Integration of circadian rhythms and immunotherapy for enhanced precision in brain cancer treatment.

Circadian rhythms significantly impact (patho)physiological processes, with disruptions linked to neurodegenerative diseases and heightened cancer vulnerability. While immunotherapy has shown promise in treating various cancers, its efficacy in brain malignancies remains limited. This review explores the nexus of circadian rhythms and immunotherapy in brain cancer treatment, emphasising precision through alignment with the body's internal clock. We evaluate circadian regulation of immune responses, including cell localisation and functional phenotype, and discuss how circadian dysregulation affects anti-cancer immunity. Additionally, we analyse and assess the effectiveness of current immunotherapeutic approaches for brain cancer including immune checkpoint blockades, adoptive cellular therapies, and other novel strategies. Future directions, such as chronotherapy and personalised treatment schedules, are proposed to optimise immunotherapy precision against brain cancers. Overall, this review provides an understanding of the often-overlooked role of circadian rhythms in brain cancer and suggests avenues for improving immunotherapeutic outcomes.

Circadian rhythms of macrophages are altered by the acidic tumor microenvironment.

Tumor-associated macrophages (TAMs) are prime therapeutic targets due to their pro-tumorigenic functions, but varying efficacy of macrophage-targeting therapies highlights our incomplete understanding of how macrophages are regulated within the tumor microenvironment (TME). The circadian clock is a key regulator of macrophage function, but how circadian rhythms of macrophages are influenced by the TME remains unknown. Here, we show that conditions associated with the TME such as polarizing stimuli, acidic pH, and lactate can alter circadian rhythms in macrophages. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate pH-driven changes in circadian rhythms are not mediated solely by cAMP signaling. Remarkably, circadian disorder of TAMs was revealed by clock correlation distance analysis. Our data suggest that heterogeneity in circadian rhythms within the TAM population level may underlie this circadian disorder. Finally, we report that circadian regulation of macrophages suppresses tumor growth in a murine model of pancreatic cancer. Our work demonstrates a novel mechanism by which the TME influences macrophage biology through modulation of circadian rhythms.

Circadian regulation of dengue virus transmission and replication: insights into vector activity and viral dynamics.

Dengue fever, caused by dengue virus, poses a significant global health challenge, particularly in tropical regions where Aedes aegypti serves as the primary vector. The circadian clock in Aedes aegypti governs key behavioral and physiological processes, including activity patterns, feeding behaviors, and susceptibility to dengue virus infection. This article explores the influence of circadian rhythms on the mosquito's ability to transmit dengue virus, emphasizing how the circadian regulation of gene expression, immune responses, and lipid metabolism in the mosquito vector creates temporal windows that affect viral replication efficiency.

Sex-Related Variation in Circadian Rhythms in the Bumble Bee Bombus terrestris.

Mating success depends on many factors, but first of all, a male and a female need to meet at the same place and time. The circadian clock is an endogenous system regulating activity and sex-related behaviors in animals. We studied bumble bees (Bombus terrestris) in which the influence of circadian rhythms on sexual behavior has been little explored. We characterized circadian rhythms in adult emergence and locomotor activity under different illumination regimes for males and gynes (unmated queens). We developed a method to monitor adult emergence from the pupal cocoon and found no circadian rhythms in this behavior for either males or gynes. These results are not consistent with the hypothesis that the circadian clock regulates emergence from the pupa in this species. Consistent with this premise, we found that both gynes and males do not show circadian rhythms in locomotor activity during the first 3 days after pupal emergence, but shortly after developed robust circadian rhythms that are readily shifted by a phase delay in illumination regime. We conclude that the bumble bees do not need strong rhythms in adult emergence and during early adult life in their protected and regulated nest environment, but do need strong activity rhythms for timing flights and mating-related behaviors. Next, we tested the hypothesis that the locomotor activity of males and gynes have a similar phase, which may improve mating success. We found that both males and gynes have strong endogenous circadian rhythms that are entrained by the illumination regime, but males show rhythms at an earlier age, their rhythms are stronger, and their phase is slightly advanced relative to that of gynes. An earlier phase may be advantageous to males competing to mate a receptive gyne. Our results are consistent with the hypothesis that sex-related variations in circadian rhythms is shaped by sexual selection.

Isoform-specific C-terminal phosphorylation drives autoinhibition of Casein kinase 1.

Casein kinase 1δ (CK1δ) controls essential biological processes including circadian rhythms and wingless-related integration site (Wnt) signaling, but how its activity is regulated is not well understood. CK1δ is inhibited by autophosphorylation of its intrinsically disordered C-terminal tail. Two CK1 splice variants, δ1 and δ2, are known to have very different effects on circadian rhythms. These variants differ only in the last 16 residues of the tail, referred to as the extreme C termini (XCT), but with marked changes in potential phosphorylation sites. Here, we test whether the XCT of these variants have different effects in autoinhibition of the kinase. Using NMR and hydrogen/deuterium exchange mass spectrometry, we show that the δ1 XCT is preferentially phosphorylated by the kinase and the δ1 tail makes more extensive interactions across the kinase domain. Mutation of δ1-specific XCT phosphorylation sites increases kinase activity both in vitro and in cells and leads to changes in the circadian period, similar to what is reported in vivo. Mechanistically, loss of the phosphorylation sites in XCT disrupts tail interaction with the kinase domain. δ1 autoinhibition relies on conserved anion-binding sites around the CK1 active site, demonstrating a common mode of product inhibition of CK1δ. These findings demonstrate how a phosphorylation cycle controls the activity of this essential kinase.

Di(2-ethylhexyl) phthalate disrupts circadian rhythm associated with changes in metabolites and cytochrome P450 gene expression in Caenorhabditis elegans.

The plasticizer di(2-ethylhexyl) phthalate (DEHP) is a widespread environmental pollutant due to its extensive use. While circadian rhythms are inherent in most living organisms, the detrimental effects of DEHP on circadian rhythm and the underlying mechanisms remain largely unknown. This study investigated the influence of early developmental exposure to DEHP on circadian rhythm and explored the possible relationship between circadian disruption and DEHP metabolism in the model organism Caenorhabditis elegans. We observed that DEHP disrupted circadian rhythm in a dose-dependent fashion. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed that DEHP-induced circadian disruption accompanies with altered proportions of DEHP metabolites in C. elegans. RNA sequencing data demonstrated that DEHP-induced circadian rhythm disruption caused differential gene expression. Moreover, DEHP-induced circadian disruption coincided with attenuated inductions of DEHP-induced cytochrome P450 genes, cyp-35A2, cyp-35A3, and cyp-35A4. Notably, cyp-35A2 mRNA exhibited circadian rhythm with entrainment, but DEHP exposure disrupted this rhythm. Our findings suggest that DEHP exposure disrupts circadian rhythm, which is associated with changes in DEHP metabolites and cytochrome P450 gene expression in C. elegans. Given the ubiquitous nature of DEHP pollution and the prevalence of circadian rhythms in living organisms, this study implies a potential negative impact of DEHP on circadian rhythm and DEHP metabolism in organisms.

Biological rhythms in premenstrual syndrome and premenstrual dysphoric disorder: a systematic review.

BACKGROUND: Women with premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) typically experience a range of psychological and physiological symptoms that negatively affect their quality of life. Disruption in biological rhythms, including alterations of the sleep-wake cycle, have been implicated in PMS/PMDD, though literature is still growing to substantiate these findings. The objective of this study is to systematically review the available literature on biological rhythms disruption in PMS/PMDD. METHODS: A literature search was conducted on four databases (Pubmed, Embase, Medline, and Web of Science) on December 3rd, 2021. This search yielded a total of 575 articles that assessed the relationship between biological rhythms and PMS/PMDD/premenstrual symptoms. RESULTS: After the exclusion of irrelevant articles and hand-searching references, 25 articles were included in this systematic review. Some studies showed that women with PMS/PMDD present lower melatonin levels, elevated nighttime core body temperature, and worse subjective perception of sleep quality when compared to women without PMS/PMDD. Other biological rhythms parameters showed either no differences between groups (wrist actimetry) or conflicting results (objective sleep parameters, cortisol, prolactin, and thyroid stimulating hormone). CONCLUSION: Current research demonstrates that women with PMS/PMDD experience lower melatonin levels, higher body temperature, and worse subjective perception of sleep quality. This review outlines some possible mechanisms behind these findings and proposes recommendations for future research. This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42020149921.

Attenuated melanopsin-mediated post-illumination pupillary response (PIPR) is associated with reduced actigraphic amplitude and mesor in older adults.

STUDY OBJECTIVES: This study aimed to explore the relationship between post-illumination pupillary response (PIPR) with sleep and circadian measures in a community sample of healthy older adults. METHODS: Eligible participants were invited to complete a one-week sleep diary, actigraphy and provide an overnight urine sample to measure urinary 6-sulfatoxymelatonin (aMT6s). PIPR was defined as the as the pupil constriction at 6s post-stimulus (PIPR-6s), and ii) for 30s beginning 10s after stimulus (PIPR-30s) normalized as a percentage to the baseline pupil diameter, after 1s of blue and 1s of red-light stimulus, respectively. The Net-PIPRs were reported by subtracting the PIPR to red stimulus from the PIPR to blue stimulus. The relationship between PIPR metrics to aMT6s and actigraphic rest-activity rhythm parameters was examined by generalized linear models. RESULTS: A total of 48 participants were recruited (Mean age: 62.6 ± 7.1 years, Male: 44%). Both Net PIPR-6s and Net PIPR-30s were significantly associated with actigraphic rest-activity amplitude (B=0.03, p=0.001 and B=0.03, p=0.01, respectively), and actigraphic rest-activity mesor (B=0.02, p=0.001 and B=0.03, p=0.004, respectively). Additionally, the Net PIPR-30s were positively associated with overnight aMT6s level (B=0.04, p=0.03), and negatively associated with actigraphic rest-activity acrophase (B=-0.01, p=0.004) in the fully adjusted models. CONCLUSION: Attenuated PIPR is associated with a reduced actigraphic amplitude and mesor. The reduced retinal light responsivity may be a potential pathway contributing to impaired photic input to the circadian clock and resulted in the age-related circadian changes in older adults.

Inclusion, reporting and analysis of demographic variables in chronobiology and sleep research.

Many aspects of sleep and circadian physiology are sensitive to participant-level characteristics. While recent research robustly highlights the importance of considering participant-level demographic information, the extent to which this information is consistently collected, and reported in the literature, remains unclear. This article investigates study sample characteristics within the published sleep and chronobiology research over the past 40 years. 6,777 articles were identified and a random sample of 20% was included. The reporting of sample size, age, sex, gender, ethnicity, level of education, socio-economic status, and profession of the study population was scored, and any reported aggregate summary statistics for these variables were recorded. We observed a significant upward trend in the reporting and analysis of demographic variables in sleep and chronobiology research. However, we found that while > 90% of studies reported age or sex, all other variables were reported in < 25% of cases. Reporting quality was highly variable, indicating an opportunity to standardize reporting guidelines for participant-level characteristics to facilitate Meta analyses.

Resilience to Chronic Stress Is Characterized by Circadian Brain-Liver Coordination.

Background: Chronic stress has a profound impact on circadian regulation of physiology. In turn, disruption of circadian rhythms increases the risk of developing both psychiatric and metabolic disorders. To explore the role of chronic stress in modulating the links between neural and metabolic rhythms, we characterized the circadian transcriptional regulation across different brain regions and the liver as well as serum metabolomics in mice exposed to chronic social defeat stress, a validated model for studying depressive-like behaviors. Methods: Male C57BL/6J mice underwent chronic social defeat stress, and subsequent social interaction screening identified distinct behavioral phenotypes associated with stress resilience and susceptibility. Stressed mice and their control littermates were sacrificed every 4 hours over the circadian cycle for comprehensive analyses of the circadian transcriptome in the hypothalamus, hippocampus, prefrontal cortex, and liver together with assessments of the circadian circulatory metabolome. Results: Our data demonstrate that stress adaptation was characterized by reprogramming of the brain as well as the hepatic circadian transcriptome. Stress resiliency was associated with an increase in cyclic transcription in the hypothalamus, hippocampus, and liver. Furthermore, cross-tissue analyses revealed that resilient mice had enhanced transcriptional coordination of circadian pathways between the brain and liver. Conversely, susceptibility to social stress resulted in a loss of cross-tissue coordination. Circadian serum metabolomic profiles corroborated the transcriptome data, highlighting that stress-resilient mice gained circadian rhythmicity of circulating metabolites, including bile acids and sphingomyelins. Conclusions: This study reveals that resilience to stress is characterized by enhanced metabolic rhythms and circadian brain-liver transcriptional coordination.

Chronic stress can have detrimental effects on both physical and mental health, often disrupting biological daily rhythms, known as circadian rhythms. To delve deeper into this phenomenon, we investigated how chronic stress affects circadian rhythms in the brain, liver, and blood metabolism of mice. Our study revealed that mice resilient to stress showed an increase in shared circadian biological processes between the liver and different brain regions together with enhanced rhythms in circulating metabolites. These findings propose an unprecedented link between stress adaptation and systemic circadian coordination and offer valuable insights into the mechanisms that underlie circadian disturbances seen in psychiatric disorders.

The chronobiology of human heart failure: clinical implications and therapeutic opportunities.

Circadian variation in cardiovascular and metabolic dynamics arises from interactions between intrinsic rhythms and extrinsic cues. By anticipating and accommodating adaptation to awakening and activity, their synthesis maintains homeostasis and maximizes efficiency, flexibility, and resilience. The dyssynchrony of cardiovascular load and energetic capacity arising from attenuation or loss of such rhythms is strongly associated with incident heart failure (HF). Once established, molecular, neurohormonal, and metabolic rhythms are frequently misaligned with each other and with extrinsic cycles, contributing to HF progression and adverse outcomes. Realignment of biological rhythms via lifestyle interventions, chronotherapy, and time-tailored autonomic modulation represents an appealing potential strategy for improving HF-related morbidity and mortality.

Diagnosing and treating hypersomnolence in depression.

Hypersomnolence, a broad presentation encompassing excessive daytime sleepiness, hypersomnia and sleep inertia, affects around 25 % of patients with a major depressive disorder. Yet, hypersomnolence is often overlook in clinical settings - which can prevent remission of the mood disorder in addition to significantly interfering with quality of life. Clinical guidelines are lacking to support clinicians in the diagnosis and treatment of hypersomnolence in depression. Pharmacological treatment with selective serotonin reuptake inhibitors is insufficient and noradrenaline and dopamine reuptake inhibitors or similar molecules are generally indicated. Low-sodium oxybate was recently approved for Idiopathic Hypersomnia, but studies are needed to assess its efficacy in patients with comorbid depression. In parallel, cognitive behavioral therapy for hypersomnia is being developed as adjunct non-pharmacological treatment. Light therapy might also be beneficial in these populations. This narrative review aims at proposing a diagnostic approach reconciliating psychiatry and sleep medicine nosologies, as well as offering a multimodal treatment algorithm for hypersomnolence in depression.

A Randomized-Controlled Trial Targeting Cognition in Early Alzheimer's Disease by Improving Sleep with Trazodone (REST).

 Alzheimer's disease (AD) is a leading cause of mortality and morbidity among aging populations worldwide. Despite arduous research efforts, treatment options for this devastating neurodegenerative disease are limited. Sleep disturbances, through their link to changes in neural excitability and impaired clearance of interstitial abnormal protein aggregates, are a key risk factor for the development of AD. Research also suggests that the neuroprotective effects of sleep are particularly active during slow wave sleep. Given the strong link between sleep disturbance and AD, targeting sleep in the prodromal stages of AD, such as in mild cognitive impairment (MCI), represents a promising avenue for slowing the onset of AD-related cognitive decline. In efforts to improve sleep in older individuals, several pharmacologic approaches have been employed, but many pose safety risks, concern for worsening cognitive function, and fail to effectively target slow wave sleep. Trazodone, a safe and widely used drug in the older adult population, has shown promise in inducing slow wave sleep in older adults, but requires more rigorous research to understand its effects on sleep and cognition in the prodromal stages of AD. In this review, we present the rationale and study design for our randomized, double-bind, placebo-controlled, crossover trial (NCT05282550) investigating the effects of trazodone on sleep and cognition in 100 older adults with amnestic MCI and sleep complaints.

Getting in the zone: Metabolite transport across liver zones.

The liver has many functions including the regulation of nutrient and metabolite levels in the systemic circulation through efficient transport into and out of hepatocytes. To sustain these functions, hepatocytes display large functional heterogeneity. This heterogeneity is reflected by zonation of metabolic processes that take place in different zones of the liver lobule, where nutrient-rich blood enters the liver in the periportal zone and flows through the mid-zone prior to drainage by a central vein in the pericentral zone. Metabolite transport plays a pivotal role in the division of labor across liver zones, being either transport into the hepatocyte or transport between hepatocytes through the blood. Signaling pathways that regulate zonation, such as Wnt/ß-catenin, have been shown to play a causal role in the development of metabolic dysfunction-associated steatohepatitis (MASH) progression, but the (patho)physiological regulation of metabolite transport remains enigmatic. Despite the practical challenges to separately study individual liver zones, technological advancements in the recent years have greatly improved insight in spatially divided metabolite transport. This review summarizes the theories behind the regulation of zonation, diurnal rhythms and their effect on metabolic zonation, contemporary techniques used to study zonation and current technological challenges, and discusses the current view on spatial and temporal metabolite transport.

The Change Rate of the Fbxl21 Gene and the Amino Acid Composition of Its Protein Correlate with the Species-Specific Lifespan in Placental Mammals.

This article proposes a methodology for establishing a relationship between the change rate of a given gene (relative to a given taxon) together with the amino acid composition of the proteins encoded by this gene and the traits of the species containing this gene. The methodology is illustrated based on the mammalian genes responsible for regulating the circadian rhythms that underlie a number of human disorders, particularly those associated with aging. The methods used are statistical and bioinformatic ones. A systematic search for orthologues, pseudogenes, and gene losses was performed using our previously developed methods. It is demonstrated that the least conserved Fbxl21 gene in the Euarchontoglires superorder exhibits a statistically significant connection of genomic characteristics (the median of dN/dS for a gene relative to all the other orthologous genes of a taxon, as well as the preference or avoidance of certain amino acids in its protein) with species-specific lifespan and body weight. In contrast, no such connection is observed for Fbxl21 in the Laurasiatheria superorder. This study goes beyond the protein-coding genes, since the accumulation of amino acid substitutions in the course of evolution leads to pseudogenization and even gene loss, although the relationship between the genomic characteristics and the species traits is still preserved. The proposed methodology is illustrated using the examples of circadian rhythm genes and proteins in placental mammals, e.g., longevity is connected with the rate of Fbxl21 gene change, pseudogenization or gene loss, and specific amino acid substitutions (e.g., asparagine at the 19th position of the CRY-binding domain) in the protein encoded by this gene.

Sex differences in the adrenal circadian clock: A role for BMAL1 in the regulation of urinary aldosterone excretion and renal electrolyte balance in mice.

Brain and muscle ARNT-Like 1 (BMAL1) is a circadian clock transcription factor that regulates physiological functions. Male adrenal-specific Bmal1 (ASCre/+::Bmal1) KO mice displayed blunted serum corticosterone rhythms, altered blood pressure rhythm, and altered timing of eating, but there is a lack of knowledge in females. This study investigates the role of adrenal BMAL1 in renal electrolyte handling and urinary aldosterone levels in response to low salt in male and female mice. Mice were placed in metabolic cages to measure 12-hour urinary aldosterone after a standard diet and 7 days low salt diet, as well as daily body weight, 12-hour food and water intake, and renal sodium and potassium balance. Adrenal glands and kidneys were collected at ZT0 or ZT12 to measure expression of aldosterone synthesis genes and clock genes. Compared to littermate controls, ASCre/+::Bmal1 KO male and female mice displayed increased urinary aldosterone in response to a low salt diet, although mRNA expression of aldosterone synthesis genes was decreased. Timing of food intake was altered in ASCre/+::Bmal1 KO male and female mice, with a blunted night/day ratio. ASCre/+::Bmal1 KO female mice displayed decreases in renal sodium excretion in response to low salt, but both male and female KO mice had changes in sodium balance that were time-of-day-dependent. In addition, sex differences were found in adrenal and kidney clock gene expression. Notably, this study highlights sex differences in clock gene expression that could contribute to sex differences in physiological functions.

Cerebellar deep brain stimulation as a dual-function therapeutic for restoring movement and sleep in dystonic mice.

Dystonia arises with cerebellar dysfunction, which plays a key role in the emergence of multiple pathophysiological deficits that range from abnormal movements and postures to disrupted sleep. Current therapeutic interventions typically do not simultaneously address both the motor and non-motor symptoms of dystonia, underscoring the necessity for a multi-functional therapeutic strategy. Deep brain stimulation (DBS) is effectively used to reduce motor symptoms in dystonia, with existing parallel evidence arguing for its potential to correct sleep disturbances. However, the simultaneous efficacy of DBS for improving sleep and motor dysfunction, specifically by targeting the cerebellum, remains underexplored. Here, we test the effect of cerebellar DBS in two genetic mouse models with dystonia that exhibit sleep defects-Ptf1aCre;Vglut2fx/fx and Pdx1Cre;Vglut2fx/fx-which have overlapping cerebellar circuit miswiring defects but differing severity in motor phenotypes. By targeting DBS to the fiber tracts located between the cerebellar fastigial and the interposed nuclei (FN â€‹+ â€‹INT-DBS), we modulated sleep dysfunction by enhancing sleep quality and timing. This DBS paradigm improved wakefulness and rapid eye movement sleep in both mutants. Additionally, the latency to reach REM sleep, a deficit observed in human dystonia patients, was reduced in both models. Cerebellar DBS also induced alterations in the electrocorticogram (ECoG) patterns that define sleep states. As expected, DBS reduced the severe dystonic twisting motor symptoms that are observed in the Ptf1aCre;Vglut2fx/fx mice. These findings highlight the potential for using cerebellar DBS to simultaneously improve sleep and reduce motor dysfunction in dystonia and uncover its potential as a dual-effect in vivo therapeutic strategy.

Corneal and intraocular pressure changes associated to the circadian rhythms: a narrative review.

AIM: To synthesize the current body of research regarding the diurnal variations in intraocular pressure (IOP) and corneal biomechanical and morphological parameters, highlighting their significance in various eye conditions. METHODS: A comprehensive review of studies on the diurnal variations of IOP and corneal parameters was conducted. Tonometry findings from various studies were assessed, including the Goldmann applanation tonometry (GAT) and non-contact tonometers. Data on the variations in central corneal thickness (CCT), corneal curvature, and corneal biomechanics measured by the Ocular Response Analyzer system across different population groups was extracted and analyzed. RESULTS: In both healthy subjects and those with Fuchs dystrophy, IOP and CCT demonstrate marked diurnal declines. GAT remains the gold standard for tonometry, with the highest reliability. However, its measurements are influenced by CCT. Keratoconus patients and those with pseudoexfoliation showed significant diurnal variations in IOP. The biomechanical parameters, especially corneal hysteresis (CH) and the corneal resistance factor (CRF), largely remain stable throughout the day for most of eye conditions, with some exceptions. Notably, the corneal morphology diurnal variation, particularly curvature, yielded mixed conclusions across studies. CONCLUSION: Circadian rhythms significantly influence various corneal parameters, most notably IOP and CCT. Further studies should emphasize standardized approaches larger sample sizes, and delve deeper into less-explored areas, such as the effects of orthokeratology lenses on diurnal biomechanical shifts.

The influence of light on Interleukin-10: A preliminary study.

Light influences circadian rhythms, including that of the stress hormone cortisol. Cortisol, in turn, has been observed to promote expression of the anti-inflammatory cytokine IL-10. It is thus of interest whether the cytokine IL-10 is also influenced by light, perhaps in accord with the diurnal variations in cortisol. Hence, this highly standardized preliminary sleep laboratory study in healthy adult men investigated a potential influence of different light exposure on IL-10 and cortisol concentrations in blood. In a between-subject design, N = 42 participants were exposed to either bright, dim, blue or red light after wake-up. Two mixed-model analyses with the factors of light condition and time (across eight IL-10 and cortisol sampling points) were conducted. Additionally, area under the curve measurements (AUCg and AUCi) were calculated for both cortisol and IL-10. Across all conditions, IL-10 and cortisol concentrations significantly changed over time. However, none of the light conditions exerted a greater influence on IL-10 or cortisol levels than others. For cortisol, there was greater total output (AUCg) in the blue-light condition in particular. Further research is needed to gain insight into whether or not types of light or cortisol levels have a hand in influencing natural IL-10 concentrations.

Bone-brain crosstalk in osteoarthritis: pathophysiology and interventions.

Osteoarthritis (OA) is a prevalent articular disorder characterized by joint degeneration and persistent pain; it imposes a significant burden on both individuals and society. While OA has traditionally been viewed as a localized peripheral disorder, recent preclinical and clinical studies have revealed the crucial interconnections between the bone and the brain, highlighting the systemic nature of OA. The neuronal pathway, molecular signaling, circadian rhythms, and genetic underpinnings within the bone-brain axis play vital roles in the complex interplay that contributes to OA initiation and progression. This review explores emerging evidence of the crosstalk between the bone and brain in OA progression, and discusses the potential contributions of the bone-brain axis to the development of effective interventions for managing OA.