Construction and validation of a nomogram to predict the overall survival of small cell lung cancer: a multicenter retrospective study in Shandong province, China.

BACKGROUND: Patients diagnosed with small cell lung cancer (SCLC) typically experience a poor prognosis, and it is essential to predict overall survival (OS) and stratify patients based on distinct prognostic risks. METHODS: Totally 2309 SCLC patients from the hospitals in 15 cities of Shandong from 2010 - 2014 were included in this multicenter, population-based retrospective study. The data of SCLC patients during 2010-2013 and in 2014 SCLC were used for model development and validation, respectively. OS served as the primary outcome. Univariate and multivariate Cox regression were applied to identify the independent prognostic factors of SCLC, and a prognostic model was developed based on these factors. The discrimination and calibration of this model were assessed by the time-dependent C-index, time-dependent receiver operator characteristic curves (ROC), and calibration curves. Additionally, Decision Curve Analysis (DCA) curves, Net Reclassification Improvement (NRI), and Integrated Discriminant Improvement (IDI) were used to assess the enhanced clinical utility and predictive accuracy of the model compared to TNM staging systems. RESULTS: Multivariate analysis showed that region (Southern/Eastern, hazard ratio [HR] = 1.305 [1.046 - 1.629]; Western/Eastern, HR = 0.727 [0.617 - 0.856]; Northern/Eastern, HR = 0.927 [0.800 - 1.074]), sex (female/male, HR = 0.838 [0.737 - 0.952]), age (46-60/≤45, HR = 1.401 [1.104 - 1.778]; 61-75/≤45, HR = 1.500 [1.182 - 1.902]; >75/≤45, HR = 1.869 [1.382 - 2.523]), TNM stage (II/I, HR = 1.119[0.800 - 1.565]; III/I, HR = 1.478 [1.100 - 1.985]; IV/I, HR = 1.986 [1.477 - 2.670], surgery (yes/no, HR = 0.677 [0.521 - 0.881]), chemotherapy (yes/no, HR = 0.708 [0.616 - 0.813]), and radiotherapy (yes/no, HR = 0.802 [0.702 - 0.917]) were independent prognostic factors of SCLC patients and were included in the nomogram. The time-dependent AUCs of this model in the training set were 0.699, 0.683, and 0.683 for predicting 1-, 3-, and 5-year OS, and 0.698, 0.698, and 0.639 in the validation set, respectively. The predicted calibration curves aligned with the ideal curves, and the DCA curves, the IDI, and the NRI collectively demonstrated that the prognostic model had a superior net benefit than the TNM staging system. CONCLUSION: The nomogram using SCLC patients in Shandong surpassed the TNM staging system in survival prediction accuracy and enabled the stratification of patients with distinct prognostic risks based on nomogram scores.

Oral P. gingivalis impairs gut permeability and mediates immune responses associated with neurodegeneration in LRRK2 R1441G mice.

BACKGROUND: The R1441G mutation in the leucine-rich repeat kinase 2 (LRRK2) gene results in late-onset Parkinson's disease (PD). Peripheral inflammation and gut microbiota are closely associated with the pathogenesis of PD. Chronic periodontitis is a common type of peripheral inflammation, which is associated with PD. Porphyromonas gingivalis (Pg), the most common bacterium causing chronic periodontitis, can cause alteration of gut microbiota. It is not known whether Pg-induced dysbiosis plays a role in the pathophysiology of PD. METHODS: In this study, live Pg were orally administrated to animals, three times a week for 1 month. Pg-derived lipopolysaccharide (LPS) was used to stimulate mononuclear cells in vitro. The effects of oral Pg administration on the gut and brain were evaluated through behaviors, morphology, and cytokine expression. RESULTS: Dopaminergic neurons in the substantia nigra were reduced, and activated microglial cells were increased in R1441G mice given oral Pg. In addition, an increase in mRNA expression of tumor necrosis factor (TNF-α) and interleukin-1ß (IL-1ß) as well as protein level of α-synuclein together with a decrease in zonula occludens-1 (Zo-1) was detected in the colon in Pg-treated R1441G mice. Furthermore, serum interleukin-17A (IL-17A) and brain IL-17 receptor A (IL-17RA) were increased in Pg-treated R1441G mice. CONCLUSIONS: These findings suggest that oral Pg-induced inflammation may play an important role in the pathophysiology of LRRK2-associated PD.

Evidence for Polyamine, Biogenic Amine, and Amino Acid Adduction Resulting from Metabolic Activation of Diosbulbin B.

Dioscorea bulbifera L. (DBL), a traditional Chinese medicine, is a well-known herb with hepatotoxicity, and the biochemical mechanisms of the toxic action remain unknown. Diosbulbin B (DSB), a major component of DBL, can induce severer liver injury which requires cytochrome P450-catalyzed oxidation of the furan ring. It is reported that a cis-enedial reactive intermediate resulting from metabolic activation of DSB can react with thiols and amines to form pyrrole or pyrroline derivatives. In this study, we investigated the interaction of the reactive intermediate with polyamines, biogenic amines, and amino acids involved in the polyamine metabolic pathway, including putrescine, spermidine, spermine, histamine, arginine, ornithine, lysine, glutamine, and asparagine. Seven DSB-derived amine adducts were detected in microsomal incubations supplemented with DSB and individual amines. Six adducts were observed in cultured rat primary hepatocytes after exposure to DSB. DSB was found to induce apoptosis and cell death in time- and concentration-dependent manners. Apparently, the observed apoptosis was associated with the detected amine adduction. The findings facilitate the understanding of the mechanisms of toxic action of DSB.

Sirt6 deacetylase activity regulates circadian rhythms via Per2.

Circadian clock relies on a transcription and translation feedback loop (TTFL). Two transcription factors, i.e. Bmal1 and Clock, activate the transcription of Period (Per) and Cryptochrome (Cry), which inhibit their own transcription when accumulated to a critical concentration. NAD+-dependent deacylase Sirt1 deacetylates Bmal1 and Per2 to regulate circadian rhythms. Sirt6 interacts with Bmal1 to regulate clock-controlled gene (CCG) expression by local chromatin remodeling. Whether Sirt6 directly modify clock components is elusive. Here, we found that loss of Sirt6 jeopardizes circadian phase. At molecular level, Sirt6 interacts with and deacetylates Per2, thus preventing its proteasomal degradation. These data highlight an important function of Sirt6 in the direct regulation of TTFL and circadian rhythms.

Glutathione Conjugation and Protein Adduction Derived from Oxidative Debromination of Benzbromarone in Mice.

Benzbromarone (BBR), a uricosuric agent, has been known to induce hepatotoxicity, and its toxicity has a close relation to cytochrome P450-mediated metabolic activation. An oxidative debromination metabolite of BBR has been reported in microsomal incubations. The present study attempted to define the oxidative debromination pathway of BBR in vivo. One urinary mercapturic acid (M1) and one glutathione (GSH) conjugate (M2) derived from the oxidative debromination metabolite were detected in BBR-treated mice after solid phase extraction. M1 and M2 shared the same chromatographic behavior and mass spectral identities as those detected in N-acetylcysteine/GSH- and BBR-fortified microsomal incubations. The structure of M1 was characterized by chemical synthesis, along with mass spectrometry analysis. In addition, hepatic protein modification that occurs at cysteine residues (M'3) was observed in mice given BBR. The observed protein adduction reached its peak 4 hours after administration and occurred in a dose-dependent manner. A GSH conjugate derived from oxidative debromination of BBR was detected in livers of mice treated with BBR, and the formation of the GSH conjugate apparently took place earlier than the protein adduction. In summary, our in vivo work provided strong evidence for the proposed oxidative debromination pathway of BBR, which facilitates the understanding of the mechanisms of BBR-induced hepatotoxicity. SIGNIFICANCE STATEMENT: This study investigated the oxidative debromination pathway of benzbromarone (BBR) in vivo. One urinary mercapturic acid (M1) and one glutathione (GSH) conjugate (M2) derived from the oxidative debromination metabolite were detected in BBR-treated mice. M1 and M2 were also observed in microsomal incubations. The structure of M1 was characterized by chemical synthesis followed by mass spectrometry analyses. More importantly, protein adduction derived from oxidative debromination of BBR (M'3) was observed in mice given BBR, and occurred in dose- and time-dependent manners. The success in detection of GSH conjugate, urinary N-acetylcysteine conjugate, and hepatic protein adduction in mice given BBR provided solid evidence for in vivo oxidative debromination of BBR. The studies allowed a better understanding of the metabolic activation of BBR.

Chemical Interaction of Protein Cysteine Residues with Reactive Metabolites of Methyleugenol.

Methyleugenol (ME), an alkenylbenzene compound, is a natural ingredient of several herbs and is used as flavoring agent in foodstuffs and fragrance in cosmetics. The hepatotoxicity, cytotoxicity, and carcinogenesis of ME have been well documented, and metabolic activation has been suggested to involve in ME-induced toxicities. The objective of this study was to identify chemical identity of interactions of protein with reactive metabolites of ME. Modification of cysteine residues of protein was observed in microsomal incubations and mice after exposure to ME. Three types of protein modification derived from the corresponding epoxide, α,ß-unsaturated aldehyde, and carbonium ion of ME were detected in vitro and in vivo. The protein adduction took place in time- and dose-dependent manners. Dexamethasone, ketoconazole, and l-buthionine sulfoximine increased the protein modification induced by ME, which was proportional to the hepatotoxicity of ME. The findings facilitate the understanding of mechanism action of ME toxicities.

Cysteine-Based Protein Adduction by Epoxide-Derived Metabolite(s) of Benzbromarone.

Benzbromarone (BBR) is a therapeutically useful uricosuric agent but can also cause acute liver injury. The hepatotoxicity of BBR is suggested to be associated with its metabolic activation. Our recent metabolic study demonstrated that BBR was metabolized to epoxide intermediate(s) by cytochrome P450 3A, and the intermediate(s) was reactive to N-acetylcysteine. The objectives of the present study were to determine the chemical identity of the interaction of protein with the epoxide intermediate(s) of BBR and to define the association of the protein modification with hepatotoxicity induced by BBR. Microsomal incubation study showed that the reactive intermediate(s) covalently modified microsomal protein at cysteine residues. Such adduction was also observed in hepatic protein obtained from liver of mice given BBR. The protein covalent binding occurred in time- and dose-dependent manners. Pretreatment with ketoconazole attenuated BBR-induced protein modification and hepatotoxicity, while pretreatment with dexamethasone or buthionine sulfoximine potentiated the protein adduction and hepatotoxicity induced by BBR. A good correlation was observed between BBR-induced hepatotoxicity and the epoxide-derived hepatic protein modification in mice. The present study provided in-depth mechanistic insight into BBR-induced hepatotoxicity.

Cortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity.

Microinfarcts are common among the elderly and patients with microinfarcts are more vulnerable to another stroke. However, the impact of microinfarcts on recurrent stroke has yet to be fully understood. The purpose of this study was to explore the negative effects of microinfarcts on recurrent stroke. To achieve this, two-photon laser was used to induce microinfarcts, while photothrombotic stroke was induced on the opposite side. The results showed that microinfarcts led to trained immunity in microglia, which worsened the pro-inflammatory response and ischemic injury in the secondary photothrombotic stroke. Additionally, the study clarified the role of NLRP3 in microglial nuclei, indicating that it interacts with the MLL1 complex through NACHT domain and increases H3K4 methylation, which suggests that NLRP3 is critical in the formation of innate immune memory caused by microinfarcts. Furthermore, the knockout of NLRP3 in microglia alleviated the trained immunity and reduced the harmful effects of microinfarcts on recurrent stroke. This study emphasizes the detrimental effect of trained immunity on recurrent stroke and highlights the critical role of NLRP3 in mediating the formation of this memory, which may offer a potential therapeutic target for mitigating recurrent strokes.

Validated LC-MS method for simultaneous quantitation of catalpol and harpagide in rat plasma: application to a comparative pharmacokinetic study in normal and diabetic rats after oral administration of Zeng-Ye-Decoction.

A simple and efficient liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for simultaneous quantitation of catalpol and harpagide in normal and diabetic rat plasma. Protein precipitation extraction with acetonitrile was carried out using salidroside as the internal standard (IS). The LC separation was performed on an Elite C18 column (150 × 4.6 mm, 5 µm) with the mobile phase consisting of acetonitrile and water within a runtime of 12.0 min. The analytes were detected without endogenous interference in the selected ion monitoring mode with positive electrospray ionization. Calibration curves offered satisfactory linearity (r > 0.99) at linear range of 0.05-50.0 µg/mL for catalpol and 0.025-5.0 µg/mL for harpagide with the lower limits of quantitation of 0.05 and 0.025 µg/mL, respectively. Intra- and inter-day precisions (RSD) were <9.4%, and accuracy (RE) was in the -6.6 to 4.9% range. The extraction efficiencies of catalpol, harpagide and IS were all >76.5% and the matrix effects of the analytes ranged from 86.5 to 106.0%. The method was successfully applied to the pharmacokinetic study of catalpol and harpagide after oral administration of Zeng-Ye-Decoction to normal and diabetic rats, respectively.

Air Pollution and Prosocial Behavior in Chinese Adolescents: The Role of Resilience and Interpersonal Relations.

Purpose: Past studies have indicated that air pollution is a major environmental factor that negatively affects prosocial behavior in adolescents. However, the mechanism underlying this negative relationship has not been fully explored. This study postulated that this impact may occur through individual resilience, a major psychological capital for adolescents. In addition, we studied interpersonal relations, namely, adolescents' perceived family and teacher support, which may moderate the proposed relationship. Methods: This study combined the three-year tracking survey data of 11-to-15 old adolescents (N=1301; approximately 48% female) in China with objective data from the air quality index (AQI) to measure the level of air pollution. Results: Findings from ordinary least squares analysis indicated that air pollution negatively influences adolescents' prosocial behavior, and their resilience mediates this negative relationship. In addition, the results showed that the negative effect of air pollution on adolescent resilience is attenuated by higher family income, whereas it is accentuated by the absence of teacher support. Conclusion: Our study provides insight into how the negative effect of air pollution on adolescents' prosocial behavior is mediated by their psychological resilience, and highlights the moderating role of adolescents' interpersonal relations in the association between air pollution and their psychological resilience. Our research also provides practical advice on how families, teachers, and psychologists can mitigate this negative impact.

Age at menopause is inversely related to the prevalence of common gynecologic cancers: a study based on NHANES.

Background: The fluctuation or even loss of estrogen level caused by menopause in women, and most gynecological cancers often occur before and after menopause, so the age of menopause may be related to the occurrence of gynecological cancer. Aim: To investigate whether the age at menopause is independently associated with the incidence of gynecological cancers and to analyze the possible influencing factors. Methods: We selected the NHANES public database to conduct the study, and by excluding relevant influencing factors, we finally included 5706 NHANES participants who had full data on age at menopause and the occurrence of gynecologic cancers to analyze the relationship between the amount of age at menopause and gynecologic cancers based on univariate or multifactorial logistic regression analysis. Further, the relationship between age at menopause and the prevalence of different gynecologic cancers was investigated, and changes in the prevalence of different gynecologic cancers by age at menopause subgroups were observed. Finally, other relevant factors affecting the prevalence of gynecologic cancers were further investigated by subgroup analysis as well as subcluster analysis. Results: Univariate logistic regression analysis between age at menopause and gynecologic tumor prevalence revealed a negative association between age at menopause and the prevalence of common gynecologic cancers ovarian and cervical cancer, and after adjusting for the effects of covariates, a higher risk of gynecologic tumors was found with statistically significant differences at earlier age at menopause. The regression results showed a negative association between age at menopause and gynecologic cancer prevalence in cervical and ovarian cancer patients (P<0.01,P<0.01). Cervical cancer (OR: 0.91, 95% CI: 0.87,0.94) and ovarian cancer (OR: 0.90, 95% CI: 0.86, 0.95) were more prevalent among those with younger age at menopause. Conclusion: Age at menopause is negatively associated with the prevalence of cervical and ovarian cancers, and the earlier the age at menopause, the greater the risk of developing gynecological cancers.

Case Report: Rapid Progression of Cognitive Dysfunction as an Initial Feature of Systemic Lupus Erythematosus With Leukoencephalopathy: A Case Report and Literature Review.

Neuropsychiatric systemic lupus erythematosus (NPSLE) has been considered to have high morbidity and mortality. Thus, earlier recognition and treatment are of great importance. However, the rapid progression of cognitive dysfunction with leukoencephalopathy as an initial presentation in SLE is rarely described. We report a case in which an elderly man experienced rapidly progressive cognitive impairment with bilateral, symmetric, and diffuse leukoencephalopathy with lasting diffusion-weighted image hyperintensity. An immunological workup showed low complement levels and positivity for antinuclear antibody -speckle and Coombs tests in the patient's serum samples. He had an appropriate improvement in cognitive function after receiving a combination of various immunotherapies. Long-term follow-up showed clinical improvement, including rheumatological labs and neuroimaging. A review of the literature on NPSLE with leukoencephalopathy and a summary of all reported cases to date are also presented. Our case indicated that isolated leukoencephalopathy in NPSLE, as an indicator of severe NPSLE, can be recognized early. Immunotherapy is warranted given the possibility of clinical improvement.

Analysis of ECG Signals by Dynamic Mode Decomposition.

OBJECTIVE: Based on cybernetics, a large system can be divided into subsystems, and the stability of each can determine the overall properties of the system. However, this stability analysis perspective has not yet been employed in electrocardiogram (ECG) signals. This is the first study to attempt to evaluate whether the stability of decomposed ECG subsystems can be analyzed in order to effectively investigate the overall performance of ECG signals, and aid in disease diagnosis. METHODS: We used seven different cardiac pathologies (myocardial infarction, cardiomyopathy, bundle branch block, dysrhythmia, hypertrophy, myocarditis, and valvular heart disease) to illustrate our method. Dynamic mode decomposition (DMD) was first used to decompose ECG signals into dynamic modes (DMs) which can be regarded as ECG subsystems. Then, the features related to the DMs stabilities were extracted, and nine common classifiers were implemented for classification of these pathologies. RESULTS: Most features were significant for differentiating the above-mentioned groups (p value<0.05 after Bonferroni correction). In addition, our method outperformed all existing methods for cardiac pathology classification. CONCLUSION: We have provided a new spatial and temporal decomposition method, namely DMD, to study ECG signals. SIGNIFICANCE: Our method can reveal new cardiac mechanisms, which can contribute to the comprehensive understanding of its underlying mechanisms and disease diagnosis, and thus, can be widely used for ECG signal analysis in the future.

Brain Network Analysis by Stable and Unstable EEG Components.

OBJECTIVE: Previous studies have already shown that electroencephalography (EEG) brain network (BN) can reflect the health status of individuals. However, novel methods are still needed for BN analysis. Therefore, in this study, BNs were constructed based on stable and unstable EEG components, and these may be implemented for disease diagnosis. METHODS: Parkinson's disease (PD) was used as an example to illustrate this method. First, EEG signals were decomposed into dynamic modes (DMs). Each DM contains one eigenvalue that can determine not only the stability of that mode, but also its corresponding oscillatory frequency. Second, the stable and unstable components of EEG signals in each frequency band (delta, theta, alpha and beta) were calculated, which are based on the stable and unstable DMs within each respective frequency band. Third, newly developed BNs were constructed, including stable brain network (SBN), unstable brain network (UBN) and inter-connected brain network (IBN). Finally, their topological attributes were extracted in order to differentiate between PD patients and healthy controls (HC). Furthermore, topological attributes were also derived from traditional brain network (TBN) for comparison. RESULTS: Most topological attributes of SBN, UBN and IBN can significantly differentiate between PD patients and HC ( p value 0.05). Furthermore, the area under the curve (AUC), precision and recall values of SBN analysis are all significantly higher than TBN. CONCLUSION: We proposed a new perspective on EEG BN analysis. SIGNIFICANCE: These newly developed BNs not only have biological significance, but also could be widely applied in most medical and engineering fields.

Gait Analysis by Causal Decomposition.

Recent studies have investigated bilateral gaits based on the causality analysis of kinetic (or kinematic) signals recorded using both feet. However, these approaches have not considered the influence of their simultaneous causation, which might lead to inaccurate causality inference. Furthermore, the causal interaction of these signals has not been investigated within their frequency domain. Therefore, in this study we attempted to employ a causal-decomposition approach to analyze bilateral gait. The vertical ground reaction force (VGRF) signals of Parkinson's disease (PD) patients and healthy control (HC) individuals were taken as an example to illustrate this method. To achieve this, we used ensemble empirical mode decomposition to decompose the left and right VGRF signals into intrinsic mode functions (IMFs) from the high to low frequency bands. The causal interaction strength (CIS) between each pair of IMFs was then assessed through the use of their instantaneous phase dependency. The results show that the CISes between pairwise IMFs decomposed in the high frequency band of VGRF signals can not only markedly distinguish PD patients from HC individuals, but also found a significant correlation with disease progression, while other pairwise IMFs were not able to produce this. In sum, we found for the first time that the frequency specific causality of bilateral gait may reflect the health status and disease progression of individuals. This finding may help to understand the underlying mechanisms of walking and walking-related diseases, and offer broad applications in the fields of medicine and engineering.

In Vitro and In Vivo Evidence for RNA Adduction Resulting from Metabolic Activation of Methyleugenol.

Methyleugenol (ME) is a ubiquitous component in spices and other culinary herbal products. A prevailing theory in ME toxicity is its ability to be metabolically activated by P450 enzymes and sulfotransferases, which initiates sequential reactions of the resulting metabolites with functional biomolecules. The present study aimed at a potential interaction between the reactive metabolites of ME and RNA. Cultured mouse primary hepatocytes were incubated with ME followed by RNA extraction and NaOH and alkaline phosphatase-based RNA hydrolysis. Three adenosine adducts were detected in the hydrolytic mixture by LC-MS/MS. The same adenosine adducts were also detected in hepatic tissues harvested from ME-treated mice. These three adducts were chemically synthesized and structurally characterized by 1H NMR. Additionally, two guanosine adducts and one cytidine adduct were detected in the in vivo samples. These results provided solid evidence that the reactive metabolites of ME attacked RNA, resulting in RNA adduction.

Assessment of Balance Control Subsystems by Artificial Intelligence.

Recent studies have shown that balance performance assessment based on artificial intelligence (AI) is feasible. However, balance control is very complex and requires different subsystems to participate, which have not been evaluated individually yet. Furthermore, these studies only classified individual's balance performance across limited grades. Therefore, in this study we attempted to implement AI to precisely evaluate different types of balance control subsystems (BCSes). First, a total of 224 commonly used and newly developed features were extracted from the center of pressure (CoP) data for each participant, respectively. Then, regressors were employed in order to map these features to the evaluation scores given by physical therapists, which include the total score in Mini-Balance-Evaluation-Systems-Tests (Mini-BESTest) and its sub-scores on BCSes, namely anticipatory postural adjustments (APA), reactive postural control (RPC), sensory orientation (SO), and dynamic gait (DG). Their scoring ranges should be 0-28, 0-6, 0-6, 0-6, and 0-10, respectively. The results show that their minimum mean absolute errors from AI estimation reach up to 2.658, 0.827, 0.970, 0.642, and 0.98, respectively. In sum, our study is a preliminary study for assessing BCSes based on AI, which shows its possibility to be used in the clinics in the future.

Extracellular ASC exacerbated the recurrent ischemic stroke in an NLRP3-dependent manner.

Using a photothrombotic mouse model of single stroke, we show that a single stroke onset increases the nuclear factor-κB (NF-κB), NLR family CARD domain containing protein 4 (NLRC4), and absent in melanoma 2 (AIM2) inflammasomes, as well as the mRNA levels of NLRP3. Next, using a photothrombotic mouse model of recurrent stroke, we found that recurrent strokes increased the activation of NLRP3, exacerbated the brain damage and the pro-inflammatory response in wild type (WT) mice, but not in NLRP3 knockout (NLRP3 KO) mice. Additionally, we found that apoptosis-associated speck-like protein containing a CARD (ASC) protein level surrounding the infarct area was comparatively increased, but that ASC specks outside of microglia in both the ipsilateral and contralateral of stroke site were decreased in NLRP3 KO mice relative to wild-type (WT) controls, and the number of ASC specks surrounding the second infarct area was positively correlated to the damage scores. Mechanistically, we found that recombinant ASC (RecASC) activated NLRP3 and induced pro-inflammatory responses, exacerbating the outcome of ischemic stroke, in WT mice, but not in NLRP3 KO mice. We therefore conclude that the NLRP3 inflammasome is activated by two attacks of stroke, which act together with ASC to exacerbate recurrent strokes.

Mesenchymal stem cell-derived exosomes improve motor function and attenuate neuropathology in a mouse model of Machado-Joseph disease.

BACKGROUND: Machado-Joseph disease is the most common autosomal dominant hereditary ataxia worldwide without effective treatment. Mesenchymal stem cells (MSCs) could slow the disease progression, but side effects limited their clinical application. Besides, MSC-derived exosomes exerted similar efficacy and have many advantages over MSCs. The aim of this study was to examine the efficacy of MSC-derived exosomes in YACMJD84.2 mice. METHODS: Rotarod performance was evaluated every 2 weeks after a presymptomatic administration of intravenous MSC-derived exosomes twice in YACMJD84.2 mice. Loss of Purkinje cells, relative expression level of Bcl-2/Bax, cerebellar myelin loss, and neuroinflammation were assessed 8 weeks following treatment. RESULTS: MSC-derived exosomes were isolated and purified through anion exchange chromatography. Better coordination in rotarod performance was maintained for 6 weeks in YACMJD84.2 mice with exosomal treatment, compared with those without exosomal treatment. Neuropathological changes including loss of Purkinje cells, cerebellar myelin loss, and neuroinflammation were also attenuated 8 weeks after exosomal treatment. The higher relative ratio of Bcl-2/Bax was consistent with the attenuation of loss of Purkinje cells. CONCLUSIONS: MSC-derived exosomes could promote rotarod performance and attenuate neuropathology, including loss of Purkinje cells, cerebellar myelin loss, and neuroinflammation. Therefore, MSC-derived exosomes have a great potential in the treatment of Machado-Joseph disease.

Chronic colitis induces meninges traffic of gut-derived T cells, unbalances M1 and M2 microglia/macrophage and increases ischemic brain injury in mice.

Ischemic stroke is one of the most common diseases leading to death and is the primary cause of physical handicap. Recent studies have reported that chronic colitis increases the risk of ischemic stroke, but it is unknown whether chronic colitis participates in ischemic brain injury directly. A combined mouse model of chronic colitis induced by dextran sodium sulfate (DSS) and ischemic stroke induced by photochemical infarction was used in this study. We demonstrated that chronic colitis significantly increased the infarction volume, activated microglia/macrophage numbers, proliferation of M1 microglia/macrophage, non-gut-derived CD4+ T lymphocyte penetration and decreased neuron numbers in the peri-infarction at 7 d after stroke. Furthermore, gut-derived CD4+ T cell accumulation on the meninges was observed at 7 d after stroke. In addition, selective depletion of meningeal macrophages resulted in a reduction of infarction volume and the non-gut-derived CD4+ T lymphocyte penetration. We concluded that chronic colitis exacerbated ischemic stroke by promoting CD4+ T cell migration from the gut to the meninges and disequilibrium of M1 and M2 microglia/macrophages. We speculated that the gut-derived CD4+ T cells may interact with meningeal macrophages and result in non-gut-derived CD4+ T lymphocyte infiltration that aggravated brain injury in ischemic stroke.