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British Journal of Anaesthesia Oct 2023The volatile anaesthetic sevoflurane induces time (single or multiple exposures)-dependent effects on tau phosphorylation and cognitive function in young mice. The...
BACKGROUND
The volatile anaesthetic sevoflurane induces time (single or multiple exposures)-dependent effects on tau phosphorylation and cognitive function in young mice. The underlying mechanism for this remains largely undetermined.
METHODS
Mice received 3% sevoflurane for 0.5 h or 2 h daily for 3 days on postnatal day (P) 6, 9, and 12. Another group of mice received 3% sevoflurane for 0.5 h or 1.5 h (3 × 0.5) on P6. We investigated effects of sevoflurane anaesthesia on tau phosphorylation on P6 or P12 mice, on cognitive function from P31 to P37, and on protein interactions, using in vivo studies, in vitro phosphorylation assays, and nanobeam single-molecule level interactions in vitro.
RESULTS
An initial sevoflurane exposure induced CaMKIIα phosphorylation (132 [11]% vs 100 [6]%, P<0.01), leading to tau phosphorylation at serine 262 (164 [7]% vs 100 [26]%, P<0.01) and tau detachment from microtubules. Subsequent exposures to the sevoflurane induced GSK3β activation, which phosphorylated detached or free tau (tau phosphorylated at serine 262) at serine 202 and threonine 205, resulting in cognitive impairment in young mice. In vitro phosphorylation assays also demonstrated sequential tau phosphorylation. Nanobeam analysis of molecular interactions showed different interactions between tau or free tau and CaMKIIα or GSK3β, and between tau and tubulin at a single-molecule level.
CONCLUSIONS
Multiple exposures to sevoflurane can induce sequential tau phosphorylation, leading to cognitive impairment in young mice, highlighting the need to investigate the underlying mechanisms of anaesthesia-induced tau phosphorylation in developing brain.
Topics: Animals; Mice; Sevoflurane; Glycogen Synthase Kinase 3 beta; Phosphorylation; Anesthetics, Inhalation; Cognitive Dysfunction; Anesthesia; Serine; tau Proteins; Mice, Inbred C57BL
PubMed: 37537117
DOI: 10.1016/j.bja.2023.06.059 -
International Journal of Molecular... Oct 2023The microtubule-associated protein tau is an intrinsically disordered protein containing a few short and transient secondary structures. Tau physiologically associates... (Review)
Review
The microtubule-associated protein tau is an intrinsically disordered protein containing a few short and transient secondary structures. Tau physiologically associates with microtubules (MTs) for its stabilization and detaches from MTs to regulate its dynamics. Under pathological conditions, tau is abnormally modified, detaches from MTs, and forms protein aggregates in neuronal and glial cells. Tau protein aggregates can be found in a number of devastating neurodegenerative diseases known as "tauopathies", such as Alzheimer's disease (AD), frontotemporal dementia (FTD), corticobasal degeneration (CBD), etc. However, it is still unclear how the tau protein is compacted into ordered protein aggregates, and the toxicity of the aggregates is still debated. Fortunately, there has been considerable progress in the study of tau in recent years, particularly in the understanding of the intercellular transmission of pathological tau species, the structure of tau aggregates, and the conformational change events in the tau polymerization process. In this review, we summarize the concepts of tau protein aggregation and discuss the views on tau protein transmission and toxicity.
Topics: Humans; tau Proteins; Protein Aggregates; Comprehension; Tauopathies; Alzheimer Disease
PubMed: 37834471
DOI: 10.3390/ijms241915023 -
Journal of Korean Medical Science May 2024The process of cancer metastasis is dependent on the cancer cells' capacity to detach from the primary tumor, endure in a suspended state, and establish colonies in... (Review)
Review
The process of cancer metastasis is dependent on the cancer cells' capacity to detach from the primary tumor, endure in a suspended state, and establish colonies in other locations. Anchorage dependence, which refers to the cells' reliance on attachment to the extracellular matrix (ECM), is a critical determinant of cellular shape, dynamics, behavior, and, ultimately, cell fate in nonmalignant and cancer cells. Anchorage-independent growth is a characteristic feature of cells resistant to anoikis, a programmed cell death process triggered by detachment from the ECM. This ability to grow and survive without attachment to a substrate is a crucial stage in the progression of metastasis. The recently discovered phenomenon named "adherent-to-suspension transition (AST)" alters the requirement for anchoring and enhances survival in a suspended state. AST is controlled by four transcription factors (IKAROS family zinc finger 1, nuclear factor erythroid 2, BTG anti-proliferation factor 2, and interferon regulatory factor 8) and can detach cells without undergoing the typical epithelial-mesenchymal transition. Notably, AST factors are highly expressed in circulating tumor cells compared to their attached counterparts, indicating their crucial role in the spread of cancer. Crucially, the suppression of AST substantially reduces metastasis while sparing primary tumors. These findings open up possibilities for developing targeted therapies that inhibit metastasis and emphasize the importance of AST, leading to a fundamental change in our comprehension of how cancer spreads.
Topics: Humans; Neoplasm Metastasis; Neoplasms; Cell Adhesion; Extracellular Matrix; Epithelial-Mesenchymal Transition; Anoikis; Transcription Factors
PubMed: 38769921
DOI: 10.3346/jkms.2024.39.e156 -
Science Advances Sep 2023Previous studies have revealed a role for proline metabolism in supporting cancer development and metastasis. In this study, we show that many cancer cells respond to...
Previous studies have revealed a role for proline metabolism in supporting cancer development and metastasis. In this study, we show that many cancer cells respond to loss of attachment by accumulating and secreting proline. Detached cells display reduced proliferation accompanied by a general decrease in overall protein production and de novo amino acid synthesis compared to attached cells. However, proline synthesis was maintained under detached conditions. Furthermore, while overall proline incorporation into proteins was lower in detached cells compared to other amino acids, there was an increased production of the proline-rich protein collagen. The increased excretion of proline from detached cells was also shown to be used by macrophages, an abundant and important component of the tumor microenvironment. Our study suggests that detachment induced accumulation and secretion of proline may contribute to tumor progression by supporting increased production of extracellular matrix and providing proline to surrounding stromal cells.
Topics: Proline; Amino Acids; Biological Transport; Extracellular Matrix; Macrophages; Neoplasms
PubMed: 37672588
DOI: 10.1126/sciadv.adh2023 -
Bio-protocol Sep 2023Administration of substances into neonatal mice is required for early treatment with pre-clinical therapeutics, delivery of recombination-inducing substances, and dosing...
Administration of substances into neonatal mice is required for early treatment with pre-clinical therapeutics, delivery of recombination-inducing substances, and dosing with viruses or toxins, amongst other things. Several injection routes into mouse pups are possible, including intravenous and intracerebroventricular, each with their own advantages and limitations. Here, we describe a simple and rapid protocol for the intraperitoneal injection of neonatal mice for systemic dosing. By detaching a 30-gauge needle from its plastic hub and inserting it into polyethylene tubing attached to a Hamilton syringe, small volumes (1-10 μL) can be accurately injected into the peritoneal cavity of pups aged 1-5 days old. The procedure can be completed within a few minutes, is generally safe and well tolerated by both pups and parents, and can be used in combination with alternative administration routes. Key features • This protocol provides a simple description to rapidly and efficiently inject mouse pups aged 1-5 days for systemic dosing. • Allows treatment of neonatal mice with substances such as viruses and compounds for research across disciplines.
PubMed: 37753468
DOI: 10.21769/BioProtoc.4826 -
Journal Francais D'ophtalmologie Sep 2023The central serous chorioretinopathy (CSCR) is characterized by serous retinal detachments SRD associated with one or several retinal pigment epithelium... (Review)
Review
The central serous chorioretinopathy (CSCR) is characterized by serous retinal detachments SRD associated with one or several retinal pigment epithelium detachments/irregularities (PEDs). The choroid is thickened with dilated choroidal veins and choroidal hyperpermeability suggesting an underlying choroidopathy. CSCR belongs to the pachychoroid spectrum. CSCR affects mostly middle-aged men and the main risk factor is the corticosteroid intake. In most cases, the subretinal detachment resolves spontaneously with a good visual prognosis. However, recurrent or chronic form of the disease can lead to irreversible retinal damage and decreased visual acuity. Laser on an extra foveal leak point or half dose/half fluence photodynamic therapy are the first-line treatment options.
Topics: Middle Aged; Male; Humans; Central Serous Chorioretinopathy; Chronic Disease; Fluorescein Angiography; Retinal Detachment; Retina; Tomography, Optical Coherence; Retrospective Studies
PubMed: 37277234
DOI: 10.1016/j.jfo.2023.02.003 -
The Journal of Clinical Investigation Dec 2023Why apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia has remained unclear, but we have suspected that the underlying cause is reduced amounts of...
Why apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia has remained unclear, but we have suspected that the underlying cause is reduced amounts of lipoprotein lipase (LPL) in capillaries. By routine immunohistochemistry, we observed reduced LPL staining of heart and brown adipose tissue (BAT) capillaries in Apoa5-/- mice. Also, after an intravenous injection of LPL-, CD31-, and GPIHBP1-specific mAbs, the binding of LPL Abs to heart and BAT capillaries (relative to CD31 or GPIHBP1 Abs) was reduced in Apoa5-/- mice. LPL levels in the postheparin plasma were also lower in Apoa5-/- mice. We suspected that a recent biochemical observation - that APOA5 binds to the ANGPTL3/8 complex and suppresses its capacity to inhibit LPL catalytic activity - could be related to the low intracapillary LPL levels in Apoa5-/- mice. We showed that an ANGPTL3/8-specific mAb (IBA490) and APOA5 normalized plasma triglyceride (TG) levels and intracapillary LPL levels in Apoa5-/- mice. We also showed that ANGPTL3/8 detached LPL from heparan sulfate proteoglycans and GPIHBP1 on the surface of cells and that the LPL detachment was blocked by IBA490 and APOA5. Our studies explain the hypertriglyceridemia in Apoa5-/- mice and further illuminate the molecular mechanisms that regulate plasma TG metabolism.
Topics: Animals; Mice; Capillaries; Hypertriglyceridemia; Lipoprotein Lipase; Receptors, Lipoprotein; Triglycerides; Apolipoprotein A-V
PubMed: 37824203
DOI: 10.1172/JCI172600 -
Biomedicine & Pharmacotherapy =... Mar 2024Vitreous replacement is a commonly employed method for treating a range of ocular diseases, including posterior vitreous detachment, complex retinal detachment, diabetic... (Review)
Review
Vitreous replacement is a commonly employed method for treating a range of ocular diseases, including posterior vitreous detachment, complex retinal detachment, diabetic retinopathy, macular hole, and ocular trauma. Various clinical substitutes for vitreous include air, expandable gas, silicone oil, heavy silicone oil, and balanced salt solution. However, these substitutes have drawbacks such as short retention time, cytotoxicity, high intraocular pressure, and the formation of cataracts, rendering them unsuitable for long-term treatment. Polymeric hydrogels possess the potential to serve as ideal vitreous substitutes due to their structure-mimicking to natural vitreous and adjustable mechanical properties. Replacement with hydrogels as the tamponade can help maintain the shape of the eyeball, apply pressure to the detached retina, and ensure the metabolic transport of substances without impairing vision. This literature review examines the required properties of artificial vitreous, including the optical properties, rheological properties, expansive force action, and physiological and biochemical functions of chemically and physically crosslinked hydrogels. The strategies for enhancing the biocompatibility and injectability of hydrogels are also summarized and discussed. From a clinical ophthalmology perspective, this paper presents the latest developments in vitreous replacement, providing clinicians with a comprehensive understanding of hydrogel clinical applications, which offers guidance for future design directions and methodologies for hydrogel development.
Topics: Humans; Hydrogels; Eye; Cataract; Diabetic Retinopathy; Ophthalmology; Polymers
PubMed: 38306844
DOI: 10.1016/j.biopha.2024.116154 -
Heliyon Mar 2024Extrachromosomal DNAs (ecDNAs) are a pervasive feature found in cancer and contain oncogenes and their corresponding regulatory elements. Their unique structural... (Review)
Review
Extrachromosomal DNAs (ecDNAs) are a pervasive feature found in cancer and contain oncogenes and their corresponding regulatory elements. Their unique structural properties allow a rapid amplification of oncogenes and alter chromatin accessibility, leading to tumorigenesis and malignant development. The uneven segregation of ecDNA during cell division enhances intercellular genetic heterogeneity, which contributes to tumor evolution that might trigger drug resistance and chemotherapy tolerance. In addition, ecDNA has the ability to integrate into or detach from chromosomal DNA, such progress results into structural alterations and genomic rearrangements within cancer cells. Recent advances in multi-omics analysis revealing the genomic and epigenetic characteristics of ecDNA are anticipated to make valuable contributions to the development of precision cancer therapy. Herein, we conclud the mechanisms of ecDNA generation and the homeostasis of its dynamic structure. In addition to the latest techniques in ecDNA research including multi-omics analysis and biochemical validation methods, we also discuss the role of ecDNA in tumor development and treatment, especially in drug resistance, and future challenges of ecDNA in cancer therapy.
PubMed: 38545177
DOI: 10.1016/j.heliyon.2024.e27733 -
Small (Weinheim An Der Bergstrasse,... Aug 2023Adhesive gels derived from biobased sustainable materials have extremely broad application prospects, such as in flexible smart materials and biomedicine fields....
Adhesive gels derived from biobased sustainable materials have extremely broad application prospects, such as in flexible smart materials and biomedicine fields. Combining high toughness and strong, persisting repeatable adhesion has always been a daunting challenge for adhesive gels. However, bulk gels based on polysaccharides as the most abundant bio-based compounds usually possess a high toughness but weak interfacial adhesion due to the strong hydration potential. Herein, a novel kind of highly tough microgel membranes with rough surfaces is fabricated using loosely chemically cross-linked dihydroxypropyl cellulose (cDHPC) microgels (average size = 1.25 ± 0.03 µm). Such microgel membranes exhibit strong, instant, and persisting adhesion to various substrates with different surface roughness. Slight chemical cross-linking and multiple physical interactions within microgels and resulting microgel membranes lead to high tensile strength and toughness of 0.23 ± 0.03 MPa and 73.8 ± 9.3 KJ m , respectively. The maximum adhesive strength and debonding work exceed 320 ± 0.50 KPa and 160.97 ± 0.20 J m , respectively. After five cycles (re-lap after detaching), the adhesive strength still remains above 200 KPa. Their adhesive properties outperform most bio-based adhesive gels and even petroleum-based gels, which are based on synergistic molecular and microscaled topological interactions.
PubMed: 37162453
DOI: 10.1002/smll.202300865