Nuciferine analogs block voltage-gated sodium, calcium and potassium channels to regulate the action potential and treat arrhythmia.

Dysfunction of the Nav1.5, Cav1.2, and Kv channels could interfere with the AP and result in arrhythmias and even heart failure. We herein present a novel library of nuciferine analogs that target ion channels for the treatment of arrhythmias. Patch clamp measurements of ventricular myocytes revealed that 6a dramatically blocked both the INa and ICa without altering the currentvoltage relationship (including the activation potential and peak potential), accelerated the inactivation of Nav and Cav channels and delayed the resurrection of these channels after inactivation. Additionally, 6a significantly decreased the APA and RMP without affecting the APD30 or APD50. The IC50 values of 6a against Nav1.5 and Cav1.2 were 4.98 µM and 4.62 µM, respectively. Furthermore, 6a (10 µM) blocked IKs, IK1, and Ito with values of 17.01 %±2.54 %, 9.09 %±2.78 %, and 11.15 %±3.52 %, respectively. Surprisingly, 6a weakly inhibited hERG channels, suggesting a low risk of proarrhythmia. The cytotoxicity evaluation of 6a with the H9c2 cell line indicated that this compound was noncytotoxic. In vivo studies suggested that these novel nuciferine analogs could shorten the time of arrhythmia continuum induced by BaCl2 and normalize the HR, QRS, QT and QTc interval and the R wave amplitude. Moreover, 6a dose-dependently affected aconitine-induced arrhythmias and notably improved the cumulative dosage of aconitine required to evoke VP, VT, VF and CA in rats with aconitine-induced arrhythmia. In conclusion, nuciferine analogs could be promising ion channel blockers that could be further developed into antiarrhythmic agents.

Amaranth Plants with Various Color Phenotypes Recruit Different Soil Microorganisms in the Rhizosphere.

To explore and utilize the abundant soil microorganisms and their beneficial functions, high-throughput sequencing technology was used to analyze soil microbial compositions in the rhizosphere of red and green amaranth varieties. The results showed that significant differences in soil microbial composition could be found in the rhizosphere of amaranth plants with different color phenotypes. Firstly, soil bacterial compositions in the rhizosphere were significantly different between red and green amaranths. Among them, Streptomyces, Pseudonocardia, Pseudolabrys, Acidibacter, norank_ f_ Micropepsaceae, Bradyrhizobium, and Nocardioides were the unique dominant soil bacterial genera in the rhizosphere of red amaranth. In contrast, Conexibacter, norank_f_norank_o_norank_c_TK10, and norank_f_ norank_o_ norank_ c_AD3 were the special dominant soil bacterial genera in the rhizosphere of green amaranth. Additionally, even though the soil fungal compositions in the rhizosphere were not significantly different between red and green amaranths, the abundance of the dominant soil fungal genera in the rhizosphere showed significant differences between red and green amaranths. For example, unclassified_k__Fungi, Fusarium, Cladophialophora, unclassified_c__Sordariomycetes and unclassified_p__Chytridiomycota significantly enriched as the dominant soil fungal genera in the rhizosphere of the red amaranth. In contrast, Aspergillues only significantly enriched as the dominant soil fungal genus in the rhizosphere of green amaranth. All of the above results indicated that amaranth with various color phenotypes exactly recruited different microorganisms in rhizosphere, and the enrichments of soil microorganisms in the rhizosphere could be speculated in contributing to amaranth color formations.

Parental Patterns of Alcohol Consumption During the COVID-19 Pandemic: Scoping Review.

BACKGROUND: The declaration of the COVID-19 pandemic led to public health restrictions that impacted the lives of people across the globe. Parents were particularly burdened with balancing multiple responsibilities, such as working from home while caring for and educating their children. Alcohol use among parents is an area that warrants further exploration. OBJECTIVE: This study aimed to investigate patterns of parental alcohol consumption during the COVID-19 pandemic, focusing on relative changes in the frequency and quantity of alcohol use compared to prepandemic use, nonparent adult samples, or both. METHODS: A scoping review informed by the methodology of Arksey and O'Malley explored patterns of parental alcohol consumption during the COVID-19 pandemic. Searches were conducted in CINAHL, Ovid MEDLINE, PsycINFO, and Web of Science. Search terms were created using the Joanna Briggs Institute framework of Population, Concept, and Context, with the population being parents and the concept being alcohol consumption during the COVID-19 pandemic. RESULTS: The database search yielded 3568 articles, which were screened for eligibility. Of the 3568 articles, 40 (1.12%) met the inclusion criteria and were included in the scoping review. Findings indicated the following: (1) having children at home was a factor associated with parental patterns of alcohol use; (2) mixed findings regarding gender-related patterns of alcohol consumption; and (3) linkages between parental patterns of alcohol use and mental health symptoms of stress, depression, and anxiety. CONCLUSIONS: This scoping review revealed heterogeneous patterns in parental alcohol use across sociocultural contexts during the COVID-19 pandemic. Given the known harms of alcohol use, it is worthwhile for clinicians to assess parental drinking patterns and initiate conversations regarding moderation in alcohol use.

Long-term efficacy and safety of PEGylated recombinant human growth hormone in treating Chinese children with growth hormone deficiency: a 5-year retrospective study.

OBJECTIVES: The study endeavored to evaluate the prolonged efficacy and safety of PEGylated rhGH (PEG-rhGH) administration in Chinese children diagnosed with growth hormone deficiency (GHD) over a 5-year period. METHODS: A retrospective analysis was conducted on children with GHD, who received a 0.2 mg/kg/week dose of PEG-rhGH between 2016 and 2023 in our department. RESULTS: The height standard deviation score (Ht SDS) exhibited a marked elevation post-PEG-rhGH administration (p<0.001), sustaining this enhancement beyond year 3, with increments recorded at 0.94±0.37, 1.49±0.48, 1.77±0.51, 2.12±0.65, and 2.15±0.58 across 5 years. Similarly, the height velocity (HV), insulin-like growth factor-1 standard deviation score (IGF-1 SDS), and bone age to chronological age ratio (BA/CA ratio) underwent significant augmentations (p<0.01). Remarkably, no signs of rapid bone maturation were detected during the 5-year observation. Among the participants, 31 patients (59.62 %) experienced adverse events, of which eight instances (15.38 %) were classified as treatment-related adverse events, but none were severe or unexpected. Additionally, high-density lipoprotein (HDL) levels rose while low-density lipoprotein (LDL) levels fell, both remaining within the standard range throughout the treatment phase. CONCLUSIONS: Administering PEG-rhGH at a dosage of 0.2 mg/kg/week proved both effective and well-tolerated in treating prepubertal children with GHD. This regimen also demonstrated positive impacts on lipid metabolism over an extended treatment period.

An Indocyanine Green-Based Nanoprobe for In Vivo Detection of Cellular Senescence.

There is an urgent need to improve conventional cancer-treatments by preventing detrimental side effects, cancer recurrence and metastases. Recent studies have shown that presence of senescent cells in tissues treated with chemo- or radiotherapy can be used to predict the effectiveness of cancer treatment. However, although the accumulation of senescent cells is one of the hallmarks of cancer, surprisingly little progress has been made in development of strategies for their detection in vivo. To address a lack of detection tools, we developed a biocompatible, injectable organic nanoprobe (NanoJagg), which is selectively taken up by senescent cells and accumulates in the lysosomes. The NanoJagg probe is obtained by self-assembly of indocyanine green (ICG) dimers using a scalable manufacturing process and characterized by a unique spectral signature suitable for both photoacoustic tomography (PAT) and fluorescence imaging. In vitro, ex vivo and in vivo studies all indicate that NanoJaggs are a clinically translatable probe for detection of senescence and their PAT signal makes them suitable for longitudinal monitoring of the senescence burden in solid tumors after chemotherapy or radiotherapy.

Efficacy and safety of leuprorelin 3-month depot (11.25 mg) for idiopathic central precocious puberty treatment of Chinese girls: a single-center retrospective study.

OBJECTIVES: This study aimed to evaluate the efficacy and safety of 3-month leuprorelin acetate (3-month LA, 11.25 mg) for the treatment of idiopathic central precocious puberty (ICPP) in Chinese girls. METHODS: We conducted a single-center retrospective study in China on 28 girls with ICPP who received at least one year of 3-month LA treatment. Data from anthropometry, biochemistry, bone age (BA), and pelvic ultrasonography were assessed before and every 6 months during medication. RESULTS: At CPP diagnosis, the mean chronological age (CA) was 7.8±0.8 years, with bone age advancement (BA-CA) of 1.5±0.8 years. After treatment initiation, growth velocity decreased significantly from 8.5±1.6 cm/year to 5.8±1.1 cm/year at month 12 (p<0.001). GnRH-stimulated peak LH ≤3IU/L, the primary efficacy criterion, was observed in 27 out of 28 (96.4 %) children at month 3. Basal estradiol <20 pg/mL was achieved by all 28 girls (100 %) at month 6 and remained stable at month 12. Basal follicle-stimulating hormone (FSH) decreased from 4.1±3.5 to 1.7±0.9 (p<0.001), and basal LH was also significantly reduced from 3.3±6.5 to 0.7±0.8 (p=0.035) at month 12. The mean predicted adult height (PAH) at treatment initiation was 152.7±5.8 cm, it increased significantly to 157.5±5.5 cm (p=0.007) after one-year treatment. Pubertal development was slowed in most patients, and in some cases, it was even reversed. Only one patient (3.6 %) reported local intolerance. CONCLUSIONS: Three-month leuprorelin acetate is a safe and effective treatment for suppressing the pituitary-gonadal axis and restoring impaired adult height in Chinese girls.

Chemical characterization and source attribution of organic pollutants in industrial wastewaters from a Chinese chemical industrial park.

Accelerated urbanization and industrialization have led to an alarming increase in the generation of wastewater with complex chemical contents. Industrial wastewaters are often a primary source of water contamination. The chemical characterization of different industrial wastewater types is an essential task to interpret the chemical fingerprints of wastewater to identify pollution sources and develop efficient water treatment strategies. In this study, we conduct a non-target chemical analysis for the source characterization of different industrial wastewater samples collected from a chemical industrial park (CIP) located in southeast China. The chemical screening identified volatile and semi-volatile organic compounds that included dibutyl phthalate at a maximum concentration of 13.4 µg/L and phthalic anhydride at 35.9 µg/L. Persistent, mobile, and toxic (PMT) substances among the detected organic compounds were identified and prioritized as high-concern contaminants given their impact on drinking water resources. Moreover, a source analysis of the wastewater collected from the wastewater outlet station indicated that the dye production industry contributed the largest quantities of toxic contaminates (62.6%), and this result was consistent with the ordinary least squares and heatmap results. Thus, our study utilized a combined approach of a non-target chemical analysis, a pollution source identification method, and a PMT assessment of different industrial wastewater samples collected from the CIP. The results of the chemical fingerprints of different industrial wastewater types as well as the results of the PMT assessment benefit risk-based wastewater management and source reduction strategies.

ZnO@Carbon Dot Nanoparticles Stimulating the Antibacterial Activity of Polyvinylidene Fluoride-Hexafluoropropylene with a Higher Electroactive Phase for Multifunctional Devices.

To further advance the application of flexible piezoelectric materials in wearable/implantable devices and robot electronic skin, it is necessary to endow them with a new function of antibacterial properties and with higher piezoelectric performance. Introducing a specially designated nanomaterial based on the nanocomposite effect is a feasible strategy to improve material properties and achieve multifunctionalization of composites. In this paper, carbon dots (CDs) were sensitized onto the surface of ZnO to form ZnO@CDs nanoparticles, which were then incorporated into polyvinylidene fluoride-hexafluoropropylene (PVDF-HFP) to obtain a multifunctional composite. On the one hand, the antibacterial property of ZnO was improved because CDs had good optical absorption of visible light and their surface functional groups were favorable for electrostatic adsorption with bacteria. Therefore, ZnO@CDs endowed the composite with an outstanding antibacterial rate of 69.1% for Staphylococcus aureus. On the other hand, CDs played a bridging role between ZnO and PVDF-HFP, reducing the negative effect of ZnO aggregation and interface incompatibility with PVDF-HFP. As a result, ZnO@CDs induced ß-phase formation of 80.4% in PVDF-HFP with a d33 value of 33.8 pC N-1. The multifunctional device exhibited excellent piezoelectric and antibacterial performance in the application of energy harvesters and self-powered pressure sensors.

Efficacy and Safety of 8 spheres Plus Cisplatin Versus Vinorelbine Plus Cisplatin in Locally Advanced Non-small Cell Lung Cancer.

Background: This study evaluated the efficacy and safety between 8 spheres plus bronchial arterial infusion (BAI) cisplatin and intravenous vinorelbine plus cisplatin as third-line treatments in locally advanced non-small cell lung cancer (NSCLC) patients. Materials and Methods: Totally, 56 locally advanced NSCLC patients with second-line chemotherapy failure were recruited. Then, 28 patients received 8 spheres plus BAI cisplatin treatment, and another 28 patients received intravenous vinorelbine plus cisplatin treatment. Results: In general, 8 spheres plus BAI cisplatin increased objective response rate (57.2% vs. 17.8%, p = 0.002) and disease control rate (78.6% vs. 42.8%, p = 0.003) compared with intravenous vinorelbine plus cisplatin; meanwhile, it also elevated quality of life (QOL) score (46.7 ± 7.1 vs. 41.5 ± 5.2, p = 0.003) compared with intravenous vinorelbine plus cisplatin. Furthermore, 8 spheres plus BAI cisplatin prolonged progression-free survival (PFS) (median [95% confidence interval, CI]: 7.9 [6.3-9.5] months vs. 4.3 [3.5-5.1] months, p < 0.001) and overall survival (OS) (median [95% CI]: 14.6 [11.0-18.2] months vs. 10.5 [10.2-10.8] months, p = 0.029) compared with intravenous vinorelbine plus cisplatin, which was further supported by multivariate Cox's regression analysis (PFS: p < 0.001; OS: p = 0.007). In addition, subgroup analyses revealed that 8 spheres plus BAI cisplatin markedly elevated treatment response, QOL, and survival compared with intravenous vinorelbine plus cisplatin in squamous cell carcinoma patients, but not in adenomatous carcinoma and adenosquamous carcinoma patients. Regarding safety, 8 spheres plus BAI cisplatin exhibited lower rates of gastrointestinal tract complication (p < 0.001) and myelosuppression (p < 0.001) than intravenous vinorelbine plus cisplatin. Conclusions: 8 spheres plus BAI cisplatin displays good efficacy and well-tolerated safety profiles in locally advanced NSCLC patients with second-line chemotherapy failure.

Clinical application of artificial intelligence in longitudinal image analysis of bone age among GHD patients.

Objective: This study aims to explore the clinical value of artificial intelligence (AI)-assisted bone age assessment (BAA) among children with growth hormone deficiency (GHD). Methods: A total of 290 bone age (BA) radiographs were collected from 52 children who participated in the study at Sun Yat-sen Memorial Hospital between January 2016 and August 2017. Senior pediatric endocrinologists independently evaluated BA according to the China 05 (CH05) method, and their consistent results were regarded as the gold standard (GS). Meanwhile, two junior pediatric endocrinologists were asked to assessed BA both with and without assistance from the AI-based BA evaluation system. Six months later, around 20% of the images assessed by the junior pediatric endocrinologists were randomly selected to be re-evaluated with the same procedure half a year later. Root mean square error (RMSE), mean absolute error (MAE), accuracy, and Bland-Altman plots were used to compare differences in BA. The intra-class correlation coefficient (ICC) and one-way repeated ANOVA were used to assess inter- and intra-observer variabilities in BAA. A boxplot of BA evaluated by different raters during the course of treatment and a mixed linear model were used to illustrate inter-rater effect over time. Results: A total of 52 children with GHD were included, with mean chronological age and BA by GS of 6.64 ± 2.49 and 5.85 ± 2.30 years at baseline, respectively. After incorporating AI assistance, the performance of the junior pediatric endocrinologists improved (P < 0.001), with MAE and RMSE both decreased by more than 1.65 years (Rater 1: ΔMAE = 1.780, ΔRMSE = 1.655; Rater 2: ΔMAE = 1.794, ΔRMSE = 1.719), and accuracy increasing from approximately 10% to over 91%. The ICC also increased from 0.951 to 0.990. During GHD treatment (at baseline, 6-, 12-, 18-, and 24-months), the difference decreased sharply when AI was applied. Furthermore, a significant inter-rater effect (P = 0.002) also vanished upon AI involvement. Conclusion: AI-assisted interpretation of BA can improve accuracy and decrease variability in results among junior pediatric endocrinologists in longitudinal cohort studies, which shows potential for further clinical application.

Indicators of glucose dysregulation and the relationship with iron overload in Chinese children with beta thalassemia major.

INTRODUCTION: Patients with beta thalassemia major (TM) have a higher risk of diabetes and an abnormal oral glucose tolerance test (OGTT), but there is no single agree monitoring parameter that reflects glycemic status. The possible mechanisms include iron overload and blood transfusion, but they require further investigation. PURPOSE: This study explored the role of glycated hemoglobin A1c (HbA1c), fructosamine, and glycated albumin (GA) in evaluating the glucose dysregulation and to determine the potential relationship between iron deposition and glucose metabolism disorder in beta TM. METHODS: A cross-sectional study was performed on 118 patients with beta TM and the control group consisted of 33 healthy children with no statistical differences in age, sex, and body mass index (BMI). Fast plasma glucose (FPG), fast insulin (FINS), insulin resistance index (HOMA-IRI), and insulin sensitivity index (HOMA-ISI) were compared between the patient and control groups. HbA1c, GA, fructosamine, and serum ferritin (SF) were measured in the patient group. OGTT, as well as heart and liver magnetic resonance imaging (MRI) T2*, was performed. For all statistical analyses, SPSS 21.0 was used and p < 0.05 was accepted as statistically significant. RESULTS: FPG, FINS, and HOMA-IRI were significantly increased while HOMA-ISI decreased in the beta TM patients when compared with those in the control group. In patients with beta TM, 17 (14.41%) of patients had been diagnosed with diabetes, while 48 (40.68%) had both impaired fasting glucose and impaired glucose tolerance. HbA1c, GA, and fructosamine were increased according to the degree of abnormal glucose metabolism. Statistically significant differences were found in age, SF, and cardiac T2* between the abnormal and normal OGTT groups. CONCLUSION: HbA1c may be used as a significant measure for monitoring glycemic levels in patients with beta TM. Furthermore, GA and fructosamine were alternative indicators of glucose status. Patients with heart iron deposition or an SF > 4000 µg/L were prone to abnormal glucose metabolism, so chelation therapy should be reinforced.

Structural and Optical Properties of Textured Silicon Substrates by Three-Step Chemical Etching.

We implemented the fabrication of hybrid structures, including pyramids, etching holes, and inverted pyramidal cavities on silicon substrates, by three-step chemical etching. To achieve this, we utilized anisotropic wet etching as the first-step etching to form pyramids of various sizes. Subsequently, metal-assisted chemical etching was performed to develop aligned etching holes on the pyramidal structure. Ultimately, anisotropic wet etching was used again as the third-step etching for the etchant to penetrate holes to form inverted pyramidal cavities. Optimizing the three-step etching treatments, large-scale textured structures with low reflectance could be obtained, and they show potential for applications in sensors, solar cells, photovoltaics, and surface-enhanced Raman scattering (SERS). Examples of using the textured silicon substrates for SERS applications were given.

Long non-coding RNA LUCAT1 promotes the progression of clear cell renal cell carcinoma via the microRNA-375/YAP1 axis.

Clear cell renal cell carcinoma (ccRCC) is a common renal cell carcinoma with a high mortality rate. Lung cancer-associated transcript 1 (LUCAT1) has been reported to be a potential biomarker of prognosis in human ccRCC. However, the underlying mechanism of the function of LUCAT1 in ccRCC remains poorly understood. The present study aimed to investigate the role and underlying mechanism of LUCAT1 in ccRCC. The expression level of LUCAT1, microRNA-375 (miR-375) and yes-associated protein 1 (YAP1) in ccRCC tissues and cells was detected by reverse transcription-quantitative PCR, and the protein level of YAP1 was detected by western blotting. The effects of LUCAT1 on cell proliferation, migration and invasion were analyzed using Cell Counting Kit-8 and Transwell assays. The association between miR-375 and LUCAT1 or miR-375 and YAP1 was predicted by lncBase Predicted v.2 or TargetScan and verified using dual-luciferase reporter assay. The effect of LUCAT1 on ccRCC progression in vivo was evaluated using a xenograft tumor model. The results revealed that LUCAT1 and YAP1 were upregulated and miR-375 was downregulated in ccRCC tissues and cells. LUCAT1 knockdown suppressed cell proliferation, migration and invasion, which were reversed by the inhibition of miR-375. In addition, YAP1 overexpression attenuated the inhibitory effects of miR-375 overexpression on cell proliferation, migration and invasion. Subsequent experiments suggested that LUCAT1 regulated YAP1 expression by sponging miR-375. Therefore, LUCAT1 exerted its role by regulating the miR-375/YAP1 axis in vitro. Moreover, LUCAT1 knockdown suppressed the growth of ccRCC xenograft tumors in vivo. These results collectively revealed that LUCAT1 promoted the proliferation, migration and invasion of ccRCC by the upregulation of YAP1 via sponging miR-375, which may be used as a potential therapeutic target for ccRCC.

Evaluating DNA damage response through immunofluorescence staining of primordial germ cells in Caenorhabditis elegans L1 larva.

C. elegans L1 larvae have two well-defined primordial germ cells embedded in a niche comprising two somatic gonad precursor cells. Thus, C. elegans provides an ideal model for studying intercellular signaling in response to DNA damage. However, existing staining protocols are focused on worms in later developmental stages and are not optimized for the L1 larvae. Here, we present a revised protocol for assessing the DNA damage response utilizing immunofluorescence staining specifically in C. elegans L1 larva. For complete details on the use and execution of this protocol, please refer to Ou et al. (2019).

Cellular senescence in cancer: from mechanisms to detection.

Senescence refers to a cellular state featuring a stable cell-cycle arrest triggered in response to stress. This response also involves other distinct morphological and intracellular changes including alterations in gene expression and epigenetic modifications, elevated macromolecular damage, metabolism deregulation and a complex pro-inflammatory secretory phenotype. The initial demonstration of oncogene-induced senescence in vitro established senescence as an important tumour-suppressive mechanism, in addition to apoptosis. Senescence not only halts the proliferation of premalignant cells but also facilitates the clearance of affected cells through immunosurveillance. Failure to clear senescent cells owing to deficient immunosurveillance may, however, lead to a state of chronic inflammation that nurtures a pro-tumorigenic microenvironment favouring cancer initiation, migration and metastasis. In addition, senescence is a response to post-therapy genotoxic stress. Therefore, tracking the emergence of senescent cells becomes pivotal to detect potential pro-tumorigenic events. Current protocols for the in vivo detection of senescence require the analysis of fixed or deep-frozen tissues, despite a significant clinical need for real-time bioimaging methods. Accuracy and efficiency of senescence detection are further hampered by a lack of universal and more specific senescence biomarkers. Recently, in an attempt to overcome these hurdles, an assortment of detection tools has been developed. These strategies all have significant potential for clinical utilisation and include flow cytometry combined with histo- or cytochemical approaches, nanoparticle-based targeted delivery of imaging contrast agents, OFF-ON fluorescent senoprobes, positron emission tomography senoprobes and analysis of circulating SASP factors, extracellular vesicles and cell-free nucleic acids isolated from plasma. Here, we highlight the occurrence of senescence in neoplasia and advanced tumours, assess the impact of senescence on tumorigenesis and discuss how the ongoing development of senescence detection tools might improve early detection of multiple cancers and response to therapy in the near future.

Gender roles and behavioral problems in children with 21-hydroxylase deficiency in Southern China.

PURPOSE: To assess the gender roles and behavioral outcomes in children with 21-hydroxylase deficiency (21-OHD) in Southern China. METHODS: A total of 50 individuals with 21-OHD participated in our study, (30 boys and 20 girls), as well as another 19 age-matched non-affected relatives of patients (12 boys and 7 girls). Psychological adjustment was assessed with a preschool activity survey and a Conner parent symptom questionnaire was modified for retrospective reporting. RESULTS: The response rate of the questionnaire in the control group was only 36.5%. All the patients were diagnosed with salt-wasting of 21-OHD. Our study revealed that the masculine score was higher in male patients with 21-OHD than male controls and female patients. Compared with that in the female 21-OHD patient group, the masculine score in the female control group was lower, while comparative masculinization was found in the male controls. Regarding behavioral problems, there was a higher incidence of parent-reported problems among children with 21-OHD than controls, including conduct problems, impulsive hyperactivity, anxiety, and hyperactivity index. CONCLUSION: Parents of 21-OHD patients in Southern China were unwilling to disclose the condition of their children to the society. Masculinization and behavioral problems were prevalent among patients with 21-OHD, which highlighted the importance of psychological and social support for 21-OHD patients and their families.

Upregulation of cervical carcinoma expressed PCNA regulatory long non-coding RNA promotes esophageal squamous cell carcinoma progression.

Cervical carcinoma expressed PCNA regulatory long non-coding (lnc)RNA (CCEPR) has recently been reported to play oncogenic roles in some common types of human cancer. However, the clinical significance of CCEPR mRNA expression levels in esophageal squamous cell carcinoma (ESCC) and the exact function of CCEPR in regulating the malignant phenotypes of ESCC cells have not been previously investigated. In the present study, CCEPR mRNA expression level was upregulated in ESCC tissues and cell lines, and overexpression of CCEPR was associated with advanced TNM stage, lymph node metastasis, and poor prognosis in ESCC. In vitro experiments showed that silencing CCEPR mRNA expression levels significantly suppressed the proliferation, migration, and invasion of ESCC cells, while inducing ESCC cell apoptosis. Furthermore, inhibition of CCEPR decreased the protein expression levels of matrix metalloproteinase (MMP)2 and MMP9 and inhibited epithelial-mesenchymal transition in ESCC cells. In conclusion, the results showed that CCEPR plays an oncogenic role in ESCC and suggests that CCEPR could be used as a potential therapeutic target for ESCC treatment.

A long lasting sunscreen controversy of 4-aminobenzoic acid and 4-dimethylaminobenzaldehyde derivatives resolved by ultrafast spectroscopy combined with density functional theoretical study.

4-Aminobenzoic acid (PABA) is one of the earliest patented and most commonly used sunscreen components. There is however a long-lasting controversy on its photo-protective efficacy owing to the lack of information on its protolytic equilibrium and photo-dynamics after absorption of ultraviolet radiation in physiologically relevant aqueous solution. The excitation dynamics in water also remains largely unknown for analogs of PABA such as 4-dimethylaminoacetophenone (DMAAP) and 4-dimethylaminobenzaldehyde (DMABA) which are recognized as prototypes for photo-induced twisted intramolecular charge transfer (TICT). Herein we report a combined application of femtosecond broadband time-resolved fluorescence and transient absorption coupled with density functional theoretical study for PABA, DMAAP, and DMABA under several solvent conditions with representative properties in terms of the pH, polarity and hydrogen bonding capacity. The results we gained demonstrate that, in a neutral aqueous solution, PABA taking the deprotonated anion form in the ground state undergoes rapid protonation after excitation, producing excited state species in the neutral form that may shift effectively by intersystem crossing (ISC) to the long-lasting triplet state capable of damaging nucleic acids. This provides evidence at the molecular level for the detrimental effect of PABA if used as a sunscreen ingredient. In contrast, our investigation on DMAAP and DMABA unveils an unusual solvent controlled deactivation dynamics rendered by the participation of the carbonyl oxygen associated nOπ* state featuring energy and structure strongly responsive to solvent properties. In particular, these molecules in water exhibit solute-solvent hydrogen bonding at the sites of the carbonyl oxygen and the amino nitrogen which is, respectively, weakened and strengthened after the excitation, leading to state reversal and formation of a nOπ* state with a peculiar non-planar structure. This quenches strongly the excitation, eliminates the TICT, suppresses the ISC and opens up the otherwise inaccessible internal conversion (IC) to account for ∼80% of the entire deactivation. The IC, observed to proceed at a rate of ∼2.5 ps, allows the effective recovery of the ground state, providing substantial protection against ultraviolet irradiation. Moreover, the revelation of highly solvent sensitive fluorescence emission from DMABA and DMAAP implies the potential application of these molecules as the functional element in the design of sensory materials for probing the polarity and hydrogen bonding character of the surrounding environment.

Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity.

Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence-associated lysosomal ß-galactosidase (SA-ß-gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose-encapsulated nanoparticles within these cells. Here, we show that galacto-conjugation of the BCL-2 family inhibitor Navitoclax results in a potent senolytic prodrug (Nav-Gal), that can be preferentially activated by SA-ß-gal activity in a wide range of cell types. Nav-Gal selectively induces senescent cell apoptosis and has a higher senolytic index than Navitoclax (through reduced activation in nonsenescent cells). Nav-Gal enhances the cytotoxicity of standard senescence-inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav-Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto-conjugation reduces Navitoclax-induced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopenia at therapeutically effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.

An Efficient Probe of Cyclometallated Phosphorescent Iridium Complex for Selective Detection of Cyanide.

A cyclometallated phosphorescent iridium-based probe to detect CN- was prepared through a cyanide alcoholize reaction based on the C^N type main ligand and N^N type ancillary ligand (2-phenyl pyridine and 1,10-phenanthroline-5-carboxaldehyde, respectively). The efficient probe exhibited good sensitivity in response to CN- in an CH3CN and H2O (95/5) mixture within a 1.23 µM detection limit. The response of PL is directly in line with the concentration of CN- from 0 to 2.0 equiv. The PL investigation of other reactive anions proved the great selectivity to CN-. Additionally, upon adding 1.0 equiv. of cyanide, the formation of cyanohydrin was correctly elucidated in 1H NMR, FT-IR, and mass spectra studies. The conspicuous results indicate that the iridium complex has the potential possibility of application in other biosystems related to CN-.