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Nature Cancer Feb 2024Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the...
Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models. Here we developed methods to somatically introduce different oncogenic lesions directly into the murine gastric epithelium. Genotypic configurations observed in patients produced metastatic gastric cancers that recapitulated the histological, molecular and clinical features of all nonviral molecular subtypes of the human disease. Applying this platform to both wild-type and immunodeficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells, which produced distinct patterns of metastasis that were mirrored in patients. Our results establish a highly portable platform for generating autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts.
Topics: Humans; Mice; Animals; Stomach Neoplasms; Disease Models, Animal; Gastric Mucosa; Genotype
PubMed: 38177458
DOI: 10.1038/s43018-023-00686-w -
Physical Chemistry Chemical Physics :... Jan 2024The design, synthesis and evaluation of a subphthalocyanine-flipper (SubPc-Flipper) amphiphilic dyad is reported. This dyad combines two fluorophores that function in...
The design, synthesis and evaluation of a subphthalocyanine-flipper (SubPc-Flipper) amphiphilic dyad is reported. This dyad combines two fluorophores that function in the visible region (420-800 nm) for the simultaneous sensing of both ordered and disordered lipidic membranes. The flipper probes part of the dyad possesses mechanosensitivity, long fluorescence lifetimes ( = 3.5-5 ns) and selective staining of ordered membranes. On the other hand, subphthalocyanines (SubPc) are short-lifetime ( = 1-2.5 ns) fluorophores that are insensitive to membrane tension. As a result of a Förster Resonance Energy Transfer (FRET) process, the dyad not only retains the mechanosensitivity of flippers but also demonstrates high selectivity and emission in different kinds of lipidic membranes. The dyad exhibits high emission and sensitivity to membrane tension (Δ = 3.5 ns) when tested in giant unilamellar vesicles (GUVs) with different membrane orders. Overall, the results of this study represent a significant advancement in the applications of flippers and dyads in mechanobiology.
PubMed: 38252531
DOI: 10.1039/d3cp05476d -
Molecules (Basel, Switzerland) Oct 2023The interactions of amyloid proteins with membranes have been subject to many experimental and computational studies, as these interactions contribute in part to... (Review)
Review
The interactions of amyloid proteins with membranes have been subject to many experimental and computational studies, as these interactions contribute in part to neurodegenerative diseases. In this review, we report on recent simulations that have focused on the adsorption and insertion modes of amyloid-β and tau proteins in membranes. The atomistic-resolution characterization of the conformational changes of these amyloid proteins upon lipid cell membrane and free lipid interactions is of interest to rationally design drugs targeting transient oligomers in Alzheimer's disease.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; tau Proteins; Lipids
PubMed: 37894559
DOI: 10.3390/molecules28207080 -
Autophagy Jul 2024Loss of proteostasis and dysregulated mitochondrial function are part of the traditional hallmarks of aging, and in their last revision impaired macroautophagy and...
Loss of proteostasis and dysregulated mitochondrial function are part of the traditional hallmarks of aging, and in their last revision impaired macroautophagy and chronic inflammation are also included. Mitophagy is at the intersection of all these processes but whether it undergoes age-associated perturbations was not known. In our recent work, we performed a systematic and systemic analysis of mitolysosome levels in mice and found that, despite the already-known decrease in nonselective macroautophagy, mitophagy remains stable or increases upon aging in all tissues analyzed and is mediated by the PINK1-PRKN-dependent pathway. Further analyses revealed a concomitant increase in mtDNA leakage into the cytosol and activation of the CGAS-STING1 inflammation axis. Notably, both phenomena are also observed in primary fibroblasts from aged human donors. We hypothesized that mitophagy might be selectively upregulated during aging to improve mitochondrial fitness and reduce mtDNA-induced inflammation. Treatment with the mitophagy inducer urolithin A alleviates age-associated neurological decline, including improved synaptic connectivity, cognitive memory and visual function. Supporting our initial hypothesis, urolithin A reduces the levels of cytosolic mtDNA, CGAS-STING1 activation and neuroinflammation. Finally, using an model of mitochondrial membrane permeabilization we validated that PINK1-PRKN-mediated mitophagy is essential to resolve cytosolic mtDNA-triggered inflammation. These findings open up an integrative approach to tackle aging and increase healthspan via mitophagy induction.
Topics: Mitophagy; Aging; Humans; Animals; Neuroinflammatory Diseases; Membrane Proteins; Protein Kinases; DNA, Mitochondrial; Mitochondria; Mice; Inflammation
PubMed: 38411192
DOI: 10.1080/15548627.2024.2322421 -
Nutrients Jun 2024Celiac disease (CeD) is an autoimmune disease with a strong association with human leukocyte antigen (HLA), characterized by the production of specific autoantibodies... (Review)
Review
Celiac disease (CeD) is an autoimmune disease with a strong association with human leukocyte antigen (HLA), characterized by the production of specific autoantibodies and immune-mediated enterocyte killing. CeD is a unique autoimmune condition, as it is the only one in which the environmental trigger is known: gluten, a storage protein present in wheat, barley, and rye. How and when the loss of tolerance of the intestinal mucosa to gluten occurs is still unknown. This event, through the activation of adaptive immune responses, enhances epithelial cell death, increases the permeability of the epithelial barrier, and induces secretion of pro-inflammatory cytokines, resulting in the transition from genetic predisposition to the actual onset of the disease. While the role of gastrointestinal infections as a possible trigger has been considered on the basis of a possible mechanism of antigen mimicry, a more likely alternative mechanism appears to involve a complex disruption of the gastrointestinal microbiota ecosystem triggered by infections, rather than the specific effect of a single pathogen on intestinal mucosal homeostasis. Several lines of evidence show the existence of intestinal dysbiosis that precedes the onset of CeD in genetically at-risk subjects, characterized by the loss of protective bacterial elements that both epigenetically and functionally can influence the response of the intestinal epithelium leading to the loss of gluten tolerance. We have conducted a literature review in order to summarize the current knowledge about the complex and in part still unraveled dysbiosis that precedes and accompanies CeD and present some exciting new data on how this dysbiosis might be prevented and/or counteracted. The literature search was conducted on PubMed.gov in the time frame 2010 to March 2024 utilizing the terms "celiac disease and microbiota", "celiac disease and microbiome", and "celiac disease and probiotics" and restricting the search to the following article types: Clinical Trials, Meta-Analysis, Review, and Systematic Review. A total of 364 papers were identified and reviewed. The main conclusions of this review can be outlined as follows: (1) quantitative and qualitative changes in gut microbiota have been clearly documented in CeD patients; (2) intestinal microbiota's extensive and variable interactions with enterocytes, viral and bacterial pathogens and even gluten combine to impact the inflammatory immune response to gluten and the loss of gluten tolerance, ultimately affecting the pathogenesis, progression, and clinical expression of CeD; (3) gluten-free diet fails to restore the eubiosis of the digestive tract in CeD patients, and also negatively affects microbial homeostasis; (4) new tools allowing targeted microbiota therapy, such as the use of probiotics (a good example being precision probiotics like the novel strain of (20220303-A2) begin to show exciting potential applications.
Topics: Celiac Disease; Humans; Gastrointestinal Microbiome; Glutens; Dysbiosis; Intestinal Mucosa
PubMed: 38931237
DOI: 10.3390/nu16121882 -
Urology Annals 2023Prolonged urinary incontinence represents one of the most severe complications after a radical prostatectomy procedure, significantly affecting patients' quality of... (Review)
Review
Prolonged urinary incontinence represents one of the most severe complications after a radical prostatectomy procedure, significantly affecting patients' quality of life. In an attempt to ameliorate postprostatectomy continence rates, several sphincter preservation techniques have been reported. The purpose of this article is to report several different sphincter preservation techniques and identify the ones which affect postoperative outcomes the most. For our narrative review, PubMed was searched using the keywords "sphincter," "continence," "preservation," "techniques," and "prostatectomy." Other potentially eligible studies were identified using the reference lists of included studies. Sphincter preservation techniques can be summarized into bladder neck preservation, minimizing injury to the external urethral sphincter, and preserving the maximal length of the external sphincter and of the membranous urethra. Three anatomical structures must be recognized and protected in an attempt to maintain the sphincter complex: the bladder neck, the external urethral sphincter and the musculature of the membranous urethra. While there is strong evidence supporting the importance of bladder neck preservation, the role of maximal preservation of the external sphincter and of the intraprostatic part of the membranous urethra in improving continence rates has not yet been reported in a statistically significant manner by high-quality studies.
PubMed: 38074182
DOI: 10.4103/ua.ua_126_22 -
The Journal of Cell Biology Oct 2023Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by a...
Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by a dynamin-related protein, Dnm1 (Drp1 in humans), that constricts and divides the mitochondria in a GTP hydrolysis-dependent manner. However, it is unclear whether factors inside mitochondria help coordinate the process and if Dnm1/Drp1 activity is sufficient to complete the fission of both mitochondrial membranes. Here, we identify an intermembrane space protein required for mitochondrial fission in yeast, which we propose to name Mdi1 (also named Atg44). Loss of Mdi1 causes mitochondrial hyperfusion due to defects in fission, but not the lack of Dnm1 recruitment to mitochondria. Mdi1 is conserved in fungal species, and its homologs contain an amphipathic α-helix, mutations of which disrupt mitochondrial morphology. One model is that Mdi1 distorts mitochondrial membranes to enable Dnm1 to robustly complete fission. Our work reveals that Dnm1 cannot efficiently divide mitochondria without the coordinated function of Mdi1 inside mitochondria.
Topics: Dynamins; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membranes; Mitochondrial Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; GTP Phosphohydrolases
PubMed: 37540145
DOI: 10.1083/jcb.202303147 -
Frontiers in Plant Science 2023The plant endomembrane system is an elaborate collection of membrane-bound compartments that perform distinct tasks in plant growth and development, and in responses to... (Review)
Review
The plant endomembrane system is an elaborate collection of membrane-bound compartments that perform distinct tasks in plant growth and development, and in responses to abiotic and biotic stresses. Most plant viruses are positive-strand RNA viruses that remodel the host endomembrane system to establish intricate replication compartments. Their fundamental role is to create optimal conditions for viral replication, and to protect replication complexes and the cell-to-cell movement machinery from host defenses. In addition to the intracellular antiviral defense, represented mainly by RNA interference and effector-triggered immunity, recent findings indicate that plant antiviral immunity also includes membrane-localized receptor-like kinases that detect viral molecular patterns and trigger immune responses, which are similar to those observed for bacterial and fungal pathogens. Another recently identified part of plant antiviral defenses is executed by selective autophagy that mediates a specific degradation of viral proteins, resulting in an infection arrest. In a perpetual tug-of-war, certain host autophagy components may be exploited by viral proteins to support or protect an effective viral replication. In this review, we present recent advances in the understanding of the molecular interplay between viral components and plant endomembrane-associated pathways.
PubMed: 37636115
DOI: 10.3389/fpls.2023.1226498 -
International Journal of Molecular... Jul 2023Polyurethane (PU) refers to the polymer containing carbamate groups in its molecular structure, generally obtained by the reaction of isocyanate and alcohol. Because of... (Review)
Review
Polyurethane (PU) refers to the polymer containing carbamate groups in its molecular structure, generally obtained by the reaction of isocyanate and alcohol. Because of its flexible formulation, diverse product forms, and excellent performance, it has been widely used in mechanical engineering, electronic equipment, biomedical applications, etc. Through physical or chemical methods, ionic groups are introduced into PU, which gives PU electrical conductivity, flame-retardant, and antistatic properties, thus expanding the application fields of PU, especially in flexible devices such as sensors, actuators, and functional membranes for batteries and gas absorption. In this review, we firstly introduced the characteristics of PU in chemical and microphase structures and their related physical and chemical performance. To improve the performance of PU, ionic liquids (ILs) were applied in the processing or synthesis of PU, resulting in a new type of PU called ionic PU. In the following part of this review, we mainly summarized the fabrication methods of IL-modified PUs via physical blending and the chemical copolymerization method. Then, we summarized the research progress of the applications for IL-modified PUs in different fields, including sensors, actuators, transistors, antistatic films, etc. Finally, we discussed the future development trends and challenges faced by IL-modified PUs.
Topics: Humans; Polyurethanes; Ionic Liquids; Polymers; Molecular Structure; Suppuration
PubMed: 37511385
DOI: 10.3390/ijms241411627