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1.
Biol Pharm Bull ; 43(8): 1172-1178, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741937

RESUMO

The sodium salt of isosteviol (STVNa) is a beyerane diterpene synthesized through acid hydrolysis of stevioside. STVNa improves multiple types of tissue injuries. However, it is not known how isosteviol sodium affects high-fat and high cholesterol diet (HFD)-induced kidney. Therefore, in this study we examined the potential molecular mechanism underlying STVNa mediated protective effect against high fat/high cholesterol-induced kidney dysfunction in HFD-induced kidney injury. Sprague-Dawley (SD) rats were allocated into six groups: the normal group, HFD group and HFD treated with three doses of STVNa, fenofibrate treatment group. The results indicated that HFD induced kidney injury evident by a 60% increase in serum creatinine (CRE) leves. In addition, there was a significant accumulation of triglycerides (approx. 60%), fatty acids (approx. 50%) and total cholesterol (approx. 2.5 fold) in the kidneys. STVNa inhibited HFD-induced kidney injury evident by reducing the increased levels of serum CRE. Specifically, STVNa attenuated HFD-induced kidney injury by inhibiting inflammation, oxidative stress, and apoptosis. These findings indicate that STVNa has a therapeutic potential for HFD-induced kidney dysfunction. The mechanisms of this pharmacological effect are through the inhibition of inflammation, oxidative stress and apoptosis.

2.
Protein Cell ; 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737864

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis due to limited therapeutic options. This study examines the roles of genome-wide association study identified PDAC-associated genes as therapeutic targets. We have identified HNF4G gene whose silencing most effectively repressed PDAC cell invasiveness. HNF4G overexpression is induced by the deficiency of transcriptional factor and tumor suppressor SMAD4. Increased HNF4G are correlated with SMAD4 deficiency in PDAC tumor samples and associated with metastasis and poor survival time in xenograft animal model and in patients with PDAC (log-rank P = 0.036; HR = 1.60, 95% CI = 1.03-2.47). We have found that Metformin suppresses HNF4G activity via AMPK-mediated phosphorylation-coupled ubiquitination degradation and inhibits in vitro invasion and in vivo metastasis of PDAC cells with SMAD4 deficiency. Furthermore, Metformin treatment significantly improve clinical outcomes and survival in patients with SMAD4-deficient PDAC (log-rank P = 0.022; HR = 0.31, 95% CI = 0.14-0.68) but not in patients with SMAD4-normal PDAC. Pathway analysis shows that HNF4G may act in PDAC through the cell-cell junction pathway. These results indicate that SMAD4 deficiency-induced overexpression of HNF4G plays a critical oncogenic role in PDAC progression and metastasis but may form a druggable target for Metformin treatment.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32627761

RESUMO

Endophytic fungi are symbiotically related to plants and spend most of their life cycle within them. In nature, they have a crucial role in plant micro-ecosystem. They are harnessed for their bioactive compounds to counter human health problems and diseases. Endophytic Diaporthe sp. is a widely distributed fungal genus that has garnered much interest within the scientific community. A substantial number of secondary metabolites have been detected from Diaporthe sp. inhabited in various plants. As such, this minireview highlights the potential of Diaporthe sp. as a rich source of bioactive compounds by emphasizing on their diverse chemical entities and potent biological properties. The bioactive compounds produced are of significant importance to act as new lead compounds for drug discovery and development.

4.
Mol Pharm ; 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32643939

RESUMO

Previous studies have shown that combining colistin (Col), a cationic polypeptide antibiotic, with ivacaftor (Iva), a cystic fibrosis (CF) drug, could achieve synergistic antibacterial effects against Pseudomonas aeruginosa. The purpose of this study was to develop dry powder inhaler formulations for co-delivery of Col and Iva, aiming to treat CF and lung infection simultaneously. In order to improve solubility and dissolution for the water-insoluble Iva, Iva was encapsulated into bovine serum albumin (BSA) nanoparticles (Iva-BSA-NPs). Inhalable composite microparticles of Iva-BSA-NPs were produced by spray-freeze-drying using water-soluble Col as the matrix material and l-leucine as an aerosol enhancer. The optimal formulation showed an irregularly shaped morphology with fine particle fraction (FPF) values of 73.8 ± 5.2% for Col and 80.9 ± 4.1% for Iva. Correlations between "[Formula: see text]" and FPF were established for both Iva and Col. The amorphous solubility of Iva is 66 times higher than the crystalline solubility in the buffer. Iva-BSA-NPs were amorphous and remained in the amorphous state after spray-freeze-drying, as examined by powder X-ray diffraction. In vitro dissolution profiles of the selected DPI formulation indicated that Col and Iva were almost completely released within 3 h, which was substantially faster regarding Iva release than the jet-milled physical mixture of the two drugs. In summary, this study developed a novel inhalable nanocomposite microparticle using a synergistic water-soluble drug as the matrix material, which achieved reduced use of excipients for high-dose medications, improved dissolution rate for the water-insoluble drug, and superior aerosol performance.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32719141

RESUMO

Bone homeostasis requires continuous remodeling of bone matrix to maintain structural integrity. This involves extensive communication between bone-forming osteoblasts and bone-resorbing osteoclasts to orchestrate balanced progenitor cell recruitment and activation. Only a few mediators controlling progenitor activation are known to date and have been targeted for intervention of bone disorders such as osteoporosis. To identify druggable pathways, we generated a medaka (Oryzias latipes) osteoporosis model, where inducible expression of receptor-activator of nuclear factor kappa-Β ligand (Rankl) leads to ectopic formation of osteoclasts and excessive bone resorption, which can be assessed by live imaging. Here we show that upon Rankl induction, osteoblast progenitors up-regulate expression of the chemokine ligand Cxcl9l. Ectopic expression of Cxcl9l recruits mpeg1-positive macrophages to bone matrix and triggers their differentiation into osteoclasts. We also demonstrate that the chemokine receptor Cxcr3.2 is expressed in a distinct subset of macrophages in the aorta-gonad-mesonephros (AGM). Live imaging revealed that upon Rankl induction, Cxcr3.2-positive macrophages get activated, migrate to bone matrix, and differentiate into osteoclasts. Importantly, mutations in cxcr3.2 prevent macrophage recruitment and osteoclast differentiation. Furthermore, Cxcr3.2 inhibition by the chemical antagonists AMG487 and NBI-74330 also reduced osteoclast recruitment and protected bone integrity against osteoporotic insult. Our data identify a mechanism for progenitor recruitment to bone resorption sites and Cxcl9l and Cxcr3.2 as potential druggable regulators of bone homeostasis and osteoporosis.

6.
Nat Commun ; 11(1): 3715, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709844

RESUMO

Esophageal squamous cell carcinoma (ESCC) is prevalent in some geographical regions of the world. ESCC development presents a multistep pathogenic process from inflammation to invasive cancer; however, what is critical in these processes and how they evolve is largely unknown, obstructing early diagnosis and effective treatment. Here, we create a mouse model mimicking human ESCC development and construct a single-cell ESCC developmental atlas. We identify a set of key transitional signatures associated with oncogenic evolution of epithelial cells and depict the landmark dynamic tumorigenic trajectories. An early downregulation of CD8+ response against the initial tissue damage accompanied by the transition of immune response from type 1 to type 3 results in accumulation and activation of macrophages and neutrophils, which may create a chronic inflammatory environment that promotes carcinogen-transformed epithelial cell survival and proliferation. These findings shed light on how ESCC is initiated and developed.

7.
Cytotechnology ; 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32691200

RESUMO

Human umbilical cord-derived mesenchymal stem cells (hUMSCs) hold strong self-renewal capacity and low immunogenicity, which have attracted attention as potential candidates for bone repair and regeneration. However, insufficient osteogenic differentiation markedly hinders the clinical applications of hUMSCs. In the present study, the effect of ß-mercaptoethanol (BME), a small molecule antioxidant which has been identified to regulate cell proliferation and differentiation, on osteogenic differentiation of hUMSCs and underlying signaling mechanism were investigated. The results indicated that under osteogenic induction conditions, BME treatment increased the alkaline phosphatase (ALP) activity and promoted calcium mineralization in hUMSCs. The gene and protein expression of osteogenesis-related markers such as ALP, osteopontin (OPN), osteocalcin (OCN) and collagen type I (COLI) were also significantly up-regulated. Besides, BME promoted the protein expression of silent information regulator type 1 (sirt1) and stimulated the activation of extracellular signal-related kinase (ERK), contributing to increased Runx2 expression. Furthermore, blocking the expression of sirt1 attenuated BME-enhanced ERK phosphorylation and osteogenic differentiation of hUMSCs. These results indicated that BME accelerated osteogenic differentiation of hUMSCs by activating the sirt1-ERK signaling pathway, thereby providing insights into the development of MSCs-based bone regeneration strategies.

8.
J Pharm Sci ; 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32534882

RESUMO

Pressure ulcers are commonly associated with microbial infections on the wounds which require an effective wound dressing for treatment. Thus far, the available silver dressing has shown tremendous result, however, it may cause argyria and complicate the internal organ function. Hence, our study aims to develop and characterize phomopsidione-loaded chitosan-polyethylene glycol nanocomposite hydrogel (C/PEG/Ph) as an antimicrobial dressing. Physically, the C/PEG/Ph hydrogel demonstrated a uniform light blue color, soft, flexible, and elastic, with no aggregation form. The evaluation via Fourier Transform Infrared (FTIR) exposed the C/PEG/Ph hydrogel has a notable shift towards lower frequency at 1600 and 1554 cm-1. For drug release test, the phomopsidione attained plateau at 24 h, with a total release of 67.9 ± 6.4% from the C/PEG/Ph hydrogel. There was a null burst release effect discovered throughout the experimental period. The C/PEG/Ph hydrogel showed significant results against all 4 Gram-negative bacteria and 1 yeast, with 99.99-100% reduction of microbial growth. The findings revealed that the C/PEG/Ph hydrogel can potentially act as an antimicrobial dressing for pressure ulcers.

9.
Am J Med Genet A ; 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32573094

RESUMO

Esophageal atresia (EA) is a congenital anomaly occurring in 2.3 per 10,000 live births. Due to advances in prenatal imaging, EA is more readily diagnosed, but data on the associated genetic diagnoses, other anomalies, and postnatal outcome for fetuses diagnosed prenatally with EA are scarce. We collected data from two academic medical centers (n = 61). Our data included fetuses with suspected EA on prenatal imaging that was confirmed postnatally and had at least one genetic test. In our cohort of 61 cases, 29 (49%) were born prematurely and 19% of those born alive died in the first 9 years of life. The most commonly associated birth defects were cardiac anomalies (67%) and spine anomalies (50%). A diagnosis was made in 61% of the cases; the most common diagnoses were vertebral defects, anal atresia, cardiac anomalies, tracheoesophageal fistula with esophageal atresia, radial or renal dysplasia, and limb anomalies association (43%, although 12% met only 2 of the criteria), trisomy 21 (5%), and CHARGE syndrome (5%). Our findings suggest that most fetuses with prenatally diagnosed EA have one or more additional major anomaly that warrants a more comprehensive clinical genetics evaluation. Fetuses diagnosed prenatally appear to represent a cohort with a worse outcome.

10.
Appl Microbiol Biotechnol ; 104(16): 6953-6966, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32577803

RESUMO

Tyrosine (Tyr) is crucial to the maintenance of the monoclonal antibody (mAb) titers and quality attributes in fed-batch cultures of recombinant Chinese hamster ovary (rCHO) cells. However, the relation between tyrosine and these aspects is not yet fully defined. In order to further elucidate such a relation, two groups of fed-batch experiments with high tyrosine (H-T) or low tyrosine (L-T) additions producing an IgG1 monoclonal antibody against CD20 were implemented to investigate the intracellular and extracellular effects of tyrosine on the culture performance. It was found that the scarcity of tyrosine led to the distinctive reduction in both viable cell density and antibody specific production rate, hence the sharply reduced titer, possibly related to the impaired translation efficiency caused by the substrate limitation of tyrosine. In addition, alterations to the critical quality attributes were detected in the L-T group, compared to those in the H-T condition. Notable decrease in the contents of intact antibody was found under the L-T condition because of the elevated reductive level in the supernatant. Moreover, the aggregate content in the L-T condition was also reduced, probably resulting from the accumulation of extracellular cystine. In particular, the lysine variant content noticeably increased with tyrosine limitation owing to the downregulation of two carboxypeptidases, i.e., CpB and CpH. Overall, understanding the role of tyrosine in these aspects is fundamental to the increase of product titers and control of critical quality attributes in the monoclonal antibody production of rCHO cell fed-batch cultures. KEY POINTS: • Tyrosine is essential in the maintenance of product titers and the control of product qualities in high cell density cultivations in rCHO cell. • This study revealed the bottleneck of decreased qmAbupon the deficiency of tyrosine. • The impact of tyrosine on the critical product qualities and the underlying mechanisms were also thoroughly assessed.

11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(3): 821-827, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32552942

RESUMO

OBJECTIVE: To analyze the relationships between expression levels of serum microRNA-146a, STAT1 protein and clinical characteristics in children with acute lymphoblastic leukemia (ALL). METHODS: A total of 102 children diagnosed as ALL in our hospital from June 2014 to June 2016 were enrolled, and were compared by into groups according to clinical characteristics including sex, age, lymphocyte type, disease risk, chemotherapy stage and gene mutation. Fifty healthy children were chosen as control group. The relative expression of microRNA-146a and STAT1 gene was detected by real-time RT-PCR and the relative level of STAT1 protein was detected by Western blot. The difference of microRNA-146a and STAT1 protein levels between clinical factors and laboratory indexs were compared. Followed-up for 3 years, The difference of overall survival (OS) rates between ALL children with different microRNA-146a and STAT1 protein were compared. RESULTS: The levels of microRNA-146a, STAT1 mRNA and protein in ALL children were significantly higher than those in control group (P<0.05), but there were no significantly differences in sex, age and lymphocyte type grouping in ALL children (P>0.05). There were significantly differences in different disease risk, chemotherapy stage and gene mutation groups in ALL children (P<0.05). Followed-up for 3 years, the OS rate of ALL children with high microRNA-146a and STAT1 protein levels were better than those with low microRNA-146a and STAT1 protein levels (P<0.05). CONCLUSION: The up-regulation of microRNA-146a and STAT1 protein may be involved in occurrence and development of ALL, which closely relates to clinical characteristics in ALL children, such as disease risk, chemotherapy stage and gene mutation.

12.
J Proteome Res ; 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32510958

RESUMO

Alzheimer's disease (AD) is closely associated with protein dysfunction and aberrant lipid metabolism in the brain. Our study could be conducive to the discovery of lipid and protein biomarkers for early diagnosis and therapy. In our current work, novel quantitative proteomic and lipidomic methods were developed for the characterization of molecular perturbation occurring in the brain in early stage AD mice. For this purpose, we performed a proteomic and lipidomic screening by liquid chromatography with mass spectrometry. Significant changes were detected, including 231 proteins and 11 lipid compounds in the AD mouse brain. Early stage AD disturbed biological pathways implicated in neuroactive ligand-receptor, complement and coagulation cascades, PI3K-Akt signaling and metabolic pathways, and glycerophospholipid metabolism. The results in the current study suggest that these significantly altered proteins and lipids may be implicated in early stage AD. Our work raises the possibility of AD diagnosis and therapy by providing new protein targets and lipid biomarkers.

13.
Genet Med ; 22(8): 1413-1417, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32366965

RESUMO

PURPOSE: This study characterizes the clinical and genetic features of nine unrelated patients with de novo variants in the NR4A2 gene. METHODS: Variants were identified and de novo origins were confirmed through trio exome sequencing in all but one patient. Targeted RNA sequencing was performed for one variant to confirm its splicing effect. Independent discoveries were shared through GeneMatcher. RESULTS: Missense and loss-of-function variants in NR4A2 were identified in patients from eight unrelated families. One patient carried a larger deletion including adjacent genes. The cases presented with developmental delay, hypotonia (six cases), and epilepsy (six cases). De novo status was confirmed for eight patients. One variant was demonstrated to affect splicing and result in expression of abnormal transcripts likely subject to nonsense-mediated decay. CONCLUSION: Our study underscores the importance of NR4A2 as a disease gene for neurodevelopmental disorders and epilepsy. The identified variants are likely causative of the seizures and additional developmental phenotypes in these patients.

14.
J Biomol Struct Dyn ; : 1-14, 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32452271

RESUMO

Glu17Lys (E17K) is one of the natural variants of Akt1, which is associated with multiple human cancers. This mutation is also indicated to affect the sensitivity of certain allosteric inhibitors. In order to explain the molecular mechanism that E17K mutation of Akt1 affects the sensitivity of allosteric inhibitors, we performed molecular dynamics simulations on Akt1 to its allosteric inhibitors for both wild type and E17K. We analyzed the simulated data in terms of structural stability, hydrogen bond formation, π-π interactions, binding free energy etc. We found that E17K substitution will affect the interaction of K297 residues with allosteric inhibitors, which was a key residue in allosteric inhibitors binding. This will eventually lead to allosteric inhibitors leaving the binding site in the E17K system. Our results can provide a theoretical basis for the design of novel allosteric inhibitors targeting E17K mutants in the future.Communicated by Ramaswamy H. Sarma.

15.
Artigo em Inglês | MEDLINE | ID: mdl-32359103

RESUMO

Volunteerism contributes significantly to the social development of a country. Although the rate of volunteerism has steadily increased over the years, the numbers of regular volunteers remains small. While the existing literature has elucidated individuals' motivations for volunteerism, research is lacking on their motivations and challenges in sustaining long-term volunteerism. A focused ethnographic approach was adopted in this study to explore 20 participants' motivations and challenges towards long-term volunteerism. Purposive sampling was used to recruit participants in one single-family service centre in Singapore from October to December 2018. Data were collected through covert observations and semi-structured interviews. Field notes, observational data and findings from the interviews were triangulated and analysed through thematic analysis. In this study, a central exhaustive description of the volunteers 'providing help while receiving good deeds' is established. This was supported with three main themes revolving around the volunteers: fulfilling life goals, deriving meaning from experiences and striking a balance in the life. These themes characterised the motivations and challenges faced by them amidst their voluntary works. They reported that the satisfaction and fulfilment through volunteering had brought personal growth, well-being and happiness to them. The sense of purpose through volunteering further enhanced their experiences. Finally, some volunteers reported that volunteering enabled them to strike a balance in their own life by engaging it as a form of solace. The findings suggest that sustained volunteerism is a multidimensional construct involving the interplay of different factors in the individual's life. By understanding motivations underlying long-term volunteerism, voluntary organisations can create volunteering opportunities that dovetail with volunteers' personal goals, thus boosting their satisfaction and incentivising their sustained engagement. Additionally, the organisations can hold regular bonding activities to promote rapport among their volunteers, beneficiaries and staff, thus encouraging the volunteers to persevere on their volunteering journey.

16.
Bioorg Med Chem ; 28(11): 115526, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32354672

RESUMO

A series of 1,3-benzothiazinone derivatives were designed and synthesized for pharmacological assessments. Among the synthesized 19 compounds, some compounds showed high activities on inhibiting LPS-induced nitrite oxide and TNF-α production, down-regulating COX-2 and increasing IL-10 production in RAW264.7 cells. All the compounds had no obvious cytotoxicity in in vitro assay. LD50 value of compound 25 was greater than 2000 mg/kg, which was safer than meloxicam. Compound 25 significantly inhibited phosphorylation of NF-κB and STAT3 in LPS-induced RAW264.7 cells. Inhibition of synthesized compounds on COX activity was weaker than meloxicam. Compound 25 displayed lower gastrointestinal toxicity than meloxicam. Besides, compound 25 decreased the swelling in carrageenan-induced paw edema models of inflammation and reduced PGE2 level significantly. In summary, 1,3-benzothiazinone derivatives are unique scaffolds with anti-inflammatory activity and low toxicity.

17.
Arch Oral Biol ; 116: 104735, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32442662

RESUMO

Tricho-rhino-phalangeal syndrome type I, an autosomal dominant condition, is caused by heterozygous pathogenic variants in a zinc finger transcription factor, TRPS1, which has important roles in development of endochondral bones, teeth, and hair. Clinical manifestations of the patients include short stature, sparse, fine and slow-growing scalp hair, bulbous nose, supernumerary teeth, hip dysplasia, brachydactyly, and cone-shaped epiphyses of the phalangeal bones. OBJECTIVE: To clinically, radiographically, and molecular genetically investigate a patient with tricho-rhino-phalangeal syndrome type I. MATERIALS AND METHODS: Clinical and radiographic examination and mutation analysis of TRPS1 were performed. RESULTS: Clinical and radiographic examination indicated the patient had tricho-rhino-phalangeal syndrome type I. Sequencing of the TRPS1 gene revealed a heterozygous pathogenic variant (c.2762G>A; p.Arg921Gln). Oral examination showed supernumerary teeth, large dental pulp spaces, dental pulp stones, microdontia of the maxillary permanent lateral incisors, absence of the mandibular left second premolar and short root of the maxillary right second premolar, and hypoplastic mandibular condyles with long condylar necks. CONCLUSION: TRPS1 has an important function in regulating bone and dentin mineralization. Having large dental pulp spaces suggests that impaired dentin mineralization was the result of the TRPS1 pathogenic variant. This is the first patient with a TRPS1 pathogenic variant who had impaired dentin mineralization. This is also the third report showing the association between TRPS1 pathogenic variants and the presence of supernumerary teeth.

18.
J Stroke Cerebrovasc Dis ; 29(6): 104801, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32249206

RESUMO

BACKGROUND: Ischemic stroke is the leading cause of disability and death globally. Micro-RNAs (miRNAs) have been reported to play important roles in the development and pathogenesis of the nervous system. However, the exact function and mechanism of miRNAs have not been fully elucidated about brain damage caused by cerebral ischemia/reperfusion (I/R). METHODS: In this study, we explored the neuroprotective effects of miR-219a-5p on brain using an in vitro ischemia model (mouse neuroblastoma N2a cells treated with oxyglucose deprivation and reperfusion), and in vivo cerebral I/R model in mice. Western blot assay and Reverse Transcription-Polymerase Chain Reaction were used to check the expression of molecules involved. Flow cytometry and cholecystokinin were used to examine cell apoptosis, respectively. RESULTS: Our research shows that miR-219a-5p gradually decreases in cerebral I/R models in vivo and in vitro. In vitro I/R, we find that miR-219a-5p mimics provided evidently protection for cerebral I/R damage, as shown by increased cell viability and decreased the release of LDH and cell apoptosis. Mechanically, our findings indicate that miR-219a-5p binds to cAMP specific 3', 5'-cyclic phosphodiesterase 4D (PDE4D) mRNA in the 3'-UTR region, which subsequently leads to a decrease in Pde4d expression in I/R N2a cells. CONCLUSIONS: Our results provide new ideas for the study of the mechanism of cerebral ischemia/reperfusion injury, and lay the foundation for further research on the treatment of brain I/R injury. Upregulation of miR-219a-5p decreases cerebral ischemia/reperfusion injury by targeting Pde4d in vitro.

19.
Carbohydr Polym ; 237: 116108, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32241448

RESUMO

The proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs) needed to be promoted for their use in stem cell-based therapy for large bone defects. This study aimed to prepare porous 2a-2 g scaffolds with antioxidant activity to reduce intracellular reactive oxygen species (ROS), which resulted in promoting the proliferation and osteogenic differentiation of MSCs. A series of novel chemically modified 2a-2 g scaffolds were fabricated by an acid-soluble/alkali-insoluble method. Besides, these 2a-2 g scaffolds had good biocompatibility, physicochemical properties and the ability to promote osteogenic differentiation of human adipose-derived stem cells (hADSCs). However, the proliferation ability of hADSCs on 2a-2f scaffolds was weakened. Interestingly, 2 g scaffold had a positive effect on hADSCs proliferation. These results indicated that the reduction of intracellular ROS was not conducive to hADSCs proliferation but beneficial to hADSCs osteogenic differentiation. Taken together, these significant results highlighted potential therapeutic benefit of 2 g scaffold in large bone defects.

20.
Mater Sci Eng C Mater Biol Appl ; 109: 110523, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32228959

RESUMO

For hepatocyte culture in vitro, the surface feature of utilized scaffolds exerts a direct impact on cell adhesion, growth and differentiated functionality. Herein, to regulate hepatocyte growth and differentiated functionality, modified microfibrous scaffolds were fabricated by surface grafting monoamine terminated lactobionic lactone (L-NH2) and gelatin onto non-woven poly(ethylene terephthalate) (PET) fibrous substrate (PET-Gal and PET-Gel), respectively. The physicochemical properties of PET scaffolds before and after modification were characterized. Upon 15-day culture, the effects of modified PET scaffolds on growth and differentiated functionality of human induced hepatocytes (hiHeps) were evaluated, compared with that of control without modification. Results demonstrated that both L-NH2 and gelatin modifications improved scaffold properties including hydrophilicity, water uptake ratio, stiffness and roughness, resulting in efficient cell adhesion, ~20-fold cell expansion and enhanced differentiated functionality. After culture for 15 days, PET-Gal cultured cells formed aggregates, displaying better cell viability and significantly higher differentiated functionality regarding albumin secretion, urea synthesis, phases I (cytochrome P450, CYP1A1/2 and CYP3A4) and II (uridine 5'-diphosphate glucuronosyltransferases, UGT) enzyme activity, biliary excretion and detoxification ability (ammonia elimination and bilirubin conjugation), compared with PET and PET-Gel cultured ones. Hence, as a three-dimensional (3D) microfibrous scaffold, PET-Gal promotes hiHeps growth and differentiated functionality maintenance, which is promisingly utilized in bioartificial liver (BAL) bioreactors.

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