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1.
Sci Rep ; 14(1): 15101, 2024 07 02.
Article in English | MEDLINE | ID: mdl-38956051

ABSTRACT

The etiology of tic disorders (TDs) is not precisely known, although several lines of evidence suggest involvement of the immune system in pathogenesis. Here, we aimed to determine the expression levels of pro-inflammatory and anti-inflammatory cytokines in children with TD and compare them with those of healthy controls. Furthermore, we also evaluated their association with clinical variables in the TD group. Within the study period, 88 children with tic disorders and 111 healthy control children were enrolled. Most children with tic disorders were diagnosed with Tourette's disorder (n = 47, 53.4%) or persistent motor tic disorder (n = 39, 44.3%), while the remainder (n = 2, 2.3%) were diagnosed with persistent vocal tic disorder. We found that children with tic disorders had significantly elevated levels of IL-1ß, TNF-α, IL-6 and IL-4 expression, while we detected lower expression levels of IL-17 in children with tic disorders. Our findings provide a molecular landscape of cytokine expression in children with TD, which may suggest a proinflammatory state not affected by the presence of comorbidity and symptom severity. Delineating the contribution of alterations in the immune system to the pathogenesis of tic disorders may pave the way for better therapeutic interventions.


Subject(s)
Cytokines , Tic Disorders , Humans , Child , Male , Female , Adolescent , Cytokines/metabolism , Case-Control Studies , Child, Preschool
2.
Oxf Med Case Reports ; 2024(3): omae014, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38532756

ABSTRACT

Metastatic breast cancer remains to be a major cause of cancer-related deaths in women. Exploring the molecular mechanisms to identify targetable alterations in progressing breast cancer and developing functional tools to predict therapy response in these patients are needed. In this report, we present a case of breast cancer patient who progressed following surgery and adjuvant endocrine therapy. Radiological and pathological analyses revealed metastasis to liver and brain. Paired liquid biopsies demonstrated acquired ERBB2 mutations in addition to TP53 and PIK3CA mutations, which were also present before progression. BH3 profiling test demonstrated decreased mitochondrial cell death priming in CTCs of the patient after progression. In conclusion, novel personalized treatment strategies are needed to monitor metastatic breast cancer patients for better clinical benefit.

3.
Toxicol In Vitro ; 95: 105757, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38061602

ABSTRACT

In the present work, the mechanism of anticancer activity of some pyrrolopyrimidine derivatives was evaluated. Compounds 5 and 8 exhibiting significant antiproliferative activity against HT-29 cells with IC50 values of 4.17 µM and 2.96, arrested the cells at the G2/M phase and significantly induced apoptosis. The apoptotic potential of the compounds has been verified via ELISA assay, which resulted in increased BAX, PUMA, BIM, and cleaved caspase 3 expression and decreased BCL-XL and MCL-1 protein levels in HT-29 cells. Moreover, the immunofluorescence technique showing that compounds 5 and 8-treatment reduced Ki67 immunolocalization and increased the caspase 3 and p53 immunolocalization confirmed the apoptotic activity. While treatment of HT-29 cells to compounds 5 and 8 inhibited Akt and ERK1/2, there are no alterations in JNK and p38 signaling pathways. According to molecular docking results, compounds 5 and 8 occupied the active site of Akt kinase and showed important hydrogen bonding interactions with key amino acids. Also, siRNA-mediated depletion of BIM, PUMA, and BAX/BAK expression decreased apoptotic response in HT-29 cells upon exposure to compound 5 and compound 8. Compounds 5 and 8 trigger the activation of mitochondrial apoptosis in HT-29 cells. Additionally, we found that proapoptotic BH3-only proteins BIM and PUMA are required for the full engagement of mitochondrial apoptosis signaling. However, p53 was dispensable for compound 5- or compound 8-induced apoptosis in HT-29 cells.


Subject(s)
Apoptosis Regulatory Proteins , Colonic Neoplasms , Pyrimidines , Pyrroles , Humans , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Caspase 3/metabolism , bcl-2-Associated X Protein/metabolism , HT29 Cells , Proto-Oncogene Proteins c-akt/metabolism , Tumor Suppressor Protein p53 , Molecular Docking Simulation , bcl-2 Homologous Antagonist-Killer Protein/metabolism , bcl-2 Homologous Antagonist-Killer Protein/pharmacology , Cell Line, Tumor , Apoptosis , Colonic Neoplasms/drug therapy , Proto-Oncogene Proteins c-bcl-2/metabolism
4.
Heliyon ; 9(10): e20766, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37867841

ABSTRACT

The aim of this study is to determine the functioning of adults with autism spectrum disorders (ASDs) diagnosed in childhood and depression and burnout levels among their parents. A total of 261 adults with ASDs and their parents were recruited for the study. Both parents completed the Beck Depression and Maslach Burnout Inventories and reported the functioning of their adult offspring with ASDs. Only 5.4 % of our sample reported "good" or "very good" outcomes. The most common psychiatric comorbidities were intellectual disabilities and attention-deficit/hyperactivity disorder. Maternal burnout and depression scores were significantly elevated compared to those of fathers. There is an undeniable urgent need for more research to identify the needs of adults and families suffering from ASD. Modifications for those with ASD may have to be made for support in workplaces, achieving driving licenses, using public transportation and attendance at tertiary education.

6.
Turk J Ophthalmol ; 52(3): 174-178, 2022 06 29.
Article in English | MEDLINE | ID: mdl-35770050

ABSTRACT

Objectives: The aim of the study was to present a new genetic association presenting with gastrointestinal tract malformations (GTMs) and familial exudative vitreoretinopathy (FEVR)-like disease and review the genetics of Hedgehog signaling. Materials and Methods: Three neonates were diagnosed with FEVR-like retinal vascular disease upon routine ophthalmological examination during hospitalization in the neonatal surgical intensive care unit for GTMs. Genetic analysis of the neonates was performed. Results: Gestational age of the neonates was 39, 38, and 39 weeks and birth weights were 3,500, 3,600, and 3,300 grams, respectively. All six eyes of the three infants were treated by laser photocoagulation. Recurrence was not seen in any of the eyes. Genetical analysis of all the neonates diagnosed with FEVR-like disease revealed defects in the Hedgehog pathway. Conclusion: FEVR is a genetically well-defined retinal vascular disease. The current study is the first to show an association between FEVR-like retinal vascular disease and GTMs. This study demonstrates the importance of the Hedgehog pathway in retinal vascular and gut development.


Subject(s)
Eye Diseases , Retinal Diseases , Vascular Diseases , Familial Exudative Vitreoretinopathies , Hedgehog Proteins/genetics , Humans , Infant , Infant, Newborn , Retinal Diseases/diagnosis
7.
Drug Metab Pers Ther ; 37(3): 261-269, 2022 09 01.
Article in English | MEDLINE | ID: mdl-35218180

ABSTRACT

OBJECTIVES: Cytochrome P450 (CYP450) is a major enzyme system involved in drug metabolism as well as regulation of brain function. Although individual variability in CYP enzymes have been studied in terms of personality traits and treatment effects, no study up to now evaluated CYP polymorphisms in children with attention deficit/hyperactivity disorder (ADHD). We aimed to define the genetic profiles of CYP2D6 and CYP2C19 relevant alleles in children with ADHD according to treatment status and compare the frequencies according to past results. METHODS: Three hundred and seventeen patients with ADHD-Combined Presentation were enrolled; symptom severity was evaluated by parents and clinicians while adverse effects of previous treatments were evaluated with parent and child reports. Reverse blotting on strip assays was used for genotyping and descriptive and bivariate analyses were conducted. A p-value was set at 0.05 (two-tailed). RESULTS: Children were divided into treatment-naïve (n=194, 61.2%) and treatment-resistant (n=123, 38.8%) groups. Within the whole sample PM, EM and UM status according to 2D6 were 3.8% (n=12), 94.3% (n=299) and 21.9% (n=6); respectively. PM, IM, EM and UM status according to 2C19 were 2.5% (n=8), 19.8% (n=63), 48.6% (n=154) and 29.0% (n=92), respectively. No relationship with treatment resistance, comorbidity or gender could be found. Importantly, CYP2C19 UMs were significantly more frequent in ADHD patients compared to previous studies in the general population. CONCLUSIONS: CYPs may be a rewarding avenue of research to elucidate the etiology and treatment of patients with ADHD.


Subject(s)
Attention Deficit Disorder with Hyperactivity , Cytochrome P-450 CYP2C19 , Cytochrome P-450 CYP2D6 , Attention Deficit Disorder with Hyperactivity/drug therapy , Attention Deficit Disorder with Hyperactivity/genetics , Child , Cytochrome P-450 CYP2C19/genetics , Cytochrome P-450 CYP2D6/genetics , Genotype , Humans
8.
Cell Death Discov ; 7(1): 189, 2021 Jul 22.
Article in English | MEDLINE | ID: mdl-34294688

ABSTRACT

Breast cancer is the most common cancer with a high rate of mortality and morbidity among women worldwide. Estrogen receptor status is an important prognostic factor and endocrine therapy is the choice of first-line treatment in ER-positive breast cancer. However, most tumors develop resistance to endocrine therapy. Here we demonstrate that BH3 profiling technology, in particular, dynamic BH3 profiling can predict the response to endocrine therapy agents as well as the development of acquired resistance in breast cancer cells independent of estrogen receptor status. Immunofluorescence analysis and subcellular fractionation experiments revealed distinct ER-α and ER-ß subcellular localization patterns in breast cancer cells, including mitochondrial localization of both receptor subtypes. shRNA-mediated depletion of ER-ß in breast cancer cells led to resistance to endocrine therapy agents and selective reconstitution of ER-ß in mitochondria restored sensitivity. Notably, mitochondria-targeted ER-α did not restore sensitivity, even conferred further resistance to endocrine therapy agents. In addition, expressing mitochondria-targeted ER-ß in breast cancer cells resulted in decreased mitochondrial respiration alongside increased total ROS and mitochondrial superoxide production. Furthermore, our data demonstrated that mitochondrial ER-ß can be successfully targeted by the selective ER-ß agonist Erteberel. Thus, our findings provide novel findings on mitochondrial estrogen signaling in breast cancer cells and suggest the implementation of the dynamic BH3 technique as a tool to predict acquired endocrine therapy resistance.

9.
Int J Biochem Cell Biol ; 137: 106028, 2021 08.
Article in English | MEDLINE | ID: mdl-34171479

ABSTRACT

Antiapoptotic and proapoptotic BCL-2 protein family members regulate mitochondrial apoptotic pathway. Small molecule inhibitors of antiapoptotic BCL-2 proteins including BCL-2-specific inhibitor ABT-199 (Venetoclax) are in clinical development. However, the efficiency of ABT-199 as a single agent in solid tumors is limited. We performed a high-throughput RNAi kinome screen targeting 691 kinases to identify potentially targetable kinases to enhance ABT-199 response in breast cancer cells. Our studies identified Wee1 as the primary target kinase to overcome resistance to ABT-199. Depletion of Wee1 by siRNA-mediated knockdown or inhibition of Wee1 by the small molecule Wee1 inhibitor AZD1775 sensitized SKBR3, MDA-MB-468, T47D and CAMA-1 breast cancer cells to ABT-199 along with decreased MCL1. BH3-only proteins PUMA and BIM functionally contribute to apoptosis signaling following co-targeting BCL-2 and Wee1. Suppression of Wee1 function increased mitochondrial cell death priming. Furthermore, we found that Wee1 inhibition altered MCL1 phosphorylation and protein stability, which led to HUWE1-mediated MCL1 degradation. Our findings suggest that Wee1 inhibition can overcome resistance to ABT-199 and provide a rationale for further translational investigation of BCL-2 inhibitor/Wee1 inhibitor combination in breast cancer.


Subject(s)
Breast Neoplasms/pathology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Cycle Proteins/antagonists & inhibitors , Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , RNA Interference , Sulfonamides/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Proliferation , Female , High-Throughput Screening Assays , Humans , Protein Kinases/chemistry , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Tumor Cells, Cultured
11.
J Autism Dev Disord ; 51(11): 4086-4099, 2021 Nov.
Article in English | MEDLINE | ID: mdl-33459915

ABSTRACT

The diagnosis of autism spectrum disorder (ASD) in a child affects family processes, increases parenting stress and marital conflicts, and may lead to parental psychopathology. It may also affect the prognosis for their children. The aim of this study is to determine depression and burnout levels as well as their predictors among parents of children with ASD compared with those of healthy children. We also sought to evaluate rate of complementary and alternative medicine (CAM) interventions among parents and explore the associations of this phenomenon in an exploratory fashion. 145 children with ASD and 127 control children were enrolled along with their mothers and fathers. Beck Depression Inventory and Maslach Burnout Inventory were used to evaluate parents' depression symptoms and burnout levels. Symptoms of children with ASDs were evaluated according to the Childhood Autism Rating Scale by the clinicians. Family, child and CAM variables were screened by means of a sociodemographic data form. Descriptive, bivariate and correlation analyses were used in statistical evaluations. Predictors of burnout were evaluated with multiple regression analysis. Burnout and depression levels among parents of children with ASD were significantly elevated compared to controls. Burnout levels of mothers were significantly elevated compared to fathers while depression scores of fathers were significantly elevated compared to mothers. Maternal burnout was significantly predicted by presence of functional speech in child while paternal burnout was significantly predicted by paternal vocation. Maternal depression was associated with paternal depression, lack of speech in child and attendance of child to special education services. Paternal depression was associated with autistic symptom severity and maternal depression. More than half the parents sought CAM interventions. Education level did not affect search for CAM interventions while both maternal and paternal psychopathology and presence of epilepsy among children increased use of CAM methods. Psychological support should be provided to both mothers and fathers of a child receiving a diagnosis of ASD. Addressing parents' burnout and stress levels and facilitating their negotiation of knowledge on etiology and treatments for ASD may be beneficial for the family unit as a whole.


Subject(s)
Autism Spectrum Disorder , Autism Spectrum Disorder/epidemiology , Burnout, Psychological/epidemiology , Case-Control Studies , Child , Cross-Sectional Studies , Depression/epidemiology , Female , Humans , Male , Mothers , Parents , Stress, Psychological
12.
Chem Biol Interact ; 330: 109236, 2020 Oct 01.
Article in English | MEDLINE | ID: mdl-32866467

ABSTRACT

A series of novel pyrrolopyrimidine urea derivatives were synthesized and evaluated for their anticancer activity against colon cancer cell lines. Compounds showed the remarkable cytotoxic activity on HCT-116 wt cell line. The most potent compound 4c (IC50 = 0.14 µM) induced apoptosis in HCT-116 wt and HCT-116 p53-/- cell lines. Otherwise, treatment of HCT-116 BAX-/-BAK-/- cells with compound 4c didn't lead to activation of apoptosis, suggesting that compound 4c induces apoptotic cell death by activating BAX/BAK-dependent pathway. Moreover, while the compound 4c increase the activation of caspase-3 and caspase-9 levels in HCT-116 wt and HCT-116 p53-/- cells, caspase-3 or caspase-9 activation was not observed in HCT-116 BAX-/-BAK-/- cells. In addition, compound 4c induced mitochondrial apoptosis in cells grown as oncospheroids, which better mimic the in vivo milieu of tumors. 4c treatment also activated JNK along with inhibition of prosurvival kinases such as Akt and ERK 1/2 in HCT-116 wt and HCT-116 p53 -/- cells as well as in HCT-116 BAX-/-BAK-/- cells. Notably, our results indicated that compound 4c induced mitochondrial apoptosis through activation p53-independent apoptotic signaling pathways.


Subject(s)
Apoptosis/drug effects , Colonic Neoplasms/drug therapy , Pyrimidines/pharmacology , Pyrroles/pharmacology , Tumor Suppressor Protein p53/physiology , Caspase 3/genetics , Caspase 9/genetics , Cell Line, Tumor , Colonic Neoplasms/pathology , Gene Knockout Techniques , HCT116 Cells , Humans , Mitochondria/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Tumor Suppressor Protein p53/genetics , bcl-2 Homologous Antagonist-Killer Protein/genetics , bcl-2-Associated X Protein/genetics
13.
Apoptosis ; 25(11-12): 799-816, 2020 12.
Article in English | MEDLINE | ID: mdl-32901335

ABSTRACT

Ovarian cancer remains one of the most frequent causes of cancer-related death in women. Many patients with ovarian cancer suffer from de novo or acquired resistance to chemotherapy. Here, we report that RAB25 suppresses chemotherapy-induced mitochondrial apoptosis signaling in ovarian cancer cell lines and primary ovarian cancer cells. RAB25 blocks chemotherapy-induced apoptosis upstream of mitochondrial outer membrane permeabilization by either increasing antiapoptotic BCL-2 proteins or decreasing proapoptotic BCL-2 proteins. In particular, BAX expression negatively correlates with RAB25 expression in ovarian cancer cells. BH3 profiling assays corroborated that RAB25 decreases mitochondrial cell death priming. Suppressing RAB25 by means of RNAi or RFP14 inhibitory hydrocarbon-stapled peptide sensitizes ovarian cancer cells to chemotherapy as well as RAB25-mediated proliferation, invasion and migration. Our data suggest that RAB25 is a potential therapeutic target for ovarian cancer.


Subject(s)
Apoptosis , Drug Resistance, Neoplasm , Ovarian Neoplasms/metabolism , rab GTP-Binding Proteins/physiology , Adult , Aged , Cell Cycle , Cell Line, Tumor , Cell Movement , Cell Proliferation , Female , Humans , Middle Aged , Mitochondria , Neoplasm Invasiveness , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Proto-Oncogene Proteins c-bcl-2/metabolism , Signal Transduction , rab GTP-Binding Proteins/metabolism
14.
Cytokine ; 133: 155152, 2020 09.
Article in English | MEDLINE | ID: mdl-32563959

ABSTRACT

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in communication and social interaction as well as restricted interests and repetitive behaviors. The pathogenesis of ASD is not completely understood, but a growing body of research has demonstrated that the immune response may be a contributing factor in the etiology and/ or ontogeny of ASD. The aim of this study was to determine the expression levels of IL-1ß, IL-1α, IL-4, IL-6, IL-17, TNF-α and TGF-ß in peripheral blood mononuclear cells of children with ASD and healthy controls in order to determine the contributions of cytokines to ASD. Within the study timeframe, 195 children with ASDs (80.5% male) and 162 controls (73.6% male) were enrolled. Most children with ASD had a comorbid disorder (n = 114, 58.5%), with the most common diagnoses as Intellectual Developmental Disorder (IDD, n = 64, 32.8%) and ADHD (n = 64, 32.8%). The majority of children with ASD had severe autistic symptoms as evaluated via Childhood Autism Rating Scale (CARS, n = 130, 64.6%). The mean CARS score in the ASD sample was 40.8 (S.D. = 7.6). The patients with ASD were found to have significantly higher levels of IL-6 (p < 0.001) and significantly lower levels of IL-17 (p < 0.05, all Bonferroni corrected). Treatment tended to affect IL-4 levels. Lastly, discriminant function analysis (DFA) revealed that a combination of IL-6, IL-17 and IL-1α correctly classified 56.6% of cases. Despite extensive immunological evidence suggesting immune system aberrations, further research is required to clarify the relationship between immune profiles and ASD symptoms.


Subject(s)
Autism Spectrum Disorder/metabolism , Autistic Disorder/metabolism , Cytokines/metabolism , Adult , Cells, Cultured , Child , Female , Humans , Immunity/physiology , Interleukin-1beta/metabolism , Leukocytes, Mononuclear/metabolism , Male , Turkey
15.
Immunobiology ; 225(3): 151913, 2020 05.
Article in English | MEDLINE | ID: mdl-32113788

ABSTRACT

Immune dysregulation may be important in the etiology of obsessive-compulsive and related disordersandbody-focusedrepetitivebehaviors, such as Trichotillomania (TTM). The role of inflammation and inflammatory markers in TTM has received relatively little attention. This study was aimed to determine the expression levels of inflammatory markers (i.e. IL-1ß, IL-1α, IL-4, IL-6, IL-17, TNF-α and TGF-ß) in peripheral blood mononuclear cells of children with TTM and healthy controls and to evaluate their association with clinical variables. Seventy-seven patients with TTM and 107 healthy controls were enrolled in the study. Peripheral blood was collected in standardized conditions. The mean age of patients and controls did not differ significantly (10.8 ± 4.4 and 12.0 ± 3.2 years; respectively). The majority of patients with TTM and controls were females (n = 55, 71.4 % and n = 55, 51.4 %; respectively); with a greater preponderance of females among TTM. Patients with TTM had significantly elevated expression levels of TNF-α, IL-6 and IL-17 compared to controls. However, the expression level of IL-4 was significantly reduced in TTM patients compared to controls. Accordingly, we found a pro-inflammatory state in TTM and those findings may suggest novel treatment options for TTM and further, cross-disciplinary studies focusing on neuro- inflammation in TTM conducted on larger samples are needed.


Subject(s)
Biomarkers , Disease Susceptibility , Immunotherapy , Trichotillomania/etiology , Trichotillomania/therapy , Adolescent , Age Factors , Case-Control Studies , Child , Cytokines/blood , Cytokines/metabolism , Disease Management , Female , Humans , Inflammation Mediators/blood , Inflammation Mediators/metabolism , Male , Phenotype , Sex Factors , Trichotillomania/diagnosis , Trichotillomania/metabolism
16.
Med Res Rev ; 39(1): 146-175, 2019 01.
Article in English | MEDLINE | ID: mdl-29846950

ABSTRACT

Circumvention of apoptotic machinery is one of the distinctive properties of carcinogenesis. Extensively established key effectors of such apoptotic bypass mechanisms, the antiapoptotic BCL-2 (apoptosis regulator BCL-2) proteins, determine the response of cancer cells to chemotherapeutics. Within this background, research and development of antiapoptotic BCL-2 inhibitors were considered to have a tremendous amount of potential toward the discovery of novel pharmacological modulators in cancer. In this review, milestone achievements in the development of selective antiapoptotic BCL-2 proteins inhibitors for BCL-2, BCL-XL (BCL-2-like protein 1), and MCL-1 (induced myeloid leukemia cell differentiation protein MCL-1) were summarized and their future implications were discussed. In the first section, the design and development of BCL-2/BCL-XL dual inhibitor navitoclax, as well as the recent advances and clinical experience with selective BCL-2 inhibitor venetoclax, were synopsized. Preclinical data from selective BCL-XL inhibitors, which are currently undergoing extensive testing as a single agent or in combination with other therapeutic agents, were further summarized. In the second section, MCL-1 inhibitors developed as potential anticancer agents were reviewed regarding their specificity toward MCL-1. Explicitly, studies leading to the identification of MCL-1, nonselective and selective targeting of MCL-1, and recently initiated clinical trials were compiled in chronological order. Based on these concepts, future directions were further discussed for increasing selectivity in the design of prosurvival BCL-2 member inhibitors.


Subject(s)
Apoptosis , Drug Delivery Systems , Neoplasms/metabolism , Neoplasms/pathology , Proto-Oncogene Proteins c-bcl-2/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Clinical Trials as Topic , Humans
17.
Bioorg Chem ; 83: 511-519, 2019 03.
Article in English | MEDLINE | ID: mdl-30458413

ABSTRACT

In this work we described the synthesis and evaluation of cytotoxic and apoptotic activity of novel pyrrolopyrimidine derivatives against A549, PC3 and MCF-7 cells. Among the synthesized compounds, 6b, 8a, 9a and 7a, 8b displayed the significant cytotoxic activities against A549 and PC3 cells with IC50 value of 0.35, 1.48, 1.56 and 1.04, 1.89 µM, respectively. It was found that A549 cells were more sensitive to synthesized compounds than PC3 and MCF-7 cells. In order to evaluate the mechanism of cytotoxic activity in A549, compounds 6b, 8a and 9a were selected for further studies. Annexin V binding assay and western blot analysis results revealed that 6b, 8a and 9a induced apoptosis in A549 cells by intrinsic apoptotic pathway through the activation pro-apoptotic proteins such as Bim, Bax, Bak, Puma and deactivation of anti-apoptotic proteins including Bcl-2, Mcl-1 and Bcl-XL accompanied by the activation of caspase-3, caspase-9 and cleavage of PARP. Also, compounds 6b, 8a and 9a triggered apoptosis in HCT116 wt cells via activation of caspase-3 and caspase-9, but not in HCT116 Bax/Bak KO cells, indicating resistance to 6b, 8a and 9a treatment.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Pyrimidines/pharmacology , Pyrroles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Caspase 3/metabolism , Caspase 9/metabolism , Cell Line, Tumor , Drug Design , Humans , Imatinib Mesylate/pharmacology , Proto-Oncogene Proteins c-bcl-2/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry
18.
Hum Mutat ; 39(10): 1344-1348, 2018 10.
Article in English | MEDLINE | ID: mdl-30058754

ABSTRACT

We present three siblings afflicted with a disease characterized by cerebellar ataxia, cerebellar atrophy, pyramidal tract damage with increased lower limb tendon reflexes, and onset of 31 to 57 years, which is not typical for a known disease. In a region of shared homozygosity in patients, exome sequencing revealed novel homozygous c.*240T > C variant in the 3'UTR of STUB1, the gene responsible for autosomal recessive spinocerebellar ataxia 16 (SCAR16). In other genes, such an alteration of the evolutionarily highly conserved polyadenylation signal from AATAAA to AACAAA is known to highly impair polyadenylation. In contrast, RNA sequencing and quantification revealed that neither polyadenylation nor stability of STUB1 mRNA is affected. In silico analysis predicted that the secondary structure of the mRNA is altered. We propose that this change underlies the extremely low amounts of the encoded protein in patient leukocytes.


Subject(s)
Genetic Variation , Poly A , Polyadenylation , Ubiquitin-Protein Ligases/genetics , 3' Untranslated Regions , Brain/abnormalities , Brain/diagnostic imaging , Cerebellar Ataxia/diagnosis , Cerebellar Ataxia/genetics , DNA Mutational Analysis , Humans , Magnetic Resonance Imaging , Pedigree
19.
EMBO Rep ; 19(9)2018 09.
Article in English | MEDLINE | ID: mdl-29987135

ABSTRACT

Akt is a pro-survival kinase frequently activated in human cancers and is associated with more aggressive tumors that resist therapy. Here, we connect Akt pathway activation to reduced sensitivity to chemotherapy via Akt phosphorylation of Bax at residue S184, one of the pro-apoptotic Bcl-2 family proteins required for cells to undergo apoptosis. We show that phosphorylation by Akt converts the pro-apoptotic protein Bax into an anti-apoptotic protein. Mechanistically, we show that phosphorylation (i) enables Bax binding to pro-apoptotic BH3 proteins in solution, and (ii) prevents Bax inserting into mitochondria. Together, these alterations promote resistance to apoptotic stimuli by sequestering pro-apoptotic activator BH3 proteins. Bax phosphorylation correlates with cellular resistance to BH3 mimetics in primary ovarian cancer cells. Further, analysis of the TCGA database reveals that 98% of cancer patients with increased BAX levels also have an upregulated Akt pathway, compared to 47% of patients with unchanged or decreased BAX levels. These results suggest that in patients, increased phosphorylated anti-apoptotic Bax promotes resistance of cancer cells to inherent and drug-induced apoptosis.


Subject(s)
Apoptosis , Drug Resistance, Neoplasm , Proto-Oncogene Proteins c-akt/metabolism , bcl-2-Associated X Protein/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Cell Membrane Permeability , Cells, Cultured , Female , Humans , MCF-7 Cells , Mitochondria/metabolism , Mutation , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Peptide Fragments/metabolism , Phosphorylation , Protein Binding , Proto-Oncogene Proteins/metabolism , bcl-2-Associated X Protein/genetics
20.
Brain Dev ; 40(10): 857-864, 2018 Nov.
Article in English | MEDLINE | ID: mdl-29921473

ABSTRACT

OBJECTIVE: Attention deficit and hyperactivity disorder (ADHD) is a neuro-developmental disorder related to internalizing and externalizing disorders as well as somatic complaints and disorders. This study was conducted to evaluate the prevalence of headache subtypes, epilepsy, atopic disorders, motion sickness and recurrent abdominal pain among children and adolescents with ADHD and their parents. METHODS: In a multi-center, cross-sectional, familial association study using case-control design, treatment naïve children and adolescents between 6 and 18 years of age diagnosed with ADHD according to the DSM-5 criteria as well as age- and gender-matched healthy controls and their parents were evaluated by a neurologist and analyzed accordingly. RESULTS: 117 children and adolescents with ADHD and 111 controls were included. Headache disorder diagnosis was common for both patients and healthy controls (59.0% vs. 37.8%), with a significantly elevated rate in the ADHD group (p = 0.002). Migraine was found in 26.0% of ADHD patients and 9.9% of healthy controls. Tension headache was found in 32.4% of ADHD patients and 27.9% of healthy controls. Headache diagnosis was also found to be significantly more common in mothers of children with ADHD than control group mothers (90.5% vs. 36.6%, p < 0.001). CONCLUSION: Headache diagnoses and specifically migraines were significantly more common among children with ADHD and their mothers, while recurrent abdominal pain was elevated in both parents and ADHD patients. Migraine is an important part of ADHD comorbidity, not only for children but also for mothers. Motion sickness may be reduced among families of ADHD probands.


Subject(s)
Attention Deficit Disorder with Hyperactivity/epidemiology , Migraine Disorders/epidemiology , Mothers/statistics & numerical data , Tension-Type Headache/epidemiology , Adolescent , Adult , Case-Control Studies , Child , Comorbidity , Cross-Sectional Studies , Female , Humans , Male , Turkey/epidemiology
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