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There is a lack of a systematic understanding of the specific mechanism of action of DL0410 in AD treatment. In this study, the combination of RNA-seq and proteomics was firstly employed to uncover the mechanism of action of DL0410 in APP/PS1 transgenic mice. The results of behavioral tests showed that oral administration of DL0410 for 8 weeks improved memory and cognition of APP/PS1 mice. DL0410 significantly reduced ß-amyloid deposition and resulted in significant upregulation of synaptophysin, PSD95 and NMDAR/ CaMKâ ¡ signaling pathway in the hippocampus and cortex, indicating that DL0410 improved synaptic plasticity in APP/PS1 mice, which agrees with the results of RNA-seq and proteomics. Furthermore, the enrichment results of differentially expressed genes identified by RNA-seq and proteomics demonstrate the potential protective effects of DL0410 against oxidative stress and mitochondrial dysfunction. As expected, DL0410 dose-dependently ameliorated oxidative damage and markedly increased the expression of PGC-1α, TFAM, SOD1 and SOD2. Mitochondrial high-resolution respirometry results revealed that mitochondrial respiratory function was significantly improved in APP/PS1 mice administered with DL0410. In addition, DL0410 treatment reduced oxidative damage, strengthened antioxidant system and improved mitochondrial function in Aß-induced HT22 cells. Altogether, our findings suggest the potential of DL0410 as a novel candidate for AD treatment.
Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Presenilina-1 , Animais , Masculino , Camundongos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Presenilina-1/genética , Proteômica/métodos , RNA-SeqRESUMO
Flubendazole, an FDA-approved anthelmintic, has been predicted to show strong VEGFR2 inhibitory activity in silico screening combined with in vitro experimental validation, and it has shown anti-cancer effects on some human cancer cell lines, but little is known about the anti-angiogenesis effects and anti-prostate cancer effects. In this study, we analyzed the binding modes and kinetic analysis of flubendazole with VEGFR2 and first demonstrated that flubendazole suppressed VEGF-stimulated cell proliferation, wound-healing migration, cell invasion and tube formation of HUVEC cells, and decreased the phosphorylation of extracellular signal-regulated kinase and serine/threonine kinase Akt, which are the downstream proteins of VEGFR2 that are important for cell growth. What's more, our results showed that flubendazole decreased PC-3 cell viability and proliferation ability, and suppressed PC-3 cell wound healing migration and invasion across a Matrigel-coated Transwell membrane in a concentration-dependent manner. The antiproliferative effects of flubendazole were due to induction of G2-M phase cell cycle arrest in PC-3 cells with decreasing expression of the Cyclin D1 and induction of cell apoptosis with the number of apoptotic cells increased after flubendazole treatment. These results indicated that flubendazole could exert anti-angiogenic and anticancer effects by inhibiting cell cycle and inducing cell apoptosis.
Assuntos
Angiogênese , Mebendazol/análogos & derivados , Fator A de Crescimento do Endotélio Vascular , Humanos , Células PC-3 , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cinética , Movimento Celular , Proliferação de Células , Inibidores da Angiogênese/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
BACKGROUND: Evidence on the association of Olfactory Impairment (OI) with age-related cognitive decline is inconclusive, and the potential influence of allergy remains unclear. OBJECTIVE: We aimed to evaluate the cross-sectional associations of allergy-related and non-allergy- related OI to cognitive function. METHODS: We included 2,499 participants from the Health and Retirement Study (HRS)-Harmonized Cognitive Assessment Protocol (HCAP) sub-study and 1,086 participants from the English Longitudinal Study of Ageing (ELSA)-HCAP. The Olfactory Function Field Exam (OFFE) using Sniffin' Stick odor pens was used to objectively assess olfactory function and an olfactory score <6/11 indicated OI. Mini-Mental Status Examination (MMSE) was used to assess global cognitive function and define cognitive impairment (<24/30). A neuropsychologic battery was used to assess five cognitive domains. RESULTS: Compared to non-OI participants, individuals with OI had lower MMSE z-score [ßHRS = -0.33, 95% Confidence Interval (CI): -0.41 to -0.24; ßELSA = -0.31, -0.43 to -0.18] and higher prevalence of cognitive impairment (Prevalence Ratio (PR)HRS = 1.46, 1.06 to 2.01; PRELSA = 1.63, 1.26 to 2.11). The associations were stronger for non-allergy-related OI (ßHRS = -0.36; ßELSA = -0.34) than for allergy-related OI (ßHRS = -0.26; ßELSA = 0.13). Similar associations were observed with domain- specific cognitive function measures. CONCLUSION: OI, particularly non-allergy-related OI, was related to poorer cognitive function in older adults. Although the current cross-sectional study is subject to several limitations, such as reverse causality and residual confounding, the findings will provide insights into the OI-cognition association and enlighten future attention to non-allergy-related OI for the prevention of potential cognitive impairment.
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Disfunção Cognitiva , Hipersensibilidade , Transtornos do Olfato , Humanos , Masculino , Feminino , Estudos Transversais , Idoso , Disfunção Cognitiva/epidemiologia , Hipersensibilidade/epidemiologia , Transtornos do Olfato/epidemiologia , Estudos Longitudinais , Testes Neuropsicológicos , Cognição/fisiologia , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Testes de Estado Mental e DemênciaRESUMO
Obtaining crystalline materials with high structural stability as well as super proton conductivity is a challenging task in the field of energy and material chemistry. Therefore, two highly stable metal-organic frameworks (MOFs) with macro-ring structures and carboxylate groups, Zr-TCPP (1) and Hf-TCPP (2) assembled from low-toxicity as well as highly coordination-capable Zr(IV)/Hf(IV) cations and the multifunctional linkage, meso-tetra(4-carboxyphenyl)porphine (TCPP) have attracted our strong interest. Note that TCPP as a large-size rigid ligand with high symmetry and multiple coordination sites contributes to the formation of the two stable MOFs. Moreover, the pores with large sizes in the two MOFs favor the entry of more guest water molecules and thus result in high H2O-assisted proton conductivity. First, their distinguished structural stabilities covering water, thermal and chemical stabilities were verified by various determination approaches. Second, the dependence of the proton conductivity of the two MOFs on temperature and relative humidity (RH) is explored in depth. Impressively, MOFs 1 and 2 demonstrated the optimal proton conductivities of 4.5 × 10-4 and 0.78 × 10-3 S·cm-1 at 100 °C/98 % RH, respectively. Logically, based on the structural information, gas adsorption/desorption features, and activation energy values, their proton conduction mechanism was deduced and highlighted.
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Although para-aminosalicylic acid (PAS) has been used to treat tuberculosis agent for decades, its mechanisms of resistance are still not thoroughly understood. Previously, sporadic studies showed that certain mutations in the thyX-hsdS.1 region caused PAS resistance in M. tuberculosis, but a comprehensive analysis is lacking. Recently, we found a G-10A mutation in thyX-hsdS.1 in a PAS-resistant clinical isolate, but it did not cause PAS resistance. SNPs in thyX-hsdS.1 in 6550 clinical isolates were analyzed, and 153 SNPs were identified. C-16 T was the most common SNP identified (54.25%, 83/153), followed by C-4T (7.19%, 11/153) and G-9A (6.54%, 10/153). Subsequently, the effects of those SNPs on the promoter activity of thyX were tested, and the results showed that mutations C-1T, G-3A, C-4T, C-4G, G-7A, G-9A, C-16T, G-18C, and C-19G led to increased promoter activity compared with the wild-type sequence, but other mutations did not. Then, thyX and wild-type thyX-hsdS.1, or thyX-hsdS.1 containing specific SNPs, were overexpressed in M. tuberculosis H37Ra. The results showed that mutations resulting in increased promoter activity also caused PAS resistance. Moreover, the results of an electrophoretic mobility shift assay showed that thyX-hsdS.1 containing the C-16T mutation had a higher binding capacity to RNA polymerase than did the wild-type sequence. Taken together, our data demonstrated that among the SNPs identified in thyX-hsdS.1 of M. tuberculosis clinical isolates, only those able to increase the promoter activity of thyX caused PAS resistance and therefore can be considered as molecular markers for PAS resistance.
Assuntos
Ácido Aminossalicílico , Mycobacterium tuberculosis , Tuberculose , Humanos , Ácido Aminossalicílico/farmacologia , Tuberculose/tratamento farmacológico , Mutação , Antituberculosos/farmacologia , Proteínas de Bactérias/genética , Testes de Sensibilidade MicrobianaRESUMO
This study aims to analyze the potential biomarkers using bioinformatics technology, explore the pathogenesis, and investigate potential Chinese herbal ingredients for the Clear cell renal cell carcinoma (ccRCC), which could provide theoretical basis for early diagnosis and effective treatment of ccRCC. The gene expression datasets GSE6344 and GSE53757 were obtained from the Gene Expression Omnibus database to screen differentially expressed genes (DEGs) involved in ccRCC carcinogenesis and disease progression. Enrichment analyses, protein-protein interaction networks construction, survival analysis and herbal medicines screening were performed with related software and online analysis platforms. Moreover, network pharmacology analysis has also been performed to screen potential target drugs of ccRCC and molecular docking analysis has been used to validate their effects. Total 274 common DEGs were extracted through above process, including 194 up-regulated genes and 80 down-regulated genes. The enrichment analysis revealed that DEGs were significantly focused on multiple amino acid metabolism and HIF signaling pathway. Ten hub genes, including FLT1, BDNF, LCP2, AGXT2, PLG, SLC13A3, SLC47A2, SLC22A8, SLC22A7, and SLC13A3, were screened. Survival analysis showed that FLT1, BDNF, AGXT2, PLG, SLC47A2, SLC22A8, and SLC12A3 were closely correlated with the overall survival of ccRCC, and AGXT2, SLC47A2, SLC22A8, and SLC22A7 were closely associated with DFS. The potential therapeutic herbs that have been screened were Danshen, Baiguo, Yinxing, Huangqin and Chuanshanlong. The active compounds which may be effective in ccRCC treatment were kaempferol, Scillaren A and (-)-epigallocatechin-3-gallate.
Assuntos
Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Fator Neurotrófico Derivado do Encéfalo , Simulação de Acoplamento Molecular , Farmacologia em Rede , Biomarcadores , Biologia Computacional , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Membro 3 da Família 12 de Carreador de SolutoRESUMO
Pterostilbene, an important analogue of the star molecule resveratrol and a novel compound naturally occurring in blueberries and grapes, exerts a significant neuroprotective effect on cerebral ischemia/reperfusion (I/R), but its mechanism is still unclear. This study aimed to follow the molecular mechanisms behind the potential protective effect of pterostilbene against I/R induced injury. For fulfilment of our aim, we investigated the protective effects of pterostilbene on I/R injury caused by middle cerebral artery occlusion (MCAO) in vivo and oxygen-glucose deprivation (OGD) in vitro. Machine learning models and molecular docking were used for target exploration and validated by western blotting. Pterostilbene significantly reduced the cerebral infarction volume, improved neurological deficits, increased cerebral microcirculation and improved blood-brain barrier (BBB) leakage. Machine learning models confirmed that the stroke target MMP-9 bound to pterostilbene, and molecular docking demonstrated the strong binding activity. We further found that pterostilbene could depolymerize stress fibers and maintain the cytoskeleton by effectively increasing the expression of the non-phosphorylated actin depolymerizing factor (ADF) in the early stage of I/R. In the late stage of I/R, pterostilbene could activate the Wnt pathway and inhibit the expression of MMP-9 to decrease the degradation of the extracellular basement membrane (BM) and increase the expression of junction proteins. In this study, we explored the protective mechanisms of pterostilbene in terms of both endothelial cytoskeleton and extracellular matrix. The early and late protective effects jointly maintain BBB stability and attenuate I/R injury, showing its potential to be a promising drug candidate for the treatment of ischemic stroke.
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Traumatismo por Reperfusão , Acidente Vascular Cerebral , Humanos , Metaloproteinase 9 da Matriz/genética , Barreira Hematoencefálica , Simulação de Acoplamento Molecular , Infarto Cerebral , Isquemia , Reperfusão , Traumatismo por Reperfusão/tratamento farmacológico , Membrana BasalRESUMO
Parkinson's disease (PD) is characterized by both motor and non-motor symptoms, including hypokinesia, postural instability, dopaminergic (DA) neurons loss, and α-synuclein (α-syn) accumulation. A growing number of patients show negative responses towards the current therapies. Thus, preventative or disease-modifying treatment agents are worth to further research. In recent years, compounds extracted from natural sources become promising candidates to treat PD. Chlorogenic acid (CGA) is a phenolic compound appearing in coffee, honeysuckle, and eucommia that showed their potential as antioxidants and neuroprotectors. In this study, we investigated the anti-PD activity of CGA by testing its effect on 1-methyl-4-phenyl-1-1,2,3,6-tetrahydropyridine (MPTP) zebrafish model of PD. It was shown that CGA relieved MPTP-induced PD-like symptoms including DA neurons and blood vessel loss, locomotion reduction, and apoptosis events in brain. Moreover, CGA modulated the expression of PD- and autophagy-related genes (α-syn, lc3b, p62, atg5, atg7, and ulk1b), showing its ability to promote the autophagy which was interrupted in the PD pathology. The unblocked effect of CGA on autophagy was further verified in 6-hydroxydopamine (6-OHDA)-modeled SHSY5Y cells. Our findings indicated that CGA might relieve PD by boosting the autophagy in neuronal cells that makes CGA a potential candidate for anti-PD treatment.
Assuntos
Fármacos Neuroprotetores , Doença de Parkinson , Animais , Camundongos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Peixe-Zebra , Ácido Clorogênico/farmacologia , Ácido Clorogênico/uso terapêutico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Autofagia , Neurônios Dopaminérgicos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
The objective of the study was to evaluate the curative effect of a modified technique of scleral suture fixation with a four-loop foldable intraocular lens (IOL) for eye with inadequate capsule support. This was a retrospective study of 22 eyes with inadequate capsule support of 20 patients who underwent the scleral suture fixation technique with 9-0 polypropylene suture and foldable four-loop IOL implant. Preoperative and follow-up data were collected for all patients. The mean follow-up was 5.08 ± 0.48 months (range: 3-12 months). The mean pre- and postoperative log of minimum angle of resolution (logMAR) uncorrected distance visual acuity was 1.11 ± 0.32 versus 0.09 ± 0.09 (P < 0.001). The mean pre- and postoperative logMAR best corrected visual acuity was 0.37 ± 0.19 versus 0.08 ± 0.07 (P < 0.001). The intraocular pressure (IOP) increased briefly (range: 21-30 mmHg) in eight eyes on the first day postoperatively and returned to normal within 1 week. No IOP drops were used postoperatively. The IOP was 12-19.3 (13.72 ± 1.28) in this follow-up, which had no significant difference compared to the preoperative IOP (t = 0.34, P = 0.74). At this follow-up, there was no hyperemia, local hyperplasia, obvious scar, suture knots, or segment ends observed under the conjunctiva, as well as no pupil deformation or vitreous hemorrhage. The mean postoperative IOL decentration degree was 0.22 ± 0.08 mm. At the 7-day follow-up postoperatively, one side of the IOL was dislocated to the vitreous cavity in one case, which was resolved by reimplantation of a new IOL in time with the same technique. Scleral suture fixation technique of a four-loop foldable IOL was a feasible operation method for an eye with inadequate capsular support.
Assuntos
Olho Artificial , Lentes Intraoculares , Humanos , Estudos Retrospectivos , Esclera , Procedimentos NeurocirúrgicosRESUMO
Chronic wounds seriously affect the quality of life of the elderly, obese people, and diabetic patients. The excessive inflammatory response is a key driver of delayed chronic wound healing. Although lavender essential oil (EO [lav]) has been proven to have anti-inflammatory and accelerate wound curative effects, the specific molecular mechanism involved is still ambiguous. The results showed that the wounds treated with lipopolysaccharide (LPS) not only had delayed healing, but also the expression levels of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and the inflammatory mediator protein, high-mobility group box 1 protein (HMGB-1), in the wound tissues were significantly increased. However, treatment of LPS-induced chronic wounds with EO (lav) accelerated wound healing and decreased IL-1ß and HMGB-1 expression levels. It was further found that LPS induced macrophage pyroptosis to produce IL-1ß. After treatment with EO (lav), the expression level of macrophage pyroptosis marker Gasdermin D (GSDMD) and pyroptosis-related cytotoxic effects were significantly reduced. Immunofluorescence results also directly indicate that EO (lav) can protect macrophages from LPS-induced pyroptosis. Moreover, EO (lav) can down-regulate expression levels of IL-1ß, GSDMD, and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) in the caspase-11-related pyroptotic signaling pathway. This study demonstrates that EO (lav) can reduce proinflammatory factor production and ameliorate inflammatory response by inhibiting macrophage pyroptosis, which accelerates LPS-induced chronic wound healing.
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Caspases , Lipopolissacarídeos , Humanos , Idoso , Lipopolissacarídeos/farmacologia , Caspases/metabolismo , Caspases/farmacologia , Piroptose , Qualidade de Vida , Macrófagos/metabolismo , Proteínas de Transporte/metabolismo , Proteínas HMGB/metabolismo , Proteínas HMGB/farmacologiaRESUMO
BACKGROUND: Advances in next-generation sequencing technologies are changing the ways cancer diagnosis and treatment, which leads to a new branch of precision medicine: "Precision Oncology". This study aims to deliver a structured overview to carry out a bibliometric analysis of precision oncology research over the past 10 years retrospectively. METHODS: Bibliometric methods including clustering analysis and co-occurrence visualized study were conducted based on publications of academic databases Web of Science Main Collection from 1st January 2012, to 31st December 2021. This study analyzed the information about related research outputs, countries, institutions, authors, cited papers, and hot topics. RESULTS: 7163 papers related to precision oncology were identified. Since 2014, the number of articles has proliferated, and oncology precision has attracted significant attention from scholars worldwide in recent years. The USA leads the research in this field, and the League of European Research Universities is the primary research institution. Research institutions from Asia paid more attention to this field through high-level international cooperation. Besides, there are still many issues expected to be explored and evaluated correctly. Such as the considerable uncertainty that pharmacogenomic methods have no significant influence on patient outcomes. CONCLUSIONS: Precision oncology serves as an essential method in clinical treatment, and is closely related to biological study, including biochemistry, molecular and genetics, advanced technology, and pharmacology discovery. The future research prospect would be the broad involvement of social participation and global cooperation in oncology precision research to acquire better results via the balance of technology and public health policy.
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Bibliometria , Neoplasias , Humanos , Estudos Retrospectivos , Oncologia , Neoplasias/terapia , Medicina de PrecisãoRESUMO
Cancer is a complex disease associated with multiple gene mutations and malignant phenotypes, and multi-target drugs provide a promising therapy idea for the treatment of cancer. Natural products with abundant chemical structure types and rich pharmacological characteristics could be ideal sources for screening multi-target antineoplastic drugs. In this paper, 50 tumor-related targets were collected by searching the Therapeutic Target Database and Thomson Reuters Integrity database, and a multi-target anti-cancer prediction system based on mt-QSAR models was constructed by using naïve Bayesian and recursive partitioning algorithm for the first time. Through the multi-target anti-cancer prediction system, some dominant fragments that act on multiple tumor-related targets were analyzed, which could be helpful in designing multi-target anti-cancer drugs. Anti-cancer traditional Chinese medicine (TCM) and its natural products were collected to form a TCM formula-based natural products library, and the potential targets of the natural products in the library were predicted by multi-target anti-cancer prediction system. As a result, alkaloids, flavonoids and terpenoids were predicted to act on multiple tumor-related targets. The predicted targets of some representative compounds were verified according to literature review and most of the selected natural compounds were found to exert certain anti-cancer activity in vitro biological experiments. In conclusion, the multi-target anti-cancer prediction system is very effective and reliable, and it could be further used for elucidating the functional mechanism of anti-cancer TCM formula and screening for multi-target anti-cancer drugs. The anti-cancer natural compounds found in this paper will lay important information for further study.
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Antineoplásicos , Medicamentos de Ervas Chinesas , Neoplasias , Antineoplásicos/farmacologia , Teorema de Bayes , Medicamentos de Ervas Chinesas/química , Humanos , Medicina Tradicional Chinesa , Neoplasias/tratamento farmacológicoRESUMO
Aquaporin 4 (AQP4) is highly expressed on astrocytes and is critical for controlling brain water transport in neurological diseases. Tumor necrosis factor (TNF)-α is a common cytokine found in disease microenvironment. The aim of the present study was to determine whether TNF-α can regulate the expression of AQP4 in astrocytes. Primary astrocyte cultures were treated with different concentrations of TNF-α and the cell viability was assessed through cell counting kit-8 (CCK-8) assay and AQP4 expression was detected by qPCR, Western blots, and immunofluorescence assays. The activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) pathway was detected by Western blot. Further, dual-luciferase reporting system and chromatin immunoprecipitation (ChIP) were used to detect the transcriptional regulation of AQP4 by p65. These experiments demonstrated that treatment with TNF-α can lead to astrocyte edema and an increase in AQP4 expression. Following TNF-α treatment, the expression levels of P-IKKα/ß-IκBα and P-p65 increased significantly over time. The results of the dual-luciferase reporter system and ChIP assays revealed that p65 protein and AQP4 promoter had a robust binding effect after TNF-α treatment, and the NF-κB pathway inhibitor, BAY 11-7082 could inhibit these effects of TNF-α. The expression level of AQP4 was significantly decreased upon p65 interference, while the astrocyte viability was significantly increased compared with that in the TNF-α only group. In conclusion, TNF-α activated NF-κB pathway, which promoted the binding of p65 to the AQP4 gene promoter region, and enhanced AQP4 expression, ultimately reducing astrocyte viability and causing cell edema.
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NF-kappa B , Fator de Necrose Tumoral alfa , Apoptose/genética , Aquaporina 4/genética , Aquaporina 4/metabolismo , Astrócitos/metabolismo , Edema , Humanos , Proteínas I-kappa B/metabolismo , Luciferases/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Heterotopic tumor is a rare disease. Thus far, no cases of heterotopic cholangiocarcinoma have been reported in the world. Cholangiocarcinoma mainly metastasizes by direct invasion, and it can lead to liver metastasis in its advanced stage. There were few clinical cases of gastric metastasis in advanced tumors, mainly seen in breast cancer, lung cancer, liver cancer, malignant melanoma, choriocarcinoma, and hematological tumors. Metastases of cholangiocarcinoma to the stomach also are exceptionally rare. CASE PRESENTATION: A 58-year-old man was admitted to the hospital because of difficulty swallowing for one year. Upon gastroscopy, we found the tumor at the region of the cardia and gastric fundus. Macroscopical appearance of the tumor suggested its malignant nature. Computed tomography (CT) findings showed that the wall of the cardia, fundus, and stomach body were thickened, suggesting a tumor. Because the patient had obvious difficulty swallowing, we invited cardiothoracic surgeons for consultation. They considered that the patient had definite mechanical obstruction in the lower esophagus; hence, they performed an operation. Immunohistochemical staining revealed low-to-medium differentiated adenocarcinoma (containing mucinous adenocarcinoma components) of biliary origin. CONCLUSIONS: We highlight the importance of the endoscopic biopsy of gastric tumor. However, when its results are inconsistent with the clinician's judgment, further examination is required. Endoscopic ultrasonography and enhanced CT may be a good choice. If necessary, on the premise of patient acceptance, the diagnosis could be confirmed after surgical excision. Here we report a case of a patient with heterotopic cholangiocarcinoma in the gastric fundus. The most common tissue ectopias in the digestive tract include esophagogastric gastric mucosal ectopia, duodenal gastric mucosal ectopia, and gastric mucosal small intestinal ectopia. Thus far, there have been no reports of ectopic cholangiocarcinoma and associated cancer in the stomach. In addition, metastases of cholangiocarcinoma to the stomach are also exceptionally rare, and most of them are due to a direct invasion. The discovery of the primary lesion is an important clue for the reliable diagnosis in such cases.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Transtornos de Deglutição , Gastrite , Neoplasias Gástricas , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos/patologia , Cárdia/patologia , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/patologia , Erros de Diagnóstico , Gastrite/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/patologiaRESUMO
Alzheimer's disease (AD) is a progressive, neurodegenerative disorder that currently has reached epidemic proportions among elderly populations around the world. In China, available traditional Chinese medicines (TCMs) that organically combine functional foods with medicinal values are named "Medicine Food Homology (MFH)". In this review, we focused on MFH varieties for their traditional functional features, substance bases, clinical uses, and mechanisms of action (MOAs) for AD prevention and treatment. We consider the antiAD active constituents from MFH species, their effects on in vitro/in vivo AD models, and their drug targets and signal pathways by summing up the literature via a systematic electronic search (SciFinder, PubMed, and Web of Science). In this paper, several MFH plant sources are discussed in detail from in vitro/in vivo models and methods, to MOAs. We found that most of the MFH varieties exert neuroprotective effects and ameliorate cognitive impairments by inhibiting neuropathological signs (Aß-induced toxicity, amyloid precursor protein, and phosphorylated Tau immunoreactivity), including anti-inflammation, antioxidative stress, antiautophagy, and antiapoptosis, etc. Indeed, some MFH substances and their related phytochemicals have a broad spectrum of activities, so they are superior to simple single-target drugs in treating chronic diseases. This review can provide significant guidance for people's healthy lifestyles and drug development for AD prevention and treatment.
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Doença de Alzheimer/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Alimento Funcional , Fármacos Neuroprotetores/uso terapêutico , Plantas Medicinais , Doença de Alzheimer/prevenção & controle , Animais , Alimento Funcional/análise , Humanos , Fármacos Neuroprotetores/análise , Extratos Vegetais/análise , Extratos Vegetais/uso terapêutico , Plantas Medicinais/químicaRESUMO
Metal oxide-based macroporous ordered double affinity molecularly imprinted polymers (D-MIPs) were developed as solid phase extraction (SPE) adsorbents for the specific identification of ovalbumin (OVA) under physiological pH conditions prior to ultraviolet visible (UV-vis) spectrophotometric detection. Herein, macroporous alumina (MA) was used as a matrix; dimercaptosuccinic acid (DMSA) and 3-aminophenylboric acid (APBA) were employed as dual-functional monomers; APBA is a self-polymerizing monomer. The effects of synthesis conditions, SPE conditions as well as selectivity, reproducibility, and reusability were studied. The co-modification of DMSA and boronate affinity renders the adsorbent exhibiting a high adsorption capacity (114.4 mg g-1) and short equilibrium time (30 min). The surface imprinting technology causes the adsorbent to have high selectivity towards OVA. The OVA recovery range is 91.1-99.6%. This study provides a promising method for the enrichment of OVA and other cis-diol-containing analytes in complex biological samples. A novel metal oxide-based macroporous ordered nanoparticle with a combination of DMSA and boronate affinity was successfully prepared for specific separation and enrichment of glycoprotein from complex biological samples.
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Óxido de Alumínio/química , Boratos/química , Contaminação de Alimentos/análise , Glicoproteínas/análise , Polímeros Molecularmente Impressos/química , Succímero/química , Análise de Alimentos , Tamanho da Partícula , Porosidade , Propriedades de SuperfícieRESUMO
COVID-19 caused by a novel coronavirus (SARS-CoV-2) has been spreading all over the world since the end of 2019, and no specific drug has been developed yet. 3C-like protease (3CLpro) acts as an important part of the replication of novel coronavirus and is a promising target for the development of anticoronavirus drugs. In this paper, eight machine learning models were constructed using naïve Bayesian (NB) and recursive partitioning (RP) algorithms for 3CLpro on the basis of optimized two-dimensional (2D) molecular descriptors (MDs) combined with ECFP_4, ECFP_6, and MACCS molecular fingerprints. The optimal models were selected according to the results of 5-fold cross verification, test set verification, and external test set verification. A total of 5766 natural compounds from the internal natural product database were predicted, among which 369 chemical components were predicted to be active compounds by the optimal models and the EstPGood values were more than 0.6, as predicted by the NB (MD + ECFP_6) model. Through ADMET analysis, 31 compounds were selected for further biological activity determination by the fluorescence resonance energy transfer (FRET) method and cytopathic effect (CPE) detection. The results indicated that (+)-shikonin, shikonin, scutellarein, and 5,3',4'-trihydroxyflavone showed certain activity in inhibiting SARS-CoV-2 3CLpro with the half-maximal inhibitory concentration (IC50) values ranging from 4.38 to 87.76 µM. In the CPE assay, 5,3',4'-trihydroxyflavone showed a certain antiviral effect with an IC50 value of 8.22 µM. The binding mechanism of 5,3',4'-trihydroxyflavone with SARS-CoV-2 3CLpro was further revealed through CDOCKER analysis. In this study, 3CLpro prediction models were constructed based on machine learning algorithms for the prediction of active compounds, and the activity of potential inhibitors was determined by the FRET method and CPE assay, which provide important information for further discovery and development of antinovel coronavirus drugs.
Assuntos
COVID-19 , SARS-CoV-2 , Antivirais/farmacologia , Teorema de Bayes , Transferência Ressonante de Energia de Fluorescência , Humanos , Inibidores de Proteases/farmacologiaRESUMO
Oxidative stress and neuroinflammation have been demonstrated to be linked with Alzheimer's disease (AD). In this study, we examined the protective effects of DL0410 in aging rats and explored the underlying mechanism against oxidative damage and neuroinflammation, which was then validated in LPS-stimulated BV2 microglia. We firstly investigated the improvement effects of DL0410 on learning and memory abilities and explored the potential mechanisms in D-gal-induced aging rats. An 8-week treatment with DL0410 significantly improved the learning and cognitive function of D-gal-stimulated Alzheimer's-like rats in the Morris water maze test, step-down test, and novel object recognition test, and the therapeutic effect of DL0410 at 10 mg/kg was even better than that of donepezil. What is more, the results showed that DL0410 alleviated neuron injury, increased the number of synapses, and improved the level of postsynaptic density protein 95 (PSD95) in the hippocampus and cortex. Next, we examined the protective effects of DL0410 against oxidative damage and neuroinflammation. Our observations indicated that DL0410 reduced the production of harmful oxidation products and promoted the antioxidative system, decreased the levels of proinflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and interleukin 6 (IL-6), and increased anti-inflammatory cytokines IL-10. Moreover, DL0410 inhibited the activation of astrocytes and microglia and suppressed the activation of the TLR4/MyD88/NF-κB signaling pathway. The anti-inflammation effect of DL0410 was further confirmed in LPS-stimulated BV2 cells, and the results showed that DL0410 reduced the level of inflammatory factors and inhibited the activation of the TLR4/MyD88/TRAF6/NF-κB signaling pathway in BV2 microglia. Molecular docking results indicated that DL0410 occupied the LPS recognition site in the TLR4/MD2 complex. Furthermore, the enhanced expression of claudin-1, claudin-5, occludin, CX43, and ZO-1 indicated that DL0410 protected the blood-brain barrier (BBB) integrity. Together, these results suggest that DL0410 exerts neuroprotective effects against hippocampus and cortex injury induced by D-galactose, and the possible mechanisms include antioxidative stress, antineuroinflammation, improving synaptic plasticity, and maintaining BBB integrity, which is mediated by the TLR4/MyD88/NF-κB signaling pathway inhibition. We suggest that DL0410 is a promising candidate for AD treatment.
Assuntos
Compostos de Bifenilo/farmacologia , Galactose/farmacologia , Transtornos da Memória/tratamento farmacológico , Fator 88 de Diferenciação Mieloide/efeitos dos fármacos , Doenças Neuroinflamatórias/tratamento farmacológico , Piperidinas/farmacologia , Animais , Galactose/metabolismo , Transtornos da Memória/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , NF-kappa B/farmacologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismoRESUMO
Alzheimer's disease (AD) is a neurodegenerative disease that seriously threatens the health of the elderly. At present, no drugs have been proven to cure or delay the progression of the disease. Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach provides an innovative and promising idea in search for new drugs against AD. In order to find potential multi-target anti-AD drugs from traditional Chinese medicine (TCM) formulae, a compound database derived from anti-AD Chinese herbal formulae was constructed and predicted by the anti-AD multi-target drug prediction platform established in our laboratory. By analyzing the results of virtual screening, 226 chemical constituents with 3 or more potential AD-related targets were collected, from which 16 compounds that were predicted to combat AD through various mechanisms were chosen for biological validation. Several cell models were established to validate the anti-AD effects of these compounds, including KCl, Aß, okadaic acid (OA), SNP and H2O2 induced SH-SY5Y cell model and LPS induced BV2 microglia model. The experimental results showed that 12 compounds including Nonivamide, Bavachromene and 3,4-Dimethoxycinnamic acid could protect model cells from AD-related damages and showed potential anti-AD activity. Furthermore, the potential targets of Nonivamide were investigated by molecular docking study and analysis with CDOCKER revealed the possible binding mode of Nonivamide with its predicted targets. In summary, 12 potential multi-target anti-AD compounds have been found from anti-AD TCM formulae by comprehensive application of computational prediction, molecular docking method and biological validation, which laid a theoretical and experimental foundation for in-depth study, also providing important information and new research ideas for the discovery of anti-AD compounds from traditional Chinese medicine.