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OBJECTIVE: Alzheimer's disease (AD) pathology is featured by the extracellular accumulation of amyloid-ß (Aß) plaques and intracellular tau neurofibrillary tangles in the brain. We studied whether Aß and tau accumulation are independently associated with future cognitive decline in the AD continuum. METHODS: Data were acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI) public database. A total of 1272 participants were selected based on the availability of Aß-PET and CSF tau at baseline and of those 777 participants with follow-up visits. RESULTS: We found that Aß-PET and CSF tau pathology were related to cognitive decline across the AD clinical spectrum, both as potential predictors for dementia progression. Among them, Aß-PET (A + T- subjects) is an independent reliable predictor of longitudinal cognitive decline in terms of ADAS-13, ADNI-MEM, and MMSE scores rather than tau pathology (A - T+ subjects), indicating tau accumulation is not closely correlated with future cognitive impairment without being driven by Aß deposition. Of note, a high percentage of APOE ε4 carriers with Aß pathology (A+) develop poor memory and learning capacity. Interestingly, this condition is not recurrence in terms of the ADNI-MEM domain when adding APOE ε4 status. Finally, the levels of Aß-PET SUVR related to glucose hypometabolism more strongly in subjects with A + T- than A - T+ both happen at baseline and longitudinal changes. CONCLUSIONS: In conclusion, Aß-PET alone without tau pathology (A + T-) measure is an independent reliable predictor of longitudinal cognitive decline but may nonetheless forecast different status of dementia progression. However, tau accumulation alone without Aß pathology background (A - T+) was not enough to be an independent predictor of cognitive worsening.
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Péptidos beta-Amiloides , Disfunción Cognitiva , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Proteínas tau/metabolismo , Femenino , Masculino , Péptidos beta-Amiloides/metabolismo , Anciano , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/patología , Tomografía de Emisión de Positrones/tendencias , Estudios Longitudinales , Anciano de 80 o más Años , Progresión de la Enfermedad , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/psicología , Persona de Mediana EdadRESUMEN
The single nucleotide polymorphism (SNP)-rs6922617 in the triggering receptor expressed on myeloid cells (TREM) gene cluster is a potential risk factor for Alzheimer's disease (AD). Here, we examined whether rs6922617 is associated with AD-defining neuropathological hallmarks and memory performance. We assessed the interaction between the variant rs6922617 and levels of beta-amyloid (Aß), tau pathology, neurodegeneration, namely amyloid-tau-neurodegeneration (ATN) framework, and cognition functions in 660 Healthy controls (HCs), 794 mild cognitively impaired (MCI), and 272 subjects with AD. We employed linear regression and linear mixed models to examine the association. Here we find that the SNP-rs6922617 in the TREM gene cluster is associated with a higher global amyloid-ligands positron emission tomography (Aß-PET) burden and lower Fluorodeoxyglucose positron emission tomography (FDG-PET) load. Interestingly, rs6922617 risk allele carriers exhibit a significantly reduced tau accumulation compared to the non-carriers, indicating a discrepant association with Aß and tau pathologies. Though the participants carrying the rs6922617 risk allele do not show a correlation with poorer cognitive performance, stronger neuropathological phenotypes, and memory impairments are evident in ApoE ε4 carriers with the rs6922617 risk allele. These results support the notion that the SNP-rs6922617 in the TREM gene cluster is associated with AD-related neuropathological hallmarks, such as Aß and FDG-mediated neurodegeneration, rather than tau accumulation. While the direct association with memory impairment in the Alzheimer's continuum remains inconclusive, our findings suggest a potential role of rs6922617 in facilitating neuropathology hallmarks.
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Backgrounds: Numerous lines of evidence support the intricate interplay between Parkinson's disease (PD) and the PINK1-dependent mitophagy process. This study aimed to evaluate differences in plasma PINK1 levels among idiopathic PD, PD syndromes (PDs), and healthy controls. Methods: A total of 354 participants were included, consisting of 197 PD patients, 50 PDs patients, and 107 healthy controls were divided into two cohorts, namely the modeling cohort (cohort 1) and the validated cohort (cohort 2). An enzyme-linked immunosorbent assay (ELISA)-based analysis was performed on PINK1 and α-synuclein oligomer (Asy-no). The utilization of the area under the curve (AUC) within the receiver-operating characteristic (ROC) curves served as a robust and comprehensive approach to evaluate and quantify the predictive efficacy of plasma biomarkers alone, as well as combined models, in distinguishing PD patients from controls. Results: PINK1 and Asy-no were elevated in the plasma of PD and PDs patients compared to healthy controls. The AUCs of PINK1 (0.771) and Asy-no (0.787) were supposed to be potentially eligible plasma biomarkers differentiating PD from controls but could not differentiate PD from PDs. Notably, the PINK + Asy-no + Clinical RBD model showed the highest performance in the modeling cohort and was comparable with the PINK1 + Clinical RBD in the validation cohort. Moreover, there is no significant correlation between PINK1 and UPDRS, MMSE, HAMD, HAMA, RBDQ-HK, and ADL scores. Conclusion: These findings suggest that elevated PINK1 in plasma holds the potential to serve as a non-invasive tool for distinguishing PD patients from controls. Moreover, the outcomes of our investigation lend support to the plausibility of implementing a feasible blood test in future clinical translation.
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Declining estrogen production in postmenopausal females causes osteoporosis in which the resorption of bone exceeds the increase in bone formation. Although clinical drugs are currently available for the treatment of osteoporosis, sustained medication use is accompanied by serious side effects. Corydalis bungeana Herba, a famous traditional Chinese herb listed in the Chinese Pharmacopoeia Commission, constitutes various traditional Chinese Medicine prescriptions, which date back to thousands of years. One of the primary active components of C. bungeana Turcz. is Corynoline (Cor), a plant isoquinoline alkaloid derived from the Corydalis species, which possesses bone metabolism disease therapeutic potential. The study aimed at exploring the effects as well as mechanisms of Cor on osteoclast formation and bone resorption. TRAcP staining, F-actin belt formation, and pit formation were employed for assessing the osteoclast function. Western blot, qPCR, network pharmacology, and docking analyses were used for analyzing the expression of osteoclast-associated genes and related signaling pathways. The study focused on investigating how Cor affected OVX-induced trabecular bone loss by using a mouse model. Cor could weaken osteoclast formation and function by affecting the biological receptor activators of NF-κB and its ligand at various concentrations. Mechanistically, Cor inhibited the NF-κB activation, and the MAPKs pathway stimulated by RANKL. Besides, Cor enhanced the protein stability of the Nrf2, which effectively abolished the RANKL-stimulated ROS generation. According to an OVX mouse model, Cor functions in restoring bone mass, improving microarchitecture, and reducing the ROS levels in the distal femurs, which corroborated with its in vitro antiosteoclastogenic effect. The present study indicates that Cor may restrain osteoclast formation and bone loss by modulating NF-κB/MAPKs and Nrf2 signaling pathways. Cor was shown to be a potential drug candidate that can be utilized for the treatment of osteoporosis.
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Alcaloides de Berberina , Resorción Ósea , Osteoporosis , Femenino , Humanos , Osteogénesis , FN-kappa B/genética , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal , Osteoclastos , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/genética , Resorción Ósea/metabolismo , Osteoporosis/tratamiento farmacológico , Osteoporosis/genética , Osteoporosis/metabolismo , Ligando RANK/genética , Ligando RANK/metabolismo , Diferenciación CelularRESUMEN
BACKGROUND: Type 2 diabetes is often linked with osteoporosis (T2DOP), a condition that accelerates bone degeneration and increases the risk of fractures. Unlike conventional menopausal osteoporosis, the diabetic milieu exacerbates the likelihood of fractures and osteonecrosis. In particular poliumoside (Pol), derived from Callicarpa kwangtungensis Chun, has shown promising anti-oxidant and anti-inflammatory effects. Yet, its influence on T2DOP remains to be elucidated. PURPOSE: The focus of this study was to elucidate the influence of Pol in HGHF-associated ferroptosis and its implications in T2DOP. STUDY DESIGN: A murine model of T2DOP was established using a minimal dosage of streptozotocin (STZ) through intraperitoneal infusion combined with a diet high in fat and sugar. Concurrently, to mimic the diabetic condition in a lab environment, bone mesenchymal stem cells (BMSCs) were maintained in a high-glucose and high-fat (HGHF) setting. METHODS: The impact of Pol on BMSCs in an HGHF setting was determined using methods, such as BODIPY-C11, FerroOrange staining, mitochondrial functionality evaluations, and Western blot methodologies, coupled with immunoblotting and immunofluorescence techniques. To understand the role of Pol in a murine T2DOP model, techniques including micro-CT, hematoxylin and eosin (H&E) staining, dual-labeling with calcein-alizarin red, and immunohistochemistry were employed for detailed imaging and histological insights. RESULTS: Our findings suggest that Pol acts against HGHF-induced bone degradation and ferroptosis, as evidenced by an elevation in glutathione (GSH) and a decline in malondialdehyde (MDA) levels, lipid peroxidation, and mitochondrial reactive oxygen species (ROS). Furthermore, Pol treatment led to increased bone density, enhanced GPX4 markers, and reduced ROS in the distal femur region. On investigating the underlying mechanism of action, it was observed that Pol triggers the Nrf2/GPX4 pathway, and the introduction of lentivirus-Nrf2 negates the beneficial effects of Pol in HGHF-treated BMSCs. CONCLUSION: Pol is effective in treating T2DOP by activating the Nrf2/GPX4 signaling pathway to inhibit ferroptosis.
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Ácidos Cafeicos , Diabetes Mellitus Tipo 2 , Ferroptosis , Glicósidos , Osteoporosis , Animales , Ratones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Factor 2 Relacionado con NF-E2 , Especies Reactivas de Oxígeno , Osteoporosis/tratamiento farmacológico , Osteoporosis/prevención & controlRESUMEN
OBJECTIVES: The ATN's different modalities (fluids and neuroimaging) for each of the Aß (A), tau (T), and neurodegeneration (N) elements are used for the biological diagnosis of Alzheimer's disease (AD). We aim to identify which ATN category achieves the highest potential for diagnosis and predictive accuracy of longitudinal cognitive decline. METHODS: Based on the availability of plasma ATN biomarkers (plasma-derived Aß42/40 , p-tau181, NFL, respectively), CSF ATN biomarkers (CSF-derived Aß42 /Aß40 , p-tau181, NFL), and neuroimaging ATN biomarkers (18F-florbetapir (FBP) amyloid-PET, 18F-flortaucipir (FTP) tau-PET, and fluorodeoxyglucose (FDG)-PET), a total of 2340 participants were selected from ADNI. RESULTS: Our data analysis indicates that the area under curves (AUCs) of CSF-A, neuroimaging-T, and neuroimaging-N were ranked the top three ATN candidates for accurate diagnosis of AD. Moreover, neuroimaging ATN biomarkers display the best predictive ability for longitudinal cognitive decline among the three categories. To note, neuroimaging-T correlates well with cognitive performances in a negative correlation manner. Meanwhile, participants in the "N" element positive group, especially the CSF-N positive group, experience the fastest cognitive decline compared with other groups defined by ATN biomarkers. In addition, the voxel-wise analysis showed that CSF-A related to tau accumulation and FDG-PET indexes more strongly in subjects with MCI stage. According to our analysis of the data, the best three ATN candidates for a precise diagnosis of AD are CSF-A, neuroimaging-T, and neuroimaging-N. CONCLUSIONS: Collectively, our findings suggest that plasma, CSF, and neuroimaging biomarkers differ considerably within the ATN framework; the most accurate target biomarkers for diagnosing AD were the CSF-A, neuroimaging-T, and neuroimaging-N within each ATN modality. Moreover, neuroimaging-T and CSF-N both show excellent ability in the prediction of cognitive decline in two different dimensions.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Neuroimagen , Disfunción Cognitiva/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Biomarcadores , Proteínas tau , Péptidos beta-AmiloidesRESUMEN
BACKGROUND: Despite extensive work to identify diagnostic plasma markers for Parkinson's disease (PD), there are still no accepted and validated surrogate biomarkers. Mitophagy-associated proteins (MAPs), including PTEN-induced putative kinase 1 (PINK1), Parkin, phosphoglycerate mutase 5 (PGAM5), BCL2 interacting protein 3 (BNIP3), and phosphorylated-TBK1 (p-TBK1), are, to our best knowledge, not well studied as a panel of biomarkers of neurodegeneration in PD. METHODS: The study population comprised 116 age-matched controls (HC), 179 PD patients, alongside and 90 PD syndromes (PDs) divided between two cohorts: (i) the modeling cohort (cohort 1), including 150 PD, 97 HC, and 80 PDs; and (ii) the validated cohort (cohort 2), including 29 PD, 19 HC, and 10 PDs. RESULTS: MAPs are elevated in the plasma of PD patients. PINK1, Parkin, and PGAM5 displayed the top three measurable increase trends in amplitude compared to BNIP3 and p-TBK1. Moreover, the area under the curve (AUC) values of PINK1, PGAM5, and Parkin were ranked the top three MAP candidates in diagnosis accuracy for PD from HC, but the MAPs make it hard to differentiate PD from PDs. In addition, there are higher plasma PINK1-Parkin levels and prominent diagnostic accuracy in A-synuclein (+) subjects than in A-synuclein (-) subjects. CONCLUSIONS: These results uncover that plasma MAPs (PINK1, Parkin, and PGAM5) may be potentially useful diagnostic biomarkers for PD diagnosis. Studies on larger cohorts would be required to test whether elevated plasma MAP levels are related to PD risk or prognosis.
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BACKGROUND: Osteoporosis is a prevalent bone metabolic disease in menopause, and long-term medication is accompanied by serious side effects. Estrogen deficiency-mediated hyperactivated osteoclasts is the initiating factor for bone loss, which is regulated by nuclear factor-κB (NF-κB) signaling. Safranal (Saf) is a monoterpene aldehyde produced from Saffron (Crocus sativus L.) and possesses multiple biological properties, particularly the anti-inflammatory property. However, Saf's role in osteoporosis remains unknown. PURPOSE: This study aims to validate the role of Saf in osteoporosis and explore the potential mechanism. STUDY DESIGN: The RANKL-exposed mouse BMM (bone marrow monocytes) and the castration-mediated osteoporosis model were applied to explore the effect and mechanism of Saf in vitro and in vivo. METHOD: The effect of Saf on osteoclast formation and function were assessed by TRAcP staining, bone-resorptive experiment, qPCR, immunoblotting and immunofluorescence, etc. Micro-CT, HE, TRAcP and immunohistochemical staining were performed to estimate the effects of Saf administration on OVX-mediated osteoporosis in mice at imaging and histological levels. RESULTS: Saf concentration-dependently inhibited RANKL-mediated osteoclast differentiation without affecting cellular viability. Meanwhile, Saf-mediated anti-osteolytic capacity and Sirt1 upregulation were also found in ovariectomized mice. Mechanistically, Saf interfered with NF-κB signaling by activating Sirt1 to increase p65 deacetylation and inactivating IKK to decrease IκBα degradation. CONCLUSION: Our results support the potential application of Saf as a therapeutic agent for osteoporosis.
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Osteoporosis , Animales , Ratones , Ratones Endogámicos C57BL , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Estrógenos/deficiencia , Estrógenos/metabolismo , Femenino , Osteoclastos , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/metabolismo , Ovariectomía , FN-kappa B/metabolismo , AcetilaciónRESUMEN
Background: We aimed to examine whether plasma-derived phosphoglycerate mutase 5 (PGAM5) can be a biomarker for Parkinson's disease (PD) diagnosis as well as its association with the severity of motor/non-motor manifestations of PD. Methods: We enrolled 124 patients with PD (PD group) and 50 healthy controls (HC group). We measured plasma PGAM5 levels using a quantitative sandwich enzyme immunoassay. Patients with PD underwent baseline evaluations using the Unified Parkinson's Disease Rating Scale (UPDRS), while participants in both groups were evaluated using scales for non-motor manifestations. Receiver operating characteristic curves were used to evaluate the predictive utility of plasma PAMG5 alone and combined with other factors. Results: Plasma PAMG5 levels were significantly higher in the PD group; the area under the curve (AUC) of plasma PGAM5 levels alone was 0.76. The AUC values for elderly participants and patients without hypertension were 0.78 and that for was 0.79. Notably, plasma PGAM5 levels combined with plasma oligomeric α-synuclein (α-syn) and the score of the REM sleep behavior disorder questionnaire-Hong Kong (RBDQ-HK) showed AUC values of 0.80 and 0.82. Multivariable logistic analysis revealed that plasma PAMG5 levels were independently associated with PD (odds ratio,1.875 [95% confidence interval 1.206-2.916], p = 0.005) but not the severity of motor/non-motor manifestations of PD. Conclusion: Plasma PGAM5 is an independent biomarker for PD, especially among elderly patients (age > 60 years) and patients without hypertension. The predictive utility of PGAM5 was improved when combined with plasma oligomeric α-syn or the RBDQ-HK score.
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Purpose: OA is a multifactorial joint disease in which inflammation plays a substantial role in the destruction of joints. Corynoline (COR), a component of Corydalis bungeana Turcz., has anti-inflammatory effects. Materials and Methods: We evaluated the significance and potential mechanisms of COR in OA development. The viabilities of chondrocytic cells upon COR exposure were assessed by CCK-8 assays. Western blot, qPCR, and ELISA were used to assess extracellular matrix (ECM) degeneration and inflammation. The NF-κB pathway was evaluated by western blot and immunofluorescence (IF). Prediction of the interacting proteins of COR was done by molecular docking, while Nrf2 knockdown by siRNAs was performed to ascertain its significance. Micro-CT, H&E, Safranin O-Fast Green (S-O), toluidine blue staining, and immunohistochemical examination were conducted to assess the therapeutic effects of COR on OA in destabilization of medial meniscus (DMM) models. Results: COR inhibited ECM degeneration and proinflammatory factor levels and modulated the NF-κB pathway in IL-1ß-treated chondrocytes. Mechanistically, COR bound Nrf2 to downregulate the NF-κB pathway. Moreover, COR ameliorated the OA process in DMM models. Conclusion: We suggest that COR ameliorates OA progress through the Nrf2/NF-κB axis, indicating COR may have a therapeutic potential for OA.
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FN-kappa B , Osteoartritis , Alcaloides de Berberina , Células Cultivadas , Condrocitos/metabolismo , Humanos , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Simulación del Acoplamiento Molecular , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismoRESUMEN
Introduction: To explore the combined diagnostic value of plasma Lewy body-associated proteins (p-Asyn at ser129, total α-syn, and oligomeric α-syn) for the diagnosis of PD versus healthy controls (HCs) and other PD syndromes (PDs), as well as clinical characteristics prediction. Methods: This study included 145 participants: 79 patients with PD, 24 patients with PDs, and 42 HCs. A panel of plasma levels of p-Asyn, total α-syn, and oligomeric α-syn was measured by enzyme-linked immunosorbent assay (ELISA). The primary outcome was the discriminative accuracy of the combined three plasma biomarkers for PD. Results: The mean age was 65.43 (SD, 7.467) in the control group, 64.49 (SD, 8.224) in participants with PD, and 69.25 (SD, 7.952) in PDs. The plasma Lewy body-associated protein levels were significantly higher in patients with PD than in age-matched HCs, However, there was no difference in patients with PD and PDs. Of note, a combination of plasma p-Asyn, total α-syn, and oligomeric α-syn was a better biomarker for discriminating PD from HCs, with an AUC of 0.8552 (p < 0.0001, 95%CI, 0.7635-0.9409), which was significantly higher than plasma p-Asyn (ΔAUC, 0.1797), total α-syn (ΔAUC, 0.0891) and oligomeric α-syn (ΔAUC, 0.1592) alone. Meanwhile, Lewy body-associated proteins had no connections between different motor stages and dementia performances. Conclusion: Our results suggested that plasma Lewy body-associated proteins, may serve as a non-invasive biomarker to aid the diagnosis of PD from HCs. In addition, increased plasma Lewy body-associated proteins were not associated with the progression of motor and non-motor symptoms.
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Intervertebral disc degeneration (IVDD) is a chronic age-related degenerative disease accompanied by complex pathophysiological mechanisms. Increasing evidence indicates that NLRP3 inflammasome mediated pyroptosis of nucleus pulposus (NP) cells displays an important role in the pathological progression of IVDD. Milk fat globule-EGF factor-8 (MFG-E8) is an endogenously secreted glycoprotein with beneficial effects of anti-inflammatory, antioxidant, and modulation of NLRP3 inflammasome. However, the effect of MFG-E8 on IVDD remains unclear. In this study, our purpose is to clarify the expression changes of MFG-E8 in the IVDD process and explore the role and mechanism of MFG-E8. We found that MFG-E8's expression was reduced in degraded nucleus pulposus tissues of humans and rats as well as hydrogen peroxide (H2O2)-treated NP cells. Exogenous supplementation of MFG-E8 could rescue H2O2-induced oxidative stress, mitochondrial dysfunction, and NLRP3 inflammasome activation and protect NP cells from pyroptosis and extracellular matrix (ECM) degradation. Mechanistically, Nrf2/TXNIP/NLRP3 axis plays a crucial role in MFG-E8-mediated suppression of the above-pathological events. In vivo, we established a rat intervertebral disc acupuncture model and found that MFG-E8 administration effectively alleviated IVDD development by imageological and histomorphological evaluation. Overall, our findings revealed the internal mechanisms underlying MFG-E8 regulation in NP cells and its intrinsic value for IVDD therapy.
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Curcumin, a polyphenolic compound extracted from curcuma longa, acts as a nontoxic matter with anti-oxidant and anti-inflammatory effects as well as antiproliferative activities. Here, our research aimed to explore the neuroprotective effects of curcumin both in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) in vivo and 6-OHDA-lesioned PC12 cells in vitro. In vitro, 6-OHDA caused a distinct decrease in cell viability of PC12 cells (150 µM). With the incubation of curcumin (1 µM), 6-OHDA-induced apoptosis was suppressed, increasing the autophagy markers (LC3-II/LC3-I, Beclin-1) and inhibiting phosphor-AKT/AKT, phosphor-mTOR/mTOR. In vivo, curcumin (50 mg/kg) reduced the accumulation of a-synuclein and led to higher parkinsonian disability scores in 6-OHDA-lesioned PD rats, contributing to induction of autophagy through inhibiting AKT/mTOR signal pathway. Moreover, treatment with autophagy inhibitors, such as 3-MA and chloroquine, abolished the neuroprotective effects of curcumin as evidence by compromised autophagy and declined motor behavior in PD rats. In conclusion, the present study demonstrated that curcumin repressed PC12 cell death in vitro and improved parkinsonian disability scores in vivo by inhibiting AKT/mTOR signaling pathway which mediated by autophagy, indicating a potential value of curcumin in the therapeutic intervention of Parkinson's disease.
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Curcumina , Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Autofagia , Curcumina/farmacología , Curcumina/uso terapéutico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Oxidopamina/toxicidad , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , RatasRESUMEN
A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer's disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-ß and tau pathologies, and improved the animals' memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational-experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.
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Enfermedad de Alzheimer , Mitofagia , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Animales , Aprendizaje Automático , Mitofagia/fisiología , Flujo de TrabajoRESUMEN
This study sought to investigate and evaluate a modified axial translaminar screw fixation for treating odontoid fractures. We performed a retrospective study at Wenzhou Medical University Affiliated Second Hospital between March 2016 and June 2018. We retrospectively collected and analyzed the medical records of 23 cases with odontoid fractures. All patients were identified as type II odontoid fractures without neurological deficiency and serious diseases following the classification of Anderson. The average age, gender ratio, and body mass index (BMI) were 54.3 ± 11.1 years, 12 men to 11 women, and 22.6 ± 2.4 kg/m2 , respectively. Patients in this study accepted screw fixation using our modified axial translaminar screw fixation combined with atlas pedicle or lateral mass screw fixation. Within the technique, a small cortical "window" was dug in the middle of the axial contralateral lamina, such that the screws in the lamina were visualized to prevent incorrectly implanting the posterior spinal canal through the visualized "window." A total of 46 bone screws were accurately inserted into the axial lamina without using fluoroscopy. The length of all translaminar screws ranged between 26 and 30 mm, while the diameter was 3.5 mm. During the follow-up survey, the visual analog scale (VAS) and neck disability index (NDI) were measured. We provide a simple modification of Wright's elegant technique with the addition of "visualized windows" at the middle of the axial lamina. In all patients, screws were inserted accurately without bony breach and the screw angle was 56.1 ± 3.0°. Mean operative time was 102 ± 28 min with an average blood loss of 50 ± 25 mL. Postoperative hemoglobin and mean length of hospital stay were 12.0 ± 1.4 g/dL and 10.4 ± 3.4 days, respectively. The average follow-up time of all cases was 14.7 months and no internal fixation displacement, loosening, or breakage was found. All patients with odontoid fractures reported being satisfied with the treatment during the recheck period and good clinical outcomes were observed. At 1, 6, and 12 months, NDI and VAS showed that the symptoms of neck pain and limitations of functional disability improved significantly during follow-up. Our results suggest that the modified translaminar screw fixation technique can efficiently treat Anderson type II odontoid fracture, followed by the benefits of less soft tissue dissection, simple operation, no fluoroscopy, and accurate placement of screws.
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Apófisis Odontoides , Fracturas de la Columna Vertebral , Fusión Vertebral , Adulto , Anciano , Tornillos Óseos , Femenino , Fijación Interna de Fracturas/métodos , Humanos , Masculino , Persona de Mediana Edad , Apófisis Odontoides/diagnóstico por imagen , Apófisis Odontoides/lesiones , Apófisis Odontoides/cirugía , Estudios Retrospectivos , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/cirugía , Fusión Vertebral/métodos , Resultado del TratamientoRESUMEN
Abnormal lipid metabolism, such as systemic increased free fatty acid, results in overproduction of pro-inflammatory enzymes and cytokines, which is crucial in the development of obesity-related osteoarthritis (OA). However, there are only a few drugs that target the lipotoxicity of OA. Recent researches have documented that the traditional Chinese medicine, Sparstolonin B (Ssn B), exerted anti-inflammatory effects in various diseases, but not yet in OA. On the basis of this evidence, our works purposed to evaluate the effect of Ssn B on free fatty acid (FFA) palmitate (PA)-stimulated human osteoarthritic chondrocytes and obesity-associated mouse OA model. We found that Ssn B suppressed PA-triggered inflammatory response and extracellular matrix catabolism in a concentration-dependent approach. In vivo, Ssn B treatment inhibited cartilage degeneration and subchondral bone calcification caused by joint mechanical imbalance and alleviated metabolic inflammation in obesity. Mechanistically, co-immunoprecipitine and molecular docking analysis showed that the formation of toll-like receptor 4 (TLR4)/myeloid differentiation protein-2 (MD-2) complex caused by PA was blocked by Ssn B. Subsequently, it leads to inactivation of PA-caused myeloid differentiation factor 88 (MyD88)-dependent nuclear factor-kappaB (NF-κB) cascade. Together, these findings demonstrated that Ssn B is a potential treatment agent for joint degenerative diseases in obese individuals.
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Condrocitos , Osteoartritis , Animales , Condrocitos/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Ratones , Ratones Obesos , Simulación del Acoplamiento Molecular , FN-kappa B/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/etiología , Osteoartritis/metabolismo , Palmitatos/farmacologíaRESUMEN
Objective: Post-stroke epilepsy (PSE) is associated with increased morbidity and mortality. Stroke-associated acute symptomatic seizures are an important risk factor: 20.8-34.3% of these patients will go on to develop PSE. Identifying these "high risk" individuals may result in earlier PSE diagnosis, treatment, and avoidance of seizure-related morbidity. This study was to identify predictors of PSE development in patients with stroke-associated acute symptomatic seizures. Participants and Methods: This was a retrospective cohort study of 167 patients with stroke-associated acute symptomatic seizures admitted to the Neurology Department of a tertiary Hospital of China, from 1 May 2006 to 30 January 2020. Both those with primary ischemic stroke and intracerebral hemorrhage were included in the study. Patient demographics, medical history, stroke-associated, and seizure-related variables were evaluated with univariable analysis and multivariable Cox regression analysis. PSE was defined as unprovoked seizures occurring > 7 days post-stroke. Data points were extracted from medical records and supplemented by tele-interview. Results: Of the 167 patients with stroke-associated acute symptomatic seizures, 49 (29.3%) developed PSE. NIHSS score > 14 [hazard ratio (HR) 2.98, 95% CI 1.57-5.67], longer interval from stroke to acute symptomatic seizures (days 4-7 post-stroke) (HR 2.51, 95% CI 1.37-4.59) and multiple acute symptomatic seizures (HR 5.08, 95% CI 2.58-9.99) were independently associated with PSE development. This association remained in the sub-analysis within the ischemic stroke cohort. In the sub-analysis of the hemorrhagic stroke cohort, multilobar involvement (HR 4.80, 95% CI 1.49-15.39) was also independently associated with development of PSE. Further, we developed a nomogram to predict individual risk of developing PSE following stroke-associated acute symptomatic seizures. The nomogram showed a C-index of 0.73. Conclusion: More severe neurofunctional deficits (NIHSS score > 14), longer interval from stroke to acute symptomatic seizures (days 4-7 post-stroke), and multiple acute symptomatic seizures were independently associated with development of PSE in patients with stroke-associated acute symptomatic seizures. This knowledge may increase clinical vigilance for development of PSE, facilitating rapid diagnosis and treatment initiation, and subsequently reduce seizure-related morbidity.
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Osteoarthritis (OA) is presently the most prevalent form of chronic degenerative joint disease, which is characterized by erosion of articular cartilage, subchondral bone sclerosis and synovitis. Accumulating evidence has revealed that 18ß-glycyrrhetinic acid (18ß-GA), a major bioactive component derived from Glycyrrhiza glabra, exerts anti-inflammatory effects on several diseases. However, the anti-inflammatory effects of 18ß-GA on OA remain undetermined. The present study aimed to investigate the anti-inflammatory effects of 18ß-GA on chondrocytes and the therapeutic effects on destabilization of the medial meniscus destabilization (DMM) mouse models of OA. For the in vivo study, we randomly divided the mice into three groups: vehicle control (n = 15), sham (n = 15) and 18ß-GA (n = 15) groups, and treated them with similar doses (50 mg kg-1 day-1) of 18ß-GA or saline. Cartilage tissues were harvested from the mice for histological analyses eight weeks after operation. For the in vitro studies, mouse chondrocytes were administered with 10 ng mL-1 interleukin-1ß (IL-1ß) after being treated with 18ß-GA at various concentrations. In vitro assays revealed that treatment with 18ß-GA considerably suppressed the expression of pro-inflammatory mediators and cytokines, including prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), nitric oxide (NO), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and interleukin-6 (IL-6), which were induced by IL-1ß. Furthermore, 18ß-GA decreased the expression of matrix-degrading proteases, including matrix metalloproteinase 13 (MMP13) and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), in a concentration-dependent manner, which mediated extracellular matrix (ECM) degradation. 18ß-GA reversed aggrecan and type II collagen degradation. Furthermore, we observed that 18ß-GA significantly suppressed IL-1ß-induced nuclear factor kappa B (NF-κB) activation by activating the nuclear factor erythroid-derived 2-like 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway in vitro and in vivo. Experiments demonstrated that 18ß-GA might alleviate the progression of OA in the DMM mouse model in vivo. The findings demonstrate that 18ß-GA reduces inflammation induced by IL-1ß in chondrocytes. Therefore, 18ß-GA could be a potential therapeutic agent for OA.
Asunto(s)
Condrocitos/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Ácido Glicirretínico/análogos & derivados , Inflamación/tratamiento farmacológico , Interleucina-1beta/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Osteoartritis/tratamiento farmacológico , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacología , Inflamación/inducido químicamente , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Factor 2 Relacionado con NF-E2/genéticaRESUMEN
Mitochondria in neurons generate adenosine triphosphate (ATP) to provide the necessary energy required for constant activity. Nicotinamide adenine dinucleotide (NAD+) is a vital intermediate metabolite involved in cellular bioenergetics, ATP production, mitochondrial homeostasis, and adaptive stress responses. Exploration of the biological functions of NAD+ has been gaining momentum, providing many crucial insights into the pathophysiology of age-associated functional decline and diseases, such as Alzheimer's disease (AD). Here, we systematically review the key roles of NAD+ precursors and related metabolites in AD models and show how NAD+ affects the pathological hallmarks of AD and the potential mechanisms of action. Advances in understanding the molecular roles of NAD+-based neuronal resilience will result in novel approaches for the treatment of AD and set the stage for determining whether the results of exciting preclinical trials can be translated into the clinic to improve AD patients' phenotypes.
RESUMEN
The main histopathology of Alzheimer's disease (AD) is featured by the extracellular accumulation of amyloid-ß (Aß) plaques and intracellular tau neurofibrillary tangles (NFT) in the brain, which is likely to result from co-pathogenic interactions among multiple factors, e.g., aging or genes. The link between defective autophagy/mitophagy and AD pathologies is still under investigation and not fully established. In this review, we consider how AD is associated with impaired autophagy and mitophagy, and how these impact pathological hallmarks as well as the potential mechanisms. This complicated interplay between autophagy or mitophagy and histopathology in AD suggests that targeting autophagy or mitophagy probably is a promising anti-AD drug candidate. Finally, we review the implications of some new insights for induction of autophagy or mitophagy as the new therapeutic way that targets processes upstream of both NFT and Aß plaques, and hence stops the neurodegenerative course in AD.