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1.
Curr Biol ; 2024 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-39265569

RESUMO

Sleeping animals can be woken up rapidly by external threat signals, which is an essential defense mechanism for survival. However, neuronal circuits underlying the fast transmission of sensory signals for this process remain unclear. Here, we report in mice that alerting sound can induce rapid awakening within hundreds of milliseconds and that glutamatergic neurons in the pontine central gray (PCG) play an important role in this process. These neurons exhibit higher sensitivity to auditory stimuli in sleep than wakefulness. Suppressing these neurons results in reduced sound-induced awakening and increased sleep in intrinsic sleep/wake cycles, whereas their activation induces ultra-fast awakening from sleep and accelerates awakening from anesthesia. Additionally, the sound-induced awakening can be attributed to the propagation of auditory signals from the PCG to multiple arousal-related regions, including the mediodorsal thalamus, lateral hypothalamus, and ventral tegmental area. Thus, the PCG serves as an essential distribution center to orchestrate a global auditory network to promote rapid awakening.

2.
J Microbiol Biotechnol ; 34(10): 1-10, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39263794

RESUMO

In response to the growing demand for immune-related products, this study evaluated the safety and immune-modulating potential of three newly discovered Lactiplantibacillus plantarum strains (GKM3, GKK1, and GKD7) through toxicity tests and whole-genome sequencing. Safety evaluations, including the analysis of antimicrobial resistance genes, virulence factors, plasmids, and prophages, classified these strains as safe for human consumption. Acute oral toxicity tests further supported their safety. To evaluate their immune-modulating potential, dendritic cells were exposed to these strains, and the secretion of key cytokines (IFN-ß and IL-12) was measured. Among the strains, GKK1 exhibited the highest enhancement of IFN-ß and IL-12 production, suggesting its potential as an immune-stimulating probiotic. Bioinformatics analysis revealed potential metabolic pathways and secondary metabolites, including predicted bacteriocins, associated with immune modulation. The presence of a nitrate reductase region in the GKK1 strain indicated its ability to produce nitric oxide, a critical molecule involved in immune regulation and host defense. The presence of glucorhamnanrelated gene clusters in GKK1 also suggested immune-enhancing effects. Nitrate reductase expression was confirmed using qPCR, with the highest levels detected in GKK1. Moreover, this study is the first to show an anti-inflammatory effect of plantaricin A, linked to its presence in strain GKM3 and its potential therapeutic applications due to sequence similarity to known antiinflammatory peptides. Overall, these three L. plantarum strains demonstrated a safe profile and GKK1 showed potential as an immunity-enhancing probiotic. However, additional investigation is required to confirm the involvement of specific metabolic pathways, secondary metabolites, and bacteriocins in immune responses.

3.
Eur Rev Med Pharmacol Sci ; 28(13): 3892-3904, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39012229

RESUMO

OBJECTIVE: Alzheimer's disease (AD), a common degenerative disease of the central nervous system in the elderly, has become the third largest health killer after cardiovascular and cerebrovascular diseases and tumors. Based on the fact that Alzheimer's disease is a disease with multiple etiologies and complex pathology, a single target is bound to have a limited curative effect, and the synergy of multiple links and multiple targets is expected to achieve a better curative effect. The aim of this study is to investigate the brain targeting of a drug modified by chitosan, based on the new nanodrug delivery system for treating Alzheimer's disease developed by the research group. MATERIALS AND METHODS: Chitosan with good biocompatibility, biosorption, and degradation products that can protect and promote the regeneration of nerve cells was selected to combine with galantamine, a natural representative cholinesterase inhibitor, to develop a new nano drug delivery system for nasal delivery of anti-Alzheimer's disease with a multi-target synergistic effect. Synchronous analysis was conducted on the blood and brain tissue drug concentrations after intravenous and nasal administration of the original drug solution and system solution. The brain targeting index (DTI) is used to evaluate the brain targeting effect of the nano-drug delivery system after intranasal administration. RESULTS: The blood concentration of galantamine original drug solution and galantamine system solution after intravenous injection and nasal show that in the two administration methods of intravenous injection and nasal administration, under the same administration method, the time point of the system reaching the highest blood drug concentration is much higher than that of the original drug. The content of galantamine in plasma samples and tissue samples indicate that after intravenous administration and intranasal administration of the galantamine system, at the same time point, the drug concentration in brain tissue was far greater than that of the original drug of galantamine, and the duration was also longer. The concentration of drugs in brain tissue decreased gradually in the order of olfactory bulb, olfactory tract, brain, and cerebellum. In the brain tissues of the olfactory bulb, olfactory tract, cerebrum, and cerebellum, the drug concentration of the galantamine system after intravenous injection is lower than that after nasal administration. CONCLUSIONS: This study concludes that compared with the original drug solution, the nano drug delivery system has significant brain targeting for nasal administration, and intravenous injection also has brain targeting. In the olfactory bulb, olfactory tract, brain, and cerebellum, the brain targeting index at the olfactory bulb is the highest, and the targeting is the best.


Assuntos
Administração Intranasal , Doença de Alzheimer , Encéfalo , Quitosana , Inibidores da Colinesterase , Sistemas de Liberação de Medicamentos , Galantamina , Doença de Alzheimer/tratamento farmacológico , Quitosana/química , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Animais , Galantamina/administração & dosagem , Galantamina/farmacocinética , Inibidores da Colinesterase/administração & dosagem , Humanos , Ratos , Masculino , Sistemas de Liberação de Fármacos por Nanopartículas/química
4.
Cancers (Basel) ; 16(14)2024 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-39061238

RESUMO

While low-dose computed tomography (LDCT) for lung cancer screening (LCS) has been recognized for its effectiveness in reducing lung cancer mortality, it often simultaneously leads to the detection of incidental findings (IFs) unrelated to the primary screening indication. These IFs present diagnostic and management challenges, potentially causing unnecessary anxiety and further invasive diagnostic procedures for patients. This review article provides an overview of IFs encountered in LDCT, emphasizing their clinical significance and recommended management strategies. We categorize IFs based on their anatomical locations (intrathoracic-intrapulmonary, intrathoracic-extrapulmonary, and extrathoracic) and discuss the most common findings. We highlight the importance of utilizing guidelines and standardized reporting systems by the American College of Radiology (ACR) to guide appropriate follow-ups. For each category, we present specific IF examples, their radiologic features, and the suggested management approach. This review aims to provide radiologists and clinicians with a comprehensive understanding of IFs in LCS for accurate assessment and management, ultimately enhancing patient care. Finally, we outline a few key aspects for future research and development in managing IFs.

5.
Curr Biol ; 34(16): 3616-3631.e5, 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39019036

RESUMO

Effective detection and avoidance from environmental threats are crucial for animals' survival. Integration of sensory cues associated with threats across different modalities can significantly enhance animals' detection and behavioral responses. However, the neural circuit-level mechanisms underlying the modulation of defensive behavior or fear response under simultaneous multimodal sensory inputs remain poorly understood. Here, we report in mice that bimodal looming stimuli combining coherent visual and auditory signals elicit more robust defensive/fear reactions than unimodal stimuli. These include intensified escape and prolonged hiding, suggesting a heightened defensive/fear state. These various responses depend on the activity of the superior colliculus (SC), while its downstream nucleus, the parabigeminal nucleus (PBG), predominantly influences the duration of hiding behavior. PBG temporally integrates visual and auditory signals and enhances the salience of threat signals by amplifying SC sensory responses through its feedback projection to the visual layer of the SC. Our results suggest an evolutionarily conserved pathway in defense circuits for multisensory integration and cross-modality enhancement.


Assuntos
Medo , Colículos Superiores , Animais , Colículos Superiores/fisiologia , Camundongos , Medo/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Percepção Visual/fisiologia , Percepção Auditiva/fisiologia , Reação de Fuga/fisiologia , Estimulação Acústica , Estimulação Luminosa , Feminino
7.
Ann Surg Oncol ; 31(6): 4061-4070, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38494565

RESUMO

BACKGROUND: The Evaluation of Groin Lymphadenectomy Extent for Melanoma (EAGLE FM) study sought to address the question of whether to perform inguinal (IL) or ilio-inguinal lymphadenectomy (I-IL) for patients with inguinal nodal metastatic melanoma who have no clinical or imaging evidence of pelvic disease. Primary outcome measure was disease-free survival at 5 years, and secondary endpoints included lymphoedema. METHODS: EAGLE FM was designed to recruit 634 patients but closed with 88 patients randomised because of slow recruitment and changes in melanoma management. Lymphoedema assessments occurred preoperatively and at 6, 12, 18, and 24 months postoperatively. Lymphoedema was defined as Inter-Limb Volume Difference (ILVD) > 10%, Lymphoedema Index (L-Dex®) > 10 or change of L-Dex® > 10 from baseline. RESULTS: Prevalence of leg lymphoedema between the two groups was similar but numerically higher for I-IL at all time points in the first 24 months of follow-up; highest at 6 months (45.9% IL [CI 29.9-62.0%], 54.1% I-IL [CI 38.0-70.1%]) and lowest at 18 months (18.8% IL [CI 5.2-32.3%], 41.4% I-IL [CI 23.5-59.3%]). Median ILVD at 24 months for those affected by lymphoedema was 14.5% (IQR 10.6-18.7%) and L-Dex® was 12.6 (IQR 9.0-17.2). There was not enough statistical evidence to support associations between lymphoedema and extent of surgery, radiotherapy, or wound infection. CONCLUSIONS: Despite a trend for patients who had I-IL to have greater lymphoedema prevalence than IL in the first 24 months after surgery, our study's small sample did not have the statistical evidence to support an overall difference between the surgical groups.


Assuntos
Canal Inguinal , Excisão de Linfonodo , Linfedema , Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/cirurgia , Melanoma/patologia , Linfedema/etiologia , Excisão de Linfonodo/efeitos adversos , Feminino , Masculino , Estudos Prospectivos , Pessoa de Meia-Idade , Seguimentos , Neoplasias Cutâneas/cirurgia , Neoplasias Cutâneas/patologia , Canal Inguinal/cirurgia , Canal Inguinal/patologia , Prognóstico , Taxa de Sobrevida , Perna (Membro) , Idoso , Adulto , Complicações Pós-Operatórias/etiologia , Estadiamento de Neoplasias
8.
Molecules ; 29(4)2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38398564

RESUMO

One new compound with an isoindolinone skeleton, along with erinacines A, C, and S, was isolated from the mycelia of Hericium erinaceus, an edible fungus with a long history of use in traditional Chinese medicine. Based on analysis of MS and NMR spectral data, the structure of the compound was identified as (2E,6E)-8-(2-(1-carboxy-3-methylbutyl)-4,6-dihydroxy-1-oxoisoindolin-5-yl)-2,6-dimethylocta-2,6-dienoic acid. In light of this discovery, we have given this compound the name erinacerin W. Using a co-culture in vitro LPS-activated BV2 microglia-induced SH-SY5Y neuroinflammation model, the results showed that erinacerin W demonstrated protection against the LPS-activated BV-2 cell-induced overexpression of IL-6, IL-1ß, and TNF-α on SH-SY5Y cells. This finding may provide potential therapeutic approaches for central nervous disorders.


Assuntos
Neuroblastoma , Fármacos Neuroprotetores , Humanos , Fármacos Neuroprotetores/farmacologia , Lipopolissacarídeos/farmacologia , Hericium
9.
Sports Biomech ; : 1-10, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38180880

RESUMO

This study aimed to investigate the kinematics and kinetics differences in ground reaction force (GRF)-time profiles with uni- and bimodal curves (UNC and BIC) during the concentric phase of the drop jump (DJ). Twenty two male Physical Education college student who met UNC (N = 11) or BIC (N = 11) of the GRF-time profile of were recruited. Two force plates and eight infrared optical cameras were synchronised to collect the GRF and motion data during DJ from a 30-cm height. The Shapiro-Wilk test was used to assess the normality of data. The Wilcoxon test was used when data were not normally distributed. Otherwise, Independent t-tests were used to compare differences between the UNC and BIC groups for each dependent variable. The UNC group demonstrated shorter ground contact time, lower jump height, greater leg stiffness, greater peak power during the eccentric phase, less work during the eccentric and concentric phases, and greater hip and knee joint flexion and extension angle displacements (p < 0.05). No significant intergroup differences were found in reactive strength index (p > 0.05). The UNC and BIC of the GRF-time profiles can indicate whether athletes can practice DJ appropriately. UNC can be representative of a better DJ performance with an efficient stretch-shortening cycle function.

10.
Nat Commun ; 14(1): 7278, 2023 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-37949869

RESUMO

In the mammalian visual system, the ventral lateral geniculate nucleus (vLGN) of the thalamus receives salient visual input from the retina and sends prominent GABAergic axons to the superior colliculus (SC). However, whether and how vLGN contributes to fundamental visual information processing remains largely unclear. Here, we report in mice that vLGN facilitates visually-guided approaching behavior mediated by the lateral SC and enhances the sensitivity of visual object detection. This can be attributed to the extremely broad spatial integration of vLGN neurons, as reflected in their much lower preferred spatial frequencies and broader spatial receptive fields than SC neurons. Through GABAergic thalamocollicular projections, vLGN specifically exerts prominent surround suppression of visuospatial processing in SC, leading to a fine tuning of SC preferences to higher spatial frequencies and smaller objects in a context-dependent manner. Thus, as an essential component of the central visual processing pathway, vLGN serves to refine and contextually modulate visuospatial processing in SC-mediated visuomotor behaviors via visually-driven long-range feedforward inhibition.


Assuntos
Corpos Geniculados , Neurônios , Camundongos , Animais , Corpos Geniculados/fisiologia , Neurônios/fisiologia , Tálamo , Vias Visuais/fisiologia , Colículos Superiores/fisiologia , Mamíferos
11.
Fitoterapia ; 171: 105695, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37797793

RESUMO

For centuries, food, herbal medicines, and natural products have been valuable resources for discovering novel antiviral drugs, uncovering new structure-activity relationships, and developing effective strategies to prevent/treat viral infections. One such resource is Phellinus linteus, a mushroom used in folk medicine in Taiwan, Japan, Korea, and China. In this rich historical context, the key metabolites of Phellinus linteus mycelia ethanolic extract (GKPL) impacting the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at multiple stages have yet to be explored. Thus, this study systematically identifies and assesses the inhibitory effect of GKPL on the SARS-CoV-2 virus. Initially, the concentrations and contact times of GKPL against SARS-CoV-2 pseudovirus were assessed in HepG2 cells. Subsequently, utilizing the Ultra Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry method, potential biomarkers in the fungal extract were discerned. Metabolomic analysis identified 18 compounds in GKPL, with hispidin and hypholomine B present in the highest amounts. These compounds were isolated using chromatographic techniques and further identified through 1D NMR spectroscopic and mass spectrometry analysis. Hispidin and hypholomine B were found to inhibit the infection of SARS-CoV-2 pseudovirus by reducing angiotensin-converting enzyme 2 gene expression in HepG2, thereby decreasing viral entry. Moreover, hispidin and hypholomine B effectively block the spike receptor-binding domain, while hypholomine B, for the first time, showed significant inhibition of 3CL protease. This suggests that GKPL, enriched with hispidin and hypholomine B, has the potential to be used as an active ingredient against SARS-CoV-2.


Assuntos
COVID-19 , Espectrometria de Massas em Tandem , Humanos , SARS-CoV-2 , Estrutura Molecular , Espectroscopia de Ressonância Magnética
12.
Neuron ; 111(22): 3650-3667.e6, 2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37652003

RESUMO

Safety assessment and threat evaluation are crucial for animals to live and survive in the wilderness. However, neural circuits underlying safety assessment and their transformation to mediate flexibility of fear-induced defensive behaviors remain largely unknown. Here, we report that distinct neuronal populations in mouse anterior cingulate cortex (ACC) encode safety status by selectively responding under different contexts of auditory threats, with one preferably activated when an animal staysing in a self-deemed safe zone and another specifically activated in more dangerous environmental settings that led to escape behavior. The safety-responding neurons preferentially target the zona incerta (ZI), which suppresses the superior colliculus (SC) via its GABAergic projection, while the danger-responding neurons preferentially target and excite SC. These distinct corticofugal pathways antagonistically modulate SC responses to threat, resulting in context-dependent expression of fear reactions. Thus, ACC serves as a critical node to encode safety/danger assessment and mediate behavioral flexibility through differential top-down circuits.


Assuntos
Giro do Cíngulo , Zona Incerta , Camundongos , Animais , Medo/fisiologia , Colículos Superiores/fisiologia
13.
J Cachexia Sarcopenia Muscle ; 14(5): 2226-2238, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37562939

RESUMO

BACKGROUND: Disuse atrophy is a frequent cause of muscle atrophy, which can occur in individuals of any age who have been inactive for a prolonged period or immobilization. Additionally, acute diseases such as COVID-19 can cause frequent sequelae and exacerbate muscle wasting, leading to additional fatigue symptoms. It is necessary to investigate potent functional nutrients for muscle reinforcement in both disuse atrophy and fatigue to ensure better physical performance. METHODS: The effects of Sanghuangporus sanghuang SS-MN4 mycelia were tested on two groups of 6-week-old male mice-one with disuse atrophy and the other with fatigue. The disuse atrophy group was divided into three sub-groups: a control group, a group that underwent hind limb casting for 7 days and then recovered for 7 days and a group that was administered with SS-MN4 orally for 14 days, underwent hind limb casting for 7 days and then recovered for 7 days. The fatigue group was divided into two sub-groups: a control group that received no SS-MN4 intervention and an experimental group that was administered with SS-MN4 orally for 39 days and tested for exhaustive swimming and running on Day 31 and Day 33, respectively. RNA sequencing (RNA-seq) and western blot analysis were conducted on C2C12 cell lines to identify the therapeutic effects of SS-MN4 treatment. RESULTS: In a disuse atrophy model induced by hind limb casting, supplementing with 250 mg/kg of SS-MN4 for 14 days led to 111.2% gastrocnemius muscle mass recovery and an 89.1% improvement in motor function on a treadmill (P < 0.05). In a fatigue animal model, equivalent SS-MN4 dosage improved swimming (178.7%) and running (162.4%) activities (P < 0.05) and reduced blood urea nitrogen levels by 18% (P < 0.05). SS-MN4 treatment also increased liver and muscle glycogen storage by 34.36% and 55.6%, respectively, suggesting a higher energy reserve for exercise. RNA-seq and western blot studies from the C2C12 myotube showed that SS-MN4 extract upregulates Myh4 and helps sustain myotube integrity against dexamethasone damage. CONCLUSIONS: Supplementation of SS-MN4 (250-mg/kg body weight) with hispidin as active compound revealed a potential usage as a muscle nutritional supplement enhancing muscle recovery, fast-twitch fibre regrowth and fatigue resistance.

14.
Front Aging Neurosci ; 15: 1213379, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37649717

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily affecting cognitive functions. However, sensory deficits in AD start to draw attention due to their high prevalence and early onsets which suggest that they could potentially serve as diagnostic biomarkers and even contribute to the disease progression. This literature review examines the sensory deficits and cortical pathological changes observed in visual, auditory, olfactory, and somatosensory systems in AD patients, as well as in various AD animal models. Sensory deficits may emerge at the early stages of AD, or even precede the cognitive decline, which is accompanied by cortical pathological changes including amyloid-beta deposition, tauopathy, gliosis, and alterations in neuronal excitability, synaptic inputs, and functional plasticity. Notably, these changes are more pronounced in sensory association areas and superficial cortical layers, which may explain the relative preservation of basic sensory functions but early display of deficits of higher sensory functions. We propose that sensory impairment and the progression of AD may establish a cyclical relationship that mutually perpetuates each condition. This review highlights the significance of sensory deficits with or without cortical pathological changes in AD and emphasizes the need for further research to develop reliable early detection and intervention through sensory systems.

15.
Nat Neurosci ; 26(9): 1529-1540, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37524978

RESUMO

Fluctuations in reproductive hormone levels are associated with mood disruptions in women, such as in postpartum and perimenopausal depression. However, the neural circuit mechanisms remain unclear. Here we report that medial preoptic area (MPOA) GABAergic neurons mediate multifaceted depressive-like behaviors in female mice after ovarian hormone withdrawal (HW), which can be attributed to downregulation of activity in Esr1 (estrogen receptor-1)-expressing GABAergic neurons. Enhancing activity of these neurons ameliorates depressive-like behaviors in HW-treated mice, whereas reducing their activity results in expression of these behaviors. Two separate subpopulations mediate different symptoms: a subpopulation projecting to the ventral tegmental area (VTA) mediates anhedonia and another projecting to the periaqueductal gray mediates immobility. These projections enhance activity of dopaminergic neurons in the VTA and serotonergic neurons in the dorsal raphe, respectively, with increased release of dopamine and serotonin, possibly through disinhibition mechanisms. Thus, the MPOA is a hub that mediates depressive-like behaviors resulting from transitions in reproductive hormone levels.


Assuntos
Área Pré-Óptica , Área Tegmentar Ventral , Camundongos , Feminino , Animais , Área Pré-Óptica/fisiologia , Área Tegmentar Ventral/fisiologia , Neurônios Dopaminérgicos/fisiologia , Neurônios GABAérgicos/fisiologia
16.
Biomed Pharmacother ; 164: 114880, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37224751

RESUMO

3,4-methylenedioxymethamphetamine (MDMA) is a popular recreational drug, however over 200 studies demonstrate that acute (e.g. hyperthermia, rhabdomyolysis) and chronic (e.g. neurotoxicity) toxicity effects of MDMA were observed in different animals. Methimazole (MMI), an inhibitor of thyroid hormone synthesis, was found to significantly reduce the HSP72 expression of heat stress induced in fibroblasts. Hence, we attempted to understand the effects of MMI on MDMA induced changes in vivo. Male SD rats were randomly divided into four groups as follows:(a) water-saline (b) water-MDMA (c) MMI-saline and (d) MMI-MDMA group. In the temperature analysis test, MMI was found to alleviate MDMA-induced hyperthermia and increase the heat loss index (HLI), revealing its peripheral vasodilation effect. PET experiment suggested that MDMA induced elevated glucose uptake by skeletal muscles, which was resolved by MMI pretreatment. IHC staining (serotonin transporter, SERT) showed the evidence of neurotoxicity caused by MDMA (serotonin fiber loss), which was alleviated by MMI. Furthermore, the animal behaviour test (forced swimming test, FST) showed higher swimming time but lower immobility time in MMI-MDMA and MMI-saline groups. Taken together, treatment of MMI shows benefits such as lowered body temperature, alleviation of neurotoxicity and excited behaviour. However, further investigations should be conducted in the future to provide in-depth evidence for its clinical use.


Assuntos
Hipertermia Induzida , N-Metil-3,4-Metilenodioxianfetamina , Síndromes Neurotóxicas , Ratos , Masculino , Animais , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Metimazol/toxicidade , Ratos Sprague-Dawley , Temperatura Corporal , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Hipertermia Induzida/efeitos adversos
17.
RSC Adv ; 13(16): 10636-10641, 2023 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-37025664

RESUMO

Covalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-2 have great potential as antivirals, but their non-specific reactivity with thiols has limited their development. In this report, we performed an 8000 molecule electrophile screen against PLpro and identified an α-chloro amide fragment, termed compound 1, which inhibited SARS-CoV-2 replication in cells, and also had low non-specific reactivity with thiols. Compound 1 covalently reacts with the active site cysteine of PLpro, and had an IC50 of 18 µM for PLpro inhibition. Compound 1 also had low non-specific reactivity with thiols and reacted with glutathione 1-2 orders of magnitude slower than other commonly used electrophilic warheads. Finally, compound 1 had low toxicity in cells and mice and has a molecular weight of only 247 daltons and consequently has great potential for further optimization. Collectively, these results demonstrate that compound 1 is a promising lead fragment for future PLpro drug discovery campaigns.

18.
Patient Prefer Adherence ; 17: 769-780, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36974078

RESUMO

Background: Adherence therapy (AT) is an intervention for improving medication adherence of people with schizophrenia spectrum disorders, but no systematic reviews have yet summarized the effectiveness and minimum treatment duration of AT. We here aimed to systematically examine the effectiveness of AT in improving outcomes versus treatment as usual (TAU) and its minimum effective duration for people diagnosed with schizophrenia spectrum disorders. Patients and Methods: Eligible randomized controlled trials were identified from four databases (Web of Science, PubMed, CINAHL and Cochrane Library) for the period 1 January 2006 to 1 January 2023. Of 1087 retrieved candidate studies, five studies with a total of 726 participants met the inclusion criteria. The search terms consisted of adherence therapy, compliance therapy, schizophrenia, schizoaffective disorder, schizophrenic disorder, medication adherence, and medication compliance (combined with OR and AND). Two investigators independently selected studies, extracted data, and conducted bias risk assessments. Random-effects models were used to analyze the pooled data. Results: Meta-analysis of the five selected studies showed that AT had a significantly greater positive effects than TAU on psychiatric symptoms, but no significant effects on adherence behaviors and attitudes. Conclusion: The AT had limited effects in terms of improving the attitudes and behaviors of people with schizophrenia spectrum disorders with respect to medication adherence, but did improve patients' psychiatric symptoms. The therapy should be performed by trained staff for maximum benefit, and the recommended duration of the intervention is 12 hours.

19.
Neuron ; 111(9): 1486-1503.e7, 2023 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-36893756

RESUMO

Extracting the valence of environmental cues is critical for animals' survival. How valence in sensory signals is encoded and transformed to produce distinct behavioral responses remains not well understood. Here, we report that the mouse pontine central gray (PCG) contributes to encoding both negative and positive valences. PCG glutamatergic neurons were activated selectively by aversive, but not reward, stimuli, whereas its GABAergic neurons were preferentially activated by reward signals. The optogenetic activation of these two populations resulted in avoidance and preference behavior, respectively, and was sufficient to induce conditioned place aversion/preference. Suppression of them reduced sensory-induced aversive and appetitive behaviors, respectively. These two functionally opponent populations, receiving a broad range of inputs from overlapping yet distinct sources, broadcast valence-specific information to a distributed brain network with distinguishable downstream effectors. Thus, PCG serves as a critical hub to process positive and negative valences of incoming sensory signals and drive valence-specific behaviors with distinct circuits.


Assuntos
Encéfalo , Neurônios GABAérgicos , Camundongos , Animais , Substância Cinzenta Periaquedutal , Afeto , Sinais (Psicologia)
20.
Int J Ment Health Nurs ; 32(4): 1008-1024, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36788653

RESUMO

Medication adherence and recovery rates are <50% among persons with schizophrenia; therefore, this health concern needs attention. Empowerment is a vital element for behavioural change, but previous studies have presented different results and lack specific connotations about empowerment. Therefore, this study systematically reviewed and meta-analysed the effects of empowerment-based illness management on the medication adherence and recovery of persons with schizophrenia. The databases searched included the PROSPERO registration network, Cochrane Library, PubMed, Embase, CINAHL, PsycAricle, and Airiti Library. The research steps were based on PRISMA. RoB 2.0 was used for article quality evaluation, the effect size was calculated using RevMan software, and the random-effect model and standardized mean differences (SMD) were established. Eight randomized controlled trials (RCTs) involving 859 participants were used to investigate the effect of empowerment on medication adherence. The trials involved the use of effective strategies as inducing medication motivation, promoting self-medication management, and providing support resources. A moderate effect was observed (SMD = 0.58, 95% CI 0.18-0.99). Ten RCTs involving 1473 participants were used to investigate the effect of empowerment on recovery. These trials involved the use of such effective strategies as using self-strength, connecting external forces, understanding personal needs, and overcoming self-stigma. A moderate effect was observed (SMD = 0.55, 95% CI 0.10-0.99). Empowerment in illness management can effectively promote the medication adherence and recovery of persons with schizophrenia. In the future, nurses can use self-strength care to promote medication motivation and connect internal and external forces to assist a person's medication adherence and recovery.


Assuntos
Adesão à Medicação , Esquizofrenia , Humanos , Motivação , Esquizofrenia/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
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