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Cardiac microvascular injury from hyperlipidaemia and hyperglycaemia is associated with increased major adverse cardiovascular events (MACE). Semaglutide, a long-acting GLP-1 receptor agonist, reduces diabetic cardiovascular complications beyond its glycaemic and weight-lowering effects. However, the impact of semaglutide on diabetes-induced coronary microvascular injury and the integrated mechanisms involved remain unclear. A combined streptozotocin (STZ) and high-fat diet (HFD) induced diabetes model was established in ApoE Diabetic mice showed disrupted cardiac microvascular structure and reduced microvascular density. Semaglutide attenuated or reversed these changes. It reduced advanced glycation end products (AGEs) and their receptors, activated the Nrf2/HO-1/NQO1 pathway, inhibited the MCP-1/CCR2a/NF-κB pathway, lowered inflammatory cytokines, and reduced apoptosis, exerting a protective effect on the cardiac microvascular system. Early and sustained semaglutide treatment mitigates diabetes-related cardiac microvascular injury via multiple mechanisms, including preserving microvascular structure and density, inhibiting perivascular fibrosis, and attenuating inflammation, oxidative stress, and apoptosis. Show less

Epithelial-mesenchymal transition (EMT) and cell migration are two essential cellular processes involved in normal biological events such as embryogenesis, organ development, and wound healing, and are also associated with pathological conditions like cancer metastasis. Recent studies have indicated that the microtubule cytoskeleton and its associated proteins play significant roles in these processes. In this study, we investigated how fidgetin, a microtubule-severing and depolymerizing enzyme, affects EMT and cell migration by depleting it in MDA-MB-231 breast cancer cells. Our data show that depletion of endogenous fidgetin reduces the cell migration rate in both wound-healing and single-cell motility assays. During EMT, transcription factors such as Snail, Slug (Snail2), Twist, and Zeb play pivotal roles by regulating the expression of EMT-related genes. In this study, we found that fidgetin depletion reduces the expression of Slug and Zeb1 in MDA-MB-231 breast cancer cells under both basal and EMT-induced conditions. Consistent with these findings, we observed that fidgetin depletion downregulates N-cadherin and vimentin expression in EMT-induced MDA-MB-231 cells, thereby influencing cell motility. Further investigations revealed that fidgetin also affects microtubule plus-end tracking proteins (+TIPs). Specifically, we detected reduced expression of CLIP-170 in fidgetin-depleted cells. Immunofluorescence analysis showed that EB1 comets occupied a smaller area at microtubule plus ends upon fidgetin depletion. Additionally, the size of focal adhesions was significantly increased, although no changes were observed in the expression levels of focal adhesion kinase (FAK). Our findings indicate that microtubule regulation by fidgetin influences cancer cell motility by altering the expression of EMT-promoting transcription factors and modulating the accumulation of focal adhesion and EB1 proteins. These results suggest that fidgetin could be a promising therapeutic target in cancer. Show less

Melanocortin 4 receptor (MC4R) gene mutations are the most common cause of monogenic non-syndromic childhood obesity, but their relationship with asthma remains unclear. We report four cases of children with the same MC4R gene variant who presented with asthma in the setting of obesity. The asthma phenotype, severity, and presentation were variable between these patients. Some but not all also had comorbid obstructive sleep apnea (OSA) and evidence of metabolic abnormalities, including insulin resistance and hypertension. These findings suggest that the MC4R mutation and its associated morbid obesity are associated with asthma. Future studies are warranted to define the underlying pathobiology of asthma among children with MC4R mutations. Show less

DUSP6, a dual-specificity phosphatase, has become a focal point in understanding the pathogenesis of various liver disorders. This study aims to investigate the role of DUSP6 in liver fibrosis and explore the underlying mechanism. Using a CCL4-induced mouse model, the consistent upregulation of DUSP6 expression was observed. Notably, when Dusp6 was knocked down, liver fibrosis showed significant improvement, revealing a protective effect intricately linked to the ERK pathway. This was accompanied by an increase in ferroptosis-related proteins SLC7A11 and GPX4, underscoring the role of ferroptosis, an iron-dependent form of regulated cell death, in this process. Transcriptomic analysis further revealed a crucial downregulation of Cyp2e1 following Dusp6 knockdown. In vitro, DUSP6 knockdown not only promoted ERK phosphorylation but also suppressed CYP2E1 expression, enhancing cell proliferation, bolstering hepatocyte resistance to ferroptosis, and alleviating hepatocyte injury. Importantly, inhibiting CYP2E1 in mouse models of liver fibrosis effectively slowed the progression. These findings illuminate a critical regulatory mechanism that DUSP6 regulates liver fibrosis via targeting ferroptosis, offering new a direction for therapeutic strategies in liver disease. Show less

KRAS We studied short-term changes in signaling and mechanisms of primary resistance to AZD4625 in twelve KRAS Sustained tumor regression in four (33%) PDXs was observed while the remaining eight models were intrinsically resistant to AZD4625. Organoid responses to AZD4625 were concordant with their derived PDXs. Acute AZD4625 exposure significantly decreased gene expression of the ERK1/2 negative regulator, DUSP6, in all models while protein MAPK and AKT/mTOR signals were downregulated more frequently in the AZD4625-sensitive than AZD4625-resistant cohorts. Analyzing PDX transcriptomes and proteomes identified mTOR signaling as a putative mechanism of primary resistance to AZD4625. Our findings confirm AZD4625 as a highly active KRAS Show less

Health-related fitness (HRF) is essential for wellbeing and daily functioning. While objective fitness assessments are preferred, self-report measures are practical for large-scale or geographically diverse studies. Existing self-report HRF measures may lack sensitivity for younger or healthy adults. Additionally, many include items with no or poorly defined reference populations, potentially limiting their validity and comparability. This study examined the reliability and validity of single-item self-reported HRF measures of aerobic fitness, muscular strength and endurance, flexibility, coordination, agility, and body composition. Between April and July 2023, University of Calgary students and staff (N.=129; mean age 28±9 years) completed the first questionnaire, with subsets completing a second questionnaire and validated fitness assessment. Nine items captured participants' self-rated HRF relative to those of the same age and gender. The nine self-reported HRF items were aggregated to obtain an estimate of overall HRF (Multidimensional Health-Related Fitness Scale, MHFS). We used intraclass correlations (ICC) to estimate test-retest reliability of the individual self-reported HRF items and MHFS. We assessed convergent validity with self-reported leisure physical activity (LPA) and concurrent validity with objective fitness measures using age- and sex-adjusted partial correlations. The single-item self-reported HRF measures (ICC=0.60-0.85) and MHFS (ICC=0.87) had acceptable test-retest reliability. The MHFS also had high internal consistency (Cronbach's α=0.87). Evidence of validity was observed with partial correlations ≥0.30 between self-reported HRF and LPA, and objective fitness measures. The MHFS provides a reliable and valid HRF indicator among younger adult populations. Show less

Injectable PCSK9 inhibitors effectively lower LDL-C levels in patients with hypercholesterolemia; however, their high cost and requirement for parenteral administration limit their widespread use. Oral PCSK9 inhibitors have emerged as a convenient alternative. This review and meta-analysis of the literature evaluate the effectiveness and safety of oral PCSK9 inhibitor treatment for adults with hypercholesterolemia. PubMed, Embase, Cochrane CENTRAL, and Scopus were searched through September 2025 for randomized controlled trials comparing oral PCSK9 inhibitors with placebo. The primary outcome was percentage change in LDL-C, with secondary lipid and safety outcomes. We used Cochrane RoB 2.0 tool to assess risk of bias, and pooled estimates were calculated using a random-effects model. Certainty of evidence was evaluated with GRADE. From 1253 records, 3 trials were included. Participants were mostly men, aged 61-65 years, with elevated baseline LDL-C. Oral PCSK9 inhibitors significantly reduced LDL-C and ApoB in a dose-dependent manner and achieved modest reductions in triglycerides (MD -6.56 mg/dL; 95% CI, -12.30 to -0.83) and total cholesterol (MD -25.25 mg/dL; 95% CI, -30.67 to -19.83). Effects on lipoprotein(a) were inconsistent. Adverse events (RR 1.06; 95% CI, 0.91-1.23) and serious adverse events (RR 1.32; 95% CI, 0.41-4.26) were comparable with placebo. According to our review, oral PCSK9 inhibitors are a promising therapeutic option for treating hypercholesterolemia because of their potent lipid-lowering effects and an overall favorable safety profile. However, more trials are needed to confirm their impact on cardiovascular outcomes. Show less

This study explored how minority stress and social safety jointly shape mental health among Taiwanese sexual minority men (SMM) through the identification of psychosocial profiles and their associations with depression. Between April and May 2023, 415 Taiwanese SMM completed an online cross-sectional survey. Latent profile analysis (LPA) identified groups based on minority stress (sexuality-related discrimination, acceptance concerns, internalized homonegativity) and social safety (identity affirmation, family support, community connectedness) indicators. Multinomial logistic regression examined sociodemographic correlates of profile membership, and linear and binary logistic regressions assessed associations with depressive symptom severity (DSS) and major depressive disorder (MDD). LPA identified three distinct profiles: "Moderate Minority Stress-Low Social Safety" (MMS-LSS; These findings revealed diverse experiences of minority stress and social safety among Taiwanese SMM and their implications for depression, supporting culturally responsive interventions. Show less

Hippocampal neuroinflammation (HNF) is a key pathological feature in neurodegenerative disorders. Milk-derived exosomes, as bioactive extracellular vesicles, have underexplored potential in regulating brain neuroinflammatory responses. This study aimed to characterize desert milk exosomes (D-Exo) and investigate their neuroprotective and anti-neuroinflammatory effects in LPS-induced HNF mice model and an LPS-stimulated BV2 microglia. Exosomes were isolated from desert and non-desert milk (ND-Exo) for proteomic analysis. After pretreating BV2 cells with exosomes and stimulating with LPS, their inflammatory responses and polarization were assessed by RT-PCR. Balb/c mice were orally gavaged with D-Exo or 0.9% NaCl for 28 days before LPS injection. Cognitive function was assessed via behavioral tests, with microglial/astrocyte activation analyzed by immunofluorescence. D-Exo exhibited superior stability and a unique proteomic profile enriched with proteins linked to neuroinflammation and blood-brain barrier (BBB) integrity, notably within the AMPK signaling pathway. In vitro, D-Exo shifted LPS-stimulated microglia from the M1 to the M2 phenotype. In vivo, it alleviated HNF and cognitive decline, reduced Aβ D-Exo is enriched with specific proteins, attenuates neuroinflammation and cognitive decline by regulating microglial M1/M2 polarization and AMPK pathway, highlighting its preventive potential. Show less

Chia (Salvia hispanica L.) is a functional food that can help control the metabolic changes caused by unbalanced diets. The aim of this study was to investigate the effects of chia flour (CF) and chia oil (CO) on satiety, inflammation, and antioxidant potential in the brain of rats fed a high-fat high-fructose diet (HFHF). Male Wistar rats were divided into two groups: AIN-93M (n = 8) and HFHF (n = 24) for 8 wk. Subsequently, HFHF-fed animals were subdivided (n = 8) into: HFHF, HFHF+CF, and HFHF+CO for 10 wk. Gene expression of satiety and inflammation-related proteins was analyzed by RT-qPCR; leptin and adiponectin levels were quantified by ELISA; and antioxidant potential was assessed via SOD and CAT activity. In silico analysis was performed using molecular docking, and the correlations were evaluated via Pearson's analyses. The HFHF+CO group showed higher POMC/CART gene expression, as well as reduced leptin levels compared to the HFHF+CF and AIN-93M groups. Both chia flour and oil reduced NPY, LEP-r, and NF-κB gene expressions compared to the HFHF group. The HFHF+CF group showed increased Nrf2 gene expression compared to the HFHF group. All main phenolic acids found in chia flour showed good interactions with the analyzed markers LEP-r, MC4R, and NPY-Y1. Main positive correlations were observed beteween adiponectin and SOD, phenolics consumption and ALA, MC4R and NPY, NPY and AgRP, and AgRP and MC4R. Thus, this study highlights chia flour and oil as potential modulators of satiety and inflammatory response in the brain, in addition to reinforcing the antioxidant effect of flour. Show less

Impaired synaptic plasticity underlies cognitive impairment as a core pathological substrate. While aerobic exercise represents a significant non-pharmacological intervention for enhancing synaptic plasticity, its precise molecular mechanisms remain incompletely defined. This study investigated whether aerobic exercise ameliorates synaptic plasticity and synaptic loss in Apolipoprotein E homozygous knockout (APOE Show less

Periodontal disease is a prevalent chronic inflammatory condition of the tooth-supporting tissues characterized by progressive loss of connective attachment and alveolar bone. The IL-12 cytokine family-comprising IL-12, IL-23, IL-27, and IL-35-plays key yet divergent roles in shaping periodontal immune responses through heterodimeric subunits and distinct JAK-STAT signaling pathways. These cytokines differentially regulate inflammation, microbial interactions, and bone resorption. This review integrates experimental and clinical evidence assessing IL-12 family members in saliva, gingival crevicular fluid, and periodontal tissues. Studies examining cytokine expression profiles, their correlation with disease activity, microbial dysbiosis, and treatment response were analyzed. Mechanistic data elucidating how IL-12 family signaling modulates inflammatory cascades and osteoclastogenic pathways were also evaluated. IL-12 and IL-23 predominantly amplify pro-inflammatory responses by promoting Th1/Th17 polarization, enhancing neutrophil recruitment, and driving osteoclastogenesis, thereby linking dysbiotic biofilms to tissue destruction. In contrast, IL-27 and IL-35 exhibit context-dependent immunoregulatory properties, inducing IL-10-mediated anti-inflammatory signaling and expanding regulatory T and B cell compartments to support the resolution of inflammation. Across clinical samples, cytokine levels consistently reflect disease severity and demonstrate modulation following periodontal therapy, underscoring their potential as adjunctive biomarkers. Members of the IL-12 cytokine family exert both pathogenic and protective influences in periodontal disease. Therapeutic strategies that suppress IL-12/IL-23-driven inflammation while augmenting IL-27/IL-35-mediated regulation show promise as host-modulatory approaches in periodontal treatment. A deeper understanding of these immunologic dynamics may advance precision-based periodontal therapies. Show less

Essential tremor (ET) is a common movement disorder, characterized by bilateral postural or kinetic tremor and associated non-motor symptoms including anxiety and cognitive impairment. Current treatments offer limited efficacy and significant side effects, highlighting the need for novel therapeutic approaches. This study investigated the therapeutic potential of memantine and vitamin D3 (vitD3) combination therapy in a harmaline-induced mouse model of essential tremor. Adult male Swiss mice were divided into eight groups (n = 8/group): control, sham, harmaline-induced ET (10 mg/kg, i.p. on days 1, 3, and 5), memantine (5 mg/kg, i.p. for 7 days), vitD3 (0.1 µg/kg, i.p. for 7 days), and combination treatment groups. Tremor severity, footprint analysis, rotarod, and wire grip tests were conducted to assess motor function. Moreover, anxiety-like behavior, depressive-like behavior, and cognitive function were examined. Expression of leucine-rich repeat and immunoglobulin domain-containing protein 1 (Lingo-1) and NMDA receptor expression in cerebellar tissue was evaluated using quantitative real-time PCR. Histological evaluation of Purkinje cell morphology was performed using hematoxylin-eosin staining. Harmaline administration induced significant tremor, motor coordination deficits, anxiety-like behaviors, and cognitive impairments. Treatment with memantine and/or vitD3 significantly reduced tremor scores on days 3 and 5 compared to harmaline alone. Combination therapy restored locomotor activity. Both individual and combination treatments demonstrated significant anxiolytic effects. VitD3 alleviated depressive-like behavior. Moreover, cognitive assessment revealed that combination therapy significantly improved passive avoidance learning and memory retention. Harmaline dramatically upregulated Lingo-1 and NMDA receptor expression, which was effectively normalized by memantine and/or vitD3 treatment. Histological examination demonstrated that vitD3 and combination therapy significantly reduced harmaline-induced Purkinje cell degeneration. Memantine and vitD3 combination therapy ameliorates both motor and non-motor symptoms in a mouse model of ET through modulation of Lingo-1 and NMDA receptor expression pathways. These findings suggest that this combination approach represents a therapeutic strategy that addresses the complex pathophysiology of ET while providing neuroprotective benefits. Show less

Breast cancer (BC) progression is intricately linked to the dysregulation of transfer RNA-derived fragments (tRFs). Through comprehensive analysis of The Cancer Genome Atlas (TCGA) data, it is demonstrated that 5'tRF-GlyGCC is overexpressed in BC tissues and negatively associated with patients' survival. Mechanistically, 5'tRF-GlyGCC binds to lactate dehydrogenase A (LDHA), enhancing its enzymatic activity and promoting glycolysis, which drives BC cell malignancy. This binding is mediated by the phosphorylation of LDHA at tyrosine 10, and facilitated by fibroblast growth factor receptor 1 (FGFR1), through the formation of a ternary complex that amplifies oncogenic signaling. Furthermore, 5'tRF-GlyGCC/LDHA axis induces macrophage infiltration and polarization toward an M2 phenotype, mediated by the chemokine CCL7, thereby reshaping the tumor microenvironment. Additionally, it is uncovered that the biogenesis of 5'tRF-GlyGCC is regulated by ALKBH3 and ANG, which also modulate LDHA activity. In vivo, targeting 5'tRF-GlyGCC/LDHA signaling significantly suppresses tumor growth and enhances the efficacy of immunotherapy. Collectively, these findings elucidate the pivotal role of 5'tRF-GlyGCC in BC progression, highlighting its potential as therapeutic target for BC treatment. Show less

Perfluorooctane sulfonate (PFOS), a pervasive environmental contaminant, is ubiquitously detected in water, air, soil, and food chains. Emerging evidence has implicated PFOS in the pathogenesis of cardiovascular diseases, particularly atherosclerosis - the fundamental pathological process underlying diverse cardiovascular and cerebrovascular disorders. A previous study demonstrated that PFOS exacerbates atherosclerosis in apolipoprotein E-deficient (ApoE Show less

The global obesity epidemic necessitates therapies that enhance energy expenditure. Non-shivering thermogenesis (NST) in brown/beige adipose tissue represents a promising target, with fibroblast growth factor 21 (FGF21) emerging as a critical regulator linking environmental stimuli to adipose plasticity and mitochondrial function. However, the precise mechanisms of FGF21 secretion and its specific role in adipose tissue browning and subsequent NST potentiation remain incompletely elucidated. FGF21 regulates NST via distinct spatiotemporal mechanisms. Acute cold exposure triggers hepatic FGF21 secretion through a β FGF21 exhibits dual regulation: hepatic (acute lipid mobilization) and adipose-based (chronic browning); adipose-targeted FGF21 delivery is essential for therapeutic efficacy, and future studies should integrate FGF21 with UCP1-independent pathways (e.g., creatine/succinate cycles) to advance obesity treatment. Show less

Brain-derived neurotrophic factor (BDNF) can protect neurons from apoptosis and maintain normal synaptic structures, indicating a significant potential for Alzheimer's disease (AD) treatment. However, the method of Show less

Anxiety is a major symptom associated with alcohol withdrawal and a major factor increasing the risk of relapse. Although fluoxetine, a selective serotonin reuptake inhibitor, is used to alleviate these symptoms, its effects on brain lipid signaling pathways involved in withdrawal-related anxiety remain unclear. This study evaluated, in a preclinical model, the behavioral and molecular effects of chronic alcohol exposure and fluoxetine treatment during early abstinence. Male Wistar rats received oral alcohol (3 g/kg) or saline for 14 days, followed by 7 days without alcohol, during which fluoxetine (10 mg/kg) was administered to designated groups. Anxiety-like behavior was assessed using the elevated plus maze. Circulating plasma levels of corticosterone, 2-arachidonoylglycerol (2-AG), lysophosphatidic acid (LPA), and interleukin-10 (IL-10) were quantified, and gene expression analyses were performed in the amygdala and medial prefrontal cortex (mPFC). Chronic alcohol administration increased anxiety-like behavior and plasma 2-AG, while reducing LPA and IL-10 levels. Fluoxetine induced an anxiolytic effect in controls but was ineffective in alcohol-exposed rats, only normalizing the alcohol-induced increase of plasma 2-AG. At the molecular level, fluoxetine modulated gene expression region-specifically, altering 2-AG-related genes in the amygdala and enhancing LPA signaling in the mPFC. Hierarchical clustering revealed coordinated downregulation of 2-AG pathway genes in the alcohol-fluoxetine group and partial restoration of anti-inflammatory markers. These findings indicate fluoxetine modulates lipid signaling and immune-related genes during alcohol withdrawal, but its anxiolytic efficacy may be limited after alcohol exposure. These findings may contribute to the development of targeted therapeutic strategies for alcohol-related anxiety and relapse prevention. Show less

Lipoprotein(a) (Lp(a)) is a genetically determined causal risk factor for cardiovascular disease, with approximately 20% of the population exhibiting elevated levels. While there are promising drugs in development, there are currently no approved therapies specifically designed to lower Lp(a) levels. For high-risk individuals with extreme levels of Lp(a), liver-directed genome editing could be an effective one-time solution. Genome editing approaches such as CRISPR and TALENs can reduce Lp(a) in LPA-transgenic mouse models, but they frequently induce large and potentially harmful genomic deletions. Here, we report the first application of TadA-derived cytosine base editing (CBE), delivered via helper-dependent adenovirus (HDAdV) and adeno-associated virus (AAV) vectors, to introduce premature stop codons into LPA. This strategy produced robust and durable lowering of circulating apolipoprotein(a) (apo(a)) in LPA-transgenic mice. Using SMRT-seq with single-molecule unique molecular identifiers, we quantified deletion events and found that CBE did not induce large deletions when targeting a single LPA site and produced only a small fraction (<4%) of large deletions when editing across multiple sites. In contrast, CRISPR-Cas9 cutting of LPA resulted primarily in large deletions. These findings demonstrate that CBE enables sustained reduction of circulating apolipoprotein(a) in an LPA-transgenic mouse model while largely preserving genomic integrity. Show less

This study aims to evaluate the association between multiple lipid indices and coronary collateral circulation (CCC) in patients diagnosed with acute ST-segment elevation myocardial infarction (STEMI). This was a cross-sectional retrospective study involving 421 patients with STEMI who underwent coronary angiography between January 2022 and December 2024. Participants were categorized into a poor CCC group (Rentrop grade 0-1) and a good CCC group (Rentrop grade 2-3) according to Rentrop grading criteria. The following lipid parameters were evaluated as both continuous and categorical variables: total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a) [Lp(a)], apolipoprotein B (ApoB), apolipoprotein A-I (ApoA-I), non-HDL-C/HDL-C, ApoB/ApoA-I, atherogenic index of plasma (AIP), and lipoprotein composite index (LCI). The associations between these lipid indices and CCC status were assessed using multivariate logistic regression and receiver operating characteristic (ROC) curve analysis. Multivariate logistic regression analysis revealed that higher HDL-C quartiles were significantly associated with reduced odds of poor CCC (odds ratio [OR]: 0.544, 95% confidence interval [CI]: 0.351-0.771, P < 0.05), whereas elevated LDL-C (OR: 29.299, 95% CI: 3.562-240.976, P < 0.05), non-HDL-C (OR: 50.140, 95% CI: 5.408-464.834, P < 0.01), and non-HDL-C/HDL-C (OR: 4.510, 95% CI: 1.186-25.368, P < 0.05) quartiles were significantly associated with increased odds of poor CCC. Receiver operating characteristic (ROC) curve analysis demonstrated that LDL-C (cutoff: 3.265, AUC: 0.647, 95% CI: 0.573-0.721, P < 0.001), non-HDL-C (cutoff: 2.735, AUC: 0.752, 95% CI: 0.688-0.816, P < 0.001), and non-HDL-C/HDL-C (cutoff: 2.393, AUC: 0.686, 95% CI: 0.611-0.761, P < 0.001) exhibited favorable predictive performance for poor CCC. Stratification analysis showed that the highest prevalence of poor CCC was observed in patients with concurrently elevated levels of LDL-C, non-HDL-C, and non-HDL-C/HDL-C. Several lipid indices-including LDL-C, non-HDL-C, and the non-HDL-C/HDL-C ratio-are significantly associated with impaired CCC in patients with STEMI. Notably, non-HDL-C exhibits the strongest association with CCC dyscrasia and therefore warrants early clinical attention. Show less

Prognostic models in Waldenström's macroglobulinemia (WM) are typically static, baseline tools applied before treatment initiation and do not account for dynamic post-treatment factors. We evaluated time to next treatment within 24 months (TTNT24), as a prognostic marker in symptomatic patients, and time to lymphoma treatment within 24 months (TTLT24) in initially observed asymptomatic patients. In this observational cohort study, patients diagnosed with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) in Region Zealand from 2000 to 2023 were identified using Danish national registries and health records. TTNT24 was defined as initiation of second-line treatment within 24 months of first-line therapy. TTLT24 was defined as lymphoma-directed treatment initiated within 24 months of diagnosis in initially asymptomatic patients. Among 526 LPL/WM patients, 218 symptomatic patients were evaluated for TTNT24 with 33 (15%) patients receiving second-line treatment within 24 months. TTNT24-positive patients demonstrated inferior overall and lymphoma-related survival compared to TTNT24-negative patients. TTNT24 remained significant in multivariate analysis. Among 310 asymptomatic patients, TTLT24 was significantly associated only with lymphoma-related survival. TTNT24 and TTLT24 may serve as dynamic prognostic markers in real-world LPL/WM populations. Their relevance in the era of targeted therapies warrants further investigation. Show less

Bovine tuberculosis (bTB) is a chronic infectious disease caused by the Mycobacterium bovis (M. bovis). Rapid, cost-effective, and accurate diagnosis of bTB remains a significant clinical challenge globally. In this study, we performed a comprehensive proteomic analysis to evaluate the discriminatory power of plasma and plasma exosomes for bTB diagnosis. We compared protein expression profiles across three groups: M. bovis-negative controls (bTB_N, n = 10), M. bovis-positive cases (bTB_P, n = 10), and co-infected animals (Other_P, n = 10) with Brucella, infectious bovine rhinotracheitis virus (IBRV), and bovine viral diarrhea-mucosal disease virus (BVDV). Quantitative analysis identified 3820 exosomal proteins-2.27-fold more than the 1686 plasma proteins detected. Exosomal proteins exhibited superior sample clustering and discriminative capacity for infected groups. Notably, 227 plasma and 861 exosome-derived proteins were uniquely differentially expressed in bTB (bTB-specific DEPs). Pathway enrichment analysis revealed that exosome-specific DEPs were significantly enriched in TB-related pathways, including neutrophil extracellular trap (NET) formation, endocytosis, and tuberculosis, exhibiting greater biological relevance compared to plasma-specific DEPs. Furthermore, eight candidate proteins (APOE, FBLN5, VDAC1, ABCE1, LMAN1, PLG, SPP1, and SRP9) demonstrated high specificity for bTB discrimination, with two (FBLN5 and SPP1) displaying stage-specific expression patterns during M. bovis infection. This study underscore plasma exosome as a highly promising source of biomarkers for bTB diagnosis, offering enhanced sensitivity and deeper mechanistic insights over conventional plasma proteome. Show less

This study aimed to investigate the relationship between blood uric acid (UA), serum lipoprotein(a) [Lp(a)], and the severity of neurological damage in patients with acute penetrating artery occlusive cerebral infarction combined with type 2 diabetes mellitus (T2DM). To evaluate the role of UA and Lp(a) levels as independent risk factors for neurological damage severity and poor prognosis, and to observe the therapeutic effect of tanshinone. Clinical data of patients were analyzed to compare differences in indicators between the mild and moderate groups, as well as between groups with good and poor prognosis. Patients in the moderate infarction group showed significantly higher levels of UA, Lp(a), and other biochemical markers, along with higher rates of unhealthy lifestyle habits and comorbidities. UA, Lp(a), and infarct diameter were independent risk factors for poor prognosis. Their combined prediction model demonstrated good sensitivity and specificity. Pre-treatment UA and Lp(a) levels were significantly positively correlated with pre-treatment NIHSS scores and post-treatment mRS scores, respectively. In patients with acute penetrating artery occlusive cerebral infarction combined with T2DM, blood uric acid and serum Lp(a) levels are associated with the severity of neurological damage and serve as independent risk factors for poor prognosis. Show less

This narrative review aims to synthesize and critically evaluate the complex molecular mechanisms by which amyloid-β (Aβ) accumulation disrupts hippocampal synaptic plasticity, the cellular cornerstone of learning and memory in Alzheimer's disease (AD). AD is characterized by progressive hippocampus-dependent cognitive decline, strongly linked to impaired synaptic plasticity, the cellular basis of learning and memory. This review deciphers how Aβ accumulation orchestrates synaptic sabotage in the hippocampus. We detail the core molecular machinery of hippocampal synaptic plasticity, emphasizing glutamate receptor trafficking (NMDAR/AMPAR), Ca Show less

We report the discovery of a chemical series that enhances ApoE secretion from human astrocytes through mechanisms independent of LXR agonism. Target deconvolution of hits from a phenotypic screen in astrocytoma cells employed chemoproteomics, photoaffinity probes, in vitro KINOMEscan analysis, and targeted siRNA knockdown experiments. Photoaffinity labeling coupled with quantitative chemical proteomics identified aryl hydrocarbon receptor (AhR), a transcription factor not previously associated with ApoE secretion, as the primary target. A diverse panel of AhR agonists and antagonists together with genetic knockdown confirmed that ApoE secretion increases when AhR activity is reduced. Using a luciferase reporter assay, we demonstrated that active series analogs exhibit AhR antagonism while inactive compounds do not. Since deletion of AhR has severe peripheral effects, chronic inhibition of AhR is not an attractive therapeutic approach for Alzheimer's disease; nevertheless, these results position AhR as a modulator of ApoE secretion and a biological pathway worth exploring. Show less

Antioxidant supplements have emerged as promising strategies to mitigate the impact of Alzheimer's disease (AD) and associated dementia. We explored the neuroprotective potential of Carvone nanoemulsion (CANO) using a rat model of AD-associated dementia. Our experimental groups comprised non-AD control rats (CON), untreated AD rats (AD), and AD rats treated with CANO at two different dosages: 40 mg/kg (CANO40) and 80 mg/kg (CANO80). We assessed various behavioral parameters, malondialdehyde (MDA) and brain-derived neurotrophic factor (BDNF) levels,ferric-reducing ability of plasma (FRAP). AD induction caused a significant reduction in step-through latency (P < 0.001), center time (P < 0.001), the number of visits (P < 0.001), and total distance traveled (P < 0.001), time spent in open arms (P < 0.001), and both FRAP (P < 0.001) and BDNF levels (P < 0.001) in comparison to the CON group, while elevating escape latency, time in target zone and platform location latency, and MDA levels (P < 0.001). Treatment with CANO, particularly at the CANO80 dosage, significantly improved these parameters compared to the AD group, resulting in decreased time in the target zone (P < 0.001), escape latency (P < 0.001), and platform location latency (P < 0.001) and higher FRAP (P < 0.05) and BDNF levels (P < 0.05), along with decreased MDA levels (P < 0.05). CANO, especially at the 80 mg/kg dosage, shows promise in alleviating symptoms associated with AD-associated dementia. However, further research is warranted to validate and expand upon these findings. Show less