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1.
Viruses ; 13(3)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799525

RESUMO

Respiratory Syncytial Virus (RSV) causes severe inflammation and airway pathology in children and the elderly by infecting the epithelial cells of the upper and lower respiratory tract. RSV replication is sensed by intracellular pattern recognition receptors upstream of the IRF and NF-κB transcription factors. These proteins coordinate an innate inflammatory response via Bromodomain-containing protein 4 (BRD4), a protein that functions as a scaffold for unknown transcriptional regulators. To better understand the pleiotropic regulatory function of BRD4, we examine the BRD4 interactome and identify how RSV infection dynamically alters it. To accomplish these goals, we leverage native immunoprecipitation and Parallel Accumulation-Serial Fragmentation (PASEF) mass spectrometry to examine BRD4 complexes isolated from human alveolar epithelial cells in the absence or presence of RSV infection. In addition, we explore the role of BRD4's acetyl-lysine binding bromodomains in mediating these interactions by using a highly selective competitive bromodomain inhibitor. We identify 101 proteins that are significantly enriched in the BRD4 complex and are responsive to both RSV-infection and BRD4 inhibition. These proteins are highly enriched in transcription factors and transcriptional coactivators. Among them, we identify members of the AP1 transcription factor complex, a complex important in innate signaling and cell stress responses. We independently confirm the BRD4/AP1 interaction in primary human small airway epithelial cells. We conclude that BRD4 recruits multiple transcription factors during RSV infection in a manner dependent on acetyl-lysine binding domain interactions. This data suggests that BRD4 recruits transcription factors to target its RNA processing complex to regulate gene expression in innate immunity and inflammation.

2.
Genes (Basel) ; 12(3)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800913

RESUMO

Whole genome sequencing (WGS) is a powerful tool for postnatal genetic diagnosis, but relevant clinical studies in the field of prenatal diagnosis are limited. The present study aimed to prospectively evaluate the utility of WGS compared with chromosomal microarray (CMA) and whole exome sequencing (WES) in the prenatal diagnosis of fetal structural anomalies. We performed trio WGS (≈40-fold) in parallel with CMA in 111 fetuses with structural or growth anomalies, and sequentially performed WES when CMA was negative (CMA plus WES). In comparison, WGS not only detected all pathogenic genetic variants in 22 diagnosed cases identified by CMA plus WES, yielding a diagnostic rate of 19.8% (22/110), but also provided additional and clinically significant information, including a case of balanced translocations and a case of intrauterine infection, which might not be detectable by CMA or WES. WGS also required less DNA (100 ng) as input and could provide a rapid turnaround time (TAT, 18 ± 6 days) compared with that (31 ± 8 days) of the CMA plus WES. Our results showed that WGS provided more comprehensive and precise genetic information with a rapid TAT and less DNA required than CMA plus WES, which enables it as an alternative prenatal diagnosis test for fetal structural anomalies.

3.
J Med Chem ; 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33822624

RESUMO

Canonical WNT signaling is an important developmental pathway that has attracted increased attention for anticancer drug discovery. From the production and secretion of WNT ligands, their binding to membrane receptors, and the ß-catenin destruction complex to the expansive ß-catenin transcriptional complex, multiple components have been investigated as drug targets to modulate WNT signaling. Significant progress in developing WNT inhibitors such as porcupine inhibitors, tankyrase inhibitors, ß-catenin/coactivators, protein-protein interaction inhibitors, casein kinase modulators, DVL inhibitors, and dCTPP1 inhibitors has been made, with several candidates (e.g., LGK-974, PRI-724, and ETC-159) in human clinical trials. Herein we summarize recent progress in the drug discovery and development of small-molecule inhibitors targeting the canonical WNT pathway, focusing on their specific target proteins, in vitro and in vivo activities, physicochemical properties, and therapeutic potential. The relevant opportunities and challenges toward maintaining the balance between efficacy and toxicity in effectively targeting this pathway are also highlighted.

4.
Sensors (Basel) ; 21(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807831

RESUMO

Piezoelectric micromachined ultrasonic transducers (PMUT) are promising elements to fabricate a two-dimensional (2D) array with a pitch small enough (approximately half wavelength) to form and receive arbitrary acoustic beams for medical imaging. However, PMUT arrays have so far failed to combine the wide, high-frequency bandwidth needed to achieve a high axial resolution. In this paper, a polydimethylsiloxane (PDMS) backing structure is introduced into the PMUTs to improve the device bandwidth while keeping a sub-wavelength (λ) pitch. We implement this backing on a 16 × 8 array with 75 µm pitch (3λ/4) with a 15 MHz working frequency. Adding the backing nearly doubles the bandwidth to 92% (-6 dB) and has little influence on the impulse response sensitivity. By widening the transducer bandwidth, this backing may enable using PMUT ultrasonic arrays for high-resolution 3D imaging.

5.
Inorg Chem ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33793227

RESUMO

Easily producible sensors for harmful industrial waste compounds are of significant interest for both human health and the environment. Three novel coordination polymers, [Ag(µ-aca)(µ4-bztpy)1/2] (1), [Ag(µ-bza)(µ-bpa)] (2), and [Ag2(µ-aca)2(µ-bpa)2]·EtOH·2H2O (3), were assembled in this study by reactions using Ag+ as a node with the pyridyl ligand 1,2,4,5-tetrakis(4-pyridyl)benzene (bztpy) or 9,10-bis(4-pyridyl)anthracene (bpa) and an auxiliary chelating carboxylic ligand. Single-crystal X-ray structural analyses revealed that compound 1 has a 3D framework consisting of 1D [Ag(aca)]∞ chains and bztpy linkers, while 2 and 3 have 2D layered structures consisting of binuclear Ag-carboxylate units and bpa linkers, respectively. Topological studies revealed that 1 has a bbf topology, while 2 and 3 are 2D [4,4] rhombic grids. The compounds were further characterized by powder X-ray diffraction, IR, elemental analysis, thermogravimetric analysis, and a luminescence study. The solids of 1-3 exhibited intense photoluminescent emission with λemmax at ca. 493, 472, and 500 nm, respectively. Remarkably, due to their excellent framework stability, 1 and 2 can act as multiresponsive luminescent sensors for nitrobenzene, Fe3+, and Cr2O72- with a high selectivity and sensitivity ascribed to their quenching effect.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33780079

RESUMO

Both elevated intolerance of uncertainty (IU) and maladaptive metacognitive beliefs (MBs) were associated with depression. However, the relationship between MBs and IU in clinical depression is unclear. The current study aimed to investigate the putative impairment of MBs and IU in MDD and explore the relationship between these two factors with depressive symptoms. Metacognition questionnaire (MCQ-30), intolerance of uncertainty scale (IUS-12), and clinical rating scales were administered to 53 patients with major depressive disorder (MDD) and 56 healthy controls (HC). Stepwise regressions were performed to explore independent contributions of MBs and IU on depression. Mediation analysis was used to examine associations among variables. Patients with MDD reported higher IUS-12 and MCQ-30 scores than HCs. Stepwise regressions revealed a unique contribution of negative MBs concerning the consequences of not controlling thoughts (MCQ-NC) on depression symptoms while controlling the effects of age, gender, anxiety symptoms, and IU. MCQ-NC and negative MBs concerning the uncontrollability and danger of negative thinking (MCQ-NEG) completely mediated the effects of IU on depression and anxiety symptoms. Our results provided clear evidence that maladaptive negative MBs are directly associated with depression symptoms, and mediated the effect of IU on depression and anxiety symptoms, suggesting that IU and MBs influence clinical symptoms in a hierarchical manner.

7.
Proc Natl Acad Sci U S A ; 118(10)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33658365

RESUMO

Oomycete pathogens such as Phytophthora secrete a repertoire of effectors into host cells to manipulate host immunity and benefit infection. In this study, we found that an RxLR effector, Avr1d, promoted Phytophthora sojae infection in soybean hairy roots. Using a yeast two-hybrid screen, we identified the soybean E3 ubiquitin ligase GmPUB13 as a host target for Avr1d. By coimmunoprecipitation (Co-IP), gel infiltration, and isothermal titration calorimetry (ITC) assays, we confirmed that Avr1d interacts with GmPUB13 both in vivo and in vitro. Furthermore, we found that Avr1d inhibits the E3 ligase activity of GmPUB13. The crystal structure Avr1d in complex with GmPUB13 was solved and revealed that Avr1d occupies the binding site for E2 ubiquitin conjugating enzyme on GmPUB13. In line with this, Avr1d competed with E2 ubiquitin conjugating enzymes for GmPUB13 binding in vitro, thereby decreasing the E3 ligase activity of GmPUB13. Meanwhile, we found that inactivation of the ubiquitin ligase activity of GmPUB13 stabilized GmPUB13 by blocking GmPUB13 degradation. Silencing of GmPUB13 in soybean hairy roots decreased P. sojae infection, suggesting that GmPUB13 acts as a susceptibility factor. Altogether, this study highlights a virulence mechanism of Phytophthora effectors, by which Avr1d competes with E2 for GmPUB13 binding to repress the GmPUB13 E3 ligase activity and thereby stabilizing the susceptibility factor GmPUB13 to facilitate Phytophthora infection. This study unravels the structural basis for modulation of host targets by Phytophthora effectors and will be instrumental for boosting plant resistance breeding.

8.
Nano Today ; : 101139, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33758593

RESUMO

Effective vaccines are vital to the fight against the COVID-19 global pandemic. As a critical component of a subunit vaccine, the adjuvant is responsible for strengthening the antigen-induced immune responses. Here, we present a new nanovaccine that comprising the Receptor-Binding Domain (RBD) of spike protein and the manganese nanoadjuvant (MnARK), which induces humoral and cellular responses. Notably, even at a 5-fold lower antigen dose and with fewer injections, mice immunized with the MnARK vaccine immunized mice showed stronger neutralizing abilities against the infection of the pseudovirus (~270-fold) and live coronavirus (>8-fold) in vitro than that of Alum-adsorbed RBD vaccine (Alu-RBD). Furthermore, we found that the effective co-delivery of RBD antigen and MnARK to lymph nodes (LNs) elicited an increased cellular internalization and the activation of immune cells, including DC cells, CD4+ and CD8+ T lymphocytes. Our findings highlight the importance of MnARK adjuvant in the design of novel coronavirus vaccines and provide a rationale strategy to design protective vaccines through promoting cellular internalization and the activation of immune-related pathways.

9.
Future Oncol ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33769072

RESUMO

Aim: This study investigated the association between clinical data and T790M mutation in rebiopsy after EGFR tyrosine kinase inhibitors (EGFR-TKIs) failure, and explored the prognosis of T790M-positive patients. Methods: Patients with non-small-cell lung cancer undergoing rebiopsy after first-generation TKI failure were reviewed. Results & conclusion: Patients with brain metastases, negative TP53, initial 19del and longer initial PFS had higher positive rate of T790M. The median progression-free survival (PFS) of T790M-positive patients with cytology and tissue rebiopsy were longer than patients with liquid rebiopsy. The median PFS of T790M-positive patients rebiopsied by ordinary bronchoscope and endobronchial ultrasound-guided transbronchial lung biopsy with a guided sheath (EBUS-GS-TBLB) were longer than that of the patients rebiopsied by EBUS transbronchial needle aspiration (TBNA).

11.
Animals (Basel) ; 11(2)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672512

RESUMO

Reproductive efficiency is the main factor limiting yak production on the Tibet Plateau. The purpose of this study was to investigate the effect of supplementation with calcium chloride (CaCl) and monocalcium phosphate (MCP) for 30 days before breeding on body weight (BW) change, serum bone metabolism biomarkers, conception rate, and calving rate of grazing yaks. Ninety 3 year old yak heifers (153.05 ± 6.56 kg BW) were assigned to three treatments (n = 30 per treatment): grazing without supplementation (CONT), grazing plus calcium chloride supplementation (CaCl), and grazing plus monocalcium phosphate supplementation (MCP). Compared with the CONT group, supplementation with CaCl increased the serum concentrations of osteocalcin and decreased the alkaline phosphatase (ALP) levels (p < 0.05); supplementation with MCP increased the average daily gain (ADG), serum concentrations of phosphorus (P) and osteocalcin, conception rate, and calving rate (p < 0.05), whereas it decreased the serum concentrations of hydroxyproline, ALP, and calcitonin (p < 0.05). Both CaCl and MCP supplementation had no effect on serum calcium (Ca) concentration. The ADG, conception rate, and calving rate were higher in the MCP group than in the CaCl group (p < 0.05), while the serum concentrations of hydroxyproline and calcitonin were lower (p < 0.05). It could be concluded that premating supplementation with MCP increased the body weight gain and subsequent conception and calving rate of grazing yaks. Supplementation with MCP had a positive effect on body condition and bone metabolism, thus providing a better estrous condition for grazing yak heifers, which could contribute to enhancing reproduction efficiency.

12.
Ying Yong Sheng Tai Xue Bao ; 32(2): 521-528, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33650361

RESUMO

The activity and stoichiometry of soil extracellular enzyme can provide a good indication for changes in soil nutrient availability and microbial demands for nutrients. However, it remains unclear how would nitrogen (N) deposition affect nutrient limitation of microbes in subtropical forest soils. We conducted a 5 years N addition experiment in a subtropical Phyllostachys pubescens forest. The soil nutrients and enzyme activities associated with carbon (C), N, and phosphorus (P) cycles were measured. We also examined the nutrient distribution of microorganisms using enzyme stoichiometry and vector analysis. The results showed that N addition significantly decreased the contents of soil soluble organic C and available P and increased that of available N. Furthermore, N addition significantly decreased ß-N-acetyl-glucosaminidase (NAG) activity and NAG/ microbial biomass carbon (MBC), and increased acid phosphatase (ACP) and ACP/MBC. The low and moderate N addition levels significantly increased enzyme C/P, vector length, and vector angle, but significantly decreased enzyme N/P. Results of redundancy analysis showed that the change in soil enzyme activity and enzymatic stoichiometry were mainly driven by soil available P content under N addition. In summary, N addition altered the microbial nutrient acquisition strategy, which increased nutrient allocation to P-acquiring enzyme production but reduced that to N-acquiring enzyme production. Moreover, N addition exacerbated the C and P limitation of soil microorganisms. Appropriate amount of P fertilizer could be applied to improve soil fertility of subtropical P. pubescens forest in the future.


Assuntos
Nitrogênio , Fósforo , Carbono/análise , China , Florestas , Nitrogênio/análise , Fósforo/análise , Solo , Microbiologia do Solo
13.
Eur J Med Chem ; 217: 113381, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33756124

RESUMO

KRAS plays an essential role in regulating cell proliferation, differentiation, migration and survival. Mutated KRAS is a major driver of malignant transformation in multiple human cancers. We showed previously that fendiline (6) is an effective inhibitor of KRAS plasma membrane (PM) localization and function. In this study, we designed, synthesized and evaluated a series of new fendiline analogs to optimize its drug properties. Systemic structure-activity relationship studies by scaffold repurposing led to the discovery of several more active KRAS PM localization inhibitors such as compounds 12f (NY0244), 12h (NY0331) and 22 (NY0335) which exhibit nanomolar potencies. These compounds inhibited oncogenic KRAS-driven cancer cell proliferation at single-digit micromolar concentrations in vitro. In vivo studies in a xenograft model of pancreatic cancer revealed that 12h and 22 suppressed oncogenic KRAS-expressing MiaPaCa-2 tumor growth at a low dose range of 1-5 mg/kg with no vasodilatory effects, indicating their potential as chemical probes and anticancer therapeutics.

14.
Chem Commun (Camb) ; 57(26): 3215-3218, 2021 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-33645613

RESUMO

Herein, we report the first use of gluthathione (GSH)-responsive nanogel-based carriers for mitochondria-targeted delivery of functional proteins and antibodies. We further demonstrated the successful co-encapsulation of a protein and small molecule (RNase A/Doxorubicin) in dual-cargo nanocapsules for mitochondria-targeted combination therapy.

15.
Med Sci Monit ; 27: e929394, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33753712

RESUMO

BACKGROUND Bladder cancer is a malignant tumor of the genitourinary system. Different subtypes of bladder cancer have different treatment methods and prognoses. Therefore, identifying hub genes affecting other genes is of great significance for the treatment of bladder cancer. MATERIAL AND METHODS We obtained expression profiles from the GSE13507 and GSE77952 datasets from the Gene Expression Omnibus database. First, principal component analysis was used to identify the difference in gene expression in different types of tissues. Differential expression analysis was used to find the differentially expressed genes between normal and tumor tissues, and between tumors with and without muscle infiltration. Further, based on differentially expressed genes, we constructed 2 decision trees for differentiating between tumor and normal tissues, and between muscle-infiltrating and non-muscle-infiltrating tumor tissues. A receiver operating characteristic curve was used to evaluate the prediction effect of the decision trees. RESULTS FAM107A and C8orf4 showed significantly lower expression in bladder cancer tissues than in normal tissues. Regarding muscle infiltration, CTHRC1 showed lower expression and HMGCS2 showed higher expression in non-muscle-infiltrating samples than in those with muscle infiltration. We constructed 2 decision trees for differentiating between tumor and normal tissue, and between tissues with and without muscle infiltration. Both decision trees showed good prediction results. CONCLUSIONS These newly discovered hub genes will be helpful in understanding the occurrence and development of different subtypes of bladder cancer, and will provide new therapeutic targets and biomarkers for bladder cancer.

16.
Zhongguo Zhong Yao Za Zhi ; 46(5): 1060-1066, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33787097

RESUMO

Rhei Radix et Rhizoma is a kind of commonly used Chinese medicinal materials. Due to the overharvesting, the wild resource is endangering. Large market demand caused severely adulterant of commercial Rhei Radix et Rhizoma medicinal materials and decoction pieces. This manuscript reviewed the advances of the original species authentication in the industrial chain of Rhei Radix et Rhizoma during the latest decade, including characteristics and microscopic features, phytochemical analysis on anthraquinones, and molecular authentication based on DNA barcoding. Accordingly, an original species authentication route for the industrial chain of Rhei Radix et Rhizoma was summarized:(1)the identification of seeds and seedlings by DNA barcoding;(2) the selection of high variable sites based on the chloroplast genome;(3)biomonitoring of the Rhei Radix et Rhizoma medicinal materials and decoction pieces by two-dimensional DNA barcode;(4)traceability of Chinese patent medicines by third-generation sequencing. In conclusion, the combination of molecular identification and traditional identification methods provides a new idea for the identification of the original species of Rhei Radix et Rhizoma in the industrial chain and a essential guidance for the research of drug safety and efficacy of Rhei Radix et Rhizoma.


Assuntos
Medicamentos de Ervas Chinesas , Rheum , Animais , Antraquinonas , Raízes de Plantas , Rizoma
17.
Inflammation ; 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33751359

RESUMO

Acute lung injury (ALI) is an urgent disease lacking effective therapies, resulting in relatively high morbidity and mortality. The pathological mechanism of ALI is reported to be related to excessive inflammation and activated oxidative stress. The present study aims to investigate the protective effects of the DPP-4 inhibitor Trelagliptin against lipopolysaccharide (LPS)-induced ALI and the underlying mechanism. LPS was used to induce ALI mice models. The pathological condition of ALI mice was evaluated using MPO activity assay, lung wet to dry weight ratio detection, and HE staining on the lung tissues. Lung function was assessed using a spirometer. The oxidative stress level in the lung tissues was checked by MDA measurement and GPx detection using commercial kits. The leukocyte and neutrophil numbers were determined using a hemocytometer and the total concentration of protein in the BALF was detected using a bicinchoninic acid method. The expression levels of TNF-α, IL-6, and CXCL2 in the lung tissues were evaluated using qRT-PCR and ELISA. Western blot analysis was used to determine the expression levels of TLR4 and p-NF-κB p65. LPS-induced elevated MPO activity, pulmonary wet to dry weight ratio, airway resistance (RAW), the total number of leukocytes and neutrophils, production of inflammatory factors, decreased pulmonary dynamic compliance (Cdyn), and peak expiratory flow (PEF), and an aggravated histopathological state (such as disordered alveolar structure, significant pulmonary interstitial edema, and large numbers of red blood cells and inflammatory cells in the alveolar cavity) were significantly reversed by the administration of Trelagliptin. The TLR4/NF-κB signaling pathway was activated and oxidative stress was induced by stimulation with LPS; however, both effects were suppressed by the administration of Trelagliptin. Trelagliptin might alleviate LPS-induced inflammation and oxidative stress in acute lung injury mice.

18.
Orthop Surg ; 13(2): 506-516, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33615746

RESUMO

OBJECTIVE: To compare the preventive effects of teriparatide and alendronate on the progression of vertebral body collapse in postmenopausal single-level Kümmell's disease (KD). METHODS: From March 2013 to December 2020, the medical records for 53 postmenopausal single-level KD patients who received conservative treatment with teriparatide (25 patients, teriparatide group) or alendronate (28 patients, alendronate group) were retrospectively reviewed. Midsagittal computed tomography (CT) images were analyzed by ImageJ to assess the intravertebral bone formation (mineralized bone) by calculating the ratio of area of intravertebral mineralized bone (AIMB) to the area of fractured vertebral body (AFVB). The changes in radiological parameters of the fractured vertebral body including kyphosis angle (KA), anterior and posterior border heights (ABH and PBH) and spinal canal diameter (SCD), bone turnover biomarkers (BTMs), and bone mineral density (BMD) were analyzed to evaluate the therapeutic effect. RESULTS: At month 12, the ratio of AIMB to AFVB was significantly greater in teriparatide group (54.28% ± 15.30%) than in alendronate group (35.57% ± 17.61%) (P < 0.001). Sagittal CT substantiated the formation of bone bridge in 16 patients in teriparatide group. No bone bridge was detected in alendronate group. The KA was significantly smaller and the ABH, PBH, and SCD was greater in teriparatide group than in alendronate group (all P < 0.001). The KA increments were significantly smaller in teriparatide group (3.98° ± 1.30°) than in alendronate group (11.43° ± 3.73°) (P < 0.001). The ABH and PBH decrement were significantly lower in teriparatide group (11.96% ± 1.93% and 2.80% ± 2.52%) than in alendronate group (37.04% ± 8.00% and 19.50% ± 8.22%) (both P < 0.001). The BTMs and BMD were significantly greater in the teriparatide group than in the alendronate group. In teriparatide group, KA increment was negatively correlated with the change in PINP (r = -0.781, P < 0.001) and the ratio of AIMB to AFVB (r = -0.592, P = 0.002) from baseline to month 12. The ABH decrement was negatively correlated with the change in PINP (r = -0.612, P = 0.001) and the ratio of AIMB to AFVB (r = -0.806, P < 0.001) from baseline to month 12. CONCLUSIONS: In postmenopausal single-level KD patients, conservative treatment with teriparatide was better than alendronate at preventing the progressive vertebral collapse.

19.
Behav Pharmacol ; 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33595955

RESUMO

The concept of 'impulse control' has its roots in early psychiatry and today has progressed into a well-described, although poorly understood, multidimensional endophenotype underlying many neuropsychiatric disorders (e.g., attention deficit hyperactivity disorder, schizophrenia, substance use disorders). There is mounting evidence suggesting that the cognitive and/or behavioral dimensions underlying impulsivity are driven by dysfunctional glutamate (Glu) neurotransmission via targeted ionotropic Glu receptor (GluR) [e.g., N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)] mechanisms and associated synaptic alterations within key brain nodes. Ketamine, a noncompetitive NMDAR antagonist and FDA-approved for treatment-resistant depression, induces a 'glutamate burst' that drives resculpting of the synaptic milieu, which lasts for several days to a week. Thus, we hypothesized that single and repeated treatment with a subanesthetic ketamine dose would normalize motor impulsivity. Next, we hypothesized that AMPAR positive allosteric modulation, alone or in combination with ketamine, would attenuate impulsivity and provide insight into the mechanisms underlying GluR dysfunction relevant to motor impulsivity. To measure motor impulsivity, outbred male Sprague-Dawley rats were trained on the one-choice serial reaction time task. Rats pretreated with single or repeated (3 days) administration of ketamine (10 mg/kg; i.p.; 24-h pretreatment) or with the AMPAkine HJC0122 (1 or 10 mg/kg; i.p.; 30-min pretreatment) exhibited lower levels of motor impulsivity vs. control. Combination of single or repeated ketamine plus HJC0122 also attenuated motor impulsivity vs. control. We conclude that ligands designed to promote GluR signaling represent an effective pharmacological approach to normalize impulsivity and subsequently, neuropsychiatric disorders marked by aberrant impulse control.

20.
Int J Mol Sci ; 22(4)2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33562748

RESUMO

Human adenoviruses (HAdVs) display a wide range of tissue tropism and can cause an array of symptoms from mild respiratory illnesses to disseminated and life-threatening infections in immunocompromised individuals. However, no antiviral drug has been approved specifically for the treatment of HAdV infections. Herein, we report our continued efforts to optimize salicylamide derivatives and discover compound 16 (JMX0493) as a potent inhibitor of HAdV infection. Compound 16 displays submicromolar IC50 values, a higher selectivity index (SI > 100) and 2.5-fold virus yield reduction compared to our hit compound niclosamide. Moreover, unlike niclosamide, our mechanistic studies suggest that the antiviral activity of compound 16 against HAdV is achieved through the inhibition of viral particle escape from the endosome, which bars subsequent uncoating and the presentation of lytic protein VI.

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