Isocitrate dehydrogenase-1 (Idh1) is an important metabolic enzyme that produces NADPH by converting isocitrate to α-ketoglutarate. Idh1 is known to reduce reactive oxygen species (ROS) induced in ...cells by treatment with lipopolysaccharide (LPS) in vitro. Here, we used Idh1-deficient knockout (Idh1 KO) mice to investigate the role of Idh1 in antioxidant defense in vivo. Idh1 KO mice showed heightened susceptibility to death induced by LPS and exhibited increased serum levels of inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. The serum of LPS-injected Idh1 KO mice also contained elevated levels of AST, a marker of inflammatory liver damage. Furthermore, after LPS injection, livers of Idh1 KO mice showed histological evidence of elevated oxidative DNA damage compared with livers of wild-type (WT) mice. Idh1 KO livers showed a faster and more pronounced oxidative stress than WT livers. In line with that, Idh1 KO hepatocytes showed higher ROS levels and an increase in the NADP(+)/NADPH ratio when compared with hepatocytes isolated from WT mice. These results suggest that Idh1 has a physiological function in protecting cells from oxidative stress by regulating the intracellular NADP(+)/NADPH ratio. Our findings suggest that stimulation of Idh1 activity may be an effective therapeutic strategy for reducing oxidative stress during inflammatory responses, including the early stages of septic shock.
Flotillin microdomains, specialized lipid raft domains in cell membranes, serve as physical platforms for many different molecules important in crucial intracellular signaling pathways. Flotillin-2 ...(Flot2), together with flotillin-1, is a marker for lipid raft microdomains distinct from caveolar lipid rafts, and has been implicated in the progression of cancer and metastasis formation. Based largely on studies in xenograft models, flotillin-2 has been implicated in the progression of multiple types of human tumors, including breast cancer. In our studies, we identified flotillin-2 as highly amplified in a high-throughput comparative genomic hybridization screen of human breast cancer cell lines and breast tumor samples. Short hairpin RNA-mediated reduction of flotillin-2 protein levels significantly reduced the tumorigenicity and metastatic capability of a human breast cancer cell line in vivo. We generated mice deficient for flotillin-2 and also found a reduction of flotillin-1 protein levels and complete absence of flotillin-specific membrane microdomains in these mice. To examine the role of Flot2 in mammary tumorigenesis and lung metastasis, we used an in vivo molecular genetics approach, crossing a well-characterized transgenic mouse model of breast cancer, the MMTV-PyMT (mouse mammary tumor virus-polyoma middle T antigen) mouse, with gene-targeted Flot2(-/-) mice. Flotillin-2 deficiency lead to a striking reduction in the number of lung metastasis observed, but had no influence on primary tumor formation in this model. Our results indicate, using a novel in vivo animal model approach, that Flot2 is an important regulator of mammary tumor-derived lung metastasis.
Phosphatidylinositol phosphate (PIP) second messengers relay extracellular growth cues through the phosphorylation status of the inositol sugar, a signal transduction system that is deregulated in ...cancer. In stark contrast to PIP inositol head-group phosphorylation, changes in phosphatidylinositol (PI) lipid acyl chains in cancer have remained ill-defined. Here, we apply a mass-spectrometry-based method capable of unbiased high-throughput identification and quantification of cellular PI acyl chain composition. Using this approach, we find that PI lipid chains represent a cell-specific fingerprint and are unperturbed by serum-mediated signaling in contrast to the inositol head group. We find that mutation of Trp53 results in PIs containing reduced-length fatty acid moieties. Our results suggest that the anchoring tails of lipid second messengers form an additional layer of PIP signaling in cancer that operates independently of PTEN/PI3-kinase activity but is instead linked to p53.
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•PI acyl chain composition varies between cancer and normal cell lines•Growth factor removal does not affect PI lipid chain composition•p53 mutation leads to changes in PI acyl chain composition
Naguib et al. use a mass-spectroscopy-based method to identify and characterize phosphatidylinositol acyl chains, the lipid scaffold that forms the basis of PI3K/AKT signal transduction. Using genetic models of cancer, they identify p53 mutation as a modulator of these molecules, finding that these lipids are changed in response to genetic alterations of this tumor suppressor.
Isocitrate dehydrogenase-1 (Idh1) is an important metabolic enzyme that produces NADPH by converting isocitrate to alpha -ketoglutarate. Idh1 is known to reduce reactive oxygen species (ROS) induced ...in cells by treatment with lipopolysaccharide (LPS) in vitro. Here, we used Idh1-deficient knockout (Idh1 KO) mice to investigate the role of Idh1 in antioxidant defense in vivo. Idh1 KO mice showed heightened susceptibility to death induced by LPS and exhibited increased serum levels of inflammatory cytokines such as tumor necrosis factor- alpha and interleukin-6. The serum of LPS-injected Idh1 KO mice also contained elevated levels of AST, a marker of inflammatory liver damage. Furthermore, after LPS injection, livers of Idh1 KO mice showed histological evidence of elevated oxidative DNA damage compared with livers of wild-type (WT) mice. Idh1 KO livers showed a faster and more pronounced oxidative stress than WT livers. In line with that, Idh1 KO hepatocytes showed higher ROS levels and an increase in the NADP super(+)/NADPH ratio when compared with hepatocytes isolated from WT mice. These results suggest that Idh1 has a physiological function in protecting cells from oxidative stress by regulating the intracellular NADP super(+)/NADPH ratio. Our findings suggest that stimulation of Idh1 activity may be an effective therapeutic strategy for reducing oxidative stress during inflammatory responses, including the early stages of septic shock.
Parents of children with autism spectrum disorders (ASD) reported higher stress than those of typically developing children. The role of child problem behaviors in the relationship between autism ...spectrum symptoms and parenting stress is little known. A total of 731 parents of 177 children with ASD and 554 typically developing children in primary schools (6–11 years old) completed an ASD screening survey containing measures of parenting stress and child problem behaviors. While autism spectrum symptoms were positively associated with parenting stress, the relationship was mediated by child problem behaviors. Results suggest neither the severity of autism spectrum symptoms nor knowledge of ASD diagnosis was a primary source of parenting stress. A hypothesized path model was tested using structural equation modeling.
Purpose
Family has been found to have an influential role on clinical and recovery outcomes of people with schizophrenia. While recovery-oriented services can facilitate service users to develop a ...rich and positive identity, it is unclear how different levels of family involvement may interact with recovery-oriented services in affecting personal recovery. The present study aimed to examine how family involvement moderates the relationship between perceived recovery-orientation of services and personal narratives of Chinese people in Hong Kong who had recent onset of schizophrenia spectrum disorder longitudinally.
Method
Multi-method approach (semi-structured interview, researcher ratings, self-report measures) was adopted. 167 participants completed assessments at baseline; 93 and 68 of them were retained at 6-month and 12-month follow-up assessment, respectively.
Results
Baseline perceived recovery orientation of services significantly predicted richer personal narratives at 6-month follow-up when baseline family involvement was optimal (
B
= 0.26,
p
= 0.03, 95% CI 0.02–0.48). As to 12-month assessment, baseline perceived recovery orientation of services significantly predicted poorer personal narratives when family was perceived as under-involved at baseline (
B
= − 0.45,
p
= 0.02, 95% CI − 0.88 to − 0.07).
Conclusion
Without proper family involvement, recovery-oriented services could be ineffectual in facilitating the development of rich personal narratives for Chinese people in Hong Kong.
Mindfulness-based interventions, self-compassion training, and cognitive behavioral therapy have garnered much evidence in its salutary effects on mental health. With increasing application of ...smartphone and mobile technology on health promotion, this study investigated the efficacy and possible moderators of mindfulness, self-compassion, and cognitive behavioral psychoeducation training mobile apps in the improvement of mental health.
The aim of this study was to examine the efficacy of 3 mobile app-based programs: mindfulness-based program, self-compassion program, and cognitive behavioral psychoeducation program in improving mental well-being and reducing psychological distress. Changes in mindful awareness and self-compassion were also assessed. To further delineate the suitability of each program for different types of individuals, individual difference variables (ie, discomfort with emotions and tolerance for ambiguity) were explored for potential moderation.
This study was a 3-arm, randomized, controlled, noninferiority trial examining the efficacy of mindfulness-based program, self-compassion program, and cognitive behavioral psychoeducation. Participants were randomized into either 1 of the 3 conditions. Throughout the 4-week, 28-session program, participants spent 10-15 min daily reviewing the course content and practicing various related exercises. At preprogram, postprogram, and 3-month follow-up, participants also completed Web-based measures of mental well-being, psychological distress, mindful-awareness, and self-compassion as well as the proposed moderators.
Among the 2161 study participants, 508 and 349 completed the post- and 3-month follow-up assessment, respectively. All 3 conditions (mindfulness-based program: N=703; cognitive behavioral psychoeducation: N=753; self-compassion program: N=705) were found to be efficacious in improving mental well-being and reducing psychological distress. All conditions enhanced mindful awareness at postprogram. Significant interaction effect was found on self-compassion; cognitive behavioral psychoeducation and self-compassion program, but not mindfulness-based program, significantly enhanced self-compassion at postprogram. No significant differences regarding usage and users' satisfaction were found among the 3 conditions. None of the proposed moderators were found to be significant.
Mindfulness-based, self-compassion, and cognitive behavioral psychoeducation mobile apps were efficacious in improving mental well-being and reducing psychological distress among adults at postprogram and 3-month follow-up. Future app-based psychological training programs should consider gamification and personalization of content or feedback to enhance engagement and mitigate the high attrition rates that are common in app-based health promotion programs.
Chinese Clinical Trial Registry (ChiCTR) ChiCTR-TRC-13003468; http://www.chictr.org.cn/hvshowproject.aspx?id=6220 (Archived by WebCite at http://www.webcitation.org/734PlOz50).
Targeted cancer therapies that use genetics are successful, but principles for selectively targeting tumor metabolism that is also dependent on the environment remain unknown. We now show that ...differences in rate-controlling enzymes during the Warburg effect (WE), the most prominent hallmark of cancer cell metabolism, can be used to predict a response to targeting glucose metabolism. We establish a natural product, koningic acid (KA), to be a selective inhibitor of GAPDH, an enzyme we characterize to have differential control properties over metabolism during the WE. With machine learning and integrated pharmacogenomics and metabolomics, we demonstrate that KA efficacy is not determined by the status of individual genes, but by the quantitative extent of the WE, leading to a therapeutic window in vivo. Thus, the basis of targeting the WE can be encoded by molecular principles that extend beyond the status of individual genes.
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•Flux control analysis reveals GAPDH as rate limiting during the Warburg effect (WE)•Koningic acid (KA) is nominated and validated as a specific GAPDH inhibitor•Machine learning shows that the quantitative extent of the WE predicts KA response•Partial GAPDH inhibition is tolerable and selective for highly glycolytic tumors
Liberti et al. use metabolic control analysis and multi-omics approaches to show that the enzyme GAPDH is rate limiting for the Warburg effect in cancer cells. They identify a therapeutic window where partial GAPDH inhibition is more selective for highly glycolytic tumors, highlighting how metabolism is an integral part of precision medicine.
Although self-compassion has been extensively studied in the recent decades, the representation of self-compassion as a unitary measure or the presence of self-warmth (i.e., presence of the positive ...components: self-kindness, common humanity, and mindfulness) and self-coldness (i.e., presence of the negative components: self-judgment, isolation, and mindfulness) remains controversial. Moreover, the differential effects of the six components of self-compassion on mental well-being and psychological distress have not been systematically investigated. To synthesize the differential effects of the six components of self-compassion and to examine how people in different cultures may associate the positive and negative components of self-compassion differentially, the present meta-analysis synthesized 183 effect sizes across 27 cultures. Results showed that the negative components of self-compassion (rs = 0.44 to 0.45) showed greater effect sizes with psychological distress than the positive counterparts (rs = −0.17 to −0.29) whereas the positive components of SCS (rs = 0.29 to.39) showed greater effect sizes with mental well-being than the negative counterparts (rs = −0.29 to −0.36), with the exception of common humanity and isolation (r = 0.29 and − 0.36). Cultural orientation of dialecticism moderated the association between the positive and the negative components of self-compassion, with dialectical cultures showing lower associations between the two opposing components. Findings have implications on the design and implementation of self-compassion interventions cross-culturally.
•Strengths of the Self-compassion Scale (SCS) components with distress and well-being were meta-analyzed.•183 effect sizes across 27 cultures with SCS, well-being, or distress were identified.•Negative SCS components have stronger associations with psychological distress.•Dialecticism moderates the association between positive and negative SCS components.
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