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1.
Neuropharmacology ; : 110156, 2024 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-39326783

RESUMO

Major depressive disorder (MDD) is a debilitating illness with a high global burden. While Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, offers rapid-acting antidepressant effects, its mechanism remains incompletely understood. Recent research suggests that dysregulation of mRNA translation via the Eukaryotic initiation factor 4E (eIF4E) pathway might contribute to depression pathophysiology. This study investigates whether Ketamine modulates eIF4E signaling in the hippocampus during its antidepressant action. Herein, adult male mice were exposed to Corticosterone, a well-established model for anxiety and depression, followed by behavioral testing and biochemical analysis. Corticosterone induced depression-like symptoms and disrupted synaptic function, including reduced TrkB/BDNF and eIF4E/MNK1/p-eIF2α/ubiquitin signaling. Ketamine treatment reversed these deficits. Notably, the eIF4E/MNK1 signaling inhibitor, eFT508, blocked Ketamine's antidepressant effect, leading to a return of depression-like phenotype and impaired synaptic signaling. Importantly, these effects were reversed by 7,8-DHF, a BDNF/TrkB signaling agonist. Mice treated with Corticosterone, Ketamine, and eFT508 and subsequently exposed to 7,8-DHF displayed normalized depression-like behaviors and restored synaptic signaling, including increased eIF4E phosphorylation and MNK1 expression. Besides, 7,8-DHF treatment enhanced p-eIF2α levels compared to the eFT508-treated group. These findings suggest that Ketamine exerts its antidepressant action through the regulation of the eIF4E/BDNF signaling pathway in the hippocampus. This study provides novel insights into the molecular mechanisms underlying Ketamine's therapeutic effects and highlights the potential of targeting this pathway for future MDD treatment strategies.

2.
Pestic Biochem Physiol ; 204: 106091, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39277418

RESUMO

The vegetable leafminer (Liriomyza sativae) is a devastating invasive pest of many vegetable crops and horticultural plants worldwide, causing serious economic loss. Conventional control strategy against this pest mainly relies on the synthetic chemical pesticides, but widespread use of insecticides easily causes insecticide resistance development and is harmful to beneficial organisms and environment. In this context, a more environmentally friendly pest management strategy based on RNA interference (RNAi) has emerged as a powerful tool to control of insect pests. Here we report a successful oral RNAi in L. sativae after feeding on pak choi (Brassica rapa ssp. chinensis) that transiently express hairpin RNAs targeting vital genes in this pest. First, potentially lethal genes are identified by searching an L. sativae transcriptome for orthologs of the widely used V-ATPase A and actin genes, then expression levels are assessed during different life stages and in different adult tissues. Interestingly, the highest expression levels for V-ATPase A are observed in the adult heads (males and females) and for actin in the abdomens of adult females. We also assessed expression patterns of the target hairpin RNAs in pak choi leaves and found that they reach peak levels 72 h post agroinfiltration. RNAi-mediated knockdown of each target was then assessed by letting adult L. sativae feed on agroinfiltrated pak choi leaves. Relative transcript levels of each target gene exhibit significant reductions over the feeding time, and adversely affect survival of adult L. sativae at 24 h post infestation in genetically unmodified pak choi plants. These results demonstrate that the agroinfiltration-mediated RNAi system has potential for advancing innovative environmentally safe pest management strategies for the control of leaf-mining species.


Assuntos
Brassica rapa , Folhas de Planta , Interferência de RNA , Folhas de Planta/parasitologia , Brassica rapa/genética , Brassica rapa/parasitologia , Animais , RNA Interferente Pequeno/genética , Feminino , Masculino
3.
J Neurosci ; 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39256048

RESUMO

Large-scale genome-wide association studies (GWAS) have associated intronic variants in PDE4B, encoding cAMP-specific phosphodiesterase-4B (PDE4B), with increased risk for post-traumatic stress disorder (PTSD), as well as schizophrenia and substance use disorders that are often comorbid with it. However, the pathophysiological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effects of PDE4B variation on phenotypes with translational relevance to psychiatric disorders, we focused on PDE4B missense variant M220T, which is present in the human genome as rare coding variant rs775201287. When expressed in HEK-293 cells, PDE4B1-M220T exhibited an attenuated response to a forskolin-elicited increase in the intracellular cAMP concentration. In behavioral tests, homozygous Pde4b M220T male mice with a C57BL/6JJcl background exhibited increased reactivity to novel environments, startle hyperreactivity, prepulse inhibition deficits, altered cued fear conditioning, and enhanced spatial memory, accompanied by an increase in cAMP signaling pathway-regulated expression of BDNF in the hippocampus. In response to a traumatic event (ten tone-shock pairings), neuronal activity was decreased in the cortex but enhanced in the amygdala and hippocampus of Pde4b M220T mice. At 24 hours post-trauma, Pde4b M220T mice exhibited increased startle hyperreactivity and decreased plasma corticosterone levels, similar to phenotypes exhibited by PTSD patients. Trauma-exposed Pde4b M220T mice also exhibited a slower decay in freezing at 15 days and 30 days post-trauma, demonstrating enhanced persistence of traumatic memories, similar to that exhibited by PTSD patients. These findings provide substantive mouse model evidence linking PDE4B variation to PTSD-relevant phenotypes, and thus highlight how genetic variation of PDE4B may contribute to PTSD risk.Significance Statement Human genetic studies have associated variants in the PDE4B gene, encoding the phosphodiesterase-4B (PDE4B) enzyme, with increased risk for post-traumatic stress disorder (PTSD) and other mental disorders that often occur with it. However, the underlying biological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effect of PDE4B variation on behaviors relevant to mental disorders, we studied male Pde4b M220T mice that carry a PDE4B variant (M220T), which is also present in humans. Pde4b M220T mice exhibited increased PTSD-like behavior in response to a traumatic event, as well as abnormal neuronal activity in the brain. Our findings provide substantive evidence linking PDE4B variation to PTSD-relevant behaviors, and thus highlight how genetic variation of PDE4B may contribute to PTSD risk.

4.
Cell Commun Signal ; 22(1): 427, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39223674

RESUMO

BACKGROUND: Depression is often linked to inflammation in the brain. Researchers have been exploring ways to reduce this inflammation to improve depression symptoms. One potential target is a protein called RIPK1, which is known to contribute to brain inflammation. However, it's unclear how RIPK1 influences depression. Our study aims to determine whether RIPK1 inhibition could alleviate neuroinflammation-associated depression and elucidate its underlying mechanisms. METHODS: To investigate our research objectives, we established a neuroinflammation mouse model by administering LPS. Behavioral and biochemical assessments were conducted on these mice. The findings were subsequently validated through in vitro experiments. RESULTS: Using LPS-induced depression models, we investigated RIPK1's role, observing depressive-like behaviors accompanied by elevated cytokines, IBA-1, GFAP levels, and increased inflammatory signaling molecules and NO/H2O2. Remarkably, Necrostatin (Nec-1 S), a RIPK1 inhibitor, mitigated these changes. We further found altered expression and phosphorylation of eIF4E, PI3K/AKT/mTOR, and synaptic proteins in hippocampal tissues, BV2, and N2a cells post-LPS treatment, which Nec-1 S also ameliorated. Importantly, eIF4E inhibition reversed some of the beneficial effects of Nec-1 S, suggesting a complex interaction between RIPK1 and eIF4E in LPS-induced neuroinflammation. Moreover, citronellol, a RIPK1 agonist, significantly altered eIF4E phosphorylation, indicating RIPK1's potential upstream regulatory role in eIF4E and its contribution to neuroinflammation-associated depression. CONCLUSION: These findings propose RIPK1 as a pivotal mediator in regulating neuroinflammation and neural plasticity, highlighting its significance as a potential therapeutic target for depression.


Assuntos
Depressão , Modelos Animais de Doenças , Lipopolissacarídeos , Doenças Neuroinflamatórias , Proteína Serina-Treonina Quinases de Interação com Receptores , Animais , Masculino , Camundongos , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
5.
Ultrasonics ; 144: 107449, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39217855

RESUMO

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is marked by the deterioration of both cortical and spinal cord motor neurons. Despite the underlying causes of the disease remain elusive, there has been a growing attention on the well-being of cortical motor neurons in recent times. Focused ultrasound combined with microbubbles (FUS/MB) for opening the blood-brain barrier (BBB) provides a means for drug delivery to specific brain regions, holding significant promise for the treatment of neurological disorders. OBJECTIVES: We aim to explore the outcomes of FUS/MB-mediated delivery of arctiin (Arc), a natural compound with anti-inflammatory activities, to the cerebral motor cortex area by using a transgenic ALS mouse model. METHODS: The ALS mouse model with the SOD1G93A mutation was used and subjected to daily Arc administration with FUS/MB treatment twice a week. After six-week treatments, the motor performance was assessed by grip strength, wire hanging, and climbing-pole tests. Mouse brains, spinal cords and gastrocnemius muscle were harvested for histological staining. RESULTS: Compared with the mice given Arc administration only, the combined treatments of FUS/MB with Arc induced further mitigation of the motor function decline, accompanied by improved health of the gastrocnemius muscle. Furthermore, notable neuroprotective effect was evidenced by the amelioration of motor neuron failure in the cortex and lumbar spinal cord. CONCLUSION: These preliminary results indicated that the combined treatment of FUS/MB and arctiin exerted a potentially beneficial effect on neuromuscular function in the ALS disease.


Assuntos
Esclerose Lateral Amiotrófica , Modelos Animais de Doenças , Camundongos Transgênicos , Córtex Motor , Animais , Camundongos , Córtex Motor/efeitos dos fármacos , Córtex Motor/fisiopatologia , Glucosídeos/farmacologia , Glucosídeos/administração & dosagem , Microbolhas , Sistemas de Liberação de Medicamentos , Terapia por Ultrassom/métodos , Superóxido Dismutase-1/genética , Furanos/farmacologia , Furanos/administração & dosagem , Masculino , Mutação
6.
Int Immunopharmacol ; 141: 113022, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39213869

RESUMO

Cholinergic circuit defects have been linked to various neurological abnormalities, yet the precise mechanisms underlying the impact of cholinergic signaling on cognitive functions, particularly in the context of neuroinflammation-associated, remain poorly understood. Similarly, while the dopamine receptor (D2R) has been implicated in the pausing of cholinergic interneurons (CIN), its relationship with behavior remains inadequately elucidated. In this study, we aimed to investigate whether D2R plays a role in the regulation of fear and memory in the Hsp60 knockout condition, given the non-canonical involvement of Hsp60 in inflammation. Using a CRE-floxed system, we selectively generated cholinergic neurons specific to Hsp60 knockout mice and subjected them to memory tests. Our results revealed a significant increase in freezing levels during recall and contextual tests in Hsp60-deprived mice. We also observed dysregulation of neurotransmitters and D2R in the hippocampus of Hsp60 knockout mice, along with enhanced impairments in cytokine levels and synaptic protein dysregulations. These changes were accompanied by alterations in PI3K/eIF4E/Jak/ERK/CREB signaling pathways. Notably, D2R agonism via Quinpirole led to a decrease in freezing levels during recall and contextual tests, alongside an increase in IBA-1 expression and improvements in inflammatory response-linked signaling pathways, including JAK/STAT/P38/JNK impairments. Given that these pathways are well-known downstream signaling cascades of D2R, our findings suggest that D2R signaling may contribute to the neuroinflammation induced by Hsp60 deprivation, potentially exacerbating memory impairments.


Assuntos
Chaperonina 60 , Neurônios Colinérgicos , Memória , Camundongos Knockout , Doenças Neuroinflamatórias , Animais , Neurônios Colinérgicos/metabolismo , Doenças Neuroinflamatórias/imunologia , Chaperonina 60/metabolismo , Chaperonina 60/genética , Camundongos , Hipocampo/metabolismo , Transdução de Sinais , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/genética , Masculino , Medo , Camundongos Endogâmicos C57BL , Citocinas/metabolismo
7.
Sci Total Environ ; 950: 175292, 2024 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-39111425

RESUMO

Thermal remediation is an effective technology for organic contaminant remediation. However, the application of thermal remediation may have negative effects on soil properties and ecological functions, which requires further investigation. Based on a pilot test of electrical resistance heating remediation (ERH), soil samples were collected at different locations after heating for 116 days. Most soil physicochemical properties were less affected by the heating temperature difference. Application of high temperature increased microbial abundance but inhibited alpha diversity of the bacterial community. More significant changes in microbial communities were observed at temperatures above 60 °C. The genera mainly affected by heating temperature included Flavobacteria, Brockia, and S085, while the increase in temperature also inhibited the abundance of nitrochlorobenzene functional genes. At 140 days after the end of the pilot test, the bacterial community affected by thermal remediation could recover effectively, and the recovery of the bacterial community was not affected by temperature difference during the heating period. This study provides valuable field evidence of the long term impact of soil ERH treatment on soil properties and microbial communities, and provides further references for optimization of remediation performance with coupled technologies.


Assuntos
Bactérias , Microbiota , Microbiologia do Solo , Solo , Solo/química , Poluentes do Solo/análise , Impedância Elétrica , Calefação , Recuperação e Remediação Ambiental/métodos , Temperatura Alta
8.
Clinics (Sao Paulo) ; 79: 100435, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38996724

RESUMO

OBJECTIVE: This study mainly explores (2R,6R; 2S,6S)-HNK and its compounds whether there are antidepressant effects. METHODS: Four HNK compounds were obtained from 2-(Chlorophenyl) Cyclopentylmethanone. Forced swimming test, locomotor sensitization test, and conditioned location preference test were used to screen the antidepressant activity of the synthesized target compounds. RESULTS: In the case of 10 mg HNK treatment, compared with saline, the immobile time of mice in the HNK group, I5 group and I6 group at 1 h and 7 days had statistical significance. In the case of 10 mg HNK treatment, compared with saline, the immobile time of compound C and D groups in the glass cylinder area was significantly different. In the locomotor sensitization test, the movement distance of compound C and D groups on day 15 and day 7 mice increased significantly compared with the first day. In the conditioned place preference experiment, compound C and compound D induced conditioned place preference in mice compared with the Veh group. CONCLUSION: The results of the forced swimming test, locomotor sensitization test, and conditioned location preference test showed that compounds C and D may have certain anti-depressant activity. However, HNK exerts a rapid and significant antidepressant effect within 1 week, but the duration is short.


Assuntos
Antidepressivos , Ketamina , Atividade Motora , Natação , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Camundongos , Masculino , Ketamina/farmacologia , Ketamina/análogos & derivados , Atividade Motora/efeitos dos fármacos , Fatores de Tempo , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Reprodutibilidade dos Testes
9.
CNS Neurosci Ther ; 30(6): e14692, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38872258

RESUMO

AIM: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive death of upper and lower motor neurons, leading to generalized muscle atrophy, paralysis, and even death. Mitochondrial damage and neuroinflammation play key roles in the pathogenesis of ALS. In the present study, the efficacy of A-1, a derivative of arctigenin with AMP-activated protein kinase (AMPK) and silent information regulator 1 (SIRT1) activation for ALS, was investigated. METHODS: A-1 at 33.3 mg/kg was administrated in SOD1G93A transgenic mice orally from the 13th week for a 6-week treatment period. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes, and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl, and immunohistochemistry staining. Protein expression was detected with proteomics analysis, Western blotting, and ELISA. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit. RESULTS: A-1 administration in SOD1G93A mice enhanced mobility, decreased skeletal muscle atrophy and fibrosis, mitigated loss of spinal motor neurons, and reduced glial activation. Additionally, A-1 treatment improved mitochondrial function, evidenced by elevated ATP levels and increased expression of key mitochondrial-related proteins. The A-1 treatment group showed decreased levels of IL-1ß, pIκBα/IκBα, and pNF-κB/NF-κB. CONCLUSIONS: A-1 treatment reduced motor neuron loss, improved gastrocnemius atrophy, and delayed ALS progression through the AMPK/SIRT1/PGC-1α pathway, which promotes mitochondrial biogenesis. Furthermore, the AMPK/SIRT1/IL-1ß/NF-κB pathway exerted neuroprotective effects by reducing neuroinflammation. These findings suggest A-1 as a promising therapeutic approach for ALS.


Assuntos
Proteínas Quinases Ativadas por AMP , Esclerose Lateral Amiotrófica , Furanos , Interleucina-1beta , Camundongos Transgênicos , NF-kappa B , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Sirtuína 1 , Animais , Sirtuína 1/metabolismo , Camundongos , NF-kappa B/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Furanos/farmacologia , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/metabolismo , Interleucina-1beta/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Lignanas/farmacologia , Lignanas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Masculino , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Neurônios Motores/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Medula Espinal/metabolismo
10.
Biochem Biophys Res Commun ; 722: 150074, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-38805785

RESUMO

Genetic knockout and pharmaceutical inhibition of the NLRP3 inflammasome enhances the extinction of contextual fear memory, which is attributed to its role in neuronal and synaptic dysregulation, concurrent with neurotransmitter function disturbances. This study aimed to determine whether NLRP3 plays a role in generalizing fear via the inflammatory axis. We established the NLRP3 KO mice model, followed by behavioral and biochemical analyses. The NLRP3 KO mice displayed impaired fear generalization, lower neuroinflammation levels, and dysregulated neurotransmitter function. Additionally, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, but not the inhibition of NMDA or 5-HT2C receptors, resulted in fear generalization in NLRP3 KO mice because TAT-GluA2 3Y, but not SB242084 and D-cycloserine, treated blocked NLRP3 deprivation effects on fear generalization. Thus, global knockout of NLRP3 is associated with aberrant fear generalization, possibly through AMPA receptor signaling.


Assuntos
Medo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Receptores de AMPA , Animais , Masculino , Camundongos , Medo/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Receptores de AMPA/metabolismo , Receptores de AMPA/genética
11.
Sci Adv ; 10(16): eadj0268, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38640247

RESUMO

Continuous monitoring of biomarkers at locations adjacent to targeted internal organs can provide actionable information about postoperative status beyond conventional diagnostic methods. As an example, changes in pH in the intra-abdominal space after gastric surgeries can serve as direct indicators of potentially life-threatening leakage events, in contrast to symptomatic reactions that may delay treatment. Here, we report a bioresorbable, wireless, passive sensor that addresses this clinical need, designed to locally monitor pH for early detection of gastric leakage. A pH-responsive hydrogel serves as a transducer that couples to a mechanically optimized inductor-capacitor circuit for wireless readout. This platform enables real-time monitoring of pH with fast response time (within 1 hour) over a clinically relevant period (up to 7 days) and timely detection of simulated gastric leaks in animal models. These concepts have broad potential applications for temporary sensing of relevant biomarkers during critical risk periods following diverse types of surgeries.


Assuntos
Implantes Absorvíveis , Transdutores , Animais , Tecnologia sem Fio , Concentração de Íons de Hidrogênio , Biomarcadores
12.
Int Immunopharmacol ; 132: 111964, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38603856

RESUMO

The link between neuroinflammation and depression is a subject of growing interest in neuroscience and psychiatry; meanwhile, the precise mechanisms are still being unrevealed. However, glial cell activation, together with cytokine level elevation, suggests a connection between neuroinflammation and the development or exacerbation of depression. Glial cells (astrocytes) communicate with neurons via their extracellular neurotransmitter receptors, including glutamate receptors NMDARs. However, these receptor roles are controversial and enigmatic in neurological disorders, including depression. Therefore, we hypothesized whether NMDAR subnit NR2C deletion in the astrocytes exhibited anti-depressive effects concurrent with neuroinflammation prevention. To assess, we prepared astrocytic-NR2C knockout mice (G-2C: GFAPCre+Grin2Cflox/flox), followed by LPS administration, behavior tests, and biochemical analysis. Stimulatingly, astrocytic-NR2C knockout mice (G-2C) did not display depressive-like behaviors, neuroinflammation, and synaptic deficits upon LPS treatment. PI3K was impaired upon LPS administration in control mice (Grin2Cflox/flox); however, they were intact in the hippocampus of LPS-treated G-2C mice. Further, PI3K activation (via PTEN inhibition by BPV) restored neuroinflammation and depressive-like behavior, accompanied by altered synaptic protein and spine numbers in G-2C mice in the presence of LPS. In addition, NF-κB and JNK inhibitor (BAY, SP600125) treatments reversed the effects of BPV. Moreover, these results were further validated with an NR2C antagonist DQP-1105. Collectively, these observations support the astrocytic-NR2C contribution to LPS-induced neuroinflammation, depression, and synaptic deficits.


Assuntos
Astrócitos , Depressão , Hipocampo , Lipopolissacarídeos , Camundongos Knockout , Doenças Neuroinflamatórias , Receptores de N-Metil-D-Aspartato , Animais , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Depressão/imunologia , Camundongos , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/tratamento farmacológico , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo
13.
Pharmaceutics ; 16(3)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38543200

RESUMO

Genistein (GEN) is an active pharmaceutical ingredient that presents the challenges of poor water solubility and low oral bioavailability. To tackle these challenges, a GEN solid dispersion was prepared by solvent rotary evaporation using polyvinylpyrrolidone K30 (PVP K30) as a carrier. The optimal formulation was determined by drug loading efficiency and in vitro release. The physical state of the solid dispersion was characterized by DSC, XRD, SEM and FT-IR. And the results of the in vitro release study indicate that the drug release of SD (1:7) increased 482-fold that of pure GEN at 60 min. Following oral administration to rats, the Cmax and AUC0-24 of SD (1:7) was increased 6.86- and 2.06-fold to that of pure GEN. The adipose fat index and body weight of the SD (1:7) group were significantly lower than those of the GEN group (p < 0.05). Meanwhile, the levels of TC and TG in the serum were significantly decreased in the SD (1:7) group compared with the GEN group (p < 0.05). All experiments revealed that solid dispersion could be a promising formulation approach to improve the dissolution rate, oral bioavailability, and effect on the reduction of lipid accumulation in high-fat diet-induced obesity mice.

14.
Opt Lett ; 49(6): 1636-1639, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38489470

RESUMO

In this Letter, we propose a novel, to the best of our knowledge, neural network pre-equalizer based on the trial-and-error (TE) mechanism for visible light communication. This approach, unlike indirect learning (IL) architecture, does not require an additional auxiliary post-equalizer. Instead, it allows the pre-equalizer to be trained directly from the transmitter side through continuous interaction with the actual system. In a 1.95-Gbps 64-QAM carrier-less amplitude phase (CAP) free space optical transmission platform, the proposed scheme demonstrates superior nonlinear approximation capabilities and noise resilience. Specifically, the TE-recurrent neural network (RNN)-based pre-equalizer exhibits signal-to-noise ratio (SNR) gains of 0.8 dB and 1.8 dB over the IL-RNN-based and IL-Volterra-based pre-equalizers, respectively. We believe this is the first application of trial-and-error learning for training pre-equalizer in visible light communications.

15.
Science ; 383(6687): 1096-1103, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38452063

RESUMO

Monitoring homeostasis is an essential aspect of obtaining pathophysiological insights for treating patients. Accurate, timely assessments of homeostatic dysregulation in deep tissues typically require expensive imaging techniques or invasive biopsies. We introduce a bioresorbable shape-adaptive materials structure that enables real-time monitoring of deep-tissue homeostasis using conventional ultrasound instruments. Collections of small bioresorbable metal disks distributed within thin, pH-responsive hydrogels, deployed by surgical implantation or syringe injection, allow ultrasound-based measurements of spatiotemporal changes in pH for early assessments of anastomotic leaks after gastrointestinal surgeries, and their bioresorption after a recovery period eliminates the need for surgical extraction. Demonstrations in small and large animal models illustrate capabilities in monitoring leakage from the small intestine, the stomach, and the pancreas.


Assuntos
Implantes Absorvíveis , Fístula Anastomótica , Trato Gastrointestinal , Ultrassom , Animais , Humanos , Homeostase , Estômago , Trato Gastrointestinal/cirurgia , Fístula Anastomótica/diagnóstico por imagem , Modelos Animais
16.
Proc Natl Acad Sci U S A ; 121(14): e2400868121, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38547066

RESUMO

Partial cystectomy procedures for urinary bladder-related dysfunction involve long recovery periods, during which urodynamic studies (UDS) intermittently assess lower urinary tract function. However, UDS are not patient-friendly, they exhibit user-to-user variability, and they amount to snapshots in time, limiting the ability to collect continuous, longitudinal data. These procedures also pose the risk of catheter-associated urinary tract infections, which can progress to ascending pyelonephritis due to prolonged lower tract manipulation in high-risk patients. Here, we introduce a fully bladder-implantable platform that allows for continuous, real-time measurements of changes in mechanical strain associated with bladder filling and emptying via wireless telemetry, including a wireless bioresorbable strain gauge validated in a benchtop partial cystectomy model. We demonstrate that this system can reproducibly measure real-time changes in a rodent model up to 30 d postimplantation with minimal foreign body response. Studies in a nonhuman primate partial cystectomy model demonstrate concordance of pressure measurements up to 8 wk compared with traditional UDS. These results suggest that our system can be used as a suitable alternative to UDS for long-term postoperative bladder recovery monitoring.


Assuntos
Bexiga Urinária , Infecções Urinárias , Animais , Humanos , Bexiga Urinária/cirurgia , Urodinâmica/fisiologia , Próteses e Implantes , Cistectomia
17.
J Cell Mol Med ; 28(7): e18160, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38506067

RESUMO

Apolipoprotein E4 (ApoE4) is involved in the stress-response processes and is hypothesized to be a risk factor for depression by means of mitochondrial dysfunction. However, their exact roles and underlying mechanisms are largely unknown. ApoE4 transgenic mice (B6. Cg-ApoEtm1Unc Cdh18Tg( GFAP-APOE i4)1Hol /J) were subjected to stress (lipopolysaccharides, LPS) to elucidate the aetiology of ApoE4-induced depression. LPS treatment significantly aggravated depression-like behaviours, concurrent with neuroinflammation and impaired mitochondrial changes, and melatonin/Urolithin A (UA) + 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR) reversed these effects in ApoE4 mice. Concurrently, ApoE4 mice exhibited mitophagy deficits, which could be further exacerbated by LPS stimulation, as demonstrated by reduced Atg5, Beclin-1 and Parkin levels, while PINK1 levels were increased. However, these changes were reversed by melatonin treatment. Additionally, proteomic profiling suggested mitochondria-related signalling and network changes in ApoE4 mice, which may underlie the exaggerated response to LPS. Furthermore, HEK 293T cells transfected with ApoE4 showed mitochondria-associated protein and mitophagy defects, including PGC-1α, TFAM, p-AMPKα, PINK1 and LC3B impairments. Additionally, it aggravates mitochondrial impairment (particularly mitophagy), which can be attenuated by triggering autophagy. Collectively, ApoE4 dysregulation enhanced depressive behaviour upon LPS stimulation.


Assuntos
Apolipoproteína E4 , Melatonina , Camundongos , Animais , Apolipoproteína E4/metabolismo , Apolipoproteína E4/farmacologia , Depressão , Melatonina/farmacologia , Melatonina/metabolismo , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Proteômica , Mitocôndrias/metabolismo , Apolipoproteínas E/metabolismo , Camundongos Transgênicos , Proteínas Quinases Ativadas por AMP/metabolismo
18.
Biosens Bioelectron ; 253: 116166, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38428069

RESUMO

Eccrine sweat can serve as a source of biomarkers for assessing physiological health and nutritional balance, for tracking loss of essential species from the body and for evaluating exposure to hazardous substances. The growing interest in this relatively underexplored class of biofluid arises in part from its non-invasive ability for capture and analysis. The simplest devices, and the only ones that are commercially available, exploit soft microfluidic constructs and colorimetric assays with purely passive modes of operation. The most sophisticated platforms exploit batteries, electronic components and radio hardware for inducing sweat, for electrochemical evaluation of its content and for wireless transmission of this information. The work reported here introduces a technology that combines the advantages of these two different approaches, in the form of a cost-effective, easy-to-use device that supports on-demand evaluation of multiple biomarkers in sweat. This flexible, skin-interfaced, miniaturized system incorporates a hydrogel that contains an approved drug to activate eccrine sweat glands, electrodes and a simple circuit and battery to delivery this drug by iontophoresis through the surface of the skin, microfluidic channels and microreservoirs to capture the induced sweat, and multiple colorimetric assays to evaluate the concentrations of chloride, zinc, and iron. As demonstrated in healthy human participants monitored before and after a meal, such devices yield results that match those of traditional laboratory analysis techniques. Clinical studies that involve cystic fibrosis pediatric patients illustrate the use of this technology as a simple, painless, and reliable alternative to traditional hospital systems for measurements of sweat chloride.


Assuntos
Técnicas Biossensoriais , Suor , Humanos , Criança , Cloretos , Colorimetria , Biomarcadores
19.
Exp Gerontol ; 187: 112375, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38320733

RESUMO

Stress response is a fundamental mechanism for cell survival, providing protection under unfavorable conditions. Mitochondrial stress, in particular, can trigger mitophagy, a process that restores cellular health. Exhaustive exercise (EE) is a form of acute mitochondrial stress. The objective of this current study is to investigate the impact of EE on tau pathology in pR5 mice, as well as the potential underlying mechanisms. To evaluate this, we examined the levels of total and phosphorylated tau in the hippocampus of pR5 mice, both with and without EE treatment. Furthermore, the application of weighted correlation network analysis (WGCNA) was employed to identify protein modules associated with the phenotype following the proteomic experiment. The findings of our study demonstrated a significant decrease in tau phosphorylation levels upon EE treatment, in comparison to the pR5 group. Moreover, the proteomic analysis provided additional insights, revealing that the mitigation of tau pathology was primarily attributed to the modulation of various pathways, such as translation factors and oxidative phosphorylation. Additionally, the analysis of heatmaps revealed a significant impact of EE treatment on the translation process and electron transport chain in pR5 mice. Furthermore, biochemical analysis provided further confirmation that EE treatment effectively modulated the ATP level in pR5 mice. In conclusion, our study suggests that the observed decrease in tau phosphorylation resulting from EE treatment may primarily be attributed to its regulation of the translation process and enhancement of mitochondrial function.


Assuntos
Doença de Alzheimer , Fenômenos Biológicos , Camundongos , Animais , Camundongos Transgênicos , Fosforilação , Proteínas tau/genética , Proteínas tau/metabolismo , Transporte de Elétrons , Proteômica , Fosforilação Oxidativa , Processamento de Proteína Pós-Traducional , Doença de Alzheimer/genética
20.
Sci Total Environ ; 919: 170897, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38346659

RESUMO

The potential increases in carbon stocks in arid regions due to recent shrub encroachment have attracted extensive interest among both ecologists and carbon policy analysts. Quantifying the shrub root biomass amount in these ecosystems is essential to understanding the ecological changes occurring. In this paper, we proposed a simple nondestructive method for estimating the coarse lateral root biomass of shrubs based on the root counts obtained from ground-penetrating radar (GPR) radargrams. Root data were gathered via field experiments using GPR with antenna center frequencies of 900 MHz and 400 MHz. Five Caragana microphylla Lam. shrubs of different sizes were selected for measuring objects, and a total of 40 GPR survey lines were established for GPR data acquisition. The soil profile wall excavation method was used to obtain the total root biomass from each radargram. A model for estimating the root biomass was built by establishing the relationship between the root biomass in each profile and the root counts interpreted from the radargrams. According to the mathematical relationship between the root diameter and root biomass, the proxy root radius was derived, which could explain the rationality of the proposed model from the biological mechanism. The established model provided high confidence in estimating the root dry biomass using the GPR data obtained at the two antenna frequencies (R2= 0.73 for 900 MHz and R2= 0.71 for 400 MHz). The leave-one-out cross-validation results showed that the model exhibits satisfactory performance. This study expands the application of geophysical methods in root research and offers a new simplified method for estimating the root biomass from GPR data under field conditions.


Assuntos
Caragana , Ecossistema , Biomassa , Radar , China , Carbono
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