Unfermented ß-fructan Fibers Fuel Inflammation in Select Inflammatory Bowel Disease Patients.

BACKGROUND & AIMS: Inflammatory bowel diseases (IBD) are affected by dietary factors, including nondigestible carbohydrates (fibers), which are fermented by colonic microbes. Fibers are overall beneficial, but not all fibers are alike, and some patients with IBD report intolerance to fiber consumption. Given reproducible evidence of reduced fiber-fermenting microbes in patients with IBD, we hypothesized that fibers remain intact in select patients with reduced fiber-fermenting microbes and can then bind host cell receptors, subsequently promoting gut inflammation. METHODS: Colonic biopsies cultured ex vivo and cell lines in vitro were incubated with oligofructose (5 g/L), or fermentation supernatants (24-hour anaerobic fermentation) and immune responses (cytokine secretion [enzyme-linked immunosorbent assay/meso scale discovery] and expression [quantitative polymerase chain reaction]) were assessed. Influence of microbiota in mediating host response was examined and taxonomic classification of microbiota was conducted with Kraken2 and metabolic profiling by HUMAnN2, using R software. RESULTS: Unfermented dietary ß-fructan fibers induced proinflammatory cytokines in a subset of IBD intestinal biopsies cultured ex vivo, and immune cells (including peripheral blood mononuclear cells). Results were validated in an adult IBD randomized controlled trial examining ß-fructan supplementation. The proinflammatory response to intact ß-fructan required activation of the NLRP3 and TLR2 pathways. Fermentation of ß-fructans by human gut whole microbiota cultures reduced the proinflammatory response, but only when microbes were collected from patients without IBD or patients with inactive IBD. Fiber-induced immune responses correlated with microbe functions, luminal metabolites, and dietary fiber avoidance. CONCLUSION: Although fibers are typically beneficial in individuals with normal microbial fermentative potential, some dietary fibers have detrimental effects in select patients with active IBD who lack fermentative microbe activities. The study is publicly accessible at the U.S. National Institutes of Health database (clinicaltrials.gov identification number NCT02865707).

NAFLD (MASLD)/NASH (MASH): Does It Bother to Label at All? A Comprehensive Narrative Review.

Nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated steatotic liver disease (MASLD), is a liver condition that is linked to overweight, obesity, diabetes mellitus, and metabolic syndrome. Nonalcoholic steatohepatitis (NASH), or metabolic dysfunction-associated steatohepatitis (MASH), is a form of NAFLD/MASLD that progresses over time. While steatosis is a prominent histological characteristic and recognizable grossly and microscopically, liver biopsies of individuals with NASH/MASH may exhibit several other abnormalities, such as mononuclear inflammation in the portal and lobular regions, hepatocellular damage characterized by ballooning and programmed cell death (apoptosis), misfolded hepatocytic protein inclusions (Mallory-Denk bodies, MDBs), megamitochondria as hyaline inclusions, and fibrosis. Ballooning hepatocellular damage remains the defining feature of NASH/MASH. The fibrosis pattern is characterized by the initial expression of perisinusoidal fibrosis ("chicken wire") and fibrosis surrounding the central veins. Children may have an alternative form of progressive NAFLD/MASLD characterized by steatosis, inflammation, and fibrosis, mainly in Rappaport zone 1 of the liver acinus. To identify, synthesize, and analyze the scientific knowledge produced regarding the implications of using a score for evaluating NAFLD/MASLD in a comprehensive narrative review. The search for articles was conducted between 1 January 2000 and 31 December 2023, on the PubMed/MEDLINE, Scopus, Web of Science, and Cochrane databases. This search was complemented by a gray search, including internet browsers (e.g., Google) and textbooks. The following research question guided the study: "What are the basic data on using a score for evaluating NAFLD/MASLD?" All stages of the selection process were carried out by the single author. Of the 1783 articles found, 75 were included in the sample for analysis, which was implemented with an additional 25 articles from references and gray literature. The studies analyzed indicated the beneficial effects of scoring liver biopsies. Although similarity between alcoholic steatohepatitis (ASH) and NASH/MASH occurs, some patterns of hepatocellular damage seen in alcoholic disease of the liver do not happen in NASH/MASH, including cholestatic featuring steatohepatitis, alcoholic foamy degeneration, and sclerosing predominant hyaline necrosis. Generally, neutrophilic-rich cellular infiltrates, prominent hyaline inclusions and MDBs, cholestasis, and obvious pericellular sinusoidal fibrosis should favor the diagnosis of alcohol-induced hepatocellular injury over NASH/MASH. Multiple grading and staging methods are available for implementation in investigations and clinical trials, each possessing merits and drawbacks. The systems primarily used are the Brunt, the NASH CRN (NASH Clinical Research Network), and the SAF (steatosis, activity, and fibrosis) systems. Clinical investigations have utilized several approaches to link laboratory and demographic observations with histology findings with optimal platforms for clinical trials of rapidly commercialized drugs. It is promising that machine learning procedures (artificial intelligence) may be critical for developing new platforms to evaluate the benefits of current and future drug formulations.

The Gut Commensal Escherichia coli Aggravates High-Fat-Diet-Induced Obesity and Insulin Resistance in Mice.

Changes in the gut microbiota have been linked to metabolic endotoxemia as a contributing mechanism in the development of obesity and type 2 diabetes. Although identifying specific microbial taxa associated with obesity and type 2 diabetes remains difficult, certain bacteria may play an important role in initiating metabolic inflammation during disease development. The enrichment of the family Enterobacteriaceae, largely represented by Escherichia coli, induced by a high-fat diet (HFD) has been correlated with impaired glucose homeostasis; however, whether the enrichment of Enterobacteriaceae in a complex gut microbial community in response to an HFD contributes to metabolic disease has not been established. To investigate whether the expansion of Enterobacteriaceae amplifies HFD-induced metabolic disease, a tractable mouse model with the presence or absence of a commensal E. coli strain was established. With an HFD treatment, but not a standard-chow diet, the presence of E. coli significantly increased body weight and adiposity and induced impaired glucose tolerance. In addition, E. coli colonization led to increased inflammation in liver and adipose and intestinal tissue under an HFD regimen. With a modest effect on gut microbial composition, E. coli colonization resulted in significant changes in the predicted functional potential of microbial communities. The results demonstrated the role of commensal E. coli in glucose homeostasis and energy metabolism in response to an HFD, indicating contributions of commensal bacteria to the pathogenesis of obesity and type 2 diabetes. The findings of this research identified a targetable subset of the microbiota in the treatment of people with metabolic inflammation. IMPORTANCE Although identifying specific microbial taxa associated with obesity and type 2 diabetes remains difficult, certain bacteria may play an important role in initiating metabolic inflammation during disease development. Here, we used a mouse model distinguishable by the presence or absence of a commensal Escherichia coli strain in combination with a high-fat diet challenge to investigate the impact of E. coli on host metabolic outcomes. This is the first study to show that the addition of a single bacterial species to an animal already colonized with a complex microbial community can increase severity of metabolic outcomes. This study is of interest to a wide group of researchers because it provides compelling evidence to target the gut microbiota for therapeutic purposes by which personalized medicines can be made for treating metabolic inflammation. The study also provides an explanation for variability in studies investigating host metabolic outcomes and immune response to diet interventions.

Epigallocatechin gallate for Parkinson's disease.

In the last couple of decades, we have experienced increased use of nutraceuticals worldwide with a demand for organic foods, which has been elevated to an extent probably unmatched with other periods of our civilization. One of the nutraceuticals that gained attention is epigallocatechin gallate (EGCG), a polyphenol in green tea. It has been suggested that diseases of the central nervous system can benefit from consuming some antioxidants, despite current results showing little evidence for their use in preventing and treating these diseases. ECGC may be beneficial in delaying the neurodegeneration of the substantia nigra regardless of the origin of Parkinson's disease (PD). This review covers the effect of EGCG on vitro and animal models of PD, the potential mechanisms of neuroprotection involved and summaries recent clinical trials in human PD. This review also aims to provide an investigative analysis of the current knowledge in this field and to identify putative crucial issues. Environmental factors such as dietary habits, drug use and social interaction are all factors that influence the evolution of neurodegenerative diseases. Therefore, the use of nutraceuticals requires further investigation.

Biliary Atresia Animal Models: Is the Needle in a Haystack?

Biliary atresia (BA) is a progressive fibro-obliterative process with a variable degree of inflammation involving the hepatobiliary system. Its consequences are incalculable for the patients, the affected families, relatives, and the healthcare system. Scientific communities have identified a rate of about 1 case per 10,000-20,000 live births, but the percentage may be higher, considering the late diagnoses. The etiology is heterogeneous. BA, which is considered in half of the causes leading to orthotopic liver transplantation, occurs in primates and non-primates. To consolidate any model, (1) more transport and cell membrane studies are needed to identify the exact mechanism of noxa-related hepatotoxicity; (2) an online platform may be key to share data from pilot projects and new techniques; and (3) the introduction of differentially expressed genes may be useful in investigating the liver metabolism to target the most intricate bilio-toxic effects of pharmaceutical drugs and toxins. As a challenge, such methodologies are still limited to very few centers, making the identification of highly functional animal models like finding a "needle in a haystack". This review compiles models from the haystack and hopes that a combinatorial search will eventually be the root for a successful pathway.

Mitochondrial Dysfunction and Induction of Apoptosis in Hepatocellular Carcinoma and Cholangiocarcinoma Cell Lines by Thymoquinone.

Thymoquinone (TQ), a plant-based bioactive constituent derived from the volatile oil of Nigella sativa, has been shown to possess some anti-neoplastic activities. The present study aimed to investigate the mitochondria and apoptosis observed when TQ is applied against hepatocellular carcinoma (HepG2) and cholangiocarcinoma (HuCCT1) cells, two of the most common primary tumors of the liver. All cell lines were treated with increasing concentrations of TQ for varying durations. The anti-proliferative effect of TQ was measured using the methoxyphenyl-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and resulted in dose- and time-dependent growth inhibition in both cell lines. Cell cycle, apoptosis, and assessment of mitochondria viability by morphology assessment and evaluation of the mitochondrial membrane potential were investigated. The present study confirms that TQ caused cell cycle arrest at different phases and induced apoptosis in both cell lines. A systematic review of rodent animal models was also carried out. Overall, our data seem to represent the most robust results, suggesting that TQ possesses promising therapeutic potential as an anti-tumor agent for the treatment of hepatocellular carcinoma and cholangiocarcinoma.

COVID-19 Molecular Pathophysiology: Acetylation of Repurposing Drugs.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated type 1 interferon (IFN-1) production, the pathophysiology of which involves sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) tetramerization and the cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. As a result, type I interferonopathies are exacerbated. Aspirin inhibits cGAS-mediated signaling through cGAS acetylation. Acetylation contributes to cGAS activity control and activates IFN-1 production and nuclear factor-κB (NF-κB) signaling via STING. Aspirin and dapsone inhibit the activation of both IFN-1 and NF-κB by targeting cGAS. We define these as anticatalytic mechanisms. It is necessary to alleviate the pathologic course and take the lag time of the odds of achieving viral clearance by day 7 to coordinate innate or adaptive immune cell reactions.

Pediatric sarcoidosis with diagnostic and therapeutical insights.

PURPOSE OF REVIEW: Sarcoidosis is a chronic granulomatous disorder involving multiple systems and organs of undefined etiology. Although most of the morbidity relies upon lung disease, the function of several systems and organs can be affected. The natural history of lung disease consists of pulmonary involvement. An exaggerated and abnormal inflammatory response accompanies this aspect. There are noncaseating confluent epithelioid granulomas and, potentially, a progressive airway obstruction ab externo. As the disease is multisystemic, there is an increased likelihood of complications that may be serious and even fatal. RECENT FINDINGS: The American Thoracic Society (ATS) Core Curriculum updates clinicians annually in adult and pediatric lung disease, critical medical care, and sleep medicine. In late 2020, the ATS targeted sarcoidosis. Also, in 2019, the French Sarcoidosis Group thoroughly revised the literature on pediatric sarcoidosis. Currently, staging is based on chest radiograph findings, and the most commonly used system is the Scadding classification, which has been applied to both children and adults alike. Treatment may consist of oral or pulsed intravenous corticosteroids, but it should be implemented in union with a rheumatologist, as there are no randomized controlled studies in children. SUMMARY: Sarcoidosis is rare in childhood. Diagnosis is complex and relies on multiple diagnostic modalities with both staging and therapy progressively mirroring the sarcoidosis, which affects adults. In the majority of patients, spontaneous resolution will occur and observation is justified above treatment. Nevertheless, in case treatment is needed corticosteroids remain the mainstay of the treatment in some pediatric patients. Relapses are not uncommon and a long-term follow-up is essential.

Co-ingestion of aspirin and acetaminophen promoting fulminant liver failure: A critical review of Reye syndrome in the current perspective at the dawn of the 21st century.

In the paediatric population, there is some evidence of possible interaction, synergism, and co-toxicity of aspirin and acetaminophen. The toxicity of salicylates such as aspirin in this population is well known and documented, specifically in the form of Reye syndrome. The possible toxic synergism with aspirin and acetaminophen, however, is not previously described; though case reports suggest such co-toxicities with low levels of aspirin and other compounds can exist. In vitro studies into mechanistic processes of salicylate toxicity propose that there is a bi-directional link and potentiation with glutathione (GSH) depletion and salicylate toxicity. Data may suggest a plausible explanation for salicylate and acetaminophen toxic synergism. Further studies investigating this potential toxic synergism are warranted. Given the lack of awareness in the clinical community about potential toxic synergism between these relatively common medications, caution is advised in the co-administration of these drugs, particularly in communities using natural or alternative therapy.

Academic Responsibilities, Obligations, and Freedom: A Call for Review - In Memory of Professor Dr. Tomás Hudlický.

The advent and dominance of social media in our daily lives is not a matter of discussion, and very few minimalistic individuals have tried to decrease this technological dependency, which can become toxic and noxious for the development of an autonomous personality and free thinking. Academic faculties claim a depauperation in terms of their freedom but are also not free from duties, responsibilities, and obligations. Here, duties, responsibilities, obligations, and freedom are addressed in historical terms as the university as an institution developed over the centuries after its founding in the 11th century is currently under attack. We premonish that these concepts must still be reiterated and divulgated to students and fellows in academia. Galilei's "Eppur si muove" ("and yet it moves") are the words pronounced by the Italian mathematician, physicist, and philosopher Galileo Galilei that should resonate in censorship bodies now and in the future.

Pediatric cancer-pathology and microenvironment influence: a perspective into osteosarcoma and non-osteogenic mesenchymal malignant neoplasms.

Pediatric cancer remains the leading cause of disease-related death among children aged 1-14 years. A few risk factors have been conclusively identified, including exposure to pesticides, high-dose radiation, and specific genetic syndromes, but the etiology underlying most events remains unknown. The tumor microenvironment (TME) includes stromal cells, vasculature, fibroblasts, adipocytes, and different subsets of immunological cells. TME plays a crucial role in carcinogenesis, cancer formation, progression, dissemination, and resistance to therapy. Moreover, autophagy seems to be a vital regulator of the TME and controls tumor immunity. Autophagy is an evolutionarily conserved intracellular process. It enables the degradation and recycling of long-lived large molecules or damaged organelles using the lysosomal-mediated pathway. The multifaceted role of autophagy in the complicated neoplastic TME may depend on a specific context. Autophagy may function as a tumor-suppressive mechanism during early tumorigenesis by eliminating unhealthy intracellular components and proteins, regulating antigen presentation to and by immune cells, and supporting anti-cancer immune response. On the other hand, dysregulation of autophagy may contribute to tumor progression by promoting genome damage and instability. This perspective provides an assortment of regulatory substances that influence the features of the TME and the metastasis process. Mesenchymal cells in bone and soft-tissue sarcomas and their signaling pathways play a more critical role than epithelial cells in childhood and youth. The investigation of the TME in pediatric malignancies remains uncharted primarily, and this unique collection may help to include novel advances in this setting.

Sudden cardiac death and post-traumatic stress disorder: More research is needed.

Sudden cardiac death is an event which is traumatic for the individuals, who survive and their relatives. Very few research is concentrated on these survivals and the symptoms arising from post-traumatic stress disorders. In this journal, Birk et al. report on twelve eligible cardiac arrest survivors contacted, of which ten were enrolled. The authors report on heart rate variability biofeedback, which is, according to the authors, a promising non-pharmacologic approach for reducing anxiety. The intervention was comprised of daily sessions of diaphragmatic paced breathing and real-time monitoring of cardiac activity guided by a smartphone app and heart rate monitor. Ninety percent of the patients had good scores for intervention acceptability and feasibility, and 80 % reported good scores for its appropriateness and usability for reducing fear. Trait anxiety decreased significantly pre-to-post intervention. We comment on this finding highlighting other studies targeting sudden cardiac death and supporting that more research with very large randomized clinical trials is needed.

Carney complex: A clinicopathologic study on a single family from several Canadian provinces.

Carney syndrome is an autosomal dominant complex involving endocrinopathy, mucocutaneous hyperpigmentation, and different tumors, including cardiac myxomas. We report on a single family with several members affected with Carney syndrome. Family and individual medical histories were investigated in several Canadian provinces. The histology slides were also reviewed. Four family members (two young women, both sisters, their mother, and maternal grandmother) were found to harbor Carney syndrome. Everyone was presented with multiple and recurrent atrial myxomas of the heart, requiring multiple open cardiac surgeries. Breast myxomas and cutaneous hyperpigmentation were also revealed in one of the sisters and their mother. Interestingly, genetic testing was positive for the female family members and negative for the father and brother. We cannot rule out that the brother may have had a new mutation or harboring a mosaic. The young woman's brother did not have cardiac myxoma but developed a unilateral Sertoli cell tumor of testis. Carney syndrome is a rare complex multisystemic genetic disorder, including multiple and recurrent cardiac myxomas. We strongly suggest that reporting familial Carney syndrome is still critical in the 21st century to augment the awareness of this situation among clinicians and pathologists.

Liver Biopsy Handling of Metabolic-Associated Fatty Liver Disease (MAFLD): the Children's Hospital of Eastern Ontario grossing protocol.

Metabolic-(non-alcoholic) associated fatty liver disease (MAFLD/NAFLD) has increasingly become a worldwide epidemic. It has been suggested that renaming NAFLD to MAFLD is critical in identifying patients with advanced fibrosis and poor cardiovascular outcomes. There are concerns that the progression to non-alcoholic steatohepatitis (NASH) may become a constant drive in the future healthcare of children and adolescents. There is a necessity to tackle the emerging risk factors for NASH-associated hepatocellular carcinoma (HCC). In this narrative review, we present the current protocol of liver biopsy separated between pre-analytical, analytical, and post-analytical handling. Genetic association investigations have identified single nucleotide polymorphisms implicated in the progression of MAFLD-HCC, many of which seem to belong to the lipid metabolism pathways. PNPLA3 rs738409 variant, TM6SF2 rs58542926 variant, MBOAT7 rs641738 variant, and GCKR variants seem to be significantly associated with NAFLD disease susceptibility. In disclosing the current comprehensive protocol performed at the Children's Hospital of Eastern Ontario, Ottawa, ON, Canada, we support the most recent Kulkarni-Sarin's pledge to rename NAFLD to MAFLD. Grossing of the liver biopsy is key to identifying histologic, immunophenotypical, and ultrastructure data and properly preserving tissue for molecular genomics data.

Handling a biopsy with fatty liver disease Fatty liver disease is increasing worldwide. There is a necessity to tackle the emerging risk factors for the development of liver cancer following years of fatty liver disease. In this paper, we show our protocol at the Children's Hospital of Eastern Ontario, University of Ottawa, Ontario, Canada.