Foam cell formation has traditionally been attributed to macrophages; however, emerging evidence highlights vascular smooth muscle cells (VSMCs) as another significant contributor. Here, we found that Show more
Foam cell formation has traditionally been attributed to macrophages; however, emerging evidence highlights vascular smooth muscle cells (VSMCs) as another significant contributor. Here, we found that TMEM41B is significantly upregulated in VSMCs of both human atherosclerotic (AS) lesions and murine models. Silencing TMEM41B in VSMCs of apolipoprotein E-deficient (ApoE Show less
Biallelic DIAPH1 mutations are linked to hereditary microcephaly syndrome, yet the underlying pathogenic mechanism remains unelucidated. This study aimed to clarify how DIAPH1 biallelic mutations caus Show more
Biallelic DIAPH1 mutations are linked to hereditary microcephaly syndrome, yet the underlying pathogenic mechanism remains unelucidated. This study aimed to clarify how DIAPH1 biallelic mutations cause microcephaly and visual impairment, focusing on the gene's regulatory role in the Wnt/β-catenin signaling pathway. Whole exome sequencing was performed on a patient's peripheral blood to identify DIAPH1 mutations. A zebrafish model was established by microinjecting mutant human DIAPH1 cDNA into one-cell embryos (no zebrafish DIAPH1 homolog exists). Phenotypic analyses (morphology, neuronal axon growth, behavior) and quantitative real-time PCR for Wnt/β-catenin pathway genes were conducted. Data were mean ± SEM; statistical tests (Student's t-test, ANOVA, χ²) used GraphPad Prism 5.0 (P < 0.05, P < 0.0001 for significance). Compound heterozygous DIAPH1 mutations (c.1051 C > T, p.R351X; c.609delA, p.E203E fs*19) were found and associated with clinical symptoms. Mutant DIAPH1 zebrafish showed abnormal eye shape, shortened body length, axis defects, impaired motor axon growth, reduced locomotor activity, upregulated WNT8A, WNT9A, LRP5, LRP6, and downregulated AXIN1, AXIN2, β-CATENIN, indicating excessive Wnt/β-catenin pathway activation. DIAPH1 compound heterozygous mutations may trigger microcephaly and visual impairment by abnormally activating the Wnt/β-catenin pathway. The zebrafish model provides a reliable in vivo system for studying DIAPH1-related microcephaly, advancing understanding of hereditary primary microcephaly pathogenesis and potential therapeutic target exploration. Show less
Wenyu Gao, Hao Chen, Fangyu Lin+7 more · 2026 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
Gastric cancer (GC) is a leading cause of cancer-related deaths and has high recurrence rate. Although fibronectin domain-containing protein 1 (FNDC1) is implicated in GC progression, its molecular me Show more
Gastric cancer (GC) is a leading cause of cancer-related deaths and has high recurrence rate. Although fibronectin domain-containing protein 1 (FNDC1) is implicated in GC progression, its molecular mechanisms remain unclear. Multi-omics analyses (TCGA, GEO datasets) were used to assess FNDC1 expression and clinical correlation. In vitro (cell proliferation, invasion, EMT markers) and in vivo (xenograft) experiments, combined with molecular assays (Co-IP, WB, ChIP), explored FNDC1's function and mechanism. FNDC1 was significantly upregulated in GC, correlating with advanced clinicopathological features and poor prognosis. Knockdown of FNDC1 suppressed GC cell proliferation, invasion, and metastasis by inhibiting EMT and Wnt/β-catenin signaling. Mechanistically, FNDC1 competitively bound the WD5 domain (residues 224-254) of Gβ2, disrupting Gβγ-Dvl1 interaction. This prevented Dvl1 degradation, promoted Axin1 ubiquitination, and destabilized the β-catenin-destruction complex (GSK3 β-APC-Axin1), leading to β-catenin accumulation and Wnt pathway activation. FNDC1 drives GC malignancy by targeting the Gβ2-Dvl1 axis to activate Wnt/β-catenin signaling, suggesting FNDC1 as a novel prognostic biomarker and therapeutic target. Show less
CTNNB1-mutated hepatocellular carcinomas are characterized by a distinctive morphology and activation of the Wnt pathway. AXIN1 also plays a key role in the Wnt pathway, but the morphology of AXIN1-mu Show more
CTNNB1-mutated hepatocellular carcinomas are characterized by a distinctive morphology and activation of the Wnt pathway. AXIN1 also plays a key role in the Wnt pathway, but the morphology of AXIN1-mutated tumors has not been examined. In addition, there are ongoing questions on the ability of AXIN1 mutations to activate the Wnt pathway in hepatocellular carcinoma. AXIN1 mutated tumors (N=18) were studied, along with control groups: CTNNB1 (N=17), APC (6), or "Other" genes in the Wnt pathway (5). Wnt pathway activation was studied by immunostains for beta-catenin and glutamine synthetase. Findings were supplemented by gene expression analysis using TCGA data. On histologic examination, the classic morphology associated with beta-catenin mutations was found in all 4 groups: 8/18 AXIN1 (44%), 10/17 CTNNB1 (59%), 4/6 APC (67%), and 1/5 Other (20%). By immunohistochemistry, Wnt pathway activation was found in 11/18 AXIN1 (61%), 15/17 CTTNB1 (88%), 6/6 APC (100%), and 5/5 (100%) of Other. In AXIN1-mutated tumors, the Wnt pathway was weakly activated. Glutamine synthetase stains also highlighted a new "progressed pattern" associated with distinct subnodules of staining. Tertiary lymphoid structures were uncommon except for cases with CTTNNB1 mutations plus additional mutations in the Wnt pathway. In summary, the classic morphology associated with CTNNB1 mutations is found in hepatocellular carcinomas with mutations in AXIN1, APC, and other Wnt genes. AXIN1 mutated tumors have Wnt activation that is detectable but at lower levels than CTNNB1 mutated tumors. As tumors progress, their level of Wnt activation can change. Show less
Endometrial carcinoma (EC) is a common malignancy of the female reproductive system. Rab35 is widely recognized as an oncogenic driver and has been implicated in the progression of various malignant t Show more
Endometrial carcinoma (EC) is a common malignancy of the female reproductive system. Rab35 is widely recognized as an oncogenic driver and has been implicated in the progression of various malignant tumors. However, its regulatory mechanism and pathobiological roles in EC remain unclear. Rab35 expression in EC was systematically profiled via integrative analysis of clinical endometrial specimens and multi-omics databases (CPTAC and GEO). The association between clinical prognosis and Rab35 expression was examined using Kaplan-Meier analysis. Mechanistic investigations included transwell assays, western blotting, and immunofluorescence in Rab35-overexpressing and CRISPR/Cas9-mediated Rab35-knockout EC cells. A mouse xenograft tumor model was established to confirm the effects of Rab35 in vivo. The Rab35 content increased gradually from normal endometrium to atypical hyperplastic endometrium to EC. Moreover, the findings indicated that elevated Rab35 expression was significantly associated with advanced disease characteristics and poor overall survival in patients with EC. In addition, Rab35 enhanced the migratory and invasive nature of EC cells. The expression of Rab35 was inversely linked to that of the β-catenin destruction complex-related proteins Axin-1 and GSK3β, leading to the increased nuclear translocation of β-catenin in EC cells. Animal experiments further verified that Rab35 augmented EC progression by regulating the nuclear translocation of β-catenin. The study revealed that high expression of Rab35 was strongly correlated with EC progression and a poor clinical outcome. Furthermore, Rab35 promoted EC cell metastasis by accelerating the nuclear translocation of β-catenin. These findings suggest that Rab35 serves as a valuable biomarker and therapeutic target for EC. Show less
Disruption of circadian rhythms is increasingly recognized as a contributor to cognitive dysfunction, but its role in gestation-associated cognitive changes remains unexplored. Here we combine human c Show more
Disruption of circadian rhythms is increasingly recognized as a contributor to cognitive dysfunction, but its role in gestation-associated cognitive changes remains unexplored. Here we combine human cognitive screening with a comprehensive longitudinal mouse model to investigate whether gestational cognitive impairment and postpartum recovery are coupled with disruption and restoration of hippocampal circadian rhythms. Cognitive function was assessed in pregnant and postpartum women using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). In mice, four reproductive stages were compared: control, gestation, 1 month postpartum, and 3 months postpartum. Serum gonadotropins and sex hormones levels were quantified using ELISA. Home-cage locomotor activity was recorded over 48 h under a 12 h:12 h light-dark cycle. Hippocampal-dependent memory was evaluated using the novel object recognition test and Barnes maze at Zeitgeber times ZT6 (day) and ZT18 (night). Hippocampal amyloid β (Aβ) deposition was visualized via immunofluorescence; protein expression of amyloid precursor protein (APP), β-site amyloid precursor protein cleaving enzyme-1 (BACE1), and phosphorylated tau was measured by Western blots. Hippocampal clock gene expression was quantified by RT-qPCR at six time points; circadian parameters (mesor, amplitude, acrophase) were derived by cosinor analysis and compared between groups. Human cognitive screening confirmed modest gestational decline with postpartum recovery. In mice, gestation disrupted daily locomotor activity rhythms and reduced nocturnal preference; both partially recovered by 1 month and fully by 3 months postpartum. Behaviourally, pregnancy impaired the normal day-night difference and performance in novel object exploration and Barnes maze, which recovered progressively. At the molecular level, gestation increased hippocampal APP and BACE1 expression, elevated Aβ42 deposition, and induced tau hyperphosphorylation at multiple sites-hallmarks of Alzheimer's disease-related pathology. These alterations partially reversed by 1 month postpartum and normalized by 3 months. Hippocampal clock genes maintained 24 h rhythmicity, but gestation induced gene-specific phase shifts, amplitude reductions, and mesor alterations. These parameters showed gradual, gene-dependent normalization postpartum. Gestational cognitive impairment and postpartum recovery are associated with reversible disruption and restoration of both hippocampal circadian rhythms and Alzheimer's disease-related molecular pathology. These findings are correlational in nature and provide a foundation for future causal investigations. Show less
Bergamottin is a natural furanocoumarin compound that possesses antioxidative and anticancer properties. However, the effect of bergamottin (BGM) on acute kidney injury (AKI) is unknown. Human renal t Show more
Bergamottin is a natural furanocoumarin compound that possesses antioxidative and anticancer properties. However, the effect of bergamottin (BGM) on acute kidney injury (AKI) is unknown. Human renal tubular HK-2 cells and mice that received cisplatin were pretreated with BGM, after which their cytotoxicity and renal function were evaluated. BGM pretreatment alleviated cisplatin-induced cytotoxicity Show less
To investigate cognitive status in patients with interstitial lung disease (ILD) and its association with lung tissue transcriptomic alterations, and to propose potential lung-brain interaction mechan Show more
To investigate cognitive status in patients with interstitial lung disease (ILD) and its association with lung tissue transcriptomic alterations, and to propose potential lung-brain interaction mechanisms and clinical implications. We enrolled 45 ILD patients and 45 age-matched controls and compared Mini-Mental State Examination (MMSE) total and subscale scores. Baseline laboratory and pulmonary function characteristics of ILD were summarized. Using lung tissue RNA-seq data from GSE213001 {29 ILD cases [20 idiopathic pulmonary fibrosis (IPF), 9 non-IPF], 14 non-diseased controls [NDC], totaling 139 samples}, we performed PCA, differential expression analysis using the limma-voom framework with the duplicate Correlation function to account for within-donor correlations (threshold |log ILD patients showed significantly lower MMSE total scores than healthy controls, with notable declines in attention/calculation and orientation. At the transcriptomic level, PCA clearly separated ILD from NDC, whereas IPF and non-IPF did not form distinct subgroups. Differential analysis identified 1,544 DEGs (1,142 upregulated; 402 downregulated). Enrichment analysis confirmed strong signals for inflammatory and fibrotic pathways. In an exploratory analysis, we also observed enrichment for terms related to nervous system function. The expression trends of several genes previously implicated in neurocognitive contexts, including PSEN1, PSEN2, BACE1, showed a directional concordance with patterns described in neurodegenerative contexts. This study provides preliminary evidence linking ILD to cognitive impairment on screening and identifies intriguing overlaps between lung tissue transcriptomic alterations and pathways relevant to brain function. These convergent observations lend biological plausibility to, and motivate further investigation of, a lung-brain axis hypothesis in ILD. The findings highlight the need to consider cognitive health in ILD management and warrant validation in longitudinal cohorts with detailed neuropsychological phenotyping. Show less
The mixed particles of Myricetin (MYR)/Chitooligosaccharide (COS)/Astaxanthin (AST) had not study to therapeutic effects on Alzheimer's disease (AD) combined with depression. In this study, the mixed Show more
The mixed particles of Myricetin (MYR)/Chitooligosaccharide (COS)/Astaxanthin (AST) had not study to therapeutic effects on Alzheimer's disease (AD) combined with depression. In this study, the mixed particles of MYR/COS/AST were investigate the inhibitory activities against cholinesterase (ChE) and monoamine oxidase (MAO), possessing good activity were further assayed to inhibit β-amyloid1-42 (Aβ ChE and MAO inhibitory activities by Ellman and Holts method. Aβ aggregation were evaluated by thioflavin T assay, BACE1 inhibition used the fluorescence resonance energy transfer (FRET)-based. The protective effect were tested by against L-Glutamate (L-Glu)-induced HT22 cell damage, Cu The results showed that the mass ratio of the mixed particles MYR/COS/AST was 10:10:3, which exhibited the best inhibitory activities on AChE, MAO, also exhibited inhibition against Aβ These studies provide the technical data for ensuring potential treatment of AD combined with depression of the mixed particles of MYR/COS/AST (10:10:3). Show less
Diabetic peripheral neuropathy (DPN), a severe complication of diabetes, is a key risk factor for diabetic foot (DF) that contributes highly to amputation and mortality. The pathogenesis of DPN remain Show more
Diabetic peripheral neuropathy (DPN), a severe complication of diabetes, is a key risk factor for diabetic foot (DF) that contributes highly to amputation and mortality. The pathogenesis of DPN remains unclear and complex, with no effective treatments currently available. Monoamine oxidase (MAO), a flavin adenine dinucleotide (FAD)-dependent enzyme, catalyzes the oxidative deamination of critical biogenic amines. The MAO family comprises two subtypes, MAOA and MAOB, which play distinct roles in pathophysiology. In this study, we identified that MAOB but not MAOA is pathologically upregulated in the sciatic nerve (SN) tissues of DPN patients and in the SN/dorsal root ganglion (DRG) tissues of DPN model mice. Notably, the selective MAOB inhibitor Khellin (Khe) effectively alleviated DPN-like pathology in mice. To explore the mechanistic role of MAOB in DPN, we performed proteomic profiling of DRG tissues from DPN mice and validated the findings using a MAOB-specific knockdown DPN mice model treated with adeno-associated virus (AAV) 8-MAOB-RNAi. Our results demonstrate that Khe targets MAOB to mitigate DPN pathology through HIF-1α/BACE1/Aβ/NLRP3/tau pathway, mediated by Schwann cell/DRG neuron crosstalk. All findings suggest that selective MAOB inhibition represents a promising therapeutic strategy for DPN, with Khe as a potential candidate for clinical translation against this disease. Show less
β-amyloid (Aβ) inhibition significantly attenuates the early-stage Alzheimer's disease (AD) progression, but the improvement in cognitive function remains limited by neuroinflammation. Here, we develo Show more
β-amyloid (Aβ) inhibition significantly attenuates the early-stage Alzheimer's disease (AD) progression, but the improvement in cognitive function remains limited by neuroinflammation. Here, we developed a bioinspired neuroenhancer that concurrently targets both Aβ aggregation and neuroinflammation. Rutin and small interfering RNA targeting beta-site amyloid precursor protein cleaving enzyme 1 (siBACE1) were co-loaded into the calcium phosphate core, which was further coated with lipid bilayers and Angiopep-2/rabies virus glycoprotein 29 peptides to form the multifunctional neuroenhancer (RB@LCP-AR). RB@LCP-AR not only releases siBACE1 to silence BACE1 expression and block Aβ production from the cleavage of amyloid precursor protein, but also releases Rutin to suppress the Aβ aggregation. Moreover, the released Rutin of RB@LCP-AR directly alleviates Aβ-induced mitochondria dysfunction and intracellular ROS production in neuronal cells. Notably, the targeting of RB@LCP-AR to neurons and the inhibition of Aβ reduce the microgliosis and astrogliosis, further alleviating neuroinflammation and synapse loss. Consequently, AD mice receiving RB@LCP-AR treatment efficiently recovered their memory and cognition. Our study thus provides a coordinated targeting of Aβ and neuroinflammation inhibition, holding considerable potential to promote the recovery of memory and cognition in AD. Show less
Oxidative stress, neuroinflammation, and β-amyloid (Aβ) deposition act synergistically to drive Alzheimer's disease (AD) progression. Effective treatment, therefore, requires multi-targeted strategies Show more
Oxidative stress, neuroinflammation, and β-amyloid (Aβ) deposition act synergistically to drive Alzheimer's disease (AD) progression. Effective treatment, therefore, requires multi-targeted strategies capable of addressing these interconnected pathological mechanisms. Here, an Odorranalectin (OL)-conjugated lipid nanoparticle (siB/QU@L-OL) was engineered for efficient intranasal delivery of β-site APP cleaving enzyme 1 (BACE1) siRNA (siB) and quercetin (QU). siB/QU@L-OL prepared via microfluidics exhibited uniform size distribution, high encapsulation efficiency, and robust stability. Following intranasal administration, OL surface modification enabled binding to L-fucose residues expressed on the olfactory epithelium, reducing mucociliary clearance and facilitating brain transport. Show less
Electroacupuncture (EA) has been widely used in the clinical treatment of cognitive impairment after cerebral ischemia (CI) in China, but the specific molecular mechanism is not fully understood yet. Show more
Electroacupuncture (EA) has been widely used in the clinical treatment of cognitive impairment after cerebral ischemia (CI) in China, but the specific molecular mechanism is not fully understood yet. In this study, permanent middle cerebral artery occlusion (pMCAO) model mice were administrated with EA therapy, Morris water maze (MWM) test was used for evaluation of cognitive function, Nissl staining was employed to quantify surviving neurons in the hippocampus, and enzyme-linked immunosorbent assay (ELISA) was utilized to detect the levels of amyloid beta (Aβ). The results showed that EA treatment obviously improved learning and memory abilities in the mice with pMCAO, inhibited neuronal loss in the hippocampus, and reduced the levels of Aβ40 and Aβ42. Meanwhile, we observed that METTL3 expression and total N6-methyladenosine (m6A) levels were significantly increased in the hippocampal tissues of pMCAO mice, which were reduced by EA therapy. Then, hippocampal neuronal cell line HT22 was induced by oxygen-glucose deprivation (OGD) to verify the molecular regulatory mechanism in vitro, and we found that METTL3 upregulated BACE1 expression in OGD-induced HT22 cells through promoting m6A enrichment on BACE1 mRNA, thus facilitating Aβ production and cell apoptosis of OGD-induced HT22 cells. Finally, through in vivo functional recovery experiments, we demonstrated that EA therapy restrained the METTL3/BACE1 axis to alleviate Aβ accumulation and cognitive dysfunction in pMCAO model mice. In summary, our data reveals that the m6A-modified BACE1 pathway is one of the molecular targeting mechanisms for EA treatment in cognitive impairment after CI. Show less
Synaptic vesicle glycoprotein 2A (SV2A), a transmembrane protein widely localized to synaptic vesicles, serves as a key indicator of synaptic loss in Alzheimer's disease (AD). In this study, adeno-ass Show more
Synaptic vesicle glycoprotein 2A (SV2A), a transmembrane protein widely localized to synaptic vesicles, serves as a key indicator of synaptic loss in Alzheimer's disease (AD). In this study, adeno-associated virus (AAV) was injected by brain stereotactic injection technique to construct SV2A-overexpressing APP/PS1 mice, then the effects of SV2A on amyloid precursor protein (APP) degradation and its molecular mechanism were further explored in vivo or in vitro. Our results demonstrated that SV2A overexpression significantly reduced Aβ plaque deposition in brain tissue of APP/PS1 mice. Mechanistically, SV2A was identified as a novel APP-binding protein that attenuated the amyloidogenic processing of APP by inhibiting its interaction with β-site APP cleaving enzyme 1 (BACE1). Furthermore, SV2A overexpression altered the subcellular distribution of APP, shifting its localization away from the endosomal-lysosomal compartments. Collectively, our findings unveil SV2A as a critical regulator of APP metabolism and propose it as a promising therapeutic target for intervening in the early pathological progression of AD. Show less
FURIN cleaves a subset of proproteins into functional mature fragments. Evidence suggests that FURIN is involved in brain development and the associated diseases, whereas the potential mechanisms rema Show more
FURIN cleaves a subset of proproteins into functional mature fragments. Evidence suggests that FURIN is involved in brain development and the associated diseases, whereas the potential mechanisms remain incompletely understood. Here, we report that cerebral FURIN-deficient mice exhibit cognitive decline and neurodegeneration. Lipid droplets (LDs) that are preferentially accumulated in astrocytes correlate with an increase of the LD markers PLIN2 and PLIN3, and conversely a decreased level of autophagic proteins including ATG5, BECN1 and MAP1LC3/LC3 as well as LAMP1. Accordingly, silencing of Show less
Chronic cerebral hypoperfusion (CCH), a subclinical state underlying mild cognitive impairment (MCI), triggers multiple pathological changes associated with Alzheimer's disease (AD) and vascular demen Show more
Chronic cerebral hypoperfusion (CCH), a subclinical state underlying mild cognitive impairment (MCI), triggers multiple pathological changes associated with Alzheimer's disease (AD) and vascular dementia (VaD), including amyloid-β (Aβ) deposition, tau phosphorylation, microglial activation and neural circuit dysfunction. Developing multitarget therapeutics to effectively prevent the transition from MCI to AD and/or VaD remains an urgent challenge. Herein, we engineered a brain-targeted dual-modified PEGylated nanoliposome (LipTM@miR-195), incorporating mannose (MAN) and the trans-activating protein of HIV type 1 (TAT), which encapsulates polyethyleneimine (PEI) complesed microRNA-195 (miR-195). In a CCH rat model, tail-vein administration of LipTM@miR-195 (0.112 mg/kg) efficiently crossed the blood-brain barrier (BBB) without detectable side effects. Treatment reversed CCH-induced spatial learning and memory deficits, rescued neural circuit dysfunction, and suppressed elevated APP, BACE1, AT8 and CD68 levels. Collectively, these findings provide compelling evidence that LipTM@miR-195 nanoliposome holds therapeutic potential for CCH-induced cognitive impairment, thereby preventing the progression from MCI to AD and/or VaD. Show less
Beta-site APP-cleaving enzyme 1 (BACE1), a critical rate-limiting enzyme that synthesizes β-amyloid peptide (Aβ), is an important marker of early pathological changes in Alzheimer's disease (AD). Earl Show more
Beta-site APP-cleaving enzyme 1 (BACE1), a critical rate-limiting enzyme that synthesizes β-amyloid peptide (Aβ), is an important marker of early pathological changes in Alzheimer's disease (AD). Early small plaques cannot be accurately detected using traditional Magnetic resonance imaging (MRI) probes. Therefore, magnetic resonance tuning (MRET) and susceptibility weighted imaging (SWI)-based smart responsive MR nanoprobes are designed to achieve the sensitive detection of BACE1 and Aβ plaques. This probe is modified with a blood-brain barrier-penetrating targeting peptide that enables its reach to the AD microenvironment. The enhancement of T1WI signals owing to the MRET effect caused by the separation of probes in response to BACE1 is used to reflect real-time BACE1 changes. When Aβ plaques are present, the remaining probes that bound around Aβ plaques underwent in situ thiol cross-linking under the action of peroxynitrite (ONOO Show less
Bazi Bushen (BZBS), a Traditional Chinese Medicine (TCM) formula, is composed of fourteen herbal ingredients, including classic tonics such as Ginseng Radix et Rhizoma and Cistanches Herba. Traditiona Show more
Bazi Bushen (BZBS), a Traditional Chinese Medicine (TCM) formula, is composed of fourteen herbal ingredients, including classic tonics such as Ginseng Radix et Rhizoma and Cistanches Herba. Traditionally used to combat fatigue and promote vitality in aging individuals, BZBS is rooted in TCM principles of kidney essence replenishment and brain function enhancement. Recent pharmacological studies have begun to validate its efficacy in age-related cognitive decline, but its effects and mechanisms in Alzheimer's disease (AD) remain unclear. This study aimed to evaluate the potential therapeutic effects of BZBS in 5 × FAD transgenic mice, a commonly used Alzheimer's disease model, and to shed light on its possible mechanisms of action. Four- and six-month-old 5 × FAD mice were treated with BZBS to examine how it might influence cognitive performance. Behavioral assessments were carried out using Y-Maze and the Morris Water Maze. To investigate the biological changes and uncover the mechanisms involved, we used a range of techniques-Thioflavin S staining, immunofluorescence, Western blotting, and qPCR-to look at Aβ plaque accumulation, Amyloid Precursor Protein C-terminal Fragments (APP-CTF) and β-secretase 1 (BACE1) expression levels, markers of inflammation, and indicators of cellular aging in hippocampus and motor cortex. In the 4-month group, where treatment was started before severe pathology developed, BZBS improved learning and memory performance. It also reduced amyloid deposition in the cortex and hippocampus, and lowered the levels of APP-CTFs and BACE1. In addition, we observed decreased mRNA expression of IL-1α, IL-6, and NF-κB, along with reduced microglial activation in the hippocampus of BZBS-treated mice. Similarly BZBS downregulated key markers of cellular senescence, including p16, p21, and senescence-associated β galactosidase (SA-β-gal) activity. In the 6-month group, which already showed signs of amyloid pathology, BZBS still had beneficial effects-improving cognition, lowering Aβ load, and reducing microglial activity-suggesting that it may be effective even after disease onset. These findings demonstrate that BZBS exerts significant therapeutic effects in 5 × FAD mice, including improved cognitive improvement, reduced Aβ deposition, suppressed microglial activation, and attenuated hippocampal cellular senescence. Notably, BZBS was effective whether administered from the early stage of pathology (at four months of age) or after established amyloidosis (at six months of age), highlighting its dual potential as both a preventive and disease-modifying intervention for Alzheimer's disease (AD). Show less
Huanshaodan (HSD) is a Traditional Chinese Medicine Compound Prescription, traditionally used in the clinical treatment of Alzheimer's disease (AD) in China. Nevertheless, its bioactive constituents a Show more
Huanshaodan (HSD) is a Traditional Chinese Medicine Compound Prescription, traditionally used in the clinical treatment of Alzheimer's disease (AD) in China. Nevertheless, its bioactive constituents and mechanistic basis remain poorly understood. To identify the components derived from HSD that inhibit SIRT2 and investigate the underlying mechanisms in mitigating AD pathogenesis. A luciferase reporter gene assay was employed to screen HSD for components that downregulate SIRT2 expression. The neuroprotective effects and the mechanisms of the screened component, ferulic acid (FA), was evaluated both in SAMP8 mice and HT22-APPswe cell using behavioral tests, H&E, immunohistochemistry, transmission electron microscopy, ELISA, MTT, Western blot, RT-qPCR, immunofluorescence and Co-immunoprecipitation, to assess its effect on SIRT2 expression, SIRT2-APP interaction, as well as the expression of proteins associated with APP proteolytic processing. SIRT2-overexpressing plasmids were transfected to assess FA's neuroprotection via SIRT2 modulation. As a component in HSD, FA inhibited SIRT2 promoter-driven transcription, ameliorated cognitive deficits, protected neuronal and synaptic structures, reduced Aβ deposition in SAMP8 mice and Aβ level in HT22-APPswe cells. FA suppressed SIRT2 expression, inhibited SIRT2-APP interaction, modulated the expression levels of proteins involved in APP proteolytic processing, namely ADAM10, sAPPα, BACE1, sAPPβ, and CTFα in vitro and in vivo. Notably, the regulatory effects of FA on APP proteolytic processing in HT22-APPswe cells were completely abolished upon SIRT2 overexpression. This study demonstrates that FA is an active component in HSD that mitigates AD pathology, potentially by modulating APP proteolytic processing through SIRT2 downregulation. Show less
Alzheimer's disease (AD), a chronic and progressive neurodegenerative disease, is the most common cause of dementia. An important pathological basis for AD lesions is the excessive generation and depo Show more
Alzheimer's disease (AD), a chronic and progressive neurodegenerative disease, is the most common cause of dementia. An important pathological basis for AD lesions is the excessive generation and deposition of β-amyloid (Aβ) caused by increased expression of the β-secretase, known as the β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Effective suppression of the BACE1 overexpression has become a key AD treatment. Nuclear factor of activated T cells (NFAT) is a key transcription factor that regulates the expression of BACE1 in AD lesions, while Calcineurin (CaN) is a key regulatory protein that affects the transcription function of NFAT. Several lines of evidence have indicated that FK506 may promote the Aβ degradation via upregulation of the matrix metalloproteinase-9 (MMP-9) expression, which is associated with reduction of Aβ plaque deposition in the cerebral cortex and hippocampus. In this study, behavioral, histological, and biochemical methods were used to investigate the key role and molecular mechanisms of CaN inhibitor FK506 in cognitive dysfunction, regulation of BACE1 expression, and Aβ production in APPswe/PS1dE9 transgenic mice. Results The results indicate that FK506 inhibits NFAT1 levels in the cerebral cortex and hippocampus, thereby reducing the expression of BACE1 and mediating APP processing towards non-amyloidosis pathways, significantly reducing Aβ overproduction, which in turn saved cognitive deficits in APPswe/PS1dE9 transgenic mice. In addition, FK506 treatment had no significant effect on the expression of a disintegrin and metalloprotease (ADAM10) in α - secretase. FK506 rescues cognitive deficits in APPswe/PS1dE9 mice by reducing Aβ production and deposition in the brain. Show less
Nutrient competition between tumor and immune cells is a hallmark of the glioblastoma (GBM) microenvironment, yet the mechanisms underlying amino acid metabolic reprogramming and immune evasion remain Show more
Nutrient competition between tumor and immune cells is a hallmark of the glioblastoma (GBM) microenvironment, yet the mechanisms underlying amino acid metabolic reprogramming and immune evasion remain incompletely understood. Here, we demonstrate that GBM cells outcompete NK cells for branched-chain amino acid (BCAA), leading to BCAA depletion, suppression of NK and CD8 Show less
Branched-chain α-amino acids (BCAAs) support protein synthesis and their oxidation is restrained by branched-chain α-keto acid dehydrogenase kinase (BCKDK). We previously observed that in the brains o Show more
Branched-chain α-amino acids (BCAAs) support protein synthesis and their oxidation is restrained by branched-chain α-keto acid dehydrogenase kinase (BCKDK). We previously observed that in the brains of Bckdk knockout (KO) mice, BCAAs fall while glutamate is preserved and other amino acids rise. We asked why this profile emerges and how it affects skeletal muscle versus brain during nutrient stress. Motor behavior, protein synthesis and nutrient signaling were compared in the skeletal muscle and brains of wildtype (WT) and Bckdk KO male mice. In addition, nitrogen delivery into brain from BCAAs was assessed using stable isotope tracing and mass spectrometry imaging. Bckdk KO showed normal grip strength but poor beam traversal and reduced wheel running during protein restriction. In skeletal muscle, leucine or protein-feeding stimulated and fasting suppressed mechanistic target of rapamycin complex 1 (mTORC1) signaling in both genotypes. Fasting reduced muscle protein synthesis in both strains without activating the integrated-stress response (ISR). In contrast, Bckdk KO brains exhibited ISR activation during fasting, and up-regulation of Atf4 and its target genes, including Slc7a5 mRNA. Tracer studies revealed lower serum [ Show less
The cardiac lymphatic system plays a crucial role in maintaining myocardial homeostasis by regulating fluid equilibrium, immune surveillance, and metabolite clearance. This review highlights recent ad Show more
The cardiac lymphatic system plays a crucial role in maintaining myocardial homeostasis by regulating fluid equilibrium, immune surveillance, and metabolite clearance. This review highlights recent advances in understanding its development, molecular regulation, dual roles in pathophysiology, and translational potential. Cardiac lymphatic endothelial cells (LECs) develop from diverse progenitors, including venous endothelium and Isl1⁺ precursors from the second heart field (SHF) under sex-specific molecular guidance. Functionally, the Vascular endothelial growth factor C (VEGFC)/Vascular endothelial growth factor receptor 3 (VEGFR3) signaling is paramount, modulated contextually by factors like adrenomedullin and branched-chain ketoacid dehydrogenase kinase (BCKDK). Lymphatic dysfunction impacts cardiovascular disease paradoxically. While protective in the acute phase of myocardial infarction by limiting inflammatory edema, it becomes detrimental in chronic hypertension and calcific aortic valve disease (CAVD). Single-cell transcriptomics (scRNA-seq) resolve this contradiction by revealing distinct functional LEC subpopulations: Transforming growth factor-beta 1 (TGF-β1)⁺/Interleukin 10 (IL-10)⁺ LECs promote post-infarction repair, while Reelin⁺/C-C motif chemokine ligand 21 (CCL21)⁺ LECs promote osteogenesis and valve calcification in CAVD. Emerging strategies focus on cardiac-targeted nanotherapeutics, epigenetic and metabolic LEC modulation, and sex-specific dosing. Critical unresolved questions involve autonomic nerve-lymphatic integration and lineage-specific epigenetic memory. Advancing precision lymphatic imaging, genotype-informed clinical trials, and spatiotemporal control of LEC phenotypes is critical for therapeutic translation. Deeper understanding promises novel treatments for heart failure, inflammatory cardiomyopathies, and fibrosis. Show less
Diabetic foot ulcer (DFU), a severe complication of diabetes, impose substantial global health burdens. Dampness-heat syndrome (DHS), a common syndrome in traditional Chinese medicine (TCM), is highly Show more
Diabetic foot ulcer (DFU), a severe complication of diabetes, impose substantial global health burdens. Dampness-heat syndrome (DHS), a common syndrome in traditional Chinese medicine (TCM), is highly prevalent among DFU patients and closely correlated with treatment response and prognosis. However, the molecular biomarkers associated with DFU in patients with DHS remain poorly understood. Serum 4D-data-independent acquisition (DIA) proteomics was performed on 16 DFU-DHS patients and six healthy controls (HCs). Differentially expressed proteins (DEPs) were screened by |fold change (FC)| > 1.2 and p < 0.05. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analyses were conducted. Key biomarkers were validated via enzyme-linked immunosorbent assay (ELISA) in 28 independent DFU-DHS cases. A total of 201 DEPs were identified between DFU-DHS patients and HCs. Bioinformatics revealed DEPs enriched in lipid metabolism (high-density lipoprotein [HDL] remodeling and cholesterol metabolism) and complement-coagulation cascades. PPI network analysis revealed a core functional module centered on four proteins, APOA1, LCAT, PLTP, and CETP. ELISA validation confirmed the significant dysregulation of these four apolipoproteins in the independent DFU-DHS cohort (all p < 0.05 vs. HCs). The combination of the biomarkers APOA1, LCAT, PLTP, and CETP exhibited a high diagnostic efficacy for DFU-DHS, with an area under the curve (AUC) of 0.9672 based on receiver operating characteristic (ROC) analysis. To our knowledge, this is the first study to employ 4D-DIA proteomics on DFU-DHS. We identified four serum biomarkers (APOA1, LCAT, PLTP, and CETP) linked to dysregulated cholesterol metabolism in DFU-DHS patients, which show diagnostic potential and provide insights for integrating TCM syndrome differentiation with precision medicine. Show less
Colorectal cancer (CRC) liver metastases remain refractory to immunotherapy due to a profoundly immunosuppressive tumor microenvironment. Here, we conducted a prospective clinical study enrolling 18 p Show more
Colorectal cancer (CRC) liver metastases remain refractory to immunotherapy due to a profoundly immunosuppressive tumor microenvironment. Here, we conducted a prospective clinical study enrolling 18 patients with microsatellite-stable CRC liver metastases treated with high-dose radiotherapy (RT) followed by anti–PD-1 immune checkpoint inhibitors (RT–ICI). Integrative analysis of single-cell RNA-sequencing, spatial transcriptomics, and peripheral immune profiling revealed that RT–ICI therapy reprograms both tumor-intrinsic and immune compartments. RT triggered the emergence of an APOA2⁺ tumor cell state characterized by enhanced lipid metabolic activity and transient elevation of circulating HDL. This metabolic reprogramming, in turn, promoted systemic activation of CETP⁺ M2-like macrophages, a population marked by high LXR/RXR transcriptional activity and enriched expression of immunosuppressive and lipid-processing genes. Despite their expansion, CETP⁺ macrophages localized preferentially to non-irradiated tumor regions, suggesting a distal immunometabolic effect driven by HDL-mediated signaling. Concurrently, combination therapy expanded GZMB⁺ effector T cells and induced a novel population of inflammatory–toxic T cells (IT_T), which exhibited high cytotoxicity and spatial co-localization with CXCL10⁺ macrophages. Ligand–receptor analysis and pseudotime modeling revealed that irradiated tumor cells acted as “in situ vaccines” by enhancing MHC–TCR interactions and promoting T cell differentiation along non-exhausted cytotoxic lineages. Together, these findings reveal a dual mechanism by which RT–ICI therapy enhances local anti-tumor immunity while modulating systemic lipid metabolism and macrophage polarization, offering insights for combinatorial immunotherapy design in immunologically “cold” tumors. The online version contains supplementary material available at 10.1186/s12964-026-02689-3. Show less
Neurodegenerative diseases, which pose significant challenges for effective treatment, often involve risk variants of lysosomal gene products that disrupt lysosomal function, leading to the accumulati Show more
Neurodegenerative diseases, which pose significant challenges for effective treatment, often involve risk variants of lysosomal gene products that disrupt lysosomal function, leading to the accumulation of indigestible materials and damage to brain cells. The lysosome is a degradative organelle and a signaling hub that senses nutrient availability. How lysosomal dysfunction contributes to neurodegenerative diseases is an important open question. In this study, we identified CLN3 (ceroid lipofuscinosis, neuronal 3), an endolysosomal protein that is linked to Batten disease, as an evolutionarily conserved protein that facilitates lysosomal chloride efflux. Additionally, we report that a natural compound with anti-inflammatory properties-the curcumin analog C1, which is a TFEB (transcription factor EB) activator-could enhance CLN3 activity and improve lysosomal function. These findings provide new insight into the role of CLN3 in lysosomal ion homeostasis and raise the possibility that modulation of the TFEB-CLN3 signaling axis may hold therapeutic potential for lysosomal storage disorders. Show less
Nitrogen metabolism plays a key role in maintaining normal physiological functions of the organism and cell proliferation and differentiation. Nitrogen metabolism in normal human body maintains a dyna Show more
Nitrogen metabolism plays a key role in maintaining normal physiological functions of the organism and cell proliferation and differentiation. Nitrogen metabolism in normal human body maintains a dynamic balance to meet the body's demand for synthesis of biological macromolecules such as proteins and nucleic acids. However, in the process of tumor development, the nitrogen metabolism of tumor cells is reprogrammed to meet the demand of rapid proliferation, showing significantly different metabolic characteristics from normal cells. Key enzymes in the tumor microenvironment affect nitrogen metabolism through multiple mechanisms, providing essential nitrogen sources and energy for tumor cells. In-depth exploration of the regulatory mechanisms of tumor nitrogen metabolism not only helps to reveal the molecular basis of tumor development, but also provides a theoretical basis for the development of new tumor therapeutic strategies. In this paper, the relationship between nitrogen metabolism and tumors is systematically elaborated from the characteristics of nitrogen metabolism in normal people, the reprogramming of nitrogen metabolism in tumor patients, the influence of key enzymes on nitrogen metabolism in the tumor microenvironment, as well as the mechanism of tumor nitrogen metabolism regulation, etc., so as to provide references for the related research. Show less