Activator Protein Research Articles

Feedback-delay dependence of the stability of cluster periodic orbits in populations of degrade-and-fire oscillators with common activator

Feedback delay has been identified as a key ingredient in the quorum sensing synchronization of synthetic gene oscillators. While this influence has been evidenced at the theoretical level in a simplified system of degrade-and-fire oscillators coupled via a common activator protein, full mathematical certifications remained to be provided. Here, we prove from a rigorous mathematical viewpoint that, for the very same model, the synchronized degrade-and-fire oscillations are 1/ unstable with respect to out-of-sync perturbations in absence of delay, and 2/ are otherwise asymptotically stable in presence of delay, no matter how small is its amplitude. To that goal, we proceed to an extensive study of the population dynamics in this system, which in particular identifies the mechanisms of, and related criteria for, the delay-dependent stability of periodic orbits with respect to out-of-sync perturbations. As an additional outcome, the analysis also reveals that, depending on the parameters, multiple stable partially synchronized periodic orbits can coexist with the fully synchronized one.

Conditional knockdown of hepatic PCSK9 ameliorates high-fat diet-induced liver inflammation in mice

InstructionAccumulating evidence has shown that proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with inflammation in the vascular system. However, the roles of PCSK9 in hepatic inflammation remain unclear. Because PCSK9 is mainly expressed in the liver and modulates lipid uptake through low-density lipoprotein receptor family members, the present study aimed to elucidate the effect of conditional knockdown of hepatic PCSK9 on hyperlipidemia-induced inflammation and the underlying mechanisms of action.MethodsPCSK9flox/flox mice were bred with ALB-Cre+ mice to obtain hepatic PCSK9(−/−), PCSK9(+/−), and PCSK9(+/+) mice. These mice were fed with a high-fat diet for 9 weeks to induce inflammation. The effects of conditional knockdown of hepatic PCSK9 on inflammation and the underlying mechanisms were investigated by molecular biological techniques. Moreover, the findings were verified in vitro using HepG2 cells.Results and DiscussionConditional knockdown of hepatic PCSK9 remarkably decreased plasma levels of total cholesterol and alleviated hyperlipidemia-induced liver injury. Mechanistically, conditional knockdown of hepatic PCSK9 significantly reduced the levels of pro-inflammatory factors by downregulating the expression of Toll-like receptors, mitogen-activated protein kinase (MAPK), and phosphoinositide-3 kinase/protein kinase B, which subsequently attenuated the expression of downstream molecules, namely nuclear factor kappa-B and activator protein-1. The related mechanisms were confirmed using lipid-loaded HepG2 cells together with PCSK9 siRNA, alirocumab (anti-PCSK9 antibody), and/or a p38-MAPK inhibitor. These findings confirmed that conditional knockdown of hepatic PCSK9 attenuates liver inflammation following hyperlipidemia induction by modulating multiple signaling pathways; this suggests that targeting PCSK9 knockdown/inhibition with appropriate agents is useful not only for treating hyperlipidemia but also for ameliorating hyperlipidemia-induced liver inflammation.

Histone acetylation alteration by KAT6A inhibitor WM-1119 suppresses IgE-mediated mast cell activation and allergic inflammation via reduction in AP-1 signaling.

Activation of immunoglobulin E (IgE)-associated mast cells (MCs) triggers the onset of pro-inflammatory signals associated with type I allergic diseases. Although histone acetylation changes have been associated with inflammatory diseases, the impact of lysine-acetyltransferase (KAT) inhibitors on IgE-mediated MCs function is unclear. Potential anti-allergic effects of the KAT6A inhibitor WM-1119 on IgE-mediated MCs activation and allergic inflammation were examined in this study. WM-1119 was observed to reduce IgE-mediated degranulation in rat basophilic leukemia-2H3 cells (RBLs) and murine bone marrow-derived mast cells (BMMCs), as demonstrated by reduced the release of β-hexosaminidase (β-hex)or histamine(HA) and decreased inflammatory cytokines. Additionally, WM-1119 attenuated allergic responses in IgE-induced passive cutaneous anaphylaxis (PCA) and active systemic anaphylaxis (ASA) mice. No WM-1119 effects on histamine-induced hypothermia in mice were observed. Mechanically, WM-1119 reduced levels of histone H3 lysine 14 acetylation (H3K14ac) and H3K27ac, while also reducing IgE-induced MAPK or NF-κB activity. Moreover, WM-1119 reduced activator protein-1 (AP-1) activity in a manner involving inhibition of c-Fos transcription and translation together with decreased AP-1 binding of its downstream promoters. KAT6A knockdown in MCs also reduced AP-1 activity by inhibiting c-Fos expression. H3K14ac enrichment in the Fos promoter was observed, indicating that H3K14ac may regulate c-Fos expression. In conclusion, KAT6A inhibition or knockdown was shown to reduce IgE-mediated MCs activation and allergic inflammation through a mechanism involving changes in c-Fos expression and downstream AP-1 activity consequent to down-regulation of histone acetylation. KAT6A inhibition may represent a new treatment strategy for suppressing MCs in treating allergic diseases.

Upregulation of haematopoetic cell kinase (Hck) activity by a secreted parasite effector protein (Ta9) drives proliferation of Theileria annulata-transformed leukocytes.

Reversible transformation of bovine leukocytes by the intracellular parasites Theileria annulata and Theileria parva is central to pathogenesis of the diseases they cause, tropical theileriosis and East Coast Fever, respectively. Parasite-dependent constitutive activation of major host transcription factors such as AP-1 (Activating Protein 1) and NF-κB (Nuclear Factor-Kappa B) sustains the transformed state. Although parasite interaction with host cell signaling pathways upstream of AP-1 have been studied, the precise contribution of Theileria encoded factors capable of modulating AP-1 transcriptional activity, and other infection-altered signaling pathways is not fully understood. We previously showed that the Ta9 protein from T. annulata (TA15705) is secreted into the host cell cytoplasm and contributes to infection-induced AP-1 transcriptional activity. The current study employed RNA-seq to investigate the ability of ectopically expressed Ta9 to modulate the gene transcription profile of a bovine macrophage cell line, BoMac. RNA-seq identified 560 (400 upregulated and 160 downregulated) differentially expressed genes. KEGG analysis predicted a high number of upregulated genes associated with carcinogenesis such as CCND1, CDKN1A, ETV4, ETV5, FLI1, FRA1, GLI2, GRO1, HCK, IL7R, MYBL1, MYCN, PIM1 and TAL1. Ta9 introduction also affected genes associated with proinflammatory processes such as cytokines, chemokines, growth factors and metalloproteinases. Enrichment analysis of differentially expressed genes revealed that Ta9 is potentially involved in activating other host cell signaling pathways in addition to those that lead to induction of AP-1. Comparing our data with data on differentially expressed BoMac genes modulated by the secreted TashAT2 factor of T. annulata identified the gene encoding the tyrosine protein kinase hematopoietic cell kinase (HCK) as common to both data sets. HCK is essential for the proliferation of T. parva-transformed B cells and herein, we demonstrate that enzymatic activity of HCK is also essential for T. annulata- and T. lestoquardi-transformed macrophage proliferation.

In vitro and in vivo anti-inflammatory and antinociceptive activities of a synthetic hydrangenol derivative: 5-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one.

In the present study, we developed and synthesized novel hydrangenol derivatives and featured their anti-inflammatory activities. Especially, a synthetic derivative 11 (compound 11), which possesses the 4H-1-benzopyran-4-one moiety, 5-hydroxyl group in A-ring, and 4'-hydroxyl group in B-ring, most dominantly downregulated nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. In addition, compound 11 suppressed the inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) expression by inhibiting nuclear factor kappa-B (NF-κB), activator protein 1 (AP-1), and signal transducer and activator of transcription protein (STAT) pathways in LPS-provoked RAW264.7 macrophages. Additionally, we confirmed that compound 11 had better plasma stability than hydrangenol with a plasma-labile δ-valerolactone moiety. In carrageenan-induced rats, compound 11 potently reduced paw inflammation (as measured by paw volume, width, and thickness) by inhibiting the iNOS and COX-2 expression in paw tissue, thereby reducing inflammatory pain. All things considered, as compound 11 shows anti-inflammatory and antinociceptive properties, converting metabolically unstable hydrangenol into a stable compound 11 could be a promising strategy for developing new drugs.

Single-cell transcriptome atlas of male mouse pituitary across postnatal life highlighting its stem cell landscape.

The pituitary represents the master gland governing the endocrine system. We constructed a single-cell (sc) transcriptomic atlas of male mouse endocrine pituitary by incorporating existing and new data, spanning important postnatal ages in both healthy and injured condition. We demonstrate strong applicability of this new atlas to unravel pituitary (patho)biology by focusing on its stem cells and investigating their complex identity (unveiling stem cell markers) and niche (pinpointing regulatory factors). Importantly, we functionally validated transcriptomic findings using pituitary stem cell organoids, revealing roles for Krüppel-like transcription factor 5 (KLF5), activator protein-1 (AP-1) complex and epidermal growth factor (EGF) pathways in pituitary stem cell regulation. Our investigation substantiated changes in stem cell dynamics during aging, reinforcing the inflammatory/immune nature in elderly pituitary and stem cells. Finally, we show translatability of mouse atlas-based findings to humans, particularly regarding aging-associated profile. This pituitary sc map is a valuable tool to unravel pituitary (patho)biology.

Mechanisms underlying the effects of the conditional knockdown of hepatic PCSK9 in attenuating lipopolysaccharide-induced acute liver inflammation.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is known to promote hyperlipidemia primarily by inducing the degradation of the low-density lipoprotein receptor. Notably, recent studies have demonstrated that PCSK9 promotes inflammation in the vascular system, however, the roles of PCSK9 in hepatic inflammation remain unclear. As PCSK9 is primarily expressed in the liver, this study aimed to elucidate the roles of PCSK9 and the underlying mechanisms in lipopolysaccharide (LPS)-challenged hepatocytes. Next-generation sequencing analysis revealed that the conditional knockdown of hepatic PCSK9 significantly reduced the plasma levels of total cholesterol and modulated the expression of hundreds of genes. Importantly, PCSK9 knockdown attenuated hepatic inflammation by suppressing several signaling pathways related to inflammation, including the Toll-like receptor, mitogen-activated protein kinase (MAPK), and phosphoinositide-3 kinase/protein kinase B pathways. This subsequently altered the expression of nuclear factor kappa-B and activator protein 1. The underlying mechanisms were further confirmed by in vitro studies using primary hepatocytes and HepG2 cells, with a p38-MAPK inhibitor, a PCSK9 antibody, and two siRNAs against PCSK9. This study is the first to report that hepatic PCSK9 knockdown ameliorates LPS-induced acute liver inflammation via modulating multiple signaling pathways, thereby suggesting therapeutic potential of PCSK9 inhibitors in treating diseases related to hepatic inflammation.

MYB proteins: Versatile regulators of plant development, stress responses, and secondary metabolite biosynthetic pathways.

MYB proteins are ubiquitous in nature, regulating key aspects of plant growth and development. Although MYB proteins are known for regulating genes involved in secondary metabolite biosynthesis, particularly phenylpropanoids, their roles in terpenoid, glucosinolate, and alkaloid biosynthesis remain less understood. This review explores the structural and functional differences between activator and repressor MYB proteins along with their roles in plant growth, development, stress responses, and secondary metabolite production. MYB proteins serve as central hubs in protein-protein interaction networks that regulate expression of numerous genes involved in the adaptation of plants to varying environmental conditions. Thus, we also highlight key interacting partners of MYB proteins and their roles in these adaptation mechanisms. We further discuss the mechanisms regulating MYB proteins, including autoregulation, epigenetics, and post-transcriptional and post-translational modifications. Overall, we propose MYB proteins as versatile regulators for improving plant traits, stress responses, and secondary metabolite production.

TFAP2E is implicated in central nervous system, orofacial and maxillofacial anomalies

BackgroundPrevious studies in mouse, Xenopus and zebrafish embryos show strong tfap2e expression in progenitor cells of neuronal and neural crest tissues suggesting its involvement in neural crest specification. However, the...

Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion.

The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because of its immunosuppressive effects, IL-10 up-regulation is a common feature of tumor progression and metastasis. Recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals. We have found that Suppressor of site IIIQo Electron Leak 1.2 (S3QEL 1.2), a specific inhibitor of reactive oxygen species (ROS) production from mitochondrial complex III, and myxothiazol, a complex III inhibitor, decrease IL-10 in lipopolysaccharide (LPS)-activated macrophages. IL-10 down-regulation is likely to be mediated by suppression of c-Fos, which is a subunit of activator protein 1 (AP1), a transcription factor required for IL-10 gene expression. S3QEL 1.2 impairs IL-10 production in vivo after LPS challenge and promotes the survival of mice bearing B16F10 melanoma by lowering tumor growth. Our data identify a link between complex III-dependent ROS generation and IL-10 production in macrophages, the targeting of which could have potential in boosting antitumor immunity.

Host microRNA-31-5p represses oncogenic herpesvirus lytic reactivation by restricting the RNA-binding protein KHDRBS3-mediated viral gene expression.

Oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV), an etiological agent of Kaposi's sarcoma and primary effusion lymphoma, employs a biphasic life cycle consisting of latency and lytic replication to achieve lifelong infection. Despite its essential role in KSHV persistence and tumorigenicity, much remains unknown about how KSHV lytic reactivation is regulated. Leveraging high-throughput transcriptomics, we identify microRNA-31-5p (miR-31-5p) as a key regulator of KSHV lytic reactivation capable of restricting KSHV entry into the lytic replication cycle. Ectopic expression of miR-31-5p impairs KSHV lytic gene transcription and production of lytic viral proteins, culminating in dramatic reduction of infectious virion production during KSHV reactivation. miR-31-5p overexpression also markedly reduces the expression of critical viral early genes, including the master regulator of the latent-lytic switch, KSHV replication and transcription activator (RTA) protein. Through mechanistic studies, we demonstrate that miR-31-5p represses KSHV lytic reactivation by directly targeting the KH domain protein KHDRBS3, an RNA-binding protein known to regulate RNA processing including alternative splicing. Our study highlights KHDRBS3 as an essential proviral host factor that is key to the successful completion of KSHV lytic replication and suggests its novel function in viral lytic gene transcription during KSHV reactivation. Taken together, these findings reveal a previously unrecognized role for the miR-31-5p/KHDRBS3 axis in regulating the KSHV latency-lytic replication switch and provide insights into gene expression regulation of lytic KSHV, which may be leveraged for lytic cycle-targeted therapeutic strategies against KSHV-associated malignancies.

The SIRT5-JIP4 interaction promotes osteoclastogenesis by modulating RANKL-induced signaling transduction

Receptor activator of nuclear factor kappa-B ligand (RANKL) initiates a complex signaling cascade that is crucial for inducing osteoclast differentiation and activation. RANKL-induced signaling has been analyzed in detail, and the involvement of TNF receptor-associated factor 6 (TRAF6), calmodulin-dependent protein kinase (CaMK), NF-κB, mitogen-activated protein kinase (MAPK), activator protein-1 (AP-1), and molecules that contain an immunoreceptor tyrosine-based activation motif (ITAM) has been reported. However, the precise molecular steps that regulate RANKL signaling remain largely unknown. Here, we revealed the indispensable role of a class III histone deacetylase (SIRT5) in the processes of RANKL-induced osteoclast differentiation and activation. SIRT5 expression in osteoclasts was increased during osteoclastogenesis upon stimulation with RANKL. The RANKL-induced signaling activation was suppressed in SIRT5-deficient osteoclasts but enhanced by SIRT5 overexpression. Mice with global or conditional monocytic lineage knockout of SIRT5 had increased bone mass and reduced osteoclast numbers. In the cytoplasm, SIRT5 interacted with the scaffold protein JNK-interacting protein 4 (JIP4) to finely regulate MAPK signaling, which was critical for osteoclast differentiation and activation. Pharmacological inhibition of the catalytic activity of SIRT5 effectively reversed bone loss in ovariectomized mice. Taken together, the results of this study reveal that the SIRT5-JIP4 axis is a novel positive regulator that finely regulates RANKL-induced osteoclast differentiation and suggest that targeting this axis is a therapeutic strategy for preventing osteoporotic bone loss.Graphical

Jun, an Oncological Foe or Friend?

Jun/JUN is a basic leucine zipper (bZIP) protein and a prototypic member of the activator protein-1 (AP-1) family of transcription factors that can act as homo- or heterodimers, interact with DNA elements and co-factors, and regulate gene transcription. Jun is expressed by both immune and inflammatory cells. Jun is traditionally seen as an oncoprotein that regulates processes involved in transformation and oncogenesis in human tumours. This article examines the traditional view that Jun plays a permissive role in cancer development and progression, whilst exploring emerging evidence supporting Jun's potential to prevent immune cell exhaustion and promote anti-tumour efficacy.

Genome-wide identification of CAMTA gene family in teak (Tectona grandis) and functional characterization of TgCAMTA1 and TgCAMTA3 in cold tolerance

BackgroundCalmodulin-binding transcription activator (CAMTA) proteins play significant roles in signal transduction, growth and development, as well as abiotic stress responses, in plants. Understanding their involvement in the low-temperature stress response of teak is vital for revealing cold resistance mechanisms.ResultsThrough bioinformatics analysis, the CAMTA gene family in teak was examined, and six CAMTA genes were identified in teak. The encoded proteins were predicted to be located in the nucleus and exhibited hydrophilic properties, with molecular weights ranging from 103.4 to 123.3 kDa and isoelectric points ranging from 5.49 to 7.55. On the basis of protein sequence homology, the CAMTA family could be divided into three subgroups. Domain and 3D structure analyses demonstrated that all the TgCAMTA proteins contained the typical CAMTA domain with the CaMBD binding domain, which was exposed on the surface. Expression analysis of different tissues revealed the expression of TgCAMTA genes in teak roots, stems, leaves, flowers, fruits, and branches. Furthermore, the promoter region contained various cis-acting elements related to light, hormone, and abiotic stress responses. After low-temperature stress treatment, different expression patterns of TgCAMTAs were observed in teak roots, stems, and leaves, with TgCAMTA1 showing the highest expression level in leaves compared with stems. Transgenic lines carrying the TgCAMTA1/3 promoter::GUS construct cold stress induction of TgCAMTA1/3 genes revealed the presence of multiple low-temperature responsive cis-acting elements in the TgCAMTA1/3 promoter region. Subcellular localization analysis indicated that these genes were functional predominantly in the nucleus. Compared with wild-type Arabidopsis, TgCAMTA1/3-overexpressing Arabidopsis presented increased tolerance to freezing stress, with increased expression of AtCOR genes. Moreover, under low-temperature conditions, TgCAMTA3-overexpressing Arabidopsis presented significantly elevated expression levels of genes related to the CBF signaling pathway, including AtCBF1/2/3.ConclusionsOur findings add significantly to the existing knowledge regarding cold stress tolerance and help elucidate cold response mechanisms in teak.

Multi-omics analysis reveals distinct gene regulatory mechanisms between primary and organoid-derived human hepatocytes.

Hepatic organoid cultures are a powerful model to study liver development and diseases in vitro. However, hepatocyte-like cells differentiated from these organoids remain immature compared to primary human hepatocytes (PHHs), which are the benchmark in the field. Here, we applied integrative single-cell transcriptome and chromatin accessibility analysis to reveal gene regulatory mechanisms underlying these differences. We found that, in mature human hepatocytes, activator protein 1 (AP-1) factors co-occupy regulatory regions with hepatocyte-specific transcription factors, including HNF4A, suggesting their potential cooperation in governing hepatic gene expression. Comparative analysis identified distinct transcription factor sets that are specifically active in either PHHs or intrahepatic cholangiocyte organoid (ICO)-derived human hepatocytes. ELF3 was one of the factors uniquely expressed in ICO-derived hepatocytes, and its expression negatively correlated with hepatic marker gene expression. Functional analysis further revealed that ELF3 depletion increased the expression of key hepatic markers in ICO-derived hepatocytes. Our integrative analysis provides insights into the transcriptional regulatory networks of PHHs and hepatic organoids, thereby informing future strategies for developing improved hepatic models.

MAP Kinase Signaling at the Crossroads of Inflammasome Activation.

Inflammasomes are crucial mediators of both antimicrobial host defense and inflammatory pathology, requiring stringent regulation at multiple levels. This review explores the pivotal role of mitogen-activated protein kinase (MAPK) signaling in modulating inflammasome activation through various regulatory mechanisms. We detail recent advances in understanding MAPK-mediated regulation of NLRP3 inflammasome priming, licensing and activation, with emphasis on MAPK-induced activator protein-1 (AP-1) signaling in NLRP3 priming, ERK1 and JNK in NLRP3 licensing, and TAK1 in connecting death receptor signaling to NLRP3 inflammasome activation. Furthermore, we discuss novel insights into MAPK signaling in human NLRP1 inflammasome activation, focusing on the MAP3K member ZAKα as a key kinase linking ribosomal stress to inflammasome activation. Lastly, we review recent work elucidating how Bacillus anthracis lethal toxin (LeTx) manipulates host MAPK signaling to induce macrophage apoptosis as an immune evasion strategy, and the counteraction of this effect through genotype-specific Nlrp1b inflammasome activation in certain rodent strains.

Efficacy and Safety of Recombinant Human Thrombopoietin (rhTPO) on Coagulation Function and Inflammatory Factors in the Treatment of Patients with Sepsis-Related Thrombocytopenia.

this study aimed to investigate the efficacy of recombinant human thrombopoietin (rhTPO) in the treatment of sepsis-associated thrombocytopenia, and to evaluate its impact on coagulation function, inflammatory markers, platelet (Plt) count, and patient prognosis. a total of 144 patients with sepsis-associated thrombocytopenia, admitted to our hospital between 2022 and 2023, were selected for the study. The patients were randomly divided into two groups using a random number table: the control group (Group C, n = 72) and the research group (Group R, n = 72). The Group C received standard treatment, while the Group R received rhTPO in addition to standard care. We compared the general demographic data, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, coagulation parameters, serum levels of Toll-like receptor 4 (TLR4), interleukin-6 (IL-6), serum creatinine (SCr), tumor necrosis factor-alpha (TNF-α), Plt count, transfusion volume, treatment duration, incidence of complications, and mortality rates between the two groups. there were no significant differences in the general demographic characteristics between the two groups (P > 0.05). After treatment, the APACHE II scores in both groups significantly decreased, with a more pronounced reduction observed in the Group R. Coagulation function indicators, including activated partial thromboplastin time (APTT), fibrinogen (FIB), plasminogen activator inhibitor-1 (PAI-1), antithrombin III (AT-III), protein C, thrombomodulin (TM), and Plt factor 4 (PF4), showed greater improvement in the Group R compared to the Group C (P < 0.05). The serum levels of TLR4, IL-6, and TNF-α in the Group R were significantly lower than those in the Group C (P < 0.05), whereas no significant difference in SCr levels was observed between the groups (P > 0.05). The Plt count in the Group R began to significantly increase on day 3 of treatment, and was consistently higher than that in the Group C on days 3, 5, and 7 (P < 0.05). The Group R required significantly fewer red blood cell transfusions compared to the Group C and did not require Plt suspension (P < 0.05). No significant differences were found between the groups in terms of mechanical ventilation time, intensive care unit (ICU) length of stay, and total hospital stay (P > 0.05). However, the ICU and overall hospital mortality rates were significantly lower in the Group R than in the Group C (P < 0.05). Multivariate logistic regression analysis indicated that rhTPO treatment was an independent protective factor for reducing mortality (OR = 0.475, P = 0.042). rhTPO treatment effectively improves coagulation function and inflammatory status in patients with sepsis-associated thrombocytopenia, increases Plt count, reduces transfusion requirements, and lowers mortality. These findings suggest that rhTPO has significant clinical application value in the management of this condition.

TFPI2 hypermethylation promotes diabetic atherosclerosis progression through the Ap2α/PPARγ axis

Diabetes mellitus significantly escalates the risk of accelerated atherosclerosis (AS), severely affecting cardiovascular health. Our research, leveraging Gene Expression Omnibus (GEO) database analysis (GSE118481), revealed diminished TFPI2 expression in diabetic patients' atherosclerotic plaques. Further validation in carotid artery plaques and an AS mouse model confirmed TFPI2's reduced expression in diabetes. Through TFPI2 knockdown in non-diabetic mice, we observed aggravated plaque burden and increased inflammatory M1 macrophage polarization. Conversely, TFPI2 overexpression in diabetic mice improved plaque stability and induced reparative M2 macrophage polarization, countering hyperglycemia's negative effects. Mechanistically, transcription factor activator protein 2α (AP-2α) is a repressor of PPPARg transcription, and the interaction of TFPI2 with the transcription factor AP-2α blocks AP-2α binding to the PPARγ gene promoter, which is essential for PPARγ-mediated transcription and the transition from M1 to M2 macrophages. Additionally, hyperglycemia-induced DNA methyltransferase 1 (DNMT1) upregulation heightens TFPI2 methylation, reducing its expression. Our findings spotlight the TFPI2/AP-2α/PPARγ axis as crucial in diabetic AS modulation, proposing its targeting as a new therapeutic strategy to halt diabetes-driven AS progression, highlighting TFPI2's therapeutic promise in addressing diabetes-related cardiovascular issues.

Clinical and biochemical abnormalities in a feline model of GM2 activator deficiency

Though it has no catalytic activity toward GM2 ganglioside, the GM2 activator protein (GM2A) is essential for ganglioside hydrolysis by facilitating the action of lysosomal ß-N-acetylhexosaminidase. GM2A deficiency results in death in early childhood due to rapid central nervous system deterioration similar to the related GM2 gangliosidoses, Tay-Sachs disease and Sandhoff disease. This manuscript further characterizes a feline model of GM2A deficiency with a focus on clinical and biochemical parameters that may be useful as benchmarks for translational therapeutic research. The GM2A deficient cat has clinical features consistent with the human condition, including isointensity of gray and white matter of the brain on T2-weighted MRI; MR spectroscopic changes of brain metabolites consistent with gliosis, neuronal injury and demyelination; rhythmical slowing of cerebral cortical activation on electroencephalography; and elevation of aspartate aminotransferase and lactate dehydrogenase in cerebrospinal fluid. Biochemically, the brain of GM2A deficient cats has storage of GM2 and GA2 ganglioside coincident with increased hexosaminidase activity toward a standard synthetic substrate. Also, the brain of GM2A deficient cats has increased levels of lyso-platelet activating factor and lyso-phosphatidylcholine, which may serve as novel biomarkers of disease progression and provide insights into pathogenic mechanisms.

Atractylodin mitigates UVB radiation-induced oxidative stress and photoaging responses by enhancing NrF2 signaling in human epidermal keratinocytes.

This study explores the protective role of Atractylodin (ATN) on ultraviolet-B (UVB) radiation-exposed oxidative damage and photoaging responses in human epidermal keratinocytes (HaCaT). In vitro, experiments involved subjecting HaCaT cells to UVB radiation (50 mJ/cm2) for a 24 h incubation period, leading to cell death, increased reactive oxygen species (ROS), and DNA damaged lesion (8-Oxo Gunosine). ATN treatment effectively mitigated cell toxicity, ROS generation, and 8-Oxo Gunosine in UVB-exposed HaCaT cells. Furthermore, ATN demonstrated its ability to counteract UVB radiation-exposed oxidative stress by inhibiting the activation of phosphorylated-extracellular signal-regulated kinase-1 (Erk-1), phosphorylated-c-Jun N-terminal kinase (p-Jnk), and phosphorylated p38 Mitogen-Activated Protein Kinase (p-p38) in HaCaT cells. Nuclear factor erythroid 2-related factor 2 (NrF2), recognized for its antioxidant properties, emerged as a key player in protecting against oxidative damage. ATN was observed to inhibit the depletion of NrF2 expression, thereby preventing the depletion of superoxide dismutase (SOD), and glutathione (GSH) in UVB-exposed HaCaT cells. Additionally, ATN inhibited activator protein-1 (AP-1) and matrix metalloproteinases such as MMP-1 and MMP-9 in UVB-exposed HaCaT cells. In conclusion, our findings highlight that ATN effectively prevents UVB-exposed skin oxidative damage and photoaging by modulating NrF2 expression.