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1.
Bol. latinoam. Caribe plantas med. aromát ; 23(4): 487-515, jul. 2024. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-1538020

RESUMO

Myrtus communis L., commonly known as true myrtle, is a medicinal plant native to the Mediterranean area. Since ancient times, the inhabitant s of this area have been using it for its cultural and medicinal properties. Because of the vast diversity of biomolecules in its aerial parts, it exhibits several biological properties, including antioxidant, antimicrobial, and anticancer properties. This review retrospect the research on the source, biological activities with empirical evidence, chemical composition, applications, and cellular targets of extracts and essential oils obtained from M. communis leaves, which provides a perspective for further studies on the applications and formulations of extract and EO of M. communis leaves. The efficacy of constituents' individually, in association with other bioactive constituents, or in combination with available commercial drugs would provide insights in to the development of these bio - actives as future drugs and their evolving future potential applications in the pharmaceutical, food, and aroma industries.


Myrtus communis L., comúnmente conocido como arrayán verdadero, es una planta medicinal originaria de la zona mediterránea. Desde la antigüedad, los habitantes de esta zona lo utilizan por sus propiedades culturales y medicinales. Debido a la gran div ersidad de biomoléculas en sus partes aéreas, exhibe varias propiedades biológicas, incluidas propiedades antioxidantes, antimicrobianas y anticancerígenas. Esta revisión retrospectiva de la investigación sobre la fuente, las actividades biológicas con evi dencia empírica, la composición química, las aplicaciones y los objetivos celulares de los extractos y aceites esenciales obtenidos de las hojas de M. communis , lo que brinda una perspectiva para futuros estudios sobre las aplicaciones y formulaciones de l os extractos y EO de M. communis . La eficacia de los componentes individualmente, en asociación con otros componentes bioactivos o en combinación con medicamentos comerciales disponibles proporcionaría información sobre el desarrollo de estos bioactivos co mo medicamentos futuros y sus futuras aplicaciones potenciales en las industrias farmacéutica, alimentaria y aromática


Assuntos
Myrtus communis/farmacologia , Plantas Medicinais , Óleos Voláteis/metabolismo , Óleos Voláteis/farmacologia , Folhas de Planta/metabolismo , Antibacterianos , Antifúngicos , Antioxidantes
2.
Bol. latinoam. Caribe plantas med. aromát ; 23(4): 568-576, jul. 2024. ilus
Artigo em Espanhol | LILACS | ID: biblio-1538065

RESUMO

This study aimed to determine the repellent and insecticidal activity of four essential oils (EOs) from plants collected in the Chocó rain forest, Colombia, against T. castaneum . Conventional hydrodistillation was used to obtain the EOs. The repellent and insecticidal activities were evaluated by the preference area and gas dispersion methods, espectively. Statistical differences (p<0.05) were determined by applying a student's t-test. EOs of Siparuna guianensis, S. conica, Piper marginatum, and Nectandra acutifolia showed excellent repellent properties as the main findings, highlighting S. conicaEO with 84% repellency (1-hµL/cm2), while P. marginatum showed to be bioactive to the dose of 500 µL/mL (72 h), inducing mortality of 100% of the exposed population. In conclusion, the results evidenced the repellent properties of the EOs evaluated against T. castaneum , which allows us to conclude that these plant species are potential natural sources producing bio-repellents that contribute to the integrated control of T. castaneum.


Se evaluaron cuatro aceites esenciales (AEs) de plantas recolectadas en la selva pluvial del Chocó, Colombia, para determinar su actividad repelente e insecticida contra T. castaneum. Los AEs fueron obtenidos por hidrodestilación convencional. Las actividades repelentes e insecticidas se evaluaron por los métodos de área de preferencia y dispersión de gas, respectivamente. Las diferencias significativas (p<0,05) fueron determinadas aplicando una prueba t de student. Los AEs de Siparuna guianensis, S. conica, Piper marginatum y Nectandra acutifolia mostraron excelentes propiedades repelentes, destacando el AE de S. conicacon un 84% de repelencia (1µL/cm2), mientras que el AE de P. marginatummostró ser bioactivo a la dosis de 500 µL/mL (72 h) al inducir la mortalidad del 100% de la población expuesta. Se concluye que estas especies de plantas son fuentes naturales potencialmente viables para la producción de biorepelentes que contribuyan en el control integrado de T. castaneum.


Assuntos
Tribolium/efeitos dos fármacos , Óleos Voláteis/farmacologia , Inseticidas/farmacologia , Colômbia , Repelentes de Insetos/farmacologia
3.
Bol. latinoam. Caribe plantas med. aromát ; 23(4): 636-644, jul. 2024. graf, tab
Artigo em Inglês | LILACS | ID: biblio-1538072

RESUMO

Thechemical composition, antioxidant and antimicrobial activities of the essential oil from aerial parts (leaves and flowers) of Chuquiraga arcuataHarling grown in the Ecuadorian Andes were studied. One hundred and twenty-six compounds were identified in the essential oil. Monoterpene hydrocarbons (45.8%) and oxygenated monoterpenes (44.1%) had the major percentages. The most abundant compounds were camphor (21.6%), myrcene (19.5%), and 1,8-cineole (13.4%). Antioxidant activity was examined using DPPH, ABTS,and FRAP assays. The essential oil had a moderate scavenging effect and reduction of ferric ion capacity through FRAP assay. Antimicrobial activity of the essential oil was observed against four pathogenic bacteria and a fungus. The essential oil exhibited activity against all microorganism strains under test, particularly against Candida albicansand Staphylococcus aureuswith MICs of 2.43-12.10 µg/mL.


Se estudió la composición química, actividades antioxidantes y antimicrobianas del aceite esencial procedente de las partes aérea (hojas y flores) de Chuquiraga arcuataHarling cultivadas en los Andes ecuatorianos. Se identificaron 126 compuestos en el aceite esencial. Los hidrocarburos monoterpénicos (45,8%) y los monoterpenos oxigenados (44,1%) tuvieron el mayor porcentaje. Los compuestos más abundantes fueron alcanfor (21,6%), mirceno (19,5%) y 1,8-cineol (13,4%). La actividadantioxidante se examinó mediante ensayos DPPH, ABTS y FRAP. El aceite esencial tuvo un efecto eliminador moderado y una reducción de la capacidad de iones férricos mediante el ensayo FRAP. Se observó actividad antimicrobiana del aceite esencial contra cuatro bacterias y un hongo patógenos. El aceite esencial mostró actividad contra todas las cepas de microorganismos bajo prueba, particularmente contra Candida albicansy Staphylococcus aureuscon CMI de 2,43-12,10 µg/mL.


Assuntos
Óleos Voláteis/química , Extratos Vegetais/química , Antioxidantes/química , Óleos Voláteis/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Flores/química , Equador , Antioxidantes/farmacologia
4.
Commun Biol ; 7(1): 539, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714886

RESUMO

Intervertebral disc degeneration (IDD) is a highly prevalent musculoskeletal disorder affecting millions of adults worldwide, but a poor understanding of its pathogenesis has limited the effectiveness of therapy. In the current study, we integrated untargeted LC/MS metabolomics and magnetic resonance spectroscopy data to investigate metabolic profile alterations during IDD. Combined with validation via a large-cohort analysis, we found excessive lipid droplet accumulation in the nucleus pulposus cells of advanced-stage IDD samples. We also found abnormal palmitic acid (PA) accumulation in IDD nucleus pulposus cells, and PA exposure resulted in lipid droplet accumulation and cell senescence in an endoplasmic reticulum stress-dependent manner. Complementary transcriptome and proteome profiles enabled us to identify solute carrier transporter (SLC) 43A3 involvement in the regulation of the intracellular PA level. SLC43A3 was expressed at low levels and negatively correlated with intracellular lipid content in IDD nucleus pulposus cells. Overexpression of SLC43A3 significantly alleviated PA-induced endoplasmic reticulum stress, lipid droplet accumulation and cell senescence by inhibiting PA uptake. This work provides novel integration analysis-based insight into the metabolic profile alterations in IDD and further reveals new therapeutic targets for IDD treatment.


Assuntos
Senescência Celular , Estresse do Retículo Endoplasmático , Degeneração do Disco Intervertebral , Gotículas Lipídicas , Núcleo Pulposo , Ácido Palmítico , Núcleo Pulposo/metabolismo , Núcleo Pulposo/efeitos dos fármacos , Núcleo Pulposo/patologia , Núcleo Pulposo/citologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácido Palmítico/metabolismo , Ácido Palmítico/farmacologia , Senescência Celular/efeitos dos fármacos , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Humanos , Gotículas Lipídicas/metabolismo , Masculino , Feminino , Adulto , Pessoa de Meia-Idade
5.
BMC Anesthesiol ; 24(1): 170, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714924

RESUMO

BACKGROUND: Dynamic fluctuations of arterial blood pressure known as blood pressure variability (BPV) may have short and long-term undesirable consequences. During surgical procedures blood pressure is usually measured in equal intervals allowing to assess its intraoperative variability, which significance for peri and post-operative period is still under debate. Lidocaine has positive cardiovascular effects, which may go beyond its antiarrhythmic activity. The aim of the study was to verify whether the use of intravenous lidocaine may affect intraoperative BPV in patients undergoing major vascular procedures. METHODS: We performed a post-hoc analysis of the data collected during the previous randomized clinical trial by Gajniak et al. In the original study patients undergoing elective abdominal aorta and/or iliac arteries open surgery were randomized into two groups to receive intravenous infusion of 1% lidocaine or placebo at the same infusion rate based on ideal body weight, in concomitance with general anesthesia. We analyzed systolic (SBP), diastolic (DBP) and mean arterial blood (MAP) pressure recorded in 5-minute intervals (from the first measurement before induction of general anaesthesia until the last after emergence from anaesthesia). Blood pressure variability was then calculated for SBP and MAP, and expressed as: standard deviation (SD), coefficient of variation (CV), average real variability (ARV) and coefficient of hemodynamic stability (C10%), and compared between both groups. RESULTS: All calculated indexes were comparable between groups. In the lidocaine and placebo groups systolic blood pressure SD, CV, AVR and C10% were 20.17 vs. 19.28, 16.40 vs. 15.64, 14.74 vs. 14.08 and 0.45 vs. 0.45 respectively. No differences were observed regarding type of surgery, operating and anaesthetic time, administration of vasoactive agents and intravenous fluids, including blood products. CONCLUSION: In high-risk vascular surgery performed under general anesthesia, lidocaine infusion had no effect on arterial blood pressure variability. TRIAL REGISTRATION: ClinicalTrials.gov; NCT04691726 post-hoc analysis; date of registration 31/12/2020.


Assuntos
Anestésicos Locais , Pressão Sanguínea , Lidocaína , Procedimentos Cirúrgicos Vasculares , Humanos , Lidocaína/administração & dosagem , Lidocaína/farmacologia , Masculino , Feminino , Pressão Sanguínea/efeitos dos fármacos , Idoso , Anestésicos Locais/administração & dosagem , Anestésicos Locais/farmacologia , Procedimentos Cirúrgicos Vasculares/métodos , Pessoa de Meia-Idade , Método Duplo-Cego , Infusões Intravenosas , Anestesia Geral/métodos , Monitorização Intraoperatória/métodos
6.
BMC Plant Biol ; 24(1): 376, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38714947

RESUMO

BACKGROUND: Casuarina equisetifolia (C. equisetifolia) is a woody species with many excellent features. It has natural resistance against drought, salt and saline-alkali stresses. WRKY transcription factors (TFs) play significant roles in plant response to abiotic stresses, therefore, molecular characterization of WRKY gene family under abiotic stresses holds great significance for improvement of forest trees through molecular biological tools. At present, WRKY TFs from C. equisetifolia have not been thoroughly studied with respect to their role in salt and saline-alkali stresses response. The current study was conducted to bridge the same knowledge gap. RESULTS: A total of 64 WRKYs were identified in C. equisetifolia and divided into three major groups i.e. group I, II and III, consisting of 10, 42 and 12 WRKY members, respectively. The WRKY members in group II were further divided into 5 subgroups according to their homology with Arabidopsis counterparts. WRKYs belonging to the same group exhibited higher similarities in gene structure and the presence of conserved motifs. Promoter analysis data showed the presence of various response elements, especially those related to hormone signaling and abiotic stresses, such as ABRE (ABA), TGACG (MeJA), W-box ((C/T) TGAC (T/C)) and TC-rich motif. Tissue specific expression data showed that CeqWRKYs were mainly expressed in root under normal growth conditions. Furthermore, most of the CeqWRKYs were up-regulated by NaCl and NaHCO3 stresses with few of WRKYs showing early responsiveness to both stresses while few others exhibiting late response. Although the expressions of CeqWRKYs were also induced by cold stress, the response was delayed compared with other stresses. Transgenic C. equisetifolia plants overexpressing CeqWRKY11 displayed lower electrolyte leakage, higher chlorophyll content, and enhanced tolerance to both stresses. The higher expression of abiotic stress related genes, especially CeqHKT1 and CeqPOD7, in overexpression lines points to the maintenance of optimum Na+/K+ ratio, and ROS scavenging as possible key molecular mechanisms underlying salt stress tolerance. CONCLUSIONS: Our results show that CeqWRKYs might be key regulators of NaCl and NaHCO3 stresses response in C. equisetifolia. In addition, positive correlation of CeqWRKY11 expression with increased stress tolerance in C. equisetifolia encourages further research on other WRKY family members through functional genomic tools. The best candidates could be incorporated in other woody plant species for improving stress tolerance.


Assuntos
Proteínas de Plantas , Fatores de Transcrição , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas , Cloreto de Sódio/farmacologia , Filogenia , Bicarbonato de Sódio/farmacologia , Estresse Salino/genética , Estresse Fisiológico/genética , Genoma de Planta
7.
Mol Cancer ; 23(1): 91, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715012

RESUMO

BACKGROUND: Recent evidence has demonstrated that abnormal expression and regulation of circular RNA (circRNAs) are involved in the occurrence and development of a variety of tumors. The aim of this study was to investigate the effects of circ_PPAPDC1A in Osimertinib resistance in NSCLC. METHODS: Human circRNAs microarray analysis was conducted to identify differentially expressed (DE) circRNAs in Osimertinib-acquired resistance tissues of NSCLC. The effect of circ_PPAPDC1A on cell proliferation, invasion, migration, and apoptosis was assessed in both in vitro and in vivo. Dual-luciferase reporter assay, RT-qPCR, Western-blot, and rescue assay were employed to confirm the interaction between circ_PPAPDC1A/miR-30a-3p/IGF1R axis. RESULTS: The results revealed that circ_PPAPDC1A was significantly upregulated in Osimertinib acquired resistance tissues of NSCLC. circ_PPAPDC1A reduced the sensitivity of PC9 and HCC827 cells to Osimertinib and promoted cell proliferation, invasion, migration, while inhibiting apoptosis in Osimertinib-resistant PC9/OR and HCC829/OR cells, both in vitro and in vivo. Silencing circ_PPAPDC1A partially reversed Osimertinib resistance. Additionally, circ_PPAPDC1A acted as a competing endogenous RNA (ceRNA) by targeting miR-30a-3p, and Insulin-like Growth Factor 1 Receptor (IGF1R) was identified as a functional gene for miR-30a-3p in NSCLC. Furthermore, the results confirmed that circ_PPAPDC1A/miR-30a-3p/IGF1R axis plays a role in activating the PI3K/AKT/mTOR signaling pathway in NSCLC with Osimertinib resistance. CONCLUSIONS: Therefore, for the first time we identified that circ_PPAPDC1A was significantly upregulated and exerts an oncogenic role in NSCLC with Osimertinib resistance by sponging miR-30a-3p to active IGF1R/PI3K/AKT/mTOR pathway. circ_PPAPDC1A may serve as a novel diagnostic biomarker and therapeutic target for NSCLC patients with Osimertinib resistance.


Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , MicroRNAs , RNA Circular , Receptor IGF Tipo 1 , Transdução de Sinais , Humanos , MicroRNAs/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Acrilamidas/farmacologia , RNA Circular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Compostos de Anilina/farmacologia , Linhagem Celular Tumoral , Animais , Camundongos , Apoptose , Movimento Celular/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Masculino , Feminino , Indóis , Pirimidinas
8.
J Nanobiotechnology ; 22(1): 228, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38715049

RESUMO

Development of ferroptosis-inducible nanoplatforms with high efficiency and specificity is highly needed and challenging in tumor ferrotherapy. Here, we demonstrate highly effective tumor ferrotherapy using iron (II)-based metal-organic framework (FessMOF) nanoparticles, assembled from disulfide bonds and ferrous ions. The as-prepared FessMOF nanoparticles exhibit peroxidase-like activity and pH/glutathione-dependent degradability, which enables tumor-responsive catalytic therapy and glutathione depletion by the thiol/disulfide exchange to suppress glutathione peroxidase 4, respectively. Upon PEGylation and Actinomycin D (ActD) loading, the resulting FessMOF/ActD-PEG nanoplatform induces marked DNA damage and lipid peroxidation. Concurrently, we found that ActD can inhibit Xc- system and elicit ferritinophagy, which further boosts the ferrotherapeutic efficacy of the FessMOF/ActD-PEG. In vivo experiments demonstrate that our fabricated nanoplatform presents excellent biocompatibility and a high tumor inhibition rate of 91.89%.


Assuntos
Dano ao DNA , Ferroptose , Ferro , Estruturas Metalorgânicas , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Ferroptose/efeitos dos fármacos , Animais , Humanos , Camundongos , Dano ao DNA/efeitos dos fármacos , Ferro/química , Linhagem Celular Tumoral , Reparo do DNA/efeitos dos fármacos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Camundongos Endogâmicos BALB C , Feminino
9.
J Exp Clin Cancer Res ; 43(1): 138, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38715057

RESUMO

BACKGROUND: Although immune checkpoint blockade (ICB) therapy has proven to be extremely effective at managing certain cancers, its efficacy in treating pancreatic ductal adenocarcinoma (PDAC) has been limited. Therefore, enhancing the effect of ICB could improve the prognosis of PDAC. In this study, we focused on the histamine receptor H1 (HRH1) and investigated its impact on ICB therapy for PDAC. METHODS: We assessed HRH1 expression in pancreatic cancer cell (PCC) specimens from PDAC patients through public data analysis and immunohistochemical (IHC) staining. The impact of HRH1 in PCCs was evaluated using HRH1 antagonists and small hairpin RNA (shRNA). Techniques including Western blot, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-PCR), and microarray analyses were performed to identify the relationships between HRH1 and major histocompatibility complex class I (MHC-I) expression in cancer cells. We combined HRH1 antagonism or knockdown with anti-programmed death receptor 1 (αPD-1) therapy in orthotopic models, employing IHC, immunofluorescence, and hematoxylin and eosin staining for assessment. RESULTS: HRH1 expression in cancer cells was negatively correlated with HLA-ABC expression, CD8+ T cells, and cytotoxic CD8+ T cells. Our findings indicate that HRH1 blockade upregulates MHC-I expression in PCCs via cholesterol biosynthesis signaling. In the orthotopic model, the combined inhibition of HRH1 and αPD-1 blockade enhanced cytotoxic CD8+ T cell penetration and efficacy, overcoming resistance to ICB therapy. CONCLUSIONS: HRH1 plays an immunosuppressive role in cancer cells. Consequently, HRH1 intervention may be a promising method to amplify the responsiveness of PDAC to immunotherapy.


Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Camundongos , Animais , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H1/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Linhagem Celular Tumoral , Feminino , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Masculino
10.
BMC Vet Res ; 20(1): 179, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715123

RESUMO

Salmonella infections pose a significant threat to animal and human health. Phytochemicals present a potential alternative treatment. Galla chinensis tannic acid (GCTA), a hydrolyzable polyphenolic compound, inhibits bacterial growth and demonstrates potential as an alternative or supplement to antibiotics to prevent Salmonella infections. However, little is known about the antimicrobial mechanism of GCTA against Salmonella. Here, we revealed 456 differentially expressed proteins upon GCTA treatment, impacting pathways related to DNA replication, repair, genomic stability, cell wall biogenesis, and lipid metabolism using TMT-labeled proteomic analysis. TEM analysis suggested altered bacterial morphology and structure post-treatment. A Salmonella-infected-mouse model indicated that GCTA administration improved inflammatory markers, alleviated intestinal histopathological alterations, and reduced Salmonella enterica serovar Enteritidis (S. Enteritidis) colonization in the liver and spleen of Salmonella-infected mice. The LD50 of GCTA was 4100 mg/kg with an oral single dose, vastly exceeding the therapeutic dose. Thus, GCTA exhibited antibacterial and anti-infective activity against S. Enteritidis. Our results provided insight into the molecular mechanisms of these antibacterial effects, and highlights the potential of GCTA as an alternative to antibiotics.


Assuntos
Proteômica , Salmonelose Animal , Salmonella enteritidis , Taninos , Animais , Salmonella enteritidis/efeitos dos fármacos , Camundongos , Taninos/farmacologia , Taninos/uso terapêutico , Salmonelose Animal/tratamento farmacológico , Salmonelose Animal/microbiologia , Feminino , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Camundongos Endogâmicos BALB C , Medicamentos de Ervas Chinesas , Polifenóis
11.
Stem Cell Res Ther ; 15(1): 135, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715130

RESUMO

BACKGROUND: Biomaterials used in bone tissue engineering must fulfill the requirements of osteoconduction, osteoinduction, and osseointegration. However, biomaterials with good osteoconductive properties face several challenges, including inadequate vascularization, limited osteoinduction and barrier ability, as well as the potential to trigger immune and inflammatory responses. Therefore, there is an urgent need to develop guided bone regeneration membranes as a crucial component of tissue engineering strategies for repairing bone defects. METHODS: The mZIF-8/PLA membrane was prepared using electrospinning technology and simulated body fluid external mineralization method. Its ability to induce biomimetic mineralization was evaluated through TEM, EDS, XRD, FT-IR, zeta potential, and wettability techniques. The biocompatibility, osteoinduction properties, and osteo-immunomodulatory effects of the mZIF-8/PLA membrane were comprehensively evaluated by examining cell behaviors of surface-seeded BMSCs and macrophages, as well as the regulation of cellular genes and protein levels using PCR and WB. In vivo, the mZIF-8/PLA membrane's potential to promote bone regeneration and angiogenesis was assessed through Micro-CT and immunohistochemical staining. RESULTS: The mineralized deposition enhances hydrophilicity and cell compatibility of mZIF-8/PLA membrane. mZIF-8/PLA membrane promotes up-regulation of osteogenesis and angiogenesis related factors in BMSCs. Moreover, it induces the polarization of macrophages towards the M2 phenotype and modulates the local immune microenvironment. After 4-weeks of implantation, the mZIF-8/PLA membrane successfully bridges critical bone defects and almost completely repairs the defect area after 12-weeks, while significantly improving the strength and vascularization of new bone. CONCLUSIONS: The mZIF-8/PLA membrane with dual osteoconductive and immunomodulatory abilities could pave new research paths for bone tissue engineering.


Assuntos
Regeneração Óssea , Regeneração Óssea/efeitos dos fármacos , Animais , Osteogênese/efeitos dos fármacos , Engenharia Tecidual/métodos , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/química , Camundongos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Membranas Artificiais , Regeneração Tecidual Guiada/métodos , Alicerces Teciduais/química , Poliésteres/química , Poliésteres/farmacologia , Ratos
12.
J Neuroinflammation ; 21(1): 117, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715127

RESUMO

BACKGROUND: Despite the high prevalence of neuropathic pain, treating this neurological disease remains challenging, given the limited efficacy and numerous side effects associated with current therapies. The complexity in patient management is largely attributed to an incomplete understanding of the underlying pathological mechanisms. Central sensitization, that refers to the adaptation of the central nervous system to persistent inflammation and heightened excitatory transmission within pain pathways, stands as a significant contributor to persistent pain. Considering the role of the cystine/glutamate exchanger (also designated as system xc-) in modulating glutamate transmission and in supporting neuroinflammatory responses, we investigated the contribution of this exchanger in the development of neuropathic pain. METHODS: We examined the implication of system xc- by evaluating changes in the expression/activity of this exchanger in the dorsal spinal cord of mice after unilateral partial sciatic nerve ligation. In this surgical model of neuropathic pain, we also examined the consequence of the genetic suppression of system xc- (using mice lacking the system xc- specific subunit xCT) or its pharmacological manipulation (using the pharmacological inhibitor sulfasalazine) on the pain-associated behavioral responses. Finally, we assessed the glial activation and the inflammatory response in the spinal cord by measuring mRNA and protein levels of GFAP and selected M1 and M2 microglial markers. RESULTS: The sciatic nerve lesion was found to upregulate system xc- at the spinal level. The genetic deletion of xCT attenuated both the amplitude and the duration of the pain sensitization after nerve surgery, as evidenced by reduced responses to mechanical and thermal stimuli, and this was accompanied by reduced glial activation. Consistently, pharmacological inhibition of system xc- had an analgesic effect in lesioned mice. CONCLUSION: Together, these observations provide evidence for a role of system xc- in the biochemical processes underlying central sensitization. We propose that the reduced hypersensitivity observed in the transgenic mice lacking xCT or in sulfasalazine-treated mice is mediated by a reduced gliosis in the lumbar spinal cord and/or a shift in microglial M1/M2 polarization towards an anti-inflammatory phenotype in the absence of system xc-. These findings suggest that drugs targeting system xc- could contribute to prevent or reduce neuropathic pain.


Assuntos
Sistema y+ de Transporte de Aminoácidos , Camundongos Endogâmicos C57BL , Neuralgia , Doenças Neuroinflamatórias , Medula Espinal , Animais , Camundongos , Neuralgia/metabolismo , Doenças Neuroinflamatórias/metabolismo , Masculino , Medula Espinal/metabolismo , Medula Espinal/patologia , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Modelos Animais de Doenças , Camundongos Knockout , Sulfassalazina/farmacologia , Sulfassalazina/uso terapêutico , Hiperalgesia/metabolismo , Hiperalgesia/etiologia , Camundongos Transgênicos
13.
Biol Direct ; 19(1): 36, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715141

RESUMO

Epidermal growth factor receptor (EGFR)-targeted therapy is an important treatment for RAS wild-type metastatic colorectal cancer (mCRC), but the resistance mechanism remains unclear. Here, the differential expression of circRNAs between Cetuximab sensitive and resistant cell lines was analyzed using whole-transcriptome sequencing. We identified that the expression of circHIF1A was significantly higher in LIM1215-R than in LIM1215. When treated with Cetuximab, downregulation of circHIF1A level weakened the proliferation and clonal formation ability of LIM1215-R, caused more cells to enter G0-G1 phase, and significantly reduced the basal respiration, ATP production, and maximal respiration, as well as the glycolytic capacity and glycolytic reserve. The response rate and prognosis of circHIF1A-positive patients were inferior to those of negative patients. Mechanistically, circHIF1A can upregulate the level of hypoxia-inducible factor 1 A (HIF1A) by competitively binding to miR-361-5p, inducing the overexpression of enzymes such as glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). In a xenograft model, inhibition of circHIF1A expression increased the sensitivity to Cetuximab treatment. In conclusion, circHIF1A can promote HIF1α-mediated glycometabolism alteration to induce Cetuximab resistance in CRC. It has the potential to become a screening indicator for the Cetuximab beneficial population in mCRC and a new therapeutic target for enhancing treatment efficacy.


Assuntos
Cetuximab , Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Cetuximab/farmacologia , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Linhagem Celular Tumoral , Camundongos , Animais , RNA Circular/genética , RNA Circular/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Antineoplásicos Imunológicos/farmacologia , Glicólise , Proliferação de Células/efeitos dos fármacos
14.
Microbiome ; 12(1): 80, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715137

RESUMO

BACKGROUND: Antibiotic exposure can occur in medical settings and from environmental sources. Long-term effects of brief antibiotic exposure in early life are largely unknown. RESULTS: Post a short-term treatment by ceftriaxone to C57BL/6 mice in early life, a 14-month observation was performed using 16S rRNA gene-sequencing technique, metabolomics analysis, and metagenomics analysis on the effects of ceftriaxone exposure. Firstly, the results showed that antibiotic pre-treatment significantly disturbed gut microbial α and ß diversities (P < 0.05). Both Chao1 indices and Shannon indices manifested recovery trends over time, but they didn't entirely recover to the baseline of control throughout the experiment. Secondly, antibiotic pre-treatment reduced the complexity of gut molecular ecological networks (MENs). Various network parameters were affected and manifested recovery trends over time with different degrees, such as nodes (P < 0.001, R2 = 0.6563), links (P < 0.01, R2 = 0.4543), number of modules (P = 0.0672, R2 = 0.2523), relative modularity (P = 0.6714, R2 = 0.0155), number of keystones (P = 0.1003, R2 = 0.2090), robustness_random (P = 0.79, R2 = 0.0063), and vulnerability (P = 0.0528, R2 = 0.28). The network parameters didn't entirely recover. Antibiotic exposure obviously reduced the number of key species in gut MENs. Interestingly, new keystones appeared during the recovery process of network complexity. Changes in network stability might be caused by variations in network complexity, which supports the ecological theory that complexity begets stability. Besides, the metabolism profiles of the antibiotic group and control were significantly different. Correlation analysis showed that antibiotic-induced differences in gut microbial metabolism were related to MEN changes. Antibiotic exposure also caused long-term effects on gut microbial functional networks in mice. CONCLUSIONS: These results suggest that short-term antibiotic exposure in early life will cause long-term negative impacts on gut microbial diversity, MENs, and microbial metabolism. Therefore, great concern should be raised about children's brief exposure to antibiotics if the results observed in mice are applicable to humans. Video Abstract.


Assuntos
Antibacterianos , Bactérias , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Antibacterianos/efeitos adversos , Camundongos , RNA Ribossômico 16S/genética , Bactérias/genética , Bactérias/classificação , Bactérias/metabolismo , Bactérias/efeitos dos fármacos , Ceftriaxona/farmacologia , Metagenômica/métodos , Masculino , Metabolômica , Fezes/microbiologia
15.
Endocrinology ; 165(6)2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38715255

RESUMO

Breast cancer bone metastases (BMET) are incurable, primarily osteolytic, and occur most commonly in estrogen receptor-α positive (ER+) breast cancer. ER+ human breast cancer BMET modeling in mice has demonstrated an estrogen (E2)-dependent increase in tumor-associated osteolysis and bone-resorbing osteoclasts, independent of estrogenic effects on tumor proliferation or bone turnover, suggesting a possible mechanistic link between tumoral ERα-driven osteolysis and ER+ bone progression. To explore this question, inducible secretion of the osteolytic factor, parathyroid hormone-related protein (PTHrP), was utilized as an in vitro screening bioassay to query the osteolytic potential of estrogen receptor- and signaling pathway-specific ligands in BMET-forming ER+ human breast cancer cells expressing ERα, ERß, and G protein-coupled ER. After identifying genomic ERα signaling, also responsibility for estrogen's proliferative effects, as necessary and sufficient for osteolytic PTHrP secretion, in vivo effects of a genomic-only ER agonist, estetrol (E4), on osteolytic ER+ BMET progression were examined. Surprisingly, while pharmacologic effects of E4 on estrogen-dependent tissues, including bone, were evident, E4 did not support osteolytic BMET progression (vs robust E2 effects), suggesting an important role for nongenomic ER signaling in ER+ metastatic progression at this site. Because bone effects of E4 did not completely recapitulate those of E2, the relative importance of nongenomic ER signaling in tumor vs bone cannot be ascertained here. Nonetheless, these intriguing findings suggest that targeted manipulation of estrogen signaling to mitigate ER+ metastatic progression in bone may require a nuanced approach, considering genomic and nongenomic effects of ER signaling on both sides of the tumor/bone interface.


Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Receptor alfa de Estrogênio , Estrogênios , Transdução de Sinais , Neoplasias Ósseas/secundário , Neoplasias Ósseas/metabolismo , Animais , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Humanos , Camundongos , Estrogênios/metabolismo , Estrogênios/farmacologia , Receptor alfa de Estrogênio/metabolismo , Linhagem Celular Tumoral , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Osteólise/metabolismo , Osteólise/patologia , Receptores de Estrogênio/metabolismo
16.
Front Cell Infect Microbiol ; 14: 1366563, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38716192

RESUMO

Background: Routine surveillance for antimalarial drug resistance is critical to sustaining the efficacy of artemisinin-based Combination Therapies (ACTs). Plasmodium falciparum kelch-13 (Pfkelch-13) and non-Pfkelch-13 artemisinin (ART) resistance-associated mutations are uncommon in Africa. We investigated polymorphisms in Plasmodium falciparum actin-binding protein (Pfcoronin) associated with in vivo reduced sensitivity to ART in Nigeria. Methods: Fifty-two P. falciparum malaria subjects who met the inclusion criteria were followed up in a 28-day therapeutic efficacy study of artemether-lumefantrine in Lagos, Nigeria. Parasite detection was done by microscopy and molecular diagnostic approaches involving PCR amplification of genes for Pf18S rRNA, varATS, telomere-associated repetitive elements-2 (TARE-2). Pfcoronin and Pfkelch-13 genes were sequenced bi-directionally while clonality of infections was determined using 12 neutral P. falciparum microsatellite loci and msp2 analyses. Antimalarial drugs (sulfadoxine-pyrimethamine, amodiaquine, chloroquine and some quinolones) resistance variants (DHFR_51, DHFR_59, DHFR_108, DHFR_164, MDR1_86, MDR1_184, DHPS_581 and DHPS_613) were genotyped by high-resolution melting (HRM) analysis. Results: A total of 7 (26.92%) cases were identified either as early treatment failure, late parasitological failure or late clinical failure. Of the four post-treatment infections identified as recrudescence by msp2 genotypes, only one was classified as recrudescence by multilocus microsatellites genotyping. Microsatellite analysis revealed no significant difference in the mean allelic diversity, He, (P = 0.19, Mann-Whitney test). Allele sizes and frequency per locus implicated one isolate. Genetic analysis of this isolate identified two new Pfcoronin SNVs (I68G and L173F) in addition to the P76S earlier reported. Linkage-Disequilibrium as a standardized association index, IAS, between multiple P. falciparum loci revealed significant LD (IAS = 0.2865, P=0.02, Monte-Carlo simulation) around the neutral microsatellite loci. The pfdhfr/pfdhps/pfmdr1 drug resistance-associated haplotypes combinations, (108T/N/51I/164L/59R/581G/86Y/184F), were observed in two samples. Conclusion: Pfcoronin mutations identified in this study, with potential to impact parasite clearance, may guide investigations on emerging ART tolerance in Nigeria, and West African endemic countries.


Assuntos
Antimaláricos , Artemisininas , Resistência a Medicamentos , Malária Falciparum , Plasmodium falciparum , Plasmodium falciparum/genética , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Nigéria , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Resistência a Medicamentos/genética , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Mutação , Proteínas de Protozoários/genética , Combinação Arteméter e Lumefantrina/uso terapêutico , Masculino , Proteínas dos Microfilamentos/genética , Feminino , Combinação de Medicamentos , Repetições de Microssatélites/genética , Genótipo , Análise de Sequência de DNA , Recidiva , Polimorfismo Genético , Adulto
17.
Mem Inst Oswaldo Cruz ; 119: e230223, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38716979

RESUMO

BACKGROUND: Conventional microscopic counting is a widely utilised method for evaluating the trypanocidal effects of drugs on intracellular amastigotes. This is a low-cost approach, but it is time-consuming and reliant on the expertise of the microscopist. So, there is a pressing need for developing technologies to enhance the efficiency of low-cost anti-Trypanosoma cruzi drug screening. OBJECTIVES: In our laboratory, we aimed to expedite the screening of anti-T. cruzi drugs by implementing a fluorescent method that correlates emitted fluorescence from green fluorescent protein (GFP)-expressing T. cruzi (Tc-GFP) with cellular viability. METHODS: Epimastigotes (Y strain) were transfected with the pROCKGFPNeo plasmid, resulting in robust and sustained GFP expression across epimastigotes, trypomastigotes, and intracellular amastigotes. Tc-GFP epimastigotes and intracellular amastigotes were exposed to a serial dilution of benznidazole (Bz). Cell viability was assessed through a combination of microscopic counting, MTT, and fluorimetry. FINDINGS: The fluorescence data indicated an underestimation of the activity of Bz against epimastigotes (IC50 75 µM x 14 µM). Conversely, for intracellular GFP-amastigotes, both fluorimetry and microscopy yielded identical IC50 values. Factors influencing the fluorimetry approach are discussed. MAIN CONCLUSIONS: Our proposed fluorometric assessment is effective and can serve as a viable substitute for the time-consuming microscopic counting of intracellular amastigotes.


Assuntos
Proteínas de Fluorescência Verde , Tripanossomicidas , Trypanosoma cruzi , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/genética , Proteínas de Fluorescência Verde/genética , Tripanossomicidas/farmacologia , Nitroimidazóis/farmacologia , Testes de Sensibilidade Parasitária , Animais , Concentração Inibidora 50 , Avaliação Pré-Clínica de Medicamentos , Sobrevivência Celular/efeitos dos fármacos
18.
Cancer Rep (Hoboken) ; 7(5): e2009, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38717954

RESUMO

Breast cancer (BC) is the most widespread cancer worldwide. Over 2 million new cases of BC were identified in 2020 alone. Despite previous studies, the lack of specific biomarkers and signaling pathways implicated in BC impedes the development of potential therapeutic strategies. We employed several RNAseq datasets to extract differentially expressed genes (DEGs) based on the intersection of all datasets, followed by protein-protein interaction network construction. Using the shared DEGs, we also identified significant gene ontology (GO) and KEGG pathways to understand the signaling pathways involved in BC development. A molecular docking simulation was performed to explore potential interactions between proteins and drugs. The intersection of the four datasets resulted in 146 DEGs common, including AURKB, PLK1, TTK, UBE2C, CDCA8, KIF15, and CDC45 that are significant hub-proteins associated with breastcancer development. These genes are crucial in complement activation, mitotic cytokinesis, aging, and cancer development. We identified key microRNAs (i.e., hsa-miR-16-5p, hsa-miR-1-3p, hsa-miR-147a, hsa-miR-195-5p, and hsa-miR-155-5p) that are associated with aggressive tumor behavior and poor clinical outcomes in BC. Notable transcription factors (TFs) were FOXC1, GATA2, FOXL1, ZNF24 and NR2F6. These biomarkers are involved in regulating cancer cell proliferation, invasion, and migration. Finally, molecular docking suggested Hesperidin, 2-amino-isoxazolopyridines, and NMS-P715 as potential lead compounds against BC progression. We believe that these findings will provide important insight into the BC progression as well as potential biomarkers and drug candidates for therapeutic development.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Mapas de Interação de Proteínas , MicroRNAs/genética , Transcriptoma , Redes Reguladoras de Genes , Transdução de Sinais/efeitos dos fármacos
19.
PLoS Negl Trop Dis ; 18(5): e0012152, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38717980

RESUMO

BACKGROUND: Each year, 3,800 cases of snakebite envenomation are reported in Mexico, resulting in 35 fatalities. The only scientifically validated treatment for snakebites in Mexico is the use of antivenoms. Currently, two antivenoms are available in the market, with one in the developmental phase. These antivenoms, produced in horses, consist of F(ab')2 fragments generated using venoms from various species as immunogens. While previous studies primarily focused on neutralizing the venom of the Crotalus species, our study aims to assess the neutralization capacity of different antivenom batches against pit vipers from various genera in Mexico. METHODOLOGY: We conducted various biological and biochemical tests to characterize the venoms. Additionally, we performed neutralization tests using all three antivenoms to evaluate their effectiveness against lethal activity and their ability to neutralize proteolytic and fibrinogenolytic activities. RESULTS: Our results reveal significant differences in protein content and neutralizing capacity among different antivenoms and even between different batches of the same product. Notably, the venom of Crotalus atrox is poorly neutralized by all evaluated batches despite being the primary cause of envenomation in the country's northern region. Furthermore, even at the highest tested concentrations, no antivenom could neutralize the lethality of Metlapilcoatlus nummifer and Porthidium yucatanicum venoms. These findings highlight crucial areas for improving existing antivenoms and developing new products. CONCLUSION: Our research reveals variations in protein content and neutralizing potency among antivenoms, emphasizing the need for consistency in venom characteristics as immunogens. While Birmex neutralizes more LD50 per vial, Antivipmyn excels in specific neutralization. The inability of antivenoms to neutralize certain venoms, especially M. nummifer and P. yucatanicum, highlights crucial improvement opportunities, given the medical significance of these species.


Assuntos
Antivenenos , Testes de Neutralização , Antivenenos/farmacologia , Antivenenos/imunologia , Animais , México , Mordeduras de Serpentes/tratamento farmacológico , Mordeduras de Serpentes/imunologia , Viperidae , Crotalus , Venenos de Crotalídeos/imunologia
20.
PLoS Pathog ; 20(5): e1012187, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38718038

RESUMO

The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) has significant challenges to human health and clinical treatment, with KPC-2-producing CRKP being the predominant epidemic strain. Therefore, there is an urgent need to identify new therapeutic targets and strategies. Non-coding small RNA (sRNA) is a post-transcriptional regulator of genes involved in important biological processes in bacteria and represents an emerging therapeutic strategy for antibiotic-resistant bacteria. In this study, we analyzed the transcription profile of KPC-2-producing CRKP using RNA-seq. Of the 4693 known genes detected, the expression of 307 genes was significantly different from that of carbapenem-sensitive Klebsiella pneumoniae (CSKP), including 133 up-regulated and 174 down-regulated genes. Both the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) analysis showed that these differentially expressed genes (DEGs) were mainly related to metabolism. In addition, we identified the sRNA expression profile of KPC-2-producing CRKP for the first time and detected 115 sRNAs, including 112 newly discovered sRNAs. Compared to CSKP, 43 sRNAs were differentially expressed in KPC-2-producing CRKP, including 39 up-regulated and 4 down-regulated sRNAs. We chose sRNA51, the most significantly differentially expressed sRNA in KPC-2-producing CRKP, as our research subject. By constructing sRNA51-overexpressing KPC-2-producing CRKP strains, we found that sRNA51 overexpression down-regulated the expression of acrA and alleviated resistance to meropenem and ertapenem in KPC-2-producing CRKP, while overexpression of acrA in sRNA51-overexpressing strains restored the reduction of resistance. Therefore, we speculated that sRNA51 could affect the resistance of KPC-2-producing CRKP by inhibiting acrA expression and affecting the formation of efflux pumps. This provides a new approach for developing antibiotic adjuvants to restore the sensitivity of CRKP.


Assuntos
Carbapenêmicos , Klebsiella pneumoniae , beta-Lactamases , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/metabolismo , Klebsiella pneumoniae/efeitos dos fármacos , beta-Lactamases/genética , beta-Lactamases/metabolismo , Carbapenêmicos/farmacologia , Humanos , Regulação Bacteriana da Expressão Gênica , Antibacterianos/farmacologia , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Pequeno RNA não Traduzido/genética , RNA Bacteriano/genética , Testes de Sensibilidade Microbiana
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