Search Results (232)

Shift work is an essential component of modern occupational systems but represents a major source of circadian misalignment associated with gastrointestinal symptoms and selected gastrointestinal disorders. The biological pathways underlying these associations remain incompletely integrated across circadian, neuroendocrine, immune, epithelial, and microbial domains. This narrative review aimed to synthesize current evidence linking shift work with gastrointestinal dysfunction and disease while distinguishing epidemiological associations from experimental mechanistic evidence and biologically plausible but insufficiently validated relationships. We conducted a structured literature search in PubMed/MEDLINE, Scopus, and Web of Science, focusing primarily on studies published between January 2020 and July 2026. We prioritized recent original studies, systematic reviews, meta-analyses, and mechanistic and translational investigations, while retaining relevant landmark studies. Evidence was organized within an integrative framework encompassing occupational exposure, circadian disruption, neuroendocrine alterations, immune dysregulation, intestinal barrier dysfunction, gut microbial and metabolic alterations, and gastrointestinal outcomes, with explicit consideration of differences in evidentiary strength across these proposed relationships. Human studies consistently support an association between night or rotating shift work and circadian disruption, whereas evidence for downstream neuroendocrine, immune, epithelial, and microbial pathways varies substantially in directness and strength. Experimental studies indicate that circadian disruption can alter inflammatory signaling, epithelial barrier function, and host–microbiota interactions, while microbial metabolites, including short-chain fatty acids, secondary bile acids, and tryptophan derivatives, may participate in reciprocal interactions with mucosal immunity and barrier integrity. Epidemiological evidence is strongest for disorders of gut–brain interaction, particularly irritable bowel syndrome, whereas evidence for functional dyspepsia, inflammatory bowel disease, and colorectal neoplasia is more limited, inconsistent, or unresolved. Candidate circadian, inflammatory, intestinal barrier, microbial, and metabolomic biomarkers remain investigational and are not currently validated for gastrointestinal risk prediction or routine occupational surveillance. Shift work is associated with selected gastrointestinal outcomes, while experimental evidence provides biological plausibility for interconnected circadian, neuroendocrine, immune, epithelial, and microbial mechanisms. However, the proposed framework should be regarded as integrative and hypothesis-generating rather than as an established linear causal cascade in human shift workers. Prospective longitudinal and interventional studies are required to establish temporal and causal relationships, validate candidate biomarkers, and determine whether occupational, behavioral, or mechanism-based interventions can produce clinically meaningful gastrointestinal benefits. Full article

Background: Treatment-resistant depression (TRD) is an operational category based on inadequate outcome after adequate antidepressant treatment. The same label may encompass insufficient treatment exposure, an incorrect primary diagnosis, clinically important comorbidity, or depressive illnesses with different maintaining mechanisms. This heterogeneity limits the clinical meaning of treatment history alone and complicates individualized care. Objective: To integrate evidence on diagnostic reassessment, suicide risk, neurobiology, psychological and functional factors, and treatment, and to define a clinically testable personalized medicine framework for TRD. Methods: Targeted PubMed/MEDLINE searches were conducted from database inception through 31 July 2026 and supplemented by reference-list searching. Two authors independently assessed publications for relevance, and disagreements were resolved by discussion and consensus. Ninety-six sources were included and synthesized narratively. Results: Inadequate exposure or adherence can produce pseudo-resistance, whereas bipolar spectrum illness, neurodevelopmental or trauma-related conditions, personality pathology, sleep or substance-related disorders, and medical disease may represent alternative diagnoses, comorbidities, or modifiers of treatment course. Glutamatergic signaling, impaired plasticity, stress-system dysregulation, inflammation, circadian disturbance, metabolism, and neural circuitry contribute to heterogeneity at the group level but do not define validated individual subtypes. Established pharmacological, psychological, and neuromodulatory interventions should be selected according to diagnosis, severity, urgency, previous response, comorbidity, functional impairment, safety, feasibility, and patient preference. Conclusions: TRD is an operational treatment-history category, not a unitary disease. A personalized medicine approach begins with confirmation of major depressive disorder, adequate treatment exposure and adherence, followed by parallel treatment of depression and clinically relevant comorbidity. Biomarkers should guide allocation only when they provide prospectively validated predictive value beyond high-quality clinical and functional assessment. Full article

Obesity affects nearly one in three women of reproductive age worldwide and consistently reduces success rates in in vitro fertilization, yet the molecular basis for this reduction remains fragmented across separate lines of evidence. Circadian clock genes, particularly BMAL1, orchestrate metabolic and reproductive physiology through transcription–translation feedback loops present in adipose tissue, ovarian granulosa cells, and endometrial stroma. Adiposity-driven metabolic shifts, including altered PPAR-γ signaling and reduced glutamine–methionine uptake, degrade BMAL1 expression and flatten its rhythmic oscillation in peripheral tissues. Within granulosa cells, loss of BMAL1 rhythmicity impairs mitochondrial biogenesis and disrupts UPRmt-mediated proteostasis, driving reactive oxygen species accumulation and compromising oocyte competence. Parallel disruption of clock-controlled transcription factors in endometrial epithelium and stroma is proposed to alter decidualization programs and displace the window of implantation, which would produce a receptivity defect independent of oocyte quality if confirmed directly in human tissue. Clinical data are consistent with a dual mechanism: obese women undergoing donor-oocyte cycles—where oocyte quality is controlled for—show reduced implantation rates in several but not all cohorts—a pattern compatible with an endometrial contribution distinct from oocyte-level damage, rather than proof of it. Synthesizing evidence from adipocyte biology, ovarian physiology, and endometrial receptivity research drawn largely from rodent models, cultured cell systems, and observational human cohorts, this review proposes BMAL1 dysregulation as a candidate unifying mechanism connecting obesity to impaired IVF outcomes at the gametic and uterine level, while acknowledging that direct causal evidence in humans is still lacking. Chronotherapeutic strategies, including melatonin supplementation and the timing of weight-loss interventions relative to ovarian stimulation, are discussed as hypotheses for future testing rather than current clinical recommendations. BMAL1 dysregulation is presented here as one candidate contributor among several interacting mechanisms, and any translational strategy would need to be part of a broader, coordinated approach to obesity-related IVF failure rather than a stand-alone intervention. Full article

The stress response is essential for cellular and organismal survival as it acts as a protective and adaptive mechanism to maintain homeostasis. At the organismal level, physical stressors induce responses in mammals that are mediated primarily by the hypothalamic–pituitary–adrenal (HPA) axis, which regulates glucocorticoid secretion. The HPA axis functions as a circadian-regulated, multi-oscillator system, in which the paraventricular nucleus, the pituitary, and the adrenal gland exhibit intrinsic rhythmicity while remaining coordinated by the output from the suprachiasmatic nucleus. Glucocorticoids act both as stress effectors and systemic zeitgebers that synchronize peripheral clocks. At the cellular level, cellular stressors are sensed by four protein kinases of eukaryotic translation initiation factor 2α (eIF2α) and activate the evolutionarily conserved integrated stress response (ISR), which converges on phosphorylation of Serine 51 on eIF2α. ISR signaling is temporally regulated by the circadian clock and controls time-of-day-dependent protein synthesis. In parallel, ISR pathways feed back onto the circadian clock through transcriptional, translational and epigenetic mechanisms, directly influencing core clock gene expression and stability of circadian oscillations. Physiological ISR activity supports circadian robustness and resetting, whereas excessive ISR activation dampens rhythmic gene expression and destabilizes behavioral rhythms. The current review summarizes recent advances in our understanding of the crosstalk mechanisms between the HPA axis, ISR, and the circadian clock to provide new insights into disease mechanisms and inform chronotherapeutic strategies to target dysregulated HPA and ISR activities and restore temporal homeostasis. Full article

Background: Acute brain injury, including traumatic brain injury (TBI), stroke, subarachnoid hemorrhage and secondary neurological injury, such as sepsis-associated encephalopathy (SAE) and delirium, is a major cause of morbidity in the intensive care unit (ICU), and few treatments alter its course once it is established. Critical illness, and brain injury in particular, rapidly disrupts the gut microbiome (GM) and the production of its metabolites. This dysbiosis matters most in neurologically injured patients, because microbial metabolites and a leaky intestinal barrier feed neuroinflammation through the gut–brain axis. Feeding timing and fasting affect circadian biology, the daily rhythm of the GM, and host metabolic pathways, such as ketogenesis, insulin signaling and autophagy. This review asks whether time-restricted or fasting-mimicking strategies can preserve these functions and reduce neuroimmune dysregulation after brain injury. Methods: In this narrative review, we searched the literature for randomized trials, crossover pilot studies, mechanistic human research, and guideline statements comparing continuous, cyclic, and intermittent enteral strategies, and evaluated translational pathways for GM-targeted feeding interventions. Results: Available studies showed no consistent difference in mortality between continuous and intermittent gastric feeding in ICU adults on mechanical ventilation, although the largest pooled analyses report more diarrhea, more abdominal distension and longer ICU stay with intermittent schedules, most pronounced in ventilated patients. While intermittent/cyclic regimens were not associated with an improvement of patient-centered outcomes, pilot studies demonstrated that short macronutrient interruptions (e.g., 12 h) reliably induced a metabolic fasting response in patients with a prolonged ICU stay. One randomized controlled trial (RCT) had GM end-points and reported feasible modulation of gut taxa and 58 differentially abundant serum metabolites with sequential (continuous-to-intermittent) feeding. Only five studies enrolled dedicated brain-injured cohorts; none was designed around neurological or gut–brain mechanistic outcomes, and none measured GM or neuroinflammation. Conclusions: Time-restricted, microbiome-protecting approaches are biologically plausible and deserve a phased translational program to test them in clinical trials. Future trials should focus on brain-injured and other neurologically relevant ICU patients, in whom the gut–brain axis is most engaged, and should pair mechanistic endpoints with clinical safety and proper control for confounders. No clinical study has yet tested whether non-continuous feeding alters neuroinflammatory or neurological outcomes after acute brain injury. There is currently no direct evidence supporting the effectiveness of this intervention in this population, and the case made here is mechanistic, not empirical. Full article

Chronic pain, sleep disturbances, and mental health disorders such as anxiety and depression disorders frequently co-occur, forming a self-reinforcing cycle that impairs daily functioning and quality of life. Chronic pain is driven by peripheral and central sensitization, the latter sustained by reciprocal microglial–astrocytic crosstalk and maladaptive neuroplasticity. Poor sleep amplifies pain through inflammation and circadian disruption. Imbalances in serotonin, dopamine, and norepinephrine, together with limbic alterations and HPA axis dysregulation, contribute to comorbid anxiety and depression. Elevated pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), NF-κB-driven neuroinflammation, and mitochondrial oxidative stress serve as key molecular links. Building on previous evidence, this review presents an updated triadic, mechanism-based framework describing the reciprocal reinforcement among chronic pain, sleep disturbances, and anxiety and depressive disorders. Consequently, therapeutic strategies targeting inflammatory cytokines, microglial and astrocytic activation, neurotransmitter imbalance, and psychological dysfunction may help address these shared neuroimmune and neuroplastic mechanisms underlying these interconnected disorders. Full article

Background/Objectives: The triglyceride–glucose (TyG) index, a surrogate marker associated with insulin resistance, has been linked to both blood pressure elevation and circadian blood pressure dysregulation; however, its relationship with ambulatory blood pressure (BP) phenotypes across the full spectrum of contemporary ambulatory BP categories remains incompletely characterised. This study investigated the association of the TyG index with ambulatory BP categories and circadian BP phenotypes in untreated adults undergoing ambulatory blood pressure monitoring (ABPM). Methods: This retrospective cross-sectional study included 723 consecutive adults with no current or previous exposure to antihypertensive medication (treatment-naïve status refers exclusively to antihypertensive pharmacotherapy) who underwent 24 h ABPM and same-day laboratory assessment at a tertiary referral centre. Participants were classified according to the 2024 European Society of Cardiology ambulatory BP thresholds into non-elevated BP (n = 199), elevated BP (n = 243), or hypertension (n = 281) groups. Circadian BP phenotypes were categorised as extreme-dippers, dippers, non-dippers, and reverse-dippers. Associations between the TyG index and ambulatory BP categories were evaluated using multivariable proportional-odds ordinal logistic regression. The joint effect of BP category and circadian phenotype was examined by adding a TyG index × circadian phenotype interaction term to the ordinal model, and circadian phenotypes were characterised using multinomial logistic regression. Results: The TyG index increased progressively across ambulatory BP categories (8.8 ± 0.5, 9.1 ± 0.5, and 9.2 ± 0.6; p-trend < 0.001). After adjustment for age, sex, HbA1c, estimated glomerular filtration rate, and body mass index, each one-standard-deviation increase in the TyG index was associated with higher ambulatory BP category (OR 1.57, 95% CI 1.34–1.83; p < 0.001). The Brant test provided no evidence against the proportional-odds assumption (p = 0.379). In an exploratory analysis, the TyG–BP category association differed across circadian phenotypes (TyG × phenotype interaction, likelihood-ratio χ² = 8.26, df = 3, p = 0.041). In multinomial analysis, a higher TyG index was associated with the reverse-dipper (OR 2.90 per SD, 95% CI 2.06–4.08) and extreme-dipper (OR 2.77, 95% CI 1.87–4.10) phenotypes relative to the results for the dippers (both p < 0.001), but not with non-dipping (OR 1.02, 95% CI 0.84–1.24; p = 0.86) after multivariable adjustment. Conclusions: Among untreated adults undergoing ABPM, higher TyG index values were associated with progressively higher ambulatory BP categories and with reverse- or extreme-dipper circadian BP phenotypes after multivariable adjustment. Because insulin resistance was not measured directly, these results describe an association between the TyG index, a surrogate marker, and ambulatory BP phenotypes; they should be interpreted as hypothesis-generating because of the retrospective cross-sectional design. Prospective studies are warranted to determine their temporal and clinical significance. Full article

Successful embryo development transpires far before fertilization inside the meticulously regulated microenvironment of the ovarian follicle. Increasing data indicates that circadian regulatory systems influence several processes that define oocyte competence, including mitochondrial activity, oxidative balance, meiotic development, and cellular metabolism. Brain and muscle ARNT-like protein 1 (BMAL1), an essential transcription factor in circadian regulation, has garnered significant interest due to its crucial involvement in ovarian physiology and reproductive function. Dysregulated BMAL1 signaling has been linked to compromised folliculogenesis, diminished steroidogenesis, mitochondrial dysfunction, elevated oxidative stress, and irregularities in meiotic spindle organization, all of which may negatively impact oocyte quality and early embryo development. Recent experimental and clinical findings indicate that results of assisted reproduction may be influenced by circadian disruption, sleep problems, obesity, ageing, and metabolic dysfunction. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which circadian rhythm disruption (CRD) emerges as both a prodromal feature and a potential pathogenic driver. Elucidating the bidirectional interplay between PD and CRD is essential for identifying early biomarkers and developing chronotherapeutic strategies. We narratively synthesized literature published over the past two decades in PubMed, Web of Science, and CNKI, focusing on molecular mechanisms, clinical manifestations, biomarker development, and interventional studies addressing the PD–CRD interface. In the CRD-PD direction, circadian disruption accelerates dopaminergic neurodegeneration through four convergent mechanisms: (i) REV-ERBα–mediated dysregulation of dopamine biosynthesis and NF-κB/NLRP3-driven neuroinflammation; (ii) impaired sleep-dependent glymphatic clearance of α-synuclein (α-syn); (iii) NAD⁺–SIRT1–BMAL1–PGC-1α axis dysfunction leading to mitochondrial bioenergetic failure; and (iv) C/EBPβ-dependent autophagic rhythm disruption coupled with pro-inflammatory microglial activation, collectively establishing a dual pro-inflammatory–autophagy-suppressive milieu permissive for α-syn aggregation. In the reverse PD-CRD direction, PD pathology destabilizes the circadian system via Braak-stage degeneration of rhythm-regulatory nuclei, retinal dopaminergic denervation attenuating SCN photic entrainment, pineal–melatonin axis suppression, iatrogenic effects of dopaminergic pharmacotherapy, and gut microbiota dysbiosis propagated through the microbiota–gut–brain axis. Emerging multi-modal chronobiomarkers—including peripheral clock gene expression profiles, melatonin secretion patterns, tryptophan–kynurenine metabolites, and gut microbial oscillation signatures—show promise for prodromal diagnosis and disease subtyping. Circadian-targeted precision interventions—encompassing timed bright light therapy, exogenous melatonin, and chronopharmacological interventions—represent a promising translational paradigm for the early identification and management of PD. Full article

Arterial hypertension in adolescents is increasingly a lifestyle-driven disorder, and a growing share of cardiovascular risk in this age group is hidden from conventional office measurement. Intensive nighttime screen use, together with the chronic sleep loss that accompanies it, may disrupt circadian control of the cardiovascular system, an effect we designate, as a proposed integrative concept, digital chronotoxicity. Through melatonin suppression, sustained sympathetic and neuroendocrine activation, oxidative stress, and metabolic dysregulation, this exposure is hypothesized to attenuate the physiological nocturnal fall in blood pressure and to contribute to the non-dipper phenotype, a predictor of early vascular aging that remains invisible to office readings. This narrative review traces the mechanistic pathway from screen exposure to the loss of nocturnal dipping and reframes the problem as a diagnostic one. Twenty-four-hour ambulatory blood pressure monitoring is positioned as the reference standard for detecting the at-risk phenotype and masked hypertension; the cardiac, vascular, renal, autonomic, and neurocognitive biomarkers of early hypertension-mediated organ damage are reviewed; and emerging wearable and artificial-intelligence tools for continuous, preventive screening are examined. An integrated screening pathway is proposed, on the premise that the evaluation of a hypertensive adolescent is incomplete without a digital and sleep history alongside ambulatory monitoring. Reframed in this way, pediatric hypertension becomes a detectable chronobiological disease. Full article

Background: Attention-deficit/hyperactivity disorder (ADHD) has traditionally been understood through executive and frontostriatal models, but increasing evidence suggests that metabolic, inflammatory, circadian, and neuroendocrine mechanisms may also contribute to clinical heterogeneity. The hypothalamus is a central regulatory hub for appetite, sleep–wake organization, stress responsivity, autonomic function, and endocrine signalling. Objective: This review evaluated evidence linking ADHD with hypothalamic inflammation and related metabolic, inflammatory, circadian, and neuroendocrine dysregulation, with particular emphasis on appetite regulation, sleep and circadian function, stress reactivity, and pharmacological treatment response and tolerability. Methods: A systematic literature search was conducted in PubMed/MEDLINE, Embase, PsycINFO, Scopus, and Web of Science Core Collection from database inception to 31 May 2026. Human observational and intervention studies formed the primary evidence base. Evidence was synthesized narratively. Where available, quantitative findings from previously published meta-analyses were summarized to provide an overview of the strength and consistency of the evidence. Results: The reviewed evidence indicates that ADHD is associated with increased obesity risk, altered appetite-related hormones, immune-inflammatory changes, delayed circadian timing, atypical cortisol responsivity, and treatment-related effects on appetite, sleep, cardiovascular physiology, and tolerability. The strongest quantitative evidence concerned obesity, inflammatory markers, appetite hormones, and type 2 diabetes risk. Direct evidence for hypothalamic inflammation in ADHD remains limited, but converging indirect findings support hypothalamic and neuroendocrine mechanisms as biologically plausible contributors in a subgroup of individuals with ADHD. Conclusions: ADHD appears to be associated with broader metabolic, inflammatory, circadian, and neuroendocrine vulnerabilities beyond its core attentional and behavioural symptoms. Hypothalamic pathways should be interpreted as a mechanistic hypothesis rather than an established causal mechanism. Future longitudinal and multimodal studies are needed to clarify causality and identify biologically defined ADHD subgroups. Full article

Background: Smith–Magenis syndrome (SMS) is a rare neurodevelopmental disorder characterized by severe sleep disturbances, circadian rhythm dysregulation, and prominent behavioral difficulties. Objective: To examine associations between subjective and objective sleep and circadian characteristics and behavioral difficulties in children with SMS in real life. Methods: Children aged 5–13 years with genetically confirmed SMS were included in a prospective single-center cohort study. Sleep and circadian rhythms were assessed using parent-reported questionnaires (Sleep Disturbance Scale for Children (SDSC), Horne and Östberg Morningness–Eveningness Questionnaire (H&O)) and 15-day home-based wrist actigraphy. Behavioral difficulties were evaluated using the Aberrant Behavior Checklist-Community (ABC-C). Associations between subjective and objective sleep and circadian measures with behavioral difficulties were studied using Spearman correlations for each ABC-C subscale. Results: Among the 20 children included (55% female, mean age 10 ± 2.5 years), 75% were carriers of a 17p11.2 microdeletion and 25% had an RAI1 mutation. Overall, 95% of children were treated with melatonin, 55% with psychostimulants and 20% with beta-blockers. According to the SDSC results, pathological sleep disturbances were present in 14/20 (70%) children and concerned mainly complaints of insomnia (10/20, 50%) and excessive daytime sleepiness (8/20, 40%). The H&O chronotypes confirmed the morning type in 70% of patients. Sleep and circadian measures obtained by actigraphy showed reduced total sleep time in 71% of the children, reduced sleep efficiency in 88%, long wake after sleep onset (WASO > 60 min) in 59%, as well as an early L5 onset (5 h period with the least movements < 23:38) and M10 onset (10 h period with the highest activity levels < 09:12) in 92% and 62% of children, respectively. The behavioral domains of the ABC-C with the highest scores were hyperactivity (mean 52.1, range 2.1–97.9) and irritability, agitation, and crying (mean 46.9, range 17.8–82.2). In the analysis of the relationship between behavior and sleep, a positive correlation was found between sleep disorders and stereotyped behaviors (r = 0.472, p = 0.048), insomnia and irritability, social withdrawal and stereotyped behaviors (r = 0.472, p = 0.048; r = 0.701, p = 0.001; and r = 0.648, p = 0.004, respectively), and non-restorative sleep and inappropriate speech (r = 0.476, p = 0.046). No significant association was found between objective sleep measures and behaviors. While subjective assessments suggested that a stronger morning chronotype was associated with lower irritability (r = −0.565, p = 0.015), actigraphy-derived circadian rhythm analyses revealed that an earlier L5 onset was associated with greater social withdrawal and hyperactivity (r = −0.556, p = 0.048 and r = −0.560, p = 0.049, respectively). Conclusions: The present cohort study of children with SMS studied in real-life conditions, using both objective and subjective measures, shows that patients continued to experience sleep and behavioral disturbances despite treatment. Exploratory analyses identified distinct associations between subjective sleep disturbances, circadian rhythm characteristics, and specific behavioral domains. While subjective sleep disturbances were associated with irritability, stereotypic behavior, and inappropriate speech, circadian rhythm parameters are specifically associated with hyperactivity. Both were also associated with social withdrawal. As these findings arise from an exploratory observational secondary analysis, they should be considered hypothesis-generating and require confirmation in larger prospective studies. If confirmed, they may help identify sleep and circadian rhythm characteristics as potential targets for future interventions in children with SMS. Full article

Acute myeloid leukaemia (AML) remains a highly lethal malignancy with poor prognosis in adults above 60 years old and often occurs after radiation exposure. Emerging evidence suggests that circadian rhythm disruption, prevalent in shift workers, may contribute to cancer development. Clock genes (CGs) regulate fundamental cellular processes, including the DNA damage response (DDR), cell cycle progression, and haematopoiesis. In the absence of substantial experimental data, this review examines the potential pathways linking circadian clock dysregulation to radiation-induced AML (rAML) and evaluates how temporal disruption may modulate leukaemogenesis and radiation-induced effects. The evidence was synthesised on core clock components (BMAL1, CLOCK, PER, CRY, REV-ERB, ROR), their dysregulation in AML, and their roles in radiation response. Epigenetic and post-transcriptional regulatory mechanisms, including m⁶A RNA modification and sirtuin-mediated chromatin remodelling, were evaluated for their contribution to circadian-regulated DNA repair capacity. Multiple CGs demonstrated aberrant expression in AML, with BMAL1 showing tissue-specific dysregulation, and PER1/2/3 was consistently downregulated in peripheral blood. Clock proteins directly regulate DNA damage checkpoints through interactions with ATM/CHK2 and p53 pathways. Circadian disruption enhances inflammatory signalling, promotes accumulation of myeloid-derived suppressor cells, and accelerates immune senescence. Moreover, radiation exposure modulates CG expression, which may alter repair fidelity and increase leukaemogenic risk. Understanding these connections in the context of disrupted circadian rhythms could help identify at-risk populations and improve shift workplace health policies. Full article

Circadian rhythms synchronize physiological processes with the light–dark cycle and regulate biological functions relevant to cancer, including cell-cycle control, metabolism, DNA repair, immunity, and tissue homeostasis. Growing evidence indicates that disruption of these temporal mechanisms contributes to tumor initiation, progression, metastasis, and treatment response. In colorectal cancer (CRC), circadian clock dysregulation has emerged as an important component of tumor biology. A systematic search identified 1338 records, of which 43 studies met the eligibility criteria (20 human, 19 experimental, and 4 chronotherapy studies). Across the included studies, statistically significant associations were consistently reported between dysregulation of clock genes such as PER1, PER3, CLOCK, BMAL1, CRY1, TIMELESS, and ARNTL2 and alterations in proliferation, metabolism, epithelial plasticity, immune regulation, metastatic potential, and treatment responsiveness. Experimental evidence also supported interactions with Wnt signaling, ferroptosis, oxidative-stress adaptation, epithelial–mesenchymal remodeling, and a proposed clock–microbiota–immune axis. Overall, the available evidence indicates that circadian dysregulation represents a systems-level disturbance that gives rise to a multidimensional biological condition, here referred to as the Tumor Temporal State, integrating the metabolic, immune, invasive, and therapeutic dimensions of colorectal cancer biology. Full article

Human African trypanosomiasis (HAT) or sleeping sickness is a neglected tropical disease with a progressive central nervous system (CNS) involvement and marked sleep and circadian rhythm abnormalities. Even though this is a prominent feature of HAT, the connection between parasite neuroinvasion, neuroinflammation, circadian dysfunction, and neurological impairment is not fully understood. This narrative review aims to summarize the most up-to-date knowledge about sleep and circadian disturbance in HAT and proposes an integrated approach for the Trypanosome-Associated Sleep Disorder (TASD). The relevant literature was identified by searching major biomedical databases for HAT, sleep disorders, circadian rhythms, neuroinflammation, and CNS invasion. The review covers the steps by which the CNS becomes invaded, how the barriers are disrupted, how the CNS becomes activated by inflammatory responses, and how the hypothalamic and circadian regulatory networks are disrupted. The evidence suggests that excessive daytime sleepiness, fragmented nocturnal sleep, circadian misalignment, and neuropsychiatric manifestations are related to the activation of inflammatory cytokines, altered neurotransmitter signaling, activation of the kynurenine pathway, dysregulation of clock genes, and disruption of the suprachiasmatic nucleus. We also discuss TASD as a syndrome-like phenotype of CNS involvement and propose a three-stage model of sleep–wake dysfunction in HAT. The review unites these integral mechanisms in a single mechanistic framework to offer a unified understanding of the sleep pathology associated with HAT. There are still important gaps in our knowledge of biomarkers, disease staging, and irreversible neuronal damage, which indicate priorities for future research and better clinical management. Full article