Identification of the central role of RNA polymerase mitochondrial for angiogenesis.

Mitochondria are central to endothelial cell activation and angiogenesis, with the RNA polymerase mitochondrial (POLRMT) serving as a key protein in regulating mitochondrial transcription and oxidative phosphorylation. In our study, we examined the impact of POLRMT on angiogenesis and found that its silencing or knockout (KO) in human umbilical vein endothelial cells (HUVECs) and other endothelial cells resulted in robust anti-angiogenic effects, impeding cell proliferation, migration, and capillary tube formation. Depletion of POLRMT led to impaired mitochondrial function, characterized by mitochondrial depolarization, oxidative stress, lipid oxidation, DNA damage, and reduced ATP production, along with significant apoptosis activation. Conversely, overexpressing POLRMT promoted angiogenic activity in the endothelial cells. In vivo experiments demonstrated that endothelial knockdown of POLRMT, by intravitreous injection of endothelial specific POLRMT shRNA adeno-associated virus, inhibited retinal angiogenesis. In addition, inhibiting POLRMT with a first-in-class inhibitor IMT1 exerted significant anti-angiogenic impact in vitro and in vivo. Significantly elevated expression of POLRMT was observed in the retinal tissues of streptozotocin-induced diabetic retinopathy (DR) mice. POLRMT endothelial knockdown inhibited pathological retinal angiogenesis and mitigated retinal ganglion cell (RGC) degeneration in DR mice. At last, POLRMT expression exhibited a substantial increase in the retinal proliferative membrane tissues of human DR patients. These findings collectively establish the indispensable role of POLRMT in angiogenesis, both in vitro and in vivo.

Cross-modal conflict deficit in children with attention-deficit/hyperactivity disorder.

The difference between the audiovisual incongruent condition and the audiovisual congruent condition is known as cross-modal conflict, which is an important behavioral index to measure the conflict control function. Previous studies have found conflict control deficits in children with attention-deficit/hyperactivity disorder (ADHD), but it is not clear whether and how cross-modal conflict occurs in children with ADHD at different processing levels. The current study adopted the cross-modal matching paradigm to recruit 25 children with ADHD (19 boys and 6 girls) and 24 TD children (17 boys and 7 girls), aiming to investigate the cross-modal conflict effect at the perception and response levels of children with ADHD. The results showed that both groups of children showed significant cross-modal conflict, and there was no significant difference between the ADHD and TD groups in the number of error trials and mean response time. However, the cross-modal conflict effect caused by auditory distractors was different between the ADHD and TD groups; the TD group had stronger auditory conflict at the response level, whereas the ADHD group had weaker auditory conflict. This indicates that the ADHD group had a deficit of auditory conflict at the response level.

Enhancement of visual dominance effects at the response level in children with attention-deficit/hyperactivity disorder.

Previous studies have widely demonstrated that individuals with attention-deficit/hyperactivity disorder (ADHD) exhibit deficits in conflict control tasks. However, there is limited evidence regarding the performance of children with ADHD in cross-modal conflict processing tasks. The current study aimed to investigate whether children with ADHD have poor conflict control, which has an impact on sensory dominance effects at different levels of information processing under the influence of visual similarity. A total of 82 children aged 7 to 14 years, including 41 children with ADHD and 41 age- and sex-matched typically developing (TD) children, were recruited. We used the 2:1 mapping paradigm to separate levels of conflict, and the congruency of the audiovisual stimuli was divided into three conditions. In C trials, the target stimulus and the distractor stimulus were identical, and the bimodal stimuli corresponded to the same response keys. In PRIC trials, the distractor stimulus differed from the target stimulus and did not correspond to any response keys. In RIC trials, the distractor stimulus differed from the target stimulus, and the bimodal stimuli corresponded to different response keys. Therefore, we explicitly differentiated cross-modal conflict into a preresponse level (PRIC > C), corresponding to the encoding process, and a response level (RIC > PRIC), corresponding to the response selection process. Our results suggested that auditory distractors caused more interference during visual processing than visual distractors caused during auditory processing (i.e., typical auditory dominance) at the preresponse level regardless of group. However, visual dominance effects were observed in the ADHD group, whereas no visual dominance effects were observed in the TD group at the response level. A possible explanation is that the increased interference effects due to visual similarity and children with ADHD made it more difficult to control conflict when simultaneously confronted with incongruent visual and auditory inputs. The current study highlights how children with ADHD process cross-modal conflicts at multiple levels of information processing, thereby shedding light on the mechanisms underlying ADHD.

Seeing is believing: Larger Colavita effect in school-aged children with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that leads to visually relevant compensatory activities and cognitive strategies in children. Previous studies have identified difficulties with audiovisual integration in children with ADHD, but the characteristics of the visual dominance effect when processing multisensory stimuli are not clear in children with ADHD. The current study used the Colavita paradigm to explore the visual dominance effect in school-aged children with ADHD. The results found that, compared with typically developing children, children with ADHD had a higher proportion of "visual-auditory" trials and a lower proportion of "simultaneous" trials. The study also found that the proportion of visual-auditory trials in children with ADHD decreased as their Swanson, Nolan, and Pelham-IV rating scale (SNAP-IV) inattention scores increased. The results showed that school-aged children with ADHD had a larger Colavita effect, which decreased with the severity of inattentive symptoms. This may be due to an overreliance on visual information and an abnormal integration time window. The connection between multisensory cognitive processing performance and clinical symptoms found in the current study provides empirical and theoretical support for the knowledge base of multisensory and cognitive abilities in disorders.

Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury.

Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.

USP18 enhances the resistance of BRAF-mutated melanoma cells to vemurafenib by stabilizing cGAS expression to induce cell autophagy.

This study aims to discern the possible molecular mechanism of the effect of ubiquitin-specific peptidase 18 (USP18) on the resistance to BRAF inhibitor vemurafenib in BRAF V600E mutant melanoma by regulating cyclic GMP-AMP synthase (cGAS). The cancer tissues of BRAF V600E mutant melanoma patients before and after vemurafenib treatment were collected, in which the protein expression of USP18 and cGAS was determined. A BRAF V600E mutant human melanoma cell line (A2058R) resistant to vemurafenib was constructed with its viability, apoptosis, and autophagy detected following overexpression and depletion assays of USP18 and cGAS. Xenografted tumors were transplanted into nude mice for in vivo validation. Bioinformatics analysis showed that the expression of cGAS was positively correlated with USP18 in melanoma, and USP18 was highly expressed in melanoma. The expression of cGAS and USP18 was up-regulated in cancer tissues of vemurafenib-resistant patients with BRAF V600E mutant melanoma. Knockdown of cGAS inhibited the resistance to vemurafenib in A2058R cells and the protective autophagy induced by vemurafenib in vitro. USP18 could deubiquitinate cGAS to promote its protein stability. In vivo experimentations confirmed that USP18 promoted vemurafenib-induced protective autophagy by stabilizing cGAS protein, which promoted resistance to vemurafenib in BRAF V600E mutant melanoma cells. Collectively, USP18 stabilizes cGAS protein expression through deubiquitination and induces autophagy of melanoma cells, thereby promoting the resistance to vemurafenib in BRAF V600E mutant melanoma.

Cross-sectional study of characteristics of body composition of 24,845 children and adolescents aged 3-17 years in Suzhou.

BACKGROUND: We aimed to analyze the characteristics of the body composition of children and adolescents aged 3-17 in Suzhou, China. METHODS: A cross-sectional study between January 2020 and June 2022 using bioelectrical impedance was conducted to determine the fat mass (FM), fat-free mass (FFM), skeletal muscle mass, and protein and mineral contents of 24,845 children aged 3-17 who attended the Department of Child and Adolescent Healthcare, Children's Hospital of Soochow University, China. Measurement data was presented in tables as mean ± SD, and groups were compared using the independent samples t-test. RESULTS: FM and fat-free mass increased with age in both boys and girls. The fat-free mass of girls aged 14-15 decreased after reaching a peak, and that of boys in the same age group was higher than that of the girls (p < 0.05). There were no significant differences in FM between boys and girls younger than 9- and 10-years old. The percentage body fat (PBF) and FM index of girls increased rapidly between 11 and 15 years of age (p < 0.05), and those of boys aged 11-14 were significantly lower (p < 0.05), suggesting that the increase in body mass index (BMI) was mainly contributed by muscle mass (MM) in boys. CONCLUSIONS: The body composition of children and adolescents varies according to their age and sex. A misdiagnosis of obesity made on the basis of BMI alone can be avoided if BMI is used in combination with FM index, percentage body fat, and other indexes.

The mitochondrial protein TIMM44 is required for angiogenesis in vitro and in vivo.

The mitochondrial integrity and function in endothelial cells are essential for angiogenesis. TIMM44 (translocase of inner mitochondrial membrane 44) is essential for integrity and function of mitochondria. Here we explored the potential function and the possible mechanisms of TIMM44 in angiogenesis. In HUVECs, human retinal microvascular endothelial cells and hCMEC/D3 brain endothelial cells, silence of TIMM44 by targeted shRNA largely inhibited cell proliferation, migration and in vitro capillary tube formation. TIMM44 silencing disrupted mitochondrial functions in endothelial cells, causing mitochondrial protein input arrest, ATP reduction, ROS production, and mitochondrial depolarization, and leading to apoptosis activation. TIMM44 knockout, by Cas9-sgRNA strategy, also disrupted mitochondrial functions and inhibited endothelial cell proliferation, migration and in vitro capillary tube formation. Moreover, treatment with MB-10 ("MitoBloCK-10"), a TIMM44 blocker, similarly induced mitochondrial dysfunction and suppressed angiogenic activity in endothelial cells. Contrarily, ectopic overexpression of TIMM44 increased ATP contents and augmented endothelial cell proliferation, migration and in vitro capillary tube formation. In adult mouse retinas, endothelial knockdown of TIMM44, by intravitreous injection of endothelial specific TIMM44 shRNA adenovirus, inhibited retinal angiogenesis, causing vascular leakage, acellular capillary growth, and retinal ganglion cells degeneration. Significant oxidative stress was detected in TIMM44-silenced retinal tissues. Moreover, intravitreous injection of MB-10 similarly induced oxidative injury and inhibited retinal angiogenesis in vivo. Together, the mitochondrial protein TIMM44 is important for angiogenesis in vitro and in vivo, representing as a novel and promising therapeutic target of diseases with abnormal angiogenesis.

PIK3R2 predicts poor outcomes for patients with melanoma and contributes to the malignant progression via PI3K/AKT/NF-kB axis

Background Melanoma is an aggressive form of skin cancer worldwide. Phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) exerts carcinogenic roles in various tumors. So far, the function and mechanism of PIK3R2 in melanoma are not been fully clarified. Objective We aimed to clarify the role of PIK3R2 in melanoma. Methods PIK3R2 expressions in melanoma clinical tissues and melanoma cells were measured using quantitative real-time PCR and Western blot. In addition, PIK3R2 expressions in different tumor stages of melanoma were determined by immunohistochemistry assay. Meanwhile, PIK3R2 function was evaluated using loss or gain-of-function assays, Cell Counting Kit-8 assay, flow cytometry, and Transwell analysis. Furthermore, PIK3R2 mechanism in melanoma was assessed by a series of rescue experiments. Results PIK3R2 was highly expressed in melanoma tissues and cells, and PIK3R2 expressions were the highest in Stage IV. Functionally, PIK3R2 knockdown repressed melanoma cell proliferation, invasion, epithelial-mesenchymal transition, and facilitated cell apoptosis. Also, PIK3R2 overexpression produced an opposite trend. Mechanistically, PIK3R2 facilitated melanoma progression by activating PI3K/AKT/NF-κB pathway. Furthermore, PIK3R2 knockdown restrained the melanoma tumor growth in vivo. Conclusions PIK3R2 aggravated melanoma by activating PI3K/AKT/NF-κB pathway, prompting that PIK3R2 might be a therapeutic target for melanoma (AU)

PIK3R2 predicts poor outcomes for patients with melanoma and contributes to the malignant progression via PI3K/AKT/NF-κB axis.

BACKGROUND: Melanoma is an aggressive form of skin cancer worldwide. Phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) exerts carcinogenic roles in various tumors. So far, the function and mechanism of PIK3R2 in melanoma are not been fully clarified. OBJECTIVE: We aimed to clarify the role of PIK3R2 in melanoma. METHODS: PIK3R2 expressions in melanoma clinical tissues and melanoma cells were measured using quantitative real-time PCR and Western blot. In addition, PIK3R2 expressions in different tumor stages of melanoma were determined by immunohistochemistry assay. Meanwhile, PIK3R2 function was evaluated using loss or gain-of-function assays, Cell Counting Kit-8 assay, flow cytometry, and Transwell analysis. Furthermore, PIK3R2 mechanism in melanoma was assessed by a series of rescue experiments. RESULTS: PIK3R2 was highly expressed in melanoma tissues and cells, and PIK3R2 expressions were the highest in Stage IV. Functionally, PIK3R2 knockdown repressed melanoma cell proliferation, invasion, epithelial-mesenchymal transition, and facilitated cell apoptosis. Also, PIK3R2 overexpression produced an opposite trend. Mechanistically, PIK3R2 facilitated melanoma progression by activating PI3K/AKT/NF-κB pathway. Furthermore, PIK3R2 knockdown restrained the melanoma tumor growth in vivo. CONCLUSIONS: PIK3R2 aggravated melanoma by activating PI3K/AKT/NF-κB pathway, prompting that PIK3R2 might be a therapeutic target for melanoma.

Discovery of novel analogs of KHS101 as transforming acidic coiled coil containing protein 3 (TACC3) inhibitors for the treatment of glioblastoma.

Transforming acidic coiled coil containing protein 3 (TACC3) is emerging as an attractive anticancer target in recent years, however, few TACC3 small-molecular inhibitors have been reported up to now. In this study, fifteen compounds were designed and synthesized based on the lead compound KHS101 to find more potent TACC3 inhibitors. Among them, the most potent compound 7g exhibited about 10-folds more potent antiproliferative activities than KHS101 in various cancer cell lines. Two different protein-drug binding assays including DARTS, and CETSA revealed TACC3 as a biologically relevant target of compound 7g. In addition, compound 7g induced cell cycle arrest at the G2/M phase and induced cell apoptosis. Furthermore, compound 7g depolarized the MMP and induced ROS generation in a dose-dependent manner in U87 cells. More importantly, 7g reduced tumor weight by 72.7% in U87 xenograft model at a dose of 20 mg/kg/day without obvious toxicity. Altogether, compound 7g deserved further investigations as a novel, safe and efficacious TACC3 inhibitor for the treatment of GBM.

Body composition in preschool children with short stature: a case-control study.

BACKGROUND: Short stature is defined as height below 2 standard deviations of the population with the same age, gender. This study is aimed to assess the characteristics of body composition in preschool children with short stature. METHODS: Anthropometric measurements and body composition were assessed in 68 preschool children aged 3 to 6 years old with short stature and 68 normal controls matched on age and gender. Height, weight and body composition (total body water, protein, minerals, body fat mass, fat-free mass, soft lean mass, skeletal muscle mass, and bone mineral contents) in the two groups were measured and compared. RESULTS: The total body water, protein, minerals, body fat mass, fat-free mass, soft lean mass, skeletal muscle mass, and bone mineral contents were lower in preschool children with short stature than controls (P < 0.05). Body mass index and fat mass index did not differ between groups. Fat-free mass index was significantly lower in short stature group than controls (t = 2.17, P = 0.03). Linear regression analysis showed that there was a positive correlation between height and fat-free mass index [ß, 1.99 (0.59, 3.39), P = 0.01], a negative correlation between height and body fat percentage [ß, - 0.20 (- 0.38, - 0.01), P = 0.04]. The proportions of fat-free mass in the upper limbs were significantly lower (Right,t = - 2.78,Left t = - 2.76, P < 0.05, respectively) in short stature, although body fat distribution was not. CONCLUSIONS: The fat-free mass such as protein and bone minerals is lower in preschool children with short stature, suggesting the monitoring of fat-free mass for early identification and intervention.

WNT signaling modulates chemoresistance to temozolomide in p53-mutant glioblastoma multiforme.

Glioblastoma multiforme (GBM) has been characterized by the high incidence, therapy tolerance and relapse. The molecular events controlling GBM resistant to chemotherapy temozolomide (TMZ) remain to be elusive. Here, we identified WNT signaling was amplified by TMZ and mediated drug response in GBM. We found O6-methylguanine DNA methyltransferase (MGMT) was redundant to WNT-mediated chemoresistance, which was highly associated with p53 mutation status. In GBM with p53 mutation, loss of function of p53 downregulated miR-34a expression, which represses transcription of WNT ligand 6 (WNT6) by directly binding to 3' UTR of WNT6 mRNA, leading to activation of WNT signaling, and the eventual WNT-mediated chemoresistance to TMZ. Combined treatment of TMZ with WNT inhibitor or miR34a mimic induced drug sensitivity of p53-mutant GBM cells and extended survival in xenograft mice in vivo. Our findings provide insight into understanding the molecular mechanism of GBM chemoresistance to TMZ and facilitating to develop novel treatment strategy to combat p53-mutant GBM by targeting miR-34a/WNT6 axis.

Ginsenoside Rg1 Attenuates Premature Ovarian Failure of D-gal Induced POF Mice Through Downregulating p16INK4a and Upregulating SIRT1 Expression.

BACKGROUND: Premature ovarian failure (POF) refers to pathological amenorrhea before 40 years. OBJECTIVE: To explore the regulatory effect of Rg1 on POF and clarify associated mechanisms. MATERIALS AND METHODS: POF mice were induced by injecting with D-galactose (D-gal, 200 mg/kg/- day). Mice were divided into phosphate buffered saline (PBS), D-gal (POF mice), D-gal/Rg1 group (POF mice administrating D-gal/Rg1). Weight growth rate and ovarian weight coefficient were measured. Serum estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH), superoxide dismutase (SOD), catalase (CAT) levels were examined using ELISA. The status of follicle and corpus luteum was determined using hematoxylin-eosin (HE) staining. P16INK4a and silent- mating type information regulation-2 homolog-1 (SIRT1) were determined using western blotting and RT-PCR. RESULTS: Weight growth rate and ovarian weight coefficient of mice in D-gal group were significantly decreased than PBS group (p<0.05). Serum E2, LH, SOD, CAT levels were significantly decreased, FSH levels were remarkably increased in D-gal group than PBS group (p<0.05). Rg1 (D-- gal/Rg1 group) significantly increased weight growth rate and ovarian weight coefficient, enhanced E2, LH, SOD, CAT levels and decreased FSH levels than D-gal group (p<0.05). HE staining demonstrated normal follicle morphology/structure of mice in PBS group and decreased the number of follicles, obvious vacuolation of corpus luteum and increased atretic follicles of mice in D-gal group. Compared with D-gal group, the number of follicles was increased, luteal follicles were decreased in mice in D-gal/Rg1 group (p<0.05). Rg1 significantly (D-gal/Rg1) downregulated p16INK4a and upregulated SIRT1 expression in ovarian tissues of mice compared to the D-gal group (p<0.05). CONCLUSION: Rg1 could delay premature ovarian failure in D-gal induced POF mouse model through downregulating p16INK4a and upregulating SIRT1 expression.

Multisensory Enhancement of Cognitive Control over Working Memory Capture of Attention in Children with ADHD.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in school-age children. Although it has been well documented that children with ADHD are associated with impairment of executive functions including working memory (WM) and inhibitory control, there is not yet a consensus as to the relationship between ADHD and memory-driven attentional capture (i.e., representations in WM bias attention toward the WM-matched distractors). The present study herein examined whether children with ADHD have sufficient cognitive control to modulate memory-driven attentional capture. 73 school-age children (36 with ADHD and 37 matched typically developing (TD) children) were instructed to perform a visual search task while actively maintaining an item in WM. In such a paradigm, the modality and the validity of the memory sample were manipulated. The results showed that under the visual WM encoding condition, no memory-driven attentional capture was observed in TD children, but significant capture was found in children with ADHD. In addition, under the audiovisual WM encoding condition, memory-matched distractors did not capture the attention of both groups. The results indicate a deficit of cognitive control over memory-driven attentional capture in children with ADHD, which can be improved by multisensory WM encoding. These findings enrich the relationship between ADHD and cognitive control and provide new insight into the influence of cross-modal processing on attentional guidance.

Carboplatin activates the cGAS-STING pathway by upregulating the TREX-1 (three prime repair exonuclease 1) expression in human melanoma.

Human melanoma is a highly aggressive type of cancer, causing significant mortalities despite the advances in treatment. Carboplatin is a cisplatin analog necessary for the treatment of various cancers and can also be used to treat human melanoma. We assessed the effects and mechanisms leading to inhibited proliferation and induced apoptosis of human melanoma after carboplatin therapy in vitro and in vivo. TREX1, cGAS/STING, and apoptotic protein expressions were determined through RT-qPCR and western blot assays. Cell proliferation was validated through MTT assays. The study used SK-MEL-1 and SK-HEP-1 tumor cell line inoculations along with carboplatin in nude mice to validate the results. The TREX1 levels were down-regulated in human melanoma cell lines. TREX1 overexpression-induced apoptosis and decreased proliferation in the human melanoma cell lines. TREX1 overexpression also activated the cGAS/STING pathway to induce apoptosis and decrease cell growth. Carboplatin activated TREX1, induced apoptosis, and decreased proliferation in the human melanoma cancerous cell lines. Finally, carboplatin reduced the in-vivo tumor size and weight. In conclusion, the study revealed that carboplatin activated TREX1 and cGAS/STING pathways to upregulate apoptosis. The work also provides in vitro and in vivo evidence to understand the effects of TREX overexpression on tumor suppression. Targeting of TREX1/cGAS/STING pathway could be an effective therapeutic alternative to human melanoma.

ß-Elemene Triggers ROS-dependent Apoptosis in Glioblastoma Cells Through Suppressing STAT3 Signaling Pathway.

Glioblastoma is one of the most aggressive primary brain tumors with few treatment strategies. ß-Elemene is a sesquiterpene known to have broad spectrum antitumor activity against various cancers. However, the signaling pathways involved in ß-elemene induced apoptosis of glioblastoma cells remains poorly understood. In this study, we reported that ß-elemene exhibited antiproliferative activity on U87 and SHG-44 cells, and induced cell death through induction of apoptosis. Incubation of these cells with ß-elemene led to the activation of caspase-3 and generation of reactive oxygen species (ROS). Western blot assay showed that ß-elemene suppressed phosphorylation of STAT3, and subsequently down-regulated the activation of p-JAK2 and p-Src. Moreover, pre-incubation of cells with ROS inhibitor N-acetyl-L-cysteine (NAC) significantly reversed ß-elemene-mediated apoptosis effect and down-regulation of JAK2/Src-STAT3 signaling pathway. Overall, our findings implied that generation of ROS and suppression of STAT3 signaling pathway is critical for the apoptotic activity of ß-elemene in glioblastoma cells.

A novel selective mitochondrial-targeted curcumin analog with remarkable cytotoxicity in glioma cells.

Naturally occurring polyphenol curcumin (4) or demethoxycurcumin (5) and their synthetic derivatives display promising anticancer activities. However, their further development is limited by low bioavailability and poor selectivity. Thus, a mitochondria-targeted compound 14 (DMC-TPP) was prepared in the present study by conjugating a triphenylphosphine moiety to the phenolic hydroxyl group of demethoxycurcumin to enhance its bioavailability and treatment efficacy. The in vitro biological experiments of DMC-TPP showed that it not only displayed higher cytotoxicity as compared with its parent compound 5, but also exhibited superior mitochondria accumulation ability. Glioma cells were more sensitive to DMC-TPP, which inhibited the proliferation of U251 cells with an IC50 of 0.42 µM. The mechanism studies showed that DMC-TPP triggers mitochondria-dependent apoptosis, caused by caspase activation, production of reactive oxygen species (ROS) and decrease of mitochondrial membrane potential (MMP). In addition, DMC-TPP efficiently inhibited cellular thioredoxin reductase, which contributed to its cytotoxicity. Significantly, DMC-TPP delayed tumor progression in a mouse xenograft model of human glioma cancer. Taken together, the potent in vitro and in vivo antitumor activity of DMC-TPP warrant further comprehensive evaluation as a novel anti-glioma agent.

Comorbidities and functional impairments in children with attention deficit hyperactivity disorder in China: a hospital-based retrospective cross-sectional study.

OBJECTIVES: The aim of this study was to assess comorbidity patterns and functional impairment in children with and without attention deficit hyperactivity disorder (ADHD). DESIGN: Hospital-based retrospective cross-sectional study; data collection occurred between 2016 and 2019. SETTINGS AND PATIENTS: A total of 8256 children and adolescents, 6-17 years of age, with suspected ADHD agreed to participate in this hospital-based cross-sectional study over a 4-year period in China. Comorbidities and social functions were assessed according to the scales Vanderbilt ADHD Diagnostic Parent Rating Scale and Weiss Functional Impairment Rating Scale-Parent Form, which were completed by the parents of the study participants. RESULTS: Of the 8256 children, 5640 were diagnosed with ADHD. Other 2616 children who did not meet the ADHD diagnostic criteria were classified as the N-ADHD group . The proportion of comorbidities (47.4%) and functional impairments (84.5%) in the ADHD group were higher than the N-ADHD group (p≤0.001). The functional impairment scores in all of the six domains, including family, academic, life skills, self-concept, social activities and risky activities, were significantly higher in the ADHD group than the N-ADHD group (p≤0.001). The functional impairment in ADHD group with comorbidities was more severe than those without comorbidities (p≤0.001). Comorbidities and core symptoms both can affect the functions of children with ADHD. Logistics regression analysis indicated that in all of the six functional domains, the effect of comorbidities on functional impairment exceeded the effects of ADHD core symptoms. CONCLUSIONS: Comorbidities had the greatest influence on different areas of adaptive functioning in children with ADHD. Clinical management of children suspected to have ADHD should address multiple comorbidities and functional impairments assessment, as well as core symptom analysis.

Anxiety in Chinese pediatric medical staff during the outbreak of Coronavirus Disease 2019: a cross-sectional study.

BACKGROUND: Our study aimed to explore the anxiety levels and possible associated factors in the pediatric medical staff in Jiangsu province during an outbreak of Coronavirus Disease 2019 (COVID-19). METHODS: Pediatric medical staff (n=534) from nine hospitals in Jiangsu province were enrolled. Their anxiety levels and quality of sleep were assessed using the online SAS and PSQI questionnaires. RESULTS: The prevalence of anxiety was 14.0% among the medical staff. In children's hospital staff, anxiety levels in outpatient and emergency departments were significantly higher than those in inpatient departments, except for the intensive care unit. The SAS scores were significantly associated with educational background, professional title, lifestyle, and physical condition. Stepwise multiple linear regression showed that physical condition, lifestyle, attention to the epidemic, professional title, and educational background all had a linear relationship with the individual's anxiety levels. Pearson correlation analysis showed that sleep quality was moderately associated with anxiety levels. CONCLUSIONS: The prevalence of anxiety was 14.0% in pediatric medical staff in Jiangsu province during an outbreak of COVID-19. Department, professional title, and educational background were associated with anxiety levels in these workers. More attention should be paid to staff who are in poor health, and this anxiety can also be accompanied by poor sleep quality. Peer support can assist with anxiety relief.