Circadian rhythmicity of amyloid-beta-related molecules is disrupted in the choroid plexus of a female Alzheimer's disease mouse model.

The choroid plexus (CP) is part of the blood-cerebrospinal fluid barrier (BCSFB) and was recently described as an important component of the circadian clock system. It is the principal source of cerebrospinal fluid (CSF) and responsible for the synthesis and secretion of various neuroprotective peptides including those involved in amyloid-ß (Aß) transport/degradation, contributing to Aß homeostasis. Inadequate Aß metabolic clearance and transport across the BCSFB have been associated with circadian dysfunctions in Alzheimer's disease (AD) patients. To investigate whether AD pathology influences Aß scavengers circadian expression, we collected CP at different time points from an AD mouse model (APP/PS1) (female and male animals, aged 6- and 12-months-old) and analyzed their mRNA expression by Real-time RT-PCR. Only angiotensin-converting enzyme (Ace) expression in 6-month-old female wild-type mice and transthyretin (Ttr) expression in 12-month-old female wild-type mice presented significant rhythmicity. The circadian rhythmicity of Ace and Ttr, prompt us to analyze the involvement of circadian rhythm in Aß uptake. A human CP papilloma (HIBCPP) cell line was incubated with Aß-488 and uptake was evaluated at different time points using flow cytometry. Aß uptake displayed circadian rhythmicity. Our results suggest that AD might affect Aß scavengers rhythmicity and that Aß clearance is a rhythmic process possibly regulated by the rhythmic expression of Aß scavengers.

Bitter taste signaling in cancer.

Pharmacoresistance of cancer cells to many drugs used in chemotherapy remains a major challenge for the treatment of cancer. Multidrug resistance transporters, especially ATP-binding cassette (ABC) transporters, are a major cause of cancer drug resistance since they translocate a broad range of drug compounds across the cell membrane, extruding them out of the cells. The regulation of ABC transporters by bitter taste receptors (TAS2Rs), which might be activated by specific bitter tasting compounds, was described in several types of cells/organs, becoming a potential target for cancer therapy. TAS2Rs expression has been reported in many organs and several types of cancer, like breast, ovarian, prostate, and colorectal cancers, where their activation was shown to be involved in various biological actions (cell survival, apoptosis, molecular transport, among others). Moreover, many TAS2Rs' ligands, such as flavonoids and alkaloids, with well-recognized beneficial properties, including several anticancer effects, have been reported as potential adjuvants in cancer therapies. In this review, we discuss the potential therapeutic role of TAS2Rs and bitter tasting compounds in different types of cancer as a possible way to circumvent chemoresistance.

Acute effects of isotonic eccentric exercise on the neuromuscular function of knee extensors vary according to the motor task: impact on muscle strength profiles, proprioception and balance.

Introduction: Eccentric exercise has often been reported to result in muscle damage, limiting the muscle potential to produce force. However, understanding whether these adverse consequences extend to a broader, functional level is of apparently less concern. In this study, we address this issue by investigating the acute and delayed effects of supramaximal isotonic eccentric exercise on neuromuscular function and motor performance of knee extensors during tasks involving a range of strength profiles, proprioception, and balance. Methods: Fifteen healthy volunteers (23.2 ± 2.9 years old) performed a unilateral isotonic eccentric exercise of the knee extensors of their dominant lower limb (4 × 10 reps at 120% of one Repetition Maximum (1RM)). The maximum voluntary isometric contraction (MVC), rate of force development (RFD), force steadiness of the knee extensors, as well as knee joint position sense and mediolateral (MLI) and anteroposterior stability (API) of the dominant lower limb, were measured pre-, immediately, and 24 h after the eccentric exercise. The EMG amplitude of the vastus medialis (VM) and biceps femoris (BF) were concomitantly evaluated. Results: MVC decreased by 17.9% immediately after exercise (P < 0.001) and remained reduced by 13.6% 24 h following exercise (P < 0.001). Maximum RFD decreased by 20.4% immediately after exercise (P < 0.001) and remained reduced by 15.5% at 24 h (P < 0.001). During the MVC, EMG amplitude of the VM increased immediately after exercise while decreasing during the RFD task. Both values returned to baseline 24 h after exercise. Compared to baseline, force steadiness during submaximal isometric tasks reduced immediately after exercise, and it was accompanied by an increase in the EMG amplitude of the VM. MLI and knee joint position sense were impaired immediately after isotonic eccentric exercise (P < 0.05). While MLI returned to baseline values 24 h later, the absolute error in the knee repositioning task did not. Discussion: Impairments in force production tasks, particularly during fast contractions and in the knee joint position sense, persisted 24 h after maximal isotonic eccentric training, revealing that neuromuscular functional outputs were affected by muscle fatigue and muscle damage. Conversely, force fluctuation and stability during the balance tasks were only affected by muscle fatigue since fully recovered was observed 24 h following isotonic eccentric exercise.

The brain as a source and a target of prolactin in mammals.

Prolactin is a polypeptide hormone associated with an extensive variety of biological functions. Among the roles of prolactin in vertebrates, some were preserved throughout evolution. This is the case of its function in the brain, where prolactin receptors, are expressed in different structures of the central nervous system. In the brain, prolactin actions are principally associated with reproduction and parental behavior, and involves the modulation of adult neurogenesis, neuroprotection, and neuroplasticity, especially during pregnancy, thereby preparing the brain to parenthood. Prolactin is mainly produced by specialized cells in the anterior pituitary gland. However, during vertebrate evolution many other extrapituitary tissues do also produce prolactin, like the immune system, endothelial cells, reproductive structures and in several regions of the brain. This review summarizes the relevance of prolactin for brain function, the sources of prolactin in the central nervous system, as well as its local production and secretion. A highlight on the impact of prolactin in human neurological diseases is also provided.

The Choroid Plexus Is an Alternative Source of Prolactin to the Rat Brain.

Among the more than 300 functions attributed to prolactin (PRL), this hormone has been associated with the induction of neurogenesis and differentiation of olfactory neurons especially during pregnancy, which are essential for maternal behavior. Despite the original hypothesis that PRL enters the central nervous system through a process mediated by PRL receptors (PRLR) at the choroid plexus (CP), recent data suggested that PRL transport into the brain is independent of its receptors. Based on transcriptomic data suggesting that PRL could be expressed in the CP, this work aimed to confirm PRL synthesis and secretion by CP epithelial cells (CPEC). The secretion of PRL and the distribution of PRLR in CPEC were further characterized using an in vitro model of the rat blood-cerebrospinal fluid barrier. RT-PCR analysis of PRL transcripts showed its presence in pregnant rat CP, in CPEC, and in the rat immortalized CP cell line, Z310. These observations were reinforced by immunocytochemistry staining of PRL in CPEC and Z310 cell cytoplasm. A 63-kDa immunoreactive PRL protein was detected by Western blot in CP protein extracts as well as in culture medium incubated with rat pituitary and samples of rat cerebrospinal fluid and serum. Positive immunocytochemistry staining of PRLR was present throughout the CPEC cytoplasm and in the apical and basal membrane of these cells. Altogether, our evidences suggest that CP is an alternative source of PRL to the brain, which might impact neurogenesis of olfactory neurons at the subventricular zone, given its proximity to the CP.