RESUMO

We previously reported that a bioactive peptide (pep3) can potently inhibit the enzyme activity of purified calcineurin (CN). In this paper, we further demonstrate that transfected pep3 can strongly inhibit CN enzyme activity in HEK293 cells. Transcription factor EB (TFEB) plays an important role in the autophagy-lysosome pathway (ALP) as one of the substrates of CN, so we study the effect of pep3 on the CN-TFEB-ALP pathway. Pep3 can significantly inhibit the mRNA levels of the TFEB downstream genes and the expression of the autophagy-associated proteins, and autophagy flux in HEK293 cells. We also validated the inhibitory effect of pep3 on autophagy in mice. These findings may provide a new idea for discovering more CN inhibitors and autophagy inhibitory drugs.

RESUMO

Protein lactylation has a poor prognosis in malignant tumors, but its impact on the prognosis of epithelial ovarian cancer (EOC) remains unknown. We analyzed 112 patients with EOC. Immunohistochemical staining was used to detect the level of pan lactylation (Pan Kla) and histone H3K18 lactylation (H3K18la) in the EOC tissues and normal ovarian tissues. The result showed that the protein lactylation level in EOC was higher than in normal tissues. Then, we analyzed the relationship between overall survival (OS), progression-free survival (PFS) of EOC, and lactylation. The result showed that patients with high histone H3K18la levels had poorer OS (p=0.028) and PFS (p<0.001). Multivariate Cox regression analysis of PFS showed histone H3K18la was an independent risk factor (p=0.001). In addition, we found that both histone H3K18la and Pan Kla in the cytoplasm were associated with platinum recurrence time (p=0.002/p=0.003). The results also indicated that the H3K18la level was related to a tumor stage (p=0.037). Furthermore, we explored the effects of lactylation on the metastasis of ovarian cancer. The results indicated a significant increase in migration in the promoter group compared to the negative control group and inhibitor group. In conclusion, high histone H3K18la level is associated with poor prognosis in EOC. Protein lactylation may have a significant impact on EOC and could potentially be used as a target for EOC therapy in the future.

Assuntos

Carcinoma Epitelial do Ovário , Histonas , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/mortalidade , Histonas/metabolismo , Prognóstico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Pessoa de Meia-Idade , Idoso , Adulto , Biomarcadores Tumorais/metabolismo

RESUMO

The development of a reversal agent that can rapidly reverse clinically used nondepolarizing neuromuscular blocking agents (NMBAs) has long been a challenge. Here, we report the synthesis of a series of highly water-soluble acyclic cucurbit[n]urils (acCBs). Systematic structure-activity relationship studies reveal that introducing two propylidene units on the peripheral benzene rings not only remarkably improves the activity of the corresponding derivative acCB6 (FY 3451) in reversing the neuromuscular block of rocuronium, cisatracurium, vecuronium, and pancuronium, the four clinically used NMBAs, through stable inclusion, but also allows for high water-solubility as well as a maximum tolerated dose (2000 mg/kg on rats). In vivo experiments with rats show that, at the identical dose of 25 mg/kg, for rocuronium, vecuronium, and pancuronium, acCB6 can achieve a recovery time shorter than that of sugammadex for rocuronium and, at the dose of 100 mg/kg, realize comparably rapid reversal for cisatracurium.

RESUMO

Ischaemic stroke (IS) is the second leading cause of death and a major cause of disability worldwide. Currently, the clinical management of IS still depends on restoring blood flow via pharmacological thrombolysis or mechanical thrombectomy, with accompanying disadvantages of narrow therapeutic time window and risk of haemorrhagic transformation. Thus, novel pathophysiological mechanisms and targeted therapeutic candidates are urgently needed. The autophagy-lysosomal pathway (ALP), as a dynamic cellular lysosome-based degradative process, has been comprehensively studied in recent decades, including its upstream regulatory mechanisms and its role in mediating neuronal fate after IS. Importantly, increasing evidence has shown that IS can lead to lysosomal dysfunction, such as lysosomal membrane permeabilization, impaired lysosomal acidity, lysosomal storage disorder, and dysfunctional lysosomal ion homeostasis, which are involved in the IS-mediated defects in ALP function. There is tightly regulated crosstalk between transcription factor EB (TFEB), mammalian target of rapamycin (mTOR) and lysosomal function, but their relationship remains to be systematically summarized. Notably, a growing body of evidence emphasizes the benefits of naturally derived compounds in the treatment of IS via modulation of ALP function. However, little is known about the roles of natural compounds as modulators of lysosomes in the treatment of IS. Therefore, in this context, we provide an overview of the current understanding of the mechanisms underlying IS-mediated ALP dysfunction, from a lysosomal perspective. We also provide an update on the effect of natural compounds on IS, according to their chemical structural types, in different experimental stroke models, cerebral regions and cell types, with a primary focus on lysosomes and autophagy initiation. This review aims to highlight the therapeutic potential of natural compounds that target lysosomal and ALP function for IS treatment.

RESUMO

Immune escape and metabolic reprogramming are two essential hallmarks of cancer. Mucin-16 (MUC16) has been linked to glycolysis and immune response in different cancers. However, its involvement in nasopharyngeal carcinoma (NPC) has not been well described. We seek to dissect the functions and detailed mechanisms of MUC16 in NPC. Bioinformatics prediction was performed to identify NPC-related molecules. MUC16 was significantly enhanced in NPC tissues, which was correlated with the advanced tumor stage of patients. Lentiviral plasmids-mediated MUC16 deletion inhibited the malignant behavior of NPC cells, and glycolysis inhibition by MUC16 deletion blocked immune escape in NPC cells. E74-like factor 3 (ELF3) bound to the MUC16 promoter to promote transcription of MUC16. MUC16 overexpression reversed the repressive effect of ELF3 silencing on glycolysis and immune escape in NPC and accelerated tumor growth in vivo. Overexpression of ELF3 in NPC was associated with reduced DNA methylation in its promoter. Our findings revealed the role of the ELF3/MUC16 axis in the immune escape and metabolic reprogramming of NPC, providing potential therapeutic targets for NPC.

RESUMO

Purpose: Ovarian cancer (OC) is a common gynecological malignancy with poor prognosis and substantial tumor heterogeneity. Due to the complex tumor immune microenvironment (TIME) among ovarian cancer, only a few patients have an immune response to immunotherapy. To investigate the differences in immune function and identify potential biomarkers in OC, we established a prognostic risk scoring model (PRSM) with differential expression of immune-related genes (IRGs) to identify critical prognostic IRG signatures. Methods: Single-sample gene set enrichment analysis (ssGSEA) was used to investigate the infiltration of various immune cells in 372 OC patients. Then, COX regression analysis and Lasso regression analysis were used to screen IRGs and construct PRSM. Next, the immunotherapy sensitivity of different risk groups regarding the immune checkpoint expression and tumor mutation burden was evaluated. Finally, a nomogram was created to guide the clinical evaluation of the patient prognosis. Results: In this study, 320 immune-related genes (IRGs) were identified, 13 of which were selectively incorporated into a Prognostic Risk Scoring Model (PRSM). This model revealed that the patients in the high-risk group were characterized as having poorer prognosis, lower expression of immune checkpoints, and decreased tumor mutation load levels compared with those in the low-risk group. The nomogram based on the risk score can distinguish the risk subtypes and individual prognosis of patients with OC. Additionally, M1 macrophages may be the critical target for immunotherapy in OC patients. Conclusion: With the in-depth analysis of the immune microenvironment of OC, the PRSM was constructed to predict the OC patient prognosis and identify the subgroup of the patients benefiting from immunotherapy.

RESUMO

Tamarixetin, a natural dietary flavone, exhibits remarkable potential for the treatment of ischemic stroke. The present article aimed to explore the impact of tamarixetin on ischemic stroke and elucidate the underlying mechanisms. Effects of tamarixetin on ischemic stroke were evaluated in rats using the middle cerebral artery occlusion and reperfusion (MCAO/R) model, by assessing the neurological deficit scores, brain water content, brain infraction, and neuronal damage. The levels of proinflammatory cytokines, NLRP3 inflammasome activation, reactive oxygen species (ROS) production, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression were measured in MCAO/R rats and lipopolysaccharide-stimulated cells. Tamarixetin administration improved the neurological dysfunction and neuronal loss in MCAO/R rats. In addition, tamarixetin reduced microglial hyperactivation and proinflammatory cytokines expression in vivo and in vitro. Tamarixetin attenuated NF-κB p65 phosphorylation and promoter activity, reduced NLRP3 expression and caspase-1 cleavage, and downregulated IL-1ß and IL-18 secretions to suppress NLRP3 inflammasome activation. The levels of superoxide anion, hydrogen peroxide, and ROS were also suppressed by tamarixetin. The downregulation of NADP+ and NADPH levels, and gp91phox expression indicated the ameliorative effects of tamarixetin on NADPH oxidase activation. In the gp91phox knockdown cells treated with lipopolysaccharide, the effects of tamarixetin on NADPH oxidase activation, ROS generation, and NLRP3 inflammasome activation were diminished. Moreover, tamarixetin protects neurons against microglial hyperactivation in vitro. Our findings support the potential of tamarixetin as a therapeutic agent for ischemic stroke, and its mechanism of action involves the inhibition of NADPH oxidase-NLRP3 inflammasome signaling.

Assuntos

Dissacarídeos , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Traumatismo por Reperfusão , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Masculino , Inflamassomos/metabolismo , Dissacarídeos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , NADPH Oxidase 2/metabolismo , NADPH Oxidases/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Modelos Animais de Doenças , Isquemia Encefálica/tratamento farmacológico , Quercetina/análogos & derivados

RESUMO

BACKGROUND: Vascular dementia (VaD) resulting from chronic cerebral hypoperfusion (CCH) induces cognitive impairment and white matter injury (WMI). We previously found that CCH induces dysfunction of the autophagy-lysosomal pathway (ALP) in white matter (WM) of rats. Enhancing oligodendrocyte autophagy to counteract ALP deficiency is beneficial for cognitive recovery. Pseudogenoside-F11 (PF11), a saponin extracted from Panax quinquefolium l., provides neuroprotective benefits in many animal models of cerebral ischemia and dementia. PURPOSE: To investigate how PF11 affects cognitive deterioration in rats with VaD induced by two vessel occlusion (2VO), and to determine if PF11 regulates ALP dysfunction in WM. METHODS: CCH-related VaD was induced in rats using the 2VO method. PF11 (6, 12, 24 mg/kg, intragastric administration) was given continuously for 4 weeks postoperatively. Behavioral tests related to cognitive function were performed on the 28th day following 2VO. Transmission electron microscopy, immunofluorescence, western blotting and Luxol fast blue staining were used to assess the WMI and the mechanism of action of PF11 in 2VO-induced VaD. RESULTS: PF11 (12 mg/kg) ameliorated 2VO-induced cognitive impairment. PF11 also alleviated WMI on the 28th day following 2VO, as characterized by reduction of neuronal axonal demyelination and axonal loss. Furthermore, PF11 prevented mature oligodendrocytes death by attenuating ALP deficiency in WM on the 14th day following 2VO, as manifested by enhancement of mechanistic target of rapamycin-mediated autophagy and lysosomal function, thereby reducing the aberrant accumulation of autophagy substrates and increasing the level of autophagosomes in WM. In addition, PF11 also prevented microglia and astrocytes from activating in WM on the 28th day following 2VO. CONCLUSION: PF11 significantly ameliorates cognitive impairment and WMI, and the mechanism is at least partly related to lessening ALP dysfunction in WM by enhancing autophagy and reducing lysosomal defects in oligodendrocytes.

Assuntos

Autofagia , Disfunção Cognitiva , Demência Vascular , Ginsenosídeos , Lisossomos , Fármacos Neuroprotetores , Ratos Sprague-Dawley , Substância Branca , Animais , Demência Vascular/tratamento farmacológico , Autofagia/efeitos dos fármacos , Masculino , Disfunção Cognitiva/tratamento farmacológico , Substância Branca/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Ginsenosídeos/farmacologia , Ratos , Fármacos Neuroprotetores/farmacologia , Modelos Animais de Doenças , Panax/química

RESUMO

Surgical removal of the tonsils and adenoids, important immune organs, is a frequent and recurrent class of surgery, and currently, there is no consensus on the effects these surgical procedures may have on the immune system. Here, we examine individual studies on tonsillectomy, adenoidectomy, and adenotonsillectomy, discuss their postoperative humoral and cellular immune changes, and explore their effects on the incidence of related diseases. There is evidence that these three surgeries have no negative effects on humoral immunity; however, there has been contrary results. Furthermore, these procedures seem to have no significant effects on cellular immunity, although tonsil and adenoid removal can cause an increased incidence of certain illnesses, especially infectious diseases. Based on this comprehensive review, we conclude that the removal of tonsils and adenoids does not negatively affect cellular and humoral immunity. However, surgery may lead to an increased incidence of related infectious diseases. This finding may inform the surgeon's decision to perform the procedure in a clinical setting.

RESUMO

Ischemic stroke (IS) is a serious threat to human health. The naturally derived small molecule (E)-5-(2-(quinolin-4-yl) ethenyl) benzene-1,3-diol (RV01) is a quinolinyl analog of resveratrol with great potential in the treatment of IS. The aim of this study was to investigate the potential mechanisms and targets for the protective effect of the RV01 on IS. The mouse middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen-glucose deprivation and reperfusion (OGD/R) models were employed to evaluate the effects of RV01 on ischemic injury and neuroprotection. RV01 was found to significantly increase the survival of SH-SY5Y cells and prevent OGD/R-induced apoptosis in SH-SY5Y cells. Furthermore, RV01 reduced oxidative stress and mitochondrial damage by promoting mitophagy in OGD/R-exposed SH-SY5Y cells. Knockdown of CK2α' abolished the RV01-mediated promotion on mitophagy and alleviation on mitochondrial damage as well as neuronal injury after OGD/R. These results were further confirmed by molecular docking, drug affinity responsive target stability and cellular thermal shift assay analysis. Importantly, in vivo study showed that treatment with the CK2α' inhibitor CX-4945 abolished the RV01-mediated alleviation of cerebral infarct volume, brain edema, cerebral blood flow and neurological deficit in MCAO/R mice. These data suggest that RV01 effectively reduces damage caused by acute ischemic stroke by promoting mitophagy through its interaction with CK2α'. These findings offer valuable insights into the underlying mechanisms through which RV01 exerts its therapeutic effects on IS.

Assuntos

Caseína Quinase II , Infarto da Artéria Cerebral Média , AVC Isquêmico , Camundongos Endogâmicos C57BL , Mitofagia , Fármacos Neuroprotetores , Resveratrol , Animais , Mitofagia/efeitos dos fármacos , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Caseína Quinase II/metabolismo , Caseína Quinase II/antagonistas & inibidores , Masculino , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/metabolismo , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Camundongos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Modelos Animais de Doenças , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Simulação de Acoplamento Molecular , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Naftiridinas , Fenazinas

RESUMO

Clinically, statins have long been used for the prevention and treatment of chronic renal diseases, however, the underlying mechanisms are not fully elucidated. The present study investigated the effects of atorvastatin on diabetes renal injury and ferroptosis signaling. A mouse model of diabetes was established by the intraperitoneal injection of streptozotocin (50 mg/kg/day) plus a high fat diet with or without atorvastatin treatment. Diabetes mice manifested increased plasma glucose and lipid profile, proteinuria, renal injury and fibrosis, atorvastatin significantly lowered plasma lipid profile, proteinuria, renal injury in diabetes mice. Atorvastatin reduced renal reactive oxygen species (ROS), iron accumulation and renal expression of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), transferrin receptor 1 (TFR1), and increased renal expression of glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor (NRF2) and ferritin heavy chain (FTH) in diabetes mice. Consistent with the findings in vivo, atorvastatin prevented high glucose-induced ROS formation and Fe2+ accumulation, an increase in the expression of 4-HNE, MDA and TFR1, and a decrease in cell viability and the expression of NRF2, GPX4 and FTH in HK2 cells. Atorvastatin also reversed ferroptosis inducer erastin-induced ROS production, intracellular Fe2+ accumulation and the changes in the expression of above-mentioned ferroptosis signaling molecules in HK2 cells. In addition, atorvastatin alleviated high glucose- or erastin-induced mitochondria injury. Ferroptosis inhibitor ferrostatin-1 and antioxidant N-acetylcysteine (NAC) equally reversed the expression of high glucose-induced ferroptosis signaling molecules. Our data support the notion that statins can inhibit diabetes-induced renal oxidative stress and ferroptosis, which may contribute to statins protection of diabetic nephropathy.

Assuntos

Atorvastatina , Nefropatias Diabéticas , Ferroptose , Estresse Oxidativo , Espécies Reativas de Oxigênio , Transdução de Sinais , Ferroptose/efeitos dos fármacos , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Masculino , Transdução de Sinais/efeitos dos fármacos , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicações , Camundongos Endogâmicos C57BL , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Linhagem Celular , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico

RESUMO

Crystalline calcium fluoride (CaF2) is drawing significant attention due to its great potential of being the gate dielectric of two-dimensional (2D) material MOSFETs. It is deemed to be superior to boron nitride and traditional silicon dioxide (SiO2) because of its larger dielectric constant, wider band gap, and lower defect density. Nevertheless, the CaF2-based MOSFETs fabricated in the experiment still present notable reliability issues, and the underlying reason remains unclear. Here, we studied the various intrinsic defects and adsorbates in CaF2/molybdenum disulfide (MoS2) and CaF2/molybdenum disilicon tetranitride (MoSi2N4) interface systems to reveal the most active charge-trapping centers in CaF2-based 2D material MOSFETs. An elaborate Table comparing the importance of different defects in both n-type and p-type devices is provided. Most impressively, the oxygen molecules (O2) adsorbed at the interface or surface, which are inevitable in experiments, are as active as the intrinsic defects in channel materials, and they can even change the MoSi2N4 to p-type spontaneously. These results mean that it is necessary to develop a high-vacuum packaging process, as well as prepare high-quality 2D materials for better device performance.

RESUMO

Depression has been reported as one of the most prevalent psychiatric illnesses globally. This study aimed to obtain information on the global burden of depression and its associated spatiotemporal variation, by exploring the correlation between the global burden of depression and the social development index (SDI) and associated risk factors. Using data from the Global Burden of Disease study from 1990 to 2019, we described the prevalence and burden of disease in 204 countries across 21 regions, including sex and age differences and the relationship between the global disease burden and SDI. The age-standardized rate and estimated annual percentage change were used to assess the global burden of depression. Individuals with documented depression globally ranged from 182,183,358 in 1990 to 290,185,742 in 2019, representing an increase of 0.59%. More patients experienced major depressive disorder than dysthymia. The incidence and disability-adjusted life years of depression were the highest in the 60-64 age group and much higher in females than in males, with this trend occurring across all ages. The age-standardized incidence and adjusted life-years-disability rates varied with different SDI levels. Relevant risk factors for depression were identified. National governments must support research to improve prevention and treatment interventions.

Assuntos

Depressão , Carga Global da Doença , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Fatores de Risco , Depressão/epidemiologia , Prevalência , Adolescente , Adulto Jovem , Incidência , Saúde Global , Transtorno Depressivo Maior/epidemiologia , Efeitos Psicossociais da Doença , Anos de Vida Ajustados por Deficiência , Análise Espaço-Temporal , Criança

RESUMO

Currently, the improvement in the processing capacity of traditional processors considerably lags behind the demands of real-time image processing caused by the advancement of photodetectors and the widespread deployment of high-definition image sensors. Therefore, achieving real-time image processing at the sensor level has become a prominent research domain in the field of photodetector technology. This goal underscores the need for photodetectors with enhanced multifunctional integration capabilities than can perform real-time computations using optical or electrical signals. In this study, we employ an innovative p-type semiconductor GaTe0.5Se0.5 to construct a polarization-sensitive wide-spectral photodetector. Leveraging the wide-spectral photoresponse, we realize three-band imaging within a wavelength range of 390-810 nm. Furthermore, real-time image convolutional processing is enabled by configuring appropriate convolution kernels based on the polarization-sensitive photocurrents. The innovative design of the polarization-sensitive wide-spectral GaTe0.5Se0.5-based photodetector represents a notable contribution to the domain of real-time image perception and processing.

RESUMO

Vertical three-dimensional integration of two-dimensional (2D) semiconductors holds great promise, as it offers the possibility to scale up logic layers in the z axis1-3. Indeed, vertical complementary field-effect transistors (CFETs) built with such mixed-dimensional heterostructures4,5, as well as hetero-2D layers with different carrier types6-8, have been demonstrated recently. However, so far, the lack of a controllable doping scheme (especially p-doped WSe2 (refs. 9-17) and MoS2 (refs. 11,18-28)) in 2D semiconductors, preferably in a stable and non-destructive manner, has greatly impeded the bottom-up scaling of complementary logic circuitries. Here we show that, by bringing transition metal dichalcogenides, such as MoS2, atop a van der Waals (vdW) antiferromagnetic insulator chromium oxychloride (CrOCl), the carrier polarity in MoS2 can be readily reconfigured from n- to p-type via strong vdW interfacial coupling. The consequential band alignment yields transistors with room-temperature hole mobilities up to approximately 425 cm2 V-1 s-1, on/off ratios reaching 106 and air-stable performance for over one year. Based on this approach, vertically constructed complementary logic, including inverters with 6 vdW layers, NANDs with 14 vdW layers and SRAMs with 14 vdW layers, are further demonstrated. Our findings of polarity-engineered p- and n-type 2D semiconductor channels with and without vdW intercalation are robust and universal to various materials and thus may throw light on future three-dimensional vertically integrated circuits based on 2D logic gates.

RESUMO

Remote sensing technology, which conventionally employs spectrometers to capture hyperspectral images, allowing for the classification and unmixing based on the reflectance spectrum, has been extensively applied in diverse fields, including environmental monitoring, land resource management, and agriculture. However, miniaturization of remote sensing systems remains a challenge due to the complicated and dispersive optical components of spectrometers. Here, m-phase GaTe0.5Se0.5 with wide-spectral photoresponses (250-1064 nm) and stack it with WSe2 are utilizes to construct a two-dimensional van der Waals heterojunction (2D-vdWH), enabling the design of a gate-tunable wide-spectral photodetector. By utilizing the multi-photoresponses under varying gate voltages, high accuracy recognition can be achieved aided by deep learning algorithms without the original hyperspectral reflectance data. The proof-of-concept device, featuring dozens of tunable gate voltages, achieves an average classification accuracy of 87.00% on 6 prevalent hyperspectral datasets, which is competitive with the accuracy of 250-1000 nm hyperspectral data (88.72%) and far superior to the accuracy of non-tunable photoresponse (71.17%). Artificially designed gate-tunable wide-spectral 2D-vdWHs GaTe0.5Se0.5/WSe2-based photodetector present a promising pathway for the development of miniaturized and cost-effective remote sensing classification technology.

RESUMO

BACKGROUND: Among adults, stroke is the main causes of mortality and permanent disability. Neuroinflammation is one of the main causes of stoke-mediated neuronal death. Our previous study revealed that (E)-5-(2-(Quinolin-4-yl) vinyl) benzene-1, 3-diol (RV01), a quinolinyl analog of resveratrol, inhibits microglia-induced neuroinflammation and safeguards neurons from inflammatory harm. The preventive role of RV01 in ischemic stroke and its underlying cellular mechanisms and molecular targets remain poorly understood. PURPOSE: To investigate whether RV01 alleviates ischemia-reperfusion (I/R) injury by inhibiting microglia-mediated neuroinflammation and determine the potential molecular mechanisms and targets by which RV01 inhibits the I/R-mediated microglia activation. METHODS: Rat middle cerebral artery occlusion and reperfusion (MCAO/R) and BV-2 or primary microglial cells oxygen-glucose deprivation and reperfusion (OGD/R) models were established. The neurological behavior scores, 2, 3, 5-triphenyl tetrazolium chloride staining and immunofluorescence were used to detect the neuroprotective effect of RV01 in the MCAO/R rats. In addition, the mRNA expression levels of IL-6, TNF-α, and IL-1ß were detected to reveal the antineuroinflammatory effect of RV01. Moreover, a western blot assay was performed to explore the protein expression changes in NF-κB-mediated neuroinflammation. Finally, we identified TLR4 as an RV01 target through molecular docking, drug sensitivity target stability analysis, cellular thermal shift analysis, and surface plasmon resonance techniques. RESULTS: RV01 reduced the infarct volume and neurological deficits, increased the rotarod duration, and decreased the number of rightward deflections in the MCAO/R rats. RV01 inhibited the NF-κB signaling pathway in vitro and in vivo, as demonstrated by the reduction in the transcription factor p65-mediated expression of several inflammatory factors including IL-6, TNF-α, and IL-1ß. Further studies showed that its protective effect was associated with targeting the TLR4 protein. Notably, the anti-inflammatory effect of RV01 was markedly reinforced by the TLR4 knockdown, but inhibited by the overexpression of TLR4. Results revealed that the conditioned medium derived from the RV01-treated BV-2 cells significantly decreased the OGD/R-mediated neuronal damage. CONCLUSION: Our results are the first to reveal the protective effects of RV01 on cerebral ischemia, depending on its inhibitory effect on the NF-κB pathway by targeting TLR4. RV01 could be a potential protective agent in ischemic stroke treatment.

Assuntos

Anti-Inflamatórios , Infarto da Artéria Cerebral Média , Microglia , Fármacos Neuroprotetores , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Resveratrol , Receptor 4 Toll-Like , Animais , Receptor 4 Toll-Like/metabolismo , Masculino , Infarto da Artéria Cerebral Média/tratamento farmacológico , Traumatismo por Reperfusão/tratamento farmacológico , Microglia/efeitos dos fármacos , Resveratrol/farmacologia , Fármacos Neuroprotetores/farmacologia , Ratos , Anti-Inflamatórios/farmacologia , AVC Isquêmico/tratamento farmacológico , Modelos Animais de Doenças , NF-kappa B/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Simulação de Acoplamento Molecular

RESUMO

BACKGROUND: Ischemic stroke (IS) is characterized as a detrimental cerebrovascular disease with high mortality and disability. Ferroptosis is a novel mechanism involved in neuronal death. There is a close connection between IS and ferroptosis, and inhibiting ferroptosis may provide an effective strategy for treating IS. Our previous investigations have discovered that kellerin, the active compound of Ferula sinkiangensis K. M. Shen, possesses the capability to shield against cerebral ischemia injury. PURPOSE: Our objective is to clarify the relationship between the neuroprotective properties of kellerin against IS and its ability to modulate ferroptosis, and investigate the underlying regulatory pathway. STUDY DESIGN: We investigated the impact and mechanism of kellerin in C57BL/6 mice underwent middle cerebral artery occlusion/reperfusion (MCAO/R) as well as SH-SY5Y cells exposed to oxygen-glucose deprivation/ re-oxygenation (OGD/R). METHODS: The roles of kellerin on neurological severity, cerebral infarction and edema were investigated in vivo. The regulatory impacts of kellerin on ferroptosis, mitochondrial damage and Akt/Nrf2 pathway were explored. Molecular docking combined with drug affinity responsive target stability assay (DARTS) and cellular thermal shift assay (CETSA) were performed to analyze the potential target proteins for kellerin. RESULTS: Kellerin protected against IS and inhibited ferroptosis in vivo. Meanwhile, kellerin improved the neuronal damage caused by OGD/R and suppressed ferroptosis by inhibiting the production of mitochondrial ROS in vitro. Further we found that kellerin directly interacted with Akt and enhanced its phosphorylation, leading to the increase of Nrf2 nuclear translocation and its downstream antioxidant genes expression. Moreover, kellerin's inhibitory effect on ferroptosis and mitochondrial ROS release was eliminated by inhibiting Akt/Nrf2 pathway. CONCLUSIONS: Our study firstly demonstrates that the neuroprotective properties of kellerin against IS are related to suppressing ferroptosis through inhibiting the production of mitochondrial ROS, in which its modulation on Akt-mediated transcriptional activation of Nrf2 plays an important role. This finding shed light on the potential mechanism that kellerin exerts therapeutic effects in IS.

Assuntos

Ferroptose , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , Fármacos Neuroprotetores , Proteínas Proto-Oncogênicas c-akt , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Ferroptose/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Masculino , Camundongos , Humanos , Fármacos Neuroprotetores/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Ativação Transcricional/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Linhagem Celular Tumoral , Simulação de Acoplamento Molecular , Transdução de Sinais/efeitos dos fármacos

RESUMO

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of confirmed cases and deaths globally. The purpose of this study was to investigate the therapeutic effect of airway clearance technology combined with prone ventilation on patients infected with COVID-19. METHODS: 38 patients with COVID-19 (severe) who were treated in the intensive rehabilitation group of Shengli Oilfield Central Hospital. They were randomly divided into a control group and an observation group. The control group received prone position ventilation intervention, and the observation group received airway clearance technology combined with prone position ventilation intervention. The changes of oxygen and index, procalcitonin (PCT), interleukin-6 (IL-6) and chest X-ray image indexes were compared between the two groups. RESULT: There was no significant difference in age, gender and other general data between the control group and the observation group. The results showed that oxygen index, PCT, IL-6 and chest X-ray image index in the observation group were better than that indexes in the control group. CONCLUSION: Airway clearance technology combined with prone ventilation intervention in patients with COVID-19 can improve the total effective rate and oxygenation index, improve the inflammatory indicators and respiratory function of patients. And it may be widely promoted and used in the treatment of patients with COVID-19 (severe).

Assuntos

COVID-19 , Humanos , Estudos Retrospectivos , Interleucina-6 , Respiração Artificial , Oxigênio

RESUMO

Compared to terrestrial transportation systems, the expansion of urban traffic into airspace can not only mitigate traffic congestion, but also foster establish eco-friendly transportation networks. Additionally, unmanned aerial vehicle (UAV) task allocation and trajectory planning are essential research topics for an Urban Air Mobility (UAM) scenario. However, heterogeneous tasks, temporary flight restriction zones, physical buildings, and environment prerequisites put forward challenges for the research. In this paper, multigene and improved anti-collision RRT* (IAC-RRT*) algorithms are proposed to address the challenge of task allocation and path planning problems in UAM scenarios by tailoring the chance of crossover and mutation. It is proved that multigene and IAC-RRT* algorithms can effectively minimize energy consumption and tasks' completion duration of UAVs. Simulation results demonstrate that the strategy of this work surpasses traditional optimization algorithms, i.e., RRT algorithm and gene algorithm, in terms of numerical stability and convergence speed.