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Background: Recent research indicates a role of gut microbiota in development and progression of life-threatening diseases such as cancer. Carcinomas of the biliary ducts, the so-called cholangiocarcinomas, are known for their aggressive tumor biology, implying poor prognosis of affected patients. An impact of the gut microbiota on cholangiocarcinoma development and progression is plausible due to the enterohepatic circulation and is therefore the subject of scientific debate, however evidence is still lacking. This review aimed to discuss the suitability of complex cell culture models to investigate the role of gut microbiota in cholangiocarcinoma progression. Main body: Clinical research in this area is challenging due to poor comparability of patients and feasibility reasons, which is why translational models are needed to understand the basis of tumor progression in cholangiocarcinoma. A promising approach to investigate the influence of gut microbiota could be an organoid model. Organoids are 3D cell models cultivated in a modifiable and controlled condition, which can be grown from tumor tissue. 3D cell models are able to imitate physiological and pathological processes in the human body and thus contribute to a better understanding of health and disease. Conclusion: The use of complex cell cultures such as organoids and organoid co-cultures might be powerful and valuable tools to study not only the growth behavior and growth of cholangiocarcinoma cells, but also the interaction with the tumor microenvironment and with components of the gut microbiota. [ABSTRACT FROM AUTHOR]

Methodological developments in biomedical research are currently moving towards single-cell approaches. This allows for a much better spatial and functional characterization of, for example, the deterioration of cells within a tissue in response to noxae. However, subcellular resolution is also essential to elucidate whether observed impairments are driven by an explicit organelle. Here, we use the Single Cellome™ System SS2000 (Yokogawa) to investigate the local effects of Aβ plaque-like deposits (characteristic for Alzheimer's disease) on mitochondria in the mouse microglial cell line SIM-A9. First, the specificity of subcellular extraction is demonstrated by detecting subcellular staining and RT-qPCR concerning marker genes by comparing nuclear and mitochondrial samples. Oxygen consumption and gene expression is then assessed in cells near and far from peptide deposits. Mostly, all analyses confirm the high specificity and integrity of the sampled material. In addition, impact of the peptide deposits occur concerning spatial distribution of the cells: e.g., oxygen consumption is only reduced in cells close to Aβ deposits but not in proximity to deposits of biologically inactive Aβ (scrambled) or in far distance. Moreover, a distance-related gene expression pattern occurs, demonstrating the local initiation of mitochondrial changes of microglia when approaching toxic peptide deposits. Aspiration of cellular content accompanied by confocal microscope-usage within the SS2000 allows investigation of organelle-enriched fractions and sheds light on selective effects of Aβ peptides. [ABSTRACT FROM AUTHOR]

The gut and the brain communicate via the nervous system, hormones, microbiota-mediated substances, and the immune system. These intricate interactions have led to the term "gut-brain axis". Unlike the brain—which is somewhat protected—the gut is exposed to a variety of factors throughout life and, consequently, might be either more vulnerable or better adapted to respond to these challenges. Alterations in gut function are common in the elder population and associated with many human pathologies, including neurodegenerative diseases. Different studies suggest that changes in the nervous system of the gut, the enteric nervous system (ENS), during aging may result in gastrointestinal dysfunction and initiate human pathologies of the brain via its interconnection with the gut. This review aims at summarizing the contribution of normal cellular aging to the age-associated physiological changes of the ENS. Morphological alterations and degeneration of the aging ENS are observed in different animal models and humans, albeit with considerable variability. The aging phenotypes and pathophysiological mechanisms of the aging ENS have highlighted the involvement of enteric neurons in age-related diseases of the central nervous system such as Alzheimer's or Parkinson's disease. To further elucidate such mechanisms, the ENS constitutes a promising source of material for diagnosis and therapeutic predictions, as it is more accessible than the brain. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common neurodegenerative disease, with two main pathological features: misfolded α-synuclein protein accumulation and neurodegeneration. Inflammation has recently been identified as a contributor to a cascade of events that may aggravate PD pathology. Inflammasomes, a group of intracellular protein complexes, play an important role in innate immune responses to various diseases, including infection. In PD research, accumulating evidence suggests that α-synuclein aggregations may activate inflammasomes, particularly the nucleotide-binding oligomerization domain-leucine-rich repeat-pyrin domain-containing 3 (NLRP3) type, which exacerbates inflammation in the central nervous system by secreting proinflammatory cytokines like interleukin (IL)-18 and IL-1β. Afterward, activated NLRP3 triggers local microglia and astrocytes to release additional IL-1β. In turn, the activated inflammatory process may contribute to additional α-synuclein aggregation and cell loss. This review summarizes current research evidence on how the NLRP3 inflammasome contributes to PD pathogenesis, as well as potential therapeutic strategies targeting the NLRP3 inflammasome in PD. [ABSTRACT FROM AUTHOR]

Background: Mutations in PTEN-induced putative kinase 1 (PINK1) cause autosomal recessive Parkinson's disease (PD) and contribute to the risk of sporadic PD. However, the relationship between PD-related PINK1 mutations and alpha-synuclein (α-syn) aggregation—a main pathological component of PD—remains unexplored. Objective: To investigate whether α-syn pathology is exacerbated in the absence of PINK1 after α-syn preformed fibril (PFF) injection in a PD mouse model and its effects on neurodegeneration. Methods: In this study, 10-week-old Pink1 knockout (KO) and wildtype (WT) mice received stereotaxic unilateral striatal injection of recombinant mouse α-syn PFF. Then, α-syn pathology progression, inflammatory responses, and neurodegeneration were analyzed via immunohistochemistry, western blot analysis, and behavioral testing. Results: After PFF injection, the total α-syn levels significantly increased, and pathological α-syn was markedly aggregated in Pink1 KO mice compared with Pink1 WT mice. Then, earlier and more severe neuronal loss and motor deficits occurred. Moreover, compared with WT mice, Pink1 KO mice had evident microglial/astrocytic immunoreactivity and prolonged astrocytic activation, and a higher rate of protein phosphatase 2A phosphorylation, which might explain the greater α-syn aggravation and neuronal death. Conclusion: The loss of Pink1 function accelerated α-syn aggregation, accumulation and glial activation, thereby leading to early and significant neurodegeneration and behavioral impairment in the PD mouse model. Therefore, our findings support the notion that PINK1 dysfunction increases the risk of synucleinopathy. [ABSTRACT FROM AUTHOR]

According to a few studies, α-synuclein (αSyn) propagation has been suggested to play a key role in the pathomechanism of Parkinson's disease (PD), but neurodegeneration and the involvement of inflammation in its pathologic progression are not well understood with regard to temporal relationship. In this study, with the help of the PD mouse model injected with intrastriatal αSyn preformed fibril (PFF), the temporal evolution of αSyn propagation, inflammation, and neurodegeneration was explored in the perspective of the striatum and the whole brain. In the PFF-injected striatum, inflammatory response cells, including microglia and astrocytes, were activated at the earliest stage and reduced with time, and the phosphorylated form of αSyn accumulation increased behind it. Afterward, the degeneration of striatal dopaminergic neurons became significant with the conspicuity of behavioral phenotype. Similar patterns of forefront eruption of inflammation and then followed by αSyn propagation were noted in the opposite striatum, which were not injured by PFF injection. In analyzing the whole brain, inflammatory responses were activated at the earliest stage, and the soluble αSyn expression increased concurrently. The inflammatory response decreased afterward, and the accumulation of the insoluble form of αSyn increased behind it. Our results suggested that the inflammatory response may precede the accumulation of the pathologic form of αSyn; thereafter, the neurodegeneration and motor dysfunction followed αSyn proliferation in the PD mouse model. From this model, recognizing the temporal relationship between inflammation, αSyn propagation, and neurodegeneration may be helpful in establishing the PD animal model and monitoring the effect of interventional therapy. [ABSTRACT FROM AUTHOR]