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1.
Immunity ; 56(11): 2508-2522.e6, 2023 Nov 14.
Article in English | MEDLINE | ID: mdl-37848037

ABSTRACT

Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) synthase (cGAS) is a universal double-stranded DNA (dsDNA) sensor that recognizes foreign and self-DNA in the cytoplasm and initiates innate immune responses and has been implicated in various infectious and non-infectious contexts. cGAS binds to the backbone of dsDNA and generates the second messenger, cGAMP, which activates the stimulator of interferon genes (STING). Here, we show that the endogenous polyamines spermine and spermidine attenuated cGAS activity and innate immune responses. Mechanistically, spermine and spermidine induced the transition of B-form DNA to Z-form DNA (Z-DNA), thereby decreasing its binding affinity with cGAS. Spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme in polyamine catabolism that decreases the cellular concentrations of spermine and spermidine, enhanced cGAS activation by inhibiting cellular Z-DNA accumulation; SAT1 deficiency promoted herpes simplex virus 1 (HSV-1) replication in vivo. The results indicate that spermine and spermidine induce dsDNA to adopt the Z-form conformation and that SAT1-mediated polyamine metabolism orchestrates cGAS activity.


Subject(s)
DNA, B-Form , DNA, Z-Form , Spermine/metabolism , Spermidine/metabolism , DNA/metabolism , Nucleotidyltransferases/metabolism , Polyamines/metabolism , Immunity, Innate/genetics
2.
Nature ; 599(7883): 125-130, 2021 11.
Article in English | MEDLINE | ID: mdl-34671159

ABSTRACT

Tissue maintenance and repair depend on the integrated activity of multiple cell types1. Whereas the contributions of epithelial2,3, immune4,5 and stromal cells6,7 in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here we uncover important roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus leads to enteric gliosis and the upregulation of an interferon gamma (IFNγ) gene signature. IFNγ-dependent gene modules were also induced in EGCs from patients with inflammatory bowel disease8. Single-cell transcriptomics analysis of the tunica muscularis showed that glia-specific abrogation of IFNγ signalling leads to tissue-wide activation of pro-inflammatory transcriptional programs. Furthermore, disruption of the IFNγ-EGC signalling axis enhanced the inflammatory and granulomatous response of the tunica muscularis to helminths. Mechanistically, we show that the upregulation of Cxcl10 is an early immediate response of EGCs to IFNγ signalling and provide evidence that this chemokine and the downstream amplification of IFNγ signalling in the tunica muscularis are required for a measured inflammatory response to helminths and resolution of the granulomatous pathology. Our study demonstrates that IFNγ signalling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFNγ-EGC-CXCL10 axis in immune response and tissue repair after infectious challenge.


Subject(s)
Homeostasis , Intestines/immunology , Intestines/physiology , Neuroglia/immunology , Neuroglia/physiology , Regeneration , Adventitia/immunology , Adventitia/parasitology , Animals , Chemokine CXCL10/immunology , Duodenum/immunology , Duodenum/parasitology , Duodenum/pathology , Duodenum/physiology , Female , Gliosis , Homeostasis/immunology , Humans , Inflammation/immunology , Inflammation/pathology , Interferon-gamma/immunology , Intestines/parasitology , Intestines/pathology , Male , Mice , Nematospiroides dubius/immunology , Nematospiroides dubius/pathogenicity , Signal Transduction/immunology , Strongylida Infections/immunology , Strongylida Infections/parasitology , Strongylida Infections/pathology
3.
PLoS Pathog ; 20(3): e1012130, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38551978

ABSTRACT

Classical Swine Fever (CSF), caused by the Classical Swine Fever Virus (CSFV), inflicts significant economic losses on the global pig industry. A key factor in the challenge of eradicating this virus is its ability to evade the host's innate immune response, leading to persistent infections. In our study, we elucidate the molecular mechanism through which CSFV exploits m6A modifications to circumvent host immune surveillance, thus facilitating its proliferation. We initially discovered that m6A modifications were elevated both in vivo and in vitro upon CSFV infection, particularly noting an increase in the expression of the methyltransferase METTL14. CSFV non-structural protein 5B was found to hijack HRD1, the E3 ubiquitin ligase for METTL14, preventing METTL14 degradation. MeRIP-seq analysis further revealed that METTL14 specifically targeted and methylated TLRs, notably TLR4. METTL14-mediated regulation of TLR4 degradation, facilitated by YTHDF2, led to the accelerated mRNA decay of TLR4. Consequently, TLR4-mediated NF-κB signaling, a crucial component of the innate immune response, is suppressed by CSFV. Collectively, these data effectively highlight the viral evasion tactics, shedding light on potential antiviral strategies targeting METTL14 to curb CSFV infection.


Subject(s)
Adenine , Classical Swine Fever Virus , Classical Swine Fever , Animals , Classical Swine Fever Virus/genetics , Immunity, Innate , Swine , Toll-Like Receptor 4
4.
J Immunol ; 212(7): 1188-1195, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38391298

ABSTRACT

STING-mediated DNA sensing pathway plays a crucial role in the innate antiviral immune responses. Clarifying its regulatory mechanism and searching STING agonists has potential clinical implications. Although multiple STING agonists have been developed to target cancer, there are few for the treatment of infectious diseases. Astaxanthin, a natural and powerful antioxidant, serves many biological functions and as a potential candidate drug for many diseases. However, how astaxanthin combats viruses and whether astaxanthin regulates the cyclic GMP-AMP synthase-STING pathway remains unclear. In this study, we showed that astaxanthin markedly inhibited HSV-1-induced lipid peroxidation and inflammatory responses and enhanced the induction of type I IFN in C57BL/6J mice and mouse primary peritoneal macrophages. Mechanistically, astaxanthin inhibited HSV-1 infection and oxidative stress-induced STING carbonylation and consequently promoted STING translocation to the Golgi apparatus and oligomerization, which activated STING-dependent host defenses. Thus, our study reveals that astaxanthin displays a strong antiviral activity by targeting STING, suggesting that astaxanthin might be a promising STING agonist and a therapeutic target for viral infectious diseases.


Subject(s)
Virus Diseases , Xanthophylls , Animals , Mice , Herpes Simplex/drug therapy , Immunity, Innate , Membrane Proteins/metabolism , Mice, Inbred C57BL , Nucleotidyltransferases/metabolism , Xanthophylls/pharmacology , Xanthophylls/therapeutic use , Virus Diseases/drug therapy
5.
J Immunol ; 212(2): 295-301, 2024 01 15.
Article in English | MEDLINE | ID: mdl-38054892

ABSTRACT

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects cytoplasmic microbial DNA and self-DNA from genomic instability, initiates innate immunity, and plays fundamental roles in defense against viruses and the development of various diseases. The cellular cGAS level determines the magnitude of the response to DNA. However, the underlying mechanisms of the control of cGAS stability, especially its feedback regulation during viral infection, remain largely unknown. In this study, we show that viral infection induces the expression of the UAF1-USP1 deubiquitinase complex in primary peritoneal macrophages (PMs) of C57BL/6J mice. UAF1-USP interacts with cGAS, selectively cleaves its K48-linked polyubiquitination, and thus stabilizes its protein expression in PMs and HEK293T cells. Concordantly, the UAF1-USP1 deubiquitinase complex enhances cGAS-dependent type I IFN responses in PMs. Uaf1 deficiency and ML323 (a specific inhibitor of UAF1-USP1 deubiquitinase complex) attenuates cGAS-triggered antiviral responses and facilitates viral replication both in vitro and in vivo. Thus, our study uncovers a positive feedback mechanism of cGAS-dependent antiviral responses and suggests the UAF1-USP1 complex as a potential target for the treatment of diseases caused by aberrant cGAS activation.


Subject(s)
Ubiquitin-Specific Proteases , Virus Diseases , Animals , Humans , Mice , Antiviral Agents , DNA , HEK293 Cells , Mice, Inbred C57BL , Nuclear Proteins/genetics , Nucleotidyltransferases/genetics , Ubiquitin-Specific Proteases/metabolism
6.
PLoS Pathog ; 19(4): e1011314, 2023 04.
Article in English | MEDLINE | ID: mdl-37023217

ABSTRACT

Stimulator-of-interferon gene (STING) is a vital element of the innate immune system against DNA viruses. Optimal activation of STING is crucial for maintaining immune homeostasis and eliminating invading viruses, and the oligomerization of STING is an essential prerequisite for STING activation. However, the mechanism of cGAMP-induced STING oligomerization in ER remains unclear. Selenoproteins are crucial for various physiological processes. Here, we identified that the endoplasmic reticulum (ER)-located transmembrane selenoprotein K (SELENOK) was induced during virus infection and facilitated innate immune responses against herpes simplex virus-1 (HSV-1). Mechanistically, SELENOK interacts with STING in the ER and promotes STING oligomerization, which in turn promotes its translocation from the ER to the Golgi. Consequently, Selenok deficiency suppresses STING-dependent innate responses and facilitates viral replication in vivo. Thus, the control of STING activation by selenium-mediated SELENOK expression will be a priming therapeutic strategy for the treatment of STING-associated diseases.


Subject(s)
Herpesvirus 1, Human , Antiviral Agents , Herpesvirus 1, Human/physiology , Immunity, Innate , Selenoproteins , Virus Replication/genetics , Humans , Animals , Mice
7.
Proc Natl Acad Sci U S A ; 119(47): e2214513119, 2022 11 22.
Article in English | MEDLINE | ID: mdl-36375055

ABSTRACT

Fungi are central to every terrestrial and many aquatic ecosystems, but the mechanisms underlying fungal tolerance to mercury, a global pollutant, remain unknown. Here, we show that the plant symbiotic fungus Metarhizium robertsii degrades methylmercury and reduces divalent mercury, decreasing mercury accumulation in plants and greatly increasing their growth in contaminated soils. M. robertsii does this by demethylating methylmercury via a methylmercury demethylase (MMD) and using a mercury ion reductase (MIR) to reduce divalent mercury to volatile elemental mercury. M. robertsii can also remove methylmercury and divalent mercury from fresh and sea water even in the absence of added nutrients. Overexpression of MMD and MIR significantly improved the ability of M. robertsii to bioremediate soil and water contaminated with methylmercury and divalent mercury. MIR homologs, and thereby divalent mercury tolerance, are widespread in fungi. In contrast, MMD homologs were patchily distributed among the few plant associates and soil fungi that were also able to demethylate methylmercury. Phylogenetic analysis suggests that fungi could have acquired methylmercury demethylase genes from bacteria via two independent horizontal gene transfer events. Heterologous expression of MMD in fungi that lack MMD homologs enabled them to demethylate methylmercury. Our work reveals the mechanisms underlying mercury tolerance in fungi, and may provide a cheap and environmentally friendly means of cleaning up mercury pollution.


Subject(s)
Mercury , Metarhizium , Methylmercury Compounds , Biodegradation, Environmental , Water , Mercury/toxicity , Phylogeny , Ecosystem , Metarhizium/genetics , Soil
8.
Plant J ; 114(1): 193-208, 2023 04.
Article in English | MEDLINE | ID: mdl-36721966

ABSTRACT

Iron (Fe) is an indispensable trace mineral element for the normal growth of plants, and it is involved in different biological processes; Fe shortage in plants can induce chlorosis and yield loss. The objective of this research is to identify novel genes that participated in the regulation of Fe-deficiency stress in Arabidopsis thaliana. A basic helix-loop-helix (bHLH) transcription factor (MYC1) was identified to be interacting with the FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR (FIT) using a yeast-two-hybrid assay. Transcript-level analysis showed that there was a decrease in MYC1 expression in Arabidopsis to cope with Fe-deficiency stress. Functional deficiency of MYC1 in Arabidopsis leads to an increase in Fe-deficiency tolerance and Fe-accumulation, whereas MYC1-overexpressing plants have an enhanced sensitivity to Fe-deficiency stress. Additionally, MYC1 inhibited the formation of FIT and bHLH38/39 heterodimers, which suppressed the expressed level for Fe acquisition genes FRO2 and IRT1 during Fe-deficiency stress. These results showed that MYC1 functions as a negative modulator of the Fe-deficiency stress response by inhibiting the formation of FIT and bHLH38/39 heterodimers, thereby suppressing the binding of FIT and bHLH38/39 heterodimers to the promoters of FRO2 and IRT1 to modulate Fe intake during Fe-deficiency stress. Overall, the findings of this study elucidated the role of MYC1 in coping with Fe-deficiency stress, and provided potential targets for the developing of crop varieties resistant to Fe-deficiency stress.


Subject(s)
Arabidopsis Proteins , Arabidopsis , Arabidopsis/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Gene Expression Regulation, Plant , Homeostasis/physiology , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Plant Roots/metabolism
9.
BMC Biotechnol ; 24(1): 2, 2024 01 10.
Article in English | MEDLINE | ID: mdl-38200466

ABSTRACT

BACKGROUND: Lytic polysaccharide monooxygenases (LPMOs) catalyzing the oxidative cleavage of different types of polysaccharides have potential to be used in various industries. However, AA13 family LPMOs which specifically catalyze starch substrates have relatively less members than AA9 and AA10 families to limit their application range. Amylase has been used in enzymatic desizing treatment of cotton fabric for semicentury which urgently need for new assistant enzymes to improve reaction efficiency and reduce cost so as to promote their application in the textile industry. RESULTS: A total of 380 unannotated new genes which probably encode AA13 family LPMOs were discovered by the Hidden Markov model scanning in this study. Ten of them have been successfully heterologous overexpressed. AlLPMO13 with the highest activity has been purified and determined its optimum pH and temperature as pH 5.0 and 50 °C. It also showed various oxidative activities on different substrates (modified corn starch > amylose > amylopectin > corn starch). The results of enzymatic textile desizing application showed that the best combination of amylase (5 g/L), AlLPMO13 (5 mg/L), and H2O2 (3 g/L) made the desizing level and the capillary effects increased by 3 grades and more than 20%, respectively, compared with the results treated by only amylase. CONCLUSION: The Hidden Markov model constructed basing on 34 AA13 family LPMOs was proved to be a valid bioinformatics tool for discovering novel starch-active LPMOs. The novel enzyme AlLPMO13 has strong development potential in the enzymatic textile industry both concerning on economy and on application effect.


Subject(s)
Hydrogen Peroxide , Starch , Humans , Polysaccharides , Amylases , Computational Biology , Mixed Function Oxygenases/genetics , Textiles
10.
New Phytol ; 242(6): 2586-2603, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38523234

ABSTRACT

Nicotianamine (NA) plays a crucial role in transporting metal ions, including iron (Fe), in plants; therefore, NICOTIANAMINE SYNTHASE (NAS) genes, which control NA synthesis, are tightly regulated at the transcriptional level. However, the transcriptional regulatory mechanisms of NAS genes require further investigations. In this study, we determined the role of bZIP44 in mediating plant response to Fe deficiency stress by conducting transformation experiments and assays. bZIP44 positively regulated the response of Arabidopsis to Fe deficiency stress by interacting with MYB10 and MYB72 to enhance their abilities to bind at NAS2 and NAS4 promoters, thereby increasing NAS2 and NAS4 transcriptional levels and promote NA synthesis. In summary, the transcription activities of bZIP44, MYB10, and MYB72 were induced in response to Fe deficiency stress, which enhanced the interaction between bZIP44 and MYB10 or MYB72 proteins, synergistically activated the transcriptional activity of NAS2 and NAS4, promoted NA synthesis, and improved Fe transport, thereby enhancing plant tolerance to Fe deficiency stress.


Subject(s)
Arabidopsis Proteins , Arabidopsis , Basic-Leucine Zipper Transcription Factors , Gene Expression Regulation, Plant , Iron Deficiencies , Stress, Physiological , Transcription Factors , Arabidopsis/genetics , Arabidopsis/metabolism , Arabidopsis Proteins/metabolism , Arabidopsis Proteins/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Stress, Physiological/genetics , Basic-Leucine Zipper Transcription Factors/metabolism , Basic-Leucine Zipper Transcription Factors/genetics , Iron/metabolism , Promoter Regions, Genetic/genetics , Protein Binding , Alkyl and Aryl Transferases/metabolism , Alkyl and Aryl Transferases/genetics , Azetidinecarboxylic Acid/analogs & derivatives , Azetidinecarboxylic Acid/metabolism , Plants, Genetically Modified
11.
Epilepsy Behav ; 154: 109748, 2024 May.
Article in English | MEDLINE | ID: mdl-38640553

ABSTRACT

OBJECTIVE: Comorbid depression and anxiety in patients with epilepsy (PWE) are common and frequently under-treated, thus, causing poor health-related quality of life (HRQoL). However, little is known regarding the interconnections between anxious/depressive symptoms and the dimensions of HRQoL. Therefore, we conducted a network analysis to explore these relationships in detail among Chinese adult PWE. METHODS: A cohort of adult PWE was consecutively recruited from the First Affiliated Hospital of Chongqing Medical University. HRQoL, depression, and anxiety were measured with Quality of Life in Epilepsy Inventory-31, Neurological Disorders Depression Inventory for Epilepsy, and Generalized Anxiety Disorder 7-Item Scale, respectively. A regularized partial correlation network was constructed to investigate the interconnections between symptoms of anxiety/depression and the dimensions of HRQoL. We calculated expected influence (EI) and bridge expected influence (BEI) values to identify the most influential nodes. RESULTS: A total of 396 PWE were enrolled in this study, 78.1% of whom had focal onset epilepsy. The prevalence of anxiety and depression was 30.3% and 28.8%, respectively. The symptoms "frustrated" and "uncontrollable worry" had the highest EI values, whereas "emotional well-being", "seizure worry", "difficulty finding pleasure", and "nervousness or anxiety" had the highest BEI values. CONCLUSION: This study provides new insights into the relationships among anxiety, depression, and HRQoL. Critical central symptoms and bridge symptoms identified in the network might help to quickly identify PWE comorbid anxiety and depression in busy outpatient settings, thereby enabling early intervention and enhancing quality of life.


Subject(s)
Anxiety , Depression , Epilepsy , Quality of Life , Humans , Quality of Life/psychology , Female , Male , Adult , Epilepsy/psychology , Epilepsy/epidemiology , Epilepsy/complications , Depression/epidemiology , Depression/psychology , Anxiety/psychology , Anxiety/epidemiology , Middle Aged , Young Adult , Psychiatric Status Rating Scales , Cohort Studies , Adolescent , Aged , Comorbidity
12.
Phys Chem Chem Phys ; 26(5): 4480-4491, 2024 Jan 31.
Article in English | MEDLINE | ID: mdl-38240307

ABSTRACT

The conversion of CO2 into valuable fuels and multi-carbon chemical substances by electrical energy is an effective strategy to solve environmental problems by using renewable energy sources. In this work, the density functional theory (DFT) method is used to reveal the electrocatalytic mechanism of CO2 reduction reaction (CO2RR) over the surface of CuAl-Cl-layered double hydroxides (LDHs) with Cu monoatoms (Cu@CuAl-Cl-LDH), Cu2 diatoms (Cu2@CuAl-Cl-LDH), orthotetrahedral Cu4 clusters (Td-Cu4@CuAl-Cl-LDH) and planar Cu4 clusters (Pl-Cu4@CuAl-Cl-LDH). The active sites, density of states, adsorption energy, charge density difference and free energy are calculated. The results show that CO2RR over all the above five catalysts can generate C2 products. Pl-Cu4@CuAl-Cl-LDH tends to generate C2H5OH, while the remaining four structures all tend to produce C2H4. Cuδ+ favors CO2RR, and Td-Cu4@CuAl-Cl-LDH with a larger positively charged area at the active site has the better electrocatalytic performance among the calculated systems with a maximum step height of 0.78 eV. The selectivity of the products C2H4 and C2H5OH depends on the dehydration of the intermediate *C2H2O to *C2H3O or *CCH; if the dehydration produces *CCH intermediate, the final product is C2H4, and if no dehydration occurs, C2H5OH is produced. This work provides theoretical information and guidance for further rational design of efficient CO2RR catalysts for energy saving and emission reduction.

13.
Arch Toxicol ; 98(7): 2269-2279, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38662237

ABSTRACT

Tobacco carcinogens metabolism-related genes (TCMGs) could generate reactive metabolites of tobacco carcinogens, which subsequently contributed to multiple diseases. However, the association between genetic variants in TCMGs and bladder cancer susceptibility remains unclear. In this study, we derived TCMGs from metabolic pathways of polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines, and then explored genetic associations between TCMGs and bladder cancer risk in two populations: a Chinese population of 580 cases and 1101 controls, and a European population of 5930 cases and 5468 controls, along with interaction and joint analyses. Expression patterns of TCMGs were sourced from Nanjing Bladder Cancer (NJBC) study and publicly available datasets. Among 43 TCMGs, we observed that rs7087341 T > A in AKR1C2 was associated with a reduced risk of bladder cancer in the Chinese population [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.72-0.97, P = 1.86 × 10-2]. Notably, AKR1C2 rs7087341 showed an interaction effect with cigarette smoking on bladder cancer risk (Pinteraction = 5.04 × 10-3), with smokers carrying the T allele increasing the risk up to an OR of 3.96 (Ptrend < 0.001). Genetically, rs7087341 showed an allele-specific transcriptional regulation as located at DNA-sensitive regions of AKR1C2 highlighted by histone markers. Mechanistically, rs7087341 A allele decreased AKR1C2 expression, which was highly expressed in bladder tumors that enhanced metabolism of tobacco carcinogens, and thereby increased DNA adducts and reactive oxygen species formation during bladder tumorigenesis. These findings provided new insights into the genetic mechanisms underlying bladder cancer.


Subject(s)
Carcinogens , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/chemically induced , Carcinogens/toxicity , Carcinogens/metabolism , Male , Female , Middle Aged , Case-Control Studies , Asian People/genetics , China/epidemiology , Nicotiana , Aged , White People/genetics , Cigarette Smoking/adverse effects , Cigarette Smoking/genetics , Nitrosamines/toxicity , Hydroxysteroid Dehydrogenases
14.
Skin Res Technol ; 30(3): e13589, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38396354

ABSTRACT

BACKGROUND: Ketoprofen is a nonsteroidal anti-inflammatory drug used for the treatment of acute and chronic pain associated with inflammatory conditions. This study aims to evaluate the in vitro percutaneous absorption of ketoprofen 10% formulated in proprietary anhydrous and aqueous gels using the Franz skin finite dose model. MATERIALS AND METHODS: The anhydrous gel was initially characterized for cytotoxicity using EpiDerm skin tissue model by cell proliferation assay and Western blot analysis. The Ultra Performance Liquid Chromatography method for measuring ketoprofen was validated and the stability of ketoprofen 10% in the anhydrous gel formulation was evaluated at 5°C and 25°C for 181 days. The percutaneous absorption of ketoprofen was determined using donated human skin. The tissue sections were mounted within Franz diffusion cells. A variable finite dose of each ketoprofen formulation in either anhydrous or aqueous gel was applied to the skin sections and receptor solutions were collected at various time points. RESULTS: Cell proliferation assay showed minimal cell death when EpiDerm skin tissue was exposed to the anhydrous gel for 24 h; the levels of protein markers of cell proliferation were not affected after 17-h exposure. Ketoprofen was stable in the anhydrous gel when stored at 5°C and 25°C. When compounded in the anhydrous and aqueous gels, ketoprofen had mean flux rate of 2.22 and 2.50 µg/cm2 /h, respectively, after 48 h. The drug was distributed to the epidermis and dermis sections of the skin. Both the anhydrous and aqueous gels facilitated the percutaneous absorption of ketoprofen without statistically significant differences. CONCLUSION: The anhydrous gel can be used as a base to facilitate the transdermal delivery of ketoprofen. Although the anhydrous and aqueous gels can deliver a similar amount of ketoprofen, the anhydrous gel (water activity below 0.6) allows for extended default beyond-use-date of compounding preparations.


Subject(s)
Ketoprofen , Humans , Ketoprofen/chemistry , Ketoprofen/metabolism , Skin Absorption , Skin/metabolism , Anti-Inflammatory Agents, Non-Steroidal , Administration, Cutaneous , Gels , Water/metabolism
15.
PLoS Genet ; 17(6): e1009636, 2021 06.
Article in English | MEDLINE | ID: mdl-34181654

ABSTRACT

Our previous studies showed that MAN3-mediated mannose plays an important role in plant responses to cadmium (Cd) stress. However, the underlying mechanisms and signaling pathways involved are poorly understood. In this study, we showed that an Arabidopsis MYB4-MAN3-Mannose-MNB1 signaling cascade is involved in the regulation of plant Cd tolerance. Loss-of-function of MNB1 (mannose-binding-lectin 1) led to decreased Cd accumulation and tolerance, whereas overexpression of MNB1 significantly enhanced Cd accumulation and tolerance. Consistently, expression of the genes involved in the GSH-dependent phytochelatin (PC) synthesis pathway (such as GSH1, GSH2, PCS1, and PCS2) was significantly reduced in the mnb1 mutants but markedly increased in the MNB1-OE lines in the absence or presence of Cd stress, which was positively correlated with Cd-activated PC synthesis. Moreover, we found that mannose is able to bind to the GNA-related domain of MNB1, and that mannose binding to the GNA-related domain of MNB1 is required for MAN3-mediated Cd tolerance in Arabidopsis. Further analysis showed that MYB4 directly binds to the promoter of MAN3 to positively regulate the transcript of MAN3 and thus Cd tolerance via the GSH-dependent PC synthesis pathway. Consistent with these findings, overexpression of MAN3 rescued the Cd-sensitive phenotype of the myb4 mutant but not the mnb1 mutant, whereas overexpression of MNB1 rescued the Cd-sensitive phenotype of the myb4 mutant. Taken together, our results provide compelling evidence that a MYB4-MAN3-Mannose-MNB1 signaling cascade regulates cadmium tolerance in Arabidopsis through the GSH-dependent PC synthesis pathway.


Subject(s)
Adaptation, Physiological/genetics , Arabidopsis/genetics , Mannose-Binding Lectins/genetics , Mannose/metabolism , Repressor Proteins/genetics , beta-Mannosidase/genetics , Aminoacyltransferases/genetics , Aminoacyltransferases/metabolism , Arabidopsis/drug effects , Arabidopsis/growth & development , Arabidopsis/metabolism , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Cadmium/toxicity , Gene Expression Regulation, Developmental , Gene Expression Regulation, Plant , Glutamate-Cysteine Ligase/genetics , Glutamate-Cysteine Ligase/metabolism , Glutathione Synthase/genetics , Glutathione Synthase/metabolism , Mannose-Binding Lectins/metabolism , Plant Leaves/drug effects , Plant Leaves/genetics , Plant Leaves/growth & development , Plant Leaves/metabolism , Plant Roots/drug effects , Plant Roots/genetics , Plant Roots/growth & development , Plant Roots/metabolism , Plant Shoots/drug effects , Plant Shoots/genetics , Plant Shoots/growth & development , Plant Shoots/metabolism , Plants, Genetically Modified , Promoter Regions, Genetic , Protein Binding , Repressor Proteins/metabolism , Signal Transduction , Soil Pollutants/toxicity , beta-Mannosidase/metabolism
16.
Biomed Chromatogr ; 38(6): e5862, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38684194

ABSTRACT

Antibiotic-associated diarrhea is a common adverse reaction caused by the widespread use of antibiotics. The decrease in probiotics is one of the reasons why antibiotics cause drug-induced diarrhea. However, few studies have addressed the intrinsic mechanism of antibiotics inhibiting probiotics. To investigate the underlying mechanism of levofloxacin against Bifidobacterium adolescentis, we used a metabolomics mass spectrometry-based approach and molecular docking analysis for a levofloxacin-induced B. adolescentis injury model. The results showed that levofloxacin reduced the survival rate of B. adolescentis and decreased the number of B. adolescentis. The untargeted metabolomics analysis identified 27 potential biomarkers, and many of these metabolites are involved in energy metabolism, amino acid metabolism and the lipid metabolism pathway. Molecular docking showed that levofloxacin can bind with aminoacyl-tRNA synthetase and lactic acid dehydrogenase. This result provides a novel insight into the mechanism of the adverse reactions of levofloxacin.


Subject(s)
Bifidobacterium adolescentis , Levofloxacin , Metabolomics , Molecular Docking Simulation , Levofloxacin/chemistry , Levofloxacin/pharmacology , Metabolomics/methods , Bifidobacterium adolescentis/metabolism , Bifidobacterium adolescentis/drug effects , Animals , Chromatography, High Pressure Liquid/methods , Metabolome/drug effects , Mass Spectrometry/methods , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry
17.
Article in English | MEDLINE | ID: mdl-38832962

ABSTRACT

Research on individuals with a younger onset age of schizophrenia is important for identifying neurobiological processes derived from the interaction of genes and the environment that lead to the manifestation of schizophrenia. Schizophrenia has long been recognized as a disorder of dysconnectivity, but it is largely unknown how brain connectivity changes are associated with psychotic symptoms. Twenty-one adolescent-onset schizophrenia (AOS) patients and 21 matched healthy controls (HCs) were recruited and underwent resting-state functional magnetic resonance imaging. Regional homogeneity (ReHo) was used to investigate local brain connectivity alterations in AOS. Regions with significant ReHo changes in patients were selected as "seeds" for further functional connectivity (FC) analysis and Granger causality analysis (GCA), and associations of the obtained functional brain measures with psychotic symptoms in patients with AOS were examined. Compared with HCs, AOS patients showed significantly increased ReHo in the right middle temporal gyrus (MTG), which was positively correlated with PANSS-positive scores, PSYRATS-delusion scores and auditory hallucination scores. With the MTG as the seed, lower connectivity with the bilateral postcentral gyrus (PCG) and higher connectivity with the right precuneus were observed in patients. The reduced FC between the right MTG and bilateral PCG was significantly and positively correlated with hallucination scores. GCA indicated decreased Granger causality from the right MTG to the left middle frontal gyrus (MFG) and from the right MFG to the right MTG in AOS patients, but such effects did not significantly associate with psychotic symptoms. Abnormalities in the connectivity within the MTG and its connectivity with other networks were identified and were significantly correlated with hallucination and delusion ratings. This region may be a key neural substrate of psychotic symptoms in AOS.

18.
Environ Toxicol ; 39(3): 1140-1162, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37860845

ABSTRACT

Sulforaphane (SFN) has attracted much attention due to its ability on antioxidant, anti-inflammatory, and anti-apoptotic properties, while its functional targets and underlying mechanism of action on brain injury caused by acute carbon monoxide poisoning (ACOP) have not been fully elucidated. Herein, we used a systematic network pharmacology approach to explore the mechanism of SFN in the treatment of brain damage after ACOP. In this study, the results of network pharmacology demonstrated that there were a total of 81 effective target genes of SFN and 36 drug-disease targets, which were strongly in connection with autophagy-animal signaling pathway, drug metabolism, and transcription disorders in cancer. Upon the further biological function and KEGG signaling pathway enrichment analysis, a large number of them were involved in neuronal death, reactive oxygen metabolic processes and immune functions. Moreover, based on the results of bioinformatics prediction associated with multiple potential targets and pathways, the AMP-activated protein kinase (AMPK) signaling pathway was selected to elucidate the molecular mechanism of SFN in the treatment of brain injury caused by ACOP. The following molecular docking analysis also confirmed that SFN can bind to AMPKα well through chemical bonds. In addition, an animal model of ACOP was established by exposure to carbon monoxide in a hyperbaric oxygen chamber to verify the predicted results of network pharmacology. We found that the mitochondrial ultrastructure of neurons in rats with ACOP was seriously damaged, and apoptotic cells increased significantly. The histopathological changes were obviously alleviated, apoptosis of cortical neurons was inhibited, and the number of Nissl bodies was increased in the SFN group as compared with the ACOP group (p < .05). Besides, the administration of SFN could increase the expressions of phosphorylated P-AMPK and MFN2 proteins and decrease the levels of DRP1, Caspase3, and Casapase9 proteins in the brain tissue of ACOP rats. These findings suggest that network pharmacology is a useful tool for traditional Chinese medicine (TCM) research, SFN can effectively inhibit apoptosis, protect cortical neurons from the toxicity of carbon monoxide through activating the AMPK pathway and may become a potential therapeutic strategy for brain injury after ACOP.


Subject(s)
Brain Injuries , Carbon Monoxide Poisoning , Drugs, Chinese Herbal , Isothiocyanates , Sulfoxides , Rats , Animals , Molecular Docking Simulation , Carbon Monoxide , AMP-Activated Protein Kinases , Network Pharmacology , Brain
19.
Genomics ; 115(6): 110740, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37923179

ABSTRACT

The Chinese chestnut, Castanea mollissima Blume, a nut-bearing tree native to China and North Korea, belongs to the Fagaceae family. As an important genetic resource, C. mollissima is vital in enhancing edible chestnut varieties and offers significant insights into the origin and evolution of chestnut species. While the chloroplast genome of C. mollissima has been sequenced, its mitochondrial genome (mitogenome) remains largely uncharted. In this study, we have characterized the C. mollissima mitogenome, assembling it utilizing reads from both BGI and Nanopore sequencing platforms, and conducted a comparative analysis with the mitochondrial genomes of closely related species. The mitogenome of C. mollissima manifests a polycyclic structure consisting of two circular molecules measuring 363,232 bp and 24,806 bp, respectively. This genome encompasses 35 unique protein-coding genes, 19 tRNA genes, and three rRNA genes. A total of 139 SSRs were identified throughout the entire C. mollissima mitogenome. Furthermore, the combined length of homologous fragments between the chloroplast and mitochondrial genomes was 5766 bp, constituting 1.49% of the mitogenome. We also predicted 484 RNA editing sites in C. mollissima, demonstrating C-to-U RNA editing. Phylogenetic analysis of related species' mitogenomes showed that C. mollissima was closely related to Lithocarpus litseifolius (Hance) Chun and Quercus acutissima Carruth. Interestingly, the mitogenome sequences of C. mollissima, L. litseifolius, Q. acutissima, Fagus sylvatica L., and Juglans mandshurica Maxim did not show conservation in their alignments, indicating frequent genome reorganization. This report marks the inaugural study of the C. mollissima mitogenome, serving as a benchmark genome for economically significant plants within the Castanea genus. Moreover, it supplies invaluable information that can guide future molecular breeding efforts and contribute to the broader understanding of chestnut genomics.


Subject(s)
Genome, Mitochondrial , Quercus , Phylogeny , Genomics , China
20.
Klin Monbl Augenheilkd ; 241(2): 221-229, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37722612

ABSTRACT

AIM: To evaluate the accuracy of the raytracing method for the calculation of intraocular lens (IOL) power in myopic eyes after small incision extraction of the lenticule (SMILE). METHODS: Retrospective study. All patients undergoing surgery for myopic SMILE between May 1, 2020, and December 31, 2020, with Scheimpflug tomography optical biometry were eligible for inclusion. Manifest refraction was performed before and 6 months after refractive surgery. One eye from each patient was included in the final analysis. A theoretical model was invited to predict the accuracy of multiple methods of lens power calculation by comparing the IOL-induced refractive error at the corneal plane (IOL-Dif) and the SMILE-induced change of spherical equivalent (SMILE-Dif) before and after SMILE surgery. The prediction error (PE) was calculated as the difference between SMILE-Dif-IOL-Dif. IOL power calculations were performed using raytracing (Olsen Raytracing, Pentacam AXL, software version 1.22r05, Wetzlar, Germany) and other formulae with historical data (Barrett True-K, Double-K SRK/T, Masket, Modified Masket) and without historical data (Barrett True-K no history, Haigis-L, Hill Potvin Shammas PM, Shammas-PL) for the same IOL power and model. In addition, subgroup analysis was performed in different anterior chamber depths, axial lengths, back-to-front corneal radius ratio, keratometry, lens thickness, and preoperative spherical equivalents. RESULTS: A total of 70 eyes of 70 patients were analyzed. The raytracing method had the smallest mean absolute PE (0.26 ± 0.24 D) and median absolute PE (0.16 D), and also had the largest percentage of eyes within a PE of ± 0.25 D (64.3%), ± 0.50 D (81.4%), ± 0.75 D (95.7%), and ± 1.00 D (100.0%). The raytracing method was significantly better than Double-K SRK/T, Haigis, Haigis-L, and Shammas-PL formulae in postoperative refraction prediction (all p < 0.001), but not better than the following formulae: Barrett True-K (p = 0.314), Barrett True-K no history (p = 0.163), Masket (p = 1.0), Modified Masket (p = 0.806), and Hill Potvin Shammas PM (p = 0.286). Subgroup analysis showed that refractive outcomes exhibited no statistically significant differences in the raytracing method (all p < 0.05). CONCLUSION: Raytracing was the most accurate method in predicting target refraction and had a good consistency in calculating IOL power for myopic eyes after SMILE.


Subject(s)
Lenses, Intraocular , Myopia , Phacoemulsification , Humans , Lens Implantation, Intraocular , Retrospective Studies , Phacoemulsification/methods , Refraction, Ocular , Myopia/diagnosis , Myopia/surgery , Biometry/methods , Optics and Photonics
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