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Parkinson’s disease (PD) is characterized by astrocyte activation and disruptions in circadian rhythm. Within the astrocyte population, two distinct reactive states exist: A1 and A2. A1 astrocytes are associated with neurotoxicity and inflammation, while A2 astrocytes exhibit neuroprotective functions. Our investigation focused on the role of REV-ERBα, a member of the nuclear receptor superfamily and a key regulator of the circadian clock, in astrocyte activation. We observed that REV-ERBα expression in A1 astrocytes was reduced to one-third of its normal level. Notably, activation of REV-ERBα prompted a transformation of astrocytes from A1 to A2. Mechanistically, REV-ERBα inhibition was linked to the classical NF-κB pathway, while it concurrently suppressed the STAT3 pathway. Furthermore, astrocytes with low REV-ERBα expression were associated with dopaminergic neurons apoptosis. Intriguingly, the opposite effect was observed when using a REV-ERBα agonist, which mitigated astrocyte activation and reduced dopaminergic neuron damage by 50%. In summary, our study elucidates the pivotal role of REV-ERBα in modulating astrocyte function and its potential implications in PD pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Epilepsy is a neurological disease characterized by recurrent seizures, hyperexcitable neurons and various behavioral comorbidities. The electrical charge during seizures depletes the antioxidant defense mechanism in the epileptic brain and increases the oxidative burden. Natural antioxidant compounds are potential therapeutics in the treatment of two major pathologies of epilepsy with their anticonvulsant and anxiolytic effects and can modulate these targets. Gum Arabic is one of the natural plant polysaccharides that is non-toxic and biodegradable. Methods and results: A total of 30 Wistar albino male rats (8–12 weeks, 350–500 g), were randomly divided into 5 groups with 6 animals in each group: 1-Control, 2-Sham (Phosphate buffer saline (PBS)), 3-PTZ, 4-Gum Arabic, 5-PTZ + Gum Arabic. PTZ was administered i.p at 35 mg/kg/day for 11 days. After 48 h, the injection was completed with 75 mg/kg PTZ. Locomotor activity, immobilization, rearing, grooming, eating, and drinking behaviors were recorded with the LABORAS behavior system for 30 min after kindling. Animals were treated with Gum Arabic (2 mg/kg/day, oral gavage) for 10 days. At the end of the period, animal behavior was recorded again. Then the hippocampus tissues were removed. Oxidative parameters (TAS and TOS), early growth response 1 (EGR1) and nuclear receptor subfamily 1 group D member 1 (Rev-erbα) gene expressions and behaviors were analyzed. Conclusion: Gum Arabic increased TAS levels (P = 0.000), decreased TOS levels (P = 0.000), and thus exhibited antioxidant properties by reducing oxidative stress burden. EGR1, which was upregulated in the seizure group, was downregulated after treatment (P = 0.000), and Rev-erbα was downregulated in seizure and upregulated after treatment (P = 0.000). Gum arabic may be an antiepileptic and anxiolytic therapeutic in improving epileptic seizures by reducing oxidative stress burden through EGR1 and Rev-erbα.0 [ABSTRACT FROM AUTHOR]

Background: Today, modern lifestyles and disrupted sleep patterns cause circadian clock rhythm impairments that are associated with altered leptin levels, which subsequently affect a wide range of physiological processes and have significant health burdens on societies. Nevertheless, there has been no systematic review of circadian clock genes and proteins, leptin, and related signaling pathways. Methods: Accordingly, we systematically reviewed circadian clock proteins, leptin, and molecular mechanisms between them by searching Pubmed, Scopus, ProQuest, Web of Sciences, and Google Scholar until September 2022. After considering the inclusion and exclusion criteria, 20 animal studies were selected. The risk of bias was assessed in each study. Results: The results clarified the reciprocal interconnected relationship between circadian clock genes and leptin. Circadian clock genes regulate leptin expression and signaling via different mechanisms, such as CLOCK-BMAL1 heterodimers, which increase the expression of PPARs. PPARs induce the expression of C/EBPα, a key factor in upregulating leptin expression. CLOCK-BMAL1 also induces the expression of Per1 and Rev-erb genes. PER1 activates mTORC1 and mTORC1 enhances the expression of C/EBPα. In addition, REV-ERBs activate the leptin signaling pathway. Also, leptin controls the expression of circadian clock genes by triggering the AMPK and ERK/MAPK signaling pathways, which regulate the activity of PPARs. Moreover, the roles of these molecular mechanisms are elucidated in different physiological processes and organs. Conclusions: Crosstalk between circadian clock genes and leptin and their affecting elements should be considered in the selection of new therapeutic targets for related disorders, especially obesity and metabolic impairments. [ABSTRACT FROM AUTHOR]

Subarachnoid hemorrhage (SAH) is associated with circadian rhythm abnormalities, in which REV-ERBα plays a major regulatory role. Our ambition was to investigate the capacity of REV-ERBα to inhibit neuronal neuroapoptosis induced by early brain injury (EBI) after SAH. The endovascular perforation model was used to produce experimental SAH in Sprague–Dawley rats. Specific small-interfering RNA was used to downregulate the expression REV-ERBα while SR9009 was used to upregulate the expression before assessments. Short- and long-term neurobehavior assessments, immunofluorescence staining, TUNEL staining, Nissl staining, brain water content, and Western blot were performed. The expression level of endogenous REVERBα tended to increase and then decrease after SAH and peaked at 48 h. REV-ERBα upregulation diminished neuronal apoptosis and enhanced neurological function deficits. Meanwhile, REV-ERBα downregulation aggravated the damage. Furthermore, the levels of downstream proteins of REV-ERBα (i.e., brain and muscle ARNT-like 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK)) changed accordingly with REV-ERBα regulation. REV-ERBα may attenuate neuronal apoptosis in EBI after SAH through the BMAL1/CLOCK pathway. [ABSTRACT FROM AUTHOR]

Although fluoxetine (FLX) is a commonly used drug in psychiatric disorders, such as major depressive disorder, anxiety disorder, panic disorder, and obsessive–compulsive disorder, the mechanism by which FLX exerts its therapeutic effect is not completely understood. In this study, we aimed to determine the possible mechanism by which FLX focuses on microglial phagocytosis. FLX reduced phagocytic function in BV2 cells and increased REV-ERBα without affecting other microglia-related genes, such as inflammation and phagocytosis. Although FLX did not change BMAL1 protein levels, it restricted the nucleocytoplasmic transport (NCT) of BMAL1, leading to its cytosolic accumulation. REV-ERBα antagonist SR8278 rescued the decreased phagocytic activity and restricted NCT of BMAL1. We also found that REV-ERBα mediates the effect of FLX via the inhibition of phospho-ERK (pERK). The ERK inhibitor FR180204 was sufficient to reduce phagocytic function in BV2 cells and restrict the NCT of BMAL1. These results were recapitulated in the primary microglia. In conclusion, we propose that FLX decreases phagocytic function and restricts BMAL1 NCT via REV-ERBα. In addition, ERK inhibition mimics the effects of FLX on microglia. [ABSTRACT FROM AUTHOR]

Most living organisms show circadian rhythms in physiology and behavior. These oscillations are generated by endogenous circadian clocks, present in virtually all cells where they control key biological processes. To study peripheral clocks in vivo, we developed an original model, the Rev-Luc mouse to follow noninvasively and longitudinally Rev-Luc oscillations in peripheral clocks using in vivo bioluminescence imaging. We found in vitro and in vivo a robust diurnal rhythm of Rev-Luc, mainly in liver, intestine, kidney and adipose tissues. We further confirmed in vivo that Rev-Luc peripheral tissues are food-entrainable oscillators, not affected by age or sex. These data strongly support the relevance of the Rev-Luc model for circadian studies, especially to investigate in vivo the establishment and the entrainment of the rhythm throughout ontogenesis. We then showed that Rev-Luc expression develops dynamically and gradually, both in amplitude and in phase, during fetal and postnatal development. We also demonstrate for the first time that the immature peripheral circadian system of offspring in utero is mainly entrained by maternal cues from feeding regimen. The prenatal entrainment will also differentially determine the Rev-Luc expression in pups before weaning underlining the importance of the maternal chrononutrition on the circadian system entrainment of the offspring. [ABSTRACT FROM AUTHOR]

Circadian rhythms are strongly affected by drugs. In rodents, chronic methamphetamine (METH) intake changes circadian activity rhythms, mainly by altering light synchronization that generates the expression of a free-running rhythm with a period longer than 24 h and a second behavioral component that is independent of the main suprachiasmatic (SCN) clock. Although a number of clock genes do not appear to be involved in the effects of METH on circadian behavior, the molecular clockwork controlling these changes is still unclear. Therefore, we investigated the role of the clock gene Rev-Erbα in METH-induced behavioral and molecular responses using knockout mice and their wild-type littermates. Chronic intake of METH alters period circadian behavior of wild-type mice. However, in mice lacking the clock gene Rev-Erbα METH had no effect on their behavioral rhythms. Furthermore, PER2 bioluminescence rhythms in two extra-SCN brain oscillators, the dorsomedial hypothalamus and the habenula, were altered by METH in wild type but not in KO mice. Together, the present results implicate Rev-Erbα in the modulation of the circadian responses to METH and may provide a better comprehension into the mechanisms underlying circadian alterations provoked by drug addiction. [ABSTRACT FROM AUTHOR]

The nuclear receptor Rev-erbβ is a potent transcriptional factor whose functional study has been limited by the lack of suitable antibodies against it. To better understand Rev-erbβ's biological roles, we generated five hybridoma cell lines secreting antibodies against human Rev-erbβ in mice immunized with the purified, prokaryotically expressed recombinant Rev-erbβ-6His fusion protein. Using Western blotting and immunofluorescence analyses, all the five monoclonal antibodies (MAbs) showed strong immunoreactivity to both prokaryotically and eukaryotically expressed recombinant Rev-erbβ. An immunoprecipitation study showed that all five monoclonal antibodies against Rev-erbβ were able to pull down the recombinant Rev-erbβ-Flag protein, but only one of the MAbs against Rev-erbβ, 37H8, could pull down the endogenous Rev-erbβ protein. Furthermore, domain specificity of these MAbs was characterized. Due to the high similarities between Rev-erbα and Rev-erbβ in the C and E domains, those C and E domain-specific anti-Rev-erbβ antibodies can react with human Rev-erbα as well. The MAbs produced in the study will provide a valuable tool for investigating the function of Rev-erbβ. [ABSTRACT FROM AUTHOR]

Objective:Circadian mechanisms underlie the physiology of mammals as an adaptation to the earth's rotation on its axis. Highly conserved core circadian regulatory proteins (CCRPs) maintain an oscillatory expression profile in the central and peripheral tissues. The CCRP include both a positive and negative arm, as well as downstream transcriptional regulators. Recent studies in murine models have determined that the mRNAs encoding the CCRP are present in multiple adipose tissue depots and exhibit a robust oscillatory expression profile. This study set out to examine the expression of CCRP mRNAs in human subcutaneous adipose tissues.Design:Retrospective analysis of total RNA isolated from subcutaneous adipose tissue.Subjects:A total of 150 healthy female and male lean (body mass index (BMI) <25), overweight (BMI between 25 and 29.99) or obese (BMI >30) subjects of varied ethnic backgrounds undergoing elective liposuction or surgical procedures.Results:The expression of the CCRP mRNAs displayed a significant correlation between each other and mRNAs representative of adipogenic biomarkers. Hierarchical cluster analyses of mRNAs isolated from the cohort of female Caucasian subjects (n=116) identified three major clusters based on expression of downstream CCRP mRNAs. The mRNAs encoding D site of albumin promoter-binding protein (DBP), E4 promoter-binding protein 4 (E4BP4), PPARγ coactivator-1β (PGC-1β) and Rev-erbα were negatively correlated with BMI in a lean cluster (n=66), positively correlated with BMI in a younger overweight/obese cluster (n=19), and not significantly correlated with BMI in an older, overweight/obese cluster (n=31).Conclusions:These data confirm and extend findings that link the CCRP and circadian mechanisms to the risk of obesity. [ABSTRACT FROM AUTHOR]