RESUMEN

Antibodies against N-methyl-D-aspartate receptors (NMDARs) are most frequently detected in persons with autoimmune encephalitis (AE) and used as diagnostic biomarkers. Elucidating the structural basis of monoclonal antibody (mAb) binding to NMDARs would facilitate the development of targeted therapy for AE. Here, we reconstructed nanodiscs containing green fluorescent protein-fused NMDARs to label and sort individual immune B cells from persons with AE and further cloned and identified mAbs against NMDARs. This allowed cryo-electron microscopy analysis of NMDAR-Fab complexes, revealing that autoantibodies bind to the R1 lobe of the N-terminal domain of the GluN1 subunit. Small-angle X-ray scattering studies demonstrated NMDAR-mAb stoichiometry of 2:1 or 1:2, structurally suitable for mAb-induced clustering and endocytosis of NMDARs. Importantly, these mAbs reduced the surface NMDARs and NMDAR-mediated currents, without tonically affecting NMDAR channel gating. These structural and functional findings imply that the design of neutralizing antibody binding to the R1 lobe of NMDARs represents a potential therapy for AE treatment.

RESUMEN

The relationship between psoriasis and site-specific cancers remains unclear. Here, we aim to investigate whether psoriasis is causally associated with site-specific cancers. We use observational and genetic data from the UK Biobank, obtaining GWAS summary data, eQTL analysis data, TCGA data, and GTEx data from public datasets. We perform PheWAS, polygenic risk score analysis, and one-sample and two-sample Mendelian randomization analyses to investigate the potential causal associations between psoriasis and cancers. In the unselected PheWAS analysis, psoriasis is associated with higher risks of 16 types of cancer. Using one-sample Mendelian randomization analyses, it is found that genetically predicted psoriasis is associated with higher risks of anal canal cancer, breast cancer, follicular non-Hodgkin's lymphoma and nonmelanoma skin cancer in women; and lung cancer and kidney cancer in men. Our two-sample Mendelian randomization analysis indicates that psoriasis is causally associated with breast cancer and lung cancer. Gene annotation shows that psoriasis-related genes, such as ERAP1, are significantly different in lung and breast cancer tissues. Taken together, clinical attention to lung cancer and breast cancer may be warranted among patients with psoriasis.

Asunto(s)

Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Psoriasis , Humanos , Psoriasis/genética , Psoriasis/epidemiología , Femenino , Masculino , Neoplasias/genética , Neoplasias/epidemiología , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Neoplasias de la Mama/genética , Neoplasias de la Mama/epidemiología , Reino Unido/epidemiología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/epidemiología , Persona de Mediana Edad , Sitios de Carácter Cuantitativo , Herencia Multifactorial/genética

RESUMEN

AIMS: Diabetic nephropathy (DN) is a major complication of diabetes mellitus (DM) without curative interventions currently. Huperzine A (Hup A), a natural alkaloid, has demonstrated significant hypoglycemic and anti-inflammatory effects. We aim to investigate the protective effects of Hup A on DN and explore the underlying mechanisms METHODS: We applied STZ induced diabetic rats as DN model and leveraged combination analysis of the transcriptome, metabolome, microbiome, and network pharmacology (NP). The total effect of Hup A on DN was detected (i.e. urine protein, renal tissue structure) and the differential genes were further verified at the level of diabetic patients, db/db mice and cells. Clinical data and small interfering RNA (siRNA)-Apoe were adopted. RESULTS: Hup A alleviated kidney injury in DN rats. Transcriptomics data and Western blot indicated that the improvement in DN was primarily associated with Apoe and Apoc2. Additionally, metabolomics data demonstrated that DN-induced lipid metabolism disruption was regulated by Hup A, potentially involving sphingosine. Hup A also enriched microbial diversity and ameliorated DN-induced microbiota imbalance. Spearman's correlation analysis demonstrated significant associations among the transcriptome, metabolome, and microbiome. Apoe level was positively correlated with clinical biomarkers in DN patients. Si-Apoe also played protective role in podocytes. NP analysis also suggested that Hup A may treat DN by modulating lipid metabolism, microbial homeostasis, and apoptosis, further validating our findings. CONCLUSIONS: Collectively, we provide the first evidence of the therapeutic effect of Hup A on DN, indicating that Hup A is a potential drug for the prevention and treatment of DN.

RESUMEN

Hyperuricemia, a prevalent metabolic disturbance intricately linked to gout and chronic kidney disease (CKD), may be relieved by traditional Chinese medicine Polygonati Rhizoma. It is derived from the rhizomes of Polygonatum sibiricum, Polygonatum kingianum, and Polygonatum cyrtonema, which are rich in polysaccharides and are effective hyperuricemia alleviators. This study investigated the potential of Polygonatum sibiricum polysaccharide (PSP) in managing hyperuricemia. PSP (125, 250, and 500 mg/kg, i.g.) or allopurinol was administered to hyperuricemia mice treated with potassium oxonate and hypoxanthine for two weeks. PSP effectively decreased serum uric acid levels by inhibiting xanthine oxidase and adenosine deaminase activity and expression in the liver and modulating uric acid-related transporters (URAT1, OAT1, and OAT3) in the kidney. PSP lowered serum creatinine and blood urea nitrogen levels, alleviating hyperuricemia-induced renal tubular epithelial-mesenchymal fibrosis. In vitro, PSP promoted mitochondrial biogenesis via the PGC-1α/NRF1/TFAM pathway, suppressed reactive oxygen species production, and prevented cytochrome C and dynamin-related protein 1 dysregulation in HK-2 cells. Furthermore, PSPA (Mw 4.0 kDa) and PSPB (Mw 112.2 kDa) isolated from PSP exhibit different uric acid-lowering mechanisms. In conclusion, our findings highlight the therapeutic potential of PSP and its nephroprotective effects in hyperuricemia, thereby supporting its development as a therapeutic agent for hyperuricemia.

RESUMEN

Evolutionary pressures sculpt population genetics, whereas immune adaptation fortifies humans against life-threatening organisms. How the evolution of selective genetic variation in adaptive immune receptors orchestrates the adaptation of human populations to contextual perturbations remains elusive. Here, we show that the G396R coding variant within the human immunoglobulin G1 (IgG1) heavy chain presents a concentrated prevalence in Southeast Asian populations. We uncovered a 190-kb genomic linkage disequilibrium block peaked in close proximity to this variant, suggestive of potential Darwinian selection. This variant confers heightened immune resilience against various pathogens and viper toxins in mice. Mechanistic studies involving severe acute respiratory syndrome coronavirus 2 infection and vaccinated individuals reveal that this variant enhances pathogen-specific IgG1+ memory B cell activation and antibody production. This G396R variant may have arisen on a Neanderthal haplotype background. These findings underscore the importance of an IGHG1 variant in reinforcing IgG1 antibody responses against life-threatening organisms, unraveling the intricate interplay between human evolution and immune adaptation.

RESUMEN

Proteins with prion-like domains (PLDs) are involved in neurodegeneration-associated aggregation and are prevalent in liquid-like membrane-less organelles. These PLDs contain amyloidogenic stretches but can maintain dynamic disordered conformations, even in the condensed phase. However, the molecular mechanism underlying such intricate conformational properties of PLDs remains elusive. Here we employed molecular dynamics simulations to investigate the conformational properties of a prototypical PLD system (i.e., FUS PLD). According to our simulation results, PLD adopts a wet collapsed conformation, wherein most residues maintain sufficient hydration with the abundance of internal water. These internal water molecules can rapidly exchange between the protein interior and the bulk, enabling intensive coupling of the entire protein with its hydration environment. The dynamic exchange of water molecules is intimately correlated to the overall conformational fluctuations of PLD. Furthermore, the abundance of dynamic internal water suppresses the formation of aggregation-prone ordered structures. These results collectively elucidate the crucial role of internal water in sustaining the dynamic disordered conformation of the PLD and inhibiting its aggregation propensity.

Asunto(s)

Simulación de Dinámica Molecular , Priones , Agua , Agua/química , Priones/química , Conformación Proteica , Dominios Proteicos

RESUMEN

Congenital cataract is one of the most common causes of childhood blindness, typically resulting from genetic mutations. Over a hundred gene mutations associated with congenital cataract have been identified, with approximately half occurring in the Crystallin genes. In this study, we identified a novel γA-crystallin pathogenic mutation (c. 29G > C, p. Arg10Pro (R10P)), from a four-generation Chinese family with congenital cataract, and investigated its potential molecular mechanisms underlying congenital cataracts. We compared the protein structure and stability of purified the wild type (WT) and R10P under physiological conditions and environmental stresses (UV irradiation, pH imbalance, heat shock, and chemical denaturation) using spectroscopic experiments, SEC analysis, and the UNcle protein analysis system. The results demonstrate that γA-R10P has no significant impact on the structure of γA-crystallin on normal condition. However, it is more sensitive to UV irradiation at high concentrations and prone to aggregation at high temperatures. Therefore, our study reveals the crucial role of the conserved site mutation R10P in maintaining protein structure and stability, providing new insights into the mechanisms of cataract formation.

RESUMEN

BACKGROUND: To investigate the effects of Isoorientin on the apoptosis, proliferation, invasion, and migration of human gastric cancer cells (HGC27 cells). METHODS: We used network pharmacology to predict the targets of drugs and diseases. The CCK-8 assay was used to determine the effects of Isoorientin on the proliferation of HGC27 cells. Flow cytometry was employed to analyze the effects of Isoorientin on cell apoptosis and cell cycle distribution of HGC27 cells. Scratch test and transwell chamber test were conducted to assess the effects of Isoorientin on invasion and migration, respectively. Additionally, qPCR and western blot were performed to examine the impact of Isoorientin on apoptosis-related genes and protein expression, respectively. RESULTS: The Isoorientin significantly inhibited the proliferation, migration, and invasion of HGC27 cells compared to the control group. Furthermore, Isoorientin induced apoptosis in HGC27 cells by upregulating the relative expression of Bax and caspase-3 while downregulating the relative expression of p-PI3K, p-AKT, and Bcl-2 proteins. CONCLUSION: The Isoorientin exhibits inhibitory effects on the proliferation, invasion, and migration of HGC27 cells, and induces apoptosis in gastric cancer cells.

Asunto(s)

Apoptosis , Movimiento Celular , Luteolina , Farmacología en Red , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Luteolina/farmacología , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Invasividad Neoplásica

RESUMEN

BACKGROUND: Captopril challenge test (CCT), seated saline infusion test (SSIT), oral sodium loading test (OSLT) and fludrocortisone suppression test (FST) are widely used diagnostic tests for primary aldosteronism (PA). These tests differ in terms of safety and complexity. Whether the simpler tests (CCT and SSIT) are comparable in diagnostic performance to the more complex ones (FST and OSLT) is unclear. PURPOSE: To compare the diagnostic accuracy of the four tests. METHODS: This is a retrospective study of hypertensive patients who were screened for PA and completed at least one confirmatory test. The patients were divided into two cohorts: one including those who completed one to three tests was used for the estimation of sensitivity and specificity. The other including those who completed four tests was used for the comparison of accuracy. Bayesian method was used to obtain the sensitivity, specificity, and Youden index of each test. RESULTS: The study included 1011 hypertensive patients. Among them, 895 patients completed one to three tests (including 889 CCT, 605 FST, 611 SSIT and 69 OSLT), and 116 patients completed four tests. SSIT had the highest sensitivity of 0.82(95% CI 0.78-0.86) but the lowest specificity of 0.76(0.70-0.80). OSLT had the lowest sensitivity of 0.65(0.56-0.75) but the highest specificity of 0.91(0.82-0.96). The sensitivity and specificity were 0.78 (95% CI, 0.75-0.82), 0.82 (95% CI, 0.78-0.85), for CCT, and 0.77 (95% CI, 0.73-0.81), 0.87 (95% CI, 0.82-0.91) for FST, respectively. The Youden index was not significantly different among the four tests[0.60(0.55-0.65) for CCT; 0.58(0.51-0.64) for SSIT; (0.64(0.57-0.69) for FST; 0.56(0.43-0.67) for OSLT]. CONCLUSION: The accuracy of simpler tests is comparable to the more complex ones. Considering the safety and simplicity of CCT, it may be a reasonable first choice when confirming the diagnosis of PA.

Asunto(s)

Teorema de Bayes , Hiperaldosteronismo , Sensibilidad y Especificidad , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/sangre , Persona de Mediana Edad , Masculino , Femenino , Estudios Retrospectivos , Adulto , Hipertensión/diagnóstico , Anciano , Captopril , Fludrocortisona/uso terapéutico

RESUMEN

Upregulation of ADAMTS-4 has been reported to have an important role in lung injury, and ADAMTS-4 expression is regulated by miR-126a-5p in abdominal aortic aneurysms. The aim of this study was to investigate whether miR-126a-5p/ADAMTS-4 plays a role in influenza-virus-induced lung injury. Lung fibroblasts were infected with H1N1 influenza virus to detect changes in miR-126a-5p and ADAMTS-4 expression, and cell viability was measured by CCK-8 assay. Inflammatory factors and matrix protease levels were examined using ELISA kits, and cell apoptosis was assessed by measuring the levels of apoptosis-related proteins. A dual luciferase assay was used to verify the regulatory relationship between miR-126a-5p and ADAMTS-4. H1N1 influenza virus reduced fibroblast viability, inhibited miR-126a-5p expression, and promoted ADAMTS-4 expression. Overexpression of miR-126a-5p attenuated the cellular inflammatory response, apoptosis, matrix protease secretion, and virus replication. Luciferase reporter assays revealed that miR-126a-5p inhibited ADAMTS-4 expression by targeting ADAMTS-4 mRNA. Further experiments showed that overexpression of ADAMTS-4 significantly reversed the inhibitory effects of miR-126a-5p on fibroblast inflammation, apoptosis, matrix protease secretion, and virus replication. Upregulation of miR-126a-5p inhibits H1N1-induced apoptosis, inflammatory factors, and matrix protease secretion, as well as virus replication in lung fibroblasts.

Asunto(s)

Proteína ADAMTS4 , Apoptosis , Fibroblastos , Inflamación , Subtipo H1N1 del Virus de la Influenza A , Pulmón , MicroARNs , MicroARNs/genética , MicroARNs/metabolismo , Fibroblastos/virología , Fibroblastos/metabolismo , Humanos , Pulmón/virología , Pulmón/patología , Proteína ADAMTS4/genética , Proteína ADAMTS4/metabolismo , Subtipo H1N1 del Virus de la Influenza A/genética , Subtipo H1N1 del Virus de la Influenza A/fisiología , Inflamación/genética , Supervivencia Celular , Replicación Viral , Gripe Humana/virología , Gripe Humana/genética , Gripe Humana/metabolismo , Línea Celular

RESUMEN

Congenital cataracts, a prevalent cause of blindness in children, are associated with protein aggregation. γD-crystallin, essential for sustaining lens transparency, exists as a monomer and exhibits excellent structural stability. In our cohort, we identified a nonsense mutation (c.451_452insGACT, p.Y151X) in the CRYGD gene. To explore the effect of truncation mutations on the structure of γD-crystallin, we examined the Y151X and T160RfsX8 mutations, both located in the Greek key motif 4 at the cellular and protein level in this study. Both truncation mutations induced protein misfolding and resulted in the formation of insoluble aggregates when overexpressed in HLE B3 and HEK 293T cells. Moreover, heat, UV irradiation, and oxidative stress increased the proportion of aggregates of mutants in the cells. We next purified γD-crystallin to estimate its structural changes. Truncation mutations led to conformational disruption and a concomitant decrease in protein solubility. Molecular dynamics simulations further demonstrated that partial deletion of the conserved domain within the Greek key motif 4 markedly compromised the overall stability of the protein structure. Finally, co-expression of α-crystallins facilitated the proper folding of truncated mutants and mitigated protein aggregation. In summary, the structural integrity of the Greek key motif 4 in γD-crystallin is crucial for overall structural stability.

Asunto(s)

Catarata , Agregado de Proteínas , Estabilidad Proteica , gamma-Cristalinas , Humanos , gamma-Cristalinas/genética , gamma-Cristalinas/química , gamma-Cristalinas/metabolismo , Catarata/genética , Catarata/metabolismo , Células HEK293 , Mutación , Simulación de Dinámica Molecular , Pliegue de Proteína , Conformación Proteica , Solubilidad , Agregación Patológica de Proteínas/genética

RESUMEN

Large prospective studies are required to better elucidate the associations of physical activity, sedentary behaviors (SBs), and sleep with overall cancer and site-specific cancer risk, accounting for the interactions with genetic predisposition. The study included 360,271 individuals in UK Biobank. After a median follow-up of 12.52 years, we found higher total physical activity (TPA) level and higher sleep scores were related to reduced risk of cancer while higher SB level showed a positive association with cancer. Compared with high TPA-healthy sleep group and low SB-healthy sleep group, low TPA-poor sleep group and high SB-poor sleep group had the highest risk for overall cancer, breast cancer, and lung cancer. Adherence to a more active exercise pattern was associated with a lower risk of cancer irrespective of genetic risk. Our study suggests that improving the quality of sleep and developing physical activity habits might yield benefits in mitigating the cancer risk.

RESUMEN

Rationale: Cataract is the leading cause of blindness and low vision worldwide, yet its pathological mechanism is not fully understood. Although macroautophagy/autophagy is recognized as essential for lens homeostasis and has shown potential in alleviating cataracts, its precise mechanism remains unclear. Uncovering the molecular details of autophagy in the lens could provide targeted therapeutic interventions alongside surgery. Methods: We monitored autophagic activities in the lens and identified the key autophagy protein ATG16L1 by immunofluorescence staining, Western blotting, and transmission electron microscopy. The regulatory mechanism of ATG16L1 ubiquitination was analyzed by co-immunoprecipitation and Western blotting. We used the crystal structure of E3 ligase gigaxonin and conducted the docking screening of a chemical library. The effect of the identified compound riboflavin was tested in vitro in cells and in vivo animal models. Results: We used HLE cells and connexin 50 (cx50)-deficient cataract zebrafish model and confirmed that ATG16L1 was crucial for lens autophagy. Stabilizing ATG16L1 by attenuating its ubiquitination-dependent degradation could promote autophagy activity and relieve cataract phenotype in cx50-deficient zebrafish. Mechanistically, the interaction between E3 ligase gigaxonin and ATG16L1 was weakened during this process. Leveraging these mechanisms, we identified riboflavin, an E3 ubiquitin ligase-targeting drug, which suppressed ATG16L1 ubiquitination, promoted autophagy, and ultimately alleviated the cataract phenotype in autophagy-related models. Conclusions: Our study identified an unrecognized mechanism of cataractogenesis involving ATG16L1 ubiquitination in autophagy regulation, offering new insights for treating cataracts.

Asunto(s)

Proteínas Relacionadas con la Autofagia , Autofagia , Catarata , Cristalino , Pez Cebra , Animales , Catarata/metabolismo , Catarata/tratamiento farmacológico , Autofagia/efectos de los fármacos , Proteínas Relacionadas con la Autofagia/metabolismo , Cristalino/metabolismo , Cristalino/efectos de los fármacos , Humanos , Ubiquitinación/efectos de los fármacos , Riboflavina/farmacología , Modelos Animales de Enfermedad , Línea Celular

RESUMEN

BACKGROUND: There is little evidence to comprehensively summarize the adverse events (AEs) profile of intermittent fasting (IF) despite its widespread use in patients with overweight or obesity. METHODS: We searched the main electronic databases and registry websites to identify eligible randomized controlled trials (RCTs) comparing IF versus control groups. A direct meta-analysis using a fixed-effect model was conducted to pool the risk differences regarding common AEs and dropouts. Study quality was assessed by using the Jadad scale. Pre-specified subgroup and sensitivity analyses were conducted to explore potential heterogeneity. RESULTS: A total of 15 RCTs involving 1,365 adult individuals were included. Findings did not show a significant difference between IF and Control in risk rate of fatigue [0%, 95% confidence interval (CI), -1% to 2%; P = 0.61], headache [0%, 95%CI: -1% to 2%; P = 0.86] and dropout [1%, 95%CI: -2% to 4%; P = 0.51]. However, a numerically higher risk of dizziness was noted among the IF alone subgroup with non-early time restricted eating [3%, 95%CI: -0% to 6%; P = 0.08]. CONCLUSIONS: This meta-analysis suggested that IF was not associated with a greater risk of AEs in adult patients affected by overweight or obesity. Additional large-scale RCTs stratified by key confounders and designed to evaluate the long-term effects of various IF regimens are needed to ascertain these AEs profile.

Asunto(s)

Ayuno Intermitente , Obesidad , Sobrepeso , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto , Humanos , Mareo , Fatiga , Cefalea , Ayuno Intermitente/efectos adversos

RESUMEN

Hydrogen sulfide (H2S) gas plays a significant role in biological regulation. With advancements in technology, H2S has been discovered across diverse fields, necessitating a comprehensive understanding of its physiological functions through monitoring changes in H2S within complex environments and physiological processes. In this study, we designed a phosphofluorene-based conjugate probe PPF-CDNB with an asymmetric π-conjugated phosphine structure and utilized dinitrophenyl ether as the recognition site for H2S. PPF-CDNB exhibited exceptional resistance to interference and demonstrated stability over a broad pH range (3.0-10.0), making it suitable for various environmental conditions. Intracellular experiments revealed that PPF-CDNB effectively monitored both endogenous and exogenous levels of H2S.

RESUMEN

Background: With the rapid development of nanotechnology, constructing a multifunctional nanoplatform that can deliver various therapeutic agents in different departments and respond to endogenous/exogenous stimuli for multimodal synergistic cancer therapy remains a major challenge to address the inherent limitations of chemotherapy. Methods: Herein, we synthesized hollow mesoporous Prussian Blue@zinc phosphate nanoparticles to load glucose oxidase (GOx) and DOX (designed as HMPB-GOx@ZnP-DOX NPs) in the non-identical pore structures of their HMPB core and ZnP shell, respectively, for photothermally augmented chemo-starvation therapy. Results: The ZnP shell coated on the HMPB core, in addition to providing space to load DOX for chemotherapy, could also serve as a gatekeeper to protect GOx from premature leakage and inactivation before reaching the tumor site because of its degradation characteristics under mild acidic conditions. Moreover, the loaded GOx can initiate starvation therapy by catalyzing glucose oxidation while causing an upgradation of acidity and H2O2 levels, which can also be used as forceful endogenous stimuli to trigger smart delivery systems for therapeutic applications. The decrease in pH can improve the pH-sensitivity of drug release, and O2 can be supplied by decomposing H2O2 through the catalase-like activity of HMPBs, which is beneficial for relieving the adverse conditions of anti-tumor activity. In addition, the inner HMPB also acts as a photothermal agent for photothermal therapy and the generated hyperthermia upon laser irradiation can serve as an external stimulus to further promote drug release and enzymatic activities of GOx, thereby enabling a synergetic photothermally enhanced chemo-starvation therapy effect. Importantly, these results indicate that HMPB-GOx@ZnP-DOX NPs can effectively inhibit tumor growth by 80.31% and exhibit no obvious systemic toxicity in mice. Conclusion: HMPB-GOx@ZnP-DOX NPs can be employed as potential theranostic agents that incorporate multiple therapeutic modes to efficiently inhibit tumors.

Asunto(s)

Doxorrubicina , Ferrocianuros , Glucosa Oxidasa , Fosfatos , Terapia Fototérmica , Compuestos de Zinc , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Animales , Glucosa Oxidasa/química , Glucosa Oxidasa/farmacología , Ratones , Ferrocianuros/química , Ferrocianuros/farmacología , Humanos , Compuestos de Zinc/química , Fosfatos/química , Fosfatos/farmacología , Terapia Fototérmica/métodos , Porosidad , Nanopartículas/química , Línea Celular Tumoral , Liberación de Fármacos , Ratones Endogámicos BALB C , Sistemas de Liberación de Medicamentos/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Portadores de Fármacos/química

RESUMEN

Protein misfolding and aggregation are crucial pathogenic factors for cataracts, which are the leading cause of visual impairment worldwide. α-crystallin, as a small molecular chaperone, is involved in preventing protein misfolding and maintaining lens transparency. The chaperone activity of α-crystallin depends on its oligomeric state. Our previous work identified a natural compound, celastrol, which could regulate the oligomeric state of αB-crystallin. In this work, based on the UNcle and SEC analysis, we found that celastrol induced αB-crystallin to form large oligomers. Large oligomer formation enhanced the chaperone activity of αB-crystallin and prevented aggregation of the cataract-causing mutant ßA3-G91del. The interactions between αB-crystallin and celastrol were detected by the FRET (Fluorescence Resonance Energy Transfer) technique, and verified by molecular docking. At least 9 binding patterns were recognized, and some binding sites covered the groove structure of αB-crystallin. Interestingly, αB-R120G, a cataract-causing mutation located at the groove structure, and celastrol can decrease the aggregates of αB-R120G. Overall, our results suggested celastrol not only promoted the formation of large αB-crystallin oligomers, which enhanced its chaperone activity, but also bound to the groove structure of its α-crystallin domain to maintain its structural stability. Celastrol might serve as a chemical and pharmacological chaperone for cataract treatment.

RESUMEN

CONTEXT: To investigate the influence of different concentrations of surfactants on the adsorption of anthracite, the nonionic surfactant alkyl polyglucoside (APG) was selected. The study examined the adsorption characteristics of different concentrations of APG on the surface of anthracite. The results revealed the existence of two modes of APG adsorption on anthracite. Under the action of 0.06 wt% APG, APG was found to adsorb in a monolayer state on the anthracite surface, with a saturation adsorption capacity of 20.06 mg/g. When the solution concentration exceeded 0.14 wt%, APG exhibited a double-layer saturation adsorption state on anthracite, with a saturation adsorption capacity of 71.71 mg/g. Molecular dynamics simulations complemented these findings, demonstrating that low concentrations of APG could reduce the mobility of water molecules and enhance the hydrophilicity of anthracite. With an increase in the number of APG molecules, multi-layer adsorption occurred on the anthracite surface, making it more hydrophobic. Therefore, the differences in wettability of anthracite induced by different concentrations of APG were primarily attributed to the spatial distribution of the surfactant at the water/coal interface. METHODS: This study analyzed the adsorption capacity of the surfactant through adsorption experiments and Fourier-transform infrared spectroscopy (FTIR) experiments. Molecular dynamics simulations were conducted to construct six concentration levels of water/APG/anthracite systems. Various aspects, including APG adsorption configurations, interaction energies, relative concentrations of each component, and the diffusion coefficient of water molecules, were discussed to elucidate the reasons for the differential wettability of anthracite induced by different concentrations of APG.

RESUMEN

Accurate and continuous monitoring of cerebral blood flow is valuable for clinical neurocritical care and fundamental neurovascular research. Transcranial Doppler (TCD) ultrasonography is a widely used non-invasive method for evaluating cerebral blood flow1, but the conventional rigid design severely limits the measurement accuracy of the complex three-dimensional (3D) vascular networks and the practicality for prolonged recording2. Here we report a conformal ultrasound patch for hands-free volumetric imaging and continuous monitoring of cerebral blood flow. The 2 MHz ultrasound waves reduce the attenuation and phase aberration caused by the skull, and the copper mesh shielding layer provides conformal contact to the skin while improving the signal-to-noise ratio by 5 dB. Ultrafast ultrasound imaging based on diverging waves can accurately render the circle of Willis in 3D and minimize human errors during examinations. Focused ultrasound waves allow the recording of blood flow spectra at selected locations continuously. The high accuracy of the conformal ultrasound patch was confirmed in comparison with a conventional TCD probe on 36 participants, showing a mean difference and standard deviation of difference as -1.51 ± 4.34 cm s-1, -0.84 ± 3.06 cm s-1 and -0.50 ± 2.55 cm s-1 for peak systolic velocity, mean flow velocity, and end diastolic velocity, respectively. The measurement success rate was 70.6%, compared with 75.3% for a conventional TCD probe. Furthermore, we demonstrate continuous blood flow spectra during different interventions and identify cascades of intracranial B waves during drowsiness within 4 h of recording.

Asunto(s)

Velocidad del Flujo Sanguíneo , Encéfalo , Circulación Cerebrovascular , Ultrasonografía , Humanos , Velocidad del Flujo Sanguíneo/fisiología , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Circulación Cerebrovascular/fisiología , Imagenología Tridimensional/instrumentación , Imagenología Tridimensional/métodos , Errores Médicos , Relación Señal-Ruido , Piel , Cráneo , Somnolencia/fisiología , Ultrasonografía/instrumentación , Ultrasonografía/métodos , Adulto

RESUMEN

The role of selenium in the developmental process of esophageal cancer (EC) requires further investigation. To explore the relationship between selenium-related factors and EC through bioinformatic analysis, a case-control study was conducted to verify the results. Utilizing the GEPIA and TCGA databases, we delineated the differential expression of glutathione peroxidase 3 (GPx3) in EC and normal tissues, identified differentially expressed genes (DEGs), and a performed visualization analysis. Additionally, 100 pairs of dietary and plasma samples from esophageal precancerous lesions (EPLs) of esophageal squamous cancer (ESCC) cases and healthy controls from Huai'an district, Jiangsu, were screened. The levels of dietary selenium, plasma selenium, and related enzymes were analyzed using inductively coupled plasma mass spectrometry (ICP-MS) or ELISA kits. The results showed lower GPx3 expression in tumor tissues compared to normal tissues. Further analysis revealed that DEGs were mainly involved in the fat digestion and absorption pathway, and the core protein fatty acid binding protein 1 (FABP1) was significantly upregulated and negatively correlated with GPx3 expression. Our case-control study found that selenium itself was not associated with EPLs risk. However, both the decreased concentration of GPx3 and the increase in FABP1 were positively correlated with the EPLs risk (p for trend = 0.035 and 0.046, respectively). The different expressions of GPx3 and FABP1 reflect the potential of selenium for preventing ESCC at the EPLs stage. GPx3 may affect myocardial infarction through FABP1, which remains to be further studied.

Asunto(s)

Biología Computacional , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Proteínas de Unión a Ácidos Grasos , Glutatión Peroxidasa , Selenio , Humanos , Selenio/sangre , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Glutatión Peroxidasa/sangre , Estudios de Casos y Controles , Neoplasias Esofágicas/prevención & control , Neoplasias Esofágicas/genética , Biología Computacional/métodos , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Unión a Ácidos Grasos/metabolismo , Carcinoma de Células Escamosas de Esófago/prevención & control , Carcinoma de Células Escamosas de Esófago/genética , Femenino , Masculino , Persona de Mediana Edad , Regulación Neoplásica de la Expresión Génica , Anciano