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Huntington's disease (HD) is associated with dysregulated choline metabolism, but the underlying mechanisms remain unclear. This study investigated the expression of key enzymes in this pathway in R6/2 HD mice and human HD postmortem brain tissues. We further explored the therapeutic potential of modulating choline metabolism for HD. Both R6/2 mice and HD patients exhibited reduced expression of glycerophosphocholine phosphodiesterase 1 (GPCPD1), a key enzyme in choline metabolism, in the striatum and cortex. The striatum of R6/2 mice also showed decreased choline and phosphorylcholine, and increased glycerophosphocholine, suggesting disruption in choline metabolism due to GPCPD1 deficiency. Treatment with citicoline significantly improved motor performance, upregulated anti-apoptotic Bcl2 expression, and reduced oxidative stress marker malondialdehyde in both brain regions. Metabolomic analysis revealed partial restoration of disrupted metabolic patterns in the striatum and cortex following citicoline treatment. These findings strongly suggest the role of GPCPD1 deficiency in choline metabolism dysregulation in HD. The therapeutic potential of citicoline in R6/2 mice highlights the choline metabolic pathway as a promising target for future HD therapies.
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Huntington's disease (HD) is characterized by progressive involuntary chorea movements and cognitive decline. Recent research indicates that metabolic disturbance may play a role in its pathogenesis. Bile acids, produced during cholesterol metabolism in the liver, have been linked to neurodegenerative conditions. This study investigated variations in plasma bile acid profiles among individuals with HD. Plasma levels of 16 primary and secondary bile acids and their conjugates were analyzed in 20 healthy controls and 33 HD patients, including 24 with symptoms (symHD) and 9 carriers in the presymptomatic stage (preHD). HD patients exhibited significantly higher levels of glycochenodeoxycholic acid (GCDCA) and glycoursodeoxycholic acid (GUDCA) compared to healthy controls. Conversely, isolithocholic acid levels were notably lower in the HD group. Neurotoxic bile acids (glycocholic acid (GCA) + glycodeoxycholic acid (GDCA) + GCDCA) were elevated in symHD patients, while levels of neuroprotective bile acids (ursodeoxycholic acid (UDCA) + GUDCA + tauroursodeoxycholic acid (TUDCA)) were higher in preHD carriers, indicating a compensatory response to early neuronal damage. These results underscore the importance of changes in plasma bile acid profiles in HD and their potential involvement in disease mechanisms. The identified bile acids (GCDCA, GUDCA, and isolithocholic acid) could potentially serve as markers to distinguish between HD stages and healthy individuals. Nonetheless, further research is warranted to fully understand the clinical implications of these findings and their potential as diagnostic or therapeutic tools for HD.
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Nociceptive pain perception is a remarkable capability of organisms to be aware of environmental changes and avoid injury, which can be accomplished by specialized pain receptors known as nociceptors with 4 vital properties including threshold, no adaptation, relaxation, and sensitization. Bioinspired systems designed using artificial devices are investigated to imitate the efficacy and functionality of nociceptive transmission. Here, an artificial pain-perceptual system (APPS) with a homogeneous material and heterogeneous integration is proposed to emulate the behavior of fast and slow pain in nociceptive transmission. Retention-differentiated poly[2-methoxy-5-(3,7-dimethyoctyoxyl)-1,4-phenylenevinylene] (MDMO-PPV) memristors with film thicknesses of 160 and 80 nm are manufactured and adopted as A-δ and C nerve fibers of nociceptor conduits, respectively. Additionally, a nociceptor mimic, the ruthenium nanoparticles (Ru-NPs)-doped MDMO-PPV piezoresistive pressure sensor, is fabricated with a noxiously stimulated threshold of 150 kPa. Under the application of pricking and dull noxious stimuli, the current flows predominantly through the memristor to mimic the behavior of fast and slow pain, respectively, in nociceptive transmission with postsynaptic potentiation properties, which is analogous to biological pain perception. The proposed APPS can provide potential advancements in establishing the nervous system, thus enabling the successful development of next-generation neurorobotics, neuroprosthetics, and precision medicine.
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Trinucleotide repeat expansion disorders, a diverse group of neurodegenerative diseases, are caused by abnormal expansions within specific genes. These expansions trigger a cascade of cellular damage, including protein aggregation and abnormal RNA binding. A key contributor to this damage is oxidative stress, an imbalance of reactive oxygen species that harms cellular components. This review explores the interplay between oxidative stress and the NRF2 pathway in these disorders. NRF2 acts as the master regulator of the cellular antioxidant response, orchestrating the expression of enzymes that combat oxidative stress. Trinucleotide repeat expansion disorders often exhibit impaired NRF2 signaling, resulting in inadequate responses to excessive ROS production. NRF2 activation has been shown to upregulate antioxidative gene expression, effectively alleviating oxidative stress damage. NRF2 activators, such as omaveloxolone, vatiquinone, curcumin, sulforaphane, dimethyl fumarate, and resveratrol, demonstrate neuroprotective effects by reducing oxidative stress in experimental cell and animal models of these diseases. However, translating these findings into successful clinical applications requires further research. In this article, we review the literature supporting the role of NRF2 in the pathogenesis of these diseases and the potential therapeutics of NRF2 activators.
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BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory demyelinating disease characterized by relapsing clinical episodes and the presence of autoantibodies. The impact of comorbidities on relapsing rate of NMOSD patients in Taiwan remains unclear. METHODS: We conducted a longitudinal retrospective study using the largest hospital system in Taiwan from 2006 to 2021. Demographic characteristics, annualized relapse rates (ARR), and comorbidities were examined. RESULTS: We identified 485 NMOSD patients from 2006 to 2021. Of these, 466 had the adult form and 19 (3.9 %) had the pediatric form of NMOSD. The median ARR was 0.51 (interquartile range (IQR): 0.26-1.11) for adults and 0.39 (IQR: 0.21-0.77) for pediatric patients. Comorbidities included malignancy (6.7 %) and autoimmune diseases (21.7 %). The recommended age for malignancy surveillance in NMOSD patients was 43.3 years. Neither malignancy nor autoimmune disease increased the ARR within 3 years post diagnosis in NMOSD patients with comorbidities compared with those without comorbidities. CONCLUSIONS: Our study revealed the ARR within the initial three years after diagnosis was significantly higher, emphasizing the importance of early treatment. We also observed an association between malignancy and NMOSD, and a significantly higher risk of malignancy in adult patients with NMOSD than in the general population (the relative risk was 5.99) that requiring further investigations into the underlying mechanisms. These findings contribute to a better understanding of NMOSD and its comorbidities in Taiwan.
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Enfermedades Autoinmunes , Comorbilidad , Neuromielitis Óptica , Recurrencia , Humanos , Neuromielitis Óptica/epidemiología , Taiwán/epidemiología , Adulto , Femenino , Estudios Longitudinales , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Enfermedades Autoinmunes/epidemiología , Adulto Joven , Neoplasias/epidemiología , Adolescente , NiñoRESUMEN
Parkinson's disease (PD) is a common neurodegenerative disease with progressive loss of dopaminergic neurons in substantia nigra and the presence of α-synuclein-immunoreactive inclusions. Gaucher's disease is caused by homozygous mutations in ß-glucocerebrosidase gene (GBA). GBA mutation carriers have an increased risk of PD. Coptis chinensis (C. chinensis) rhizome extract is a major herb widely used to treat human diseases. This study examined the association of GBA L444P mutation with Taiwanese PD in 1016 cases and 539 controls. In addition, the protective effects of C. chinensis rhizome extract and its active constituents (berberine, coptisine, and palmatine) against PD were assayed using GBA reporter cells, LC3 reporter cells, and cells expressing mutated (A53T) α-synuclein. Case-control study revealed that GBA L444P carriers had a 3.93-fold increased risk of PD (95% confidence interval (CI): 1.37-11.24, p = 0.006) compared to normal controls. Both C. chinensis rhizome extract and its constituents exhibited chemical chaperone activity to reduce α-synuclein aggregation. Promoter reporter and endogenous GBA protein analyses revealed that C. chinensis rhizome extract and its constituents upregulated GBA expression in 293 cells. In addition, C. chinensis rhizome extract and its constituents induced autophagy in DsRed-LC3-expressing 293 cells. In SH-SY5Y cells expressing A53T α-synuclein, C. chinensis rhizome extract and its constituents reduced α-synuclein aggregation and associated neurotoxicity by upregulating GBA expression and activating autophagy. The results of reducing α-synuclein aggregation, enhancing GBA expression and autophagy, and protecting against α-synuclein neurotoxicity open up the therapeutic potentials of C. chinensis rhizome extract and constituents for PD.
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Berberina , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Humanos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Berberina/análogos & derivados , Estudios de Casos y Controles , Coptis chinensis , Neuronas Dopaminérgicas/metabolismo , Mutación , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , RizomaRESUMEN
At least seven dominantly inherited spinocerebellar ataxias (SCA) are caused by expansions of polyglutamine (polyQ)-encoding CAG repeat. The misfolded and aggregated polyQ-expanded proteins increase reactive oxygen species (ROS), cellular toxicity, and neuroinflammation in the disease pathogenesis. In this study, we evaluated the anti-inflammatory potentials of coumarin derivatives LM-021, LMDS-1, LMDS-2, and pharmacological chaperone tafamidis using mouse BV-2 microglia and SCA3 ataxin-3 (ATXN3)/Q75-GFP SH-SY5Y cells. The four tested compounds displayed anti-inflammatory activity by suppressing nitric oxide (NO), interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α production, and CD68 antigen (CD68) and histocompatibility-2 (MHCII) expression in lipopolysaccharides (LPS)/interferon (IFN)-γ-stimulated BV-2 microglia. In retinoic acid-differentiated ATXN3/Q75-GFP-expressing SH-SY5Y cells inflamed with LPS/IFN-γ-primed BV-2 conditioned medium, treatment with test compounds mitigated the increased caspase 1 activity and lactate dehydrogenase release, reduced ROS and ATXN3/Q75 aggregation, and promoted neurite outgrowth. Examination of IL-1ß and IL-6-mediated signaling pathways revealed that LM-021, LMDS-1, LMDS-2, and tafamidis decreased NLR family pyrin domain containing 1 (NLRP1), c-Jun N-terminal kinase/c-Jun proto-oncogene (JNK/JUN), inhibitor of kappa B (IκBα)/P65, mitogen-activated protein kinase 14/signal transducer and activator of transcription 1 (P38/STAT1), and/or Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling. The study results suggest the potential of LM-021, LMDS-1, LMDS-2, and tafamidis in treating SCA3 and probable other polyQ diseases.
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Enfermedad de Machado-Joseph , Neuroblastoma , Animales , Humanos , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Interleucina-1beta/antagonistas & inhibidores , Interleucina-6 , Lipopolisacáridos/farmacología , Enfermedad de Machado-Joseph/tratamiento farmacológico , Enfermedad de Machado-Joseph/genética , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de SeñalRESUMEN
The incidence of ischemic stroke (IS) is higher in nephrotic syndrome (NS) patients compared to general population. However, there is limited information on the specific characteristics to stroke patients with NS. In this study, we aimed to examine the clinical manifestations of acute IS in a large group of NS patients, comparing to those without NS. We conducted a retrospective cohort study to compare the clinical presentations of acute IS in patients with and without NS. This study was a multi-institutional study and used data from Chang Gung Research Database of Taiwan from 1 January 2001, to 31 December 2017. A total of 233 IS patients with NS and 1358 IS patients without NS were enrolled. The median age of participants was 68 (range: 59-79) years. The risk of dependent functional status (modified Rankin Scale scoreâ§3) after IS was higher in NS patients compared to those without NS (Odd ratio (OR) 4.02, 95% confidence interval (CI) 2.39 to 6.76, p < 0.001), particularly in stroke subtypes as small-artery occlusion (OR 8.02, 95% CI 3.94 to 16.32, p < 0.001), and stroke of undetermined etiology (OR 2.47, CI 1.06 to 5.76, p = 037). The risks of mortality or stroke recurrence within 30 days were similar between the two groups for all stroke subtypes. In conclusion, NS was associated with a higher risk of functional dependence following IS. Intensive treatment and rehabilitation should be considered for IS patients with NS.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Síndrome Nefrótico , Accidente Cerebrovascular , Anciano , Humanos , Persona de Mediana Edad , Isquemia Encefálica/epidemiología , Isquemia Encefálica/etiología , Isquemia Encefálica/terapia , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/etiología , Síndrome Nefrótico/complicaciones , Síndrome Nefrótico/epidemiología , Estudios Retrospectivos , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Taiwán/epidemiología , Resultado del TratamientoRESUMEN
BACKGROUND: Distal symmetric sensorimotor polyneuropathy (DSPN) is a common neurologic complication of type 2 diabetes mellitus (T2DM), but the underlying mechanisms and changes in serum metabolites remain largely undefined. This study aimed to characterize the plasma metabolite profiles of participants with T2DM using targeted metabolomics analysis and identify potential biomarkers for DSPN. METHODS: A combined liquid chromatography MS/MS and direct flow injection were used to quantify plasma metabolite obtained from 63 participants with T2DM, 81 with DSPN, and 33 nondiabetic control participants. A total of 130 metabolites, including amino acids, biogenic amines, sphingomyelins (SM), phosphatidylcholines, carnitines, and hexose, were analyzed. RESULTS: A total of 16 plasma metabolites and 3 cholesterol-related laboratory parameters were found to have variable importance in the projection score >1.0 and false discovery rate <5.0% between control, T2DM, and DSPN. Among these variables, five serum metabolites, including phenylalanine (AUC = 0.653), alanine (AUC = 0.630), lysine (AUC = 0.622) tryptophan (AUC = 0.620), and SM C16:0 (AUC = 0.630), are potential biomarkers (all p < .05) in distinguishing T2DM with DSPN from those without (AUC = 0.720). CONCLUSIONS: In this cross-sectional study, derangement of several metabolites in the plasma was observed in T2DM with and without DSPN, and these metabolites may be potential biomarkers for predicting DSPN. Longitudinal studies are warranted.
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Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Polineuropatías , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Estudios Transversales , Espectrometría de Masas en Tándem , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/etiología , Polineuropatías/diagnóstico , Polineuropatías/etiología , BiomarcadoresRESUMEN
Objectives: Endoscopic thoracic sympathectomy may be complicated by the onset of disabling compensatory sweating (CS). The objective of this case series is to report the 2-year outcomes after robotic sympathetic trunk reconstruction (STR) for the reversal of CS in patients who had undergone endoscopic thoracic sympathectomy. Methods: We prospectively followed-up a total of 23 patients who had undergone robotic STR because of intolerable CS between October 2017 and January 2021. A visual analog scale ranging from 0 to 10 (with 10 indicating the highest degree) was used to assess the severity of CS at different anatomical locations, thermoregulatory alterations, and gustatory hyperhidrosis. Measurements were performed before STR and at 6-month and 2-year follow-up. Results: The mean age of the study participants was 43.3 ± 7.8 years, and 20 (87%) were men. The reversal procedure was performed after a mean of 19.6 ± 7.8 years from endoscopic thoracic sympathectomy. In all patients, nerve defects were successfully bridged using sural nerves (mean length, 9.7 cm on the right and 9.8 cm on the left). No cases of Horner syndrome were noted. At 6 postoperative months, the severity of CS decreased significantly at all body surface areas. The observed improvements were effectively maintained at 24 post-STR months. There was no evidence of either recurrent hyperhidrosis at the primary site or transition of CS to other anatomical locations. Similar improvements were evident for thermoregulatory alterations and gustatory hyperhidrosis. Conclusions: Robotic STR is safe and effective in reversing intolerable CS after endoscopic thoracic sympathectomy.
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Parkinson's disease (PD) is featured mainly by the loss of dopaminergic neurons and the presence of α-synuclein-containing aggregates in the substantia nigra of brain. The α-synuclein fibrils and aggregates lead to increased oxidative stress and neural toxicity in PD. Chronic inflammation mediated by microglia is one of the hallmarks of PD pathophysiology. In this report, we showed that coumarin-chalcone hybrid LM-021 and indole derivative NC009-1 reduced the expression of major histocompatibility complex-II, NLR family pyrin domain containing (NLRP) 3, caspase-1, inducible nitric oxide synthase, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α in α-synuclein-activated mouse BV-2 microglia. Release of pro-inflammatory mediators including nitric oxide, IL-1ß, IL-6 and TNF-α was also mitigated. In BE(2)-M17 cells expressing A53T α-synuclein aggregates, LM-021 and NC009-1 reduced α-synuclein aggregation, neuroinflammation, oxidative stress and apoptosis, and promoted neurite outgrowth. These protective effects were mediated by downregulating NLRP1, IL-1ß and IL-6, and their downstream pathways including nuclear factor (NF)-κB inhibitor alpha (IκBα)/NF-κB P65 subunit (P65), c-Jun N-terminal kinase (JNK)/proto-oncogene c-Jun (JUN), mitogen-activated protein kinase 14 (P38)/signal transducer and activator of transcription (STAT) 1, and Janus kinase 2 (JAK2)/STAT3. The study results indicate LM-021 and NC009-1 as potential new drug candidates for PD.
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Chalconas , Enfermedad de Parkinson , Ratones , Animales , alfa-Sinucleína/metabolismo , Chalconas/farmacología , Interleucina-6/metabolismo , Inflamación/metabolismo , Estrés Oxidativo , Indoles/farmacología , FN-kappa B/metabolismo , Enfermedad de Parkinson/metabolismo , Microglía/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Cumarinas/farmacología , Lipopolisacáridos/farmacologíaRESUMEN
BACKGROUND: Approximately 10% to 20% of myasthenia gravis (MG) patients have experienced a myasthenic crisis (MC), which contributes to morbidity and mortality. MC triggered by infection is associated with poor outcomes. However, there is a lack of prognostic factors that clinicians can utilize to target interventions for preventing recurrent infection-triggered MC. This study aimed to characterize clinical manifestations, comorbidities, and biochemical profiles associated with recurrent infection-triggered MC in MG patients. METHODS: This retrospective study included 272 MG patients hospitalized with an infection requiring at least 3 days of antibiotics from January 2001 to December 2019. Patients were further stratified into non-recurrent or recurrent infection groups. Clinical features such as gender, age, concomitant diseases, acetylcholine receptor antibodies and biochemical data (including electrolytes and coagulants), muscle strength of pelvic and shoulder girdle, bulbar and respiratory function, management with an endotracheal tube, Foley catheter, or plasmapheresis, duration of hospitalization, and culture pathogens were recorded. RESULTS: The recurrent infection group was significantly older than the non-recurrent group (median age, 58.5 versus 52.0 years). Pneumonia was the most common infection and Klebsiella pneumoniae was the most common pathogen. The presence of concomitant diabetes mellitus, activated partial thromboplastin time prolongation, the duration of hospitalization, and hypomagnesaemia were independently associated with recurrent infection. The presence of deep vein thrombosis, thymic cancer, and electrolyte imbalances i.e., hypokalemia, and hypoalbuminemia were significantly associated with a risk for infection. The influence of endotracheal intubation, anemia, and plasmapheresis during hospitalization were inconsistent. CONCLUSIONS: The independent risk factors for recurrent infections in MG patients identified in this study include the presence of concomitant diabetes mellitus, hypomagnesaemia, activated partial thromboplastin time prolongation, and longer duration of hospitalization, highlighting the need for targeted interventions to prevent recurrent infections in this population. Further research and prospective studies are warranted to validate these findings and refine interventions for optimizing patient care.
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Miastenia Gravis , Reinfección , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Reinfección/complicaciones , Miastenia Gravis/complicaciones , Miastenia Gravis/epidemiología , Factores de Riesgo , Receptores ColinérgicosRESUMEN
Increased oxidative stress and neuroinflammation play a crucial role in the pathogenesis of Parkinson's disease (PD). In this study, the expression levels of 52 genes related to oxidative stress and inflammation were measured in peripheral blood mononuclear cells of the discovery cohort including 48 PD patients and 25 healthy controls. Four genes, including ALDH1A, APAF1, CR1, and CSF1R, were found to be upregulated in PD patients. The expression patterns of these genes were validated in a second cohort of 101 PD patients and 61 healthy controls. The results confirmed the upregulation of APAF1 (PD: 0.34 ± 0.18, control: 0.26 ± 0.11, p < 0.001) and CSF1R (PD: 0.38 ± 0.12, control: 0.33 ± 0.10, p = 0.005) in PD patients. The expression level of APAF1 was correlated with the scores of the Unified Parkinson's Disease Rating Scale (UPDRS, r = 0.235, p = 0.018) and 39-item PD questionnaire (PDQ-39, r = 0.250, p = 0.012). The expression level of CSF1R was negatively correlated with the scores of the mini-mental status examination (MMSE, r = -0.200, p = 0.047) and Montréal Cognitive Assessment (MoCA, r = -0.226, p = 0.023). These results highly suggest that oxidative stress biomarkers in peripheral blood may be useful in monitoring the progression of motor disabilities and cognitive decline in PD patients.
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Factor Apoptótico 1 Activador de Proteasas , Factor Estimulante de Colonias de Macrófagos , Enfermedad de Parkinson , Humanos , Factor Apoptótico 1 Activador de Proteasas/genética , Disfunción Cognitiva , Leucocitos Mononucleares , Pruebas de Estado Mental y Demencia , Enfermedad de Parkinson/diagnóstico , Proteínas Tirosina Quinasas Receptoras/genética , Receptores del Factor Estimulante de Colonias/genética , Regulación hacia Arriba , Factor Estimulante de Colonias de Macrófagos/metabolismoRESUMEN
Huntington's disease (HD) is a progressive and devastating neurodegenerative disease marked by inheritable CAG nucleotide expansion. For offspring of HD patients carrying abnormal CAG expansion, biomarkers that predict disease onset are crucially important but still lacking. Alteration of brain ganglioside patterns has been observed in the pathology of patients carrying HD. Here, by using a novel and sensitive ganglioside-focused glycan array, we examined the potential of anti-glycan auto-antibodies for HD. In this study, we collected plasma from 97 participants including 42 control (NC), 16 pre-manifest HD (pre-HD), and 39 HD cases and measured the anti-glycan auto-antibodies by a novel ganglioside-focused glycan array. The association between plasma anti-glycan auto-antibodies and disease progression was analyzed using univariate and multivariate logistic regression. The disease-predictive capacity of anti-glycan auto-antibodies was further investigated by receiver operating characteristic (ROC) analysis. We found that anti-glycan auto-antibodies were generally higher in the pre-HD group when compared to the NC and HD groups. Specifically, anti-GD1b auto-antibody demonstrated the potential for distinguishing between pre-HD and control groups. Moreover, in combination with age and the number of CAG repeat, the level of anti-GD1b antibody showed excellent predictability with an area under the ROC curve (AUC) of 0.95 to discriminate between pre-HD carriers and HD patients. With glycan array technology, this study demonstrated abnormal auto-antibody responses that showed temporal changes from pre-HD to HD.
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Enfermedad de Huntington , Enfermedades Neurodegenerativas , Humanos , Enfermedad de Huntington/patología , Enfermedades Neurodegenerativas/patología , Encéfalo/patología , BiomarcadoresRESUMEN
Alterations in lipid composition and disturbed lipoprotein metabolism are involved in the pathomechanism of Huntington's disease (HD). Here, we measured 112 lipoprotein subfractions and components in the plasma of 20 normal controls, 24 symptomatic (sympHD) and 9 presymptomatic (preHD) HD patients. Significant changes were found in 30 lipoprotein subfractions and components in all HD patients. Plasma levels of total cholesterol (CH), apolipoprotein (Apo)B, ApoB-particle number (PN), and components of low-density lipoprotein (LDL) were lower in preHD and sympHD patients. Components of LDL4, LDL5, LDL6 and high-density lipoprotein (HDL)4 demonstrated lower levels in preHD and sympHD patients compared with controls. Components in LDL3 displayed lower levels in sympHD compared with the controls, whereas components in very low-density lipoprotein (VLDL)5 were higher in sympHD patients compared to the controls. The levels of components in HDL4 and VLDL5 demonstrated correlation with the scores of motor assessment, independence scale or functional capacity of Unified Huntington's Disease Rating Scale. These findings indicate the potential of components of VLDL5, LDL3, LDL4, LDL5 and HDL4 to serve as the biomarkers for HD diagnosis and disease progression, and demonstrate substantial evidence of the involvement of lipids and apolipoproteins in HD pathogenesis.
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Enfermedad de Huntington , Humanos , Triglicéridos , Enfermedad de Huntington/diagnóstico , Lipoproteínas , Lipoproteínas LDL/metabolismo , Apolipoproteínas B , BiomarcadoresRESUMEN
Misfolded aggregation of the hyperphosphorylated microtubule binding protein Tau in the brain is a pathological hallmark of Alzheimer's disease (AD). Tau aggregation downregulates brain-derived neurotrophic factor (BDNF)/tropomycin receptor kinase B (TRKB) signaling and leads to neurotoxicity. Therefore, enhancement of BDNF/TRKB signaling could be a strategy to alleviate Tau neurotoxicity. In this study, eight compounds were evaluated for the potential of inhibiting Tau misfolding in human neuroblastoma SH-SY5Y cells expressing the pro-aggregator Tau folding reporter (ΔK280 TauRD-DsRed). Among them, coumarin derivative ZN-015 and quinoline derivatives VB-030 and VB-037 displayed chemical chaperone activity to reduce ΔK280 TauRD aggregation and promote neurite outgrowth. Studies of TRKB signaling revealed that ZN-015, VB-030 and VB-037 treatments significantly increased phosphorylation of TRKB and downstream Ca2+/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinase 1/2 (ERK) and AKT serine/threonine kinase (AKT), to activate ribosomal S6 kinase (RSK) and cAMP response element-binding protein (CREB). Subsequently, p-CREB enhanced the transcription of pro-survival BDNF and BCL2 apoptosis regulator (BCL2), accompanied with reduced expression of anti-survival BCL2-associated X protein (BAX) in ΔK280 TauRD-DsRed-expressing cells. The neurite outgrowth promotion effect of ZN-015, VB-030 and VB-037 was counteracted by a RNA interference-mediated knockdown of TRKB, suggesting the role of these compounds acting as TRKB agonists. Tryptophan fluorescence quenching analysis showed that ZN-015, VB-030 and VB-037 interacted directly with a Pichia pastoris-expressed TRKB extracellular domain, indirectly supporting the role through TRKB signaling. The results of up-regulation in TRKB signaling open up the therapeutic potentials of ZN-015, VB-030 and VB-037 for AD.
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Enfermedad de Alzheimer , Neuroblastoma , Humanos , Enfermedad de Alzheimer/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteínas Proto-Oncogénicas c-akt , Neuroblastoma/metabolismo , Proteínas tau/metabolismo , Receptor trkB/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2RESUMEN
Neuroinflammation and oxidative stress have been emerging as important pathways contributing to Parkinson's disease (PD) pathogenesis. In PD brains, the activated microglia release inflammatory factors such as interleukin (IL)-ß, IL-6, tumor necrosis factor (TNF)-α, and nitric oxide (NO), which increase oxidative stress and mediate neurodegeneration. Using 1-methyl-4-phenylpyridinium (MPP+)-activated human microglial HMC3 cells and the sub-chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, we found the potential of indole derivative NC009-1 against neuroinflammation, oxidative stress, and neurodegeneration for PD. In vitro, NC009-1 alleviated MPP+-induced cytotoxicity, reduced NO, IL-1ß, IL-6, and TNF-α production, and suppressed NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in MPP+-activated HMC3 cells. In vivo, NC009-1 ameliorated motor deficits and non-motor depression, increased dopamine and dopamine transporter levels in the striatum, and reduced oxidative stress as well as microglia and astrocyte reactivity in the ventral midbrain of MPTP-treated mice. These protective effects were achieved by down-regulating NLRP3, CASP1, iNOS, IL-1ß, IL-6, and TNF-α, and up-regulating SOD2, NRF2, and NQO1. These results strengthen the involvement of neuroinflammation and oxidative stress in PD pathogenic mechanism, and indicate NC009-1 as a potential drug candidate for PD treatment.
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Enfermedad de Parkinson , Ratones , Humanos , Animales , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Neurotoxinas/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Enfermedades Neuroinflamatorias , Interleucina-6/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Microglía/metabolismo , 1-Metil-4-fenilpiridinio/toxicidad , Estrés Oxidativo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversosRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease with progressive memory loss and the cognitive decline. AD is mainly caused by abnormal accumulation of misfolded amyloid ß (Aß), which leads to neurodegeneration via a number of possible mechanisms such as down-regulation of brain-derived neurotrophic factor-tropomyosin-related kinase B (BDNF-TRKB) signaling pathway. 7 ,8-Dihydroxyflavone (7,8-DHF), a TRKB agonist, has demonstrated potential to enhance BDNF-TRKB pathway in various neurodegenerative diseases. To expand the capacity of flavones as TRKB agonists, two natural flavones quercetin and apigenin, were evaluated. With tryptophan fluorescence quenching assay, we illustrated the direct interaction between quercetin/apigenin and TRKB extracellular domain. Employing Aß folding reporter SH-SY5Y cells, we showed that quercetin and apigenin reduced Aß-aggregation, oxidative stress, caspase-1 and acetylcholinesterase activities, as well as improved the neurite outgrowth. Treatments with quercetin and apigenin increased TRKB Tyr516 and Tyr817 and downstream cAMP-response-element binding protein (CREB) Ser133 to activate transcription of BDNF and BCL2 apoptosis regulator (BCL2), as well as reduced the expression of pro-apoptotic BCL2 associated X protein (BAX). Knockdown of TRKB counteracted the improvement of neurite outgrowth by quercetin and apigenin. Our results demonstrate that quercetin and apigenin are to work likely as a direct agonist on TRKB for their neuroprotective action, strengthening the therapeutic potential of quercetin and apigenin in treating AD.
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Glycogen synthase kinase-3ß (GSK-3ß) is an important serine/threonine kinase that implicates in multiple cellular processes and links with the neurodegenerative diseases including Alzheimer's disease (AD). In this study, structure-based virtual screening was performed to search database for compounds targeting GSK-3ß from Enamine's screening collection. Of the top-ranked compounds, 7 primary hits underwent a luminescent kinase assay and a cell assay using human neuroblastoma SH-SY5Y cells expressing Tau repeat domain (TauRD) with pro-aggregant mutation ΔK280. In the kinase assay for these 7 compounds, residual GSK-3ß activities ranged from 36.1% to 90.0% were detected at the IC50 of SB-216763. In the cell assay, only compounds VB-030 and VB-037 reduced Tau aggregation in SH-SY5Y cells expressing ΔK280 TauRD-DsRed folding reporter. In SH-SY5Y cells expressing ΔK280 TauRD, neither VB-030 nor VB-037 increased expression of GSK-3α Ser21 or GSK-3ß Ser9. Among extracellular signal-regulated kinase (ERK), AKT serine/threonine kinase 1 (AKT), mitogen-activated protein kinase 14 (P38) and mitogen-activated protein kinase 8 (JNK) which modulate Tau phosphorylation, VB-037 attenuated active phosphorylation of P38 Thr180/Tyr182, whereas VB-030 had no effect on the phosphorylation status of ERK, AKT, P38 or JNK. However, both VB-030 and VB-037 reduced endogenous Tau phosphorylation at Ser202, Thr231, Ser396 and Ser404 in neuronally differentiated SH-SY5Y expressing ΔK280 TauRD. In addition, VB-030 and VB-037 further improved neuronal survival and/or neurite length and branch in mouse hippocampal primary culture under Tau cytotoxicity. Overall, through inhibiting GSK-3ß kinase activity and/or p-P38 (Thr180/Tyr182), both compounds may serve as promising candidates to reduce Tau aggregation/cytotoxicity for AD treatment.
RESUMEN
Exosome-based regenerative therapies are potentially easier to manufacture and safer to apply compared to cell-based therapies. However, many questions remain about how to bio-manufacture reproducible and potent exosomes using animal-free reagents. Here we evaluate the hypothesis that designer biomaterial substrates can be used to alter the potency of exosomes secreted by human induced pluripotent stem cells (iPSCs). Two animal-free designer matrices were fabricated based on recombinant elastin-like polypeptides (ELPs): one including a cell-adhesive RGD ligand and a second with a non-adhesive RDG peptide. While iPSCs cultured on these two substrates and Matrigel-coated controls had similar levels of proliferation, the RDG-ELP substrate significantly increased protein expression of stemness markers OCT4 and SOX2 and suppressed spontaneous differentiation compared to those on RGD-ELP. The pro-survival potency of iPSC-derived exosomes was evaluated using three distinct stress tests: serum starvation in murine fibroblasts, hypoxia in human endothelial cells, and hyperosmolarity in canine kidney cells. In all three cases, exosomes produced by iPSCs grown on RDG-ELP substrates had similar pro-survival effects to those produced using iPSCs grown on Matrigel, while use of RGD-ELP substrates led to significantly reduced exosome potency. These data demonstrate that recombinant substrates can be designed for the robust bio-manufacturing of iPSC-derived, pro-survival exosomes.