Search Results (301)

3-Nitropropionic acid (3-NPA) is an irreversible inhibitor of succinate dehydrogenase (SDH; mitochondrial complex II) that is widely used to model mitochondrial metabolic stress. Direct reproductive studies now show that 3-NPA can increase ovarian oxidative stress, granulosa-cell apoptosis, follicular atresia, alter ovarian reserve, impair oocyte maturation, and reduce fertility in experimental models. However, no ovarian study has yet demonstrated the complete succinate–HIF-1α–NLRP3 cascade proposed here. We therefore propose a testable framework in which SDH inhibition causes succinate accumulation and impaired respiratory electron flux, while redox stress provides an additional signal for HIF-1α stabilization and NLRP3 activation. Succinate-mediated inhibition of prolyl hydroxylases provides a mechanistic route to HIF-1α stabilization under normoxic or near-normoxic conditions, whereas NLRP3 activation may integrate mitochondrial danger signals with inflammatory signaling. Importantly, HIF-1α is not intrinsically pathogenic in the ovary: physiological HIF-1α signaling supports angiogenesis, ovulation, granulosa-cell survival, autophagy, and luteal remodeling, whereas persistent or excessive activation may become maladaptive. We further refine the proposed metabolic–inflammatory threshold as a measurable state in which combined succinate/redox burden and inflammasome activation exceed the adaptive capacity of a follicular unit. The model predicts that time-resolved measurements of succinate, SDH activity, HIF-1α stabilization, NLRP3 activation, and follicular outcomes should reveal ordered relationships that can be tested by pharmacological and genetic intervention. This review distinguishes direct ovarian evidence from cross-system mechanistic evidence and identifies the experiments required to establish causality. Full article

Articular cartilage exists under hypoxic conditions, where hypoxia-inducible factor (HIF)-1α plays a critical role in maintaining its homeostasis. In osteoarthritis (OA), however, this hypoxic environment is disrupted, and decreased HIF-1α expression contributes to disease progression. HIF-prolyl hydroxylase (HIF-PH) inhibitors stabilize HIF-1α and are clinically used to treat renal anemia; therefore, they may also exert therapeutic effects in OA through the same mechanism. However, their effects on articular cartilage remain unclear. In this study, we investigated the effects of Roxadustat, a HIF-PH inhibitor, both in vitro using rat chondrocytes and in vivo using a monosodium iodoacetate (MIA)-induced rat OA model. Roxadustat showed no cytotoxicity and significantly increased the protein expression of HIF-1α, SRY-box transcription factor 9 (SOX9), and Aggrecan in monolayer cultures. In three-dimensional spheroid cultures, Roxadustat enhanced Safranin O staining and extracellular matrix production and significantly upregulated SOX9 and ACAN mRNA expression. Furthermore, intra-articular administration of Roxadustat in the MIA-induced OA model suppressed cartilage degeneration and significantly reduced the Modified Mankin score. These findings demonstrate that Roxadustat promotes anabolic responses in chondrocytes through stabilization of HIF-1α and suppresses cartilage degeneration in OA. Intra-articular administration of HIF-PH inhibitors may represent a novel disease-modifying therapeutic strategy for OA. Full article

Bacterial wilt, caused by the bacterium Ralstonia solanacearum, is a devastating disease that limits peanut production. The molecular mechanisms that distinguish between resistant and susceptible responses are being continuously explored; however, there is limited data with regard to the interaction between lipid metabolism and transcriptional reprogramming. Here we performed integrated sphingolipidomics and transcriptomics on the roots of the resistant peanut variety Zhonghua 6 (ZH6) and the susceptible variety Zhonghua 12 (ZH12) at pre-disease, early-onset, and late stages of infection. The resistant ZH6 variety exhibited the early accumulation of specific glucosylceramides (GluCer t18:1/h25:0 and GluCer t18:0/h23:0) and inositol phosphoceramide (IPC t18:0/h24:0). Metabolic stabilization occurred, with no significant lipid changes observed between the early and late stages. This response was supported by transcriptional activation of fatty acid α-hydroxylase (0538LJ), neutral/alkaline ceramidases (IX12GR, KZ47MP.1), and ABA signaling components (ABA receptor, SRK2A-like). In contrast, susceptible ZH12 displayed progressive sphingosine depletion and delayed accumulation of VLCFA-ceramide d18:0/16:0 and sterols. KCS4 was upregulated in ZH12, providing a transcriptional basis for VLCFA-ceramide accumulation. Hormone signaling divergence was evident: ZH6 exhibited early ABA signaling, followed by transcriptional stasis, whereas ZH12 displayed delayed ACS4/ACS11 hyper-induction after pathological ceramide accumulation. This was accompanied by auxin depletion (GH3.9 upregulation), failure of the cytokinin phosphorelay (HPt6 suppression), and decoupling of SA signaling (PR-1 induction without TGA activation). Resistance is therefore defined by early, coordinated sphingolipid remodeling and ABA signaling leading to homeostatic stabilization. In contrast, susceptibility represents delayed ceramide accumulation and multi-hormone signaling suppression. This multi-omics framework provides detailed lipidomic and transcriptomic signatures to identify candidate genes and lipid biomarkers for marker-assisted breeding of bacterial wilt-resistant peanut varieties. Full article

Neurons of the arcuate nucleus (AN) produce dopamine, which inhibits prolactin secretion. Tyrosine hydroxylase (TH), the key enzyme of dopamine synthesis, is expressed in AN in dopaminergic neurons and in neurons expressing only TH or both enzymes but lacking the dopamine transporter. These neurons are distributed differently between the ventrolateral and dorsomedial regions of the AN (further—ventrolateral or dorsomedial AN). We hypothesized that noradrenaline released by noradrenergic afferents inhibits TH synthesis in AN neurons postnatally. To test this hypothesis, we assessed: (i) adrenoreceptors gene expression in the ventrolateral and dorsomedial AN of intact rats at postnatal days (P) 5 and 60 and (ii) TH levels in sections of each AN region from rats at P5 and P60 after 6 h incubation in the absence or presence of noradrenaline, as well as noradrenaline with adrenoreceptor antagonists. It was shown that (i) AN neurons express genes for all types of adrenoreceptors in each region of AN on P5 and P60; (ii) neurons in both regions of AN synthesize TH, but to a greater extent at P60 than at P5; and (iii) noradrenaline inhibits TH synthesis, but only in the ventrolateral AN at P60—this action is mediated via α1-adrenoreceptors. Full article

Hyperlipidemia (HL) is a major metabolic disorder and a critical risk factor for cardiovascular diseases, closely associated with oxidative stress, inflammation, and disrupted cholesterol homeostasis. Freeze-dried Poecilobdella manillensis powder (FDPMP), a traditional medicinal product, has shown therapeutic potential against hyperlipidemia; however, its underlying mechanisms remain largely unclear. In this study, HL was induced in ApoE^−/− mice by feeding a high-fat diet (HFD) for eight weeks, during which FDPMP or simvastatin (positive control) was orally administered daily. Concurrently, an in vitro foam cell model was established by exposing RAW264.7 macrophages to oxidized low-density lipoprotein (ox-LDL, 80 μg/mL) for 24 h, with FDPMP pretreatment applied 30 min prior to ox-LDL stimulation. Following intervention, serum lipid profiles, hepatic oxidative stress markers, histopathological changes, and cholesterol metabolism-related gene and protein expression were systematically evaluated. FDPMP administration significantly improved serum lipid profiles by reducing triglycerides, total cholesterol, and low-density lipoprotein cholesterol, while increasing high-density lipoprotein cholesterol levels. Additionally, FDPMP alleviated histopathological damage in the liver, kidney, and heart, enhanced antioxidant enzyme activities, and attenuated oxidative stress. Untargeted metabolomic analysis revealed that FDPMP markedly modulated key metabolic pathways, including choline metabolism, glycerophospholipid metabolism, and arachidonic acid metabolism. Mechanistically, FDPMP restored cholesterol homeostasis through dual regulation of cholesterol metabolism, characterized by upregulation of cholesterol 7α-hydroxylase (CYP7A1) to promote bile acid-mediated cholesterol excretion, alongside downregulation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and synthase (HMGCS1) to inhibit cholesterol biosynthesis. In vitro, FDPMP effectively suppressed ox-LDL-induced foam cell formation, reduced intracellular lipid accumulation, and mitigated oxidative stress in macrophages. Collectively, these findings demonstrate that FDPMP ameliorates hyperlipidemia through coordinated regulation of cholesterol synthesis and excretion, coupled with systemic metabolic reprogramming and antioxidative effects. This study provides mechanistic insights supporting FDPMP as a promising natural therapeutic candidate for hyperlipidemia and related metabolic disorders. Full article

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra. Oxidative stress, neuroinflammation, and α-synuclein aggregation are central pathological features of PD. Zanthoxylum piperitum DC, commonly known as Korean pepper or chopi, is a traditional dietary spice in Eastern Asia and has been reported to possess antioxidant and anti-inflammatory properties. This study investigated the neuroprotective and motor function–enhancing effects of distilled extract of Z. piperitum (deZP) in 1-Methyl-4-phenylpyridinium (MPP⁺)-treated Caenorhabditis elegans and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse models of PD. Methods: In the C. elegans model, dopaminergic neurotoxicity was induced by MPP⁺, and deZP was tested at 0.25, 0.5, and 1% (v/v) to evaluate neuronal preservation through GFP-labeled dopaminergic neurons and α-synuclein expression. Concurrently, in the MPTP-induced mouse model, deZP was administered intranasally at a fixed dose of 20 μL/mouse, equivalent to 5 mg/mouse. Motor function was assessed using the rota-rod test, pole test, and grip strength test, while dopaminergic neuronal survival was evaluated by tyrosine hydroxylase (TH) immunostaining. Results: In MPP⁺-treated C. elegans, deZP significantly restored green fluorescent protein (GFP) fluorescence in dopaminergic neurons and reduced α-synuclein expression, with the most pronounced effects observed at 1% (v/v). In the MPTP-induced mouse model, deZP at this fixed intranasal dose significantly improved motor performance and preserved TH-positive neurons in the substantia nigra. Conclusions: These findings suggest that deZP may represent a promising preclinical candidate for further investigation in PD-related neurodegeneration. Full article

Cerebellar climbing fiber–Purkinje cell (CF–PC) long-term depression (LTD) plays a critical role in motor learning and is modulated by locus coeruleus (LC) noradrenergic afferents via distinct adrenergic receptor (AR) subtypes. Nevertheless, the mechanisms underlying LC noradrenergic neuron-mediated regulation of CF–PC LTD remain poorly understood. Here, we investigated the effects of chemogenetic activation of LC noradrenergic afferents on CF–PC LTD in cerebellar slices from dopamine β-hydroxylase (DBH)-Cre mice using electrophysiology, glutamate sensor imaging, immunofluorescence and pharmacological approaches. Tetanic stimulation (5 Hz) of CFs induced CF–PC LTD under control conditions, and this LTD was enhanced by chemogenetic activation of LC noradrenergic afferents. Blockade of group I metabotropic glutamate receptors (mGluR1) abolished LTD under control conditions, whereas chemogenetic activation of LC noradrenergic afferents triggered a novel form of CF–PC LTD accompanied by an increased N2/N1 ratio. With mGluR1 blocked, chemogenetic activation of LC noradrenergic afferents failed to trigger the novel CF–PC LTD following blockade of α₂-AR or α₂A-AR, but not α₂B-AR or α₂C-AR. Importantly, chemogenetic activation of LC noradrenergic afferents triggered LTD of glutamate fluorescence at CF terminals, which was abolished by blockade of α_2-AR or α₂A-AR, but not α₂B-AR or α₂C-AR. Notably, inhibition of either cyclin-dependent kinase 5 (CDK5) or presynaptic, but not postsynaptic, protein kinase A (PKA) completely abolished the CF–PC LTD triggered by chemogenetic activation of LC noradrenergic afferents in mouse cerebellar slices. Immunofluorescence results showed robust α₂A-AR expression throughout the cerebellar molecular layer, with intense signals along PC dendrites and clear colocalization with vesicular glutamate transporter 2 (vGluT2) at cerebellar CF terminals. These results indicate that activation of LC noradrenergic afferents potentiates CF–PC LTD by triggering Glu-LTD at CF terminals through the α₂A-AR/CDK5/PKA signaling cascade in the mouse cerebellar cortex. Full article

Chronic ultraviolet B (UVB) radiation drives cutaneous photoaging—clinically manifesting as erythema, edema, scaling, deep wrinkling, loss of elasticity, and barrier disruption—through mitochondrial reactive oxygen species (mtROS) overproduction and quality-control failure. Here we identify α-ketoglutarate (AKG; also known as 2-oxoglutarate), a TCA-cycle intermediate and essential co-substrate for α-ketoglutarate-dependent dioxygenases (α-KGDDs), as a metabolic corrector of mitochondrial redox homeostasis in UVB-induced photoaging. In a 10-week chronic UVB SKH1 hairless mouse model, microneedle-assisted transdermal delivery of AKG dose-dependently attenuated macroscopic erythema, scaling, and erosive lesions, restored skin barrier function and dermal elasticity, preserved epidermal–dermal architecture, and protected collagen and elastic fiber integrity, with efficacy comparable to all-trans retinoic acid. Mechanistically, AKG reactivated α-KGDD/prolyl hydroxylase (PHD) catalytic function and promoted proteasomal clearance of aberrantly stabilized HIF-1α under normoxia; this was accompanied by restored AMPK Thr172 phosphorylation downstream of constitutive LKB1 and recovery of PGC-1α-driven mitochondrial biogenesis. AKG preferentially attenuated mitochondrial superoxide over total cellular ROS through a co-substrate-mediated mechanism distinct from direct radical scavenging, and its protective effects were largely abrogated by DMOG (an α-KGDD inhibitor) or compound C (an AMPK inhibitor). These findings position AKG, delivered via microneedle-assisted topical application, as a candidate metabolite-based intervention targeting the α-KGDD/HIF-1α/AMPK axis for photoaging. Full article

Background/Objectives. Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder characterized by dopaminergic neuron loss, α-synuclein pathology, neuroinflammation, and cognitive decline. Synaptamide (N-Docosahexaenoylethanolamine (DHEA)) is an endogenous lipid mediator with documented anti-inflammatory and neurogenic properties, but its effects in PD models remain unexplored. This study aimed to evaluate the neuroprotective potential of synaptamide in a subchronic MPTP-induced mouse model of PD. Methods. Male C57BL/6 mice received MPTP (30 mg/kg/day, i.p., 5 days) with or without synaptamide (10 mg/kg/day, s.c., 13 days). Behavioral tests (open field, Y-maze, elevated plus maze, novel object recognition (NOR)) were performed, followed by immunohistochemical analysis of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra, and Western blotting for α-synuclein, p-α-synuclein, TH, and IL1β in brain homogenates and serum. In vitro Neuro-2a cells were co-treated with MPP⁺ (100 µM) and synaptamide (0.1–10 µM) for cytotoxicity assessment (MTS assay). Results. Synaptamide (10 µM) significantly attenuated MPP⁺-induced cytotoxicity in Neuro-2a cells. In vivo, MPTP caused a marked loss of TH⁺-neurons in the substantia nigra, which was prevented by synaptamide treatment. Importantly, this subchronic MPTP model recapitulates early biochemical alterations (e.g., α-synuclein phosphorylation at Ser129) rather than mature Lewy body pathology, a limitation that should be considered when interpreting these findings. Although no motor deficits or anxiety-like behavior were observed, the NOR test revealed MPTP-induced long-term memory impairment, which was fully restored by synaptamide. Conclusions. These findings suggest that synaptamide may exert effects on pathological processes associated with PD, warranting further investigation into its potential role in combination or supportive therapy for this disease. Full article

Carnitine plays an essential role in fatty acid metabolism, and its biosynthesis is tightly regulated by γ-butyrobetaine hydroxylase (BBOX), an Fe(II)/α-ketoglutarate-dependent dioxygenase. BBOX is the target of mildronate (THP), a clinically used drug for treating ischemic heart diseases. However, the detailed mechanisms of BBOX-catalyzed hydroxylation and the atypical oxidative rearrangement underlying THP inhibition remain elusive. In this study, we employed combined quantum mechanics/molecular mechanics (QM/MM) methods to systematically elucidate these mechanisms at the atomic level. Our calculations reveal that the hydroxylation of γBB proceeds via a classical three-step mechanism in the quintet state, with hydrogen atom abstraction as the rate-determining step. Remarkably, substitution of the C4 methylene group in γBB with an amino group in THP redirects the reaction pathway, as the lone pair electrons on the adjacent nitrogen atom render N-N bond cleavage kinetically favored over hydroxyl rebound, thereby blocking carnitine synthesis. Through systematic evaluation of possible rearrangement pathways, we rule out the previously proposed direct 1,2-H migration and suggest a revised mechanism featuring imine-mediated hydrogen transfer, hydroxyl rebound preceding C-C bond formation, and final radical coupling. This work provides a detailed atomic-level understanding of both the catalytic and inhibitory mechanisms of BBOX, revealing how substrate electronic effects dictate reaction outcomes. The elucidated mechanistic insights offer a theoretical foundation for understanding the catalytic versatility of the αKG-dependent dioxygenase family and provide valuable guidance for the rational design of novel BBOX inhibitors. Full article

Background and Objectives: Vitamin D signaling plays critical roles in immune regulation, bone metabolism, and cellular differentiation across multiple tissues. However, the spatial and temporal expression patterns of key vitamin D signaling components—the vitamin D receptor (VDR) and the enzyme 1α-hydroxylase (encoded by CYP27B1)—during human nephrogenesis have not been mapped at the protein level. The primary objective of this study was to characterize VDR and 1α-hydroxylase expression across critical stages of human kidney development, complementing prior transcriptomic and single-cell descriptions, and to contextualize these developmental observations against the dysregulation of vitamin D pathway genes in adult renal and urothelial malignancies. Materials and Methods: Immunofluorescence analysis was performed on FFPE kidney tissue from 12 specimens (3 per stage) at 10, 22 and 38 gestational weeks and postnatally at 1.5 years. For each specimen, at least three non-adjacent sections were stained and 6 non-overlapping cortical fields were imaged at ×40 (18 fields per stage). Fluorescence-area percentages were quantified in ImageJ 1.54g, and group differences were assessed by one-way ANOVA with Tukey’s post hoc test at both field- and specimen-level. An accompanying bioinformatic analysis evaluated the differential expression of VDR, CYP27B1, and CYP24A1 in adult renal and urothelial malignancies (TCGA cohorts: KICH, KIRC, KIRP, BLCA) using unpaired Welch’s t-test, with Benjamini–Hochberg FDR correction applied across all 16 tumor-versus-normal comparisons (12 gene-wise + 4 post hoc log₂(CYP24A1/CYP27B1) ratios). Results: VDR showed its highest mean fluorescence area at 10 weeks (3.40% (95% CI 3.24–3.56); field-level Tukey p < 0.0001 versus other stages) and its lowest at 22 weeks (0.69% (0.64–0.74)). 1α-hydroxylase was also highest at 10 weeks (5.44% (5.29–5.60); p < 0.0001) and stabilized at lower levels thereafter (3.04–4.26%). Co-expression of both proteins was observed throughout development except in 22-week glomeruli. In TCGA, all 12 significant gene-wise comparisons retained significance after BH FDR correction (q < 0.05). VDR showed cohort-specific dysregulation: reduced in KICH (q = 2 × 10⁻⁴) but increased in KIRC and KIRP (q = 2 × 10⁻⁴ for both). CYP24A1 was reduced in all three renal cohorts (q ≤ 0.029) and unchanged in BLCA. CYP27B1 showed cohort-specific direction (reduced in KIRC; increased in KICH, KIRP, and BLCA). Conclusions: This study provides an initial immunofluorescence-based spatial description of VDR and 1α-hydroxylase across human kidney development, revealing a coordinated redistribution from immature glomeruli at 10 weeks to mature tubular segments at later stages. The TCGA analysis demonstrates that vitamin D pathway dysregulation in renal carcinoma is cohort-specific and is not abolished by multiple-testing correction. Together, these results indicate that the developmentally engaged vitamin D pathway retains kidney-specific functional relevance in adult renal pathology and provide a baseline reference for future mechanistic studies. Full article

Environmental exposure to neurotoxicants during critical developmental windows may program long-term susceptibility to neurodegenerative diseases such as Parkinson’s disease. Here, we investigated whether rotenone exposure during neurodevelopment induces a more severe Parkinsonian phenotype during aging than adult-onset exposure. Wistar rats were exposed to rotenone (1 mg/kg/day) either during gestation and lactation or from postnatal day 60 to 102. Motor performance was assessed longitudinally, and neurobiological analyses were conducted at 12 months of age. Developmental rotenone exposure induced persistent and severe motor deficits from early adulthood, whereas adult exposure resulted in a progressive phenotype. These alterations were accompanied by greater loss of tyrosine hydroxylase-positive dopaminergic neurons and a marked reduction in Nurr1 expression in the substantia nigra. Developmental exposure also increased cellular senescence, dendritic atrophy and spine loss in striatal medium spiny neurons, insoluble α-synuclein accumulation, and global DNA hypomethylation. Despite low residual serum rotenone levels, neurodegenerative alterations persisted, supporting a hit-and-run mechanism. These findings suggest that early-life rotenone exposure induces long-lasting epigenetic and cellular reprogramming that enhances nigrostriatal vulnerability and accelerates Parkinsonian neurodegeneration during aging. Full article

To explore the molecular basis of hypoxia tolerance variation within euteleosts, we compared the hypoxia-inducible factor (HIF) pathways of the highly tolerant Nile tilapia (Oreochromis niloticus) and the hypoxia-sensitive rainbow trout (Oncorhynchus mykiss). Evolutionary analysis revealed that Nile tilapia possesses single copies of Hif-1α and prolyl hydroxylase domain protein 2 (Phd2), whereas rainbow trout retains two and three copies, respectively. The Leu-X-X-Leu-Ala-Pro (LXXLAP) motifs in the oxygen-dependent degradation (ODD) domain of Hif-1α and the interacting loop region of Phd2 are highly conserved, indicating a conserved core mechanism for regulating Hif-1α stability. However, differences in charged residue composition flanking the Phd2 loop (e.g., fewer positively charged residues in Nile tilapia) were identified. Molecular dynamics simulations revealed that the complex formed by Nile tilapia Phd2 and the Hif-1α LXXLAP motif was unstable across physiological temperatures, suggesting potential impairment of the catalytic geometry compatible with hydroxylation and elevated normoxic Hif-1α stability. In contrast, the corresponding complexes in rainbow trout were more stable, particularly at low temperatures. Expression profiling revealed that Nile tilapia tissues, including the heart, maintain higher basal expression of glycolytic genes, may help support energy production during hypoxia. Our findings indicate that a weakened protein interaction and high constitutive expression is predicted to enhance HIF pathway responsiveness, potentially priming vital tissues for glycolytic energy production and may contribute to this species’ hypoxia tolerance. Full article

Type II diabetes mellitus (T2DM), a chronic metabolic disorder characterized by insulin resistance, is often accompanied by dysregulated bile acid metabolism. Although gastrodin, a bioactive compound derived from Gastrodia elata, has demonstrated potential in diabetes management, its therapeutic mechanisms remain incompletely understood. The aim of this study is to investigate the therapeutic effects and potential mechanisms of gastrodin on T2DM mice from the perspective of bile acid metabolism. In this study, we found that gastrodin could not only reduce lipid accumulation, reduce inflammation, improve antioxidant capacity, alleviate oxidative stress, change the composition of intestinal flora, and improve the disorder of flora caused by the disease in T2DM mice, but also target Yin yang 1 (YY1) to reduce the expression level of YY1 in the liver under a high-fat diet condition. At the same time, YY1 negatively regulates the expression level of Farnesoid X Receptor (FXR), which increases the expression level of FXR, inhibits the enzyme activity of Cholesterol-7α-hydroxylase (CYP7A1) through Small Heterodimer Partner (SHP), reduces the production of chenodeoxycholic acid (CDCA) in the liver, and further affects the production of secondary bile acids through liver–intestinal circulation, promoting the secretion of Glucagon-Like Peptide-1 (GLP-1) and insulin, thereby reducing blood glucose. At the same time, combined with the results of HE staining, gastrodin can reduce the pathological damage of the liver and pancreas in type II diabetic mice, repairing their normal morphology and function. It provides a direct pathological basis for the improvement of diabetes and liver complications, provides theoretical support for the subsequent research and development of precision targeted drugs, provides experimental basis for the development of new natural hypoglycemic drugs, and promotes the transformation and application of the modernization of traditional Chinese medicine in the field of metabolic diseases. Full article

This study aimed to identify candidate molecular pathways mediating dopaminergic dysfunction induced by PFAS mixture exposure, with a focus on the TM/5-HT signaling axis and calcium-linked lipid metabolites, and to explore potential gut-brain axis involvement. Adult mice were exposed to a PFAS mixture. Behavioral tests assessed spatial memory, spontaneous activity, and motor coordination. Histopathological and ultrastructural analyses examined neuronal atrophy, mitochondrial damage, α-synuclein (α-syn), and tyrosine hydroxylase (TH). Transcriptomics, metabolomics, and gut microbiota profiling (16S rRNA sequencing) were performed, followed by integrated multi-omics and correlation analyses. PFAS exposure was associated with PD-relevant motor and cognitive impairments, including impaired spatial memory, reduced spontaneous activity, and motor coordination deficits. Neuronal atrophy, mitochondrial structural damage, upregulation of α-syn, and downregulation of TH were observed. Transcriptomics identified 315 differentially expressed genes (DEGs) enriched in ciliary movement, neuroactive ligand-receptor interactions, and serotonergic synapses. Metabolomics identified 130 differentially abundant metabolites involved in arachidonic acid metabolism and serotonergic synapses. Integrated analysis highlighted correlative changes in the TM/5-HT signaling pathway. Phosphatidylinositol PI(16:0/20:2(11Z,14Z)) showed a strong positive correlation with Dbh gene expression, suggesting a candidate association between Dbh expression and phosphatidylinositol alterations. Gut microbiota analysis revealed compositional alterations (e.g., Muribaculaceae, Ileibacterium) and predicted functional shifts (e.g., tryptophan metabolism–related modules) were observed; these findings are exploratory. This study identifies multi-omics signatures associated with PFAS mixture-induced dopaminergic dysfunction in mice. The TM/5-HT pathway emerges as a candidate molecular axis requiring further investigation. Gut microbiota alterations suggest a potential peripheral component, but causality and gut-brain axis involvement remain hypothetical and need direct experimental validation. Full article