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1.
Fly (Austin) ; 16(1): 13-23, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34609266

RESUMO

Dendritic morphogenesis requires dynamic microtubules (MTs) to form a coordinated cytoskeletal network during development. Dynamic MTs are characterized by their number, polarity and speed of polymerization. Previous studies described a correlation between anterograde MT growth and terminal branch extension in Drosophila dendritic arborization (da) neurons, suggesting a model that anterograde MT polymerization provides a driving force for dendritic branching. We recently found that the Ste20-like kinase Tao specifically regulates dendritic branching by controlling the number of dynamic MTs in a kinase activity-dependent fashion, without affecting MT polarity or speed. This finding raises the interesting question of how MT dynamics affects dendritic morphogenesis, and if Tao kinase activity is developmentally regulated to coordinate MT dynamics and dendritic morphogenesis. We explored the possible correlation between MT dynamics and dendritic morphogenesis together with the activity changes of Tao kinase in C1da and C4da neurons during larval development. Our data show that spatiotemporal changes in the number of dynamic MTs, but not polarity or polymerization speed, correlate with dendritic branching and Tao kinase activity. Our findings suggest that Tao kinase limits dendritic branching by controlling the abundance of dynamic MTs and we propose a novel model on how regulation of MT dynamics might influence dendritic morphogenesis.

2.
J Sport Health Sci ; 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34606977

RESUMO

PURPOSE: To identify the prevalence of meeting the muscle-strengthening exercise (MSE) recommendations and its correlates among Chinese children and adolescents. METHODS: Cross-sectional data from 80,413 Chinese children and adolescents (mean age = 13.7 years; 53.9% girls) and their parents were analyzed. Self-reported data on MSE, demographics (sex, grade, ethnicity, residence location, height, weight, family composition and income, and parental education level), behavior (sport skills, moderate-to-vigorous physical activity, screen time, and sleep duration), psychology (exercise intention), and sociocultural background (peer and parental support and parental MSE) were obtained. Logistic regression models were used to determine the correlates of meeting the recommendations. RESULTS: Overall, 39.3% of children and adolescents met the MSE recommendations. At the demographic level, girls, 10th-12th graders, those who were overweight or obese, minorities, and those with lower income and lower parental education levels were less likely to meet the MSE recommendations. At the behavioral level, children proficient in ≥2 sport skills were more likely to meet the MSE recommendations (odds ratio (OR) = 1.44, 95% confidence interval (95%CI): 1.26-1.66), as were those with more moderate-to-vigorous physical activity (OR = 1.57, 95%CI: 1.53-1.61). At the psychological level, children with high exercise intention were more likely to meet the MSE recommendations (OR = 1.59, 95%CI: 1.51-1.68). At the sociocultural level, children whose parents met the adult MSE recommendations (OR = 1.46, 95%CI: 1.40-1.53) and who received high peer (OR = 1.27, 95%CI: 1.20-1.35) and parental support (OR = 1.08, 95%CI: 1.03-1.12) had a greater chance of meeting the MSE recommendations. CONCLUSION: Less than two-fifths of Chinese children and adolescents met the MSE recommendations. Sex, age, weight status, ethnicity, family income, parental education level, sport skills, moderate-to-vigorous physical activity, exercise intention, peer and parental support, and parental MSE were significantly associated with meeting the recommendations.

3.
BMC Cancer ; 21(1): 1084, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620113

RESUMO

BACKGROUND & AIMS: Little is known on the gender-specific effect and potential role of non-linear associations between metabolic syndrome (MetS) components and liver cancer risk. We evaluated these associations based on the UK Biobank cohort. METHODS: We included 474,929 individuals without previous cancer based on the UK Biobank cohort. Gender-specific hazard ratios (HRs) and 95% confidence interval (CIs) were calculated by Cox proportional hazards regression, adjusting for potential confounders. Non-linear associations for individual MetS components were assessed by the restricted cubic spline method. RESULTS: Over a median follow-up of 6.6 years, we observed 276 cases of liver cancer (175 men, 101 women). MetS [HR 1.48, 95% CI 1.27-1.72] and central obesity [HR 1.65, 95% CI 1.18-2.31] were associated with higher risk of liver cancer in men but not in women. Participants with hyperglycaemia has higher risk of liver cancer. High waist circumference and blood glucose were dose-dependently associated with increased liver cancer risk in both genders. For high density lipoprotein (HDL) cholesterol (both genders) and blood pressure (women), U-shaped associations were observed. Low HDL cholesterol (< 1.35 mmol/L) in men and high HDL cholesterol in women (> 1.52 mmol/L) were associated with increased liver cancer risk. CONCLUSIONS: MetS components showed gender-specific linear or U- shaped associations with the risk of liver cancer. Our study might provide evidence for individualized management of MetS for preventing liver cancer.

4.
Math Biosci Eng ; 18(5): 6620-6637, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34517548

RESUMO

For the existing Closed Set Recognition (CSR) methods mistakenly identify unknown jamming signals as a known class, a Conditional Gaussian Encoder (CG-Encoder) for 1-dimensional signal Open Set Recognition (OSR) is designed. The network retains the original form of the signal as much as possible and deep neural network is used to extract useful information. CG-Encoder adopts residual network structure and a new Kullback-Leibler (KL) divergence is defined. In the training phase, the known classes are approximated to different Gaussian distributions in the latent space and the discrimination between classes is increased to improve the recognition performance of the known classes. In the testing phase, a specific and effective OSR algorithm flow is designed. Simulation experiments are carried out on 9 jamming types. The results show that the CSR and OSR performance of CG-Encoder is better than that of the other three kinds of network structures. When the openness is the maximum, the open set average accuracy of CG-Encoder is more than 70%, which is about 30% higher than the worst algorithm, and about 20% higher than the better one. When the openness is the minimum, the average accuracy of OSR is more than 95%.


Assuntos
Algoritmos , Redes Neurais de Computação , Simulação por Computador , Distribuição Normal
5.
Acta Biomater ; 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34571271

RESUMO

The continuous activation and expansion of tumor-specific T cells by various means are the main goal of cancer immunotherapy. Tumor cells overexpress fibrinogen-like protein 1 (FGL1) and programmmed death-ligand 1 (PD-L1), which respectively bind to lymphocyte-activation gene 3 (LAG-3) and programmmed death-1(PD-1) on T cells, forming important signaling pathways (FGL1/LAG-3 and PD-1/PD-L1) that negatively regulate immune responses. In order to interfere with the inhibitory function of FGL1 and PD-L1 proteins, we designed a new type of reactive oxygen species (ROS)-sensitive nanoparticles to load FGL1 siRNA (siFGL1) and PD-L1 siRNA (siPD-L1), which was formed from a stimuli-responsive polymer with a poly-l-lysine-thioketal and modified cis-aconitate to facilitate endosomal escape. Moreover, tumor-penetrating peptide iRGD and ROS-responsive nanoparticles were co-administered to further enhance the delivery efficiency of siFGL1 and siPD-L1, thereby significantly reducing the protein levels of FGL1 and PD-L1 in tumor cells. Our findings indicated that the dual delivery of FGL1/PD-L1 siRNA was a new and powerful treatment method, which was characterized by increasing the infiltration of effector CD4+ and CD8+ T cells, effectively alleviating the tumor immunosuppressive microenvironment. These findings also supported the superiority and feasibility of nanoparticle-mediated tumor immunotherapy, and may provide a different perspective for cancer treatment. STATEMENT OF SIGNIFICANCE: In addition to the idea that cancer vaccines can promote T cell immune responses, nanoparticle delivery modulators (such as small interfering RNA (siRNA) targeting immunosuppressive pathways) may provide more information for the research of nanoparticle-mediated cancer immunotherapy. In this study, we designed a new intelligent nano-delivery system for co-delivery of siFGL1 and siPD-L1, and demonstrated the ability to down-regulate the expression levels of FGL1 and PD-L1 proteins in tumor cells in vitro and in vivo. The constructed nanoparticle had a good tumor microenvironment responsiveness, and the delivery efficiency was enhanced by co-injection with tumor penetrating peptide iRGD. This project proposed a new strategy for tumor immunotherapy based on smart nano-delivery systems, and explored more possibilities for tumor therapy.

6.
Int J Med Sci ; 18(15): 3533-3543, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522180

RESUMO

Importance: Despite the availability of a vaccine against the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), humans will have to live with this virus and the after-effects of the coronavirus disease 2019 (COVID-19) infection for a long time. Cholesterol plays an important role in the infection and prognosis of SARS-CoV-2, and the study of its mechanism is of great significance not only for the treatment of COVID-19 but also for research on generic antiviral drugs. Observations: Cholesterol promotes the development of atherosclerosis by activating NLR family pyrin domain containing 3 (NLRP3), and the resulting inflammatory environment indirectly contributes to COVID-19 infection and subsequent deterioration. In in vitro studies, membrane cholesterol increased the number of viral entry sites on the host cell membrane and the number of angiotensin-converting enzyme 2 (ACE2) receptors in the membrane fusion site. Previous studies have shown that the fusion protein of the virus interacts with cholesterol, and the spike protein of SARS-CoV-2 also requires cholesterol to enter the host cells. Cholesterol in blood interacts with the spike protein to promote the entry of spike cells, wherein the scavenger receptor class B type 1 (SR-B1) plays an important role. Because of the cardiovascular protective effects of lipid-lowering therapy and the additional anti-inflammatory effects of lipid-lowering drugs, it is currently recommended to continue lipid-lowering therapy for patients with COVID-19, but the safety of extremely low LDL-C is questionable. Conclusions and Relevance: Cholesterol can indirectly increase the susceptibility of patients to SARS-CoV-2 and increase the risk of death from COVID-19, which are mediated by NLRP3 and atherosclerotic plaques, respectively. Cholesterol present in the host cell membrane, virus, and blood may also directly participate in the virus cell entry process, but the specific mechanism still needs further study. Patients with COVID-19 are recommended to continue lipid-lowering therapy.


Assuntos
COVID-19/complicações , Hipercolesterolemia/complicações , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/uso terapêutico , Aterosclerose/fisiopatologia , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/terapia , Membrana Celular/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Endocitose , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/terapia , Inflamação , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/sangue , Prognóstico , SARS-CoV-2 , Receptores Depuradores Classe B/metabolismo
7.
J Dairy Sci ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34538488

RESUMO

Bovine mammary epithelial cells undergo an increase in metabolic rate, mitochondrial dysfunction, and oxidative stress after calving. Nuclear factor erythroid 2-related factor 2 (NFE2L2), a master regulator of cellular redox homeostasis, plays crucial roles in the regulation of mitochondrial function. The objective of this study was to investigate the role of NFE2L2 on mitochondrial function in bovine mammary epithelial cells under hyperlipidemic conditions. Three experiments were conducted as follows: (1) the immortalized bovine mammary epithelial cell line MAC-T was treated with various concentrations of free fatty acids (FFA; 0, 0.6, 1.2, or 2.4 mM) for 24 h to induce stress; (2) MAC-T cells were transfected with small interfering RNA targeting NFE2L2 (si-NFE2L2) and scrambled nontarget negative control (si-Control) for 48 h; and (3) MAC-T cells were pretreated with 10 µM sulforaphane (SFN), an activator of NFE2L2, for 24 h followed by treatment with 1.2 mM FFA for an additional 24 h. Results indicated that exogenous FFA challenge induced linear and quadratic increases in concentrations of mitochondrial reactive oxygen species (ROS). Compared with 0 mM FFA, mitochondrial membrane potential, mRNA abundance of oxidative phosphorylation complexes (CO I-V), protein abundance of nuclear respiratory factor 1 (NRF1), peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α), mitochondrial transcription factor A (TFAM), and NFE2L2 along with the contents of ATP, mitochondrial DNA (mtDNA), and total mitochondria were greater in the MAC-T challenged with 0.6 mM FFA group, but lower in the 1.2 and 2.4 mM FFA cultures. Knockdown of NFE2L2 via small interfering RNA led to greater mitochondrial ROS content and lower mitochondrial membrane potential along with contents of ATP, mtDNA, and total mitochondria. The SFN pretreatment upregulated protein abundance of NFE2L2 and attenuated the downregulation of NFE2L2 induced by FFA. Pretreatment with SFN attenuated the downregulation induced by FFA of PGC-1α, NRF1, and TFAM protein abundance along with contents of mtDNA and total mitochondria. Furthermore, SFN pretreatment attenuated the upregulation of mitochondrial ROS content, the downregulation of mitochondrial membrane potential, and the decreases in ATP, mtDNA, and mitochondrial content induced by FFA. Overall, data indicated that FFA inhibit NFE2L2, resulting in mitochondrial dysfunction and ROS production in bovine mammary epithelial cells. Thus, NFE2L2 may be a promising therapeutic target against metabolic challenge-driven mitochondrial dysfunction and oxidative stress in bovine mammary epithelial cells.

8.
J Occup Environ Med ; 63(9): e641-e649, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34491972

RESUMO

According to the decibel level of noise detection in the working environment, the research objects were divided into high noise group (more than 85 dB), low noise group (55 to 85 dB), and control group (less than 55 dB), the neurobehavioral core test battery (NCTB) was used to systematic tests all workers, radioimmunoassay was used to detect plasma catecholamine levels, and the relationship between noise intensities and the levels of plasma catecholamine was analyzed by canonical correlation. The result shows noise exposure will affect workers' neurological function and the influence of noise on neurobehavioral function may be related to the increase of the levels of norepinephrine and dopamine in the plasma and the inhibition of the synthesis of epinephrine of noise-exposed workers.

9.
Biol Res ; 54(1): 27, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488902

RESUMO

BACKGROUND: Demethylzeylasteral (T-96) is a pharmacologically active triterpenoid monomer extracted from Tripterygium wilfordii Hook F (TWHF) that has been reported to exhibit anti-neoplastic effects against several types of cancer cells. However, the potential anti-tumour effects of T-96 against human Prostate cancer (CaP) cells and the possible underlying mechanisms have not been well studied. RESULTS: In the current study, T-96 exerted significant cytotoxicity to CaP cells in vitro and induced cell cycle arrest at S-phase in a dose-dependent manner. Mechanistically, T-96 promoted the initiation of autophagy but inhibited autophagic flux by inducing ROS-mediated endoplasmic reticulum (ER) stress which subsequently activated the extrinsic apoptosis pathway in CaP cells. These findings implied that T-96-induced ER stress activated the caspase-dependent apoptosis pathway to inhibit proliferation of CaP cells. Moreover, we observed that T-96 enhances the sensitivity of CaP cells to the chemotherapeutic drug, cisplatin. CONCLUSIONS: Taken together, our data demonstrated that T-96 is a novel modulator of ER stress and autophagy, and has potential therapeutic applications against CaP in the clinic.


Assuntos
Autofagia , Neoplasias da Próstata , Apoptose , Linhagem Celular Tumoral , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Espécies Reativas de Oxigênio , Triterpenos
10.
Artigo em Inglês | MEDLINE | ID: mdl-34480736

RESUMO

INTRODUCTION: At present, some studies have reported that nasal rosacea may be an independent disease, but phenotypic characteristics and risk factors for nasal rosacea remain unknown. This study aimed to clarify the clinical features and explore the risk factors for nasal rosacea. METHODS: A hospital-based retrospective study was conducted, including 1615 rosacea patients and 1501 healthy individuals. The patients were divided into three groups based on the involved areas of the lesions (non-nasal, intermediate and nasal rosacea group). Their demographic data and clinical features were obtained from patients' medical records, and risk factors of nasal rosacea were analyzed. RESULTS: There were 927 (57.4%), 647 (40.1%) and 41 (2.5%) cases in the non-nasal, intermediate and nasal rosacea groups, respectively. Of 41 patients with nasal rosacea, all (100.0%) had fixed erythema and 17 cases (41.5%) had phymatous changes. Compared with control group, male gender (adjusted odds ratio [aOR] = 2.39, 95% confidence interval [CI] = 1.14, 4.99), obesity (aOR = 3.19, 95% CI 1.86, 11.79) and alcohol use (aOR = 1.58, 95% CI 1.22, 5.40) were risk factors for nasal rosacea, but these three factors were not risk factors for non-nasal rosacea and intermediate rosacea groups. Among patients with nasal lesions (compared with patients without nasal phymatous changes), family history of rosacea was a risk factor (aOR = 2.12, 95% CI 1.01, 4.46) for nasal phymatous changes and Fitzpatrick IV skin type was a protective factor (aOR = 0.49, 95% CI 0.28, 0.86). CONCLUSION: Nasal rosacea has relatively specific clinical features and independent risk factors, suggesting that it may be a special type of rosacea.

11.
Mol Psychiatry ; 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385597

RESUMO

Aberrant topological organization of whole-brain networks has been inconsistently reported in studies of patients with major depressive disorder (MDD), reflecting limited sample sizes. To address this issue, we utilized a big data sample of MDD patients from the REST-meta-MDD Project, including 821 MDD patients and 765 normal controls (NCs) from 16 sites. Using the Dosenbach 160 node atlas, we examined whole-brain functional networks and extracted topological features (e.g., global and local efficiency, nodal efficiency, and degree) using graph theory-based methods. Linear mixed-effect models were used for group comparisons to control for site variability; robustness of results was confirmed (e.g., multiple topological parameters, different node definitions, and several head motion control strategies were applied). We found decreased global and local efficiency in patients with MDD compared to NCs. At the nodal level, patients with MDD were characterized by decreased nodal degrees in the somatomotor network (SMN), dorsal attention network (DAN) and visual network (VN) and decreased nodal efficiency in the default mode network (DMN), SMN, DAN, and VN. These topological differences were mostly driven by recurrent MDD patients, rather than first-episode drug naive (FEDN) patients with MDD. In this highly powered multisite study, we observed disrupted topological architecture of functional brain networks in MDD, suggesting both locally and globally decreased efficiency in brain networks.

12.
Dis Markers ; 2021: 5031479, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336003

RESUMO

Lung adenocarcinoma (LUAD) is the most prevalent histologic type of lung cancer, associated with a high incidence rate and substantial mortality rate worldwide. Accumulating evidence shows that the aberrant expression of neuromedin U (NMU) contributes to the initiation and progression of cancer. Herein, we explored whether NMU could be adopted as a new diagnostic and therapeutic marker in LUAD. The UALCAN and GEPIA web resources were employed to assess data on the NMU expression in LUAD. The STRING web resource was used to develop the PPI (protein-protein interaction) network of NMU, whereas Cytoscape was applied for module analysis. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of NMU and the interacting proteins were examined using the WebGestalt tool. Survival analysis was performed with the Kaplan-Meier plotter tool. Results revealed that the NMU expression in LUAD was significantly higher than in the nonmalignant tissues. Moreover, higher NMU levels were dramatically related to shorter overall survival, first progression survival, and postprogression survival. The specific gene mutations G45V, R143T, and F152L of NMU occurred in LUAD samples and were associated with a worse prognosis in patients. KEGG and western blot analyses demonstrated an association of NMU with the cell cycle and the cAMP signaling cascade. Bioinformatic analysis and the in vitro experiments implicated NMU as a promising prognostic signature and treatment target for LUAD.

13.
Langmuir ; 37(36): 10657-10667, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34449220

RESUMO

Bacterial infection and blockage are severe problems for polyurethane (PU) catheters and there is an urgent demand for surface-functionalized polyurethane. Herein, a cationic alternating copolymer comprising allyl-substituted ornithine and glycine (allyl-substituted poly(Orn-alter-Gly)) with abundant carbon-carbon double bond functional groups (C═C) is designed. Polyurethane is prepared with a large quantity of C═C groups (PU-D), and different amounts of allyl-substituted poly(Orn-alter-Gly) are grafted onto the PU-D surface (PU-D-2%AMPs and PU-D-20%AMPs) via the C═C functional groups. The chemical structures of the allyl-substituted poly(Orn-alter-Gly) and polyurethane samples (PU, PU-D, PU-D-2%AMPs, and PU-D-20%AMPs) are characterized and the results reveal that allyl-substituted poly(Orn-alter-Gly) is decorated on the polyurethane. PU-D-20%AMPs shows excellent antibacterial activity against Escherichia coli, Enterococcus faecalis, and Staphylococcus aureus because of the high surface potential caused by cationic allyl-substituted poly(Orn-alter-Gly), and it also exhibits excellent long-term antibacterial activity and antibiofilm properties. PU-D-20%AMPs also has excellent antifouling properties because the cationic copolymer is fixed at multiple reactive sites, thus avoiding the formation of movable long chain brush. A strong surface hydration barrier is also formed to prevent adsorption of proteins and ions, and in vivo experiments reveal excellent biocompatibility. This flexible strategy to prepare dual-functional polyurethane surfaces with antibacterial and antifouling properties has large potential in biomedical implants.


Assuntos
Incrustação Biológica , Poliuretanos , Antibacterianos/toxicidade , Incrustação Biológica/prevenção & controle , Peptídeos/farmacologia , Poliuretanos/toxicidade , Staphylococcus aureus , Propriedades de Superfície
14.
J Virol ; 95(21): e0094421, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34406863

RESUMO

Porcine deltacoronavirus (PDCoV) is a recently discovered coronavirus that poses a potential threat to the global swine industry. Although we know that aminopeptidase N (APN) is important for PDCoV replication, it is unclear whether it is the primary functional receptor, and the mechanism by which it promotes viral replication is not fully understood. Here, we systematically investigated the roles of porcine APN (pAPN) during PDCoV infection of nonsusceptible cells, including in viral attachment and internalization. Using a viral entry assay, we found that PDCoV can enter nonsusceptible cells but then fails to initiate efficient replication. pAPN and PDCoV virions clearly colocalized with the endocytotic markers RAB5, RAB7, and LAMP1, suggesting that pAPN mediates PDCoV entry by an endocytotic pathway. Most importantly, our study shows that regardless of which receptor PDCoV engages, only entry by an endocytotic route ultimately leads to efficient viral replication. This knowledge should contribute to the development of efficient antiviral treatments, which are especially useful in preventing cross-species transmission. IMPORTANCE PDCoV is a pathogen with the potential for transmission across diverse species, although the mechanism of such host-switching events (from swine to other species) is poorly understood. Here, we show that PDCoV enters nonsusceptible cells but without efficient replication. We also investigated the key role played by aminopeptidase N in mediating PDCoV entry via an endocytotic pathway. Our results demonstrate that viral entry via endocytosis is a major determinant of efficient PDCoV replication. This knowledge provides a basis for future studies of the cross-species transmissibility of PDCoV and the development of appropriate antiviral drugs.

15.
Front Immunol ; 12: 712556, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367175

RESUMO

Poly (adenosine diphosphate-ribose) polymerases (PARPs) are a family of proteins responsible for transferring ADP-ribose groups to target proteins to initiate the ADP-ribosylation, a highly conserved and fundamental post-translational modification in all organisms. PARPs play important roles in various cellular functions, including regulating chromatin structure, transcription, replication, recombination, and DNA repair. Several studies have recently converged on the widespread involvement of PARPs and ADP-Ribosylation reaction in mammalian innate immunity. Here, we provide an overview of the emerging roles of PARPs family and ADP-ribosylation in regulating the host's innate immune responses involved in cancers, pathogenic infections, and inflammations, which will help discover and design new molecular targets for cancers, pathogenic infections, and inflammations.

16.
Hepatology ; 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34396571

RESUMO

BACKGROUND & AIM: HBV DNA can be reduced using antiviral drugs in patients with chronic hepatitis B (CHB); however, the rate of HBeAg seroconversion remains low. A clinical trial was conducted to assess the efficacy and safety of a de novo designed liposome-based nanoparticle lipopeptide vaccine, εPA-44, for CHB. APPROACH & RESULTS: A two-stage phase II trial, which included a 76-week, randomized, double-blind, placebo-controlled trial (stage 1) and a 68-week open-label extension (stage 2), was conducted in 15 centers across China (Clinicaltrials.gov number, NCT00869778). In stage 1, 360 HLA-A2-positive and HBeAg-positive patients were randomly and equally distributed to receive six subcutaneous injections of 600 µg or 900 µg εPA-44 or placebo at week 0, 4, 8, 12, 20, and 28. In stage 2, 183 patients received extended 900 µg εPA-44 and 26 patients were observed for relapse without further treatment. The primary endpoint was the percentage of patients with HBeAg seroconversion at week 76. At week 76, patients receiving 900 µg εPA-44 achieved significantly higher HBeAg seroconversion rate (38.8%) vs. placebo (20.2%) (95% CI, 6.9-29.6%; P=0.002). With a combined endpoint of HBeAg seroconversion, ALT normalization and HBV DNA <2000 IU/mL, both 900 µg (18.1%) and 600 µg (14.3%) resulted in significantly higher rate vs. placebo (5.0%) (P=0.002 and P=0.02, respectively) at week 76. In stage 2, none (0/20) of 900 µg εPA-44 treated patients experienced serologic relapse. The safety profile of εPA-44 was comparable to that of placebo. CONCLUSIONS: Among progressive CHB patients with HLA-A2-positive, a finite duration of 900 µg εPA-44 monotherapy resulted in significantly higher HBeAg seroconversion rate than placebo and sustained off-treatment effect. A phase III trial is ongoing (ChiCTR2100043708).

17.
Adv Healthc Mater ; 10(19): e2100799, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34310079

RESUMO

Lactate, as the most abundant component with concentrations of 4-40 mm in tumors, contributes to the regulation of metabolic pathways, angiogenesis, and immunosuppression, exhibiting remarkable potential in cancer treatment. Therefore, a codelivery strategy that combined the cascaded enzymes Lactate oxidase/Catalase (LOx/CAT) and vascular endothelial growth factor (VEGF) siRNA (siVEGF) to suppress tumor proliferation and angiogenesis synergistically is creatively proposed. In brief, the cationic liposomes (LIP) encapsulated with LOx/CAT and siVEGF via hydrophilic interaction and electrostatic adsorption followed by coating with PEGylated phenylboronic acid (PP) is established (PPL@[LOX+CAT]). Moreover, a simple 3-aminophenylboronic acid (PBA)-shielded strategy via fructose (Fru) is applied to further enhance the targeting efficiency in the tumor site. The obtained co-encapsulated nanoparticles (NPs) can simultaneous intracellular release of LOx/CAT and siVEGF, and the collaborative use of LOx and CAT can promote lactate consumption even under a hypoxic tumor microenvironment (TME) without producing systemic toxicity. The combined application of lactate depletion and VEGF silencing demonstrated the efficient migration suppression of 4T1 cells in vitro and superior antitumor and antimetastatic properties in vivo. This work offers a promising tumor treatment strategy via integrating cascaded enzymes and gene therapy, and explores a promising therapy regimen for 4T1 triple-negative breast cancer.


Assuntos
Nanopartículas , Neoplasias , Animais , Linhagem Celular Tumoral , Ácido Láctico , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , RNA Interferente Pequeno , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/genética
18.
Front Neural Circuits ; 15: 688234, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194303

RESUMO

Oxytocin (OT) is a neuropeptide produced by hypothalamic neurons and is known to modulate social behavior among other functions. Several experiments have shown that OT modulates neuronal activity in many brain areas, including sensory cortices. OT neurons thus project axons to various cortical and subcortical structures and activate neuronal subpopulations to increase the signal-to-noise ratio, and in turn, increases the saliency of social stimuli. Less is known about the origin of inputs to OT neurons, but recent studies show that cells projecting to OT neurons are often located in regions where the OT receptor (OTR) is expressed. Thus, we propose the existence of reciprocal connectivity between OT neurons and extrahypothalamic OTR neurons to tune OT neuron activity depending on the behavioral context. Furthermore, the latest studies have shown that OTR-expressing neurons located in social brain regions also project to other social brain regions containing OTR-expressing neurons. We hypothesize that OTR-expressing neurons across the brain constitute a common network coordinated by OT.

20.
J Appl Microbiol ; 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34319629

RESUMO

AIMS: Treatment and preventive control strategies for Brucella melitensis (B. melitensis) and Brucella abortus (B. abortus) infection differ. A lateral flow immunoassay (LFIA) for the rapid typing and detection of brucellosis by using polychromatic dye-doped latex microspheres (LMs) as a labelling material was developed. METHODS AND RESULTS: This LFIA utilizes a double-antigen sandwich method in which the BP26 protein is used as the diagnostic antigen to detect brucellosis infection and the OMP31 protein is used as the identified antigen to distinguish between bovine and sheep brucellosis. Thus, people and animals infected with brucellosis can be diagnosed according to the different colours of the signals displayed on the detection lines. The results indicated that the accuracy of this assay was found to reach 98%, and the immunochromatographic test strip is highly accurate, shows good sensitivity and can facilitate typing diagnosis, among other features. CONCLUSIONS: The established LFIA can distinguish B. melitensis infection from B. abortus infection and produces results in a short period of time while retaining the advantages of LFIAs. SIGNIFICANCE AND IMPACT OF THE STUDY: This technology lays a foundation for the development of multi-disease test strips and the establishment of methods for rapid, multi-specimen quantitative detection and is thus of great importance for the development of medical diagnostic technologies.

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