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1.
J Enzyme Inhib Med Chem ; 39(1): 2305856, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38326989

RESUMO

A novel series of 1,2,3-triazole/1,2,4-oxadiazole hybrids (7a-o) was developed as dual inhibitors of EGFR/VEGFR-2. Compounds 7a-o were evaluated as antiproliferative agents with Erlotinib as the reference drug. Results demonstrated that most of the tested compounds showed significant antiproliferative action with GI50 values ranging from 28 to 104 nM, compared to Erlotinib (GI50 = 33 nM), and compounds 7i-m were the most potent. Compounds 7h, 7i, 7j, 7k, and 7l were evaluated as dual EGFR/VEGFR-2 inhibitors. These in vitro experiments demonstrated that compounds 7j, 7k, and 7l are potent antiproliferative agents that may operate as dual EGFR/VEGFR-2 inhibitors. Compounds 7j, 7k, and 7l were evaluated for their apoptotic potential activity, where findings indicated that compounds 7j, 7k, and 7l promote apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking simulations show the binding mode of the most active antiproliferative compounds within EGFR and VEGFR-2 active sites.


Assuntos
Antineoplásicos , Triazóis , Estrutura Molecular , Relação Estrutura-Atividade , Cloridrato de Erlotinib/farmacologia , Simulação de Acoplamento Molecular , Triazóis/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Antineoplásicos/química , Receptores ErbB/metabolismo , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral
2.
Theranostics ; 14(3): 1181-1194, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38323312

RESUMO

Rationale: Antimicrobial peptide LL-37 has been recognized as a favorable alternative to antibiotics due to its broad antibacterial spectrum, low resistance development and diverse biological activities. However, its high manufactory cost, poor proteolytic stability, and unpredictable cytotoxicity seriously hindered its medical translation. Methods: To push the frontiers of its clinical application, all-hydrocarbon stapling strategy was exploited here for the structural modification of KR-12, the core and minimal fragment of LL-37. Results: Based on a library of KR-12 derivatives that designed and synthesized to be stapled at positions of either i, i+4 or i, i+7, structure to activity relationship was investigated. Among them, KR-12(Q5, D9) with the glutamine and aspartic acid residues stapled displayed increased helical content and positive charge. The reinforced α-helical conformation not only protected it from proteolytic hydrolysis but also improved its antibacterial efficacy via effective membrane perturbation and anti-inflammatory efficacy via compact LPS binding. Besides, the increased positive charge endowed it with an enhanced therapeutic index. On infected wound mouse model, it was demonstrated to eliminate bacteria and promote wound closure and regeneration effectively. Conclusion: Overall, the all-hydrocarbon stapling was proven to lay the foundation for the future development of antibacterial agents. KR-12(Q5, D9) could serve as a lead compound for the clinical treatment of bacterial infections.


Assuntos
Antibacterianos , Peptídeos Catiônicos Antimicrobianos , Animais , Camundongos , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/química , Hidrocarbonetos , Bactérias , Anti-Inflamatórios
3.
Nat Commun ; 15(1): 1080, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316777

RESUMO

The structure and design flexibility of aerogels make them promising for soft tissue engineering, though they tend to come with brittleness and low elasticity. While increasing crosslinking density may improve mechanics, it also imparts brittleness. In soft tissue engineering, resilience against mechanical loads from mobile tissues is paramount. We report a hybrid aerogel that consists of self-reinforcing networks of micro- and nanofibers. Nanofiber segments physically entangle microfiber pillars, allowing efficient stress distribution through the intertwined fiber networks. We show that optimized hybrid aerogels have high specific tensile moduli (~1961.3 MPa cm3 g-1) and fracture energies (~7448.8 J m-2), while exhibiting super-elastic properties with rapid shape recovery (~1.8 s). We demonstrate that these aerogels induce rapid tissue ingrowth, extracellular matrix deposition, and neovascularization after subcutaneous implants in rats. Furthermore, we can apply them for engineering soft tissues via minimally invasive procedures, and hybrid aerogels can extend their versatility to become magnetically responsive or electrically conductive, enabling pressure sensing and actuation.


Assuntos
Nanofibras , Resiliência Psicológica , Ratos , Animais , Nanofibras/química , Elasticidade , Engenharia Tecidual/métodos
4.
Sci Rep ; 14(1): 2988, 2024 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316805

RESUMO

Ginger has been associated with a decreased incidence of colorectal cancer (CRC) through reduction in inflammatory pathways and inhibition of tumor growth. Recent pre-clinical models have implicated changes in the gut microbiome as a possible mediator of the ginger effect on CRC. We hypothesized that, in adults previously diagnosed with a colorectal adenoma, ginger supplementation would alter the fecal microbiome in the direction consistent with its CRC-inhibitory effect. Sixty-eight adults were randomized to take either ginger or placebo daily for 6 weeks, with a 6-week washout and longitudinal stool collection throughout. We performed 16S rRNA sequencing and evaluated changes in overall microbial diversity and the relative abundances of pre-specified CRC-associated taxa using mixed-effects logistic regression. Ginger supplementation showed no significant effect on microbial community structure through alpha or beta diversity. Of 10 pre-specified CRC-associated taxa, there were significant decreases in the relative abundances of the genera Akkermansia (p < 0.001), Bacteroides (p = 0.018), and Ruminococcus (p = 0.013) after 6-week treatment with ginger compared to placebo. Ginger supplementation led to decreased abundances of Akkermansia and Bacteroides, which suggests that ginger may have an inhibitory effect on CRC-associated taxa. Overall, ginger supplementation appears to have a limited effect on gut microbiome in patients with colorectal adenomas.


Assuntos
Adenoma , Neoplasias Colorretais , Microbiota , Adulto , Humanos , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/análise , Neoplasias Colorretais/patologia , Fezes/química , Adenoma/tratamento farmacológico , Suplementos Nutricionais
5.
Sci Rep ; 14(1): 2921, 2024 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316894

RESUMO

The application of natural extracts to vegetable plants can increase production, optimize nutrient and water uptake, and mitigate the effects of stress on vegetable plants by enhancing primary and secondary metabolism. In this study, Acacia saligna (Labill.) H.L.Wendl. fruit aqueous extract (FAE) was applied as a foliar application to assess and demonstrate its effects on growth, productivity, and phytochemicals of coriander (Coriandrum sativum L.) plants. A. saligna FAE (2%, 4%, and 6%), each combined with 50% of the recommended dose of N fertilizer was applied to coriander plants over the course of two successive seasons in the field. These treatments were compared with the control treatment, which used a 100% recommended dose of N. The four tested treatments were set up in a randomized complete block design with three replicates for a total of 12 experimental plots. Each replicate (experimental plot) was 3 m2 (2 × 1.5 m2) in size and included 300 seeds/m2. The phytochemicals were examined using chromatographic and spectrophotometric methods, where the essential oils (EOs) extracted from leaves were analyzed by Gas chromatography-mass spectrometry (GC-MS), while the phenolic and flavonoid compounds were analyzed by High Performance Liquid Chromatography (HPLC). With the application of A. saligna FAE (4%) + 50% N fertilizer, the levels of total solid content, total carbohydrates, total protein, total phenols, and total antioxidant activity, as well as chlorophyll a, chlorophyll b, chlorophyll a + b, and carotenoids, were increased at harvest. The treatment A. saligna FAE at 6% + 50% N fertilizer did not observe significant improvement in the growth parameters of coriander plants because of the anticipated allelopathic effects. By GC-MS analysis, the major compounds in the EO from control treatment were 2-octyn-1-ol (23.93%), and 2-butyl-1-octanol (8.80%), in treated plants with 2% of A. saligna FAE + 50% N fertilizer were (E)-2-decen-1-ol (32.00%), and 1-methoxymethoxy-oct-2-yne (13.71%), in treated plants with 4% A. saligna FAE + 50% N fertilizer were E-2-undecen-1-ol (32.70%), and 3,5,5-trimethyl-1-hexene (8.91%), and in the treated plants with A. saligna FAE (6%) + 50% N fertilizer were phytol (80.44%), and (Z)6,(Z)9-pentadecadien-1-ol (13.75%). The flavonoid components 7-hydroxyflavone, naringin, rutin, quercetin, kaempferol, luteolin, apigenin, and catechin were presented with variable concentrations according to the treatments utilized as identified by HPLC analysis from the methanol extracts of the treated plants with the combination treatments of A. saligna FAE (2, 4, and 6%) and N fertilization (50% from the recommended dose) and control coriander plants (100% N recommended dose). The combination of 50% N fertilizer treatment and the biostimulant A. saligna FAE (4%) seems to improve coriander plant growth while simultaneously lowering N fertilizer consumption. Future research will be needed to further study the effectiveness of several concentrations of A. saligna FAE in various conditions and/or species.


Assuntos
Acacia , Coriandrum , Coriandrum/química , Clorofila A/metabolismo , Fertilizantes , Frutas/química , Compostos Fitoquímicos/análise , Antioxidantes/metabolismo , Flavonoides/metabolismo , Plantas
6.
Sci Rep ; 14(1): 2986, 2024 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316914

RESUMO

Cattle dung treatments in Taiwan have developed a process called Black soldier fly larvae (BSFL) treatment, which can digest cow dung and generate the frass (larvae drops), the residue fiber in cow dung. This study aims to assess frass for its potential in pulp and papermaking, considering its chemical compositions, appearance, and fiber morphology, and also evaluate its suitability for pulping by soda method to create added value. The frass exhibits favorable material properties for pulping and papermaking, including a high holocellulose (67.37%) and α-cellulose (48.00%) content, along with a lower ash content (4.61%); the microstructure and surface mesoporous pores benefit for pulping; and the nonwood-fiber-like fiber morphology. The pulping experiment shows that 7% NaOH and 75 min of pulping conditions result in proper disintegration of fiber, and the highest accepts ratio (34.06%). The NaOH causes fiber disintegration during pulping, resulting in a higher strength property of the handsheet. The frass pulp blended with TOCC can achieve the ring crush index standards required for cardboard products. In summary, the frass from BSFL treatment of cattle dung can be utilized in pulp and papermaking to enhance circular utilization value.


Assuntos
Dípteros , Feminino , Bovinos , Animais , Larva , Hidróxido de Sódio/química , Celulose/química , Fezes
7.
Nat Microbiol ; 9(2): 421-433, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38316928

RESUMO

Soil microbiomes are highly diverse, and to improve their representation in biogeochemical models, microbial genome data can be leveraged to infer key functional traits. By integrating genome-inferred traits into a theory-based hierarchical framework, emergent behaviour arising from interactions of individual traits can be predicted. Here we combine theory-driven predictions of substrate uptake kinetics with a genome-informed trait-based dynamic energy budget model to predict emergent life-history traits and trade-offs in soil bacteria. When applied to a plant microbiome system, the model accurately predicted distinct substrate-acquisition strategies that aligned with observations, uncovering resource-dependent trade-offs between microbial growth rate and efficiency. For instance, inherently slower-growing microorganisms, favoured by organic acid exudation at later plant growth stages, exhibited enhanced carbon use efficiency (yield) without sacrificing growth rate (power). This insight has implications for retaining plant root-derived carbon in soils and highlights the power of data-driven, trait-based approaches for improving microbial representation in biogeochemical models.


Assuntos
Microbiota , Rizosfera , Raízes de Plantas/microbiologia , Microbiologia do Solo , Solo/química , Plantas , Carbono
8.
Nat Microbiol ; 9(2): 405-420, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38316932

RESUMO

Tc toxins are virulence factors of bacterial pathogens. Although their structure and intoxication mechanism are well understood, it remains elusive where this large macromolecular complex is assembled and how it is released. Here we show by an integrative multiscale imaging approach that Yersinia entomophaga Tc (YenTc) toxin components are expressed only in a subpopulation of cells that are 'primed' with several other potential virulence factors, including filaments of the protease M66/StcE. A phage-like lysis cassette is required for YenTc release; however, before resulting in complete cell lysis, the lysis cassette generates intermediate 'ghost' cells, which may serve as assembly compartments and become packed with assembled YenTc holotoxins. We hypothesize that this stepwise mechanism evolved to minimize the number of cells that need to be killed. The occurrence of similar lysis cassettes in diverse organisms indicates a conserved mechanism for Tc toxin release that may apply to other extracellular macromolecular machines.


Assuntos
Fatores de Virulência , Yersinia , Yersinia/química , Endopeptidases
9.
Cell Mol Biol Lett ; 29(1): 24, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317065

RESUMO

BACKGROUND: Chronic nonhealing wounds remain a considerable challenge in clinical treatment due to excessive inflammation and impeded reepithelialization and angiogenesis. Therefore, the discovery of novel prohealing agents for chronic skin wounds are urgent and important. Amphibian-derived prohealing peptides, especially immunomodulatory peptides, provide a promising strategy for the treatment of chronic skin trauma. However, the mechanism of immunomodulatory peptides accelerating the skin wound healing remains poorly understood. METHODS: The prohealing ability of peptide Andersonin-W1 (AW1) was assessed by cell scratch, cell proliferation, transwell, and tube formation. Next, full-thickness, deep second-degree burns and diabetic full-thickness skin wounds in mice were performed to detect the therapeutic effects of AW1. Moreover, the tissue regeneration and expression of inflammatory cytokines were evaluated by hematoxylin and eosin (H&E), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry staining. Molecular docking, colocalization, and western blotting were used to explore the mechanism of AW1 in promoting wound healing. RESULTS: We provide solid evidence to display excellent prohealing effects of AW1, identified as a short antimicrobial peptide in our previous report. At relative low concentration of nM, AW1 promoted the proliferation, migration, and scratch repair of keratinocyte, macrophage proliferation, and tube formation of HUVEC. AW1 also facilitated reepithelialization, granulation regeneration, and angiogenesis, thus significantly boosting the healing of full-thickness, deep second-degree burns and diabetic skin wounds in mice. Mechanistically, in macrophages, AW1 directly bound to Toll-like receptor 4 (TLR4) in the extracellular region and regulated the downstream nuclear factor-κB (NF-κB) signaling pathway to facilitate the inflammatory factor secretion and suppress excessive inflammation induced by lipopolysaccharide (LPS). Moreover, AW1 regulated macrophage polarization to promote the transition from the inflammatory to the proliferative phase and then facilitated reepithelialization, granulation regeneration, and angiogenesis, thus exhibiting excellent therapeutic effects on diabetic skin wounds. CONCLUSIONS: AW1 modulates inflammation and the wound healing process by the TLR4/NF-κB molecular axis, thus facilitating reepithelialization, granulation regeneration, and angiogenesis. These findings not only provided a promising multifunctional prohealing drug candidate for chronic nonhealing skin wounds but also highlighted the unique roles of "small" peptides in the elucidation of "big" human disease mechanisms.


Assuntos
Queimaduras , Diabetes Mellitus , Humanos , Camundongos , Animais , Pele/metabolismo , Receptor 4 Toll-Like/metabolismo , NF-kappa B/metabolismo , Simulação de Acoplamento Molecular , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Peptídeos/química , Diabetes Mellitus/metabolismo , Queimaduras/tratamento farmacológico , Queimaduras/metabolismo , Inflamação/metabolismo
10.
BMC Gastroenterol ; 24(1): 63, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317108

RESUMO

BACKGROUND AND AIMS: Severe acute pancreatitis (SAP) is potentially lethal. Considering the role of inflammation in the progression of acute pancreatitis (AP), this study aims to develop a model based on inflammatory indexes for identifying the presence of SAP. METHODS: Overall, 253 patients with AP who were consecutively admitted between July 2018 and November 2020 were screened, of whom 60 had SAP. Systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), neutrophil-to-platelet ratio (NPR), systemic inflammation response index (SIRI), platelet-to-albumin ratio (PAR), C-reactive protein-to-albumin ratio (CAR), C-reactive protein-to-lymphocyte ratio (CLR), and triglyceride glucose (TyG) index were calculated. Multivariate logistic regression analyses were performed to identify independent risk factors of SAP. Then, inflammation-based models were established. Receiver operating characteristics (ROC) curve analyses were performed. Area under ROC curve (AUROC) was calculated. RESULTS: Diabetes mellitus, fatty liver, high white blood cell count (WBC), C-reactive protein (CRP), red blood cell distribution width (RDW), procalcitonin (PCT), SII, NLR, NPR, CAR, CLR, and TyG index, and a low LMR were significantly associated with SAP. Considering the collinearity among these variables, 10 multivariate logistic regression analyses were separately performed. Finally, four independent inflammation-based models were established. Of them, the best one, which was calculated as follows: 1.204*fatty liver (yes = 1; no = 0) + 0.419*PCT + 0.005*CLR - 2.629, had an AUROC of 0.795 with a specificity of 73.4% and a sensitivity of 71.7%. CONCLUSION: The inflammation-based model consisting of fatty liver, PCT, and CLR has a good diagnostic performance for SAP.


Assuntos
Fígado Gorduroso , Pancreatite , Humanos , Estudos Retrospectivos , Proteína C-Reativa/análise , Doença Aguda , Inflamação , Linfócitos/química , Albuminas , Fígado Gorduroso/complicações , Prognóstico
11.
Respir Res ; 25(1): 75, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317149

RESUMO

BACKGROUND: Electronic cigarettes (EC) have gained popularity, especially among young people, with the introduction of fourth-generation devices based on e-liquids containing nicotine salts that promise a smoother vaping experience than freebase nicotine. However, the toxicological effects of nicotine salts are still largely unknown, and the chemical diversity of e-liquids limits the comparison between different studies to determine the contribution of each compound to the cytotoxicity of EC aerosols. Therefore, the aim of this study was to evaluate the toxicological profile of controlled composition e-liquid aerosols to accurately determine the effects of each ingredient based on exposure at the air-liquid interface. METHODS: Human lung epithelial cells (A549) were exposed to undiluted aerosols of controlled composition e-liquids containing various ratios of propylene glycol (PG)/vegetable glycerin (VG) solvents, freebase nicotine, organic acids, nicotine salts, and flavoured commercial e-liquids. Exposure of 20 puffs was performed at the air-liquid interface following a standard vaping regimen. Toxicological outcomes, including cytotoxicity, inflammation, and oxidative stress, were assessed 24 h after exposure. RESULTS: PG/VG aerosols elicited a strong cytotoxic response characterised by a 50% decrease in cell viability and a 200% increase in lactate dehydrogenase (LDH) production, but had no effects on inflammation and oxidative stress. These effects occurred only at a ratio of 70/30 PG/VG, suggesting that PG is the major contributor to aerosol cytotoxicity. Both freebase nicotine and organic acids had no greater effect on cell viability and LDH release than at a 70/30 PG/VG ratio, but significantly increased inflammation and oxidative stress. Interestingly, the protonated form of nicotine in salt showed a stronger proinflammatory effect than the freebase nicotine form, while benzoic acid-based nicotine salts also induced significant oxidative stress. Flavoured commercial e-liquids was found to be cytotoxic at a threshold dose of ≈ 330 µg/cm². CONCLUSION: Our results showed that aerosols of e-liquids consisting only of PG/VG solvents can cause severe cytotoxicity depending on the concentration of PG, while nicotine salts elicit a stronger pro-inflammatory response than freebase nicotine. Overall, aerosols from fourth-generation devices can cause different toxicological effects, the nature of which depends on the chemical composition of the e-liquid.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Vaping , Humanos , Adolescente , Nicotina/toxicidade , Vaping/efeitos adversos , Sais , Solventes , Propilenoglicol/toxicidade , Propilenoglicol/química , Glicerol/química , Glicerol/farmacologia , Aerossóis , Aromatizantes , Inflamação
12.
Virol J ; 21(1): 37, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38317249

RESUMO

BACKGROUND: To stop the spread of the COVID-19 disease, it is crucial to create molecular tools to investigate and diagnose COVID-19. Current efforts focus on developing specific neutralizing monoclonal antibodies (NmAbs) elicited against the receptor-binding domain (RBD). METHODS: In the present study, recombinant RBD (rRBD) protein was produced in E. coli, followed by immunizing mice with purified rRBD. ELISA was applied to screen the hybridomas for positive reactivity with rRBD protein. The linear and conformational epitopes of the mAbs were subsequently identified using western blot. Finally, the reactivity, affinity, and neutralization activity of the purified mAbs were evaluated using ELISA. RESULTS: All mAbs exhibited similar reactivity trends towards both eukaryotic RBD and prokaryotic rRBD in ELISA. Among them, 2E7-D2 and 2B4-G8 mAbs demonstrated higher reactivity than other mAbs. Additionally, in western blot assays, these two mAbs could detect reducing and non-reducing rRBD, indicating recognition of linear epitopes. Notably, five mAbs effectively blocked rRBD- angiotensin-converting enzyme 2 (ACE2) interaction, while two high-affinity mAbs exhibited potent neutralizing activity against eukaryotic RBD. CONCLUSION: In the current study, we generated and characterized new RBD-specific mAbs using the hybridoma technique that recognized linear and conformational epitopes in RBD with neutralization potency. Our mAbs are novel candidates for diagnosing and treating SARS-CoV-2.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Camundongos , Epitopos , Anticorpos Antivirais , Escherichia coli/metabolismo , COVID-19/diagnóstico , Anticorpos Neutralizantes , Anticorpos Monoclonais , Glicoproteína da Espícula de Coronavírus/química
13.
PLoS One ; 19(2): e0295806, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38319909

RESUMO

In Brazil, the genus Bothrops is responsible for most ophidian accidents. Snake venoms have a wide variety of proteins and peptides exhibiting a broad repertoire of pharmacological and toxic effects that elicit systemic injury and characteristic local effects. The snakes' natural resistance to envenomation caused by the presence of inhibitory compounds on their plasma have been extensively studied. However, the presence of these inhibitors in different developmental stages is yet to be further discussed. The aim of this study was to evaluate the ontogeny of Bothrops jararaca plasma inhibitor composition and, to this end, plasma samples of B. jararaca were obtained from different developmental stages (neonates, youngs, and adults) and sexes (female and male). SDS-PAGE, Western blotting, affinity chromatography, and mass spectrometry were performed to analyze the protein profile and interaction between B. jararaca plasma and venom proteins. In addition, the presence of γBjPLI, a PLA2 inhibitor previously identified and characterized in B. jararaca serum, was confirmed by Western blotting. According to our results, 9-17% of plasma proteins were capable of binding to venom proteins in the three developmental stages. The presence of different endogenous inhibitors and, more specifically, different PLA2 inhibitor (PLI) classes and antihemorrhagic factors were confirmed in specimens of B. jararaca from newborn by mass spectrometry. For the first time, the αPLI and ßPLI were detected in B. jararaca plasma, although low or no ontogenetic and sexual correlation were found. The γPLI were more abundant in adult female, than in neonate and young female, but similar to neonate, young and adult male according to the results of mass spectrometry analysis. Our results suggest that there are proteins in the plasma of these animals that can help counteract the effects of self-envenomation from birth.


Assuntos
Bothrops , Venenos de Crotalídeos , Animais , Masculino , Feminino , Proteômica/métodos , Inibidores de Fosfolipase A2 , Bothrops/metabolismo , Fosfolipases A2/metabolismo , Venenos de Crotalídeos/química
14.
J R Soc Interface ; 21(211): 20230478, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38320599

RESUMO

Collagen accumulation is often used to characterize skeletal muscle fibrosis, but the role of collagen in passive muscle mechanics remains debated. Here we combined finite-element models and experiments to examine how collagen organization contributes to macroscopic muscle tissue properties. Tissue microstructure and mechanical properties were measured from in vitro biaxial experiments and imaging in dystrophin knockout (mdx) and wild-type (WT) diaphragm muscle. Micromechanical models of intramuscular and epimuscular extracellular matrix (ECM) regions were developed to account for complex microstructure and predict bulk properties, and directly calibrated and validated with the experiments. The models predicted that intramuscular collagen fibres align primarily in the cross-muscle fibre direction, with greater cross-muscle fibre alignment in mdx models compared with WT. Higher cross-muscle fibre stiffness was predicted in mdx models compared with WT models and differences between ECM and muscle properties were seen during cross-muscle fibre loading. Analysis of the models revealed that variation in collagen fibre distribution had a much more substantial impact on tissue stiffness than ECM area fraction. Taken together, we conclude that collagen organization explains anisotropic tissue properties observed in the diaphragm muscle and provides an explanation for the lack of correlation between collagen amount and tissue stiffness across experimental studies.


Assuntos
Colágeno , Matriz Extracelular , Fenômenos Biomecânicos , Colágeno/química , Matriz Extracelular/química , Músculos , Músculo Esquelético/fisiologia
15.
Sci Rep ; 14(1): 3031, 2024 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321082

RESUMO

This innovative work aims to develop highly biocompatible and degradable nanoparticles by encapsulating haemoglobin (Hb) within poly-ε-caprolactone for novel biomedical applications. We used a modified double emulsion solvent evaporation method to fabricate the particles. A Scanning electron microscope (SEM) characterized them for surface morphology. Fourier Transform Infrared Spectroscopy (FTIR) and Ultraviolet-visible spectroscopies (UV-visible) elucidated preserved chemical and biological structure of encapsulated haemoglobin. The airproof equilibrium apparatus obtained the oxygen-carrying capacity and P50 values. The DPPH assay assessed free radical scavenging potential. The antibacterial properties were observed using four different bacterial strains by disk diffusion method. The MTT assay investigates the cytotoxic effects on mouse fibroblast cultured cell lines (L-929). The MTT assay showed that nanoparticles have no toxicity over large concentrations. The well-preserved structure of Hb within particles, no toxicity, high oxygen affinity, P50 value, and IC50 values open the area of new research, which may be used as artificial oxygen carriers, antioxidant, and antibacterial agents, potential therapeutic agents as well as drug carrier particles to treat the cancerous cells. The novelty of this work is the antioxidant and antibacterial properties of developed nanoparticles are not been reported yet. Results showed that the prepared particles have strong antioxidant and antibacterial potential.


Assuntos
Antioxidantes , Nanopartículas Metálicas , Animais , Camundongos , Antioxidantes/farmacologia , Oxigênio , Polímeros , Nanopartículas Metálicas/química , Antibacterianos/farmacologia , Hemoglobinas , Espectroscopia de Infravermelho com Transformada de Fourier , Extratos Vegetais/química
16.
Sci Rep ; 14(1): 3026, 2024 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321125

RESUMO

[NiFe]-hydrogenases have a bimetallic NiFe(CN)2CO cofactor in their large, catalytic subunit. The 136 Da Fe(CN)2CO group of this cofactor is preassembled on a distinct HypC-HypD scaffold complex, but the intracellular source of the iron ion is unresolved. Native mass spectrometric analysis of HypCD complexes defined the [4Fe-4S] cluster associated with HypD and identified + 26 to 28 Da and + 136 Da modifications specifically associated with HypC. A HypCC2A variant without the essential conserved N-terminal cysteine residue dissociated from its complex with native HypD lacked all modifications. Native HypC dissociated from HypCD complexes isolated from Escherichia coli strains deleted for the iscS or iscU genes, encoding core components of the Isc iron-sulfur cluster biogenesis machinery, specifically lacked the + 136 Da modification, but this was retained on HypC from suf mutants. The presence or absence of the + 136 Da modification on the HypCD complex correlated with the hydrogenase enzyme activity profiles of the respective mutant strains. Notably, the [4Fe-4S] cluster on HypD was identified in all HypCD complexes analyzed. These results suggest that the iron of the Fe(CN)2CO group on HypCD derives from the Isc machinery, while either the Isc or the Suf machinery can deliver the [4Fe-4S] cluster to HypD.


Assuntos
Proteínas de Escherichia coli , Hidrogenase , Proteínas Ferro-Enxofre , Escherichia coli/genética , Ferro/metabolismo , Proteínas de Escherichia coli/metabolismo , Hidrogenase/metabolismo , Domínio Catalítico , Cisteína/química
17.
Sci Rep ; 14(1): 3019, 2024 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321176

RESUMO

Mixing animal waste and agricultural waste in certain proportions forms agricultural compost through appropriate air, time, and water supply. One of their use areas is directly used as fertilizer, and the other one is used as a material that can partially or completely replace P (peat) in the PGM (plant growth media). In this study, the initial mixtures with an appropriate C/N ratio and moisture content, which were created by mixing cow manure, chicken manure, hazelnut husk, hazelnut pruning wastes, vegetable and fruit wastes, and dry leaves, were composted for 180 days. The physicochemical properties of the mature composts were determined. Their effects on the fruit yield (weight of fruits) and plant height of pepper seedlings were evaluated in pot and field experiments. N (nitrogen), P (phosphorus), Cu (copper), and Zn (zinc) content were the highest in C4 (2.59%, 1.12%, 83.11 mg/kg, and 605.3 mg/kg). K (potassium) and Mn (manganese) content in C3 (1.79% and 750.5 mg/kg) and Fe (iron) content in C1 (4025 mg/kg) were determined to be the highest. There was no phytotoxic effect of all composts on Lepidium sativum seeds. Except for pH and organic matter, C1 45%, C1 20%, C4 45%, C4 20%, and P 90% met the requirements for ideal media. The mean height of eight-week seedlings increased in media of C1 20%, C1 45%, C2 20%, C2 45%, and C4 20%, but decreased in media of C3 90%. In field studies, while the highest yield was determined in C3 as 1530 g/plant, the lowest yield was 765.5 g/plant in control. The highest mean height was observed in C3 at 76.33 cm; the lowest was 63.03 cm in control.


Assuntos
Capsicum , Compostagem , Corylus , Animais , Plântula , Esterco , Solo/química
18.
Sci Rep ; 14(1): 3035, 2024 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321263

RESUMO

Arterial hypertension (AH) is a multifactorial and asymptomatic disease that affects vital organs such as the kidneys and heart. Considering its prevalence and the associated severe health repercussions, hypertension has become a disease of great relevance for public health across the globe. Conventionally, the classification of an individual as hypertensive or non-hypertensive is conducted through ambulatory blood pressure monitoring over a 24-h period. Although this method provides a reliable diagnosis, it has notable limitations, such as additional costs, intolerance experienced by some patients, and interferences derived from physical activities. Moreover, some patients with significant renal impairment may not present proteinuria. Accordingly, alternative methodologies are applied for the classification of individuals as hypertensive or non-hypertensive, such as the detection of metabolites in urine samples through liquid chromatography or mass spectrometry. However, the high cost of these techniques limits their applicability for clinical use. Consequently, an alternative methodology was developed for the detection of molecular patterns in urine collected from hypertension patients. This study generated a direct discrimination model for hypertensive and non-hypertensive individuals through the amplification of Raman signals in urine samples based on gold nanoparticles and supported by chemometric techniques such as partial least squares-discriminant analysis (PLS-DA). Specifically, 162 patient urine samples were used to create a PLS-DA model. These samples included 87 urine samples from patients diagnosed with hypertension and 75 samples from non-hypertensive volunteers. In the AH group, 35 patients were diagnosed with kidney damage and were further classified into a subgroup termed (RAH). The PLS-DA model with 4 latent variables (LV) was used to classify the hypertensive patients with external validation prediction (P) sensitivity of 86.4%, P specificity of 77.8%, and P accuracy of 82.5%. This study demonstrates the ability of surface-enhanced Raman spectroscopy to differentiate between hypertensive and non-hypertensive patients through urine samples, representing a significant advance in the detection and management of AH. Additionally, the same model was then used to discriminate only patients diagnosed with renal damage and controls with a P sensitivity of 100%, P specificity of 77.8%, and P accuracy of 82.5%.


Assuntos
Hipertensão , Nefropatias , Nanopartículas Metálicas , Humanos , Análise Espectral Raman/métodos , Ouro , Monitorização Ambulatorial da Pressão Arterial , Nanopartículas Metálicas/química , Nefropatias/diagnóstico , Urinálise/métodos , Hipertensão/urina
19.
BMC Biotechnol ; 24(1): 8, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321442

RESUMO

Silver nanoparticles (Ag-NPs) have a unique mode of action as antibacterial agents in addition to their anticancer and antioxidant properties. In this study, microbial nanotechnology is employed to synthesize Ag-NPs using the cell filtrate of Streptomyces enissocaesilis BS1. The synthesized Ag-NPs are confirmed by ultraviolet-visible (UV-Vis), Fourier transform infrared (FT-IR), X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Also, the effects of different factors on Ag-NPs synthesis were evaluated to set the optimum synthesis conditions. Also, the antibacterial, antibiofilm, and anticancer activity of Ag-NPs was assessed. The X-ray diffraction (XRD) analysis confirmed the crystalline nature of the sample and validated that the crystal structure under consideration is a face-centered cubic (FCC) pattern. The TEM examination displayed the spherical particles of the Ag-NPs and their average size, which is 32.2 nm. Fourier transform infrared spectroscopy (FTIR) revealed significant changes in functionality after silver nanoparticle dispersion, which could be attributed to the potency of the cell filtrate of Streptomyces enissocaesilis BS1 to act as both a reducing agent and a capping agent. The bioactivity tests showed that our synthesized Ag-NPs exhibited remarkable antibacterial activity against different pathogenic strains. Also, when the preformed biofilms of Pseudomonas aeruginosa ATCC 9027, Salmonella typhi ATCC 12023, Escherichia coli ATCC 8739, and Staphylococcus aureus ATCC 6598 were exposed to Ag NPs 50 mg/ml for 24 hours, the biofilm biomass was reduced by 10.7, 34.6, 34.75, and 39.08%, respectively. Furthermore, the Ag-NPs showed in vitro cancer-specific sensitivity against human breast cancer MCF-7 cell lines and colon cancer cell line Caco-2, and the IC50 was 0.160 mg/mL and 0.156 mg/mL, respectively. The results of this study prove the ease and efficiency of the synthesis of Ag-NPs using actinomycetes and demonstrate the significant potential of these Ag-NPs as anticancer and antibacterial agents.


Assuntos
Nanopartículas Metálicas , Prata , Streptomyces , Humanos , Prata/química , Nanopartículas Metálicas/química , Espectroscopia de Infravermelho com Transformada de Fourier , Células CACO-2 , Antibacterianos/farmacologia , Escherichia coli , Extratos Vegetais/farmacologia , Biofilmes , Testes de Sensibilidade Microbiana
20.
Biomed Res Int ; 2024: 1236910, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38322303

RESUMO

Objective: Oral squamous cell carcinoma (OSCC) is the most frequent oral cancer, constituting more than 90% of all oral carcinomas. The 5-year survival rate of OSCC patients is not satisfactory, and therefore, there is an urgent need for new practical therapeutic approaches besides the current therapies to overcome OSCC. Scutellaria baicalensis Georgi (SBG) is a plant of the family Lamiaceae with several pharmaceutical properties such as antioxidant, anti-inflammatory, and anticancer effects. Previous studies have demonstrated the curative effects of SBG in OSCC. Methods: A systems biology approach was conducted to identify differentially expressed miRNAs (DEMs) in OSCC patients with a dismal prognosis compared to OSCC patients with a favorable prognosis. A protein interaction map (PIM) was built based on DEMs targets, and the hub genes within the PIM were indicated. Subsequently, the prognostic role of the hubs was studied using Kaplan-Meier curves. Next, the binding affinity of SBG's main components, including baicalein, wogonin, oroxylin-A, salvigenin, and norwogonin, to the prognostic markers in OSCC was evaluated using molecular docking analysis. Results: Survival analysis showed that overexpression of CAV1, SERPINE1, ACTB, SMAD3, HMGA2, MYC, EIF2S1, HSPA4, HSPA5, and IL6 was significantly related to a poor prognosis in OSCC. Besides, molecular docking analysis demonstrated the ΔGbinding and inhibition constant values between SBG's main components and SERPINE1, ACTB, HMGA2, EIF2S1, HSPA4, and HSPA5 were as <-8.00 kcal/mol and nanomolar concentration, respectively. The most salient binding affinity was observed between wogonin and SERPINE1 with a criterion of ΔGbinding < -10.02 kcal/mol. Conclusion: The present results unraveled potential mechanisms involved in therapeutic effects of SBG in OSCC based on systems biology and structural bioinformatics analyses.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço , Scutellaria baicalensis/química , Simulação de Acoplamento Molecular , Neoplasias Bucais/patologia , Biologia Computacional , Biologia de Sistemas
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