Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome that elevates the risk of hepatocellular carcinoma (HCC). Although alteration of lipid metabolism has ...been increasingly recognized as a hallmark of cancer cells, the deregulated metabolic modulation of HCC cells in the NAFLD progression remains obscure. Here, we discovers an endoplasmic reticulum-residential protein, Nogo-B, as a highly expressed metabolic modulator in both murine and human NAFLD-associated HCCs, which accelerates high-fat, high-carbohydrate diet-induced metabolic dysfunction and tumorigenicity. Mechanistically, CD36-mediated oxLDL uptake triggers CEBPβ expression to directly upregulate Nogo-B, which interacts with ATG5 to promote lipophagy leading to lysophosphatidic acid-enhanced YAP oncogenic activity. This CD36-Nogo-B-YAP pathway consequently reprograms oxLDL metabolism and induces carcinogenetic signaling for NAFLD-associated HCCs. Targeting the Nogo-B pathway may represent a therapeutic strategy for HCC arising from the metabolic syndrome.
Cardiac contractility is mediated by a variable flux in intracellular calcium (Ca2+), thought to be integrated into mitochondria via the mitochondrial calcium uniporter (MCU) channel to match ...energetic demand. Here, we examine a conditional, cardiomyocyte-specific, mutant mouse lacking Mcu, the pore-forming subunit of the MCU channel, in adulthood. Mcu−/− mice display no overt baseline phenotype and are protected against mCa2+ overload in an in vivo myocardial ischemia-reperfusion injury model by preventing the activation of the mitochondrial permeability transition pore, decreasing infarct size, and preserving cardiac function. In addition, we find that Mcu−/− mice lack contractile responsiveness to acute β-adrenergic receptor stimulation and in parallel are unable to activate mitochondrial dehydrogenases and display reduced bioenergetic reserve capacity. These results support the hypothesis that MCU may be dispensable for homeostatic cardiac function but required to modulate Ca2+-dependent metabolism during acute stress.
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•The MCU is dispensable for baseline homeostatic cardiac function•Deletion of Mcu protects against myocardial IR injury by reducing MPTP activation•The MCU is required to match energetics with contractile demand during stress•A slow MCU-independent uptake mechanism may maintain basal matrix mCa2+ content
Luongo et al. show, using a conditional knockout mouse model, that the mitochondrial Ca2+ uniporter (MCU), although dispensable for homeostatic function, is necessary for the cardiac “fight-or-flight” contractile response and a significant contributor to mitochondrial permeability transition during ischemia-reperfusion injury.
Fecal microbiota transplantation (FMT) is effective in treating recurrent Clostridium difficile infection (CDI). Bacterial colonization in recipients after FMT has been studied, but little is known ...about the role of the gut fungal community, or mycobiota. Here, we show evidence of gut fungal dysbiosis in CDI, and that donor-derived fungal colonization in recipients is associated with FMT response. CDI is accompanied by over-representation of Candida albicans and decreased fungal diversity, richness, and evenness. Cure after FMT is associated with increased colonization of donor-derived fungal taxa in recipients. Recipients of successful FMT ("responders") display, after FMT, a high relative abundance of Saccharomyces and Aspergillus, whereas "nonresponders" and individuals treated with antibiotics display a dominant presence of Candida. High abundance of C. albicans in donor stool also correlates with reduced FMT efficacy. Furthermore, C. albicans reduces FMT efficacy in a mouse model of CDI, while antifungal treatment reestablishes its efficacy, supporting a potential causal relationship between gut fungal dysbiosis and FMT outcome.
TRPM channels are a subgroup of the transient receptor potential (TRP) channel superfamily whose members have important roles in cell proliferation and survival. TRPM2, the second subfamily member to ...be cloned, is expressed in many tissues including brain, heart, vasculature and haematopoietic cells. TRPM2 is activated by oxidative stress and several other extracellular signals including tumour necrosis factor α (TNF‐α) and amyloid β‐peptide, which increase production of ADP‐ribose (ADPR). ADPR binds to the TRPM2 C‐terminal NUDT9‐H domain, activating the channel. Early studies support the paradigm that TRPM2 activation induces cell death by sustained Ca2+ influx or by enhancing cytokine production, aggravating inflammation and tissue injury. However, more recent data show that for a number of physiological processes, TRPM2 is protective. TRPM2 protects lungs from endotoxin‐induced injury by reducing reactive oxygen species (ROS) production by phagocytes. It protects hearts from oxidative damage after ischaemia–reperfusion or hypoxia–reoxygenation by maintaining better mitochondrial bioenergetics and by decreasing ROS. Sustained Ca2+ entry through TRPM2 is required to maintain cellular bioenergetics and protect against hypoxia–reoxygenation injury. TRPM2 also protects neuroblastoma from moderate oxidative stress by decreasing ROS through increased levels of forkhead box transcription factor 3a (FOXO3a) and a downstream effector, superoxide dismutase 2. TRPM2 is important for tumour growth and cell survival through modulation of hypoxia‐inducible transcription factor expression, mitochondrial function and mitophagy. These findings in cardiac ischaemia and in neuroblastoma suggest that TRPM2 has a basic role in sustaining mitochondrial function and in cell survival that applies to a number of physiological systems and pathophysiological processes including ischaemia–reperfusion injury.
Although activation of the ion channel TRPM2 can induce cell death in some circumstances, TRPM2 can also preserve cell viability and protect against tissue damage following oxidative stress and ischaemia–reperfusion. TRPM2 dependent Ca2+ entry can modulate HIF‐1/2α expression. One mechanism through which this may occur is through enhancement of calcineurin activity through TRPM2‐dependent Ca2+ entry, which may increase HIF‐1/2α stability. HIF‐1/2α enhances expression of a number of target genes including those involved in energy metabolism, antioxidant expression and mitophagy. Ca2+ entry through TRPM2 may also directly influence mitochondrial Ca2+ uptake. Together, the impact on mitochondrial function results in reduced ROS production and reduced cell death. In contrast, in the TRPM2 KO, Ca2+ influx is reduced after oxidative stress and HIF‐1/2α expression is decreased, as are proteins downstream of HIF‐1/2α including BNIP3, SOD1/2, and NDUFA4L2. In addition, mitochondrial Ca2+ uptake is reduced, which may contribute to dysfunctional mitochondria along with decreased NDUFA4L2, and reduced mitochondrial bioenergetics. Decreased BNIP3, which results in reduced mitophagy, contributes to an accumulation of dysfunctional mitochondria and along with decreased SOD1/2 antioxidant activity, increased ROS. The cell has reduced tolerance to a further rise in ROS, for example following ischaemia or doxorubicin, leading to reduced cell survival and increased cell death in the absence of TRPM2.
In this randomized study of patients with upper gastrointestinal bleeding, infusion of omeprazole, as compared with placebo, before endoscopy reduced the incidence of endoscopic treatment (19.1% vs. ...28.4%, P=0.007) and, among patients with peptic ulcers, resulted in fewer actively bleeding ulcers and more ulcers with clean bases. These findings suggest that infused omeprazole is beneficial for patients with upper gastrointestinal bleeding who are awaiting endoscopy.
In patients with upper gastrointestinal bleeding, infusion of omeprazole before endoscopy reduced the incidence of endoscopic treatment (19.1% vs. 28.4%) and, among patients with peptic ulcers, resulted in fewer actively bleeding ulcers and more ulcers with clean bases.
In patients with bleeding peptic ulcers, we previously showed that infusion of a high-dose proton-pump inhibitor after hemostasis had been achieved during endoscopy reduced recurrent bleeding and improved clinical outcomes.
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The adjuvant use of high-dose proton-pump inhibitors in endoscopic therapy has also been endorsed in two consensus statements
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,
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and confirmed in two meta-analyses.
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,
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Clot formation over arteries is pH dependent; a gastric pH above 6 is thought to be critical for platelet aggregation.
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When given intravenously and at a high dose, proton-pump inhibitors can be used to maintain a neutral gastric pH.
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In clinical practice, treatment with proton-pump . . .
ObjectiveThe pathogenesis of UC relates to gut microbiota dysbiosis. We postulate that alterations in the viral community populating the intestinal mucosa play an important role in UC pathogenesis. ...This study aims to characterise the mucosal virome and their functions in health and UC.DesignDeep metagenomics sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on the rectal mucosa of 167 subjects from three different geographical regions in China (UC=91; healthy controls=76). Virome and bacteriome alterations in UC mucosa were assessed and correlated with patient metadata. We applied partition around medoids clustering algorithm and classified mucosa viral communities into two clusters, referred to as mucosal virome metacommunities 1 and 2.ResultsIn UC, there was an expansion of mucosa viruses, particularly Caudovirales bacteriophages, and a decrease in mucosa Caudovirales diversity, richness and evenness compared with healthy controls. Altered mucosal virome correlated with intestinal inflammation. Interindividual dissimilarity between mucosal viromes was higher in UC than controls. Escherichia phage and Enterobacteria phage were more abundant in the mucosa of UC than controls. Compared with metacommunity 1, metacommunity 2 was predominated by UC subjects and displayed a significant loss of various viral species. Patients with UC showed substantial abrogation of diverse viral functions, whereas multiple viral functions, particularly functions of bacteriophages associated with host bacteria fitness and pathogenicity, were markedly enriched in UC mucosa. Intensive transkingdom correlations between mucosa viruses and bacteria were significantly depleted in UC.ConclusionWe demonstrated for the first time that UC is characterised by substantial alterations of the mucosa virobiota with functional distortion. Enrichment of Caudovirales bacteriophages, increased phage/bacteria virulence functions and loss of viral-bacterial correlations in the UC mucosa highlight that mucosal virome may play an important role in UC pathogenesis.
Bcl2-associated athanogene-3 (BAG3) is expressed ubiquitously in humans, but its levels are highest in the heart, the skeletal muscle, and the central nervous system; it is also elevated in many ...cancers. BAG3's diverse functions are supported by its multiple protein-protein binding domains, which couple with small and large heat shock proteins, members of the Bcl2 family, other antiapoptotic proteins, and various sarcomere proteins. In the heart, BAG3 inhibits apoptosis, promotes autophagy, couples the beta-adrenergic receptor with the L-type Ca.sup.2+ channel, and maintains the structure of the sarcomere. In cancer cells, BAG3 binds to and supports an identical array of prosurvival proteins, and it may represent a therapeutic target. However, the development of strategies to block BAG3 function in cancer cells may be challenging, as they are likely to interfere with the essential roles of BAG3 in the heart. In this Review, we present the current knowledge regarding the biology of this complex protein in the heart and in cancer and suggest several therapeutic options.
Transient receptor potential channel TRPM2 is highly expressed in many cancers and involved in regulation of key physiological processes including mitochondrial function, bioenergetics, and oxidative ...stress. In Stage 4 non-MYCN amplified neuroblastoma patients, high TRPM2 expression is associated with worse outcome. Here, neuroblastoma cells with high TRPM2 expression demonstrated increased migration and invasion capability. RNA sequencing, RT-qPCR, and Western blotting demonstrated that the mechanism involved significantly greater expression of integrins α1, αv, β1, and β5 in cells with high TRPM2 expression. Transcription factors HIF-1α, E2F1, and FOXM1, which bind promoter/enhancer regions of these integrins, were increased in cells with high TRPM2 expression. Subcellular fractionation confirmed high levels of α1, αv, and β1 membrane localization and co-immunoprecipitation confirmed the presence of α1β1, αvβ1, and αvβ5 complexes. Inhibitors of α1β1, αvβ1, and αvβ5 complexes significantly reduced migration and invasion in cells highly expressing TRPM2, confirming their functional role. Increased pAkt
and pERK
, which promote migration through mechanisms including integrin activation, were found in cells highly expressing TRPM2. TRPM2 promotes migration and invasion in neuroblastoma cells with high TRPM2 expression through modulation of integrins together with enhancing cell survival, negatively affecting patient outcome and providing rationale for TRPM2 inhibition in anti-neoplastic therapy.
The number of artificial intelligence (AI) studies in medicine has exponentially increased recently. However, there is no clear quantification of the clinical benefits of implementing AI-assisted ...tools in patient care.
This study aims to systematically review all published randomized controlled trials (RCTs) of AI-assisted tools to characterize their performance in clinical practice.
CINAHL, Cochrane Central, Embase, MEDLINE, and PubMed were searched to identify relevant RCTs published up to July 2021 and comparing the performance of AI-assisted tools with conventional clinical management without AI assistance. We evaluated the primary end points of each study to determine their clinical relevance. This systematic review was conducted following the updated PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines.
Among the 11,839 articles retrieved, only 39 (0.33%) RCTs were included. These RCTs were conducted in an approximately equal distribution from North America, Europe, and Asia. AI-assisted tools were implemented in 13 different clinical specialties. Most RCTs were published in the field of gastroenterology, with 15 studies on AI-assisted endoscopy. Most RCTs studied biosignal-based AI-assisted tools, and a minority of RCTs studied AI-assisted tools drawn from clinical data. In 77% (30/39) of the RCTs, AI-assisted interventions outperformed usual clinical care, and clinically relevant outcomes improved with AI-assisted intervention in 70% (21/30) of the studies. Small sample size and single-center design limited the generalizability of these studies.
There is growing evidence supporting the implementation of AI-assisted tools in daily clinical practice; however, the number of available RCTs is limited and heterogeneous. More RCTs of AI-assisted tools integrated into clinical practice are needed to advance the role of AI in medicine.
PROSPERO CRD42021286539; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=286539.
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