Recent studies have demonstrated the intimate relationship between depression and immune disturbances. Aware of the efficacy limits of existing antidepressant drugs and the potential ...anti-inflammatory properties of propentofylline, we sought to evaluate the use of propentofylline as a depression treatment. We used a rat model of depression induced by repetitive lipopolysaccharide (LPS) administrations. We have studied sickness behavior, by assessing daily body weight, open field behavior, and TNF-α plasmatic levels. Anxiety-like behavior (light-dark test), depressive-like behavior (forced swim test), plasmatic levels of the brain-derived neurotrophic factor (BDNF, depression biomarker), and central glial fibrillary acidic protein (GFAP) expression (an astrocyte biomarker) were also evaluated. LPS induced body weight loss, open field behavior impairments (decreased locomotion and rearing, and increased immobility), and increased TNF-α levels in rats, compared with control group. Thus, LPS induced sickness behavior. LPS also increased the immobility and reduced climbing in the forced swim test, when compared with the control group, i.e., LPS induced depressive-like behavior in rats. Propentofylline prevented sickness behavior after four days of consecutive treatment, as well as prevented the depressive-like behavior after five days of consecutive treatments. Propentofylline also prevented the increase in GFAP expression induced by LPS. Neither LPS nor propentofylline has influenced the anxiety and BDNF levels of rats. In conclusion, repetitive LPS administrations induced sickness behavior and depressive-like behavior in rats. Propentofylline prevented both sickness behavior and depressive-like behavior via neuroinflammatory pathway. The present findings may contribute to a better understanding and treatment of depression and associated diseases.
Autism is characterized by social deficits, communication abnormalities, and repetitive behaviors. The risk factors appear to include genetic and environmental conditions, such as prenatal infections ...and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infections by gram-negative bacteria, induces autistic-like behaviors. No effective treatment yet exists for autism. Therefore, we used our rat model to test a possible treatment for autism. We selected pioglitazone to block or ease the impairments induced by LPS because although this drug was designed as an anti-diabetic drug (it has an insulin effect), it also exerts anti-inflammatory effects. Juvenile offspring were treated daily with pioglitazone, and the main behaviors related to autism, namely, socialization (play behavior) and communication (50-kHz ultrasonic vocalizations), were studied. Biomarkers linked to autism and/or pioglitazone were also studied to attempt to understand the mechanisms involved, namely, IL-6, TNF-alpha, MCP-1, insulin, and leptin. Prenatal LPS exposure induced social deficits and communicational abnormalities in juvenile rat offspring as well as elevated plasma IL-6 levels. Daily postnatal pioglitazone treatment blocked the impairments found in terms of the time spent on social interaction, the number of vocalizations (i.e., autistic-like behaviors) and the elevated plasma IL-6 levels. Thus, pioglitazone appears to be a relevant candidate for the treatment of autism. The present findings may contribute to a better understanding and treatment of autism and associated diseases.
•We studied the self-grooming microstructure and neurochemistry after prenatal LPS.•Our model induced restricted and repetitive stereotyped behaviors.•It also induced dopaminergic hypoactivity in the ...hypothalamus.•Together with our previous data our model induced autistic-like behaviors.•The dopaminergic impairments may explain the autistic-like behaviors.
Previous investigations by our group have shown that prenatal exposure to lipopolysaccharide (LPS), which mimics infection by gram-negative bacteria, induces social, cognitive, and communication deficits. For a complete screening of autistic-like behaviors, the objective of this study was to evaluate if our rat model also induces restricted and repetitive stereotyped behaviors. Thus, we studied the self-grooming microstructure. We also studied the neurochemistry of hypothalamus and frontal cortex, which are brain areas related to autism to better understand central mechanisms involved in our model. Prenatal LPS exposure on gestational day 9.5 increased the head washing episodes (frequency and time), as well as the total self-grooming. However, body grooming, paw/leg licking, tail/genital grooming, and circling behavior/tail chasing did not vary significantly among the groups. Moreover, prenatal LPS induced dopaminergic hypoactivity (HVA metabolite and turnover) in the hypothalamus. Therefore, our rat model induced restricted and repetitive stereotyped behaviors and the other main symptoms of autism experimentally studied in rodent models and also found in patients. The hypothalamic dopaminergic impairments seem to be associated with the autistic-like behaviors.
Chimeric Antigen Receptor (CAR) T cell therapies have received increasing attention, showing promising results in the treatment of acute lymphoblastic leukaemia and aggressive B cell lymphoma. Unlike ...typical cancer treatments, autologous CAR T cell therapies are patient-specific; this makes them a unique therapeutic to manufacture and distribute. In this work, we focus on the development of a computer modelling tool to assist the design and assessment of supply chain structures that can reliably and cost-efficiently deliver autologous CAR T cell therapies. We focus on four demand scales (200, 500, 1000 and 2000 patients annually) and we assess the tool's capabilities with respect to the design of responsive supply chain candidate solutions while minimising cost.
Ceria (CeO2) is being increasingly used as support of metallic nanoparticles in catalysis due to its unique redox properties. Shedding light into the nature of the strong metal support interaction ...(SMSI) effect in CeO2-containing catalysts is important since it has a strong influence on the catalytic properties of the system. In this work, Cu/CeO2 and Ni/CeO2 nanoparticles are characterized when submitted to a reduction treatment at 500 °C in H2 atmosphere with a combination of in situ (XAS – X-ray absorption spectroscopy and time-resolved XAS) and ex situ (TEM – transmission electron microscopy and XPS - X-ray photoelectron spectroscopy) techniques. The existence of a capping layer decorating the Ni/CeO2 nanoparticles after the reduction treatment is shown, representing evidence for the SMSI effect. The kinetics of the SMSI occurrence is elucidated. It is proposed that the electronic factor of the SMSI effect has a strong influence on the reduction properties of the Ni nanoparticles supported on CeO2, decreasing its reduction temperature if compared to nonsupported Ni nanoparticles. The same phenomenon is not observed for Cu/CeO2 nanoparticles, where there is no evidence for the SMSI effect, and no changes on the reduction properties between supported and nonsupported Cu nanoparticles are observed.
The tea made with the fruits of Luffa operculata (L.) Cogn. (Cucurbitaceae; EBN) is popularly used as abortive.
The present work aimed at accessing how the exposition of female Wistar rats to ...1.0 mg/kg of EBN (experimental group, EG), or distilled water (control group, CG), by gavage, at gestational days (GD) 17–21 interfered with the reproductive performance, and with dams’ behavior after weaning.
At post-natal day 2 (PND2), the number of male and female pups was evaluated, as well as their weight. After weaning (PND21), dams were euthanized, and their liver and kidneys were removed for histological and biochemical analyses, while the blood was used in the evaluation of cytokines IL-1α, IL-1β, IL-6 and TNF-α, corticosterone, adrenocorticotrophic hormone, melatonin, AST, ALT and creatinine levels.
Dams that were treated with EBN showed an anxiety-like behavior, weight loss at the end of gestation and weight gain at weaning, accompanied with a significant decrease in pro-inflammatory cytokines and in the melatonin level. No significant histological or biochemical alterations have occurred in the liver or kidneys. The number of female pups was significantly higher in the EG. The male pups showed weight gain at PND60.
The presence of cucurbitacins is probably involved in the dysregulations that were found, due to their polycyclic steroid triterpene structure.
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•EBN has diminished melatonin serum levels in female rats at PND21.•EBN has diminished female rats' weight at GD21 and augmented at PND21.•EBN vertical administration augmented male pups weight gain at PND60.
Previous investigations by our group have shown that prenatal exposure to lipopolysaccharide (LPS), which mimics infections by Gram-negative bacteria, induced autistic-like behavior. No effective ...treatment yet exists for autism. Therefore, we used our rat model to test a possible treatment for autism. We selected zinc as the prenatal treatment to prevent or ease the impairments induced by LPS because LPS induces hypozincaemia.
We evaluated the effects of LPS and zinc on female reproductive performance. Communication, which is impaired in autism, was tested in pups by ultrasonic vocalizations. Plasma levels of brain-derived neurotrophic factor (BDNF) were determined because it has been considered an autism important biomarker.
Prenatal LPS exposure reduced offspring number and treatment with zinc prevented this reduction. Moreover, pups that were prenatally exposed to LPS spent longer periods without calling their mothers, and posttreatment with zinc prevented this impairment induced by LPS to the same levels as controls. Prenatal LPS also increased BDNF levels in adult offspring, and posttreatment with zinc reduced the elevation of BDNF to the same levels as controls.
BDNF hyperactivity was also found in several studies of autistic patients. Together with our previous studies, our model of prenatal LPS induced autistic-like behavioral, brain, and immune disturbances. This suggests that it is a valid rat model of autism. Prenatal zinc prevented reproductive, communication, and BDNF impairments. The present study revealed a potential beneficial effect of prenatal zinc administration for the prevention of autism with regard to the BDNF pathway.
•Mixed Integer Linear Programming formulation to describe current supply chain networks in personalised medicine.•Assessment of storage as means to increase network flexibility.•Assessment of therapy ...manufacturing time on cost and responsiveness of the network.
Chimeric Antigen Receptor (CAR) T cell therapies are a type of patient-specific cell immunotherapy demonstrating promising results in the treatment of aggressive blood cancer types. CAR T cells follow a 1:1 business model, translating into manufacturing lines and distribution nodes being exclusive to the production of a single therapy, hindering volumetric scale up. In this work, we address manufacturing capacity bottlenecks via a Mixed Integer Linear Programming (MILP) model. The proposed formulation focuses on the design of candidate supply chain network configurations under different demand scenarios. We investigate the effect of an intermediate storage upstream of the network to: (a) debottleneck manufacturing lines and (b) increase facility utilisation. In this setting, we assess cost-effectiveness and flexibility of the supply chain and we evaluate network performance with respect to: (a) average production cost and (b) average response treatment time. The trade-off between cost-efficiency and responsiveness is examined and discussed.
Sickness behavior is considered part of the specific beneficial adaptive behavioral and neuroimmune changes that occur in individuals in response to infectious/inflammatory processes. However, in ...dangerous and stressful situations, sickness behavior should be momentarily abrogated to prioritize survival behaviors, such as fight or flight. Taking this assumption into account, we experimentally induced sickness behavior in rats using lipopolysaccharides (LPS), an endotoxin that mimics infection by gram-negative bacteria, and then exposed these rats to a restraint stress challenge. Zinc has been shown to play a regulatory role in the immune and nervous systems. Therefore, the objective of this study was to examine the effects of zinc treatment on the sickness response of stress-challenged rats. We evaluated 22-kHz ultrasonic vocalizations, open-field behavior, tumor necrosis factor α (TNF-α), corticosterone, and brain-derived neurotrophic factor (BDNF) plasma levels. LPS administration induced sickness behavior in rats compared to controls, i.e., decreases in the distance traveled, average velocity, rearing frequency, self-grooming, and number of vocalizations, as well as an increase in the plasma levels of TNF-α, compared with controls after a stressor challenge. LPS also decreased BDNF expression but did not influence anxiety parameters. Zinc treatment was able to prevent sickness behavior in LPS-exposed rats after the stress challenge, restoring exploratory/motor behaviors, communication, and TNF-α levels similar to those of the control group. Thus, zinc treatment appears to be beneficial for sick animals when they are facing risky/stressful situations.
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