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Introduction: There have been large geographical differences in the infection and death rates of COVID-19. Foods and beverages containing high amounts of phytochemicals with bioactive properties were suggested to prevent contracting and to facilitate recovery from COVID-19. The goal of our study was to determine the correlation of the type of foods/beverages people consumed and the risk reduction of contracting COVID-19 and the recovery from COVID-19. Methods: We developed an online survey that asked the participants whether they contracted COVID-19, their symptoms, time to recover, and their frequency of eating various types of foods/beverages. The survey was developed in 10 different languages. Results: The participants who did not contract COVID-19 consumed vegetables, herbs/spices, and fermented foods/beverages significantly more than the participants who contracted COVID-19. Among the six countries (India/Iran/Italy/Japan/Russia/Spain) with over 100 participants and high correspondence between the location of the participants and the language of the survey, in India and Japan the people who contracted COVID-19 showed significantly shorter recovery time, and greater daily intake of vegetables, herbs/spices, and fermented foods/beverages was associated with faster recovery. Conclusions: Our results suggest that phytochemical compounds included in the vegetables may have contributed in not only preventing contraction of COVID-19, but also accelerating their recovery.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. The etiology of sporadic ALS (sALS) has not yet been clarified. An increasing body of evidence suggests the involvement of viral infections and interferons (IFNs). Human myxovirus resistance protein A (MxA) is an IFN-induced dynamin-like GTPase that acts as a potent antiviral factor. This study examined MxA expression in ALS patient spinal cords using immunohistochemistry. Thirty-two cases of sALS (pathologically proven ALS-TDP), 10 non-ALS, other neurological disease control cases were examined. In most ALS cases, MxA cytoplasmic condensates were observed in the remaining spinal anterior horn neurons. The ALS group had a significantly higher rate of MxA-highly expressing neurons than the non-ALS group. Colocalization of MxA cytoplasmic condensate and transactive response DNA-binding protein 43 kDa (TDP-43)-positive inclusions was rarely observed. Because MxA has antiviral activity induced by IFNs, our results suggest that IFNs are involved in the pathogenesis of ALS in spinal cord anterior horn neurons. Our study also suggests that monitoring viral infections and IFN activation in patients with ALS may be critically important.
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Esclerosis Amiotrófica Lateral , Proteínas de Resistencia a Mixovirus , Médula Espinal , Humanos , Proteínas de Resistencia a Mixovirus/genética , Proteínas de Resistencia a Mixovirus/metabolismo , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/genética , Femenino , Masculino , Persona de Mediana Edad , Anciano , Médula Espinal/metabolismo , Médula Espinal/patología , Adulto , Anciano de 80 o más Años , Células del Asta Anterior/patología , Células del Asta Anterior/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genéticaRESUMEN
BACKGROUND: Smell disorders are commonly reported with COVID-19 infection. The smell-related issues associated with COVID-19 may be prolonged, even after the respiratory symptoms are resolved. These smell dysfunctions can range from anosmia (complete loss of smell) or hyposmia (reduced sense of smell) to parosmia (smells perceived differently) or phantosmia (smells perceived without an odor source being present). Similar to the difficulty that people experience when talking about their smell experiences, patients find it difficult to express or label the symptoms they experience, thereby complicating diagnosis. The complexity of these symptoms can be an additional burden for patients and health care providers and thus needs further investigation. OBJECTIVE: This study aims to explore the smell disorder concerns of patients and to provide an overview for each specific smell disorder by using the longitudinal survey conducted in 2020 by the Global Consortium for Chemosensory Research, an international research group that has been created ad hoc for studying chemosensory dysfunctions. We aimed to extend the existing knowledge on smell disorders related to COVID-19 by analyzing a large data set of self-reported descriptive comments by using methods from natural language processing. METHODS: We included self-reported data on the description of changes in smell provided by 1560 participants at 2 timepoints (second survey completed between 23 and 291 days). Text data from participants who still had smell disorders at the second timepoint (long-haulers) were compared with the text data of those who did not (non-long-haulers). Specifically, 3 aims were pursued in this study. The first aim was to classify smell disorders based on the participants' self-reports. The second aim was to classify the sentiment of each self-report by using a machine learning approach, and the third aim was to find particular food and nonfood keywords that were more salient among long-haulers than those among non-long-haulers. RESULTS: We found that parosmia (odds ratio [OR] 1.78, 95% CI 1.35-2.37; P<.001) as well as hyposmia (OR 1.74, 95% CI 1.34-2.26; P<.001) were more frequently reported in long-haulers than in non-long-haulers. Furthermore, a significant relationship was found between long-hauler status and sentiment of self-report (P<.001). Finally, we found specific keywords that were more typical for long-haulers than those for non-long-haulers, for example, fire, gas, wine, and vinegar. CONCLUSIONS: Our work shows consistent findings with those of previous studies, which indicate that self-reports, which can easily be extracted online, may offer valuable information to health care and understanding of smell disorders. At the same time, our study on self-reports provides new insights for future studies investigating smell disorders.
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COVID-19 , Procesamiento de Lenguaje Natural , Trastornos del Olfato , Autoinforme , Humanos , COVID-19/complicaciones , COVID-19/epidemiología , Trastornos del Olfato/epidemiología , Trastornos del Olfato/etiología , Estudios Transversales , Masculino , Femenino , Estudios Longitudinales , Persona de Mediana Edad , Adulto , Anciano , Adulto JovenRESUMEN
Prion disease is an infectious and fatal neurodegenerative disease. Western blotting (WB)-based identification of proteinase K (PK)-resistant prion protein (PrPres) is considered a definitive diagnosis of prion diseases. In this study, we aimed to detect PrPres using formalin-fixed paraffin-embedded (FFPE) specimens from cases of sporadic Creutzfeldt-Jakob disease (sCJD), Gerstmann-Sträussler-Scheinker disease (GSS), glycosylphosphatidylinositol-anchorless prion disease (GPIALP), and V180I CJD. FFPE samples were prepared after formic acid treatment to inactivate infectivity. After deparaffinization, PK digestion was performed, and the protein was extracted. In sCJD, a pronounced PrPres signal was observed, with antibodies specific for type 1 and type 2 PrPres exhibited a strong or weak signals depending on the case. Histological examination of serial sections revealed that the histological changes were compatible with the biochemical characteristics. In GSS and GPIALP, prion protein core-specific antibodies presented as PrPres bands at 8-9 kDa and smear bands, respectively. However, an antibody specific for the C-terminus presented as smears in GSS, with no PrPres detected in GPIALP. It was difficult to detect PrPres in V180I CJD. Collectively, our findings demonstrate the possibility of detecting PrPres in FFPE and classifying the prion disease types. This approach facilitates histopathological and biochemical evaluation in the same sample and is safe owing to the inactivation of infectivity. Therefore, it may be valuable for the diagnosis and research of prion diseases.
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Síndrome de Creutzfeldt-Jakob , Enfermedad de Gerstmann-Straussler-Scheinker , Enfermedades Neurodegenerativas , Enfermedades por Prión , Priones , Humanos , Proteínas Priónicas , Proteínas PrPSc/metabolismo , Adhesión en Parafina , Enfermedades por Prión/diagnóstico , Enfermedades por Prión/metabolismo , Síndrome de Creutzfeldt-Jakob/patología , Priones/metabolismo , Enfermedad de Gerstmann-Straussler-Scheinker/metabolismo , Endopeptidasa K , Anticuerpos , FormaldehídoRESUMEN
BACKGROUND/AIM: Capecitabine plus oxaliplatin (CapeOX) therapy is used as an adjuvant chemotherapy regimen for patients with colorectal cancer (CRC). Although oxaliplatin induces thrombocytopenia, the risk factors for thrombocytopenia in oxaliplatin-treated patients with CRC are not well established. We aimed to investigate the risk factors for thrombocytopenia in CapeOX-treated patients with CRC. In addition, we evaluated platelet counts and non-invasive liver fibrosis indices, specifically the aspartate aminotransferase-to-platelet ratio index (APRI) and the fibrosis-4 index (FIB-4), during CapeOX therapy in these patients. PATIENTS AND METHODS: Between July 2017 and June 2020, we enrolled CapeOX-treated patients with high-risk stage II or stage III CRC at seven hospitals collaborating with the Division of Oncology, Aichi Prefectural Society of Hospital Pharmacists (Aichi prefecture, Japan). In this retrospective study, we investigated patients' backgrounds, laboratory data, concomitant medications, number of cycles of CapeOX and oxaliplatin, cumulative dose of oxaliplatin, and administration period. The cut-off values were calculated using receiver operating characteristic analysis of platelet counts and APRI and FIB-4 scores. RESULTS: Fifty-five patients without thrombocytopenia and 44 patients with thrombocytopenia were enrolled. During CapeOX therapy, the thrombocytopenia group showed a significant decrease in platelet count and a significant increase in APRI and FIB-4 scores compared to the non-thrombocytopenia group. Baseline albumin level ≤3.5 g/dl and platelet count ≤238×103/µl were independently associated with ≥grade 2 thrombocytopenia in CapeOX-treated patients. CONCLUSION: Baseline albumin level and platelet count may be useful for predicting thrombocytopenia in CapeOX-treated patients with high-risk stage II or stage III CRC.
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Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina , Neoplasias Colorrectales , Oxaliplatino , Trombocitopenia , Humanos , Capecitabina/efectos adversos , Capecitabina/administración & dosificación , Trombocitopenia/inducido químicamente , Masculino , Femenino , Oxaliplatino/efectos adversos , Oxaliplatino/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Anciano , Persona de Mediana Edad , Factores de Riesgo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recuento de Plaquetas , Estudios Retrospectivos , Anciano de 80 o más Años , AdultoRESUMEN
The hypothalamus is the region of the brain that integrates the neuroendocrine system and whole-body metabolism. Patients with Alzheimer's disease (AD) have been reported to exhibit pathological changes in the hypothalamus, such as neurofibrillary tangles (NFTs) and amyloid plaques (APs). However, few studies have investigated whether hypothalamic AD pathology is associated with clinical factors. We investigated the association between AD-related pathological changes in the hypothalamus and clinical pictures using autopsied brain samples obtained from deceased residents of a Japanese community. A total of 85 autopsied brain samples were semi-quantitatively analyzed for AD pathology, including NFTs and APs. Our histopathological studies showed that several hypothalamic nuclei, such as the tuberomammillary nucleus (TBM) and lateral hypothalamic area (LHA), are vulnerable to AD pathologies. NFTs are observed in various neuropathological states, including normal cognitive cases, whereas APs are predominantly observed in AD. Regarding the association between hypothalamic AD pathologies and clinical factors, the degree of APs in the TBM and LHA was associated with a lower body mass index while alive, after adjusting for sex and age at death. However, we found no significant association between hypothalamic AD pathology and the prevalence of hypertension, diabetes, or dyslipidemia. Our study showed that a lower BMI, which is a poor prognostic factor of AD, might be associated with hypothalamic AP pathology and highlighted new insights regarding the disruption of the brain-whole body axis in AD.
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Neuronal intranuclear inclusions (NIIs) are common key structures in polyglutamine (polyQ) diseases such as Huntington disease (HD), spinocerebellar ataxia type 1 (SCA1), and SCA3. Marinesco bodies (MBs) of dopaminergic neurons in the substantia nigra are also intranuclear structures and are frequently seen in normal elderly people. Ribosomal dysfunction is closely related to two differential processes; therefore, we aimed to identify the pathological characteristics of ribosomal protein SA (RPSA), a ribosomal protein, in both states. To this end, we evaluated the autopsy findings in four patients with HD, two SCA3, and five normal elderly cases (NCs). Immunohistochemical studies demonstrated that both NIIs and MBs contain RPSA. In polyQ diseases, RPSA was co-localized with polyQ aggregations, and 3D-reconstructed images revealed their mosaic-like distribution. Assessments of the organization of RPSA and p62 in NIIs showed that RPSA was more localized toward the center than p62 and that this unique organization was more evident in the MBs. Immunoblotting of the temporal cortices revealed that the nuclear fraction of HD patients contained more RPSA than that of NCs. In conclusion, our study revealed that RPSA is a common component of both NIIs and MBs, indicating that a similar mechanism contributes to the formation of polyQ NIIs and MBs.
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Encéfalo , Cuerpos de Inclusión Intranucleares , Anciano , Humanos , Encéfalo/patología , Cuerpos de Inclusión Intranucleares/metabolismo , Péptidos/metabolismo , Proteínas Ribosómicas/metabolismoRESUMEN
FUS mutations are one of the major mutations in familial amyotrophic lateral sclerosis (ALS). The pathological hallmark is FUS-positive neuronal cytoplasmic inclusions (FUS-NCI), known as FUS proteinopathy. Human myxovirus resistance protein 1 (MxA) is an IFN-induced dynamin-like GTPase that acts as antiviral factor. In this study, we examined the expression of MxA in neurons bearing FUS-NCI. We performed immunohistochemistry for FUS and MxA to examine the expression of MxA in two autopsy cases with different FUS gene mutations localized at the nuclear localization signal site (Case 1, H517P; Case 2, R521C). MxA. Most neurons bearing FUS-NCI have increased cytoplasmic MxA expression. Increased cytoplasmic MxA showed several distribution patterns in relation to FUS-NCIs such as the following: colocalization with NCI, distribution more widely than NCI, and different distribution peaks from NCI. Our results suggested that antiviral signaling IFNs are involved upstream in the formation of FUS-NCI in ALS-FUS patients.
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Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/patología , Antivirales/metabolismo , Mutación , Neuronas/patología , Proteína FUS de Unión a ARN/genéticaRESUMEN
BACKGROUND: Alcohol-associated liver disease (ALD) is a syndrome of progressive inflammatory liver injury and vascular remodeling associated with long-term heavy intake of ethanol. Elevated miR-34a expression, macrophage activation, and liver angiogenesis in ALD and their correlation with the degree of inflammation and fibrosis have been reported. The current study aims to characterize the functional role of miR-34a-regulated macrophage- associated angiogenesis during ALD. METHODS RESULTS: We identified that knockout of miR-34a in 5 weeks of ethanol-fed mice significantly decreased the total liver histopathology score and miR-34a expression, along with the inhibited liver inflammation and angiogenesis by reduced macrophage infiltration and CD31/VEGF-A expression. Treatment of murine macrophages (RAW 264.7) with lipopolysaccharide (20 ng/mL) for 24 h significantly increased miR-34a expression, along with the enhanced M1/M2 phenotype changes and reduced Sirt1 expression. Silencing of miR-34a significantly increased oxygen consumption rate (OCR) in ethanol treated macrophages, and decreased lipopolysaccharide-induced activation of M1 phenotypes in cultured macrophages by upregulation of Sirt1. Furthermore, the expressions of miR-34a and its target Sirt1, macrophage polarization, and angiogenic phenotypes were significantly altered in isolated macrophages from ethanol-fed mouse liver specimens compared to controls. TLR4/miR-34a knockout mice and miR-34a Morpho/AS treated mice displayed less sensitivity to alcohol-associated injury, along with the enhanced Sirt1 and M2 markers in isolated macrophages, as well as reduced angiogenesis and hepatic expressions of inflammation markers MPO, LY6G, CXCL1, and CXCL2. CONCLUSION: Our results show that miR-34a-mediated Sirt1 signaling in macrophages is essential for steatohepatitis and angiogenesis during alcohol-induced liver injury. These findings provide new insight into the function of microRNA-regulated liver inflammation and angiogenesis and the implications for reversing steatohepatitis with potential therapeutic benefits in human alcohol-associated liver diseases.
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Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Hígado Graso , Hepatopatías Alcohólicas , MicroARNs , Animales , Humanos , Ratones , Etanol/toxicidad , Hígado Graso/patología , Inflamación/genética , Lipopolisacáridos/toxicidad , Hepatopatías Alcohólicas/genética , Hepatopatías Alcohólicas/patología , Macrófagos/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Células RAW 264.7RESUMEN
Background: Sudden chemosensory changes were considered an early predictor of COVID-19. Here, the effects of comorbidities on changes in taste and smell in COVID-19 patients were investigated based on a worldwide study. Methods: Data analyzed here were collected from the Global Consortium for Chemosensory Research (GCCR) core questionnaire, including questions regarding preexisting disease conditions. Overall, the final sample of 12,438 participants who were diagnosed with COVID-19 included patients with preexisting conditions. Mixed linear regression models were used to test our hypothesis, and the p-value of interaction was examined. Results: A total of 61,067 participants completed the GCCR questionnaire, including 16,016 participants had preexisting diseases. The multivariate regression analysis showed that individuals with high blood pressure, lung disease, or sinus problems, or neurological diseases exhibited worse self-reported smell loss (p < .05), but no apparent significant differences in the smell or taste recovery. COVID-19 patients with seasonal allergy/hay fever lost their olfactory ability more than patients who did not have it (with 11.90 [9.67, 14.13] vs. without 6.97 [6.04, 7.91], p < .0001). The taste ability, smell loss and taste loss after COVID-19 recovery also decreased in the COVID-19 patients with seasonal allergy/hay fever (p < .001). Preexisting condition of diabetes did not worsen to chemosensory disorder but also had no obvious impact on the chemosensory recovery after acute infection. Preexisting diseases also affected the type of smell change in the COVID-19 patients with seasonal allergy/hay fever or sinus problems (p < .05). Conclusions: COVID-19 patients with high blood pressure, lung disease, or sinus problems, or neurological diseases exhibited worse self-reported smell loss, but no differences in the smell or taste recovery. COVID-19 patients with seasonal allergy/hay fever had greater loss of smell and taste, poorer smell and taste recovery. Level of Evidence: 4.
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Fused in sarcoma (FUS), coded by FUS, is a heterogeneous nuclear ribonucleoprotein (hnRNP). FUS mutations are among the major mutations in familial amyotrophic lateral sclerosis (ALS-FUS: ALS6). The pathological hallmarks of ALS-FUS are FUS-positive neuronal cytoplasmic inclusions (NCI). We examined various hnRNPs in FUS NCIs in the hippocampus in ALS-FUS cases with different FUS mutations (Case 1, H517P; Case 2, R521C). We also examined TDP43-positive NCIs in sporadic ALS hippocampi. Immunohistochemistry was performed using primary antibodies against FUS, p-TDP43, TDP43, hnRNPA1, hnRNPD, PCBP1, PCBP2, and p62. Numerous FUS inclusions were found in the hippocampal granule and pyramidal cell layers. Double immunofluorescence revealed colocalization of FUS and p-TDP43, and FUS and PCBP2 (p-TDP43/FUS: 64.3%, PCBP2/FUS: 23.9%). Colocalization of FUS and PCBP1, however, was rare (PCBP1/FUS: 7.6%). In the hippocampi of patients with sporadic ALS, no colocalization was observed between TDP43-positive inclusions and other hnRNPs. This is the first study to show that FUS inclusions colocalize with other hnRNPs, such as TDP43, PCBP2, and PCBP1. These findings suggest that in ALS-FUS, FUS inclusions are the initiators, followed by alterations of multiple other hnRNPs, resulting in impaired RNA metabolism.
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Esclerosis Amiotrófica Lateral , Proteína FUS de Unión a ARN , Humanos , Esclerosis Amiotrófica Lateral/patología , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Cuerpos de Inclusión/patología , Mutación/genética , Proteína FUS de Unión a ARN/genética , Proteína FUS de Unión a ARN/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
Gulf War Illness (GWI) has been reported in 25%-35% of veterans returned from the Gulf war. Symptoms of GWI are varied and include both neurological and gastrointestinal symptoms as well as chronic fatigue. Development of GWI has been associated with chemical exposure particularly with exposure to pyridostigmine bromide (PB) and permethrin. Recent studies have found that the pathology of GWI is connected to changes in the gut microbiota, that is the gut dysbiosis. In studies using animal models, the exposure to PB and permethrin resulted in similar changes in the gut microbiome as these found in GW veterans with GWI. Studies using animal models have also shown that phytochemicals like curcumin are beneficial in reducing the symptoms and that the extracellular vesicles (EV) released from gut bacteria and from the intestinal epithelium can both promote diseases and suppress diseases through the intercellular communication mechanisms. The intestinal epithelium cells produce EVs and these EVs of intestinal epithelium origin are found to suppress inflammatory bowel disease severity, suggesting the benefits of utilizing EV in treatments. On the contrary, EV from the plasma of septic mice enhanced the level of proinflammatory cytokines in vitro and neutrophils and macrophages in vivo, suggesting differences in the EV depending on the types of cells they were originated and/or influences of environmental changes. These studies suggest that targeting the EV that specifically have positive influences may become a new therapeutic strategy in the treatment of veterans with GWI.
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Microbioma Gastrointestinal , Síndrome del Golfo Pérsico , Ratones , Animales , Permetrina , Disbiosis , Guerra del Golfo , Síndrome del Golfo Pérsico/microbiología , Bromuro de Piridostigmina , Modelos Animales de EnfermedadRESUMEN
One of the unique symptoms of COVID-19 is chemosensory dysfunction. Almost three years since the beginning of the pandemic of COVID-19, there have been many studies on the symptoms, progress, and possible causes, and also studies on methods that may facilitate recovery of the senses. Studies have shown that some people recover their senses even within a couple of weeks whereas there are other patients that fail to recover chemosensory functions fully for several months and some never fully recover. Here we summarize the symptoms and the progress, and then review the papers on the causation as well as the treatments that may help facilitate the recovery of the symptoms. Depending on the differences in the levels of severity and the locations where the main pathological venues are, what is most effective in facilitating recovery can vary largely across patients and thus may require individualized strategies for each patient. The goal of this paper is to provide some thoughts on these choices depending on the differences in the causes and severity.
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COVID-19 , Trastornos del Olfato , Humanos , COVID-19/complicaciones , SARS-CoV-2 , Trastornos del Olfato/diagnóstico , Olfato , PandemiasRESUMEN
Here we present the autopsy case of an 80-year-old woman with a 9-year history of motor neuron disease and atypical Parkinsonism. Her initial symptom was gait disturbance, and she subsequently developed limb weakness and Parkinsonism without response to levodopa. Her motor symptoms progressed to bulbar palsy, and she died of respiratory failure. Postmortem examination revealed characteristic findings of amyotrophic lateral sclerosis (ALS), including motor neuronal loss with astrogliosis, corticospinal tract degeneration, and TAR DNA-binding protein of 43 kDa abnormalities, including nuclear loss and skein-like inclusions. In contrast, severe tau pathological changes were seen in the frontotemporal lobes and pallido-nigral system. Tau pathologies affected not only neuronal components, such as neurofibrillary tangles and neuropil threads, but also glial cells (astrocytes and oligodendrocytes). Some glial tau pathologies exhibited peculiar round accumulations, reminiscent of globular glial inclusions (GGIs) in globular glial tauopathy. This unique autopsy case demonstrates that ALS with TDP-43 could be comorbid with globular glial tau inclusions and indicates that common pathological mechanisms exist among ALS and GGI formation.
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Esclerosis Amiotrófica Lateral , Trastornos Parkinsonianos , Femenino , Humanos , Esclerosis Amiotrófica Lateral/patología , Neuroglía/patología , Neuronas/patología , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Proteínas de Unión al ADN/metabolismoRESUMEN
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by inflammatory responses and fibrotic scar formation leading to cholestasis. Ductular reaction and liver fibrosis are typical liver changes seen in human PSC and cholestasis patients. The current study aimed to clarify the role of liver-specific microRNA-34a in the cholestasis-associated ductular reaction and liver fibrosis. We demonstrated that miR-34a expression was significantly increased in human PSC livers along with the enhanced ductular reaction, cellular senescence, and liver fibrosis. A liver-specific miR-34a knockout mouse was established by crossing floxed miR-34a mice with albumin-promoter-driven Cre mice. Bile duct ligation (BDL) induced liver injury characterized by necrosis, fibrosis, and immune cell infiltration. In contrast, liver-specific miR-34a knockout in BDL mice resulted in decreased biliary ductular pathology associated with the reduced cholangiocyte senescence and fibrotic responses. The miR-34a-mediated ductular reactions may be functioning through Sirt-1-mediated senescence and fibrosis. The hepatocyte-derived conditioned medium promoted LPS-induced fibrotic responses and senescence in cholangiocytes, and miR-34a inhibitor suppressed these effects, further supporting the involvement of paracrine regulation. In conclusion, we demonstrated that liver-specific miR-34a plays an important role in ductular reaction and fibrotic responses in a BDL mouse model of cholestatic liver disease.
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Colestasis , Hepatopatías , MicroARNs , Humanos , Ratones , Animales , Hígado/metabolismo , Cirrosis Hepática/metabolismo , Colestasis/genética , Colestasis/patología , Conductos Biliares/cirugía , Conductos Biliares/metabolismo , Conductos Biliares/patología , Fibrosis , Hepatopatías/metabolismo , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
Liver fibrosis is a complicated process that involves different cell types and pathological factors. The excessive accumulation of extracellular matrix (ECM) and the formation of fibrotic scar disrupt the tissue homeostasis of the liver, eventually leading to cirrhosis and even liver failure. Myofibroblasts derived from hepatic stellate cells (HSCs) contribute to the development of liver fibrosis by producing ECM in the area of injuries. It has been reported that the secretion of the neuroendocrine hormone in chronic liver injury is different from a healthy liver. Activated HSCs and cholangiocytes express specific receptors in response to these neuropeptides released from the neuroendocrine system and other neuroendocrine cells. Neuroendocrine hormones and their receptors form a complicated network that regulates hepatic inflammation, which controls the progression of liver fibrosis. This review summarizes neuroendocrine regulation in liver fibrosis from three aspects. The first part describes the mechanisms of liver fibrosis. The second part presents the neuroendocrine sources and neuroendocrine compartments in the liver. The third section discusses the effects of various neuroendocrine factors, such as substance P (SP), melatonin, as well as α-calcitonin gene-related peptide (α-CGRP), on liver fibrosis and the potential therapeutic interventions for liver fibrosis.
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Células Estrelladas Hepáticas , Cirrosis Hepática , Humanos , Cirrosis Hepática/metabolismo , Células Estrelladas Hepáticas/metabolismo , Miofibroblastos/metabolismo , Sistemas Neurosecretores/metabolismoRESUMEN
GPI anchorless prion diseases (GPIALPs) show numerous coarse prion protein (PrP) deposits in the CNS but neuropil spongiform changes are mild and the incidence of dementia is low. Here, we examined differences in resident microglial phenotypes between GPIALP (D178fs25) and the other prion diseases Gerstmann-Sträussler-Scheinker (GSS) disease and sporadic Creutzfeldt-Jakob disease (sCJD) with respect to homeostasis and activation. Immunohistochemistry was performed on 2 GPIALP (D178fs25), 4 GSS (P102L), and 4 sCJD cases. Homeostatic microglia expressing TMEM119 and P2RY12 were preserved in GPIALP compared to GSS and sCJD. Microglia/macrophage activation in GSS and sCJD was associated with the extent of spongiform change. Immunoelectron microscopy revealed TMEM119 and P2RY12 in PrP plaque cores. Activated microglia/macrophages expressing HLA-DR and CD68 were predominant in GSS and sCJD whereas in GPIALP, homeostatic microglia were retained and activated microglia/macrophages were rarely observed. These data suggest that PrP deposition in GPIALP is less toxic and that microglia may be immune-tolerant to PrP deposition. This may be associated with milder tissue damage and a low incidence of dementia. Whereas microglia/macrophage activation is considered to be a reaction to tissue injury, this study shows that the degree of microglia/macrophage activity might influence the extent of tissue damage.
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Síndrome de Creutzfeldt-Jakob , Enfermedad de Gerstmann-Straussler-Scheinker , Proteínas de la Membrana , Microglía , Receptores Purinérgicos P2Y12 , Humanos , Síndrome de Creutzfeldt-Jakob/metabolismo , Enfermedad de Gerstmann-Straussler-Scheinker/genética , Microglía/metabolismo , Proteínas Priónicas/genética , Proteínas Priónicas/metabolismo , Receptores Purinérgicos P2Y12/genética , Receptores Purinérgicos P2Y12/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismoRESUMEN
Prion disease is an infectious and fatal neurodegenerative disease. Human prion disease autopsy studies have revealed abnormal prion protein (PrPSc) deposits in the central nervous system and systemic organs. In deer, chronic wasting disease has also become a global problem, with PrPSc in saliva and feces. Therefore, understanding normal cellular prion proteins (PrPc) characteristics in human systemic organs is important since they could be a PrPSc source. This study used western blotting and immunohistochemistry to investigate endocrine and exocrine tissues, such as the human pituitary, adrenal, submandibular glands and the pancreas. All tissues had 30-40 kDa PrP signals, which is a slightly higher molecular weight than normal brain tissue. Most cytoplasmic PrP-positive adenohypophyseal cells were immunopositive for nuclear pituitary-specific positive transcription factor 1. The adrenal medulla and islet cells of the pancreas were PrP-positive and colocalized with chromogranin A. The duct epithelium in the submandibular gland and pancreas were immunopositive for PrP. This study reports the characteristic molecular properties and detailed tissue localization of PrPc in endocrine and exocrine tissues, which is important for infection control and diagnosis.
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Proteínas Priónicas/química , Animales , Ciervos , Humanos , Especificidad de Órganos , Enfermedades por Prión/metabolismoRESUMEN
The differential effects of sporadic Creutzfeldt-Jakob disease (sCJD) on the hippocampus and other neocortical areas are poorly understood. We aimed to reveal the histological patterns of cellular prion protein (PrPC) and abnormal prion protein (PrPSc) in hippocampi of sCJD patients and normal controls (NCs). Our study examined 18 postmortem sCJD patients (MM1, 14 cases; MM1 + 2c, 3 cases; MM1 + 2t, 1 case) and 12 NCs. Immunohistochemistry was conducted using 4 primary antibodies, of which 3 targeted the N-terminus of the prion protein (PrP), and 1 (EP1802Y) targeted the C-terminal domain. PrPC expression was abundant in the hippocampus of NCs, and the distribution of PrPC at CA3/4 was reminiscent of synaptic complexes. In sCJD cases with a disease history of <2 years, antibodies against the N-terminus could not detect synapse-like PrP expression at CA4; however, EP1802Y could characterize the synapse-like expression. PrPSc accumulation and spongiform changes became evident after 2 years of illness, when PrPSc deposits were more noticeably detected by N-terminal-specific antibodies. Our findings highlighted the chronology of histopathological alterations in the CA4 region in sCJD patients.