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BACKGROUND AND PURPOSE: Scientists have been exploring anti-angiogenic strategies to inhibit angiogenesis and prevent tumor growth. Vasculogenic mimicry (VM) in glioblastoma multiforme (GBM) poses a challenge, complicating anti-angiogenesis therapy. A novel drug, GN25 (3-[{1,4-dihydro-5,8-dimethoxy-1,4-dioxo-2-naphthalenyl}thio]-propanoic acid), can inhibit tumor formation. This study aims to investigate the microenvironmental effects and molecular mechanisms of GN25 in anti-angiogenesis and anti-VM. EXPERIMENTAL APPROACH: MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay was used to evaluate the cell viability of different concentrations of GN25 in human umbilical vein endothelial cells (HUVEC) and Uppsala 87 malignant glioma (U87MG) cells. Functional assays were used to investigate the effects of GN25 on angiogenesis-related processes, whereas gelatin zymography, enzyme-linked immunosorbent assays, and Western blotting were utilized to assess the influence on matrix metalloproteinase (MMP)-2 and vascular endothelial growth factor (VEGF) secretion and related signaling pathways. KEY RESULTS: GN25 suppressed migration, wound healing, and tube formation in HUVECs and disrupted angiogenesis in a rat aorta ring and zebrafish embryo model. GN25 dose-dependently reduced phosphatidylinositol 3-kinase/AKT and inhibited MMP-2/VEGF secretion in HUVECs. In U87MG cells, GN25 inhibited migration, wound healing, and VM, accompanied by a decrease in MMP-2 and VEGF secretion. The results indicate that GN25 effectively inhibits angiogenesis and VM formation in HUVECs and U87MG cells without affecting preexisting vascular structures. CONCLUSION AND IMPLICATIONS: This study elaborated GN25's potential as an anti-angiogenic agent by elucidating its inhibitory effects on classical angiogenesis. VM provides valuable insights for developing novel therapeutic strategies against tumor progression and angiogenesis-related diseases. These results indicate the potential of GN25 as a promising candidate for angiogenesis-related diseases.
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Glioblastoma multiforme (GBM) is an aggressive brain cancer that occurs more frequently than other brain tumors. The present study aimed to reveal a novel mechanism of temozolomide resistance in GBM using bioinformatics and wet lab analyses, including meta-Z analysis, Kaplan-Meier survival analysis, protein-protein interaction (PPI) network establishment, cluster analysis of co-expressed gene networks, and hierarchical clustering of upregulated and downregulated genes. Next-generation sequencing and quantitative PCR analyses revealed downregulated [tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 1 (TIE1), calcium voltage-gated channel auxiliary subunit α2Δ1 (CACNA2D1), calpain 6 (CAPN6) and a disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6)] and upregulated [serum amyloid (SA)A1, SAA2, growth differentiation factor 15 (GDF15) and ubiquitin specific peptidase 26 (USP26)] genes. Different statistical models were developed for these genes using the Z-score for P-value conversion, and Kaplan-Meier plots were constructed using several patient cohorts with brain tumors. The highest number of nodes was observed in the PPI network was for ADAMTS6 and TIE1. The PPI network model for all genes contained 35 nodes and 241 edges. Immunohistochemical staining was performed using isocitrate dehydrogenase (IDH)-wild-type or IDH-mutant GBM samples from patients and a significant upregulation of TIE1 (P<0.001) and CAPN6 (P<0.05) protein expression was demonstrated in IDH-mutant GBM in comparison with IDH-wild-type GBM. Structural analysis revealed an IDH-mutant model demonstrating the mutant residues (R132, R140 and R172). The findings of the present study will help the future development of novel biomarkers and therapeutics for brain tumors.
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Early-term neonates (with a gestational age (GA) of 37 and 0/7 weeks to 38 and 6/7 weeks) face higher morbidities, including respiratory and neurodevelopmental issues, than full-term (39 and 0/7 weeks to 40 and 6/7 weeks) infants. This study explores whether hyperbilirubinemia necessitating phototherapy also differs between these groups. A retrospective study was conducted on neonates born from January 2021-June 2022, excluding those with specific conditions. Evaluated factors included GA, birth weight, bilirubin levels, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and feeding type, with phototherapy given as per AAP guidelines. Of 1085 neonates, 356 met the criteria. When stratifying the neonates based on the need for phototherapy, a higher proportion of early-term neonates required phototherapy compared to full-term (p < 0.05). After factoring in various risks (GA; birth weight; gender; feeding type; G6PD deficiency; transcutaneous bilirubin levels at 24 h and 24-48 h postpartum; maternal diabetes; and the presence of caput succedaneum or cephalohematoma), early-term neonates were more likely to need phototherapy than full-term babies (OR: 2.15, 95% CI: 1.21 to 3.80). The optimal cut-off for transcutaneous bilirubin levels 24-48 h postpartum that were used to predict phototherapy need was 9.85 mg/dl. In conclusion, early-term neonates are at a greater risk for developing jaundice and requiring phototherapy than full-term neonates. Monitoring bilirubin 24-48 h postpartum enhances early prediction and intervention.
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Bronchopulmonary dysplasia (BPD) is a major respiratory condition mainly affecting premature infants. Although its occurrence is global, risk factors may differ regionally. This study, involving 3111 infants with birth weight ≤ 1500 gm or gestational age (GA) < 30 weeks, aimed to identify risk factors for BPD and BPD/mortality in Taiwan using data from the Taiwan Neonatal Network. The BPD criteria were based on the National Institute of Child Health and Human Development standards. Average GA was 27.5 weeks, with 23.7% classified as small for GA (SGA). Multivariate analysis highlighted low GA, low birth weight, and other perinatal factors as significant risk indicators for BPD. For moderate-to-severe BPD, additional risk factors included male gender and SGA, endotracheal intubation (ETT) or cardiopulmonary cerebral resuscitation (CPCR) in initial resuscitation. In the moderate-to-severe BPD/death group, SGA and ETT or CPCR in initial resuscitation remained the only additional risk factors. The study pinpoints male gender, SGA and ETT or CPCR as key risk factors for moderate-to-severe BPD/death in low-birth-weight infants in Taiwan, offering a basis for focused interventions and further research.
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BACKGROUND/PURPOSE: This study examined the practice rate of Anticipatory Guidance (AG) and the gap between knowledge and practice among caregivers. METHODS: We retrospectively collected data from caregivers who brought their children for seven age-based well-child visits (birth to 7 years old) and seven corresponding AG checklists for practice (each ranged from 16 to 19 guidance items, 118 items in total) between 2015 and 2017. Practice rates of guidance items and their association with children's sex, age, residence, and body mass index were collected and analyzed. RESULTS: We enrolled 2310 caregivers (330 per well-child visit). Average practice rates of guidance items in the seven AG checklists were 77.6%-95.1%, generally without significant differences between urban/rural or male/female children. However, lower (<80%) rates were observed for 32 items, including dental check-ups (38.9%), use of fluoride toothpaste (44.6%), screen time (69.4%), and drinking less sugar-sweetened beverages (SSBs) (75.5%), with corresponding knowledge-to-practice gap rates of 55.5%, 47.9%, 30.3%, and 23.8%, respectively. "Drinking less SSBs" was the only item with a higher obesity rate in the non-achieved group versus the achieved group (16.7% vs. 7.4%, p = 0.036; odds ratio: 3.509, 95% CI: 1.153-10.677, p = 0.027). CONCLUSION: Caregivers in Taiwan practiced most AG recommendations. However, dental check-ups, fluoride toothpaste use, drinking less SSBs, and limiting screen time were less executed items. A higher obesity rate was found among 3-7-year-old children whose caregivers failed to practice the "Drink less SSBs" guidance. Strategies to overcome the gap between knowledge and practice are needed to improve these less-achieved guidance items.
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Bebidas , Cuidadores , Humanos , Masculino , Feminino , Pré-Escolar , Criança , Estudos Retrospectivos , Fluoretos , Lacunas da Prática Profissional , Taiwan , Cremes Dentais , ObesidadeRESUMO
BACKGROUND: Gastroesophageal reflux disease (GERD) is associated with lower esophageal sphincter (LES) incompetence. In some patients, GERD is refractory to acid reduction therapy which is the main treatment for GERD. So far, medications that can increase LES tone are few. Arecae pericarpium (A. pericarpium) is a medication in Traditional Chinese Medicine known to promote intestinal motility. METHODS: We investigated the effect of A. pericarpium extracts on porcine LES motility. In addition, we used tetrodotoxin (TTX) and atropine to study the underlying mechanism of A. pericarpium extracts-induced contractions of LES. RESULTS: The results of this study showed that A. pericarpium extracts and their main active ingredient, arecoline, can induce the contractions of porcine LES sling and clasp muscles in a dose-response manner. TTX did not have an inhibitory effect on the contractions induced by A. pericarpium extracts and arecoline in LES. However, atropine significantly inhibited A. pericarpium extracts- and arecoline-induced contractions of LES. CONCLUSION: A. pericarpium extracts can induce the contractions of porcine LES in a dose dependent manner, possibly through muscarinic receptors, and hence, may be worth developing as an alternative therapy for GERD.
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Esfíncter Esofágico Inferior/efeitos dos fármacos , Extratos Vegetais/farmacologia , Receptores Muscarínicos/metabolismo , Animais , Areca , Refluxo Gastroesofágico/tratamento farmacológico , Técnicas In Vitro , Suínos , TaiwanRESUMO
Sudden infant death syndrome (SIDS) has always been a regrettable issue for families. After sleeping in the supine position was proposed, the incidence of SIDS declined dramatically worldwide. However, SIDS still accounts for the top 10 causes of infant deaths in Taiwan. Recognizing the risk factors and attempting to minimize these cases are imperative. We obtained information on cases with SIDS from the National Health Insurance Research Database in Taiwan and interconnected it with the Taiwan Maternal and Child Health Database to acquire infant-maternal basal characteristics between 2004 and 2017. The SIDS subjects were matched 1:10 considering gestational age to normal infants. After case selection, a total of 953 SIDS cases were included. Compared with healthy infants, SIDS infants had younger parents, lower birth weight, and lower Apgar scores. After adjusting for potential confounders, infants with mothers aged <20 years had 2.81 times higher risk of SIDS. Moreover, infants in the non-eastern region had a significantly lower risk of SIDS than those in the eastern region. We concluded that infants of young mothers (especially maternal age <20 years) and infants in the eastern region of Taiwan had a higher risk of SIDS than their counterparts.
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Prenatal opioid exposure might disturb epigenetic programming in the brain of neonatal offspring with various consequences for gene expressions and behaviors. This study determined whether altered trimethylation of histone 3 at lysine 4 (H3K4me3) in the promoter of the tumor necrosis factor-α (tnf-α) gene with neural cell apoptosis was involved in the ventral-medial striatum, an important brain region for withdrawal symptoms, of neonatal rat offspring from morphine-addicted mothers. Female adult rats were injected with morphine before gestation and until 14 days after giving birth. On postnatal day 14 (P14), rat offspring from morphine-addicted mothers were subjected to an opioid-withdrawal protocol and were analyzed 2 or 8 h after administration of that protocol. Expressions of the TNF-α protein, H3K4me3 in the tnf-α promoter gene, and neural cell apoptosis within the ventral-medial striatum of neonatal rat offspring were evaluated. In the absence of significant opioid withdrawal (2 h after initiation of the opioid-withdrawal protocol on P14), prenatal morphine exposure led to increased levels of H3K4me3 in the tnf-α promoter gene, of the TNF-α protein, and of neural cell apoptosis within the ventral-medial striatum of neonatal rat offspring. Following opioid withdrawal (8 h after initiation of the opioid-withdrawal protocol on P14), differential expression of H3K4me3 in the tnf-α promoter gene locus and upregulation of the level of TNF-α protein expression were further enhanced in these offspring. In addition, increased levels of caspase-3 and neural cell apoptosis were also observed. Taken together, this study revealed that prenatal opioid exposure can activate an epigenetic histone mechanism which regulates proinflammatory factor generation, which hence, led to cell apoptotic damage within the ventral-medial striatum of neonatal rat offspring from morphine-addicted mothers. More importantly, the opioid-withdrawal episode may provide augmented effects for the abovementioned alterations and could lead to deleterious effects in the neonatal brain of such offspring.
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Apoptose , Histonas/metabolismo , Dependência de Morfina/metabolismo , Morfina , Prenhez , Regiões Promotoras Genéticas , Fator de Necrose Tumoral alfa/genética , Analgésicos Opioides , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Caspase 3/metabolismo , Corpo Estriado , Epigênese Genética , Feminino , Exposição Materna , Metilação , Gravidez , Ratos , Ratos Sprague-Dawley , Síndrome de Abstinência a Substâncias/patologiaRESUMO
Di-(2-ethylhexyl) phthalate (DEHP), a common plasticizer, has been detected in breast milk in many countries; however, whether phthalate metabolite concentration and the detection rate in breast milk change postpartum is still unknown. We measured phthalate metabolite concentrations in breast milk in the first 6 months postpartum in women enrolled in the E-Da hospital from January to July 2017. A total of 56 breastfeeding mothers and 66 samples were included in this study. We analyzed the samples' concentration of eight phthalate metabolites using liquid chromatography mass spectrometry. The concentration of mono-2-ethylhexyl phthalate (MEHP) was significantly higher in the first month, and then decreased over time. The detection rate of ono-isobutyl phthalate (MiBP) and mono-n-butyl phthalate (MBP) was low in the first month and then increased over time. Compared with a previous study published in 2011, the levels of MEHP and MiBP in breast milk were much lower in the present study, suggesting an increased awareness of the health risks of phthalate exposure after a food scandal occurred in Taiwan. This study provides information for evaluating newborns' exposure to different kinds of phthalate through human milk in the postpartum period.
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Dietilexilftalato , Poluentes Ambientais , Ácidos Ftálicos , Exposição Ambiental/análise , Poluentes Ambientais/análise , Feminino , Humanos , Recém-Nascido , Leite Humano/química , Ácidos Ftálicos/análise , Período Pós-Parto , TaiwanRESUMO
Determining the optimal endotracheal tube (ETT) depth in neonates remains challenging for neonatologists. The guideline for optimal ETT depth is based on the patients' weight or gestational age. However, there is a discrepancy in the suggested ETT depth between these two parameters. The aim of this retrospective study was to compare the recommended weight-based and age-based formulas for optimal ETT depth and obtain the optimal reference before intubation. Participants were assigned to group 1 if the recommended ETT insertion depth based on weight was concordant with the recommended depth based on gestational age, and to group 2 if the weight and age-based depth recommendations were discordant. After exclusion, 180 patients were included in the analysis. Results indicated that the predicted ETT depth suggested by age required more adjustment than by weight (p < 0.05). Furthermore, the required adjustment in the weight-based formula was smaller than the age-based formula (p < 0.05). Multivariate linear regression analysis revealed that weight was the key factor affecting the optimal depth (p < 0.001). These results imply that when there is a discrepancy in ETT depth between the weight-based and age-based recommendation, the weight-based one will be more accurate than the age-based one.
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Osteoarthritis (OA) is the most common joint disorder and is classically defined as a progressively degenerative disease of articular cartilage. It manifests as joint pain and disability and currently has no comprehensive treatments. The primary purpose of the present study was to test the effects of probiotics, Streptococcus thermophilus (TCI633), on anterior cruciate ligament transection (ACLT)-induced experimental osteoarthritis (OA) in rats. In the current study, the experimental groups were given TCI633 (5x109, 5x1010 and 5x1011 CFU/kg/day) and glucosamine sulfate (250 mg/kg) between week 8 and 20 following ACLT. The results showed that oral administration of TCI633 and glucosamine had significant therapeutic effects on pain behaviors and knee swelling. Dose-dependent effects of TCI633 were also observed in ACLT-treated rats. Histopathological analysis demonstrated that ACLT+TCI633 (5x109, 5x1010 and 5x1011 CFU/kg/day) improved the synovial inflammation and cartilage damage of ACLT rats. Histology evaluation using the Osteoarthritis Research Society International system and synovial inflammatory score analysis showed the dose-dependent inhibition of TCI633 on synovial inflammation and cartilage damage. Immunohistochemical staining and TUNEL apoptosis staining showed that TCI633 could effectively increase the expression of type II collagen and reduce the amount of chondrocyte apoptosis in cartilage. Therefore, the present study demonstrated that oral intake of TCI633 could significantly suppressing pain behavior, reduce joint swelling and synovial tissue inflammation and increase type II collagen expression in cartilage. There was also a reduction in chondrocyte apoptosis and decreased progression of OA in ACLT-treated rats.
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The activation of microglial cells plays an important role in the cascade of events leading to inflammation-mediated neurodegenerative disorders. Precision therapeutics require that adjunctively feasible drugs be found to prevent microglial cell activation and prevent inflammation-mediated neuronal injury. Dextromethorphan (DM) has been reported to possess neuroprotective effects in lipopolysaccharide- (LPS-) stimulated animals; however, it remains unclear whether epigenetic regulatory mechanisms in microglial cells are involved in such DM-mediated neuroprotective effects. In this study, DM simultaneously suppressed LPS-induced activation of tumor necrosis factor- (TNF-) α expression and subsequent caspase-3 signaling in primary microglial cells associated with notable morphological changes. Furthermore, therapeutic action sites of DM involved differential enhanced trimethylation of H3K4 modifications in the promoter region of tnf-α gene locus in primary microglial cells. In summary, DM may exert neuroprotective and anti-inflammatory effects through differential epigenetic histone modifications of TNF-α expression in microglial cells and might therefore raise the possibility of providing an adjunctively beneficial role for a tentative therapeutic strategy in neurodegenerative diseases resulting from inflammation.
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Anti-Inflamatórios/farmacologia , Dextrometorfano/farmacologia , Epigênese Genética/efeitos dos fármacos , Histonas/metabolismo , Microglia/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Animais , Caspase 3/fisiologia , Células Cultivadas , Lipopolissacarídeos/farmacologia , Microglia/fisiologia , Regiões Promotoras Genéticas , Ratos , Ratos Sprague-DawleyRESUMO
Glioblastoma multiforme (GBM) is a cancer of the central nervous system with limited therapeutic outcomes. Infiltrating cancer cells are the contributing factor to high GBM malignancy. The intracranial brain cancer cell infiltration is a complex cascade involving adhesion, migration, and invasion. An arsenal of natural products has been under exploration to overcome GBM malignancy. This study applied the antimicrobial peptide tilapia piscidin 3 (TP3) to GBM8401, U87MG, and T98G cells. The cellular assays and microscopic observations showed that TP3 significantly attenuated cell adhesion, migration, and invasion. A live-cell video clip showed the inhibition of filopodia protrusions and cell attachment. Probing at the molecular levels showed that the proteolytic activities (from secretion), the mRNA and protein expression levels of matrix metalloproteinases-2 and -9 were attenuated. This result strongly evidenced that both invasion and metastasis were inhibited, although metastatic GBM is rare. Furthermore, the protein expression levels of cell-mobilization regulators focal adhesion kinase and paxillin were decreased. Similar effects were observed in small GTPase (RAS), phosphorylated protein kinase B (AKT) and MAP kinases such as extracellular signal-regulated kinases (ERK), JNK, and p38. Overall, TP3 showed promising activities to prevent cell infiltration and metastasis through modulating the tumor microenvironment balance, suggesting that TP3 merits further development for use in GBM treatments.
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Biomarcadores Tumorais/metabolismo , Movimento Celular , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Glioblastoma/imunologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Invasividade Neoplásica , Células Tumorais Cultivadas , Microambiente Tumoral/imunologiaRESUMO
Two 11,20-epoxybriaranes, including a known compound, juncenolide K (1), as well as a new metabolite, fragilide X (2), have been isolated from gorgonian Junceella fragilis collected off the waters of Taiwan. The absolute configuration of juncenolide K (1) was determined by single-crystal X-ray diffraction analysis for the first time in this study and the structure, including the absolute configuration of briarane 2 was established on the basis of spectroscopic analysis and compared with that of model compound 1. One aspect of the stereochemistry of the known compound 1 was revised. Briarane 2 was found to enhance the generation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) release from RAW 264.7 cells.
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Antozoários/química , Diterpenos/farmacologia , Mediadores da Inflamação/farmacologia , Animais , Ciclo-Oxigenase 2/metabolismo , Diterpenos/química , Diterpenos/isolamento & purificação , Mediadores da Inflamação/química , Mediadores da Inflamação/isolamento & purificação , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Taiwan , Difração de Raios XRESUMO
Osteosarcoma (OSA) is the most common type of cancer that originates in the bone and usually occurs in young children. OSA patients were treated with neoadjuvant chemotherapy and surgery, and the results were disappointing. Marine antimicrobial peptides (AMPs) have been the focus of antibiotic research because they are resistant to pathogen infection. Piscidin-1 is an AMP from the hybrid striped bass (Morone saxatilis × M. chrysops) and has approximately 22 amino acids. Research has shown that piscidin-1 can inhibit bacterial infections and has antinociception and anti-cancer properties; however, the regulatory effects of piscidin-1 on mitochondrial dysfunction in cancer cells are still unknown. We aimed to identify the effects of piscidin-1 on mitochondrial reactive oxygen species (mtROS) and apoptosis in OSA cells. Our analyses indicated that piscidin-1 has more cytotoxic effects against OSA cells than against lung and ovarian cancer cells; however, it has no effect on non-cancer cells. Piscidin-1 induces apoptosis in OSA cells, regulates mtROS, reduces mitochondrial antioxidant manganese superoxide dismutase and mitochondrial transmembrane potential, and decreases adenosine 5'-triphosphate production, thus leading to mitochondrial dysfunction and apoptosis. The mitochondrial antioxidant, mitoTempo, reduces the apoptosis induced by piscidin-1. Results suggest that piscidin-1 has potential for use in OSA treatment.
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Peptídeos Catiônicos Antimicrobianos/farmacologia , Antineoplásicos , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/patologia , Proteínas de Peixes/farmacologia , Mitocôndrias/metabolismo , Osteossarcoma/patologia , Espécies Reativas de Oxigênio/metabolismo , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/metabolismo , Sequência de Aminoácidos , Animais , Peptídeos Catiônicos Antimicrobianos/química , Bass , Proteínas de Peixes/química , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/enzimologia , Superóxido Dismutase/metabolismo , Tionucleotídeos/metabolismo , Células Tumorais CultivadasRESUMO
Two new steroids, dendronesterones D (1) and E (2), featuring with 1,4-dienone moiety, along with three known steroids, methyl 3-oxochola-4,22-diene-24-oate (3), 5α,8α-epidioxy-24(S)- methylcholesta-6,22-dien-3ß-ol (4), and 5α,8α-epidioxy-24(S)-methylcholesta-6,9(11),22-trien-3ß-ol (5), were isolated from an octocoral Dendronephthya sp. The structures of steroids 1 and 2 were elucidated by using spectroscopic methods and steroid 1 was found to exhibit significant in vitro anti-inflammatory activity in lipopolysaccharides (LPS)-induced RAW264.7 macrophage cells by inhibiting the expression of the iNOS protein.
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Antozoários/química , Anti-Inflamatórios/farmacologia , Esteroides/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Camundongos , Estrutura Molecular , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Células RAW 264.7 , Esteroides/isolamento & purificaçãoRESUMO
Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases, and neuroinflammation has been identified as one of its key pathological characteristics. Triggering receptors expressed on myeloid cells-1 (TREM-1) amplify the inflammatory response and play a role in sepsis and cancer. Recent studies have demonstrated that the attenuation of TREM-1 activity produces cytoprotective and anti-inflammatory effects in macrophages. However, no study has examined the role of TREM-1 in neurodegeneration. We showed that LP17, a synthetic peptide blocker of TREM-1, significantly inhibited the lipopolysaccharide (LPS)-induced upregulation of proinflammatory cascades of inducible nitric oxide synthase (iNOS), cyclooxygenase-2, and nuclear factor-kappa B. Moreover, LP17 enhanced the LPS-induced upregulation of autophagy-related proteins such as light chain-3 and histone deacetylase-6. We also knocked down TREM-1 expression in a BV2 cell model to further confirm the role of TREM-1. LP17 inhibited 6-hydroxydopamine-induced locomotor deficit and iNOS messenger RNA expression in zebrafish. We also observed therapeutic effects of LP17 administration in 6-hydroxydopamine-induced PD syndrome using a rat model. These data suggest that the attenuation of TREM-1 could ameliorate neuroinflammatory responses in PD and that this neuroprotective effect might occur via the activation of autophagy and anti-inflammatory pathways.
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Postnatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a common plasticizer, is associated with allergy development in childhood, suggesting that DEHP exposure may dysregulate immune response in infants. We investigated whether DEHP exposure in newborns through medical treatment affected the gut microbiota pattern and vaccine response, which are both related to immune development. In this prospective cohort study from May 1, 2016 through July 31, 2017, newborns with respiratory distress who were given intravenous infusions (IVs) were enrolled as the DEHP group, and newborns who did not receive IVs were enrolled as the control group. We excluded patients with perinatal maternal probiotics, vaginal delivery, antibiotic treatment, and exclusive human milk or formula feeding. Of 118 infants, urinary phthalate metabolite analysis revealed that the calculated DEHP concentrations of the newborns treated with IVs (nâ¯=â¯15) were higher than those in the control group (nâ¯=â¯10) (pâ¯=â¯0.0001). DEHP exposure altered bacterial communities both in composition and diversity, particularly decreases in Rothia sp. and Bifidobacterium longum in the DEHP group. Furthermore, DEHP exposure significantly enhanced anti-HBsAg-IgM responses in the DEHP group (pâ¯=â¯0.013). Early-life DEHP exposure alter gut microbiota of newborns and may change their immune responses in later life.
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Dietilexilftalato/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Vacinas contra Hepatite B/administração & dosagem , Imunoglobulina M/sangue , Plastificantes/farmacologia , Dietilexilftalato/urina , Feminino , Hidratação , Humanos , Imunoglobulina M/imunologia , Recém-Nascido , Infusões Intravenosas , Masculino , Plastificantes/análiseRESUMO
BACKGROUND: Overweight and obesity among children can cause metabolic syndrome in adulthood and are a significant public health issue. Some studies suggest that maternal pre-pregnancy body mass index (BMI) and excessive gestational weight gain during pregnancy are associated with overweight and obesity in offspring. However, it is difficult to collect information on accurate pre-pregnancy BMI and pregnancy weight gain for women living in areas where medical resources are scarce. Maternal pre-delivery BMI might be predictive of the risk of overweight and obesity among offspring of pregnant mothers living in suburban areas. METHODS: We retrospectively collected data on term neonates with appropriate weights for their gestational age born between April 2013 and October 2015. We excluded neonates with major congenital anomalies or diseases and incomplete data. Mothers with systemic diseases or drug abuse were also excluded. Offspring body weights and heights at 1- and 2-years-old were recorded. Maternal pre-delivery BMI was divided into following groups: <25, 25-29.9, and â§30 kg/m2. RESULTS: We included 261 mother-child pairs in this study. The BMIs of the offspring differed significantly among the three maternal pre-delivery BMI groups at the age of 2 years (15.18 ± 1.04, 15.83 ± 1.28, and 16.29 ± 1.61 kg/m2, p < 0.001, respectively). After adjusting for potential cofounders possibly affecting weight using multivariate linear regression, the children's BMIs (adjusted 95% CI: 0.71 [0.31-1.11]; p = 0.001) and BMI percentiles (adjusted 95% CI 15.80 [7.32-24.28]; p < 0.001) at the age of 2 years were significantly higher in those born to mothers with pre-delivery BMIs of 25-29.9 kg/m2 compared to mothers with pre-delivery BMIs <25 kg/m2. Maternal pre-delivery BMI â§30 kg/m2 was significantly associated with increased BMIs (adjusted 95% CI: 1.17 [0.72-1.63]; p < 0.001) and BMI percentiles (adjusted 95% CI: 23.48 [13.87-33.09]; p < 0.001) in their children. A maternal pre-delivery BMI of 27.16 kg/m2 was the optimal cut-off for predicting offspring overweight/obesity at the age of 2 years. DISCUSSION: Our results indicate that the maternal pre-delivery BMI was significantly associated with offspring BMI and weight gain at the age of 2 years. A maternal pre-delivery BMI of 27.16 kg/m2 might be a useful predictor for estimating the risk of overweight or obesity in offspring at the age of 2 years.
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BACKGROUND: To determine the association of prior traumatic brain injury (TBI) with subsequent diagnosis of neurodegeneration disease. METHODS: All studies from 1980 to 2016 reporting TBI as a risk factor for diagnoses of interest were identified by searching PubMed, Embase, study references, and review articles. The data and study design were assessed by 2 investigators independently. A meta-analysis was performed by RevMan 5.3. RESULTS: There were 18 studies comprising 3,263,207 patients. Meta-analysis revealed a significant association of prior TBI with subsequent dementia. The pooled odds ratio (OR) for TBI on development of dementia, FTD and TDP-43 associated disease were 1.93 (95% CI 1.47-2.55, p < 0.001), 4.44 (95% CI 3.86-5.10, p < 0.001), and 2.97 (95% CI 1.35-6.53, p < 0.001). However, analyses of individual diagnoses found no evidence that the risk of Alzheimer's disease, and Parkinson's disease in individuals with previous TBI compared to those without TBI. CONCLUSIONS: History of TBI is not associated with the development of subsequent neurodegeneration disease. Care must be taken in extrapolating from these results because no suitable criteria define post TBI neurodegenerative processes. Therefore, further research in this area is needed to confirm these questions and uncover the link between TBI and neurodegeneration disease.