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1.
Bioact Mater ; 10: 93-106, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34901532

RESUMO

Engineering a complete, physiologically functional, periodontal complex structure remains a great clinical challenge due to the highly hierarchical architecture of the periodontium and coordinated regulation of multiple growth factors required to induce stem cell multilineage differentiation. Using biomimetic self-assembly and microstamping techniques, we construct a hierarchical bilayer architecture consisting of intrafibrillarly mineralized collagen resembling bone and cementum, and unmineralized parallel-aligned fibrils mimicking periodontal ligament. The prepared biphasic scaffold possesses unique micro/nano structure, differential mechanical properties, and growth factor-rich microenvironment between the two phases, realizing a perfect simulation of natural periodontal hard/soft tissue interface. The interconnected porous hard compartment with a Young's modulus of 1409.00 ± 160.83 MPa could induce cross-arrangement and osteogenic differentiation of stem cells in vitro, whereas the micropatterned soft compartment with a Young's modulus of 42.62 ± 4.58 MPa containing abundant endogenous growth factors, could guide parallel arrangement and fibrogenic differentiation of stem cells in vitro. After implantation in critical-sized complete periodontal tissue defect, the biomimetic bilayer architecture potently reconstructs native periodontium with the insertion of periodontal ligament fibers into newly formed cementum and alveolar bone by recruiting host mesenchymal stem cells and activating the transforming growth factor beta 1/Smad3 signaling pathway. Taken together, integration of self-assembly and microstamping strategies could successfully fabricate a hierarchical bilayer architecture, which exhibits great potential for recruiting and regulating host stem cells to promote synergistic regeneration of hard/soft tissues.

2.
J Colloid Interface Sci ; 606(Pt 2): 1410-1420, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492476

RESUMO

Utilizing the synergistic effect of multiple components in heterostructured composites has been regarded as a promising strategy for achieving high-performance electromagnetic wave absorption. Nonetheless, rationally collocate the components of absorbers in order to legitimately achieve synergy remains an intractable problem. By adjusting the NiS and ZnS composition ratios in the ZnS/NiS/C composites, the optimal impedance matching and dissipation capability can be obtained. The formation of a ZnS/NiS heterostructure is found to significantly enhance polarization relaxation, and the relative ratios of ZnS and NiS have a significant effect on the electromagnetic properties. The optimal performance was obtained on Z1N2, with a minimum reflection loss of -51.45 dB at 4.72 GHz and -56.69 dB at 11.12 GHz, respectively, and an effective absorption bandwidth of up to 3.68 GHz at 1.16 mm. The potential of heterogeneous bimetal sulfides as high-performance absorbers is demonstrated in this study.

3.
CNS Neurosci Ther ; 2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-34951123

RESUMO

AIMS: To identify novel pathogenic gene of febrile seizures (FS)/epilepsy with antecedent FS (EFS+). METHODS: The trio-based whole-exome sequencing was performed in a cohort of 462 cases with FS/EFS+. Silico programs, sequence alignment, and protein modeling were used to predict the damaging of variants. Statistical testing was performed to analyze gene-based burden of variants. RESULTS: Five heterozygous missense variants in CELSR3 were detected in five cases (families) with eight individuals (five females, three males) affected. Two variants were de novo, and three were identified in families with more than one individual affected. All the variants were predicted to be damaging in silico tools. Protein modeling showed that the variants resulted in disappearance of multiple hydrogen bonds and one disulfide bond, which potentially caused functional impairments of protein. The frequency of CELSR3 variants identified in this study was significantly higher than that in controls. All affected individuals were diagnosed with FS/EFS+, including six patients with FS and two patients with EFS+. All cases presented favorable outcomes without neurodevelopmental disorders. CONCLUSIONS: CELSR3 variants are potentially associated with FS/EFS+.

4.
Cell Rep ; 37(5): 109912, 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34731622

RESUMO

Fetal growth restriction (FGR) increases the risk for impaired cognitive function later in life. However, the precise mechanisms remain elusive. Using dexamethasone-induced FGR and protein restriction-influenced FGR mouse models, we observe learning and memory deficits in adult FGR offspring. FGR induces decreased hippocampal neurogenesis from the early post-natal period to adulthood by reducing the proliferation of neural stem cells (NSCs). We further find a persistent decrease of Tet1 expression in hippocampal NSCs of FGR mice. Mechanistically, Tet1 downregulation results in hypermethylation of the Dll3 and Notch1 promoters and inhibition of Notch signaling, leading to reduced NSC proliferation. Overexpression of Tet1 activates Notch signaling, offsets the decline in neurogenesis, and enhances learning and memory abilities in FGR offspring. Our data indicate that a long-term decrease in Tet1/Notch signaling in hippocampal NSCs contributes to impaired neurogenesis following FGR and could serve as potential targets for the intervention of FGR-related cognitive disorders.

5.
J Mater Chem B ; 9(43): 8951-8961, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34606554

RESUMO

Bacteria can evade the immune system once they are engulfed by phagocytic host cells. This protects them against the bactericidal action of antibiotics and allows the infection to remain latent or to recur. Reactive oxygen species (ROS)-related stress has been implicated in various pathological conditions such as inflammatory diseases involving infections of host cells and can serve as a useful trigger for intracellular controlled drug delivery. We herein report on a fluorescent ROS-sensitive intracellular antibiotic delivery nanoparticle for encapsulation of rifampin (RIF) based on the principles of Förster Resonance Energy Transfer (FRET) that is capable of ratiometrically sensing H2O2 levels and monitoring the drug release process. The fluorescent micelles (MFs) are formed through the self-assembly of amphiphilic diblock copolymers consisting of a poly(ethylene glycol) (PEG) segment and a fluorescent oxidation-responsive hydrophobic phenylboronic pinacol ester (PBA) block. Specifically, MFs could encapsulate the model antibiotic RIF (MF/RIF) and ROS-triggered controlled release of RIF within infected macrophages (where ROS levels are elevated) improved the elimination of intracellular bacteria compared to MF or RIF alone. This antibiotic delivery system may be especially effective at fighting intracellular pathogens that have managed to evade the immune system and could minimize exposure of normal cells and tissues to high drug concentrations.

6.
Cell Cycle ; : 1-16, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34592887

RESUMO

Preeclampsia (PE) is a pregnancy-associated disorder caused by poor placentation. METTL3 as an RNA methyltransferase that plays an essential role in the regulation of the m6A modification. This work investigated the regulation of METTL3-mediated mature miR-497-5p/195-5p cluster in PE progression and identified the downstream mechanisms involved. Differentially expressed miRNAs in PE were obtained from the GSE96983 dataset. The miR-497-5p/195-5p levels in placental samples collected from 20 cases of PE patients and 18 cases of normal controls were measured by RT-qPCR. Effects of miR-497-5p/195-5p and WWP1 on trophoblast proliferation, migration, and invasion were analyzed by CCK8, EdU, wound healing and Transwell assays. Luciferase reporter and RIP experiments were conducted to verify the interaction of WWP1 with miR-497-5p/195-5p. Dot blot assay was performed to determine the m6A levels in PE. The m6A modification of pri-miR-497-5p/195-5p was determined by Me-RIP assay. Immunochemistry (IHC) and western blotting were used to examine the immunoreactivities and protein levels of METTL3 and WWP1 in placental samples from PE patients and normal controls. The miR-497-5p/195-5p levels were high in PE placenta. Functionally, overexpression of miR-497-5p/195-5p prevented trophoblast migration, invasion, and proliferation. WWP1 overexpression enhanced trophoblast migration, invasion, and proliferation. Mechanistically, WWP1 was verified to be targeted by miR-497-5p/195-5p. Moreover, METTL3 promoted the recognition of pri-miR-497-5p/195-5p by DGCR8 and enhanced the formation of mature miR-497-5p/195-5p in an m6A manner. We demonstrated that METTL3-mediated m6A modification promotes the transition of pri-miR-497-5p/195-5p to mature miRNAs, thereby upregulating miR-497-5p/195-5p to aggravate PE progression by targeting WWP1.

7.
Materials (Basel) ; 14(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34500887

RESUMO

High-performance extruded aluminum alloys with complex textures suffer significant dimension variation under environmental temperature fluctuations, dramatically decreasing the precision of navigation systems. This research mainly focuses on the effect of the texture of extruded pure aluminum on its dimensional stability after various annealing processes. The result reveals that a significant increment in the area fraction of recrystallized grains with <100> orientation and a decrement in the area fraction of grains with <111> orientation were found with increasing annealing temperature. Moreover, with the annealing temperature increasing from 150 °C to 400 °C, the residual plastic strain after twelve thermal cycles with a temperature range of 120 °C was changed from -1.6 × 10-5 to -4.5 × 10-5. The large amount of equiaxed grains with <100> orientation was formed in the microstructure of the extruded pure aluminum and the average grain size was decreased during thermal cycling. The area fraction of grain with <100> crystallographic orientation of the sample annealed at 400 °C after thermal cycling was 30.9% higher than annealed at 350 °C (23.7%) or at 150 °C (18.7%). It is attributed to the increase in the proportion of recrystallization grains with <100> direction as the annealing temperature increases, provided more nucleation sites for the formation of fine equiaxed grains with <100> orientation. The main orientation of the texture was rotated from parallel to <111> to parallel to <100> after thermal cycling. The change in the orientation of grains contributed to a change in interplanar spacing, which explains the change in the dimension along the extrusion direction during thermal cycling.

8.
Transl Androl Urol ; 10(8): 3432-3439, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34532268

RESUMO

Background: To perform a prospective, randomized, single center study to investigate the efficacy of combined use of curcumin, an anti-inflammatory agent, with the best standard management (BSM, tamsulosin and finasteride) in benign prostatic hyperplasia (BPH) patients. Methods: One hundred and twenty-two consecutive patients were randomized to receive tamsulosin 0.2 mg, finasteride 5 mg, and curcumin 2,250 mg once a day (curcumin + BSM group, n=61) versus tamsulosin 0.2 mg, finasteride 5 mg, and placebo (BSM group, n=61) for 6 months. The safety of treatments and their efficacy on improving waist circumference (WC), periprostatic fat thickness (PPFT), lower urinary tract symptoms (LUTS), and sexual function were assessed at baseline and month 6. Results: One hundred and sixteen patients completed the whole procedure (116/122, 95.1%). There were significant improvements in prostate volume (PV), maximum flow rate (Qmax), the International Prostate Symptom Score (IPSS), IPSS-voiding subscore (IPSS-V), IPSS-storage subscore (IPSS-S), and quality of life (QoL) from baseline after treatment in both groups. Additionally, both WC and PPFT decreased significantly after treatments than those at baseline in the curcumin + BSM group. Also, WC and PPFT in the curcumin + BSM group were significantly lower than those in the BSM group. In addition, IPSS-S, QoL score, and the 5-item version of the International Index of Erectile Function (IIEF-5) in the curcumin + BSM group improved significantly compared with those in the BSM group. Conclusions: We conclude that curcumin combined with tamsulosin and finasteride has more beneficial effects in reducing PPFT, protecting erectile function, improving urinary retention symptoms, and QoL scores in BPH patients compared to tamsulosin and finasteride alone. Trial Registration: Chinese Clinical Trial Registry ChiCTR2100043800.

10.
J Alzheimers Dis ; 83(2): 799-818, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34366339

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a degenerative disorder, accompanied by progressive cognitive decline, for which there is no cure. Recently, the close correlation between AD and type 2 diabetes mellitus (T2DM) has been noted, and a promising anti-AD strategy is the use of anti-T2DM drugs. OBJECTIVE: To investigate if the novel glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist DA4-JC shows protective effects in the triple APP/PS1/tau mouse model of AD. METHODS: A battery of behavioral tests were followed by in vivo recording of long-term potentiation (LTP) in the hippocampus, quantified synapses using the Golgi method, and biochemical analysis of biomarkers. RESULTS: DA4-JC improved cognitive impairment in a range of tests and relieved pathological features of APP/PS1/tau mice, enhanced LTP in the hippocampus, increased numbers of synapses and dendritic spines, upregulating levels of post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), normalized volume and numbers of mitochondria and improving the phosphatase and tensin homologue induced putative kinase 1 (PINK1) - Parkin mitophagy signaling pathway, while downregulating amyloid, p-tau, and autophagy marker P62 levels. CONCLUSION: DA4-JC is a promising drug for the treatment of AD.

11.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(3): 240-246, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34374234

RESUMO

Objective: To investigate the effects of novel BimunoGalactooligosaccharides (B-GOS) on cognitive behavior and depression of APP/PS1/tau Alzheimer's disease transgenic mice. Methods: Five-month-old male APP/PS1/tau AD transgenic mice and C57BL/6J control mice were divide into C57+Vehicle group, C57+B-GOS group, APP/PS1/tau+Vehicle group and APP/PS1/tau+B-GOS group, with 10 mice in each group. After continuous administration of B-GOS for 5 months, the cognitive behavior and depressive mood changes of mice in each group were detected by open field experiment, new object recognition experiment, Y maze experiment, Morris water maze experiment, tail suspension test, forced swimming test and conditioned fear experiment, respectively. Results: ①Open field experiment: the percentage of activity time in the central area of open field in APP/PS1/tau+Vehicle group mice was significantly lower than that in C57+Vehicle group mice (P<0.01), and was remarkably increased after B-GOS intervention (P<0.05). ② New object recognition experiment: the new object recognition index (NOI) of APP/PS1/tau+Vehicle group mice was significantly lower than that of C57+Vehicle group mice (P<0.01), and was observably increased after B-GOS intervention (P<0.05). ③ Y maze experiment: the spontaneous alternation correct rate of APP/PS1/tau+Vehicle group mice was notably lower than that in C57+Vehicle group (P<0.01), and was distinctly increased after B-GOS intervention (P<0.01). ④ Classical water maze experiment: the escape latency of APP/PS1/tau+Vehicle group mice on the 4th and 5th days was significantly longer than that of C57+Vehicle group mice (P<0.01), which was markedly shortened after B-GOS intervention (P<0.05). During the space exploration phase, the percentage of swimming time in the target quadrant and the times of crossing the platform in APP/PS1/tau+Vehicle group mice were significantly lower than those in C57+Vehicle group mice (P<0.01), which were notably increased after B-GOS intervention (P<0.01). ⑤ Tail suspension test and forced swimming test: the percentage of immobility time in APP/PS1/tau+Vehicle group mice was dramatically higher than that in C57+Vehicle group mice (P<0.01), and was obviously reduced after B-GOS intervention (P< 0.01). ⑥ Conditioned fear experiment: before conditioned stimulus (CS), the freezing ratio of mice in each group had no statistical difference (P>0.05). After CS, the freezing ratio of APP/PS1/tau+Vehicle group mice was significantly lower than that of C57+Vehicle group mice (P<0.01), and was notably increased after B-GOS intervention (P<0.01). Conclusion: B-GOS could reverse the cognitive behavioral impairment of APP/PS1/tau mice and alleviate their depression to a large extent.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animais , Cognição , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Presenilina-1/genética
12.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(4): 397-401, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34374260

RESUMO

Objective: To study the protective effects and mechanisms of total saponins of Codonopsis (TSC) on ulcerative colitis in rats. Methods: Fifty male Wistar rats were randomly divided into 5 groups: control group, model group, salazosulfadiazine (SASP) positive control group (0.3 g/kg), TSC high- and low-dose experimental groups(1.2, 0.4 g/kg). UC rat model was established by trinitrobenzene sulfonic acid (TNBS)/ ethanol enema. After administration for 21 days, the rats' symptoms and signs, disease activity index (DAI), colonic mucosal injury index (CMDI) and colonic tissue morphology were observed. The contents of superoxide dismutase (SOD), malondialdehyde (MDA), inflammatory cytokines interleukin-6 (IL-6), interleukin-10 (IL-10) and tumor necrosis factor (TNF-α) in colon tissues were determined. Protein expression of nuclear nuclear transcription factor-κB (NF-κB) in colon tissues was detected. Finally, the effect of TCS therapy was evaluated. Results: Compared with the control group, the DAI and CMDI scores of the rats in the model group were increased significantly, meanwhile the colonic mucosa was seriously damaged, indicating that the model was successful. Compared with the model group, the TSC high and low dose groups could significantly reduce the DAI and CMDI score (P<0.05) and improve the colonic mucosa form. TSC also could increase the SOD activity and decrease MDA content in colon tissues(P<0.05), while inhibit the levels of IL-6 and TNF-α mRNA in the colon tissues and promote the expression of IL-10 mRNA (P<0.01). At the same time, TSC reduced the expressions of NF-κB protein in the colon (P<0.01). The TSC high-dose group was superior to the low-dose group (P<0.05). Conclusion: TSC has significant protective effects on ulcerative colonic mucosal damage in UC rats, and there is a dose-dependent relationship; its mechanism may be related to anti-lipid peroxidation and inhibiting the NF-κB signaling pathway to regulate the release of inflammatory factors.


Assuntos
Codonopsis , Colite Ulcerativa , Saponinas , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colo , Masculino , NF-kappa B , Ratos , Ratos Wistar , Saponinas/farmacologia , Ácido Trinitrobenzenossulfônico
13.
Nanomicro Lett ; 13(1): 75, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-34138308

RESUMO

HIGHLIGHTS: Non-magnetic bimetallic MOF-derived porous carbon-wrapped TiO2/ZrTiO4 composites are firstly used for efficient electromagnetic wave absorption. The electromagnetic wave absorption mechanisms including enhanced interfacial polarization and essential conductivity are intensively discussed. Modern communication technologies put forward higher requirements for electromagnetic wave (EMW) absorption materials. Metal-organic framework (MOF) derivatives have been widely concerned with its diverse advantages. To break the mindset of magnetic-derivative design, and make up the shortage of monometallic non-magnetic derivatives, we first try non-magnetic bimetallic MOFs derivatives to achieve efficient EMW absorption. The porous carbon-wrapped TiO2/ZrTiO4 composites derived from PCN-415 (TiZr-MOFs) are qualified with a minimum reflection loss of - 67.8 dB (2.16 mm, 13.0 GHz), and a maximum effective absorption bandwidth of 5.9 GHz (2.70 mm). Through in-depth discussions, the synergy of enhanced interfacial polarization and other attenuation mechanisms in the composites is revealed. Therefore, this work confirms the huge potentials of non-magnetic bimetallic MOFs derivatives in EMW absorption applications.

14.
Nanomicro Lett ; 13(1): 135, 2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34138364

RESUMO

To tackle the aggravating electromagnetic wave (EMW) pollution issues, high-efficiency EMW absorption materials are urgently explored. Metal-organic framework (MOF) derivatives have been intensively investigated for EMW absorption due to the distinctive components and structures, which is expected to satisfy diverse application requirements. The extensive developments on MOF derivatives demonstrate its significantly important role in this research area. Particularly, MOF derivatives deliver huge performance superiorities in light weight, broad bandwidth, and robust loss capacity, which are attributed to the outstanding impedance matching, multiple attenuation mechanisms, and destructive interference effect. Herein, we summarized the relevant theories and evaluation methods, and categorized the state-of-the-art research progresses on MOF derivatives in EMW absorption field. In spite of lots of challenges to face, MOF derivatives have illuminated infinite potentials for further development as EMW absorption materials.

15.
J Cell Physiol ; 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34189751

RESUMO

In mammals, oocytes are arrested at G2/prophase for a long time, which is called germinal vesicle (GV) arrest. After puberty, fully-grown oocytes are stimulated by a gonadotropin surge to resume meiosis as indicated by GV breakdown (GVBD). CCNB1 is accumulated to a threshold level to trigger the activation of maturation promoting factor (MPF), inducing the G2/M transition. It is generally recognized that the anaphase-promoting complex/cyclosome (APC/C) and its cofactor CDH1 (also known as FZR1) regulates the accumulation/degradation of CCNB1. Here, by using small interfering RNA (siRNA) and messenger RNA (mRNA) microinjection, immunofluorescence and confocal microscopy, immunoprecipitation, time-lapse live imaging, and immunoblotting analysis, we showed that Septin 4 regulates the G2/M transition by regulating the accumulation of CCNB1 via APC/CCDC20 . Depletion of Septin 4 caused GV arrest by reducing CCNB1 accumulation. Unexpectedly, the expression level of CDC20 was higher in Septin 4 siRNA-injected oocytes than in control oocytes, but there was no significant change in the expression level of CDH1. Importantly, the reduced GVBD after Septin 4 depletion could be rescued not only by over-expressing CCNB1 but also could be partially rescued by depleting CDC20. Taken together, our results demonstrate that Septin 4 may play a critical role in meiotic G2/M transition by indirect regulation of CCNB1 stabilization in mouse oocytes.

16.
BMC Oral Health ; 21(1): 266, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001101

RESUMO

BACKGROUND: Salivary interleukin (IL)-1ß, matrix metalloproteinase (MMP)-8, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and Porphyromonas gingivalis (Pg) are related to periodontitis. This study aimed to investigate the diagnostic potential of these biomarkers and to build a prediction panel for diagnosing periodontal disease. METHODS: A total of 80 participants were enrolled in a cross-sectional study and divided into healthy (n = 25), gingivitis (n = 24), and periodontitis (n = 31) groups based on their periodontal exam results. A full mouth periodontal examination was performed and unstimulated saliva was collected. Salivary IL-1ß, MMP-8, ICTP, and Pg were assessed using enzyme-linked immunosorbent assay (ELISA) and quantitative real time PCR (qPCR). Their potentials for diagnosing periodontal disease were analyzed and combined prediction panels of periodontal disease were evaluated. RESULTS: As a single marker, IL-1ß showed the best diagnostic value of the four markers evaluated and exhibited an area under the curve (AUC) value of 0.88 with 90% sensitivity and 76% specificity for discriminating periodontitis subjects from healthy subjects, an AUC value of 0.80 with 83% sensitivity and 76% specificity for discriminating gingivitis subjects from healthy subjects and an AUC value of 0.66 with 68% sensitivity and 64% specificity for differentiating periodontitis subjects from gingivitis subjects. The combination of IL-1ß, ICTP, and Pg exhibited the highest efficacy for discriminating periodontitis subjects from healthy subjects (AUC = 0.94) and gingivitis subjects (AUC = 0.77). The combination of IL-1ß and MMP-8 exhibited the best ability to discriminate gingivitis from healthy subjects (AUC = 0.84). CONCLUSIONS: Salivary IL-1ß, MMP-8, ICTP, and Pg showed significant effectiveness for diagnosing periodontal disease. The combination of IL-1ß, ICTP, and Pg can be used to discriminate periodontitis subjects from healthy subjects and gingivitis subjects, and the combination of IL-1ß and MMP-8 can be used to discriminate gingivitis subjects from healthy subjects.


Assuntos
Gengivite , Periodontite , Biomarcadores , Estudos Transversais , Gengivite/diagnóstico , Humanos , Periodontite/diagnóstico , Saliva
17.
Naunyn Schmiedebergs Arch Pharmacol ; 394(9): 1893-1905, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33959780

RESUMO

The purpose of this research was to evaluate the clinical efficacy and safety of pramipexole plus levodopa/benserazide (P+LB) combination therapy in the treatment of Parkinson's disease (PD) compared to that of LB monotherapy, in order to confer a reference for clinical practice. Randomized controlled trials (RCTs) of P+LB for PD published up to April 2020 were retrieved. Heterogeneity and sensitivity analysis were executed. Twenty-nine RCTs with 3017 participants were included. Clinical efficacy of P+LB combination therapy was significantly better than LB monotherapy (RR 1.27, 95% CI 1.22 to 1.32, P<0.00001). Compared with LB monotherapy, the pooled effects of P+LB combination therapy on UPDRS score were (SMD -1.41, 95% CI -1.71 to -1.11, P<0.00001) for motor UPDRS score, (SMD -1.65, 95% CI -2.25 to -1.04, P<0.00001) for activities of daily living UPDRS score, (SMD -2.20, 95% CI -3.32 to -1.09, P=0.0001) for mental UPDRS score, and (SMD -1.60, 95% CI -2.06 to -1.15, P<0.00001) for complication UPDRS score. The HAMD score showed significant decrease in the P+LB combination therapy compared to LB monotherapy (SMD -1.32, 95% CI -1.80 to -0.84, P<0.00001). In contrast to LB monotherapy, P+LB combination therapy decreased the number of any adverse events obviously in PD patients (RR 0.53, 95% CI 0.45 to 0.63, P<0.00001). In conclusion, P+LB combination therapy is superior to LB monotherapy for improvement of clinical symptoms in PD patients. Moreover, the safety profile of P+LB combination therapy is better than that of LB monotherapy. Further well-designed, multi-center RCTs needed to identify these findings.

19.
Brain ; 144(10): 3050-3060, 2021 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-33876820

RESUMO

The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13-2 (Munc13-2), which is highly expressed in the brain-predominantly in the cerebral cortex-and plays an essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of the UNC13B mutation in human disease is not known. In this study, we screened for novel genetic variants in a cohort of 446 unrelated cases (families) with partial epilepsy without acquired causes by trio-based whole-exome sequencing. UNC13B variants were identified in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families. The eight probands all had focal seizures and focal discharges in EEG recordings, including two patients who experienced frequent daily seizures and one who showed abnormalities in the hippocampus by brain MRI; however, all of the patients showed a favourable outcome without intellectual or developmental abnormalities. The identified UNC13B variants included one nonsense variant, two variants at or around a splice site, one compound heterozygous missense variant and four missense variants that cosegregated in the families. The frequency of UNC13B variants identified in the present study was significantly higher than that in a control cohort of Han Chinese and controls of the East Asian and all populations in the Genome Aggregation Database (gnomAD). Computational modelling, including hydrogen bond and docking analyses, suggested that the variants lead to functional impairment. In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila. Electrophysiological recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability. These results indicate that UNC13B is potentially associated with epilepsy. The frequent daily seizures and hippocampal abnormalities but ultimately favourable outcome under anti-epileptic therapy in our patients indicate that partial epilepsy caused by UNC13B variant is a clinically manageable condition.

20.
Acta Biomater ; 126: 384-393, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33705987

RESUMO

Multidrug resistant (MDR) Gram-negative bacteria are an urgent global health threat. We report on the design and evaluation of a xenosiderophore-conjugated cationic random copolymer (pGQ-DG) which exhibits selective antibacterial activity against Pseudomonas aeruginosa (P. aeruginosa) by targeting select outer membrane (OM) receptors for scavenging xenosiderophores such as deferoxamine (DFO), while possessing favorable cytocompatibility and exhibiting low hemolysis, to enhance and safely damage the bacterial OM. pGQ-DG demonstrated synergistic properties in combination with vancomycin (VAN) when evaluated in vitro against P. aeruginosa. In addition, pGQ-DG plus VAN cleared the P. aeruginosa infection and efficiently accelerated healing in a murine wound healing model as effectively as colistin, suggesting that this strategy could serve as an alternative to colistin against MDR bacteria. STATEMENT OF SIGNIFICANCE: P. aeruginosa exhibits intrinsic antibiotic resistance due to limited permeability of its outer membrane (OM). A triple combination antipseudomonal approach was investigated by 1) selectively targeting P. aeruginosa through the complex DFO:gallium, 2) disrupting the OM through a cationic random copolymer, and 3) enhancing bacteria sensitivity to VAN as a result of the OM disruption. Synthesis and characterization of the lead polymer pGQ-DG, mechanism of action, antimicrobial activity, and biocompatibility were investigated in vitro and in vivo. Overall pGQ-DG plus VAN cleared the P. aeruginosa infection and accelerated wound healing in mice as effectively as colistin, suggesting that this strategy could serve as an alternative to colistin against multidrug resistant P. aeruginosa.


Assuntos
Gálio , Pseudomonas aeruginosa , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Colistina/farmacologia , Desferroxamina/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Polímeros , Cicatrização
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