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Idiopathic pulmonary fibrosis (IPF) is a fatal pulmonary disease that requires further investigation to understand its pathogenesis. The present study demonstrated that secreted phosphoprotein 1 (SPP1) was aberrantly highly expressed in the lung tissue of patients with IPF and was significantly positively associated with macrophage and Tcell activity. Cell localization studies revealed that SPP1 was primarily overexpressed in macrophages, rather than in T cells. Functionally, knocking down SPP1 expression in vitro inhibited the secretion of fibrosisrelated factors and M2 polarization in macrophages. Furthermore, knocking down SPP1 expression inhibited the macrophageinduced epithelialtomesenchymal transition in both epithelial and fibroblastic cells. Treatment with SPP1 inhibitors in vivo enhanced lung function and ameliorated pulmonary fibrosis. Mechanistically, SPP1 appears to promote macrophage M2 polarization by regulating the JAK/STAT3 signaling pathway both in vitro and in vivo. In summary, the present study found that SPP1 promotes M2 polarization of macrophages through the JAK2/STAT3 signaling pathway, thereby accelerating the progression of IPF. Inhibition of SPP1 expression in vivo can effectively alleviate the development of IPF, indicating that SPP1 in macrophages may be a potential therapeutic target for IPF.
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Fibrosis Pulmonar Idiopática , Janus Quinasa 2 , Macrófagos , Osteopontina , Factor de Transcripción STAT3 , Transducción de Señal , Factor de Transcripción STAT3/metabolismo , Janus Quinasa 2/metabolismo , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/metabolismo , Macrófagos/metabolismo , Humanos , Animales , Masculino , Ratones , Osteopontina/metabolismo , Osteopontina/genética , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/genética , Femenino , Ratones Endogámicos C57BL , Persona de Mediana EdadRESUMEN
Background: Noonan syndrome (NS) and Noonan-like syndrome with loose anagen hair (NS/LAH) are neurodevelopmental syndromes resulting from germline mutations in genes that participate in the rat sarcoma/mitogen-activated protein kinases (RAS/MAPK) pathway. The aim of this retrospective study was to describe common and rare manifestations of NS and NS/LAH. Methods: We collected and analyzed clinical and genetic data from 25 patients with NS and NS/LAH. Results: The patients' median age was 6.3 years (range, 1-13 years), and the male-to-female ratio was 18:7. In total, 19 patients had NS caused by a mutation in PTPN11. Another causative gene was found in six patients, including two patients with a SHOC2 mutation, one patient with a KRAS mutation, one patient with an LZTR1 mutation, one patient with a BRAF mutation, and one patient with a PPP1CB mutation. Short stature was detected in 100% of the patients. This study provides an overview of the clinical features of NS, including unique facial features, short stature, congenital heart defects, and other manifestations. Notably, systemic lupus erythematosus (SLE) was found in two SHOC2-positive patients. One patient had a posterior urethral valve, which is very rare in NS patients. Conclusions: Our study identified several clinical features that were previously poorly related to NS, including SLE. We concluded that SHOC2-related NS is associated with a particularly high risk of SLE, which may have a significant impact on quality of life, and a posterior urethral valve is a novel phenotype. These findings could be helpful in enhancing the understanding of the clinical spectrum of NS.
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Background: The association between 25(OH)D and pubertal timing has not been well studied. The aim of this study was to assess the relationship between 25(OH)D levels and pubertal timing in children. Methods: Participants aged 6-14 years who had available nutritional and serum sex hormone (total testosterone (TT) and estradiol (E2)) information (n =1318) were included. We conducted a cross-sectional analysis of the associations between 25(OH)D and sex steroid hormones among children in the National Health and Nutrition Examination Survey, 2015-2016. Puberty was indicated by high levels of steroid hormones (TT≥50 ng/dL in men, E2≥20 pg/ml in women) or menarche. Results: Serum 25(OH)D and pubertal status showed the same trend in both males and females. In the male population, the OR values of serum 25(OH)D between 50 and <75 and ≥75 nmol/L were 0.52 (0.25, 1.08) and 0.64 (0.23, 1.75), respectively, compared with serum 25(OH)D<50 nmol/L. The OR of serum 25(OH)D ≥50 nmol/L compared with <50 nmol/L was 0.54 (0.26, 1.10), and the P value was statistically significant (P=0.048). In the female population, when the serum 25(OH)D concentration was <50 nmol/L, the ORs corresponding to a serum 25(OH)D concentration between 50 and <75 and ≥75 nmol/L were 0.53 (0.29, 0.98) and 0.50 (0.19, 1.30), respectively. The OR of serum 25(OH)D≥50 nmol/L compared with <50 nmol/L was 0.52 (0.19, 0.96), and the P value was statistically significant (P=0.037). Conclusions: A lower 25(OH)D level was associated with earlier puberty in both girls and boys. There was a negative association between 25(OH)D concentrations and pubertal timing.
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Encuestas Nutricionales , Pubertad , Vitamina D , Humanos , Femenino , Masculino , Niño , Vitamina D/sangre , Vitamina D/análogos & derivados , Adolescente , Estudios Transversales , Pubertad/sangre , Testosterona/sangre , Estradiol/sangre , Menarquia/sangreRESUMEN
Background: In traditional Mongolian or Tibetan medicine in China, Chebulae Fructus (CF) is widely used to process or combine with aconitums to decrease the severe toxicity of aconitums. Researches in this area have predominantly focused on tannins, with few research on other major CF components for cardiotoxicity mitigation. The present study aimed to clarify whether triterpenoids can attenuate the cardiotoxicity caused by mesaconitine (MA) and investigate the mechanism of cardiotoxicity attenuation. Methods: Firstly, the pharmacophore model, molecular docking, and 3D-QSAR model were used to explore the mechanism of CF components in reducing the toxicity of MA mediated by the TRPV1 channel. Then three triterpenoids were selected to verify whether the triterpenoids had the effect of lowering the cardiotoxicity of MA using H9c2 cells combined with MTT, Hoechst 33258, and JC-1. Finally, Western blot, Fluo-3AM, and MTT assays combined with capsazepine were used to verify whether the triterpenoids reduced H9c2 cardiomyocyte toxicity induced by MA was related to the TRPV1 channel. Results: Seven triterpenoids in CF have the potential to activate the TRPV1 channel. And they exhibited greater affinity for TRPV1 compared to other compounds and MA. However, their activity was relatively lower than that of MA. Cell experiments revealed that MA significantly reduced H9c2 cell viability, resulting in diminished mitochondrial membrane potential and nuclear pyknosis and damage. In contrast, the triterpenoids could improve the survival rate significantly and counteract the damage of MA to the cells. We found that MA, arjungenin (AR), and maslinic acid (MSA) except corosolic acid (CRA) upregulated the expression of TRPV1 protein. MA induced a significant influx of calcium, whereas all three triterpenoids alleviated this trend. Blocking the TRPV1 channel with capsazepine only increased the cell viability that had been simultaneously treated with MA, and AR, or MSA. However, there was no significant difference in the CRA groups treated with or without capsazepine. Conclusion: The triterpenoids in CF can reduce the cardiotoxicity caused by MA. The MSA and AR function as TRPV1 agonists with comparatively reduced activity but a greater capacity to bind to TRPV1 receptors, thus antagonizing the excessive activation of TRPV1 by MA.
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Liver metastasis is the leading cause of mortality in patients with colorectal cancer. Given the significance of both epithelial-mesenchymal transition (EMT) of tumor cells and the immune microenvironment in colorectal cancer liver metastasis (CRLM), the interplay between them could hold the key for developing improved treatment options. We employed multiomics analysis of 130 samples from 18 patients with synchronous CRLM integrated with external datasets to comprehensively evaluate the interaction between immune cells and EMT of tumor cells in liver metastasis. Single-cell RNA sequencing analysis revealed distinct distributions of nonmalignant cells between primary tumors from patients with metastatic colorectal cancer (mCRC) and non-metastatic colorectal cancer, showing that Th17 cells were predominantly enriched in the primary lesion of mCRC. TWEAK, a cytokine secreted by Th17 cells, promoted EMT by binding to receptor Fn14 on tumor cells, and the TWEAK-Fn14 interaction enhanced tumor migration and invasion. In mouse models, targeting Fn14 using CRISPR-induced knockout or lipid nanoparticle-encapsulated siRNA alleviated metastasis and prolonged survival. Mice lacking Il17a or Tnfsf12 (encoding TWEAK) exhibited fewer metastases compared with wild-type mice, while cotransfer of Th17 with tumor cells promoted liver metastasis. Higher TWEAK expression was associated with a worse prognosis in patients with colorectal cancer. In addition, CD163L1+ macrophages interacted with Th17 cells, recruiting Th17 via the CCL4-CCR5 axis. Collectively, this study unveils the role of immune cells in the EMT process and identifies TWEAK secreted by Th17 as a driver of CRLM. SIGNIFICANCE: TWEAK secreted by Th17 cells promotes EMT by binding to Fn14 on colorectal cancer cells, suggesting that blocking the TWEAK-Fn14 interaction may be a promising therapeutic approach to inhibit liver metastasis.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Animales , Ratones , Células Th17 , Citocina TWEAK , Transición Epitelial-Mesenquimal/genética , Pronóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Receptor de TWEAK/genética , Línea Celular Tumoral , Movimiento Celular/genética , Microambiente TumoralRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease characterized by severe pulmonary fibrosis, for which there is an urgent need for effective therapeutic agents. Mefloquine (Mef) is a quinoline compound primarily used for the treatment of malaria. However, high doses (>25 mg/kg) may lead to side effects such as cardiotoxicity and psychiatric disorders. Here, we found that low-dose Mef (5 mg/kg) can safely and effectively treat IPF mice. Functionally, Mef can improve the pulmonary function of IPF mice (PIF, PEF, EF50, VT, MV, PENH), alleviating pulmonary inflammation and fibrosis by inhibiting macrophage activity. Mechanically, Mef probably regulates the Jak2/Stat3 signaling pathway by binding to the 492HIS site of Potassium voltage-gated channel subfamily H member 2 (KCNH2) protein in macrophages, inhibiting the secretion of macrophage inflammatory and fibrotic factors. In summary, Mef may inhibit macrophage activity by binding to KCNH2 protein, thereby slowing down the progress of IPF.
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Fibrosis Pulmonar Idiopática , Mefloquina , Humanos , Ratones , Animales , Mefloquina/uso terapéutico , Macrófagos/metabolismo , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Pulmón/patología , Fibrosis , Transducción de Señal , Bleomicina/farmacología , Canal de Potasio ERG1/metabolismoRESUMEN
OBJECTIVES: The GnRH stimulation test has been used as the gold standard for the diagnosis of central precocious puberty (CPP), but it has some practical barriers. This study intends to build a diagnostic model of CPP in girls based on the population in northern China. METHODS: A total of 163 girls with precocious puberty (PP) were included from December 2018 to December 2019. Multifactor logistic regression analysis was conducted. Based on the results of multivariate logistic regression analysis, a nomogram was established for clinical application. RESULTS: A multi logistic regression model showed that LH (OR=1.238, 95â¯% CI: 1.067-1.436, p=0.005), inhibin B (OR=1.066, 95â¯% CI: 1.032-1.100, p<0.001), bone age (OR=1.563, 95â¯% CI: 1.037-2.358, p=0.033), and uterine length (OR=1.180, 95â¯% CI: 1.034-1.348, p=0.014) were diagnostic factors for CPP. The prediction model AUC was 0.906 (95â¯% CI: 0.852-0.959, p<0.001). CONCLUSIONS: We successfully developed a nomogram model for CPP patients based on clinical data. The diagnostic prediction model included four indicators: basal LH, inhibin B, bone age, and uterine body length.
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Pubertad Precoz , Femenino , Humanos , Pubertad Precoz/diagnóstico , Hormona Luteinizante , Hormona Folículo Estimulante , Estatura , Útero , Hormona Liberadora de GonadotropinaRESUMEN
According to the family stress model, this study examined the relationship between parenting stress and preschoolers' approaches to learning (ATL) in China, as well as the mediating effect of authoritative parenting and the moderating effect of household residency (migrant and native). A survey of 5,047 preschoolers' parents (2,186 natives and 2,861 migrants) supports the proposed moderated mediation model. The results showed that after controlling for gender and age, parenting stress affected preschoolers' development of ATL negatively. Authoritative parenting mediates the relationship between parenting stress and preschoolers' ATL. Further, household residency moderated the relationship between authoritative parenting and preschoolers' ATL. The findings of this study suggest that high levels of parenting stress are detrimental to the development of preschoolers' ATL. And parents with low parenting stress are more likely to adopt authoritative parenting, which in turn fosters preschoolers' ATL. In addition, native families' authoritative parenting style are more conducive to fostering preschoolers' ATL than migrant families. Finally, this study contributes to previous research by examining the mechanisms of parenting stress on preschoolers' ATL and provides support for the extension of the family stress model. Importantly, it also informs efforts to improve ATL among preschoolers in Chinese migrant and native families.
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The unrestrained Li dendrite growth impedes the performance of Li metal batteries (LMBs) and brings safety concerns. To mitigate the unfavorable effect of Li dendrites, in this work, a shield-like artificial interlayer composed of Si3N4 is employed to achieve the desirable electrochemical performance of LMBs. The Si3N4-based interlayer can in-situ electrochemically react with Li to generate inorganic Li3N and LixSi alloys: the former with high ionic conductivity can effectively enhance the Li+ transference, while the latter with reversibility for Li+ insertion/deinsertion can act as Li+ reservoir to modulate Li+ platting/stripping. Thus, the Si3N4-derived compound shield effectively defends against the attack of Li dendrites and suppresses their growth, with which the Li||Li cells can cycle at 1 mA cm-2 (1 mAh cm-2) up to 500 h and the LiFePO4 (LFP) ||Li batteries can operate 400 cycles at 1C with 91.5 % capacity retention.
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BACKGROUND & AIMS: RNA N6-methyladenosine (m6A) reader protein YTHDF1 has been implicated in cancer; however, its role in hepatocellular carcinoma (HCC), especially in non-alcoholic steatohepatitis-associated HCC (NASH-HCC), remains unknown. Here, we investigated the functional role of YTHDF1 in NASH-HCC and its interplay with the tumor immune microenvironment. METHODS: Hepatocyte-specific Ythdf1-overexpressing mice were subjected to a NASH-HCC-inducing diet. Tumor-infiltrating immune cells were profiled with single-cell RNA-sequencing, flow cytometry, and immunostaining. The molecular target of YTHDF1 was elucidated with RNA-sequencing, m6A-sequencing, YTHDF1 RNA immunoprecipitation-sequencing, proteomics, and ribosome-profiling. Ythdf1 in NASH-HCC models was targeted by lipid nanoparticle (LNP)-encapsulated small-interfering Ythdf1. RESULTS: YTHDF1 is overexpressed in tumor tissues compared to adjacent peri-tumor tissues from patients with NASH-HCC. Liver-specific Ythdf1 overexpression drives tumorigenesis in dietary models of spontaneous NASH-HCC. Single-cell RNA-sequencing and flow cytometry revealed that Ythdf1 induced accumulation of myeloid-derived suppressor cells (MDSCs) and suppressed cytotoxic CD8+ T-cell function. Mechanistically, Ythdf1 expression in NASH-HCC cells induced the secretion of IL-6, which mediated MDSC recruitment and activation, leading to CD8+ T-cell dysfunction. EZH2 mRNA was identified as a key YTHDF1 target. YTHDF1 binds to m6A-modified EZH2 mRNA and promotes EZH2 translation. EZH2 in turn increased expression and secretion of IL-6. Ythdf1 knockout synergized with anti-PD-1 treatment to suppress tumor growth in NASH-HCC allografts. Furthermore, therapeutic targeting of Ythdf1 using LNP-encapsulated small-interfering RNA significantly increased the efficacy of anti-PD-1 blockade in NASH-HCC allografts. CONCLUSIONS: We identified that YTHDF1 promotes NASH-HCC tumorigenesis via EZH2-IL-6 signaling, which recruits and activates MDSCs to cause cytotoxic CD8+ T-cell dysfunction. YTHDF1 may be a novel therapeutic target to improve responses to anti-PD-1 immunotherapy in NASH-HCC. IMPACT AND IMPLICATIONS: YTHDF1, a N6-methyladenosine reader, is upregulated in patients with non-alcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC); however, its role in modulating the tumor immune microenvironment in NASH-HCC remains unclear. Here, we show that Ythdf1 mediates immunosuppression in NASH-HCC and that targeting YTHDF1 in combination with immune checkpoint blockade elicits robust antitumor immune responses. Our findings suggest novel therapeutic targets for potentiating the efficacy of immune checkpoint blockade in NASH-HCC and provide the rationale for developing YTHDF1 inhibitors for the treatment of NASH-HCC.
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Li metal is a potential anode material for the next generation high-energy-density batteries because of its high theoretical specific capacity. However, the inhomogeneous lithium dendrite growth restrains corresponding electrochemical performance and brings safety concerns. In this contribution, the Li3Bi/Li2O/LiI fillers are generated by the in-situ reaction between Li and BiOI nanoflakes, which promises corresponding Li anodes (BiOI@Li) showing favorable electrochemical performance. This can be attributed to the bulk/liquid dual modulations: (1) The three-dimensional Bi-based framework in the bulk-phase lowers the local current density and accommodates the volume variation; (2) The LiI dispersed within Li metal is slowly released and dissolved into the electrolyte with the consumption of Li, which will form I-/I3- electron pair and further reactivate the inactive Li species. Specifically, the BiOI@Li//BiOI@Li symmetrical cell shows small overpotential and enhanced cycle stability over 600 h at 1 mA cm-2. Matched with an S-based cathode, the full Li-S battery demonstrates desirable rate performance and cycling stability.
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Lenvatinib is emerging as the first-line therapeutic option for advanced hepatocellular carcinoma (HCC), but drug resistance remains a major hurdle for its long-term therapy efficiency in clinic. N6-methyladenosine (m6A) is the most abundant mRNA modification. Here, we aimed to investigate the modulatory effects and underlying mechanisms of m6A in lenvatinib resistance in HCC. Our data revealed that m6A mRNA modification was significantly upregulated in the HCC lenvatinib resistance (HCC-LR) cells compared to parental cells. Methyltransferase-like 3 (METTL3) was the most significantly upregulated protein among the m6A regulators. Either genetic or pharmacological inhibition of m6A methylation through METTL3 deactivation in primary resistant cell line MHCC97H and acquired resistant Huh7-LR cells decreased cell proliferation and increased cell apoptosis upon lenvatinib treatment in vitro and in vivo. In addition, the specific METTL3 inhibitor STM2457 improved tumor response to lenvatinib in multiple mouse HCC models, including subcutaneous, orthotopic and hydrodynamic models. The MeRIP-seq results showed that epidermal growth factor receptor (EGFR) was a downstream target of METTL3. EGFR overexpression abrogated the METTL3 knocked down-induced cell growth arrest upon lenvatinib treatment in HCC-LR cells. Thus, we concluded that targeting METTL3 using specific inhibitor STM2457 improved the sensitivity to lenvatinib in vitro and in vivo, indicating that METTL3 may be a potential therapeutic target to overcome lenvatinib resistance in HCC.
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Carcinoma Hepatocelular , Resistencia a Antineoplásicos , Neoplasias Hepáticas , Animales , Ratones , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Receptores ErbB/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Metiltransferasas/genética , ARN Mensajero , Humanos , Resistencia a Antineoplásicos/genéticaRESUMEN
The high reactivity of Li metal and the inhomogeneous Li deposition leads to the formation of Li dendrites and "dead" Li, which impedes the performance of Li metal batteries (LMBs) with high energy density. The regulating and guiding the Li dendrite nucleation is a desirable tactic to realize concentrated distribution of Li dendrites instead of completely inhibiting dendrite formation. Here, a Fe-Co-based Prussian blue analog with hollow and open framework (H-PBA) is employed to modify the commercial polypropylene separator (PP@H-PBA). This functional PP@H-PBA can guide the lithium dendrite growth to form uniform lithium deposition and activate the inactive Li. In details, the H-PBA with macroporous structure and open framework can induce the growth of lithium dendrites via space confinement, while the positive Fe/Co-sites lowered by polar cyanide (-CN) of PBA can reactivate the inactive Li. Thus, the Li|PP@H-PBA|Li symmetric cells exhibit long-term stability at 1 mA cm-2 for 1 mAh cm-2 over 500 h. And the Li-S batteries with PP@H-PBA deliver favorable cycling performance at 500 mA g-1 for 200 cycles.
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Long noncoding RNAs (lncRNAs) are related to the development of atherosclerosis (AS). However, the role of lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in tumor necrosis factorα (TNFα)induced rat aortic endothelial cell (RAOEC) pyroptosis, as well as the underlying mechanisms, remain unclear. RAOEC morphology was assessed using an inverted microscope. The mRNA and/or protein expression levels of MALAT1, microRNA(miR)30c5p and connexin 43 (Cx43) were assessed using reverse transcriptionquantitative PCR (RTqPCR) and/or western blotting, respectively. The relationships among these molecules were validated by dualluciferase reporter assays. Biological functions, such as LDH release, pyroptosisassociated protein levels and the proportion of PIpositive cells, were evaluated using a LDH assay kit, western blotting and Hoechst 33342/PI staining, respectively. The present study demonstrated that compared with the control group, the mRNA expression levels of MALAT1 and protein expression levels of Cx43 were significantly upregulated, whereas miR30c5p mRNA expressions levels were significantly decreased in TNFαtreated RAOEC pyroptosis. Knockdown of MALAT1 or Cx43 significantly attenuated the increase in LDH release, pyroptosisassociated protein expression and PIpositive cell numbers among RAOEC treated using TNFα, whereas an miR30c5p mimic exerted the opposite effect. Furthermore, miR30c5p was demonstrated to be a negative regulator of MALAT1 and could also target Cx43. Finally, cotransfection with siMALAT1 and miR30c5p inhibitor could attenuate the protective effect of MALAT1 knockdown against TNFαmediated RAOEC pyroptosis by upregulation of Cx43 expression. In conclusion, MALAT1 might serve an important role in TNFαmediated RAOEC pyroptosis by regulating the miR30c5p/Cx43 axis, which would provide a potential novel diagnostic and therapeutic target for AS.
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MicroARNs , ARN Largo no Codificante , Ratas , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Piroptosis/genética , Conexina 43/genética , MicroARNs/genética , MicroARNs/metabolismo , Células Endoteliales/metabolismo , ARN MensajeroRESUMEN
Background: The most common cause of primary adrenal insufficiency (PAI) in children is congenital adrenal hyperplasia; however, other genetic causes occur. There is limited epidemiological and clinical information regarding non-CAH PAI. Methods: Data for patients diagnosed from January 2015 to December 2021 at a tertiary hospital in northern China were retrospectively analyzed. We excluded those with CAH, which is the most common pathogenic disease among PAI patients. Next-generation sequencing was used for genetic analysis. Results: This retrospective study included 16 children (14 males and 2 females) with PAI. A genetic diagnosis was obtained for 14/16 (87.5%) individuals. Pathogenic variants occurred in 6 genes, including ABCD1 (6/16, 37.5%), NR0B1 (4/16, 25.0%), NR5A1/steroidogenic factor-1 (2/16; 12.5%), AAAS (1/16, 6.25%), and NNT (1/16, 6.25%). No genetic cause of PAI diagnosis was found in 2 girls (2/16, 12.5%). Conclusions: Causes of PAI in children are diverse and predominantly affect males. Most PAI in children is congenital, and ABCD1 gene defects account for the largest proportion of PAI cases. Whole-exome sequencing is a tool for diagnosis. However, diagnoses are unclear in some cases.
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OBJECTIVE: To explore the clinical and genetic basis for a patient with isolated 17,20 lyase deficiency presenting with pubertal gynecomastia. METHODS: Clinical manifestation, steroid analysis as well as genetic testing were carried out for a 14-year-old boy featuring puberty gynecomastia. RESULTS: The patient was admitted due to puberty gynecomastia for 2 years. Physical examination showed Tanner B5, G2 and normal blood pressure. Laboratory examination showed normal range of serum potassium and blood gas. Steroid analysis revealed extremely high pregnenolone, progesterone, 17-hydropregnenolone and 17-hydroprogesterone, Correspondingly, the DHEA, androstenedione, testosterone and dihydrotestosterone were low. He was found to harbor compound heterozygous variants of CYP17A1 gene (c.1304T>C/p.F435S and c.1346G>A/p.R449H), among which the R449H variant may result in isolated 17,20 lyase deficiency by altering the structure of redox-partner binding site. CONCLUSION: Isolated 17,20 lyase is a rare cause for puberty gynecomastia. The p.R449H variant of the CYP17A1 gene can result in isolated 17,20 lyase deficiency.
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Ginecomastia , Esteroide 17-alfa-Hidroxilasa , Adolescente , Pruebas Genéticas , Ginecomastia/genética , Humanos , Masculino , Esteroide 17-alfa-Hidroxilasa/genéticaRESUMEN
The present study investigated the influence of heating and honey addition on the appearance, chemical component content, and pharmacological activity of Codonopsis Radix decoction pieces in the honey-frying process, and explored the processing mechanism of honey-fried Codonopsis Radix. The color, sweetness, and content of macromolecular components(e.g., oligosaccharides and polysaccharides) and small molecular components(e.g., lobetyolin and atractylenolide â ¢) of raw Codonopsis Radix, fried Codonopsis Radix, honey-mixed Codonopsis Radix, and honey-fried Codonopsis Radix were determined, and the antioxidant activities in vitro of their water extract, polysaccharide extract, and oligosaccharide extract were compared. The results showed that in terms of color and sweetness, compared with the raw Codonopsis Radix, the fried Codonopsis Radix slightly changed, the honey-mixed Codonopsis Radix changed significantly, and the honey-fried Codonopsis Radix changed with high significance. In terms of the content of lobetyolin, atractylenolide â ¢, and polysaccharides, the samples were ranked as raw Codonopsis Radix > fried Codonopsis Radix > honey-mixed Codonopsis Radix > honey-fried Codonopsis Radix, which indicated that heating and honey addition could reduce the content of these three components. In terms of the content of oligosaccharides, the samples were ranked as honey-fried Codonopsis Radix ≈ honey-mixed Codonopsis Radix > fried Codonopsis Radix ≈ raw Codonopsis Radix, indicating that honey addition could increase the content of oligosaccharides. In terms of antioxidant activity in vitro, ABTS radical scavenging ability of water extract, polysaccharides, and oligosaccharides of honey-fried Codonopsis Radix was most potent, while the change of antioxidant activity in vitro of each extract in the other three processed products was different. In short, both heating and honey addition can affect the appearance, chemical component content, and antioxidant activity in vitro of Codonopsis Radix decoction pieces, but the effect of the combination of the two factors is the best. The comprehensive analysis of the effects of heating and honey addition on Codonopsis Radix decoction pieces indicates that honey addition followed by heating at high temperature is the necessary condition for honey-fried Codonopsis Radix to enhance its activity.
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Codonopsis , Medicamentos Herbarios Chinos , Miel , Antioxidantes/análisis , Codonopsis/química , Medicamentos Herbarios Chinos/química , Polisacáridos/análisis , AguaRESUMEN
Background: Alstrom syndrome (ALMS) is a rare genetic disorder. ALMS is characterized by progressive bilateral sensorineural hearing impairment, cone-rod dystrophy, infantile-onset cardiomyopathy, hypertriglyceridemia, accelerated non-alcoholic fatty liver disease, renal dysfunction and insulin-resistant diabetes mellitus (DM). DM typically develop in childhood or adolescence. Dilated cardiomyopathy may arise in infancy. Clinical symptoms appear with great variability and severity. Several cases have been reported worldwide; however, diagnosis remains challenging. Case Description: We report an 8-year-and-11-month-old female diagnosed with ALMS who had a long history of obesity and amblyopia from infancy. We found high levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in this patient. She showed no hearing disfunction. Recently, she presented with sudden-onset insulin-resistant DM. Genetic analysis revealed the heterozygous mutations c.8366delT, p.L2789* and c.6829C>T, p.R2277*. c.8366delT, which results in premature protein termination, has not been reported previously in ALMS1. Although the patient's two sisters died of acute heart failure following infection at 4 and 14 months respectively, she showed no signs of cardiomyopathy until now. Conclusions: This case provides an unusual cause of genetic syndrome associated with diabetes. A detailed medical history, physical examination and appropriate gene analysis are critical for diagnosis. Our case identifies a novel ALMS1 mutation and reaffirms the great clinical variation of this disease even within families.
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Aconiti Kusnezoffii Radix (Caowu) is often combined or processed with Chebulae Fructus (Hezi) to achieve attenuation purposes in Mongolian medicine. Mesaconitine (MA), a main bioactive ingredient of Caowu, is also famous for its high cardiotoxicity while exerting good anti-inflammatory and analgesic properties. Gallic acid (GA), one of the leading chemical components in Hezi, possesses cardiac protection. This study aimed to clarify the detoxification effects of GA from Hezi on MA-induced cardiotoxicity and whether the detoxification mechanism is related to the TRPV1 channel. Cell viability was determined by methyl thiazol tetrazolium (MTT), and lactate dehydrogenase (LDH) leakage rate was determined by ELISA. Hoechst 33258, JC-1, DCFH-DA, and Fluo-3 AM staining were conducted to detect apoptosis, mitochondrial membrane potential, reactive oxygen species (ROS), and Ca2+ respectively; TRPV1 channel current was recorded by whole-cell patch-clamp technology to observe the effect of GA and MA alone or in combination on TRPV1 channel. The results showed that GA exhibited pronounced detoxification effects on MA-induced cardiotoxicity. GA significantly inhibited the MA-induced decrease in cell viability; suppressed the MA-induced LDH leakage rate, apoptosis, and the release of ROS and Ca2+; and alleviated the reduction of mitochondrial membrane potential. We found that MA-induced cardiotoxicity was significantly attenuated in H9c2 cells pretreated with the TRPV1 antagonist BCTC. In the whole-cell patch-clamp experiment, the TRPV1 channel current increase was caused by the GA and MA treatment, whereas it was reduced by the cotreatment of GA and MA. Our data demonstrate that GA in Hezi can reduce MA-induced cardiotoxicity by inhibiting intracellular Ca2+ influx, restoring mitochondrial membrane potential, and reducing apoptosis. The detoxification mechanism may be related to the desensitization of the TRPV1 channel by the combined application of MA and GA.
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OBJECTIVE: Two brothes with Seckel's syndrome 1(SCKL1) were reported and a literature review was carried to provide clinical and genetic information of this rare disease. METHODS: Clinical data of the two children were collected, and the peripheral blood was extracted for whole exome sequencing. Literature of the disease were reviewed. RESULTS: The two patients were 11 years and 9.5 years old when examined for short stature. They presented with intrauterine growth retardation, intellectual disability, microcephaly, birdhead-like face and coffee au lait spots. The bone age was more than 2 years behind the chronical age and the growth hormone levels were normal. Whole exome sequencing revealed novel compound heterozygous variants c.1A>G (p.M1?) and c.4853-18A>G of ART gene in both children. CONCLUSION: Children with prenatal onset short stature, developmental delay, microcephaly and special facial featuresshould be considered for the possibility of Seckel's syndrome, whole exome sequencing could help to confirm the clinical diagnosis.