSH, thus leading to further enhanced SDT action. As such, composite hydrogel-mediated enhanced SDT can obviously inhibit the growth of subcutaneous colorectal cancer in mouse models. This study thus offers a tumor microenvironment modulating platform for enhanced therapy of colorectal cancer.


Assuntos
Neoplasias Colorretais , Microambiente Tumoral , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Glutationa/metabolismo , Humanos , Hidrogéis/farmacologia , Compostos de Manganês , Camundongos , Oxirredução , Óxidos , Qualidade de Vida
14.
Pharmaceuticals (Basel) ; 16(1)2022 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-36678499

RESUMO

One effective treatment for postmenopausal osteoporosis is to inhibit osteoclasts and subsequent bone resorption. In our study, we demonstrated that acacetin, a flavone with potential therapeutic effects in infections, cancers, and several metabolic disorders, inhibited osteoclast differentiation and bone resorption in vitro. For improving the efficacy of acacetin in vivo, we developed an acid-sensitive bone-targeting delivery system composed of an acid-sensitive linker (N-ε-maleimidocaproic acid hydrazide, EMCH) for ensuring an effective release of acacetin at the site of action and a hydrophilic aspartic acid hexapeptide ((Asp)6, D6) as the effective bone targeting agent. Our results revealed that Acacetin-EMCH-D6 specifically bound to the bone surface once administrated in vivo, prolonged the retention time in bone and released acacetin at the osteoclastic bone resorption sites where the acidity is higher. We further demonstrated that, in ovariectomy-induced osteoporosis mice, treatment with Acacetin-EMCH-D6 inhibited osteoclast formation and increased trabecular bone mass. On the contrary, neither acacetin nor EMCH-D6 with the same dosage alone showed significant anti-osteoporosis effects in vivo. Mechanistically, targeted delivery of acacetin to the bone resorption sites by Acacetin-EMCH-D6 inhibited autophagy through activating PI3K/AKT/mTOR pathway in osteoclasts, while the activation of autophagy by rapamycin partially reversed the inhibitory effects of acacetin in vitro and in vivo. In summary, our study, for the first time, showed that the acid-sensitive bone-targeting delivery system carrying acacetin was effective for the treatment of postmenopausal osteoporosis. Thus, targeted delivery of acacetin using Acacetin-EMCH-D6 to bone resorption sites is a promising therapy for osteoporosis.

15.
Gels ; 7(4)2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34842679

RESUMO

Accumulating evidence has suggested the significant potential of chemically modified hydrogels in bone regeneration. Despite the progress of bioactive hydrogels with different materials, structures and loading cargoes, the desires from clinical applications have not been fully validated. Multiple biological behaviors are orchestrated precisely during the bone regeneration process, including bone marrow mesenchymal stem cells (BMSCs) recruitment, osteogenic differentiation, matrix calcification and well-organized remodeling. Since matrix metalloproteinases play critical roles in such bone metabolism processes as BMSC commitment, osteoblast survival, osteoclast activation matrix calcification and microstructure remodeling, matrix metalloproteinase (MMP) cleavable peptides-based hydrogels could respond to various MMP levels and, thus, accelerate bone regeneration. In this review, we focused on the MMP-cleavable peptides, polymers, functional modification and crosslinked reactions. Applications, perspectives and limitations of MMP-cleavable peptides-based hydrogels for bone regeneration were then discussed.

16.
Nanoscale ; 13(37): 15755-15762, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34528043

RESUMO

Incorporation of ultrathin nanosheets with dopants/defects shows great potential to enable metal (oxy)-hydroxide electrocatalysts with enhanced oxygen evolution reaction (OER) performance via the regulation of atomic structure and bonding arrangements. However, it remains challenging in synthesis especially for such dual control and at large scale. In this study, we present a stepwise chemical oxidation route, involving phase transition and reconstruction processes, to access ultrathin CoOOH nanosheets with a thickness of ca. 4 nm and abundant oxygen vacancies. Other transition metals were also doped into CoOOH nanosheets through this strategy. Among them, the optimized FeCoOOH nanosheets demonstrated an efficient OER activity with overpotential as low as 252 mV (current density: 10 mA cm-2) and excellent stability. A high and stable solar-to-hydrogen efficiency of 10.5% was acquired when FeCoOOH nanosheets were used as the anode in a constructed water splitting device driven by solar energy. This study offers a noble and facile strategy for potentially scalable preparation of atom-modulated ultrathin metal (oxy)-hydroxide nanosheets, and also demonstrates the OER applications.

17.
Biochem Pharmacol ; 188: 114541, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33812857

RESUMO

The acute phase response, as a component of the innate immune system, is part of the first line of defense against invading pathogens. The Stimulator of Interferon Genes (STING) pathway initiates innate immune responses upon recognition of exogenous bacterial and viral DNA. However, whether STING signaling pathway plays any roles in regulating acute phase response during bacterial infection remains unknown. In this study, we used STING-deficient (Tmem173gt) and wildtype mice to investigate acute phase responses to bacterial infection (Escherichia coli, E. coli) and test the effect of exogenous cyclic GMP-AMP (cGAMP, a STING agonist) treatment. Bacterial infection of STING-deficient mice resulted in an increase in mortality and bacterial dissemination. Also, inflammation-induced acute phase response was drastically reduced in STING-deficient mice, showing significant reduction in expression of cytokine TNF-α and acute phase proteins. In contrast, exogenous cGAMP treatment enhanced inflammation-induced acute phase response by increasing the expression of TNF-α and acute phase proteins. Also, cGAMP accelerated bacterial clearance and improved survival rate of wildtype mice, but not STING-deficient mice. Interestingly, cGAMP treatment mitigated bacterial infection induced liver injury in both wildtype and STING-deficient mice. Further in vitro evidence showed that cGAMP treatment retarded TNF-α-mediated hepatocyte apoptosis, potentially accelerating autophagy. Taken together, our results indicated that cGAMP/STING signaling pathway is critical for organism to initiate blood-borne innate immune-responses to defend bacterial infection, and cGAMP is envisaged as a drug candidate for further clinical trial.


Assuntos
Reação de Fase Aguda/metabolismo , Reação de Fase Aguda/prevenção & controle , AMP Cíclico/administração & dosagem , GMP Cíclico/administração & dosagem , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/prevenção & controle , Proteínas de Membrana/deficiência , Reação de Fase Aguda/genética , Animais , Escherichia coli , Infecções por Escherichia coli/genética , Hepatócitos/metabolismo , Hepatócitos/microbiologia , Masculino , Proteínas de Membrana/agonistas , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
18.
J Nanobiotechnology ; 19(1): 31, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33482834

RESUMO

BACKGROUND: Effective methods to deliver therapeutic genes to solid tumors and improve their bioavailability are the main challenges of current medical research on gene therapy. The development of efficient non-viral gene vector with tumor-targeting has very important application value in the field of cancer therapy. Proteolipid integrated with tumor-targeting potential of functional protein and excellent gene delivery performance has shown potential for targeted gene therapy. RESULTS: Herein, we prepared transferrin-modified liposomes (Tf-PL) for the targeted delivery of acetylcholinesterase (AChE) therapeutic gene to liver cancer. We found that the derived Tf-PL/AChE liposomes exhibited much higher transfection efficiency than the commercial product Lipo 2000 and shown premium targeting efficacy to liver cancer SMMC-7721 cells in vitro. In vivo, the Tf-PL/AChE could effectively target liver cancer, and significantly inhibit the growth of liver cancer xenografts grafted in nude mice by subcutaneous administration. CONCLUSIONS: This study proposed a transferrin-modified proteolipid-mediated gene delivery strategy for targeted liver cancer treatment, which has a promising potential for precise personalized cancer therapy.


Assuntos
Acetilcolinesterase/genética , Técnicas de Transferência de Genes , Lipossomos/química , Neoplasias Hepáticas/terapia , Plasmídeos/genética , Transferrina/química , Animais , Linhagem Celular Tumoral , Feminino , Terapia Genética , Humanos , Neoplasias Hepáticas/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Plasmídeos/administração & dosagem , Plasmídeos/uso terapêutico , Transfecção
19.
Biomed Pharmacother ; 131: 110643, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32846329

RESUMO

Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has been widely spread in the world with a high mortality. Cytokine storm syndrome (CSS) and acute lung injury caused by SARS-CoV-2 infection severely threaten the patients. With the purpose to find effective and low-toxic drugs to mitigate CSS, entecavir and imipenem were identified to reduce TNF-α using a LPS-induced macrophage model from the anti-infective drug library. Entecavir and imipenem efficiently suppressed the release of inflammatory cytokines by partly intervention of NF-κB activity. The acute lung injury was also alleviated and the survival time was prolonged in mice. In addition, entecavir and imipenem inhibited the release of TNF-α and IL-10 in human peripheral blood mononuclear cells (hPBMCs). Collectively, we proposed that entecavir and imipenem might be candidates for the treatment of CSS.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Guanina/análogos & derivados , Imipenem/farmacologia , Pneumonia Viral/tratamento farmacológico , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/virologia , Animais , COVID-19 , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/virologia , Citocinas/imunologia , Reposicionamento de Medicamentos , Guanina/farmacologia , Humanos , Interleucina-10/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Lipopolissacarídeos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pandemias , Pneumonia Viral/complicações , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Tratamento Farmacológico da COVID-19
20.
Phys Chem Chem Phys ; 22(25): 14255-14260, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32555873

RESUMO

Water oxidation is a vital step in both natural and artificial photosynthetic processes. However, the effect of second coordination sphere for efficient oxygen evolution electrocatalysts has rarely been studied, becoming a bottleneck in many energy-related issues. In this article, the cobalt phosphonate (NH3C6H4NH3)Co2(hedpH)2·H2O (Co-PDA) displayed decent electrocatalytic water oxidation activity in 50 mM PBS solution (pH 7.0), comparable to the activity of state-of-the-art IrO2. Moreover, it exhibited a 160 mV lower onset potential and 6 times higher TOF than those of the counterpart, (NH4)2Co2(hedpH)2 (Co-NH4+), which existed with the same Co active center, while surrounded by different ligands. The related mechanistic studydemonstrates that the ligand in Co-PDA would benefit the proton-coupled electron transfer (PCET) processes and the formation of high valence state Co(iv).

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