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1.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1867(1): 159059, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34619367

RESUMO

Eicosapentaenoic acid (EPA) ethyl esters are of interest given their clinical approval for lowering circulating triglycerides and cardiometabolic disease risk. EPA ethyl esters prevent metabolic complications driven by a high fat diet in male mice; however, their impact on female mice is less studied. Herein, we first investigated how EPA influences the metabolic profile of female C57BL/6J mice consuming a high fat diet. EPA lowered murine fat mass accumulation, potentially through increased biosynthesis of 8-hydroxyeicosapentaenoic acid (HEPE), as revealed by mass spectrometry and cell culture studies. EPA also reversed the effects of a high fat diet on circulating levels of insulin, glucose, and select inflammatory/metabolic markers. Next, we studied if the improved metabolic profile of obese mice consuming EPA was associated with a reduction in the abundance of key gut Gram-negative bacteria that contribute toward impaired glucose metabolism. Using fecal 16S-ribosomal RNA gene sequencing, we found EPA restructured the gut microbiota in a time-dependent manner but did not lower the levels of key Gram-negative bacteria. Interestingly, EPA robustly increased the abundance of the Gram-negative Akkermansia muciniphila, which controls glucose homeostasis. Finally, predictive functional profiling of microbial communities revealed EPA-mediated reversal of high fat diet-associated changes in a wide range of genes related to pathways such as Th-17 cell differentiation and PI3K-Akt signaling. Collectively, these results show that EPA ethyl esters prevent some of the deleterious effects of a high fat diet in female mice, which may be mediated mechanistically through 8-HEPE and the upregulation of intestinal Akkermansia muciniphila.

3.
Oncogene ; 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34819634

RESUMO

N6-methyladenosine (m6A), the most abundant mRNA modification in mammals, is involved in the metabolism of mRNA. KIAA1429 is regarded as the largest m6A methyltransferase and plays an important role in m6A modification. However, the prognostic value and function of KIAA1429 in colorectal cancer (CRC) are unclear. Quantitative real-time PCR and immunohistochemical assays were performed to evaluate the expression of KIAA1429 in CRC tissues. Kaplan-Meier survival curves and log-rank tests were used to assess the association between KIAA1429 expression and the prognosis of patients with CRC. CCK-8 assays, colony formation assays, cell cycle assays, and xenograft experiments were performed to investigate the effect of KIAA1429 on cell proliferation. RNA immunoprecipitation, methylated RNA immunoprecipitation assays, and RNA stability assays were conducted to explore the underlying mechanism. KIAA1429 was significantly upregulated in CRC tissues compared with adjacent normal tissues. Patients with higher expression of KIAA1429 had shorter overall survival than those with lower expression. Functionally, KIAA1429 promoted CRC cell proliferation in vitro and in vivo. Mechanistically, KIAA1429 negatively regulated the expression of WEE1 by decreasing its stability in an m6A-independent manner by binding to the third segment in the 3'-UTR of WEE1 mRNA. Moreover, butyrate decreased the expression of KIAA1429 by downregulating the level of the transcription factor NFκB1. Our findings indicated that KIAA1429 plays an oncogenic role in CRC cells by inhibiting the expression of WEE1 in an m6A-independent manner and is associated with poor survival in CRC patients. These results suggested that KIAA1429 might be a potential prognostic marker for CRC.

4.
Microb Pathog ; 161(Pt B): 105284, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34767930

RESUMO

Chlamydia pneumoniae (Cpn) has been reported to be involved in the pathogenesis of early atherosclerosis by inducing macrophage-derived foam cell formation in the presence of low-density lipoprotein (LDL). However, the biochemical mechanisms underlying Cpn-induced foam cell formation are still not fully elucidated. The present study showed that in LDL-treated THP-1-derived macrophages, Cpn not only upregulated the expression of scavenger receptor A1 (SR-A1) and acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1), but it also downregulated the expression of ATP binding cassette transporters (ABCA1 and ABCG1) at both the mRNA and protein levels. These processes facilitated cholesterol accumulation and promoted macrophage-derived foam cell formation. Treatment with the peroxisome proliferator-activated receptor (PPAR)-γ agonist rosiglitazone or the PPARα agonist fenofibrate decreased the number of foam cells induced by Cpn, while the PPARγ antagonist GW9662, the PPARα antagonist MK886, or PPARα/γ siRNAs enhanced the effect of Cpn on foam cell formation and gene expression of SR-A1, ACAT1, and ABCA1/G1. Moreover, the PPARγ agonist rosiglitazone reversed the downregulation of CD36 by Cpn, while PPARγ siRNA and the PPARγ inhibitor GW9662 further suppressed CD36 expression. However, the PPARα agonist, inhibitor, and siRNA all showed no effect on CD36 expression. In conclusion, the PPARα and PPARγ pathways are both involved in Cpn-induced macrophage-derived foam cell formation by upregulating SR-A1 and ACAT1 and downregulating ABCA1/G1 expression.

5.
Mol Ecol Resour ; 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34652864

RESUMO

Rhododendron henanense subsp. lingbaoense (hereafter referred to as R. henanense) is an endemic species naturally distributed in the Henan province, China, with high horticultural, ornamental and medicinal value. Herein, we report a de novo genome assembly for R. henanense using a combination of PacBio long read and Illumina short read sequencing technologies. In total, we assembled 634.07 Mb with a contig N50 of 2.5 Mb, representing ~96.93% of the estimated genome size. By applying Hi-C data, 13 pseudochromosomes of R. henanense genome were assembled, covering ~98.21% of the genome assembly. The genome was composed of ~65.76% repetitive sequences and 31,098 protein-coding genes, 88.77% of which could be functionally annotated. Rhododendron henanense displayed a high level of synteny with other Rhododendron species from the Hymenanthes subgenus. Our data also suggests that R. henanense genes related to stress responses have undergone expansion, which may underly the unique abiotic and biotic stress resistance of the species. This alpine Rhododendron chromosome-scale genome assembly provides fundamental molecular resources for germplasm conservation, breeding efforts, evolutionary studies, and elucidating the unique biological characteristics of R. henanense.

6.
J Biomater Appl ; : 8853282211051501, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34708663

RESUMO

OBJECTIVE: We sought to determine the biocompatibility of electrospun regenerated silk fibroin (RSF) mats with inner ear progenitors, especially their effect on the differentiation of inner ear progenitors into hair cells. METHODS: Neonatal mouse cochleae (n = 20) were collected and digested and allowed to form spheres over several days. Cells digested from the spheres were then seeded onto aligned or random RSF mats, with laminin-coated coverslips serving as controls. The inner ear progenitor cell mortality was examined by TUNEL labeling, and the adhesion of cells to the RSF mats or coverslip was determined by scanning electron microscopy. Finally, the number of hair cells that differentiated from inner ear progenitors was determined by Myosin7a expression. Unpaired Student's t-tests and one-way ANOVA followed by a Dunnett's multiple comparisons test were used in this study (p < 0.05). RESULTS: After 5 days of culture, the inner ear progenitors had good adhesion to both the aligned and random RSF mats and there was no significant difference in TUNEL+ cells between the mats compared to the coverslip (p > 0.05). After 7 days of in vitro differentiation culture, the percentage of differentiated hair cells on the control, aligned, and random RSF mats was 2.5 ± 0.5%, 2.7 ± 0.4%, and 2.4 ± 0.2%, respectively, and there was no significant difference between Myosin7a+ cells on either RSF mat compared to controls (p > 0.05). CONCLUSION: The aligned and random RSF mats had excellent biocompatibility with inner ear progenitors and helped the inner ear progenitors maintain their stemness. Our results thus indicate that RSF mats represent a useful scaffold for the development of new strategies for inner ear tissue engineering research.

7.
Eur J Med Chem ; 227: 113871, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638033

RESUMO

The ubiquitination of the hypoxia-inducible factor-1α (HIF-1α) is mediated by interacting with the von Hippel-Lindau protein (VHL), and is associated with cancer, chronic anemia, and ischemia. VHL, an E3 ligase, has been reported to degrade HIF-1 for decades, however, there are few successful inhibitors currently. Poor understanding of the binding pocket and a lack of in-depth exploration of the interactions between two proteins are the main reasons. Hence, we developed an effective strategy to identify and design new inhibitors for protein-protein interaction targets. The hydroxyproline (Hyp564) of HIF-1α contributed the key interaction between HIF-1α and VHL. In this study, detailed information of the binding pocket were explored by alanine scanning, site-directed mutagenesis and molecular dynamics simulations. Interestingly, we found the interaction(s) between Y565 and H110 played a key role in the binding of VHL/HIF-1α. Based on the interactions, 8 derivates of VH032, 16a-h, were synthesized by introducing various groups bounded to H110. Further assay on protein and cellular level exhibited that 16a-h accessed higher binding affinity to VHL and markable or modest improvement in stabilization of HIF-1α or HIF-1α-OH in HeLa cells. Our work provides a new orientation for the modification or design of VHL/HIF-1α protein-protein interaction inhibitors.

8.
Plant Biotechnol J ; 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34665915

RESUMO

Seed vigour is an imperative trait for the direct seeding of rice. In this study, we examined the genetic regulation of seedling percentage at the early germination using a genome-wide association study in rice. One major quantitative trait loci qSP3 for seedling percentage was identified, and the candidate gene was validated as qSP3, encoding a cupin domain protein OsCDP3.10 for the synthesis of 52 kDa globulin. Disruption of this gene in Oscdp3.10 mutants reduced the seed vigour, including the germination potential and seedling percentage, at the early germination in rice. The lacking accumulation of 52 kDa globulin was observed in the mature grains of the Oscdp3.10 mutants. The significantly lower amino acid contents were observed in the mature grains and the early germinating seeds of the Oscdp3.10 mutants compared with those of wild-type. Rice OsCDP3.10 regulated seed vigour mainly via modulating the amino acids e.g. Met, Glu, His, and Tyr that contribute to hydrogen peroxide (H2 O2 ) accumulation in the germinating seeds. These results provide important insights into the application of seed priming with the amino acids and the selection of OsCDP3.10 to improve seed vigour in rice.

9.
Laryngoscope ; 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34591990

RESUMO

OBJECTIVES/HYPOTHESIS: Vocal fold (VF) fibroblasts are the central target for developing new strategies for the treatment of VF scarring and fibrosis. Asiatic acid (AA) is a triterpenoid derivate with antifibrotic properties. However, the effect of AA in VF scarring is poorly understood. The objective of this study was to investigate the potential application of AA as a therapeutic treatment in VF scarring. STUDY DESIGN: Xxxxx. METHODS: The functional expression of SMAD7 was knocked down with recombinant adenoviruses and adeno-associated viruses carrying shRNAs in the in vitro and in vivo models, which were constructed to investigate AA's antifibrotic function. The expression of collagens and SMADs in cultured human and rabbit cell lines and animal models was evaluated with quantitative reverse transcription polymerase chain reaction and immunohistochemistry labeling, respectively. Cell migration capacity and contraction in VF fibroblast cell lines were also evaluated. RESULTS: AA downregulated the downstream fibrotic activation in a dose-dependent manner. Meanwhile, AA attenuated VF scarring/fibrosis by reducing collagen deposition. Furthermore, the antifibrotic effects of AA were associated with the upregulation of SMAD7. In contrast, knockdown of SMAD7 inhibited the effect of AA on transforming growth factor-beta-1 (TGF-ß1) stimulation, which suggests a central role for SMAD7 in AA-induced antifibrotic activities during VF fibrosis. CONCLUSION: We concluded that AA, which is a novel therapeutic candidate for preventing VF scarring/fibrosis, might exert its antifibrotic effect via the TGF-ß1/SMAD signaling pathway. LEVEL OF EVIDENCE: N/A Laryngoscope, 2021.

10.
Nutr Neurosci ; : 1-17, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34565305

RESUMO

OBJECTIVE: Western diet consumption during adolescence results in hippocampus (HPC)-dependent memory impairments and gut microbiome dysbiosis. Whether these adverse outcomes persist in adulthood following healthy dietary intervention is unknown. Here we assessed the short- and long-term effects of adolescent consumption of a Western diet enriched with either sugar or both sugar and fat on metabolic outcomes, HPC function, and gut microbiota. METHODS: Adolescent female rats (PN 26) were fed a standard chow diet (CHOW), chow with access to 11% sugar solution (SUG), or a junk food cafeteria-style diet (CAF) containing various foods high in fat and/or sugar. During adulthood (PN 65+), metabolic outcomes, HPC-dependent memory, and gut microbial populations were evaluated. In a subsequent experiment, these outcomes were evaluated following a 5-week dietary intervention where CAF and SUG groups were maintained on standard chow alone. RESULTS: Both CAF and SUG groups demonstrated impaired HPC-dependent memory, increased adiposity, and altered gut microbial populations relative to the CHOW group. However, impaired peripheral glucose regulation was only observed in the SUG group. When examined following a healthy dietary intervention in a separate experiment, metabolic dysfunction was not observed in either the CAF or SUG group, whereas HPC-dependent memory impairments were observed in the CAF but not the SUG group. In both groups the composition of the gut microbiota remained distinct from CHOW rats after the dietary intervention. CONCLUSIONS: While the metabolic impairments associated with adolescent junk food diet consumption are not present in adulthood following dietary intervention, the HPC-dependent memory impairments and the gut microbiome dysbiosis persist.

11.
Artigo em Inglês | MEDLINE | ID: mdl-34498048

RESUMO

PURPOSE: We assessed the effect of untreated HIV infection as well as different antiretroviral therapy (ART) on the metabolome/lipidome. METHODS: Widely-targeted plasma metabolomic and lipidomic profiling was performed on HIV-seronegative individuals and persons living with HIV (PLHIV) before and after initiating ART [tenofovir/emtricitabine plus atazanavir/ritonavir (ATV/r) or darunavir/ritonavir (DRV/r) or raltegravir (RAL)]. Orthogonal partial least squares discriminant analysis was used to assess metabolites/lipid subspecies that discriminated between groups. Graphical lasso estimated group-specific metabolite/lipid subspecies networks associated with the Homeostatic Model Assessment-Insulin Resistance (HOMA-IR). Correlations between inflammatory markers and metabolites/lipid subspecies were visualized using heat maps. RESULTS: Of 435 participants, 218 were PLHIV. Compared to HIV-seronegative individuals, ART-naïve PLHIV exhibited higher levels of saturated triaclyglycerols (TAGs) and 3-hydroxy-kynurenine, lower levels of unsaturated TAGs and N-acetyl-tryptophan, and a sparser and less heterogeneous network of metabolites/lipid subspecies associated with HOMA-IR. PLHIV on RAL vs. ATV/r or DRV/r had lower saturated and unsaturated TAGs. Positive correlations were found between medium-long chain acylcarnitines (C14-C6 ACs), palmitate and HOMA-IR for RAL but not ATV/r or DRV/r. Stronger correlations were seen for TAGs with IL-6 and hsCRP after RAL vs ATV/r or DRV/r initiation; these correlations were absent in ART-naïve PLHIV. CONCLUSION: Alterations in the metabolome/lipidome suggest increased lipogenesis for ART-naïve PLHIV vs. HIV-seronegative individuals, increased TAG turnover for RAL vs. ATV/r or DRV/r, and increased inflammation associated with this altered metabolome/lipidome after initiating ART. Future studies are needed to understand cardiometabolic consequences of lipogenesis and inflammation in PLHIV.

12.
Adv Healthc Mater ; 10(22): e2101260, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34523248

RESUMO

Understanding the bionanoscale recognition of nanostructured architectures is critical to the design and application of nanomaterials, but the related information is not well understood. In this study, it is found that bionanoscale recognition underlies cell fate and therapy. For example, 1T phase (octahedral coordination) monolayer MoS2 exhibits a markedly stronger affinity for fibronectin than the 2H structure (triangular prism coordination) and promotes cell spreading and differentiation. The van der Waals energy and increased turn components contribute to the high adhesion of fibronectin onto the 1T-MoS2 structure. 1T-MoS2 exhibits a significantly stronger affinity (KD , 6.59 × 10-7 m) for liposomes than 2H-MoS2 (1.21 × 10-6 m) due to strong hydrophobic interactions. The existence of octahedrally coordinated atomic structures that improve cell viability by enhancing the neurite length is first proven by random forest and structural equation models. Consequently, octahedral coordination disaggregates α-synuclein (e.g., by decreasing ß-sheets and increasing coil structures) and protects cells and hosts against Parkinson's disease. As a proof-of-principle demonstration, these findings indicate that bionanoscale recognition underlies the design of biomaterials and cell therapeutics.


Assuntos
Nanoestruturas , Diferenciação Celular , Modelos Teóricos
13.
Theor Appl Genet ; 134(12): 4067-4076, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34546380

RESUMO

KEY MESSAGE: A candidate gene cytochrome b5 for the major QTL qSRMP9 for rice seed reserve mobilization was validated during seed germination using a genome-wide association study approach. Seed reserve mobilization plays important roles in the early seedling growth in rice. However, the genetic basis underlying this process is poorly understood. In this study, the genetic architecture of variation in seed reserve mobilization during seed germination was studied using a genome-wide association study approach in rice. Three quantitative trait loci (QTL) including qSRMP6, qSRMP9, and qSRMP12 for seed reserve mobilization percentage were identified. In which, the candidate gene cytochrome b5 (OsCyb5) for the major QTL qSRMP9 was validated. Disruption of this gene in Oscyb5 mutants reduced the seed reserve mobilization and seedling growth compared with wild-type (WT) in rice. There were no significant differences of grain size, starch, protein and total soluble sugar content in the mature grains between Oscyb5 mutants and WT. However, the α-amylase activity in the germinating seeds of Oscyb5 mutants was significantly decreased compared to that of WT, and then, the starch and sugar mobilization and the glucose accumulation during seed germination were significantly decreased in Oscyb5 mutants. Two elite haplotypes of OsCyb5 associated with the higher seed reserve mobilization percentage and its elite single nucleotide polymorphism variations were mainly existed in the INDICA and AUS accessions. The natural variation of OsCyb5 contributing to seed reserve mobilization might be useful for the future rice breeding.

14.
RSC Med Chem ; 12(7): 1232-1238, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34355187

RESUMO

The oncoprotein and Parkinson's disease-associated enzyme DJ-1/PARK7 has emerged as a promiscuous deglycase that can remove methylglyoxal-induced glycation adducts from both proteins and nucleotides. However, dissecting its structural and enzymatic functions remains a challenge due to the lack of potent, specific, and pharmacokinetically stable inhibitors targeting its catalytic site (including Cys106). To evaluate potential drug-like leads against DJ-1, we leveraged its deglycase activity in an enzyme-coupled, fluorescence lactate-detection assay based on the recent understanding of its deglycation mechanism. In addition, we developed assays to directly evaluate DJ-1's esterase activity using both colorimetric and fluorescent substrates. The resulting optimized assay was used to evaluate a library of potential reversible and irreversible DJ-1 inhibitors. The deglycase activity-oriented screening strategy described herein establishes a new platform for the discovery of potential anti-cancer drugs.

15.
J Pediatr Pharmacol Ther ; 26(6): 624-631, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421413

RESUMO

OBJECTIVE: Combination antifungal therapy (CAF) may be prescribed to treat invasive fungal infections (IFIs). Data on the incidence of CAF among the pediatric population are limited. Antimicrobial stewardship for CAF includes therapeutic drug monitoring (TDM) and monitoring for adverse events. Primary outcome was to determine the incidence of CAF prescribed for documented proven, probable, and possible IFI. Secondary outcomes were to determine initial dose of antifungal therapy, determine incidence of adverse events, and evaluate our practice of TDM. METHODS: Medical charts of patients who received CAF for proven, probable, or possible IFI within 6 years were reviewed. Patients age ≤18 years, prescribed CAF (defined as a second antifungal therapy started ≤72 hours of initial antifungal therapy) for at least 72 hours, and with normal liver function test results were included. RESULTS: 57 patients received CAF for 72 separate episodes: 35 episodes were proven IFI, 11 were probable IFI, and 26 were possible IFI. Initial dose of antifungal therapy varied, and 29.1% received a loading dose. A total of 10 patients experienced 14 adverse events that were related to antifungal therapy. In 63.8% of CAF episodes, TDM was conducted. Target antifungal concentrations were documented for 10 CAF episodes. Reason for discontinued of CAF was documented for 35 episodes. Of these episodes, 74% were discontinued after therapeutic antifungal concentrations were achieved. CONCLUSIONS: There are opportunities for antimicrobial stewardship interventions in the method of TDM and monitoring for adverse events that could aid in management of CAF.

16.
Arthritis Rheumatol ; 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34423918

RESUMO

OBJECTIVE: To test the hypothesis that an altered gut microbiota (dysbiosis) plays a role in obesity-associated osteoarthritis (OA). METHODS: Stool and blood samples were collected from 92 participants with BMI ≥ 30 kg/m2 recruited from the Johnston County Osteoarthritis Project. OA cases (n=50) had hand plus knee OA (Kellgren-Lawrence [KL] grade ≥2 or arthroplasty). Controls (N=42) had no hand OA and KL grade 0-1 knees. Compositional analysis of stool samples was carried out by 16S rRNA amplicon sequencing. Alpha and beta diversity and differences in taxa relative abundances were determined. Blood samples were used for multiplex cytokine analysis and measures of lipopolysaccharide (LPS) and LPS binding protein. Germ-free mice were gavaged with case or control pooled fecal samples and placed on a 40% fat, high sucrose diet for 40 weeks. Knee OA was evaluated histologically. RESULTS: OA cases were slightly older with more females and higher BMI, WOMAC pain and KL grades than controls. There were no significant differences in alpha or beta diversity or genus level composition between cases and controls. Cases had higher plasma levels of osteopontin (p=0.01) and serum LPS (p<0.0001). Mice transplanted with case or control microbiota exhibited a significant difference in alpha diversity (p=0.02) and beta diversity but no differences in OA severity. CONCLUSION: The lack of differences in the gut microbiota yet increased serum LPS levels suggest the possibility that increased intestinal permeability allowing for greater absorption of LPS, rather than a dysbiotic microbiota, may contribute to development of OA associated with obesity.

17.
Pediatr Res ; 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446848

RESUMO

BACKGROUND: Early-life metabolic derangements in HIV-exposed uninfected (HEU) infants have been reported. METHODS: Pregnant women with HIV and HIV-uninfected pregnant women were enrolled with their newborns in a US cohort from 2011 to 2015. We measured cord insulin, C-peptide, and metabolic cytokines of HEU and HIV-unexposed uninfected (HUU) newborns using ELISA and metabolites, lipid subspecies, and eicosanoids via liquid chromatography/mass spectrometry. Linear regression was employed to assess the association of intrauterine HIV/ART with insulin and C-peptide. Graphical lasso regression was used to identify differences between metabolite/lipid subspecies networks associated with C-peptide. RESULTS: Of 118 infants, 56 were HEU, ART exposed. In adjusted analyses, mean cord insulin (ß = 0.295, p = 0.03) and C-peptide (ß = 0.522, p < 0.01) were significantly higher in HEU vs. HUU newborns. HEU neonates exhibited primarily positive associations between complex lipids and C-peptide, indicative of fuel storage, and augmented associations between cord eicosanoids and cytokines. HUU neonates exhibited negative associations with lipids and C-peptide indicative of increased fuel utilization. CONCLUSION: Higher cord insulin and C-peptide in HEU vs. HUU newborns as well as differences in cord metabolites, metabolic-related cytokines, and eicosanoids may reflect a propensity for fuel storage and an inflammatory milieu suggestive of fetal metabolic changes associated with in utero HIV/ART exposure. IMPACT: There is a paucity of studies assessing cord blood and neonatal metabolic health in HIV-exposed uninfected (HEU) newborns, an increasing population worldwide. Compared to HIV-unexposed uninfected (HUU) newborns, HEU newborns exhibit alterations in fuel homeostasis and an inflammatory milieu associated with in utero HIV/antiretroviral therapy (ART) exposure. The long-term implications of these neonatal findings are as yet unknown, but merit continued evaluation as this important and growing population ages into adulthood.

18.
Plant J ; 108(2): 478-491, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34376020

RESUMO

Seed vigor is an important trait for the direct seeding of rice (Oryza sativa L.). In this study, we examined the genetic architecture of variation in the germination rate using a diverse panel of rice accessions. Four quantitative trait loci for germination rate were identified using a genome-wide association study during early germination. One candidate gene, encoding the 2-oxoglutarate/malate translocator (OsOMT), was validated for qGR11. Disruption of this gene (Osomt mutants) reduced seed vigor, including seed germination and seedling growth, in rice. Functional analysis revealed that OsOMT influences seed vigor mainly by modulating amino acid levels and glycolysis and tricarboxylic acid cycle processes. The levels of most amino acids, including the Glu family (Glu, Pro, Arg, and GABA), Asp family (Asp, Thr, Lys, Ile, and Met), Ser family (Ser, Gly, and Cys), and others (His, Ala, Leu, and Val), were significantly reduced in the mature grains and the early germinating seeds of Osomt mutants compared to wild type (WT). The glucose and soluble sugar contents, as well as adenosine triphosphate levels, were significantly decreased in germinating seeds of Osomt mutants compared to WT. These results provide important insights into the role of OsOMT in seed vigor in rice.

19.
Sci Adv ; 7(29)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34272236

RESUMO

Niemann-Pick C1-like 1 (NPC1L1) protein plays a central role in the intestinal cholesterol absorption and is the target of a drug, ezetimibe, which inhibits NPC1L1 to reduce cholesterol absorption. Here, we present cryo-electron microscopy structures of human NPC1L1 in apo state, cholesterol-enriched state, and ezetimibe-bound state to reveal molecular details of NPC1L1-mediated cholesterol uptake and ezetimibe inhibition. Comparison of these structures reveals that the sterol-sensing domain (SSD) could respond to the cholesterol level alteration by binding different number of cholesterol molecules. Upon increasing cholesterol level, SSD binds more cholesterol molecules, which, in turn, triggers the formation of a stable structural cluster in SSD, while binding of ezetimibe causes the deformation of the SSD and destroys the structural cluster, leading to the inhibition of NPC1L1 function. These results provide insights into mechanisms of NPC1L1 function and ezetimibe action and are of great significance for the development of new cholesterol absorption inhibitors.

20.
Environ Sci Technol ; 55(14): 9938-9948, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34232619

RESUMO

The application of graphene-based nanomaterials (GBNs) has attracted global attention in various fields, and understanding defense mechanisms against the phytotoxicity of GBNs is crucial for assessing their environmental risks and safe-by-design. However, the related information is lacking, especially for edible vegetable crops. In the present study, GBNs (0.25, 2.5, and 25 mg/kg plant fresh weight) were injected into the stems of pepper plants. The results showed that the plant defense was regulated by reducing the calcium content by 21.7-48.3%, intercellular CO2 concentration by 12.0-35.2%, transpiration rate by 8.7-40.2%, and stomatal conductance by 16.9-50.5%. The defense pathways of plants in response to stress were further verified by the downregulation of endocytosis and transmembrane transport proteins, leading to a decrease in the nanomaterial uptake. The phytohormone gibberellin and abscisic acid receptor PYL8 were upregulated, indicating the activation of defense systems. However, reduced graphene oxide and graphene oxide quantum dots trigger stronger oxidative stress (e.g., H2O2 and malondialdehyde) than graphene oxide in fruits due to the breakdown of antioxidant defense systems (e.g., cytochrome P450 86A22 and P450 77A1). Both nontargeted proteomics and metabolomics consistently demonstrated that the downregulation of carbohydrate and upregulation of amino acid metabolism were the main mechanisms underlying the phytotoxicity and defense mechanisms, respectively.


Assuntos
Grafite , Nanoestruturas , Mecanismos de Defesa , Grafite/toxicidade , Peróxido de Hidrogênio , Estresse Oxidativo
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