Maternal Fructose Intake Causes Developmental Reprogramming of Hepatic Mitochondrial Catalytic Activity and Lipid Metabolism in Weanling and Young Adult Offspring

Excess dietary fructose is a major public health concern, yet little is known about its influence on offspring development and later-life disease when consumed in excess during pregnancy. To determine whether increased maternal fructose intake could have long-term consequences on offspring health, we investigated the effects of 10% w/v fructose water intake during preconception and pregnancy in guinea pigs. Female Dunkin Hartley guinea pigs were fed a control diet (CD) or fructose diet (FD; providing 16% of total daily caloric intake) ad libitum 60 days prior to mating and throughout gestation. Dietary interventions ceased at day of delivery. Offspring were culled at day 21 (D21) (weaning) and at 4 months (4 M) (young adult). Fetal exposure to excess maternal fructose intake significantly increased male and female triglycerides at D21 and 4 M and circulating palmitoleic acid and total omega-7 through day 0 (D0) to 4 M. Proteomic and functional analysis of significantly differentially expressed proteins revealed that FD offspring (D21 and 4 M) had significantly increased mitochondrial metabolic activities of β-oxidation, electron transport chain (ETC) and oxidative phosphorylation and reactive oxygen species production compared to the CD offspring. Western blotting analysis of both FD offspring validated the increased protein abundances of mitochondrial ETC complex II and IV, SREBP-1c and FAS, whereas VDAC1 expression was higher at D21 but lower at 4 M. We provide evidence demonstrating offspring programmed hepatic mitochondrial metabolism and de novo lipogenesis following excess maternal fructose exposure. These underlying asymptomatic programmed pathways may lead to a predisposition to metabolic dysfunction later in life.     

Teriflunomide Preserves Neuronal Activity and Protects Mitochondria in Brain Slices Exposed to Oxidative Stress

Teriflunomide (TFN) limits relapses in relapsing–remitting multiple sclerosis (RRMS) by reducing lymphocytic proliferation through the inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) and the subsequent modulation of de novo pyrimidine synthesis. Alterations of mitochondrial function as a consequence of oxidative stress have been reported during neuroinflammation. Previously, we showed that TFN prevents alterations of mitochondrial motility caused by oxidative stress in peripheral axons. Here, we aimed to validate TFN effects on mitochondria and neuronal activity in hippocampal brain slices, in which cellular distribution and synaptic circuits are largely preserved. TFN effects on metabolism and neuronal activity were investigated by assessing oxygen partial pressure and local field potential in acute slices. Additionally, we imaged mitochondria in brain slices from the transgenic Thy1-CFP/COX8A)S2Lich/J (mitoCFP) mice using two-photon microscopy. Although TFN could not prevent oxidative stress-related depletion of ATP, it preserved oxygen consumption and neuronal activity in CNS tissue during oxidative stress. Furthermore, TFN prevented mitochondrial shortening and fragmentation of puncta-shaped and network mitochondria during oxidative stress. Regarding motility, TFN accentuated the decrease in mitochondrial displacement and increase in speed observed during oxidative stress. Importantly, these effects were not associated with neuronal viability and did not lead to axonal damage. In conclusion, during conditions of oxidative stress, TFN preserves the functionality of neurons and prevents morphological and motility alterations of mitochondria.     

COVID-19 and Lung Mast Cells: The Kallikrein–Kinin Activation Pathway

Mast cells (MCs) have relevant participation in inflammatory and vascular hyperpermeability events, responsible for the action of the kallikrein–kinin system (KKS), that affect patients inflicted by the severe form of COVID-19. Given a higher number of activated MCs present in COVID-19 patients and their association with vascular hyperpermeability events, we investigated the factors that lead to the activation and degranulation of these cells and their harmful effects on the alveolar septum environment provided by the action of its mediators. Therefore, the pyroptotic processes throughout caspase-1 (CASP-1) and alarmin interleukin-33 (IL-33) secretion were investigated, along with the immunoexpression of angiotensin-converting enzyme 2 (ACE2), bradykinin receptor B1 (B1R) and bradykinin receptor B2 (B2R) on post-mortem lung samples from 24 patients affected by COVID-19. The results were compared to 10 patients affected by H1N1pdm09 and 11 control patients. As a result of the inflammatory processes induced by SARS-CoV-2, the activation by immunoglobulin E (IgE) and degranulation of tryptase, as well as Toluidine Blue metachromatic (TB)-stained MCs of the interstitial and perivascular regions of the same groups were also counted. An increased immunoexpression of the tissue biomarkers CASP-1, IL-33, ACE2, B1R and B2R was observed in the alveolar septum of the COVID-19 patients, associated with a higher density of IgE⁺ MCs, tryptase⁺ MCs and TB-stained MCs, in addition to the presence of intra-alveolar edema. These findings suggest the direct correlation of MCs with vascular hyperpermeability, edema and diffuse alveolar damage (DAD) events that affect patients with a severe form of this disease. The role of KKS activation in events involving the exacerbated increase in vascular permeability and its direct link with the conditions that precede intra-alveolar edema, and the consequent DAD, is evidenced. Therapy with drugs that inhibit the activation/degranulation of MCs can prevent the worsening of the prognosis and provide a better outcome for the patient.     

Aptamer-based electrochemical detection of picomolar platelet-derived growth factor directly in blood serum

We report an electrochemical, aptamer-based (E-AB) sensor for the detection of platelet-derived growth factor (PDGF) directly in blood serum. The E-AB approach employs alternating current voltammetry to monitor target-induced folding in a methylene blue-modified, PDGF-binding aptamer. The sensor is sensitive, highly selective, and essentially reagentless: we readily detect the BB variant of PDGF at 1 nM directly in undiluted, unmodified blood serum and at 50 pM (1.25 ng/mL) in serum-diluted 2-fold with aqueous buffer. The sensitivity and selectivity achieved by this sensor match or significantly exceed those of the best analogous optical approaches. For example, the detection limit attained in 50% serum is achieved against a >25 million-fold excess of contaminating blood proteins and represents a 4 order of magnitude improvement over the most sensitive optical PDGF aptasensor reported to date. Moreover, the E-AB sensor combines these promising attributes in a platform that is reusable, label-free, and electronic. Given these advantages, E-AB sensors appear well suited for implementation in portable microdevices directed at the direct detection of proteins and small molecules in complex, largely unprocessed clinical samples.     

Dopamine D? receptor stimulation of the nucleus accumbens or the medial preoptic area promotes the onset of maternal behavior in pregnancy-terminated rats.

There is good evidence that interference with the mesolimbic dopamine (DA) system results in impaired maternal responding in postpartum female rats. However, whether activation of the mesolimbic DA system is capable of promoting maternal behavior has not been investigated. This study examined whether increasing DA activity in various brain regions of pregnancy-terminated, naive female rats would stimulate the onset of maternal behavior. Experiments 1 and 2 examined the effects of microinjection of various doses (0, 0.2, or 0.5 μg/0.5 μl/side) of a D? DA receptor agonist, SKF 38393, or a D? DA receptor agonist, quinpirole, into the nucleus accumbens (NA) on latency to show full maternal behavior, and Experiment 3 determined the effects of SKF 38393 injection into a control site. Finally, because the medial preoptic area (MPOA) is also important for maternal behavior, receives DA input, and expresses DA receptors, the authors examined whether microinjection of SKF 38393 into MPOA was capable of stimulating the onset of maternal behavior. Results indicated that microinjection of SKF 38393 into either the NA or the MPOA facilitates maternal responding in pregnancy-terminated rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of the syllable in the processing of spoken English: Evidence from a nonword comparison task.

Previous research using monitoring tasks suggests that syllables do not play a role in the initial processing of speech by English listeners. The role of syllables in a different task, 1 involving the speeded comparison of 2 nonwords, was investigated. In 2 experiments, responses to nonword pairs that shared a complete syllable were significantly faster than responses to pairs that shared part of a syllable when the shared unit was at the beginning or in the middle of the nonwords. Results were mixed when the shared unit was at the end of the nonwords, possibly reflecting a confounding effect of rhyme. Findings suggest that syllabified representations of the nonwords may be used in a comparison task, even in English. Results are interpreted relative to different demands of the nonword comparison and monitoring tasks. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Measuring Developmental Changes in Alcohol Expectancies.

The goal of this study was to measure shifts in alcohol expectancies from childhood into adolescence while controlling for changes in the psychometric properties of the instrument. One thousand nine hundred ninety-three 4th-grade and 1,632 9th-grade students from South Dakota rated the likelihood that 23 outcomes would result from alcohol use. These expectancies were modeled using a 2-factor confirmatory factor analysis. After differences in the psychometric properties of the instrument were controlled, the cohorts were distinguished by a large difference in Alcohol Positivity, with older participants viewing alcohol's effects more positively. Additionally, older participants displayed greater Alcohol Potency, believing that alcohol has a larger impact on all outcomes. There were also significant differences in the interpretation of the alcohol expectancies items across cohorts. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impaired control of visual attention in schizophrenia.

To investigate attentional impairment in schizophrenia, the authors examined the performance of 22 patients with schizophrenia and 16 healthy control subjects in 4 visual search tasks that varied in perceptual requirements and in the need for precise attentional control. The rate of search was slowed in the patients in all tasks. However, the degree of slowing was largest in tasks requiring precise attentional control and smallest in tasks that were perceptually difficult but required less attentional control. This pattern of results indicates that the primary impairment of attention in schizophrenia lies in the control of attention and not in the selection processes that operate once attention has been directed to an object. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Rapid Development of Fasting-Induced Hepatic Lipidosis in the American Mink (<Emphasis Type=Italic>Neovison vison</Emphasis>): Effects of Food Deprivation and Re-Alimentation on Body Fat Depots,Tissue Fatty Acid Profiles,Hematology and Endocrinology

Hepatic lipidosis is a common pathological finding in the American mink (Neovison vison) and can be caused by nutritional imbalance due to obesity or rapid body weight loss. The objectives of the present study were to investigate the timeline and characterize the development of hepatic lipidosis in mink in response to 0–7 days of food deprivation and liver recovery after 28 days of re-feeding. We report here the effects on hematological and endocrine variables, body fat mobilization, the development of hepatic lipidosis and the alterations in the liver lipid classes and tissue fatty acid (FA) sums. Food deprivation resulted in the rapid mobilization of body fat, most notably visceral, causing elevated hepatosomatic index and increased liver triacylglycerol content. The increased absolute amounts of liver total phospholipids and phosphatidylcholine suggested endoplasmic reticulum stress. The hepatic lipid infiltration and the altered liver lipid profiles were associated with a significantly reduced proportion of n-3 polyunsaturated FA (PUFA) in the livers and the decrease was more evident in the females. Likewise, re-feeding of the female mink resulted in a more pronounced recovery of the liver n-3 PUFA. The rapid decrease in the n-3/n-6 PUFA ratio in response to food deprivation could trigger an inflammatory response in the liver. This could be a key contributor to the pathophysiology of fatty liver disease in mink influencing disease progression.