Activation Of Signaling Cascades Research Articles

Nuclear translocation of RON receptor tyrosine kinase. New mechanistic and functional insights.

Receptor tyrosine kinases (RTKs) are membrane sensors that monitor alterations in the extracellular milieu and translate this information into appropriate cellular responses. Epidermal growth factor receptor (EGFR) is the most well-known model in which gene expression is upregulated by mitogenic signals through the activation of multiple signaling cascades or by nuclear translocation of the full-length EGFR protein. RON (Receptuer d'Origine Nantatise, also known as macrophage stimulating 1 receptor, MST1R) has recently gained attention as a therapeutic target for human cancer. This review summarizes the recent understanding of the unusual nuclear translocation of uncleaved RON receptor proteins in response to cellular stresses, such as serum starvation, hormonal deprivation, hypoxia, and genotoxicity. This nonligand mechanism, achieved by RON per se or by interaction with EGFR, may directly activate the transcriptional machinery necessary for cancer cells to survive. In vitro experiments have demonstrated the importance of tyrosine kinase of RON in binding to and activating the c-JUN promoter, HIF-1α, DNA helicase 2, DNA-dependent protein kinase catalytic subunit, and other stress-responsive networks. Nuclear RON-activated nonhomologous end joining repair confers chemoresistance to drugs that induce double-strand breaks (DSBs) in cancer cells. Tyrosine kinase inhibitors or monoclonal antibodies targeting RON kinase may therefore be useful treatments for patients with RON-overexpressing tumors. DSB-inducing anticancer drugs are not recommended for these cancer patients. Moreover, multi-RTK inhibition is a more rational strategy for patients with RON- and RTK-coexpressing human cancer.

Her2 promotes early dissemination of breast cancer by inhibiting the p38 pathway through the downregulation of MAP3K4

Early dissemination refers to the process by which cancer cells spread to distant organs at an early stage of the disease, often before the primary tumor is clinically detectable. Experimental studies have demonstrated that Her2 promotes early dissemination of breast cancer by inhibiting the p38 signaling pathway. However, the precise mechanism by which Her2 suppresses the activation of p38 signaling in early-stage cancer cells (ECCs) remains unclear. Here, we report that MAP3K4, an upstream kinase of p38, is downregulated in Her2 + ductal carcinoma in situ (DCIS) cells and tissues, which is required for Her2-induced early dissemination of DCIS cells by regulating the activation of the p38 signaling cascade. Furthermore, Her2 suppresses the transcription of MAP3K4 by downregulating the expression of HOXB13, a crucial transcription factor contributing to MAP3K4 expression in DCIS cells. Together, these findings unveil a novel downstream regulatory mechanism through which Her2 inhibits the activation of p38 signaling and facilitates early dissemination of breast cancer, offering insights into the development of effective diagnostic methods and targeted therapies for inhibiting the early dissemination of Her2 + breast cancer.

Lighting the Path: How Light Signaling Regulates Stomatal Movement and Plant Immunity.

Stomata, the small pores on the surfaces of leaves and stems, are crucial for gas exchange in plants and also play a role in defense against pathogens. The stomatal movement is not only influenced by surrounding light conditions but also by the presence of foliar pathogens. To put it more crisply, certain light wavelengths such as blue or strong red light, cause stomatal opening, which tragically makes it easier for bacteria to enter through opened stomata and causes disease progression in plants. Illumination of blue or intense red light autophosphorylates phototropin, a blue light photoreceptor protein kinases that in turn activates signaling cascade to open stomata. Undoubtedly stomatal defense is a fascinating aspect of plant immunology, especially in plant-foliar pathogen interaction. During these interactions, stomata fundamentally serve as entry points for intrusive pathogens and initiate plant defense signaling cascade. The present review highlights how the light-activated photoreceptors like cryptochromes (CRYs), phytochromes (phys), and UV-receptors (UVRs) influence the stomatal movement and defense signaling after foliar pathogen intrusion. It also explores the link between stomatal defense, light signaling, and plant immunity, which is vital for safeguarding crops against pathogens.

Sulforaphane treatment mimics contractile activity-induced mitochondrial adaptations in muscle myotubes.

Mitochondria are metabolic hubs that govern skeletal muscle health. While exercise has been established as a powerful inducer of quality control processes that ultimately enhance mitochondrial function, there are currently limited pharmaceutical interventions available that emulate exercise-induced mitochondrial adaptations. To investigate a novel candidate for this role, we examined Sulforaphane (SFN), a naturally occurring compound found in cruciferous vegetables. SFN has been documented as a potent antioxidant inducer through its activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) antioxidant response pathway. However, its effects on muscle health have been underexplored. To investigate the interplay between chronic exercise and SFN, C2C12 myotubes were electrically stimulated to model chronic contractile activity (CCA) in the presence or absence of SFN. SFN promoted Nrf-2 nuclear translocation, enhanced mitochondrial respiration, and upregulated key antioxidant proteins including catalase and glutathione reductase. These adaptations were accompanied by reductions in cellular and mitochondrial ROS emission. Signaling towards biogenesis was enhanced, demonstrated by increases in mitochondrial transcription factor A (TFAM), Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α nuclear translocation, PGC-1α promoter activity, mitochondrial content, and organelle branching, suggestive of a larger, more interconnected mitochondrial pool. These mitochondrial adaptations were accompanied by an increase in lysosomal proteins, suggesting coordinated regulation. There was no difference in mitochondrial and antioxidant-related proteins between CCA and non-CCA SFN-treated cells. Our data suggests that SFN activates signaling cascades that are common to those produced by contractile activity, indicating that SFN-centered therapeutic strategies may improve the mitochondrial phenotype in skeletal muscle.

Activation of P38 MAPK Signaling Cascade is Linked with Clinical Outcomes and Therapeutic Responses in Human Cancers

Activation of P38 MAPK Signaling Cascade is Linked with Clinical Outcomes and Therapeutic Responses in Human Cancers

A170: Effects of Exercise on Liver Function and Inflammatory Markers in NAFLD Patients

Background/Purpose: Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition globally, often linked to sedentary behaviors and central obesity. It is characterized by the activation of multiple signaling cascades leading to inflammation, which plays a critical role in the occurrence and progression of NAFLD liver damage. With the absence of targeted pharmacological treatments, lifestyle and dietary adjustments remain primary interventions for many patients. However, the optimal exercise intensity for managing NAFLD remains unclear, with conflicting evidence on its effectiveness in modulating inflammation. This study aimed to clarify the impact of different exercise types and intensities on liver function and inflammation in NAFLD patients. Methods: Using keywords such as “exercise,” “NAFLD,” and “inflammation,” we searched related studies published in the PubMed, Embase, Cochrane Library, and Web of Science databases. Inclusion criteria were randomized controlled trials (RCTs) with an exercise intervention lasting over four weeks, involving NAFLD or NASH patients (≥18 years) diagnosed through clinical, laboratory, and biopsy data, with a focus on liver enzymes and inflammatory markers as outcomes. Results: Twelve RCTs encompassing 543 NAFLD patients were included. Exercise interventions ranged from 12 weeks to 8.6 months, with frequencies of 2 to 5 times weekly and durations of 30 to 90 minutes per session. Overall, the results of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels following aerobic and resistance training were significantly affected (all P < 0.05). However, high-intensity interval training and combined aerobic-resistance exercise showed negligible effects on ALT and AST levels (all P > 0.05). Regarding the effect of exercise on inflammatory factors, exercise training reduced IL-6 levels in six trials (P < 0.05). However, no specific exercise type was found to reduce IL-6 levels. Exercise training had no significant effect on reducing TNF-Α levels, and no specific exercise reduced TNF-Α levels across five trials. Conclusion/Discussion: Exercise, particularly aerobic and resistance training, positively affected liver function in NAFLD patients by reducing liver enzymes and IL-6 levels. Despite these promising findings, the analysis faces limitations, including the heterogeneity of IL-6 and TNF-Α outcomes and insufficient RCTs for high-intensity interval training subgroups. Further research is essential to explore the specific connections between exercise, inflammation, and NAFLD progression.

Tendon Cell Biology: Effect of Mechanical Loading.

Tendons play a crucial role in the musculoskeletal system, connecting muscles to bones and enabling efficient force transfer. However, they are prone to acute and chronic injuries, which, if not properly repaired, can significantly impair function. Tendinopathy, a prevalent condition affecting approximately 20% of musculoskeletal complaints, arises from an imbalance between micro-injury accumulation and repair processes. The extracellular matrix (ECM) of tendons is a hierarchical structure comprising collagen fibrils, proteoglycans, and glycoproteins that regulate organization, hydration, and mechanical properties. Mechanotransduction pathways, mediated by integrins and focal adhesion complexes, activate signaling cascades such as MAPK/ERK and PI3K/Akt, driving tenocyte gene expression and ECM remodeling. Adaptations to load involve region-specific remodeling, with tensile regions favoring aligned Type I collagen and compressive regions promoting proteoglycans like aggrecan. Stress shielding or reduced loading disrupts these pathways, leading to matrix disorganization and inflammation, predisposing tendons to degenerative changes. Insights into these molecular mechanisms inform rehabilitation strategies to enhance tendon repair and mitigate tendinopathy progression in both athletic and general populations.

THE ROLE OF INTRACELLULAR SIGNALING PATHWAYS IN THE DEVELOPMENT OF TROPHIC PATHOLOGIES OF THE LOWER EXTREMITIES AND THEIR REGENERATION UNDER TYPE 2 DIABETES (PART 1)

Introduction. This review article addresses the critical issue of the development and regeneration of chronic trophic ulcers in the context of type 2 diabetes. This pathological process is associated with inhibited cell proliferation, impaired differentiation of various cell types, and disrupted mechanisms that regulate cell death. An analysis of recent scientific literature also highlights the involvement of key intracellular signaling pathways in the development of chronic ulcerative pathologies of the lower extremities, as observed in both experimental animal models and patients with type II diabetes. Despite advancements, this issue remains insufficiently explored in both theory and practice, underscoring its ongoing relevance. The aim of this study is to identify the roles of key signaling pathways—transforming growth factor β (TGF-β), phosphatidylinositol 3-kinase/serine-threonine kinase (PI3K/Akt), and Wnt/β-catenin—in the inflammatory response, regenerative mechanisms, and healing processes of soft tissue damage and trophic ulcers in experimental animals and patients with type II diabetes. Materials and Methods. This study is based on an analysis of current scientific literature that addresses this topic. Results. It has been found out that changes in the content and activity of key molecules of signaling pathways lead to disruption of carbohydrate homeostasis and the occurrence of structural and functional dysfunction in damaged tissues against the background of type II diabetes. These include TGF-β, PI3K, Akt and β-catenin. Analysis of experimental data demonstrated that both under the conditions of type II diabetes development and in the occurrence of chronic ulcers of the lower extremities, against the background of this endocrine disease, there is an increase in the level of TGF-β. At the same time the activity of the PI3K/Akt signaling pathway in the above-mentioned studied groups was reduced. The relationship between the development of type II diabetes and the Wnt/β-catenin signaling pathway has been established. Suppression of its activity was accompanied by impaired regeneration of chronic trophic ulcers in type II diabetes. Conclusion. Thus, the mechanism of type II diabetes and chronic peptic ulcer disease, in the same pathology, is associated with a impaired activity of signaling cascades. This concerns the following cellular systems such as TGF-β, PI3K/Akt and Wnt/β-catenin. They can be considered as potential therapeutic targets for the development of newest methods for the treatment of chronic trophic ulcers in type II diabetes in order to accelerate the recovery process of volumetric tissue damage of the lower extremities.

Decursin protects against DSS-induced experimental colitis in mice by inhibiting the cGAS-STING signaling pathway.

While studies have shown that Angelica gigas Nakai (A. gigas) can alleviate ulcerative colitis in mice, the therapeutic role of its main active ingredient, decursin, is uncertain. Therefore, we aimed to investigate the protective effect and mechanism of decursin against inflammatory bowel disease (IBD) in vivo using mice. IBD was simulated via induction with 3% dextran sodium sulfate (DSS), with or without daily treatment with decursin (10 mg/kg or 20 mg/kg) or 5-amino salicylic acid (5-ASA; 100 mg/kg) for 14 days. Mice were weighed and monitored daily for disease activity index (DAI) scoring. Colon tissues were collected for histopathological staining analysis, and serum was collected for ELISA measurement of proinflammatory cytokines. Western blotting was employed to analyze colonic expression levels of the tight junction-related proteins ZO-1, Occludin, and Claudin 1, as well as cGAS-STING signaling pathway-associated proteins. The expression levels of major proteins were verified using immunohistochemistry and immunofluorescence. Compared with the control group, DSS-induced mice showed decreased body weight, increased DAI scores, shortening of the colon, disrupted colon tissue structure, increased serum levels of proinflammatory cytokines, increased expression of factors involved in activating the cGAS-STING signaling pathway, and reduced expression of ZO-1, Occludin, and Claudin 1. Under decursin treatment, the pathological state of IBD was less severe, proinflammatory factors were downregulated, and activation of the cGAS-STING signaling pathway was inhibited. Our findings indicate that decursin helps restore the intestinal mucosal barrier and prevents activation of the cGAS-STING signaling cascade, alleviating experimental IBD in mice.

Tumor Cytobiology of IGF-1R in Breast Tumor Activation and Propagation; And the Role of Celecoxib in its Inhibition

The Insulin-like Growth Factor 1 Receptor (IGF-1R) stands as a central orchestrator in cellular signaling, governing pivotal processes encompassing growth, proliferation, and differentiation. Its aberrant activation is intricately intertwined with the pathogenesis and progression of breast cancer, a heterogeneous disease presenting formidable clinical challenges. Amidst the burgeoning landscape of therapeutic interventions, Celecoxib, a nonsteroidal anti-inflammatory drug (NSAID), has emerged as a promising candidate for targeting the dysregulated IGF-1R pathway. This review delineates the intricate molecular mechanisms underlying Celecoxib's modulation of the IGF-1R pathway, elucidating its pharmacokinetic properties and therapeutic implications in breast cancer management. Celecoxib exerts inhibitory effects on IGF-1R through multifaceted molecular interactions, impeding receptor activation and downstream signaling cascades pivotal for tumor proliferation and metastasis. Furthermore, it regulates IGF-1R expression at both transcriptional and translational levels, exerting nuanced control over cellular responses. Moreover, Celecoxib's therapeutic impact transcends mere IGF-1R inhibition, as it potentiates pro-apoptotic pathways and disrupts tumor-permissive microenvironments. A nuanced understanding of Celecoxib's pharmacokinetic profile is imperative, considering its sustained and targeted inhibition of IGF-1R signaling, and its potential synergistic effects in combinatorial therapeutic regimens for breast cancer. This comprehensive elucidation underscores the paramount importance of deciphering Celecoxib's intricate molecular interplay with the IGF-1R pathway, heralding novel avenues for precision medicine and tailored therapeutic interventions in the management of breast cancer.

Toxicological Effects and Mechanisms of 2,2',4,4'-Tetrabromodiphenyl Ether (BDE-47) on Marine Organisms.

2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is a widely used brominated flame retardant belonging to persistent organic pollutants (POPs). After being released into the marine environment, BDE-47 can cause a range of toxic effects on marine organisms through bioaccumulation, biomagnification, and intergenerational transmission. These effects include lethality, impaired motility, photosynthetic toxicity, immune damage, liver toxicity, developmental impairments, and reproductive toxicity. This article reviews the latest research progress on the toxic effects and molecular mechanisms of BDE-47 mentioned above. The primary mechanisms underlying its toxicity include oxidative stress, DNA damage, cellular apoptosis, impaired metabolism, and activation of the MAPK signaling cascade.

Humulus lupulus L.: Evaluation of Phytochemical Profile and Activation of Bitter Taste Receptors to Regulate Appetite and Satiety in Intestinal Secretin Tumor Cell Line (STC-1 Cells).

Inflorescences of the female hop plant (Humulus lupulus L.) contain biologically active compounds, most of which have a bitter taste. Given the rising global obesity rates, there is much increasing interest in bitter taste receptors (TAS2Rs). Intestinal TAS2Rs can have beneficial effects on obesity when activated by bitter agonists. This study aims to investigate the mechanism of action of a hydroalcoholic hop extract in promoting hormone secretion that reduces the sense of hunger at the intestinal level through the interaction with TAS2Rs. The results demonstrate that the hop extract is a rich source of bitter compounds (mainly α-, β-acids) that stimulate the secretion of anorexigenic peptides (glucagon-like peptide 1 [GLP-1], cholecystokinin [CCK]) in a calcium-dependent manner while reducing levels of hunger-related hormones like ghrelin. This effect is mediated through interaction with TAS2Rs, particularly Tas2r138 and Tas2r120, and through the activation of downstream signaling cascades. Knockdown of these receptors using siRNA transfection and inhibition of Trpm5, Plcβ-2, and other calcium channels significantly reduces the hop-induced calcium response as well as GLP-1 and CCK secretion. This study provides a potential application of H. lupulus extract for the formulation of food supplements with satiating activity capable of preventing or combating obesity.

Development and safety of investigational and approved drugs targeting the RAS function regulation in RAS mutant cancers.

The RAS gene family holds a central position in controlling key cellular activities such as migration, survival, metabolism, and other vital biological processes. The activation of RAS signaling cascades is instrumental in the development of various cancers. Although several RAS inhibitors have gained approval from the US Food and Drug Administration for their substantial antitumor effects, their widespread and severe adverse reactions significantly curtail their practical usage in the clinic. Thus, there exists a pressing need for a comprehensive understanding of these adverse events, ensuring the clinical safety of RAS inhibitors through the establishment of precise management guidelines, suitable intermittent dosing schedules, and innovative combination regimens. This review centers on the evolution of RAS inhibitors in cancer therapy, delving into the common adverse effects associated with these inhibitors, their underlying mechanisms, and the potential strategies for mitigation.

Genomic investigation of innate sensing pathways in the tumor microenvironment

The innate immune system is the first responder to infectious agents, cellular debris, and cancerous growths. This system plays critical roles in the antitumor immune responses by boosting and priming T cell-mediated cytotoxicity but is understudied due to the complexity and redundancy of its various downstream signaling cascades. We utilized a mathematical tool to holistically quantify innate immune signaling cascades and immunophenotype over 8,000 tumors from The Cancer Genome Atlas (TCGA). We found that innate immune activation was predictive of patient mortality in a subset of cancers. Further analysis identified PHF genes as transcripts that were associated with genomic stability and innate activation. Knockdown of PHF gene transcripts in vitro led to an increase in cell death and IFNB1 expression in a cGAS-dependent manner, validating PHF genes as potential anti-tumor targets. We also found an association between innate immune activation and both tumor immunogenicity and intratumor microbes, which highlights the versatility of this model. In conclusion, interrogating activation of innate immune signaling cascades demonstrated the importance of studying innate signaling in cancer and broadened the search for new therapeutic adjuvants.

A molten globule ensemble primes Arf1–GDP for the nucleotide switch

The adenosine di-phosphate (ADP) ribosylation factor (Arf) small guanosine tri-phosphate (GTP)ases function as molecular switches to activate signaling cascades that control membrane organization in eukaryotic cells. In Arf1, the GDP/GTP switch does not occur spontaneously but requires guanine nucleotide exchange factors (GEFs) and membranes. Exchange involves massive conformational changes, including disruption of the core β-sheet. The mechanisms by which this energetically costly switch occurs remain to be elucidated. To probe the switch mechanism, we coupled pressure perturbation with nuclear magnetic resonance (NMR), Fourier Transform infra-red spectroscopy (FTIR), small-angle X-ray scattering (SAXS), fluorescence, and computation. Pressure induced the formation of a classical molten globule (MG) ensemble. Pressure also favored the GDP to GTP transition, providing strong support for the notion that the MG ensemble plays a functional role in the nucleotide switch. We propose that the MG ensemble allows for switching without the requirement for complete unfolding and may be recognized by GEFs. An MG-based switching mechanism could constitute a pervasive feature in Arfs and Arf-like GTPases, and more generally, the evolutionarily related (Ras-like small GTPases) Rags and Gα GTPases.

Heavy mechanical force decelerates orthodontic tooth movement via Piezo1-induced mitochondrial calcium down-regulation

Orthodontic tooth movement (OTM) depends on periodontal ligament cells (PDLCs), which sense biomechanical stimuli and initiate alveolar bone remodeling. Light (optimal) forces accelerate OTM, whereas heavy forces decelerate it. However, the mechanisms by which PDLCs sense biomechanical stimuli and affect osteoclastic activities under different mechanical forces (MFs) remain unclear. This study demonstrates that mechanosensitive ion channel Piezo1-mediated Ca2+ signal conversion is crucial for sensing and delivering biomechanical signals in PDLCs under heavy-force conditions. Heavy MF up-regulated Piezo1 in PDLCs, reducing mitochondrial Ca2+ influx by inhibiting ITPR3 expression in mitochondria-associated membranes. Decreased mitochondrial calcium uptake led to reduced cytoplasmic release of mitochondrial DNA and inhibited the activation of the cGAS‒STING signaling cascade, subsequently inhibiting monocyte-to-osteoclast differentiation. Inhibition of Piezo1 or up-regulation of STING expression under heavy MF conditions significantly increased osteoclast activity and accelerated OTM. These findings suggest that heavy MF-induced Piezo1 expression in PDLCs is closely related to the control of osteoclast activity during OTM and plays an essential role in alveolar bone remodeling. This mechanism may be a potential therapeutic target for accelerating OTM.

The anti-inflammatory and tolerogenic potential of small spleen peptides.

Maintaining peripheral immune tolerance and preventing harmful autoimmune reactions is a fundamental task of the immune system. However, these essential functions are significantly compromised during autoimmune disorders, creating a major challenge in treating these conditions. In this context, we provide an overview of research on small spleen polypeptides (SSPs) that naturally regulate peripheral immune tolerance. Alongside outlining the observed effects of SSPs, we summarize here the findings on the cellular and molecular mechanisms that underlie their regulatory impact. Specifically, SSPs have demonstrated remarkable effectiveness in halting the progression of developing or established autoimmune disorders like psoriasis or arthritis in animal models. They primarily target dendritic cells (DCs), swiftly prompting the production of extracellular ATP, which is then degraded and sensed by adenosine receptors. This process triggers the mTOR signaling cascade, similar to powerful immune triggers, but instead of a rapid and intense reaction, it leads to a moderate yet significant activation of the mTOR signaling cascade. This induces a tolerogenic state in dendritic cells, ultimately leading to the generation of Foxp3+ immunosuppressor Treg cells. In addition, SSPs may indirectly attenuate the autoimmune response by reducing extracellular ATP synthesis in non-immune cells, such as endothelial cells, when exposed to elevated levels of proinflammatory cytokines. SSPs thus have the potential to contribute to the restoration of peripheral immune tolerance and may offer valuable therapeutic benefits in treating autoimmune diseases.

Microglial PCGF1 alleviates neuroinflammation associated depressive behavior in adolescent mice.

Epigenetics plays a crucial role in regulating gene expression during adolescent brain maturation. In adolescents with depression, microglia-mediated chronic neuroinflammation may contribute to the activation of cellular signaling cascades and cause central synapse loss. However, the exact mechanisms underlying the epigenetic regulation of neuroinflammation leading to adolescent depression remain unclear. In this study, we found that the expression of polycomb group 1 (PCGF1), an important epigenetic regulator, was decreased both in the plasma of adolescent major depressive disorder (MDD) patients and in the microglia of adolescent mice in a mouse model of depression. We demonstrated that PCGF1 alleviates neuroinflammation mediated by microglia in vivo and in vitro, reducing neuronal damage and improving depression-like behavior in adolescent mice. Mechanistically, PCGF1 inhibits the transcription of MMP10 by upregulating RING1B/H2AK119ub and EZH2/H3K27me3 in the MMP10 promoter region, specifically inhibiting microglia-mediated neuroinflammation. These results provide valuable insights into the pathogenesis of adolescent depression, highlighting potential links between histone modifications, neuroinflammation and nerve damage. Potential mechanisms of microglial PCGF1 regulates depression-like behavior in adolescent mice. Microglial PCGF1 inhibits NF-κB/MAPK pathway activation through regulation of RING1B/H2AK119ub and EZH2/H3K27me3 in the MMP10 promoter region, which attenuates neuroinflammation and ameliorates depression-like behaviors in adolescent mice.

Cold-induced phosphatidylethanolamine synthesis in liver and brown adipose tissue of mice

Increasing energy expenditure in brown adipose (BAT) tissue by cold-induced lipolysis is discussed as a potential strategy to counteract imbalanced lipid homeostasis caused through unhealthy lifestyle and cardiometabolic disease. Yet, it is largely unclear how liberated fatty acids (FA) are metabolized. We investigated the liver and BAT lipidome of mice housed for 1 week at thermoneutrality, 23 °C and 4 °C using quantitative mass spectrometry-based lipidomics. Housing at temperatures below thermoneutrality triggered the generation of phosphatidylethanolamine (PE) in both tissues. Particularly, the concentrations of PE containing polyunsaturated fatty acids (PUFA) in their acyl chains like PE 18:0_20:4 were increased at cold. Investigation of the plasma's FA profile using gas chromatography coupled to mass spectrometry revealed a negative correlation of PUFA with unsaturated PE in liver and BAT indicating a flux of FA from the circulation into these tissues. Beta-adrenergic stimulation elevated intracellular levels of PE 38:4 and PE 40:6 in beige wildtype adipocytes, but not in adipose triglyceride lipase (ATGL)-deficient cells. These results imply an induction of PE synthesis in liver, BAT and thermogenic adipocytes after activation of the beta-adrenergic signaling cascade.

Neuroprotection of low dose carbon monoxide in Parkinson’s disease models commensurate with the reduced risk of Parkinson’s among smokers

Paradoxically, cigarette smoking is associated with a reduced risk of Parkinson’s Disease (PD). This led us to hypothesize that carbon monoxide (CO) levels, which are constitutively but modestly elevated in smokers, might contribute to neuroprotection. Using rodent models of PD based on α-synuclein (αSyn) accumulation and oxidative stress, we show that low-dose CO mitigates neurodegeneration and reduces αSyn pathology. Oral CO administration activated signaling cascades mediated by heme oxygenase-1 (HO-1), which have been implicated in limiting oxidative stress, and in promoting αSyn degradation, thereby conferring neuroprotection. Consistent with the neuroprotective effect of smoking, HO-1 levels in cerebrospinal fluid were higher in human smokers compared to nonsmokers. Moreover, in PD brain samples, HO-1 levels were higher in neurons without αSyn pathology. Thus, CO in rodent PD models reduces pathology and increases oxidative stress responses, phenocopying possible protective effects of smoking evident in PD patients. These data highlight the potential for low-dose CO-modulated pathways to slow symptom onset and limit pathology in PD patients.