Nonlinear relationship between oxidative balance score and hyperuricemia: analyses of NHANES 2007-2018.

BACKGROUND: Limited data regarding the correlation between oxidative balance score (OBS) and hyperuricemia highlights the necessity for thorough investigations. This study aims to examine the link between OBS, which incorporates dietary and lifestyle factors, and the occurrence of hyperuricemia. METHODS: We conducted a cross-sectional study involving 13,636 participants from the 2007-2018 National Health and Nutrition Examination Survey (NHANES). The oxidative balance score (OBS) was determined based on four lifestyle factors and sixteen dietary nutrients. We assessed the levels of serum uric acid (SUA) and the occurrence of hyperuricemia as outcomes. Weighted logistic regression and linear models were used for statistical analysis, using Restricted Cubic Splines (RCS) to examine potential nonlinear associations. Subgroup analysis and sensitivity assessments were performed to identify any variations and ensure the robustness of the findings. RESULTS: Higher OBS was consistently correlated with decreased SUA levels and a reduced prevalence of hyperuricemia. RCS highlighted a significant negative nonlinear association, particularly in females. Subgroup analysis revealed gender-based differences and interactive correlation, providing additional insights regarding OBS and hyperuricemia relationship. CONCLUSION: This study underscores a robust negative correlation between OBS and SUA levels as well as the incidence of hyperuricemia, emphasizing the importance of dietary and lifestyle factors. Incorporating RCS, subgroup analysis, and sensitivity assessments enhances the depth of our findings, providing valuable insights for further research.

U3 snoRNA inter-regulates with DDX21 in the perichromosomal region to control mitosis.

U3 snoRNA is essential for ribosome biogenesis during interphase. Upon mitotic onset, the nucleolus disassembles and U3 snoRNA relocates to the perichromosomal region (PR) to be considered as a chromosome passenger. Whether U3 controls mitosis remains unknown. Here, we demonstrate that U3 snoRNA is required for mitotic progression. We identified DDX21 as the predominant U3-binding protein during mitosis and confirmed that U3 snoRNA colocalizes with DDX21 in the PR. DDX21 knockdown induces mitotic catastrophe and similar mitotic defects caused by U3 snoRNA depletion. Interestingly, the uniform PR distribution of U3 snoRNA and DDX21 is interdependent. DDX21 functions in mitosis depending on its PR localization. Mechanistically, U3 snoRNA regulates DDX21 PR localization through maintaining its mobility. Moreover, Cy5-U3 snoRNA downsizes the fibrous condensates of His-DDX21 at proper molecular ratios in vitro. This work highlights the importance of the equilibrium between U3 snoRNA and DDX21 in PR formation and reveals the potential relationship between the PR assembly and mitotic regulation.

Age and mean platelet volume-based nomogram for predicting the therapeutic efficacy of metoprolol in Chinese pediatric patients with vasovagal syncope.

BACKGROUND: Vasovagal syncope (VVS) is the most common type of orthostatic intolerance in children. We investigated whether platelet-related factors related to treatment efficacy in children suffering from VVS treated with metoprolol. METHODS: Metoprolol-treated VVS patients were recruited. The median duration of therapy was three months. Patients were followed and divided into two groups, treament-effective group and treatment-ineffective group. Logistic and least absolute shrinkage selection operator regressions were used to examine treatment outcome variables. Receiver-operating characteristic (ROC) curves, precision-recall (PR) curves, calibration plots, and decision curve analyses were used to evaluate the nomogram model. RESULTS: Among the 72 patients who complete the follow-up, treatment-effective group and treatment-ineffective group included 42 (58.3%) and 30 (41.7%) cases, respectively. The patients in the treatment-effective group exhibited higher mean platelet volume (MPV) [(11.0 ± 1.0) fl vs. (9.8 ± 1.0) fl, P < 0.01] and platelet distribution width [12.7% (12.3%, 14.3%) vs. 11.3% (10.2%, 12.2%), P < 0.01] than those in the treatment-ineffective group. The sex ratio was significantly different (P = 0.046). A fit model comprising age [odds ratio (OR) = 0.766, 95% confidence interval (CI) = 0.594-0.987] and MPV (OR = 5.613, 95% CI = 2.297-13.711) might predict therapeutic efficacy. The area under the curve of the ROC and PR curves was computed to be 0.85 and 0.9, respectively. The P value of the Hosmer-Lemeshow test was 0.27. The decision curve analysis confirmed that managing children with VVS based on the predictive model led to a net advantage ranging from 0.01 to 0.58. The nomogram is convenient for clinical applications. CONCLUSION: A novel nomogram based on age and MPV can predict the therapeutic benefits of metoprolol in children with VVS.

Localized calcium transients in phragmoplast regulate cytokinesis of tobacco BY-2 cells.

KEY MESSAGE: Plants exhibit a unique pattern of cytosolic Ca2+ dynamics to correlate with microtubules to regulate cytokinesis, which significantly differs from those observed in animal and yeast cells. Calcium (Ca2+) transients mediated signaling is known to be essential in cytokinesis across eukaryotic cells. However, the detailed spatiotemporal dynamics of Ca2+ during plant cytokinesis remain largely unexplored. In this study, we employed GCaMP5, a genetically encoded Ca2+ sensor, to investigate cytokinetic Ca2+ transients during cytokinesis in Nicotiana tabacum Bright Yellow-2 (BY-2) cells. We validated the effectiveness of GCaMP5 to capture fluctuations in intracellular free Ca2+ in transgenic BY-2 cells. Our results reveal that Ca2+ dynamics during BY-2 cell cytokinesis are distinctly different from those observed in embryonic and yeast cells. It is characterized by an initial significant Ca2+ spike within the phragmoplast region. This spike is followed by a decrease in Ca2+ concentration at the onset of cytokinesis in phragmoplast, which then remains elevated in comparison to the cytosolic Ca2+ until the completion of cell plate formation. At the end of cytokinesis, Ca2+ becomes uniformly distributed in the cytosol. This pattern contrasts with the typical dual waves of Ca2+ spikes observed during cytokinesis in animal embryonic cells and fission yeasts. Furthermore, applications of pharmaceutical inhibitors for either Ca2+ or microtubules revealed a close correlation between Ca2+ transients and microtubule organization in the regulation of cytokinesis. Collectively, our findings highlight the unique dynamics and crucial role of Ca2+ transients during plant cell cytokinesis, and provides new insights into plant cell division mechanisms.

Spatial distribution dynamics for Epimedium brevicornum Maxim. from 1970 to 2020.

At different time scales, a species will experience diverse distribution changes. For Epimedium brevicornum Maxim, the phenomenon is obvious, but the understanding of the spatial dynamics of E. brevicornum under distinct time scales is poor. In this study, we modeled the potential distribution for E. brevicornum for five time scales, 1970-1979, 1980-1989, 1990-1999, 2000-2009, and 2010-2019, with different occurrence data, and the Kuenm package was used to optimize the parameter combination. Then, SDM tools and a Venn diagram were utilized to simulate the changes in highly suitable areas and spatial dynamics, respectively. Comprehensive results show that temperature seasonality (BIO4, 37.54%) has the greatest effect on the distribution of E. brevicornum, followed by minimum temperature (TMIN, 21.42%). The areas of distribution for E. brevicornum are 35.06 × 105 km2, 25.7 × 105 km2, 67.64 × 105 km2, 27.29 × 105 km2, and 9.87× 105 km2, which are mainly concentrated in Gansu, Shaanxi, Shanxi, and Henan, respectively. In addition, the largest regions for expansion, stability, and contraction under various time scales are 5.6 × 105 km2, 3.54 × 105 km2, and 3.47 × 105 km2, respectively. These changes indicate that approximately 7.96% of the regions are highly stable, and three critical counties, Wanyuan, Chenggu, and Hechuan, and Xixiang, have become significant areas for migration. Overall, our results indicate that there are different spatial distribution patterns and dynamics for E. brevicornum for different time scales. Given these results, this study also proposes comprehensive strategies for the conservation and management of E. brevicornum, which will further improve the current resource utilization status.

HDA6 modulates Arabidopsis pavement cell morphogenesis through epigenetic suppression of ROP6 GTPase expression and signaling.

The transcriptional regulation of Rho-related GTPase from plants (ROPs), which determine cell polarity formation and maintenance during plant development, still remains enigmatic. In this study, we elucidated the epigenetic mechanism of histone deacetylase HDA6 in transcriptional repression of ROP6 and its impact on cell polarity and morphogenesis in Arabidopsis leaf epidermal pavement cells (PCs). We found that the hda6 mutant axe1-4 exhibited impaired jigsaw-shaped PCs and convoluted leaves. This correlated with disruptions in the spatial organizations of cortical microtubules and filamentous actin, which is integral to PC indentation and lobe formation. Further transcriptional analyses and chromatin immunoprecipitation assay revealed that HDA6 specifically represses ROP6 expression through histone H3K9K14 deacetylation. Importantly, overexpression of dominant negative-rop6 in axe1-4 restored interdigitated cell morphology. Our study unveils HDA6 as a key regulator in Arabidopsis PC morphogenesis through epigenetic suppression of ROP6. It reveals the pivotal role of HDA6 in the transcriptional regulation of ROP6 and provides compelling evidence for the functional interplay between histone deacetylation and ROP6-mediated cytoskeletal arrangement in the development of interdigitated PCs.

Serum uric acid predicts therapeutic response to midodrine hydrochloride in children with vasovagal syncope: a pilot study.

Serum uric acid (UA) level has been proven to be related to several cardiovascular and metabolic diseases. In the present study, we examined if baseline serum UA level could predict the therapeutic efficacy of midodrine hydrochloride on vasovagal syncope (VVS) in children. The pediatric VVS patients who received midodrine hydrochloride from November 2008 to October 2022 were enrolled. After a median treatment duration of 3 months, the therapeutic effect was evaluated. According to the patients' responses to midodrine hydrochloride, which was determined by the recurrence of syncope, they were divided into effective and ineffective groups. The baseline variables were explored using univariable and multivariate logistic analysis. The predictive efficacy was assessed by receiver operating characteristic curve (ROC), precision-recall curve (PR), Hosmer-Lemeshow test, calibration curve, and decision curve analysis (DCA). Totally, 53 participants were included in the study. Among the 51 patients who were successfully followed up, 29 (56.9%) responded to midodrine hydrochloride (effective group), and the other 22 (43.1%) failed to respond to midodrine hydrochloride (ineffective group). The participants in effective group had lower baseline serum UA level than those in ineffective group (276.5 ± 73 µmol/L vs. 332.7 ± 56 µmol/L, p = 0.004). Multivariable logistic analysis showed that serum UA was associated with the therapeutic response (odds ratio (OR): 0.985, 95% confidence interval (CI): 0.974-0.997, p = 0.01). ROC analysis indicated that using baseline serum UA < 299 µmol/L as a threshold value yielded a sensitivity of 77.3% and a specificity of 79.3% in predicting the treatment response to midodrine hydrochloride. The area under the PR curve was 0.833. Hosmer-Lemeshow test yielded a p value of 0.58, and calibration plot indicated that the model was well-fitted. DCA demonstrated that treatment decision depending on the baseline serum UA level resulted in a favorable net benefit.   Conclusion: This pilot study suggested that the baseline serum UA level could be taken as a predictor of therapeutic effect of midodrine hydrochloride on VVS in children. What is Known: • Empirical and unselected use of midodrine hydrochloride has an unfavorable therapeutic effect on VVS in children. Serum uric acid (UA) is closely linked to cardiovascular events. What is New: • A low baseline serum UA level successfully predicts the therapeutic effectiveness of midodrine hydrochloride on VVS in children.

lnc-HC ameliorates steatosis by promoting miR-130b-3p biogenesis and the assembly of an RNA-induced silencing complex.

Hepatic lipid deposition is the main cause of non-alcoholic fatty liver disease (NAFLD). Our previous study identified that lnc-HC prevents NAFLD by increasing the expression of miR-130b-3p. In the present study, we show that lnc-HC, an lncRNA derived from hepatocytes, positively controls miR-130b-3p maturation at multiple levels and contributes to its action by enhancing the assembly of an RNA-induced silencing complex (RISC). lnc-HC negatively regulates the downstream target genes of miR-130b-3p, including peroxisome proliferator-activated receptor gamma (PPARγ) and acyl-CoA synthetase long-chain family member 1 and 4 (Acsl1 and Acsl4, respectively), thus suppressing hepatic lipid droplet accumulation. Mechanistically, lnc-HC enhanced the promoter activity of miR-130b-3p by positively regulating the expression of transcription factors MAF bZIP transcription factor B (Mafb) and Jun proto-oncogene (Jun). Then, lnc-HC contributed the processing step of primary (pri-) miR-130b and strengthened the interaction between Drosha enzyme and the 5'-flanking sequence of pri-miR-130b to produce more precursor transcripts. Through direct binding with the chaperone heat shock protein 90 alpha family class A member 1 (HSP90AA1), lnc-HC contributed to RISC assembly, which was composed of HSP90AA1, argonaute RISC catalytic component 2 (AGO2) and miR-130b-3p. In a high-fat, high-cholesterol-induced hepatic lipid disorder E3 model, we confirmed that the hepatic expression of lnc-HC/miR-130b-3p negatively correlated with that of the target genes and was closely associated with liver triglycerides concentration. These findings provide a deeper understanding of the regulatory roles of lnc-HC in hepatic lipid metabolism and NAFLD development.

Hypoxia inducible factor-1α is an important regulator of macrophage biology.

Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor composed of the α and ß subunits, regulates cellular adaptive responses to hypoxia. Macrophages, which are derived from monocytes, function as antigen-presenting cells that activate various immune responses. HIF-1α regulates the immune response, viability, migration, phenotypic plasticity, and metabolism of macrophages. Specifically, macrophage-derived HIF-1α can prevent excessive pro-inflammatory responses by attenuating the transcriptional activity of nuclear factor-kappa B in vivo and in vitro. HIF-1α modulates macrophage migration by inducing the release of various chemokines and providing necessary energy. HIF-1α promotes macrophage M1 polarization by targeting glucose metabolism. Additionally, HIF-1α induces the upregulation of glycolysis-related enzymes and intermediates of the tricarboxylic acid cycle and pentose phosphate pathway. HIF-1α promotes macrophage apoptosis, necroptosis and reduces autophagy. The current review highlights the mechanisms associated with the regulation of HIF-1α stabilization in macrophages as well as the role of HIF-1α in modulating the physiological functions of macrophages.

Predicting therapeutic efficacy of oral rehydration salts in children with vasovagal syncope.

Objective: This study was designed to develop an easy-to-perform and inexpensive measure to predict efficacy of the oral rehydration salts (ORS) in children with vasovagal syncope (VVS). Materials and methods: Children diagnosed with VVS and treated with ORS for a median of 3 months at the Peking University First Hospital, China, were enrolled and followed up. Demographic data, clinical hemodynamic parameters, and variables related to red blood cells were collected at the baseline. On the basis of changes in symptom scores after treatment, participants were divided into effective or ineffective groups at the end of the follow-up. Logistic regression analysis was used to investigate parameters related to therapeutic efficacy of ORS and a predictive model of ORS effectiveness was created. The predictive efficiency was evaluated using the receiver operating characteristic curve. The accuracy/consistency was evaluated by the Hosmer-Lemeshow test and calibration curve. Internal validation was done using the bootstrap approach. Results: Totally 97 pediatric participants were included in the study and 4 (4.1%) were lost during the follow-up. ORS therapy was effective in 46 children and ineffective in 47 children. Children in the effective group had higher baseline red blood cell count, hemoglobin, and hematocrit than those in the ineffective group (p < 0.01). Through logistic regression analysis, the baseline hematocrit and body mass index (BMI) were included in predictive model for the response to ORS treatment. The predictive efficacy of the model showed an area under the curve of 0.77 (p < 0.01). The predicted probability cut-off value of 0.5 was found to be optimal, with a resulting sensitivity of 67.4% and specificity of 80.9%. In the Hosmer-Lemeshow test, p-value was 0.75, and the calibration plot showed a good model fitness. Internal validation was performed using the bootstrap approach (n = 1,000), showing 95% confidence interval of 0.67-0.86. Conclusion: Hemoglobin combined with BMI was useful for predicting the therapeutic efficacy of ORS in children with VVS.

Activation of ACLY by SEC63 deploys metabolic reprogramming to facilitate hepatocellular carcinoma metastasis upon endoplasmic reticulum stress.

BACKGROUND: Tumor cells display augmented capability to maintain endoplasmic reticulum (ER) homeostasis and hijack ER stress pathway for malignant phenotypes under microenvironmental stimuli. Metabolic reprogramming is a well-known hallmark for tumor cells to provide specific adaptive traits to the microenvironmental alterations. However, it's unknown how tumor cells orchestrate metabolic reprogramming and tumor progression in response to ER stress. Herein, we aimed to explore the pivotal roles of SEC63-mediated metabolic remodeling in hepatocellular carcinoma (HCC) cell metastasis after ER stress. METHODS: The expression levels of SEC63 in HCC tissues and adjacent non-cancerous tissues were determined by immunohistochemistry and western blot. The regulatory roles of SEC63 in HCC metastasis were investigated both in vitro and in vivo by RNA-sequencing, metabolites detection, immunofluorescence, and transwell migration/invasion analyses. GST pull-down, immunoprecipitation/mass spectrometry and in vivo ubiquitination/phosphorylation assay were conducted to elucidate the underlying molecular mechanisms. RESULTS: We identified SEC63 as a new regulator of HCC cell metabolism. Upon ER stress, the phosphorylation of SEC63 at T537 by IRE1α pathway contributed to SEC63 activation. Then, the stability of ACLY was upregulated by SEC63 to increase the supply of acetyl-CoA and lipid biosynthesis, which are beneficial for improving ER capacity. Meanwhile, SEC63 also entered into nucleus for increasing nuclear acetyl-CoA production to upregulate unfolded protein response targets to improve ER homeostasis. Importantly, SEC63 coordinated with ACLY to epigenetically modulate expression of Snail1 in the nucleus. Consequently, SEC63 promoted HCC cell metastasis and these effects were reversed by ACLY inhibition. Clinically, SEC63 expression was significantly upregulated in HCC tissue specimens and was positively correlated with ACLY expression. Importantly, high expression of SEC63 predicted unfavorable prognosis of HCC patients. CONCLUSIONS: Our findings revealed that SEC63-mediated metabolic reprogramming plays important roles in keeping ER homeostasis upon stimuli in HCC cells. Meanwhile, SEC63 coordinates with ACLY to upregulate the expression of Snail1, which further promotes HCC metastasis. Metastasis is crucial for helping cancer cells seek new settlements upon microenvironmental stimuli. Taken together, our findings highlight a cancer selective adaption to ER stress as well as reveal the potential roles of the IRE1α-SEC63-ACLY axis in HCC treatment.

A review of edible plant-derived natural compounds for the therapy of liver fibrosis.

Liver fibrosis has a high incidence worldwide and is the common pathological basis of many chronic liver diseases. Liver fibrosis is caused by the excessive deposition of extracellular matrix and concomitant collagen accumulation in livers and can lead to the development of liver cirrhosis and even liver cancer. A large number of studies have provided evidence that liver fibrosis can be blocked or even reversed by appropriate medical interventions. However, the antifibrosis drugs with ideal clinical efficacy are still insufficient. The edible plant-derived natural compounds have been reported to exert effective antifibrotic effects with few side-effects, representing a kind of promising source for the treatment of liver fibrosis. In this article, we reviewed the current progress of the natural compounds derived from dietary plants in the treatment of liver fibrosis, including phenolic compounds (capsaicin, chlorogenic acid, curcumin, ellagic acid, epigallocatechin-3-gallate, resveratrol, sinapic acid, syringic acid, vanillic acid and vitamin E), flavonoid compounds (genistein, hesperidin, hesperetin, naringenin, naringin and quercetin), sulfur-containing compounds (S-allylcysteine, ergothioneine, lipoic acid and sulforaphane) and other compounds (betaine, caffeine, cucurbitacin B, lycopene, α-mangostin, γ-mangostin, ursolic acid, vitamin C and yangonin). The pharmacological effects and related mechanisms of these compounds in in-vivo and in-vitro models of liver fibrosis are focused.

Autophagy and its mediated mitochondrial quality control maintain pollen tube growth and male fertility in Arabidopsis.

Macroautophagy/autophagy, a major catabolic pathway in eukaryotes, participates in plant sexual reproduction including the processes of male gametogenesis and the self-incompatibility response. Rapid pollen tube growth is another essential reproductive process that is metabolically highly demanding to drive the vigorous cell growth for delivery of male gametes for fertilization in angiosperms. Whether and how autophagy operates to maintain the homeostasis of pollen tubes remains unknown. Here, we provide evidence that autophagy is elevated in growing pollen tubes and critically required during pollen tube growth and male fertility in Arabidopsis. We demonstrate that SH3P2, a critical non-ATG regulator of plant autophagy, colocalizes with representative ATG proteins during autophagosome biogenesis in growing pollen tubes. Downregulation of SH3P2 expression significantly disrupts Arabidopsis pollen germination and pollen tube growth. Further analysis of organelle dynamics reveals crosstalk between autophagosomes and prevacuolar compartments following the inhibition of phosphatidylinositol 3-kinase. In addition, time-lapse imaging and tracking of ATG8e-labeled autophagosomes and depolarized mitochondria demonstrate that they interact specifically via the ATG8-family interacting motif (AIM)-docking site to mediate mitophagy. Ultrastructural identification of mitophagosomes and two additional forms of autophagosomes imply that multiple types of autophagy are likely to function simultaneously within pollen tubes. Altogether, our results suggest that autophagy is functionally crucial for mediating mitochondrial quality control and canonical cytoplasm recycling during pollen tube growth.Abbreviations: AIM: ATG8-family interacting motif; ATG8: autophagy related 8; ATG5: autophagy related 5; ATG7: autophagy related 7; BTH: acibenzolar-S-methyl; DEX: dexamethasone; DNP: 2,4-dinitrophenol; GFP: green fluorescent protein; YFP: yellow fluorescent protein; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PVC: prevacuolar compartment; SH3P2: SH3 domain-containing protein 2.

Impacts of aerobic exercise on the physical fitness of shot put athletes / Impactos do exercício aeróbico na aptidão física dos atletas de arremesso / Efectos del ejercicio aeróbico en la aptitud física de los atletas de lanzamiento

ABSTRACT Introduction: Shot put is a competitive sport that combines speed, strength, and explosiveness. Training the skill with aerobic exercise has attracted the attention of many coaches and scholars on competitive sports training. Shot put is a fast-powered activity, and its shooting speed is the determining factor for sports performance. It is believed that aerobic exercise can improve the ability of its practitioners. Objective: To analyze the impacts of aerobic exercise on the physical fitness of shot put athletes. Methods: 18 shot put athletes were randomly selected as volunteers for research that consisted of a random division between experimental and control groups. The experimental group received a protocol involving aerobic training, while the control group received regular training before, during, and after the experiment. The maximal strength and explosive power of the two groups of athletes were tested before and after the intervention, and mathematical-statistical methods were used to process the collected data. Results: The maximum strength index of both groups was improved; however, the improvement in the experimental group was statistically relevant(P<0.05). The values of the pressure index, power, and balance of the athletes from the experimental group were statistically altered to those before the experiment (P<0.01). Conclusion: The implementation of aerobic exercise in the routine of shot put athletes can effectively improve the performance in the sport and the special abilities of its practitioners. The training method analyzed was also shown to improve specific performance in the shot put athletes. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução: O arremesso é um esporte de competição que combina velocidade, força e explosividade. O treinamento da capacidade com exercício aeróbico atraiu a atenção de muitos treinadores e estudiosos sobre treinamento esportivo de competição. O arremesso é uma atividade de potência rápida, e sua velocidade de tiro é o fator determinante para o desempenho esportivo. Acredita-se que o exercício aeróbico possa melhorar a habilidade de seus praticantes. Objetivo: Analisar os impactos do exercício aeróbico na aptidão física dos atletas de arremesso. Métodos: 18 praticantes de arremesso foram selecionados aleatoriamente como voluntários para uma pesquisa que consistiu na divisão aleatória entre grupos experimental e de controle. O grupo experimental recebeu um protocolo envolvendo o treinamento aeróbico, enquanto o grupo de controle recebeu seu treinamento regular antes, durante e depois do experimento. A força máxima e o poder explosivo dos dois grupos de atletas foram testados antes e após a intervenção, foram usados métodos estatísticos matemáticos para processar os dados coletados. Resultados: O índice de força máxima dos dois grupos foi aprimorado, porém a melhoria no grupo experimental foi estatisticamente relevante(P<0,05). Os valores do índice de pressão, potência e balanço dos atletas do grupo experimental foram estatisticamente alterados em relação aqueles anteriores ao experimento (P<0,01). Conclusão: A implementação do exercício aeróbico na rotina dos atletas de arremesso pode efetivamente melhorar o desempenho no esporte e as habilidades especiais dos seus praticantes. O método de treinamento analisado também demonstrou melhorar o desempenho específico nos esportistas de arremesso. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

Resumen Introducción: El lanzamiento es un deporte de competición que combina velocidad, fuerza y explosividad. El entrenamiento de la capacidad con ejercicios aeróbicos ha atraído la atención de muchos entrenadores y estudiosos del entrenamiento deportivo de competición. El lanzamiento es una actividad de potencia rápida, y su velocidad de tiro es el factor determinante para el rendimiento deportivo. Se cree que el ejercicio aeróbico puede mejorar la capacidad de sus practicantes. Objetivo: Analizar los impactos del ejercicio aeróbico en la condición física de los atletas de lanzamiento. Métodos: Se seleccionaron aleatoriamente 18 practicantes de lanzamiento como voluntarios para una investigación que consistió en la división aleatoria entre los grupos experimental y de control. El grupo experimental recibió un protocolo de entrenamiento aeróbico, mientras que el grupo de control recibió su entrenamiento habitual antes, durante y después del experimento. Se comprobó la fuerza máxima y la potencia explosiva de los dos grupos de atletas antes y después de la intervención, y se utilizaron métodos estadísticos matemáticos para procesar los datos recogidos. Resultados: El índice de fuerza máxima de ambos grupos mejoró, aunque la mejora en el grupo experimental fue estadísticamente relevante (P<0,05). Los valores del índice de presión, la potencia y el equilibrio de los atletas del grupo experimental estaban estadísticamente alterados en relación con los anteriores al experimento (P<0,01). Conclusión: La implementación del ejercicio aeróbico en la rutina de los atletas de lanzamiento puede mejorar efectivamente el rendimiento en el deporte y las habilidades especiales de sus practicantes. El método de entrenamiento analizado también ha demostrado mejorar el rendimiento específico de los atletas de lanzamiento. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Molecular mechanism of substrate recognition by folate transporter SLC19A1.

Folate (vitamin B9) is the coenzyme involved in one-carbon transfer biochemical reactions essential for cell survival and proliferation, with its inadequacy causing developmental defects or severe diseases. Notably, mammalian cells lack the ability to de novo synthesize folate but instead rely on its intake from extracellular sources via specific transporters or receptors, among which SLC19A1 is the ubiquitously expressed one in tissues. However, the mechanism of substrate recognition by SLC19A1 remains unclear. Here we report the cryo-EM structures of human SLC19A1 and its complex with 5-methyltetrahydrofolate at 3.5-3.6 Å resolution and elucidate the critical residues for substrate recognition. In particular, we reveal that two variant residues among SLC19 subfamily members designate the specificity for folate. Moreover, we identify intracellular thiamine pyrophosphate as the favorite coupled substrate for folate transport by SLC19A1. Together, this work establishes the molecular basis of substrate recognition by this central folate transporter.

The Systematic Analyses of RING Finger Gene Signature for Predicting the Prognosis of Patients with Hepatocellular Carcinoma.

RING finger (RNF) proteins are frequently dysregulated in human malignancies and are tightly associated with tumorigenesis. However, the expression profiles of RNF genes in hepatocellular carcinoma (HCC) and their relations with prognosis remain undetermined. Here, we aimed at constructing a prognostic model according to RNF genes for forecasting the outcomes of HCC patients using the data from The Cancer Genome Atlas (TCGA) program. We collected HCC datasets to validate the values of our model in predicting prognosis of HCC patients from International Cancer Genome Consortium (ICGC) platform. Then, functional experiments were carried out to explore the roles of the representative RNF in HCC progression. A total of 107 differentially expressed RNFs were obtained between TCGA-HCC tumor and normal tissues. After comprehensive evaluation, a prognostic signature composed of 11 RNFs (RNF220, RNF25, TRIM25, BMI1, RNF216P1, RNF115, RNF2, TRAIP, RNF157, RNF145, and RNF19B) was constructed based on TCGA cohort. Then, the Kaplan-Meier (KM) curves and the receiver operating characteristic curve (ROC) were employed to evaluate predictive power of the prognostic model in testing cohort (TCGA) and validation cohort (ICGC). The KM and ROC curves illustrated the good predictive power in testing and validation cohort. The areas under the ROC curve are 0.77 and 0.76 in these two cohorts, respectively. Among the prognostic signature genes, BMI1 was selected as a representative for functional study. We found that BMI1 protein level was significantly upregulated in HCC tissues. Moreover, the inhibitor of BMI1, PTC-209, displayed an excellent anti-HCC effect in vitro. Enrichment analysis of BMI1 downstream targets showed that BMI1 might be involved in tumor immunotherapy. Together, our overall analyses revealed that the 11-RNFs prognostic signature might provide us latent chances for evaluating HCC prognosis and developing novel HCC therapy.

Adipokines, Hepatokines and Myokines: Focus on Their Role and Molecular Mechanisms in Adipose Tissue Inflammation.

Chronic low-grade inflammation in adipose tissue (AT) is a hallmark of obesity and contributes to various metabolic disorders, such as type 2 diabetes and cardiovascular diseases. Inflammation in ATs is characterized by macrophage infiltration and the activation of inflammatory pathways mediated by NF-κB, JNK, and NLRP3 inflammasomes. Adipokines, hepatokines and myokines - proteins secreted from AT, the liver and skeletal muscle play regulatory roles in AT inflammation via endocrine, paracrine, and autocrine pathways. For example, obesity is associated with elevated levels of pro-inflammatory adipokines (e.g., leptin, resistin, chemerin, progranulin, RBP4, WISP1, FABP4, PAI-1, Follistatin-like1, MCP-1, SPARC, SPARCL1, and SAA) and reduced levels of anti-inflammatory adipokines such as adiponectin, omentin, ZAG, SFRP5, CTRP3, vaspin, and IL-10. Moreover, some hepatokines (Fetuin A, DPP4, FGF21, GDF15, and MANF) and myokines (irisin, IL-6, and DEL-1) also play pro- or anti-inflammatory roles in AT inflammation. This review aims to provide an updated understanding of these organokines and their role in AT inflammation and related metabolic abnormalities. It serves to highlight the molecular mechanisms underlying the effects of these organokines and their clinical significance. Insights into the roles and mechanisms of these organokines could provide novel and potential therapeutic targets for obesity-induced inflammation.

Twenty-Four-Hour Urinary Sodium Excretion Predicts Therapeutic Effectiveness of Oral Rehydration Saline in Pediatric Vasovagal Syncope.

The study was designed to explore whether 24-hour urinary sodium excretion could predict the therapeutic effectiveness of oral rehydration saline in pediatric cases of vasovagal syncope. Eighty children suffering from vasovagal syncope with oral rehydration saline treatment in Department of Pediatrics, Peking University First Hospital, China, were recruited into the study. They were followed up for 3 (2, 3) months after treatment. Pre-treatment demographic, clinical, head-up tilt test-based hemodynamic and laboratory variables were compared between responders and non-responders. After univariate analysis, variables with p value < 0.05 in the comparison between responders and non-responders were further analyzed by binary logistic regression analysis. Receiver operating characteristic (ROC) curve was conducted to assess the value in predicting effectiveness of oral rehydration saline treatment. The results showed that 33 cases were responders, and 47 were non-responders. Blood sodium (138 ± 2 mmol/L vs. 139 ± 2 mmol/L, p < 0.05) and pre-treatment 24-hour urinary sodium excretion (74 ± 29 mmol/24 h vs. 109 (93, 141) mmol/24 h, p < 0.001) were lower in responders than in non-responders. The baseline 24-hour urinary sodium excretion was positively correlated to the duration from tilting to the positive response appearance in head-up tilt test (r = 0.289, p < 0.01). The cut-off value of baseline 24-hour urinary sodium excretion of the therapeutic effectiveness of oral rehydration saline on vasovagal syncope cases was 83 mmol/24 h, yielding a sensitivity of 87% and a specificity of 73% with AUC of 0.842 (p < 0.001). In conclusion, 24-hour urinary sodium excretion could be a useful biomarker to predict the therapeutic response to oral rehydration saline in pediatric cases of vasovagal syncope.

Cholesterol-induced leucine aminopeptidase 3 (LAP3) upregulation inhibits cell autophagy in pathogenesis of NAFLD.

OBJECTIVES: Leucine aminopeptidase 3 (LAP3), an M1 member of leucine aminopeptidase, was reported to be significantly upregulated in serum of nonalcoholic fatty liver disease (NAFLD) patients. However, the underlying mechanisms of LAP3 in NAFLD pathogenesis are still unknown. We aim to investigate the role of LAP3 in NAFLD pathogenesis and explore whether LAP3 has the potential to be a candidate biomarker in serum for NAFLD diagnosis. METHODS: Liver tissues and serum from NASH rats, serum from patients with NAFLD were obtained to evaluate the LAP3 expression. Detection of GSSG/GSH, intracellular reactive oxygen species (ROS), and LC3 expression by elevation/ reduction of LAP3 expression to determine the role of LAP3 in NAFLD pathogenesis. Finally, the correlation analysis was conducted to evaluate the association between LAP3 expression and clinical indexes of NAFLD. RESULTS: LAP3 expression was upregulated in hepatocytes and serum in E3 rats with NASH after 6-month HFD feeding. Cholesterol (CHO) dramatically upregulated LAP3 in LO2 cells, and then lead to negative regulation of autophagy. Moreover, LAP3 levels were also significantly increased in NAFLD patients compared to healthy controls. Correlation analysis revealed that serum LAP3 levels were positively correlated with TG, γ-glutamyltranspeptidase (GGT), and fasting blood glucose levels, while there was a negative correlation with HDL levels. CONCLUSIONS: The cholesterol-dependent upregulation of LAP3 in hepatocytes plays a critical role in the pathogenesis of NAFLD via inhibiting autophagy. Moreover, LAP3 could serve as a potential novel candidate biomarker for the diagnosis of NAFLD.

PPP1R26 drives hepatocellular carcinoma progression by controlling glycolysis and epithelial-mesenchymal transition.

BACKGROUND: Hepatocellular carcinoma (HCC) is usually diagnosed at an advanced stage due to rapid progression. Glycolysis supports anabolic growth and metastasis to promote HCC progression. However, the molecular mechanisms linking glycolysis and metastasis in HCC are not completely defined. METHODS: The expression of PPP1R26 in human HCC tissues was evaluated by immunohistochemistry, and the clinical significance of PPP1R26 in the progression and prognosis of the HCC patients were analyzed. The PPP1R26-binding proteins were determined by mass spectrometry analysis. The function of PPP1R26 in glycolysis, EMT and tumorigenesis were evaluated in HCC cells. Glucose uptake and tumor growth were evaluated using PET imaging in mouse xenografts in vivo. Protein binding was confirmed by co-immunoprecipitation and immunofluorescence co-localization. Protein-RNA binding was determined by RNA-immunoprecipitation (RIP) experiment. The binding of protein on the promoter was evaluated by chromatin immunoprecipitation assay (ChIP). RESULTS: PPP1R26 is upregulated in human HCC tissues and its upregulation is significantly associated with metastasis and the poor survival of the patients. PPP1R26 activates glycolysis in HCC cells and in mouse xenografts in vivo. PPP1R26 drives glycolysis by binding to PTBP1 to facilitate the mRNA splicing of PKM2. Simultaneously, overexpressed PPP1R26 induces the nuclear accumulation of PKM2 to inhibit the expression of E-cadherin further to drive EMT. Mechanistically, PPP1R26 binds with Ser37-phosphorylated PKM2 and TGIF2 in the nucleus and blocks the binding of TGIF2 with CDH1 promoter to inhibit the transcription of CDH1. CONCLUSION: PPP1R26 promotes glycolysis by enhancing PKM2 splicing and simultaneously activates EMT by forming a PPP1R26-PKM2-TGIF2 complex to drive HCC progression. Therefore, targeting PPP1R26 attenuates HCC progression and provides a potential therapeutic strategy for the HCC patients with upregulation of PPP1R26.