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The inhibition of the autophagolysosomal pathway mediated by transcription factor EB (TFEB) inactivation in proximal tubular epithelial cells (TECs) is a key mechanism of TEC injury in diabetic kidney disease (DKD). Acetylation is a novel mechanism that regulates TFEB activity. However, there are currently no studies on whether the adjustment of the acetylation level of TFEB can reduce the damage of diabetic TECs. In this study, we investigated the effect of Trichostatin A (TSA), a typical deacetylase inhibitor, on TFEB activity and damage to TECs in both in vivo and in vitro models of DKD. Here, we show that TSA treatment can alleviate the pathological damage of glomeruli and renal tubules and delay the DKD progression in db/db mice, which is associated with the increased expression of TFEB and its downstream genes. In vitro studies further confirmed that TSA treatment can upregulate the acetylation level of TFEB, promote its nuclear translocation, and activate the expression of its downstream genes, thereby reducing the apoptosis level of TECs. TFEB deletion or HDAC6 knockdown in TECs can counteract the activation effect of TSA on autophagolysosomal pathway. We also found that TFEB enhances the transcription of Tfeb through binding to its promoter and promotes its own expression. Our results, thus, provide a novel therapeutic mechanism for DKD that the alleviation of TEC damage by activating the autophagic lysosomal pathway through upregulating TFEB acetylation can, thus, delay DKD progression.
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Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Nefropatias Diabéticas , Células Epiteliais , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos , Túbulos Renais Proximais , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Nefropatias Diabéticas/metabolismo , Camundongos , Acetilação , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Ácidos Hidroxâmicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Autofagia/efeitos dos fármacos , Apoptose/efeitos dos fármacosRESUMO
The 6:2 fluorotelomer sulfonamide (6:2 FTSAm)-based compounds signify a prominent group of per- and polyfluoroalkyl substances (PFAS) widely used in contemporary aqueous film-forming foam (AFFF) formulations. Despite their widespread presence, the biotransformation behavior of these compounds in wastewater treatment plants remains uncertain. This study investigated the biotransformation of 6:2 FTSAm-based amine oxide (6:2 FTNO), alkylbetaine (6:2 FTAB), and 6:2 fluorotelomer sulfonic acid (6:2 FTSA) in aerobic sludge over a 100-day incubation period. The biotransformation of 6:2 fluorotelomer sulfonamide alkylamine (6:2 FTAA), a primary intermediate product of 6:2 FTNO, was indirectly assessed. Their stability was ranked based on the estimated half-lives (t1/2): 6:2 FTAB (no obvious products were detected) â« 6:2 FTSA (t1/2 ≈28.8 days) > 6:2 FTAA (t1/2 ≈11.5 days) > 6:2 FTNO (t1/2 ≈1.2 days). Seven transformation products of 6:2 FTSA and 15 products of 6:2 FTNO were identified through nontarget and suspect screening using high-resolution mass spectrometry. The transformation pathways of 6:2 FTNO and 6:2 FTSA in aerobic sludge were proposed. Interestingly, 6:2 FTSAm was hardly hydrolyzed to 6:2 FTSA and further biotransformed to perfluoroalkyl carboxylic acids (PFCAs). Furthermore, the novel pathways for the generation of perfluoroheptanoic acid (PFHpA) from 6:2 FTSA were revealed.
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Fluorocarbonos , Poluentes Químicos da Água , Esgotos/química , Óxidos , Aminas , Fluorocarbonos/análise , Biotransformação , Sulfonamidas/metabolismo , Poluentes Químicos da Água/análiseRESUMO
The contamination status of novel organophosphate esters (NOPEs) and their precursors organophosphite antioxidants (OPAs) and hydroxylated/diester transformation products (OH-OPEs/di-OPEs) in soils across a large-scale area in China were investigated. The total concentrations of the three test NOPEs in soil were 82.4-716 ng g-1, which were considerably higher than those of traditional OPEs (4.50-430 ng g-1), OPAs (n.d.-30.8 ng g-1), OH-OPEs (n.d.-0.49 ng g-1), and di-OPEs (0.57-21.1 ng g-1). One NOPE compound, i.e., tris(2,4-di-tert-butylphenyl) phosphate (AO168 = O) contributed over 65% of the concentrations of the studied OPE-associated contaminants. A 30-day soil incubation experiment was performed to confirm the influence of AO168 = O on soil bacterial communities. Specific genera belonging to Proteobacteria, such as Lysobacter and Ensifer, were enriched in AO168 = O-contaminated soils. Moreover, the ecological function of methylotrophy was observed to be significantly enhanced (t-test, p < 0.01) in soil treated with AO168 = O, while nitrogen fixation was significantly inhibited (t-test, p < 0.01). These findings comprehensively revealed the contamination status of OPE-associated contaminants in the soil environment and provided the first evidence of the effects of NOPEs on soil microbial communities.
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Antioxidantes , Ésteres , Organofosfatos , Microbiologia do Solo , Poluentes do Solo , Solo , Solo/química , Bactérias , ChinaRESUMO
Methicillin-resistant Staphylococcus aureus (MRSA)-infected skin wounds have caused a variety of diseases and seriously endanger global public health. Therefore, multidimensional strategies are urgently to find antibacterial dressings to combat bacterial infections. Antibacterial hydrogels are considered potential wound dressing, while their clinical translation is limited due to the unpredictable risks and high costs of carrier excipients. it is found that the natural star antibacterial and anti-inflammatory phytochemicals baicalin (BA) and sanguinarine (SAN) can directly self-assemble through non-covalent bonds such as electrostatic attraction, π-π stacking, and hydrogen bonding to form carrier-free binary small molecule hydrogel. In addition, BA-SAN gel exhibited a synergistic inhibitory effect on MRSA. And its plasticity and injectability allowed it to be applied as a wound dressing. Due to the matched physicochemical properties and synergistic therapeutic effects, BA-SAN gel can inhibit bacterial virulence factors, alleviate wound inflammation, promote wound healing, and has good biocompatibility. The current study not only provided an antibacterial hydrogel with clinical value but also opened up new prospects that carrier-free hydrogels can be designed and originated from clinically used small-molecule phytochemicals.
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Hidrogéis , Staphylococcus aureus Resistente à Meticilina , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Hidrogéis/farmacologia , CicatrizaçãoRESUMO
With the soaring number of multidrug-resistant bacteria, it is imperative to develop novel efficient antibacterial agents and discovery new antibacterial pathways. Herein, we designed and synthesized a series of structurally novel glycyrrhetinic acid (GA) derivatives against multidrug-resistant Staphylococcus aureus (MRSA). The in vitro antibacterial activity of these compounds was evaluated using the microbroth dilution method, agar plate coating experiments and real-time growth curves, respectively. Most of the target derivatives showed moderate antibacterial activity against Staphylococcus aureus (S. aureus) and MRSA (MIC = 3.125-25 µM), but inactivity against Escherichia coli (E. Coli) and Pseudomonas aeruginosa (P. aeruginosa) (MIC > 200 µM). Among them, compound 11 had the strongest antibacterial activity against MRSA, with an MIC value of 3.125 µM, which was 32 times and 64 times than the first-line antibiotics penicillin and norfloxacin, respectively. Additionally, transcriptomic (RNA-seq) and quantitative polymerase chain reaction (qPCR) analysis revealed that the antibacterial mechanism of compound 11 was through blocking the arginine biosynthesis and metabolic and the H2S biogenesis. Importantly, compound 11 was confirmed to have good biocompatibility through the in vitro hemolysis tests, cytotoxicity assays and the in vivo quail chicken chorioallantoic membrane (qCAM) experiments. Current study provided new potential antibacterial candidates from glycyrrhetinic acid derivatives for clinical treatment of MRSA infections.
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Antibacterianos , Arginina , Desenho de Fármacos , Ácido Glicirretínico , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Antibacterianos/farmacologia , Arginina/biossíntese , Escherichia coli/efeitos dos fármacos , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Sulfeto de Hidrogênio/metabolismoRESUMO
Diclofenac (DCF) is a pharmaceutically active contaminant frequently found in aquatic ecosystems. The transformation pathways and microbiology involved in the biodegradation of DCF, particularly under anoxic conditions, remain poorly understood. Here, we demonstrated microbially mediated reductive dechlorination of DCF in anaerobic enrichment culture derived from contaminated river sediment. Over 90% of the initial 76.7 ± 3.6 µM DCF was dechlorinated at a maximum rate of 1.8 ± 0.3 µM day-1 during a 160 days' incubation. Mass spectrometric analysis confirmed that 2-(2-((2-chlorophenyl)amino)phenyl)acetic acid (2-CPA) and 2-anilinophenylacetic acid (2-APA) were formed as the monochlorinated and nonchlorinated DCF transformation products, respectively. A survey of microbial composition and Sanger sequencing revealed the enrichment and dominance of a new Dehalogenimonas population, designated as Dehalogenimonas sp. strain DCF, in the DCF-dechlorinating community. Following the stoichiometric conversion of DCF to 2-CPA (76.0 ± 2.1 µM) and 2-APA (3.7 ± 0.8 µM), strain DCF cell densities increased by 24.4 ± 4.4-fold with a growth yield of 9.0 ± 0.1 × 108 cells per µmol chloride released. Our findings expand the metabolic capability in the genus Dehalogenimonas and highlight the relevant roles of organohalide-respiring bacteria for the natural attenuation of halogenated contaminants of emerging concerns (e.g., DCF).
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Chloroflexi , Biodegradação Ambiental , Chloroflexi/metabolismo , Diclofenaco/metabolismo , Ecossistema , RespiraçãoRESUMO
Through the self-assembled strategy to improve the clinical efficacy of the existing drugs is the focus of current research. Herbal formula granule is a kind of modern dosage form of traditional Chinese medicine (TCM) which has sprung up in recent decades. However, whether it is equivalent to the TCM decoction that has been used for thousands of years has always been a controversial issue. In this paper, taking the herb pair of Coptidis Rhizoma-Scutellariae Radix and its main component berberine-baicalin as examples, the differences and mechanisms of self-assemblies originated from the co-decoction and physical mixture were studied, respectively. Moreover, the relationship between the morphology and antibacterial effects of self-assemblies was illuminated via multi-technology. Our study revealed that the physical mixture's morphology of both the herb pair and the phytochemicals was nanofibers (NFs), while their co-decoction's morphology was nanospheres (NPs). We also found that the antibacterial activity was enhanced with the change of self-assemblies' morphology after the driving by thermal energy. This might be attributed to that NPs could influence amino acid biosynthesis and metabolism in bacteria. Current study provides a basis that co-decoction maybe beneficial to enhance activity and reasonable use of herbal formula granule in clinic.
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Berberina , Medicamentos de Ervas Chinesas , Humanos , Antibacterianos/farmacologia , Berberina/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Medicina Tradicional ChinesaRESUMO
The anti-cancer role of local anesthetics has garnered attention in recent years because increasing evidence show that local anesthetics reduce the risk of tumor metastasis and recurrence. Angiogenesis, the formation of new blood vessels, is fundamental for tumor growth and metastasis. The role of local anesthetics on tumor angiogenesis still remains unknown. Using human lung tumor-associated endothelial cell (HLT-EC) and angiogenesis models, our work shows that ropivacaine at the clinically relevant concentration is active against multiple biological functions of HLT-EC but not lung tumor cells. Ropivacaine inhibits HLT-EC capillary network formation, growth and survival. The anti-angiogenic activity of ropivacaine is further confirmed in in vivo angiogenesis mouse model. Mechanistically, we show that ropivacaine inhibits HLT-EC mitochondrial respiration via specifically targeting mitochondrial respiratory complex II. As a consequence of mitochondrial respiration inhibition, we observe the energy depletion, oxidative stress and damage in HLT-EC after ropivacaine exposure. Additionally, an antioxidant agent completely reverses the inhibitory effects of ropivacaine, suggesting that oxidative stress is required for the action of ropivacaine in HLT-EC. Interestingly, mitochondrial dysfunction and oxidative stress induced by ropivacaine is sodium channel-independent. Our work demonstrates the potent inhibitory effects of ropivacaine in lung tumor angiogenesis by inducing mitochondrial dysfunction. These findings provide significant insight into the potential mechanisms by which local anaesthetics may negatively affect tumor reoccurrence and metastasis.
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Mitocôndrias/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Ropivacaina/farmacologia , Canais de Sódio/metabolismo , Células A549 , Animais , Humanos , Camundongos , Mitocôndrias/patologia , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologiaRESUMO
OBJECTIVE: To investigate the potential association between the polymorphism of N- acetyltransferase 2 (NAT2) gene and anti-tuberculosis drug-induced hepatotoxicity (ATDH) in Han population. METHODS: The SNP rs1495741 was genotyped by using multiplex ligation detection reaction (MLDR) technique, and logistic regression analysis was used to analyze the association between this SNP and the susceptibility of ATDH. RESULTS: There were 247 PTB patients enrolled in this study, including 24 ATDH, and 223 controls (PTB without ATDH). No significant difference in genotype and allele distribution was observed for rs1495741 in NAT2 between the controls and ATDH group. After adjusting age, sex, body mass index (BMI) and smoking history, the SNP of rs1495741 showed a significant association with ATDH ãodds ratio (OR)=2.728 (95% confidence interval: 1.022-7.281)ã under recessive model (AA vs. GA+GG). CONCLUSIONS: The rs1495741 in NAT2 seems related to the development of ATDH among PTB patients, AA genotype of rs1495741 may be a causative factor for increased susceptibility to ATDH.
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The recovery of valuable metals from spent lithium-ion batteries using deep eutectic solvents (DESs) is an environmentally and economically beneficial process. In this study, a method has been developed for recovering LiNi0.33Co0.33Mn0.33O2. Our process operates under mild conditions and with a little oxalic acid as a reducing agent, dissolving lithium, cobalt, manganese, and nickel completely utilizing a DES that is composed of tetrabutylammonium chloride and of monochloroacetic acid. Lithium and nickel were selectively precipitated using oxalic acid. Cobalt and manganese were precipitated as oxalates by adding an oxalic acid aqueous solution. Finally, the DES can be regenerated by evaporating the water. Importantly, valuable metals can be recovered with a 100 % yield through the process of DES recycling. This environmentally friendly and recyclable process is suitable for the recycling of spent lithium-ion batteries industry.
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BACKGROUND: Mahuang Fuzi decoction (MGF) is composed of three herb medicines that has been clinically used to treat inflammatory diseases for a long history. At present, more and more active phytochemicals' aggregations have been found during the thermodynamic process of herb medicine decoction, and revealing the clinical efficacy of herb medicine through supramolecular strategies is the focus of current research. However, it is not clear whether decoction induced supermolecules' morphological changes to modify activity. METHODS: Dynamic light scattering (DLS) and field emission scanning electron microscopy (FESEM) were used to analyze the micromorphology of MGF, MGF SA (MGF supermolecules), and MIX (physical mixture of MGF single decoction). The interaction and thermodynamic parameters of single herbs in a decoction were investigated by Isothermal titration calorimetry (ITC). The phytochemicals were systematically analyzed by ultra high performance liquid chromatography-Q Exactive hybrid quadrupole-orbitrap high-resolution accurate mass spectrometry (UHPLC-Q-Orbitrap HRMS). Under the safe dose on RAW264.7 cells, NO, IL-6 and TNF-α were determined by Enzyme-Linked ImmunoSorbent Assay (ELISA) method. NF-κB p65 translocation from the cytoplasm into the nucleus was examined using the immunofluorescence assay and the western blot, respectively. Furthermore, Metabolomics was used to discover potential biomarkers and the associated metabolic pathways of MGF SA treatment. RESULTS: There were nanoscale aggregations in MGF, and the micromorphology of the extracted MGF SA consisted of uniform particles; while the MIX micromorphology had no uniformity. ITC showed that the interaction MH-GC and FZ-GC were a spontaneous exothermic reaction, indicating that their phytochemicals had the property of self-assembly. Though the micromorphology between MGF, MGF SA, and MIX was obviously different, UHPLC-Q-Orbitrap HRMS results displayed that the main phytochemicals of MGF and MIX had nearly the same components. Interestingly, MGF and MGF SA could significantly inhibit the production of NO, and had better inhibition effect on the expression of nuclear protein NF-κB p65 than MIX, among which MGF SA had the best effect. Further investigation indicated that the perturbance of metabolic profiling in RAW264.7 inflammatory cells was obviously reversed by MGF SA. CONCLUSIONS: The decoction enriched the key active phytochemicals and regulated the formation of homogeneous nanoparticles in MGF SA. The supermolecules in MGF SA significantly enhanced its anti-inflammatory activity, primarily affecting the NF-κB signaling pathway and the biosynthesis and metabolism of arginine in RAW264.7 inflammatory cells. Current study displayed that co-decocting herbal medicine were beneficial to the treatment of diseases than the mixture of the single herbs' extraction.
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Studies have confirmed that the spatial arrangement of chiral molecules has a decisive influence on supramolecular assembly. However, the effect of epimerization caused by the change of a single chiral center on the self-assembly of chiral molecules has not been reported. Herein, we explored a pair of epimers 18 α-glycyrrhetinic acid and 18 ß-glycyrrhetinic acid from Glycyrrhiza uralensis Fisch, which had completely different medicinal activities. In this study, we found that these epimers of glycyrrhetinic acid showed distinct self-assembly properties under the condition of the deionized water and a small amount of DMSO solution. Interestingly, the cis-configured 18 ß-GA could form a 'head-to-tail' interlaced structure and further self-assembled to form nanoparticles, while trans-configured 18 α-GA was connected in a "head-to-head" manner, and due to the excessive steric hindrance that made it difficult to assemble. This work not only clearly demonstrates the impact of epimerization due to changes in a single chiral center on the self-assembly of chiral molecules as well as biological activity, but also provides new insights into the self-assembly of natural organic molecules in the development of nanomedicines and biofunctional materials.
Assuntos
Antibacterianos , Ácido Glicirretínico , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacologia , Ácido Glicirretínico/análogos & derivados , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Estereoisomerismo , Testes de Sensibilidade Microbiana , Nanopartículas/química , Glycyrrhiza uralensis/química , Escherichia coli/efeitos dos fármacos , Tamanho da Partícula , Staphylococcus aureus/efeitos dos fármacosRESUMO
Cardiac hypertrophy is a key factor driving heart failure (HF), yet its pathogenesis remains incompletely elucidated. Mettl1-catalyzed RNA N7-methylguanosine (m7G) modification has been implicated in ischemic cardiac injury and fibrosis. This study aims to elucidate the role of Mettl1 and the mechanism underlying non-ischemic cardiac hypertrophy and HF. It is found that Mettl1 is upregulated in human failing hearts and hypertrophic murine hearts following transverse aortic constriction (TAC) and Angiotensin II (Ang II) infusion. YY1 acts as a transcriptional factor for Mettl1 during cardiac hypertrophy. Mettl1 knockout alleviates cardiac hypertrophy and dysfunction upon pressure overload from TAC or Ang II stimulation. Conversely, cardiac-specific overexpression of Mettl1 results in cardiac remodeling. Mechanically, Mettl1 increases SRSF9 expression by inducing m7G modification of SRSF9 mRNA, facilitating alternative splicing and stabilization of NFATc4, thereby promoting cardiac hypertrophy. Moreover, the knockdown of SRSF9 protects against TAC- or Mettl1-induced cardiac hypertrophic phenotypes in vivo and in vitro. The study identifies Mettl1 as a crucial regulator of cardiac hypertrophy, providing a novel therapeutic target for HF.
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Cardiomegalia , Modelos Animais de Doenças , Animais , Cardiomegalia/genética , Cardiomegalia/metabolismo , Camundongos , Fatores de Processamento de Serina-Arginina/metabolismo , Fatores de Processamento de Serina-Arginina/genética , Humanos , Metiltransferases/metabolismo , Metiltransferases/genética , Masculino , Fatores de Transcrição NFATC/metabolismo , Fatores de Transcrição NFATC/genética , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Ferroptosis is a nonapoptotic form of regulated cell death that has been reported to play a central role in cardiac ischemiaâreperfusion (I/R) injury. N-acetyltransferase 10 (NAT10) contributes to cardiomyocyte apoptosis by functioning as an RNA ac4c acetyltransferase, but its role in cardiomyocyte ferroptosis during I/R injury has not been determined. This study aimed to elucidate the role of NAT10 in cardiac ferroptosis as well as the underlying mechanism. The mRNA and protein levels of NAT10 were increased in mouse hearts after I/R and in cardiomyocytes that were exposed to hypoxia/reoxygenation. P53 acted as an endogenous activator of NAT10 during I/R in a transcription-dependent manner. Cardiac overexpression of NAT10 caused cardiomyocyte ferroptosis to exacerbate I/R injury, while cardiomyocyte-specific knockout of NAT10 or pharmacological inhibition of NAT10 with Remodelin had the opposite effects. The inhibition of cardiomyocyte ferroptosis by Fer-1 exerted superior cardioprotective effects against the NAT10-induced exacerbation of post-I/R cardiac damage than the inhibition of apoptosis by emricasan. Mechanistically, NAT10 induced the ac4C modification of Mybbp1a, increasing its stability, which in turn activated p53 and subsequently repressed the transcription of the anti-ferroptotic gene SLC7A11. Moreover, knockdown of Mybbp1a partially abolished the detrimental effects of NAT10 overexpression on cardiomyocyte ferroptosis and cardiac I/R injury. Collectively, our study revealed that p53 and NAT10 interdependently cooperate to form a positive feedback loop that promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury, suggesting that targeting the NAT10/Mybbp1a/p53 axis may be a novel approach for treating cardiac I/R.
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Ferroptose , Traumatismo por Reperfusão Miocárdica , Miócitos Cardíacos , Proteína Supressora de Tumor p53 , Animais , Humanos , Masculino , Camundongos , Acetiltransferases/metabolismo , Acetiltransferases/genética , Apoptose , Modelos Animais de Doenças , Retroalimentação Fisiológica , Ferroptose/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genéticaRESUMO
Organelles are functional areas where eukaryotic cells perform processes necessary for life. Each organelle performs specific functions; however, highly coordinated crosstalk occurs between them. Disorder of organelle networks often occur in various diseases. The endoplasmic reticulum (ER) and mitochondria are crucial organelles in eukaryotic cells as they are the material synthesis and oxidative metabolism centers, respectively. Homeostasis and orchestrated interactions are essential for maintaining the normal activities of cells. However, the mode and mechanism of organelle crosstalk is still a research challenge. Furthermore, the intricate association between organelle dyshomeostasis and the progression of many human diseases remains unclear. This paper systematically summarized the latest research advances in the synergistic mechanism between the endoplasmic reticulum and mitochondria and their crosstalk with other organelles based on recent literature. It also highlights the application potential of organelle homeostasis maintenance as a preventative and treatment strategy for diseases.
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ETHNOPHARMACOLOGICAL RELEVANCE: Glycyrrhiza uralensis Fisch (RC) and Coptis chinensis Franch (RG) are traditional Chinese medicines, which are classic drug pair in prescriptions to treat gastrointestinal diseases. Multi-herb therapy is one of the most important features of traditional Chinese medicine, but due to the complex components of herbal decoctions, the substances that actually exert their medicinal effects have not been fully elucidated. The discovery of Glycyrrhiza uralensis Fisch and Coptis chinensis Franch supramolecular parts (RC-RG SA) can provide a new perspective for explaining the mechanism of drug-pair compatibility. AIM OF THE STUDY: The purpose of this study was to explore the active composition and identification of chemical constituents of RC-RG SA, and to explore the inhibitory effects of supramolecular parts on S. aureus and biofilm. MATERIALS AND METHODS: The micromorphology of RC-RG SA was characterized by SEM and DLS. Intermolecular forces between Glycyrrhiza uralensis Fisch and Coptis chinensis Franch determined by ITC. The chemical constituents of RC-RG SA were systematically analyzed by UPLC-ESI-MSn. The inhibitory effect of RC-RG SA on S. aureus was determined by turbidimetric method and plate coating method. The scavenging effect of RC-RG SA supramolecular parts on S. aureus biofilm were observed by MTT method, SEM and LSCM, respectively. RESULTS: The microstructure of RC-RG SA was spherical with a particle size of 161.6 nm. ITC proved that the reaction between decoction of RC and RG was exothermic. A total of 70 compounds were preliminarily identified in RC-RG SA, including 34 flavonoids, 34 alkaloids and 2 triterpenoids. The inhibitory effect of RC-RG supramolecular parts on S. aureus proliferation and the ability to clear S. aureus biofilm were better than RC-RG co-decoction and RC-RG non-supramolecular parts. CONCLUSIONS: The Glycyrrhiza uralensis Fisch and Coptis chinensis Franch co-decoctions' supramolecular components were an important substance that exerts its medicinal effect. Current study provided supramolecular strategies to reveal the active ingredients and the medicinal effect of the traditional Chinese medicine decoction.
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Alcaloides , Medicamentos de Ervas Chinesas , Glycyrrhiza uralensis , Triterpenos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides , Glycyrrhiza uralensis/química , Medicina Tradicional Chinesa , Staphylococcus aureusRESUMO
Per- and polyfluoroalkyl substances (PFASs) have attracted extensive attention because of their persistence, long-distance migration ability, bioaccumulation, and biological toxicity. Currently, regulatory strategies concerning PFASs in the environment primarily focus on perfluoroalkyl acids (PFAAs). However, most polyfluoroalkyl compounds can be degraded to PFAAs by environmental microorganisms, also known as precursors. Exploring the microbial transformation behavior of precursors is fundamental to comprehensively evaluate the environmental risk of PFASs and formulate control and remediation schemes of PFAS-contaminated sites. Furthermore, anaerobic microbial reductive defluorination of PFAAs is a potential and challenging remediation technology. This review summarizes degradation rules and transformation pathways of precursors (fluorotelomer compounds and perfluorooctane sulfonamide derivatives), PFAAs, and novel PFASs by microorganisms and discusses factors affecting the microbial degradation. Finally, the future research directions are put forward.
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Fluorocarbonos , Poluentes Químicos da Água , Poluentes Químicos da Água/análise , Fluorocarbonos/metabolismoRESUMO
Background: Deaths from bacterial infections have risen year by year. This trend is further aggravated as the overuse antibiotics and the bacterial resistance to all known antibacterial agents. Therefore, new therapeutic alternatives are urgently needed. Methods: Enlightenment the combination usage of traditional herb medicine, one carrier-free binary nanoparticles (GA-BBR NPs) was discovered, which was self-assembled from gallic acid and berberine through electrostatic interaction, π-π stacking and hydrophobic interaction; and it could be successfully prepared by a green, cost-effective and "one-pot" preparation process. Results: The nanoparticles exhibited strong antibacterial activity and biofilm removal ability against multidrug-resistant S. aureus (MRSA) by downregulating mRNA expression of rpsF, rplC, rplN, rplX, rpsC, rpmC and rpsH to block bacterial translation mechanisms in vitro and in vivo, and it had well anti-inflammatory activity and a promising role in promoting angiogenesis to accelerate the wound healing on MRSA-infected wounds model in vivo. Additionally, the nanoparticles displayed well biocompatibility without cytotoxicity, hemolytic activity, and tissue or organ toxicity. Conclusion: GA-BBR NPs originated from the drug combination has potential clinical transformation value, and this study provides a new idea for the design of carrier-free nanomedicine derived from natural herbals.
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Berberina , Staphylococcus aureus Resistente à Meticilina , Nanomedicina , Antibacterianos/farmacologia , Anti-Inflamatórios , Berberina/farmacologia , ExcipientesRESUMO
BACKGROUND: The effect of Zanthoxylum bungeanum Maxim. (ZBM) on anti-obesity, lipid-lowering and liver protection has been identified, but the effect on the development of NAFLD induced by high-fat diet remains unclear. PURPOSE: To evaluate the alleviation effect of ZBM on NAFLD in vivo and explore the mechanisms by analyzing the liver transcriptome, microbiota and fecal metabolites. METHODS: NAFLD model was induced in C57BL/6J mice by feeding with high-fat diet (HFD). The potential mechanism of ZBM in improving NAFLD was studied by liver transcriptome analysis, real-time PCR, immunofluorescence, 16s rRNA sequencing and non-targeted metabonomics. RESULTS: ZBM has alleviation effects on HFD-induced NAFLD. The liver transcriptome, real-time PCR and immunofluorescence analysis showed that ZBM could efficiently regulate fatty acid and cholesterol metabolism. The 16S rRNA sequencing and LC-MS based metabonomic demonstrated that ZBM could rebalance gut microbiota dysbiosis and regulate metabolic profiles in HFD-induced NAFLD mice. Spearman correlation analysis revealed a strong correlation between gut microbiota and biochemical, pathological indexes and differential metabolic biomarkers. CONCLUSION: ZBM ameliorates HFD-induced NAFLD by regulating fatty acid and cholesterol metabolism, gut microbiota and metabolic profile.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Zanthoxylum , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , RNA Ribossômico 16S/genética , Multiômica , Camundongos Endogâmicos C57BL , Fígado , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Colesterol/metabolismoRESUMO
Ischemic heart failure (HF) remains a leading cause of morbidity and mortality. Maintaining homeostasis of cardiac function and preventing cardiac remodeling deterioration are critical to halting HF progression. Methyltransferase-like protein 13 (Mettl13) has been shown to regulate protein translation efficiency by acting as a protein lysine methyltransferase, but its role in cardiac pathology remains unexplored. This study aims to characterize the roles and mechanisms of Mettl13 in cardiac contractile function and HF. We found that Mettl13 was downregulated in the failing hearts of mice post-myocardial infarction (MI) and in a cellular model of oxidative stress. Cardiomyocyte-specific overexpression of Mettl13 mediated by AAV9-Mettl13 attenuated cardiac contractile dysfunction and fibrosis in response to MI, while silencing of Mettl13 impaired cardiac function in normal mice. Moreover, Mettl13 overexpression abrogated the reduction in cell shortening, Ca2+ transient amplitude and SERCA2a protein levels in the cardiomyocytes of adult mice with MI. Conversely, knockdown of Mettl13 impaired the contractility of cardiomyocytes, and decreased Ca2+ transient amplitude and SERCA2a protein expression in vivo and in vitro. Mechanistically, Mettl13 impaired the stability of c-Cbl by inducing lysine methylation of c-Cbl, which in turn inhibited ubiquitination-dependent degradation of SERCA2a. Furthermore, the inhibitory effects of knocking down Mettl13 on SERCA2a protein expression and Ca2+ transients were partially rescued by silencing c-Cbl in H2O2-treated cardiomyocytes. In conclusion, our study uncovers a novel mechanism that involves the Mettl13/c-Cbl/SERCA2a axis in regulating cardiac contractile function and remodeling, and identifies Mettl13 as a novel therapeutic target for ischemic HF.