Decreased Glucose Metabolism Research Articles

The Differential Phosphorylation-Dependent Signaling and Glucose Immunometabolic Responses Induced during Infection by Salmonella Enteritidis and Salmonella Heidelberg in Chicken Macrophage-like cells.

Salmonella is a burden to the poultry, health, and food safety industries, resulting in illnesses, food contamination, and recalls. Salmonella enterica subspecies enterica Enteritidis (S. Enteritidis) is one of the most prevalent serotypes isolated from poultry. Salmonella enterica subspecies enterica Heidelberg (S. Heidelberg), which is becoming as prevalent as S. Enteritidis, is one of the five most isolated serotypes. Although S. Enteritidis and S. Heidelberg are almost genetically identical, they both are capable of inducing different immune and metabolic responses in host cells to successfully establish an infection. Therefore, using the kinome peptide array, we demonstrated that S. Enteritidis and S. Heidelberg infections induced differential phosphorylation of peptides on Rho proteins, caspases, toll-like receptors, and other proteins involved in metabolic- and immune-related signaling of HD11 chicken macrophages. Metabolic flux assays measuring extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) demonstrated that S. Enteritidis at 30 min postinfection (p.i.) increased glucose metabolism, while S. Heidelberg at 30 min p.i. decreased glucose metabolism. S. Enteritidis is more invasive than S. Heidelberg. These results show different immunometabolic responses of HD11 macrophages to S. Enteritidis and S. Heidelberg infections.

Palbociclib treatment alters nucleotide biosynthesis and glutamine dependency in A549 cells

BackgroundAberrant activity of cell cycle proteins is one of the key somatic events in non-small cell lung cancer (NSCLC) pathogenesis. In most NSCLC cases, the retinoblastoma protein tumor suppressor (RB) becomes inactivated via constitutive phosphorylation by cyclin dependent kinase (CDK) 4/6, leading to uncontrolled cell proliferation. Palbociclib, a small molecule inhibitor of CDK4/6, has shown anti-tumor activity in vitro and in vivo, with recent studies demonstrating a functional role for palbociclib in reprogramming cellular metabolism. While palbociclib has shown efficacy in preclinical models of NSCLC, the metabolic consequences of CDK4/6 inhibition in this context are largely unknown.MethodsIn our study, we used a combination of stable isotope resolved metabolomics using [U-13C]-glucose and multiple in vitro metabolic assays, to interrogate the metabolic perturbations induced by palbociclib in A549 lung adenocarcinoma cells. Specifically, we assessed changes in glycolytic activity, the pentose phosphate pathway (PPP), and glutamine utilization. We performed these studies following palbociclib treatment with simultaneous silencing of RB1 to define the pRB-dependent changes in metabolism.ResultsOur studies revealed palbociclib does not affect glycolytic activity in A549 cells but decreases glucose metabolism through the PPP. This is in part via reducing activity of glucose 6-phosphate dehydrogenase, the rate limiting enzyme in the PPP. Additionally, palbociclib enhances glutaminolysis to maintain mitochondrial respiration and sensitizes A549 cells to the glutaminase inhibitor, CB-839. Notably, the effects of palbociclib on both the PPP and glutamine utilization occur in an RB-dependent manner.ConclusionsTogether, our data define the metabolic impact of palbociclib treatment in A549 cells and may support the targeting CDK4/6 inhibition in combination with glutaminase inhibitors in NSCLC patients with RB-proficient tumors.

The Blood-Brain Barrier Interface in Diabetes Mellitus: Dysfunctions, Mechanisms and Approaches to Treatment

Diabetes mellitus (DM) is one of the most common diseases in the world. Among its effects are an increase in the risk of cognitive impairment, including Alzheimer's disease, and blood-brain barrier (BBB) dysfunction. DM is characterized by high blood glucose levels that are caused by either lack of insulin (Type I) or resistance to the actions of insulin (Type II). The phenotypes of these two types are dramatically different, with Type I animals being thin, with low levels of leptin as well as insulin, whereas Type II animals are often obese with high levels of both leptin and insulin. The best characterized change in BBB dysfunction is that of disruption. The brain regions that are disrupted, however, vary between Type I vs Type II DM, suggesting that factors other than hyperglycemia, perhaps hormonal factors such as leptin and insulin, play a regionally diverse role in BBB vulnerability or protection. Some BBB transporters are also altered in DM, including P-glycoprotein, lowdensity lipoprotein receptor-related protein 1, and the insulin transporter as other functions of the BBB, such as brain endothelial cell (BEC) expression of matrix metalloproteinases (MMPs) and immune cell trafficking. Pericyte loss secondary to the increased oxidative stress of processing excess glucose through the Krebs cycle is one mechanism that has shown to result in BBB disruption. Vascular endothelial growth factor (VEGF) induced by advanced glycation endproducts can increase the production of matrix metalloproteinases, which in turn affects tight junction proteins, providing another mechanism for BBB disruption as well as effects on P-glycoprotein. Through the enhanced expression of the redox-related mitochondrial transporter ABCB10, redox-sensitive transcription factor NF-E2 related factor-2 (Nrf2) inhibits BEC-monocyte adhesion. Several potential therapies, in addition to those of restoring euglycemia, can prevent some aspects of BBB dysfunction. Carbonic anhydrase inhibition decreases glucose metabolism and so reduces oxidative stress, preserving pericytes and blocking or reversing BBB disruption. Statins or N-acetylcysteine can reverse the BBB opening in some models of DM, fibroblast growth factor-21 improves BBB permeability through an Nrf2-dependent pathway, and nifedipine or VEGF improves memory in DM models. In summary, DM alters various aspects of BBB function through a number of mechanisms. A variety of treatments based on those mechanisms, as well as restoration of euglycemia, may be able to restore BBB functions., including reversal of BBB disruption.

Personality factors and cerebral glucose metabolism in community-dwelling older adults.

Personality factors have been associated with Alzheimer's disease (AD) and dementia, but they have not been examined against markers of regional brain glucose metabolism (a primary measure of brain functioning) in older adults without clinically diagnosed cognitive impairment. The relationship between personality factors derived from the five-factor model and cerebral glucose metabolism determined using positron emission tomography (PET) with [18F]-2-fluoro-2-deoxy-D-glucose (18F-FDG-PET) was examined in a cohort of 237 non-demented, community-dwelling older adults aged 60-89years (M ± SD = 73.76 ± 6.73). Higher neuroticism and lower scores on extraversion and conscientiousness were significantly associated with decreased glucose metabolism in brain regions typically affected by AD neuropathological processes, including the hippocampus and entorhinal cortex. Furthermore, while there were significant differences between apolipoprotein E (APOE) ε4 allele carriers and non-carriers on 18F-FDG-PET results in the neocortex and other brain regions (p < 0.05), there was no significant difference between carriers and non-carriers on personality factors and no significant interactions were found between APOE ε4 carriage and personality factors on brain glucose metabolism. In conclusion, we found significant relationships between personality factors and glucose metabolism in neural regions more susceptible to AD neuropathology in older adults without clinically significant cognitive impairment. These findings support the need for longitudinal research into the potential mechanisms underlying the relationship between personality and dementia risk, including measurement of change in other AD biomarkers (amyloid and tau imaging) and how they correspond to change in personality factors. Future research is also warranted to determine whether timely psychological interventions aimed at personality facets (specific aspects or characteristics of personality factors) can affect imaging or other biomarkers of AD resulting in delay or ideally preventing the onset of the cognitive impairment.

Decreased Glucose Utilization Contributes to Memory Impairment in Patients with Glufosinate Ammonium Intoxication.

The symptoms of glufosinate ammonium (GLA) intoxication include gastrointestinal and neurologic symptoms, respiratory failure, and cardiovascular instability. Among these, neurologic symptoms including loss of consciousness, memory impairment, and seizure are characteristic of GLA poisoning. However, the mechanism of brain injury by GLA poisoning is still poorly understood. We investigated nine patients who had performed an F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) scan because of memory impairment caused by GLA ingestion. FDG-PET images of patients with GLA intoxication were compared with 24 age- and sex-matched healthy controls to evaluate whether the patients had abnormal patterns of glucose metabolism in the brain. Decreased glucose metabolism was observed in the inferior frontal and temporal lobes of these patients with GLA intoxication when compared with 24 age- and sex-matched healthy controls. Three patients performed follow-up FDG-PET scans. However, it was shown that the results of the follow-up FDG-PET scans were determined to be inconclusive. Our study showed that memory impairment induced by GLA intoxication was associated with glucose hypometabolism in the inferior frontal and temporal lobes in the brain.

Brain adaptations of insulin signaling kinases, GLUT 3, p-BADser155 and nitrotyrosine expression in various hypoglycemic models of mice

Aim and objectiveInsulin-induced moderate or severe hypoglycemia (MH or SH) impairs cognition and SH causes neuronal death. On the contrary, alternate day fasting (ADF) protects the brain during excitotoxic stress and improves cognitive function. Unlike the scenario in the periphery, insulin and its relationship towards brain glucose uptake and metabolism are considered to be less significant. Yet, the hypoglycemia associated brain metabolism is not clearly understood. The authors broadly investigated the brain metabolism in various hypoglycemic models such as insulin-induced MH, SH, SH with glucose reperfusion, 24 h fasting and ADF in the cortex or hippocampus of C57BL6/J mice. The authors analyzed the protein expression of insulin signaling kinases (plays a key role in neuronal survival and memory), Bcl-2 associated death promoter (p-BADser155) (dephosphorylation inhibits glucokinase activity and reduces glucose or increases ketone body metabolism in the brain), neuronal-specific glucose transporter 3 (GLUT 3) and nitrotyrosine (marker of nitric oxide which is involved in neuronal glucose uptake via GLUT 3) using western blotting analysis. ResultsInsulin-induced MH or SH differentially regulated the brain insulin signaling kinases. The expression of p-BADser155 decreased in all hypoglycemic models except the insulin-induced MH in hippocampus. The trended higher GLUT 3 and increased nitrotyrosine expression of insulin-induced SH were restored after glucose reperfusion. The trended higher or increased GLUT 3 and nitrotyrosine expression of ADF were positively correlated with serum beta-hydroxybutyrate levels. ConclusionDuring hypoglycemia, it can be suggested that the brain might decrease glucose metabolism via glycolysis or prefer ketone body metabolism (except the insulin-induced MH in hippocampus) by modifying the p-BADser155 expression. In addition to the ketone body metabolism, the brain might adapt to uptake glucose in insulin-induced SH or ADF by modifying the GLUT 3 or nitrotyrosine expression.

Malin, an E3 Ubiquitin Ligase, Modulates glycogen metabolism in multiple cellular compartments

Glycogen is the primary source of storage carbohydrate in mammals. Glycogen synthesis and degradation either consumes or produces glucose‐6‐phosphate (G6P), a key metabolite essential for central carbon metabolism. Several studies have reported glycogen accumulation in specific sub‐cellular organelles, suggesting that glycogen localization is not random. Nuclear glycogen was first reported in the 1890s in hepatocytes, and subsequent reports identified glycogen accumulation near the ER, and mitochondria. Cumulatively, these data suggest compartment‐specific roles for glycogen that have yet to be fully elucidated. The E3 ubiquitin ligase malin is a modulator of glycogen architecture through ubiquitination of multiple glycogen metabolic enzymes. Our previous work and that of others demonstrated that malin activity is required for normal glycogen architecture as somatic loss‐of‐function mutations in malin results in aberrant glycogen. We report that decreased levels of malin in human NSCLC samples results in aberrant accumulation of nuclear and cytoplasmic glycogen followed by glucose metabolism. We employed ultra‐pure nuclear preparations coupled with stable isotope technology to define the origin and biological destiny of nuclear and cytoplasmic glycogen. We show that malin is required to maintain compartmentalized glycogen metabolism, and loss of malin in NSCLC results in 1) the accumulation of nuclear glycogen and reduced histone acetylation in the nucleus, and 2) aberrant accumulation of cytoplasmic glycogen accompanied by increased glucose central carbon metabolism. Re‐expression of malin in model NSCLC cell lines, normalized both nuclear and cytoplasmic glycogen, and decreased glucose metabolism both in vitro and in vivo. Finally, malin expression blunted in vivo xenograft growth of model NSCLC cell lines. These data provide new insights for an alternative signaling pathway that regulates metabolism in NSCLC to drive tumor progression.

MUC1 promotes glycolysis through inhibiting BRCA1 expression in pancreatic cancer.

Enhanced glucose metabolism is one of the hallmarks of pancreatic cancer. MUC1, a transmembrane protein, is a global regulator of glucose metabolism and essential for progression of pancreatic cancer. To clarify the role of MUC1 in glucose metabolism, we knocked out MUC1 in Capan-1 and CFPAC-1 cells. MUC1 knockout (KO) cells uptook less glucose and secreted less lactate with a much lower proliferating rate. The mRNA level of key enzymes in glycolysis also decreased significantly in MUC1 KO cells. We also observed increased expression of breast cancer type 1 susceptibility protein (BRCA1) in MUC1 KO cells. Since BRCA1 has a strong inhibitory effect on glycolysis, we want to know whether the decreased glucose metabolism in MUC1 KO cells is due to increased BRCA1 expression. We treated wild type (WT) and MUC1 KO cells with BRCA1 inhibitor. BRCA1 inhibition significantly enhanced glucose uptake and lactate secretion in both WT and MUC1 KO cells. Expression of key enzymes in glycolysis also elevated after BRCA1 inhibition. Elevated glucose metabolism is known to facilitate cancer cells to gain chemoresistance. We treated MUC1 KO cells with gemcitabine and FOLFIRINOX in vitro and in vivo. The results showed that MUC1 KO sensitized pancreatic cancer cells to chemotherapy both in vitro and in vivo. In conclusion, we demonstrated that MUC1 promotes glycolysis through inhibiting BRCA1 expression. MUC1 may be a therapeutic target in pancreatic cancer treatment.

Ovariectomy-induced depressive-like behavior and brain glucose metabolism changes in female rats are not affected by chronic mild stress

The increased incidence of depression in women going through peri-menopause suggests that fluctuations in estrogen levels may increase the risk of developing depression. Nonetheless, this psychiatric disorder is likely to be multifactorial and consequently an additional trigger may be needed to induce depression in this population. Stress could be such a trigger. We therefore investigated the effect of ovarian estrogen depletion and chronic mild stress (CMS) on depressive-like behavior and brain metabolism in female rats.Approximately 2 and 9 weeks after estrogen depletion by ovariectomy, behavioral changes were assessed in the open-field test and the forced swim test, and brain metabolism was measured with [18F]FDG PET imaging. A subset of animals was subjected to a 6-weeks CMS protocol starting 17 days after ovariectomy.Short-term estrogen depletion had a significant effect on brain metabolism in subcortical areas, but not on behavior. Differences in depressive-like behavior were only found after prolonged estrogen depletion, leading to an increased immobility time in the forced swim test. Prolonged estrogen depletion also resulted in an increase in glucose metabolism in frontal cortical areas and hippocampus, whereas a decrease glucose metabolism was found in temporal cortical areas, hypothalamus and brainstem. Neither short-term nor prolonged estrogen depletion caused anxiety-like behavior. Changes in body weight, behavior and brain glucose metabolism were not significantly affected by CMS.In conclusion, ovarian estrogen depletion resulted in changes in brain metabolism and depressive-like behavior, but these changes were not enhanced by CMS.

Spatially Distributed Amyloid-β Reduces Glucose Metabolism in Mild Cognitive Impairment.

Background:Several positron emission tomography (PET) studies have explored the relationship between amyloid-β (Aβ), glucose metabolism, and the APOE ɛ4 genotype. It has been reported that APOE ɛ4, and not aggregated Aβ, contributes to glucose hypometabolism in pre-clinical stages of Alzheimer’s disease (AD) pathology.Objective:We hypothesize that typical measurements of Aβ taken either from composite regions-of-interest with relatively high burden actually cover significant patterns of the relationship with glucose metabolism. In contrast, spatially weighted measures of Aβ are more related to glucose metabolism in cognitively normal (CN) aging and mild cognitive impairment (MCI).Methods:We have generated a score of amyloid burden based on a joint singular value decomposition (SVD) of the cross-correlation structure between glucose metabolism, as measured by [18F]2-fluoro-2-deoxyglucose (FDG) PET, and Aβ, as measured by [18F]florbetapir PET, from the Alzheimer’s Disease Neuroimaging Initiative study. This SVD-based score reveals cortical regions where a reduced glucose metabolism is maximally correlated with distributed patterns of Aβ.Results:From an older population of CN and MCI subjects, we found that the SVD-based Aβ score was significantly correlated with glucose metabolism in several cortical regions. Additionally, the corresponding Aβ network has hubs that contribute to distributed glucose hypometabolism, which, in turn, are not necessarily foci of Aβ deposition.Conclusions:Our approach uncovered hidden patterns of the glucose metabolism-Aβ relationship. We showed that the SVD-based Aβ score produces a stronger relationship with decreasing glucose metabolism than either APOE ɛ4 genotype or global measures of Aβ burden.

Combined 18F-fluorodeoxyglucose positron emission tomography and event-related potentials study of the cognitive impairment mechanisms in Parkinson’s disease

This study aimed to analyze positron emission tomography with 18F-fluorodeoxyglucose data and event-related potentials in the Go/NoGo paradigm in patients with Parkinson’s disease with and without cognitive impairment. In the group of cognitively impaired patients, glucose metabolism was decreased in the frontal, parietal, cingulate and posterior temporal cortex. Correlations were found between the cognitive scores and cerebral glucose metabolism in those areas. Event-related potentials analysis revealed a decrease in the amplitude of the late positive wave (P300 NoGo wave) in the group of cognitively impaired patients. The analysis revealed that decline in amplitude of P300 wave was accompanied by decreased glucose metabolism in several cortical areas associated with cognitive impairment in Parkinson’s disease. Correlations of glucose metabolism in these areas with event-related potentials amplitude in the NoGo condition confirm the important role of executive functions disorders in the pathogenesis of cognitive impairment in Parkinson’s disease.

FDG-PET assessment and metabolic patterns in Lafora disease.

To describe cerebral glucose metabolism pattern as assessed by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in Lafora disease (LD), a rare, lethal form of progressive myoclonus epilepsy caused by biallelic mutations in EPM2A or NHLRC1. We retrospectively included patients with genetically confirmed LD who underwent FDG-PET scan referred to three Italian epilepsy centers. FDG-PET images were evaluated both visually and using SPM12 software. Subgroup analysis was performed on the basis of genetic and clinical features employing SPM. Moreover, we performed a systematic literature review of LD cases that underwent FDG-PET assessment. Eight Italian patients (3M/5F, 3 EPM2A/5 NHLRC1) underwent FDG-PET examination after a mean of 6years from disease onset (range 1-12years). All patients showed bilateral hypometabolic areas, more diffuse and pronounced in advanced disease stages. Most frequently, the hypometabolic regions were the temporal (8/8), parietal (7/8), and frontal lobes (7/8), as well as the thalamus (6/8). In three cases, the FDG-PET repeated after a mean of 17months (range 7-36months) showed a metabolic worsening compared with the baseline examination. The SPM subgroup analysis found no significant differences based on genetics, whereas it showed a more significant temporoparietal hypometabolism in patients with visual symptoms compared with those without. In nine additional cases identified from eight publications, FDG-PET showed heterogeneous findings, ranging from diffusely decreased cerebral glucose metabolism to unremarkable examinations in two cases. FDG-PET seems highly sensitive to evaluate LD at any stage and may correlate with disease progression. Areas of decreased glucose metabolism in LD are extensive, often involving multiple cortical and subcortical regions, with thalamus, temporal, frontal, and parietal lobes being the most severely affected. Prospective longitudinal collaborative studies are needed to validate our findings.

Development of a Theranostic Convergence Bioradiopharmaceutical for Immuno-PET Based Radioimmunotherapy of L1CAM in Cholangiocarcinoma Model.

Cholangiocarcinoma is a malignancy of bile duct with a poor prognosis. Conventional chemotherapy and radiotherapy are generally ineffective, and surgical resection is the only curative treatment for cholangiocarcinoma. L1-cell adhesion molecule (L1CAM) has been known as a novel prognostic marker and therapeutic target for cholangiocarcinoma. This study aimed to evaluate the feasibility of immuno-PET imaging-based radioimmunotherapy using radiolabeled anti-L1CAM antibody in cholangiocarcinoma xenograft model. We prepared a theranostic convergence bioradiopharmaceutical using chimeric anti-L1CAM antibody (cA10-A3) conjugated with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator and labeled with 64Cu or 177Lu and evaluated the immuno-PET or SPECT/CT imaging and biodistribution with 64Cu-/177Lu-cA10-A3 in various cholangiocarcinoma xenograft models. Therapeutic efficacy and response monitoring were performed by 177Lu-cA10-A3 and 18F-FDG-PET, respectively, and immunohistochemistry was done by TUNEL and Ki-67. Radiolabeled cA10-A3 antibodies specifically recognized L1CAM in vitro, clearly visualized cholangiocarcinoma tumors in immuno-PET and SPECT/CT imaging, and differentiated the L1CAM expression level in cholangiocarcinoma xenograft models. 177Lu-cA10-A3 (12.95 MBq/100 μg) showed statistically significant reduction in tumor volumes (P < 0.05) and decreased glucose metabolism (P < 0.01). IHC analysis revealed 177Lu-cA10-A3 treatment increased TUNEL-positive and decreased Ki-67-positive cells, compared with saline, cA10-A3, or 177Lu-isotype. Anti-L1CAM immuno-PET imaging using 64Cu-cA10-A3 could be translated into the clinic for characterizing the pharmacokinetics and selecting appropriate patients for radioimmunotherapy. Radioimmunotherapy using 177Lu-cA10-A3 may provide survival benefit in L1CAM-expressing cholangiocarcinoma tumor. Theranostic convergence bioradiopharmaceutical strategy would be applied as imaging biomarker-based personalized medicine in L1CAM-expressing patients with cholangiocarcinoma.

CD147 promotes glucose metabolism, invasion and metastasis via PI3K/AKT pathway in oral squamous cell carcinomas

Background: The incidence of oral cancers, especially that of oral squamous cell carcinoma (OSCC), has increased significantly in the last few decades. Aggressive tumor progression and metastasis are the key factors responsible for the high mortality rate associated with OSCC. CD147 is known to play a key role in tumor metastasis and is associated with poor prognosis in oral cancer. It is also a crucial regulator of glucose metabolism in cancer cells. The aim of this study was to determine the effect of CD147 on OSCC invasiveness, metastasis and glucose metabolism, as well as the underlying mechanism. Methods: CD147 was knocked down in the human OSCC lines SCC-25 and CAL-27, and both the wild-type and knockdown cells were then stably transfected with PI3K cDNA. Glucose metabolism and in vitro migration of the OSCC cells were respectively analyzed by glucose uptake and lactate secretion assays, and transwell assay. Results: Knocking down CD147 in the OSCC cells significantly reduced their migration, and decreased glucose metabolism. The inhibitory effects of blocking CD147 were reversed upon PI3K overexpression. Conclusions: CD147 mediates its oncogenic effects via the PI3K/AKT pathway, and is a potential prognostic factor and therapeutic target for OSCC.

CD147 promotes glucose metabolism, invasion and metastasis via PI3K/AKT pathway in oral squamous cell carcinomas.

BackgroundThe incidence of oral cancers, especially that of oral squamous cell carcinoma (OSCC), has increased significantly in the last few decades. Aggressive tumor progression and metastasis are the key factors responsible for the high mortality rate associated with OSCC. CD147 is known to play a key role in tumor metastasis and is associated with poor prognosis in oral cancer. It is also a crucial regulator of glucose metabolism in cancer cells. The aim of this study was to determine the effect of CD147 on OSCC invasiveness, metastasis and glucose metabolism, as well as the underlying mechanism.MethodsCD147 was knocked down in the human OSCC lines SCC-25 and CAL-27, and both the wild-type and knockdown cells were then stably transfected with PI3K cDNA. Glucose metabolism and in vitro migration of the OSCC cells were respectively analyzed by glucose uptake and lactate secretion assays, and transwell assay.ResultsKnocking down CD147 in the OSCC cells significantly reduced their migration, and decreased glucose metabolism. The inhibitory effects of blocking CD147 were reversed upon PI3K overexpression.ConclusionsCD147 mediates its oncogenic effects via the PI3K/AKT pathway, and is a potential prognostic factor and therapeutic target for OSCC.

Sex differences in the effects of acute stress on cerebral glucose metabolism: A microPET study

Stress has been considered as a risk factor for the development and aggravation of several diseases. The hypothalamic-pituitary-adrenal axis (HPA) is one of the main actors for the stress response and homeostasis maintenance. Positron emission tomography (PET) has been used to evaluate neuronal activity and to study brain regions that may be related to the HPA axis response. Since neuroimaging is an important tool in detecting neuroendocrine-related changes, we used fluorodeoxyglucose-18 (18F-FDG) and positron emission microtomography (microPET) to evaluate sexual differences in the glucose brain metabolism after 10, 30 and 40 min of acute stress in Balb/c mice. We also investigated the effects of restraint stress in blood, liver and adrenal gland 18F-FDG biodistribution using a gamma counter. A decreased glucose uptake in the whole brain in both females and males was found. Additionally, there were time and sex-dependent alterations in the 18F-FDG uptake after restraint stress in specific brain regions, indicating that males could be more vulnerable to the short-term effects of acute stress. According to the gamma counter biodistribution, only females showed a significant decreased glucose uptake in the blood, liver and right adrenal after restraint stress. In addition, in comparisons between the sexes, males showed a decreased glucose uptake in the whole brain and in several brain regions compared to females. In conclusion, exposure to acute restraint stress resulted in significant decreased glucose metabolism in the brain, with particular effects in different regions and organs in a sex-specific manner.

The circadian protein CLOCK regulates cell metabolism via the mitochondrial carrier SLC25A10

Physiological function and metabolic regulation are the most important outputs of circadian clock controls in mammals. Mitochondrial respiration and ROS production show rhythmic activity. Mitochondrial carriers, which are responsible for mitochondrial substance transfer, are vital for mitochondrial metabolism. Clock (Circadian Locomotor Output Cycles Kaput) is the first core circadian gene identified in mammalian animals. However, whether CLOCK protein can regulate mitochondrial functions via mitochondrial carriers is unclear. Here, we showed that CLOCK can bind to the mitochondrial carrier SLC25A10. For further analysis, we established a Slc25a10−/−-Hepa1-6 cell line using CRISPR/Cas9 gene-editing technology. Slc25a10−/−-Hepa1-6 cells showed disordered glucose homeostasis, increased oxidative stress levels, and damaged electron transport chains. Next, using an immunoprecipitation assay, we found that amino acids 43–84 and 169–210 in SLC25A10 are key sites that respond to CLOCK binding. Finally, forced expression of wild-type SLC25A10 in Slc25a10−/−-Hepa1-6 cells could compensate for the loss of SLC25A10; the decreased glucose metabolism, severe oxidative stress and damaged electron transport chain were recovered. In addition, a mutant Slc25a10 with changes in two key sites did not show a rescue effect. In conclusion, we identified a new protein-protein interaction mechanism in which CLOCK can directly regulate cell metabolism via the mitochondrial membrane transporter SLC25A10. Our study might provide some new insights into the relationship between circadian clock and mitochondrial metabolism.

CD146-Targeted Multimodal Image-Guided Photoimmunotherapy of Melanoma.

For melanoma resistant to molecularly targeted therapy and immunotherapy, new treatment strategies are urgently needed. A molecularly targeted theranostic pair may thus be of importance, where the diagnostic probe facilitates patient stratification and the therapeutic companion treats the selected cases. For this purpose, flow cytometry is used to assess the CD146 level in melanoma cells. Based on YY146, a CD146‐specific monoclonal antibody, an imaging probe 89Zr‐Df‐YY146 is synthesized and its diagnostic performance is evaluated by positron emission tomography (PET) imaging. Furthermore, a photoimmunotherapy (PIT) agent IR700‐YY146 is developed and the therapeutic effect of IR700‐YY146 PIT is assessed comprehensively. CD146 is highly expressed in A375 and SK‐MEL‐5 cells. 89Zr‐Df‐YY146 PET readily detects CD146‐positive A375 melanomas. Tumor accumulation of 89Zr‐Df‐YY146 peaks at 72 h with an uptake value of 26.48 ± 3.28%ID g−1, whereas the highest uptake of the nonspecific 89Zr‐Df‐IgG is 4.80 ± 1.75%ID g−1. More importantly, IR700‐YY146 PIT effectively inhibits the growth of A375 tumors, owing to production of reactive oxygen species, decreased glucose metabolism, and reduced expression of CD146. To conclude, 89Zr‐Df‐YY146 and IR700‐YY146 are a promising theranostic pair with the former revealing CD146 expression in melanoma as a PET probe and the latter specifically treating CD146‐positive melanoma as an effective PIT agent.

The effects of perinatal bisphenol A exposure on thyroid hormone homeostasis and glucose metabolism in the prefrontal cortex and hippocampus of rats.

IntroductionBisphenol A (BPA) is an endocrine disruptor widely used to manufacture consumer goods. Although the thyroid hormone (TH) disrupting potential of BPA has been thought to be responsible for the neuropsychiatric deficits in the animals that experienced perinatal BPA exposure, the TH availability change at the level of specific brain structures has not been subject to systematic investigation.MethodsIn the present study the impacts of perinatal BPA exposure (0.1 mg/L in drinking water) spanning gestation and lactation on TH homeostasis in the prefrontal cortex (PFC) and hippocampus were assessed in male Sprague–Dawley rats at postnatal day 21 (PND21) and PND90. As TH regulates brain glucose metabolism at multiple levels，the effects of BPA treatment on glucose metabolism in the brain tissues were also assessed in adult rats.ResultsThe results showed heterogeneous changes in TH concentration induced by BPA between serum and brain tissues, additionally, in the BPA–treated pups, up–regulated expression of the TH transporter monocarboxylate 8 mRNA at PND21 and increased type 3 iodothyronine deiodinase mRNA expressions at PND21 and PND90 were observed. Meanwhile, decreased glucose metabolism was seen in the PFC and hippocampus, while deficits in locomotor activity, spatial memory and social behaviors occurred in BPA‐treated groups.ConclusionThese data support the concept that the developing brain possesses potent mechanisms to compensate for a small reduction in serum TH, such as serum hypothyrodism induced by BPA exposure, however, the long‐term negative effect of BPA treatment on TH homeostasis and glucose metabolism may be attributable to neuropsychiatric deficits after mature.

A ketogenic diet diminishes behavioral responses to cocaine in young adult male and female rats

Ketogenic diets (KDs) are high fat, low carbohydrate formulations traditionally used to treat epilepsy; more recently, KDs have shown promise for a wide range of other neurological disorders. Drug addiction studies suggest that repeated exposure to drugs of abuse, including cocaine, results in a suite of neurobiological changes that includes neuroinflammation, decreased glucose metabolism, and disordered neurotransmission. Given that KDs positively regulate these factors, we addressed whether administration of a KD has potential as a novel therapy for drug addiction. In this study, male and female Sprague-Dawley rats were placed on a KD or a control diet (CD), beginning at five weeks of age and continuing through the end of behavioral testing. Three weeks after initiation of dietary treatments, rats received daily i.p. injections of cocaine (15 mg/kg) or saline vehicle for one week, were drug free for a subsequent week, and then all animals received a final challenge injection of 15 mg/kg cocaine. In the absence of cocaine injections, stereotyped locomotor responses were minimal and were unaffected by dietary treatment. In contrast, both males and females fed a KD exhibited decreased cocaine-induced stereotyped responses as compared to CD-fed rats. The sensitization of ambulatory responses was also disrupted in KD-fed rats. These results suggest that KDs directly impact dopamine-mediated behaviors, and hence may hold potential as a therapy for drug addiction.