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1.
Am J Sports Med ; 48(10): 2481-2488, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32736506

RESUMO

BACKGROUND: The molecular mechanism of how femoroacetabular impingement (FAI) morphology leads to hip osteoarthritis (OA) is yet to be determined. The expression and location of inflammation-related molecules during early- and late-stage FAI have not been previously described. Moreover, the characterization of intra-articular inflammation away from the cam deformity as well as the nature of adjacent synovial tissue have also not been extensively reported. HYPOTHESIS: Early-stage FAI has a similar expression of inflammation-related markers in the head-neck and acetabular cartilage but less synovitis than late-stage FAI. STUDY DESIGN: Controlled laboratory study. METHODS: Head-neck cartilage, acetabular cartilage, and synovial samples were obtained from patients undergoing hip preservation surgery for the treatment of symptomatic cam FAI (early FAI group; n = 15) and advanced OA secondary to cam FAI (late FAI group; n = 15). Samples procured from healthy young adult donors served as the control group (n = 7). Cartilage degeneration was assessed by histology, and the expression of inflammation-related proteins (interleukin-1 beta [IL-1ß], matrix metalloproteinase-13 [MMP-13], a disintegrin and metalloproteinase with thrombospondin motifs-4 [ADAMTS-4], type II collagen [COL2], and aggrecan neoepitope [NITEGE]) was measured by immunostaining. Synovial samples in the early and late FAI groups were examined for synovitis and the expression of IL-1ß. RESULTS: Head-neck cartilage in the early FAI group showed significantly more degeneration than the control group and an increased expression of inflammation-related proteins (IL-1ß: 69.7% ± 18.1% vs 20.2% ± 4.9%, respectively; MMP-13: 79.6% ± 12.6% vs 25.3% ± 9.5%; ADAMTS-4: 83.9% ± 12.2% vs 24.3% ± 11.1%; NITEGE: 89.7% ± 7.7% vs 39.8% ± 20.5%) (P < .001). Head-neck and acetabular cartilage in the early and late FAI groups showed a similar degree of degeneration. Moreover, a similar expression of inflammation-related proteins was observed between the early and late FAI groups for head-neck cartilage (IL-1ß: 69.7% ± 18.1% vs 72.5% ± 13.2%; MMP-13: 79.6% ± 12.6% vs 71.4% ± 18.8%; ADAMTS-4: 83.9% ± 12.2% vs 82.6% ± 12.5%; COL2: 93.6% ± 3.9% vs 92.5% ± 5.8%; NITEGE: 89.7% ± 7.7% vs 95.7% ± 4.7%) and acetabular cartilage (IL-1ß: 83.3% ± 24.8% vs 80.7% ± 15.6%; MMP-13: 94.3% ± 9.7% vs 85.2% ± 12.3%; ADAMTS-4: 98.5% ± 2.3% vs 98.4% ± 3.4%; COL2: 99.8% ± 0.7% vs 99.7% ± 1.1%; NITEGE: 96.7% ± 6.7% vs 99.2% ± 2.2%). In contrast, synovitis was minimal with a low expression of IL-1ß in the early FAI group compared with the late FAI group. CONCLUSION: Hip cartilage exhibited an OA phenotype in patients with early-stage FAI, similar to what was observed in hip OA secondary to FAI. Severe synovitis was only evident with late-stage FAI. CLINICAL RELEVANCE: This study supports the concept that early hip impingement is associated with cartilage degeneration and catabolism.

2.
Transl Psychiatry ; 10(1): 209, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32606422

RESUMO

We conducted a cross-trait meta-analysis of genome-wide association study on schizophrenia (SCZ) (n = 65,967), bipolar disorder (BD) (n = 41,653), autism spectrum disorder (ASD) (n = 46,350), attention deficit hyperactivity disorder (ADHD) (n = 55,374), and depression (DEP) (n = 688,809). After the meta-analysis, the number of genomic loci increased from 14 to 19 in ADHD, from 3 to 10 in ASD, from 45 to 57 in DEP, from 8 to 54 in BD, and from 64 to 87 in SCZ. We observed significant enrichment of overlapping genes among different disorders and identified a panel of cross-disorder genes. A total of seven genes were found being commonly associated with four out of five psychiatric conditions, namely GABBR1, GLT8D1, HIST1H1B, HIST1H2BN, HIST1H4L, KCNB1, and DCC. The SORCS3 gene was highlighted due to the fact that it was involved in all the five conditions of study. Analysis of correlations unveiled the existence of two clusters of related psychiatric conditions, SCZ and BD that were separate from the other three traits, and formed another group. Our results may provide a new insight for genetic basis of the five psychiatric disorders.

3.
Sci Rep ; 10(1): 12326, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32704112

RESUMO

The clinical features of EBV-positive diffuse large B cell lymphoma (DLBCL) indicate a poorer prognosis than EBV-negative DLBCL. Currently, there is no efficacious drug for EBV-positive DLBCL. The cytokine interleukin-21 (IL-21) has been reported to be pro-apoptotic in DLBCL cell lines and is being explored as a new therapeutic strategy for this type of lymphomas. However, our previous studies showed that IL-21 stimulation of EBV-positive DLBCL cell lines leads to increased proliferation. Here, analysis of a rare clinical sample of EBV-positive DLBCL, in combination with a NOD/SCID mouse xenograft model, confirmed the effect of IL-21 on the proliferation of EBV-positive DLBCL cells. Using RNA-sequencing, we identified the pattern of differentially-expressed genes following IL-21 treatment and verified the expression of key genes at the protein level using western blotting. We found that IL-21 upregulates expression of the host MYC and AP-1 (composed of related Jun and Fos family proteins) and STAT3 phosphorylation, as well as expression of the viral LMP-1 protein. These proteins are known to promote the G1/S phase transition to accelerate cell cycle progression. Furthermore, in NOD/SCID mouse xenograft model experiments, we found that IL-21 treatment increases glucose uptake and angiogenesis in EBV-positive DLBCL tumours. Although more samples are needed to validate these observations, our study reconfirms the adverse effects of IL-21 on EBV-positive DLBCL, which has implications for the drug development of DLBCL.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32633130

RESUMO

Unbalanced charge injection is one of the major issues that hampers the efficiency of perovskite light-emitting diodes (PeLEDs). Through engineering the device structure with multiple hole transport layers (HTLs), i.e. poly (9,9-dioctyl-fluorene-co-N-(4-butylphenyl) dipheny-lamine) (TFB)/poly(9-vinylcarbazole) (PVK) and nickel oxide (NiOx)/TFB/PVK, efficient PeLED devices have been successfully demonstrated. However, in a typical solution-processed PeLED with multiple HTLs, the underlying conjugated HTL could be easily re-dissolved by the ink of the following one, which not only dramatically deteriorates the electrical property of HTLs, but also influences the quality of the top perovskite films. In this work, through inserting a thin atomic layer deposited aluminum oxide (Al2O3) layer between HTLs and perovskite layer, an improved interfacial contact can be achieved, which enables us to obtain perovskite films with enhanced characteristics and balanced charge injection in the resultant PeLEDs. In addition, because of the proper refractive index (r), the presence of Al2O3 layer also favors the light out-coupling of PeLEDs. As a result, we fabricate green PeLEDs with good repeatability and an external quantum efficiency of 17.0%, which is approximately 60% higher than that of the control device without Al2O3. Our work provides a promising avenue to enhance interfacial contact between charge transport layer and perovskite for efficient perovskites-based optoelectronic devices.

6.
Transl Psychiatry ; 10(1): 234, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665544

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32689788

RESUMO

Great progress in modification and optimization of the emission layer (EML) in the perovskite light emitting diodes (PeLEDs) results in a significant improvement in the device efficiency. However, so far less attention has been paid on the exploration of hole/electron injection and transporting layers to maximize the utilization of the charge carriers for efficient and stable PeLEDs. At present, the low electron mobility of the electron transport layer (ETL) causes an unbalanced charge injection, and the defects at the ETL/perovskite interface limits the formation and utilization of generated excitons. Here, a series of compounds (BPBiTP, BPBiPN, and BPBiPA) flanked by diphenyl-1H-benzo[d]imidazole end groups have been developed as ETL materials, where the bridging units (benzene, naphthalene, anthracene) are manipulated to achieve dual functionality, namely the high charge carrier mobility and effective passivation of perovskite surface. The coordinating end groups effectively reduce the trap state density at the interface of ETL and EML due to their strong nucleophilic quality. H-aggregation of anthracene units and large transfer integral in BPBiPA leads to its superior electron mobility of 8.4 ×10-4 cm2V-1s-1 in the solid state, over one order higher than that of the typical one (TPBi). Consequently, green PeLEDs yielding maximum external quantum efficiency (EQE) of 19.7% with reduced efficiency roll-off as well as extended operational lifetime have been achieved without any out-coupling technique. Our result demonstrated that optimization of ETL materials via improving both passivation capability and electron mobility is a powerful strategy for high performance PeLEDs.

8.
Epigenomics ; 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32700969

RESUMO

Aim: To illustrate the expression profile of transfer RNA-derived fragments and reveal their putative role in the pathogenesis of diabetic cataract (DC) rats. Materials & methods: Small RNA sequencing was conducted in the lens epithelium of rats lens. The data were validated by quantitative real-time PCR, and bioinformatic analysis was performed to explore the roles of the fragments in DC pathogenesis. Results: A total of 213 differentially expressed tRNA-related fragments were identified, in which 111 were upregulated and 102 were downregulated in DC rats. Bioinformatics analysis revealed that several associated pathways might participate in the development of DC rats. Conclusion: tRNA-derived fragments may be involved in the pathogenesis of DC rats.

9.
Oxid Med Cell Longev ; 2020: 2308017, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655762

RESUMO

This study demonstrates that Thelephora ganbajun had a strong ability to absorb zinc, and zinc can be compartmentally stored in the small vesicles and mainly accumulated in the form of zinc-enriched polysaccharides (zinc content was 25.0 ± 1.27 mg/g). Mycelia zinc polysaccharides (MZPS) and its fractions were isolated. The main fraction (MZPS-2) with the highest antioxidant activity in vitro was composed of mannose : galacturonic acid : glucose : galactose in a molar ratio of 61.19 : 1 : 39.67 : 48.67, with a weight-averaged molecular weight of 5.118 × 105 Da. MZPS-2 had both α-pyranose and ß-pyranose configuration and had a triple helical conformation. By establishing zebrafish models, we found that MZPS-2 can significantly scavenge free radicals, reduce the generation of reactive oxygen species caused by inflammation, and inhibit the recruitment of neutrophils toward the injury site. Therefore, MZPS-2 exhibited antioxidant and anti-inflammatory effects and can be used as a zinc supplement with specific biological activities to alleviate zinc deficiency complications, such as chronic oxidative stress or inflammation.

10.
Bioresour Technol ; 313: 123609, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32506034

RESUMO

Simultaneous denitrification and antibiotics (oxytetracycline, OTC and ciprofloxacin, CFX) degradation was evaluated using a typical aerobic denitrifying strain Marinobacter hydrocarbonoclasticus RAD-2. There was no significant influence on the aerobic nitrate removal efficiency of strain RAD-2 in the presence of these two antibiotics. Along with denitrification, the average degradation rate of 2.92 µg OTC L-1h-1 was achieved, while no degradation was observed for CFX. The growth behavior indicated that an insignificant inhibition effect could have occurred at an antibiotics dosage lower than 300 µg/L. The transcriptional results revealed that antibiotics exposure caused (<2h) down-regulation of the denitrifying related genes, but triggered a significant subsequent up-regulation (4 h). Less nitrous oxide productions were observed in both aerobic and anoxic denitrification processes with antibiotics. Overall, the hormesis effect caused by antibiotics exposure indicated a potential approach to enhance the co-metabolism degradation performance for nitrate and antibiotics in aerobic denitrification.


Assuntos
Desnitrificação , Marinobacter , Aerobiose , Antibacterianos , Nitratos , Nitrogênio
11.
Arterioscler Thromb Vasc Biol ; 40(8): 1830-1837, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32522007

RESUMO

OBJECTIVE: Adrenal gland secretes stress-induced glucocorticoids (iGCs) to coping with stress. Previous study showed that SR-BI (scavenger receptor BI) null (SR-BI-/-) mice failed to generate iGC in stress conditions, suggesting that SR-BI-mediated cholesterol uptake from HDL (high-density lipoprotein) is a key regulator for iGC production. However, the LDL (low-density lipoprotein)/LDLr (LDL receptor) pathway can also provide cholesterol for iGC synthesis, but rodents have limited LDL levels in circulation. Here, we generated SR-BI-/-ApoBtg (apolipoprotein B transgenic) mice with normal LDL levels in circulation to determine the relative contribution of the HDL/SR-BI and LDL/LDLr pathways to iGC production in stress conditions. Approach and Results: To obtain mouse models with normal LDL levels, SR-BI-/- mice were bred to ApoBtg mice. Then, the F1 SR-BI±ApoBtg mice were backcrossed to SR-BI-/- to obtain SR-BI-/-ApoBtg, SR-BI-/-ApoBwt (apolipoprotein B wild type), and SR-BI+/+ApoBtg mice. We first examined the lipoprotein profile, which shows a 6.5-fold increase in LDL levels in SR-BI-/-ApoBtg mice compared with SR-BI-/-ApoBwt mice. Then, we induced stress with adrenocorticotropic hormone and cecal ligation and puncture. One hour after adrenocorticotropic hormone stimulation, SR-BI+/+ApoBtg control mice produced iGC (14.9-fold), but both SR-BI-/-ApoBwt and SR-BI-/-ApoBtg showed no iGC production (P<0.001). Three hours after cecal ligation and puncture treatment, SR-BI+/+ApoBtg control mice showed iGC production (6.4-fold), but both SR-BI-/-ApoBwt and SR-BI-/-ApoBtg mice showed no iGC production (P<0.001). CONCLUSIONS: SR-BI-/-ApoBtg mice fail to produce iGC in stress conditions even though with restored LDL levels in circulation. These findings clarify that the HDL/SR-BI, not LDL/LDLr, pathway is responsible for iGC production in stress conditions.

12.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 34(6): 775-780, 2020 Jun 15.
Artigo em Chinês | MEDLINE | ID: mdl-32538571

RESUMO

Objective: To explore the effectiveness of liposuction technique assisted superomedial pedicle with a vertical incision in reduction mammaplasty. Methods: Between March 2014 and March 2019, 65 patients (127 sides) with breast hypertrophy had undergone breast reduction by using liposuction technique assisted superomedial pedicle with a vertical incision. The patients were 21 to 58 years old, with an average of 42.2 years. Body mass index ranged from 18.8 to 26.5 kg/m 2, with an average of 21.3 kg/m 2. Among them, 62 cases were bilateral operations and 3 cases were unilateral operation. The degree of mastoptosis was rated as degreeⅡ in 73 sides and degree Ⅲ in 54 sides according to the Regnault criteria. Results: The unilateral breast removed 432 g on average (range, 228-932 g); the distance of nipple upward was 4.5-9.5 cm (mean, 6.5 cm); the volume of unilateral liposuction was 50-380 mL (mean, 148 mL). There were 2 sides (1.58%) of unilateral intramammary hematomas after operation, 4 sides (3.15%) of bilateral breast vertical incisions slightly split, and 1 side (0.79%) of the nipple-areola epidermis necrosis. All patients were followed up 6 months to 5 years, with an average of 18 months. During the follow-up, there was no evident re-dropping of the breast and no enlargement of the areola. No patient underwent scar excision. At last follow-up, the effectiveness was evaluated by the surgeons. There were 52 cases with very satisfactory, 10 cases with satisfactory, and 3 cases with unsatisfactory for the breast shape and symmetry. There were 51 cases with very satisfactory, 11 cases with satisfactory, and 3 cases with unsatisfactory for the nipple position and areola diameter. The incision scar was obvious in 25 cases and was not obvious in 40 cases. The results of self-assessment showed very satisfactory for the breast shape in 48 cases, satisfactory in 12 cases, and unsatisfactory in 5 cases; very satisfactory for the incision scar in 40 cases, satisfactory in 17 cases, and unsatisfactory in 8 cases. Overall evaluation of the patient was very satisfactory in 52 cases, satisfactory in 7 cases, and unsatisfactory in 6 cases. Conclusion: The liposuction technique assisted superomedial pedicle with a vertical incision in reduction mammaplasty is a safe and reliable surgical method with a satisfactory result.

13.
Microb Ecol ; 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32588072

RESUMO

Fusarium wilt of tomato caused by the pathogen Fusarium oxysporum f. sp. lycopersici (Fol) is one of the most devastating soilborne diseases of tomato. To evaluate whether microbial community composition associated with Fol-infected tomato is different from healthy tomato, we analyzed the tomato-associated microbes in both healthy and Fol-infected tomato plants at both the taxonomic and functional levels; both bacterial and fungal communities have been characterized from bulk soil, rhizosphere, rhizoplane, and endosphere of tomatoes using metabarcoding and metagenomics approaches. The microbial community (bacteria and fungi) composition of healthy tomato was significantly different from that of diseased tomato, despite similar soil physicochemical characteristics. Both fungal and bacterial diversities were significantly higher in the tomato plants that remained healthy than in those that became diseased; microbial diversities were also negatively correlated with the concentration of Fol pathogen. Network analysis revealed the microbial community of healthy tomato formed a larger and more complex network than that of diseased tomato, probably providing a more stable community beneficial to plant health. Our findings also suggested that healthy tomato contained significantly greater microbial consortia, including some well-known biocontrol agents (BCAs), and enriched more functional genes than diseased tomato. The microbial taxa enriched in healthy tomato plants are recognized as potential suppressors of Fol pathogen invasion.

14.
J Sci Food Agric ; 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483817

RESUMO

BACKGROUND: Artificial sweeteners have been used widely as substitutes for sugar for several decades. In recent years they have been reported to be harmful to human health - especially to glucose absorption. However, as conclusions from previous studies using a single Caco-2 cell model were not consistent, further studies with a more suitable cell model are needed. RESULTS: We established a co-culture model with enterocyte Caco-2 and enteroendocrine NCI-H716 cell lines cultured in transwell inserts. The effects of artificial sweeteners, enhancing the glucose transport rate, lasted for 60 min and then began to diminish. Most importantly, different artificial sweeteners with the same sweetness intensity had similar effects on glucose transport. The sodium / glucose co-transporter member 1 (SGLT1) mRNA expression levels increased significantly with an initial glucose concentration of 20 mM, while glucose transporter 2 (GLUT2) mRNA expression significantly increased with initial glucose concentrations of 20 mM and 60 mM. CONCLUSION: Based on the Caco-2/NCI-H716 co-culture model, SGLT1 and GLUT2 mediated the enhancing effects of artificial sweeteners on glucose transport, depending on the sweetness intensity and initial glucose concentration.

15.
J Natl Cancer Inst ; 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32497200

RESUMO

BACKGROUND: Neoadjuvant FOLFIRINOX and chemoradiation have been utilized to downstage borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC). Whether neoadjuvant therapy-induced tumor immune response contributes to the improved survival is unknown. Therefore, we evaluated whether neoadjuvant therapy induces an immune response towards PDAC. METHODS: Clinicopathologic variables were collected for surgically resected PDACs at the Massachusetts General Hospital (1998-2016). Neoadjuvant regimens included FOLFIRINOX with/without chemoradiation, proton chemoradiation (25Gy), photon chemoradiation (50.4Gy) or no neoadjuvant therapy. HLA class I and II expression, and immune cell infiltration (CD4+, FoxP3+, CD8+, Granzyme B+ cells and M2 macrophages) were analyzed immunohistochemically and correlated with clinicopathologic variables. The antitumor immune response was compared among neoadjuvant therapy regimens. All statistical tests were two-sided. RESULTS: Two hundred forty-eight PDAC patients were included. Median age was 64y; 50.0% were female. HLA-A defects were less frequent in the FOLFIRINOX cohort (p=.006). HLA class II expression was lowest in photon and highest in proton patients (p=.02). The FOLFIRINOX cohort exhibited the densest CD8+ cell infiltration (p<.001). FOLFIRINOX and proton patients had the highest CD4+ and lowest T regulatory (FoxP3+) cell density, respectively. M2 macrophage density was statistically significantly higher in the treatment-naïve group (p<.001), in which dense M2 macrophage infiltration was an independent predictor of poor OS. CONCLUSIONS: Neoadjuvant FOLFIRINOX with/without chemoradiation may induce immunologically relevant changes in the tumor microenvironment. It may reduce HLA-A defects, increase CD8+ cell density and decrease T regulatory cell and M2 macrophage density. Therefore, neoadjuvant FOLFIRINOX therapy may benefit from combinations with checkpoint inhibitors, which can enhance patients' antitumor immune response.

16.
Biol Res ; 53(1): 20, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381120

RESUMO

BACKGROUND: The role of interleukin family in colon cancer remained controversial. The purpose of this study was to investigate the association between interleukin family and colon cancer progression through bioinformatics methods and to validate such association in clinical patients. METHODS: A total of 15 differentially expressed interleukins between the colon cancer tissue and normal colon tissue were evaluated from the Cancer Genome Atlas (TCGA) database with R software and only interleukin-7 (IL-7) was significantly associated with survival. The signaling pathway associated with IL-7 was then investigated using gene enrichment analysis. In addition, subsets of TNM were analyzed in detail and univariate and multivariate COX regression analysis were conducted. Finally, we performed western blotting, immunohistochemistry, cell proliferation and cell apoptosis analysis to examine the expression of IL-7 in patients with intestinal cancer. RESULTS: The study demonstrated that IL-7 could inhibit the progression of colon cancer. In addition, IL-7 was found to be associated with overall survival (OS) and pathological stage. Further analysis of IL-7 expression with clinical data indicated that IL-7 was a key factor in inhibiting colon cancer progression. CONCLUSION: IL-7 was a key factor in inhibiting the progression of colon cancer and was closely related to overall survival.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias do Colo/metabolismo , Interleucina-7/metabolismo , Idoso , Apoptose , Western Blotting , Proliferação de Células , Biologia Computacional , Progressão da Doença , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Masculino , Estadiamento de Neoplasias , Transdução de Sinais
18.
Int J Biol Macromol ; 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32407946

RESUMO

In this study, a crude and purified polysaccharide from Cyclocarya paliurus (CPP, CPP0.05) were performed with chlorosulfonic acid-pyridine (CSA-Pyr) method to obtain sulfated derivatives (S-CPP, S-CPP0.05). After comparatively investigating, characterization results showed that the modifications were successful. Polysaccharides were used to culture mouse bone marrow-derived dendritic cells (BM-DCs) to evaluate their immunomodulatory activity and explore mechanism. The functional activity of CPP was significantly stronger than that of the purified polysaccharide CPP0.05. Meanwhile, S-CPP showed stronger immunomodulatory activity than CPP through determination of cytokine expression levels. We found that p-JNK, p-p38MAPK and NF-κB p65 proteins were significantly increased by stimulus of CPP and S-CPP, blocking TLR2/4 could significantly decreased proteins above which proved that immune regulation effect of CPP and S-CPP on DCs was performed via MAPK and NF-κB signaling pathways by triggering TLR2/4. S-CPP could serve as potential immunomodulatory agents used as complementary medicine or functional foods.

19.
Am J Physiol Heart Circ Physiol ; 318(6): H1474-H1486, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32330092

RESUMO

The gut microbe-derived metabolite trimethylamine-N-oxide (TMAO) has recently been linked to cardiovascular disease (CVD) pathogenesis, prompting the development of therapeutic strategies to reduce TMAO. Previous work has shown that experimental alteration of circulating TMAO levels via dietary alterations or inhibition of the host TMAO producing enzyme flavin containing monooxygenase 3 (FMO3) is associated with reorganization of host cholesterol and bile acid metabolism in mice. In this work, we set out to understand whether recently developed nonlethal gut microbe-targeting small molecule choline trimethylamine (TMA) lyase inhibitors also alter host cholesterol and bile acid metabolism. Treatment of mice with the mechanism-based choline TMA lyase inhibitor, iodomethylcholine (IMC), increased fecal neutral sterol loss in the form of coprostanol, a bacteria metabolite of cholesterol. In parallel, IMC treatment resulted in marked reductions in the intestinal sterol transporter Niemann-pick C1-like 1 (NPC1L1) and reorganization of the gut microbial community, primarily reversing choline supplemented diet-induced changes. IMC also prevented diet-driven hepatic cholesterol accumulation, causing both upregulation of the host hepatic bile acid synthetic enzyme CYP7A1 and altering the expression of hepatic genes critical for bile acid feedback regulation. These studies suggest that the gut microbiota-driven TMAO pathway is closely linked to both microbe and host sterol and bile acid metabolism. Collectively, as gut microbe-targeting choline TMA lyase inhibitors move through the drug discovery pipeline from preclinical models to human studies, it will be important to understand how these drugs impact both microbe and host cholesterol and bile acid metabolism.NEW & NOTEWORTHY The gut microbe-dependent metabolite trimethylamine-N-oxide (TMAO) has been strongly associated with cardiovascular mortality, prompting drug discovery efforts to identify points of therapeutic intervention within the microbe host TMAO pathway. Recently, mechanism-based small molecule inhibitors of the major bacterial trimethylamine (TMA) lyase enzymes have been developed, and these drugs show efficacy as anti-atherothrombotic agents. The novel findings of this study are that small molecule TMA lyase inhibition results in beneficial reorganization of host cholesterol and bile acid metabolism. This study confirms previous observations that the gut microbial TMAO pathway is intimately linked to host cholesterol and bile acid metabolism and provides further rationale for the development of small molecule choline TMA lyase inhibitors for the treatment of cardiometabolic disorders.


Assuntos
Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal/metabolismo , Animais , Colina/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Camundongos
20.
Org Biomol Chem ; 18(20): 3818-3822, 2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32297605

RESUMO

Tricolorin A, a bioactive resin glycoside, was synthesized stepwise or in one pot based on interrupted Pummerer reaction-mediated (IPRm) glycosylation. The stepwise synthesis adopted a [2 + 2] assembly sequence, and all of the glycosidic bonds were constructed efficiently by IPRm glycosylation. The one-pot synthesis employed our recently developed one-pot relay glycosylation strategy, in which two different glycosidic bonds were sequentially connected with only one equivalent of external activator.

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