Search Results (361)

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

Attention deficit hyperactivity disorder (ADHD), a prevalent neurodevelopmental disorder characterized by inattention, impulsivity, and hyperactivity, is associated with monoaminergic dysfunction, neuronal damage, and gut microbiota disorders. Low molecular weight fucoidan (LMWF) is a sulfated polysaccharide extracted from Saccharina japonica (Phaeophyta), processes antioxidant, anti-inflammatory, and neuroprotective properties, suggesting its potential relevance for ADHD-related pathophysiology. This study investigated the therapeutic effects of LMWF on ADHD-like symptoms in spontaneously hypertensive rats (SHR). Behavioral tests revealed that LMWF reduced hyperactivity and anxiety-related behavior in the open field test, and improved spatial memory in the Morris water maze test. LMWF treatment significantly increased dopamine (DA), norepinephrine (NE), and 5-hydroxyindoleacetic acid (5-HIAA) levels in the prefrontal cortex (PFC). The transcript levels of tyrosine hydroxylase (Th) and synaptosome-associated protein-25 (Snap25) were upregulated, while dopamine transport (Dat) was downregulated in the PFC. TH protein expression was elevated in the striatum (STR), and neuronal integrity was preserved in the STR and cerebellum. LMWF also reshaped gut microbiota composition and enhanced microbial diversity, contributing to improved gut-brain axis homeostasis. These findings suggest that LMWF may serve as a promising dietary intervention for ADHD through neurochemical restoration and microbiota modulation. Full article

Background/Objectives: Biological factors such as genetics contribute to nutrition-related outcomes, but nutritional epidemiological studies often lack consideration of genetics despite evidence of their functional impacts on health and cognition. Phenylalanine hydroxylase (PAH) genetic variation has been hypothesized to influence health and cognitive outcomes due to evidence of metabolic perturbations in L-phenylalanine to L-tyrosine hydroxylation, including plausible downstream effects on catecholamine neurotransmitters among not only individuals with phenylketonuria (PKU) [homozygotes for PAH mutations] but also PKU carriers [heterozygotes]. Related to these metabolic perturbations, diminished executive functioning has been observed in individuals with PKU, even when treated, but research is lacking exploring this outcome in PKU carriers. The present study aims to detail methods for stratifying populations based on genetic variation, for use in epidemiological precision nutrition research. It further provides an exploratory exemplar of such research through population stratification by PAH genetic variation (i.e., PKU carriers vs. non-carriers), while providing the first descriptive data on executive functioning skills using the validated Executive Skills Questionnaire—Revised (ESQ-R) tool with PAH-genetically stratified groups (PKU carriers and non-carriers). Methods: Participants were ≥18 years of age and PAH heterozygotes (PKU carriers) or non-carriers. Levels of executive functioning were self-reported anonymously online and included the validated Executive Skills Questionnaire—Revised (ESQ-R) tool. Data were analyzed using t-tests, chi-square tests, ANOVAs, and ANCOVAs. Results: Respondents (n = 99, n = 79 carriers and n = 20 non-carriers) consisted of males (22.2%) and females (77.8%), primarily of European ancestry. There were no significant differences between groups (carriers vs. non-carriers) for total scores (mean ± SD ESQ-R score carriers = 17.41 ± 14.01; non-carriers = 14.95 ± 10.00), but carriers scored significantly worse than non-carriers for the ESQ-R item “I have trouble making a plan” in the adjusted model. Conclusions: This study provides a methodological exemplar for exploring genetically stratified subpopulations in epidemiological precision nutrition research. Full article

Background/Objectives: Phenylketonuria (PKU) is a rare autosomal recessive disorder caused by phenylalanine hydroxylase (PAH) deficiency, impairing the conversion of phenylalanine (Phe) to tyrosine. Although early diagnosis and intervention yield excellent outcomes, dietary adherence often declines in adulthood, potentially leading to poor metabolic control and adverse nutritional consequences. This study aimed to evaluate physical activity levels, nutritional status, metabolic control, and anthropometric outcomes in adults with classic PKU, which have not been sufficiently researched in the current literature. Methods: This cross-sectional study included 100 adults with classical PKU (cPKU; baseline phenylalanine levels ≥ 1200 µmol/L) under regular follow-up at the Division of Metabolism, Hacettepe İhsan Doğramacı Childrens’ Hospital. Sociodemographic traits and dietary behaviors were evaluated through structured interviews carried out by a dietitian. Dietary intake was assessed by using a 24 h dietary recall method, and nutrient analyses were performed with the Bebis 7.2 software program. Using the short version of the International Physical Activity Questionnaire (IPAQ), physical activity levels were specified, and participants were categorized according to established scoring criteria. Results: A hundred adults with classical PKU took part in the study, including 47 males and 53 females, with a mean age of 23.84 ± 5.41 years; 5% of participants were underweight, 40% had normal weight, 39% were overweight, and 16% were listed as obese. The intake of mean daily energy is 2443.8 ± 384.6 kcal for men and 1822.5 ± 312.7 kcal for women. Carbohydrates contributed approximately 61% of total daily energy intake in both genders, whereas protein accounted for 12–13% and fat for approximately 26–27% of total energy intake; 17% of participants were physically inactive, 40% were minimally active, and 43% met criteria for sufficient physical activity according to IPAQ-based classification. Energy intake, the use of Phe-free protein substitutes, and BMI were significantly higher in the sufficiently active group compared to the low-active group in men, while no significant differences were observed between physical activity groups among women. Conclusions: Adults with classical PKU showed a high prevalence of overweight and obesity, together with differences in dietary intake and physical activity patterns. Physical activity levels were associated with several nutritional and metabolic characteristics; however, further long-term research is required to fully understand these connections. 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

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

The role of endogenous salicylic acid (SA), a major signaling molecule, was addressed in relation to the waterlogging (WL) stress response, including redox homeostasis and senescence. Wild-type and salicylate hydroxylase-expressing (NahG) tobacco plants were studied to reveal the stress-related effects of the transgene, which is known to deplete the endogenous SA pool. In control conditions, SA levels of the top leaves of NahG plants were moderately lower than those of wild-type, while SA was considerably reduced in the bottom leaves. WL conditions triggered a rise in H₂O₂ concentrations in young leaves, which was exaggerated in NahG plants, pointing to a mitigating effect of SA against the stress-associated oxidative burden. The NahG transgenic leaves displayed lower protein levels than their wild-type counterparts, indicating a role of SA in protein retention. In non-stressed NahG plants, young (top) leaves showed an increased level of protein nitration. WL treatment triggered decreased protein contents in the leaves of both genotypes. This coincided with the high H₂O₂ content of old leaves exceeding that of young leaves in most cases. The expression of the senescence marker gene Cysteine protease 1 was upregulated in WL-stressed bottom leaves. According to this marker, senescence progressed faster in NahG leaves. Links between SA, protein nitration, and leaf senescence were discussed. Additionally, a stimulating effect of the NahG transgene was confirmed on adventitious roots (AR) formation, which may have helped root functions and thus probably contributed to maintaining the growth of the WL-stressed plants. Our results have implications for how endogenous SA levels influence plants in a WL stress situation. According to our findings, the depletion of SA may trigger protein loss and tyrosine nitration, but at the same time accelerates AR formation in WL-stressed tobacco. Full article

Background: The absence of disease-modifying treatments for Parkinson’s disease (PD)—a neurodegenerative condition with escalating global incidence—represents a critical unmet medical need. Traditionally utilized for both dietary consumption and medicinal preparations, the fruit derived from Rosa roxburghii Tratt demonstrates a remarkably rich profile of biologically active compounds, with flavonoids, triterpenoids, and organic acids representing the predominant classes. Experimental evidence indicates that these compounds elicit robust antioxidative, anti-inflammatory, and neuroprotective effects, making them promising candidates for neurodegenerative disease modulation. This study aimed to systematically evaluate the neuroprotective effects of Rosa roxburghii Tratt juice concentrate powder (RRJCP) across the preventive, interventional, and therapeutic stages of PD and to elucidate its underlying molecular mechanisms. Methods: Rosa roxburghii Tratt juice was subjected to rotary evaporation concentration and vacuum freeze-drying to obtain the juice concentrate powder. C57BL/6 mice were randomly assigned to three main groups (prevention, intervention, and treatment), each containing subgroups including a normal control, an MPTP model group, low-, medium-, and high-dose RRCJP groups (50, 100, and 200 mg/kg), and a positive control Madopar group, totaling 18 subgroups. A chronic MPTP-induced PD mouse model was established. Motor function was assessed via the open field test, pole test, and wire hang test. Substantia nigra neuronal morphology was examined by hematoxylin and eosin staining. The area of tyrosine hydroxylase (TH)-positive regions was measured by immunohistochemistry. The levels of oxidative stress indicators in serum were measured using biochemical kits. Network pharmacology was employed to predict core targets, and the expression of PI3K/AKT pathway and apoptosis-related proteins was determined by Western blotting. Results: Compared with the MPTP model group, RRCJP (200 mg/kg) significantly increased the total distance traveled in the open field, shortened the pole climbing time, and improved the wire hang score. It attenuated the morphological disorganization and nuclear pyknosis of substantia nigra neurons, increased the TH-positive area and TH protein expression, reduced serum MDA content, and elevated the activities of SOD and GSH-Px. Network pharmacology analysis indicated that the PI3K/AKT signaling pathway was among the core targets. Western blotting results further showed that the juice concentrate powder upregulated the expression of p-PI3K, p-AKT, and Bcl-2, while downregulating Bax and Cleaved Caspase-3 levels, which was consistent with the network pharmacology prediction. Conclusions: RRCJP exerts neuroprotective effects across the preventive, interventional, and therapeutic stages in PD model mice, the mechanisms of which may be associated with activation of the PI3K/AKT signaling pathway, attenuation of oxidative stress, and inhibition of neuronal apoptosis. Full article

Compensatory mechanisms are thought to maintain sufficient dopamine (DA) signaling to mitigate locomotor impairment during progressive nigrostriatal neuron loss in Parkinson’s disease (PD). Recent evidence indicated augmented DA tissue content in the substantia nigra (SN), not striatum, compensates for tyrosine hydroxylase (TH) and neuronal loss, and alleviates the severity of hypokinesia during neuronal loss. Here, we determined if increased extracellular DA in the SN may also be a compensatory mechanism to augment DA signaling. Following unilateral 6-hydroxydopamine (6-OHDA) lesion or sham-operation, we contemporaneously evaluated extracellular DA against both DA tissue and TH levels in striatum and SN at 7 and 28 days. At 7 days post-lesion, TH loss exceeded ~90% in striatum, and ~70% in the SN. The severity of DA tissue loss coincided with TH protein loss only in striatum (>90%) on both days after lesion, whereas in the SN, DA loss was absent on day 7 and significantly less than TH loss by day 28. Whereas there was a robust increase in extracellular DA in striatum in our sham-operation group, the severe TH and DA tissue loss in striatum practically abolished KCl (K⁺)-stimulated extracellular DA by day 7. In contrast, whereas striatal K⁺-stimulation had no effect on extracellular DA in the SN in sham-operation group, extracellular DA levels increased in the SN 7 days after nigrostriatal lesion: an increase no longer apparent by day 28. Thus, despite significant loss of TH protein loss in the SN, extracellular and tissue DA tissue levels were augmented during neuronal loss. These results build upon evidence that compensatory mechanisms to augment DA signaling are not engaged in striatum, and point to the SN as the locus of augmented DA signaling to offset loss of TH during nigrostriatal neuron loss. Full article

Phenylketonuria (PKU) is an autosomal recessive disorder characterised by an inborn error of phenylalanine (Phe) metabolism. Such errors are attributed to pathogenic gene variants causing phenylalanine hydroxylase (PAH) deficiency, impairing the hydroxylation of phenylalanine to tyrosine in the Phe metabolic pathway. This defect leads to plasma Phe concentrations above the normal range. If untreated, hyperphenylalaninemia can adversely affect brain function, leading to severe intellectual disability and seizures. Since 1969, the newborn dried blood spot test has remained the main method of early screening and diagnosis for PKU. The primary therapeutic management is a lifelong phenylalanine-restricted diet with the aim of decreasing plasma Phe levels. The recommended diet consists of avoiding high-protein foods such as meat, fish, eggs and nuts, and can be supplemented with high-protein medical formulas which are low in phenylalanine. Pharmacological interventions such as sapropterin, sepiapterin and pegvaliase can also be used as treatment adjuncts in patients with PKU. Currently, small-molecule inhibitors reducing renal phenylalanine reabsorption are being explored as a potential therapeutic intervention. Furthermore, novel gene-editing techniques are under evaluation as potential curative strategies, with preclinical studies showing promising results in correcting pathogenic phenylalanine hydroxylase variants. This non-systematic review synthesises current literature on the management of PKU, with a focus on dietary interventions and recommendations. Full article

In recent years, significant progress has been made in understanding that Parkinson’s disease (PD) is associated not only with the dopamine (DA) but also with the norepinephric (NE) system. In order to investigate the potential involvement of NE in the development of the early motor symptoms of PD, we studied the effects of reducing its levels in a norepinephrine transporter knockout mouse (NET-KO). Due to the absence of NET, all the norepinephrine needed must be synthesized de novo. NET-KO mice were injected intraperitoneally with α-methyl-p-tyrosine (AMPT), a blocker of tyrosine hydroxylase, to induce a hyponoradrenergic state. Changes in tissue NE content in the frontal cortex and DA content in the striatum were evaluated using HPLC. We also measured the motor activity parameters of NET-KO mice after AMPT injection. The hyponorepinephric state induced by AMPT administration in NET-KO mice did not lead to severe motor impairments, as occurs in PD models. However, NET-KO mice did exhibit abnormal hindlimb extension, which began three hours after AMPT administration. This symptom may be interpreted as an early symptom preceding PD. These results suggest that the potential involvement of different neurotransmitter systems in motor abnormalities relevant to Parkinson’s disease warrants further investigation. Full article

Unbiased stereology represents the most accurate approach for estimating the total number of neurons of specific brain regions; however, its reliability critically depends on the use of rigorously defined and anatomically appropriate sampling parameters. The brain nucleus Locus Coeruleus (LC) plays a key role in several brain functions. LC impairment has been associated with a range of disorders affecting individuals across the lifespan, from infancy to adulthood. In animal models of these conditions, precise estimation of LC neuronal number is essential. The LC analysis poses specific methodological challenges due to its small size, indistinct anatomical boundaries, and age-dependent changes in neuronal density. In this study, we present a detailed and reproducible stereological workflow for the quantification of LC neurons in the mouse brain across the lifespan. Using C57BL/6J mice at postnatal, adult, and aged stages, we optimized all key components of the Optical Fractionator method, LC neurons were identified by immunoperoxidase staining for tyrosine hydroxylase (TH) and quantified using systematic-random sampling implemented in Stereo Investigator^® software. We show that age-specific adjustment of stereological parameters is necessary to obtain reliable estimates, particularly at early postnatal stages characterized by high neuronal packing density. With the optimized protocols described here, TH+ LC neuron counts consistently met accepted precision criteria, as assessed by the Gundersen coefficient of error. Full article

Background and Objectives: Parkinson’s disease (PD) is a neurodegenerative disorder marked by bradykinesia, rigidity, and tremor. While deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) effectively alleviates motor symptoms, the potential of targeting the substantia nigra pars reticulata (SNr) is less understood. This study investigates the effects of mid-term DBS of the SNr on motor function and neuroplasticity in a 6-hydroxydopamine (6-OHDA) rat model of PD. Methods: Adult male Sprague-Dawley rats (280–300 g) were divided into healthy control (n = 10), PD (n = 9), sham-DBS (n = 7), and SNr-DBS (n = 7) groups. Bilateral striatal 6-OHDA lesions induced PD. High-frequency (130 Hz, 60 µs) SNr-DBS was delivered for 14 days. Locomotor activity (open-field), gait (footprint method), and motor coordination (rotarod) were assessed. Tyrosine hydroxylase (TH) expression in the SN and c-Fos and BDNF expression in the cerebellum, prefrontal cortex (PFC), and ventrolateral thalamus were analyzed histologically. Results: SNr-DBS significantly improved ambulation and horizontal activity compared to the PD group (p < 0.05). Gait analysis showed significant improvements in forelimb/hindlimb stride length and stance width, while rotarod performance indicated enhanced motor coordination (p < 0.05). Histology revealed increased TH expression in the SN and elevated c-Fos and BDNF levels in the cerebellum, PFC, and thalamus in the SNr-DBS group vs. PD rats (p < 0.05). Conclusions: Mid-term SNr-DBS produced significant functional gains in motor activity and coordination in a 6-OHDA PD model, together with molecular evidence of dopaminergic enhancement and neuroplastic activation. These translational findings suggest that targeting the SNr may offer a clinically relevant alternative for patients with PD, particularly for those who may not optimally respond to conventional STN or GPi stimulation. Full article

Human hair performs a number of important physiological and esthetic functions. Hair loss and alopecia are complex disorders which affect people all over the world. Hair loss can be an early manifestation of various autoimmunological disorders. Despite a growing interest of researchers in the role of immune factors—especially autoantibodies—in the etiology of certain types of alopecia, their role in alopecia remains uncertain. Several potential autoantigens of follicular components, mainly derived from keratinocytes and melanocytes of the hair follicles, have been found to play a role in the development of alopecia areata. The list of autoantigens includes trichohyalin, keratin 16, fibroblast growth factor receptor 3, glycoprotein-100, melanoma-associated antigen recognized by T cells 1, dopachrome tautomerase/tyrosinase-related protein 2, tyrosinase, and tyrosine hydroxylase. This narrative review presents different aspects of immunopathogenesis of alopecia, from physiology (hair follicle immune privilege) to pathology (disruption of hair follicle immune privilege) and signaling pathways. Identification of key autoantigens could potentially pave the way for the development of new, effective, and more targeted immunotherapies for alopecia. Full article

Parkinson’s disease (PD) is a neurodegenerative disorder caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Lipid metabolism, especially phospholipids, has been reported to be altered in PD. The purpose of this study is to investigate the temporal expression and spatial distribution of phospholipids in the motor cortex and striatum at different time points of PD using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mouse model. Mice were injected with saline (NSS) or MPTP at two different time points to create acute and subacute models. Motor analysis was performed at 0, 3, 7, 14, and 21 days post-injection. Tyrosine hydroxylase (TH) staining revealed progressive damage of neurons in the substantia nigra compacta (SNc) and reduced striatal fibers in MPTP-treated animals. By using MALDI-MSI, we identified changes in phosphatidylcholine (PC) profiles in the brains of MPTP-treated animals. Polyunsaturated PCs, including PC 36:4 (16:0/20:4), PC 38:6 (16:0/22:6), and PC 40:8 (18:2/22:6), were decreased in the MPTP-treated groups. These reductions were time-dependent and were more pronounced in the subacute MPTP-treated group. The loss of dopamine neurons caused by MPTP may be associated with the selective loss of polyunsaturated PCs in brain membranes, indicating that lipid metabolism and membrane structural alterations may contribute to the pathology of PD. Full article