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1.
Plants (Basel) ; 12(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36679080

RESUMO

The cytochrome P450 (CYP450) monooxygenase superfamily, which is involved in the biosynthesis pathways of many primary and secondary metabolites, plays prominent roles in plant growth and development. However, systemic information about CYP450s in Brassica napus (BnCYP450) was previously undiscovered and their biological significance are far from understood. Members of clan 86 CYP450s, such as CYP704Bs, are essential for the formation of pollen exine in plant male reproduction, and the targeted mutagenesis of CYP704B genes has been used to create new male sterile lines in many crops. In the present study, a total of 687 BnCYP450 genes were identified in Brassica napus cultivar "Zhongshuang 11" (ZS11), which has nearly 2.8-fold as many CYP450 members as in Arabidopsis thaliana. It is rationally estimated since Brassica napus is a tetraploid oil plant with a larger genome compared with Arabidopsis thaliana. The BnCYP450 genes were divided into 47 subfamilies and clustered into nine clans. Phylogenetic relationship analysis reveals that CYP86 clan consists of four subfamilies and 109 BnCYP450s. Members of CYP86 clan genes display specific expression profiles in different tissues and in response to ABA and abiotic stresses. Two BnCYP450s within the CYP704 subfamily from CYP86 clan, BnCYP704B1a and BnCYP704B1b, display high similarity to MS26 (Male Sterility 26, also known as CYP704B1). These two BnCYP704B1 genes were specifically expressed in young buds. We then simultaneously knocked-out these two BnCYP704B1 genes through a clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) genome engineering system. The edited plants displayed a pollenless, sterile phenotype in mature anthers, suggesting that we successfully reproduced genic male sterility (GMS, also known as nuclear male sterility) lines in Brassica napus. This study provides a systemic view of BnCYP450s and offers a strategy to facilitate the commercial utility of the CRISPR/Cas9 system for the rapid generation of GMS in rapeseed via knocking-out GMS controlling genes.

2.
Blood Adv ; 2023 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-36652689

RESUMO

Abnormal erythrocyte adhesion due to polymerization of sickle hemoglobin is central to the pathophysiology of sickle cell disease (SCD). Mature erythrocytes constitute >80% of all erythrocytes in SCD, and the relative contributions made by erythrocytes to acute and chronic vasculopathy in SCD are not well understood. Here, we show that the bending stress exerted on the erythrocyte plasma membrane by the sickle hemoglobin polymerization under hypoxia enhances sulfatide-mediated abnormal mature erythrocyte adhesion. We hypothesized that sphingomyelinase activity that is upregulated by accumulated bending energy leads to elevated membrane sulfatide availability and thus hypoxic mature erythrocyte adhesion. We found that mature erythrocyte adhesion to laminin in controlled microfluidic experiments is significantly greater under hypoxia than under normoxia (1856±481 vs. 78±23, mean±SEM), while sickle reticulocyte (early erythrocyte) adhesion, high to begin with, does not change (1281 ±299 vs. 1258±328, mean±SEM). We show that greater mean accumulated bending energy of adhered mature erythrocytes is associated with higher acid SMase activity and increased mature erythrocyte adhesion (p=0.022, for the acid SMase activity and p=0.002 for the increase in mature erythrocyte adhesion with hypoxia, N=5). In addition, hypoxia results in sulfatide exposure on the erythrocyte membrane, and sphingomyelinase increases while anti-sulfatide inhibits the enhanced adhesion of erythrocytes. These results suggest that lipid components of the plasma membrane contribute to the complications in SCD. Therefore, sulfatide and the components of its upregulation pathway, particularly sphingomyelinase should be further explored as potential therapeutic targets to inhibit sickle erythrocyte adhesion.

3.
Curr Res Food Sci ; 6: 100445, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36699115

RESUMO

Maillard reaction products (MRPs) with roasted/broth flavors were prepared and analyzed for the resulting flavor differences. The identification of volatile compounds in MRPs was carried out by GC-MS and GC × GC-ToF-MS. A total of 88 compounds were identified by GC-MS; 130 compounds were identified by GC × GC-ToF-MS, especially acids and ketones were identified. Principal component analysis (PCA) was used to visualize the volatile compounds, and the roasted/broth flavors were differentiated. The contents and types of pyrazines were more in roasted flavors; thiol sulfides and thiophenes were more in broth flavors. All in all, the differences in volatile compounds producing roasted/broth flavors were studied through the cysteine-xylose-glutamate Maillard reaction system, which provided a theoretical basis for the future use of Maillard reaction to simulate meat flavor.

4.
Mater Today Bio ; 18: 100539, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36686035

RESUMO

Hydrogel-based micro-tissue engineering technique, a bottom-up approach, is promising in constructing soft tissue of large size with homogeneous spatial distribution and superior regeneration capacity compared to the top-down approach. However, most of the studies employed micro-tissues with simple mesenchymal stem cells, which could hardly meet the growth of matrix and vessels. Therefore, we recommend a dual micro-tissues assembly strategy to construct vascularized tissue-engineered breast grafts (TEBGs). Adipose micro-tissues (AMs) and vessel micro-tissues (VMs) were fabricated by seeding adipose-derived stem cells (ADSCs) and human umbilical vein endothelial cells (HUVECs) on collagen microgels (COLs) with a uniform diameter of ∼250 â€‹µm, respectively. TEBGs were constructed by injecting the dual micro-tissues into 3D printed breast-like Thermoplastic Urethane (TPU) scaffolds, then implanted into the subcutaneous pockets on the back of nude mice. After 3 months of implantation, TEBGs based on dual micro-tissues performed larger volume of adipose tissue regeneration and neo-vessel formation compared to TEBGs based on single AMs. This study extends the application of micro-tissue engineering technique for the construction of soft grafts, and is expected to be useful for creating heterogeneous tissue constructs in the future.

5.
Water Res ; 231: 119629, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36689882

RESUMO

Environmental pollution of antibiotic resistance genes (ARGs) has been a great public concern. Integrons, as mobile genetic elements, with versatile gene acquisition systems facilitate the horizontal gene transfer (HGT) and pollution disseminations of ARGs. However, little is understood about the characteristics of ARGs mediated by integrons, which hampers our monitoring and control of the mobile antimicrobial resistance risks. To address these issues, we reviewed 3,322 publications concerning detection methods and pipeline, ARG diversity and evolutionary progress, environmental and geographical distribution, bacterial hosts, gene cassettes arrangements, and based on which to identify ARGs with high risk levels mediated by integrons. Diverse ARGs of 516 subtypes attributed to 12 types were capable of being carried by integrons, with 62 core ARG subtypes prevalent in pollution source, natural and human-related environments. Hosts of ARG-carrying integrons reached 271 bacterial species, most frequently carried by opportunistic pathogens Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. Moreover, the observed emergence of ARGs together with their multiple arrangements indicated the accumulation of ARGs mediated by integrons, and thus pose increasing HGT risks under modern selective agents. With the concerns of public health, we urgently call for a better monitoring and control of these high-risk ARGs. Our identified Risk Rank I ARGs (aacA7, blaOXA10, catB3, catB8, dfrA5) with high mobility, reviewed key trends and noteworthy advancements, and proposed future directions could be reference and guidance for standard formulation.

6.
Diagnostics (Basel) ; 13(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36673135

RESUMO

Optical coherence tomography angiography (OCT-A) provides depth-resolved visualization of the retinal microvasculature without intravenous dye injection. It facilitates investigations of various retinal vascular diseases and glaucoma by assessment of qualitative and quantitative microvascular changes in the different retinal layers and radial peripapillary layer non-invasively, individually, and efficiently. Deep learning (DL), a subset of artificial intelligence (AI) based on deep neural networks, has been applied in OCT-A image analysis in recent years and achieved good performance for different tasks, such as image quality control, segmentation, and classification. DL technologies have further facilitated the potential implementation of OCT-A in eye clinics in an automated and efficient manner and enhanced its clinical values for detecting and evaluating various vascular retinopathies. Nevertheless, the deployment of this combination in real-world clinics is still in the "proof-of-concept" stage due to several limitations, such as small training sample size, lack of standardized data preprocessing, insufficient testing in external datasets, and absence of standardized results interpretation. In this review, we introduce the existing applications of DL in OCT-A, summarize the potential challenges of the clinical deployment, and discuss future research directions.

7.
Artigo em Inglês | MEDLINE | ID: mdl-36674272

RESUMO

Modern environmental philosophy is a new type of philosophy for humans re-examining the relationship between man and nature and provides the value guidance for modern environmental law. China's environmental crime legislation has gone through the exploration period, establishment period, and optimization period. The environmental philosophy behind this is worth discussing and determines the direction China will take environmental crime in the future and whether China's environmental strategy can really be implemented. At present, the disputes about the environmental philosophy of environmental crime in China are mainly reflected in the contention between anthropocentrism, ecocentrism, and eco-anthropocentrism. There are radical risks of pure human centrism or pure ecological centrism, and these two theories struggle to serve as a value basis for environmental crime legislation. Although eco-anthropocentrism seems to be comprehensive, it is actually ambiguous, and it is still difficult to deal with the conflict between people and nature. In recent years, China has continuously emphasized the construction of ecological civilization construction and written this into the constitution. Therefore, in the environmental philosophy issues of environmental crimes in China, we should consider absorbing the advantages of anthropocentrism, ecocentrism, and eco-anthropocentrism, while taking the original Chinese ecological civilization philosophy as the value foundation.


Assuntos
Civilização , Filosofia , Humanos , Crime , China
8.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675089

RESUMO

Active packaging materials protect food from deterioration and extend its shelf life. In the quest to design intriguing packaging materials, biocomposite ZnO/plant polyphenols/cellulose/polyvinyl alcohol (ZnPCP) was prepared via simple hydrothermal and casting methods. The structure and morphology of the composite were fully analyzed using XRD, FTIR, SEM and XPS. The ZnO particles, plant polyphenols (PPL) and cellulose were found to be dispersed in PVA. All of these components share their unique functions with the composite's properties. This study shows that PPL in the composite not only improves the ZnO dispersivity in PVA as a crosslinker, but also enhances the water barrier of PVA. The ZnO, PPL and cellulose work together, enabling the biocomposite to perform as a good food packaging material with only a 1% dosage of the three components in PVA. The light shielding investigation showed that ZnPCP-10 can block almost 100% of both UV and visible light. The antibacterial activities were evaluated by Gram-negative Escherichia coli (E. coli) and Gram-positive staphylococcus aureus (S. aureus), with 4.4 and 6.3 mm inhibition zones, respectively, being achieved by ZnPCP-10. The enhanced performance and easy degradation enables the biocomposite ZnPCP to be a prospect material in the packaging industry.


Assuntos
Quitosana , Óxido de Zinco , Embalagem de Alimentos , Álcool de Polivinil/química , Celulose/química , Óxido de Zinco/química , Quitosana/química , Staphylococcus aureus , Escherichia coli , Antibacterianos/farmacologia , Antibacterianos/química
9.
J Inflamm Res ; 16: 19-33, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36636249

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system worldwide, and there is a lack of effective treatment for late-stage HCC. Recent experimental studies have demonstrated that dysfunction of the intestinal flora has a significant impact on hepatocarcinogenesis. The pathophysiological link between the intestine, its microbiota, and the liver has been described as the "gut-liver axis". Dysbiosis of the intestinal flora and increased permeability of the intestinal wall are closely associated with liver pathology through the immune response. The "gut-liver axis" theory has been applied to the clinical study of the pathogenesis and treatment of HCC. The intestinal fungal community, as part of the gut microbiome, has a significant impact on human health and disease, while relatively little research has been done in HCC. In this study, we performed a comprehensive analysis of the expression and potential biological functions of the fungal recognition receptors C-type lectin receptors (CLRs) (Dectin-1, Dectin-2, Dectin-3, and Mincle) in HCC. We found that CLRs were downregulated in HCC, and their expressions were correlated with the clinical prognosis of HCC patients. Further studies suggested that the expression of CLRs were significantly correlated with immune infiltration and immunotherapy efficacy in HCC. Based on previous studies and our findings, we hypothesize that intestinal fungal communities and CLRs-triggered antifungal immunity have a key role in the pathogenesis of HCC, and these findings may provide new perspectives and targets for HCC immunotherapy.

10.
Apoptosis ; 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36652132

RESUMO

microRNA-1827 (miR-1827) is proposed to be enriched in exosomes from mesenchymal stem cells (MSCs-Exos). A recent study has addressed the suppressive effect of exosomes from human umbilical cord mesenchymal stem cells (hUC-MSCs-Exos) on colorectal cancer (CRC) metastasis. Hence, our study aims at investigating whether hUC-MSCs-Exos can modulate the liver metastasis in CRC by mediating miR-1827. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were used to identify hUC-MSCs-Exos. Using gain- and loss-of-function approaches, the expression of miR-1827 and succinate receptor 1 (SUCNR1) was altered. Consequently, the biological functions of CRC cells were assessed by CCK-8 and Transwell assays and macrophage M2 polarization was assayed by flow cytometry. Dual-luciferase reporter assay was applied to clarify interaction between miR-1827 and SUCNR1. CRC cells were incubated with hUC-MSCs-Exos and tumor-bearing mice were injected with hUC-MSCs-Exos to examine the effects on CRC cell growth and metastasis. SUCNR1, lowly expressed in CRC, could promote CRC cell growth and macrophage M2 polarization. miR-1827 could target SUCNR1 and hence suppress the progression and metastasis of CRC. hUC-MSCs-Exos carried miR-1827 to inhibit M2 macrophage polarization by downregulating SUCNR1 expression, and inhibited proliferating, migrating and invading properties of CRC cells. Furthermore, hUC-MSCs-Exos carrying miR-1827 blocked CRC liver metastasis in vivo. These findings indicate hUC-MSCs-Exos as an inhibitor of M2 macrophage polarization and liver metastasis in CRC through inducing miR-1827-targeted inhibition of SUCNR1. This provides a theoretical basis for understanding the mechanisms underlying Exos-based target therapy for CRC.

11.
Sci Rep ; 13(1): 750, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639385

RESUMO

Acellular matrix is a commonly used biomaterial in the field of biomedical engineering and revascularization is the key process to affect the effect of acellular matrix on tissue regeneration. The application of bioactive factors related to angiogenesis has been popular in the regulation of revascularization, but the immune system clearance, uncontrollable systemic reactions, and other factors make this method face challenges. Recent reports showed that engineered cells into nanovesicles can reorganize cell membranes and encapsulate cellular active factors, extending the in vitro preservation of cytokines. However, the problems of exogenous biological contamination and tumorigenicity restricted the clinical transformation and wide application of this method. Here, we for the first time engineer stromal vascular fraction (SVF) which is extracted from fat into nanovesicles (SVF-EVs) for angiogenesis in the acellular matrix. SVF-EVs not only promote the migration of vascular endothelial cells in vitro, but also facilitate the lipogenic differentiation of mesenchymal stem cells. In vivo, SVF-EVs enhanced the retention of decellularized adipose tissue after transplanting to the subcutaneous area of nude mice. Immunofluorescence staining further showed that SVF-EVs promoted the formation of vascular networks with large lumen diameter in the grafted acellular matrix, accompanied by adipocyte regeneration peripherally. These findings reveal that SVF-EVs can be a viable method for accelerating revascularization in acellular matrix, and this process of squeezing tissue into nanovesicles shows the potential for rapid clinical transformation.


Assuntos
Adipogenia , Fração Vascular Estromal , Camundongos , Animais , Células Endoteliais , Camundongos Nus , Células Estromais/metabolismo , Tecido Adiposo
12.
Br J Haematol ; 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36604837

RESUMO

Endothelial activation and sickle red blood cell (RBC) adhesion are central to the pathogenesis of sickle cell disease (SCD). Quantitatively, RBC-derived extracellular vesicles (REVs) are more abundant from SS RBCs compared with healthy RBCs (AA RBCs). Sickle RBC-derived REVs (SS REVs) are known to promote endothelial cell (EC) activation through cell signalling and transcriptional regulation at longer terms. However, the SS REV-mediated short-term non-transcriptional response of EC is unclear. Here, we examined the impact of SS REVs on acute microvascular EC activation and RBC adhesion at 2 h. Compared with AA REVs, SS REVs promoted human pulmonary microvascular ECs (HPMEC) activation indicated by increased von Willebrand factor (VWF) expression. Under microfluidic conditions, we found abnormal SS RBC adhesion to HPMECs exposed to SS REVs. This enhanced SS RBC adhesion was reduced by haeme binding protein haemopexin or VWF cleaving protease ADAMTS13 to a level similar to HPMECs treated with AA REVs. Consistent with these observations, haemin- or SS REV-induced microvascular stasis in SS mice with implanted dorsal skin-fold chambers that was inhibited by ADAMTS13. The adhesion induced by SS REVs was variable and was higher with SS RBCs from patients with increased markers of haemolysis (lactate dehydrogenase and reticulocyte count) or a concomitant clinical diagnosis of deep vein thrombosis. Our results emphasise the critical contribution made by REVs to the pathophysiology of SCD by triggering acute microvascular EC activation and abnormal RBC adhesion. These findings may help to better understand acute pathophysiological mechanism of SCD and thereby the development of new treatment strategies using VWF as a potential target.

13.
CNS Neurosci Ther ; 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627756

RESUMO

AIM: Psilocin is an active metabolite form of psilocybin and exerts psychoactive effects. Recent studies suggest that psilocin may have regulatory effects on abuse drugs, but the mechanisms remain unclear. In this study, we want to explore the effects of psilocin on methamphetamine (METH)-induced alterations of behavior in mice and its molecular mechanisms. METHODS: Acute METH administration model and conditioned place preference (CPP) model were used to investigate the effects of psilocin on METH-induced alterations of behavior. Western blot was used to detect the expression of proteins. RESULTS: In the acute 2 mg/kg METH administration model, 1 mg/kg psilocin counteracted METH-induced elevation of activity. In the 1 mg/kg METH-induced CPP model, 1 mg/kg psilocin inhibited CPP formation during the acquisition phase. However, psilocin did not impact METH extinction and relapse. Molecular results showed that the regulatory effect of psilocin on METH was underscored by altered expression of dopamine 2 receptor (D2R) and phosphorylated extra-cellular signal-regulated kinase (p-ERK) in the prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA). Trifluoperazine (TFP)-2HCl is a D2R inhibitor, and SCH772984 is a selective extra-cellular signal-regulated kinase (ERK) inhibitor that effectively inhibits ERK1/2 phosphorylation. The results indicated that 2 mg/kg TFP-2HCl and 10 mg/kg SCH772984 blocked METH-induced hyperactivity and acquisition of METH-induced CPP. CONCLUSION: Psilocin has regulatory effects on METH-induced alterations of behavior in mice via D2R-mediated signal regulation of ERK phosphorylation.

14.
Cancer Nurs ; 46(1): E41-E61, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35439200

RESUMO

BACKGROUND: Family caregivers of head and neck cancer (HNC) patients undertook heavy care tasks and role responsibilities. They were facing multiple challenges during the patients' cancer trajectory. OBJECTIVE: The aim of this study was to synthesize existing qualitative evidence regarding family caregivers' experiences of caring for HNC patients. METHODS: A meta-aggregation approach was used. Articles were collected from MEDLINE, EMBASE, CINAHL, Web of Science, PsycINFO, and Cochrane Library. Supplementary resources were collected by scrutinizing reference lists and performing citation tracking. RESULTS: A total of 20 studies were included and synthesized. Three meta-themes covering "accepting the diagnosis and treatment on patients: a distressing process," "facing changes of life and adapting to new roles," and "appreciating the external supports" were identified with 10 subthemes. There was high confidence in the evidence for "facing changes of life and adapting to new roles" and moderate confidence in the evidence for the other 2 meta-themes. CONCLUSIONS: Taking care of HNC patients is a distressing process. Caregivers took on role responsibilities and developed strategies to make adjustments to life changes, so as to provide better care for patients. External supports regarding caregiving and self-care were desired. IMPLICATIONS FOR PRACTICE: Psychological distress was common among caregivers and calls for routine clinical screening. Providing caregivers with practical strategies to deal with daily caregiving tasks was crucial. Healthcare workers can play a critical role in providing tailored support in different caregiving stages. The findings informed the interventions and future research to improve HNC caregivers' experiences.


Assuntos
Neoplasias de Cabeça e Pescoço , Angústia Psicológica , Humanos , Cuidadores/psicologia , Pesquisa Qualitativa , Neoplasias de Cabeça e Pescoço/terapia , Assistência ao Paciente , Família/psicologia
15.
Neurosci Lett ; 792: 136952, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36336087

RESUMO

Drug addiction, including methamphetamine (METH) addiction, is a significant public health and social issue. Perturbations in intracellular Ca2+ homeostasis are associated with drug addiction. K+-dependent Na+/Ca2+ exchanger 2 (NCKX2) is located on neuronal cell membranes and constitutes a Ca2+ clearance mechanism, with key roles in synaptic plasticity. NCKX2 is associated with motor learning, memory, and cognitive functions. However, the role of NCKX2 in METH addiction remains unclear. In this study, we investigated the expression levels of NCKX2 in four addiction-related brain regions: the prefrontal cortex (PFc), nucleus accumbens (NAc), dorsal striatum (DS), and hippocampus (Hip) in a C57/BL6 mouse model of METH-induced conditioned place preference (CPP) and behavioral sensitization. Levels of NCKX2 were unchanged in these brain regions in mice with METH-induced CPP but were decreased in the PFc and NAc of mice with METH-induced behavioral sensitization. Adeno-associated virus (AAV)-mediated overexpression of NCKX2 in the PFc attenuated the expression phase of METH-induced behavioral sensitization in mice, whereas AAV-mediated knockdown of NCKX2 enhanced the effects of METH. Collectively, our results suggest that NCKX2 is involved in METH-induced behavioral sensitization but does not affect conditioned reward-related memory, highlighting the potential of NCKX2 as a molecular target for studying the mechanisms underscoring METH addiction.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Estimulantes do Sistema Nervoso Central , Metanfetamina , Animais , Camundongos , Metanfetamina/farmacologia , Trocador de Sódio e Cálcio/metabolismo , Núcleo Accumbens/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Recompensa , Estimulantes do Sistema Nervoso Central/farmacologia
16.
Biosens Bioelectron ; 222: 114921, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36521205

RESUMO

Neutrophil recruitment to the inflamed endothelium is a multistep process and is of utmost importance in the development of the hallmark vaso-occlusive crisis in sickle cell disease (SCD). However, there lacks a standardized, clinically feasible approach for assessing neutrophil recruitment to the inflamed endothelium for individualized risk stratification and therapeutic response prediction in SCD. Here, we describe a microfluidic device functionalized with E-selectin, a critical endothelial receptor for the neutrophil recruitment process, as a strategy to assess neutrophil binding under physiologic flow in normoxia and clinically relevant hypoxia in SCD. We show that hypoxia significantly enhances neutrophil binding to E-selectin and promotes the formation of neutrophil-platelet aggregates. Moreover, we identified two distinct patient populations: a more severe clinical phenotype with elevated lactate dehydrogenase levels and absolute reticulocyte counts but lowered fetal hemoglobin levels associated with constitutively less neutrophil binding to E-selectin. Mechanistically, we demonstrate that the extent of neutrophil activation correlates with membrane L-selectin shedding, resulting in the loss of ligand interaction sites with E-selectin. We also show that inhibition of E-selectin significantly reduces leukocyte recruitment to activated endothelial cells. Our findings add mechanistic insight into neutrophil-endothelial interactions under hypoxia and provide a clinically feasible means for assessing neutrophil binding to E-selectin using clinical whole blood samples, which can help guide therapeutic decisions for SCD patients.


Assuntos
Anemia Falciforme , Técnicas Biossensoriais , Humanos , Selectina E/uso terapêutico , Células Endoteliais/metabolismo , Infiltração de Neutrófilos , Adesão Celular , Endotélio/metabolismo , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/metabolismo , Dispositivos Lab-On-A-Chip , Hipóxia
17.
Chin Med ; 17(1): 134, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36471367

RESUMO

BACKGROUND: Hypoxia-induced pulmonary hypertension (HPH) is one of the fatal pathologies developed under hypobaric hypoxia and eventually leads to right ventricular (RV) remodeling and RV failure. Clinically, the mortality rate of RV failure caused by HPH is high and lacks effective drugs. Xinyang Tablet (XYT), a traditional Chinese medicine exhibits significant efficacy in the treatment of congestive heart failure and cardiac dysfunction. However, the effects of XYT on chronic hypoxia-induced RV failure are not clear. METHODS: The content of XYT was analyzed by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS). Sprague-Dawley (SD) rats were housed in a hypobaric chamber (equal to the parameter in altitude 5500 m) for 21 days to obtain the RV remodeling model. Electrocardiogram (ECG) and hemodynamic parameters were measured by iWorx Acquisition & Analysis System. Pathological morphological changes in the RV and pulmonary vessels were observed by H&E staining and Masson's trichrome staining. Myocardial apoptosis was tested by TUNEL assay. Protein expression levels of TNF-α, IL-6, Bax, Bcl-2, and caspase-3 in the RV and H9c2 cells were detected by western blot. Meanwhile, H9c2 cells were induced by CoCl2 to establish a hypoxia injury model to verify the protective effect and mechanisms of XYT. A CCK-8 assay was performed to determine the viability of H9c2 cells. CoCl2-induced apoptosis was detected by Annexin-FITC/PI flow cytometry and Hoechst 33,258 staining. RESULTS: XYT remarkably improved RV hemodynamic disorder and ECG parameters. XYT attenuated hypoxia-induced pathological injury in RV and pulmonary vessels. We also observed that XYT treatment decreased the expression levels of TNF-α, IL-6, Bax/Bcl-2 ratio, and the numbers of myocardial apoptosis in RV. In H9c2 myocardial hypoxia model, XYT protected H9c2 cells against Cobalt chloride (CoCl2)-induced apoptosis. We also found that XYT could antagonize CoCl2-induced apoptosis through upregulating Bcl-2, inhibiting Bax and caspase-3 expression. CONCLUSIONS: We concluded that XYT improved hypoxia-induced RV remodeling and protected against cardiac injury by inhibiting apoptosis pathway in vivo and vitro models, which may be a promising therapeutic strategy for clinical management of hypoxia-induced cardiac injury.

18.
Zhongguo Zhong Yao Za Zhi ; 47(20): 5584-5590, 2022 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-36471976

RESUMO

Danzhi Xiaoyao Powder is a classical prescription for anxiety. This study aims to analyze the effect of this medicine on mitochondrial morphology and function of anxiety rats and explore the mechanism of it against anxiety. Specifically, uncertain empty bottle drinking water stimulation(21 days) was employed to induce anxiety in rats. The elevated plus-maze test and open field test were respectively performed on the 7 th, the 14 th, and the 21 st days of the stimulation, so as to detect the anxiety-related protein index brain-derived neurotrophic factor(BDNF) and evaluate the anxiety level of animals. On this basis, the effect of this prescription on anxiety rats was preliminarily evaluated. After the behavioral test on the 21 st day, rats were killed and the brain tissues were separated for the observation of the mitochondrial morphology and the determination of mitochondrial function-related indicators and the adenosine 5'-monophosphate-activated protein kinase(AMPK) level. The results showed that Danzhi Xiaoxiao Powder could alleviate the anxiety-like behavior of rats, significantly increase the percentage of time in open arm in elevated plus-maze test and the ration of activity time in the central area of the field, dose-dependently raise the activity levels of respiratory chain complex Ⅰ,Ⅱ,Ⅲ and Ⅳ and the adenosine triphosphate(ATP) content, and elevate the levels of BDNF and phosphorylated AMPK(p-AMPK). Clear structure and intact morphology of mitochondrial cristae in medial prefrontal cortex cells and amygdala were observed in the Danzhi Xiaoyao Powder group. In summary, Danzhi Xiaoyao Powder exerts therapeutic effect on anxiety, and the mechanism is the likelihood that p-AMPK protects the structure and maintains the function of mitochondria.


Assuntos
Proteínas Quinases Ativadas por AMP , Fator Neurotrófico Derivado do Encéfalo , Ratos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Pós , Ansiedade/tratamento farmacológico , Mitocôndrias
19.
Nature ; 2022 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-36535326

RESUMO

Continuous evolution of Omicron has led to a rapid and simultaneous emergence of numerous variants that display growth advantages over BA.5 1. Despite their divergent evolutionary courses, mutations on their receptor-binding domain (RBD) converge on several hotspots. The driving force and destination of such sudden convergent evolution and its impact on humoral immunity remain unclear. Here, we demonstrate that these convergent mutations can cause striking evasion of neutralizing antibody (NAb) drugs and convalescent plasma, including those from BA.5 breakthrough infection, while maintaining sufficient ACE2 binding capability. BQ.1.1.10 (BQ.1.1+Y144del), BA.4.6.3, XBB, and CH.1.1 are the most antibody-evasive strains tested. To delineate the origin of the convergent evolution, we determined the escape mutation profiles and neutralization activity of monoclonal antibodies (mAbs) isolated from BA.2 and BA.5 breakthrough-infection convalescents 2,3. Due to humoral immune imprinting, BA.2 and especially BA.5 breakthrough infection reduced the diversity of the NAb binding sites and increased proportions of non-neutralizing antibody clones, which in turn focused humoral immune pressure and promoted convergent evolution in the RBD. Moreover, we showed that the convergent RBD mutations could be accurately inferred by deep mutational scanning (DMS) profiles 4,5, and the evolution trends of BA.2.75/BA.5 subvariants could be well-foreseen through constructed convergent pseudovirus mutants. These results suggest current herd immunity and BA.5 vaccine boosters may not efficiently prevent the infection of Omicron convergent variants.

20.
Heliyon ; 8(12): e11778, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36478812

RESUMO

Hemoglobin (Hb) disorders affect nearly 7% of the world's population. Globally, around 400,000 babies are born annually with sickle cell disease (SCD), primarily in sub-Saharan Africa where morbidity and mortality rates are high. Screening, early diagnosis, and monitoring are not widely accessible due to technical challenges and cost. We hypothesized that multispectral imaging will allow sensitive hemoglobin variant identification in existing affordable paper-based Hb electrophoresis. To test this hypothesis, we developed the first integrated point-of-care multispectral Hb variant test: Gazelle-Multispectral. Here, we evaluated the accuracy of Gazelle-Multispectral for Hb variant newborn screening in 265 newborns with known hemoglobin variants including hemoglobin A (Hb A), hemoglobin F (Hb F), hemoglobin S (Hb S) and hemoglobin C (Hb C). Gazelle-Multispectral detected levels of Hb A, Hb F, Hb S, and Hb C/E/A2, demonstrated high correlations with the results reported by laboratory gold standard high performance liquid chromatography (HPLC) at Pearson Correlation Coefficient = 0.97, 0.97, 0.93, and 0.95. Gazelle-Multispectral demonstrated accuracy of 96.8% in subjects of 0-3 days, and 96.9% in newborns. The ability to obtain accurate results on newborn samples suggest that Gazelle-Multispectral can be suitable for large-scale newborn screening and for diagnosis of SCD in low resource settings.

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