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1.
PLoS Pathog ; 20(4): e1012141, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38626263

ABSTRACT

Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus etiologically associated with multiple malignancies. Both latency and sporadic lytic reactivation contribute to KSHV-associated malignancies, however, the specific roles of many KSHV lytic gene products in KSHV replication remain elusive. In this study, we report that ablation of ORF55, a late gene encoding a tegument protein, does not impact KSHV lytic reactivation but significantly reduces the production of progeny virions. We found that cysteine 10 and 11 (C10 and C11) of pORF55 are palmitoylated, and the palmytoilation is essential for its Golgi localization and secondary envelope formation. Palmitoylation-defective pORF55 mutants are unstable and undergo proteasomal degradation. Notably, introduction of a putative Golgi localization sequence to these palmitoylation-defective pORF55 mutants restores Golgi localization and fully reinstates KSHV progeny virion production. Together, our study provides new insight into the critical role of pORF55 palmitoylation in KSHV progeny virion production and offers potential therapeutic targets for the treatment of related malignancies.


Subject(s)
Golgi Apparatus , Herpesvirus 8, Human , Lipoylation , Viral Proteins , Virion , Virus Replication , Herpesvirus 8, Human/physiology , Herpesvirus 8, Human/metabolism , Golgi Apparatus/metabolism , Golgi Apparatus/virology , Humans , Virion/metabolism , Viral Proteins/metabolism , Viral Proteins/genetics , Virus Replication/physiology , HEK293 Cells
2.
PLoS Pathog ; 20(1): e1011943, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38215174

ABSTRACT

Deubiquitinases (DUBs) remove ubiquitin from substrates and play crucial roles in diverse biological processes. However, our understanding of deubiquitination in viral replication remains limited. Employing an oncogenic human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) to probe the role of protein deubiquitination, we found that Ovarian tumor family deubiquitinase 4 (OTUD4) promotes KSHV reactivation. OTUD4 interacts with the replication and transcription activator (K-RTA), a key transcription factor that controls KSHV reactivation, and enhances K-RTA stability by promoting its deubiquitination. Notably, the DUB activity of OTUD4 is not required for K-RTA stabilization; instead, OTUD4 functions as an adaptor protein to recruit another DUB, USP7, to deubiquitinate K-RTA and facilitate KSHV lytic reactivation. Our study has revealed a novel mechanism whereby KSHV hijacks OTUD4-USP7 deubiquitinases to promote lytic reactivation, which could be potentially harnessed for the development of new antiviral therapies.


Subject(s)
Herpesvirus 8, Human , Immediate-Early Proteins , Sarcoma, Kaposi , Humans , Immediate-Early Proteins/metabolism , Ubiquitin-Specific Peptidase 7/genetics , Ubiquitin-Specific Peptidase 7/metabolism , Trans-Activators/genetics , Herpesvirus 8, Human/genetics , Virus Replication , Gene Expression Regulation, Viral , Virus Activation , Ubiquitin-Specific Proteases/metabolism
3.
EMBO Rep ; 24(12): e57724, 2023 Dec 06.
Article in English | MEDLINE | ID: mdl-38277394

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells by first engaging its cellular receptor angiotensin converting enzyme 2 (ACE2) to induce conformational changes in the virus-encoded spike protein and fusion between the viral and target cell membranes. Here, we report that certain monoclonal neutralizing antibodies against distinct epitopic regions of the receptor-binding domain of the spike can replace ACE2 to serve as a receptor and efficiently support membrane fusion and viral infectivity in vitro. These receptor-like antibodies can function in the form of a complex of their soluble immunoglobulin G with Fc-gamma receptor I, a chimera of their antigen-binding fragment with the transmembrane domain of ACE2 or a membrane-bound B cell receptor, indicating that ACE2 and its specific interaction with the spike protein are dispensable for SARS-CoV-2 entry. These results suggest that antibody responses against SARS-CoV-2 may help expand the viral tropism to otherwise nonpermissive cell types with potential implications for viral transmission and pathogenesis.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Angiotensin-Converting Enzyme 2 , Spike Glycoprotein, Coronavirus/genetics , Carrier Proteins/metabolism , Cells, Cultured , Protein Binding
4.
Cell Biol Int ; 48(6): 795-807, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38436106

ABSTRACT

Mitochondrial dysfunction and myocardial remodeling have been reported to be the main underlying molecular mechanisms of doxorubicin-induced cardiotoxicity. SIRT6 is a nicotinamide adenine dinucleotide-dependent enzyme that plays a vital role in cardiac protection against various stresses. Moreover, previous studies have demonstrated that FSTL1 could alleviate doxorubicin-induced cardiotoxicity by inhibiting autophagy. The present study investigated the probable mechanisms of FSTL1 on doxorubicin-induced cardiotoxicity in vivo and in vitro. We confirmed that FSTL1 exerted a pivotal protective role on cardiac tissue in vivo and on doxorubicin-induced cell injury in vitro. Furthermore, FSTL1 can alleviate doxorubicin-induced mitochondrial dysfunction by inhibiting autophagy and apoptosis. Further studies demonstrated that FSTL1 can activate SIRT6 signaling by restoring the SIRT6 protein expression in doxorubicin-induced myocardial injury. SIRT6 activation elevated the protein expression of Nrf2 in doxorubicin-induced H9C2 injury. Treatment with the Nrf2 inhibitor ML385 partially antagonized the cardioprotective role of SIRT6 on doxorubicin-induced autophagy or apoptosis. These results suggested that the protective mechanism of FSTL1 on doxorubicin-induced cardiotoxicity may be related with the inhibition of autophagy and apoptosis, partly through the activation of SIRT6/Nrf2.


Subject(s)
Apoptosis , Autophagy , Cardiotoxicity , Doxorubicin , Follistatin-Related Proteins , NF-E2-Related Factor 2 , Signal Transduction , Sirtuins , Sirtuins/metabolism , Doxorubicin/adverse effects , Doxorubicin/toxicity , Animals , NF-E2-Related Factor 2/metabolism , Signal Transduction/drug effects , Cardiotoxicity/metabolism , Cardiotoxicity/prevention & control , Rats , Apoptosis/drug effects , Male , Autophagy/drug effects , Follistatin-Related Proteins/metabolism , Mitochondria/metabolism , Mitochondria/drug effects , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Mice , Cell Line , Mice, Inbred C57BL
5.
J Nanobiotechnology ; 22(1): 261, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38760744

ABSTRACT

Delayed repair of fractures seriously impacts patients' health and significantly increases financial burdens. Consequently, there is a growing clinical demand for effective fracture treatment. While current materials used for fracture repair have partially addressed bone integrity issues, they still possess limitations. These challenges include issues associated with autologous material donor sites, intricate preparation procedures for artificial biomaterials, suboptimal biocompatibility, and extended degradation cycles, all of which are detrimental to bone regeneration. Hence, there is an urgent need to design a novel material with a straightforward preparation method that can substantially enhance bone regeneration. In this context, we developed a novel nanoparticle, mPPTMP195, to enhance the bioavailability of TMP195 for fracture treatment. Our results demonstrate that mPPTMP195 effectively promotes the differentiation of bone marrow mesenchymal stem cells into osteoblasts while inhibiting the differentiation of bone marrow mononuclear macrophages into osteoclasts. Moreover, in a mouse femur fracture model, mPPTMP195 nanoparticles exhibited superior therapeutic effects compared to free TMP195. Ultimately, our study highlights that mPPTMP195 accelerates fracture repair by preventing HDAC4 translocation from the cytoplasm to the nucleus, thereby activating the NRF2/HO-1 signaling pathway. In conclusion, our study not only proposes a new strategy for fracture treatment but also provides an efficient nano-delivery system for the widespread application of TMP195 in various other diseases.


Subject(s)
Cell Differentiation , Histone Deacetylases , Mesenchymal Stem Cells , Nanoparticles , Animals , Mice , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Nanoparticles/chemistry , Cell Differentiation/drug effects , Histone Deacetylases/metabolism , NF-E2-Related Factor 2/metabolism , Mice, Inbred C57BL , Osteoclasts/drug effects , Osteoclasts/metabolism , Osteoblasts/drug effects , Signal Transduction/drug effects , Heme Oxygenase-1/metabolism , Male , Bone Regeneration/drug effects , Osteogenesis/drug effects , Cell Nucleus/metabolism , Fracture Healing/drug effects , Humans , Membrane Proteins
6.
Environ Toxicol ; 39(5): 2610-2622, 2024 May.
Article in English | MEDLINE | ID: mdl-38205621

ABSTRACT

Perfluorotetradecanoic acid (PFTeDA) is a novel perfluoroalkyl substance that ubiquitously exists in the environment. However, whether PFTeDA affects adrenal cortex function remains unclear. Male Sprague-Dawley rats (age of 60 days) were daily administered with PFTeDA (0, 1, 5, and 10 mg/kg body weight) through gavage for 28 days. PFTeDA did not change body and adrenal gland weights. PFTeDA markedly elevated serum corticosterone level at 10 mg/kg but lowering serum aldosterone level at this dosage without influencing serum adrenocorticotropic hormone level. PFTeDA thickened zona fasciculata without affecting zona glomerulosa. PFTeDA remarkably upregulated the expression of corticosterone biosynthetic genes (Mc2r, Scarb1, Star, Cyp21, Cyp11b1, and Hsd11b1) and their proteins, whereas downregulating aldosterone biosynthetic enzyme Cyp11b2 and its protein, thereby distinctly altering their serum levels. PFTeDA markedly downregulated the expression of antioxidant genes (Sod1 and Sod2) and their proteins at 10 mg/kg. PFTeDA significantly decreased SIRT1/PGC1α and AMPK signaling while stimulating AKT1/mTOR signaling. Corticosterone significantly inhibited testosterone production by adult Leydig cells at >0.1 µM in vitro; however aldosterone significantly stimulated testosterone production at 0.1 nM. In conclusion, exposure to PFTeDA at male rat adulthood causes corticosterone excess and aldosterone deficiency via SIRT1/PGC1α, AMPK, and AKT1/mTOR signals, which in turn additively leads to testosterone deficiency.


Subject(s)
Aldosterone , Corticosterone , Fluorocarbons , Rats , Male , Animals , Corticosterone/metabolism , Aldosterone/metabolism , Sirtuin 1/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , AMP-Activated Protein Kinases/metabolism , Rats, Sprague-Dawley , TOR Serine-Threonine Kinases/metabolism , Testosterone
7.
Environ Toxicol ; 39(5): 2560-2571, 2024 May.
Article in English | MEDLINE | ID: mdl-38189224

ABSTRACT

Chlorinated bisphenol A (BPA) derivatives are formed during chlorination process of drinking water, whereas bisphenol S (BPS) and brominated BPA and BPS (TBBPA and TBBPS) were synthesized for many industrial uses such as fire retardants. However, the effect of halogenated BPA and BPS derivatives on glucocorticoid metabolizing enzyme 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) remains unclear. The inhibitory effects of 6 BPA derivatives in the inhibition of human and rat 11ß-HSD1 were investigated. The potencies for inhibition on human 11ß-HSD1 were TBBPA (IC50, 3.87 µM) = monochloro BPA (MCBPA, 4.08 µM) = trichloro BPA (TrCBPA, 4.41 µM) > tetrachloro BPA (TCBPA, 9.75 µM) > TBBPS (>100 µM) = BPS (>100 µM), and those for rat 11ß-HSD1 were TrCBPA (IC50, 2.76 µM) = MCBPA (3.75 µM) > TBBPA (39.58 µM) > TCBPA = TBBPS = BPS. All these BPA derivatives are mixed/competitive inhibitors of both human and rat enzymes. Molecular docking studies predict that MCBPA, TrCBPA, TCBPA, and TBBPA all bind to the active site of human 11ß-HSD1, forming hydrogen bonds with catalytic residue Ser170 except TCBPA. Regression of the lowest binding energy with IC50 values revealed a significant inverse linear regression. In conclusion, halogenated BPA derivatives are mostly potent inhibitors of human and rat 11ß-HSD1, and there is structure-dependent inhibition.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1 , Benzhydryl Compounds , Phenols , Polybrominated Biphenyls , Humans , Rats , Animals , Molecular Docking Simulation , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Structure-Activity Relationship
8.
Angew Chem Int Ed Engl ; 63(20): e202400515, 2024 May 13.
Article in English | MEDLINE | ID: mdl-38494466

ABSTRACT

Cyclobutanes with a gem-dimethyl group are common motifs in natural products. However, strategies for constructing enantioenriched gem-dimethyl cyclobutanes are still underdeveloped. Herein, we report an enantioselective approach to synthesize a broad group of chiral 2,3-disubstituted cyclobutanones through sequential 1,4-conjugate addition/trapping/cross-coupling of readily available cyclobutenones. The intermediate 2-bromocyclobutanone provides a valuable synthetic handle for further coupling transformations. In addition, this strategy was successfully utilized to synthesize gem-dimethyl cyclobutane-containing natural products, including (+)-ß-caryophyllene, (-)-raikovenal, (-)-1ß,9αH-5-linoleoyloxy-4,5-secocaryophyllen-4-one, and (-)-rumphellanones A-C.

9.
J Lipid Res ; 64(6): 100354, 2023 06.
Article in English | MEDLINE | ID: mdl-36958720

ABSTRACT

Apolipoprotein ε allele 4 (APOE4) influences the metabolism of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA). The entorhinal cortex (EC) in the brain is affected early in Alzheimer's disease and is rich in DHA. The purpose of this study is to identify the effect of APOE4 and DHA lipid species on the EC. Plasma and cerebrospinal fluid (CSF) lipidomic measurements were obtained from the DHA Brain Delivery Pilot, a randomized clinical trial of DHA supplementation (n = 10) versus placebo (n = 12) for six months in nondemented older adults stratified by APOE4 status. Wild-type C57B6/J mice were fed a high or low DHA diet for 6 months followed by plasma and brain lipidomic analysis. Levels of phosphatidylcholine DHA (PC 38:6) and cholesterol ester DHA (CE 22:6) had the largest increases in CSF following supplementation (P < 0.001). DHA within triglyceride (TG) lipids in CSF strongly correlated with corresponding plasma TG lipids, and differed by APOE4, with carriers having a lower increase than noncarriers. Changes in plasma PC DHA had the strongest association with changes in EC thickness in millimeters, independent of APOE4 status (P = 0.007). In mice, a high DHA diet increased PUFAs within brain lipids. Our findings demonstrate an exchange of DHA at the CSF-blood barrier and into the brain within all lipid species with APOE having the strongest effect on DHA-containing TGs. The correlation of PC DHA with EC suggests a functional consequence of DHA accretion in high density lipoprotein for the brain.


Subject(s)
Apolipoprotein E4 , Docosahexaenoic Acids , Animals , Mice , Apolipoprotein E4/genetics , Apolipoprotein E4/metabolism , Diet , Dietary Supplements , Docosahexaenoic Acids/metabolism , Entorhinal Cortex/metabolism , Fatty Acids, Unsaturated
10.
Small ; 19(1): e2205329, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36344449

ABSTRACT

The exotic electronic properties of topological semimetals (TSs) have opened new pathways for innovative photonic and optoelectronic devices, especially in the highly pursuit terahertz (THz) band. However, in most cases Dirac fermions lay far above or below the Fermi level, thus hindering their successful exploitation for the low-energy photonics. Here, low-energy type-II Dirac fermions in kitkaite (NiTeSe) for ultrasensitive THz detection through metal-topological semimetal-metal heterostructures are exploited. Furthermore, a heterostructure combining two Dirac materials, namely, graphene and NiTeSe, is implemented for a novel photodetector exhibiting a responsivity as high as 1.22 A W-1 , with a response time of 0.6 µs, a noise-equivalent power of 18 pW Hz-0.5 , with outstanding stability in the ambient conditions. This work brings to fruition of Dirac fermiology in THz technology, enabling self-powered, low-power, room-temperature, and ultrafast THz detection.

11.
Opt Lett ; 48(13): 3371-3374, 2023 Jul 01.
Article in English | MEDLINE | ID: mdl-37390133

ABSTRACT

Micro-spectrometers have great potential in various fields such as medicine, agriculture, and aerospace. In this work, a quantum-dot (QD) light-chip micro-spectrometer is proposed in which QDs emit different wavelengths of light that are combined with a spectral reconstruction (SR) algorithm. The QD array itself can play the roles of both the light source and the wavelength division structure. The spectra of samples can be obtained by using this simple light source with a detector and algorithm, and the spectral resolution reaches 9.7 nm in the wavelength range from 580 nm to 720 nm. The area of the QD light chip is 4 × 7.5 mm2, which is 20 times smaller than the halogen light sources of commercial spectrometers. It does not need a wavelength division structure and greatly reduces the volume of the spectrometer. Such a micro-spectrometer can be used for material identification: in a demonstration, three kinds of transparent samples, real and fake leaves, and real and fake blood were classified with an accuracy of 100%. These results indicate that the spectrometer based on a QD light chip has broad application prospects.


Subject(s)
Algorithms , Plant Leaves
12.
BMC Pregnancy Childbirth ; 23(1): 193, 2023 Mar 18.
Article in English | MEDLINE | ID: mdl-36934233

ABSTRACT

BACKGROUND: The current detection of fetal chromosomal abnormalities by non-invasive prenatal testing (NIPT) mainly relies on the cell free DNA(cfDNA) in the maternal blood. However, a gestational age of less than 12 weeks or a high maternal BMI affects cfDNA fetal fraction and further the detection by NIPT negatively. In this study, we aim to retrieve the trophoblast cells from the maternal cervix to develop a new sampling method for NIPT enabling an earlier use of NIPT. METHODS: We enrolled three patients who wanted to undergo induced abortion at Beijing Hospital between January 2022 and March 2022. Peripheral blood, cervix specimen, and the abortion tissue were collected and processed for each patient. Allele frequencies of the mutated gene loci of the maternal blood and the cervix sample were compared and the Sex Determining Region Y (SRY) gene was tested. RESULTS: The allele frequencies of the mutated gene loci showed no significant difference between the maternal blood and the cervix sample. But we successfully detected signal of the SRY gene in the cervix sample of the only patient carrying a male fetus. CONCLUSIONS: The detection of the SRY gene in a cervix sample indicated a successful retrieval of trophoblast cells from the cervix canal. Further study needs to be conducted to verify our finding before its application to the clinical settings.


Subject(s)
Cell-Free Nucleic Acids , Prenatal Diagnosis , Pregnancy , Female , Humans , Male , Infant , Prenatal Diagnosis/methods , Trophoblasts , Pilot Projects , Cervix Uteri
13.
Appl Opt ; 62(18): 4860-4865, 2023 Jun 20.
Article in English | MEDLINE | ID: mdl-37707261

ABSTRACT

We demonstrate a chiral metasurface that exhibits a giant chiroptical response as well as functions as an optical diode due to geometrical asymmetry for circularly polarized light (CPL). Engineering the Mie-type multipole radiation using geometrical features led to performance values in terms of near-unity transmission and circular dichroism (CD) efficiency (about 0.96) and an extinction ratio of  ∼3.8×104 for 1550 nm wavelength. A continuous stopband of 1538-1556 nm is achieved for an unchosen component of CPL while keeping the transmission efficiency of the chosen CPL component larger than 0.9. Because of the high extinction ratio and CD efficiency, the proposed metasurface has the potential for chiroptical applications including high-contrast polarization imaging, precise Stokes parameters measurement, optical diodes, and polarization detection for CPL.

14.
Appl Opt ; 62(18): 4813-4819, 2023 Jun 20.
Article in English | MEDLINE | ID: mdl-37707256

ABSTRACT

Metallic microparticles larger than the illumination wavelength are commonly considered poor optical trapping candidates due to their high extinction coefficient. This paper presents a numerical and experimental study on the three-dimensional (3D) trapping of gold microparticles using a centrally obstructed Gaussian beam based on the T-matrix method. The range of particle size for stable optical trapping is determined. For the trapping numerical aperture of 1.32 and illumination wavelength of 1.064 µm, numerical analysis proves that 3D trapping of gold microparticles with a radius bigger than 1.0 µm can be readily achieved. By imprinting a digital lens to the spatial light modulator, we slightly defocus the centrally obstructed Gaussian beam to shift the trapping location to the focal plane for clear observation. Experimental results demonstrate stable trapping of gold microparticles with a radius greater than 1.4 µm at high-power illumination, agreeing well with the theoretical predictions. The presented work should be of interest to the community applying metallic microparticles to relevant research.

15.
Ecotoxicol Environ Saf ; 267: 115638, 2023 Nov 15.
Article in English | MEDLINE | ID: mdl-37918333

ABSTRACT

Bisphenol A (BPA) analogues are developed to replace BPA usage. However, their effects on 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) are largely unknown. The inhibitory effects of BPA and 10 BPA analogues with the substituents on the bridge moiety on human and rat 11ß-HSD1 were explored in human and rat liver microsomes. The strength of inhibiting human 11ß-HSD1 was bisphenol FL (IC50, 3.87 µM) > bisphenol Z (6.86 µM) > bisphenol AF (9.42 µM) > bisphenol C (16.14 µM) > bisphenol AP (32.14 µM) = bisphenol B (32.34 µM) > 4,4'-thiodiphenol (67.35 µM) > BPA (297.35 µM) > other BPA analogues (ineffective at 100 µM). The strength of inhibiting rat 11ß-HSD1 was bisphenol Z (IC50, 14.44 µM) > 4,4'-thiodiphenol (19.01 µM) > bisphenol B (20.13 µM) > bisphenol F (22.10 µM) > bisphenol E (33.04 µM) > bisphenol AF (49.67 µM) > bisphenol C > (56.97 µM) > bisphenol AP (62.71 µM) >bisphenol FL (96.31 µM) > other BPA analogues (ineffective at 100 µM). Bisphenol A, AF, AP, B, C, F, FL, Z, and 4,4'-thiodiphenol bind to the active sites of human and rat 11ß-HSD1. Regression of LogP and molecular weight with IC50 values revealed distinct inhibitory pattern (negative correlation for human 11ß-HSD1 vs. positive correlation for rat enzyme). Regression of the lowest binding energy with IC50 values revealed a significant positive regression. 3D QSAR pharmacophore analysis showed one hydrogen bond acceptor and two hydrogen bond donors for human 11ß-HSD1. In conclusion, most BPA analogues are more potent inhibitors of human and rat 11ß-HSD1 enzymes and there is structure-dependent and species-dependent inhibition.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1 , Quantitative Structure-Activity Relationship , Humans , Animals , Rats , Molecular Docking Simulation
16.
Ecotoxicol Environ Saf ; 254: 114715, 2023 Apr 01.
Article in English | MEDLINE | ID: mdl-36871355

ABSTRACT

Bisphenols (BPs) as endocrine-disrupting compounds have drawn attention to their health hazards. Whether a BP interferes with glucocorticoid metabolism remains unclear. 11ß-Hydroxysteroid dehydrogenase 2 (11ß-HSD2) is a key glucocorticoid-metabolizing enzyme that controls fetal glucocorticoid levels across the placental barrier and mineralocorticoid receptor specificity in the kidney. In this study, 11 BPs were tested to inhibit human placental and rat renal 11ß-HSD2 and were analyzed for inhibitory potency, mode action, and docking parameters. BPs had inhibitory potency against human 11ß-HSD2: BPFL>BPAP>BPZ>BPB>BPC>BPAF>BPA>TDP and the IC10 values were 0.21, 0.55, 1.04, 2.04, 2.43, 2.57, 14.43, and 22.18 µM, respectively. All BPs are mixed inhibitors except BPAP, which is a competitive inhibitor for human 11ß-HSD2. Some BPs also inhibited rat renal 11ß-HSD2, with BPB (IC50, 27.74 ± 0.95) > BPZ (42.14 ± 0.59) > BPAF (54.87 ± 1.73) > BPA (77.32 ± 1.20) > other BPs (about 100 µM). Docking analysis showed that all BPs bound to the steroid-binding site, interacting with the catalytic residue Tyr232 of both enzymes and the most potent human 11ß-HSD2 inhibitor BPFL acts possibly due to its large fluorene ring that has hydrophobic interaction with residues Glu172 and Val270 and π-stacking interaction with catalytic residue Tyr232. The increase in the size of substituted alkanes and halogenated groups in the methane moiety of the bridge of BPs increases its inhibitory potency. Regressions of the lowest binding energy with inhibition constant indicated that there was an inverse regression. These results indicated that BPs significantly inhibited human and rat 11ß-HSD2 activity and that there were species-dependent differences.


Subject(s)
Glucocorticoids , Placenta , Rats , Humans , Pregnancy , Female , Animals , Glucocorticoids/metabolism , 11-beta-Hydroxysteroid Dehydrogenases/metabolism , Placenta/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 2/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , Structure-Activity Relationship
17.
Molecules ; 28(13)2023 Jun 21.
Article in English | MEDLINE | ID: mdl-37446556

ABSTRACT

Bisphenol A (BPA) analogues substituted on the benzene ring are widely used in a variety of industrial and consumer materials. However, their effects on the glucocorticoid-metabolizing enzyme 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) remain unclear. The inhibitory effects of 6 BPA analogues on the inhibition of human and rat 11ß-HSD1 were investigated. The potencies of inhibition on human 11ß-HSD1 were bisphenol H (IC50, 0.75 µM) > bisphenol G (IC50, 5.06 µM) > diallyl bisphenol A (IC50, 13.36 µM) > dimethyl bisphenol A (IC50, 30.18 µM) > bisphenol A dimethyl ether (IC50, 33.08 µM) > tetramethyl bisphenol A (>100 µM). The inhibitory strength of these chemicals on rat 11ß-HSD1 was much weaker than that on the human enzyme, ranging from 74.22 to 205.7 µM. All BPA analogues are mixed/competitive inhibitors of both human and rat enzymes. Molecular docking studies predict that bisphenol H and bisphenol G both bind to the active site of human 11ß-HSD1, forming a hydrogen bond with catalytic residue Ser170. The bivariate correlation of IC50 values with LogP (lipophilicity), molecular weight, heavy atoms, and molecular volume revealed a significant inverse regression and the correlation of IC50 values with ΔG (low binding energy) revealed a positive regression. In conclusion, the lipophilicity, molecular weight, heavy atoms, molecular volume, and binding affinity of a BPA analogue determine the inhibitory strength of human and rat 11ß-HSD isoforms.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1 , Benzhydryl Compounds , Humans , Rats , Animals , Molecular Docking Simulation , Benzhydryl Compounds/pharmacology , Phenols/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 2
18.
BMC Microbiol ; 22(1): 205, 2022 08 22.
Article in English | MEDLINE | ID: mdl-35996113

ABSTRACT

BACKGROUND: Bacteria usually secrete a variety of extracellular enzymes to degrade extracellular macromolecules to meet their nutritional needs and enhance their environmental adaptability. Bacillus cereus 0-9, a biocontrol bacterial strain isolated from wheat roots, has three genes annotated as encoding amylases in the genome, but their functions are unknown, and whether they are involved in the colonization process of the bacterium remains to be further studied. METHODS: Mutant gene strains and fluorescently tagged strains were constructed by homologous recombination, and amylase protein was expressed in the prokaryotic Escherichia coli BL21(DE3) expression system. The iodine staining method was used to measure the activity of amylase proteins. We further observed the colonization abilities of the test strains in wheat roots through frozen section technology. RESULTS: The results showed that there were three amylase-encoding genes, amyC, amyP and amyS, in the B. cereus 0-9 genome. Among the three amylase encoding genes, only amyS produced extracellular amylase whose secretion was related to signal peptide at position 1-27. The AmyS protein encoded by the amyS gene is an α-amylase. The growth of Rhizoctonia cerealis was inhibited 84.7% by B. cereus 0-9, but the biocontrol ability of the ΔamyS strain decreased to 43.8% and that of ΔamyS/amyS was restored when the amyS gene was complemented. Furthermore, the biocontrol ability of the ΔamySec strain was decreased to 46.8%, almost the same as that of the ΔamyS mutant. Due to the deletion of the amyS gene, the colonization capacities of ΔamyS (RFP) and ΔamySec (RFP) in wheat roots decreased, while that of ΔamyS/amyS (RFP) was restored after the amyS gene was complemented, indicating that the amyS gene influences the colonization of B. cereus 0-9 in wheat roots. In addition, the colonization and biocontrol abilities of the mutant were restored after the addition of sugars, such as glucose and maltose. CONCLUSIONS: B. cereus 0-9 encodes three genes annotated as amylases, amyC, amyP and amyS. Only the deletion of the amyS gene with a signal peptide did not produce extracellular amylase. The AmyS protein encoded by the amyS gene is an α-amylase. Our results indicated that the amyS gene is closely related to the colonization abilities of B. cereus 0-9 in wheat roots and the biocontrol abilities of B. cereus 0-9 to fight against R. cerealis. The extracellular amylase produced by B. cereus 0-9 can hydrolyze starch and use glucose, maltose and other nutrients to meet the needs of bacterial growth. Therefore, it is very possible that the secretion and hydrolytic activities of extracellular amylase can promote the colonization of B. cereus 0-9 in wheat roots and play important roles in the prevention and control of plant diseases. Our results contribute to exploring the mechanisms of microbial colonization in plant roots.


Subject(s)
Bacillus cereus , Triticum , Amylases/genetics , Amylases/metabolism , Bacillus cereus/genetics , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Escherichia coli/metabolism , Glucose/metabolism , Maltose , Plant Roots/microbiology , Protein Sorting Signals , Triticum/microbiology , alpha-Amylases/genetics , alpha-Amylases/metabolism
19.
J Med Virol ; 94(6): 2787-2795, 2022 06.
Article in English | MEDLINE | ID: mdl-34859449

ABSTRACT

OBJECTIVES: The prevalence of human papillomavirus (HPV) infection and HPV genotypes varies in different regions. However, there is little data on HPV prevalence and genotyping in Guangxi Province, South China. This study conducted a 10-year survey in a health center, to estimate the prevalence characteristics of HPV genotypes. METHODS: By using polymerase chain reaction (PCR) amplification and nucleic acid molecular hybridization, the HPV genotypes were detected from 77,756 females who were patients of the Department of Obstetrics and Gynecology and those who visited the Health Management Center for a physical examination between August 2011 and November 2020. The prevalence, genotypes, age-related HPV infections, as well as chronological change of HPV prevalence, and the HPV genotype distribution were analyzed. RESULTS: The overall prevalence of HPV infection was 21.14% (16,439/77,756). The HPV infection rate differed significantly between the patients of the Department of Obstetrics and Gynecology and the women who underwent a physical examination (22.98% vs. 9.88%, p < 0.05). The prevalence rates of high-risk HPV, low-risk HPV, mixed HPV (mixed high-risk, and low-risk HPV infection), and multiple HPV infections were 18.96% (14,739/77,756), 4.09% (3178/77,756), 1.90% (1478/77,756), and 4.94% (3838/77,756), respectively. The most prevalent genotypes were HPV 52, 16, and 58. The age-associated HPV prevalence showed bimodal curves, with the first peak at <25 years and the second peak at >56 years. CONCLUSIONS: This study provides baseline data on the HPV prevalence in the general female population of Nanning, Guangxi Province. Women <25 and >56 years old faced the greatest threat of HPV infection, and HPV 52, 16, and 58 were the most common genotypes.


Subject(s)
Alphapapillomavirus , Papillomavirus Infections , Uterine Cervical Neoplasms , Adult , China/epidemiology , Female , Genotype , Humans , Male , Middle Aged , Papillomaviridae/genetics , Papillomavirus Infections/epidemiology , Prevalence
20.
Opt Lett ; 47(21): 5700-5703, 2022 Nov 01.
Article in English | MEDLINE | ID: mdl-37219307

ABSTRACT

To date, the helix-like assemblies are known for delivering the most broadband chiroptic response; however, as their dimensions shrink to the nanoscale, it becomes increasingly difficult to realize three-dimensional (3D) building blocks and accurate alignments. In addition, a continuous optical channel requirement hinders the downsizing for integrated photonics. Here, we introduce an alternative approach based on two assembled layers of dielectric-metal nanowires to demonstrate that chiroptic effects similar to helix-like metamaterials can be realized with an ultracompact planar structure by creating dissymmetry using orientation and making use of interference phenomena. We constructed two polarization filters for the near-(NIR) and the mid-infrared (MIR) spectrums that exhibit a broadband (0.835-2.11 µm and 3.84-10.64 µm) chiroptic response with maximum transmission and circular dichroism (CD) of approximately 0.965 and extinction ratio > 600. The structure is easy to fabricate, independent of alignments, and scalable from the visible to MIR range for applications including imaging, medical diagnostics, polarization conversion, and optical communication.

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