RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-attributed mortality and the primary liver malignancy in the world. Echinacoside is a phenylethanoid glycoside derived from traditional Chinese medicinal herbs which possessed multiple health benefits on humans, including anti-tumor effects. OBJECTIVE: This study aimed to demonstrate the function of echinacoside in HCC progression and the involvement of miR-30c-5p/FOXD1/KLF12 axis. METHODS: The HepG2 cells were treated by different dose of echinacoside, miR-30c-5p mimic, miR-30c-5p inhibitor, and FOXD1 overexpression lentiviruses or siRNA individually or simultaneously. The cell invasion and migration were measured by transwell assay. RNA and protein levels were tested by RT-PCR and western blot, respectively. The regulatory function of miR-30c-5p on Forkhead box D1 (FOXD1), FOXD1 on Krüppel-like factor 12 (KLF12) was tested by luciferase reporter assay or/and ChIP assay. Meanwhile, a liver cancer lung metastasis mice model was used to examine the functions of echinacoside and miR-30c-5p on HCC metastasis in vivo. Moreover, the correlations among miR-30c-5p, FOXD1, KLF12, and HCC prognosis was analyzed using clinical sample and TCGA database. RESULTS: Based on both in vitro and in vivo investigations, we found that echinacoside could inhibit HCC cell migration, invasiveness, and tumor metastasis, and associated with the enhanced miR-30c-5p/FOXD1/KLF12 axis. Furthermore, through analyzing the interactions among intermediate molecules, we revealed that miR-30c-5p, FOXD1, and KLF12üere clinically relevant with each other in HCC patients, correlated with HCC prognosis, and regulated by echinacoside to contribute in the inhibition of HCC progression. CONCLUSIONS: These findings suggest that echinacoside could inhibit HCC progression, and the mechanism related to the enhanced miR-30c-5p/FOXD1/KLF12 axis. Moreover, the abovementioned intermediate molecules might serve as prospective biomarkers for HCC prognosis.

RESUMO

When plants are subjected to mechanical wounding(MW)caused by insect feeding, extreme weather, and human factors, they rapidly initiate a series of response mechanisms at the transcriptional and metabolic levels, leading to changes in the content of phytohormone and secondary metabolites in plants. In this study, using the medicinal model plant Danshen(Salvia miltiorrhiza) as an example, the effect of MW on the metabolism of medicinal plants was evaluated. By virtue of qRT-PCR and LC-MS, the changes in the biosynthetic genes and contents of jasmonates(JAs) and tanshinones in response to leaf damage stimulation were detected to reveal the related patterns of transcription and metabolism in leaves and roots at different time points after MW treatment, thus exploring the response mechanism of Danshen to MW stress. The results showed that MW induction could transiently increase the expression of biosynthetic genes of Jas, with AOC and JAR beginning to increase and peaking at 2 h after induction, while AOS and OPR3 peaked at 4 h. Correspondingly, the content of OPDA, JA, and JA-Ile all peaked at 2 h. In the biosynthesis of tanshinones, the diterpene synthase genes CPS1 and KSL1 both peaked at 2 h, while the subsequent modification genes CYP450s all peaked at 4 h. The content of the four tanshinones showed a continuous increase trend within 8 h. This study provides a reference for revealing the research on secondary metabolite accumulation under MW stress and lays a foundation for further understanding the role of Jas in enhancing plant resistance, promoting the accumulation of active ingredients, and improving the quality of medicinal materials under MW stress.

Assuntos

Abietanos , Ciclopentanos , Oxilipinas , Salvia miltiorrhiza , Salvia miltiorrhiza/genética , Salvia miltiorrhiza/metabolismo , Salvia miltiorrhiza/química , Oxilipinas/metabolismo , Ciclopentanos/metabolismo , Ciclopentanos/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Medicamentos de Ervas Chinesas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo

RESUMO

BACKGROUND & AIMS: Malnutrition is prevalent among hospitalised patients, and increases the morbidity, mortality, and medical costs; yet nutritional assessments on admission are not routine. This study assessed the clinical and economic benefits of using an artificial intelligence (AI)-based rapid nutritional diagnostic system for routine nutritional screening of hospitalised patients. METHODS: A nationwide multicentre randomised controlled trial was conducted at 11 centres in 10 provinces. Hospitalised patients were randomised to either receive an assessment using an AI-based rapid nutritional diagnostic system as part of routine care (experimental group), or not (control group). The overall medical resource costs were calculated for each participant and a decision-tree was generated based on an intention-to-treat analysis to analyse the cost-effectiveness of various treatment modalities. Subgroup analyses were performed according to clinical characteristics and a probabilistic sensitivity analysis was performed to evaluate the influence of parameter variations on the incremental cost-effectiveness ratio (ICER). RESULTS: In total, 5763 patients participated in the study, 2830 in the experimental arm and 2933 in the control arm. The experimental arm had a significantly higher cure rate than the control arm (23.24% versus 20.18%; p = 0.005). The experimental arm incurred an incremental cost of 276.52 CNY, leading to an additional 3.06 cures, yielding an ICER of 90.37 CNY. Sensitivity analysis revealed that the decision-tree model was relatively stable. CONCLUSION: The integration of the AI-based rapid nutritional diagnostic system into routine inpatient care substantially enhanced the cure rate among hospitalised patients and was cost-effective. REGISTRATION: NCT04776070 (https://clinicaltrials.gov/study/NCT04776070).

Assuntos

Inteligência Artificial , Análise Custo-Benefício , Hospitalização , Desnutrição , Avaliação Nutricional , Humanos , Masculino , Feminino , Inteligência Artificial/economia , Idoso , Pessoa de Meia-Idade , Desnutrição/diagnóstico , Desnutrição/economia , Hospitalização/economia , Estado Nutricional , Idoso de 80 Anos ou mais , Adulto

RESUMO

The exposure of protein molecules to interfaces may cause protein aggregation and particle formation in protein formulations, especially hydrophobic interfaces, which may promote protein aggregation in solution. In this study, we found that modification of the surface properties by application of a hydrophobic Octadecyltrichlorosilane (OTS) could reduce the generation of protein aggregates and particles in protein solution induced by fluid shear. A stable protein adsorption layer was formed at the hydrophobic interface through the strong hydrophobic interaction between the protein and hydrophobic surface, which could prevent the aggregated protein from falling off into the bulk solution to form subvisible particles and insoluble protein aggregates. In addition, human complement enzyme linked immunosorbent assay results showed that the particles that were generated in the OTS-coated container did not activate human complement which indicated the OTS-coated container could be used as primary containers for certain types of monoclonal antibody formulation.

RESUMO

Background: Gut microbiota (GM) and metabolic alterations play pivotal roles in lung cancer (LC) development and host genetic variations are known to contribute to LC susceptibility by modulating the GM. However, the causal links among GM, metabolite, host genes, and LC remain to be fully delineated. Method: Through bidirectional MR analyses, we examined the causal links between GM and LC, and utilized two-step mediation analysis to identify potential mediating blood metabolite. We employed diverse MR methods, including inverse-variance-weighted (IVW), weighted median, MR-Egger, weighted mode, and simple mode, to ensure a robust examination of the data. MR-Egger intercept test, Radial MR, MR-PRESSO, Cochran Q test and Leave-one-out (LOO) analysis were used for sensitivity analyses. Analyses were adjusted for smoking, alcohol intake frequency and air pollution. Linkage disequilibrium score regression and Steiger test were used to probe genetic causality. The study also explored the association between specific host genes and the abundance of gut microbes in LC patients. Results: The presence of Bacteroides clarus was associated with an increased risk of LC (odds ratio [OR] = 1.07, 95% confidence interval [CI]: 1.03-1.11, p = 0.012), whereas the Eubacteriaceae showed a protective effect (OR = 0.82, 95% CI: 0.75-0.89, p = 0.001). These findings remained robust after False Discovery Rate (FDR) correction. Our mediator screening identified 13 blood metabolites that significantly influence LC risk after FDR correction, underscoring cystine and propionylcarnitine in reducing LC risk, while linking specific lipids and hydroxy acids to an increased risk. Our two-step mediation analysis demonstrated that the association between the bacterial pathway of synthesis of guanosine ribonucleotides and LC was mediated by Fructosyllysine, with mediated proportions of 11.38% (p = 0.037). LDSC analysis confirmed the robustness of these associations. Our study unveiled significant host genes ROBO2 may influence the abundance of pathogenic gut microbes in LC patients. Metabolic pathway analysis revealed glutathione metabolism and glutamate metabolism are the pathways most enriched with significant metabolites related to LC. Conclusion: These findings underscore the importance of GM in the development of LC, with metabolites partly mediating this effect, and provide dietary and lifestyle recommendations for high-risk lung cancer populations.

RESUMO

Psoriasis is a recurrent autoimmune disease characterized by seasonal and latitudinal variations. Double-stranded DNA (dsDNA) is a crucial component of nucleic acids and nucleosomes that provoke innate immune responses. Given the potential influence of climate on immunity and the development of autoimmune diseases, a comprehensive quantitative analysis of dsDNA levels in the population is warranted. In this case-control study conducted from 2016 to 2020, 10,110 psoriasis patients and matched controls from 12 regions in China were included. This study examined variations in serum dsDNA levels based on season and latitude. The results revealed significant associations between geographical location, climatic conditions, and season with serum dsDNA concentration. Individuals residing in Northern China exhibited significantly higher serum dsDNA levels compared to those in the South (1.00 vs. 0.96 ng/ml), and those in medium latitude regions had higher levels than their counterparts in areas with extreme latitudes (0.98 vs. 0.96 ng/ml). Furthermore, individuals in regions with low to medium ultraviolet exposure demonstrated higher serum dsDNA concentrations than those in areas with high ultraviolet levels (1.03 vs. 0.93 ng/ml), and individuals in winter showed higher levels than those in summer (1.03 vs. 0.92 ng/ml). Factors such as sex, UV index, humidity, and sunshine duration were inversely related to serum dsDNA levels, while age and daylight hours showed a positive association. These findings suggest that meteorological and climatic factors play a role in influencing serum dsDNA levels.

RESUMO

Owing to patient-derived tumor tissues and cells, significant advances have been made in personalized cancer treatment and precision medicine, with cancer stem cell-derived three-dimensional tumor organoids serving as crucial in vitro models that accurately replicate the structural, phenotypic, and genetic characteristics of tumors. However, despite their extensive use in drug testing, genome editing, and transplantation for facilitating personalized treatment approaches in clinical practice, the inadequate capacity of these organoids to effectively model immune cells and stromal components within the tumor microenvironment limits their potential. Additionally, effective clinical immunotherapy has led the tumor immune microenvironment to garner considerable attention, increasing the demand for simulating patient-specific tumor-immune interactions. Consequently, co-culture techniques integrating tumor organoids with immune cells and tumor microenvironment constituents have been developed to expand the possibilities for personalized drug response investigations, with recent advancements enhancing the understanding of the strengths, limitations, and applicability of the co-culture approach. Herein, the recent advancements in the field of tumor organoids have been comprehensively reviewed, specifically highlighting the tumor organoid co-culture-related developments with various immune cell models and their implications for clinical research. Furthermore, this review delineates the current state of research and application of organoid models regarding the therapeutic approaches and related challenges for gynecological tumors. This study may provide a theoretical basis for further research on the use of patient-derived organoids in tumor immunity, drug development, and precision medicine.

Assuntos

Neoplasias dos Genitais Femininos , Organoides , Microambiente Tumoral , Humanos , Organoides/imunologia , Microambiente Tumoral/imunologia , Feminino , Neoplasias dos Genitais Femininos/imunologia , Neoplasias dos Genitais Femininos/patologia , Neoplasias dos Genitais Femininos/terapia , Técnicas de Cocultura , Medicina de Precisão , Imunoterapia/métodos

RESUMO

KEY MESSAGE: We identified a pivotal transcription factor TaABI5-A4 that is significantly associated with pre-harvest sprouting in wheat; its function in regulating seed dormancy was confirmed in transgenic rice. ABI5 is a critical transcription factor in regulation of crop seed maturation, dormancy, germination, and post-germination. Sixteen copies of homologous sequences of ABI5 were identified in Chinese wheat line Zhou 8425B. Cultivars of two haplotypes TaABI5-A4a and TaABI5-A4b showed significantly different seed dormancies. Based on two SNPs between the sequences of TaABI5-A4a and TaABI5-A4b, two complementary dominant sequence-tagged site (STS) markers were developed and validated in a natural population of 103 Chinese wheat cultivars and advanced lines and 200 recombinant inbred lines (RILs) derived from the Yangxiaomai/Zhongyou 9507 cross; the STS markers can be used efficiently and reliably to evaluate the dormancy of wheat seeds. The transcription level of TaABI5-A4b was significantly increased in TaABI5-A4a-GFP transgenic rice lines compared with that in TaABI5-A4b-GFP. The average seed germination index of TaABI5-A4a-GFP transgenic rice lines was significantly lower than those of TaABI5-A4b-GFP. In addition, seeds of TaABI5-A4a-GFP transgenic lines had higher ABA sensitivity and endogenous ABA content, lower endogenous GA content and plant height, and thicker stem internodes than those of TaABI5-A4b-GFP. Allelic variation of TaABI5-A4-affected wheat seed dormancy and the gene function was confirmed in transgenic rice. The transgenic rice lines of TaABI5-A4a and TaABI5-A4b had significantly different sensitivities to ABA and contents of endogenous ABA and GA in mature seeds, thereby influencing the seed dormancy, plant height, and stem internode length and diameter.

Assuntos

Alelos , Germinação , Oryza , Dormência de Plantas , Plantas Geneticamente Modificadas , Sementes , Triticum , Triticum/genética , Triticum/crescimento & desenvolvimento , Dormência de Plantas/genética , Plantas Geneticamente Modificadas/crescimento & desenvolvimento , Plantas Geneticamente Modificadas/genética , Sementes/crescimento & desenvolvimento , Sementes/genética , Germinação/genética , Oryza/genética , Oryza/crescimento & desenvolvimento , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação da Expressão Gênica de Plantas , Polimorfismo de Nucleotídeo Único , Haplótipos

RESUMO

Influence of climate change on the geospatial heterogeneity in agricultural production remains poorly understood. In this study, heterogeneity in climate's impacts on wheat production across the North China Plain (NCP) was explored by integrating APSIM model, process-based factor-control quantitative approach, and geostatistical analyses. The results indicated that increased precipitation and minimum temperature boosted yields, while elevated maximum temperature and reduced radiation exerted adverse effects. The most pronounced negative impact arose from the coupling variation between maximum temperature and radiation, contributing to yields' variations of -5.84% from 2000 to 2010 and -5.22% from 2010 to 2020. In last two decades, climate change has augmented the overall geospatial heterogeneity degree in wheat yields. The chief factor contributing to yields' heterogeneity was the maximum temperature during anthesis-maturation stage, explaining an average of 37.6% of yields' heterogeneity, followed by precipitation throughout the whole growth period and the anthesis-maturation stage, explaining 36.1% and 34.5% respectively. A reciprocal enhancement mechanism exists between factors in driving yields' heterogeneity. Wheat yields in the southwestern NCP benefited more from increased precipitation and minimum temperature. Between 2000 and 2010, yields in the central NCP (junctions of Henan, Hebei, and Shandong) experienced the most pronounced adverse impact from increased maximum temperature. However, by 2010-2020, significant adverse impact shifted to western NCP, expanding spatially. During 2010-2020, the geospatial scope of radiation's significant negative impact expanded compared to the preceding decade, particularly affecting the yields in central and eastern NCP. The identified geospatial heterogeneity pattern of climate's impacts can guide spatially-matched climate-adaptive management adjustments. For instance, intensifying the defense against high-temperature's impacts in northwestern Henan, southern Hebei, and western Shandong, while improving the adaptation to radiation reduction in the central and eastern NCP. The findings are expected to advance regional-scale climate-smart agricultural development.

Assuntos

Agricultura , Mudança Climática , Triticum , Triticum/crescimento & desenvolvimento , China , Temperatura , Clima

RESUMO

Individuals with class III obesity (body mass index [BMI] > 40 kg/m2) are at increased risk of cesarean delivery and peripartum complications. We ascertained compositive neonatal and maternal adverse outcomes among individuals with class III obesity who labored versus had planned cesarean delivery (CD). This was a retrospective cohort study from 2016-2021 using the National Vital Statistics System database. Nulliparous individuals with class III obesity pre-pregnancy were included if they had singleton, non-anomalous pregnancies and delivered at 37 to 41 weeks of gestation. Individuals were excluded if they had hypertensive disorders or diabetes. The primary outcome was a composite neonatal adverse outcome (CNAO), consisting of Apgar score less than 5 at 5 minutes, assisted ventilation > 6 hours, neonatal seizure, or neonatal death. The secondary outcome was a composite maternal adverse outcome (CMAO) that included admission to the intensive care unit (ICU), maternal transfusion, uterine rupture, or unplanned hysterectomy. A sensitivity analysis using a CMAO without transfusion was performed. A multivariable Poisson regression model was performed to calculate adjusted relative risks (RR) with 95% confidence intervals (CI). Of 192,298 individuals who met inclusion criteria, 169,676 (88.2%) labored and 22,622 (11.8%) had a planned CD. Compared to neonates delivered by planned CD, the risk of CNAO was significantly lower in those who delivered after labor (aRR 0.79, 95% CI 0.71 - 0.87). There was no significant difference in the risk of CMAO between groups (aRR 1.11, 95% CI 0.87-1.41). However, the risk of CMAO without transfusion was lower in individuals who labored (aRR 0.57, 95% CI 0.40 - 0.83). In nulliparous individuals with class III obesity, the risk of CNAO and of CMAO without transfusion were significantly lower in individuals who labored, versus those who had a planned cesarean delivery.

RESUMO

BACKGROUND: Despite the recognition of the impact of childhood psychological abuse, self-efficacy, and psychological resilience on cyberbullying, there is still a gap in understanding the specific mechanisms through which childhood psychological abuse impacts cyberbullying via self-efficacy and psychological resilience. METHODS: Based on the Social Cognitive Theory, this study aims to investigate the link between childhood psychological abuse and cyberbullying in adolescents, mediated by the sequential roles of self-efficacy and psychological resilience. The sample consisted of 891 students (M = 15.40, SD = 1.698) selected from four public secondary schools in Jiangsu Province, Eastern China. All the participants filled in the structured self-report questionnaires on childhood psychological abuse, self-efficacy, psychological resilience, and cyberbullying. The data were analyzed using SPSS 24.0 and structural equation modeling (SEM) in AMOS 24.0. RESULTS: The findings of this study are as follows: (1) Childhood psychological abuse is positively associated with adolescent cyberbullying; (2) Self-efficacy plays a mediating role between childhood psychological abuse and adolescent cyberbullying; (3) Psychological resilience plays a mediating role between childhood psychological abuse and adolescent cyberbullying; (4) Self-efficacy and psychological resilience play a chain mediation role between childhood psychological abuse and adolescent cyberbullying. CONCLUSION: This study contributes to a deeper understanding of the underlying mechanisms linking childhood psychological abuse to adolescent cyberbullying, shedding light on potential pathways for targeted interventions and support programs to promote the well-being of adolescents in the face of early adversity.

Assuntos

Cyberbullying , Resiliência Psicológica , Autoeficácia , Humanos , Adolescente , Masculino , Feminino , Cyberbullying/psicologia , China/epidemiologia , Criança , Maus-Tratos Infantis/psicologia , Inquéritos e Questionários , Autorrelato

RESUMO

OBJECTIVES: Disaster experiences have long-term effects on disaster preparedness. This study examined the long-term (10-y) effect of disaster severity of the 2008 Wenchuan earthquake on survivors' disaster preparedness and the moderating effects of household vulnerability. METHODS: The data were collected in January 2018 covering 30 counties in Wenchuan earthquake-stricken areas. The dependent variable was survivors' disaster preparedness (including overall, material, knowledge and awareness, and action preparedness) in 2018. Disaster severity included survivors' housing damage and county death rate caused by the earthquake in 2008. Household vulnerability is a set of conditions that negatively affects the ability of people to prepare for and withstand disaster, proxied by households' per-capita income and the highest years of schooling of household members. We performed multivariable linear regression models to answer the research questions. RESULTS: A higher county death rate was associated with better overall preparedness (ß = 0.043; P < 0.05) and knowledge and awareness preparedness (ß = 0.018; P < 0.05), but housing damage was not significantly associated with disaster preparedness. The positive association of county death rate with overall preparedness (ß = -0.065; P < 0.05) becomes weaker when a household has a higher per-capita income. Also, with the household per-capita income increasing, the associations of county death rate with material preparedness (ß = -0.037; P < 0.05) and action preparedness (ß = -0.034; P < 0.01) become weaker. CONCLUSIONS: Disaster severity has positive and long-term effects on survivors' disaster preparedness. Also, the positive and long-term effects are affected by household vulnerability. Specifically, the positive and long-term effects of disaster severity on disaster preparedness are more substantial when a household is more vulnerable.

Assuntos

Terremotos , Sobreviventes , Humanos , China/epidemiologia , Sobreviventes/estatística & dados numéricos , Sobreviventes/psicologia , Terremotos/estatística & dados numéricos , Inquéritos e Questionários , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Defesa Civil/estatística & dados numéricos , Defesa Civil/métodos , Defesa Civil/normas , Planejamento em Desastres/métodos , Planejamento em Desastres/estatística & dados numéricos

RESUMO

BACKGROUND: Inflammatory markers for the prognosis of acute ischemic stroke (AIS) with endovascular therapy remain unclear. The purpose of this study was to investigate the association between the systemic inflammatory response index (SIRI) and neutrophil-to-lymphocyte ratio (NLR) with unfavorable functional outcomes at 90-day in individuals of AIS who underwent endovascular therapy. METHODS: A total of 128 AIS patients who had endovascular therapy were enrolled from the Nanjing Stroke Registry between September 2019 and November 2022. Peripheral venous blood was collected from patients within 24 h of admission for information on the following parameters: neutrophil count, lymphocyte count, and monocyte count. Then, the SIRI and NLR values were calculated and the association among SIRI, NLR, and modifled Rankin Scale scores 90 days after endovascular therapy was examined via univariate and multivariate logistic analyses. Receiver operating characteristic curves were utilized to determine the best threshold for SIRI and NLR in predicting negative neurological outcomes following endovascular treatment for patients with AIS. RESULTS: A total of 128 participants were evaluated, among which 50% had unfavorable outcomes. Linear regression analysis showed that the best threshold for SIRI was >1.407 (odds ratio = 1.265; 95% confidence interval, 1.071-1.493; P = 0.006), and for NLR it was >5.347 (odds ratio = 1.088; 95% confidence interval, 1.007-1.175; P = 0.033). These results revealed NLR and SIRI as significant predictors of unfavorable outcomes at 90 days. The area under the curve for SIRI and NLR in predicting 90-day adverse outcomes was 0.643 and 0.609, respectively. CONCLUSIONS: Higher SIRI and NLR levels at admission may lead to unfavorable outcomes at 90 days for AIS patients with endovascular therapy.

RESUMO

BACKGROUND: The striped stem borer (SSB, Chilo suppressalis) is one of the most destructive insect pests on rice. As a chewing insect, SSB larval feeding causes a dramatic increase in rice defense responses. However, the effects of oral secretions (OSs) during SSB feeding on rice defense remain largely unexplored. RESULTS: In this study, based on transcriptome analysis results, treatment with SSB OSs regulated the expression of genes involved in the plant defense-related pathways of calcium, mitogen-activated protein kinases, reactive oxygen species, jasmonic acid (JA), herbivore-induced plant volatiles (HIPVs), and protease inhibitors. Unsurprisingly, treatment with SSB OSs elicited the accumulation of JA and JA-isoleucine in rice. The defense mechanisms activated by the cascade not only induced the expression of trypsin inhibitors, inhibiting the normal growth of SSB larvae but also induced HIPVs emission, rendering rice attractive to a common larval parasitoid. High-throughput proteome sequencing of SSB OSs led to 534 proteins being identified and 343 proteins with two or more unique peptides being detected. CONCLUSION: The study demonstrates that SSB OSs trigger both direct and indirect defense mechanisms in rice, akin to the effects of SSB feeding. It identifies specific proteins in SSB OSs that may influence the interactions between SSB and rice during feeding, providing valuable insights for effectors research. © 2024 Society of Chemical Industry.

RESUMO

Amphotericin B has long been crucial for treating many serious infectious diseases, such as invasive fungal infections and visceral leishmaniasis, particularly for patients who are immunocompromised, including those with advanced HIV infection. The conventional amphotericin B deoxycholate formulation has largely been replaced in high-income countries with liposomal amphotericin B (LAmB), which has many advantages, including lower rates of adverse events, such as nephrotoxicity and anaemia. Despite an evident need for LAmB in low-income and middle-income countries, where mortality from invasive fungal infections is still substantial, many low-income and middle-income countries still often use the amphotericin B deoxycholate formulation because of a small number of generic formulations and the high price of the originator LAmB. The pricing of LAmB is also highly variable between countries. Overcoming supply barriers through the availability of additional quality-assured, generic formulations of LAmB at accessible prices would substantially facilitate equitable access and have a substantial effect on mortality attributable to deadly fungal infections.

Assuntos

Anfotericina B , Antifúngicos , Humanos , Anfotericina B/economia , Antifúngicos/economia , Antifúngicos/provisão & distribuição , Antifúngicos/uso terapêutico , Acessibilidade aos Serviços de Saúde , Saúde Global , Países em Desenvolvimento , Medicamentos Genéricos/economia , Medicamentos Genéricos/provisão & distribuição

RESUMO

Endoplasmic reticulum (ER)-endolysosome interactions regulate cholesterol exchange between the ER and the endolysosome. ER-endolysosome membrane contact sites mediate the ER-endolysosome interaction. VAP-ORP1L (vesicle-associated membrane protein-associated protein- OSBP-related protein 1L) interaction forms the major contact site between the ER and the lysosome, which is regulated by Rab7. RILP (Rab7-interacting lysosomal protein) is the downstream effector of Rab7, but its role in the organelle interaction between the ER and the lysosome is not clear. In this study, we found RILP interacts with ORP1L to competitively inhibit the formation of the VAP-ORP1L contact site. Immunofluorescence microscopy revealed that RILP induces late endosome/lysosome clustering, which reduces the contact of endolysosomes with the ER, interfering with the ER-endolysosome interaction. Further examination demonstrated that over-expression of RILP results in the accumulation of cholesterol in the clustered endolysosomes, which triggers cellular autophagy depending on RILP. Our results suggest that RILP interferes with the ER-endolysosome interaction to inhibit cholesterol flow from the endolysosome to the ER, which feedbacks to trigger autophagy.

Assuntos

Colesterol , Retículo Endoplasmático , Endossomos , Lisossomos , Lisossomos/metabolismo , Colesterol/metabolismo , Retículo Endoplasmático/metabolismo , Humanos , Endossomos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Autofagia , Células HeLa , Receptores de Esteroides/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Ligação Proteica , proteínas de unión al GTP Rab7 , Células HEK293

RESUMO

The chemokine co-receptors CXCR4 and CCR5 mediate HIV entry and signal transduction necessary for viral infection. However, to date only the CCR5 antagonist maraviroc is approved for treating HIV-1 infection. Given that approximately 50% of late-stage HIV patients also develop CXCR4-tropic virus, clinical anti-HIV CXCR4 antagonists are needed. Here, we describe a novel allosteric CXCR4 antagonist TIQ-15 which inhibits CXCR4-tropic HIV-1 infection of primary and transformed CD4 T cells. TIQ-15 blocks HIV entry with an IC50 of 13 nM. TIQ-15 also inhibits SDF-1α/CXCR4-mediated cAMP production, cofilin activation, and chemotactic signaling. In addition, TIQ-15 induces CXCR4 receptor internalization without affecting the levels of the CD4 receptor, suggesting that TIQ-15 may act through a novel allosteric site on CXCR4 for blocking HIV entry. Furthermore, TIQ-15 did not inhibit VSV-G pseudotyped HIV-1 infection, demonstrating its specificity in blocking CXCR4-tropic virus entry, but not CXCR4-independent endocytosis or post-entry steps. When tested against a panel of clinical isolates, TIQ-15 showed potent inhibition against CXCR4-tropic and dual-tropic viruses, and moderate inhibition against CCR5-tropic isolates. This observation was followed by a co-dosing study with maraviroc, and TIQ-15 demonstrated synergistic activity. In summary, here we describe a novel HIV-1 entry inhibitor, TIQ-15, which potently inhibits CXCR4-tropic viruses while possessing low-level synergistic activities against CCR5-tropic viruses. TIQ-15 could potentially be co-dosed with the CCR5 inhibitor maraviroc to block viruses of mixed tropisms.

Assuntos

Infecções por HIV , HIV-1 , Receptores CXCR4 , Internalização do Vírus , Humanos , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Internalização do Vírus/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Inibidores da Fusão de HIV/farmacologia , Maraviroc/farmacologia , Triazóis/farmacologia , Fármacos Anti-HIV/farmacologia , Células HEK293

RESUMO

Background: The impact of corticosteroids on humoral responses in coronavirus disease 2019 (COVID-19) survivors during the acute phase and subsequent 6-month period remains unknown. This study aimed to determine how the use of corticosteroids influences the initiation and duration of humoral responses in COVID-19 survivors 6 months after infection onset. Methods: We used kinetic antibody data from the lopinavir-ritonavir trial conducted at Jin Yin-Tan Hospital in January 2020, which involved adults hospitalized with severe COVID-19 (LOTUS, ChiCTR2000029308). Antibody samples were collected from 192 patients during hospitalization, and kinetic antibodies were monitored at all available time points after recruitment. Additionally, plasma samples were collected from 101 COVID-19 survivors for comprehensive humoral immune measurement at the half-year follow-up visit. The main focus was comparing the humoral responses between patients treated with systemic corticosteroid therapy and the non-corticosteroid group. Results: From illness onset to day 30, the median antibody titre areas under the receiver operating characteristic curve (AUCs) of nucleoprotein (N), spike protein (S), and receptor-binding domain (RBD) immunoglobulin G (IgG) were significantly lower in the corticosteroids group. The AUCs of N-, S-, and RBD-IgM as well as neutralizing antibodies (NAbs) were numerically lower in the corticosteroids group compared with the non-corticosteroid group. However, peak titres of N, S, RBD-IgM and -IgG and NAbs were not influenced by corticosteroids. During 6-month follow-up, we observed a delayed decline for most binding antibodies, except N-IgM (ß -0.05, 95% CI [-0.10, 0.00]) in the corticosteroids group, though not reaching statistical significance. No significant difference was observed for NAbs. However, for the half-year seropositive rate, corticosteroids significantly accelerated the decay of IgA and IgM but made no difference to N-, S-, and RBD-IgG or NAbs. Additionally, corticosteroids group showed a trend towards delayed viral clearance compared with the non-corticosteroid group, but the results were not statistically significant (adjusted hazard ratio 0.71, 95% CI 0.50-1.00; P = 0.0508). Conclusion: Our findings suggested that corticosteroid therapy was associated with impaired initiation of the antibody response but this did not compromise the peak titres of binding and neutralizing antibodies. Throughout the decay phase, from the acute phase to the half-year follow-up visit, short-term and low-dose corticosteroids did not significantly affect humoral responses, except for accelerating the waning of short-lived antibodies.