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1.
Curr Issues Mol Biol ; 46(2): 1308-1317, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38392201

RESUMO

We performed a large-scale flow cytometric analysis to determine whether M1 macrophage (M1Ø) and M2 macrophage (M2Ø) polarization in white adipose tissue (WAT) was altered immediately after exercise. Additionally, we comprehensively investigated the effects of obesity, exercise intensity, and recovery time on macrophage polarization in WAT. A single exercise bout of various intensities (ND, non-exercise control; -LIE, low-intensity exercise; -MIE, mid-intensity exercise; -HIE, high-intensity exercise) was performed by normal mice (ND) and obese mice (HFD). To confirm differences in M1Ø/M2Ø polarization in WAT based on the recovery time after a single exercise bout, WAT was acquired at 2 h, 24 h, and 48 h after exercise (total n = 168, 7 mice × 4 groups × 2 diets × 3 recovery time). The harvested WAT was immediately analyzed by flow cytometry, and macrophages were fluorescently labeled using F4/80, as well as M1Ø with CD11c and M2Øs with CD206. After a single bout of exercise, the M2Ø/M1Ø polarization ratio of WAT increases in both normal and obese mice, but differences vary depending on recovery time and intensity. Regardless of obesity, our findings showed that there could be a transient increase in M1Ø in WAT over a short recovery time (24 h) post-exercise (in ND-MIE, ND-HIE, and HFD-HIE). Furthermore, it was observed that the greater the exercise intensity in obese mice, the more effective the induction of M2Ø polarization immediately after exercise, as well as the maintenance of high M2Ø polarization, even after a prolonged recovery time.

2.
Biochem Biophys Res Commun ; 646: 36-43, 2023 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-36701893

RESUMO

Exercise can afford several benefits to combat mood disorders in both rodents and humans. Engagement in various physical activities upregulates levels of neurotrophic factors in several brain regions and improves mental health. However, the type of exercise that regulates mood and the underlying mechanisms in the brain remain elusive. Herein, we performed two distinct types of exercise and RNA sequencing analyses to investigate the effect of exercise on mood-related behaviors and explain the distinct patterns of gene expression. Specifically, resistance exercise exhibited reduced immobility time in the forced swim test when compared with both no exercise and treadmill exercise (in the aerobic training [AT] group). Interestingly, anxiety-like behaviors in the open field and nest-building tests were ameliorated in the AT group when compared with those in the control group; however, this was not observed in the RT group. To elucidate the mechanism underlying these different behavioral changes caused by distinct exercise types, we examined the shift in the gene expression pattern in the hippocampus, a brain region that plays a critical role in regulating mood. We discovered that 38 and 40 genes were altered in the AT and RT groups, respectively, compared with the control group. Both exercises regulated 16 common genes. Compared with the control group, mitogen-activated protein kinase (MAPK) was enriched in the AT group and phosphatidylinositol-3-kinase (PI3K)/AKT and neurotrophin signaling pathways were enriched in the RT group, as determined by bioinformatics pathway analysis. PCR results revealed that Cebpß expression was increased in AT group, and Dcx expression was upregulated in both groups. Our findings indicate that different exercise types may exert substantially distinct effects on mood-like behaviors. Accordingly, appropriate types of exercise can be undertaken based on the mood disorder to be regulated.


Assuntos
Encéfalo , Depressão , Humanos , Camundongos , Animais , Encéfalo/metabolismo , Depressão/metabolismo , Ansiedade/metabolismo , Natação , Transdução de Sinais/fisiologia , Hipocampo/metabolismo
3.
Pharm Res ; 40(12): 3059-3071, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37914841

RESUMO

PURPOSE: For successful delivery of a solid vaccine formulation into the skin using microneedles, the solubility of an adjuvant should be considered because the decrease in the dissolution rate by the addition of adjuvant decreases the delivery efficiency of the vaccine. METHODS: In this study, cholera toxin A subunit 1 (CTA1) was examined as an adjuvant to Hepatitis B vaccine (HBV) microneedles because of its good water solubility, improved safety, and positive effect as shown in intramuscular administration of a liquid vaccine. RESULTS: All solid formulations with CTA 1 dissolved in in vivo mouse skin within 30 min, and they were successfully delivered into the skin. In experiments with mice, the addition of CTA1 led to improved IgG immune response compared to the use of an aluminum hydroxide-based formulation and intramuscular administration of HBV. In addition, CTA1 induced CD8 + T cell response as much as in which the aluminum hydroxide-based formulation induced. CONCLUSIONS: CTA1 is an adjuvant that satisfies both the delivery efficiency and the immunological characteristics required for vaccine microneedles. CTA1 will be used as a potential adjuvant through vaccine microneedles.


Assuntos
Toxina da Cólera , Vacinas contra Hepatite B , Camundongos , Animais , Preparações Farmacêuticas , Hidróxido de Alumínio , Adjuvantes Imunológicos
4.
Mar Drugs ; 20(3)2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35323494

RESUMO

Six new ß-resorcylic acid derivatives (1-5 and 7) were isolated from a halophyte-associated fungus, Colletotrichum gloeosporioides JS0419, together with four previously reported ß-resorcylic acid lactones (RALs). The relative and absolute stereochemistry of 1 was completely established by a combination of spectroscopic data and chemical reactions. The structures of the isolated compounds were elucidated by analysis of HRMS and NMR data. Notably, compounds 1-3 had a ß-resorcylic acid harboring a long unesterified aliphatic side chain, whereas the long aliphatic chains were esterified to form macrolactones in 4-9. Among the isolated compounds, monocillin I and radicicol showed potent antifungal activities against Cryptococcus neoformans, comparable to clinically available antifungal agents and radicicol showed weak antifungal activity against Candida albicans. These findings provide insight into the chemical diversity of fungal RAL-type compounds and their pharmacological potential.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Chenopodiaceae/microbiologia , Colletotrichum/química , Cryptococcus neoformans/efeitos dos fármacos , Hidroxibenzoatos/farmacologia , Plantas Tolerantes a Sal/microbiologia , Antifúngicos/química , Antifúngicos/isolamento & purificação , Candida albicans/crescimento & desenvolvimento , Cryptococcus neoformans/crescimento & desenvolvimento , Hidroxibenzoatos/química , Hidroxibenzoatos/isolamento & purificação , Estrutura Molecular , Estereoisomerismo
5.
Lancet Oncol ; 22(11): e474-e487, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34735817

RESUMO

The increasing burden of cancer represents a substantial problem for Latin America and the Caribbean. Two Lancet Oncology Commissions in 2013 and 2015 highlighted potential interventions that could advance cancer care in the region by overcoming existing challenges. Areas requiring improvement included insufficient investment in cancer control, non-universal health coverage, fragmented health systems, inequitable concentration of cancer services, inadequate registries, delays in diagnosis or treatment initiation, and insufficient palliative services. Progress has been made in key areas but remains uneven across the region. An unforeseen challenge, the COVID-19 pandemic, strained all resources, and its negative effect on cancer control is expected to continue for years. In this Series paper, we summarise progress in several aspects of cancer control since 2015, and identify persistent barriers requiring commitment of additional resources to reduce the cancer burden in Latin America and the Caribbean.


Assuntos
COVID-19/epidemiologia , Neoplasias/prevenção & controle , SARS-CoV-2 , Região do Caribe/epidemiologia , Efeitos Psicossociais da Doença , Atenção à Saúde/economia , Detecção Precoce de Câncer , Acessibilidade aos Serviços de Saúde , Humanos , América Latina/epidemiologia , Oncologia/educação , Neoplasias/epidemiologia
6.
Am J Physiol Heart Circ Physiol ; 309(3): H425-33, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26024684

RESUMO

The concept of enhancing structural integrity of mitochondria has emerged as a novel therapeutic option for cardiovascular disease. Flow-induced increase in laminar shear stress is a potent physiological stimulant associated with exercise, which exerts atheroprotective effects in the vasculature. However, the effect of laminar shear stress on mitochondrial remodeling within the vascular endothelium and its related functional consequences remain largely unknown. Using in vitro and in vivo complementary studies, here, we report that aerobic exercise alleviates the release of endothelial microparticles in prehypertensive individuals and that these salutary effects are, in part, mediated by shear stress-induced mitochondrial biogenesis. Circulating levels of total (CD31(+)/CD42a(-)) and activated (CD62E(+)) microparticles released by endothelial cells were significantly decreased (∼40% for both) after a 6-mo supervised aerobic exercise training program in individuals with prehypertension. In cultured human endothelial cells, laminar shear stress reduced the release of endothelial microparticles, which was accompanied by an increase in mitochondrial biogenesis through a sirtuin 1 (SIRT1)-dependent mechanism. Resveratrol, a SIRT1 activator, treatment showed similar effects. SIRT1 knockdown using small-interfering RNA completely abolished the protective effect of shear stress. Disruption of mitochondrial integrity by either antimycin A or peroxisome proliferator-activated receptor-γ coactivator-1α small-interfering RNA significantly increased the number of total, and activated, released endothelial microparticles, and shear stress restored these back to basal levels. Collectively, these data demonstrate a critical role of endothelial mitochondrial integrity in preserving endothelial homeostasis. Moreover, prolonged laminar shear stress, which is systemically elevated during aerobic exercise in the vessel wall, mitigates endothelial dysfunction by promoting mitochondrial biogenesis.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Exercício Físico , Células Endoteliais da Veia Umbilical Humana/metabolismo , Renovação Mitocondrial , Pré-Hipertensão/metabolismo , Selectina E/genética , Selectina E/metabolismo , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Pré-Hipertensão/sangue , Fluxo Sanguíneo Regional , Resveratrol , Sirtuína 1/genética , Sirtuína 1/metabolismo , Estilbenos/farmacologia , Estresse Mecânico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
7.
Ethn Dis ; 25(4): 413-8, 2015 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-26674844

RESUMO

BACKGROUND: African Americans have a predisposition to heightened systemic inflammation and a high prevalence of hypertension. OBJECTIVE: The purpose of this study was to evaluate the influence of interleukin-10 (IL-10) and laminar shear stress (LSS) on African American endothelial cells by measuring total endothelial nitric oxide synthase (eNOS) protein expression and its phosphorylated form (p-eNOS) at Serine 1177, and nitric oxide (NO) levels, in response to IL-10 incubation and high physiological levels of LSS, used as an in vitro mimetic for aerobic exercise training (AEXT). DESIGN: Human umbilical vein endothelial cells (HUVEC) from an African American donor were cultured. The experimental conditions included Static, Static with IL-10 Incubation, LSS at 20 dynes/cm², and LSS at 20 dynes/cm² with IL-10 Incubation. Western blotting was used to measure eNOS and p-eNOS protein expression in the cells. A modified Griess assay was used to measure NO metabolites in the cell culture media. RESULTS: There were significant increases in p-eNOS, eNOS, and NO in the LSS at 20 dynes/cm² and LSS at 20 dynes/cm² with IL-10 Incubation experimental conditions when compared to the Static experimental condition. There were no other statistically significant differences demonstrating that IL-10 did not have an additive effect on eNOS activity in our study. CONCLUSION: The significant increases in p-eNOS, eNOS, and NO as a result of LSS in African American HUVECs suggest that AEXT may be a viable, nonpharmacologic method to improve vascular inflammation status and vasodilation, and thereby contribute to hypertension reduction in the African American population.


Assuntos
Negro ou Afro-Americano , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Interleucina-10/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Estresse Mecânico , Técnicas de Cultura de Células , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Resistência ao Cisalhamento
8.
J Microbiol Biotechnol ; 34(7): 1-11, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38881183

RESUMO

The rise of Candida auris, a multidrug-resistant fungal pathogen, across more than 40 countries, has signaled an alarming threat to global health due to its significant resistance to existing antifungal therapies. Characterized by its rapid spread and robust drug resistance, C. auris presents a critical challenge in managing infections, particularly in healthcare settings. With research on its biological traits and genetic basis of virulence and resistance still in the early stages, there is a pressing need for a concerted effort to understand and counteract this pathogen. This review synthesizes current knowledge on the epidemiology, biology, genetic manipulation, pathogenicity, diagnostics, and resistance mechanisms of C. auris, and discusses future directions in research and therapeutic development. By exploring the complexities surrounding C. auris, we aim to underscore the importance of advancing research to devise effective control and treatment strategies.

9.
Clin Res Hepatol Gastroenterol ; 48(1): 102263, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38061546

RESUMO

BACKGROUND: The involvement of monoacylglycerol O-acyltransferase 1 (MOGAT1) in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) has been recognized. While exercise is recommended for the improvement of obesity and MASLD, the impact of exercise intensity remains unclear. This study aimed to examine the influence of exercise intensity on MOGAT1 expression in high-fat diet (HFD)-induced obese mice with MASLD. METHOD: Male C57BL/6 mice aged 6 weeks were subjected to either a regular or HFD with 60 % fat content for 8 weeks. The mice were categorized into 5 groups based on their diet and exercise intensity: normal diet group (ND), HFD group, low-intensity exercise with HFD group (HFD+LIE), moderate-intensity exercise with HFD group (HFD+MIE), and high-intensity exercise (HIE) with HFD group (HFD+HIE). The duration of running was adjusted to ensure uniform exercise load across groups (total distance = 900 m): HFD+LIE at 12 m/min for 75 min, HFD+MIE at 15 m/min for 60 min, and HFD+HIE at 18 m/min for 50 min. RESULTS: Lipid droplet size and MASLD activity score were significantly lower in the HFD+HIE group compared to other exercise-intensity groups (p < 0.05). Among the 3 intensity exercise groups, the lowest MOGAT1 protein expression was found in the HFD+HIE group (p < 0.05). CONCLUSION: This study reveals that high-intensity exercise has the potential to mitigate MASLD development, partly attributed to the downregulation of MOGAT1 expression.


Assuntos
Fígado Gorduroso , Monoglicerídeos , Animais , Masculino , Camundongos , Aciltransferases , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL
10.
Adv Sci (Weinh) ; : e2402872, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38946604

RESUMO

In an era marked by increasing environmental challenges affecting human well-being, traditional acoustic materials struggle to effectively handle the diverse and multi-frequency nature of harmful environmental noises. This has spurred a demand for innovative acoustic metamaterial solutions by utilizing sustainable design strategies. This research introduces tunable Schwarz metamaterial capable of transforming into a soft meta-foam to solve the complex problems of varying environmental noises. This study primarily focuses on adjusting single to multiple sound-blocking bandgaps mechanism using a multi-layered approach, incorporating the Schwarz P-type triply periodic minimal surface (TPMS) and its elective soft foam counterpart, known as tunable Schwarz meta-foams (TSMF-x). The tunable design parameters of the unit cell, multi-layered TPMS, and soft programmable TSMF-lichen version are comprehensively explored including a fire-safety test. The results demonstrate these enhanced flame retardant meta-foam families have the potential to be used for mid-to-high-frequency environmental noises in industrial equipment and smart homes for sustainable architecture and environmental health applications.

11.
Adv Mater ; 36(26): e2312340, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38578242

RESUMO

The advancement of active electrode materials is essential to meet the demand for multifaceted soft robotic interactions. In this study, a new type of porous carbonaceous sphere (PCS) for a multimodal soft actuator capable of both magnetoactive and electro-ionic responses is reported. The PCS, derived from the simultaneous oxidative and reductive breakdown of specially designed cobalt-based metal-organic frameworks (Co-MOFs) with varying metal-to-ligand ratios, exhibits a high specific surface area of 529 m2 g-1 and a saturated magnetization of 142.7 Am2 kg-1. The size of the PCS can be controlled through the Ostwald ripening mechanism, while the porous structure can be regulated by adjusting the metal-to-ligand mol ratio. Its exceptional compatibility with poly(3,4-ethylene-dioxythiophene)-poly(styrenesulfonate) enables the creation of uniform electrode, crucial for producing soft actuators that work in both magnetic and electrical fields. Operated at an ultralow voltage of 1 V, the PCS-based actuator generates a blocking force of 47.5 mN and exhibits significant bending deflection even at an oscillation frequency of 10 Hz. Employing this simultaneous multimodal actuation ensures the dynamic and complex motions of a balancing bird robot and a dynamic eagle robot. This advancement marks a significant step toward the realization of more dynamic and versatile soft robotic systems.

12.
Adv Sci (Weinh) ; 11(14): e2307656, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38286669

RESUMO

Considerable research has been conducted on the application of functional nano-fillers to enhance the power generation capabilities of triboelectric nanogenerators (TENGs). However, these additives often exhibit a decrease in output power at higher concentration. Here, a Janus cobalt metal-organic framework-SEBS (JCMS) membrane is reported as a dual-purpose dielectric layer capable of efficiently capturing and blocking charges for high-performance TENGs. The JCMS is produced asymmetrically through gravitational sedimentation, employing spherical CoMOFs within a diluted SEBS solution. Beyond its dual dielectric characteristics, the JCMS showcases exceptional mechanical durability, displaying notable stretchability of up to 475% and remarkable resilience when subjected to diverse mechanical pressures. Consequently, the JCMS-TENG produces a maximum peak-to-peak voltage of 936 V, a current of 42.8 µA, and a power density of 10.89 W m- 2 when exposed to an external force of 10 N at a 5 Hz frequency. This investigation highlights the potential of JCMS-TENGs with unique structures, known for their exceptional energy harvesting capabilities, mechanical strength, and flexibility. Additionally, the promising prospects of easily produced asymmetric structures is emphasized with bifunctionalities for developing efficient and flexible MOFs-based TENGs. These advancements are well-suited for self-powered wearables, rehabilitation devices, and energy harvesters.

13.
Am J Physiol Regul Integr Comp Physiol ; 305(8): R927-38, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23904108

RESUMO

Mitochondria are dynamic organelles forming a tubular network that is continuously fusing and dividing to control their morphology and functions. Recent literature has shed new light on a potential link between the dynamic behavior of mitochondria and muscle development. In this study, we investigate the role of mitochondrial fission factor dynamin-related protein 1 (Drp1) in myogenic differentiation. We found that differentiation of C2C12 myoblasts induced by serum starvation was accompanied by a gradual increase in Drp1 protein expression (to ∼350% up to 3 days) and a fast reduction of Drp1 phosphorylation at Ser-637 (to ∼30%) resulting in translocation of Drp1 protein from the cytosol to mitochondria. During differentiation, treatment of myoblasts with mitochondrial division inhibitor (mdivi-1), a specific inhibitor of Drp1 GTPase activity, caused extensive formation of elongated mitochondria, which coincided with increased apoptosis evidenced by both enhanced caspase-3 activity and increased number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells. Furthermore, the mdivi-1-treated myotubes (day 3 in differentiation media) showed a reduction in mitochondrial DNA content, mitochondrial mass, and membrane potential in a dose-dependent manner indicating defects in mitochondrial biogenesis during myogenic differentiation. Most interestingly, mdivi-1 treatment significantly suppressed myotube formation in both C2C12 cells and primary myoblasts. Likewise, stable overexpression of a dominant negative mutant Drp1 (K38A) dramatically reduced myogenic differentiation. These data suggest that Drp-1-dependent mitochondrial division is a necessary step for successful myogenic differentiation, and perturbation of mitochondrial dynamics hinders normal mitochondrial adaptations during muscle development. Therefore, in the present study, we report a novel physiological role of mitochondrial dynamics in myogenic differentiation.


Assuntos
Proteínas Quinases Associadas com Morte Celular/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/fisiologia , Desenvolvimento Muscular/fisiologia , Mioblastos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Caspase 3/metabolismo , Linhagem Celular , Proteínas Quinases Associadas com Morte Celular/genética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Desenvolvimento Muscular/efeitos dos fármacos , Mioblastos/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Quinazolinonas/farmacologia
14.
Exp Dermatol ; 22(5): 369-71, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23614749

RESUMO

Despite the increasing use of topical tacrolimus, there is little information about its effect on skin wound healing. To determine effects on acute cutaneous wound healing, two full-thickness skin wounds were imparted on the backs of 45 hairless mice, which were then divided into vehicle-, topical tacrolimus- and topical steroid-treated group. Each drug was topically applied once daily. The wound area was assessed by using dermoscopic images every two days after wounding. At 3, 7 and 11 days after wounding, 10 wounds in each group were collected for semi-quantitative analysis of histological features including re-epithelialization, polymorphonuclear leucocytes, fibroblasts and collagen. We also checked the mRNA expression levels of EGF, TGF-ß, TNF-α and IL-1α. While topical application of clobetasol propionate was found to delay re-epithelialization and infiltration of polymorphonuclear leucocyte, topical treatment with tacrolimus showed patterns similar to that of the vehicle. In the tacrolimus-treated group, mRNA expression levels of IL-1α and TGF-ß were slightly decreased, while the others were similar with the vehicle-treated group. Unlike steroid, topical tacrolimus, therefore, did not disturb the wound healing process in a murine skin wound model.


Assuntos
Imunossupressores/farmacologia , Pele/lesões , Tacrolimo/farmacologia , Cicatrização/efeitos dos fármacos , Doença Aguda , Administração Tópica , Animais , Camundongos , Camundongos Pelados , Pele/efeitos dos fármacos , Esteroides/farmacologia
16.
Antioxidants (Basel) ; 12(9)2023 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-37760005

RESUMO

Candida auris, a multidrug-resistant fungal pathogen, significantly threatens global public health. Recent studies have identified melanin production, a key virulence factor in many pathogenic fungi that protects against external threats like reactive oxygen species, in C. auris. However, the melanin regulation mechanism remains elusive. This study explores the role of the Ras/cAMP/PKA signaling pathway in C. auris melanization. It reveals that the catalytic subunits Tpk1 and Tpk2 of protein kinase A (PKA) are essential, whereas Ras1, Gpr1, Gpa2, and Cyr1 are not. Under melanin-promoting conditions, the tpk1Δ tpk2Δ strain formed melanin granules in the supernatant akin to the wild-type strain but failed to adhere them properly to the cell wall. This discrepancy is likely due to a decreased expression of chitin-synthesis-related genes. Our findings also show that Tpk1 primarily drives melanization, with Tpk2 having a lesser impact. To corroborate this, we found that C. auris must deploy Tpk1-dependent melanin deposition as a defensive mechanism against antioxidant exposure. Moreover, we confirmed that deletion mutants of multicopper oxidase and ferroxidase genes, previously assumed to influence C. auris melanization, do not directly contribute to the process. Overall, this study sheds light on the role of PKA in C. auris melanization and enhances our understanding of the pathogenicity mechanisms of this emerging fungal pathogen.

17.
Microbiol Spectr ; : e0215223, 2023 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-37671881

RESUMO

The emergence of multidrug-resistant fungal pathogens is a significant concern for global public health. Candida auris poses a considerable threat as a multidrug-resistant fungal pathogen. Our recent study revealed that the adenylyl cyclase Cyr1 and protein kinase A (PKA) pathways play distinct and redundant roles in drug resistance and pathogenicity of C. auris. However, the upstream and negative feedback regulatory mechanisms of C. auris are not yet fully understood. In this study, we discovered that the small GTPase Ras1, along with its nucleotide exchange factor Cdc25 and GTPase-activating protein Ira2, plays a major role in regulating cAMP/PKA-dependent traits, while G-protein-coupled receptor Gpr1 and heterotrimeric G-protein α subunit Gpa2 play a minor role. Pde2 plays a major role in negative feedback regulation of the cAMP/PKA pathway, while Pde1 plays a minor role. Hyperactivation of the Ras/cAMP/PKA pathway by deleting PDE2 or BCY1 renders C. auris cells thermosensitive and susceptible to nutrient deficiency, which leads to attenuated virulence. Our study demonstrates the distinct contributions of hyperactivation of the Ras/cAMP/PKA signaling pathway to C. auris pathogenesis and suggests potential therapeutic targets for C. auris-mediated candidiasis. IMPORTANCE Candida auris is a major concern as a multidrug-resistant fungal pathogen. While our previous studies highlighted the crucial roles of the cAMP/protein kinase A (PKA) pathway in regulating drug resistance, stress responses, morphogenesis, ploidy change, biofilm formation, and pathogenicity in this pathogen, their regulatory mechanism remains unclear. In our study, we provided evidence that the cAMP/PKA signaling pathway in C. auris is primarily governed by the small GTPase RAS rather than a G-protein-coupled receptor. Additionally, we discovered that the negative feedback regulation of cAMP, controlled by phosphodiesterases, is vital for C. auris virulence by promoting resistance to high temperatures and nutrient deficiencies. These findings underscore the diverse pathobiological significance of the Ras/cAMP/PKA signaling pathway in C. auris, shedding light on potential therapeutic targets and strategies for combating this multidrug-resistant fungal pathogen.

18.
Front Cell Infect Microbiol ; 13: 1257897, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37780854

RESUMO

The surge of multidrug-resistant fungal pathogens, especially Candida auris, poses significant threats to global public health. Candida auris exhibits resistance to multiple antifungal drugs, leading to major outbreaks and a high mortality rate. With an urgent call for innovative therapeutic strategies, this study focused on the regulation and pathobiological significance of secreted aspartyl proteinases (SAPs) in C. auris, as these enzymes play pivotal roles in the virulence of some fungal species. We delved into the Ras/cAMP/PKA signaling pathway's influence on SAP activity in C. auris. Our findings underscored that the Ras/cAMP/PKA pathway significantly modulates SAP activity, with PKA catalytic subunits, Tpk1 and Tpk2, playing a key role. We identified a divergence in the SAPs of C. auris compared to Candida albicans, emphasizing the variation between Candida species. Among seven identified secreted aspartyl proteases in C. auris (Sapa1 to Sapa7), Sapa3 emerged as the primary SAP in the pathogen. Deletion of Sapa3 led to a significant decline in SAP activity. Furthermore, we have established the involvement of Sapa3 in the biofilm formation of C. auris. Notably, Sapa3 was primarily regulated by Tpk1 and Tpk2. Deletion of SAPA3 significantly reduced C. auris virulence, underscoring its pivotal role in C. auris pathogenicity. The outcomes of this study provide valuable insights into potential therapeutic targets, laying the groundwork for future interventions against C. auris infection.


Assuntos
Ácido Aspártico Proteases , Candida auris , Virulência , Ácido Aspártico Proteases/genética , Ácido Aspártico Proteases/metabolismo , Candida/genética , Candida albicans , Antifúngicos/farmacologia , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo
19.
J Physiol Biochem ; 79(1): 71-81, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36127549

RESUMO

Aquaporins (AQPs) are water channels in the cell membrane that regulate osmosis in response to rapid changes in intracellular and extracellular fluid concentration caused by extrinsic factors. While there are so many studies on the association of AQPs with muscular atrophy, sarcopenia, and Duchenne muscular dystrophy (DMD), the expression of AQP has not been verified in naturally aging mice or humans. Notably, due to the characteristics of AQPs, the difference in function cannot be evaluated without extrinsic factors such as acute water restriction. The purpose of this study was to investigate the changes in AQPs expression and function due to natural aging under acute water restriction conditions in aging mice. The expression of AQP4 was shown to decrease with aging similar to previous studies. However, for the first time, this study results confirmed that AQP1 expression increased in aging mice. In addition, the expression of Aqp1 decreased in the acute water restricted group compared to the control group after acute water restriction in aging mice. These results suggest that although the expression of AQP1 increases with aging, its function is reduced. We also confirmed that overexpression of Aqp1 can inhibit myotube differentiation and that knockdown can promote myotube differentiation through in vitro experiments. In conclusion, based on our results, we suggest that the AQP1 is an important factor in sarcopenia caused by natural aging accompanied by chronic dehydration.


Assuntos
Aquaporinas , Sarcopenia , Animais , Humanos , Camundongos , Aquaporinas/metabolismo , Membrana Celular/metabolismo , Sarcopenia/metabolismo , Água
20.
Adv Mater ; 35(47): e2304442, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37724828

RESUMO

Wearable haptic interfaces prioritize user comfort, but also value the ability to provide diverse feedback patterns for immersive interactions with the virtual or augmented reality. Here, to provide both comfort and diverse tactile feedback, an easy-to-wear and multimodal wearable haptic auxetic fabric (WHAF) is prepared by knotting shape-memory alloy wires into an auxetic-structured fabric. This unique meta-design allows the WHAF to completely expand and contract in 3D, providing superior size-fitting and shape-fitting capabilities. Additionally, a microscale thin layer of Parylene is coated on the surface to create electrically separated zones within the WHAF, featuring zone-specified actuation for conveying diverse spatiotemporal information to users with using the WHAF alone. Depending on the body part it is worn on, the WHAF conveys either cutaneous or kinesthetic feedback, thus, working as a multimodal wearable haptic interface. As a result, when worn on the forearm, the WHAF intuitively provides spatiotemporal information to users during hands-free navigation and teleoperation in virtual reality, and when worn on the elbow, the WHAF guides users to reach the desired elbow flexion, like a personal exercise advisor.


Assuntos
Percepção do Tato , Dispositivos Eletrônicos Vestíveis , Interface Háptica , Retroalimentação , Tecnologia Háptica , Desenho de Equipamento , Interface Usuário-Computador
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