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The extensively applied triazine herbicides are easily transported by ocean currents over long distances. This study analyzed ten triazine herbicides in the Antarctic marginal seas and the Southern Indian Ocean during the austral summer for the first time, addressing their largely unexplored behavior in remote marine environments. The total triazine herbicides showed great spatial heterogeneity, with a range of 20-790 pg/L and an average of 31 ± 66 pg/L. The waterborne transport of triazine herbicides in the Antarctic was affected by hydrological processes, especially the blocking and accumulation effect of the polar front. Variations in sea ice extent and temperature were also important influencing factors, resulting in elevated triazine herbicides in surface seawater of East Antarctica, but reduced levels in West Antarctica. Furthermore, the source apportionment results indicated that approximately 55 % of the herbicides originated from sugarcane cultivation, 28 % from algaecide use, and 16 % from corn and sorghum farming.
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Cold rolling has been used as a real-time surface oxidation control method to create colored strips on flexible substrates. By controlling the extrusion rate in real time, a variety of colored strips have been fabricated on Ga-based liquid metal (LM) strips. X-ray photoelectron spectroscopy (XPS) analysis shows that the surfaces of the colored strips, which were obtained through extrusion rate control of LM-Al, consist primarily of metal oxide composites, including Ga2O3, Ga2O, Al2O3, SnO2, and In2O3. The colors of the strip surfaces are directly correlated with the oxide film thickness. Additionally, these cold-rolled colored thin strips demonstrate high conductivity and have significant potential for use as conductive flexible components with indicator functions in the flexible electronics realm.
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The influence of tree age on the growth response of Picea likiangensis, a predominant timber species in southwestern China, to climatic factors has been under-researched. In this study, we examined the relationships between tree age and the response of P. likiangensis to climatic factors and extreme drought events using tree-ring samples procured from the southeastern edge of the Tibetan Plateau. The results revealed differential responses of the radial growth of P. likiangensis trees of varying ages to climatic factors and extreme drought events. Specifically, deficient water availability during the early growing season emerged as the principal factor constraining radial growth across all age classes. Young and middle-aged trees (<100 years) demonstrated greater responsiveness to water availability than did mature trees (>100 years). Mature trees, in contrast, demonstrated markedly greater resistance to extreme drought events than young and middle-aged trees. Comparative studies of individual trees across different ages revealed negligible differences in the response of young and middle-aged trees to climatic factors and extreme drought events. Given these responses, future forest management practices should prioritize young and middle-aged trees that are more affected by drought to maximize the ecological value of the species. According to the specific research objectives, sample collection processes should classify mature trees and young and middle-aged trees, to minimize the influence of tree age on the final findings of the study.
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Clima , Sequías , Picea , Picea/crecimiento & desarrollo , Picea/fisiología , Cambio Climático , China , Árboles/crecimiento & desarrolloRESUMEN
BACKGROUND: Cisplatin (DDP) as the first-line drug has been used in cancer therapy. However, side effects and drug resistance are the challenges of DDP. Disordered lipid metabolism is related to DDP resistance. STUDY DESIGN: In this study, formosanin C (FC) as the main compound of Rhizoma Paridis saponins (RPS) inhibits pulmonary metastasis by targeting stearyl CoA desaturase-1. METHODS AND RESULTS: RPS prolonged the survival period of mice, reduced pulmonary metastases and alleviated colon toxicity caused by DDP. FC as the main compound of RPS enhanced the anti-tumor and anti-metastatic effects of DDP. FC decreased the mRNA level of SCD1 and the content of lipid droplets (LDs) in lung cancer cells. Molecular dynamics and isothermal titration calorimetry verified the binding stability and spontaneously between FC and SCD1. SiSCD1 reduced the content of LDs in cell lines and increased mitochondria (mtROS), which was consistent with the results of FC treatment. The combination group decreased DNA repair associated protein as well as DDP resistance markers such as ERCC1 and 53bp1, and increased DNA damage marker like γH2AX, which indirectly confirmed the occurrence of mtROS. In addition, FC combination with DDP also affected epithelial-mesenchymal transition-related protein like VIM and CDH1 in vivo experiments, and thereby inhibited pulmonary metastasis. CONCLUSION: Our research indicated that the FC as the main compound of RPS targeted the CY2 domain of SCD1, inhibited lipid metabolism in mice, and thereby suppressed cancer metastases. This provided support for use of FC to treat cancer based on lipid metabolism pathway.
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Cisplatino , Neoplasias Pulmonares , Saponinas , Estearoil-CoA Desaturasa , Animales , Humanos , Masculino , Ratones , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Cisplatino/farmacología , Gotas Lipídicas/efectos de los fármacos , Gotas Lipídicas/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Ratones Endogámicos BALB C , Saponinas/farmacología , Estearoil-CoA Desaturasa/metabolismo , Estearoil-CoA Desaturasa/genéticaRESUMEN
Pyroptosis, a novel type of programmed cell death (PCD), which provides a feasible therapeutic option for the treatment of tumors. However, due to the hypermethylation of the promoter, the critical protein Gasdermin E (GSDME) is lacking in the majority of cancer cells, which cannot start the pyroptosis process and leads to dissatisfactory therapeutic effects. Additionally, the quick clearance, systemic side effects, and low concentration at the tumor site of conventional pyroptosis reagents restrict their use in clinical cancer therapy. Here, we described a combination therapy that induces tumor cell pyroptosis via the use of ultrasound-targeted microbubble destruction (UTMD) in combination with DNA demethylation. The combined application of UTMD and hydralazine-loaded nanodroplets (HYD-NDs) can lead to the rapid release of HYD (a demethylation drug), which can cause the up-regulation of GSDME expression, and produce reactive oxygen species (ROS) by UTMD to cleave up-regulated GSDME, thereby inducing pyroptosis. HYD-NDs combined with ultrasound (US) group had the strongest tumor inhibition effect, and the tumor inhibition rate was 87.15% (HYD-NDs group: 51.41 ± 3.61%, NDs + US group: 32.73%±7.72%), indicating that the strategy had a more significant synergistic anti-tumor effect. In addition, as a new drug delivery carrier, HYD-NDs have great biosafety, tumor targeting, and ultrasound imaging performance. According to the results, the combined therapy reasonably regulated the process of tumor cell pyroptosis, which offered a new strategy for optimizing the therapy of GSDME-silenced solid tumors.
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Neoplasias , Piroptosis , Humanos , Piroptosis/fisiología , Microburbujas , Neoplasias/tratamiento farmacológico , Apoptosis , Hidralazina/farmacología , Hidralazina/uso terapéuticoRESUMEN
Scorpio, a commonly used animal medicine in China, is derived from Buthus martensii as recorded in the Chinese Pharmacopoeia. China harbors rich species of Scorpionida and adulterants exist in the raw medicinal material and deep-processed products of Scorpio. The microscopic characteristics of the deep-processed products may be incomplete or lost during processing, which makes the identification difficult. In this study, the maximum likelihood(ML) tree was constructed based on the morphology and cytochrome C oxidase subunit I(COâ ) to identify the species of Scorpio products. The results showed that the main adulterant of Scorpio was Lychas mucronatus. According to the specific SNP sites in the COâ sequence of B. martensii, the stable primers were designed for the identification of the medicinal material and formula granules of Scorpio. The polymerase chain reaction(PCR) at the annealing temperature of 61 â and 30 cycles produced bright specific bands at about 150 bp for both B. martensii and its formula particles and no band for adulterants. The adaptability of the method was investigated, which showed that the bands at about 150 bp were produced for Scorpio medicinal material, lyophilized powder, and formula granules, and commercially available formula granules. The results showed that the established method could be used to identify the adulterants of Scorpio and its formula granules, which could help to improve the quality control system and ensure the safe clinical application of Scorpio formula granules.
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Animales Ponzoñosos , Medicamentos Herbarios Chinos , Escorpiones , Animales , Reacción en Cadena de la Polimerasa/métodosRESUMEN
Mitochondria play roles in the resistance of Caenorhabditis elegans against pathogenic bacteria by regulating mitochondrial unfolded protein response (UPRmt). Caffeic acid (CA) (3,4-dihydroxy cinnamic acid) is a major phenolic compound present in several plant species, which exhibits biological activities such as antioxidant, anti-fibrosis, anti-inflammatory, and anti-tumor properties. However, whether caffeic acid influences the innate immune response and the underlying molecular mechanisms remains unknown. In this study, we find that 20 µM caffeic acid enhances innate immunity to resist the Gram-negative pathogen Pseudomonas aeruginosa infection in C. elegans. Meanwhile, caffeic acid also inhibits the growth of pathogenic bacteria. Furthermore, caffeic acid promotes host immune response by reducing the bacterial burden in the intestine. Through genetic screening in C. elegans, we find that caffeic acid promotes innate immunity via the transcription factor ATFS-1. In addition, caffeic acid activates the UPRmt and immune response genes for innate immune response through ATFS-1. Our work suggests that caffeic acid has the potential to protect patients from pathogen infection.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Ácidos Cafeicos , Animales , Humanos , Caenorhabditis elegans/microbiología , Proteínas de Caenorhabditis elegans/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Mitocondrias/metabolismoRESUMEN
PD-1/PD-L1-based immune checkpoint blockade therapy has shown limited benefits in tumor patients, partially attributed to the inadequate infiltration of immune effector cells within tumors. Here, we established a nanoplatform named DPPA/IL-15 NPs to target PD-L1 for the tumor delivery of IL-15 messenger RNA (mRNA). DPPA/IL-15 NPs were endowed with ultrasound responsiveness and contrast-enhanced ultrasound (CEUS) imaging performance. They effectively protected IL-15 mRNA from degradation and specifically transfected it into tumor cells through the utilization of ultrasound-targeted microbubble destruction (UTMD). This resulted in the activation of IL-15-related immune effector cells while blocking the PD-1/PD-L1 pathway. In addition, UTMD could generate reactive oxygen species (ROS) that induce endoplasmic reticulum (ER) stress-driven immunogenic cell death (ICD), initiating anti-tumor immunity. In vitro and in vivo studies revealed that this combination therapy could induce a robust systemic immune response and enhance anti-tumor efficacy. Thus, this combination therapy has the potential for clinical translation through enhanced immunotherapy and provides real-time ultrasound imaging guidance.
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Antígeno B7-H1 , Neoplasias , Humanos , Microburbujas , Receptor de Muerte Celular Programada 1/metabolismo , Interleucina-15/genética , Neoplasias/terapia , Inmunoterapia/métodos , Microambiente Tumoral , Línea Celular TumoralRESUMEN
The function of Biliverdin Reductase A (BLVRA) in hepatocellular carcinoma (HCC) cells proliferation, invasion and migration remains unclear. Therefore, this research intends to explore the effect of BLVRA on HCC cells growth and metastasis. BLVRA expression was analyzed in public dataset and examined by using western blot. The malignant function of BLVRA in HCC cell lines and its effect on Wnt/ß-catenin pathway were measured. Analysis from GEPIA website showed that BLVRA expression was significantly increased in HCC tissues, and high expression of BLVRA resulted in worse prognosis of HCC patients. Results from western blot showed that BLVRA expression was obviously increased in HCC cell lines. Moreover, HepG2 and Hep3B cells in si-BLVRA-1 or si-BLVRA-2 group displayed an obvious reduction in its proliferation, cell cycle, invasion and migration compared to those in the si-control group. Additionally, si-BLVRA-1 or si-BLVRA-2 transfection significantly reduced the protein levels of Vimentin, Snail1 and Snail2, as well as decreased Bcl-2 expression and increased Bax and cleaved-caspase 3 expression. Furthermore, si-BLVRA treatment inhibited the protein levels of c-MYC, ß-catenin, and Cyclin D1. After IWP-4 (Wnt/ß-catenin inhibitor) treatment, the proliferation ability of HCC cells was significantly reduced. BLVRA expression was significantly increased in HCC tissues and cell lines, and knocked down of BLVRA could suppress the proliferation, invasion and migration in HCC cell lines, as well as induce cell apoptosis. Moreover, si-BLVRA transfection blocked the activation of Wnt/ß-catenin pathway.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , beta Catenina/metabolismo , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/metabolismo , Vía de Señalización WntRESUMEN
The relationship between erythrocyte membrane n-3 PUFA and breast cancer risk is controversial. We aimed to examine the associations of erythrocyte membrane n-3 PUFA with odds of breast cancer among Chinese women by using a relatively large sample size. A case-control study was conducted including 853 newly diagnosed, histologically confirmed breast cancer cases and 892 frequency-matched controls (5-year interval). Erythrocyte membrane n-3 PUFA were measured by GC. Logistic regression and restricted cubic spline were used to quantify the association between erythrocyte membrane n-3 PUFA and odds of breast cancer. Erythrocyte membrane α-linolenic acid (ALA), docosapentaenoic acid (DPA) and total n-3 PUFA were inversely and non-linearly associated with odds of breast cancer. The OR values (95 % CI), comparing the highest with the lowest quartile (Q), were 0·57 (0·43, 0·76), 0·43 (0·32, 0·58) and 0·36 (0·27, 0·49) for ALA, DPA and total n-3 PUFA, respectively. Erythrocyte membrane EPA and DHA were linearly and inversely associated with odds of breast cancer ((EPA: ORQ4 v. Q1 (95 % CI) = 0·59 (0·45, 0·79); DHA: ORQ4 v. Q1 (95 % CI) = 0·50 (0·37, 0·67)). The inverse associations were observed between ALA and odds of breast cancer in postmenopausal women, and between DHA and oestrogen receptor+ breast cancer. This study showed that erythrocyte membrane total and individual n-3 PUFA were inversely associated with odds of breast cancer. Other factors, such as menopause and hormone receptor status, may warrant further investigation when examining the association between n-3 PUFA and odds of breast cancer.
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Neoplasias de la Mama , Ácidos Grasos Omega-3 , Humanos , Femenino , Membrana Eritrocítica , Neoplasias de la Mama/epidemiología , Estudios de Casos y Controles , Modelos Logísticos , China/epidemiología , Ácido Eicosapentaenoico , Ácidos DocosahexaenoicosRESUMEN
Tea (Camellia sinensis) is a well-known beverage crop rich in polyphenols with health benefits for humans. Understanding how tea polyphenols participate in plant resistance is beneficial to breeding resistant varieties and uncovering the resistance mechanisms. Here, we report that a Colletotrichum infection-induced 'pink ring' symptom appeared outside the lesion, which is highly likely to occur in resistant cultivars. By identifying morphological feature-specific metabolites in the pink ring and their association with disease resistance, and analysis of the association between metabolite and gene expression, the study revealed that the accumulation of anthocyanin-3-O-galactosides, red phytotoxin compounds resistant to anthracnose, plays a pivotal role in the hypersensitive response surrounding infection sites in tea plants. The results of genetic manipulation showed that the expression of CsF3Ha, CsANSa, CsUGT78A15, CsUGT75L43, and CsMYB113, which are involved in anthocyanin biosynthesis, is positively correlated with anthracnose-resistance and the formation of the pink ring. Further phosphorus quantification and fertilization experiments confirmed that phosphate deficiency caused by anthracnose is involved in the occurrence of the pink ring. Genetic manipulation studies indicated that altering the expression levels of Pi transporter proteins (CsPHT2-1, CsPHT4;4) and phosphate deprivation response transcription factors (CsWRKY75-1, CsWRKY75-2, CsMYB62-1) enhances resistance to anthracnose and the formation of the pink ring symptom in tea plants. This article provides the first evidence that anthocyanin-3-O-galactosides are the anthracnose-resistant phytoalexins among various polyphenols in tea plants, and this presents an approach for identifying resistance genes in tea plants, where genetic transformation is challenging.
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Introduction: The hepatobiliary-specific phase can help in early detection of changes in lesion tissue density, internal structure, and microcirculatory perfusion at the microscopic level and has important clinical value in hepatocellular carcinoma (HCC). Therefore, this study aimed to construct a preoperative nomogram for predicting the positive expression of glypican-3 (GPC3) based on gadoxetic acid-enhanced (Gd-EOB-DTPA) MRI hepatobiliary phase (HBP) radiomics, imaging and clinical feature. Methods: We retrospectively included 137 patients with HCC who underwent Gd-EOB-DTPA-enhanced MRI and subsequent liver resection or puncture biopsy at our hospital from January 2017 to December 2021 as training cohort. Subsequently collected from January 2022 to June 2023 as a validation cohort of 49 patients, Radiomic features were extracted from the entire tumor region during the HBP using 3D Slicer software and screened using a t-test and least absolute shrinkage selection operator algorithm (LASSO). Then, these features were used to construct a radiomics score (Radscore) for each patient, which was combined with clinical factors and imaging features of the HBP to construct a logistic regression model and subsequent nomogram model. The clinicoradiologic, radiomics and nomogram models performance was assessed by the area under the curve (AUC), calibration, and decision curve analysis (DCA). In the validation cohort,the nomogram performance was assessed by the area under the curve (AUC). Results: In the training cohort, a total of 1688 radiomics features were extracted from each patient. Next, radiomics with ICCs<0.75 were excluded, 1587 features were judged as stable using intra- and inter-class correlation coefficients (ICCs), 26 features were subsequently screened using the t-test, and 11 radiomics features were finally screened using LASSO. The nomogram combining Radscore, age, serum alpha-fetoprotein (AFP) >400ng/mL, and non-smooth tumor margin (AUC=0.888, sensitivity 77.7%, specificity 91.2%) was superior to the radiomics (AUC=0.822, sensitivity 81.6%, specificity 70.6%) and clinicoradiologic (AUC=0.746, sensitivity 76.7%, specificity 64.7%) models, with good consistency in calibration curves. DCA also showed that the nomogram had the highest net clinical benefit for predicting GPC3 expression.In the validation cohort, the ROC curve results showed predicted GPC3-positive expression nomogram model AUC, sensitivity, and specificity of 0.800, 58.5%, and 100.0%, respectively. Conclusion: HBP radiomics features are closely associated with GPC3-positive expression, and combined clinicoradiologic factors and radiomics features nomogram may provide an effective way to non-invasively and individually screen patients with GPC3-positive HCC.
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Background: Several studies have investigated the population pharmacokinetics (popPK) of valproic acid (VPA) in children with epilepsy. However, the predictive performance of these models in the extrapolation to other clinical environments has not been studied. Hence, this study evaluated the predictive abilities of pediatric popPK models of VPA and identified the potential effects of protein binding modeling strategies. Methods: A dataset of 255 trough concentrations in 202 children with epilepsy was analyzed to assess the predictive performance of qualified models, following literature review. The evaluation of external predictive ability was conducted by prediction- and simulation-based diagnostics as well as Bayesian forecasting. Furthermore, five popPK models with different protein binding modeling strategies were developed to investigate the discrepancy among the one-binding site model, Langmuir equation, dose-dependent maximum effect model, linear non-saturable binding equation and the simple exponent model on model predictive ability. Results: Ten popPK models were identified in the literature. Co-medication, body weight, daily dose, and age were the four most commonly involved covariates influencing VPA clearance. The model proposed by Serrano et al. showed the best performance with a median prediction error (MDPE) of 1.40%, median absolute prediction error (MAPE) of 17.38%, and percentages of PE within 20% (F20, 55.69%) and 30% (F30, 76.47%). However, all models performed inadequately in terms of the simulation-based normalized prediction distribution error, indicating unsatisfactory normality. Bayesian forecasting enhanced predictive performance, as prior observations were available. More prior observations are needed for model predictability to reach a stable state. The linear non-saturable binding equation had a higher predictive value than other protein binding models. Conclusion: The predictive abilities of most popPK models of VPA in children with epilepsy were unsatisfactory. The linear non-saturable binding equation is more suitable for modeling non-linearity. Moreover, Bayesian forecasting with prior observations improved model fitness.
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Despite rapid advances in metabolic therapies over the past decade, their efficacy in melanoma has been modest, largely due to the interaction between cancer-associated fibroblasts (CAFs) and cancer cells to promote cancer growth. Altering the tumor microenvironment (TME) is challenging and elusive. CAFs is critical for glutamine deprivation survival in melanoma. In this research, we assembled a CAFs-targeted, controlled-release nanodroplets for the combined delivery of the amino acid transporter ASCT2 (SLC1A5) inhibitor V9302 and GLULsiRNA (siGLUL). The application of ultrasound-targeted microbubble disruption (UTMD) allows for rapid release of V9302 and siGLUL, jointly breaking the glutamine metabolism interaction between CAFs and cancer cells on one hand, on the other hand, blocking activated CAFs and reducing the expression of extracellular matrix (ECM) to facilitate drug penetration. In addition, ultrasound stimulation made siGLUL more accessible to tumor cells and CAFs, downregulating GLUL expression in both cell types. FH-V9302-siGLUL-NDs also serve as contrast-enhanced ultrasound imaging agents for tumor imaging. Our study developed and reported FH-NDs as nanocarriers for V9302 and siGLUL, demonstrating that FH-V9302-siGLUL-NDs have potential bright future applications for integrated diagnostic therapy. Graphical Abstract.
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Fibroblastos Asociados al Cáncer , Melanoma , Neoplasias , Humanos , Fibroblastos Asociados al Cáncer/patología , Glutamina , Microambiente Tumoral/fisiología , Neoplasias/patología , Melanoma/metabolismo , Ultrasonografía , Antígenos de Histocompatibilidad Menor/metabolismo , Sistema de Transporte de Aminoácidos ASC/metabolismoRESUMEN
Liver metastasis is the main cause of death in patients with colorectal cancer (CRC); thus, necessitating effective biomarkers and therapeutic targets for colorectal cancer liver metastasis (CRLM). Fibroblast growth factor 19 (FGF19) is a protumorigenic gene in numerous human malignancies. In this study, it is shown that FGF19 plays an indispensable role in CRLM. FGF19 expression and secretion are markedly correlated with liver metastasis and lower overall survival rates of patients with CRC. An in vivo metastasis model shows that FGF19 overexpression confers stronger liver-metastatic potential in CRC cells. Mechanistically, FGF19 exerts an immunomodulatory function that creates an environment conducive for metastasis in CRLM. FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer-associated fibroblasts (iCAFs) by activating the autocrine effect of IL-1α via the FGFR4-JAK2-STAT3 pathway. FGF19-induced iCAFs promote neutrophil infiltration and mediate neutrophil extracellular trap (NET) formation in liver metastatic niches via the production of complement C5a and IL-1ß, which in turn accelerates the liver colonization of CRC cells. Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19-induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention.
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Neoplasias Colorrectales , Trampas Extracelulares , Neoplasias Hepáticas , Animales , Ratones , Humanos , Trampas Extracelulares/metabolismo , Línea Celular Tumoral , Neoplasias Hepáticas/metabolismo , Transducción de Señal , Neoplasias Colorrectales/genética , Factores de Crecimiento de Fibroblastos/metabolismoRESUMEN
Objective: This study sought to investigate the parasitic diseases of neglected tropical diseases defined by the World Health Organization based on the Global Burden of Disease Study (GBD) database. Importantly, we analyzed the prevalence and burden of these diseases in China from 1990 to 2019 to provide valuable information to formulate more effective measures for their management and prevention. Methods: Data on the prevalence and burden of neglected parasitic diseases in China from 1990 to 2019 were extracted from the global health data exchange (GHDx) database, including the absolute number of prevalence, age-standardized prevalence rate, disability-adjusted life year (DALY) and age-standardized DALY rate. Descriptive analysis was used to analyze the prevalence and burden changes, sex and age distribution of various parasitic diseases from 1990 to 2019. A time series model [Auto-Regressive Integrated Moving Average (ARIMA)] was used to predict the DALYs of neglected parasitic diseases in China from 2020 to 2030. Results: In 2019, the number of neglected parasitic diseases in China was 152518062, the age-standardized prevalence was 11614.1 (95% uncertainty interval (UI) 8758.5-15244.5), the DALYs were 955722, and the age-standardized DALY rate was 54.9 (95% UI 26.0-101.8). Among these, the age-standardized prevalence of soil-derived helminthiasis was the highest (9370.2/100,000), followed by food-borne trematodiases (1502.3/100,000) and schistosomiasis (707.1/100,000). The highest age-standardized DALY rate was for food-borne trematodiases (36.0/100,000), followed by cysticercosis (7.9/100,000) and soil-derived helminthiasis (5.6/100,000). Higher prevalence and disease burden were observed in men and the upper age group. From 1990 to 2019, the number of neglected parasitic diseases in China decreased by 30.4%, resulting in a decline in DALYs of 27.3%. The age-standardized DALY rates of most diseases were decreased, especially for soil-derived helminthiasis, schistosomiasis and food-borne trematodiases. The ARIMA prediction model showed that the disease burden of echinococcosis and cysticercosis exhibited an increasing trend, highlighting the need for further prevention and control. Conclusion: Although the prevalence and disease burden of neglected parasitic diseases in China have decreased, many issues remain to be addressed. More efforts should be undertaken to improve the prevention and control strategies for different parasitic diseases. The government should prioritize multisectoral integrated control and surveillance measures to prioritize the prevention and control of diseases with a high burden of disease. In addition, the older adult population and men need to pay more attention.
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Cisticercosis , Helmintiasis , Enfermedades Parasitarias , Masculino , Humanos , Anciano , Carga Global de Enfermedades , Prevalencia , Años de Vida Ajustados por Calidad de VidaRESUMEN
Numerous secondary metabolites in medicinal food homology plants such as Allium inhibit the activity of acetylcholinesterase (AChE), but the current understanding of the inhibition mechanism is limited. In this study, we employed ultrafiltration, spectroscopic, molecular docking, and matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF-MS/MS) techniques to investigate the inhibition mechanism of AChE by garlic organic sulfanes, including diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS). The results of UV-spectrophotometry and ultrafiltration experiments showed the inhibition of AChE activity by DAS and DADS was reversible (competitive inhibition), but inhibition by DATS was irreversible. Molecular fluorescence and molecular docking indicated DAS and DADS changed the positions of key amino acids inside the catalytic cavity through hydrophobic interactions with AChE. By using MALDI-TOF-MS/MS, we found DATS irreversibly inhibited AChE activity by opening disulfide-bond switching of disulfide bond 1 (Cys-69 and Cys-96) and disulfide bond 2 (Cys-257 and Cys-272) in AChE, as well as by covalently modifying Cys-272 in disulfide bond 2 to generate AChE-SSA derivatives (strengthened switch). This study provides a basis for further exploration of natural AChE inhibitors using organic active substances in garlic and presents a hypothesis of U-shaped spring force arm effect based on the disulfide bond-switching reaction of DATS that can be used to evaluate the stability of disulfide bonds in proteins.
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Compuestos Alílicos , Ajo , Plantas Medicinales , Ajo/química , Acetilcolinesterasa , Simulación del Acoplamiento Molecular , Espectrometría de Masas en Tándem , Sulfuros/química , Disulfuros/farmacología , Antioxidantes/farmacología , Compuestos Alílicos/farmacología , Compuestos Alílicos/químicaRESUMEN
Introduction: Triple-negative breast cancer (TNBC) is known to be the most aggressive form of breast cancer. Due to its high recurrence and mortality rates, the treatment of TNBC is a significant challenge for the medical community. Besides, ferroptosis is an emerging regulatory cell death that may provide new insights into the treatment of TNBC. As a central inhibitor of the ferroptosis process, the selenoenzyme glutathione peroxidase 4 (GPX4) is its classical therapeutic target. However, inhibition of GPX4 expression is quite detrimental to normal tissues. Ultrasound contrast agents, as an emerging visualization precision treatment, may provide a solution to the existing problem. Methods: In this study, nanodroplets (NDs) carrying simvastatin (SIM) were constructed using the homogeneous/emulsification method. Then, the characterization of SIM-NDs was systematically evaluated. Meanwhile, in this study, the ability of SIM-NDs combined with ultrasound-targeted microbubble disruption (UTMD) to initiate ferroptosis and its respective mechanisms of ferroptosis induction were verified. Finally, the antitumor activity of SIM-NDs was investigated in vitro and in vivo using MDA-MB-231 cells and TNBC animal models. Results: SIM-NDs exhibited excellent pH- and ultrasound-responsive drug release and noticeable ultrasonographic imaging ability, also showing good biocompatibility and biosafety. UTMD could promote increased intracellular reactive oxygen species and consume intracellular glutathione. However, SIM-NDs were efficiently internalized into cells under ultrasound irradiation, followed by the rapid release of SIM, which inhibited intracellular mevalonate production, and synergistically downregulated GPX4 expression, thereby promoting ferroptosis. Moreover, this combined treatment demonstrated strong antitumor ability in vitro and in vivo. Conclusion: The combination of UTMD and SIM-NDs presents a promising avenue for harnessing ferroptosis in the treatment of malignant tumors.