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Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder marked by severe hypertriglyceridemia and characteristic clinical manifestations, particularly acute pancreatitis. Conventional triglyceride-lowering therapy is largely ineffective. Apolipoprotein (apo) C-III has emerged as a key therapeutic target to lower triglycerides in FCS. This review compares FCS with more common multifactorial chylomicronemia. We searched PubMed for all English language literature focusing on the search terms 'chylomicronemia,' 'hypertriglyceridemia,' 'APOC3 inhibition,' 'plozasiran,' 'olezarsen,' and 'volanesorsen.' We outline traditional management strategies and their limited role in FCS and explore non-traditional therapies including orlistat, lomitapide, inhibitors of angiopoietin like protein 3 (ANGPTL3), and analogues of fibroblast growth factor 21 (FGF21). The primary focus is on RNA-based gene silencing therapeutics that target apo C-III, particularly the small interfering RNA plozasiran and the allele specific oligonucleotides volanesorsen and olezarsen, highlighting key differences in efficacy and tolerability. In a phase 3 trial of plozasiran, at 10 months, median placebo-adjusted reductions in apo C-III were approximately -90%, while TG levels were reduced up to -59%. Thus, plozasiran and alternative RNA-based therapeutics directed against APOC3 represent transformational therapies for patients with FCS and related phenotypes characterized by severe recalcitrant hypertriglyceridemia. Show less

Familial chylomicronemia syndrome (FCS) is a rare, inherited lipid disorder characterized by severe hypertriglyceridemia and a risk of recurrent pancreatitis. Patients with biallelic pathogenic variants affecting lipoprotein lipase (LPL)-mediated triglyceride metabolism may remain refractory to conventional lipid-lowering therapies and strict dietary control, leading to recurrent critical illness and progressive multisystem complications. We report a female patient with genetically confirmed FCS and persistent triglyceride levels typically in the 4,000-5,000 mg/dL range despite adherence to diet and lipid-lowering therapy, without clear secondary contributors to severe hypertriglyceridemia. Her course included recurrent intensive care unit (ICU) admissions for hypertriglyceridemia-associated pancreatitis requiring insulin drips, with progression to chronic pancreatitis, pancreatic insufficiency requiring enzyme replacement, insulin-dependent diabetes with continuous glucose monitoring (CGM), chronic pain syndrome with opioid dependence concerns, and psychiatric comorbidity. During a hospitalization approximately 10 months prior to the most recent follow-up, the patient underwent placement of a right chest tunneled central venous catheter and initiated therapeutic plasmapheresis. She was concurrently followed by a triglyceride clinic and continued on olezarsen. At follow-up on February 25, 2025, she reported no hospitalizations since April 2024. A triglyceride value of 4,700 mg/dL was documented shortly before a scheduled plasmapheresis session. This case highlights the complexity of severe FCS when hypertriglyceridemia remains refractory to conventional management and illustrates a care pathway in which chronic outpatient plasmapheresis combined with emerging RNA-based therapy was associated with stabilization and avoidance of recurrent hospitalization. Sustained outpatient success required multidisciplinary coordination, addressing pancreatitis sequelae, glycemic management, chronic pain, psychiatric disease, and central-line monitoring. These observations are hypothesis-generating and highlight the potential role of coordinated outpatient plasmapheresis and emerging RNA-based therapies in the management of severe FCS. To our knowledge, reports describing long-term outpatient stabilization of severe FCS using combined chronic plasmapheresis and apolipoprotein C-III (APOC3)-targeted RNA therapy remain limited, and this case highlights a potential care pathway for patients with refractory disease. Show less

Genetic determinants play a central role in the development of dyslipidemias, which are major contributors to atherosclerotic cardiovascular disease (ASCVD), aortic valve disease, and acute pancreatitis. With conventional lipid-lowering therapies, such as statins, many patients with genetic dyslipidemias remain inadequately controlled while other patients are unable to tolerate them, necessitating ongoing research and development of innovative therapies. Several therapeutic lipid targets-including proprotein convertase subtilisin/kexin type 9 (PCSK9), lipoprotein(a) [Lp(a)], apolipoprotein (apo) C-III (APOC3), and angiopoietin-like protein 3 (ANGPTL3)-have been identified and validated through human genetic and epidemiologic studies. Emerging ribonucleic acid (RNA) targeting and gene-editing therapies now offer the potential for durable correction of these metabolic disturbances. Small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) targeting PCSK9, Lp(a), apo C-III and ANGPTL3 have shown marked efficacy in lowering atherogenic lipoproteins and triglycerides, while DNA base-editing approaches including clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR associated protein 9 (Cas9) and related base-editing techniques, aim to provide long-term or even permanent gene silencing to control atherogenic lipids. Together, these innovations mark a paradigm shift toward precision, gene-based lipid management, expanding therapeutic options, improving clinical outcomes, and addressing unmet medical needs in patients with severe or refractory dyslipidemias or in those unable to tolerate standard therapies. Show less

Chylomicronemia, defined by fasting triglycerides ≥10 mmol/L (≥885 mg/dL), has diverse etiologies. When clinical features such as abdominal pain, lipemia retinalis, eruptive xanthomas, hepatosplenomegaly, pancreatitis, or visibly lipemic plasma accompany the biochemical disturbance, the condition is called chylomicronemia syndrome. Subtypes include rare monogenic familial chylomicronemia syndrome (FCS), the more common multifactorial chylomicronemia syndrome (MCS), autoimmune chylomicronemia, and lipodystrophy-associated chylomicronemia. Patients are at risk for acute pancreatitis and sometimes atherosclerotic cardiovascular disease. Accurate diagnosis includes medical history, physical exam, laboratory testing (including plasma apolipoprotein B and the ratio of triglyceride to total cholesterol), clinical scoring systems, as well as selective use of genetic testing when FCS is suspected. In adults, the overwhelming majority of patients with chylomicronemia have MCS and not FCS. Treatment centers on dietary fat restriction, total alcohol avoidance, management of secondary factors, and traditional triglyceride-lowering therapies such as fibrates and omega-3 fatty acids. Acute pancreatitis management requires stabilization, analgesia, supportive care, and preventive management of hypertriglyceridemia. Emerging RNA-based therapies targeting apolipoprotein C-III (eg, volanesorsen, olezarsen, and plozasiran) offer transformative potential for FCS and for some refractory patients with other chylomicronemia subtypes. A multidisciplinary approach-integrating clinical, biochemical, and genetic assessment-guides therapy and reduces pancreatitis risk. Show less

Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a key enzyme in amyloid-β generation and remains an important target in Alzheimer's disease (AD) drug discovery. Here, we present NeuroBACE-ML, a reliability-aware screening framework for high-throughput prioritization of potent BACE1 inhibitors from small-molecule libraries. Human BACE1 bioactivity records were curated from ChEMBL and standardized on a pIC Show less

As a complex physiological and psychological phenomenon, pain has a wide impact on the quality of life of patients. Chronic pain represents one of the most challenging public health issues, and ensuring effective pain management is not only a fundamental right of individuals but also a sacred duty of healthcare providers. This review focuses on recent advancements (within the past five years) in understanding how electroacupuncture (EA) alleviates pain-related affective disorders, such as anxiety and depression. By integrating findings from clinical trials and mechanistic studies, we highlight three key mechanisms: (1)Brain functional regulation: EA modulates brain regions (e.g., prefrontal cortex, insula, thalamus) and networks (default mode network, salience network) via functional magnetic resonance imaging (fMRI)-observed functional connectivity changes. (2)Neurotransmitter and receptor modulation: EA regulates pain and emotions by altering BDNF, β-endorphin, TRPV1, NMDARs, and P2Y12 receptor signaling, supported by studies on chronic pain and depression models. (3)Immune factor adjustment: EA reduces neuroinflammation by targeting TLR4/NF-κB pathways and pro-inflammatory cytokines (IL-1β, TNF-α), improving pain-related affective disorders. Clinical and preclinical evidence demonstrates EA's safety, efficacy, and multi-target effects, however, optimal treatment parameters and individualized strategies require further investigation. Future research should combine multi-omics, large-scale multi-center clinical studies , and precision medicine approaches to deepen understanding of EA's mechanisms and clinical applications. Show less

We investigated the relationship between cerebrospinal fluid (CSF) and plasma biomarkers of inflammation, neurodegeneration, and neurocognitive performance in people with HIV (PWH), using longitudinal samples from two previously published cohorts: ACTG A5090 (virally suppressed on antiretroviral therapy, ART) and A736 (ART-naïve or failing). We analyzed paired CSF and plasma samples, as well as 7-domain standardized neurocognitive test scores, at baseline and 24 weeks. Biomarkers included markers of inflammation (e.g., TNF-α, IL-6, IP-10) and neurodegeneration (e.g., NFL, p-Tau217, Aβ42), which were quantified via high-sensitivity immunoassays. Associations with cognition were tested using regression, mediation, and interaction models. Cross-sectional analyses revealed nominal associations between inflammatory markers and cognitive performance, with plasma IL-6 and IP-10 at baseline, and CSF TNFα at week 24 showing the strongest correlations (p < 0.05, uncorrected); however, none survived correction for multiple comparisons. Conversely, higher CSF Aβ42 and plasma BDNF were positively associated with memory and executive function. Longitudinally, biomarker changes did not significantly predict change in global cognition (ΔNPZ-8); the strongest trend (p-Tau217, ρ = -0.12, p = 0.38) was not statistically significant, and multivariate models failed to identify robust predictors (R These results suggest a potential role of CSF TNFα in mediating the neurocognitive effects of HIV and highlight compartment-specific inflammatory dynamics. Plasma TNFα, GFAP, and NFL may serve as peripheral indicators of CNS pathology, though with only moderate concordance. Astrocyte-tau interactions require cautious interpretation pending replication in larger cohorts. Show less

Hypertriglyceridemia (HTG) is a heterogeneous metabolic disorder driven by both genetic susceptibility and secondary factors. Most cases of severe HTG (triglyceride [TG] >10 mmol/L [>885 mg/dL]) have multifactorial chylomicronemia syndrome (MCS) while only a few have familial chylomicronemia syndrome (FCS), a rare autosomal recessive condition. We summarize the pathophysiology of severe HTG, emphasizing impaired intravascular lipolysis of TG-rich lipoproteins and the regulatory role of apolipoproteins (apo), particularly apo C-III. We outline features that distinguish FCS from MCS and discuss diagnostic strategies, including clinical scoring systems and targeted genetic testing. Current management approaches, including responses to conventional TG-lowering therapies and emerging biologic therapies targeting apo C-III, are examined. We searched PubMed for all English language literature focusing on the search terms 'chylomicronemia,' 'familial chylomicronemia syndrome,' 'multifactorial chylomicronemia syndrome,' 'hypertriglyceridemia,' 'APOC3 inhibition,' 'antisense oligonucleotides,' and 'apolipoprotein C-III.' Differentiating FCS from MCS is critical because RNA-based inhibition of apo C-III has transformed the therapeutic landscape for FCS patients. These agents provide substantial, durable TG lowering and meaningful reductions in pancreatitis risk, although cardiovascular benefit remains uncertain. Future efforts should focus on optimizing diagnostic pathways, assessing cardiovascular outcomes, and determining long-term safety of novel biologic therapies. Show less

Insufficient physical activity is prevalent among perinatal women, and digital health interventions offer a promising avenue to promote engagement in physical activity within this population. However, previous studies have relied heavily on self-reported data, lacking a systematic synthesis based on objective measurements. This study aims to systematically evaluate the effects of digital health interventions on objectively measured physical activity and sedentary behavior in perinatal women. A systematic search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library databases from inception to December 20, 2025. Fourteen randomized controlled trials (RCTs) involving 2,101 participants were included. The Risk of Bias 2.0 (RoB 2.0) tool was used to assess bias risk, random-effects models were employed to pool effect sizes, and the quality of evidence was evaluated using the GRADE system. The meta-analysis showed that, following the exclusion of outliers via sensitivity analysis, digital health interventions significantly increased daily step counts (MD = 0.68, Digital health interventions can effectively and robustly enhance daily baseline activity levels in perinatal women, with the observed increments potentially reaching the minimal effective dose for improving metabolic health. However, current intervention designs face challenges in driving high-intensity behavior change and disrupting sedentary habits. Future research should explore more targeted and personalized intervention strategies. This systematic review and meta-analysis has been registered in PROSPERO (www.crd.york.ac.uk/prospero), identifier CRD420261280936. Show less

Epidemiological studies have consistently shown that chronic kidney disease is associated with increased Alzheimer disease risk. However, the underlying genetic architecture connecting these two conditions remains largely unexplored beyond genome-wide correlation analyses. Here, we conducted the first comprehensive, multi-ancestry, large-scale genetic investigation to identify shared genetic components between kidney function and Alzheimer disease. We leveraged large-scale genome-wide association study summary statistics for estimated glomerular filtration rate (N≈1.5 million European, N≈145,000 African ancestry) and late-onset Alzheimer disease (N=63,926 and N=398,058 in two European cohorts; N=9,168 in African ancestry) corrected for competing risk bias. We deployed a novel analytical framework integrating linkage disequilibrium score regression and polygenic risk score analysis, local analysis of [co]variant association, conjunctional false discovery rate analysis with Bayesian colocalization and fine-mapping, and bidirectional cis-Mendelian randomization to identify vertical pleiotropy. Despite the absence of genome-wide genetic correlation (r Show less

Depression is a major global health burden, and current treatments are limited by delayed onset and incomplete efficacy, highlighting the need for novel, mechanism-based therapies. Chronic restraint stress (CRS) induces behavioral, hormonal, and synaptic changes relevant to depression, but the role of adiponectin signaling remains unclear. Here, we examined whether the adiponectin receptor agonist AdipoRon exerts antidepressant-like effects via brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling in mice subjected to 14 days of CRS. CRS produced anxiety- and depression-like behaviors, elevated plasma corticosterone, reduced circulating adiponectin, and selectively decreased hippocampal adiponectin and adiponectin receptor 2 (AdipoR2), accompanied by reduced PSD-95 and GluA1 in CA3 and the dentate gyrus (DG). AdipoRon treatment (20 mg/kg, days 8-14) prevented behavioral deficits, normalized corticosterone and adiponectin levels, and restored hippocampal AdipoR2, PSD-95, and GluA1 expression in CA3 and DG. AdipoRon also reversed CRS-induced decreases in hippocampal phosphorylated AMPK (p-AMPK), PPARα, BDNF, and phosphorylated TrkB (p-TrkB), with p-AMPK/AMPK and PPARα levels positively correlating with BDNF. Immunofluorescence confirmed BDNF recovery in CA3 and DG. Importantly, pretreatment with the TrkB antagonist ANA-12 abolished the behavioral, hormonal, and molecular effects of AdipoRon, indicating that its actions require BDNF-TrkB activation. These findings suggest that AdipoRon mitigates CRS-induced deficits via hippocampal AdipoR2-AMPK-PPARα-BDNF-TrkB signaling and highlight AdipoR2 as a promising target for depression therapy under chronic stress. Show less

Discordance between apolipoprotein B (apoB) and low-density lipoprotein cholesterol (LDL-C) levels is frequently observed in individuals with metabolic disorders and may contribute to underestimated cardiovascular risk. Population-based data on LDL-C discordance in East Asians, particularly in metabolically healthy individuals, remain limited. We aimed to investigate the distribution of apoB relative to LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) levels and assess the prevalence and determinants of apoB-LDL-C discordance. We analyzed data from 411,125 Korean adults who underwent health checkups between 2011 and 2023. Participants with a history of cardiovascular disease or lipid-lowering therapy were excluded from the study. ApoB-LDL-C (and apoB-non-HDL-C) discordance was quantified using residuals from a linear regression model. Individuals were classified as discordant-high (residuals > 75th percentile), discordant-low (residuals < 25th percentile), or concordant (residuals between the 25th and 75th percentiles). Subgroup analyses were performed for metabolic status, obesity phenotype, and lifestyle or family risk factors. Substantial variability in apoB levels was observed at each LDL-C and non-HDL-C level. ApoB-LDL-C discordance patterns between apoB and non-HDL-C were similar to those observed with apoB and LDL-C, though with smaller residual differences. Discordance was most pronounced in metabolically unhealthy obese individuals, followed by metabolically unhealthy lean individuals, and metabolically healthy individuals (P < .001), indicating that metabolic health is a stronger determinant of discordance than obesity. ApoB-LDL-C discordance is common, even among metabolically healthy individuals, and is primarily driven by metabolic dysfunction rather than by obesity. ApoB measurements should be included in routine cardiovascular risk assessments. Show less

Multiple sclerosis (MS) is a chronic neurodegenerative disorder for which dysregulated ferroptosis and necroptosis have demonstrated pathological associations but these lack causal validation in disease susceptibility. This study employed proteome-wide Mendelian randomization (MR) to investigate causal links between ferroptosis/necroptosis pathways, their upstream regulators, immune interactions, and MS risk. Transcriptomic validation utilized bulk RNA-seq and single-cell RNA-seq data. MR identified IFNA4 (OR = 0.24) and TNFAIP3 (OR = 2.0) as key causal ferroptosis/necroptosis-related proteins for MS risk. Analysis revealed 15 upstream regulators significantly associated with MS (FDR < 0.05; e.g., GZMA, CXCL3, APOE, CFB, CA6, KIR2DL2/3). Transcriptomic validation consistently identified ceruloplasmin (CP) as upregulated in MS microglia and lesions. Mediation analyses established two complete causal pathways: an IFNA4-mediated pathway wherein five upstream immune regulators (KIR2DL2, KIR2DL3, CFB, GZMA, and CA6) influence MS susceptibility through IFNA4 regulation, with all component effects statistically significant; and an APOE-driven pathway operating via TNFAIP3, demonstrating significant total effects and near-significant mediator-outcome effects on MS risk. While 59 immune traits were MS-associated, only TNFAIP3 showed a suggestive association with CD27⁺ memory B cells. This study establishes ferroptosis/necroptosis pathways as causal drivers of MS susceptibility, highlighting TNFAIP3, IFNA4, CP, and APOE as therapeutically actionable targets. Show less

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor with limited effective treatments. This study explores the anti-GBM potential of an α-conopeptide isolated from the venom of Conus planorbis, a marine cone snail from Rameswaram, India. Peptide extraction and BCA assay quantified an average concentration of 473.34 ± 70.07 µg/mL. Structural analysis via Show less

Recent work by Mu et al. identifying irisin as a modulator of adipose tissue IL-33 and regulatory T cells introduces a new paradigm in immunometabolic biology, shifting attention from thermogenesis alone toward immune-stromal crosstalk as a determinant of metabolic health. By inducing IL-33 production in adipose mesenchymal stromal cells, irisin preserves ST2+ regulatory T cells (Tregs) in visceral adipose tissue, thereby restraining inflammation, improving insulin sensitivity, and promoting metabolic homeostasis. This mechanism expands the concept of exercise-induced metabolic protection by highlighting adipose tissue immune niches as critical targets of myokine action. In parallel, emerging evidence from preclinical models indicates that irisin-driven IL-33 signaling in subcutaneous adipose tissue contributes to thermogenic activation through mechanisms distinct from Treg-mediated immune regulation, highlighting depot-specific effects of this pathway. Beyond adipose tissue, irisin has emerged as a pleiotropic mediator with reported roles in glucose homeostasis, cardiovascular protection, and neurobiology. Importantly, accumulating evidence indicates that irisin may also exert neuroprotective effects, including the induction of brain-derived neurotrophic factor (BDNF), amyloid-β (Aβ) clearance, and α-synuclein degradation, thereby linking metabolic and neurodegenerative pathways. Although the findings of Mu et al. derive from preclinical models, they provide a conceptual model for therapeutic strategies aimed at reproducing selected benefits of exercise in obesity, metabolic and neurodegenerative disorders. Notably, these effects appear to depend on sustained irisin exposure in preclinical systems, supporting a role for irisin as a regulator of long-term immunometabolic homeostasis. Collectively, these observations position the irisin/IL-33/Treg axis as a promising link between exercise, adipose tissue immunity, and systemic metabolic regulation, suggesting that targeting immunometabolic circuits, rather than energy balance alone, may open new avenues for future therapeutic intervention. Show less

Prenatal exposure to opioids such as morphine poses significant risks to fetal neurodevelopment, particularly in brain regions critical for cognition, such as the hippocampus. Despite the prescription and use of opioids during pregnancy, the molecular and histological consequences of such exposure remain insufficiently explored. To evaluate the effects of short-term prenatal morphine exposure on the expression of key neurodevelopmental genes and the structural integrity of the hippocampus in neonatal rats. Pregnant Sprague Dawley rats were administered intraperitoneal injections of morphine sulfate (10 mg/kg) on gestational days 15 and 16. On postnatal day 12, offspring (n = 6 per group) were euthanized, and their hippocampal tissues were collected. Quantitative real-time PCR was performed to assess the expression levels of neurodevelopmental genes, including MDH2, Neurog1, and BDNF. Histological evaluations were conducted using hematoxylin and eosin and cresyl violet staining to assess cellular architecture and neuronal viability. Immunohistochemical staining for GFAP, S100, and synaptophysin was used to evaluate astrocytic integrity and synaptic density. The morphine-exposed group showed significant up-reglation of MDH2, Neurog1, and BDNF ( Prenatal morphine exposure leads to marked molecular and histopathological changes in the developing hippocampus, suggesting long-term risks for neurocognitive dysfunction. These findings emphasize the importance of limiting opioid use during pregnancy and identifying molecular targets for future therapeutic interventions. Show less

Fentanyl is a potent, fast-acting synthetic opioid that has played a major role in the opioid overdose crisis in the United States for over five decades, with opioid-related deaths increasing sharply in recent years. This study investigates the behavioral, histological, and molecular changes in the hippocampus of rats subjected to sub-acute fentanyl exposure. Two groups of rats were studied: one group received multiple fentanyl injections over approximately one week, while the control group received no fentanyl. A battery of behavioral tests related to memory and depression-including the Y-maze, shuttle box, tail suspension test, elevated plus maze, Barnes maze, Morris water maze, and forced swimming test-was administered. Electrophysiological assessments, including field potential recording and electromyography (EMG), were conducted to evaluate neural activity. Western blot analysis was performed to quantify the expression of brain-derived neurotrophic factor (BDNF) and RE1-silencing transcription factor (REST), while immunohistochemical analyses assessed hippocampal cellular alterations. Results showed that sub-acute fentanyl administration impaired behavioral performance in memory assessment tests (Y maze ( Show less

Latino persons with chronic spine pain (CSP) face challenges engaging in physical activity (PA) and minimizing sedentary behavior (SB). This study aimed to objectively characterize PA and identify correlates of PA and SB in Latino persons with CSP. Cross-sectional baseline data from Latino participants who were enrolled in a clinical trial for CSP near the U.S.-Mexico border were utilized. Blockwise regression assessed the association between sociodemographic, clinical, interpersonal, and environmental factors with light PA (LPA), moderate-to-vigorous PA (MVPA), and SB. Participants (N = 154, Mage = 47.5 ± 12.1 years) spent 342.8 ± 111.6 min/day in LPA, 56.1 ± 71.1 min/day in MVPA, and 550.3 ± 140.9 min/day in SB. Seventy-five percent of participants met national PA guidelines. Lower income and higher pain interference were associated with lower LPA (R2 = 9%, p < .05). Younger age and lower income were associated with higher MVPA (R2 = 13%, p < .05). Lower income was associated with lower SB (R2 = 5%, p < .05). Younger age (OR 95% confidence interval [CI] [0.87, 0.98]) and higher exercise self-efficacy (OR 95% CI [1.06, 8.09]) increased the odds of meeting PA guidelines. Participants with CSP exhibited greater levels of LPA, MVPA, and SB compared with prior studies of Latino persons without pain. Sociodemographic variables including age and income were most consistently associated with PA and SB outcomes. Future research is needed to identify other relevant intrapersonal, interpersonal, and environmental determinants of PA and SB in this clinical population. (PsycInfo Database Record (c) 2025 APA, all rights reserved). Show less

This study was designed to explore the effects of esketamine on cognitive deficits and blood-brain barrier (BBB) dysfunction in sepsis-associated encephalopathy (SAE). An in vivo SAE model was generated through the administration of lipopolysaccharide (LPS), and LPS-induced cognitive impairment in rats was evaluated using the Morris water maze (MWM) test. BBB disruption in vivo was assessed by measuring brain water content together with Evans blue dye penetration, while LPS-induced endothelial hyperpermeability in vitro was examined through FITC-dextran leakage. The protein expression of claudin-3 and ZO-1 was determined by western blotting. In addition, the levels of pro-inflammatory cytokines, cell apoptosis, autophagy, and the activity of the BDNF/TrkB pathway were examined. Rapamycin (Rap, an autophagy inducer) and K252a (a BDNF inhibitor) were used to determine whether the protective effects of esketamine were associated with autophagy and BDNF/TrkB signaling. Esketamine treatment significantly improved the LPS-induced cognitive dysfunction and neurological injury observed in vivo, and it also inhibited the production of pro-inflammatory cytokines and reduced cell apoptosis both in vivo and in LPS-treated hCMEC/D3 cells. Importantly, esketamine alleviated BBB hyperpermeability in vivo and prevented LPS-induced endothelial leakage in vitro. Moreover, esketamine suppressed LPS-induced autophagy, and the influence of esketamine on claudin-3 and ZO-1 expression was reversed when Rap was applied. Esketamine activated the BDNF/TrkB pathway, and the protective effects of esketamine on BBB integrity and autophagy in response to LPS were abolished by K252a. Taken together, these findings indicate that esketamine protects the BBB against SAE by activating the BDNF/TrkB pathway and inhibiting autophagy, providing a potential therapeutic strategy for SAE. Show less

Radiation-induced brain injury causes significant neurotoxicity and cognitive dysfunction in patients undergoing radiotherapy for brain tumors. This study aimed to evaluate the neuroprotective effects of intranasal ketamine on radiation-induced brain injury, specifically focusing on its modulation of perineuronal networks (PNNs), extracellular matrix components, and neuroinflammation. Eighteen male New Zealand White Rabbits were divided into three groups: normal controls, irradiation (IR) with saline (IR + saline), and IR with ketamine (IR + ketamine). Whole-brain IR (20 Gy) was applied to the IR groups, and ketamine (2 mg/kg/day) was administered intranasally for 15 days. Biochemical markers, including malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), brain-derived neurotrophic factor (BDNF), ADAMTS4, and syndecan-1 levels, were measured. Histopathological analysis of hippocampal and cerebellar regions assessed neuronal survival and astrogliosis. Magnetic resonance spectroscopy (MRS) evaluated lactate and Ketamine administration significantly reduced oxidative stress (MDA) and inflammatory markers (TNF-α) while restoring BDNF levels compared to the IR + saline group. ADAMTS4 and syndecan-1 levels were reduced, changes consistent with PNN-associated extracellular matrix dynamics, but without direct confirmation by core PNN markers such as aggrecan or WFA staining. Histopathology showed increased neuronal survival and decreased reactive astrogliosis in ketamine-treated groups. Intranasal ketamine demonstrates significant neuroprotective effects in a radiation-induced brain injury model by reducing oxidative stress and inflammation, modulating extracellular matrix components, and preserving neuronal integrity. These findings highlight ketamine's potential as a therapeutic agent, although direct PNN markers and broader cytokine panels were not assessed. Overall, ketamine showed neuroprotective effects across biochemical, histological, and MRS-supported metabolic readouts. Show less

Drug-induced hyperpigmentation (DIH) represents a significant subset of acquired pigmentation disorders and poses diagnostic challenges due to delayed onset and polypharmacy. This systematic review and meta-analysis aimed to identify medications significantly associated with DIH and evaluate their reported incidence. A systematic search was conducted across PubMed, Scopus, Web of Science, and Cochrane Library for studies published between 2002 and June 2024. Eligible studies reported DIH as an outcome with incidence or descriptive data. Pooled proportions were calculated using a random-effects model, and heterogeneity was assessed via the I Twenty-two studies met the inclusion criteria. The overall pooled incidence of DIH was 36.7% (95% CI: 0.291-0.444). Subgroup analyses revealed the highest incidences with tyrosine kinase inhibitors (89.2%) and MC4R agonists (71.4%), followed by antibiotics (52.0%), antineoplastic agents (35.5%), and antimalarials (29.0%). Commonly implicated agents included minocycline, hydroxychloroquine, and hydroxyurea. DIH is a prevalent adverse drug reaction with considerable variation in incidence across drug classes. Recognition of high-risk medications is essential for prompt diagnosis and clinical management. The study protocol was pre-registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42024529250). Show less

G protein-coupled receptors (GPCRs) recognize ligands on the cell surface, initiating intracellular signaling pathways that control a variety of biological processes, from neurotransmission and hormone regulation to light detection and smell. As entryways into these pathways, GPCRs are key pharmacological targets, with 30% of FDA-approved drugs targeting them. High-throughput GPCR-based sensors in yeast are proven platforms for the identification of novel GPCR ligands. Most human GPCRs (hGPCRs), however, led to small increases in the signal after activation, hindering the development of high-throughput (HT) assays. To streamline the generation of HT assays for biomedically important hGPCRs, here we analyze five fluorescent reporters in the context of hGPCR-based sensors. Using the serotonin receptor 4 (HTR4)-based sensor as a testbed, we identify YPet, a yellow fluorescent protein previously evolved for improved intracellular fluorescence, as the optimal fluorescent reporter when using flow cytometry, fluorescence-activated cell sorting, or a fluorescent plate reader. YPet increases the dynamic range of hGPCR-based sensors in general, enabling the engineering of HTR4-, MC4R- S1PR2-, HTR1A-, and Mel1A-based sensors with vastly higher increases in signal than previously engineered sensors. YPet even allowed the construction of a functional HTR1D-based sensor, a sensor that had been difficult for the field to construct. Finally, the fast maturation of YPet reduces the time to readout from 4 h to 30 min, unlocking point-of-care diagnostic applications previously inaccessible to hGPCR-based sensors in yeast. Looking ahead, the identification of YPet as the optimal fluorescent reporter for yeast hGPCR-based sensors opens the door to the standardized generation of hGPCR high-throughput assays in this host, and sets the stage for ultrahigh-throughput single-cell experiments toward the identification of new ligands for known GPCRs, GPCR deorphanization, and GPCR engineering to bind designer ligands. Show less

The rising global prevalence of obesity and its impact on health and economy make finding available safe treatment an urgent need. Ketogenic diet represents trendy dietary intervention, while underlying molecular mechanisms remains unclear. Twenty-four male Sprague-Dawley rats were randomized into three groups: Control (maintained on conventional chow diet for 24 weeks), HFD (fed High-fat diet (HFD) for 24 weeks), keto (fed HFD for 12 weeks, then ketogenic diet for additional 12 weeks). Effect of ketogenic diet on serum metabolomics using Ultra Performance Liquid Chromatography coupled with Liquid Chromatography on both positive and negative modes; hepatic tissue using histopathological examination, enzyme-linked immunosorbent assay (ELISA), Real time Polymerase Chain Reaction, proteome array detection; intestinal tissue using histopathological examination, ELISA and adipose tissue using histopathological examination were evaluated. The ketogenic diet reduced rat weight, food intake, epididymal fat mass, and blood glucose level compared to HFD group. Furthermore, it resulted in a decrease in serum methionine, linolenic acid, Lyso Phosphatidylcholine (PC) (15.0:0.0), Lyso PC (18.0:0.0) with hepatic repression of fibroblast growth factor 21 (FGF21), and type II cell surface protein/ Dipeptidyl peptidase 4, Intercellular Adhesion Molecule 1, Insulin growth factor-1, Lipocalin-2, Serpin E1, tissue inhibitor of matrix metalloproteinase-1, receptor for advanced glycation end products and induction of Farnesoid X receptor (FXR), hepatocyte growth factor (HGF) which leads to hepatic antioxidant effects and histopathological amelioration. In addition, the ketogenic diet caused intestinal induction of melanocortin-4 receptors/ glucagon-like peptide 1 pathway, which causes intestinal antioxidant effects and histopathological amelioration. Thus, ketogenic diet stated potential anti-obesity effect that mitigates HFD-induced organ damage through the modulation of key metabolic and signaling networks. Show less

Speed capability is critical for early childhood development, but troubling patterns are emerging in the motor fitness of Chinese preschoolers (3-6 years). This study investigated how compositional 24-h movement behaviours (sleep, sedentary behaviour [SB], light physical activity [LPA] and moderate-to-vigorous physical activity [MVPA]) relate to speed capability. Via compositional data analysis and isotemporal substitution modelling, we assessed relationships between 24-h movement behaviours (sleep, SB, LPA and MVPA) and speed capability in 275 preschoolers (mean age 4.98 ± 0.76 years). Participants completed 20-m sprint tests and 7-day accelerometry. Time-reallocation effects were quantified through pairwise behavioural substitutions (5- to 30-min durations), with all models adjusted for age, sex and BMI z scores (z-BMI). Higher relative MVPA time significantly predicted faster sprint times (β = -1.302, p < 0.001), while higher LPA predicted slower times (β = 1.570, p = 0.003). Reallocating 15 min from sleep, SB or LPA to MVPA reduced sprint times by 0.176, 0.201 and 0.385 s, respectively (all p < 0.05). Conversely, reallocating MVPA to other behaviours worsened performance. The effects exhibited asymmetry: displacing time away from MVPA impaired speed capability to a greater extent than equivalent gains in MVPA time improved it. MVPA is the strongest positive predictor of speed capability in preschoolers. Optimizing 24-h movement patterns by reallocating time from LPA or SB to MVPA is associated with enhanced speed performance, supporting targeted interventions for early childhood development. Show less

The bioactive peptide setmelanotide is a validated MC4R agonist, yet its clinical utility is constrained by poor aqueous solubility and dose-limiting, off-target hyperpigmentation. To overcome these dual liabilities, we executed a synergistic optimization strategy guided by detailed SAR investigation. This approach unveiled two critical design principles: a C-terminal "cationic imperative", where lysine uniquely conferred a > 20-fold solubility enhancement while retaining potency, and rational manipulation of the core pharmacophore, which imparted >100-fold selectivity over MC1R/MC3R. This synergy yielded the lead compound SC19, which integrates these features into a balanced profile of sub-nanomolar potency (EC₅₀ = 0.12 nM; pEC₅₀ = 9.93), exceptional selectivity, and high aqueous solubility. In a diet-induced obesity model, SC19 demonstrated robust efficacy comparable to setmelanotide in reducing weight gain and improving lipid profiles, affirming its therapeutic potential. This work not only presents a promising lead compound but also validates a synergistic optimization blueprint for concurrently enhancing the pharmacological and drug-like properties of therapeutic peptides. Show less

This comprehensive review examines the synergistic effects of physical exercise and polyphenolic compounds, such as flavonoids, curcumin, and resveratrol, on spatial learning and memory. The interplay between these interventions highlights their potential to enhance cognitive function by promoting neurogenesis, synaptic plasticity, and resilience against oxidative stress and inflammation. Mechanistic insights reveal that exercise and polyphenols activate complementary neuroprotective pathways, including the upregulation of BDNF and CREB, as well as the modulation of antioxidant defenses via Nrf2. Evidence from both animal and human studies demonstrates significant improvements in spatial memory and hippocampal function when these strategies are combined. Despite promising findings, challenges related to bioavailability, dosing, and long-term efficacy remain, underscoring the need for further investigation. This review emphasizes the potential clinical applications of these combined approaches for preventing cognitive decline and promoting brain health during aging and in neurodegenerative conditions. Show less