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1.
Artigo em Inglês | MEDLINE | ID: mdl-38299562

RESUMO

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis of sensitive cancer cells, including colorectal cancer (CRC). Due to its short biological half-life after intravenous administration and related clinical ineffectiveness, novel formulations of TRAIL need to be developed. Here we propose Lactococcus lactis bacteria as a vehicle for local delivery of human soluble TRAIL (hsTRAIL) in CRC. The use of common probiotics targeting guts as carriers for TRAIL could ensure its sustained release at the tumor site and extend the duration of its activity. We have already engineered hsTRAIL-secreting L.lactis bacteria and showed their effectiveness in elimination of human CRC cells in vitro and in vivo in a mouse subcutaneous model. Here, L.lactis(hsTRAIL+) were administered by gastric gavage to SCID mice with orthotopically developed HCT116 tumor in cecum, in monotherapy or in combination with metformin (MetF), already shown to enhance the hsTRAIL anti-tumor activity in subcutaneous CRC model. Oral administration of L.lactis(hsTRAIL+) resulted in significant progression of HCT116 tumors and shortening of the colon crypts. Secretion of hsTRAIL in the colon was accompanied by infiltration of the primary tumor with M2-macrophages, while MetF promoted transient colonization of the gut by L.lactis. Our study indicates that L.lactis bacteria after oral administration enable delivery of biologically active hsTRAIL to colon, however its potential therapeutic effect in CRC treatment is abolished by its pro-tumorigenic signalling, leading to the recruitment of M2-macrophages and tumor growth promotion.


Assuntos
Neoplasias Colorretais , Lactococcus lactis , Camundongos , Animais , Humanos , Camundongos SCID , Ligantes , Apoptose , Neoplasias Colorretais/terapia
2.
Artigo em Inglês | MEDLINE | ID: mdl-38299563

RESUMO

Venous thromboembolism, encompassing acute pulmonary embolism (APE) and deep vein thrombosis (DVT), is a potentially fatal disease with complex pathophysiology. Traditionally, the Virchow triad provided a framework for understanding the pathogenic contributors to thrombus formation, which include endothelial dysfunction, alterations in blood flow and blood hypercoagulability. In the last years, it has become apparent that immunity plays a central role in thrombosis, interacting with classical prothrombotic mechanisms, oxidative stress and vascular factors. Thrombosis amplifies inflammation, and exaggerated inflammatory processes can trigger thrombosis mainly due to the activation of leukocytes, platelets, and endothelial cells. APE-related endothelium injury is a major trigger for immune system activation. Endothelium is also a key component mediating inflammatory reaction and it is relevant to maintain vascular permeability. Exaggerated right ventricular wall stress and overload, with coexisting systemic hypotension and hypoxemia, result in myocardial injury and necrosis. Hypoxia, tissue factor activation and cytokine storm are engaged in the thrombo-inflammatory processes. Thrombus development is characterized by inflammatory state vascular wall caused mainly by an early extravasation of leukocytes and intense selectins and cytokines production. Nevertheless, immunity of DVT is well described, little is known about potential chemokine and cellular differences between thrombus that develops in the vein and thrombus that detaches and lodges in the pulmonary circulation being a cause of APE. There is a paucity of data considering inflammatory state in the pulmonary artery wall during an acute episode of pulmonary embolism. The main aim of this review is to summarize the knowledge of immunity in acute phase of pulmonary embolism in experimental models.


Assuntos
Hominidae , Embolia Pulmonar , Trombose , Animais , Células Endoteliais , Embolia Pulmonar/complicações , Trombose/complicações , Inflamação , Modelos Animais
3.
Curr Microbiol ; 81(3): 85, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38300357

RESUMO

A strictly aerobic Gram-negative bacterium, designated 2012CJ34-2T, was isolated from marine sponge to Chuja-do in Jeju-island, Republic of Korea and taxonomically characterized. Cells were catalase- and oxidase-positive, and non-motile rods (without flagella). Growth was observed at 15-42 °C (optimum, 30 °C), pH 6-9 (optimum, pH 7), and in the presence of 0.5-10% (w/v) NaCl (optimum, 2-3%). The major cellular fatty acid and respiratory quinones were identified summed feature 3 (C16:1 ω7c/C16:1 ω6c), and Q-8 and Q-9, respectively. The polar lipids comprised diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, an unidentified aminophospholipid, two unidentified phospholipids, and three unidentified lipids. The DNA G+C content was 48.0 mol%. Phylogenetic analyses based on 16S rRNA gene and whole genome sequences showed that strain 2012CJ34-2T formed a clade with Parendozoicomonas haliclonae S-B4-1UT and Sansalvadorimonas verongulae LMG 29871T within the family Endozoicomodaceae. Genome relatedness values, including dDDH, ANI and AF, and AAI and POCP, among strain 2012CJ34-2T, P. haliclonae S-B4-1UT, and S. verongulae LMG 29871T were within the range of the bacterial genus cut-off values. Based on the phylogenetic, chemotaxonomic, and genomic analyses, strain 2012CJ34-2T represents a novel bacterial species of the family Endozoicomodaceae, for which the name Parendozoicomonas callyspongiae sp. nov. is proposed. The type strain is 2012CJ34-2T (= KACC 22641T = LMG 32581T). Additionally, we proposed the reclassification of Sansalvadorimonas verongulae of the family Hahellaceae as Parendozoicomonas verongulae of the family Endozoicomonadaceae.


Assuntos
Callyspongia , Gammaproteobacteria , Poríferos , Animais , Filogenia , RNA Ribossômico 16S/genética , Ácidos Graxos
4.
Cell Death Dis ; 15(2): 105, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302438

RESUMO

Aconitate decarboxylase 1 (ACOD1) is the enzyme synthesizing itaconate, an immuno-regulatory metabolite tuning host-pathogen interactions. Such functions are achieved by affecting metabolic pathways regulating inflammation and microbe survival. However, at the whole-body level, metabolic roles of itaconate remain largely unresolved. By using multiomics-integrated approaches, here we show that ACOD1 responds to high-fat diet consumption in mice by promoting gut microbiota alterations supporting metabolic disease. Genetic disruption of itaconate biosynthesis protects mice against obesity, alterations in glucose homeostasis and liver metabolic dysfunctions by decreasing meta-inflammatory responses to dietary lipid overload. Mechanistically, fecal metagenomics and microbiota transplantation experiments demonstrate such effects are dependent on an amelioration of the intestinal ecosystem composition, skewed by high-fat diet feeding towards obesogenic phenotype. In particular, unbiased fecal microbiota profiling and axenic culture experiments point towards a primary role for itaconate in inhibiting growth of Bacteroidaceae and Bacteroides, family and genus of Bacteroidetes phylum, the major gut microbial taxon associated with metabolic health. Specularly to the effects imposed by Acod1 deficiency on fecal microbiota, oral itaconate consumption enhances diet-induced gut dysbiosis and associated obesogenic responses in mice. Unveiling an unrecognized role of itaconate, either endogenously produced or exogenously administered, in supporting microbiota alterations underlying diet-induced obesity in mice, our study points ACOD1 as a target against inflammatory consequences of overnutrition.


Assuntos
Microbioma Gastrointestinal , Succinatos , Animais , Camundongos , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo
5.
Clin Orthop Surg ; 16(1): 157-167, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38304211

RESUMO

Background: In bone sarcomas, chemotherapy has improved the prognosis with advances in diagnostic and surgical technologies, which has led to attempts to save limbs. As early detection and multidisciplinary treatment have improved the survival rate, curative surgery is considered for selected patients with metastatic bone carcinomas. Limb salvage procedures may vary in relation to the reconstruction method, which is accompanied by different complications. To overcome them, we devised a novel concept, in-situ local tumor ablation and recycling machine based on radiofrequency (RF)-induced heating and intended experiments to demonstrate its feasibility. Methods: The fresh femurs of 6-month-old pigs were used after removing the epiphyses; the distal parts were placed in a heating chamber. Fiber-optic temperature sensors were inserted in the metaphysis, meta-diaphysis, and diaphysis. Temperatures were measured six times each during heating at 27.12 MHz at various powers. Additionally, the compressive and bending stiffnesses were measured six times each for the unprocessed, RF-treated, and pasteurized bones, and the results were compared. Results: Under 200 W power output, the temperatures at all measurement sites reached 70 ℃ or higher in 6 minutes, and the temperatures were maintained. The median compressive stiffness of RF-heated bones was 79.2% higher than that of pasteurized bones, but the difference was statistically insignificant. The median bending stiffness of RF-heated bones was approximately 66.3% of that of unprocessed bones, which was 20% higher than that of pasteurized bones. Conclusions: The feasibility to rapidly attain and maintain temperatures for tumor ablation is shown, which favorably preserves bone stiffness through the in-situ local tumor ablation and recycling based on RF heating. The problem of nonuniform temperature distribution might be solved by an optimal design determined from simulation research and additional experiments.


Assuntos
Ablação por Cateter , Neoplasias , Animais , Simulação por Computador , Estudos de Viabilidade , Calefação , Temperatura Alta , Suínos
6.
Bioinspir Biomim ; 19(2)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38305303

RESUMO

The field of animal-robot and organism-robot interaction systems (ARIS, ORIS) is a currently rapidly emerging field in biorobotics. In this special issue we aim for providing a comprehensive overview of the cutting-edge advancements and pioneering breakthroughs within this scientific and engineering discipline. Therefore, we collected scientific articles that delineate and expound upon the complexity of these remarkable biohybrid systems. These configurations stand as engineered conduits, facilitating the accurate investigation and profound exploration of the multifaceted interactions between robotic devices and biological entities, including various fish species, honeybees and plants. Also the human factor plays a role in this collection, as we also include a philosophical perspective on such systems as well as an augmented reality setup that brings humans into the loop with living fish. Within our editorial purview, we categorize the scientific contributions based on their focal points, differentiating between examinations of singular agent-to-agent interactions, extensions to the social stratum, and further expansions to the intricate levels of swarm dynamics, colonies, populations, and ecosystems. Considering potential applications, we delve into the multifaceted domains wherein these biohybrid systems might be applied. This discourse culminates in a tentative glimpse into the future trajectories these technologies might traverse, elucidating their promising prospects for both scientific advancement and societal enrichment. In sum, this special issue aims at facilitating the convergence of diverse insights, at encapsulating the richness of the ARIS and ORIS domain, and at charting a course toward the untapped prospects lying at the nexus of biology and robotics.


Assuntos
Robótica , Animais , Humanos , Abelhas , Biologia , Ecossistema
7.
Trop Anim Health Prod ; 56(2): 65, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38305980

RESUMO

The aim of the present study was to determine the nutritional value of black soldier fly (BSF) larvae meal for quail (experiment I) and the dose-response effects of BSF levels on growth performance, relative organ weight, and body composition of growing quails (experiment II). In experiment I, 100 35-day-old quail were distributed in a completely randomized design, with two treatments (reference and test diet) and 10 replicates. The experimental period consisted of 5 days of adaptation, followed by 5 days of total excreta collection. The experimental feed consisted of a reference diet and a test diet formulated with 850 g/kg reference diet and 150 g/kg BSF. In experiment II, 1000 1-day-old quail were distributed in a completely randomized design, with five dietary levels of BSF (0, 25, 50, 75, and 100 g/kg). At 42 days of age, birds were slaughtered, and the relative organ weight and body composition were determined. Apparent metabolizable energy values corrected for nitrogen retention of BSF meal were 13.8 MJ/kg. Across the starter (1-14 days) and overall period (1-42 days), increasing BSF levels had a quadratic effect on body weight and body weight gain. Feed conversion ratio was quadratically affected during the starter phase and linearly reduced over the overall period. Additionally, the BSF levels linearly decreased the small intestine's relative weight at 42 days and had a quadratic effect on the rate of protein deposition. We concluded that the inclusion of 100 g/kg BSF meal improves feed conversion ratio for growing quail.


Assuntos
Dípteros , Codorniz , Animais , Ração Animal/análise , Dieta/veterinária , Larva/fisiologia , Aumento de Peso
8.
Parasit Vectors ; 17(1): 51, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38308372

RESUMO

BACKGROUND: Babesia canis is a clinically relevant vector-borne pathogen in dogs, and its presence is expanding. The efficacy of Simparica Trio® (Zoetis) in the prevention of B. canis transmission was evaluated at the minimum recommended label dose of 1.2 mg/kg sarolaner, 24 µg/kg moxidectin and 5 mg/kg pyrantel per kg bodyweight. METHODS: Twenty-four (24) dogs were randomly allocated to either a placebo-treated group or one of two treatment groups with Simparica Trio. Dogs were infested with B. canis-infected Dermacentor reticulatus ticks 21 or 28 days after treatment administration. Blood samples for antibody and DNA detection were collected from each dog prior to tick infestation until 28 days after infestation. A dog was defined as being B. canis positive if it tested positive by both an indirect immunofluorescence assay (IFA) and PCR at any time during the study. RESULTS: No treatment-related adverse reactions were recorded during the study. All placebo-treated animals displayed clinical signs due to babesiosis and tested positive on both IFA and PCR. None of the Simparica Trio-treated animals displayed any clinical symptoms or tested positive, resulting in a 100% efficacy in the prevention of canine babesiosis (P < 0.0001). CONCLUSIONS: A single treatment with Simparica Trio at the minimum recommended label dose of 1.2 mg/kg sarolaner, 24 µg/kg moxidectin and 5 mg/kg pyrantel per kg bodyweight prevents the transmission of B. canis by infected D. reticulatus to dogs for at least 28 days.


Assuntos
Acaricidas , Babesia , Babesiose , Doenças do Cão , Animais , Cães , Acaricidas/uso terapêutico , Administração Oral , Azetidinas , Babesia/genética , Babesiose/prevenção & controle , Dermacentor , Doenças do Cão/tratamento farmacológico , Doenças do Cão/prevenção & controle , Macrolídeos , Pirantel/uso terapêutico , Compostos de Espiro , Infestações por Carrapato/tratamento farmacológico , Infestações por Carrapato/prevenção & controle , Infestações por Carrapato/veterinária
9.
Parasit Vectors ; 17(1): 52, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38308365

RESUMO

BACKGROUND: Tsetse flies (Glossina spp.) are the definitive biological vectors of African trypanosomes in humans and animals. Controlling this vector is the most promising method of preventing trypanosome transmission. This requires a comprehensive understanding of tsetse biology and host preference to inform targeted design and management strategies, such as the use of olfaction and visual cues in tsetse traps. No current review exists on host preference and blood meal analyses of tsetse flies. METHODS: This review presents a meta-analysis of tsetse fly blood meal sources and the methodologies used to identify animal hosts from 1956 to August 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRIMA-ScR) was applied. This focused on tsetse-endemic countries, blood meal analysis methodologies and the blood meal hosts identified. The articles were retrieved and screened from databases using predetermined eligibility criteria. RESULTS: Only 49/393 of the articles retrieved matched the inclusion criteria. Glossina's main hosts in the wild included the bushbuck, buffalo, elephant, warthog, bushpig and hippopotamus. Pigs, livestock and humans were key hosts at the domestic interface. The least studied species included Glossina fuscipleuris, G. fusca, G. medicorum, G. tabaniformis and G. austeni. In the absence of preferred hosts, Glossina fed opportunistically on a variety of hosts. Precipitin, haemagglutination, disc diffusion, complement fixation, ELISA and PCR-based assays were used to evaluate blood meals. Cytochrome b (Cyt b) was the main target gene in PCR to identify the vertebrate hosts. CONCLUSIONS: Tsetse blood meal sources have likely expanded because of ecological changes that could have rendered preferred hosts unavailable. The major approaches for analysing tsetse fly blood meal hosts targeted Cyt b gene for species identification by Sanger sequencing. However, small-fragment DNAs, such as the mammalian 12S and 16S rRNA genes, along with second- and third-generation sequencing techniques, could increase sensitivity for host identification in multiple host feeders that Sanger sequencing may misidentify as "noise". This review of tsetse fly blood meal sources and approaches to host identification could inform strategies for tsetse control.


Assuntos
Trypanosoma , Tripanossomíase Africana , Moscas Tsé-Tsé , Animais , Humanos , Citocromos b , Mamíferos/genética , RNA Ribossômico 16S , Suínos , Trypanosoma/genética , Moscas Tsé-Tsé/genética
10.
J Oleo Sci ; 73(2): 219-230, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38311411

RESUMO

Ginsenosides Rg3 and Rg5 obtained from Panax (ginseng) have shown significant anticancer activity via the PI3K-Akt signaling pathway. This study evaluated the anticancer and antimetastatic effects of a combination of Rg3 and Rg5 on lung cancer cells. A combination of Rg3 and Rg5 was treated for lung cancer cell line A549 and human lung tumor xenograft mouse model, and anti-metastatic effects on Matrigel plug implantation in mice. The combination of Rg3 and Rg5 showed potent antiproliferative effects on A549 cells with IC50 values of 44.6 and 36.0 µM for Rg3 and Rg5 respectively. The combination of Rg3 and Rg5 (30 µM each) showed 48% cell viability as compared to Rg3 (72% viability) and Rg5 (64% viability) at 30 µM concentrations. The combination of Rg3 and Rg5 induced apoptosis in A549 cells characterized by activation of caspase-9 and caspase-3 and cleavage of PARP, as well as suppression of the autophagic marker LC3A/B. The antitumoral potentials of the combination of Rg3 and Rg5 were ascertained in a lung tumor xenograft mouse model with high efficacy as compared to individual ginsenosides. The metastasislimiting properties of the combination of Rg3 and Rg5 were assessed in Matrigel plug implantation in mice which showed the potent efficacy of the combination as compared to individual ginsenoside. Mechanistically, the combination of Rg3 and Rg5 inhibited the expression of PI3K/Akt/mTOR and EGFR/VEGF signaling pathways in lung cancer cells. Results suggest that the combination of Rg3 and Rg5 suppressed the tumor cell proliferation in lung cancer cells and limited the rate of metastasis which further suggest that the combination has a significant effect as compared to the administration of single ginsenoside.


Assuntos
Ginsenosídeos , Neoplasias Pulmonares , Humanos , Camundongos , Animais , Neoplasias Pulmonares/tratamento farmacológico , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Linhagem Celular Tumoral , Apoptose , Proliferação de Células , Receptores ErbB/metabolismo , Receptores ErbB/farmacologia
11.
J Oleo Sci ; 73(2): 239-251, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38311413

RESUMO

Frog oil has been recognized for its nutritional and medicinal value. However, there is limited research on the role of frog oil in preventing obesity. In this study, we aimed to investigate the lipid composition of Quasipaa spinosa oil (QSO) and Rana catesbeiana oil (RCO) using lipidomics analysis. We compared the lipid accumulation effects of these two kinds of frog oils and soybean oil (SO) in Caenorhabditis elegans (C. elegans). Additionally, we determined the gene expression related to lipid metabolism and used the nhr-49 mutant (RB1716) and sir-2.1 mutant (VC199) for validation experiments. The results showed that the lipid composition of QSO and RCO was significantly different (p < 0.05), and QSO was rich in more polyunsaturated fatty acids (PUFAs). After feeding C. elegans, the lipid accumulation of the QSO group was the lowest among the three dietary oil groups. In addition, compared with RCO and SO, QSO significantly inhibited the production of malondialdehyde (MDA) and increased the activity of superoxide dismutase (SOD). The effects of three kinds of dietary oils on the fatty acid composition of C. elegans were significantly different. Compared with SO and RCO, QSO significantly up-regulated (p < 0.05) the expression of sir-2.1 and ech-1 genes. The results showed that QSO might reduce lipid accumulation through the SIRT1 and nuclear hormone signaling pathways. Such a situation was verified experimentally by the nhr-49 mutant (RB1716) and sir-2.1 mutant (VC199). This study proposed a new functional oil, laying the groundwork for developing functional foods from Quasipaa spinosa.


Assuntos
Caenorhabditis elegans , Gorduras Insaturadas na Dieta , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Rana catesbeiana/metabolismo , Ácidos Graxos/metabolismo , Ácidos Graxos Insaturados/metabolismo , Gorduras Insaturadas na Dieta/farmacologia , Óleo de Soja/metabolismo , Metabolismo dos Lipídeos/genética
12.
Life Sci Alliance ; 7(4)2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38320810

RESUMO

The cellular response to a decrease in protein degradation by 26S proteasomes in chronic diseases is poorly understood. Pharmacological inhibition of proteasomes increases the expression of proteasome subunits and Proteasome Activator 200 (PA200), an alternative proteasome activator. In the S63del mouse model of the peripheral neuropathy Charcot Marie Tooth 1B (CMT1B), proteasomal protein degradation is decreased and proteasome gene expression is increased. Here, we show an increase in PA200 and PA200-bound proteasomes in the peripheral nerves of S63del mice. To test genetically whether the upregulation of PA200 was compensatory, we generated S63del//PA200-/- mice. Unexpectedly, in the sciatic nerves of these mice, there was greater proteasomal protein degradation than in S63del, less polyubiquitinated proteins and markers of the unfolded protein response, and a greater amount of assembled, active 26S proteasomes. These changes were not seen in PA200-/- controls and were therefore specific to the neuropathy. Furthermore, in S63del//PA200-/- mice, myelin thickness and nerve conduction were restored to WT levels. Thus, the upregulation of PA200 is maladaptive in S63del mice and its genetic ablation prevented neuropathy.


Assuntos
Doença de Charcot-Marie-Tooth , Complexo de Endopeptidases do Proteassoma , Camundongos , Animais , Complexo de Endopeptidases do Proteassoma/metabolismo , Camundongos Knockout , Doença de Charcot-Marie-Tooth/genética , Proteólise , Citoplasma/metabolismo
13.
Nature ; 626(7998): 271-279, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38326590

RESUMO

Mitochondria retain bacterial traits due to their endosymbiotic origin, but host cells do not recognize them as foreign because the organelles are sequestered. However, the regulated release of mitochondrial factors into the cytosol can trigger cell death, innate immunity and inflammation. This selective breakdown in the 2-billion-year-old endosymbiotic relationship enables mitochondria to act as intracellular signalling hubs. Mitochondrial signals include proteins, nucleic acids, phospholipids, metabolites and reactive oxygen species, which have many modes of release from mitochondria, and of decoding in the cytosol and nucleus. Because these mitochondrial signals probably contribute to the homeostatic role of inflammation, dysregulation of these processes may lead to autoimmune and inflammatory diseases. A potential reason for the increased incidence of these diseases may be changes in mitochondrial function and signalling in response to such recent phenomena as obesity, dietary changes and other environmental factors. Focusing on the mixed heritage of mitochondria therefore leads to predictions for future insights, research paths and therapeutic opportunities. Thus, whereas mitochondria can be considered 'the enemy within' the cell, evolution has used this strained relationship in intriguing ways, with increasing evidence pointing to the recent failure of endosymbiosis being critical for the pathogenesis of inflammatory diseases.


Assuntos
Inflamação , Mitocôndrias , Modelos Biológicos , Simbiose , Humanos , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Dieta/efeitos adversos , Homeostase , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias/fisiologia , Proteínas Mitocondriais/metabolismo , Ácidos Nucleicos/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologia , Fosfolipídeos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Simbiose/fisiologia , Animais
14.
FASEB J ; 38(3): e23472, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38329323

RESUMO

Allergic asthma development and pathogenesis are influenced by airway epithelial cells in response to allergens. Heme oxygenase-1 (HO-1), an inducible enzyme responsible for the breakdown of heme, has been considered an appealing target for the treatment of chronic inflammatory diseases. Herein, we report that alleviation of allergic airway inflammation by HO-1-mediated suppression of pyroptosis in airway epithelial cells (AECs). Using house dust mite (HDM)-induced asthma models of mice, we found increased gasdermin D (GSDMD) in the airway epithelium. In vivo administration of disulfiram, a specific inhibitor of pore formation by GSDMD, decreased thymic stromal lymphopoietin (TSLP) release, T helper type 2 immune response, alleviated airway inflammation, and reduced airway hyperresponsiveness (AHR). HO-1 induction by hemin administration reversed these phenotypes. In vitro studies revealed that HO-1 restrained GSDMD-mediated pyroptosis and cytokine TSLP release in AECs by binding Nuclear Factor-Kappa B (NF-κB) p65 RHD domain and thus controlling NF-κB-dependent pyroptosis. These data provide new therapeutic indications for purposing HO-1 to counteract inflammation, which contributes to allergic inflammation control.


Assuntos
Asma , Heme Oxigenase-1 , NF-kappa B , Animais , Camundongos , Citocinas/metabolismo , Células Epiteliais/metabolismo , Heme Oxigenase-1/metabolismo , Inflamação/metabolismo , NF-kappa B/metabolismo , Piroptose , Linfopoietina do Estroma do Timo
15.
FASEB J ; 38(3): e23459, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38329343

RESUMO

Wound healing is facilitated by neoangiogenesis, a complex process that is essential to tissue repair in response to injury. MicroRNAs are small, noncoding RNAs that can regulate the wound healing process including stimulation of impaired angiogenesis that is associated with type-2 diabetes (T2D). Expression of miR-409-3p was significantly increased in the nonhealing skin wounds of patients with T2D compared to the non-wounded normal skin, and in the skin of a murine model with T2D. In response to high glucose, neutralization of miR-409-3p markedly improved EC growth and migration in human umbilical vein endothelial cells (HUVECs), promoted wound closure and angiogenesis as measured by increased CD31 in human skin organoids, while overexpression attenuated EC angiogenic responses. Bulk mRNA-Seq transcriptomic profiling revealed BTG2 as a target of miR-409-3p, where overexpression of miR-409-3p significantly decreased BTG2 mRNA and protein expression. A 3' untranslated region (3'-UTR) luciferase assay of BTG2 revealed decreased luciferase activity with overexpression of miR-409-3p, while inhibition had opposite effects. Mechanistically, in response to high glucose, miR-409-3p deficiency in ECs resulted in increased mTOR phosphorylation, meanwhile BTG-anti-proliferation factor 2 (BTG2) silencing significantly decreased mTOR phosphorylation. Endothelial-specific and tamoxifen-inducible miR-409-3p knockout mice (MiR-409IndECKO ) with hyperglycemia that underwent dorsal skin wounding showed significant improvement of wound closure, increased blood flow, granulation tissue thickness (GTT), and CD31 that correlated with increased BTG2 expression. Taken together, our results show that miR-409-3p is a critical mediator of impaired angiogenesis in diabetic skin wound healing.


Assuntos
Diabetes Mellitus Tipo 2 , Proteínas Imediatamente Precoces , MicroRNAs , Proteínas Supressoras de Tumor , Animais , Humanos , Camundongos , Proliferação de Células/fisiologia , Diabetes Mellitus Tipo 2/genética , Glucose , Células Endoteliais da Veia Umbilical Humana/metabolismo , Proteínas Imediatamente Precoces/genética , Luciferases , Camundongos Obesos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro , Serina-Treonina Quinases TOR , Proteínas Supressoras de Tumor/genética , Cicatrização/genética
16.
Dis Model Mech ; 17(1)2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38299666

RESUMO

Platyfish and swordtails of the genus Xiphophorus provide a well-established model for melanoma research and have become well known for this feature. Recently, modelling approaches for other human diseases in Xiphophorus have been developed or are emerging. This Review provides a comprehensive summary of these models and discusses how findings from basic biological and molecular studies and their translation to medical research demonstrate that Xiphophorus models have face, construct and predictive validity for studying a broad array of human diseases. These models can thus improve our understanding of disease mechanisms to benefit patients.


Assuntos
Ciprinodontiformes , Melanoma , Animais , Humanos
17.
Gut Microbes ; 16(1): 2310894, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38312103

RESUMO

Gut microbiota and related metabolites are both crucial factors that significantly influence how individuals with Crohn's disease respond to immunotherapy. However, little is known about the interplay among gut microbiota, metabolites, Crohn's disease, and the response to anti-α4ß7-integrin in current studies. Our research utilized 2,4,6-trinitrobenzene sulfonic acid to induce colitis based on the humanized immune system mouse model and employed a combination of whole-genome shotgun metagenomics and non-targeted metabolomics to investigate immunotherapy responses. Additionally, clinical cases with Crohn's disease initiating anti-α4ß7-integrin therapy were evaluated comprehensively. Particularly, 16S-rDNA gene high-throughput sequencing and targeted bile acid metabolomics were conducted at weeks 0, 14, and 54. We found that anti-α4ß7-integrin therapy has shown significant potential for mitigating disease phenotypes in remission-achieving colitis mice. Microbial profiles demonstrated that not only microbial composition but also microbially encoded metabolic pathways could predict immunotherapy responses. Metabonomic signatures revealed that bile acid metabolism alteration, especially elevated secondary bile acids, was a determinant of immunotherapy responses. Especially, the remission mice significantly enriched the proportion of the beneficial Lactobacillus and Clostridium genera, which were correlated with increased gastrointestinal levels of BAs involving lithocholic acid and deoxycholic acid. Moreover, most of the omics features observed in colitis mice were replicated in clinical cases. Notably, anti-α4ß7 integrin provided sustained therapeutic benefits in clinical remitters during follow-up, and long-lasting remission was linked to persistent changes in the microbial-related bile acids. In conclusion, gut microbiota-mediated bile acid metabolism alteration could play a crucial role in regulating immunotherapy responses to anti-α4ß7-integrin in Crohn's disease. Therefore, the identification of prognostic microbial signals facilitates the advancement of targeted probiotics that activate anti-inflammatory bile acid metabolic pathways, thereby improving immunotherapy responses. The integrated multi-omics established in our research provide valuable insights into potential mechanisms that impact treatment responses in complex diseases.


Assuntos
Colite , Doença de Crohn , Microbioma Gastrointestinal , Animais , Camundongos , Doença de Crohn/tratamento farmacológico , Multiômica , Integrinas/genética , Integrinas/uso terapêutico , Colite/induzido quimicamente , Colite/terapia , Ácidos e Sais Biliares/uso terapêutico , Imunoterapia
18.
Gut Microbes ; 16(1): 2309683, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38312099

RESUMO

Diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder with limited effective interventions available. A novel approach to address this issue is through gut microbiota-based therapy. In our study, we utilized multi-omics analysis to identify Phocaeicola vulgatus (P. vulgatus) as a potential probiotic for the treatment of MASLD. Our findings from murine models clearly illustrate that the supplementation of P. vulgatus mitigates the development of MASLD. This beneficial effect is partly attributed to the metabolite 3-Hydroxyphenylacetic acid (3-HPAA) produced by P. vulgatus, which reduces the acetylation levels of H3K27 and downregulates the transcription of Squalene Epoxidase (SQLE), a rate-limiting enzyme in steroid biosynthesis that promotes lipid accumulation in liver cells. This study underscores the significant role of P. vulgatus in the development of MASLD and the critical importance of its metabolite 3-HPAA in regulating lipid homeostasis. These findings offer a promising avenue for early intervention therapy in the context of MASLD.


Assuntos
Bacteroides , Fígado Gorduroso , Microbioma Gastrointestinal , Doenças Metabólicas , Animais , Camundongos , Histonas , Acetilação , Dieta , Progressão da Doença , Lipídeos
19.
Hum Vaccin Immunother ; 20(1): 2304372, 2024 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38314761

RESUMO

The mechanisms of Pythium insidiosum-antigen (PIA) immunotherapy activating a patient's immune system are unknown. We evaluated the interleukin-8 (IL-8) serum levels during P. insidiosum infection and after vaccination with PIA in vascular pythiosis cases. Furthermore, we studied the anti-P. insidiosum activity of neutrophils stimulated with various concentrations of PIA ex vivo in 3 strains of P. insidiosum isolated from vascular pythiosis patients. IL-8 serum levels were evaluated using the ELISA technique. We assessed the effect of PIA-stimulated neutrophils on the viability of zoospores using MTT assay, visualized neutrophil extracellular trap (NET) formation via microscopy, and measured the levels of double-stranded DNA (dsDNA) using PicoGreen dsDNA quantitation assay in 3 strains of P. insidiosum isolated from vascular pythiosis patients. Serum levels of IL-8 gradually lowered from the early to the end phases of vaccination with PIA among the surviving group of vascular pythiosis cases. Neutrophils stimulated with 0.01 µg/ml PIA reduced zoospore viability significantly compared to PIA-unstimulated neutrophils for strain 1 and strain 3 (p < .05). Neutrophils stimulated with 0.01, 0.1, 1, and 10 µg/ml PIA exhibited significantly lower zoospore viability than PIA-unstimulated neutrophils for strain 2 (p < .05). IL-8 can be used as a biomarker for monitoring vascular pythiosis cases treated with the PIA vaccine. Also, anti-P. insidiosum activity of PIA-stimulated neutrophils was probably due to the disruption of cellular activity in zoospores rather than the mechanisms based on the formation of NETs.


Assuntos
Pitiose , Pythium , Animais , Humanos , Interleucina-8/farmacologia , Pythium/genética , Pitiose/terapia , Neutrófilos , Ensaio de Imunoadsorção Enzimática
20.
Plant Signal Behav ; 19(1): 2310963, 2024 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38314783

RESUMO

In higher plants, the regulatory roles of cAMP (cyclic adenosine 3',5'-monophosphate) signaling remain elusive until now. Cellular cAMP levels are generally much lower in higher plants than in animals and transiently elevated for triggering downstream signaling events. Moreover, plant adenylate cyclase (AC) activities are found in different moonlighting multifunctional proteins, which may pose additional complications in distinguishing a specific signaling role for cAMP. Here, we have developed rapeseed (Brassica napus L.) transgenic plants that overexpress an inducible plant-origin AC activity for generating high AC levels much like that in animal cells, which served the genetic model disturbing native cAMP signaling as a whole in plants. We found that overexpression of the soluble AC activity had significant impacts on the contents of indole-3-acetic acid (IAA) and stress phytohormones, i.e. jasmonic acid (JA), abscisic acid (ABA), and salicylic acid (SA) in the transgenic plants. Acute induction of the AC activity caused IAA overaccumulation, and upregulation of TAA1 and CYP83B1 in the IAA biosynthesis pathways, but also simultaneously the hyper-induction of PR4 and KIN2 expression indicating activation of JA and ABA signaling pathways. We observed typical overgrowth phenotypes related to IAA excess in the transgenic plants, including significant increases in plant height, internode length, width of leaf blade, petiole length, root length, and fresh shoot biomass, as well as the precocious seed development, as compared to wild-type plants. In addition, we identified a set of 1465 cAMP-responsive genes (CRGs), which are most significantly enriched in plant hormone signal transduction pathway, and function mainly in relevance to hormonal, abiotic and biotic stress responses, as well as growth and development. Collectively, our results support that cAMP elevation impacts phytohormone homeostasis and signaling, and modulates plant growth and development. We proposed that cAMP signaling may be critical in configuring the coordinated regulation of growth and development in higher plants.


Assuntos
Brassica napus , Ciclopentanos , Oxilipinas , Reguladores de Crescimento de Plantas , Animais , Reguladores de Crescimento de Plantas/metabolismo , Brassica napus/genética , Brassica napus/metabolismo , Ácido Abscísico/metabolismo , Proteínas de Plantas/metabolismo , Folhas de Planta/metabolismo , Plantas Geneticamente Modificadas/metabolismo
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