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1.
Microb Biotechnol ; 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35006649

RESUMO

3, 4-Dihydroxyphenyl-l-alanine (l-DOPA) is a compound of high medical value and is considered effective as a treatment for Parkinson's disease. Currently, bioproduction of l-DOPA is mainly carried out by whole-cell catalysis mediated by recombinant Escherichia coli carrying heterogeneous tyrosine phenol lyase. Vibrio natriegens is increasingly attracting attention owing to its superiority, including extremely rapid growth and high soluble protein expression capacity. In this study, we attempt to develop an efficient whole-cell catalyst for l-DOPA production using V. natriegens as the chassis. The maximum soluble protein expression by V. natriegens was accomplished in 4 h at 37°C, which was equivalent to that achieved by E. coli in 16 h at 16°C. Furthermore, the maximum productivity reached over 10.0 g l-1 h-1 in the early stage of biocatalysis, nearly two-fold higher than previously reported. Approximately 54.0 g l-1 l-DOPA was obtained with a catechol conversion rate greater than 95%. In conclusion, V. natriegens displays advantages, including rapid protein expression and catalytic rate in the catalysis process for l-DOPA production. These findings strongly suggest that V. natriegens has remarkable potential as a whole-cell catalysis chassis for the production of valuable chemicals.

2.
Microbiol Spectr ; : e0086021, 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35019682

RESUMO

Human neutrophil peptide-1 (HNP-1) is a promising antibiotic candidate, but its clinical applications have been hampered by challenges during mass production and an inadequate understanding of its bactericidal mechanisms. In this study, we demonstrated that Escherichia coli expressing full-length preproHNP-1 secretes a soluble form of HNP-1, which can be recovered from the total cell lysate after isopropyl thio-ß-d-galactoside (IPTG) induction and ultrafiltration. Label-free quantitative proteomics and co-immunoprecipitation experiments revealed that HNP-1 induces cell apoptosis in bacteria by causing DNA and membrane damage. Notably, we found that HNP-1 disrupts the DNA damage response pathway by interfering with the binding of RecA to single-stranded DNA (ssDNA). Further experiments demonstrated that HNP-1 encapsulated in liposomes inhibits the growth of methicillin-resistant Staphylococcus aureus (MRSA) and meropenem-resistant Pseudomonas aeruginosa (MRPA). These results indicated that recombinant protein expression may be a simple and cost-effective solution to produce HNP-1 and that RecA inhibition via HNP-1 may serve as an alternative strategy to counteract antibiotic resistance. IMPORTANCE Human neutrophil peptide-1 (HNP-1) is a promising antibiotic candidate, but its clinical application has been hampered by the difficulty of mass production and an inadequate understanding of its bactericidal mechanisms. In this study, we demonstrated that recombinant protein expression combined with ultrafiltration may be a simple and cost-effective solution to HNP-1 production. We further found that HNP-1 induces bacterial apoptosis and prevents its SOS repair pathway from binding to the RecA protein, which may be a new antibacterial mechanism. In addition, we showed that HNP-1 encapsulated in liposomes inhibits the growth of methicillin-resistant Staphylococcus aureus (MRSA) and meropenem-resistant Pseudomonas aeruginosa (MRPA). These results provide new insights into the production and antibacterial mechanism of HNP-1, both of which may promote its clinical application.

3.
mBio ; : e0360421, 2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35038913

RESUMO

Membrane proteins, particularly those that are α-helical, such as transporters and G-protein-coupled receptors (GPCRs), have significant biological relevance. However, their expression and purification pose difficulties because of their poor water solubilities, which impedes progress in this field. The QTY method, a code-based protein-engineering approach, was recently developed to produce soluble transmembrane proteins. Here, we describe a comprehensive Web server built for QTY design and its relevance for in silico analyses. Typically, the simple design model is expected to require only 2 to 4 min of computer time, and the library design model requires 2 to 5 h, depending on the target protein size and the number of transmembrane helices. Detailed protocols for using the server with both the simple design and library design modules are provided. Methods for experiments following the QTY design are also included to facilitate the implementation of this approach. The design pipeline was further evaluated using microbial transmembrane proteins and structural alignment between the designed proteins and their origins by employing AlphaFold2. The results reveal that mutants generated by the developed pipeline were highly identical to their origins in terms of three-dimensional (3D) structures. In summary, the utilization of our Web server and associated protocols will enable QTY-based protein engineering to be implemented in a convenient, fast, accurate, and rational manner. The Protein Solubilizing Server (PSS) is publicly available at http://pss.sjtu.edu.cn. IMPORTANCE Water-soluble expression and purification are of considerable importance for protein identification and characterization. However, there has been a lack of an effective method for water-soluble expression of membrane proteins, which has severely hampered their studies. Here, an enabling comprehensive Web server, PSS, was developed for designing water-soluble mutants of α-helical membrane proteins, based on QTY design, a code-based protein-engineering approach. With microbial transmembrane proteins and GPCRs as examples, we systematically evaluated the server and demonstrated its successful performance. PSS is readily available for worldwide users as a Web-based tool, rendering QTY-based protein engineering convenient, efficient, accurate, and rational.

4.
Health Qual Life Outcomes ; 20(1): 13, 2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35062969

RESUMO

BACKGROUND: Urinary incontinence is a common and distressing condition affecting women worldwide. However, urinary incontinence during pregnancy was less studied. The study aims to investigate the prevalence and risk factors of urinary incontinence during pregnancy, its impact on health-related quality of life as well as associated help-seeking behavior. METHODS: Eligible women were enrolled in the obstetric wards of a tertiary maternity hospital. Urinary incontinence, generic and specific health-related quality of life were assessed using the International Consultation on Incontinence Modular Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF), the 12-Item Short Form Health Survey version 2 (SF-12v2), Urogenital Distress Inventory short form (UDI-6) and Incontinence Impact Questionnaire short form (IIQ-7), respectively. Multiple logistic regression and multiple linear regression analysis were used to examine risk factors of urinary incontinence during pregnancy and the impact of incontinence on health-related quality of life of pregnant women, respectively. RESULTS: A total of 1243 women were enrolled in the study. The prevalence of urinary incontinence during pregnancy was 52.0%. Most women suffered from mild or moderate incontinence. Five risk factors were identified by multiple logistic regression. Urinary incontinence before pregnancy was the strongest predictor for incontinence during pregnancy (OR = 4.178, 95% CI = 2.690-6.490), followed by history of vaginal birth, coffee consumption, childhood enuresis and history of urinary tract infection. Urinary incontinence had significant impact on health-related quality of life during pregnancy. Only 14.8% of pregnant women sought professional help for urinary symptoms. CONCLUSIONS: Urinary incontinence was highly prevalent in pregnant women, with a broad detrimental effect on health-related quality of life. Five factors were confirmed to be associated with increasing the risk of developing urinary incontinence during pregnancy. The help-seeking behavior during pregnancy was discouraging. Targeted interventions are warranted to facilitate the prevention of urinary incontinence and improvement of health-related quality of life in pregnant women.

5.
Biochem Pharmacol ; 197: 114913, 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35032461

RESUMO

Nitazoxanide and related thiazolides are a novel class of anti-infectious agents against protozoan parasites, bacteria and viruses. In recent years, it is demonstrated that thiazolides can also induce cell cycle arrest and apoptotic cell death in cancer cells. Due to their fast proliferating nature, cancer cells highly depend on the proteasome system to remove aberrant proteins. Many of these aberrant proteins are regulators of cell cycle progression and apoptosis, such as the cyclins, BCL2 family members and nuclear factor of κB (NF-κB). Here, we demonstrate at both molecular and cellular levels that the 20S proteasome is a direct target of NTZ and related thiazolides. By concurrently inhibiting the multiple catalytic subunits of 20S proteasome, NTZ promotes cell cycle arrest and triggers cell death in colon cancer cells, either directly or as a sensitizer to other anti-tumor agents, especially doxorubicin. We further show that the binding mode of NTZ in the ß5 subunit of the 20S proteasome is different from that of bortezomib and other existing proteasome inhibitors. These findings provide new insights in the design of novel small molecular proteasome inhibitors as anti-tumor agents suitable for solid tumor treatment in an oral dosing form.

6.
Phytochemistry ; 195: 113073, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34974412

RESUMO

Six flavonoids, namely, three undescribed biflavonoids, one undescribed 8-aryl flavonoid, and two known compounds, were isolated from Selaginella tamariscina (P.Beauv.) Spring. The structures and absolute configurations of those undescribed compounds were established by NMR spectroscopy data, HRESIMS analyses and electronic circular dichroism (ECD) analyses. In addition, all the isolates were evaluated for their hypoglycemic activity in HepG2 cells. Involvenflavone H, I, and J significantly increased glucose consumption in both normal and insulin-resistant HepG2 cells. Interestingly, these three compounds can effectively upregulate the protein expression of glucokinase (GCK) and adenylate cyclases (ADCYs). These results suggested that involvenflavone H, I, and J (especially involvenflavone J) may have potent hypoglycemic activity, which also provided promising molecular targets for the treatment of diabetes.


Assuntos
Selaginellaceae , Flavonoides/farmacologia , Hipoglicemiantes/farmacologia , Insulina , Estrutura Molecular
7.
J Neurogastroenterol Motil ; 28(1): 95-103, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34980692

RESUMO

Background/Aims: Antidepressants are effective in patients with functional dyspepsia (FD). However, stigma associated with FD and antidepressants may affect treatment adherence. This study aims to explore possible communication strategies to alleviate stigma and improve adherence in patients with FD. Methods: In this randomized, single-center, and single-blind trial, 160 patients with FD initiating antidepressant treatment were recruited. Different communication strategies were performed when prescribing antidepressants. Participants in Group 1 were told that brain is the "headquarters" of gut, and that antidepressants could act as neuromodulators to relieve symptoms of FD through regulating the functions of gut and brain. Participants in Group 2 were told that antidepressants were empirically effective for FD. Stigma scores, medication-related stigma, treatment compliance, and efficacy were analyzed. Results: After 8-week antidepressant treatment, the proportion of patients with FD with decreased stigma scores in Group 1 was significantly higher than in Group 2 (internalized stigma: 64.10% vs 12.00%; perceived stigma: 55.13% vs 13.33%; P < 0.01). Medication-related stigma was lower in Group 1 than in Group 2 (P < 0.05 for 3 of 4 questions). Concurrently, patients in Group 1 had better treatment compliance (0.71 ± 0.25 vs 0.60 ± 0.25, P < 0.01) and efficacy. In Group 1, participants with decreased post-treatment stigma scores showed better treatment compliance and efficacy than those with non-decreased scores. Decrease in stigma scores positively correlated with treatment compliance. Conclusion: Improving knowledge of patients with FD of the disease and antidepressants via proper communication may be an effective way to alleviate stigma and promote adherence.

8.
Small ; : e2105972, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34989114

RESUMO

Water electrolysis affords a promising approach to large-scale hydrogen yield, but its efficiency is restrained by the sluggish water dissociation kinetics. Here, an efficient bifunctional electrocatalyst of in situ formed crystalline nickel metaphosphate on amorphous NiMoOx nanoarrays supported on nickel foam (c-Ni2 P4 O12 /a-NiMoOx /NF) for both hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) in alkaline solution is reported. The c-Ni2 P4 O12 /a-NiMoOx /NF can deliver a current density of 10 mA cm-2 at a low potential of 78 mV for HER, and a current density of 20 mA cm-2 at an overpotential of 250 mV for OER. Moreover, it only requires a small cell voltage of 1.55 V at 10 mA cm-2 for robust water splitting with outstanding long-term durability over 84 h. Various spectroscopic studies reveal that in situ surface reconstruction is crucial for the enhanced catalytic activity, where c-Ni2 P4 O12 /a-NiMoOx is transformed into c-Ni2 P4 O12 /a-NiMoO4 during the HER process, and into c-Ni2 P4 O12 /a-NiOOH in the OER process. This work may provide a new strategy for uncovering the catalytic mechanism of crystalline-amorphous catalysts.

9.
J Exp Anal Behav ; 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35025105

RESUMO

Two experiments examined the effect of risk on waiting preference and temporal preference reversal. Participants made binary choices between smaller-sooner (SS) and larger-later (LL) options following a 2 (time: immediate choices vs. non-immediate choices) x 4 (risk condition) within-subjects design. Risk conditions varied in whether the SS and/or the LL was risky or certain. Experiment 1 focused on choices with small magnitudes of payoffs and delays, whereas Experiment 2 focused on large magnitudes. Both experiments showed that making one option risky increased preference for the other option, whereas making both options risky had no impact on waiting preference. Pooling risk conditions together, participants in both experiments demonstrated temporal preference reversal. However, participants showed preference reversal in all 4 risk conditions in Experiment 2, but only in the risky (SS)-certain (LL) and risky-risky conditions in Experiment 1. This finding indicates for uncertain outcomes, people were at least equally (if not more) likely to reverse their choices, compared to certain outcomes.

10.
Cell Rep ; 38(3): 110271, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-35026155

RESUMO

The utility of the urinary proteome in infectious diseases remains unclear. Here, we analyzed the proteome and metabolome of urine and serum samples from patients with COVID-19 and healthy controls. Our data show that urinary proteins effectively classify COVID-19 by severity. We detect 197 cytokines and their receptors in urine, but only 124 in serum using TMT-based proteomics. The decrease in urinary ESCRT complex proteins correlates with active SARS-CoV-2 replication. The downregulation of urinary CXCL14 in severe COVID-19 cases positively correlates with blood lymphocyte counts. Integrative multiomics analysis suggests that innate immune activation and inflammation triggered renal injuries in patients with COVID-19. COVID-19-associated modulation of the urinary proteome offers unique insights into the pathogenesis of this disease. This study demonstrates the added value of including the urinary proteome in a suite of multiomics analytes in evaluating the immune pathobiology and clinical course of COVID-19 and, potentially, other infectious diseases.

11.
Artigo em Inglês | MEDLINE | ID: mdl-35051334

RESUMO

The drift or fall of stretchable neural microelectrodes from the surface of wet and dynamic tissues severely hampers the adoption of microelectrodes for electrophysiological signal monitoring. Endowing the stretchable electrodes with adhesive ability is an effective way to overcome these problems. Current adhesives form tough adhesion to tissues by covalent interaction, which decreases the biocompatibility of the adhesives. Here, we fabricate a strong electrostatic adhesive (noncovalent interaction), highly conformal, stretchable microelectrode arrays (MEAs) for the electrophysiological interface. This MEA was composed of polypyrrole (PPy) as the electrode material and hydrogel as the stretchable substrate [the cross-linked and copolymerized hydrogel of 2-acrylamido-2-methylpropane sulfonic acid (AMPS), gelatin, chitosan, 2-methoxyethyl acrylate, and acrylic acid is named PAGMA]. Strong and stable electrostatic adhesion (85 kPa) and high stretchability (100%) allow for the integration of PPy MEAs based on the PAGMA hydrogel substrate (PPy-PAGMA MEAs) on diverse wet dynamic tissues. Additionally, by adjusting the concentration of AMPS in PAGMA, the hydrogel (PAGMA-1) can produce tough adhesion to many inorganic and elastomer materials. Finally, the PPy-PAGMA MEAs were toughly and conformally adhered on the rat's subcutaneous muscle and beating heart, and the rat's electrophysiological signals were successfully recorded. The development of these adhesive MEAs offers a promising strategy to establish stable and compliant electrode-tissue interfaces.

12.
Bioengineered ; 13(1): 440-454, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34967281

RESUMO

Circ_0005320 was found to be elevated in oral squamous cell carcinoma (OSCC) and accelerated OSCC progression. Here, the potential mechanism of circ_0005320 in OSCC tumorigenesis was explored. The quantitative real-time polymerase chain reaction (qRT-PCR) assay was used to detect the expression of circ_0005320, miR-486-3p, and miR-637. In vitro assays were conducted using cell counting kit-8, colony formation, transwell, angiogenesis, and flow cytometry assays. The targeting relationship between microRNA (miR)-486-3p and miR-637 or circ_0005320 was confirmed using the dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. The Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway-related proteins were analyzed using Western blot. The murine xenograft model was established to perform in vivo assay. Circ_0005320 expression was higher in OSCC tissues and cells. Knockdown of circ_0005320 suppressed OSCC cell growth, migration, invasion, and induced cell apoptosis in vitro, as well as impeded tumor growth in vivo. Mechanistically, miR-486-3p or miR-637 were confirmed to be a target of circ_0005320. Moreover, the inhibitory effects of circ_0005320 silencing on OSCC growth were reversed by the inhibition of miR-486-3p or miR-637. We also found that circ_0005320-miR-486-3p/miR-637 axis mediated the activation of JAK2/STAT3 pathway. This study revealed a novel regulatory network of circ_0005320-miR-486-3p/miR-637 axis in OSCC progression, suggesting that circ_0005320 might be a potential biomarker and therapeutic target for OSCC.

13.
Genomics ; 114(1): 292-304, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34915127

RESUMO

Mycobacterium tuberculosis (MTB) is a severe causing agent of tuberculosis (TB). Although H37Rv, the type strain of M. tuberculosis was sequenced in 1998, annotation errors of encoding genes have been frequently reported in hundreds of papers. This phenomenon is particularly severe at the 5' end of the genes. Here, we applied a TMPP [(N-Succinimidyloxycarbonylmethyl) tris (2,4,6-trimethoxyphenyl) phosphonium bromide] labeling combined with StageTip separating strategy on M. tuberculosis H37Rv to characterize the N-terminal start sites of its annotated encoding genes. Totally, 1047 proteins were identified with 2058 TMPP labeled N-terminal peptides from all the 2625 mass spectrometer (MS) sequenced proteins. Comparative genomics analysis allowed the re-annotation of 43 proteins' N-termini in H37Rv and 762 proteins in Mycobacteriaceae. All revised N-termini start sites were distributed in 5'-UTR of annotated genes due to over-annotation of previous N-terminal initiation codon, especially the ATG. In addition, we identified and verified a novel gene Rv1078A in +3 frame different from the annotated gene Rv1078 in +2 frame. Altogether, our findings contribute to the better understanding of N-terminal of H37Rv and other species from Mycobacteriaceae that can assist future studies on biological study.

14.
J Immunol Methods ; 501: 113211, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34971632

RESUMO

OBJECTIVES: The detection of autoantibody to glycoprotein 210 (gp210 Ab) against a 15 amino-acid peptide epitope by enzyme-linked immunosorbent assay (ELISA) has been widely used in the diagnosis of primary biliary cholangitis (PBC). However, this small peptide antigen presents spatial limitations for antibody access, which reduces the sensitivity of autoantibody detection. A recombinant gp210 antigen was constructed for increased sensitivity in antibody detection is described here. METHODS: The gp210 C terminal 18 amino acid coding sequence was ligated to the modified C-terminal 108 amino acid coding sequence of human serum albumin (mHSA108) and produced as a recombinant gp210 antigen mHSA108-gp210-C18. Measurements of gp210 Ab using the gp210 C-terminal 25 amino acid peptide (gp210-C25) and mHSA108-gp210-C18 by in-house ELISA were compared. ELISAs with mHSA108-gp210-C18 and commercial INOVA kit for gp210 Ab detection were also compared in PBC patients and healthy controls. The correlation between the two assays was analyzed and their efficiency in diagnosing was compared. RESULTS: Of 86 PBC samples, 35 (40.70%) and 44 (52.33%) positive samples were detected for anti-gp210 Ab using gp210-C25 and mHSA108-gp210-C18, respectively. Of 252 samples from PBC, 114 (45.24%) were positive for mHSA108-gp210-C18 ELISA whereas 94 (37.3%) for commercial ELISA (INOVA). All positive samples detected with commercial ELISA kit were also tested positive in mHSA108-gp210-C18 ELISA. Among 374 patients with other autoimmune diseases, anti-gp210 Ab were detected by mHSA108-gp210-C18 ELISA in 0.95% systemic lupus erythematosus (SLE) patients (2/210), 13.04% rheumatoid arthritis (RA) patients (13/97), and 1.47% of Sjögren's Syndrome (SS) patients (1/67). CONCLUSIONS: Compared to the gp210 peptide antigen, the sensitivity of the ELISA system using mHSA108-gp210-C18 antigen was improved. The novel gp210 antigen could be useful for screening patients known to be at increased risk of developing PBC.

15.
J Chromatogr A ; 1663: 462767, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-34971862

RESUMO

In the present work, influence of solvent strength of aqueous phase for two frequently-used biphasic solvent system in partition coefficient (K) of selected solutes were mainly studied, and a new method for selection of biphasic solvent system was proposed for high-speed countercurrent chromatographic separations. Solvent strength was referred to the typical theory that was deeply investigated in conventional reversed-phase liquid chromatography. Experimental results showed that a linear relationship between log(K) of solutes and apparent content of methanol in biphasic solvent system was found for the biphasic solvent system hexane-ethyl acetate-methanol-water (HEMWat), which was consistent with the relationship between real content and apparent content of methanol in this system. Meanwhile, a quadratic relationship was found between log(K) of solutes and apparent content of methanol in biphasic solvent system chloroform-methanol-water (ChMWat), in which it was found that the relationship between real content and apparent content of methanol in this system was also quadratic. In addition, a visual and simple method was proposed to select a suitable biphasic solvent system for separation of target compounds by high-speed countercurrent chromatography with isocratic elution, which saves a lot of manpower and material resources in order to find a suitable two-solvent system. An optimal biphasic solvent system for isolation of several tested compounds by high-speed countercurrent chromatography was easily obtained using our proposed method.


Assuntos
Distribuição Contracorrente , Água , Cromatografia Líquida de Alta Pressão , Metanol , Extratos Vegetais , Solventes
16.
J Hazard Mater ; 426: 128063, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-34920221

RESUMO

Copper (Cu) is an essential but potentially toxic element in rice. Little is known about the mechanism of rice grain Cu accumulation. In this study, we identified a high copper accumulation in grain 1 (oshc1) mutant from the wild type indica rice cultivar 9311 (WT) mutant bank. Compared with those in WT, more Cu was shown to accumulate in the shoots of seedlings and the above-ground tissues except nodes although less total Cu content in oshc1. Further analysis showed that the mutant had an accelerated Cu transport ratio from roots to shoots and higher Cu concentration in xylem sap than WT. This phenomenon in oshc1 was controlled by a single recessive gene, which was identified as BGIOSGA007732, and named OsHMA4. The eight base frame-shift from 1021 to 1028 bp in the coding sequence of OsHMA4 led to a modification after the 341st amino acid and resulted in premature translation termination of OsHMA4 at the 377th amino acid. This may change the function of OsHMA4. Furthermore, the up-regulated OsCOPT7 and OsATX1 and down-regulated OsHMA4 probably decrease Cu compartmentalization in roots of oshc1. In summary, the frame-shift in OsHMA4 changes the function of OsHMA4 and the expression of genes relative to Cu transport in the mutant, which leads to more Cu transport upward and higher Cu accumulation in the rice grains. Moreover, oshc1 was more tolerance to Cu-shortage than WT, while more sensitive to Cu excess exposure than WT. However, RNA-Seq analysis shown that changes in transcription levels of genes in oshc1 involving in molecular function of ions binding and biological processes of cell wall organization and defense response to bio-stress. Which indicates that oshc1 is advantage to Cu limited condition than WT. This work reveals the mechanism of high Cu accumulation in the grains of oshc1 and provides a material to breed new cultivars with optimum levels of Cu in brown rice by crossing with other dominant varieties, which can be planted in different soils to ensure the yield and quality of rice.

17.
Bioorg Med Chem Lett ; 56: 128486, 2021 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-34875389

RESUMO

A new biflavonoid, (2''S)-6''-methyl-2'',3''-dihydroochnaflavone (1), along with two known ochnaflavones (2, 3), four known amentoflavones (4-7) and two known robustaflavones (8, 9) were obtained from the 70% EtOH extract of Selaginella trichoclada. The chemical structures of isolated compounds were elucidated by extensive spectroscopic analyses. Overall, compounds 1-9 displayed moderate cytotoxic effects against human breast cancer MCF-7 cell lines. Among them, compounds 2 and 8 exhibited relatively strong cytotoxic effects against MCF-7 cells with an IC50 value of 7.7 and 6.9 µΜ, respectively. The results of RNA-sequencing and KEGG functional enrichment analysis showed that 8 could induce ferroptosis in MCF-7 cells by down-regulating the expression of ferroptosis-related genes including ACSL4, NOXO1, NOXA1, ACSL5, STEAP3, LPCAT3, ATG7 and TP53. Then 8 could inhibit the expression of ACSL4 proteins through molecule docking analysis, which showed a strong interaction of - 11.89 Kcal/mol binding energy. Those results indicate that 8 could be chemotherapy agents to fight drug resistance in breast cancer by down-regulating the expression level of ACSL4 proteins via ferroptosis, which needs to be further certified in vitro.

18.
Nat Commun ; 12(1): 7108, 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34876568

RESUMO

D-2-Hydroxyglutarate (D-2-HG) is a metabolite involved in many physiological metabolic processes. When D-2-HG is aberrantly accumulated due to mutations in isocitrate dehydrogenase or D-2-HG dehydrogenase, it functions in a pro-oncogenic manner and is thus considered a therapeutic target and biomarker in many cancers. In this study, DhdR from Achromobacter denitrificans NBRC 15125 is identified as an allosteric transcriptional factor that negatively regulates D-2-HG dehydrogenase expression and responds to the presence of D-2-HG. Based on the allosteric effect of DhdR, a D-2-HG biosensor is developed by combining DhdR with amplified luminescent proximity homogeneous assay (AlphaScreen) technology. The biosensor is able to detect D-2-HG in serum, urine, and cell culture medium with high specificity and sensitivity. Additionally, this biosensor is used to identify the role of D-2-HG metabolism in lipopolysaccharide biosynthesis of Pseudomonas aeruginosa, demonstrating its broad usages.

19.
Acta Biomater ; 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34879294

RESUMO

As the incidence of diabetes increases, its complication, diabetic foot ulcers, has become the main type of clinically chronic refractory wounds. Due to the hyperglycemic microenvironment of the diabetic wound, which leads to vascular defects and bacterial growth, the therapeutic effect of wound dressings lacking strategic design is relatively limited. In this study, we designed an injectable, "self-healing", and glucose-responsive multifunctional metal-organic drug-loaded hydrogel (DG@Gel) for diabetic wound healing. The functionalized hydrogel was prepared by phase-transfer-mediated metallo-nanodrugs, which were made by co-assembling zinc ions, organic ligands, and a small-molecule drug, deferoxamine mesylate (DFO), and the programmed loading of glucose oxidase (GOX). When injected into a diabetic wound, the GOX in DG@Gel changed the hyperglycemic wound microenvironment by decomposing excess glucose into hydrogen peroxide and glucuronic acid, which decreased the pH of the wound site. The low pH promoted the release of zinc ions and DFO, which exhibited synergistic antibacterial and angiogenesis activity for diabetic wound repair. In vitro experiments revealed the antibacterial activity and the cell proliferation, migration, and tube formation ability of DG@Gel. Moreover, in vivo experiments showed that DG@Gel can induce re-epithelialization, collagen deposition, and angiogenesis during wound healing in diabetic mice with good biocompatibility and biodegradability. The results suggest that this hydrogel is a promising innovative dressing for the treatment of diabetic wounds. STATEMENT OF SIGNIFICANCE: Diabetic ulcers, as one of the main types of chronic refractory wounds, are not treated effectively in the clinic due to a lack of strategic approach. In this study, we designed a glucose-responsive multifunctional metal-organic drug-loaded hydrogel (DG@Gel), which can change the hyperglycemic wound microenvironment by decomposing excess glucose into hydrogen peroxide and glucuronic acid. This in turn promoted the release of zinc ions and deferoxamine mesylate (DFO) in the hydrogel, which exhibited synergistic antibacterial and angiogenic activity for diabetic wound repair. Furthermore, the DG@Gel exhibited good biocompatibility and biodegradability in vivo. In general, this innovative strategy design may have great application potential in the treatment of various chronic wounds.

20.
Hypertension ; : HYPERTENSIONAHA12118363, 2021 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-34865521

RESUMO

Incomplete spiral artery remodeling, caused by impaired extravillous trophoblast invasion, is a fundamental pathogenic process associated with malplacentation and the development of preeclampsia. Nevertheless, the mechanisms controlling this regulation of trophoblast invasion are largely unknown. We report that sphingosine-1-phosphate synthesis and expression is abundant in healthy trophoblast, whereas in pregnancies complicated by preeclampsia the placentae are associated with reduced sphingosine-1-phosphate and lower SPHK1 (sphingosine kinase 1) expression and activity. In vivo inhibition of sphingosine kinase 1 activity during placentation in pregnant mice led to decreased placental sphingosine-1-phosphate production and defective placentation, resulting in a preeclampsia phenotype. Moreover, sphingosine-1-phosphate increased HTR8/SVneo (immortalized trophoblast cells) cell invasion in a Hippo-signaling-dependent transcriptional coactivator YAP (Yes-associated protein) dependent manner, which is activated by S1PR2 (sphingosine-1-phosphate receptor-2) and downstream RhoA/ROCK induced actin polymerization. Mutation-based YAP-5SA demonstrated that sphingosine-1-phosphate activation of YAP could be either dependent or independent of Hippo signaling. Together, these findings suggest a novel pathogenic pathway of preeclampsia via disrupted sphingosine-1-phosphate metabolism and signaling-induced, interrupted actin dynamics and YAP deactivation; this may lead to potential novel intervention targets for the prevention and management of preeclampsia.

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