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1.
Front Nutr ; 8: 756565, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34722615

RESUMO

Scope: Gut microbiome-derived metabolites are the major mediators of diet-induced host-microbial interactions. Aryl hydrocarbon receptor (AHR) plays a crucial role in glucose, lipid, and cholesterol metabolism in the liver. In this study, we aimed to investigate the role of indole-3-acetic acid (IAA) and AHR in sulforaphane (SFN) alleviates hepatic steatosis in mice fed on a high-fat diet (HFD). Methods and Results: The HFD-fed male C57BL/6 mice were intervened with SFN for 6 weeks. HFD-mice showed classical pathophysiological characteristics of hepatic steatosis. The results showed that SFN significantly reduced body weight, liver inflammation and hepatic steatosis in HFD-fed mice. SFN reduced hepatic lipogenesis by activating AHR/SREBP-1C pathway, which was confirmed in HepG2 cell experiments. Moreover, SFN increased hepatic antioxidant activity by modulating Nrf-2/NQO1 expression. SFN increased serum and liver IAA level in HFD mice. Notably, SFN manipulated the gut microbiota, resulting in reducing Deferribacteres and proportions of the phylum Firmicutes/Bacteroidetes and increasing the abundance of specific bacteria that produce IAA. Furthermore, SFN upregulated Ahr expression and decreased the expression of inflammatory cytokines in Raw264.7 cells. Conclusions: SFN ameliorated hepatic steatosis not only by modulating lipid metabolism via AHR/SREBP-1C pathway but regulating IAA and gut microbiota in HFD-induced NAFLD mice.

2.
Nat Commun ; 12(1): 6574, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34772929

RESUMO

Electrocatalytic acetylene semihydrogenation is a promising alternative to thermocatalytic acetylene hydrogenation due to its environmental benignity and economic efficiency, but its performance is far below that of the thermocatalytic reaction because of strong competition from side reactions, including hydrogen evolution, overhydrogenation and carbon-carbon coupling reactions. We develop N-heterocyclic carbene-metal complexes, with electron-rich metal centers owing to the strongly σ-donating N-heterocyclic carbene ligands, as electrocatalysts for selective acetylene semihydrogenation. Experimental and theoretical investigations reveal that the copper sites in N-heterocyclic carbene-copper facilitate the absorption of electrophilic acetylene and the desorption of nucleophilic ethylene, ultimately suppressing the side reactions during electrocatalytic acetylene semihydrogenation, and exhibit superior semihydrogenation performance, with faradaic efficiencies of ≥98 % under pure acetylene flow. Even in a crude ethylene feed containing 1 % acetylene (1 × 104 ppm), N-heterocyclic carbene-copper affords a specific selectivity of >99 % during a 100-h stability test, continuous ethylene production with only ~30 ppm acetylene, a large space velocity of up to 9.6 × 105 mL·gcat-1·h-1, and a turnover frequency of 2.1 × 10-2 s-1, dramatically outperforming currently reported thermocatalysts.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34773583

RESUMO

Access to financial services is regarded as one of the most pressing issues confronting communities worldwide sequel to the COVID-19 pandemic. In this regard, FinTech applications such as mobile financial service (MFS) play an essential role in building resilience during the pandemic. Hence, the aim of the study is to investigate the role of MFS platforms in economic resilience by empirically evaluating the determinants that influence the intention of Bangladeshi users toward adopting MFS platforms during the COVID-19 pandemic, through an extension of the Unified Theory of Acceptance and Use of Technology (UTAUT). Using the core structures of the UTAUT, the theoretical model was constructed based on the consumption attributes of financial services such as perceived value, as well as additional situational factors from the extended valence framework, including risk and trust. To test the model, data was obtained from 227 potential MFS users in Bangladesh with the aid of a structured questionnaire survey. Subsequently, the Structural Equation Modeling (SEM) approach was used to analyze the data. The findings showed that social influence, perceived trust, and perceived value are strongly related to the intention of users to adopt MFS platforms, whereas, perceived risk, performance expectancy, and effort expectancy were observed to influence users' perceived value of the MFS platforms during the COVID-19 pandemic. Interestingly, the study results indicated that the users' perceived risk did not influence their intention to adopt MFS platforms during the pandemic. Therefore, the suggested adoption of the MFS framework during and after the pandemic could contribute to the existing research on the adoption of information technology (IT) through the expansion of the UTAUT, in which the performance and effort expectancy of users influence their intention to indirectly adopt MFS through perceived value. Finally, the significant policy implications and future research directions are further addressed.

4.
Dalton Trans ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34787610

RESUMO

Biomass-derived carbon-based energy materials are receiving extensive attention nowadays. With the widespread use of traditional Chinese medicines in the treatment of diseases and health care, a great deal of herb residues are thrown away after the unique decoction process. Here, through hydrothermal carbonization combined with KOH activation, a micropore-rich and nitrogen-doped porous carbon framework (MRNCF) is prepared from the waste roots of a kind of well-known and widely used traditional Chinese medicine, Acanthopanax senticosus. Compared with ordinary carbon-based sulfur host materials, the MRNCFs can effectively hinder the shuttling effect and dissolution of polysulfides through the synergistic action of physical confinement in micropores and chemical anchoring for nitrogen doping, and the lithium-sulfur batteries using MRNCF as the host present superior electrochemical performance. In a high sulfur content of over 75%, the as-prepared electrodes exhibit a highly reversible specific capacity of 540.4 mA h g-1 at a current density of 0.5C after 150 cycles and an excellent rate capability at different current densities.

5.
Cell Immunol ; 371: 104452, 2021 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-34784561

RESUMO

Atopic dermatitis (AD) is a common inflammatory skin disorder that affects children and adults. Despite the pathology of AD involves in immune dysfunction and epidermal barrier function destruction has been found, the mechanism of immune activation and barrier damage remain largely unknown. In the present study, The TNF-α/IFN-γ-stimulated HaCaTs, organotypic AD-like 3D skin equivalents and AD-like mouse model were constructed. The mRNA, histological morphology, protein levels, cytokines were detected by real-time quantitative polymerasechain reaction (RT-qPCR), hematoxylin and eosin (H & E) staining, Immunohistochemistry (IHC), immunoblotting, immunofluorescence (IF) staining, and enzyme linked immunosorbent assay (ELISA), respectively. Cell viability, cell cycle, and apoptosis were respectively calculated using a Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay and flow cytometry. A dual-luciferase reporter gene system was used to investigate the relationship between miR-1294 and STAT3. Compared with the control group, the expression of miR-1294 decreased in TNF-α/IFN-γ-stimulated HaCaTs (P < 0.001), AD-like skin model, and AD-like mouse model (P < 0.001). Moreover, STAT3 was documented as a direct target of miR-1294. Inflammation (P < 0.05) and epidermal barrier function destruction (P < 0.05) in AD was suppressed by overexpression of miR-1294 but enhanced by STAT3 upregulation and its downstream NF-κB pathway. We also found miR-1294 upregulation inhibited inflammation and epidermal barrier function destruction via targeting STAT3 to suppress NF-κB pathway activation in AD.

6.
Front Med (Lausanne) ; 8: 770914, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34796190

RESUMO

Psychological distress were found to be associated with chronic conditions and persistent pain. However, few studies explored the underlying pathways between them. This study aimed to analyze the path of chronic conditions and persistent pain on psychological distress through sleep quality and self-rated health. A total of 2,748 rural older people in Shandong, China were included in this study. Path analysis was performed by using Mplus 8.3 to examine the associations between chronic conditions, persistent pain, sleep quality, self-rated health, and psychological distress after adjusting for age, gender, education, and household income. The prevalence of psychological distress among the older adults in this study was 47.49%. Chronic conditions and persistent pain were indirectly associated with psychological distress through six mediating pathways: (1) the path from chronic conditions to psychological distress through sleep quality (ß = 0.041, 95%CI: 0.015-0.067) and self-rated health (ß = 0.064, 95%CI: 0.038-0.091), respectively, and a chain mediation existed (ß = 0.007, 95% CI: 0.000-0.014); (2) the path of persistent pain and psychological distress through sleep quality (ß = 0.058, 95% CI: 0.014-0.102) and self-rated health (ß = 0.048, 95% CI: 0.000-0.096), respectively, also the chain mediation found (ß = 0.009, 95% CI: 0.005-0.014). Psychological distress was associated with chronic conditions and persistent pain through decreased sleep quality and self-rated health among Chinese rural older people. Multi-pronged targeted intervention should be taken for older adults with chronic conditions and persistent pain.

7.
J Affect Disord ; 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34808134

RESUMO

BACKGROUND: many studies explore the relationship between social capital and self-rated health. However, few studies clarified the mechanisms underlying the relationship between social capital and self-rated health among Chinese rural empty nesters. This study aimed to explore the multiple mediating roles of sleep quality and psychological distress between this relationship. METHODS: A total of 2,254 rural empty-nest older adults were included in the analysis. A descriptive analysis was conducted to describe the sample characteristics. Logistic regressions were performed to assess the relationships between social capital and self-rated health. The multiple mediating roles of sleep quality and psychological distress was analyzed using Mplus 8.3. RESULTS: we found that social capital has a significant directly affect self-rated health (ß=0.127, 68.65% CI=0.082-0.171), and through three significantly mediation pathways: (1) the path through sleep quality (ß=0.013, 95% CI=0.005-0.021), which accounted for 7.03 % of the total effect; (2) the path through psychological distress (ß=0.037, 95% CI=0.024-0.049), which accounted for 20.00 % of the total effect; (3) the path through sleep quality and psychological distress (ß=0.008, 95% CI=0.004-0.013), which accounted for 4.32 % of the total effect. The total mediating effect was 31.35%. CONCLUSIONS: sleep quality and psychological distress mediate the relationship between social capital and self-rated health. Attention should be paid to mental health and sleep quality of empty nester through primary health, strengthen the attention to social resources, provide intervention and treatment for the empty nesters with sleep problem and psychological distress.

8.
Circ Res ; 129(Suppl_1): AMP265, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34735298

RESUMO

Cyclic nucleotide phosphodiesterases (PDEs), through the degradation of cyclic nucleotides, play critical roles in cardiovascular biology and disease. PDE10A is able to hydrolyze both cAMP and cGMP. Its high expression in medium spiny neurons of the human striatum has led to the development of several PDE10A inhibitors with the intent to treat various psychiatric/neurodegenerative disorders, such as schizophrenia and Huntington's disease. Our previous study has reported the upregulation of PDE10A expression in failing hearts and demonstrated the protective effects of PDE10A deficiency/inhibition against cardiac hypertrophy, fibrosis, and dysfunction in mouse models of heart failure. Doxorubicin (DOX) is an effective chemotherapeutic agent against a variety of cancers. While its therapeutic utility is limited by the development of dose-dependent cardiotoxicity. In the current study, we aim to determine the role of PDE10A in cancer and cardiotoxicity induced by DOX. We found that PDE10A inhibition or deficiency alleviated DOX-induced cardiotoxicity in vivo, as well as cardiac myocyte (CM) death and atrophy in vitro. In ovarian cancer cells, PDE10A inhibition induced cell death and reduced cell proliferation; as well as potentiated the effect of DOX on antagonizing cancer cells. Interestingly, in nude mice with ovarian cancer xenografts, PDE10A inhibition attenuated ovarian tumor growth while protected DOX-induced cardiotoxicity. RNAseq and bioinformatics analysis uncovered a number of PDE10A-regulated signaling pathways and cellular processes involved in DOX-induced cardiotoxicity. Mechanistic studies further revealed that PDE10A regulates CM death and atrophy via different mechanistic actions: regulating CM death via a cGMP-dependent while cAMP-independent mechanism; and regulating CM atrophy via a mechanism dependent on both cGMP and cAMP. Several PDE10A inhibitors have been tested in humans and successfully passed phase I clinical trials for safety. Thus, our findings suggest that PDE10A may be a safe "druggable" target for cancer therapy by simultaneously preventing DOX-induced cardiotoxicity and antagonizing tumor growth.

9.
Br J Haematol ; 2021 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-34741461

RESUMO

Haploidentical allogeneic haematopoietic stem cell transplantation (haplo-HSCT) is a significant alternative treatment for severe aplastic anaemia (SAA). To improve this process by modifying the risk stratification system, we conducted a retrospective study using our database. 432 SAA patients who received haplo-HSCT between 2006 and 2020 were enrolled. These patients were divided into a training (n = 288) and a validation (n = 144) subset randomly. In the training cohort, longer time from diagnosis to transplantation, poorer Eastern Cooperative Oncology Group (ECOG) status and higher haematopoietic cell transplantation-specific comorbidity index (HCT-CI) score were independent risk factors for worse treatment-related mortality (TRM) in the final multivariable model. The haplo-HSCT scoring system was developed by these three parameters. Three-year TRM after haplo-HSCT were 6% [95% confidence interval (CI), 1-21%], 21% (95% CI, 7-40%), and 47% (95% CI, 20-70%) for the low-, intermediate-, and high-risk group, respectively (P < 0·0001). In the validation cohort, the haplo-HSCT scoring system also separated patients into three risk groups with increasing risk of TRM: intermediate-risk [hazard ratio (HR) 2·45, 95% CI, 0·92-6·53] and high-risk (HR 11·74, 95% CI, 3·07-44·89) compared with the low-risk group (P = 0·001). In conclusion, the haplo-HSCT scoring system could effectively predict TRM after transplantation.

10.
BMC Genomics ; 22(1): 790, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732130

RESUMO

BACKGROUND: The complexity of physical activity (PA) and DNA methylation interaction in the development of cardiovascular disease (CVD) is rarely simultaneously investigated in one study. We examined the role of DNA methylation on the association between PA and CVD. RESULTS: The Multi-Ethnic Study of Atherosclerosis (MESA) cohort Exam 5 data with 1065 participants free of CVD were used for final analysis. The quartile categorical total PA variable was created by activity intensity (METs/week). During a median follow-up of 4.0 years, 69 participants developed CVD. Illumina HumanMethylation450 BeadChip was used to provide genome-wide DNA methylation profiles in purified human monocytes (CD14+). We identified 23 candidate DNA methylation loci to be associated with both PA and CVD. We used the structural equation modeling (SEM) approach to test the complex relationships among multiple variables and the roles of mediators. Three of the 23 identified loci (corresponding to genes VPS13D, PIK3CD and VPS45) remained as significant mediators in the final SEM model along with other covariates. Bridged by the three genes, the 2nd PA quartile (ß = - 0.959; 95%CI: - 1.554 to - 0.449) and the 3rd PA quartile (ß = - 0.944; 95%CI: - 1.628 to - 0.413) showed the greatest inverse associations with CVD development, while the 4th PA quartile had a relatively weaker inverse association (ß = - 0.355; 95%CI: - 0.713 to - 0.124). CONCLUSIONS: The current study is among the first to simultaneously examine the relationships among PA, DNA methylation, and CVD in a large cohort with long-term exposure. We identified three DNA methylation loci bridged the association between PA and CVD. The function of the identified genes warrants further investigation in the pathogenesis of CVD.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Aterosclerose/genética , Doenças Cardiovasculares/genética , Metilação de DNA , Grupos Étnicos , Exercício Físico , Humanos , Fatores de Risco
11.
Beilstein J Org Chem ; 17: 2425-2432, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621404

RESUMO

The p-TsOH-catalyzed Diels-Alder reaction of 3-(indol-3-yl)maleimides with chalcone in toluene at 60 °C afforded two diastereoisomers of tetrahydropyrrolo[3,4-c]carbazoles, which can be dehydrogenated by DDQ oxidation in acetonitrile at room temperature to give the aromatized pyrrolo[3,4-c]carbazoles in high yields. On the other hand, the one-pot reaction of 3-(indol-3-yl)-1,3-diphenylpropan-1-ones with chalcones or benzylideneacetone in acetonitrile in the presence of p-TsOH and DDQ resulted in polyfunctionalized carbazoles in satisfactory yields. The reaction mechanism included the DDQ oxidative dehydrogenation of 3-(indol-3-yl)-1,3-diphenylpropan-1-ones to the corresponding 3-vinylindoles, their acid-catalyzed Diels-Alder reaction and sequential aromatization process.

12.
Antimicrob Agents Chemother ; : AAC0129521, 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34662187

RESUMO

The emergence of daptomycin-resistant (DAP-R) Staphylococcus aureus strains has become a global problem. Point mutations in mprF are the main cause of daptomycin (DAP) treatment failure. However, the impact of these specific point-mutations in methicillin-resistant S. aureus (MRSA) strains associated with DAP resistance and the "see-saw effect" of distinct beta-lactams remains unclear. In this study, we used three series of clinical MRSA strains with three distinct mutated mprF alleles from clone complexes (CC) 5 and 59 to explore the "see-saw effect" and the combination effect of DAP plus beta-lactams. Through construction of mprF deletion and complementation strains of SA268, we determined that mprF-S295A, mprF-S337L and one novel mutation of mprF-I348del within the bifunctional domain lead to DAP resistance. Compared with wild-type mprF cloned from a DAP-susceptible (DAP-S) strain, these three mprF mutations conferred the "see-saw effect" to distinct beta-lactams in the SA268ΔmprF strains and mutated-mprF (I348del and S337L) did not alter the cell surface positive charge (P > 0.05). The susceptibility to beta-lactams increased significantly in DAP-R CC59 strains and the "see-saw effect" was found to be associated with distinct mutated mprF alleles and the category of beta-lactams. The synergistic activity of DAP plus oxacillin was detected in all DAP-R MRSA strains. Continued progress in understanding the mechanism of restoring susceptibility to beta-lactam antibiotics mediated by the mprF mutation and its impact on beta-lactam combination therapy will provide fundamental insights into treatment of MRSA infections.

13.
BMC Geriatr ; 21(1): 579, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34670516

RESUMO

BACKGROUND: Family doctor policy is an important part of deepening healthcare reform in China. The study aimed to explore the association between cardiovascular-metabolic multimorbidity and the status of signing a contract for family doctor services among the older people in rural Shandong, China. METHODS: A cross-sectional study was conducted in 3 cities of Shandong province, China. A total of 1395 rural residents over 60 years of age were included in this study using a multistage stratified random sampling method. Covariates included demographic and socioeconomic characteristics, health-related characteristics, health service utilization, and awareness of family doctor contract services. The univariate and multivariate regression logistic analysis was used to analyze the data. RESULTS: There were 28.2% of the rural older people contracted for the family doctor contract services. The contract rate of seniors with cardiovascular-metabolic multimorbidity was statistically higher than those without cardiovascular-metabolic multimorbidity (OR = 1.67, 95%CI, 1.21-2.32) after controlling for confounding factors. In addition, occupation, physical activities, self-rated health status, distance from the village clinic, the awareness of family doctor contract services were found to be associated with the signing behavior among the rural older adults. CONCLUSION: This study demonstrated that the rural older people with cardiovascular-metabolic multimorbidity had a higher family doctor contract rate than those without cardiovascular-metabolic multimorbidity, and there was a gap between the current signing rate and the policy goal. To increase the rate of signing for family doctor contract services, the government should take joint efforts to expand the publicity and coverage, and give priority to meeting the healthcare demands of rural older adults with cardiovascular-metabolic multimorbidity.


Assuntos
Multimorbidade , Médicos de Família , Idoso , China/epidemiologia , Estudos Transversais , Humanos , Pessoa de Meia-Idade , População Rural
14.
BMC Fam Pract ; 22(1): 203, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34649515

RESUMO

BACKGROUND: Rural residents with chronic conditions have a stronger need for health services, which should make using family doctor contract services a priority. This study aimed to evaluate the rate of willingness among rural residents with chronic conditions to contract with family doctors and examine its determinants. METHODS: A cross-sectional study was conducted from May, 2018 to June, 2018 in Shandong Province in China. A total of 769 rural unsigned residents with chronic conditions were included in the analysis. Using the Andersen model as the theoretical framework, logistic regression models were chosen to analyse the factors associated with willingness to contract with family doctors. RESULTS: This study found that the rate of willingness to contract with family doctors among chronic patients in rural Shandong was 46.7%. A higher willingness was observed in those living a further distance from the village clinic (more than 600 m: OR = 1.85, 95%CI =1.17-2.93), having received publicity for family doctor contract services (OR = 1.71, 95% CI = 1.06-2.76), reporting need for utilizing a chronic disease management program (OR = 3.36, 95% CI = 2.20-5.23), and reporting need for higher medical insurance reimbursement (OR = 1.91, 95% CI = 1.28-2.83). CONCLUSIONS: The prevalence of contract willingness was relatively low among unsigned rural residents with chronic conditions in rural Shandong, China. The need factors were powerful factors affecting their willingness to contract with family doctors. The government should therefore strengthen targeted publicity and education to rural residents with chronic conditions and provide targeted healthcare services, such as chronic disease management programs and medical services with higher reimbursement rates, to promote their willingness to contract with family doctors.


Assuntos
Médicos de Família , População Rural , China , Doença Crônica , Estudos Transversais , Humanos
15.
J Cosmet Dermatol ; 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34599626

RESUMO

Acne is a common but chronic skin disease that influence large population especially juvenile. Acne can continue, begin, or grow into severe form in adult age, affecting face, back, and chest. It may be a serious issue if not cared or treated timely. Even if acne got treated it leaves a persistent scar, which is difficult to alleviate. These acne lesions are long-lasting and result in significant impact on mental and physical health of an individual. There are four mechanisms that are involved in acne lesion formation. However, the accurate series of events of the interaction among the factors in acne pathogenesis is still unsettled. Pubescent acne is due to increase hormone levels, when in fact adult acne is due to fluctuation in hormone levels. There are various approaches for the treatment of acne, including oral medications, creams or gels, acupuncture. Traditional Chinese Medicine stated acne as a infection that is associated with the pathogenic influence of damp heat and heat on specific meridians. As an ancient and integral part of Chinese medicine acupuncture therapy is employed in the treatment of many diseases including acne. It functions by ameliorating the deep-rooted mechanisms playing crucial role in acne development. In this review, we have explained the acne causes, pathogenesis, and its available treatment options. Additionally, we also discussed the acupuncture therapy methods, devices, different techniques. and its mechanism of action in treating acne. Furthermore, clinical trials studies motivated us to highlight the scope of acupuncture in the growing system of medicine.

16.
Front Plant Sci ; 12: 639431, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34539684

RESUMO

Seed production is critical for watermelon production, which mostly involves first-generation hybrid varieties. However, watermelon hybrid seed production currently requires complex procedures, including artificial isolation and pollination. Therefore, the development and use of a male-sterile system to generate watermelon hybrids can simplify the process. The scarcity of male-sterile watermelon germplasm resources necessitates the use of molecular breeding methods. Unfortunately, the genes responsible for male sterility in watermelon have not been cloned. Thus, the genetic basis of the male sterility remains unknown. In this study, two DNA pools derived from male-sterile and normal plants in the F2 population were used for whole-genome resequencing. The Illumina high-throughput sequencing resulted in 62.99 Gbp clean reads, with a Q30 of 80% after filtering. On the basis of the SNP index association algorithm, eight candidate regions (0.32 Mb) related to specific traits were detected on chromosome 6. Expression pattern analyses and watermelon transformation studies generated preliminary evidence that Cla006625 encodes a pollen-specific leucine-rich repeat protein (ClaPEX1) influencing the male sterility of watermelon. The identification and use of genic male sterility genes will promote watermelon male sterility research and lay the foundation for the efficient application of seed production technology.

17.
Artigo em Inglês | MEDLINE | ID: mdl-34545167

RESUMO

Objective: Defects in the human solute carrier family 26 member 4 (SLC26A4) gene are reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify SLC26A4 mutations in Chinese patients with CH and analyze the function of the mutations. Methods: 273 patients with primary CH were screened for 21 CH candidate genes mutations by targeted next-generation sequencing. All the exons and exon-intron boundaries of SLC26A4 were found and analyzed. The function of 6 missense mutation in SLC26A4 were further investigated in vitro. Results: Among 273 patients with CH, 7 distinct SLC26A4 heterozygous mutations (p.S49R, p.I363L, p.R409H, p.T485M, p.D661E, p.H723R, c.919-2A>G) were identified in 10 patients (3.66%, 10/273). In vitro experiments showed that mutation p.I363L, p.R409H,p.H723R affect the membrane location and ion transport of SLC26A4, ,while p.S49R did not.Mutation p.T485M and p.D661E only affect the ion transport, but has no effect on the membrane location. Conclusion: Our study indicated that the prevalence of SLC26A4 mutations was 3.66% in the Chinese patients with CH. Five mutations (p.I363L, p.R409H, p.T485M, p.D661E and p.H723R) impaired the membrane location or ion transport function of SLC26A4,which revealed important role of the Ile363,Arg409, Thr485, Asp661, His723 residues in function of SLC26A4. Because these mutations are heterozygous mutations, the pathogenesis of these patients cannot be explained, and the pathogenesis of these patients needs further study.

18.
Eur Heart J ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34570211

RESUMO

AIMS: Our previous study demonstrated that Ca2+ influx through the Orai1 store-operated Ca2+ channel in macrophages contributes to foam cell formation and atherosclerosis via the calcineurin-ASK1 pathway, not the classical calcineurin-nuclear factor of activated T-cell (NFAT) pathway. Moreover, up-regulation of NFATc3 in macrophages inhibits foam cell formation, suggesting that macrophage NFATc3 is a negative regulator of atherogenesis. Hence, this study investigated the precise role of macrophage NFATc3 in atherogenesis. METHODS AND RESULTS: Macrophage-specific NFATc3 knockout mice were generated to determine the effect of NFATc3 on atherosclerosis in a mouse model of adeno-associated virus-mutant PCSK9-induced atherosclerosis. NFATc3 expression was decreased in macrophages within human and mouse atherosclerotic lesions. Moreover, NFATc3 levels in peripheral blood mononuclear cells from atherosclerotic patients were negatively associated with plaque instability. Furthermore, macrophage-specific ablation of NFATc3 in mice led to the atherosclerotic plaque formation, whereas macrophage-specific NFATc3 transgenic mice exhibited the opposite phenotype. NFATc3 deficiency in macrophages promoted foam cell formation by potentiating SR-A- and CD36-meditated lipid uptake. NFATc3 directly targeted and transcriptionally up-regulated miR-204 levels. Mature miR-204-5p suppressed SR-A expression via canonical regulation. Unexpectedly, miR-204-3p localized in the nucleus and inhibited CD36 transcription. Restoration of miR-204 abolished the proatherogenic phenotype observed in the macrophage-specific NFATc3 knockout mice, and blockade of miR-204 function reversed the beneficial effects of NFATc3 in macrophages. CONCLUSION: Macrophage NFATc3 up-regulates miR-204 to reduce SR-A and CD36 levels, thereby preventing foam cell formation and atherosclerosis, indicating that the NFATc3/miR-204 axis may be a potential therapeutic target against atherosclerosis.

20.
Cardiovasc Res ; 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34550322

RESUMO

AIMS: Intimal hyperplasia is a common feature of vascular remodeling disorders. Accumulation of synthetic smooth muscle cell (SMC)-like cells is the main underlying cause. Current therapeutic approaches including drug-eluting stents are not perfect due to the toxicity on endothelial cells and novel therapeutic strategies are needed. Our preliminary screening for dysregulated cyclic nucleotide phosphodiesterases (PDEs) in growing SMCs revealed the alteration of PDE10A expression. Herein, we investigated the function of PDE10A in SMC proliferation and intimal hyperplasia both in vitro and in vivo. METHODS AND RESULTS: RT-qPCR, immunoblot, and in situ proximity ligation assay were performed to determine PDE10A expression in synthetic SMCs and injured vessels. We found that PDE10A mRNA and/or protein levels are up-regulated in cultured SMCs upon growth stimulation, as well as in intimal cells in injured mouse femoral arteries. To determine the cellular functions of PDE10A, we focused on its role in SMC proliferation. The anti-mitogenic effects of PDE10A on SMCs were evaluated via cell counting, BrdU incorporation, and flow cytometry. We found that PDE10A deficiency or inhibition arrested the SMC cell cycle at G1-phase with a reduction of cyclin D1. The anti-mitotic effect of PDE10A inhibition was dependent on cGMP-dependent protein kinase Iα (PKGIα), involving C-natriuretic peptide (CNP) and particulate guanylate cyclase natriuretic peptide receptor 2 (NPR2). In addition, the effects of genetic depletion and pharmacological inhibition of PDE10A on neointimal formation were examined in a mouse model of femoral artery wire injury. Both PDE10A knockout and inhibition decreased injury-induced intimal thickening in femoral arteries by at least 50%. Moreover, PDE10A inhibition decreased ex vivo remodeling of cultured human saphenous vein segments. CONCLUSIONS: Our findings indicate that PDE10A contributes to SMC proliferation and intimal hyperplasia at least partially via antagonizing CNP/NPR2/cGMP/PKG1α signaling, and suggest that PDE10A may be a novel drug target for treating vascular occlusive disease. TRANSLATIONAL PERSPECTIVE: Coronary artery disease is currently the leading cause of death worldwide. SMCs are a major contributor to angioplasty restenosis, graft stenosis, and accelerated atherosclerosis. Current therapeutic approaches including drug-eluting stents targeting cell growth still have limitations. By combining studies on cultured SMCs in vitro, animal surgical models in vivo, and a human organ culture model ex vivo, we revealed an important role of PDE10A in modulating SMC proliferation and injury-induced intimal thickening. Given that PDE10A has been proven to be a safe drug target, its inhibition may represent a novel therapeutic strategy for vascular diseases associated with intimal hyperplasia.

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