RESUMEN
Phytophthora parasitica causes diseases on a broad range of host plants. It secretes numerous effectors to suppress plant immunity. However, only a few virulence effectors in P. parasitica have been characterized. Here, we highlight that PpE18, a conserved RXLR effector in P. parasitica, was a virulence factor and suppresses Nicotiana benthamiana immunity. Utilizing luciferase complementation, co-immunoprecipitation, and GST pull-down assays, we determined that PpE18 targeted NbAPX3-1, a peroxisome membrane-associated ascorbate peroxidase with reactive oxygen species (ROS)-scavenging activity and positively regulates plant immunity in N. benthamiana. We show that the ROS-scavenging activity of NbAPX3-1 was critical for its immune function and was hindered by the binding of PpE18. The interaction between PpE18 and NbAPX3-1 resulted in an elevation of ROS levels in the peroxisome. Moreover, we discovered that the ankyrin repeat-containing protein NbANKr2 acted as a positive immune regulator, interacting with both NbAPX3-1 and PpE18. NbANKr2 was required for NbAPX3-1-mediated disease resistance. PpE18 competitively interfered with the interaction between NbAPX3-1 and NbANKr2, thereby weakening plant resistance. Our results reveal an effective counter-defense mechanism by which P. parasitica employed effector PpE18 to suppress host cellular defense, by suppressing biochemical activity and disturbing immune function of NbAPX3-1 during infection.
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Ascorbato Peroxidasas , Nicotiana , Peroxisomas , Phytophthora , Inmunidad de la Planta , Especies Reactivas de Oxígeno , Factores de Virulencia , Phytophthora/patogenicidad , Phytophthora/fisiología , Nicotiana/microbiología , Especies Reactivas de Oxígeno/metabolismo , Ascorbato Peroxidasas/metabolismo , Factores de Virulencia/metabolismo , Peroxisomas/metabolismo , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/inmunología , Unión Proteica , Resistencia a la Enfermedad , Repetición de AnquirinaRESUMEN
Antimicrobial peptides (AMPs), which have a low probability of developing resistance, are considered the most promising antimicrobial agents for combating antibiotic resistance. Feleucin-K3 is an amphiphilic cationic AMP that exhibits broad-spectrum antimicrobial activity. In our previous research, the first phenylalanine residue was identified as the critical position affecting its biological activity. Here, a series of Feleucin-K3 analogs containing hydrophobic D-amino acids were developed, leveraging the low sensitivity of proteases to unnatural amino acids and the regulatory effect of hydrophobicity on antimicrobial activity. Among them, K-1dF, which replaced the phenylalanine of Feleucin-K3 with its enantiomer (D-phenylalanine), exhibited potent antimicrobial activity with a therapeutic index of 46.97 and MICs between 4 to 8 µg/ml against both sensitive and multidrug-resistant Acinetobacter baumannii. The introduction of D-phenylalanine increased the salt tolerance and serum stability of Feleucin-K3. Moreover, K-1dF displayed a rapid bactericidal effect, a low propensity to develop resistance, and a synergistic effect when combined with antibiotics. More importantly, it exhibited considerable or superior efficacy to imipenem against pneumonia and skin abscess infection. In brief, the K-1dF obtained by simple and effective modification strategy has emerged as a promising candidate antimicrobial agent for tackling multidrug-resistant Acinetobacter baumannii infections.
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Acinetobacter baumannii , Antibacterianos , Farmacorresistencia Bacteriana Múltiple , Pruebas de Sensibilidad Microbiana , Acinetobacter baumannii/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/fisiología , Animales , Antibacterianos/farmacología , Antibacterianos/administración & dosificación , Sustitución de Aminoácidos , Ratones , Péptidos Catiónicos Antimicrobianos/farmacología , Péptidos Catiónicos Antimicrobianos/administración & dosificación , Péptidos Catiónicos Antimicrobianos/química , Péptidos Antimicrobianos/farmacología , Péptidos Antimicrobianos/química , Péptidos Antimicrobianos/administración & dosificación , Estabilidad de Medicamentos , FemeninoRESUMEN
The emergence and increasing prevalence of multidrug-resistant (MDR) bacteria have posed an urgent demand for novel antibacterial drugs. Currently, antimicrobial peptides (AMPs), potential novel antimicrobial agents with rare antimicrobial resistance, represent an available strategy to combat MDR bacterial infections but suffer the limitation of protease degradation. In this study, we developed a highly effective method for optimizing the stability of AMPs by introducing fluorinated sulfono-γ-AApeptides, and successfully synthesized novel Feleucin-K3-analogs. The results demonstrated that the incorporation of fluorinated sulfono-γ-AA into Feleucin-K3 effectively improved stability and afforded optimal peptides, such as CF3-K11, which exhibited 8-9 times longer half-lives than Feleucin-K3. Moreover, CF3-K11 displayed potent antimicrobial activity against clinically isolated Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), excellent biosafety, low resistance propensity, and possessed powerful antimicrobial efficacy for both local skin infection and pneumonia infection. The optimal CF3-K11 exhibited strong therapeutic potential and offered a superior approach for treating MDR bacterial infections.
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Antiinfecciosos , Staphylococcus aureus Resistente a Meticilina , Infecciones por Pseudomonas , Humanos , Péptidos Catiónicos Antimicrobianos/farmacología , Péptidos Antimicrobianos , Antiinfecciosos/farmacología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones por Pseudomonas/tratamiento farmacológico , Pruebas de Sensibilidad MicrobianaRESUMEN
Pulmonary fibrosis (PF) is a pathological change caused by repeated injuries and repair dysfunction of the alveolar epithelium. Our previous study revealed that the residues Asn3 and Asn4 of peptide DR8 (DHNNPQIR-NH2) could be modified to improve stability and antifibrotic activity, and the unnatural hydrophobic amino acids α-(4-pentenyl)-Ala and d-Ala were considered in this study. DR3penA (DHα-(4-pentenyl)-ANPQIR-NH2) was verified to have a longer half-life in serum and to significantly inhibit oxidative damage, epithelial-mesenchymal transition (EMT) and fibrogenesis in vitro and in vivo. Moreover, DR3penA has a dosage advantage over pirfenidone through the conversion of drug bioavailability under different routes of administration. A mechanistic study revealed that DR3penA increased the expression of aquaporin 5 (AQP5) by inhibiting the upregulation of miR-23b-5p and the mitogen-activated protein kinase (MAPK) pathway, indicating that DR3penA may alleviate PF by regulating MAPK/miR-23b-5p/AQP5. Safety evaluation showed that DR3penA is a peptide drug without obvious toxicity or acute side effects and has significantly improved safety compared to DR8. Thus, our findings suggest that DR3penA, as a novel and low-toxic peptide, has the potential to be a leading compound for PF therapy, which provides a foundation for the development of peptide drugs for fibrosis-related diseases.
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The prevalence of multidrug-resistant bacterial infections has led to dramatically increased morbidity and mortality. Antimicrobial peptides (AMPs) have great potential as new therapeutic agents to reverse this dangerous trend. Herein, a series of novel AMP Feleucin-K3 analogues modified with unnatural peptidomimetic sulfono-γ-AA building blocks were designed and synthesized. The structure-activity, structure-toxicity, and structure-stability relationships were investigated to discover the optimal antimicrobial candidates. Among them, K122 exhibited potent and broad-spectrum antimicrobial activity and high selectivity. K122 had a rapid bactericidal effect and a low tendency to induce resistance. Surprisingly, K122 showed excellent effectiveness against bacterial pneumonia. For biofilm and local skin infections, K122 significantly decreased the bacterial load and improved tissue injury at a dose of only 0.25 mg/kg, which was 160 times lower than the concentration deemed to be safe for local dermal applications. In summary, K122 is an outstanding candidate for the treatment of multidrug-resistant bacteria and biofilm infections.
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Antiinfecciosos , Staphylococcus aureus Resistente a Meticilina , Pseudomonas aeruginosa , Péptidos Catiónicos Antimicrobianos/farmacología , Péptidos Catiónicos Antimicrobianos/uso terapéutico , Antiinfecciosos/farmacología , Antibacterianos/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4) is an important soilborne fungal pathogen that causes the most devastating banana disease. Effectors secreted by microbes contribute to pathogen virulence on host plants in plant-microbe interactions. However, functions of Foc TR4 effectors remain largely unexplored. In this study, we characterized a novel cupin_1 domain-containing protein (FoCupin1) from Foc TR4. Sequence analysis indicated that the homologous proteins of FoCupin1 in phytopathogenic fungi were evolutionarily conserved. Furthermore, FoCupin1 could suppress BAX-mediated cell death and significantly downregulate the expression of defense-related genes in tobacco by using the Agrobacterium-mediated transient expression system. FoCupin1 was highly induced in the early stage of Foc TR4 infection. The deletion of FoCupin1 gene did not affect Foc TR4 growth and conidiation. However, FoCupin1 deletion significantly reduced Foc TR4 virulence on banana plants, which was further confirmed by biomass assay. The expression of the defense-related genes in banana was significantly induced after inoculation with FoCupin1 mutants. These results collectively indicate FoCupin1 is a putative effector protein that plays an essential role in Foc TR4 pathogenicity. These findings suggest a novel role for cupin_1 domain-containing proteins and deepen our understanding of effector-mediated Foc TR4 pathogenesis.
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Pulmonary fibrosis (PF), which is characterized by enhanced extracellular matrix (ECM) deposition, is an interstitial lung disease that lacks an ideal clinical treatment strategy. It has an extremely poor prognosis, with an average survival of 3-5 years after diagnosis. Our previous studies have shown that the antioxidant peptide DR8 (DHNNPQIR-NH2), which is extracted and purified from rapeseed, can alleviate PF and renal fibrosis. However, natural peptides are easily degraded by proteases in vivo, which limits their potency. We have since synthesized a series of DR8 analogs based on amino acid scanning substitution. DR7dA [DHNNPQ (D-alanine) R-NH2] is an analog of DR8 in which L-isoleucine (L-Ile) is replaced with D-alanine (D-Ala), and its half-life is better than that of DR8. In the current study, we verified that DR7dA ameliorated tumor growth factor (TGF)-ß1-induced fibrogenesis and bleomycin-induced PF. The results indicated that DR7dA reduced the protein and mRNA levels of TGF-ß1 target genes in TGF-ß1-induced models. Surprisingly, DR7dA blocked fibrosis in a lower concentration range than DR8 in cells. In addition, DR7dA ameliorated tissue pathologic changes and ECM accumulation in mice. BLM caused severe oxidative damage, but administration of DR7dA reduced oxidative stress and restored antioxidant defense. Mechanistic studies suggested that DR7dA inhibits ERK, P38, and JNK phosphorylation in vivo and in vitro All results indicated that DR7dA attenuated PF by inhibiting ECM deposition and oxidative stress via blockade of the mitogen-activated protein kinase (MAPK) pathway. Hence, compared with its parent peptide, DR7dA has higher druggability and could be a candidate compound for PF treatment in the future. SIGNIFICANCE STATEMENT: In order to improve druggability of DR8, we investigated the structure-activity relationship of it and replaced the L-isoleucine with D-alanine. We found that the stability and antifibrotic activity of DR7dA were significantly improved than DR8, as well as DR7dA significantly attenuated tumor growth factor (TGF)-ß1-induced fibrogenesis and ameliorated bleomycin-induced fibrosis by inhibiting extracellular matrix deposition and oxidative stress via blockade of the MAPK pathway, suggesting DR7dA may be a promising candidate compound for the treatment of PF.
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Antioxidantes , Fibrosis Pulmonar , Alanina/química , Angiotensina II , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Bleomicina , Fibrosis , Isoleucina/química , Pulmón/metabolismo , Ratones , Proteínas Quinasas Activadas por Mitógenos , Péptidos/química , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/metabolismo , Factor de Crecimiento Transformador beta1RESUMEN
BACKGROUND: As the use of diamide insecticides on corn continues to increase, there is growing concern about their residue levels on corn and dietary risks to populations. In this study, the distribution, dispersion and transfer efficiency of two diamide insecticides (tetrachlorantraniliprole (TCAP) and cyantraniliprole (CNAP)) in different parts of corn and soil were investigated in a 1-year field trial in Guangzhou and Lanzhou using two different application methods - spray and drip irrigation, respectively - and the dietary risk of the insecticides to different consumer populations was assessed under the two application methods. RESULTS: The results showed that drip irrigation had a longer persistence period than spraying, and there was a hysteresis in the absorption distribution of the agent in different parts of corn, which was gradually transferred to the leaves after absorption from the roots. The average TE1 (transfer efficiency) and TE2 were 0.230-0.261 and 1.749-1.851 for TCAP and 0.168-0.187 and 2.363-2.815 for CNAP, respectively. At corn harvest, both TCAP and CNAP were below detectable levels in soil and corn. For different consumer populations, hazard quotients ranged from 0.001 to 0.066 for TCAP and from 0.003 to 0.568 for CNAP - both well below 100%. CONCLUSION: This study indicates that TCAP and CNAP applied by spray or drip irrigation are safe for long-term risk of human intake and also provides guidance for the use of both insecticides in agricultural production to control corn pests, especially in arid and semi-arid areas. © 2022 Society of Chemical Industry.
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Insecticidas , Plaguicidas , Acetofenonas , Riego Agrícola/métodos , Diamida , Humanos , Pirazoles , Medición de Riesgo , Suelo/química , Zea mays , ortoaminobenzoatosRESUMEN
PURPOSE: Both poor sleep and diabetic kidney disease are closely associated with inflammation. However, the correlation between poor sleep and diabetic kidney disease has not been well clarified. Thus, the aim of this study was to determine the mediating role that inflammatory markers play in the pathogenic effect of poor sleep on the severity of diabetic kidney disease (DKD). METHODS: A cross-sectional survey was conducted on 336 patients with type 2 diabetes (T2D). DKD was diagnosed according to the guidelines of the National Kidney Foundation-Kidney Disease Outcome Quality Initiative (NKF-K/DOQI). The Pittsburg Sleep Quality Index (PSQI) score was applied to assess patients for the quality of their sleep. Patients with a PSQI score of more than 5 were assigned to the poor sleep group, and the rest of the patients were assigned to the good sleep group. Circulating levels of six inflammatory biomarkers related to poor sleep and DKD were measured. RESULTS: The prevalence of DKD was higher in patients with poor sleep quality than in those with good sleep quality (42% vs. 25%, P = 0.002). After adjustment, poor sleep quality (PSQI score OR 1.075 [95%CI 1.018-1.135], P = 0.009) remained independently associated with DKD. PSQI score was found to be positively related to fibroblast growth factor (FGF23), interleukin 6 (IL-6), P-selectin, and intercellular adhesion molecule-1 (ICAM-1) (P < 0.01), rather than fibrinogen and C-reactive protein (CRP) in linear regression models. As revealed by multiple mediation analysis, FGF23 and IL-6 mediated 26% and 23% of the relationship between PSQI score and urinary microalbumin (UMA), respectively. Similarly, the FGF23 and ICAM-1, instead of IL-6 and P-selectin, mediated 32% and 24% of the association between PSQI and estimated glomerular filtration rate (eGFR), respectively. CONCLUSIONS: Poor sleep quality is independently associated with DKD. These results suggest that inflammatory markers contribute to a pathogenic connection between poor sleep and DKD.
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Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/complicaciones , Calidad de Vida , Índice de Severidad de la Enfermedad , Trastornos del Sueño-Vigilia/complicaciones , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medición de RiesgoRESUMEN
Pulmonary fibrosis is a chronic progressive lung disease that lacks effective treatments in clinic. It is characterized by repair disorder of epithelial cells, formation of fibroblast foci as well as destruction of alveolar structure. Previously we first determined that parent peptide DR8 (DHNNPQIR-NH2) has anti-fibrotic activity in bleomycin-induced mice. In order to further improve the druggability of DR8, including anti-fibrotic activity, stability and security, the structure-activity relationship was investigated using a series of D-amino acid and alanine scanning analogs of DR8. The results indicated that peptides DR8-3D and DR8-8A exhibited potent anti-fibrotic activity and better stability. Further mechanism research revealed that DR8-3D and DR8-8A ameliorated lung fibrosis by inhibiting TGF-ß1 mediated epithelial-mesenchymal transition process and ERK1/2 signaling pathway in vitro and in vivo. Moreover, we found that anti-fibrotic activity of DR8 was closely related to the residues aspartic acid (Asp)1, histidine (His)2, proline (Pro)5 and glutamine (Gln)6, which suggested that the position of residues asparagine (Asn)3, asparagine (Asn)4, isoleucine (Ile)7 and arginine (Arg)8 could be further modified to optimized its anti-fibrotic effect. Therefore, we consider that DR8-3D and DR8-8A not only could be used as a potential leading compound for the treatment of bleomycin-induced lung fibrosis but also laid a foundation for the development of new anti-fibrotic drugs.
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Fibrosis Pulmonar , Factor de Crecimiento Transformador beta1 , Animales , Bleomicina , Transición Epitelial-Mesenquimal , Pulmón/metabolismo , Sistema de Señalización de MAP Quinasas , Ratones , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to have higher pathogenicity among patients with obesity. Obesity, termed as body mass index greater than 30 kg/m2, has now been demonstrated to be important comorbidity for disease severity during coronavirus disease 2019 (COVID-19) pandemic and associated with adverse events. Unraveling mechanisms behind this phenomenon can assist scientists, clinicians, and policymakers in responding appropriately to the COVID-19 pandemic. In this review, we systemically delineated the potential mechanistic links between obesity and worsening COVID-19 from altered physiology, underlying diseases, metabolism, immunity, cytokine storm, and thrombosis. Problematic ventilation caused by obesity and preexisting medical disorders exacerbate organ dysfunction for patients with obesity. Chronic metabolic disorders, including dyslipidemia, hyperglycemia, vitamin D deficiency, and polymorphisms of metabolism-related genes in obesity, probably aid SARS-CoV-2 intrusion and impair antiviral responses. Obesity-induced inadequate antiviral immunity (interferon, natural killer cells, invariant natural killer T cell, dendritic cell, T cells, B cell) at the early stage of SARS-CoV-2 infection leads to delayed viral elimination, increased viral load, and expedited viral mutation. Cytokine storm, with the defective antiviral immunity, probably contributes to tissue damage and pathological progression, resulting in severe symptoms and poor prognosis. The prothrombotic state, driven in large part by endothelial dysfunction, platelet hyperactivation, hypercoagulability, and impaired fibrinolysis in obesity, also increases the risk of severe COVID-19. These mechanisms in the susceptibility to severe condition also open the possibility for host-directed therapies in population with obesity. By bridging work done in these fields, researchers can gain a holistic view of the paths forward and therapeutic opportunities to break the vicious cycle of obesity and its devastating complications in the next emerging pandemic.
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COVID-19 , Inmunidad Innata , Obesidad/epidemiología , Pandemias , Animales , COVID-19/epidemiología , COVID-19/inmunología , Comorbilidad , Humanos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The purpose of this study was to explore the role of protein kinase C (PKC) isozymes and reactive oxygen species (ROS) in hypoxia and angiotensin (Ang) II-induced autophagy. METHODS: Primary cardiomyocytes were isolated from Sprague-Dawley (SD) neonatal rats and cultured in hypoxia and/or Ang II conditions. Dihydroethidium fluorescence staining was used to detect the content of ROS. Cardiomyocyte autophagy was determined using Monodansylcadaverine fluorescence staining and Western blot. We also inhibited ROS production to explore the relationship between ROS and autophagy. ELISA was used to detect the contents of PKC δ and PKC ε. After inhibition of PKC δ activation and PKC ε expression by lentiviral siRNA, ROS content and autophagy of cultured cardiomyocytes were detected. RESULTS: Hypoxia and Ang II stimulation increased autophagy in cardiomyocytes, accompanied by increased intracellular ROS production. Inhibiting ROS following hypoxia or Ang II stimulation significantly suppressed autophagy in comparison with hypoxia or Ang II stimulation group. Inhibiting PKC δ significantly reduced ROS production and autophagy activity following hypoxia or accompanied with Ang II stimulation except Ang II stimulation alone. Knockdown of PKC ε notably decreased ROS production and autophagy in response to Ang II alone and in combination with hypoxia rather than hypoxia alone. CONCLUSIONS: Both hypoxia and Ang II stimulation can induce autophagy in cardiomyocytes through increasing intracellular ROS. However, hypoxia and Ang II stimulation induced myocardial autophagy via PKC δ and PKC ε, respectively.
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The dramatic increase in antimicrobial resistance (AMR) highlights an urgent need to develop new antimicrobial therapies. Thus, antimicrobial peptides (AMPs) have emerged as promising novel antibiotic alternatives. Feleucin-K3 is an amphiphilic α-helical nonapeptide that has powerful antimicrobial activity. In our previous study, it was found that the fourth residue of Feleucin-K3 is important for antimicrobial activity. After α-(4-pentenyl)-Ala was introduced into this position, both the antimicrobial activity and stability were greatly improved. Herein, to improve the limitations of Feleucin-K3, this unnatural amino acid was further introduced into different positions of Feleucin-K3. Among these synthetic Feleucin-K3 analogs, the N-terminal-substituted analog Feleucin-K65 (K65) and C-terminal-substituted analog Feleucin-K70 (K70) had preferable antimicrobial activity. In particular, their antimicrobial activities against multidrug-resistant bacteria were more potent than that of antibiotics. The stabilities of these peptides in salt and serum environments were improved compared with those of Feleucin-K3. In addition, these analogs had low hemolytic activity and AMR. More importantly, they effectively inhibited biofilm formation and exhibited considerable efficacy compared with traditional antibiotics against biofilm infection caused by methicillin-resistant Staphylococcus aureus (MRSA). In antimicrobial mechanism studies, K65 and K70 mainly permeated the outer membrane and depolarized the cytoplasmic membrane, resulting in cellular component leakage and cell death. In summary, analogs K65 and K70 are potential antimicrobial alternatives to solve the antibiotic crisis.
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Antibacterianos/administración & dosificación , Péptidos Catiónicos Antimicrobianos/administración & dosificación , Biopelículas/crecimiento & desarrollo , Staphylococcus aureus Resistente a Meticilina/fisiología , Infecciones Estafilocócicas/tratamiento farmacológico , Alanina/química , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/síntesis química , Péptidos Catiónicos Antimicrobianos/química , Biopelículas/efectos de los fármacos , Estabilidad de Medicamentos , Femenino , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Secundaria de Proteína , Sales (Química)/química , Suero/químicaRESUMEN
The development of antimicrobial compounds is now regarded as an urgent problem. Antimicrobial peptides (AMPs) have great potential to become novel antimicrobial drugs. Feleucin-K3 is an α-helical cationic AMP isolated from the skin secretion of the Asian bombinid toad species Bombina orientalis and has antimicrobial activity. In our previous studies, amino acid scanning of Feleucin-K3 was performed to determine the key site affecting its activity. In this study, we investigated and synthesized a series of analogues that have either a natural or an unnatural hydrophobic amino acid substitution at the fourth amino acid residue of Feleucin-K3. Among these analogues, Feleucin-K59 (K59), which has an α-(4-pentenyl)-Ala substitution, was shown to have increased antimicrobial activity against both standard and drug-resistant strains of clinical common bacteria, improved stability, no hemolytic activity at antimicrobial concentrations, and no resistance. In addition, K59 has potent antibiofilm activity in vitro. More importantly, K59 showed better antimicrobial and antibiofilm activities against drug-resistant bacteria in in vivo experiments in mice than traditional antibiotics. In this preliminary study of the mechanism of action, we found that K59 could rapidly kill bacteria by a dual-action mechanism of disrupting the cell membrane and binding to intracellular DNA, thus making it difficult for bacteria to develop resistance.
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Antiinfecciosos , Péptidos Catiónicos Antimicrobianos , Animales , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Biopelículas , Ratones , Pruebas de Sensibilidad MicrobianaRESUMEN
The evolution of Staphylococcus aureus (S. aureus) with the ability to acquire and develop resistance to antibiotics has been described as a distinct strain emergence event. Methicillin-resistant S. aureus (MRSA) is responsible for most global S. aureus bacteremia cases. Bacterial biofilms are one of the primary reasons for drug resistance. Biofilms formed by S. aureus are the most common cause of biofilm-associated infections, which increase the difficulty of treatment. Antimicrobial peptides (AMPs) represent promising candidates for the future treatment of antibiotic-resistant bacterial and biofilm-associated infections. In this study, we designed and synthesized a series of analogs to increase the druggability of the natural antimicrobial peptide CPF-C1. Among the analogs, CPF-2 showed high antimicrobial activity against MRSA and multidrug-resistant S. aureus isolated from clinics. In the serum and physiological salt environment, CPF-2 also exhibited effective antimicrobial activity. Importantly, CPF-2 did not determine resistance and showed no hemolytic activity at the active concentration. Concerning the mechanism of action, CPF-2 produced a rapid bactericidal effect by interrupting the bacterial membranes. Even more surprisingly, CPF-2 showed an excellent ability to prevent and eradicate biofilms caused by S. aureus and MRSA not only in vitro but also in vivo. Our results suggested that CPF-2 has potential as a lead compound to treat infections caused by S. aureus and MRSA, including the associated biofilms.
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Antibacterianos , Péptidos Catiónicos Antimicrobianos , Biopelículas , Staphylococcus aureus Resistente a Meticilina/fisiología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/síntesis química , Péptidos Catiónicos Antimicrobianos/química , Péptidos Catiónicos Antimicrobianos/farmacología , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , RatonesRESUMEN
Induced autophagy is protective against myocardial hypoxia/ischemia (H/I) injury, but evidence regarding the extent of autophagic clearance under H/I and the molecular mechanisms that influence autophagic flux has scarcely been presented. Here, we report that CD38 knockout improved cardiac function and autophagic flux in CD38-/- mice and CD38-/- neonatal cardiomyocytes (CMs) under H/I conditions. Mechanistic studies demonstrated that overexpression of CD38 specifically downregulated the expression of Rab7 and its adaptor protein pleckstrin homology domain-containing protein family member 1 (PLEKHM1) through nicotinamide adenine dinucleotide (NAD)-dependent and non-NAD-dependent pathways, respectively. Loss of Rab7/PLEKHM1 impaired the fusion of autophagosomes and lysosomes, resulting in autophagosome accumulation in the myocardium and consequent cardiac dysfunction under H/I conditions. Thus, CD38 mediated autophagic flux blockade and cardiac dysfunction in a Rab7/PLEKHM1-dependent manner. These findings suggest a potential therapeutic strategy involving targeted suppression of CD38 expression.
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Human angiotensin-converting enzyme 2 (ACE2) facilitates cellular entry of severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 as their common receptor. During infection, ACE2-expressing tissues become direct targets, resulting in serious pathological changes and progressive multiple organ failure or even death in severe cases. However, as an essential component of renin-angiotensin system (RAS), ACE2 confers protective effects in physiological circumstance, including maintaining cardiovascular homeostasis, fluid, and electrolyte balance. The absence of protective role of ACE2 leads to dysregulated RAS and thus acute changes under multiple pathological scenarios including SARS. This potentially shared mechanism may also be the molecular explanation for pathogenesis driven by SARS-CoV-2. We reasonably speculate several potential directions of clinical management including host-directed therapies aiming to restore dysregulated RAS caused by ACE2 deficiency. Enriched knowledge of ACE2 learned from SARS and COVID-19 outbreaks can provide, despite their inherent tragedy, informative clues for emerging pandemic preparedness.
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Betacoronavirus/fisiología , Infecciones por Coronavirus/enzimología , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/enzimología , Síndrome Respiratorio Agudo Grave/enzimología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , Internalización del Virus , Enzima Convertidora de Angiotensina 2 , COVID-19 , Sistemas de Liberación de Medicamentos , Humanos , Pandemias , Peptidil-Dipeptidasa A/deficiencia , SARS-CoV-2RESUMEN
Burns are tissue injuries caused by high temperature, chemicals or electricity. Severe burns may involve all of the organs and tissues of the human body, leading to a series of pathophysiological processes and even death. The present study reviewed the clinical data of burn patients, including cases of burn-associated death, to provide evidence for the strategy of burn prevention. Basic information from 13,205 inpatients treated between January 1, 2009 and December 31, 2016 was extracted from the database of the Institute of Burn Research at Southwest Hospital (Chongqing, China). After excluding 3,426 inpatients who were not primarily treated for burns, 9,779 patients remained; among them, 68 cases (0.7%) had died as a direct consequence of the burns. Based on baseline data, the mortality rate, total body surface area of the burn (TBSA), age, sex, cause of injury and complications were analysed. In general, males accounted for a higher percentage than female burn patients. Of the patients, 95.54% had a TBSA of <50%, and the rate of mortality of the patients was increased when the TBSA was ≥50%. The major causes of injury were scalds (41.60%), fire (26.92%) and electricity (15.29%), and the majority of victims were 14 years or younger. With improvements in burn treatment technology in recent years, burn patient mortality was significantly reduced. Complications, including multiple organ failure and severe systemic infection, may reduce the survival rate of patients. The major risk factors for death included burns resulting from explosions, as well as shock, age (aged 0-1 or ≥50 years), greater TBSA and full-thickness burn area. With increasing length of stay at the hospital, patient mortality decreased. The renewal of treatment concepts and refined patient management contributed to the shorter LOS and lower mortality in 2015 and 2016.
RESUMEN
Inhalation injury is often associated with burns and significantly increases morbidity and mortality. The main toxic components of fire smoke are carbon monoxide, hydrogen cyanide, and irritants. In the case of an incident at a nuclear power plant or recycling facility associated with fire, smoke may also contain radioactive material. Medical treatments may vary in different countries, and in this paper, we discuss the similarities and differences in the treatments between China and Germany. Carbon monoxide poisoning is treated by 100% oxygen administration and, if available, hyperbaric oxygenation in China as well as in Germany. In addition, antidotes binding the cyanide ions and relieving the respiratory chain are important. Methemoglobin-forming agents (e.g., nitrites, dimethylaminophenol) or hydroxocobalamin (Vitamin B12) are options. The metabolic elimination of cyanide may be enhanced by sodium thiosulfate. In China, sodium nitrite with sodium thiosulfate is the most common combination. The use of dimethylaminophenol instead of sodium nitrite is typical for Germany, and hydroxocobalamin is considered the antidote of choice if available in cases of cyanide intoxications by fire smoke inhalation as it does not further reduce oxygen transport capacity. Systematic prophylactic use of corticosteroids to prevent toxic pulmonary edema is not recommended in China or Germany. Stable iodine is indicated in the case of radioiodine exposure and must be administered within several hours to be effective. The decorporation of metal radionuclides is possible with Ca (DTPA) or Prussian blue that should be given as soon as possible. These medications are used in both countries, but it seems that Ca (DTPA) is administered at lower dosages in China. Although the details of the treatment of inhalation injury and radionuclide(s) decorporation may vary, the general therapeutic strategy is very similar in China and Germany.