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1.
Proc Natl Acad Sci U S A ; 121(11): e2321722121, 2024 Mar 12.
Article in English | MEDLINE | ID: mdl-38446858

ABSTRACT

Aromatic polyketides are renowned for their wide-ranging pharmaceutical activities. Their structural diversity is mainly produced via modification of limited types of basic frameworks. In this study, we characterized the biosynthesis of a unique basic aromatic framework, phenyldimethylanthrone (PDA) found in (+)/(-)-anthrabenzoxocinones (ABXs) and fasamycin (FAS). Its biosynthesis employs a methyltransferase (Abx(+)M/Abx(-)M/FasT) and an unusual TcmI-like aromatase/cyclase (ARO/CYC, Abx(+)D/Abx(-)D/FasL) as well as a nonessential helper ARO/CYC (Abx(+)C/Abx(-)C/FasD) to catalyze the aromatization/cyclization of polyketide chain, leading to the formation of all four aromatic rings of the PDA framework, including the C9 to C14 ring and a rare angular benzene ring. Biochemical and structural analysis of Abx(+)D reveals a unique loop region, giving rise to its distinct acyl carrier protein-dependent specificity compared to other conventional TcmI-type ARO/CYCs, all of which impose on free molecules. Mutagenic analysis discloses critical residues of Abx(+)D for its catalytic activity and indicates that the size and shape of its interior pocket determine the orientation of aromatization/cyclization. This study unveils the tetracyclic and non-TcmN type C9 to C14 ARO/CYC, significantly expanding our cognition of ARO/CYCs and the biosynthesis of aromatic polyketide framework.


Subject(s)
Aromatase , Polyketides , Cyclization , Acyl Carrier Protein , Catalysis
2.
J Am Chem Soc ; 146(13): 9036-9044, 2024 Apr 03.
Article in English | MEDLINE | ID: mdl-38507821

ABSTRACT

Two-dimensional conductive metal-organic frameworks (2D c-MOFs), which feature high electrical conductivity and large charge carrier mobility, hold great promise in electronics and optoelectronics. Nevertheless, the limited solubility of commonly used planar ligands inevitably brings challenges in synthesis and purification and causes laborious coordination conditions for screening. Moreover, most reported 2D c-MOFs are polycrystalline powders with relatively low crystallinity and irregular morphology, hindering the unveiling of the detailed structure-function relationship. Herein, we developed a "rotor-stator" molecular design strategy to construct 2D c-MOFs using a delicately designed nonplanar biscarbazole ligand (8OH-DCB). Benefiting from the special "rotor-stator" structure of the ligand, crystals of Cu-DCB-MOF were successfully prepared, allowing for the precise determination of their crystal structure. Interestingly, the crystals of Cu-DCB-MOF can be obtained in various organic solvents, indicating excellent solvent compatibility. The versatility of the "rotor-stator" molecular design strategy was further demonstrated by another two new ligands with a "rotor-stator" structure, and afford corresponding 2D c-MOF crystals (Cu-DCBT-MOF and Cu-DCBBT-MOF). The current work presents a facile approach toward the rational design and direct construction of highly crystalline 2D c-MOFs using nonplanar ligands.

3.
Angew Chem Int Ed Engl ; 63(29): e202405168, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38668683

ABSTRACT

2D conjugated metal-organic frameworks (2D c-MOFs) with large pore sizes and high surface areas are advantageous for adsorbing iodine species to enhance the electrochemical performance of aqueous dual-ion batteries (ADIBs). However, most of the reported 2D c-MOFs feature microporous structures, with few examples exhibiting mesoporous characteristics. Herein, we developed two mesoporous 2D c-MOFs, namely PA-TAPA-Cu-MOF and PA-PyTTA-Cu-MOF, using newly designed arylimide based multitopic catechol ligands (6OH-PA-TAPA and 8OH-PA-PyTTA). Notably, PA-TAPA-Cu-MOF exhibits the largest pore sizes (3.9 nm) among all reported 2D c-MOFs. Furthermore, we demonstrated that these 2D c-MOFs can serve as promising cathode host materials for polyiodides in ADIBs for the first time. The incorporation of triphenylamine moieties in PA-TAPA-Cu-MOF resulted in a higher specific capacity (423.4 mAh g-1 after 100 cycles at 1.0 A g-1) and superior cycling performance, retaining 96 % capacity over 1000 cycles at 10 A g-1 compared to PA-PyTTA-Cu-MOF. Our comparative analysis revealed that the increased number of N anchoring sites and larger pore size in PA-TAPA-Cu-MOF facilitate efficient anchoring and conversion of I3 -, as supported by spectroscopic electrochemistry and density functional theory calculations.

4.
Angew Chem Int Ed Engl ; : e202408189, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38774981

ABSTRACT

Two-dimensional conjugated metal-organic frameworks (2D c-MOFs) have emerged as promising candidates in gas sensing, owing to their tunable porous structure and conductivity. Nevertheless, the reported gas sensing mechanisms heavily relied on electron transfer between metal nodes and gas molecules. Normally, the strong interaction between the metal sites and target gas molecule would result poor recovery and thus bad recycling property. Herein, we propose a redox synergy strategy to overcome this issue by balancing the reactivity of metal sites and ligands. A 2D c-MOF, Zn3(HHTQ)2, was prepared for nitrogen dioxide (NO2) sensing, which was constructed from active ligands (hexahydroxyltricycloquinazoline, HHTQ) and inactive transition-metal ions (Zn2+). Substantial characterizations and theoretical calculations demonstrated that by utilizing only the redox interactions between ligands and NO2, not only high sensitivity and selectivity, but also excellent cycling stability in NO2 sensing could be achieved. In contrast, control experiments employing isostructural 2D c-MOFs with Cu/Ni metal nodes exhibited irreversible NO2 sensing. Our current work provides a new design strategy for gas sensing materials, emphasizing harnessing the redox activity of only ligands to enhance the stability of MOF sensing materials.

5.
Chemistry ; 29(36): e202300869, 2023 Jun 27.
Article in English | MEDLINE | ID: mdl-37071487

ABSTRACT

As an emerging class of porous crystalline material, covalent organic frameworks (COFs) have received considerable research interests in terms of exploring new architectures and functions. Herein, we developed an unprecedented "H-shaped" monomer, upon self-polycondensation, which facilely produced a benzoimidazole-based COF (H-BIm-COF) with a rarely reported brick-wall topology. H-BIm-COF displayed high crystallinity, nano-sized porosity, and high thermal and chemical stabilities. Interestingly, H-BIm-COF based membranes showed selective permeability towards different solvents, which related to the size and polarity of the guest molecule. Additionally, initial study suggested the COF displayed excellent rejection efficiency towards ionic dyes, for example chromium black T (99.7 %) and rhodamine B (97.3 %). This work provides insights into developing new topological COFs by designing monomers with new configurations.

6.
Macromol Rapid Commun ; 44(11): e2200894, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36583705

ABSTRACT

Covalent organic frameworks (COFs) have attracted increasing research interest due to their intriguing topological structures and fascinating properties. Diverse COFs with different shapes and sizes are developed by the design of appropriate building blocks. However, the heteroporous COFs to date are still in their infancy due to the relatively limited configuration of precursors. Herein, it is ingeniously designed and synthesized a new K-shaped "two-in-one" building unit (3',6'-bis(4-(5,5-dimethyl-1,3-dixoan-2-yl)phenyl)-[1,1':2',1"-terphenyl]-4,4"-diamine, BPTD), thus realizing the construction of triangular dual microporous COF (BPTD-COF) via self-polycondensation of the K-shaped monomer. The super micropore (0.76 nm) of BPTD-COF endows the higher density of amine activity sites, while the other aperture size (1.35 nm) meets the need for accommodating cationic dyes (rhodamine B, methylene blue), thus BPTD-COF displays a distinctive selective adsorption for cationic dyes with good reusability.


Subject(s)
Amines , Metal-Organic Frameworks , Metal-Organic Frameworks/chemical synthesis , Metal-Organic Frameworks/chemistry , Amines/chemistry , Coloring Agents/chemistry , Environmental Pollutants/chemistry , Environmental Restoration and Remediation , Adsorption
7.
BMC Cardiovasc Disord ; 23(1): 376, 2023 07 28.
Article in English | MEDLINE | ID: mdl-37507655

ABSTRACT

BACKGROUND: The molecular biological mechanisms underlying heart failure (HF) remain poorly understood. Therefore, it is imperative to use innovative approaches, such as high-throughput sequencing and artificial intelligence, to investigate the pathogenesis, diagnosis, and potential treatment of HF. METHODS: First, we initially screened Two data sets (GSE3586 and GSE5406) from the GEO database containing HF and control samples from the GEO database to establish the Train group, and selected another dataset (GSE57345) to construct the Test group for verification. Next, we identified the genes with significantly different expression levels in patients with or without HF and performed functional and pathway enrichment analyses. HF-specific genes were identified, and an artificial neural network was constructed by Random Forest. The ROC curve was used to evaluate the accuracy and reliability of the constructed model in the Train and Test groups. Finally, immune cell infiltration was analyzed to determine the role of the inflammatory response and the immunological microenvironment in the pathogenesis of HF. RESULTS: In the Train group, 153 significant differentially expressed genes (DEGs) associated with HF were found to be abnormal, including 81 down-regulated genes and 72 up-regulated genes. GO and KEGG enrichment analyses revealed that the down-regulated genes were primarily enriched in organic anion transport, neutrophil activation, and the PI3K-Akt signaling pathway. The upregulated genes were mainly enriched in neutrophil activation and the calcium signaling. DEGs were identified using Random Forest, and finally, 16 HF-specific genes were obtained. In the ROC validation and evaluation, the area under the curve (AUC) of the Train and Test groups were 0.996 and 0.863, respectively. CONCLUSIONS: Our research revealed the potential functions and pathways implicated in the progression of HF, and designed an RNA diagnostic model for HF tissues using machine learning and artificial neural networks. Sensitivity, specificity, and stability were confirmed by ROC curves in the two different cohorts.


Subject(s)
Artificial Intelligence , Heart Failure , Humans , Phosphatidylinositol 3-Kinases , Reproducibility of Results , Heart Failure/diagnosis , Heart Failure/genetics , Area Under Curve
8.
Arch Gynecol Obstet ; 308(2): 319-339, 2023 08.
Article in English | MEDLINE | ID: mdl-35916961

ABSTRACT

INTRODUCTION: Despite intensive research, preterm birth (PTB) rates have not decreased significantly in recent years due to a lack of understanding of the underlying causes and insufficient treatment options for PTB. We are committed to finding promising biomarkers for the treatment of PTB. METHODS: An extensive search of the literature was conducted with MEDLINE/PubMed, and in total, 151 studies were included and summarized in the present review. RESULTS: Substantial evidence supports that the infection and/or inflammatory cascade associated with infection is an early event in PTB. Toll-like receptor (TLR) is a prominent pattern recognition receptor (PRR) found on both immune and non-immune cells, including fetal membrane cells. The activation of TLR downstream molecules, followed by TLR binding to its ligand, is critical for infection and inflammation, leading to the involvement of the TLR signaling pathway in PTB. TLR ligands are derived from microbial components and molecules released by damaged and dead cells. Particularly, TLR4 is an essential TLR because of its ability to recognize lipopolysaccharide (LPS). In this comprehensive overview, we discuss the role of TLR signaling in PTB, focus on numerous host-derived genetic and epigenetic regulators of the TLR signaling pathway, and cover ongoing research and prospective therapeutic options for treating PTB by inhibiting TLR signaling. CONCLUSION: This is a critical topic because TLR-related molecules and mechanisms may enable obstetricians to better understand the physiological changes in PTB and develop new treatment and prevention strategies.


Subject(s)
Premature Birth , Female , Infant, Newborn , Humans , Premature Birth/etiology , Toll-Like Receptors/metabolism , Signal Transduction , Inflammation , Ligands
9.
Angew Chem Int Ed Engl ; 62(41): e202305408, 2023 Oct 09.
Article in English | MEDLINE | ID: mdl-37258996

ABSTRACT

The intrinsic properties of predesignable topologies and tunable electronic structures, coupled with the increase of electrical conductivity, make two-dimensional metal-organic frameworks (2D MOFs) highly prospective candidates for next-generation electronic/spintronic devices. In this Minireview, we present an outline of the design principles of 2D MOF-based spintronics materials. Then, we highlight the spin-transport properties of 2D MOF-based organic spin valves (OSVs) as a notable achievement in the progress of 2D MOFs for spintronics devices. After that, we discuss the potential for spin manipulation in 2D MOFs with bipolar magnetic semiconductor (BMS) properties as a promising field for future research. Finally, we provide a brief summary and outlook to encourage the development of novel 2D MOFs for spintronics applications.

10.
Angew Chem Int Ed Engl ; 62(22): e202302645, 2023 May 22.
Article in English | MEDLINE | ID: mdl-36959095

ABSTRACT

As an emerging class of promising porous materials, the development of two-dimensional conductive metal organic frameworks (2D c-MOFs) is hampered by the few categories and tedious synthesis of the specific ligands. Herein, we developed a nonplanar hexahydroxyl-functionalized Salphen ligand (6OH-Salphen) through a facile two-step synthesis, which was further applied to construct layered 2D c-MOFs through in situ one pot synthesis based on the synergistic metal binding effect of the N2 O2 pocket of Salphen. Interestingly, the C2v -symmetry of ligand endows Cu-Salphen-MOF with periodically heterogeneous pore structures. Benefitting from the higher metal density and shorter in-plane metal-metal distance, Cu-Salphen-MOF showcased excellent NO2 sensing performance with good sensitivity, selectivity and reversibility. The current work opens up a new avenue to construct 2D c-MOF directly from nonplanar ligands, which greatly simplifies the synthesis and provides new possibilities for preparing different topological 2D c-MOF based functional materials.

11.
J Nat Prod ; 85(4): 943-950, 2022 04 22.
Article in English | MEDLINE | ID: mdl-35325544

ABSTRACT

Genome mining and biocatalytic modification of chemical structures are critical methods to develop new antibiotics. In this study, eight new fasamycins (3, 4, 6, and 8-12) along with five known analogues (1, 2, 5, 7, and 13) were obtained by the overexpression of two phosphopantetheinyl transferases (PPtases) in Streptomyces kanamyceticus and biocatalytic transformation with two halogenases. These new compounds displayed significant activity against Staphylococcus aureus and Bacillus subtilis, in particular, C-29-methyl and C-2/C-22-halogen derivatives. This study increases the chemical diversity of bioactive fasamycin derivatives and provides useful halogenation tools for engineering their scaffolds.


Subject(s)
Bacillus subtilis , Halogenation , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Biocatalysis , Staphylococcus aureus
12.
Angew Chem Int Ed Engl ; 61(19): e202201900, 2022 May 02.
Article in English | MEDLINE | ID: mdl-35235246

ABSTRACT

The intrinsic hydrophobicity and limited light absorption especially in the near-infrared (NIR) region of porous organic polymers are two bottlenecks impeding their applications in solar steam generation (SSG). Herein, we develop a 1,4,5,8-tetrakis(phenylamino)anthracene-9,10-dione (TPAD)-based covalent organic framework (COF) (TPAD-COF) featuring both superhydrophilicity and broad light absorption covering from the entire UV/Vis to NIR regions for SSG. TPAD-COF serving as a highly efficient photothermal conversion material without any additives displays an excellent water evaporation of 1.42 kg m-2 h-1 and achieves a high energy conversion efficiency of 94 % under 1 sun irradiation. Further extension of the light absorption range of the TPAD-based COF is realized through post-synthetic modification by chelating BF2 moieties. Systematic control experiments and analysis confirm that the hydrophilicity of photothermal conversion materials plays a more dominant role in the current TPAD-based COFs for SSG.

13.
Angew Chem Int Ed Engl ; 61(19): e202200879, 2022 05 02.
Article in English | MEDLINE | ID: mdl-35218125

ABSTRACT

ß-Ketoacyl-ACP synthase III (KAS III) is a class of important C-C bond-forming enzymes that mostly catalyze the initiation of polyketide and fatty acid biosynthesis. In this study, we elucidated an unusual polyketide synthase (PKS) system that involves two unique KAS IIIs (AsuC3 and C4) in the biosynthesis of the upper triene chain of asukamycin. Significantly, AsuC3 and C4 have both initiation and iterative elongation activity, while being functionally biased toward the elongation and initiation steps, respectively. Mutational analysis revealed that their catalytic activities rely on the catalytic triad Cys-His-Asn. Unlike other KAS IIIs, AsuC3 and C4 are very promiscuous and can accept various lengths of acyl-CoAs with either cyclic, branched or linear acyl moieties. By cooperation with the permissive ketoreductase (AsuC7) and dehydratase (AsuC8/C9), a large variety of polyenes can be efficiently synthesized. This study significantly broadens the understanding of KAS IIIs and polyketide biosynthesis.


Subject(s)
Polyenes , Polyketides , Acyl Coenzyme A , Polyketide Synthases/genetics
14.
Angew Chem Int Ed Engl ; 61(43): e202208734, 2022 10 24.
Article in English | MEDLINE | ID: mdl-36074522

ABSTRACT

Acyl-CoAs are key precursors of primary and secondary metabolism. Their efficient biosynthesis is often impeded by the limited substrate specificity and low in vivo activity of acyl-CoA synthetases (ACSs) due to regulatory acylation of the catalytically important lysine residue in motif A10 (Lys-A10). In this study, we identified an unusual ACS (UkaQ) from the UK-2A biosynthetic pathway that naturally lacks the Lys-A10 residue and exhibits extraordinarily broad substrate specificity. Protein engineering significantly improved its stability and catalytic activity, enabling it to synthesize a large variety of acyl-CoAs with highly robust activity. By combining it with permissive carboxylases, we produced a large array of polyketide extender units and obtained six novel halobenzyl-containing antimycin analogues through an engineered biosynthetic pathway. This study significantly expands the catalytic mode of ACSs and provides a potent tool for the biosynthesis of acyl-CoA-derived natural products.


Subject(s)
Biological Products , Polyketides , Polyketides/chemistry , Lysine , Carbon , Acyl Coenzyme A/metabolism , Substrate Specificity , Biological Products/metabolism , Polyketide Synthases/metabolism
15.
BMC Cancer ; 19(1): 505, 2019 May 28.
Article in English | MEDLINE | ID: mdl-31138169

ABSTRACT

BACKGROUND: Gastric cancer (GC) is one of the most common human cancers with the high rate of recurrence, metastasis and mortality. Aberrantly expressed microRNAs (miRNAs) are associated with invasion and metastasis in various human cancers. Recently, miR-188-5p has been indicated as an oncogene in GC since it promotes GC cell growth and metastasis. However, the underlying molecular mechanism remains to be fully defined. METHODS: Using Significance Analysis of Microarrays (SAM) screening, we identified that miR-188-5p is associated with overall survival and lymph node metastasis in patients with GC. The functional impact of miR-188-5p on GC metastasis was validated using in vitro and in vivo assays. The regulatory function of miR-188-5p on Wnt/ß-catenin signaling activation through directly targeting PTEN was proven using quantitative real-time PCR, western blot analysis, a dual-luciferase assay, a Transwell assay, and immunofluorescence. Immunohistochemical analyses further confirmed the clinical significance of miR-188-5p in GC. RESULTS: MiR-188-5p diminishes tumor suppressor PTEN expression, and further increases phospho-Ser9 of GSK3ß to activate Wnt/ß-catenin signaling in GC. Consequently, miR-188-5p enhanced the migration and invasion of GC cells in vitro and tumor metastasis in vivo, whereas inhibition of miR-188-5p had the opposite effects. Moreover, miR-188-5p was negatively correlated with PTEN expression but positively correlated with nuclear ß-catenin staining in GC samples. CONCLUSIONS: Our findings revealed a model of the miR-188-5p-PTEN-ß-catenin axis in GC, which mediates the constitutive activation of Wnt/ß-catenin signaling and promotes tumor metastasis, inferring that miR-188-5p is a potential therapeutic target to treat GC.


Subject(s)
Lymphatic Metastasis/genetics , MicroRNAs/genetics , PTEN Phosphohydrolase/genetics , Stomach Neoplasms/pathology , Wnt Signaling Pathway , Animals , Cell Line, Tumor , Cell Movement , Gene Expression Regulation, Neoplastic , Humans , Mice , Neoplasm Invasiveness , Neoplasm Transplantation , PTEN Phosphohydrolase/metabolism , Prognosis , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Survival Analysis , Up-Regulation
16.
Molecules ; 24(4)2019 Feb 15.
Article in English | MEDLINE | ID: mdl-30769954

ABSTRACT

A facile and sustainable electrochemical umpolung of bromide ion protocol was developed under mild reaction conditions. Transition metal catalysts and exogenous chemical oxidants were obviated for the bromination of C⁻H bond. Notably, graphite rod, which is commercially available at supermarkets and is inexpensive, was employed as the electrode material. This operationally easy and environmentally friendly approach accomplished the synthesis of 3-bromoindole in excellent yield and regioselectivity.


Subject(s)
Bromides/chemistry , Electrochemical Techniques , Bromides/analysis , Carbon/chemistry , Hydrogen/chemistry , Indoles/chemistry , Magnetic Resonance Spectroscopy , Spectrophotometry, Infrared
17.
Phys Chem Chem Phys ; 20(3): 2022-2027, 2018 Jan 17.
Article in English | MEDLINE | ID: mdl-29300058

ABSTRACT

The violent reaction processing and required high-temperature environment involved in growing carbon onions make it difficult to obtain an insight into their evolution mechanism. By using deionized water as the medium of arc discharge, we successfully froze the synthetic reaction at intermediary stages and observed detailed structures of the obtained intermediates of carbon onions. Here we present the atomic-scale scanning transmission electron microscopy investigation of carbon onions produced by arc discharge in water. We directly observed that carbon onions at intermediary growth stage are characterized by unclosed few-layer graphene shells. Meanwhile, a kind of graphene flakes composed of 3 layers or less were also observed in the sample. The kindred evolution linkage was induced to exist among these few-layer graphene flakes and carbon onions in the arc discharge synthetic process. On the basis of microscopy observations, we propose that carbon onions are constructed by curling few-layer graphene flakes, which is beneficial for structural designs and controls of related carbon materials used in different fields.

18.
Int Orthop ; 42(3): 519-527, 2018 03.
Article in English | MEDLINE | ID: mdl-29411078

ABSTRACT

PURPOSE: Knee osteoarthritis (KOA) is the most common joint pathology worldwide and a major cause of later disability. It is unknown if the bone mass density (BMD) is correlated with KOA. This study aimed to investigate the prevalence of radiographic KOA among retired professional football players by comparing with matched nonsportsmen, and assess the correlation between BMD and KOA. METHODS: A cross-sectional, descriptive study was performed on a group of retired professional football players without history of knee injury. A control group of nonsporting volunteers was matched to the football player group in terms of age, height, weight, and body mass index (BMI). Uni- and multivariate analyses were performed to identify risk factors for KOA and predictors for knee function. RESULTS: Eighty-six retired male professional football players, with a mean age of 53 (51-58) years and an average period of professional career of 19.8 ± 6.3 years, were enrolled into the study group. Eighty-six subjects were included in the control group. Radiographic KOA was more common in the control group (45.3%) than in the study group (15.1%; χ 2 = 18.633, P < 0.001). While the HSS, IKS score, and BMD of spine, femoral neck, and trochanter were all higher among sportsmen than the nonsportsmen (z = 10.250, z = 10.450, z = 7.237, z = 8.826, z = 8.776, all P < 0.001). Independent risk factors for ROA were age (55-60 + years, aOR 9.159, P < 0.001) and BMD (decrease, aOR 16.226, P = 0.001; osteoporosis, aOR 8.176, P = 0.005). The mathematical model of multiple linear regression for the HSS and IKS score were Y = 127.217-3.334 age + 8.971 BMD + 4.752 occupation and Y = 57.784-3.022 age + 7.241 BMD + 4.730 occupation, respectively. CONCLUSIONS: This study reveals that low BMD and advanced age are independent risk factors for KOA. High BMD and regular exercise have a positive impact on knee function as evaluated with the use of HSS and IKS. Our findings guarantee further study to investigate the possibility that KOA may be caused by low BMD.


Subject(s)
Bone Density/physiology , Football/statistics & numerical data , Osteoarthritis, Knee/etiology , Absorptiometry, Photon/methods , Aged , Cross-Sectional Studies , Humans , Knee Joint/diagnostic imaging , Knee Joint/pathology , Male , Middle Aged , Multivariate Analysis , Osteoarthritis, Knee/diagnostic imaging , Osteoarthritis, Knee/epidemiology , Prevalence , Risk Factors
19.
J Virol ; 90(4): 1729-40, 2016 02 15.
Article in English | MEDLINE | ID: mdl-26637457

ABSTRACT

UNLABELLED: Hepatitis B virus (HBV) has been implicated as a potential trigger of hepatic steatosis although molecular mechanisms involved in the pathogenesis of HBV-associated hepatic steatosis still remain elusive. Our prior work has revealed that the expression level of liver fatty acid binding protein 1 (FABP1), a key regulator of hepatic lipid metabolism, was elevated in HBV-producing hepatoma cells. In this study, the effects of HBV X protein (HBx) mediated FABP1 regulation on hepatic steatosis and the underlying mechanism were determined. mRNA and protein levels of FABP1 were measured by quantitative RT-PCR (qPCR) and Western blotting. HBx-mediated FABP1 regulation was evaluated by luciferase assay, coimmunoprecipitation, and chromatin immunoprecipitation. Hepatic lipid accumulation was measured by using Oil-Red-O staining and the triglyceride level. It was found that expression of FABP1 was increased in HBV-producing hepatoma cells, the sera of HBV-infected patients, and the sera and liver tissues of HBV-transgenic mice. Ectopic overexpression of HBx resulted in upregulation of FABP1 in HBx-expressing hepatoma cells, whereas HBx abolishment reduced FABP1 expression. Mechanistically, HBx activated the FABP1 promoter in an HNF3ß-, C/EBPα-, and PPARα-dependent manner, in which HBx increased the gene expression of HNF3ß and physically interacted with C/EBPα and PPARα. On the other hand, knockdown of FABP1 remarkably blocked lipid accumulation both in long-chain free fatty acids treated HBx-expressing HepG2 cells and in a high-fat diet-fed HBx-transgenic mice. Therefore, FABP1 is a key driver gene in HBx-induced hepatic lipid accumulation via regulation of HNF3ß, C/EBPα, and PPARα. FABP1 may represent a novel target for treatment of HBV-associated hepatic steatosis. IMPORTANCE: Accumulating evidence from epidemiological and experimental studies has indicated that chronic HBV infection is associated with hepatic steatosis. However, the molecular mechanism underlying HBV-induced pathogenesis of hepatic steatosis still remains to be elucidated. In this study, we found that expression of liver fatty acid binding protein (FABP1) was dramatically increased in the sera of HBV-infected patients and in both sera and liver tissues of HBV-transgenic mice. Forced expression of HBx led to FABP1 upregulation, whereas knockdown of FABP1 remarkably diminished lipid accumulation in both in vitro and in vivo models. It is possible that HBx promotes hepatic lipid accumulation through upregulating FABP1 in the development of HBV-induced nonalcoholic fatty liver disease. Therefore, inhibition of FABP1 might have therapeutic value in steatosis-associated chronic HBV infection.


Subject(s)
Fatty Acid-Binding Proteins/biosynthesis , Fatty Liver/pathology , Fatty Liver/virology , Hepatitis B/complications , Hepatitis B/pathology , Host-Pathogen Interactions , Trans-Activators/metabolism , Animals , Artificial Gene Fusion , Blotting, Western , Disease Models, Animal , Fatty Acid-Binding Proteins/genetics , Gene Expression Profiling , Genes, Reporter , Hep G2 Cells , Hepatocytes/pathology , Hepatocytes/virology , Humans , Immunoprecipitation , Luciferases/analysis , Luciferases/genetics , Male , Mice, Transgenic , Real-Time Polymerase Chain Reaction , Viral Regulatory and Accessory Proteins
20.
J Med Virol ; 89(4): 589-597, 2017 04.
Article in English | MEDLINE | ID: mdl-27632796

ABSTRACT

Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are two common viral pathogens in acute lower respiratory tract infections (ALRTI). However, the association of viral load with clinical characteristics is not well-defined in ALRTI. To explore the correlation between viral load and clinical characteristics of RSV and HMPV in children hospitalized for ALRTI in Lanzhou, China. Three hundred and eighty-seven children hospitalized for ALRTI were enrolled. Nasopharyngeal aspirates (NPAs) were sampled from each children. Real-time PCR was used to screen RSV, HMPV, and twelve additional respiratory viruses. Bronchiolitis was the leading diagnoses both in RSV and HMPV positive patients. A significantly greater frequency of wheezing (52% vs. 33.52%, P = 0.000) was noted in RSV positive and negative patients. The RSV viral load was significant higher in children aged <1 year (P = 0.003), children without fever and wheezing (P = 0.015 and P = 0.000), days of illness <14 days (P = 0.002), children with bronchiolitis (P = 0.012) and children with RSV single infections (P = 0.000). No difference was found in the clinical features of HMPV positive and negative patients. The HMPV viral load had no correlation with any clinical characteristics. The incidences of severe disease were similar between single infection and coinfection for the two viruses (RSV, P = 0.221; HMPV, P = 0.764) and there has no statistical significance between severity and viral load (P = 0.166 and P = 0.721). Bronchiolitis is the most common disease caused by RSV and HMPV. High viral load or co-infection may be associated with some symptoms but neither has a significant impact on disease severity for the two viruses. J. Med. Virol. 89:589-597, 2017. © 2016 Wiley Periodicals, Inc.


Subject(s)
Metapneumovirus/isolation & purification , Paramyxoviridae Infections/pathology , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus, Human/isolation & purification , Respiratory Tract Infections/pathology , Viral Load , Adolescent , Child , Child, Preschool , China , Female , Hospitalization , Humans , Infant , Infant, Newborn , Male , Nasopharynx/virology , Paramyxoviridae Infections/virology , Real-Time Polymerase Chain Reaction , Respiratory Syncytial Virus Infections/virology , Respiratory Tract Infections/virology
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