RESUMO
PURPOSE: The study explored the enhanced skin moisturizing capabilities and moisture retention effects achieved by forming a polyion complex using sulfated glycosaminoglycan (GAG), specifically chondroitin sulfate (CS), and amino acids (AA) such as glutamine (Q) and arginine (R). The overall hydration effect of this CS-AA complex was examined. METHODS: After analyzing the CS-AA polyion complex structure using spectroscopic methods, the ex vivo moisture retention ability was assessed under dry conditions using porcine skin samples. Additionally, the efficacy of the CS-AA polyion complex in reducing transepidermal water loss (TEWL) and improving skin hydration was evaluated on human subjects using a digital evaporimeter and a corneometer, respectively. RESULTS: Validating a systematic reduction in particle size, the following order was observed: CS > CS/AA simple mixture > CS-AA complex based on dynamic light scattering (DLS) and transmission electron microscopy (TEM) analysis. Furthermore, observations revealed that the CS-AA complex exhibits negligible surface charge. Additionally, Fourier-transform infrared spectroscopy (FT-IR) analysis demonstrated a distinct peak shift in the complex, confirming the successful formation of the CS-AA complex. Subsequently, the water-holding effect through porcine skin was assessed, revealing a notable improvement in moisture retention (weight loss) for the CS-Q complex: 40.6% (1 h), 20.5% (2 h), and 18.7% (4 h) compared to glycerin. Similarly, the CS-R complex demonstrated enhancements of 50.2% (1 h), 37.5% (2 h), and 33% (4 h) compared to glycerin. Furthermore, TEWL improvement efficacy on human skin demonstrated approximately 25% improvement for both the CS-Q complex and CS-R complex, surpassing the modest 12.5% and 18% improvements witnessed with water and glycerin applications, respectively. Finally, employing a corneometer, hydration changes in the skin were monitored over 4 weeks. Although CS alone exhibited nominal alterations, the CS-Q complex and CS-R complex showed a significant increase in moisture levels after 4 weeks of application. CONCLUSION: In this study, polyion complexes were successfully formed between CS, a sulfated GAG, and AA. Comparisons with glycerin, a well-known moisturizing agent, confirmed that the CS-AA complex exhibits superior moisturizing effects in various aspects. These findings suggest that the CS-AA complex is a more effective ingredient than CS or AA alone in terms of efficacy.
Assuntos
Sulfatos de Condroitina , Cosméticos , Perda Insensível de Água , Humanos , Animais , Suínos , Perda Insensível de Água/efeitos dos fármacos , Cosméticos/farmacologia , Cosméticos/química , Sulfatos de Condroitina/química , Sulfatos de Condroitina/farmacologia , Feminino , Pele/química , Pele/efeitos dos fármacos , Pele/metabolismo , Adulto , Aminoácidos/química , Aminoácidos/farmacologia , Emolientes/farmacologia , Emolientes/administração & dosagem , Emolientes/química , Polímeros/farmacologia , Polímeros/química , Glutamina/farmacologia , PolieletrólitosRESUMO
The growing problem of herbicide resistance necessitates the development of novel herbicidal active ingredients, together with other integrated weed management approaches. Natural products are a major source of inspiration for novel actives. In previous research, we identified a 3-acyltetramic acid of microbial origin that inhibited algal growth in marine biofilms, at least in part through inhibition of photosystem II. In this work, we demonstrate the herbicidal effect of this lead compound and construct multiple libraries to test the impact of the different substituents of the central scaffold in order to study the structure-activity relationships. Among these analogues, the highest activities were found for medium- to long-chain acyl groups and apolar secondary amino acid residues. Finally, we provide first insights into the herbicidal mechanisms and present preliminary field-trial and ecotoxicological results for TA12-Pro, the most active analogue in our library. Together, this research shows the potential of 3-acyltetramic acids for herbicide development.
Assuntos
Aminoácidos , Herbicidas , Herbicidas/farmacologia , Herbicidas/química , Relação Estrutura-Atividade , Aminoácidos/química , Aminoácidos/farmacologia , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/crescimento & desenvolvimento , Ácido Tenuazônico/farmacologia , Ácido Tenuazônico/química , Estrutura MolecularRESUMO
To date, the use of corannulene has been restricted in the area of material science, but its application in biomedical research has yet to be established due to its nonsolubility in an aqueous environment and synthetic infeasibility. Herein, we detail the development of a new family of highly curved π-conjugated corannulene-containing unnatural α-amino acid (CAA) derivatives to overcome this challenge. These CAAs have been extended as novel constituents for the synthesis of corannulene-containing water-soluble cationic peptides (CCPs), which display inhibitory activity against broad-spectrum pathogenic bacteria along with drug-resistant bacteria via a membrane-damaging mechanism. Importantly, several of the synthesized peptides were found to be appreciably nonhemolytic against hRBCs and noncytotoxic against mammalian 3T3 cells. In vivo efficacy studies of the potent and least cytotoxic peptide 6a demonstrated clearance of bacteria from the spleen, liver, lung, and blood of mice infected with S. aureus ATCC 25923.
Assuntos
Aminoácidos , Antibacterianos , Testes de Sensibilidade Microbiana , Solubilidade , Água , Animais , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Camundongos , Aminoácidos/química , Aminoácidos/farmacologia , Água/química , Humanos , Staphylococcus aureus/efeitos dos fármacos , Hidrocarbonetos Policíclicos Aromáticos/farmacologia , Hidrocarbonetos Policíclicos Aromáticos/química , Hidrocarbonetos Policíclicos Aromáticos/síntese química , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/síntese química , Relação Estrutura-Atividade , Infecções Estafilocócicas/tratamento farmacológicoRESUMO
The immune response varies between pigs, as not all pigs have the same response to a stressor. This variation may exist between individuals due to body weight (BW) or body composition, which may impact the capacity for coping with an immune challenge (IC). Tryptophan (Trp), threonine (Thr), and methionine (Met) requirements might also play a considerable part in supporting immune system activation while reducing variation between pigs; however, the latter has yet to be reported. This exploratory study investigated the effect of initial BW (light vs. heavy-weight) and supplementation of Trp, Thr, and Met above National Research Council (NRC) requirements on feeding behavior and the coping capacity of growing pigs under an IC. Eighty gilts were categorized into 2 groups according to BW: light-weight (LW, 22.5 kg) and heavy-weight pigs (HW, 28.5 kg). Both BW groups were group-housed for a 28-d trial in a good or poor sanitary condition (SC). Pigs within a poor SC were orally inoculated with 2â ×â 109 colony units of Salmonella Typhimurium, and fresh manure from a pig farm was spread on the floor. Pigs within good SC were not inoculated, nor was manure spread. Two diets were provided within each SC: control (CN) or supplemented (AA+) with Trp, Thr, and Met at 120% of NRC recommended levels. A principal component analysis was performed in R, and a feeding behavior index was calculated in SAS. Results showed that LW and HW pigs were clustered separately on day 0, where LW pigs had a positive correlation with body lipid percentage (râ =â 0.83), and HW pigs had a positive correlation with body protein percentage (râ =â 0.75). After the IC, the cluster configuration changed, with diets influencing LW more than HW pigs within poor SC. On day 14, LW fed AAâ +â diet in poor SC was clustered separately from LW pigs fed CN diet, whereas LW fed AAâ +â and CN diets in good SC were clustered together. For feeding behavior, in both analyzed periods (period 1: days 7 to 14; period 2: days 21 to 28), LW had lower total feed intake and shorter meals than HW pigs (Pâ <â 0.10), independent of the SC. Furthermore, LW pigs fed AAâ +â diet had a more regular feed intake pattern than those fed CN diet, while a more irregular pattern was observed for HW pigs fed AAâ +â diet than CN diet at period 2. These findings suggest that supplementing Trp, Thr, and Met above requirements may be a nutritional strategy for LW pigs under IC by improving feed intake regularity and reducing the probability of being susceptible to IC.
An immune challenge impacts pig welfare and may decrease growth and protein deposition. These may happen due to the different nutrient requirements of immune-challenged pigs compared to non-challenged. Dietary supplementation of tryptophan, threonine, and methionine has been proven to be a strategy to mitigate performance losses by supporting immune system functioning, maintaining gut barrier integrity, and reducing oxidative status. However, individuals within a population with similar age and genetics have distinct responses to dietary strategies due to different coping abilities to an immune challenge, which may be due to body weight (BW)/body composition and feeding behavior patterns. In this context, this study investigated the effect of BW (light-weight vs. heavy-weight) and tryptophan, threonine, and methionine supplementation on feeding behavior and the coping capacity of growing pigs under an immune challenge. Heavy-weight pigs had greater feed intake regularity and coping abilities over time when compared to light-weight pigs. However, increasing the amino acid level in the diet improved feed intake regularity in light-weight pigs. The amino acid supplementation may be a potential precision nutrition strategy for light-weight pigs by improving feed intake regularity over time, reducing susceptibility to an immune challenge.
Assuntos
Aminoácidos , Ração Animal , Peso Corporal , Dieta , Suplementos Nutricionais , Animais , Feminino , Suplementos Nutricionais/análise , Ração Animal/análise , Dieta/veterinária , Peso Corporal/efeitos dos fármacos , Suínos/fisiologia , Suínos/imunologia , Aminoácidos/metabolismo , Aminoácidos/farmacologia , Metionina/administração & dosagem , Metionina/farmacologia , Fenômenos Fisiológicos da Nutrição Animal , Comportamento Alimentar/efeitos dos fármacos , Triptofano/farmacologia , Triptofano/administração & dosagem , Treonina/farmacologia , Treonina/administração & dosagemRESUMO
Presently, the non-biodegradable polypropylene (PP) patches frequently used for hernia repair can cause fibrous tissue growth and adhesions. This study created a Janus Patch with anti-adhesion and antimicrobial properties to improve hernia repair while promoting tissue repair. The biologically active 4arm-PLGA-BLPD was initially synthesized through the modification of 4arm-PLGA with lysine, followed by the fabrication of a Janus patch using a layer-by-layer electrostatic spinning technique. This patch consisted of three layers: a repair layer composed of 4arm-PLGA-BLPD/PCL fiber membrane, a mechanical layer of 4arm-PLGA/PCL fiber membrane, and an antimicrobial layer of EMO-4arm-PLGA/PCL fiber membrane loaded with Emodin (EMO). The results showed that Janus patch exhibited notable tensile strength and elongation at break, enabling it to offer enhanced mechanical reinforcement for abdominal wall defects. In addition, it slowly releases lysine for repair and inhibits bacterial growth with EMO. In vivo experiments demonstrated that the patch effectively induced neovascularization, reduced collagen ac-cumulation, and stabilized the expression of relevant proteins through the up-regulation of MMP1 and MMP9. This facilitated successful repair of the abdominal wall defect model and prevented adhesions. In summary, the Janus patch offers both practical application and theoretical insight for hernia repair.
Assuntos
Antibacterianos , Herniorrafia , Animais , Antibacterianos/farmacologia , Antibacterianos/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Emodina/farmacologia , Emodina/química , Aminoácidos/química , Aminoácidos/farmacologia , Lisina/química , Lisina/farmacologia , Masculino , Camundongos , Resistência à TraçãoRESUMO
Proteolysis-targeting chimeras (PROTACs) selectively eliminate detrimental proteins by exploiting the ubiquitin-proteasome system (UPS), representing a promising therapeutic strategy against various diseases. Effective adaptations of degradation signal sequences and E3 ligases for PROTACs remain limited. Here, we employed three amino acidsâGly, Pro, and Lysâas the ligand to recruit the corresponding E3 ligases: CRL2ZYG11B/ZER1, GID4, and UBRs, to degrade EML4-ALK and mutant EGFR, two oncogenic drivers in NSCLC. We found that the extent of EML4-ALK and EGFR reduction can be easily fine-tuned by using different degradation signals. These amino acid-based PROTACs, termed AATacs, hindered proliferation and induced cell cycle arrest and apoptosis of NSCLC cells in vitro. Compared to other PROTACs, AATacs are small, interchangeable but with different degradation efficiency. Our study further expands the repertoire of E3 ligases and their ligands for PROTAC application, improving the versatility and utility of targeted protein degradation for therapeutic purposes.
Assuntos
Aminoácidos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteólise , Ubiquitina-Proteína Ligases , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteólise/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Aminoácidos/farmacologia , Aminoácidos/metabolismo , Aminoácidos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Quimera de Direcionamento de ProteóliseRESUMO
Nutrition and resilience are linked, though it is not yet clear how diet confers stress resistance or the breadth of stressors that it can protect against. We have previously shown that transiently restricting an essential amino acid can protect Drosophila melanogaster against nicotine poisoning. Here, we sought to characterize the nature of this dietary-mediated protection and determine whether it was sex, amino acid and/or nicotine specific. When we compared between sexes, we found that isoleucine deprivation increases female, but not male, nicotine resistance. Surprisingly, we found that this protection afforded to females was not replicated by dietary protein restriction and was instead specific to individual amino acid restriction. To understand whether these beneficial effects of diet were specific to nicotine or were generalizable across stressors, we pre-treated flies with amino acid restriction diets and exposed them to other types of stress. We found that some of the diets that protected against nicotine also protected against oxidative and starvation stress, and improved survival following cold shock. Interestingly, we found that a diet lacking isoleucine was the only diet to protect against all these stressors. These data point to isoleucine as a critical determinant of robustness in the face of environmental challenges.
Assuntos
Drosophila melanogaster , Nicotina , Estresse Fisiológico , Animais , Drosophila melanogaster/efeitos dos fármacos , Feminino , Masculino , Nicotina/farmacologia , Estresse Fisiológico/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Aminoácidos/farmacologia , Aminoácidos/metabolismo , Isoleucina/farmacologiaRESUMO
The development of tuberculosis (TB) therapy has been marked by the discovery of natural-product-derived streptomycin, followed by the introduction of NP-derived rifampicin, representing a significant milestone in the history of TB management. However, TB remains a global challenge, with the emergence of multidrug-resistant Mycobacterium tuberculosis highlighting the need for novel therapeutic agents. In this study, a bioinformatic approach was employed to investigate d-amino acid-activating adenylation domains, leading to the identification of cordysetin A (1), a novel trans-decalin tetramic acid antibiotic from the ascomycete fungi Cordyceps militaris. Cordysetin A (1) exhibits considerable activity against M. tuberculosis in vitro and in vivo while maintaining low cytotoxicity. These results reveal that the d-configuration of the amino acid within this hybrid polyketide-nonribosomal antibiotic is crucial for preserving its anti-tuberculosis efficacy. These findings emphasize the significant translational potential of cordysetin A as a promising candidate for TB treatment, furthering our understanding of bioinformatic approaches in the development of effective anti-tuberculosis agents.
Assuntos
Antituberculosos , Biologia Computacional , Cordyceps , Mycobacterium tuberculosis , Cordyceps/química , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/farmacologia , Antituberculosos/química , Testes de Sensibilidade Microbiana , Aminoácidos/química , Aminoácidos/farmacologia , Animais , Humanos , Estrutura Molecular , Antibacterianos/farmacologia , Antibacterianos/química , Tuberculose/tratamento farmacológicoRESUMO
The rise in antimicrobial resistance, the increasing occurrence of bacterial, and fungal infections, and the challenges posed by polymicrobial biofilms necessitate the exploration of innovative therapeutic strategies. Silver-based antimicrobials have garnered attention for their broad-spectrum activity and multimodal mechanisms of action. However, their effectiveness against single-species or polymicrobial biofilms remains limited. In this study, we present the fabrication of polymer-silver bromide nanocomposites using amino acid conjugated polymers (ACPs) through a green and water-based in situ technique. The nanocomposite architecture facilitated prolonged and controlled release of the active components. Remarkably, the nanocomposites exhibited broad-spectrum activity against multidrug-resistant (MDR) human pathogenic bacteria (MIC = 2-16 µg/mL) and fungi (MIC = 1-8 µg/mL), while displaying no detectable toxicity to human erythrocytes (HC50 > 1024 µg/mL). In contrast to existing antimicrobials and silver-based therapies, the nanocomposite effectively eradicated bacterial, fungal, and polymicrobial biofilms, and prevented the development of microbial resistance due to their membrane-active properties. Furthermore, the lead polymer-silver bromide nanocomposite demonstrated a 99% reduction in the drug-resistant Pseudomonas aeruginosa burden in a murine model of burn wound infection, along with excellent in vivo biocompatibility.
Assuntos
Biofilmes , Queimaduras , Testes de Sensibilidade Microbiana , Nanocompostos , Polímeros , Infecção dos Ferimentos , Biofilmes/efeitos dos fármacos , Nanocompostos/química , Animais , Camundongos , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/microbiologia , Humanos , Queimaduras/tratamento farmacológico , Polímeros/química , Polímeros/farmacologia , Compostos de Prata/farmacologia , Compostos de Prata/química , Antibacterianos/farmacologia , Antibacterianos/química , Aminoácidos/química , Aminoácidos/farmacologia , Brometos/química , Brometos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias/efeitos dos fármacosRESUMO
The airway epithelium plays a pivotal role in regulating mucosal immunity and inflammation. Epithelial barrier function, homeostasis of luminal fluid, and mucociliary clearance are major components of mucosal defense mechanisms. The epithelial sodium channel (ENaC) is one of the key players in controlling airway fluid volume and composition, and characteristic cytokines cause ENaC and barrier dysfunctions following pulmonary infections or allergic reactions. Given the limited understanding of the requisite duration and magnitude of cytokines to affect ENaC and barrier function, available treatment options for restoring normal ENaC activity are limited. Previous studies have demonstrated that distinct amino acids can modulate epithelial ion channel activities and barrier function in intestines and airways. Here, we have investigated the time- and concentration-dependent effect of representative cytokines for Th1- (IFN-γ and TNF-α), Th2- (IL-4 and IL-13), and Treg-mediated (TGF-ß1) immune responses on ENaC activity and barrier function in human bronchial epithelial cells. When cells were exposed to Th1 and Treg cytokines, ENaC activity decreased gradually while barrier function remained largely unaffected. In contrast, Th2 cytokines had an immediate and profound inhibitory effect on ENaC activity that was subsequently followed by epithelial barrier disruption. These functional changes were associated with decreased membrane protein expression of α-, ß-, and γ-ENaC, and decreased mRNA levels of ß- and γ-ENaC. A proprietary blend of amino acids was developed based on their ability to prevent Th2 cytokine-induced ENaC dysfunction. Exposure to the select amino acids reversed the inhibitory effect of IL-13 on ENaC activity by increasing mRNA levels of ß- and γ-ENaC, and protein expression of γ-ENaC. This study indicates the beneficial effect of select amino acids on ENaC activity in an in vitro setting of Th2-mediated inflammation suggesting these amino acids as a novel therapeutic approach for correcting this condition.
Assuntos
Aminoácidos , Brônquios , Citocinas , Células Epiteliais , Canais Epiteliais de Sódio , Canais Epiteliais de Sódio/metabolismo , Canais Epiteliais de Sódio/genética , Humanos , Brônquios/citologia , Brônquios/metabolismo , Brônquios/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Citocinas/metabolismo , Aminoácidos/farmacologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Linhagem Celular , Células Th1/imunologia , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Interleucina-13/metabolismoRESUMO
Cancer cells require substantial amounts of energy and substrates for their metabolic hyperactivity, enabling the synthesis of new cells at the expense of healthy ones. Preliminary in vitro data suggest that a mix of free essential amino acids (EAA-mix) can promote cancer cell apoptosis by enhancing autophagy. This study aimed to confirm, both in vitro and in vivo, whether EAA intake could influence the development of colon cancer in mice. We investigated changes in cancer proliferation in CT26 cells treated with EAA-mix and in mice fed with EAA-rich modified diets (EAARD) as compared to those on a standard laboratory diet (StD). CT26 cells were injected subcutaneously (s.c.) or intraperitoneally (i.p.). After 21 days, tumors were removed and measured. In vitro data corroborated that EAA-mix impairs cancer growth by inducing apoptosis. In vivo data revealed that mice on StD developed significantly larger (s.c.) and more numerous (i.p.) cancers than those on EAARD. EAA administration appears to influence cancer cell survival with notable antiproliferative properties.
Assuntos
Apoptose , Proliferação de Células , Neoplasias do Colo , Animais , Neoplasias do Colo/patologia , Neoplasias do Colo/metabolismo , Camundongos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Aminoácidos/farmacologia , Camundongos Endogâmicos BALB C , Aminoácidos Essenciais/farmacologiaRESUMO
Cycloicaritin (CICT), a bioactive flavonoid derived from the genus Epimedium, exhibits a variety of beneficial biological activities, including promising anticancer effects. However, its poor oral bioavailability is attributed to its extremely low aqueous solubility and rapid elimination via phase II conjugative metabolism. To overcome these limitations, we designed and synthesized a series of carbamate-bridged prodrugs, protecting the hydroxyl group at the 3-position of cycloicaritin by binding with the N-terminus of a natural amino acid. The optimal prodrug 4b demonstrated a significant increase in aqueous solubility as compared to CICT, as well as improved stability in phase II metabolism, while allowing for a rapid release of CICT in the blood upon gastrointestinal absorption. The prodrug 4b also facilitated oral absorption through organic anion-transporting polypeptide 2B1-mediated transport and exhibited moderate cytotoxicity. Importantly, the prodrug enhanced the oral bioavailability of CICT and displayed dose-dependent antitumor activity with superior safety. In summary, the prodrug 4b is a novel potential antitumor drug candidate, and the carbamate-bridged amino acid prodrug approach is a promising strategy for the oral delivery of CICT.
Assuntos
Aminoácidos , Antineoplásicos , Carbamatos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pró-Fármacos , Solubilidade , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Humanos , Carbamatos/química , Carbamatos/farmacologia , Carbamatos/síntese química , Carbamatos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Animais , Relação Estrutura-Atividade , Aminoácidos/química , Aminoácidos/farmacologia , Aminoácidos/síntese química , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Camundongos , Água/química , Linhagem Celular Tumoral , Flavonoides/química , Flavonoides/farmacologia , Flavonoides/síntese química , Flavonoides/farmacocinética , MasculinoRESUMO
Diabetes mellitus (DM) is a metabolic disorder impacting cerebral function. The administration of Streptozotocin (STZ) is a well-known animal model of insulinopenic type 1 DM in rats. STZ-induced DM results in a myriad of alteration in the periphery and central nervous system (CNS). Cerebrolysin (CBL) is a neuropeptide preparation that promotes synaptic and neuronal plasticity in various animal models. In all cases, CBL was administered when the model was established. This research aims to investigate the neuroprotective and neurorepair effect of CBL on the cytoarchitecture of neurons and spine density in pyramidal neurons of the prefrontal (PFC) and the CA1 region of the dorsal hippocampus, as well as spheroidal neurons of the dentate gyrus (DG), in STZ-induced DM. In the first experimental condition, STZ and CBL are administered at the same time to evaluate the potential preventive effect of CBL. In the second experimental condition, CBL was administered two months after establishing the DM model to measure the potential neurorepair effect of CBL. STZ-induced hyperglycemia remained unaltered by the administration of CBL in both experimental conditions. In the first experimental condition, CBL treatment preserved the neuronal morphology in PFC layer 3, PFC layer 5 and the DG of the hippocampus, while also maintaining spine density in the PFC-3, DG and CA1 hippocampus. Furthermore, CBL induced neurorepair in neurons within the PFC-3, PFC-5 and CA1 regions of the hippocampus, along with an increase in spine density in the PFC-3, DG and CA1 hippocampus. These findings suggest that CBL´s effects on neuroplasticity could be observed before or after the damage was evident.
Assuntos
Aminoácidos , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Fármacos Neuroprotetores , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Diabetes Mellitus Tipo 1/tratamento farmacológico , Aminoácidos/farmacologia , Aminoácidos/administração & dosagem , Masculino , Diabetes Mellitus Experimental/tratamento farmacológico , Estreptozocina/farmacologia , Modelos Animais de Doenças , Ratos Wistar , Ratos , Células Piramidais/efeitos dos fármacos , Células Piramidais/patologia , Córtex Pré-Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacosRESUMO
The severe acute respiratory syndrome coronavirus (SARS-CoV-2) pandemic has triggered a significant impact on global public health security, it is urgent to develop effective antiviral drugs. Previous studies have found that binding to ACE2 is a key step in the invasion of SARS-CoV-2 into host cells, so virus invasion can be inhibited by blocking ACE2, but there are few reports on this kind of specific inhibitor. Our previous study found that Harringtonine (HT) can inhibit the entry of SARS-CoV-2 spike pseudovirus into ACE2h cells, but its relatively high cytotoxicity limits its further development. Amino acid modification of the active components can increase their solubility and reduce their cytotoxicity. Therefore, in this study, seven new derivatives were synthesized by amino acid modification of its core structure Cephalotaxine. The target compounds were evaluated by cell viability assay and the SARS-CoV-2 spike pseudovirus entry assay. Compound CET-1 significantly inhibited the entry of pseudovirus into ACE2h cells and showed less cytotoxicity than HT. Molecular docking results showed that CET-1 could bind TYR83, an important residue of ACE2, just like HT. In conclusion, our study provided a novel compound with more potential activity and lower toxicity than HT on inhibiting the SARS-CoV-2 spike pseudovirus infection, which makes it possible to be a lead compound as an antiviral drug in the future.
Assuntos
Enzima de Conversão de Angiotensina 2 , Antivirais , Tratamento Farmacológico da COVID-19 , Mepesuccinato de Omacetaxina , Simulação de Acoplamento Molecular , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , Aminoácidos/química , Aminoácidos/farmacologia , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Sobrevivência Celular/efeitos dos fármacos , COVID-19/virologia , Mepesuccinato de Omacetaxina/farmacologia , Mepesuccinato de Omacetaxina/química , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/química , Internalização do Vírus/efeitos dos fármacos , Harringtoninas/química , Harringtoninas/farmacologiaRESUMO
Skeletal muscle atrophy (SMA) is caused by a rise in muscle breakdown and a decline in protein synthesis, with a consequent loss of mass and function. This study characterized the effect of an amino acid mixture (AA) in models of SMA, focusing on mitochondria. C57/Bl6 mice underwent immobilization of one hindlimb (I) or cardiotoxin-induced muscle injury (C) and were compared with controls (CTRL). Mice were then administered AA in drinking water for 10 days and compared to a placebo group. With respect to CTRL, I and C reduced running time and distance, along with grip strength; however, the reduction was prevented by AA. Tibialis anterior (TA) muscles were used for histology and mitochondria isolation. I and C resulted in TA atrophy, characterized by a reduction in both wet weight and TA/body weight ratio and smaller myofibers than those of CTRL. Interestingly, these alterations were lightly observed in mice treated with AA. The mitochondrial yield from the TA of I and C mice was lower than that of CTRL but not in AA-treated mice. AA also preserved mitochondrial bioenergetics in TA muscle from I and C mice. To conclude, this study demonstrates that AA prevents loss of muscle mass and function in SMA by protecting mitochondria.
Assuntos
Aminoácidos , Metabolismo Energético , Camundongos Endogâmicos C57BL , Músculo Esquelético , Atrofia Muscular , Animais , Camundongos , Metabolismo Energético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Aminoácidos/farmacologia , Aminoácidos/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/patologia , Atrofia Muscular/etiologia , Masculino , Modelos Animais de Doenças , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/patologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacosRESUMO
Isoliquiritigenin (ISL) is a chalcone that has shown great potential in the treatment of cancer. However, its relatively weak activity and low water solubility limit its clinical application. In this study, we designed and synthesized 21 amino acid ester derivatives of ISL and characterized the compounds using 1H NMR and 13C NMR. Among them, compound 9 (IC50 = 14.36 µM) had a better inhibitory effect on human cervical cancer (Hela) than ISL (IC50 = 126.5 µM), and it was superior to the positive drug 5-FU (IC50 = 33.59 µM). The mechanism of the action experiment showed that compound 9 could induce Hela cell apoptosis and autophagy through the PI3K/Akt/mTOR pathway.
Assuntos
Aminoácidos , Antineoplásicos , Apoptose , Chalconas , Desenho de Fármacos , Ésteres , Chalconas/farmacologia , Chalconas/química , Chalconas/síntese química , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Células HeLa , Aminoácidos/química , Aminoácidos/farmacologia , Ésteres/química , Ésteres/farmacologia , Ésteres/síntese química , Apoptose/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-Atividade , Fosfatidilinositol 3-Quinases/metabolismo , Autofagia/efeitos dos fármacos , Estrutura MolecularRESUMO
Antifungal peptides are an appealing alternative to standard antifungal medicines due to their unique mechanism of action and low-level resistance. However, their susceptibility to protease degradation keeps hindering their future development. Herein, a library was established to design peptides with protease resistance and high antifungal activity. The peptides were incorporated with minimal D-amino acids to further improve the protease stability. The most active peptide, IR3, demonstrated good antifungal activity and low toxicity, and its molecular integrity was maintained after protease hydrolysis for 8 h at 2 mg/mL. Furthermore, IR3 could permeate the fungal cell wall, disrupt the cell membrane, produce reactive oxygen species, and induce apoptosis in fungal cells. In vivo experiments confirmed that IR3 could effectively treat fungal keratitis. Collectively, these findings suggest that IR3 is a promising antifungal agent and may be beneficial in the design and development of protease-resistant antifungal peptides.
Assuntos
Aminoácidos , Antifúngicos , Testes de Sensibilidade Microbiana , Antifúngicos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Aminoácidos/química , Aminoácidos/farmacologia , Aminoácidos/metabolismo , Desenho de Fármacos , Animais , Proteólise/efeitos dos fármacos , Peptídeos/farmacologia , Peptídeos/química , Peptídeos/metabolismo , Candida albicans/efeitos dos fármacos , Ceratite/tratamento farmacológico , Ceratite/microbiologia , Peptídeo Hidrolases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Apoptose/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A nucleus-targeted nanocomposite was prepared by clickable amino acid-tuned one-step co-assembly of proteins and chemotherapeutics. The nanocomposite with favorable pharmacokinetic behavior can effectively accumulate in the nucleus, thereby significantly enhancing the anticancer therapeutic effect both in vitro and in vivo.
Assuntos
Aminoácidos , Antineoplásicos , Pró-Fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Aminoácidos/química , Aminoácidos/farmacologia , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Animais , Núcleo Celular/metabolismo , Química Click , Camundongos , Linhagem Celular Tumoral , Nanocompostos/química , Neoplasias/tratamento farmacológicoRESUMO
An experiment was conducted to assess the effects of porcine somatotropin (pST) on the responses to a near-ideal blend of AA on the AA composition of empty, whole-empty body (WEB) protein and WEB essential AA accretion rate in pigs from 22 to 60 kg BW. Forty Hampshireâ ×â Yorkshire gilts were individually penned and assigned to a 4â ×â 2 factorial arrangement of treatments consisting of four diets with and without pST injection. A fortified corn-soybean meal basal diet was formulated to contain 1.50% total Lys with Thr, Met, and Trp added to obtain a near-ideal blend of these AA relative to Lys. In three additional diets, Lys was reduced to 1.25%, 1.00%, and 0.75% by diluting the basal diet with cornstarch, cellulose, and sand such that the diets also contained the same ratios of AA. Pigs that received pST were administered a daily i.m. injection of 2 mg of pST. At 60 kg BW, the WEB (carcass, head, viscera, blood, nails, and hair) was ground and analyzed for proximate and AA composition. Administration of pST increased (Pâ <â 0.001) accretion rates of WEB protein and essential AA. Increasing dietary essential AA increased (quadratic, Pâ <â 0.03) accretion rate of WEB protein, His, Leu, Trp, and Val in pST-treated pigs, but not in untreated pigs. Lysine composition in the accreted WEB protein was not affected (Pâ >â 0.05) by dietary Lys. The efficiency of Lys utilization for WEB Lys accretion was linearly affected (Pâ <â 0.01) by dietary Lys. These results indicated that the dietary Lys needed to achieve maximum WEB Lys accretion is markedly increased by pST administration.
This study evaluated the effects of two factors, porcine somatotropin and graded levels of amino acids, on the total accumulation and the accretion rate of amino acids across a broad range of protein deposition rates in growing pigs. Treatments included 1) with or without a daily injection of porcine somatotropin and 2) graded levels of total dietary lysine from 0.75% to 1.50%. As expected, both the administration of porcine somatotropin and increased dietary lysine increased both the amount and the rate of amino acid accretion. However, the amount and rate of amino acid accretion from increased dietary amino acids were markedly greater in pigs treated with porcine somatotropin. Thus, the extent to which the genetic potential for protein deposition is achieved depends on both the anabolic capacity of the pig and the amino acid concentration of the diet provided.
Assuntos
Aminoácidos , Ração Animal , Fenômenos Fisiológicos da Nutrição Animal , Dieta , Hormônio do Crescimento , Lisina , Animais , Ração Animal/análise , Lisina/farmacologia , Lisina/administração & dosagem , Lisina/química , Dieta/veterinária , Feminino , Hormônio do Crescimento/farmacologia , Aminoácidos/metabolismo , Aminoácidos/farmacologia , Suínos/crescimento & desenvolvimento , Suplementos Nutricionais/análise , Composição Corporal/efeitos dos fármacosRESUMO
OBJECTIVES: Amino acids play an essential role in protein synthesis, metabolism, and survival of pancreatic acini. Adequate nutritional support is important for acute pancreatitis treatment. However, high concentrations of arginine and lysine may induce acute pancreatitis. The study aimed to identify the most suitable l -amino acids as safe energy sources for pancreatic acinar cells. MATERIALS AND METHODS: Pancreatic acini were isolated from male Wistar rats. Effects of amino acids (0.1-20 mM) on uncoupled respiration of isolated acini were studied with a Clark electrode. Cell death was evaluated with fluorescent microscopy and DNA gel electrophoresis. RESULTS: Among the tested amino acids, glutamate, glutamine, alanine, lysine, and aspartate were able to stimulate the uncoupled respiration rate of isolated pancreatic acini, whereas arginine, histidine, and asparagine were not. Lysine, arginine, and glutamine (20 mM) caused complete loss of plasma membrane integrity of acinar cells after 24 hours of incubation. Glutamine also caused early (2-4 hours) cell swelling and blebbing. Aspartate, asparagine, and glutamate only moderately decreased the number of viable cells, whereas alanine and histidine were not toxic. DNA fragmentation assay and microscopic analysis of nuclei showed no evidence of apoptosis in cells treated with amino acids. CONCLUSIONS: Alanine and glutamate are safe and effective energy sources for mitochondria of pancreatic acinar cells.