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Background: Lipid droplets (LD), lipid-storing organelles containing neutral lipids like glycerolipids and cholesterol, are increasingly accepted as hallmarks of inflammation. The nuclear paraspeckle assembly transcript 1 (NEAT1), a long non-coding RNA with over 200 nucleotides, exerts an indispensable impact on regulating both LD agglomeration and autophagy in multiple neurological disorders. However, knowledge as to how NEAT1 modulates the formation of LD and associated signaling pathways is limited. Methods: In this study, primary microglia were isolated from newborn mice and exposed to oxygen-glucose-deprivation/reoxygenation (OGD/R). To further explore NEAT1-dependent mechanisms, an antisense oligonucleotide (ASO) was adopted to silence NEAT1 under in vitro conditions. Studying NEAT1-dependent interactions with regard to autophagy and LD agglomeration under hypoxic conditions, the inhibitor and activator of autophagy 3-methyladenine (3-MA) and rapamycin (RAPA) were used, respectively. In a preclinical stroke model, mice received intraventricular injections of ASO NEAT1 or control vectors in order to yield NEAT1 knockdown. Analysis of readout parameters included qRT-PCR, immunofluorescence, western blot assays, and behavioral tests. Results: Microglia exposed to OGD/R displayed a temporal pattern of NEAT1 expression, peaking at four hours of hypoxia followed by six hours of reoxygenation. After effectively silencing NEAT1, LD formation and autophagy-related proteins were significantly repressed in hypoxic microglia. Stimulating autophagy in ASO NEAT1 microglia under OGD/R conditions by means of RAPA reversed the downregulation of LD agglomeration and perilipin 2 (PLIN2) expression. On the contrary, application of 3-MA promoted repression of both LD agglomeration and expression of the LD-associated protein PLIN2. Under in vivo conditions, NEAT1 was significantly increased in mice at 24 h post-stroke. Knockdown of NEAT1 significantly alleviated LD agglomeration and inhibited autophagy, resulting in improved cerebral perfusion, reduced brain injury and increased neurological recovery. Conclusion: NEAT1 is a key player of LD agglomeration and autophagy stimulation, and NEAT1 knockdown provides a promising therapeutic value against stroke. [ABSTRACT FROM AUTHOR]

Hypoxia triggers reactive microglial inflammation and lipid droplet (LD) accumulation under stroke conditions, although the mutual interactions between these two processes are insufficiently understood. Hence, the involvement of transforming growth factor (TGF)-β1 in inflammation and LD accumulation in cultured microglia exposed to hypoxia were analyzed herein. Primary microglia were exposed to oxygen-glucose deprivation (OGD) injury and lipopolysaccharide (LPS) stimulation. For analyzing the role of TGF-β1 patterns under such conditions, a TGF-β1 siRNA and an exogenous recombinant TGF-β1 protein were employed. Further studies applied Triacsin C, an inhibitor of LD formation, in order to directly assess the impact of LD formation on the modulation of inflammation. To assess mutual microglia-to-neuron interactions, a co-culture model of these cells was established. Upon OGD exposure, microglial TGF-β1 levels were significantly increased, whereas LPS stimulation yielded decreased levels. Elevating TGF-β1 expression proved highly effective in suppressing inflammation and reducing LD accumulation in microglia exposed to LPS. Conversely, inhibition of TGF-β1 led to the promotion of microglial cell inflammation and an increase in LD accumulation in microglia exposed to OGD. Employing the LD formation inhibitor Triacsin C, in turn, polarized microglia towards an anti-inflammatory phenotype. Such modulation of both microglial TGF-β1 and LD levels significantly affected the resistance of co-cultured neurons. This study provides novel insights by demonstrating that TGF-β1 plays a protective role against microglia-mediated neuroinflammation through the suppression of LD accumulation. These findings offer a fresh perspective on stroke treatment, suggesting the potential of targeting this pathway for therapeutic interventions. [ABSTRACT FROM AUTHOR]

This review summarizes the implications of the primary tumor suppressor protein phosphatase and tensin homolog (PTEN) in aggressive cancer development. PTEN interacts with other cellular proteins or factors suggesting the existence of an intricate molecular network that regulates their oncogenic function. Accumulating evidence has shown that PTEN exists and plays a role in the cytoplasmic organelles and in the nucleus. PTEN blocks phosphoinositide 3‐kinases (PI3K)–protein kinase B–mammalian target of rapamycin signaling pathway by dephosphorylating phosphatidylinositol (PI)‐3,4,5‐triphosphate to PI‐4,5‐bisphosphate thus counteracting PI3K function. Studies have shown that PTEN expression is tightly regulated at transcriptional, posttranscriptional, and posttranslational levels (including protein–protein interactions and posttranslational modifications). Despite recent advances in PTEN research, the regulation and function of the PTEN gene remain largely unknown. How mutation or loss of specific exons in the PTEN gene occurs and involves in cancer development is not clear. This review illustrates the regulatory mechanisms of PTEN expression and discusses how PTEN participates in tumor development and/or suppression. Future prospects for the clinical applications are also highlighted. [ABSTRACT FROM AUTHOR]

We have carried out the reactive force field simulations on the pyrolysis process of the transformer insulating oil at different temperatures from 2900 to 3500 K. The selected principal components of the oil molecules are alkanes (C15H32), cycloalkanes (C15H28), and aromatics (C15H16). The effects of formic acid (HCOOH) and acetic acid (CH3COOH) on the pyrolysis mechanism of insulating oils are also studied. The calculated results suggest that with the increasing temperatures, the cracking process of three types of oil molecules accelerates and their speeds of cracking decrease in this order: C15H32 > C15H28 > C15H16. The main pyrolysis products are C2H4, CH4, C2H2, ·CH3, ·C2H3, etc. For the mixture of three types of hydrocarbons, the C2H4 is initially the most abundant product but its concentration decreases gradually and finally the C2H2 and CH4 become the major products. The variation trend of the number of C‒C bonds indicates that the C‒C bonds of oil molecules (especially C15H32 molecules) are broken rapidly at the early stage of pyrolysis process to produce small molecular fragments and then these small fragments are recombined into new pyrolysis products. The evolution of the different types of carbon atoms (sp3-C, sp2-C, sp-C) shows that the sp3-C atoms are initially converted to sp2-C atoms. After the early stage of reactions, many sp2-C atoms are finally turned into sp-C atoms. The addition of formic acid and acetic acid in the insulating oils leads to the formation of the CO and H2O molecules. Both the acetic acid and formic acid could accelerate the pyrolysis process of oil molecules and could further increase the degree of unsaturation of products, which is consistent with the experimental observations. [ABSTRACT FROM AUTHOR]

[Display omitted] • The cracking speeds of oil molecules are in this order: C 17 H 36 > C 17 H 32 > C 17 H 20. • The C 2 H 4 is the initial product but the C 2 H 2 and CH 4 are the final major products. • Formic acid is unfavorable for polymerization process of molecular fragments. • Acetic acid could make the pyrolysis process faster than formic acid. • The pyrolysis mechanisms of transformer oil molecules have been proposed. The reactive force field (ReaxFF) simulations have been performed to investigate the pyrolysis process of the transformer insulating oil from 2900 to 3500 K. We selected C 17 H 36 , C 17 H 32 , and C 17 H 20 as the principal components of the oil molecules and studied the effects of formic acid (HCOOH) and acetic acid (CH 3 COOH) on the pyrolysis mechanism of insulating oils. The calculated results show that the cracking process are accelerated at high temperatures and the speeds of cracking are in this order: C 17 H 36 > C 17 H 32 > C 17 H 20. The predicted main pyrolysis products are H 2 , C 2 H 4 , CH 4 , C 2 H 2 , CH 3 , C 2 H 3 , etc. Except for H 2 molecules, the C 2 H 4 is initially the most abundant product but its number decreases gradually and finally the C 2 H 2 and CH 4 are the major products. The evolution of the number of C–C bonds suggests that the C–C bonds of oil molecules are recombined from the early stage of pyrolysis process to the final equilibration state. The pyrolysis mechanisms of transformer oil have been proposed. The typical elementary steps are H 2 C = CH 2 → H-H + H-C≡C-H, CH 4 → H-H + CH 2 , 2(H 2 C = CH 2) → H-H + 2(H 2 C = CH), and 2(H 2 C = CH) → H-H + 2(H-C≡C-H). Formic acid (HCOOH) could be decomposed into CO, H 2 O, and CO 2 by the following reactions: HCOOH → COH + O-H, COH → CO + H, H + O-H → H 2 O, and HCOOH → CO 2 + H-H. The similar steps are found for acetic acid (CH 3 COOH). Both the acetic acid and formic acid could increase the degree of unsaturation of products, which is consistent with the experimental results. [ABSTRACT FROM AUTHOR]

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor protein predominantly expressed in microglia within the central nervous system (CNS). TREM2 regulates multiple microglial functions, including lipid metabolism, immune reaction, inflammation, and microglial phagocytosis. Recent studies have found that TREM2 is highly expressed in activated microglia after ischemic stroke. However, the role of TREM2 in the pathologic response after stroke remains unclear. Herein, TREM2-deficient microglia exhibit an impaired phagocytosis rate and cholesteryl ester (CE) accumulation, leading to lipid droplet formation and upregulation of Perilipin-2 (PLIN2) expression after hypoxia. Knockdown of TREM2 results in increased lipid synthesis (PLIN2, SOAT1) and decreased cholesterol clearance and lipid hydrolysis (LIPA, ApoE, ABCA1, NECH1, and NPC2), further impacting microglial phenotypes. In these lipid droplet-rich microglia, the TGF-β1/Smad2/3 signaling pathway is downregulated, driving microglia towards a pro-inflammatory phenotype. Meanwhile, in a neuron-microglia co-culture system under hypoxic conditions, we found that microglia lost their protective effect against neuronal injury and apoptosis when TREM2 was knocked down. Under in vivo conditions, TREM2 knockdown mice express lower TGF-β1 expression levels and a lower number of anti-inflammatory M2 phenotype microglia, resulting in increased cerebral infarct size, exacerbated neuronal apoptosis, and aggravated neuronal impairment. Our work suggests that TREM2 attenuates stroke-induced neuroinflammation by modulating the TGF-β1/Smad2/3 signaling pathway. TREM2 may play a direct role in the regulation of inflammation and also exert an influence on the post-ischemic inflammation and the stroke pathology progression via regulation of lipid metabolism processes. Thus, underscoring the therapeutic potential of TREM2 agonists in ischemic stroke and making TREM2 an attractive new clinical target for the treatment of ischemic stroke and other inflammation-related diseases. [Display omitted] • TREM2 regulates multiple microglial functions including lipid metabolism, inflammation, and microglial phagocytosis. • TREM2-deficient microglia exhibit an impaired phagocytosis rate and lipid droplet accumulation. • TREM2 knockdown leads lower TGF-β1 levels and less anti-inflammatory M2 phenotype microglia. • TREM2-deficient microglia display a lower neuroprotective potential. • TREM2 regulates post-ischemic inflammation in both a direct and an indirect way by modulating lipid metabolism. [ABSTRACT FROM AUTHOR]