ABSTRACT
Gastric cancer (GC) is a major global health concern with poor outcomes. Heterogeneous nuclear ribonucleoprotein U (HNRNPU) is a multifunctional protein that participates in pre-mRNA packaging, alternative splicing regulation, and chromatin remodeling. Its potential role in GC remains unclear. In this study, the expression characteristics of HNRNPU were analyzed by The Cancer Genome Atlas data, Gene Expression Omnibus data, and then further identified by real-time quantitative PCR and immunohistochemistry using tissue specimens. From superficial gastritis, atrophic gastritis, and hyperplasia to GC, the in situ expression of HNRNPU protein gradually increased, and the areas under the curve for diagnosis of GC and its precancerous lesions were 0.911 and 0.847, respectively. A nomogram integrating HNRNPU expression, lymph node metastasis, and other prognostic indicators exhibited an area under the curve of 0.785 for predicting survival risk. Knockdown of HNRNPU significantly inhibited GC cell proliferation, migration, and invasion and promoted apoptosis in vitro. In addition, RNA-sequencing analysis showed that HNRNPU could affect alternative splicing events in GC cells, with functional enrichment analysis revealing that HNRNPU may exert malignant biological function in GC progression through alternative splicing regulation. In summary, the increased expression of HNRNPU was significantly associated with the development of GC, with a good performance in diagnosing and predicting the prognostic risk of GC. Functionally, HNRNPU may play an oncogenic role in GC by regulating alternative splicing.
Subject(s)
Stomach Neoplasms , Humans , Alternative Splicing , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Heterogeneous-Nuclear Ribonucleoprotein U/genetics , Prognosis , Stomach Neoplasms/diagnosis , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolismABSTRACT
The cuticular wax that covers the surfaces of plants is the first barrier against environmental stresses and increasingly accumulates with light exposure. However, the molecular basis of light-responsive wax biosynthesis remains elusive. In grape (Vitis vinifera), light exposure resulted in higher wax terpenoid content and lower decay and abscission rates than controls kept in darkness. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA-seq data were integrated to draw the chromatin accessibility and cis-elements regulatory map to identify the potential action sites. Terpenoid synthase 12 (VvTPS12) and 3-Hydroxy-3-methylglutaryl-CoA reductase 2 (VvHMGR2) were identified as grape wax biosynthesis targets, while VvHYH and VvGATA24 were identified as terpenoid biosynthesis activators, as more abundant wax crystals and higher wax terpenoid content were observed in transiently overexpressed grape berries and Nicotiana benthamiana leaves. The interaction between VvHYH and the open chromatin of VvTPS12 was confirmed qualitatively using a dual luciferase assay and quantitatively using surface plasma resonance, with an equilibrium dissociation constant of 2.81 nM identified via the latter approach. Molecular docking simulation implied the structural nature of this interaction, indicating that 24 amino acid residues of VvHYH, including Arg106A, could bind to the VvTPS12 G-box cis-element. VvGATA24 directly bound to the open chromatin of VvHMGR2, with an equilibrium dissociation constant of 8.59 nM. 12 amino acid residues of VvGATA24, including Pro218B, interacted with the VvHMGR2 GATA-box cis-element. Our work characterizes the mechanism underlying light-mediated wax terpenoid biosynthesis and provides gene targets for future molecular breeding.
ABSTRACT
The tumor microenvironment (TME) assumes a pivotal role in the treatment of oncological diseases, given its intricate interplay of diverse cellular components and extracellular matrices. This dynamic ecosystem poses a serious challenge to traditional research methods in many ways, such as high research costs, inefficient translation, poor reproducibility, and low modeling success rates. These challenges require the search for more suitable research methods to accurately model the TME, and the emergence of 3D bioprinting technology is transformative and an important complement to these traditional methods to precisely control the distribution of cells, biomolecules, and matrix scaffolds within the TME. Leveraging digital design, the technology enables personalized studies with high precision, providing essential experimental flexibility. Serving as a critical bridge between in vitro and in vivo studies, 3D bioprinting facilitates the realistic 3D culturing of cancer cells. This comprehensive article delves into cutting-edge developments in 3D bioprinting, encompassing diverse methodologies, biomaterial choices, and various 3D tumor models. Exploration of current challenges, including limited biomaterial options, printing accuracy constraints, low reproducibility, and ethical considerations, contributes to a nuanced understanding. Despite these challenges, the technology holds immense potential for simulating tumor tissues, propelling personalized medicine, and constructing high-resolution organ models, marking a transformative trajectory in oncological research.
Subject(s)
Bioprinting , Printing, Three-Dimensional , Tumor Microenvironment , Humans , Bioprinting/methods , Neoplasms/pathology , Animals , Tissue Engineering/methods , Biocompatible Materials/chemistry , Tissue Scaffolds/chemistryABSTRACT
A new disaccharide glycoside, franchoside A (1), and 17 known compounds were isolated from the tubers of Arisaema franchetianum Engler. The chemical structure of the previously undescribed compound 1 was elucidated on the basis of detailed spectroscopic analyses. Compounds 1, 2, 6, 10, 14 and 18 showed significant cytotoxic activities at varying IC50 values in the range of 4.0-10.6 µM against five cancer cell lines. Compounds 8, 10, 13 and 17 (10 µM) exhibited moderate anti-inflammatory activities by inhibiting the NF-κB signaling pathway and the release of NO from RAW264.7 macrophages induced by lipopolysaccharide (LPS), while compounds 1, 9, 14, 15 and 16 showed weak anti-inflammatory activities.
Subject(s)
Antineoplastic Agents , Arisaema , Glycosides/pharmacology , Glycosides/chemistry , Cell Line , Anti-Inflammatory Agents/pharmacology , Lipopolysaccharides/pharmacologyABSTRACT
In recent years, there has been a significant increase in the prevalence of thyroid diseases, particularly hypothyroidism. In this study, we investigated the impact and mechanisms of Chemical permeation enhancement(CPE) on transdermal permeation of levothyroxine sodium (L-T4) patches.We found that the combination of oleic acid (OA) and Azone (NZ) yielded the best transdermal permeation effect for L-T4.Subsequently, we also investigated the relevant propermeability mechanism.The results demonstrate that the combined application of OA and NZ significantly enhances the transdermal permeation of L-T4 compared to individual applications,it is attributed to two mechanisms: firstly, OA improves drug release by increasing the flowability of the pressure-sensitive adhesive (PSA) matrix; secondly, both OA and NZ act on the stratum corneum, especially facilitating L-T4 permeation through the hair follicle pathway. No skin irritation or cytotoxicity is observed with these final patches, which exhibit a remarkable therapeutic effect on hypothyroidism. this study contributes to the development of transdermal formulations of L-T4.
Subject(s)
Administration, Cutaneous , Oleic Acid , Skin Absorption , Thyroxine , Oleic Acid/chemistry , Thyroxine/administration & dosage , Thyroxine/pharmacology , Thyroxine/pharmacokinetics , Animals , Skin Absorption/drug effects , Transdermal Patch , Skin/metabolism , Skin/drug effects , Drug Liberation , Mice , Permeability , Hypothyroidism/drug therapy , Hypothyroidism/metabolism , Humans , Chemistry, Pharmaceutical/methods , MaleABSTRACT
BACKGROUND: Glutamate dysregulation is one of the key pathogenic mechanisms of major depressive disorder (MDD), and glutamate chemical exchange saturation transfer (GluCEST) has been used for glutamate measurement in some brain diseases but rarely in depression. PURPOSE: To investigate the GluCEST changes in hippocampus in MDD and the relationship between glutamate and hippocampal subregional volumes. STUDY TYPE: Cross-sectional. SUBJECTS: Thirty-two MDD patients (34% males; 22.03 ± 7.21 years) and 47 healthy controls (HCs) (43% males; 22.00 ± 3.28 years). FIELD STRENGTH/SEQUENCE: 3.0 T; magnetization prepared rapid gradient echo (MPRAGE) for three-dimensional T1-weighted images, two-dimensional turbo spin echo GluCEST, and multivoxel chemical shift imaging (CSI) for proton magnetic resonance spectroscopy (1 H MRS). ASSESSMENT: GluCEST data were quantified by magnetization transfer ratio asymmetry (MTRasym ) analysis and assessed by the relative concentration of 1 H MRS-measured glutamate. FreeSurfer was used for hippocampus segmentation. STATISTICAL TESTS: The independent sample t test, Mann-Whitney U test, Spearman's correlation, and partial correlation analysis were used. P < 0.05 was considered statistically significant. RESULTS: In the left hippocampus, GluCEST values were significantly decreased in MDD (2.00 ± 1.08 [MDD] vs. 2.62 ± 1.41 [HCs]) and showed a significantly positive correlation with Glx/Cr (r = 0.37). GluCEST values were significantly positively correlated with the volumes of CA1 (r = 0.40), subiculum (r = 0.40) in the left hippocampus and CA1 (r = 0.51), molecular_layer_HP (r = 0.50), GC-ML-DG (r = 0.42), CA3 (r = 0.44), CA4 (r = 0.44), hippocampus-amygdala-transition-area (r = 0.46), and the whole hippocampus (r = 0.47) in the right hippocampus. Hamilton Depression Rating Scale scores showed significantly negative correlations with the volumes of the left presubiculum (r = -0.40), left parasubiculum (r = -0.47), and right presubiculum (r = -0.41). DATA CONCLUSION: GluCEST can be used to measure glutamate changes and help to understand the mechanism of hippocampal volume loss in MDD. Hippocampal volume changes are associated with disease severity. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.
Subject(s)
Depressive Disorder, Major , Male , Humans , Female , Depressive Disorder, Major/diagnostic imaging , Glutamic Acid , Cross-Sectional Studies , Depression , Hippocampus/diagnostic imaging , Magnetic Resonance Imaging/methodsABSTRACT
Al-KBC was produced through the simple pyrolysis of Al-modified kapok fibres at high temperatures. Using the N2 adsorption Brunauer Emmett Teller (BET) process, Fourier transforms infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), the energy-dispersive X-ray spectroscopy (EDS) spectroscopy, and X-ray photoelectron spectroscopy (XPS), the sorbent changes and characteristics were analysed. As a result of Al's addition to the fibre's surface, Al-KBC exhibited superior As(V) adsorption performance compared to KBC due to better pore structures. Experiments on the kinetics of As(V) adsorption revealed that the adsorption followed the pseudo-second-order model and that intradiffusion was not the only factor governing the adsorption. Experiments with isotherms indicated that the adsorption mechanism corresponded to the Langmuir model, and the adsorption capacity Qm of Al-KBC at 25 °C was 483 µg/g. The thermodynamic experiments suggested that the adsorption reactions were spontaneous endothermic with a random approach at the adsorption interface. 25 mg/L of coexisting ions such as sulphate and phosphate reduced the sorbent As(V) removal ability to 65% and 39%. After seven cycles of adsorption/desorption, Al-KBC demonstrated satisfactory performance in terms of reusability, adsorbing 53% of 100 µg/L As(V) from the water. This novel BC can probably be used as a filter to purify groundwater with high As(V) concentration in the rural zone.
Subject(s)
Arsenates , Water Pollutants, Chemical , Adsorption , Spectroscopy, Fourier Transform Infrared , Water Pollutants, Chemical/chemistry , Kinetics , Water , Hydrogen-Ion ConcentrationABSTRACT
Circadian systems provide a fitness advantage to organisms by allowing them to adapt to daily changes of environmental cues, such as light/dark cycles. The molecular mechanism underlying the circadian clock has been well characterized. However, how internal circadian clocks are entrained with regular daily light/dark cycles remains unclear. By collecting and analyzing indirect calorimetry (IC) data from more than 2000 wild-type mice available from the International Mouse Phenotyping Consortium (IMPC), we show that the onset time and peak phase of activity and food intake rhythms are reliable parameters for screening defects of circadian misalignment. We developed a machine learning algorithm to quantify these two parameters in our misalignment screen (SyncScreener) with existing datasets and used it to screen 750 mutant mouse lines from five IMPC phenotyping centres. Mutants of five genes (Slc7a11, Rhbdl1, Spop, Ctc1 and Oxtr) were found to be associated with altered patterns of activity or food intake. By further studying the Slc7a11tm1a/tm1a mice, we confirmed its advanced activity phase phenotype in response to a simulated jetlag and skeleton photoperiod stimuli. Disruption of Slc7a11 affected the intercellular communication in the suprachiasmatic nucleus, suggesting a defect in synchronization of clock neurons. Our study has established a systematic phenotype analysis approach that can be used to uncover the mechanism of circadian entrainment in mice.
Subject(s)
Circadian Rhythm/genetics , Amino Acid Transport System y+/genetics , Animals , Machine Learning , Male , Mice , Mice, Inbred C57BL , Mutation , Receptors, Oxytocin/genetics , Repressor Proteins/genetics , Serine Endopeptidases/genetics , Telomere-Binding Proteins/genetics , Ubiquitin-Protein Ligase Complexes/geneticsABSTRACT
A Gram-stain-positive, anaerobic, spore-forming, rod-shaped (0.4-0.6 µm×2.5-3.2 µm), flagellated bacterium, designated strain YB-6T, was isolated from activated sludge of an anaerobic tank at Weizhou marine oil mining wastewater treatment plant in Beihai, Guangxi, PR China. The culture conditions were 25-45 °C (optimum, 37 °C), pH 4-12 (pH 7.0) and NaCl concentration of 0-7â% w/v (0%). Strain YB-6T grew slowly in petroleum wastewater and removed 68.2â% of the total organic carbon in petroleum wastewater within 10 days. Concentrations of naphthalene, anthracene and phenanthrene at an initial concentration of 50 mg l-1 were reduced by 32.8, 40.4 and 14.6â%, respectively, after 7 days. Phylogenetic analysis of the 16S rRNA gene sequence indicated that strain YB-6T belongs to Clostridium cluster I and is most closely related to Clostridium uliginosum CK55T (98.5â% similarity). The genome size of strain YB-6T was 3.96 Mb, and the G+C content was 26.5 mol%. The average nucleotide identity value between strain YB-6T and C. uliginosum CK55T was 81.9â%. The major fatty acids in strain YB-6T were C14â:â0 FAME, C16â:â0 FAME and summed feature 4 (unknown 14.762 and/or C15â:â2 FAME). The main polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, five unidentified aminophospholipids, one unidentified glycolipid and one unidentified aminolipid. Diaminopimelic acid was not detected in the strain YB-6T cell walls. Whole-cell sugars mainly consisted of ribose and galactose. Based on the results of phenotypic and genotypic analyses, strain YB-6T represents a novel species of the genus Clostridium, for which the name Clostridium weizhouense sp. nov. is proposed. The type strain is YB-6T (=GDMCC 1.2529T=JCM 34754T).
Subject(s)
Petroleum , Sewage , Anaerobiosis , Bacteria, Anaerobic/genetics , Bacterial Typing Techniques , Base Composition , China , Clostridium , DNA, Bacterial/genetics , Fatty Acids/chemistry , Phospholipids/chemistry , Phylogeny , RNA, Ribosomal, 16S/genetics , Sequence Analysis, DNA , Sewage/microbiology , Wastewater/microbiologyABSTRACT
Follistatin-like 1 (FSTL1) is a matricellular protein that is upregulated during development and disease, including idiopathic pulmonary fibrosis (IPF), keloid, and arthritis. The profibrotic and pro-inflammatory roles of FSTL1 have been intensively studied during the last several years, as well as in this report. We screened and identified epitope-specific monoclonal neutralizing antibodies (nAbs) to functionally block FSTL1. FSTL1 nAbs attenuated bleomycin-induced pulmonary and dermal fibrosis in vivo and transforming growth factor (TGF)-ß1-induced dermal fibrosis ex vivo in human skin. In addition, FSTL1 nAbs significantly reduced existing lung fibrosis and skin fibrosis in experimental models. FSTL1 nAbs exerted their potent antifibrotic effects via reduced TGF-ß1 responsiveness and subsequent myofibroblast activation and extracellular matrix production. We also observed that FSTL1 nAbs attenuated the severity of collagen-induced arthritis in mice, which was accompanied by reduced inflammatory responses in vitro. Our findings suggest that FSTL1 nAbs are a promising new therapeutic strategy for the treatment of multiple organ fibrosis and systemic autoimmune diseases.
Subject(s)
Autoimmune Diseases/etiology , Autoimmune Diseases/metabolism , Biomarkers , Disease Susceptibility , Follistatin-Related Proteins/metabolism , Idiopathic Pulmonary Fibrosis/etiology , Idiopathic Pulmonary Fibrosis/metabolism , Animals , Autoimmune Diseases/drug therapy , Autoimmune Diseases/pathology , Disease Models, Animal , Drug Discovery , Fibrosis , Follistatin-Related Proteins/antagonists & inhibitors , Follistatin-Related Proteins/genetics , Gene Expression , Humans , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/pathology , Mice , Molecular Targeted Therapy , Transforming Growth Factor beta1/metabolismABSTRACT
With the application of the concept of supramolecular chemistry to various fields, a large number of supramolecules have been discovered. The chemical components of traditional Chinese medicine have various sources and unique structures. During the high-temperature boiling process, various active components form supramolecules due to complex interactions. The supramolecular structure in a traditional Chinese medicine decoction can not only be used as a drug carrier to promote the absorption and distribution of medicinal components but may also have biological activities superior to those of single active ingredients or their physical mixtures. By summarizing the relevant research results over recent years, this paper introduces the research progress regarding supramolecules in various decoctions, laying a foundation for further research into supramolecules in traditional Chinese medicine decoctions, and provides a new perspective for revealing the compatibility mechanisms of traditional Chinese medicine, guiding clinical medications, and developing new nanometers materials.
Subject(s)
Drugs, Chinese Herbal , Medicine, Chinese Traditional , Drugs, Chinese Herbal/chemistryABSTRACT
5-Hydroxymethyl-2'-deoxycytidine (5hmdC) phosphoramidite and triphosphate are important building blocks in 5hmdC-containing DNA synthesis for epigenetic studies. However, efficient and practical methods for the synthesis of these compounds are still limited. The current research provides an intensively improved synthetic method that enables the preparation of commercially available cyanoethyl-protected 5hmdC phosphoramidite with an overall yield of 39% on 5 g scale. On the basis of facile and efficient accesses to cyanoethyl protected-5hmdU and 5hmdC intermediates, two efficient synthetic routes for 5hmdC triphosphate were also developed.
ABSTRACT
Hafnium(IV) triflate (Hf(OTf)4) has been identified as a potent catalyst for the direct three-component synthesis of ß-carbamate ketones. This new method, featuring a low catalyst loading, fast reaction rate, and solvent-free conditions, provided facile access to a diversity of carbamate-protected Mannich bases. A mechanistic investigation indicated that the three-component reaction proceeds via sequential aldol condensation and aza-Michael addition, but not the Mannich-type pathway.
ABSTRACT
In the past decade, selenocyclization has been extensively exploited for the preparation of a wide range of selenylated heterocycles with versatile activities. Previously, selenium electrophile-based and FeCl3-promoted methods were employed for the synthesis of selenylated benzoxazines. However, these methods are limited by starting material availability and low atomic economy, respectively. Inspired by the recent catalytic selenocyclization approaches based on distinctive pathways, we rationally constructed an efficient and greener double-redox catalytic system for the access to diverse selenylated benzoxazines. The coupling of I2/I- and Fe3+/Fe2+ catalytic redox cycles enables aerial O2 to act as the driving force to promote the selenocyclization. Control and test redox experiments confirmed the roles of each component in the catalytic system, and a PhSeI-based pathway is proposed for the selenocyclization process.
Subject(s)
Oxygen , Selenium , Oxygen/metabolism , Benzoxazines , Oxidation-Reduction , CatalysisABSTRACT
Etomidate is a potent and rapidly acting anesthetic with high therapeutic index (TI) and superior hemodynamic stability. However, side effect of suppressing adrenocortical function limits its clinical use. To overcome this side effect, we designed a novel etomidate analog, EL-0052, aiming to retain beneficial properties of etomidate and avoid its disadvantage of suppressing adrenocortical steroid synthesis. Results exhibited that EL-0052 enhanced GABAA receptors currents with a concentration for EC50 of 0.98 ± 0.02 µM, which was about three times more potent than etomidate (3.07 ± 1.67 µM). Similar to hypnotic potency of etomidate, EL-0052 exhibited loss of righting reflex with ED50s of 1.02 (0.93-1.20) mg/kg in rats and 0.5 (0.45-0.56) mg/kg in dogs. The TI of EL-0052 in rats was 28, which was higher than 22 of etomidate. There was no significant difference in hypnotic onset time, recovery time, and walking time between EL-0052 and etomidate in rats. Both of them had minor effects on mean arterial pressure in dogs. EL-0052 had no significant effect on adrenocortical function in dogs even at a high dose (4.3 × ED50), whereas etomidate significantly inhibited corticosteroid secretion. The inhibition of cortisol synthesis assay showed that EL-0052 had a weak inhibition on cortisol biosynthesis in human H259 cells with an IC50 of 1050 ± 100 nM, which was 2.09 ± 0.27 nM for etomidate. EL-0052 retains the favorable properties of etomidate, including potent hypnotic effect, rapid onset and recovery, stable hemodynamics, and high therapeutic index without suppression of adrenocortical function. SIGNIFICANCE STATEMENT: The novel etomidate analog EL-0052 retains the favorable properties of etomidate without suppressing adrenocortical function and provides a new strategy to optimize the structure of etomidate.
Subject(s)
Adrenal Cortex/drug effects , Blood Pressure/drug effects , Etomidate/analogs & derivatives , Etomidate/pharmacology , Hemodynamics/drug effects , Hypnotics and Sedatives/pharmacology , Adrenal Cortex/metabolism , Animals , Blood Pressure/physiology , Corticosterone/blood , Dogs , Dose-Response Relationship, Drug , Female , HEK293 Cells , Hemodynamics/physiology , Humans , Male , Rats , Rats, Wistar , Reflex, Righting/drug effects , Reflex, Righting/physiologyABSTRACT
Chemotherapy causes various side effects, including cognitive impairment, known as 'chemobrain'. In this study, we determined whether a novel acupuncture mode called electroacupuncture trigeminal nerve stimulation plus body acupuncture (EA/TNS + BA) could produce better outcomes than minimum acupuncture stimulation (MAS) as controls in treating chemobrain and other symptoms in breast cancer patients. In this assessor- and participant-blinded, randomized controlled trial, 93 breast cancer patients under or post chemotherapy were randomly assigned to EA/TNS + BA (n = 46) and MAS (n = 47) for 2 sessions per week over 8 weeks. The Montreal Cognitive Assessment (MoCA) served as the primary outcome. Digit span test was the secondary outcomes for attentional function and working memory. The quality of life and multiple functional assessments were also evaluated. EA/TNS + BA treated group had much better performance than MAS-treated group on reverse digit span test at Week 2 and Week 8, with medium effect sizes of 0.53 and 0.48, respectively, although no significant differences were observed in MoCA score and prevalence of chemobrain between the two groups. EA/TNS + BA also markedly reduced incidences of diarrhoea, poor appetite, headache, anxiety, and irritation, and improved social/family and emotional wellbeing compared to MAS. These results suggest that EA/TNS + BA may have particular benefits in reducing chemotherapy-induced working memory impairment and the incidence of certain digestive, neurological, and distress-related symptoms. It could serve as an effective intervention for breast cancer patients under and post chemotherapy (trial registration: https://www.clinicaltrials.gov: NCT02457039).
Subject(s)
Acupuncture Therapy , Breast Neoplasms , Chemotherapy-Related Cognitive Impairment , Cognitive Dysfunction , Electroacupuncture , Breast Neoplasms/complications , Breast Neoplasms/drug therapy , Cognitive Dysfunction/chemically induced , Humans , Quality of Life , Treatment Outcome , Trigeminal NerveABSTRACT
BACKGROUND: Hepatic fibrosis is a pathological response of the liver to a variety of chronic stimuli. Hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. Follistatin like 1 (Fstl1) is a secreted glycoprotein induced by transforming growth factor-ß1 (TGF-ß1). However, the precise functions and regulation mechanisms of Fstl1 in liver fibrogenesis remains unclear. METHODS: Hepatic stellate cell (HSC) line LX-2 stimulated by TGF-ß1, primary culture of mouse HSCs and a model of liver fibrosis induced by CCl4 in mice was used to assess the effect of Fstl1 in vitro and in vivo. RESULTS: Here, we found that Fstl1 was significantly up regulated in human and mouse fibrotic livers, as well as activated HSCs. Haplodeficiency of Fstl1 or blockage of Fstl1 with a neutralizing antibody 22B6 attenuated CCl4-induced liver fibrosis in vivo. Fstl1 modulates TGF-ß1 classic Samd2 and non-classic JNK signaling pathways. Knockdown of Fstl1 in HSCs significantly ameliorated cell activation, cell migration, chemokines C-C Motif Chemokine Ligand 2 (CCL2) and C-X-C Motif Chemokine Ligand 8 (CXCL8) secretion and extracellular matrix (ECM) production, and also modulated microRNA-29a (miR29a) expression. Furthermore, we identified that Fstl1 was a target gene of miR29a. And TGF-ß1 induction of Fstl1 expression was partially through down regulation of miR29a in HSCs. CONCLUSIONS: Our data suggests TGF-ß1-miR29a-Fstl1 regulatory circuit plays a key role in regulation the HSC activation and ECM production, and targeting Fstl1 may be a strategy for the treatment of liver fibrosis. Video Abstract.
Subject(s)
Antibodies, Neutralizing/therapeutic use , Follistatin-Related Proteins/antagonists & inhibitors , Liver Cirrhosis/therapy , MicroRNAs/genetics , Transforming Growth Factor beta1/metabolism , Animals , Carbon Tetrachloride , Cells, Cultured , Follistatin-Related Proteins/genetics , Follistatin-Related Proteins/metabolism , Gene Expression Regulation/drug effects , Haploidy , Humans , Liver Cirrhosis/chemically induced , Liver Cirrhosis/genetics , Liver Cirrhosis/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , MicroRNAs/metabolismABSTRACT
Biomimetic total syntheses of baefrutones A-D (1-4), baeckenon B (5), and frutescones A, D-F (6-9), isolated from the leaves of Baeckea frutescens, were achieved in 9, 8, and 5 steps, respectively, in moderate to good yields (72-83%). The synthetic routes feature the Michael addition, oxidative [4 + 2] cycloaddition, and water-promoted Diels-Alder click reactions as the key steps. This study helped gain thorough mechanistic insights into the biosynthetic origins and provided a facile approach for the construction of a library of natural tasmanone-based meroterpenoid analogues. Moreover, compounds 1-9 show potent inhibitory effects against S. paratyphi and/or C. albicans with MIC values of 3.125-25 µg mL-1, and they could be promising lead molecules for the design of new antibiotic agents.
Subject(s)
Biomimetic Materials/pharmacology , Monoterpenes/pharmacology , Terpenes/pharmacology , Biomimetic Materials/chemical synthesis , Biomimetic Materials/chemistry , Candida albicans/drug effects , Cycloaddition Reaction , Density Functional Theory , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Monoterpenes/chemical synthesis , Monoterpenes/chemistry , Oxidation-Reduction , Pseudomonas aeruginosa/drug effects , Salmonella/drug effects , Staphylococcus aureus/drug effects , Stereoisomerism , Structure-Activity Relationship , Terpenes/chemical synthesis , Terpenes/chemistryABSTRACT
BACKGROUND: Coronovirus disease 2019 (COVID-19) first broke out in Wuhan, Hubei Province, China, in 2019, and now it spreads in more than 100 countries around the world. On January 30th, the World Health Organization (WHO) declared COVID-19 a public health emergency of international concern. It was classified as a pandemic by the WHO on March 11, 2020. With the increase in the number of cases reported by various countries every day, the COVID-19 pandemic has attracted more and more attention around the world. At the same time, this public health emergency has caused a variety of psychological problems, such as panic disorder, anxiety, and depression. In addition, the Wuhan Mental Health Center's analysis of 2144 calls from the psychological hotline from February 4 to February 20, 2020, showed that the general public accounted for 70%, medical workers accounted for 2.2%, patients with mental disorders accounted for 19.5%, and other personnel accounted for 8.3% (https://mp.weixin.qq.com/s/kmff1vnaLsT2d9xQkK5pwg). CONCLUSION: Therefore, while controlling the pandemic, the government should also pay attention to the mental health of the general public, medical workers, and patients with mental disorders. Community mental health service systems, online mental health services, telemedicine, and other measures for patients with mental disorders may play a vital role during the pandemic.
Subject(s)
Communicable Disease Control , Coronavirus Infections , Delivery of Health Care , Health Personnel/psychology , Mental Disorders/psychology , Pandemics , Pneumonia, Viral , Betacoronavirus , COVID-19 , Community Mental Health Services , Humans , Internet , Mental Health , Mental Health Services , SARS-CoV-2 , TelemedicineABSTRACT
Yellow rust is the most extensive disease in wheat cultivation, seriously affecting crop quality and yield. This study proposes sensitive wavelet features (WFs) for wheat yellow rust monitoring based on unmanned aerial vehicle hyperspectral imagery of different infestation stages [26 days after inoculation (26 DAI) and 42 DAI]. Furthermore, we evaluated the monitoring ability of WFs and vegetation indices on wheat yellow rust through linear discriminant analysis and support vector machine (SVM) classification frameworks in different infestation stages, respectively. The results show that WFs-SVM have promising potential for wheat yellow rust monitoring in both the 26 DAI and 42 DAI stages.