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1.
Biosci Rep ; 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31654067

RESUMO

Reprogrammed metabolism is an important hallmark of cancer cells. Pyruvate kinase is one of the major rate-limiting enzymes in glucose metabolism. The M2 isoform of Pyruvate kinase (PKM2), this is, PKM2, is considered to be an important marker of metabolic reprogramming and one of key enzymes. Recently, through the continuous development of genome-wide analysis and functional studies, accumulating evidence has demonstrated that long noncoding RNAs (LncRNAs) play vital regulatory roles in cancer progression by acting as either potential oncogenes or tumor suppressors. Furthermore, several studies have shown that up-regulation of PKM2 in cancer tissues is associated with LncRNAs expression and patient survival. Thus, scientists have begun to unveil the mechanism of LncRNA-associated PKM2 in cancer metabolic progression. Based on these novel findings, in this mini-review, we summarize the detailed molecular mechanisms of LncRNA related to PKM2 in cancer metabolism. We expect that this work will promote a better understanding of the molecular mechanisms of PKM2, and provide a profound potential for targeting PKM2 to treat tumors.

2.
Biomed Mater ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31574486

RESUMO

Reconstruction of osteochondral tissues remains a challenging task in clinical therapy because of their heterogeneous structure. The best way to face the challenge is to develop a biomimetic construct to mimic the multilayered gradient from cartilage, to calcified cartilage and subchondral bone. In this study, bone marrow mesenchymal stromal cells (BMSCs) were cultured on electrospun fibrous meshes and cell sheets were incubated. The fibrous meshes were composed of 50% poly(L-lactide) and 50% gelatin, displaying excellent biocompatibility, cell affinity and degradability. Differentiation of BMSC sheets on fibrous meshes was induced chondrogenically or osteogenically. In particular, the BMSC sheets were able to be efficiently induced differentiating towards calcified cartilage by using a 1:1 (v/v) mixed medium of chondrogenic and osteogenic inductive media. Thus, a gradient three-dimensional construct was built by stacking the differently pre-differentiated cell/mesh complexes layer-by-layer from top-to-down to mimic the cartilage-to-bone transition. With this gradient construct being implanted in the rabbit knee osteochondral defect, it was confirmed that it could promote the tissue regeneration with intact cartilage layer formation in comparison with the multilayered construct while without a gradient. The strategy of using properly pre-differentiated BMSC sheet on fibrous mesh to build the osteochondral interface was thus suggested being feasible and effective in mimicking its hierarchical complexity, and favored the repairing of injured joint cartilage.

3.
Andrologia ; : e13421, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31637747

RESUMO

Many researchers have shown that renin-angiotensin system (RAS) is involved in various important aspects of male reproduction. In this study, we assessed whether abnormal levels of seminal angiotensinogen (AGT) may be associated with semen parameters in infertile males. A total of 115 male patients were recruited, and semen parameters, seminal AGT and the electrolytes including K+ , Na+ , Cl- , P and Ca were evaluated. According to the World Health Organization (WHO) 2010 criteria, the patients were divided into two groups: G1 group with normal semen parameters (n = 42) and G2 group with subnormal semen parameters (n = 73). The level of seminal AGT was significantly higher in G2 group compared with G1 group. Moreover, the level of AGT was negatively correlated with the percentage of total motility (r = -.322, p = .000), progressive motility (PR) (r = -.339, p = .000) and morphologically normal forms (r = -.263, p = .004). This study suggests that elevated seminal AGT level is associated with increased risk of asthenospermia and teratozoospermia.

4.
Chem Commun (Camb) ; 55(87): 13116-13119, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31616864

RESUMO

Two 42-metal lanthanide coordination nanorings [Ln42L14(OH)28(OAc)84] (Ln = Nd (1), La (2)) were prepared using a vanillin type ligand. The Nd42 cluster exhibits interesting NIR luminescence sensing behavior to metal ions and nitro explosives.

5.
Sensors (Basel) ; 19(16)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31395842

RESUMO

Existing hop-by-hop congestion control algorithms are mainly divided into two categories: those improving the sending rate and those suppressing the receiving rate. However, these congestion control algorithms have problems with validity and limitations. It is likely that the network will be paralyzed due to the unreasonable method of mitigating congestion. In this paper, we present a contention-based hop-by-hop bidirectional congestion control algorithm (HBCC). This algorithm uses the congestion detection method with queue length as a parameter. By detecting the queue length of the current node and the next hop node, the congestion conditions can be divided into the following four categories: 0-0, 0-1, 1-0, 1-1 (0 means no congestion, 1 means congestion). When at least one of the two nodes is congested, the HBCC algorithm adaptively adjusts the contention window of the current node, which can change the priority of the current node to access the channel. In this way, the buffer queue length of the congested node is reduced. When the congestion condition is 1-1, the hop-by-hop priority congestion control (HPCC) method proposed in this paper is used. This algorithm adaptively changes the adjustment degree of the current node competition window and improves the priority of congestion processing of the next hop node. The NS2 simulation shows that by using the HBCC algorithm, when compared with distributed coordination function (DCF) without congestion control, the proposed unidirectional congestion control algorithms hop-by-hop receiving-based congestion control (HRCC) and hop-by-hop sending-based congestion control (HSCC), and the existing congestion control algorithm congestion alleviation-MAC (CA-MAC), the average saturation throughput increased by approximately 90%, 62%, 12%, and 62%, respectively, and the buffer overflow loss ratio reduced by approximately 80%, 79%, 44%, and 79%.

6.
Phys Chem Chem Phys ; 21(39): 21726-21737, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31372612

RESUMO

Graphene (GN) nanofillers have been widely used to enhance the overall performance of polymer composites due to their various superior properties, which strongly rely on the uniform dispersion and strong interfacial bonding of GN with high-quality polymer matrices. In the present study, the strengthening and functional effects of polydopamine-coated edge-carboxylated graphene (p-ECG) on the mechanical, moisture-barrier and electromagnetic properties of epoxy (EP)-based composites were systematically evaluated. p-ECG was successfully prepared via one-step high-pressure ball milling through the edge-selective functionalization and exfoliation of pristine graphite in the presence of dry ice, followed by synchronous reduction and coating via the mild oxidative polymerization of mussel-inspired dopamine. p-ECG showed prominent advantages of a small sheet size, excellent dispersibility and high chemical reactivity in the EP matrix. Obvious enhancements were achieved in the tensile and flexural properties and moisture-barrier performance of EP composites as well as the interlaminar shear strength (ILSS) and transverse fiber bundle tensile (TFBT) strength of carbon fiber (CF)/EP composites, which confirmed the excellent dispersion and chemically strengthened interfacial bonding of p-ECG in the EP matrix. More importantly, p-ECG introduced onto the surface of desized CF led to significant enhancement in the electromagnetic interference (EMI) shielding capability of CF/EP composites, which was primarily ascribed to the polarization relaxation effect induced by the defects and functional groups in p-ECG as well as the increase in electrical conductivity derived from the "bridging effect" of p-ECG. Specifically, with p-ECG content of 0.5 wt%, the increments in tensile strength, TFBT strength, shielding effectiveness (total, SET) and shielding effectiveness (reflection loss, SER) were as high as 33.3, 34.3, 31.3 and 71.0%, respectively.

7.
Science ; 365(6453): 599-604, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31395785

RESUMO

TP53, which encodes the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic human leukemia cell lines of the most common TP53 missense mutations. Functional, DNA-binding, and transcriptional analyses revealed loss of function but no GOF effects. Comprehensive mutational scanning of p53 single-amino acid variants demonstrated that missense variants in the DNA-binding domain exert a dominant-negative effect (DNE). In mice, the DNE of p53 missense variants confers a selective advantage to hematopoietic cells on DNA damage. Analysis of clinical outcomes in patients with acute myeloid leukemia showed no evidence of GOF for TP53 missense mutations. Thus, a DNE is the primary unit of selection for TP53 missense mutations in myeloid malignancies.

8.
ACS Appl Mater Interfaces ; 11(34): 30596-30609, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31373193

RESUMO

Biomaterials that have capacities to simultaneously induce bone regeneration and kill bacteria are in demand because bone defects face risks of severe infection in clinical therapy. To meet the demand, multifunctional biodegradable microspheres are fabricated, which contain vancomycin to provide antibacterial activity and strontium-doped apatite to provide osteocompatibility. Moreover, the strontium component shows activity in promoting angiogenesis, which further favors osteogenesis. For producing the microspheres, vancomycin is loaded into mesoporous silica and embedded in polylactide-based microspheres via the double emulsion technique and the strontium-doped apatite is deposited onto the microspheres via biomineralization in strontium-containing simulated body fluid. Sustained release behaviors of both vancomycin and Sr2+ ions are achieved. The microspheres exhibit strong antibacterial effect against Staphylococcus aureus, while demonstrating excellent cell/tissue compatibility. Studies of differentiation confirm that the introduction of strontium element strengthens the angiogenic and osteogenic expressions of mesenchymal stromal cells. Subcutaneous injection of the microspheres into rabbit's back confirms their effectiveness in inducing neovascularization and ectopic osteogenesis. Finally, an infected rabbit femoral condyle defect model is created with S. aureus infection and the multifunctional microspheres are injected, which display significant antibacterial activity in vivo and achieve efficient new bone formation in comparison with biomineralized microspheres without vancomycin loading. The vancomycin- and strontium-loaded microspheres, being biomineralized, injectable, and biodegradable, are attractive because of their flexibility in integrating multiple functions into one design, whose potentials in treating infected bone defects are highly expected.

9.
Arch Pharm (Weinheim) ; 352(9): e1900075, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31339189

RESUMO

Biguanides, including metformin and phenformin, have emerged as promising anticancer agents. However, the high dose needed for their efficient anticancer properties restricts their clinical application. In an attempt to obtain higher active compounds than these parent compounds, pyrazole-containing biguanide derivatives were synthesized and screened for in vitro cytotoxicity against human cancer cell lines. Clonogenic assays and scratch wound healing assays demonstrated that these new derivatives profoundly inhibit cell proliferation and migration. Compounds 10b and 10d exhibited strong potency with low IC50 values in the range of 6.9-28.3 µM, far superior to phenformin and metformin. Moreover, 20 µM 10b and 10d resulted in 72.3-88.2% (p < 0.001) inhibition of colony formation and 29.3-60.7% (p < 0.05) inhibition of cell migration. Mechanistically, 10b and 10d activated adenosine monophosphate-activated protein kinase, leading to inactivation of the mammalian target of rapamycin (mTOR) signaling pathway with the regulation of 4EBP1 and p70S6K. These results suggest the value of these novel biguanide derivatives as candidates with therapeutic potential for the treatment of bladder and ovarian cancer.

10.
Cancer Med ; 8(14): 6195-6211, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31305011

RESUMO

BACKGROUND: Cervical cancer is a major public health concern in China. We report the end-of-study results of a phase II/III trial to assess the efficacy, immunogenicity, and safety of the AS04-human papillomavirus (HPV)-16/18 vaccine in Chinese women aged 18-25 years followed for up to 72 months after first vaccination. Results of approximately 57 months following first vaccination have been previously reported. METHODS: Healthy 18-25-year-old women (N = 6051) were randomized (1:1) to receive three doses of AS04-HPV-16/18 vaccine or Al(OH)3 (control) at Months 0-1-6. Vaccine efficacy against HPV-16/18 infection and cervical intraepithelial neoplasia (CIN), cross-protective vaccine efficacy against infections and lesions associated with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. Efficacy was assessed in the according-to-protocol efficacy (ATP-E) cohort (vaccine N = 2888; control N = 2892), total vaccinated cohort for efficacy (TVC-E; vaccine N = 2987; control N = 2985) and TVC-naïve (vaccine N = 1660; control N = 1587). RESULTS: In initially HPV-16/18 seronegative/DNA-negative women, vaccine efficacy against HPV-16/18-associated CIN grade 2 or worse was 87.3% (95% CI: 5.5, 99.7) in the ATP-E, 88.7% (95% CI: 18.5, 99.7) in the TVC-E, and 100% (95% CI: 17.9, 100) in the TVC-naïve. Cross-protective efficacy against incident infection with HPV-31, HPV-33 and HPV-45 was 59.6% (95% CI: 39.4, 73.5), 42.7% (95% CI: 15.6, 61.6), and 54.8% (95% CI: 19.3, 75.6), respectively (ATP-E). At Month 72, >95% of initially seronegative women who received HPV vaccine in the ATP cohort for immunogenicity (N = 664) remained seropositive for anti-HPV-16/18 antibodies; anti-HPV-16 and anti-HPV-18 geometric mean titers were 678.1 EU/mL (95% CI: 552.9, 831.5) and 343.7 EU/mL (95% CI: 291.9, 404.8), respectively. Serious adverse events were infrequent (1.9% vaccine group [N = 3026]; 2.7% control group [N = 3025]). Three and zero women died in the control group and the vaccine group respectively. New onset autoimmune disease was reported in two women in the vaccine group and two in the control group. CONCLUSIONS: This is the first large-scale randomized clinical trial of HPV vaccination in China. High and sustained vaccine efficacy against HPV-16/18-associated infection and cervical lesions was demonstrated up to Month 72. The vaccine had an acceptable safety profile. Combined with screening, prophylactic HPV vaccination could potentially reduce the high burden of HPV infection and cervical cancer in China. TRIAL REGISTRATION: NCT00779766.

11.
Sensors (Basel) ; 19(12)2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216666

RESUMO

The random placement of a large-scale sensor network in an outdoor environment often causes low coverage. In order to effectively improve the coverage of a wireless sensor network in the monitoring area, a coverage optimization algorithm for wireless sensor networks with a Virtual Force-Lévy-embedded Grey Wolf Optimization (VFLGWO) algorithm is proposed. The simulation results show that the VFLGWO algorithm has a better optimization effect on the coverage rate, uniformity, and average moving distance of sensor nodes than a wireless sensor network coverage optimization algorithm using Lévy-embedded Grey Wolf Optimizer, Cuckoo Search algorithm, and Chaotic Particle Swarm Optimization. The VFLGWO algorithm has good adaptability with respect to changes of the number of sensor nodes and the size of the monitoring area.

12.
BMC Med Genet ; 20(1): 80, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088393

RESUMO

BACKGROUND: Intellectual disability/developmental delay is a complex condition with extraordinary heterogeneity. A large proportion of patients lacks a specific diagnosis. Next generation sequencing, enabling identification of genetic variations in multiple genes, has become an efficient strategy for genetic analysis in intellectual disability/developmental delay. METHODS: Clinical data of 112 Chinese families with unexplained intellectual disability/developmental delay was collected. Targeted next generation sequencing of 454 genes related to intellectual disability/developmental delay was performed for all 112 index patients. Patients with promising variants and their other family members underwent Sanger sequencing to validate the authenticity and segregation of the variants. RESULTS: Fourteen promising variants in genes EFNB1, MECP2, ATRX, NAA10, ANKRD11, DHCR7, LAMA1, NFIX, UBE3A, ARID1B and PTPRD were identified in 11 of 112 patients (11/112, 9.82%). Of 14 variants, eight arose de novo, and 13 are novel. Nine patients (9/112, 8.03%) got definite molecular diagnoses. It is the first time to report variants in EFNB1, NAA10, DHCR7, LAMA1 and NFIX in Chinese intellectual disability/developmental delay patients and first report about variants in NAA10 and LAMA1 in affected individuals of Asian ancestry. CONCLUSIONS: Targeted next generation sequencing of 454 genes is an effective test strategy for patients with unexplained intellectual disability/developmental delay. Genetic heterogenicity is significant in this Chinese cohort and de novo variants play an important role in the diagnosis. Findings of this study further delineate the corresponding phenotypes, expand the mutation spectrum and support the involvement of PTPRD in the disease.


Assuntos
Deficiências do Desenvolvimento/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Deficiência Intelectual/genética , Mutação , Adolescente , Criança , Pré-Escolar , China , Cromossomos Humanos X , Feminino , Genes Dominantes , Genes Recessivos , Heterogeneidade Genética , Humanos , Lactente , Masculino , Linhagem , Fenótipo
13.
Circulation ; 140(2): 126-137, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31116951

RESUMO

BACKGROUND: The health-promoting and disease-limiting abilities of resveratrol, a natural polyphenol, has led to considerable interest in understanding the mechanisms of its therapeutic actions. The polyphenolic rings of resveratrol enable it to react with and detoxify otherwise injurious oxidants. Whilst the protective actions of resveratrol are commonly ascribed to its antioxidant activity, here we show that this is a misconception. METHODS: The ability of resveratrol to oxidize cGMP-dependent PKG1α (protein kinase 1α) was assessed in isolated rat aortic smooth muscle cells, and the mechanism of action of this polyphenol was characterized using in vitro experiments, mass spectrometry and electron paramagnetic resonance. The blood pressure of wild-type and C42S knock-in mice was assessed using implanted telemetry probes. Mice were made hypertensive by administration of angiotensin II via osmotic mini-pumps and blood pressure monitored during 15 days of feeding with chow diet containing vehicle or resveratrol. RESULTS: Oxidation of the phenolic rings of resveratrol paradoxically leads to oxidative modification of proteins, explained by formation of a reactive quinone that oxidizes the thiolate side chain of cysteine residues; events that were enhanced in cells under oxidative stress. Consistent with these observations and its ability to induce vasodilation, resveratrol induced oxidative activation of PKG1α and lowered blood pressure in hypertensive wild-type mice, but not C42S PKG1α knock-in mice that are resistant to disulfide activation. CONCLUSIONS: Resveratrol mediates lowering of blood pressure by paradoxically inducing protein oxidation, especially during times of oxidative stress, a mechanism that may be a common feature of antioxidant molecules.

14.
Macromol Biosci ; 19(6): e1800464, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31050390

RESUMO

Amino acid ester substituted polyphosphazenes are osteoactive benefiting from their phosphorus-containing chemical structure, which highlights interests in bone tissue engineering. To correlate their chemical structures with cell activities, in this study, poly[(ethyl alanato)0.3 (ethyl glycinato)0.7 phosphazene] (PAGP) and poly[(ethyl phenylalanato)0.3 (ethyl glycinato)0.7 phosphazene] (PPGP) are synthesized to carry out studies on cell osteogenic differentiation. In the non-contact culture manner, bone mesenchymal stromal cells (BMSCs) are cultured in transwell chambers containing PAGP or PPGP films, while the cells and the materials do not contact. In the contact culture manner, BMSCs are cultured on the PAGP or PPGP films. In the meantime, solutions containing PAGP or PPGP degradation products (i.e., phosphate, ammonium, and corresponding amino acids) are applied for cell culture using inorganic phosphate (Pi) ion as control. Thus, the influences from substrate surface and degradation products can be identified separately. The results reveal that both the phosphorus-containing surface of PAGP and PPGP films and their degradation products play significant roles in regulating cell behaviors. In comparison with PAGP, PPGP seems able to provide relatively stable phosphorus-containing surface to strengthen the cell-scaffold interaction because of its slower degradation rate and higher Young's modulus, leading to greater promotion in osteogenic differentiation via contact effect.

15.
Protein Expr Purif ; 161: 78-83, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31051245

RESUMO

Human cytomegalovirus (HCMV), a member of the human herpesvirus family, is a common opportunistic virus causing severe ailments and deaths in people with immature or compromised immune systems. UL23 is a virion protein found in the tegument and is expressed in the cytoplasm in HCMV infected cells. However, UL23 is dispensable for viral replication in cultured cells and little is currently known about its function. In order to further study of UL23, polyclonal antibody of UL23 was prepared. UL23 gene fragment was cloned from HCMV Towne by PCR and ligated into pET28a (+). The recombinant plasmid pET28a (+)-UL23 was transformed into E.coli BL21(DE3) to induce expression of the target protein. Then we efficiently purified the recombinant protein affinity chromatography under unique denaturation conditions. Recombinant UL23 protein was used as immunogen to inoculate New Zealand white rabbits and the sera was collected after the fourth immunization. UL23 Polyclonal antibody was purified from antisera using CNBr-activated Sepharose 4 beads. Our UL23 Polyclonal antibody showed specific reaction with UL23 in ELISA, Western-blot and immunofluorescence. More importantly, UL23 Polyclonal antibody could specifically recognize UL23 protein in HCMV infected cells, which laid a foundation for further study of HCMV UL23.

16.
Mater Sci Eng C Mater Biol Appl ; 100: 789-797, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30948116

RESUMO

Mesoporous silica nanoparticles (MSNs) have been widely studied as drug carriers to get sustained release behaviors, however, their application in sustained release of metoprolol tartrate (MPT) is limited. The possible reason is due to MPT molecule being bulky, while normal type MSNs like MCM-41 and SBA-15 have pore sizes of only 3-6 nm. In this study, two MCF-26 type MSNs were prepared with pore size of 11 or 15 nm, and used to conduct MPT release in comparison with MCM-41 and SBA-15. Both molecular simulation and MPT release experiments were performed to identify the pore size effect on adsorption and diffusion (release) of MPT in these MSNs. Finally, a kind of pH-sensitive MPT drug delivery system was obtained by coating the chosen MCF-26@MPT with an enteric polymer, which might find promising application in treating morning hypertension attack by orally administrating the drug delivery system before bedtime.


Assuntos
Liberação Controlada de Fármacos , Metoprolol/farmacologia , Simulação de Dinâmica Molecular , Dióxido de Silício/química , Resinas Acrílicas/química , Adsorção , Difusão Dinâmica da Luz , Concentração de Íons de Hidrogênio , Metoprolol/química , Conformação Molecular , Nanopartículas/química , Nanopartículas/ultraestrutura , Nitrogênio/química , Tamanho da Partícula , Porosidade
17.
Mater Sci Eng C Mater Biol Appl ; 100: 862-873, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30948124

RESUMO

Mineralization capability is an important issue in developing bone repairing biomaterials, while it is not quite clear how this feature would act in the presence of cells and influence cell osteogenic differentiation without adding extra osteoinductive factors such as ß­sodium glycerophosphate and dexamethasone. Poly(l­lactide) (PLLA) and gelatin composite fibers (PG, 1:1 in weight) were electrospun, treated with CaCl2 solution (PG-Ca), and used for mineralization studies by using cell culture media (αMEM, and αMEM + serum). Bone mesenchymal stromal cells (BMSCs) were then seeded and cultured on both PG and PG-Ca fibrous mats for 28 days by only using αMEM + serum. Interestingly, mineral depositions on both PG and PG-Ca fibers were detected in the environment of αMEM or αMEM + serum, in which, PG-Ca fibers demonstrated stronger ability in inducing hydroxyapatite formation than PG fibers, especially in the presence of fetal bovine serum. When BMSCs were cultured on the two kinds of fibrous mats, apatite depositions were still clearly detected, while the depositing amounts decreased in comparison with corresponding cell-free cases. It was ascribed to the consumption of ions by the continuously proliferating BMSCs, whose osteogenic differentiation was significantly promoted even without extra osteoinductive factors, especially on PG-Ca fibrous mats, in comparison with the control group. Therefore, it was confirmed the capability of scaffolding materials in enriching ions like calcium and phosphate around cells was an efficient way to promote bone regeneration.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Meios de Cultura/farmacologia , Gelatina/farmacologia , Células-Tronco Mesenquimais/citologia , Minerais/química , Osteogênese/efeitos dos fármacos , Poliésteres/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Cloreto de Cálcio/farmacologia , Bovinos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células-Tronco Mesenquimais/efeitos dos fármacos , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria , Difração de Raios X
18.
Can J Physiol Pharmacol ; 97(8): 753-765, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30998852

RESUMO

Myocardial infarction (MI) in mice results in cardiac rupture at 4-7 days after MI, whereas cardiac fibrosis and dysfunction occur later. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) has anti-inflammatory, anti-fibrotic, and pro-angiogenic properties. We hypothesized that Ac-SDKP reduces cardiac rupture and adverse cardiac remodeling, and improves function by promoting angiogenesis and inhibiting detrimental reactive fibrosis and inflammation after MI. C57BL/6J mice were subjected to MI and treated with Ac-SDKP (1.6 mg/kg per day) for 1 or 5 weeks. We analyzed (1) intercellular adhesion molecule-1 (ICAM-1) expression; (2) inflammatory cell infiltration and angiogenesis; (3) gelatinolytic activity; (4) incidence of cardiac rupture; (5) p53, the endoplasmic reticulum stress marker CCAAT/enhancer binding protein homology protein (CHOP), and cardiomyocyte apoptosis; (6) sarcoplasmic reticulum Ca2+ ATPase (SERCA2) expression; (7) interstitial collagen fraction and capillary density; and (8) cardiac remodeling and function. Acutely, Ac-SDKP reduced cardiac rupture, decreased ICAM-1 expression and the number of infiltrating macrophages, decreased gelatinolytic activity, p53 expression, and myocyte apoptosis, but increased capillary density in the infarction border. Chronically, Ac-SDKP improved cardiac structures and function, reduced CHOP expression and interstitial collagen fraction, and preserved myocardium SERCA2 expression. Thus, Ac-SDKP decreased cardiac rupture, ameliorated adverse cardiac remodeling, and improved cardiac function after MI, likely through preserved SERCA2 expression and inhibition of endoplasmic reticulum stress.

19.
Biomed Mater ; 14(4): 045001, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-30939454

RESUMO

Hydrogels are normally not robust enough to meet the repairing requirements of bone defects, therefore, cryogels of higher mechanical properties are developed as the more proper candidates for the purpose. In view of the organic-inorganic composition of natural bone tissues, hydroxyapatite (HA) is envisioned as a good additive for protein cryogels to achieve biomimetic compositions, additionally, as an excellent reinforcement to increase the mechanical properties of cryogels. In this study, methacrylated gelatin (GelMA) was synthesized and corresponding 3D-structured cryogel was fabricated, followed by the incorporation of HA nanowires (HANWs) at different amounts as reinforcements. The results showed that the GelMA/HANW composite cryogels possessed highly porous structure with HANWs being homogeneously distributed. The compressive strengths and mechanical stability of the composite cryogels were improved alongside the increasing contents of HANWs. These composite cryogels were proven non-cytotoxic, able to support cell proliferation and promote osteogenic differentiation of bone mesenchymal stromal cells. More importantly, their porous structure allowed cell migration within the matrix, which was normally hard to be achieved in GelMA hydrogel. With improved performance, GelMA/HANW composite cryogels were thus possibly serving as a new type of bone repair materials.

20.
BMC Nephrol ; 20(1): 135, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30999892

RESUMO

AIMS: Sphingosine-1-phosphate receptor 2 (S1PR2) is a G-protein-coupled receptor that regulates sphingosine-1-phosphate-triggered cellular response. However, the role of S1PR2 in diabetes-induced glomerular endothelial cell dysfunction remains unclear. This study aims to investigate the effect of S1PR2 blockade on the morphology and function of mitochondria in human renal glomerular endothelial cells (HRGECs). METHODS: HRGECs were pretreated with a S1PR2 antagonist (JTE-013) or a Rho-associated coiled coil-containing protein kinase 1 (ROCK1) inhibitor (Y27632) for 30 min and then cultured with normal glucose (5.5 mM) or high glucose (30 mM) for 72 h. The protein expression levels of RhoA, ROCK1, and Dynmin-related protein-1(Drp1) were evaluated by immunoblotting; mitochondrial morphology was observed by electron microscopy; intracellular levels of ATP, ROS, and Ca2+ were measured by ATPlite, DCF-DA, and Rhod-2 AM assays, respectively. Additionally, the permeability, apoptosis, and migration of cells were determined to evaluate the effects of S1PR2 and ROCK1 inhibition on high glucose-induced endothelial dysfunction. RESULTS: High glucose induced mitochondrial fission and dysfunction, indicated by increased mitochondrial fragmentation, ROS generation, and calcium overload but decreased ATP production. High glucose also induced endothelial cell dysfunction, indicated by increased permeability and apoptosis but decreased migration. However, inhibition of either S1PR2 or ROCK1 almost completely blocked these high glucose-mediated cellular responses. Furthermore, inhibiting S1PR2 resulted in the deceased expression of RhoA, ROCK1, and Drp1 while inhibiting ROCK1 led to the downregulated expression of Drp1. CONCLUSIONS: S1PR2 antagonist modulates the morphology and function of mitochondria in HRGECs via the positive regulation of the RhoA/ROCK1/Drp1 signaling pathway, suggesting that the S1PR2/ROCK1 pathway may play a crucial role in high glucose milieu.

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