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1.
J Dermatol ; 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36317385

RESUMO

Nagashima-type palmoplantar keratoderma (NPPK) is the most prevalent hereditary palmoplantar keratoderma (PPK) in China, but there is a paucity of epidemiological data on the Chinese population. To explore the clinical and genetic characteristics, evaluate the demographic distribution, and estimate the burden of disease of NPPK. A total of 234 Chinese patients with NPPK were enrolled from two medical centers and an online PPK support group. Next-generation sequencing and Sanger sequencing were performed to screen out and confirm pathogenic mutations in SERPINB7. Clinical features and quality of life (QOL) were evaluated using self-completed questionnaires. In total, 14 pathogenic mutations were identified in SERPINB7 from the cohort. The top four recurrent mutations were c.796C>T (355, 75.9%), c.522dupT (66, 14.1%), c.650_653delCTGT (24, 5.1%), and c.455G>T (12, 2.6%), accounting for 97.6% of Chinese NPPK patients. Other mutations (11, 2.4%) include c.455-1G>T, c.336+2T>G, c.635delG and seven novel mutations c.2T>C, c.434delG, c.455-16A>G, c.656T>C, c.745-553T>G, c.832C>T, c.1036G>T. The estimated prevalence of NPPK in China was found to be 0.975/10 000 based on Chinese databases. Clinically, there were no apparent genotype-phenotype correlations in NPPK patients. Pediatric patients mainly presented with palmoplantar peeling, while adults presented with scale (p < 0.001). The most common comorbidities in NPPK patients were onychomycosis (40.0%), eczema (36.8%), and tinea pedis (30.3%). As for burden of disease, NPPK patients' QOL was decreased by a moderate degree. In this study, pathogenic mutations' allele frequencies in SERPINB7 were updated, and prevalence of NPPK in China was estimated. This large-scale cohort study provides evidence-based recommendations for patient management. Identification of new mutations are important for timely diagnosis of NPPK. Palmoplantar peeling in children can be used as a hallmark for early recognition of NPPK.

2.
PLoS Pathog ; 18(11): e1010953, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36327346

RESUMO

Campylobacter jejuni is a food-borne zoonotic pathogen of worldwide concern and the leading cause of bacterial diarrheal disease. In contrast to other enteric pathogens, C. jejuni has strict growth and nutritional requirements but lacks many virulence factors that have evolved for pathogenesis or interactions with the host. It is unclear how this bacterium has adapted to an enteric lifestyle. Here, we discovered that the CheO protein (CJJ81176_1265) is required for C. jejuni colonization of mice gut through its role in chemotactic control of flagellar rotation in oxygen-limiting environments. CheO interacts with the chemotaxis signaling proteins CheA and CheZ, and also with the flagellar rotor components FliM and FliY. Under microaerobic conditions, CheO localizes at the cellular poles where the chemosensory array and flagellar machinery are located in C. jejuni and its polar localization depends on chemosensory array formation. Several chemoreceptors that mediate energy taxis coordinately determine the bipolar distribution of CheO. Suppressor screening for a ΔcheO mutant identified that a single residue variation in FliM can alleviate the phenotype caused by the absence of CheO, confirming its regulatory role in the flagellar rotor switch. CheO homologs are only found in species of the Campylobacterota phylum, mostly species of host-associated genera Campylobacter, Helicobacter and Wolinella. The CheO results provide insights into the complexity of chemotaxis signal transduction in C. jejuni and closely related species. Importantly, the recruitment of CheO into chemosensory array to promote chemotactic behavior under hypoxia represents a new adaptation strategy of C. jejuni to human and animal intestines.


Assuntos
Infecções por Campylobacter , Campylobacter jejuni , Camundongos , Humanos , Animais , Campylobacter jejuni/genética , Flagelos/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Quimiotaxia , Hipóxia/metabolismo , Infecções por Campylobacter/metabolismo
3.
Sci Adv ; 8(46): eabo2098, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36383661

RESUMO

Major depressive disorder (MDD) is a devastating mental disorder that affects up to 17% of the population worldwide. Although brain-wide network-level abnormalities in MDD patients via resting-state functional magnetic resonance imaging (rsfMRI) exist, the mechanisms underlying these network changes are unknown, despite their immense potential for depression diagnosis and management. Here, we show that the astrocytic calcium-deficient mice, inositol 1,4,5-trisphosphate-type-2 receptor knockout mice (Itpr2-/- mice), display abnormal rsfMRI functional connectivity (rsFC) in depression-related networks, especially decreased rsFC in medial prefrontal cortex (mPFC)-related pathways. We further uncover rsFC decreases in MDD patients highly consistent with those of Itpr2-/- mice, especially in mPFC-related pathways. Optogenetic activation of mPFC astrocytes partially enhances rsFC in depression-related networks in both Itpr2-/- and wild-type mice. Optogenetic activation of the mPFC neurons or mPFC-striatum pathway rescues disrupted rsFC and depressive-like behaviors in Itpr2-/- mice. Our results identify the previously unknown role of astrocyte dysfunction in driving rsFC abnormalities in depression.

5.
Adv Sci (Weinh) ; 9(28): e2201889, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35975461

RESUMO

Chemotherapeutics remain the first choice for advanced gastric cancers (GCs). However, drug resistance and unavoidable severe toxicity lead to chemotherapy failure and poor prognosis. Long noncoding RNAs (lncRNAs) play critical roles in tumor progression in many cancers, including GC. Here, through RNA screening, an apoptotic protease-activating factor 1 (APAF1)-binding lncRNA (ABL) that is significantly elevated in cancerous GC tissues and an independent prognostic factor for GC patients is identified. Moreover, ABL overexpression inhibits GC cell apoptosis and promotes GC cell survival and multidrug resistance in GC xenograft and organoid models. Mechanistically, ABL directly binds to the RNA-binding protein IGF2BP1 via its KH1/2 domain, and then IGF2BP1 further recognizes the METTL3-mediated m6A modification on ABL, which maintains ABL stability. In addition, ABL can bind to the WD1/WD2 domain of APAF1, which competitively prevent cytochrome c from interacting with APAF1, blocking apoptosome assembly and caspase-9/3 activation; these events lead to resistance to cell death in GC cells. Intriguingly, targeting ABL using encapsulated liposomal siRNA can significantly enhance the sensitivity of GC cells to chemotherapy. Collectively, the results suggest that ABL can be a potential prognostic biomarker and therapeutic target in GC.


Assuntos
RNA Longo não Codificante , Neoplasias Gástricas , Apoptose/genética , Apoptossomas/metabolismo , Fator Apoptótico 1 Ativador de Proteases/genética , Fator Apoptótico 1 Ativador de Proteases/metabolismo , Biomarcadores , Caspase 9/metabolismo , Citocromos c/metabolismo , Citocromos c/uso terapêutico , Resistência a Múltiplos Medicamentos , Humanos , Metiltransferases/metabolismo , Metiltransferases/uso terapêutico , RNA Longo não Codificante/genética , RNA Interferente Pequeno/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
7.
Front Surg ; 9: 870044, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35903265

RESUMO

Background: One of the most drastic complications of median sternal incision is deep sternal wound infection (DSWI), as it can lead to prolonged hospitalization, increased expected costs, re-entry into the ICU and even reoperation. Since the pectoralis major muscle flap (PMMF) technique was proposed in the 1980s, it has been widely used for sternal reconstruction after debridement. Although numerous studies on DSWI have been conducted over the years, the literature on DSWI in Chinese population remains limited. The purpose of this study was to investigate the clinical characteristics of DSWI in patients and the clinical effect of the PMMF at our institution. Methods: This study retrospectively analyzed all 14,250 consecutive patients who underwent cardiac surgery in the Department of Cardiothoracic Surgery of Drum Tower Hospital from 2001 to 2020. Ultimately, 134 patients were diagnosed with DSWI.,31 of whom had recently undergone radical debridement and transposition of the PMMF in the cardiothoracic surgery or burns and plastic surgery departments because of DSWIs, while the remaining patients had undergone conservative treatment or other methods of dressing debridement. Results: In total, 9,824 patients were enrolled in the study between 2001 and 2020, of whom 134 met the DSWI criteria and 9690 served as controls. Body mass index (OR = 1.08; P = 0.02; 95% CI, 1.01∼1.16) and repeat sternotomy (OR = 5.93; P < 0.01; 95% CI, 2.88∼12.25) were important risk factors for DSWI. Of the 134 patients with DSWI, 31 underwent the PMMF technique, and the remaining 103 served as controls. There were significant differences in coronary artery bypass grafting (CABG) (P < 0.01), valve replacement (P = 0.04) and repeat sternotomy (P < 0.01) between the case group and the control group. The postoperative extubation time (P < 0.001), ICU time (P < 0.001), total hospitalization time (P < 0.001) and postoperative hospitalization time (P < 0.001) in the PMMF group were significantly lower than those in the control group. The results of multivariate regression analysis showed that PMMF surgery was an important protective factor for the postoperative survival of DSWI patients (OR = 0.12; P = 0.04; 95% CI, 0.01∼0.90). Conclusions: Staphylococcus aureus was the most common bacteria causing DSWI, which was associated with BMI and reoperation, and can be validly treated with PMMF.

8.
Biomater Sci ; 10(15): 4356-4366, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35786722

RESUMO

Hepatitis B represents a major global public health burden, which is caused by the hepatitis B virus (HBV) with a high infection rate. Although several anti-HBV drugs have been developed for clinical treatment of hepatitis B, the current therapeutic strategies still suffer from undeniable adverse effects, insufficient efficacy after systemic administration and chronic inflammation. Here, we develop a carrier-free metal-organic hybrid nanoassembly that is co-loaded with tenofovir (TFV), an anti-viral agent and phosphorylated glycyrrhetinic acid (GAP), an anti-inflammatory compound (TFV/GAP/NA) to enhance the anti-HBV effect and alleviate the inflammatory response for hepatitis B treatment. The nanoassembly is easily prepared through the ionic interactions between the anionic phosphonate/phosphate groups from TFV/GAP and the zirconium cation, which has a stable nanostructure and a high drug-loading capacity. The nanoassembly prolongs the circulation time with reduced drug leakage in the blood and elevates drug accumulation in the liver after intravascular administration. After internalization mediated by the GAP ligand-GA receptor interaction, TFV/GAP/NA disassembles by the phosphatase-triggered degradation of the phosphate ester bonds in GAP and releases TFV, GAP and GA within the HBV-positive hepatocytes. The released TFV interferes with the HBV polymerase to inhibit the viral DNA replication, while the released GAP and GA suppress the pro-inflammatory protein expression. In mouse models, treatment with TFV/GAP/NA inhibits HBV production and alleviates inflammation-mediated liver injury.


Assuntos
Antivirais , Hepatite B , Adenina/farmacologia , Animais , Antivirais/farmacologia , Replicação do DNA , DNA Viral/farmacologia , DNA Viral/uso terapêutico , Hepatite B/tratamento farmacológico , Vírus da Hepatite B/metabolismo , Inflamação/tratamento farmacológico , Camundongos , Organofosfatos , Fosfatos , Tenofovir/farmacologia , Tenofovir/uso terapêutico , Replicação Viral
9.
PLoS Genet ; 18(7): e1010316, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35834583

RESUMO

The evolution of macromolecular complex is a fundamental biological question, which is related to the origin of life and also guides our practice in synthetic biology. The chemosensory system is one of the complex structures that evolved very early in bacteria and displays enormous diversity and complexity in terms of composition and array structure in modern species. However, how the diversity and complexity of the chemosensory system evolved remains unclear. Here, using the Campylobacterota phylum with a robust "eco-evo" framework, we investigated the co-evolution of the chemosensory system and one of its important signaling outputs, flagellar machinery. Our analyses show that substantial flagellar gene alterations will lead to switch of its primary chemosensory class from one to another, or result in a hybrid of two classes. Unexpectedly, we discovered that the high-torque generating flagellar motor structure of Campylobacter jejuni and Helicobacter pylori likely evolved in the last common ancestor of the Campylobacterota phylum. Later lineages that experienced significant flagellar alterations lost some key components of complex scaffolding structures, thus derived simpler structures than their ancestor. Overall, this study revealed the co-evolutionary path of the chemosensory system and flagellar system, and highlights that the evolution of flagellar structural complexity requires more investigation in the Bacteria domain based on a resolved phylogenetic framework, with no assumptions on the evolutionary direction.


Assuntos
Campylobacter jejuni , Helicobacter pylori , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Campylobacter jejuni/genética , Flagelos/genética , Filogenia
10.
Heart Vessels ; 37(12): 2039-2048, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35778638

RESUMO

The present study aimed to evaluate sex-specific association between admission systolic blood pressure (SBP) and in-hospital prognosis in patients with acute decompensated heart failure (ADHF) admitted to intensive care unit (ICU). In this retrospective, observational study, 1268 ADHF patients requiring intensive care were consecutively enrolled and divided by sex. Patients were divided into three subgroups according to SBP tertiles: high (≥ 122 mmHg), moderate (104-121 mmHg) and low (< 104 mmHg). The primary endpoint was either all-cause mortality, cardiac arrest or utilization of mechanical support devices during hospitalization. Female patients were more likely to be older, have poorer renal function and higher ejection fractions (p < 0.001). The C statistics of SBP was 0.665 (95%CI 0.611-0.719, p < 0.001) for men and 0.548 (95% CI 0.461-0.634, p = 0.237) for women, respectively. Multivariate analysis demonstrated that admission SBP as either a continuous (OR = 0.984, 95% CI 0.973-0.996) or a categorical (low vs. high, OR = 3.293, 95% CI 1.610-6.732) variable was an independent predictor in male but the risk did not statistically differ between the moderate and high SBP strata (OR = 1.557, 95% CI 0.729-3.328). In female, neither low (OR = 1.135, 95% CI 0.328-3.924) nor moderate (OR = 0.989, 95% CI 0.277-3.531) SBP had a significant effect on primary endpoint compared with high SBP strata. No interaction was detected between left ventricular ejection fraction (LVEF) and SBP (p for interaction = 0.805). In ADHF patients admitted to ICU, SBP showed a sex-related prognostic effect on primary endpoint. In male, lower SBP was independently associated with an increased risk of primary endpoint. Conversely, in female, no relationship was observed.


Assuntos
Insuficiência Cardíaca , Função Ventricular Esquerda , Humanos , Feminino , Masculino , Volume Sistólico/fisiologia , Pressão Sanguínea/fisiologia , Prognóstico , Função Ventricular Esquerda/fisiologia , Estudos Retrospectivos , Estado Terminal , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/terapia
11.
BMC Cardiovasc Disord ; 22(1): 331, 2022 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-35879670

RESUMO

BACKGROUND: Sleep apnea is a risk factor for atrial fibrillation (AF) but it is underdiagnosed. Whether obstructive sleep apnea (OSA) is correlated with thrombotic risk in AF remains unclear. The aim of the present study was to analyze the clinical characteristics and assess the thrombotic risk of AF with OSA. METHODS: In the present registry study,1990 consecutive patients with AF from 20 centers were enrolled. The patients were divided into 2 groups depending on whether they presented with both AF and OSA. All the patients were followed up for 1 year to evaluate the incidences of stroke and non-central nervous system (CNS) embolism. RESULTS: Of the 1990 AF patients, 70 (3.5%) and 1920 (96.5%) patients were in the OSA group and non-OSA group, respectively. The results of the multivariate logistic model analysis showed that male sex, body mass index (BMI), smoking, and major bleeding history were independent risk factors for patients with AF and OSA. The comparison of the Kaplan-Meier curves using the log-rank test revealed that AF with OSA was correlated with an increased risk of non-CNS embolism (p < 0.01). After multivariate adjustments were performed, OSA remained an independent risk factor for non-CNS embolism (HR 5.42, 95% CI 1.34-22.01, p = 0.02), but was not correlated with the risk of stroke in patients with AF. CONCLUSIONS: The present study revealed that male sex, high BMI values, smoking, and major bleeding history were independent risk factors for patients with AF and OSA. Moreover, OSA was an independent risk factor for non-CNS embolism in AF. Our results indicate that non-CNS embolism requires focus in patients with AF and OSA.


Assuntos
Fibrilação Atrial , Apneia Obstrutiva do Sono , Acidente Vascular Cerebral , Trombose , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Humanos , Masculino , Sistema de Registros , Fatores de Risco , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/epidemiologia , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Trombose/complicações
12.
Cell Mol Life Sci ; 79(6): 294, 2022 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-35562616

RESUMO

Exposure to maternal stress irreversibly impairs neurogenesis of offspring by inducing life-long effects on interaction between neurons and glia under raging differentiation process, culminating in cognitive and neuropsychiatric abnormalities in adulthood. We identified that prenatal exposure to stress-responsive hormone glucocorticoid impaired neurogenesis and induced abnormal behaviors in ICR mice. Then, we used human induced pluripotent stem cell (iPSC)-derived neural stem cell (NSC) to investigate how neurogenesis deficits occur. Following glucocorticoid treatment, NSC-derived astrocytes were found to be A1-like neurotoxic astrocytes. Moreover, cortisol-treated astrocytic conditioned media (ACM) then specifically downregulated AMPA receptor-mediated glutamatergic synaptic formation and transmission in differentiating neurons, by inhibiting localization of ionotropic glutamate receptor (GluR)1/2 into synapses. We then revealed that downregulated astrocytic fibroblast growth factor 2 (FGF2) and nuclear fibroblast growth factor receptor 1 (FGFR1) of neurons are key pathogenic factors for reducing glutamatergic synaptogenesis. We further confirmed that cortisol-treated ACM specifically decreased the binding of neuronal FGFR1 to the synaptogenic NLGN1 promoter, but this was reversed by FGFR1 restoration. Upregulation of neuroligin 1, which is important in scaffolding GluR1/2 into the postsynaptic compartment, eventually normalized glutamatergic synaptogenesis and subsequent neurogenesis. Moreover, pretreatment of FGF2 elevated neuroligin 1 expression and trafficking of GluR1/2 into the postsynaptic compartment of mice exposed to prenatal corticosterone, improving spatial memory and depression/anxiety-like behaviors. In conclusion, we identified neuroligin 1 restoration by astrocytic FGF2 and its downstream neuronal nuclear FGFR1 as a critical target for preventing prenatal stress-induced dysfunction in glutamatergic synaptogenesis, which recovered both neurogenesis and hippocampal-related behaviors.


Assuntos
Astrócitos , Células-Tronco Pluripotentes Induzidas , Adulto , Animais , Astrócitos/metabolismo , Moléculas de Adesão Celular Neuronais , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Glucocorticoides/metabolismo , Hipocampo/metabolismo , Humanos , Hidrocortisona/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Neurogênese , Neurônios/metabolismo , Gravidez , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo
13.
mBio ; 13(3): e0076422, 2022 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-35536007

RESUMO

Microbes rely on signal transduction systems to sense and respond to environmental changes for survival and reproduction. It is generally known that niche adaptation plays an important role in shaping the signaling repertoire. However, the evolution of bacterial signaling capacity lacks systematic studies with a temporal direction. In particular, it is unclear how complexity evolved from simplicity or vice versa for signaling networks. Here, we examine the evolutionary processes of major signal transduction systems in Campylobacterota (formerly Epsilonproteobacteria), a phylum with sufficient evolutionary depth and ecological diversity. We discovered that chemosensory system increases complexity by horizontal gene transfer (HGT) of entire chemosensory classes, and different chemosensory classes rarely mix their components. Two-component system gains complexity by atypical histidine kinases fused with receiver domain to achieve multistep or branched signal transduction process. The presence and complexity of c-di-GMP-mediated system is related to the size of signaling network, and c-di-GMP pathways are easy to rewire, since enzymes and effectors can be linked without direct protein-protein interaction. Overall, signaling capacity and complexity rise and drop together in Campylobacterota, determined by sensory demand, genetic resources, and coevolution within the genomic context. These findings reflect plausible evolutionary principles for other cellular networks and genome evolution of the Bacteria domain. IMPORTANCE Bacteria are capable of sensing and responding to environmental changes by several signal transduction systems with different mechanisms. Much attention is paid to model organisms with complex signaling networks to understand their composition and function, but how a complicated network evolved from a simple one or vice versa lacks systematic studies. Here, we tracked the evolutionary process of each signaling system in a bacterial phylum with robust "eco-evo" framework and summarized the general principles of signaling network evolution. Our findings bridge the gaps in bacterial signaling capacity from highly sophisticated to extremely streamlined, shedding light on rational design of genetic circuitry. This study may serve as a paradigm to examine the complex construction of other cellular networks and genome evolution.


Assuntos
GMP Cíclico , Transdução de Sinais , Adaptação Fisiológica , Bactérias/genética , Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , GMP Cíclico/metabolismo , Regulação Bacteriana da Expressão Gênica , Histidina Quinase/genética , Histidina Quinase/metabolismo
14.
J Biomed Sci ; 29(1): 17, 2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35255899

RESUMO

BACKGROUND: Androgenetic alopecia (AGA) is a genetic disorder caused by dihydrotestosterone (DHT), accompanied by the senescence of androgen-sensitive dermal papilla cells (DPCs) located in the base of hair follicles. DHT causes DPC senescence in AGA through mitochondrial dysfunction. However, the mechanism of this pathogenesis remains unknown. In this study, we investigated the protective role of cyanidins on DHT-induced mitochondrial dysfunction and DPC senescence and the regulatory mechanism involved. METHODS: DPCs were used to investigate the effect of DHT on mitochondrial dysfunction with MitoSOX and Rhod-2 staining. Senescence-associated ß-galactosidase activity assay was performed to examine the involvement of membrane AR-mediated signaling in DHT-induced DPC senescence. AGA mice model was used to study the cyanidins on DHT-induced hair growth deceleration. RESULTS: Cyanidin 3-O-arabinoside (C3A) effectively decreased DHT-induced mtROS accumulation in DPCs, and C3A reversed the DHT-induced DPC senescence. Excessive mitochondrial calcium accumulation was blocked by C3A. C3A inhibited p38-mediated voltage-dependent anion channel 1 (VDAC1) expression that contributes to mitochondria-associated ER membrane (MAM) formation and transfer of calcium via VDAC1-IP3R1 interactions. DHT-induced MAM formation resulted in increase of DPC senescence. In AGA mice models, C3A restored DHT-induced hair growth deceleration, which activated hair follicle stem cell proliferation. CONCLUSIONS: C3A is a promising natural compound for AGA treatments against DHT-induced DPC senescence through reduction of MAM formation and mitochondrial dysfunction.


Assuntos
Di-Hidrotestosterona , Folículo Piloso , Animais , Antocianinas , Senescência Celular , Di-Hidrotestosterona/metabolismo , Di-Hidrotestosterona/farmacologia , Camundongos , Mitocôndrias
15.
Nano Lett ; 22(6): 2419-2428, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-35254834

RESUMO

Antibody-based therapeutics, which induce apoptosis of malignant cells by selectively binding to their receptors, hold tremendous promise for clinical cancer therapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received considerable interest due to its favorable capability of activating apoptosis in cancer cells by interacting with death receptors (DRs). However, cancer stem-like cells (CSCs) show deficient or lower DR and are highly resistant to TRAIL-mediated apoptosis limiting the therapeutic efficacy. Here, we report a liposome-mediated acclimatization strategy to overcome the CSC-emanated TRAIL resistance. The liposomal assemblies coencapsulating plasmid DNA encoding TRAIL and salinomycin enable cancer cells as protein generators to express TRAIL, and more importantly, can acclimatize resistant CSCs to be sensitized to the TRAIL-triggered apoptosis by salinomycin-induced upregulation of DR expression on CSCs. This programmable liposome-based drug codelivery system shows the potential to efficiently eliminate CSCs and inhibit CSC-enriched tumor growth in the orthotopic colon tumor mouse model.


Assuntos
Lipossomos , Neoplasias , Aclimatação , Animais , Apoptose , Linhagem Celular Tumoral , Lipossomos/metabolismo , Camundongos , Neoplasias/patologia , Células-Tronco Neoplásicas , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF
16.
Br J Dermatol ; 187(2): 267-270, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35199331

RESUMO

1. We extend the spectrum of SERPINA12 variants in palmoplantar keratodermas. 2. The recurrent variant c.970_971del, mainly prevalent in the East Asia population, was proved to be a founder variant. 3. Considerable SERPINA12-related palmoplantar keratoderma patients could be identified from autosomal recessive, non-mutilating, diffused palmoplantar keratoderma patients. 4. Other serpin family members or their co-effect may participate in the etiologies of underexplored hereditary palmoplantar keratodermas.


Assuntos
Ceratodermia Palmar e Plantar , Serpinas , China , Efeito Fundador , Humanos , Ceratodermia Palmar e Plantar/genética , Serpinas/genética
17.
Reprod Domest Anim ; 57(4): 418-428, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35014107

RESUMO

The reproductive function of animals is often affected by climatic conditions. High-temperature conditions can cause damage to oocyte maturation and embryonic development in a variety of ways. The purpose of this study was to prove that supplementation idebenone (IDB) to the maturation medium can improve the maturation and development of porcine oocytes after heat stress (HS). Porcine cumulus-oocyte complexes (COCs) were cultured in the maturation medium with different concentrations of IDB (0, 0.1, 1 and 10 µM) for 44 hr at either 38.5°C or under the HS conditions. The cumulus oophorus expansion, nuclear maturation and blastocyst rate after parthenogenetic activation (PA) were measured. We found that HS (in vitro maturation 20-24 hr, 42°C) exposure significantly reduced cumulus expansion index and maturation rate of oocytes and the blastocyst rate of PA embryos, while IDB supplementation significantly improved oocyte maturation and development to the blastocysts stage after PA. Moreover, the addition of IDB decreased the intracellular level of ROS and increased GSH content, hence enhancing the antioxidant capacity of oocytes under HS. Meanwhile, IDB treatment also obviously improved the mitochondrial membrane potential and ATP synthesis of oocytes under HS conditions. Furthermore, IDB treatment increased the expression of GDF9 and BMP15 in IVM oocytes which attribute to improve the quality and outcome of IVM oocytes and the development competence of PA embryos in pigs. In summary, we demonstrated that IDB supplementation into the maturation medium exerted protective effects and improved the ability of maturation and developmental competence of porcine oocytes exposed to HS.


Assuntos
Técnicas de Maturação in Vitro de Oócitos , Oócitos , Animais , Blastocisto/fisiologia , Desenvolvimento Embrionário/fisiologia , Feminino , Resposta ao Choque Térmico , Técnicas de Maturação in Vitro de Oócitos/veterinária , Oócitos/fisiologia , Gravidez , Suínos , Ubiquinona/análogos & derivados
18.
Catheter Cardiovasc Interv ; 99(1): 98-113, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33909311

RESUMO

OBJECTIVES: To determine the association of extended-term (>12-month) versus short-term dual antiplatelet therapy (DAPT) with ischemic and hemorrhagic events in high-risk "TWILIGHT-like" patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) in clinical practice. BACKGROUND: Recent emphasis on shorter DAPT regimen after PCI irrespective of indication for PCI may fail to account for the substantial residual risk of recurrent atherothrombotic events in ACS patients. METHODS: All consecutive patients fulfilling the "TWILIGHT-like" criteria undergoing PCI were identified from the prospective Fuwai PCI Registry. High-risk patients (n = 8,358) were defined by at least one clinical and one angiographic feature based on TWILIGHT trial selection criteria. The primary ischemic endpoint was major adverse cardiac and cerebrovascular events at 30 months, composed of all-cause mortality, myocardial infarction, or stroke while BARC type 2, 3, or 5 bleeding was key secondary outcome. RESULTS: Of 4,875 high-risk ACS patients who remained event-free at 12 months after PCI, DAPT>12-month compared with shorter DAPT reduced the primary ischemic endpoint by 63% (1.5 vs. 3.8%; HRadj: 0.374, 95% CI: 0.256-0.548; HRmatched: 0.361, 95% CI: 0.221-0.590). The HR for cardiovascular death was 0.049 (0.007-0.362) and that for MI 0.45 (0.153-1.320) and definite/probable stent thrombosis 0.296 (0.080-1.095) in propensity-matched analyses. Rates of BARC type 2, 3, or 5 bleeding (0.9 vs. 1.3%; HRadj: 0.668 [0.379-1.178]; HRmatched: 0.721 [0.369-1.410]) did not differ significantly between two groups. CONCLUSIONS: Among high-risk ACS patients undergoing PCI, long-term DAPT, compared with shorter DAPT, reduced ischemic events without a concomitant increase in clinically meaning bleeding events, suggesting that prolonged DAPT can be considered in ACS patients who present with a particularly higher risk for thrombotic complications without excessive risk of bleeding.


Assuntos
Síndrome Coronariana Aguda , Intervenção Coronária Percutânea , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/terapia , Quimioterapia Combinada , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Estudos Prospectivos , Resultado do Tratamento
19.
Artigo em Inglês | MEDLINE | ID: mdl-34899947

RESUMO

Sheng Jing Decoction (SJD), as a traditional Chinese medicine prescription, is mainly be used to treat male infertility. However, the pharmacological functions and molecular mechanisms of SJD are poorly understood. In this study, we investigated the functions of SJD on spermatogenesis and sperm motility and explored the potential mechanisms involved. Here, we demonstrated that high, medium, and low doses of SJD are effective in restoring the impairments of the whole body and testicular tissue by cyclophosphamide inducing and to rescue the damage of testicular tissue cells including Sertoli cells and germ cells. SJD can partly restore the decrease in sperm concentration, sperm vitality, sperm motility, and normal sperm morphology rate in oligozoospermic mouse models. Ki67 staining analyses confirm SJD can promote testicular tissue cell proliferation. Real-time RT-PCR analyses also reveal that SJD can upregulate the expression of proliferation-associated gene Lin28a and differentiation-associated genes Kit, Sohlh2, and Stra8. SJD can also reduce the impairment of mitochondrial membrane potential (MMP) and sperm plasma membrane integrity by cyclophosphamide inducing. Our results reveal that SJD is effective in improving both sperm quantity and quality by increasing the sperm concentration, sperm vitality, sperm motility, and normal sperm morphology rate. SJD can promote spermatogenesis by upregulating the expression of the proliferation-associated gene Lin28a and the differentiation-associated genes (Kit, Sohlh2, and Stra8). SJD can sustain MMP and sperm plasma membrane integrity to increase sperm motility.

20.
Heart Surg Forum ; 24(6): E968-E976, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34962479

RESUMO

BACKGROUND: Atrial fibrillation (AF) recurrence after ablation will increase mortality and morbidity during follow up. We attempted to evaluate the relationship between circular RNAs (circRNA) and AF recurrence to establish a predictive model for early intervention. METHODS: Patients who received surgical ablation retrospectively were analyzed. The expression of circRNAs were detected in the left atrial appendage. The independent risk factors of late recurrence were analyzed by multivariate analysis. The predictive model was visualized by Nomogram and tested by receiver operating characteristic curve and calibration plot. Kaplan-Meier plot was used to compare the rate of freedom from AF recurrence after surgery. The relationships between circRNAs and clinical characteristics were detected by Spearman's correlation analysis. RESULTS: A total of 136 patients were enrolled from September 2018 to June 2019, 55 patients experienced late recurrence during one-year follow up. Increased age, longer AF duration and increased circ 81906-RYR2, circ 44782-LAMA2, circ 418-KCNN2 and circ 35880-ANO5 were detected in recurrent patients. Multivariate analysis revealed that increased age (odds ratio (OR)=1.072, P = 0.006), longer AF duration (OR=1.007, P = 0.036) and increased circ 81906-RYR2 (OR=2.210, P < 0.001) were independent risk factors for late recurrence. Area under the curve was 0.77, and the cut-off value was 70 points of the predictive model. Kaplan-Meier plots showed that patients over 70 points tended to experience AF recurrence. CONCLUSION: Circ 81906-RYR2 could be a new predictor of late recurrence after surgical ablation. A predictive model consists of age, atrial fibrillation duration, and circ 81906-RYR2 was alternative for early intervention of AF recurrence.


Assuntos
Apêndice Atrial , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/cirurgia , Ablação por Cateter , RNA Circular/genética , Fatores Etários , Idoso , Fibrilação Atrial/genética , Biomarcadores , Feminino , Seguimentos , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Nomogramas , Curva ROC , Recidiva , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
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