Search Results (1,159)

Background: Ischemic stroke remains a leading cause of mortality and disability worldwide. Despite extensive preclinical research, most neuroprotective strategies have failed to translate into clinical benefit, partly due to methodological variability. The transient intraluminal filament middle cerebral artery occlusion (tifMCAO) model is widely used, yet its implementation lacks consistency. This review aimed to characterize tifMCAO methodologies in adult rats and examine how experimental variability relates to reported outcomes. Methods: A systematic review was conducted following PRISMA guidelines. Studies using tifMCAO in adult rats were included. MEDLINE (PubMed), Web of Science, and Scopus were searched up to March 2025. Risk of bias was assessed using the SYRCLE tool and reporting quality using the ARRIVE checklist. The protocol was registered in PROSPERO (CRD420251140869). Results were synthesized narratively. Results: A total of 125 studies were included. A commonly used framework involved male Sprague–Dawley rats (6–12 weeks), silicone-coated monofilaments, occlusion durations of 60–120 min (most frequently 90 min), and isoflurane anesthesia, although this reflects methodological convergence rather than true standardization. Substantial variability was observed across methodological parameters. Variations in ischemia duration, filament properties, and anesthesia were associated with differences in infarct size, blood–brain barrier disruption, and functional outcomes. Conclusions: The tifMCAO model shows partial methodological convergence alongside significant variability influencing outcomes. Improved standardization and reporting are essential to enhance reproducibility and translational relevance. Full article

Background: While trefoil factor 3 (TFF3) has been linked to cardiovascular disease, its role in peripheral artery disease (PAD) remains largely unexplored. In this prospective study, we assessed three pre-selected circulating biomarkers and found that TFF3 demonstrated the strongest association with the presence of PAD. Building on this finding, we integrated plasma TFF3 concentrations with clinical characteristics to construct predictive models aimed at identifying individuals with PAD and estimating their risk of major adverse limb events (MALE) over a two-year follow-up period. Methods: A total of 476 individuals were prospectively recruited, including 312 patients with PAD and 164 controls without PAD. At study entry, circulating concentrations of TFF3, oncostatin M (OSM), and brain-derived neurotrophic factor (BDNF) were quantified, and all participants were subsequently monitored for a two-year period. The primary endpoint was the occurrence of MALE within two years, comprising acute limb ischemia, major amputation, or lower extremity revascularization by either open surgical or endovascular approaches. PAD diagnosis served as the secondary outcome and was established by an ankle–brachial index (ABI) ≤ 0.9 or toe–brachial index (TBI) ≤ 0.67 in the presence of reduced or absent pedal pulses. For predictive model development, the cohort was randomly divided into training (70%) and testing (30%) sets. A random forest algorithm incorporating clinical variables and plasma TFF3 levels was developed and optimized using 10-fold cross-validation. Model discrimination was quantified using the area under the receiver operating characteristic curve (AUROC). For prognostic evaluation, patients were classified into low- and high-risk groups based on the optimal ROC-derived probability threshold of 0.60, and MALE-free survival between groups was assessed using Cox proportional hazards regression. Results: Among the three candidate biomarkers evaluated, only TFF3 demonstrated a significant association with PAD. Patients with PAD exhibited higher circulating TFF3 concentrations than those without PAD (7.27 ± 3.36 vs. 5.89 ± 2.67 pg/mL; p < 0.001), whereas OSM and BDNF showed no significant differences between groups. Over the two-year follow-up period, MALE occurred in 28 patients (9%). Predictive models combining plasma TFF3 measurements with clinical variables achieved strong performance for both PAD detection and 2-year MALE risk estimation, yielding AUROCs of 0.79 and 0.85, respectively. Furthermore, patients classified as high risk by the model experienced a significantly increased hazard of MALE during follow-up (HR 1.12, 95% CI 1.10–1.19; p = 0.003). Variable importance analysis revealed that TFF3 was the most influential predictor of MALE, followed by age and smoking history. Conclusions: Combining plasma TFF3 levels with readily available clinical characteristics enabled the development of a predictive model with good discriminatory ability for both PAD diagnosis and estimation of 2-year MALE risk. Such an approach may enhance risk stratification by identifying patients at elevated risk earlier in their disease course, thereby informing decisions related to vascular testing, referral for specialist evaluation, and implementation of targeted treatment strategies. Full article

Objective: Cerebral ischemia/reperfusion (I/R) injury triggers oxidative stress, neuroinflammation, neuronal degeneration, and white matter damage not only in directly affected cerebral regions but also in remote brain areas such as the cerebellum. Skimmianine, a naturally occurring furoquinoline alkaloid, has been reported to possess antioxidant and anti-inflammatory properties. This study investigated the protective effects of skimmianine pretreatment against secondary cerebellar injury following experimental cerebral I/R. Materials and Methods: Thirty-two female Wistar rats were randomly assigned to sham, Skimmianine, I/R, and I/R + Skimmianine groups (n = 8/group). Cerebral I/R was induced by transient middle cerebral artery occlusion for 60 min followed by 23 h reperfusion. Skimmianine (40 mg/kg/day, intraperitoneally) was administered for 14 days before ischemia induction. Oxidative stress markers, neuroinflammatory mediators, histopathological alterations, behavioral outcomes, and ultrastructural changes were evaluated. In addition, network pharmacology and molecular docking analyses were performed to explore potential molecular mechanisms. Results: Cerebral I/R significantly decreased TAS levels compared with sham (0.89 ± 0.15 vs. 1.52 ± 0.18 mmol Trolox Eq/L) and increased TOS (15.60 ± 3.03 vs. 6.80 ± 1.41 µmol H₂O₂ Eq/L), OSI (17.48 ± 0.50 vs. 4.43 ± 0.47), TNF-α (68.4 ± 10.2 vs. 18.6 ± 4.4 pg/mL), Iba1 (41.3 ± 9.7 vs. 11.7 ± 1.6 pg/mL), and GFAP levels (334.5 ± 12.5 vs. 87.7 ± 9.5 ng/mL; all p < 0.001). I/R also impaired motor performance, as shown by increased beam crossing time (11.7 ± 2.2 vs. 4.8 ± 0.7 s) and grid foot fault rate (18.6 ± 4.0% vs. 3.4 ± 1.1%). Skimmianine pretreatment significantly improved these alterations, increasing TAS to 1.29 ± 0.20 mmol Trolox Eq/L and reducing TOS, OSI, TNF-α, Iba1, and GFAP levels to 9.20 ± 2.04, 7.07 ± 0.47, 34.9 ± 7.4, 24.2 ± 6.9, and 237.0 ± 7.9, respectively, compared with the untreated I/R group. Histopathological scores for Purkinje cell loss, edema, vascular congestion, and TNF-α expression were also significantly reduced by skimmianine. Quantitative TEM analysis showed that I/R reduced myelin thickness (0.29 ± 0.05 vs. 0.53 ± 0.07 µm), increased G-ratio values (0.75 ± 0.05 vs. 0.63 ± 0.04), and increased vacuolized fibers (24.70 ± 4.20% vs. 3.20 ± 1.10%), whereas skimmianine partially restored myelin thickness (0.42 ± 0.07 µm), reduced the G-ratio (0.68 ± 0.05), and decreased vacuolized fibers (11.20 ± 2.80%; p < 0.05 vs. I/R). Molecular docking demonstrated favorable binding between skimmianine and TNF-α, with a predicted binding energy of −6.953 kcal/mol. Conclusions: These findings indicate that skimmianine exerts neuroprotective effects against secondary cerebellar injury following cerebral I/R through coordinated modulation of oxidative stress, systemic neuroinflammatory responses, astroglial injury-associated pathways, and inflammation-related mechanisms. Full article

Hypoxic–ischemic brain injury remains the leading cause of death and neurological disability after cardiac arrest. Although targeted temperature management (TTM) and other neuroprotective strategies have demonstrated promising results in preclinical studies, large randomized controlled trials have largely failed to show consistent clinical benefit. This review examines two major limitations that may contribute to these translational failures: delayed initiation of therapy beyond a time-limited therapeutic window and the lack of baseline injury severity stratification. Evidence from both experimental and clinical studies suggests that the opportunity to modify neurological injury may be confined to the first few hours after return of spontaneous circulation (ROSC). Delayed intervention may occur after irreversible neuronal injury, microvascular dysfunction, and impaired cerebrovascular autoregulation have already become established. In addition, cardiac arrest survivors represent a heterogeneous population. Patients with minimal injury may recover with standard supportive care, whereas those with severe irreversible injury are unlikely to benefit from neuroprotective interventions. Patients with moderate-severity brain injury may represent the subgroup most likely to respond to targeted therapies. Ultra-early stratification using neuroimaging, electroencephalography, circulating biomarkers, and clinical risk scores may help identify patients with therapeutic potential. This review proposes that future post-cardiac arrest research should integrate both time-sensitive intervention strategies and early injury severity stratification. Large prospective studies and randomized controlled trials are needed to determine not only whether interventions are effective, but also when they should be initiated and which patients are most likely to benefit. Full article

Purpose: Acute ischemic stroke (AIS) is the most prevalent stroke subtype. Given the brain–heart interaction, this study investigated the association between cardiac parameters on admission routine preoperative chest CT and recanalization following thrombectomy in AIS patients. Method: We retrospectively analyzed 215 AIS patients (August 2018–June 2022) who underwent admission of none contrast chest computed tomography (NCCT) and thrombectomy within 24 h. Successful recanalization was defined as modified Treatment in Cerebral Ischemia (mTICI) score 2b-3. Multivariable logistic regression identified independent predictors. A nomogram was developed and validated using ROC, calibration, and decision curve analyses. Result: The cohort had a median age of 72 years; 63.7% were male. Hypertension (65.1%), atrial fibrillation (25.1%), and pleural effusion (56.3%) were prevalent. Successful recanalization occurred in 172 patients (80%). Independent predictors included mean arterial pressure (OR: 1.022, CI: 1.003–1.041, p = 0.025), left pulmonary artery diameter (OR: 0.838, CI: 0.733–0.958, p = 0.010), RV/A ratio (standardized) (OR:1.908, CI: 1.293–2.817, p = 0.001), septal angle (OR: 1.055, CI: 1.018–1.094, p = 0.004), and intraventricular septal angle (OR: 0.973, CI: 0.952–0.995, p = 0.015). The model achieved an AUC of 0.774 (p < 0.001) with strong calibration and net benefit. Conclusions: Cardiac parameters on routine preoperative chest CT correlate with recanalization following thrombectomy in AIS patients. The developed nomogram offers a reliable tool for clinical risk stratification. Full article

Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive sphingolipid that regulates key cellular processes, like proliferation, apoptosis, inflammation, and vascular homeostasis. S1P acts as a signaling molecule both inside and outside cells by interacting with five G-protein-coupled S1P receptors (S1PR1–S1PR5). Accumulating evidence indicates that dysregulation of S1P signaling is implicated in the pathophysiology of cerebral ischemia/reperfusion (I/R) injury and Alzheimer’s disease (AD). In I/R injury, S1P signaling regulates vascular permeability, immune cell infiltration, and neuronal survival and death. In AD, alterations in S1P metabolism are associated with β-amyloid deposition, tau hyperphosphorylation, synaptic dysfunction, and sustained neuroinflammation. S1P receptor (S1PR) modulators represent promising therapeutic agents in both preclinical and clinical studies. Fingolimod was the first oral disease-modifying therapy approved for the treatment of multiple sclerosis and, at the same time, the first S1PR modulator introduced into clinical practice. New selective S1PR-targeting agents, including siponimod and ozanimod (S1PR1 and S1PR5), as well as the S1PR1-selective agent ponesimod, have also been approved for clinical use. In addition to their immunomodulatory properties, S1PR modulators have direct effects in the central nervous system, facilitating the maintenance of blood–brain barrier integrity, reducing microglial activation, and enhancing neuronal survival pathways. Building on this knowledge, we discuss the role of S1P signaling, highlighting recent advances in S1PR modulators as promising therapeutic agents for cerebral I/R injury and AD. Full article

Clinical outcomes after acute ischemic stroke remain highly heterogeneous, even among patients with comparable lesion characteristics and successful reperfusion, challenging traditional lesion-based models. Increasing evidence suggests that stroke should be conceptualized as a disorder of distributed brain networks, yet the mechanisms linking focal ischemia to large-scale dysfunction remain incompletely understood. In this review, we propose that diaschisis constitutes a central physiological mechanism underlying this transition from focal injury to network-level impairment. Building on advances in functional imaging, connectomics, and cerebellar physiology, we propose that diaschisis may be conceptualized, at least in part, as a disruption of cerebello-cortical loop dynamics rather than solely a nonspecific remote effect. These closed, polysynaptic circuits linking cortex, cerebellum, and thalamus support the integration of motor and cognitive processes and are particularly vulnerable to perturbation. Focal ischemia may therefore induce a cascade of dysfunction that propagates across these loops, leading to widespread impairment despite limited structural damage. Within this framework, outcome variability emerges from the interaction of three key factors: lesion characteristics, brain reserve and network vulnerability, and the extent of diaschisis. We further highlight that functional suppression of cerebellar output, even in the absence of structural degeneration, may play a critical role in mediating network dysfunction. This circuit-based perspective provides a mechanistic explanation for inter-individual variability in stroke outcomes and shifts the focus from lesion localization to network dynamics. Understanding diaschisis as a potential manifestation of cerebello-cortical loop dysfunction opens new avenues for prognosis and therapeutic intervention, emphasizing the potential of targeting network-level restoration to improve recovery after stroke. Full article

We previously demonstrated that fatty acid-binding protein 3 (FABP3) is significantly upregulated in ischemic neurons, and its inhibition mitigates ischemic brain injury in mice and attenuates mitochondrial damage under rotenone-induced oxidative stress. These findings suggest a potential role for FABP3 in mitochondrial dysfunction in ischemic neurons, although the underlying mechanism remains unclear. In this study, we further investigated the role of FABP3 in mitochondrial injury and apoptosis in ischemic neurons. Our findings indicated that FABP3 deficiency significantly decreased infarct volume following middle cerebral artery occlusion/reperfusion (MCAO/R) in mice, improved cognitive and spontaneous activity deficits, and suppressed BAX activation and mitochondrial translocation, caspase-3 activation, and cytochrome c release. In HT22 cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), FABP3 deficiency increased cell viability, reduced apoptosis, and alleviated the loss of mitochondrial membrane potential. Conversely, FABP3 overexpression further exacerbated mitochondrial dysfunction and apoptosis, effects that were partially reversed by the BAX inhibitor BAI1. Furthermore, FABP3 overexpression promoted abnormal mitochondrial lipid accumulation and increased lipid peroxidation. Both the mitochondria-targeted antioxidant MitoQ and the ferroptosis inhibitor Ferrostatin-1 alleviated FABP3 overexpression-induced mitochondrial damage and apoptotic signaling. Collectively, our findings suggest that FABP3 is an important promoter of cerebral ischemia–reperfusion injury. FABP3 may aggravate ischemic neuronal injury by promoting abnormal mitochondrial lipid accumulation and lipid peroxidation, thereby enhancing BAX-dependent mitochondrial apoptotic signaling. Targeting FABP3 may provide a potential therapeutic strategy for neuroprotection in ischemic stroke. Full article

Background: High inter-rater variability in DWI-FLAIR mismatch assessments for acute ischemic stroke (AIS) has spurred interest in assisting automated imaging measures. In this study, we explored whether DWI-FLAIR mismatch assessment and automated quantification of FLAIR hyperintensity, DWI-FLAIR volume ratio, and DWI volume could predict changes in NIHSS score following intravenous thrombolysis (IVT) in patients with AIS of unknown time since onset (TSO). We also exploratively compared radiological DWI-FLAIR mismatch assessments and imaging measures between patients who received IVT and those who did not. Methods: We conducted a retrospective, exploratory, single-center study analyzing brain MRIs from a consecutive cohort of patients with suspected AIS and unknown TSO admitted over two years. Patients with DWI hyperintensity lesions related to ischemia, identified automatically and subsequently verified radiologically, were included. We examined the correlation between automated imaging measures, retrospective DWI-FLAIR mismatch assessments, and changes in NIHSS score from baseline to 24 h post-treatment. Results: Of 333 patients included, 109 received IVT (mean age 68.9 ± 15.2 years) and 224 did not (mean age 70.8 ± 13.8 years). The median baseline NIHSS score was 5 in both groups, improving to 2 after IVT. The DWI volume significantly correlated with changes in NIHSS score (p = 0.002); FLAIR intensity demonstrated borderline significance (p = 0.056); and DWI-FLAIR volume ratio showed no statistically significant association in this cohort (p = 0.511). We did not find statistical evidence that the retrospective binary mismatch assessment was correlated with differences in outcome (p > 0.145). Conclusions: This study supports moving beyond binary DWI-FLAIR mismatch, suggesting that continuous, automated imaging parameters could potentially assist the radiologist in AIS management. As evidence remains preliminary, large-scale research is needed to establish clinical utility. Full article

Syrian hamsters (SHs) are widely used in research and as pets. However, their head anatomy has not yet been evaluated using sectional anatomy and imaging despite their unique features, which are important for studying ischemia–reperfusion injury, cancer, oral tumors, and common stomatognathic and ocular conditions. This study was conducted to correlate the planar anatomy of the heads of eight healthy male and female SHs with micro-CT and MRI images to establish a descriptive, imaging-based anatomical reference. Clinically important head structures observed in transverse, dorsal, and sagittal anatomical sections were correspondingly identified on micro-CT and/or MRI images. In SHs, head micro-CT was shown to be particularly effective for visualizing mineralized structures (e.g., dental and osseous tissues) and air-filled cavities (e.g., the ear canal and tympanic bulla), whereas MRI was demonstrated to provide superior assessment of soft tissues, including the brain, vertebral canal and spinal cord, musculature, intervertebral disks, major salivary glands, eye, and harderian and extraorbital lacrimal glands. The present investigation provides a descriptive and imaging-based anatomical reference of the SH head by integrating anatomical sections, in situ topographical anatomy, and dry-skull photographs with micro-CT and MRI datasets, thereby serving as a foundational resource for the interpretation of cross-sectional imaging in both research and clinical contexts. Full article

Background/Objectives: Artificial intelligence (AI) tools are increasingly integrated into acute stroke imaging workflows, but real-world performance for ischemia detection on non-contrast CT (NCCT) remains incompletely validated by investigators independent of the developer. This study externally validated the BrainScan AI system in an unselected, consecutively enrolled emergency cohort. Methods: Consecutive adult patients undergoing NCCT under the routine acute stroke protocol at a single tertiary centre between January and December 2025 were prospectively enrolled. The reference standard was the post-consensus radiological diagnosis, supplemented where available by follow-up imaging and clinical course. Primary outcomes were diagnostic accuracy for ischemia and intracranial haemorrhage detection, assessed by sensitivity, specificity, predictive values, likelihood ratios, and area under the ROC curve (AUC; DeLong). Pre-specified secondary analyses included regional sensitivity, confidence-score behaviour, artefact robustness, threshold sensitivity, a cluster-robust bootstrap for within-patient correlation, and a quantitative bias analysis under non-differential reference-standard misclassification. Sample size adequacy was assessed using a precision-based framework. Results: A total of 1419 NCCT examinations from 1260 patients were analysed. Ischemia sensitivity was 59.2% (95% CI 52.1–66.1) and specificity was 99.8% (99.4–100), with an AUC of 0.930 (0.906–0.954). The Youden-optimal threshold (0.055) recovered sensitivity to 86.1% with negligible specificity loss, reflecting a markedly bimodal score distribution. Regional sensitivity was lower in infratentorial structures. Bias-corrected estimates were stable across all reference-standard parameters consistent with the data. Haemorrhage detection performed substantially better (sensitivity 96.7%; AUC 0.983). Conclusions: The system shows excellent specificity and strong discrimination but moderate sensitivity for ischemia, supporting its role as a rule-in adjunct rather than a stand-alone tool, pending multicentre validation and site-specific threshold recalibration. Full article

Pterostilbene (Pts), a small molecule stilbenoid and a dimethyl analogue of the star molecule resveratrol, exerts significant blood–brain barrier protection on cerebral ischemia-reperfusion injury and has received extensive attention. This study performed structural optimizations on Pts to obtain a series of derivatives and investigated their anti-ischemic activities both in vitro and in vivo, aiming to identify candidates with high safety and improved efficacy compared with Pts. The ADMET method was used to predict the drug-likeness of a series of Pts derivatives, and in vitro MTT cell viability analysis was conducted on neuroblastoma cells (SH-SY5Y) and brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation/reperfusion (OGD/R) injury. On the basis of the cytotoxicity results, four derivatives (NO. 1, NO. 3, NO. 5, and NO. 7) were selected for subsequent in vitro and in vivo biological activities evaluation. These compounds exhibited significantly higher TI values (18.29–30.61) in OGD/R-injured hBMECs compared with Pts (7.63) and effectively suppressed apoptosis, promoted cell migration, and enhanced tube formation capacity. In vivo, NO. 3 (5 mg/kg, ip., 7 d) demonstrated superior efficacy compared to Pts in improving cerebral blood flow, reducing infarction volume, enhancing neurological function, and modulating serum biomarker levels in middle cerebral artery occlusion/reperfusion (MCAO/R) rats, whereas NO. 1 and NO. 7 showed comparable efficacy to Pts. The acute intraperitoneal toxicity of NO. 3 was conducted and showed that the LD₅₀ of NO. 3 was estimated to be more than 300 mg/kg. In this study, the rational design and comprehensive evaluation of Pts derivatives were reported. Compound NO. 3 demonstrated superior pharmacological efficacy to Pts both in vitro and in vivo, and it may be a promising therapeutic candidate for ischemic stroke intervention. Full article

Microfluidic systems are increasingly used in neuroprotection research, but their clearest value may be to show why candidate compounds fail before costly downstream models. This critical framework review examines CNS-relevant microfluidic studies through a within-program triage logic linking chemistry-aware prescreening, blood-brain barrier/neurovascular unit (BBB/NVU) filtering, and timed validation in neuronal ischemia/reperfusion models, and treats non-CNS organ-on-a-chip and analytical microfluidic studies as engineering analogies only. The available evidence most strongly supports BBB/NVU chips as exposure- and safety-aware filters and compartmentalized neuronal oxygen-glucose deprivation platforms as timing-sensitive validation tools; droplet microfluidics contributes mainly upstream through dense dose mapping, aggregation assays and counterscreens for assay interference. A compound-centered reading also suggests that apparent activity often fails for distinct reasons, including timing mismatch, poor solubility, surface adsorption, optical artifact, inadequate multicellular context, or loss of efficacy under transport-aware testing. Taken together, the literature supports a cautious, within-program triage logic in which microfluidics is used not as a universal disease model, but as an operational framework for exposing transport, barrier, timing and assay liabilities early in neuroprotective discovery. Full article

Background/Objectives: Cardiovascular disease (CVD), particularly coronary artery disease (CAD), is increasingly linked to microvascular inflammation driven by interactions between immune, vascular, and neuroendocrine systems. Mast cells (MCs), strategically positioned near blood vessels, play pivotal roles in this process through the release of inflammatory and vasoactive mediators, contributing to increased vascular permeability, endothelial dysfunction, and tissue inflammation in conditions including ischemia–reperfusion (I/R) and CVD. This comprehensive review examines the cellular and molecular mechanisms underlying MC-mediated microvascular inflammation, with emphasis on neuroimmune regulation through the heart–brain axis, and evaluates the therapeutic potential of flavonoids. Methods: A review of in vitro, animal, and clinical studies was conducted to assess MC-mediated cardiovascular pathology and the pharmacological effects of natural flavonoids on MC activation and microvascular inflammation. Results: Psychological and physical stress activates hypothalamic corticotropin-releasing hormone (CRH) signaling, directly triggering coronary MC degranulation via CRHR-1 and CRHR-2 receptors, while co-released neuropeptides, including neurotensin and urocortin, amplify this neuroimmune cascade. Traumatic brain injury, autonomic dysregulation, and atrial fibrillation further perpetuate this bidirectional heart–brain axis, linking neurological stress to microvascular injury and adverse cardiac remodeling. An autocrine–paracrine CRH amplification loop sustains chronic coronary microvascular inflammation, contributing to heart failure with preserved ejection fraction (HFpEF) and MC activation disease (MCAD)-related cardiovascular manifestations. Natural flavonoids were found to inhibit MC activation, suppress inflammatory mediator synthesis, and protect microvascular integrity through multiple molecular targets, including calcium signaling, transcription factors, oxidative stress pathways, and CRHR-1-mediated neuroimmune signaling. Conclusions: While challenges remain regarding bioavailability and standardization, multi-compound formulations targeting multiple risk factors hold promise for preventing CVD progression. Future research directions for advancing these natural compounds toward clinical implementation are identified. Full article

Brain and muscle Arnt-like protein 1 (BMAL1) is a transcription factor that forms heterodimers with circadian locomotor output cycles kaput (CLOCK) and drives transcription from E-box elements, thereby regulating the circadian rhythms of gene expression. The kidney expresses numerous rhythmic genes and exhibits circadian physiological function regulation. Circadian rhythm abnormalities, such as sleep disorders and excessive daytime sleepiness, are particularly frequent in patients with chronic kidney disease (CKD). Furthermore, reduced amplitude and phase disruption in clock gene expression rhythms have been reported in mouse CKD models. These results suggest that circadian disruption is associated with renal pathophysiology. However, the role of BMAL1 in the repair process following acute kidney injury (AKI) remains unclear; therefore, this study aimed to elucidate its role in kidney repair following ischemia–reperfusion injury (IRI). We found that the tamoxifen (TAM)-inducible global Bmal1 knockout (BKO) mouse kidneys exhibited increased lipid accumulation, enhanced fibrosis, and delayed kidney repair post-IRI, and that these abnormalities were associated with reduced Peroxisome proliferator-activated receptor alpha (Pparα) expression. Furthermore, treatment with a PPARα agonist reduced these abnormalities in BKO mice. Collectively, our findings demonstrate that the BMAL1–PPARα axis promotes post-AKI kidney repair. Full article