The mechanism of HMGB1 secretion and release

Experimental & Molecular Medicine, Journal Year: 2022, Volume and Issue: 54(2), P. 91 - 102

Published: Feb. 1, 2022

Abstract High mobility group box 1 (HMGB1) is a nonhistone nuclear protein that has multiple functions according to its subcellular location. In the nucleus, HMGB1 DNA chaperone maintains structure and function of chromosomes. cytoplasm, can promote autophagy by binding BECN1 protein. After active secretion or passive release, extracellular usually acts as damage-associated molecular pattern (DAMP) molecule, regulating inflammation immune responses through different receptors direct uptake. The release fine-tuned variety factors, including posttranslational modification (e.g., acetylation, ADP-ribosylation, phosphorylation, methylation) machinery cell death apoptosis, pyroptosis, necroptosis, alkaliptosis, ferroptosis). this minireview, we introduce basic focus on regulatory mechanism release. Understanding these topics may help us develop new HMGB1-targeted drugs for various conditions, especially inflammatory diseases tissue damage.

Language: Английский

---

Role of Calcium Modulation in the Pathophysiology and Treatment of Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 9067 - 9067

Published: May 22, 2023

Alzheimer’s disease (AD) is a chronic neurodegenerative and the most frequent cause of progressive dementia in senior adults. It characterized by memory loss cognitive impairment secondary to cholinergic dysfunction N-methyl-D-aspartate (NMDA)-mediated neurotoxicity. Intracellular neurofibrillary tangles, extracellular plaques composed amyloid-β (Aβ), selective neurodegeneration are anatomopathological hallmarks this disease. The dysregulation calcium may be present all stages AD, it associated with other pathophysiological mechanisms, such as mitochondrial failure, oxidative stress, neuroinflammation. Although cytosolic alterations AD not completely elucidated, some calcium-permeable channels, transporters, pumps, receptors have been shown involved at neuronal glial levels. In particular, relationship between glutamatergic NMDA receptor (NMDAR) activity amyloidosis has widely documented. Other mechanisms dyshomeostasis include activation L-type voltage-dependent transient potential ryanodine receptors, among many others. This review aims update calcium-dysregulation discuss targets molecules therapeutic based on their modulation.

Language: Английский

---

The Alteration of Microglial Calcium Homeostasis in Central Nervous System Disorders: A Comprehensive Review

Neuroglia, Journal Year: 2024, Volume and Issue: 5(4), P. 410 - 444

Published: Oct. 21, 2024

Microglia, the unique and motile immune cells of central nervous system (CNS), function as a security guard in maintaining CNS homeostasis, primarily through calcium signaling. The dynamics microglia control important functions such phagocytosis, cytokine release, migration. Calcium dysregulation has been linked to several disorders, like Alzheimer’s disease (AD), Parkinson’s (PD), multiple sclerosis (MS), ischemic stroke (IS). entering channels voltage-gated (VGCCs), store-operated entry (SOCE), transient receptor potential (TRP) is essential for microglial activation pro-inflammatory responses. Under pathological conditions, formation amyloid-β plaques AD, aggregation α-synuclein PD, oxidative stress MS, exacerbates neuroinflammation, mitochondrial dysfunction, neurodegeneration. Therapeutic strategies targeting signaling pathways, using channel blockers antioxidant interventions, show promise alleviating slowing down progression. This review summarizes underlying mechanisms therapeutic benefits restoring balance disorders.

Language: Английский

---

Bioinformatics investigation on blood-based gene expressions of Alzheimer's disease revealed ORAI2 gene biomarker susceptibility: An explainable artificial intelligence-based approach

Metabolic Brain Disease, Journal Year: 2023, Volume and Issue: 38(4), P. 1297 - 1310

Published: Feb. 21, 2023

The progressive, chronic nature of Alzheimer's disease (AD), a form dementia, defaces the adulthood elderly individuals. pathogenesis condition is primarily unascertained, turning treatment efficacy more arduous. Therefore, understanding genetic etiology AD essential to identifying targeted therapeutics. This study aimed use machine-learning techniques expressed genes in patients with identify potential biomarkers that can be used for future therapy. dataset accessed from Gene Expression Omnibus (GEO) database (Accession Number: GSE36980). subgroups (AD blood samples frontal, hippocampal, and temporal regions) are individually investigated against non-AD models. Prioritized gene cluster analyses conducted STRING database. candidate were trained various supervised (ML) classification algorithms. interpretation model prediction perpetrated explainable artificial intelligence (AI) techniques. experiment revealed 34, 60, 28 as target mapped regions. It identified ORAI2 shared biomarker all three areas strongly associated AD's progression. pathway analysis showed STIM1 TRPC3 ORAI2. We found hub genes, TPI1, STIM1, TRPC3, network might involved molecular AD. Naive Bayes classified different groups by fivefold cross-validation 100% accuracy. AI ML promising tools disease-associated will advance field therapeutics diseases.

Language: Английский

---

Bafilomycin A1 Molecular Effect on ATPase Activity of Subcellular Fraction of Human Colorectal Cancer and Rat Liver

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(3), P. 1657 - 1657

Published: Jan. 29, 2024

Bafilomycin A1 inhibits V-type H+ ATPases on the molecular level, which acidifies endo-lysosomes. The main objective of study was to assess effect bafilomycin Ca2+ content, NAADP-induced release, and ATPase activity in rat hepatocytes human colon cancer samples. Chlortetracycline (CTC) used for a quantitative measure stored calcium permeabilized hepatocytes. determined by orthophosphate content released after ATP hydrolysis subcellular post-mitochondrial fraction obtained from liver as well patients’ samples mucosa colorectal In hepatocytes, decreased prevented NAADP Ca2+. This dependent EGTA–Ca2+ buffers medium. significantly increased endoplasmic reticulum (EPR), but not plasma membrane (PM) liver. also these pumps. addition, reduced Na+/K+ basal Mg2+ Concomitant administration enhanced effects. EPR normal tissue contrast, it PM caused no changes cancer. It can be concluded that targets NAADP-sensitive acidic stores, effectively modulates activity, assumes link between stores EPR. may useful therapy.

Language: Английский

---

Coupling BCP Ceramics with Micro‐Vibration Stimulation Field for Cascade Amplification from Immune Activation to Bone Regeneration

Advanced Functional Materials, Journal Year: 2023, Volume and Issue: 33(24)

Published: March 14, 2023

Abstract The osteoimmunology has revealed that immune system plays an important role in maintaining bone metabolism and remodeling. As long‐term physiological factor bone, mechanical stimulation such as micro‐vibration (MVS) exerts effects on regulating osteogenesis response. In this study, the osteo‐immunodulatory of bicalcium phosphate (BCP) ceramics coupled with MVS are investigated. This results find combination BCP may exert synergistic polarization functional status macrophages through activating plasma membrance Ca 2+ ATPase (PMCA) channel, reducing intracellular calcium ion concentration, inhibiting downstream extracellular signal‐regulated kinase (ERK)1/2 signaling pathway. could drive macrophage to wound‐healing M2 phenotype decrease production pro‐inflammatory factors, enhance secretion anti‐inflammatory cytokines growth factors transforming (TGF)‐β1 morphogenetic protein (BMP)‐2. Moreover, MVS‐modulated pattern can trigger BMP/TGF‐Smad pathways induce osteoblastic differentiation marrow mesenchymal stromal cells (BM‐MSCs) vitro, maintain cellular viability promote formation collagen‐rich osteoid like tissues mature blood vessels vivo. study demonstrates introduction stimuli non‐invasive is effective strategy improve repair biomaterials endowing them superior capacity.

Language: Английский

---

A pH-sensitive closed-loop nanomachine to control hyperexcitability at the single neuron level

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 4, 2024

Abstract Epilepsy affects 1% of the general population and 30% patients are resistant to antiepileptic drugs. Although optogenetics is an efficient strategy, difficulty illuminating deep brain areas poses translational challenges. Thus, search alternative light sources strongly needed. Here, we develop pH-sensitive inhibitory luminopsin (pHIL), a closed-loop chemo-optogenetic nanomachine composed luciferase-based generator, fluorescent sensor intracellular pH (E 2 GFP), optogenetic actuator (halorhodopsin) for silencing neuronal activity. Stimulated by coelenterazine, pHIL experiences bioluminescence resonance energy transfer between luciferase E GFP which, under conditions acidic pH, activates halorhodopsin. In primary neurons, senses drop associated with hyperactivity optogenetically aborts paroxysmal activity elicited administration convulsants. The expression in hippocampal pyramidal neurons effective decreasing duration increasing latency pilocarpine-induced tonic-clonic seizures upon vivo coelenterazine administration, without affecting higher functions. same treatment markedly seizure manifestations murine model genetic epilepsy. results indicate that represents potentially promising strategy treat drug-refractory

Language: Английский

---

PLA2G6 and NOTCH3 variants associated with familial Parkinson's disease in two suspected families based on whole genome sequencing

Human Gene, Journal Year: 2025, Volume and Issue: unknown, P. 201393 - 201393

Published: Feb. 1, 2025

Language: Английский

---

CLN3, at the crossroads of endocytic trafficking

Neuroscience Letters, Journal Year: 2021, Volume and Issue: 762, P. 136117 - 136117

Published: July 16, 2021

Language: Английский

---

Experimental platform for the functional investigation of membrane proteins in giant unilamellar vesicles

Soft Matter, Journal Year: 2022, Volume and Issue: 18(31), P. 5877 - 5893

Published: Jan. 1, 2022

Giant unilamellar vesicles (GUVs) are micrometer-sized model membrane systems that can be viewed directly under the microscope. They serve as scaffolds for bottom-up creation of synthetic cells, targeted drug delivery and have been widely used to study related phenomena in vitro. GUVs also interest functional investigation proteins carry out many key cellular functions. A major hurdle a wider application this field is diversity existing protocols optimized individual proteins. Here, we compare PVA assisted electroformation techniques GUV formation physiologically relevant conditions, analyze effect immobilization on vesicle structure tightness towards small substrates protons. There, differences terms yield, size, leakage produced by swelling were found, dependent salt buffer composition. Using fusion oppositely charged membranes reconstitute protein, find empty proteoliposomes show similar behavior, which allows rapid estimation protein incorporation using fluorescent lipids.

Language: Английский

---