Sex differences are evident in the presentation of metabolic symptoms. A shift of sex hormones that signal the onset of puberty combined with a poor diet consumed in adolescence is likely to have ...sex-specific, long-term impacts on adult physiology. Here, we expanded on existing literature to elucidate the sex-specific mechanisms driving physiological deficits following high fructose consumption. Male and female Wistar rats were fed a high-fructose (55%) diet beginning immediately postweaning for 10 wk. Female rats fed the high-fructose diet displayed elevated weight gain and extensive liver pathology consistent with markers of nonalcoholic fatty liver disease (NAFLD). Male rats fed the high-fructose diet exhibited increased circulating glucose along with moderate hepatic steatosis. Levels of cytokines and gene expression of inflammatory targets were not altered by fructose consumption in either sex. However, circulating levels of markers for liver health, including alanine transaminase and uric acid, and markers for epithelial cell death were altered by fructose consumption. From the alterations in these markers for liver health, along with elevated circulating triglycerides, it was evident that liver health had deteriorated significantly and that a number of factors were at play. Both adult fructose-fed male and female rats displayed motor deficits that correlated with aberrant structural changes at the neuromuscular junction; however, these deficits were exacerbated in males. These data indicate that consumption of a high-fructose diet beginning in adolescence leads to adult pathology that is modified by sex. Identification of these sex-specific changes has implications for treatment of clinical presentation of metabolic syndrome and related disorders.
Chronic stress exposure during development can have lasting behavioral consequences that differ in males and females. More specifically, increased depressive behaviors in females, but not males, are ...observed in both humans and rodent models of chronic stress. Despite these known stress-induced outcomes, the molecular consequences of chronic adolescent stress in the adult brain are less clear. The stress hormone corticosterone activates the glucocorticoid receptor, and activity of the receptor is regulated through interactions with co-chaperones-such as the immunophilin FK506 binding proteins 5 (FKBP5). Previously, it has been reported that the adult stress response is modified by a history of chronic stress; therefore, the current study assessed the impact of chronic adolescent stress on the interactions of the glucocorticoid receptor (GR) with its regulatory co-chaperone FKBP5 in response to acute stress in adulthood. Although protein presence for FKBP5 did not differ by group, assessment of GR-FKBP5 interactions demonstrated that adult females with a history of chronic adolescent stress had elevated GR-FKBP5 interactions in the hippocampus following an acute stress challenge which could potentially contribute to a reduced translocation pattern given previous literature describing the impact of FKBP5 on GR activity. Interestingly, the altered co-chaperone interactions of the GR in the stressed female hippocampus were not coupled to an observable difference in transcription of GR-regulated genes. Together, these studies show that chronic adolescent stress causes lasting changes to co-chaperone interactions with the glucocorticoid receptor following stress exposure in adulthood and highlight the potential role that FKBP5 plays in these modifications. Understanding the long-term implications of adolescent stress exposure will provide a mechanistic framework to guide the development of interventions for adult disorders related to early life stress exposures.
The hormones estrogen and progesterone alter physiological functions, including the estrus cycle and relevant neurological and synaptic activity. Here, we determined the extent to which estrus cycle ...stage interacts with an inflammatory stimulus, lipopolysaccharide (LPS), to alter synaptic mitochondrial respiration in female rats. LPS elevated synaptic mitochondrial respiration of rats in estrus, but not diestrus. Likewise, estrogen concentration correlated with multiple respiratory metrics in LPS treated females in estrus. These data suggest estrogen likely modulates synaptic mitochondrial respiration in a high progesterone environment.
AbstractObjective People living with HIV (PLWH) experience high rates of childhood maltreatment, which increases risk for posttraumatic stress disorder (PTSD). Thus, it is important to understand how ...HIV status interacts with childhood maltreatment to influence PTSD symptom severity and underlying psychophysiology.Methods The current study assessed whether HIV status interacts with childhood maltreatment to influence PTSD symptom severity and heart rate variability during a dark-enhanced startle (DES) task in 88 Black women with (n=30) and without HIV (n=58).Results HIV was associated with greater PTSD symptom severity only in women with low levels of childhood maltreatment (p=.024). Startle potentiation during DES was highest in women living without HIV and with high childhood maltreatment (p=.018). In women who had experienced low levels of childhood maltreatment, respiratory sinus arrhythmia (RSA) was lower during the dark phase of DES in women living without HIV than women living with HIV (WLWH), (p=.046). RSA during the light phase of DES was lower in WLWH than in women living without HIV (p=.042).Conclusion In the current sample of Black women, HIV status was associated with PTSD symptom severity in a manner dependent on level of childhood maltreatment, suggesting that HIV status may be an important factor to consider for behavioral and pharmacological treatment strategies for PTSD. Additionally, HIV status is associated with lower percent potentiation to darkness and lower RSA during the light phase of DES, suggesting physiological mechanisms by which HIV may contribute to PTSD symptoms in individuals exposed to low levels of childhood maltreatment.
•A life history of chronic predatory stress increases synaptosomal respiration in females.•A life history of chronic inflammation increases synaptosomal respiration in females.•A history of stress ...and inflammation impairs synaptosomal respiration in females.•Male synaptosome respiration is sensitive to combined stress and chronic inflammation.•Chronic stress produces physical changes and increased TNFα months after stress.
Repeated exposures to chronic stress can lead to long lasting negative behavioral and metabolic outcomes. Here, we aim to determine the impact of chronic stress and chronic low-level inflammation on behavior and synaptosomal metabolism.
Male (n = 31) and female (n = 32) C57Bl/6 mice underwent chronic repeated predation stress or daily handling for two rounds of 15 consecutive days of exposure during the adolescent and early adult timeframes. Subsequently, mice were exposed to repeated lipopolysaccharide (LPS; 7.5 × 105 EU/kg) or saline injections every third day for eight weeks. Exploratory and social behaviors were assessed in the open field and social interaction tests prior to examination of learning and memory with the Barnes Maze. Mitochondrial function and morphology were assessed in synaptosomes post-mortem using the Cell Mito Stress test and Seahorse XFe24 analyzer, TEM, and western analysis, respectively. In addition, expression of TNF-α, IL-1ß, and ROMO1 were examined in the hippocampus and prefrontal cortex with Taqman qPCR. Circulating pro- and anti-inflammatory cytokines in the periphery were assessed using the MSD V-plex Proinflammatory Panel 1 following the first and last LPS injection as well as at the time of tissue collection. Circulating ROMO1 was assessed in terminal samples via ELISA.
Exposure to repeated predatory stress increased time spent in the corners of the open field, suggestive of anxiety-like behavior, in both males and females. There were no significant group differences in the social interaction test and minimal effects were evident in the Barnes maze. A history of chronic stress interacted with chronic LPS in male mice to lead to a deficit in synaptosomal respiration. Female mice were more sensitive to both chronic stress and chronic LPS such that either a history of chronic stress or chronic LPS exposure was sufficient to disrupt synaptosomal respiration in females. Both stress and chronic LPS were sufficient to increase inflammation and reactive oxygen in males centrally and peripherally. Females had increased markers of peripheral inflammation following acute LPS but no evidence of peripheral or central increases in inflammatory factors or reactive oxygen following chronic exposures.
Collectively, these data suggest that while metrics of inflammation and reactive oxygen are disrupted in males following chronic stress and chronic LPS, only the combined condition is sufficient to alter synaptosomal respiration. Conversely, although evidence of chronic inflammation or chronic elevation in reactive oxygen is absent, females demonstrate profound shifts in synaptosomal mitochondrial function with either a history of chronic stress or a history of chronic inflammation. These data highlight that different mechanisms are likely in play between the sexes and that sex differences in neural outcomes may be precipitated by sex-specific effects of life experiences on mitochondrial function in the synapse.
•High fructose diet causes divergent behavioral phenotypes in males and females.•Synaptic respiration is divergently altered by diet in males and females.•Acute stress differentially impacted ...synaptic respiration in males and females.•Diet-induced alterations to neural function and physiology are sex-specific.•Synaptic mitochondrial function may contribute to the behavioral differences.
The consequences of excessive fructose intake extend beyond those of metabolic disorder to changes in emotional regulation and cognitive function. Long-term consumption of fructose, particularly common when begun in adolescence, is more likely to lead to deleterious consequences than acute consumption. These long-term consequences manifest differently in males and females, suggesting a sex-divergent mechanism by which fructose can impair physiology and neural function. The purpose of the current project was to investigate a possible sex-specific mechanism by which elevated fructose consumption drives behavioral deficits and accompanying metabolic symptoms – specifically, synaptic mitochondrial function. Male and female rats were fed a high fructose diet beginning at weaning and maintained into adulthood. Measures of physiological health across the diet consumption period indicated that females were more likely to gain weight than males while both displayed increased circulating blood glucose. As adults, females fed the high fructose diet displayed increased floating behavior in the forced swim task while males exhibited increased exploratory behavior in the open field. Synaptic respiration was altered by diet in both females and males but the effect was sex-divergent – fructose-fed females had increased synaptic respiration while males showed a decrease. When exposed to an acute energetic challenge, the pattern was reversed. Taken together, these data indicate that diet-induced alterations to neural function and physiology are sex-specific and highlight the need to consider sex as a biological variable when treating metabolic disease. Furthermore, these data suggest that synaptic mitochondrial function may contribute directly to the behavioral consequences of elevated fructose consumption.
Multi-drug resistance (MDR) develops because cancer cells evade toxicity of several structurally unrelated drugs. Besides other mechanisms, MDR is linked to the overexpression of ATP Binding Cassette ...(ABC), transporters, among which ABCB1 is the best characterized one. Since overactivation of PI3K/Akt/mTOR plays a pivotal role in the growth of human cancers, we hypothesized whether dual PI3K and mTOR inhibitor, BEZ235 (BEZ, dactolisib) reverses resistance to doxorubicin (DOX).
Ovarian (A2780) and pancreatic (MiaPaca2) cancer cells were used to generate DOX-resistant clones by overexpressing ABCB1 or stepwise treatment of DOX. Intracellular accumulation of DOX was measured by flow cytometry after treatment with BEZ.
BEZ treatment caused an increase in intracellular levels of DOX which was almost identical to the naïve parental cell lines. BEZ was found to be a weak substrate for ABCB1 as demonstrated by minimal increase in ATPase activity. BEZ treatment caused a dose-dependent decrease in cell viability in combination with DOX, which was associated with an increase in cleaved PARP expression in the drug resistant clones.
These results suggest that BEZ is a non-substrate inhibitor of ABCB1 and is able to effectively re-sensitize cells overexpressing ABCB1 to the effects of DOX.
Dual PI3 Kinase/mTOR inhibitor, BEZ, has the potential to reverse MDR in cancer patients.
•Multidrug Resistance (MDR) decreases effectiveness of cancer drugs.•Targeting ATP Binding Cassette (ABC) transporters is known to reverse MDR.•Dual PI3Kinase/mTOR Inhibitor BEZ235 increased doxorubicin accumulation in drug-resistant cancer cells.•BEZ235 improved doxorubicin-induced cancer cell killing.•MDR in cancer cells can be reversed by BEZ235.
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