Search Results (264)

Background/Objectives: Spironolactone (SP) has been used off-label in pediatrics since its approval, but its use is challenged by limited pharmacokinetic (PK) data in adults and especially in children. Methods: Physiologically based pharmacokinetic (PBPK) models for SP and its active metabolites, canrenone (CAN) and 7α thio-methyl spironolactone (TMS), in adults were developed. These models aim to enhance understanding of SP’s PK and provide a basis for predicting PK and optimizing SP dosing in infants and neonates. Given SP’s complex metabolism, we assumed complete conversion to CAN and TMS by CES1 enzymes, fitting CES1-mediated metabolism to the parent-metabolite model using PK data. We incorporated ontogeny for CES1 and CYP3A4 and other age-related physiological changes into the model to anticipate PK in the pediatric population. Results: The PBPK models for SP, CAN, and TMS accurately captured the observed PK data in healthy adults across various dosing regimens, including the impact of food on drug exposure. The pediatric PBPK model was evaluated using PK data from infants and neonates. Simulations indicate that 2.5 mg/kg in 6-month to 2-year infants and 2 mg/kg in 1–6-months infants matched the total unbound systemic exposure equivalent to the standard recommended daily maintenance dose of 100 mg in adults for treating edema. Conclusions: The developed PBPK model provides valuable insights for dosing decisions and optimizing therapeutic outcomes, especially in populations where clinical studies are challenging. Full article

Background: Children in pediatric oncology report unmet needs related to communication and information about the illness, care involvement, and psychosocial support. Supporting the whole family involves challenges, with a risk that children’s voices are not heard above those of the adults. Article 12 of the UNCRC has been a catalyst in supporting children’s voices and their right to participate in processes that affect them. The aim of this study was to explore how children with cancer and their siblings experienced participation in a family-centered psychosocial support intervention, the Family Talk Intervention (FTI). Methods: Interviews were held with 35 children (ill and siblings) from 26 families in pediatric oncology after having completed the FTI. A combined deductive and inductive qualitative content analysis was undertaken, guided by the Lundy model of child participation. Results: Children’s experiences of being able to express their views, being listened to, and being involved during FTI were mainly positive. This was related to their participation in individual meetings where they could raise their concerns and views, undertake small activities while talking, and have their voices and needs mediated to relevant adults, such as parents and professionals. Conclusions: The findings of this study showed that the FTI for families in pediatric oncology created opportunities to promote child participation. These findings indicate that, by offering children an individual space where they can express themselves freely and supporting them in various ways to do so, the children’s voices and involvement are strengthened. Full article

Background/Objectives: Motor creativity and physical activity are essential to early childhood development, impacting physical, cognitive, and socio-emotional development. This study investigates the relationships among motor creativity, motor working memory (MSTM), screen time, and physical activity (PA) in kindergarten children, focusing on the mediating roles of cognitive functions and screen time. Methods: Data were collected from 124 Arab Israeli kindergarten children through assessments of Thinking Creatively in Action and Movement (TCAM) for motor creativity and the Hand Movement Test for MSTM. Parents reported the children’s screen time and days engaged in moderate-to-vigorous physical activity (MVPA). Results: The results show significant positive associations between motor creativity and both MSTM and PA, underscoring the role of cognitive processes in creative motor expression. Linear regression and mediation analyses showed that MSTM significantly mediates the relationship between PA and motor creativity. Conversely, screen time negatively correlates with PA and motor creativity, serving as a significant mediator that restricts opportunities for physical and creative activities. Conclusions: This study emphasizes the bidirectional relationship between PA and motor creativity, wherein diverse physical activities stimulate creativity, and creative movements encourage active participation. The combined mediating effects of MSTM and screen time highlight the complexity of these relationships, suggesting the need for integrated interventions. The findings inform early childhood education by advocating for strategies that promote physical activity, enhance cognitive functions, and limit excessive screen time, fostering holistic development in young children. Full article

Background: Bispecific antibodies represent a promising class of biologics for cancer treatment. However, their dual specificity and complex structure pose challenges in the engineering process, often resulting in molecules with good functional but poor physicochemical properties. Method: To overcome limitations in the properties of an anti-5T4 x anti-CD3 (α5T4 x αCD3) DART molecule, a phage-display method was developed, which succeeded in simultaneously engineering cross-reactivity to the cynomolgus 5T4 ortholog, improving thermostability and the elevating expression level. Results: This approach generated multiple DART molecules that exhibited significant improvements in all three properties. The lead DART molecule demonstrated potent in vitro and in vivo anti-tumor activity. Although its clearance in human FcRn-transgenic mice was comparable to that of the parental molecule, faster clearance was observed in cynomolgus monkeys. The lead α5T4 x αCD3 DART molecule displayed no evidence of off-target binding or polyspecificity, suggesting that the increased affinity for the target may account for its accelerated clearance in cynomolgus monkeys. Conclusions: This may reflect target-mediated drug disposition (TMDD), a potential limitation of targeting 5T4, despite its limited expression in healthy tissues. Full article

Background/Objectives Bacterial ghosts (BGs), non-living empty envelopes of bacteria, are produced either through genetic engineering or chemical treatment of bacteria, retaining the shape of their parent cells. BGs are considered vaccine candidates, promising delivery systems, and vaccine adjuvants. The practical use of BGs in vaccine development for humans is limited because of concerns about the preservation of viable bacteria in BGs. Methods: To increase the efficiency of Klebsiella pneumoniae BG formation and, accordingly, to ensure maximum killing of bacteria, we exploited previously designed plasmids with the lysis gene E from bacteriophage φX174 or with holin–endolysin systems of λ or L-413C phages. Previously, this kit made it possible to generate bacterial cells of Yersinia pestis with varying degrees of hydrolysis and variable protective activity. Results: In the current study, we showed that co-expression of the holin and endolysin genes from the L-413C phage elicited more rapid and efficient K. pneumoniae lysis than lysis mediated by only single gene E or the low functioning holin–endolysin system of λ phage. The introduction of alternative lysing factors into K. pneumoniae cells instead of the E protein leads to the loss of the murein skeleton. The resulting frameless cell envelops are more reminiscent of bacterial sacs or bacterial skins than BGs. Although such structures are less naive than classical bacterial ghosts, they provide effective protection against infection by a hypervirulent strain of K. pneumoniae and can be recommended as candidate vaccines. For our vaccine candidate generated using the O1:K2 hypervirulent K. pneumoniae strain, both safety and immunogenicity aspects were evaluated. Humoral and cellular immune responses were significantly increased in mice that were intraperitoneally immunized compared with subcutaneously vaccinated animals (p < 0.05). Conclusions: Therefore, this study presents novel perspectives for future research on K. pneumoniae ghost vaccines. Full article

Background/Objectives: The COVID-19 pandemic created a growing need for insights into the mental health of children and youth and their use of coping mechanisms during this period. We assessed mood symptoms and related factors among children and youth in Saskatchewan. We examined if coping abilities mediated the relationship between risk factors and mood states. Methods: “See Us, Hear Us 2.0”, a cross-sectional study of 563 child–parent dyads, provided the data. The dependent variable, current mood state, was measured by the CoRonavIruS health Impact Survey (CRISIS) scale. Independent variables included sociodemographics, behaviors, household conditions, and coping ability. Multiple linear regression and mediation analyses were conducted, ensuring sample representativeness with sampling weights and addressing missing data through multiple imputations. Results: The participants reported mood symptoms (“moderate” to “extreme”) ranging from 23% to 38% on the CRISIS scale. Factors such as older children, hybrid learning, disrupted activities, and increased screen time worsened moods. The ethnic minority groups (BIPOC) living in mid-sized cities/towns experienced more negative moods compared to Whites residing in cities. Coping ability mediated the relationship between extracurricular activities and mood states. Conclusions: Our results underscore the importance of tailored interventions, recognizing the diverse needs of specific age groups, gender identities, and ethnicities and addressing the adverse effects of the pandemic-related disruptions on the mental health and well-being of school children in Saskatchewan. Our study also suggests prioritizing the diverse needs of children and youth during the planning and implementation of mental health services in the province. Full article

Background: 3-O-acetyl-11-keto-β-boswellic acid (β-AKBA), a triterpene natural product, is one of the main natural products of Boswellia sacra resin (BSR) and has reported biological and immunomodulatory effects. 1H-1,2,3-triazole derivatives of β-AKBA (named 6a–6d) were synthesized from β-AKBA. The 1H-1,2,3-triazole compounds are also known to have a wide range of biological and pharmacological properties as demonstrated by in vitro and in vivo studies. This study aimed to investigate the effects of these 1H-1,2,3-triazole derivatives of β-AKBA on human T-cell proliferation and activation. Methods: PBMCs isolated from healthy donors were activated by anti-CD3/CD28 monoclonal antibodies in the presence of β-AKBA (1) or 1H-1,2,3-triazole derivatives of β-AKBA or DMSO controls. Results: We found that similar to the parent compound β-AKBA (1), derivatives 6a, 6b, and 6d significantly inhibited T-cell expansion/proliferation and reduced the levels of CD25 activation marker on CD4⁺ and CD8⁺ T cells without exerting significant cytotoxic effects on T-cell viability at a concentration of 25 µM. However, compound 6c further inhibited T-cell expansion/proliferation and CD25 expression, but had a significant cytotoxic effect on cell viability at similar concentrations of 25 µM. Conclusions: These findings demonstrate the immunoinhibitory effects of β-AKBA (1) and its corresponding triazole derivatives on T-cell proliferation and activation, highlighting the promising therapeutic potential of these compounds in T-cell-mediated diseases. Full article

Synthetic cannabinoids (SCs) are one of the largest groups of new psychoactive substances (NPSs). However, the relationship between their chemical structure and the affinity to human CB₁ receptors (hCB₁), which mediates their psychotropic activity, is not well understood. Herein, the synthesis of the 2-, 4-, 5-, 6- and 7-chloroindole analogues of the synthetic cannabimimetic MDMB-CHMICA, along with their analytical characterization via ultraviolet–visible (UV/VIS), infrared (IR), nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry, is described. Furthermore, all five derivatives of MDMB-CHMICA were analyzed for their hCB₁ binding affinities. Chlorination at position 4 and 5 of the indole core reduced the binding affinity compared to MDMB-CHMICA, while the test compounds chlorinated in positions 2, 6, and 7 largely retained their binding affinities relative to the non-chlorinated parent compound. Full article

Peroxisome proliferator-activated receptors (PPARs), including PPAR-α, PPAR-β/δ, and PPAR-γ, are involved in various cellular responses, including metabolism and cell proliferation. Increasing evidence suggests that PPARs are closely associated with tumorigenesis and metastasis. However, the exact role of PPARs in energy metabolism and cancer stem cell (CSC) proliferation remains unclear. This study investigated the role of PPARs in energy metabolism and tumorigenesis in ovarian CSCs. The expression of PPARs and fatty acid consumption as an energy source increased in spheroids derived from A2780 ovarian cancer cells (A2780-SP) compared with their parental cells. GW6471, a PPARα inhibitor, induced apoptosis in A2780-SP. PPARα silencing mediated by small hairpin RNA reduced A2780-SP cell proliferation. Treatment with GW6471 significantly inhibited the respiratory oxygen consumption of A2780-SP cells, with reduced dependency on fatty acids, glucose, and glutamine. In a xenograft tumor transplantation mouse model, intraperitoneal injection of GW6471 inhibited in vivo tumor growth of A2780-SP cells. These results suggest that PPARα plays a vital role in regulating the proliferation and energy metabolism of CSCs by altering mitochondrial activity and that it offers a promising therapeutic target to eradicate CSCs. Full article

Background: LEGO^®-based therapy is a social development protocol that uses LEGO^® activities to support the development of a wide range of interaction skills, enhancing prosocial behaviors and mitigating the challenges associated with mental health difficulties and behavioral issues commonly observed in children with autism spectrum disorder (ASD). Objectives: This study aimed to explore the effects of LEGO^®-based therapy on the social behavior and mental health of children with ASD, comparing stimulation mediated by expert and stimulation mediated by non-autistic peers. This study was approved by the Ethical Committee at Mackenzie Presbyterian University, ensuring adherence to ethical standards throughout the research process. Methods: This study involved 18 children with ASD, levels 1 or 2, with an intelligence quotient (IQ) above 70, and three typically developing peers, intelligence quotient (IQ) above 80, aged between 5 and 8 years old, of both sexes. Participants were randomized into three groups for stimulation (stimulation mediated by expert, by a non-autistic peer and control group). The measures were the Wechsler Abbreviated Scale of Intelligence, the Strengths and Difficulties Questionnaire (parent and teacher versions), the Inventory of Difficulties in Executive Functions, Regulation, and Aversion to Delay—Child Version, the Developmental Coordination Disorder Questionnaire, the Autism Behavior Checklist, and the Autistic Behavior Inventory. Results: After 14 sessions of 45 min in school settings, the participants of both groups (mediated by experts and non-autistic children) showed significant gains on social behavior. A statistically significant difference was observed between baseline sessions and probes (χ² (5) = 25.905, p < 0.001). These gains were maintained in both follow-up points, 30 and 90 days after the completion of the stimulation sessions. Additionally, maladaptive behavior showed a significant decline when compared pre- and post-intervention. These improvements were sustained during follow-up assessments at 30 and 90 days. Conclusions: The results suggest that a structured intervention combined with peer-mediated stimulation may be an effective method for promoting adaptive and prosocial behaviors in children with ASD. Full article

Microplastics and nanoplastics (MNPs) are ubiquitous environmental contaminants. Their prevalence, persistence, and increasing industrial production have led to questions about their long-term impact on human and animal health. This narrative review describes the effects of MNPs on oxidative stress, inflammation, and aging. Exposure to MNPs leads to increased production of reactive oxygen species (ROS) across multiple experimental models, including cell lines, organoids, and animal systems. ROS can cause damage to cellular macromolecules such as DNA, proteins, and lipids. Direct interaction between MNPs and immune cells or an indirect result of oxidative stress-mediated cellular damage may lead to increased production of pro-inflammatory cytokines throughout different MNP-exposure conditions. This inflammatory response is a common feature in the pathogenesis of neurodegenerative, cardiovascular, and other age-related diseases. MNPs also act as cell senescence inducers by promoting mitochondrial dysfunction, impairing autophagy, and activating DNA damage responses, exacerbating cellular aging altogether. Increased senescence of reproductive cells and transfer of MNPs/induced damages from parents to offspring in animals further corroborates the transgenerational health risks of the tiny particles. This review aims to provoke a deeper investigation into the notorious effects these pervasive particles may have on human well-being and longevity. Full article

The purpose of this study is to analyze the effects of parental academic achievement pressure and physical activity on body image mediated by self-esteem. By examining a total of 1328 South Korean adolescents, this study yielded the following results. First, parental academic achievement pressure negatively affects self-esteem directly. Second, physical activity positively affects self-esteem directly. Third, self-esteem positively influences body image directly. Fourth, parental academic achievement pressure has a negative indirect effect on body image through the mediation of self-esteem. Fifth, physical activity has a positive indirect effect on body image through the mediation of self-esteem. These findings underscore the importance of appropriate physical activity, especially for adolescents under significant academic pressure. Physical activity can directly enhance self-esteem, which in turn improves body image. This study highlights the role of physical activity in mitigating the negative impact of parental academic achievement pressure on body image through self-esteem. Full article

Background/objectives: Euchromatic histone lysine methyltransferase 2 (EHMT2, also known as G9a) is a mammalian histone methyltransferase that catalyzes the dimethylation of histone 3 lysine 9 (H3K9). On human chromosome 15, the parental-specific expression of Prader–Willi Syndrome (PWS)-related genes, such as SNRPN and SNORD116, are regulated through the genetic imprinting of the PWS imprinting center (PWS-IC). On the paternal allele, PWS genes are expressed whereas the epigenetic maternal silencing of PWS genes is controlled by the EHMT2-mediated methylation of H3K9 in PWS-IC. Here, we measured the effects of RNA interference of EHMT2 on the maternal expression of genes deficient in PWS in mouse model and patient iPSC-derived cells. Methods: We used small interfering RNA (siRNA) oligonucleotides and lentiviral short harpin RNA (shRNA) to reduce Ehtm2/EHMT2 expression in mouse Snord116 deletion primary neurons, PWS patient-derived induced pluripotent stem cell (iPSC) line and PWS iPSC-derived neurons. We then measured the expression of transcript or protein (if relevant) of PWS genes normally silenced on the maternal allele. Results: With an approximate reduction of 90% in EHMT2 mRNA and more than 80% of the EHMT2 protein, we demonstrated close to a 2-fold increase in the expression of maternal transcripts for SNRPN and SNORD116 in PWS iPSCs treated with siEHMT2 compared to PWS iPSC siControl. A similar increase in SNORD116 and SNRPN RNA expression was observed in PWS iPSC-derived neurons treated with shEHMT2. Conclusions: RNAi reduction in EHMT2 activates maternally silenced PWS genes. Further studies are needed to determine whether the increase is therapeutically relevant. This study confirms the role of EHMT2 in the epigenetic regulation of PWS genes. Full article

Background/Objectives: The beneficial effects of the flavonoid chrysin can be reduced by its poor oral bioavailability. It has been shown that chrysin-8-C-glucoside (1) has a better absorption capability. The aim of this study was to evaluate the antioxidant and anti-inflammatory activity of this glucoside, as well as the respective hexa-acetate derivative 1a and the hexa-ethyl carbonate derivative 1b since the inclusion of moieties in bioactive molecules may increase or modify their biological effects. Methods: THP-1 macrophages were used to determine the viability in the presence of chrysin derivatives, and non-cytotoxic concentrations were selected. Subsequently, lipopolysaccharide (LPS)-induced reactive oxygen species (ROS) production and inflammatory mediators were examined. The involvement of chrysin derivatives with the Keap1 and Nrf2 antioxidant system was determined by docking and Western blotting studies. Results: Our data demonstrated, for the first time, that pretreatment with the three compounds caused a significant reduction in LPS-induced reactive oxygen species (ROS) production and pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) levels, as well as in cyclooxygenase 2 (COX-2) expression. The mechanisms underlying these protective effects were related, at least in part, to the competitive molecular interactions of these phenolic compounds with Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2), which would allow the dissociation of Nrf2 and its translocation into the nucleus and the subsequent up-regulation of hemo-oxygenase 1 (HO-1) expression. Conclusions: Compared to the 8-C-glucoside parent chrysin, compound 1a exhibited the strongest antioxidant and anti-inflammatory activity. We hypothesized that the incorporation of an acetate group (1a) may reduce its polarity and, thus, increase membrane permeability, leading to better pharmacological activity. These findings support the potential use of these phenolic compounds as Nrf2 activators against oxidative-stress-related inflammatory diseases. Full article

The soybean cyst nematode (SCN), Heterodera glycines Ichinohe, 1952, is one of the most destructive plant-parasitic nematodes in soybean production worldwide. The use of resistant soybean is the most effective alternative for its management. However, SCN-resistant soybean cultivars with increased yield and favorable agronomic traits remain limited in the market. Here, we developed a new SCN-resistant soybean cultivar Nongqing 28 from the cross of the female parent cultivar An 02-318 and a male parent line F2 (Hei 99-980 × America Xiaoheidou). Resistance evaluation suggested that Nongqing 28 displayed stable resistance to SCN race 3 in pot assays and the 5-year field experiments, including inhibition of SCN development and reduction in female and cyst numbers. The average yields of Nongqing 28 were 2593 kg/ha and 2660 kg/ha in the 2-year regional trails and the 1-year production trials, with a yield increase of 6.2% and 8.1% compared with the local cultivar Nengfeng 18, respectively. The average seed fat contents in Nongqing 28 reached 21.26%. Additionally, RNA-seq analysis revealed that the resistance of Nongqing 28 to SCN infection is involved in pathogen perception and defense activation, such as reactive oxygen species burst, calcium-mediated defense signaling, hormonal signaling, the MAPK signaling cascade, and phenylpropanoid biosynthesis. In summary, this study provides a detailed characterization of a novel SCN-resistant soybean cultivar with high oil and yield potential. Full article