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Intestinal tuft cells, a kind of epithelial immune cells, rapidly expand in response to pathogenic infections, which is associated with infection-induced interleukin 25 (IL-25) upregulation. However, the metabolic mechanism of IL-25-induced tuft cell expansion is largely unknown. Folate metabolism provides essential purine and methyl substrates for cell proliferation and differentiation. Thus, we aim to investigate the roles of folate metabolism playing in IL-25-induced tuft cell expansion by enteroviral infection and recombinant murine IL-25 (rmIL-25) protein-stimulated mouse models. At present, enteroviruses, such as EV71, CVA16, CVB3, and CVB4, upregulated IL-25 expression and induced tuft cell expansion in the intestinal tissues of mice. However, EV71 did not induce intestinal tuft cell expansion in IL-25-/- mice. Interestingly, compared to the mock group, folate was enriched in the intestinal tissues of both the EV71-infected group and the rmIL-25 protein-stimulated group. Moreover, folate metabolism supported IL-25-induced tuft cell expansion since both folate-depletion and anti-folate MTX-treated mice had a disrupted tuft cell expansion in response to rmIL-25 protein stimulation. In summary, our data suggested that folate metabolism supported intestinal tuft cell expansion in response to enterovirus-induced IL-25 expression, which provided a new insight into the mechanisms of tuft cell expansion from the perspective of folate metabolism.
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Infecções por Enterovirus , Ácido Fólico , Células em Tufo , Animais , Camundongos , Proliferação de Células , Enterovirus/metabolismo , Infecções por Enterovirus/metabolismo , Interleucina-17/metabolismo , Células em Tufo/metabolismo , Ácido Fólico/farmacologiaRESUMO
Herpes simplex virus-1 (HSV-1) infection of the eyes leads to herpes simplex virus keratitis (HSK), the main cause of infectious blindness in the world. As the current therapeutics for HSV-1 infection are rather limited and prolonged use of acyclovir (ACV)/ganciclovir (GCV) and in immunocompromised patients lead to the rise of drug resistant mutants, it underlines the urgent need for new antiviral agents with distinct mechanisms. Our study attempted to establish ras-related C3 botulinum toxin substrate 1 (Rac1) as a new therapeutic target for HSV-1 infection by using Rac1-specific inhibitors to evaluate the in vitro inhibition of virus growth. Our results showed that increased Rac1 activity facilitated HSV-1 replication and inhibition of Rac1 activity by NSC23766 and Ehop016 significantly reduced HSV-1 replication. Thus, we identified NSC23766 and Ehop016 as possessing potent anti-HSV-1 activities by suppressing the Rac1 activity, suggesting that Rac1 is a potential target for treating HSV-1-related diseases.
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Aminoquinolinas/farmacologia , Antivirais/farmacologia , Carbazóis/farmacologia , Herpes Simples/tratamento farmacológico , Pirimidinas/farmacologia , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Aminoquinolinas/uso terapêutico , Animais , Antivirais/uso terapêutico , Carbazóis/uso terapêutico , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Células HeLa , Herpes Simples/virologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/fisiologia , Humanos , Pirimidinas/uso terapêutico , Células Vero , Replicação Viral/efeitos dos fármacos , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
One-dimensional noble-metal Ag nanoparticle chains have been prepared by electrodepositing Ag/Bi superlattice nanowires in a porous anodic alumina oxide (AAO) template and following an annealing process in vacuum. It is found that Bi, as a sacrificial metal, can be removed completely after annealing at 450 °C with a vacuum degree of 10(-5) Torr. The regulation of particle size, shape and interparticle spacing of Ag NP chains has been realized by adjusting the segment length of the Ag/Bi superlattice nanowires and the annealing condition. With an extension of the annealing time, it is observed that Ag particles display the transform trend from ellipsoid to sphere. Our findings could inspire further investigation on the design and fabrication of metal nanoparticle chains.
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The tyrosine and phosphoinositide kinases play crucial roles in the regulation of many cancer cell processes including cell survival and cell motility. Anaplastic thyroid carcinoma (ATC) is a rare and deadly type of thyroid cancer, and so far, there are no effective therapeutic compounds for ATC. Herein, we investigate the anticancer activities of PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, in ATC therapy. We found that PP121 is effective at suppressing cell viability, inducing cell apoptosis, and inhibiting cell migration and invasion. The potential anticancer mechanism for PP121 might be its inhibitory effects on phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways in ATC cells. Furthermore, PP121 is effective at suppressing ATC tumor growth in vivo. In summary, our studies suggest that PP121 might be a promising therapeutic compound for ATC treatment, which might shed new light on ATC therapy.
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Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , 1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , 1-Fosfatidilinositol 4-Quinase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Imuno-Histoquímica , Camundongos Nus , Microscopia de Fluorescência , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carcinoma Anaplásico da Tireoide/metabolismo , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Purpose: To determine the effects of EV-A71 (Enterovirus A71) infection on ocular surface and its mechanism. Methods: AG6 mice aged two to three weeks were randomly divided into control and EV-A71 infected groups. Slit-lamp observation, fluorescein staining, and phenol red thread test were used to assess symptoms of ocular surface at 4 dpi (days post infection). The pathological changes of cornea and lacrimal gland were observed by H&E staining, PAS staining, TUNEL assay, IHC staining and qRT-PCR. Corneas and lacrimal glands from mice were obtained and processed for RNA sequencing analysis. Newly diagnosed HFMD patients caused by EV-A71 were recruited and ensured they met the inclusion criteria. Ocular surface parameters (TMH and NIKBUT) were measured using the OCULUS Keratograph 5M. Tear samples were taken to examine Cxcl1 and IL-6 levels through the ELISA method. Results: Mice studies revealed that EV-A71 infection caused tear film instability, decreased tear secretions, decreased in lacrimal gland size, and distinct goblet cell loss. It also resulted in increased large vacuoles within acinar cells and structural damage in lacrimal gland. Apart from minor damage to the epidermis, there was no obvious inflammatory changes or apoptosis in the cornea. However, there were significant inflammatory injury and apoptosis in the lacrimal gland. RNA-seq analysis showed IL-17 and NF-κB signaling pathways were activated in the lacrimal glands of mice infected with EV-A71. In HFMD patients, the THM was in a low range and NITBUT was significantly shorter than the control group by Oculus Keratograph 5M. ELISA assay showed a higher tear Cxcl1 and IL-6 level in them. Conclusion: EV-A71 infection affected lacrimal gland structure and function and induced dry eye-like symptoms.
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Síndromes do Olho Seco , Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Aparelho Lacrimal , Humanos , Animais , Camundongos , Interleucina-6 , Síndromes do Olho Seco/etiologiaRESUMO
Varicella zoster virus (VZV) is associated with herpes zoster (HZ) or herpes zoster ophthalmicus (HZO). All antiviral agents currently licensed for the management of VZV replication via modulating different mechanisms, and the resistance is on the rise. There is a need to develop new antiviral agents with distinct mechanisms of action and adequate safety profiles. Pralatrexate (PDX) is a fourth-generation anti-folate agent with an inhibitory activity on folate (FA) metabolism and has been used as an anti-tumor drug. We observed that PDX possessed potent inhibitory activity against VZV infection. In this study, we reported the antiviral effects and the underlying mechanism of PDX against VZV infection. The results showed that PDX not only inhibited VZV replication in vitro and in mice corneal tissues but also reduced the inflammatory response and apoptosis induced by viral infection. Furthermore, PDX treatment showed a similar anti-VSV inhibitory effect in both in vitro and in vivo models. Mechanistically, PDX inhibited viral replication by interrupting the substrate supply for de novo purine and thymidine synthesis. In conclusion, this study discovered the potent antiviral activity of PDX with a novel mechanism and presented a new strategy for VZV treatment that targets a cellular metabolic mechanism essential for viral replication. The present study provided a new insight into the development of broad-spectrum antiviral agents.
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Aminopterina/análogos & derivados , Herpes Zoster , Estomatite Vesicular , Animais , Camundongos , Herpesvirus Humano 3 , Estomatite Vesicular/tratamento farmacológico , Herpes Zoster/tratamento farmacológico , Vírus da Estomatite Vesicular Indiana , Vesiculovirus , Antivirais/farmacologia , Antivirais/uso terapêutico , Replicação ViralRESUMO
Solar energy interfacial evaporation represents a promising and sustainable approach with considerable potential for seawater desalination and wastewater treatment. Nonetheless, creating durable evaporators for continuous operation presents a challenge. Motivated by natural self-healing mechanisms, this study developed a novel 3D hybrid aero-hydrogel, which exhibited a self-healing efficiency of 89.4 % and an elongation at break post-healing of 637.7 %, featuring self-healing capabilities and continuous operation potential. Especially, the incorporation of hyperbranched water-soluble polymers (peach gum polysaccharide) endow the final solar water evaporators with a lower evaporation enthalpy of water, resulting in that the refined SVG3, with a notable water surface architecture and an expanded evaporation area, achieved a steam generation rate of 2.13 kg m-2 h-1 under 1 Sun. Notably, SVG2 achieved a high evaporation rate of 2.43 kg m-2 h-1 with the combined energy input of 1 Sun and 6 V, significantly surpassing the rate of 1.96 kg m-2 h-1 without voltage input. The results indicate that electrical energy significantly enhances and synergizes with SVG, facilitating continuous operation both day and night through the combined use of solar energy and electrical input. This study offers insightful perspectives for the strategic design of multifunctional hydrogels for solar water evaporation.
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Hidrogéis , Gomas Vegetais , Polissacarídeos , Energia Solar , Gomas Vegetais/química , Hidrogéis/química , Polissacarídeos/química , Vapor , Prunus armeniaca/química , Água/químicaRESUMO
The severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel phlebovirus, recently being officially renamed as Dabie bandavirus, and a causative agent for an emerging infectious disease associated with high fatality. Effective therapeutics and vaccines are lacking and disease pathogenesis is yet to be fully elucidated. In our effort to identify new SFTSV inhibitory molecules, 6-Thioguanine (6-TG) was found to potently inhibit SFTSV infection. 6-TG has been widely used as therapeutic agent since the approval of the Food and Drug Administration in the 1960s. In the current study, we showed that 6-TG was a potent inhibitor of SFTSV infection with 50% effective concentrations (EC50) of 3.465 µM in VeroE6 cells, and 1.848 µM in HUVEC cells. The selectivity index (SI) was >57 in VeroE6 cells and >108 in HUVEC cells, respectively. The SFTSV RNA transcription, protein synthesis, and progeny virions were reduced in a dose dependent manner by the presence of 6-TG in the in vitro infection assay. Further study on the mechanism of the anti-SFTSV activity showed that 6-TG downregulated the production of early growth response gene-1 (EGR1). Using gene silencing and overexpression, we further confirmed that EGR1 was a host restriction factor against SFTSV. Meanwhile, treatment of infected experimental animals with 6-TG inhibited SFTSV infection and alleviated multi-organ dysfunction. In conclusion, we have identified 6-TG as an effective inhibitor of SFTSV replication via the inhibition of EGR1 expression. Further studies are needed to evaluate of 6-TG as a potential therapeutic for treating SFTS.
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Antivirais , Proteína 1 de Resposta de Crescimento Precoce , Células Endoteliais da Veia Umbilical Humana , Phlebovirus , Tioguanina , Replicação Viral , Animais , Phlebovirus/efeitos dos fármacos , Humanos , Replicação Viral/efeitos dos fármacos , Tioguanina/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Camundongos , Células Vero , Antivirais/farmacologia , Chlorocebus aethiops , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/genética , Febre Grave com Síndrome de Trombocitopenia/tratamento farmacológico , Febre Grave com Síndrome de Trombocitopenia/virologia , Linhagem CelularRESUMO
RATIONALE: Hypoglycemia may cause diverse neurological manifestations, ranging from focal neurological deficits to irreversible coma. Severe and persistent hypoglycemia can lead to hypoglycemic encephalopathy (HE). Imaging findings of HE at different stages of 18F-FDG positron emission tomography/computed tomography (PET/CT) have rarely been reported. Herein, we describe a case of HE occurring in the medial frontal cortex, cerebellar cortex, and dentate nucleus using 18F-FDG PET/CT images from different periods. 18F-FDG PET/CT has a high value in displaying the lesion range and indicating the prognosis. PATIENT CONCERNS: A 57-year-old male patient with type 2 diabetes (T2D) was transferred to the hospital with a history of unconsciousness for 1 night. The patient showed a significant decrease in blood glucose levels. DIAGNOSES: The patient was initially diagnosed with a hypoglycemic coma. INTERVENTIONS: The patient subsequently underwent a comprehensive treatment. The 18F-FDG PET/CT examination on the fifth day after admission revealed a significant symmetrical fluorodeoxyglucose (FDG)-positive accumulation in the bilateral medial frontal gyrus, cerebellar cortex, and dentate nucleus. A follow-up PET/CT examination 6 months later revealed hypometabolism in the bilateral medial frontal gyrus and no abnormalities in FDG uptake in the bilateral cerebellar cortex and dentate nucleus. OUTCOMES: The patient condition was stable 6 months later, with a slow response, memory deterioration, occasional dizziness, and episodes of hypoglycemia. LESSONS: HE lesions with a high metabolic status may be related to a metabolic compensation mechanism in response to gray matter loss. Some of the more severely damaged cells eventually die even after the blood sugar levels return to normal. Less damaged nerve cells can be recovered. 18F-FDG PET/CT has high value in indicating the lesion range and prognosis of HE.
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Diabetes Mellitus Tipo 2 , Hipoglicemia , Masculino , Humanos , Pessoa de Meia-Idade , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Diabetes Mellitus Tipo 2/complicações , Hipoglicemia/diagnóstico por imagem , Hipoglicemia/etiologia , Compostos RadiofarmacêuticosRESUMO
BACKGROUND: Folate (FA) is an essential cofactor in the one-carbon (1C) metabolic pathway and participates in amino acid metabolism, purine and thymidylate synthesis, and DNA methylation. FA metabolism has been reported to play an important role in viral replications; however, the roles of FA metabolism in the antiviral innate immune response are unclear. OBJECTIVE: To evaluate the potential regulatory role of FA metabolism in antiviral innate immune response, we establish the model of FA deficiency (FAD) in vitro and in vivo. The molecular and functional effects of FAD on 2'-5'-oligoadenylate synthetases (OAS)-associated antiviral innate immunity pathways were assessed; and the potential relationship between FA metabolism and the axis of adenosine deaminases acting on RNA 3 (ADAR3)/endogenous double-stranded RNA (dsRNA)/OAS was further explored in the present study, as well as the potential translatability of these findings in vivo. METHODS: FA-free RPMI 1640 medium and FA-free feed were used to establish the model of FAD in vitro and in vivo. And FA and homocysteine (Hcy) concentrations in cell culture supernatants and serum were used for FAD model evaluation. Ribonucleoprotein immunoprecipitation assay was used to enrich endogenous dsRNA, and dot-blot was further used for quantitative analysis of endogenous dsRNA. Western-blot assay, RNA isolation and quantitative real-time PCR, immunofluorescence assay, and other molecular biology techniques were used for exploring the potential mechanisms. RESULTS: In this study, we observed that FA metabolism negatively regulated OAS-mediated antiviral innate immune response. Mechanistically, FAD induced ADAR3, which interacted with endogenous dsRNA, to inhibit deaminated adenosine (A) being converted into inosine (I), leading to the cytoplasmic accumulation of dsRNA. Furthermore, endogenous dsRNA accumulated in cytoplasm triggered the host immune activation, thus promoting the expression of OAS2 to suppress the replication of viruses. Additionally, injection of 8-Azaadenosine to experimental animals, an A-to-I editing inhibitor, efficiently enhanced OAS-mediated antiviral innate immune response to reduce the viral burden in vivo. CONCLUSIONS: Taken together, our present study provided a new perspective to illustrate a relationship between FA metabolism and the axis of ADAR3/endogenous dsRNA/OAS, and a new insight for the treatment of RNA viral infectious diseases by targeting the axis of ADAR3/endogenous dsRNA/OAS.
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Antivirais , RNA de Cadeia Dupla , Animais , Adenosina , Antivirais/farmacologia , Imunidade Inata , Proteínas de Ligação a RNA/metabolismo , Adenosina Desaminase/metabolismoRESUMO
Herpes simplex keratitis (HSK) is a blinding eye disease that is initiated by the herpes simplex virus type 1 (HSV-1). Resistance to acyclovir (ACV) and the side effects of corticosteroid drugs have become concerning issues, so it is crucial to develop new antivirals for treating HSK. In this study, we report that biochanin A (BCA), a naturally occurring flavonoid compound, provides multifaceted protective effects with anti-viral, anti-inflammatory, anti-oxidative stress and anti-apoptotic activities to alleviate HSK. The results show that BCA significantly inhibited HSV-1 replication in vitro and further proved that BCA principally influenced the early stage of virus infection. We reveal that BCA downregulated the expression of pro-inflammatory factors triggered by HSV-1, including TNF-α, RANTES, IL-1ß and IL-6. Furthermore, BCA treatment alleviated oxidative stress and apoptotic arising from HSV-1 infection. Lastly, we induced HSK in male C57BL/6 mice and treated them with either BCA or phosphate buffer solution (PBS) eye drops. We observed the ocular surface lesions; determined the virus load in the tear fluid, corneas as well as trigeminal ganglions (TGs); and detected the levels of inflammation and apoptosis in the corneas simultaneously. These results show that BCA inhibits HSV-1 and alleviates the corneal lesion degree. Our study illustrates that BCA is a promising therapeutic approach for application in treating HSK.
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PURPOSE: EV71 (Enterovirus 71) is a major causative agent of the outbreaks of HFMD (hand, foot, and mouth disease), which is associated with neurological damage caused by permeability disruption of BBB (blood-brain barrier). HMGB1 (high-mobility group box 1) is a widely expressed nuclear protein that triggers host inflammatory responses. Our work aimed to explore the function of HMGB1 in EV71 infection and its contributions to EV71-related BBB damage. METHODS: HeLa cells, HT-29 cells and AG6 mice were used to explore the translocation of HMGB1 in EV71 infection in vitro and in vivo. The roles of released HMGB1 on EV71 replication and associated inflammatory cytokines were investigated using recombinant HMGB1 in HeLa cells. The mechanisms of released HMGB1 in EV71-induced BBB injury were explored using recombinant HMGB1 and anti-HMGB1 neutralizing antibodies in monolayer HCMECs (immortalized human brain microvascular endothelial cells) and AG6 mice brain. RESULTS: EV71 induced HMGB1 nucleocytoplasmic translocation and extracellular release in vitro and in vivo. Released HMGB1 acted as an inflammatory mediator in EV71 infection rather than affecting viral replication in vitro. Released HMGB1 disrupted BBB integrity by enhancing VE-cadherin phosphorylation at tyrosine 685 in HCMECs, and reducing total VE-cadherin levels in HCMECs and AG6 mice in EV71 infection. And released HMGB1 induced an increase in activated astrocytes. Neutralization of HMGB1 reversed the increased endothelial hyperpermeability and phosphorylation of VE-cadherin in HCMECs. CONCLUSION: The inflammatory mediator HMGB1 released by EV71 exacerbated BBB disruption by enhancing VE-cadherin phosphorylation, which in turn aggravated EV71-induced neuroinflammation.
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Barreira Hematoencefálica , Proteína HMGB1 , Humanos , Camundongos , Animais , Barreira Hematoencefálica/metabolismo , Células Endoteliais/metabolismo , Proteína HMGB1/metabolismo , Proteína HMGB1/farmacologia , Fosforilação , Células HeLa , Mediadores da Inflamação/metabolismoRESUMO
Folate receptor alpha (FOLR1) is vital for cells ingesting folate (FA). FA plays an indispensable role in cell proliferation and survival. However, it is not clear whether the axis of FOLR1/FA has a similar function in viral replication. In this study, we used vesicular stomatitis virus (VSV) to investigate the relationship between FOLR1-mediated FA deficiency and viral replication, as well as the underlying mechanisms. We discovered that FOLR1 upregulation led to the deficiency of FA in HeLa cells and mice. Meanwhile, VSV replication was notably suppressed by FOLR1 overexpression, and this antiviral activity was related to FA deficiency. Mechanistically, FA deficiency mainly upregulated apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) expression, which suppressed VSV replication in vitro and in vivo. In addition, methotrexate (MTX), an FA metabolism inhibitor, effectively inhibited VSV replication by enhancing the expression of APOBEC3B in vitro and in vivo. Overall, our present study provided a new perspective for the role of FA metabolism in viral infections and highlights the potential of MTX as a broad-spectrum antiviral agent against RNA viruses.
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Receptor 1 de Folato , Vírus da Estomatite Vesicular Indiana , Humanos , Animais , Camundongos , Células HeLa , Receptor 1 de Folato/farmacologia , Vírus da Estomatite Vesicular Indiana/genética , Antivirais/farmacologia , Replicação Viral , Ácido Fólico/farmacologia , Citidina Desaminase/genética , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/farmacologia , Desaminases APOBECRESUMO
Background: The current diagnosis of Parkinson's disease (PD) is mainly based on the typical clinical manifestations. However, 60% dopaminergic neurons have died when the typical clinical manifestations occur. Predictive neurobiomarkers may help identify those PD patients having non-motor disorders or in different stage and achieving the aim of early diagnosis. Up to date, few if any neuroimaging techniques have been described useful for non-movement disorders diagnosis in PD patients. Here, we investigated the alteration of metabolites in PD patients in different stage of PD and non-motor symptoms including sleep, gastrointestinal and cognitive dysfunction, by using the 1H-MRS. Methods: A total of 48 subjects were included between 2017 and 2019: 37 PD (15 men, age 47-82 years) and 11 healthy people (8 men, age 49-74 years). All participants underwent MRI and multi-voxel 1H-MRS examination within 3 days in admission. Six kinds of metabolites, such as creatine (Cr), N-acetyl aspartate/creatine (NAA/Cr), N-acetyl aspartate/choline (NAA/Cho), choline/creatine (Cho/Cr), lipid/creatine (LL/Cr), and myo-Inositol/creatine ratio (mI/Cr) were tested among the PD group and the control groups. Statistical analyses and correlation analyses were performed by using SPSS. The p < 0.05 was considered statistically significant. Results: Compared late PD group with a control group or early group, higher Cr ratio and lower NAA/Cr ratio were observed in the late PD group (p < 0.05). The mI/Cr in the late PD group was also lower than that in the early PD group (p < 0.05). Regarding the relationship between metabolites and NMS, Cho/Cr was higher in the sleep disorder group, whereas mI/Cr was lower in the gastrointestinal dysfunction group in comparison with the non-symptom groups. Moreover, Cr, Cho/Cr, mI/Cr, and LL/Cr were identified to have higher concentrations in the cognitive group in thalamus. Conclusions: Proton magnetic resonance spectroscopy is an advanced tool to quantify the metabolic changes in PD. Three biomarkers (Cr, NAA/Cr, and mI/Cr) were detected in the late stage of PD, suggesting that these markers might be potential to imply the progression of PD. In addition, subgroups analysis showed that MRS of thalamus is a sensitive region for the detection of cognitive decline in PD, and the alteration of neurochemicals (involving Cr, Cho, mI, and LL) may be promising biomarkers to predict cognitive decline in PD.
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Herpes simplex virus type 1 (HSV-1) infection induces various clinical disorders, such as herpes simplex encephalitis (HSE), herpes simplex keratitis (HSK), and genital herpes. In clinical intervention, acyclovir (ACV) is the major therapeutic drug used to suppress HSV-1; however, ACV-resistant strains have gradually increased. In the present study, harringtonine (HT) significantly inhibited infection of HSV-1 as well as two ACV-resistant strains, including HSV-1 blue and HSV-1 153. Time-of-drug addition assay further revealed that HT mainly reduced the early stage of HSV-1 infection. We also demonstrated that HT mainly affected herpes virus entry mediator (HVEM) expression as shown by qPCR, Western Blot, and Immunofluorescence. Collectively, HT showed antiviral activity against HSV-1 and ACV-resistant strains by targeting HVEM and could be a promising therapeutic candidate for mitigating HSV-1-induced-pathogenesis.
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Herpes simplex virus 1 (HSV-1) infects eye corneal tissues leading to herpetic stromal keratitis (HSK), which is one of the leading causes of blindness. Here in our study, we found that 6-thioguanine (6-TG), a once clinically approved medication for child acute myelogenous leukemia, inhibited multiple strains of HSV-1 infection in vitro and in vivo. 6-TG is more potent than acyclovir (ACV) and ganciclovir (GCV), with the 50% inhibitory concentration (IC50) of 6-TG at 0.104 µM with high stimulation index (SI) (SI = 6,475.48) compared to the IC50 of ACV at 1.253 µM and the IC50 of GCV at 1.257 µM. In addition, 6-TG at 500 µM topically applied to the eyes with HSV-1 infection significantly inhibits HSV-1 replication, alleviates virus-induced HSK pathogenesis, and improves eye conditions. More importantly, 6-TG is effective against ACV-resistant HSV-1 strains, including HSV-1/153 and HSV-1/blue. Knockdown of Rac1 with small interfering RNA (siRNA) negatively affected HSV-1 replication, suggesting that Rac1 facilitated HSV-1 replication. Following HSV-1 infection of human corneal epithelial cells (HCECs), endogenous Rac1 activity was upregulated by glutathione S-transferase (GST) pulldown assay. We further found that Rac1 was highly expressed in the corneal tissue of HSK patients compared to normal individuals. Mechanistic study showed that 6-TG inhibited HSV-1 replication by targeting Rac1 activity in HSV-1 infected cells, and the Rac1 is critical in the pathogenesis of HSK. Our results indicated that 6-TG is a promising therapeutic molecule for the treatment of HSK. IMPORTANCE We reported the discovery of 6-TG inhibition of HSV-1 infection and its inhibitory roles in HSK both in vitro and in vivo. 6-TG was shown to possess at least 10× more potent inhibitory activity against HSV-1 than ACV and GCV and, more importantly, inhibit ACV/GCV-resistant mutant viruses. Animal model studies showed that gel-formulated 6-TG topically applied to eyes locally infected with HSV-1 could significantly inhibit HSV-1 replication, alleviate virus-induced HSK pathogenesis, and improve eye conditions. Further study showed that HSV-1 infection upregulated Rac1 expression, and knockdown of Rac1 using siRNA markedly restricted HSV-1 replication, suggesting that Rac1 is required for HSV-1 replication. In addition, we also documented that Rac1 is highly expressed in corneal tissues from HSK patients, indicating that Rac1 is associated with HSK pathogenesis. In view of the high potency of 6-TG, low cytotoxicity, targeting a distinct therapeutic target, we suggest that 6-TG is a potential candidate for development as a therapeutic agent for HSK therapy.
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Antivirais/administração & dosagem , Herpesvirus Humano 1/efeitos dos fármacos , Ceratite Herpética/tratamento farmacológico , Tioguanina/administração & dosagem , Animais , Antivirais/química , Ganciclovir/farmacologia , Herpes Simples , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/fisiologia , Humanos , Ceratite Herpética/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Tioguanina/química , Replicação Viral/efeitos dos fármacosRESUMO
OBJECTIVE: To investigate the relationship between serum omega-3 polyunsaturated fatty acid (omega-3PUFA) and insulin resistance (IR) in patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease (NAFLD). METHODS: This trial involved 51 patients of type 2 diabetes mellitus with NAFLD (G4 group), 50 patients of type 2 diabetes alone (G3 group), 45 patients of NAFLD alone (G2 group) and 42 healthy control subjects (G1 group). Serum omega-3PUFA profile was analyzed with capillary gas chromatography. Insulin resistance was assessed by homeostasis model assessment (HOMA-IR). ALT, AST, gamma-glutamyltransferase (GGT) and serum lipids were measured. RESULTS: The levels of HOMA-IR were higher in G4 group than those in G3, G2 and G1 group (4.90 + or - 2.54 vs 2.38 + or - 1.23, 2.20 + or - 1.15, 1.13 + or - 0.42; P < 0.05). The level of ALT, AST, GGT, TC, TG, LDL-C were higher in G4 group than those in G3, G2 and G1 group (P < 0.05). The level of omega-3PUFA was significantly lower in G4 group than those in G3, G2 and G1 group (5.68 + or - 2.02 vs 7.17 + or - 2.38, 6.97 + or - 2.32, 10.08 + or - 2.76; P < 0.05). omega-3PUFA concentration was negatively correlated with HOMA-IR, TC, TG and LDL-C (r = -0.491, -0.376, -0.462, -0.408, P < 0.05). CONCLUSIONS: Serum omega-3PUFA is significantly decreased in patients with type 2 diabetes mellitus and NAFLD. Serum omega-3PUFA is negatively correlated with insulin resistance. omega-3PUFA plays a very important role in the development of diabetes mellitus and NAFLD.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Ácidos Graxos Ômega-3/sangue , Fígado Gorduroso/sangue , Resistência à Insulina , Idoso , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Fígado Gorduroso/complicações , Fígado Gorduroso/metabolismo , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Screening for secondary traumatic stress (STS) is lacking in China. It is unclear whether Western models of STS can be adapted satisfactorily for use in non-Western regions. The 20-item Secondary Trauma Questionnaire (STQ) is a self-report measure of traumatic stress symptoms in individuals who have been influenced indirectly by suicide or violent injury of people important to the respondents. METHODS: Here, we assessed the psychometric properties of a newly developed Chinese version of the STQ in a potentially traumatized sample (N = 875) composed of doctors, nurses, teachers, civic administration staff, and social workers in China. We performed reliability and validity analyses. Subsequently, we split the total sample into two subsamples for exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) for measurement invariance analyses. RESULTS: The full scale demonstrated good internal consistency (Cronbach's α = 0.95-0.97), convergent validity, discriminant validity, and factorial validity. CFA affirmed a one-factor structure; the configural, metric, scalar, and strict invariances of the STQ were acceptable across genders. CONCLUSION: The present results indicate that the STQ is a reliable and valid self-report assessment for use with potentially traumatized people in China, and further supports the notion that the STQ is amenable to additional future cross-cultural adaptation.
RESUMO
Posttraumatic growth (PTG) is defined as positive psychological change in the wake of highly challenging circumstances. Healthcare workers in particular are more vulnerable to stressors and trauma than the general population. The current study examined the use and effectiveness of a novel positive psychological intervention based on Chinese traditional culture to improve PTG in hospital healthcare workers. The intervention was provided to 579 healthcare workers at hospitals in Guilin, Shenzhen and Xiangtan. Scores on the Posttraumatic Growth Inventory (PTGI) and its subscales were significantly higher after intervention than before (p < 0.001). Of the five aspects of PTG, the aspect of "new possibilities" benefited the most from intervention (Cohen's d = 0.45). PTG in women, nurses and college graduates increased to a greater extent than other participants after intervention. It was concluded that our novel intervention is effective at improving PTG in medical staff.
Assuntos
Adaptação Psicológica , Pessoal de Saúde/psicologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Adulto , Ansiedade/patologia , Depressão/patologia , Feminino , Educação em Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Recursos Humanos de Enfermagem Hospitalar/psicologia , Avaliação de Programas e Projetos de Saúde , Estudos Prospectivos , Psicometria/métodos , Fatores Sexuais , Transtornos de Estresse Pós-Traumáticos/patologia , Inquéritos e Questionários , TraduçãoRESUMO
The phosphatidylinositol-3-kinase/Akt pathway and receptor tyrosine kinases regulate many tumorigenesis related cellular processes including cell metabolism, cell survival, cell motility, and angiogenesis. Anaplastic thyroid carcinoma (ATC) is a rare type of thyroid cancer with no effective systemic therapy. It has been shown that Akt activation is associated with tumor progression in ATC. Here we observed the additive effect between an Akt inhibitor (MK-2206) and a novel platelet-derived growth factor receptor inhibitor (tyrphostin AG 1296) in ATC therapy. We found an additive effect between MK-2206 and tyrphostin AG 1296 in suppressing ATC cell viability. The combination of MK-2206 and tyrphostin AG 1296 induces additive apoptosis, additive suppression of the Akt signaling pathway, as well as additive inhibition of cell migration and invasion of ATC cells. Furthermore, the combination of MK-2206 and tyrphostin AG 1296 induced additive suppression of ATC tumor growth in vivo. In summary, our studies suggest that the combination of Akt and receptor tyrosine kinase inhibitors may be an efficient therapeutic strategy for ATC treatment, which might shed new light on ATC therapy.