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In recent years, anger has emerged as a crucial category for analyzing contemporary political phenomena such as democratic elections, protests, collective violence, social movements, and crises of institutional representation. However, it has also become a vague or empty signifier among commentators and journalists trying to describe these events. This article begins with a brief philosophical overview of anger, tracing its evolution from Greco-Roman antiquity to the French Revolution. This historical journey sets the stage for the second part, where the article proposes a conceptualization of political anger through three contemporary shifts: first, a shift toward a realistic understanding that diminishes the relevance of the negationist perspective rooted in ancient and Enlightenment moral, philosophical, and theological views; second, a shift toward a collective and political dimension that has overshadowed individual ethical or religious interpretations; and third, a shift toward the ethical and moral legitimization of anger. For political anger to transcend its status as an empty signifier, as has often happened in Western public debate since 2016, it must be conceptualized as an emotion that is explanatory—identifying the passionate motivation or justice-driven response behind countless recent political phenomena—political—recognizing the latent presence of thymos in various contemporary expressions—and comparative— considering historical, geographical, national contexts and related emotions like hatred and resentment. The ways in which anger is used, abused, expressed, and represented are shaped by the contexts, actors, and causes in which it is experienced as a potentially explosive passion. [ABSTRACT FROM AUTHOR]

Anger outbursts (AO) are associated with severe symptoms, impairment and poorer treatment outcomes for anxious children, though limited research has examined AO in youth with co-occurring autism and anxiety disorders. This study examined AO in children with autism and anxiety by evaluating clinical characteristics, family accommodation, and changes in AO following anxiety-focused treatment. The sample comprised 167 youth with autism and anxiety enrolled in a multi-site randomized clinical trial comparing standard care CBT for anxiety, CBT adapted for youth with autism, and usual care. Most participants (60%) had AO, which contributed to impairment above and beyond anxiety and autism. AO impacted functional impairment indirectly through a pathway of parental accommodation. AO reduced with anxiety-focused treatment. Findings highlight that AO are common in this population and uniquely contribute to functional impairment, indicating a need for direct targeting in treatment. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a severe disease in older adults and in individuals with associated comorbidities such as diabetes mellitus. Patients with diabetes infected with SARS-CoV-2 are more likely to develop severe pneumonia, hospitalization, and mortality compared with infected non-diabetic patients. During diabetes, hyperglycemia contributes to the maintenance of a low-grade inflammatory state which has been implicated in the microvascular and macrovascular complications associated with this pathology. The receptor for advanced glycation end products (RAGE) is a multi-ligand pattern recognition receptor, expressed on a wide variety of cells, which participates as an important mediator of inflammatory responses in many diseases, including lung diseases. This review highlights the role of RAGE in the pathophysiology of COVID-19 with special emphasis on diabetic patients. These data could explain the severity of the disease, positioning it as a key therapeutic target in the clinical management of this infection. [ABSTRACT FROM AUTHOR]

Simple Summary: The RAGE signaling pathway is associated with many chronic disorders. One of them may be endometrial cancer (EC). EC is one of the most common gynecologic cancers among women. The aim of our considerations was to decipher the role of RAGE and its ligands in the progression of EC. We confirmed that disruptions in the RAGE signaling pathways may be a reason for EC progression. The cross-talk between RAGE and Diaph1 plays a crucial role in downstream signaling pathways during EC progression. However, we assume that DNA methylation may regulate the activity of the RAGE signaling pathways in the endometrium. Thus, DNA methylation may create an epigenetic memory that may trigger perturbations in the endometrium. Endometrial cancer (EC) is the most common gynecological malignancy. EC is associated with metabolic disorders that may promote non-enzymatic glycation and activate the receptor for advanced glycation end-products (RAGE) signaling pathways. Thus, we assumed that RAGE and its ligands may contribute to EC. Of particular interest is the interaction between diaphanous-related formin 1 (Diaph1) and RAGE during the progression of human cancers. Diaph1 is engaged in the proper organization of actin cytoskeletal dynamics, which is crucial in cancer invasion, metastasis, angiogenesis, and axonogenesis. However, the detailed molecular role of RAGE in EC remains uncertain. In this review, we discuss epigenetic factors that may play a key role in the RAGE-dependent endometrial pathology. We propose that DNA methylation may regulate the activity of the RAGE pathway in the uterus. The accumulation of negative external factors, such as hyperglycemia, inflammation, and oxidative stress, may interfere with the DNA methylation process. Therefore, further research should take into account the role of epigenetic mechanisms in EC progression. [ABSTRACT FROM AUTHOR]

George Floyd's murder by a white policeman has sparked the largest urban uprising in US cities since the 1960s. By contextualising this wave of uprisings in the broader context of similar uprisings in twenty‐first‐century US cities, this paper shows that such an uprising has long been in the making with the violence, murders and revolts that have marked US cities since the turn of the century. My argument in this paper is against the pathological framing of these uprisings that evokes the alleged irrational anger of those who participate in the uprisings and the bad behaviour of a few police officers. Such a framing directs attention away from the structural violence that is at the source of these uprisings, and perpetuates racialised images of those who participate in the uprisings as irrational and impulsive. These uprisings, I argue, are not the actions of irrationally angry individuals mindlessly following the crowds; they cannot be reduced to gratuitous looting and burning, and they are not triggered by some police officers behaving badly. The sources of this urban rage lie in systematic, mostly unchecked, violence. The rage that erupts in these uprisings is a political emotion guided by cognition and judgements about right and wrong, just and unjust, rather than a pathological reaction spurred by uncontrollable impulses. It is a deliberate response to white contempt and the violence associated with it. This article is an attempt to reflect on the political aspects of rage as an emotion. By exploring recent urban uprisings, I argue that the pathological framing of rage that erupts in such events is misleading, as it diverts attention away from the structural violence that produces them. The rage that erupts in urban uprisings is a political emotion and a deliberate response to violence, rather than a pathological reaction. [ABSTRACT FROM AUTHOR]

Objective: Abdominal aortic aneurysms (AAA) are a common critical cardiovascular disease with high morbidity and mortality rates. Quercetin, a flavonoid and a traditional Chinese medicinal ingredient commonly found in vegetables and fruits, has a favorable inhibitory effect on experimental aneurysms without side effects. This study aimed to model elastase AAA and investigate the mechanism of action of quercetin in alleviating AAA. Methods: Quercetin was administered at a dose of 60 mg/kg once daily starting on the day of AAA induction for 5 weeks. The therapeutic effect of quercetin on AAA was demonstrated using biochemical assays, observation of pathological tissue sections, Elastic Van Gieson staining, immunohistochemistry, molecular docking simulations, and Western blot protein validation. Results: Our study showed that quercetin treatment significantly alleviated abdominal aortic vessel wall dilatation, elastin degradation and adhesion to surrounding tissues caused by elastase. Additionally, quercetin significantly inhibited the mRNA and protein expression of the receptor for advanced glycation end products(RAGE)/ phosphatidylinositol 3-kinase (PI3K)/ phosphatidylinositol 3-kinase (AKT) / mammlian target of rapamycin (mTOR) pathway. Conclusion: Quercetin can alleviate abdominal aortic injury caused by elastase via RAGE/PI3K/AKT/mTOR and provide experience in clinical use. [ABSTRACT FROM AUTHOR]

In recent years, anger has emerged as a crucial category for analyzing contemporary political phenomena such as democratic elections, protests, collective violence, social movements, and crises of institutional representation. However, it has also become a vague or empty signifier among commentators and journalists trying to describe these events. This article begins with a brief philosophical overview of anger, tracing its evolution from Greco-Roman antiquity to the French Revolution. This historical journey sets the stage for the second part, where the article proposes a conceptualization of political anger through three contemporary shifts: first, a shift toward a realistic understanding that diminishes the relevance of the negationist perspective rooted in ancient and Enlightenment moral, philosophical, and theological views; second, a shift toward a collective and political dimension that has overshadowed individual ethical or religious interpretations; and third, a shift toward the ethical and moral legitimization of anger. For political anger to transcend its status as an empty signifier, as has often happened in Western public debate since 2016, it must be conceptualized as an emotion that is explanatory—identifying the passionate motivation or justice-driven response behind countless recent political phenomena—political—recognizing the latent presence of thymos in various contemporary expressions—and comparative—considering historical, geographical, national contexts and related emotions like hatred and resentment. The ways in which anger is used, abused, expressed, and represented are shaped by the contexts, actors, and causes in which it is experienced as a potentially explosive passion.

This study aimed to identify the potential of natural compounds in tomatoes for diabetic complications intervention using amino acid profile, HP-TLC, antioxidant assay, enzymatic inhibitor assay, and in silico approach. Fresh air-dried tomatoes were analyzed for several screening assays including amino acid determination, HP-TLC, antioxidant activity using FRAP, α-amylase, and α-glucosidase enzyme inhibition. Virtual screening, molecular docking and molecular dynamics were performed using Molinspiration, pKcSM, AutoDock Vina, Discovery Studio, PyMOL, and Yasara software. Tomato bioactive compounds showed promising drug-likeness, antioxidant and α-amylase/glucosidase inhibitory activities, and potential for AGE-RAGE interaction. Out of 19 compounds from whole tomatoes complying with Lipinski’s rule of five, genistein, apigenin, and naringenin exhibited high oral absorption potential. Tomato contains genistein compound based on HP-TLC and the compound has high antioxidant and antidiabetic activities. Genistein has a stronger binding affinity with RAGE compared to AGE, indicating its potential as a competitive inhibitor. Additionally, genistein displayed stable ligand movements and higher binding energy values in MD simulations compared to the control. These findings suggest the potential of tomato bioactive compounds for further development as antidiabetic agents targeting AGE-RAGE interaction. In conclusion, genistein in tomatoes is indicated as a candidate for anti-complications of diabetes mellitus.

Abstract Background This study aimed to investigate functions of GLP-1R agonist by liraglutide (LIRA) and revealing the mechanism related to AGEs/RAGE in chondrocytes. Methods To illustrate potential effect of GLP-1R agonist on AGEs induced chondrocytes, chondrocytes were administrated by AGEs with LIRA and GLP-1R inhibitor exendin. Inflammatory factors were assessed using ELISA. Real-time PCR was used to evaluate the catabolic activity MMPs and ADAMTS mRNA level, as well as anabolic activity (aggrecan and collagen II). RAGE expression was investigated by Western blotting. TUNEL, caspase3 activity and immunofluorescence were performed to test the apoptotic activity. Results Our results showed that treatment with LIRA at > 100 nM attenuated the AGE-induced chondrocyte viability. Western bolt demonstrated that GLP-1R activation by LIRA treatment reduced RAGE protein expression compared with the AGEs groups. ELISA showed that LIRA hindered the AGEs-induced production of inflammatory cytokines (IL-6, IL-12 and TNF-α) in primary chondrocytes. AGEs induced catabolism levels (MMP-1, -3, -13 and ADAMTS-4, 5) are also attenuated by LIRA, causing the retention of more extracellular matrix (Aggrecan and Collagen II). TUNEL, caspase3 activity and immunofluorescence results indicated that LIRA inhibited the AGEs-induced production of inflammatory cytokines in primary chondrocytes and attenuated the caspase 3 level, leading to the reduced apoptotic activity. All the protective effects are reversed by exendin (GLP-1R blockers). Conclusions The present study demonstrates for the first time that LIRA, an agonist for GLP-1R which is commonly used in type 2 diabetes reverses AGEs induced chondrocyte inflammation and apoptosis through suppressing RAGE signaling, contributing to reduced catabolism and retention of more extracellular matrix. The above results indicate the possible effect of GLP-1R agonist on treating OA.

Abstract Background The discovery of new prognostic biomarkers following spinal cord injury (SCI) is a rapidly growing field that could help uncover the underlying pathological mechanisms of SCI and aid in the development of new therapies. To date, this search has largely focused on the initial days after the lesion. However, during the subacute stage of SCI (weeks to months after the injury), there remains potential for sensorimotor recovery, and numerous secondary events develop in various organs. Additionally, the confounding effects of early interventions after the injury are less likely to interfere with the results. Methods In this study, we conducted an untargeted proteomics analysis to identify biomarkers of recovery in blood serum samples during the subacute phase of SCI patients, comparing those with strong recovery to those with no recovery between 30 and 120 days. We analyzed the fraction of serum that is depleted of the most abundant proteins to unmask proteins that would otherwise go undetected. Linear models were used to identify peptides and proteins related to neurological recovery and we validated changes in some of these proteins using Enzyme-linked Immunosorbent Assay (ELISA). Results Our findings reveal that differences in subacute recovery after SCI (from 30 to 120 days) are associated with an enrichment in proteins involved in inflammation, coagulation, and lipid metabolism. Technical validation using commercial ELISAs further confirms that high levels of SERPINE1 and ARHGAP35 are associated with strong neurological recovery, while high levels of CD300a and DEFA1 are associated with a lack of recovery. Conclusions Our study identifies new candidates for biomarkers of neurological recovery and for novel therapeutic targets after SCI.

RAGE (receptor for advanced glycation end-products) represents a class of multi-ligand pattern recognition receptors highly expressed in the vertebrate lung. Our previous work demonstrated unique patterns of RAGE expression in the developing murine lung and regulation by key transcription factors including NKX2.1 and FoxA2. The current investigation employed conditional lung-specific upregulation via a TetOn transgenic mouse model (RAGE TG) and nontransgenic controls. RAGE expression was induced in RAGE TG mice throughout gestation (embryonic day, E0-E18.5) or from E15.5-E18.5 and compared to age-matched controls. High-resolution respirometry was used to assess mitochondrial respiration and context was provided by quantifying ATP and reactive oxygen species (ROS) generation. Lung lysates were also screened by immunoblotting for MAPK/PI3K signaling intermediates. RAGE upregulation increased mitochondrial oxygen consumption in the E0-E18.5 and E15.5-E18.5 groups compared to controls. RAGE TG mice also had increased ATP concentrations, which persisted even after controlling for oxygen consumption. In contrast, ROS generation was diminished in RAGE TG animals compared to controls. Lastly, in both RAGE TG groups, pERK and pp38 were significantly decreased, whereas pAKT was significantly elevated, suggesting that RAGE signaling is likely perpetuated via pAKT pathways. Together, these data demonstrate that despite lung hypoplasia in RAGE TG mice, the remaining tissue experiences a favorable shift in mitochondrial bioenergetics without excessive redox assault and a preference for AKT signaling over ERK or p38.

Visual and written accounts of rage in popular media tend to associate rage with violent masculinities.1 Filicide brings women’s rage into sharp relief. By reading South African women in relation to their ancestral peer, Sila van den Kaap and through a ‘black deformative’ analysis of media accounts and an interview of filicide in South Africa, this paper asserts that black women have ample cause for rage. Filicide brings the purportedly personal into public light and compels a response. Although the response tends to pathologise filicidal women, it calls attention to the conditions of impoverishment that black women live under. The paper suggests that filicidal women’s refusal of the conditions of mothering, may also be an enactment of a strike against gendered scripts of care. Their own subsequent suicide might simultaneously be read as an opting out and as reaching for freedom beyond the interdiction of impoverishment. The findings suggest that rage is a crucial action-oriented affect in the expression and striving for black freedoms of which women are always core protagonists. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether quercetin reduces neuroinflammation in epileptic rats by regulating high mobility group protein B1 （HMGB1）, receptor for advanced glycation end products （RAGE） and nuclear factor kappa-B （NF-κB）, and to explore the possibility of HMGB1/RAGE/NF-κB pathway as a new target of quercetin. Methods: Twelve SD rats were randomly selected from 60 SD rats as healthy group, and the remaining rats were used to construct experimental models of epilepsy rats. Rats that were successfully modeled were divided into model group, high-dose quercetin group, low-dose quercetin group, quercetin+pathway activator group, with 12 rats in each group. Pathological changes of hippocampal tissue of rats were observed; neurobehavioral function of rats was evaluated; levels of tumor necrosis factor-α （TNF-α）, IL-6 and IL-1β, and mRNA and protein expression levels of HMGB1, RAGE, NF-κB in hippocampal tissue of rats were detected. Results: Structure of hippocampus of rats in healthy group was complete; compared with healthy group, structure of hippocampal tissue of rats in model group was scattered, the number of surviving neurons was observably reduced, apoptotic index was observably increased, the Racine grade was observably increased, TNF-α, IL-1β, IL-6 contents and mRNA and protein expression levels of HMGB1, RAGE, NF-κB in hippocampal tissue were significantly increased; compared with model group, structure of hippocampal tissue of rats in low- and high-dose quercetin groups was relatively complete, the number of surviving neurons was observably increased, apoptotic index was observably decreased, the Racine grade was significantly decreased, TNF-α, IL-1β, IL-6 contents and mRNA and protein expression levels of HMGB1, RAGE, NF-κB were significantly reduced, and the improvement effect of high-dose quercetin group was better; compared with high-dose quercetin group, the number of surviving neurons in quercetin+pathway activator group was significantly reduced, apoptotic index was significantly increased, the Racine grade was significantly increased, TNF-α, IL-1β, IL-6 contents and mRNA and protein expression levels of HMGB1, RAGE, NF-κB in hippocampal tissue were significantly increased. Conclusion: Quercetin can effectively reduce neuroinflammation in epileptic rats by inhibiting the HMGB1/RAGE/NF-κB pathway and reducing the mRNA and protein expressions of related genes. [ABSTRACT FROM AUTHOR]

The receptor for advanced glycation end products (RAGE) is a transmembrane receptor that belongs to the immunoglobulin superfamily and is extensively associated with chronic inflammation in non‐transmissible diseases. As chronic inflammation is consistently present in neurodegenerative diseases, it was largely assumed that RAGE could act as a critical modulator of neuroinflammation in Parkinson's disease (PD), similar to what was reported for Alzheimer's disease (AD), where RAGE is postulated to mediate pro‐inflammatory signaling in microglia by binding to amyloid‐β peptide. However, accumulating evidence from studies of RAGE in PD models suggests a less obvious scenario. Here, we review physiological aspects of RAGE and address the current questions about the potential involvement of this receptor in the cellular events that may be critical for the development and progression of PD, exploring possible mechanisms beyond the classical view of the microglial activation/neuroinflammation/neurodegeneration axis that is widely assumed to be the general mechanism of RAGE action in the adult brain. [ABSTRACT FROM AUTHOR]

The influence of chronic diseases on various facets of macrophage cellular senescence is poorly understood. This study evaluated the impact of chronic hyperglycemia on the induction of cellular senescence and subsequent immunosurveillance functions in RAW264.7 macrophages. Macrophages were cultured under normal glucose (NG; 5 mM), high glucose (HG; 20 mM), and very high glucose (VHG; 40 mM) conditions and assessed for markers of cellular senescence. Hyperglycemia induced strong upregulation of SA-β-gal activity, and loss of PCNA and Lamin B1 gene expression while markers of cell cycle arrest generally decreased. Non-significant changes in SASP-related proteins were observed while ROS levels slightly decreased and mitochondrial membrane potential increased. Protein concentration on the exosome membrane surface and their stability appeared to increase under hyperglycemic conditions. However, when macrophages were exposed to the secretory media (SM) of senescent preadipocytes, a dramatic increase in the levels of all inflammatory proteins was recorded especially in the VHG group that was also accompanied by upregulation of NF-κB and NLRP3 gene expression. SM treatment to hyperglycemic macrophages activated the TLR-2/Myd88 pathway but decreased the expression of scavenger receptors RAGE, CD36, and Olr-1 while CD44 and CXCL16 expression increased. On exposure to LPS, a strong upregulation in NO, ROS, and inflammatory cytokines was observed. Together, these results suggest that primary markers of cellular senescence are aberrantly expressed under chronic hyperglycemic conditions in macrophages with no significant SASP activation. Nonetheless, hyperglycemia strongly deregulates macrophage functions leading to impaired immunosurveillance of senescent cells and aggravation of inflamm-aging. This work provides novel insights into how hyperglycemia-induced dysfunctions can impact the potency of macrophages to manage senescent cell burden in aging tissues. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by the accumulation of aggregated amyloid peptides in the brain parenchyma and within the walls of cerebral vessels. The hippocampus—a complex brain structure with a pivotal role in learning and memory—is implicated in this disease. However, there is limited data on vascular changes during AD pathological degeneration in this susceptible structure, which has distinctive vascular traits. Our aim was to evaluate vascular alterations in the hippocampus of AD patients and PDAPP-J20 mice—a model of AD—and to determine the impact of Aβ40 and Aβ42 on endothelial cell activation. We found a loss of physical astrocyte-endothelium interaction in the hippocampus of individuals with AD as compared to non-AD donors, along with reduced vascular density. Astrocyte-endothelial interactions and levels of the tight junction protein occludin were altered early in PDAPP-J20 mice, preceding any signs of morphological changes or disruption of the blood–brain barrier in these mice. At later stages, PDAPP-J20 mice exhibited decreased vascular density in the hippocampus and leakage of fluorescent tracers, indicating dysfunction of the vasculature and the BBB. In vitro studies showed that soluble Aβ40 exposure in human brain microvascular endothelial cells (HBMEC) was sufficient to induce NFκB translocation to the nucleus, which may be linked with an observed reduction in occludin levels. The inhibition of the membrane receptor for advanced glycation end products (RAGE) prevented these changes in HBMEC. Additional results suggest that Aβ42 indirectly affects the endothelium by inducing astrocytic factors. Furthermore, our results from human and mouse brain samples provide evidence for the crucial involvement of the hippocampal vasculature in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate functions of GLP-1R agonist by liraglutide (LIRA) and revealing the mechanism related to AGEs/RAGE in chondrocytes. Methods: To illustrate potential effect of GLP-1R agonist on AGEs induced chondrocytes, chondrocytes were administrated by AGEs with LIRA and GLP-1R inhibitor exendin. Inflammatory factors were assessed using ELISA. Real-time PCR was used to evaluate the catabolic activity MMPs and ADAMTS mRNA level, as well as anabolic activity (aggrecan and collagen II). RAGE expression was investigated by Western blotting. TUNEL, caspase3 activity and immunofluorescence were performed to test the apoptotic activity. Results: Our results showed that treatment with LIRA at > 100 nM attenuated the AGE-induced chondrocyte viability. Western bolt demonstrated that GLP-1R activation by LIRA treatment reduced RAGE protein expression compared with the AGEs groups. ELISA showed that LIRA hindered the AGEs-induced production of inflammatory cytokines (IL-6, IL-12 and TNF-α) in primary chondrocytes. AGEs induced catabolism levels (MMP-1, -3, -13 and ADAMTS-4, 5) are also attenuated by LIRA, causing the retention of more extracellular matrix (Aggrecan and Collagen II). TUNEL, caspase3 activity and immunofluorescence results indicated that LIRA inhibited the AGEs-induced production of inflammatory cytokines in primary chondrocytes and attenuated the caspase 3 level, leading to the reduced apoptotic activity. All the protective effects are reversed by exendin (GLP-1R blockers). Conclusions: The present study demonstrates for the first time that LIRA, an agonist for GLP-1R which is commonly used in type 2 diabetes reverses AGEs induced chondrocyte inflammation and apoptosis through suppressing RAGE signaling, contributing to reduced catabolism and retention of more extracellular matrix. The above results indicate the possible effect of GLP-1R agonist on treating OA. [ABSTRACT FROM AUTHOR]

Background: The discovery of new prognostic biomarkers following spinal cord injury (SCI) is a rapidly growing field that could help uncover the underlying pathological mechanisms of SCI and aid in the development of new therapies. To date, this search has largely focused on the initial days after the lesion. However, during the subacute stage of SCI (weeks to months after the injury), there remains potential for sensorimotor recovery, and numerous secondary events develop in various organs. Additionally, the confounding effects of early interventions after the injury are less likely to interfere with the results. Methods: In this study, we conducted an untargeted proteomics analysis to identify biomarkers of recovery in blood serum samples during the subacute phase of SCI patients, comparing those with strong recovery to those with no recovery between 30 and 120 days. We analyzed the fraction of serum that is depleted of the most abundant proteins to unmask proteins that would otherwise go undetected. Linear models were used to identify peptides and proteins related to neurological recovery and we validated changes in some of these proteins using Enzyme-linked Immunosorbent Assay (ELISA). Results: Our findings reveal that differences in subacute recovery after SCI (from 30 to 120 days) are associated with an enrichment in proteins involved in inflammation, coagulation, and lipid metabolism. Technical validation using commercial ELISAs further confirms that high levels of SERPINE1 and ARHGAP35 are associated with strong neurological recovery, while high levels of CD300a and DEFA1 are associated with a lack of recovery. Conclusions: Our study identifies new candidates for biomarkers of neurological recovery and for novel therapeutic targets after SCI. [ABSTRACT FROM AUTHOR]

This essay critically examines Peter Sloterdijk’s Zorn und Zeit. Politisch-psychologischer Versuch (Rage and Time. A Psychopolitical Investigation) and his attempt to rehabilitate a culture of thymos, i.e. a culture of self-confidence and self-assertion, whose emotional agent Sloterdijk sees in rage. As an alternative to Achilles’ rage in Homer’s Iliad, Sloterdijk’s ancient reference, I will propose Ovid’s Metamorphoses as another literary origin of thymos. Against this background, I aim to defend the legitimacy of thymos, but to give it a different profile than Sloterdijk does, namely that of a creative and culturally productive energy that dismantles the tradition of warlike heroism and is pacifist at its core. [ABSTRACT FROM AUTHOR]

Aim: The systematic review aimed to compare the levels of advanced glycation end products (AGEs) and RAGE (AGE receptors) expression in diabetic periodontitis patients with non‐diabetic periodontitis patients and to identify the relationship of AGE and RAGE levels with periodontal disease severity. Materials and Methods: The literature search was carried out according to PRISMA guidelines by two independent researchers using four online databases: PubMed, Scopus, Web of Science Core Collection, and Pro‐Quest. Relevant studies published between 2000 and March 2023 were included in this review. The association of diabetes and AGE/RAGE levels on periodontal health, periodontal pocket depth (PPD), and clinical attachment loss (CAL) was studied. Results: Sixteen cross‐sectional studies, including 2794 patients (age range 15–75 years), were identified in the final stage. An elevated AGE level was observed among patients with diabetes and chronic periodontal disease compared to the non‐diabetic group. Furthermore, the levels of AGE and RAGE are associated with CAL and PPD. Potential confounding factors like genetic and methodological differences were also responsible for AGE and RAGE variation. Conclusion: Levels of AGEs and RAGE expressions in diabetic periodontitis patients differ from non‐diabetic periodontitis patients. The differences may impact the course and severity of periodontal disease. [ABSTRACT FROM AUTHOR]

There are many common malignant tumors in clinic. Among them, lung cancer is caused by the failure of suction system, which seriously threatens the life safety of patients. Recent studies have found that anesthetics have achieved certain efficacy in many cancers. Isoflurane, an inhaled anesthetic, is used in this study to explore whether it can prevent the lung cancer development. The A549 and H1299 were purchased. Cell viability was tested by CCK-8 experiment. Cell death and pyroptosis were analyzed by PI staining as well as flow cytometry. HMGB1 as well as RAGE protein levels were tested by Western blot. The same is true of pyroxin-related proteins. The HMGB1 as well as RAGE levels in the lung cancer tissues were determined by Western blot along with immunohistochemistry. Isoflurane treatment can reduce cell viability and promote cell pyroptosis. Additionally, the protein levels of cleaved caspase-1, IL-1β, GSDMD-N, NLRP3, HMGB1, and RAGE were dramatically up-regulated in the lung cancer after isoflurane treatment. Down-regulated proteins in lung cancer tissues include HMGB1 and RAGE proteins. After HMGB1 knockdown or FPS-ZM1 treatment, the role of isoflurane in the lung cancer was neutralized. This study demonstrated that isoflurane induced the cell pyroptosis in the lung cancer through activating the HMGB1/RAGE pathway. [ABSTRACT FROM AUTHOR]

Thymocyte selection--associated high-mobility group box (TOX) is a transcription factor that is crucial for T cell exhaustion during chronic antigenic stimulation, but its role in inflammation is poorly understood. Here, we report that TOX extracellularly mediates drastic inflammation upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by binding to the cell surface receptor for advanced glycation end-products (RAGE). In various diseases, including COVID-19, TOX release was highly detectable in association with disease severity, contributing to lung fibroproliferative acute respiratory distress syndrome (ARDS). Recombinant TOX-induced blood vessel rupture, similar to a clinical signature in patients experiencing a cytokine storm, further exacerbating respiratory function impairment. In contrast, disruption of TOX function by a neutralizing antibody and genetic removal of RAGE diminished TOX-mediated deleterious effects. Altogether, our results suggest an insight into TOX function as an inflammatory mediator and propose the TOX--RAGE axis as a potential target for treating severe patients with pulmonary infection and mitigating lung fibroproliferative ARDS. [ABSTRACT FROM AUTHOR]

Dysregulation of the insulin-like growth factor (IGF) system determines the onset of various pathological conditions, including cancer. Accordingly, therapeutic strategies have been developed to block this system in tumor cells, but the results of clinical trials have been disappointing. After decades of research in the field, it is safe to say that one of the major reasons underlying the poor efficacy of anti-IGF-targeting agents is derived from an underestimation of the molecular complexity of this axis. Genetic, transcriptional, post-transcriptional and functional interactors interfere with the activity of canonical components of this axis, supporting the need for combinatorial approaches to effectively block this system. In addition, cancer cells interface with a multiplicity of factors from the extracellular compartment, which strongly affect cell destiny. In this review, we will cover novel extracellular mechanisms contributing to IGF system dysregulation and the implications of such dangerous liaisons for cancer hallmarks and responses to known and new anti-IGF drugs. A deeper understanding of both the intracellular and extracellular microenvironments might provide new impetus to better decipher the complexity of the IGF axis in cancer and provide new clues for designing novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Context: In the pursuit of novel therapeutic possibilities, repurposing existing drugs has gained prominence as an efficient strategy. The findings from our study highlight the potential of repurposed drugs as promising candidates against receptor for advanced glycation endproducts (RAGE) that offer therapeutic implications in cancer, neurodegenerative conditions and metabolic syndromes. Through careful analyses of binding affinities and interaction patterns, we identified a few promising candidates, ultimately focusing on sertindole and temoporfin. These candidates exhibited exceptional binding affinities, efficacy, and specificity within the RAGE binding pocket. Notably, they displayed a pronounced propensity to interact with the active site of RAGE. Our investigation further revealed that sertindole and temoporfin possess desirable pharmacological properties that highlighted them as attractive candidates for targeted drug development. Overall, our integrated computational approach provides a comprehensive understanding of the interactions between repurposed drugs, sertindole and temoporfin and RAGE that pave the way for future experimental validation and drug development endeavors. Methods: We present an integrated approach utilizing molecular docking and extensive molecular dynamics (MD) simulations to evaluate the potential of FDA-approved drugs, sourced from DrugBank, against RAGE. To gain deeper insights into the binding mechanisms of the elucidated candidate repurposed drugs, sertindole and temoporfin with RAGE, we conducted extensive all-atom MD simulations, spanning 500 nanoseconds (ns). These simulations elucidated the conformational dynamics and stability of the RAGE-sertindole and RAGE-temoporfin complexes. [ABSTRACT FROM AUTHOR]

Introduction: Frailty is prevalent among older adults with diabetes mellitus. Elevated serum levels of the soluble receptor for advanced glycation-end products (sRAGE) predict mortality in frail older adults. The evidence that sRAGE is also related to higher mortality in older adults with diabetes mellitus is inconsistent. Therefore, this study explored if frailty status influences the relationship between sRAGE and mortality in older adults with this condition. Methods: We analysed data of 391 participants with diabetes mellitus (median age, 76 years) from four European cohorts enrolled in the FRAILOMIC project. Frailty was evaluated at baseline using Fried's criteria. Serum sRAGE was determined by ELISA. Participants were stratified by frailty status (n = 280 non-frail and 111 frail). Multivariate Cox proportional hazards regression and Kaplan-Meier survival analysis were used to assess the relationship between sRAGE and mortality. Results: During 6 years of follow-up, 98 participants died (46 non-frail and 52 frail). Non-survivors had significantly higher baseline levels of sRAGE than survivors (median [IQR]: 1,392 [962–2,043] pg/mL vs. 1,212 [963–1,514], p = 0.008). High serum sRAGE (>1,617 pg/mL) was associated with increased mortality in the whole diabetes sample after adjustment for relevant confounders (HR 2.06, 95% CI: 1.36–3.11, p < 0.001), and there was an interaction between sRAGE and frailty (p = 0.006). Accordingly, the association between sRAGE and mortality was stronger in the frail group compared to the non-frail group (HR 2.52, 95% CI: 1.30–4.90, p = 0.006 vs. HR 1.71, 95% CI: 0.91–3.23, p = 0.099, respectively). Likewise, Kaplan-Meier curves showed a significant difference in survival rates between frail participants with high sRAGE and those with low sRAGE (p = 0.001), whereas no survival difference was seen in the non-frail group (p = 0.09). Conclusions: Frailty status influences the relationship between sRAGE and mortality in older adults with diabetes mellitus. Determination of sRAGE in this population could be a useful tool for risk stratification. [ABSTRACT FROM AUTHOR]

Sarcopenia manifests as muscle atrophy and loss that is complicated with malignancy. This study explored the mechanism of extracellular vesicles (EVs) in multiple myeloma (MM) with sarcopenia. SP2/0 conditioned medium (CM) was collected to isolate SP2/0-EVs. C2C12 cells were incubated with SP2/0 CM or SP2/0-EVs. ROS, TNF-α, IL-6, MuRF1 and MyHC levels were detected by DCF-DA fluorescent probe, ELISA, and Western blot. GW4869 was used to inhibit EV secretion in SP2/0 to confirm its effect on muscle atrophy. Serum was collected from MM patients with or without sarcopenia to detect RAGE mRNA expression. SP2/0 cells were transfected with RAGE siRNA and C2C12 cells were treated with the isolated si-RAGE-EVs or/and TLR4 agonist. SP2/0 tumor-bearing mouse model was established. Healthy mice and SP2/0-tumor bearing mice were treated with SP2/0-EVs or si-RAGE-EVs. SP2/0 CM or SP2/0-EVs stimulated ROS, inflammatory responses, and myotube atrophy in C2C12 cells. GW4869 blocked EV secretion and the effects of SP2/0 CM. RAGE mRNA expression in serum EVs was increased in MM&Sarcopenia patients and RAGE knockdown in SP2/0-EVs partially nullified SP2/0-EVs' effects. SP2/0-EVs activated the TLR4/NF-κB p65 pathway by translocating RAGE. SP2/0-EVs-derived RAGE elevated ROS production, inflammation, and myotube atrophy in C2C12 cells and caused muscle loss in SP2/0 tumor-bearing mice by activating the TLR4/NF-κB p65 pathway. SP2/0-EVs partially recapitulated muscle loss in healthy mice. SP2/0-EVs-derived RAGE increased ROS production, inflammation, and myotube atrophy in MM through TLR4/NF-κB p65 pathway activation. [ABSTRACT FROM AUTHOR]

Corylin is an isoflavone derived from Psoralea Fructus with multiple biological activities. However, its biological functions in renal cell carcinoma (RCC) remain unexplored. Our objective in this study was to delve into the activity of corylin in RCC and to analyze the molecular mechanisms of its actions. In this study, we discovered corylin can significantly attenuate cell viability in a dose-dependent manner and enhance drug sensitivity of RCC cells. Corylin suppresses the malignant behaviors of RCC cells both in vitro and in vivo, such as cellular proliferation, self-renewal, migration and invasion, glycolysis and mitochondrial respiration, tumor formation and metastasis. Further studies revealed corylin conducts it suppressive actions through repressing RAGE (Receptor for Advanced Glycation End Products) expression epigenetically, and corylin facilitates the hypermethylation of RAGE promoter. In conclusion, our findings demonstrated the tumor-suppressive role of corylin in RCC and uncovered its novel molecular mechanism for therapeutic effects on RCC treatment.

Abstract Alkaline burns to the cornea lead to loss of corneal transparency, which is essential for normal vision. We used a rat corneal alkaline burn model to investigate the effect of ophthalmic trimebutine solution on healing wounds caused by alkaline burns. Trimebutine, an inhibitor of the high-mobility group box 1-receptor for advanced glycation end products, when topically applied to the burned cornea, suppressed macrophage infiltration in the early phase and neutrophil infiltration in the late phase at the wound site. It also inhibited neovascularization and myofibroblast development in the late phase. Furthermore, trimebutine effectively inhibited interleukin-1β expression in the injured cornea. It reduced scar formation by decreasing the expression of type III collagen. These findings suggest that trimebutine may represent a novel therapeutic strategy for corneal wounds, not only through its anti-inflammatory effects but also by preventing neovascularization.

La cohabitation entre les animaux domestiques, sauvage et les populations humaines est à l’origine de certains problèmes de santé publique majeurs dont la rage. Cette étude a révélé la faible connaissance des prestataires sur la prise en charge des victimes de morsures par des animaux suspects de rage et plus grave encore sur la connaissance de l’approche une santé en raison des résultats non satisfaisants obtenus lors de nos analyses par rapport au protocole conventionnel de l’OMS sur la prise en charge.

BackgroundUnderstanding the intricate signaling network involved in triple-negative breast cancer (TNBC) represents a challenge for developing novel therapeutic approaches. Here, we aim to provide novel mechanistic insights on the function of the S100A8/A9-RAGE system in TNBC.MethodsTNM plot analyzer, Kaplan-Meier plotter, Meta-analysis, GEPIA2 and GOBO publicly available datasets were used to evaluate the clinical significance of S100A8/A9 and expression levels of S100A8/A9, RAGE and Filamin family members in breast cancer (BC) subtypes. METABRIC database and Cox proportional hazard model defined the clinical impact of high RAGE expression in BC patients. Multiple bioinformatics programs identified the main enriched pathways within high RAGE expression BC cohorts. By lentiviral system, TNBC cells were engineered to overexpress RAGE. Western blotting, immunofluorescence, nucleus/cytoplasm fractionation, qRT-PCR, gene silencing and luciferase experiments were performed to identify signal transduction mediators engaged by RAGE upon stimulation with S100A8/A9 in TNBC cells. Proliferation, colony formation and transwell migration assays were carried out to evaluate the growth and migratory capacity of TNBC cells. Statistical analysis was performed by ANOVA and independent t-tests.ResultsWe found a remarkable high expression of S100A8 and S100A9 in BC, particularly in HER2-positive and TNBC, with the latter associated to worst clinical outcomes. In addition, high RAGE expression correlated with a poor overall survival in BC. Next, we determined that the S100A8/A9-RAGE system triggers FAK activation by engaging a cytoskeleton mechanosensing complex in TNBC cells. Through bioinformatics analysis, we identified the Hippo pathway as the most enriched in BC patients expressing high RAGE levels. In accordance with these data, we demonstrated the involvement of S100A8/A9-RAGE-FAK signaling in the control of Hippo/YAP activities, and we established the crucial contribution of RAGE-FAK-YAP circuitry in the growth and migratory effects initiated by S100A8/A9 in TNBC cells.ConclusionsThe present study provides novel mechanistic insights on RAGE actions in TNBC. Moreover, our findings suggest that RAGE-FAK-YAP transduction pathway could be exploited as a druggable system halting the aggressive TNBC subtype.

Alkaline burns to the cornea lead to loss of corneal transparency, which is essential for normal vision. We used a rat corneal alkaline burn model to investigate the effect of ophthalmic trimebutine solution on healing wounds caused by alkaline burns. Trimebutine, an inhibitor of the high-mobility group box 1-receptor for advanced glycation end products, when topically applied to the burned cornea, suppressed macrophage infiltration in the early phase and neutrophil infiltration in the late phase at the wound site. It also inhibited neovascularization and myofibroblast development in the late phase. Furthermore, trimebutine effectively inhibited interleukin-1β expression in the injured cornea. It reduced scar formation by decreasing the expression of type III collagen. These findings suggest that trimebutine may represent a novel therapeutic strategy for corneal wounds, not only through its anti-inflammatory effects but also by preventing neovascularization. [ABSTRACT FROM AUTHOR]

Over the past few decades, diabetes gradually has become one of the top non‐communicable disorders, affecting 476.0 million in 2017 and is predicted to reach 570.9 million people in 2025. It is estimated that 70 to 100% of all diabetic patients will develop some if not all, diabetic complications over the course of the disease. Despite different symptoms, mechanisms underlying the development of diabetic complications are similar, likely stemming from deficits in both neuronal and vascular components supplying hyperglycaemia‐susceptible tissues and organs. Diaph1, protein diaphanous homolog 1, although mainly known for its regulatory role in structural modification of actin and related cytoskeleton proteins, in recent years attracted research attention as a cytoplasmic partner of the receptor of advanced glycation end‐products (RAGE) a signal transduction receptor, whose activation triggers an increase in proinflammatory molecules, oxidative stressors and cytokines in diabetes and its related complications. Both Diaph1 and RAGE are also a part of the RhoA signalling cascade, playing a significant role in the development of neurovascular disturbances underlying diabetes‐related complications. In this review, based on the existing knowledge as well as compelling findings from our past and present studies, we address the role of Diaph1 signalling in metabolic stress and neurovascular degeneration in diabetic complications. In light of the most recent developments in biochemical, genomic and transcriptomic research, we describe current theories on the aetiology of diabetes complications, highlighting the function of the Diaph1 signalling system and its role in diabetes pathophysiology. [ABSTRACT FROM AUTHOR]

The transmembrane receptor for advanced glycation end products (RAGE) is a signaling receptor for many damage‐ and pathogen‐associated molecules. Activation of RAGE is associated with inflammation and an increase in reactive oxygen species (ROS) production. Although several sources of ROS have been previously suggested, how RAGE induces ROS production is still unclear, considering the multiple targets of pathogen‐associated molecules. Here, using acute brain slices and primary co‐culture of cortical neurons and astrocytes, we investigated the effects of a range of synthetic peptides corresponding to the fragments of the RAGE V‐domain on redox signaling. We found that the synthetic fragment (60–76) of the RAGE V‐domain induces activation of ROS production in astrocytes and neurons from the primary co‐culture and acute brain slices. This effect occurred through activation of RAGE and could be blocked by a RAGE inhibitor. Activation of RAGE by the synthetic fragment stimulates ROS production in NADPH oxidase (NOX). This RAGE‐induced NOX activation produced only minor decreases in glutathione levels and increased the rate of lipid peroxidation, although it also reduced basal and β‐amyloid induced cell death in neurons and astrocytes. Thus, specific activation of RAGE induces redox signaling through NOX, which can be a part of a cell protective mechanism. [ABSTRACT FROM AUTHOR]

The receptor for advanced glycation end-products (RAGE) has a central function in orchestrating inflammatory responses in multiple disease states including chronic obstructive pulmonary disease (COPD). RAGE is a transmembrane pattern recognition receptor with particular interest in lung disease due to its naturally abundant pulmonary expression. Our previous research demonstrated an inflammatory role for RAGE following acute exposure to secondhand smoke (SHS). However, chronic inflammatory mechanisms associated with RAGE remain ambiguous. In this study, we assessed transcriptional outcomes in mice exposed to chronic SHS in the context of RAGE expression. RAGE knockout (RKO) and wild-type (WT) mice were delivered nose-only SHS via an exposure system for six months and compared to control mice exposed to room air (RA). We specifically compared WT + RA, WT + SHS, RKO + RA, and RKO + SHS. Analysis of gene expression data from WT + RA vs. WT + SHS showed FEZ1, Slpi, and Msln as significant at the three-month time point; while RKO + SHS vs. WT + SHS identified cytochrome p450 1a1 and Slc26a4 as significant at multiple time points; and the RKO + SHS vs. WT + RA revealed Tmem151A as significant at the three-month time point as well as Gprc5a and Dynlt1b as significant at the three- and six-month time points. Notable gene clusters were functionally analyzed and discovered to be specific to cytoskeletal elements, inflammatory signaling, lipogenesis, and ciliogenesis. We found gene ontologies (GO) demonstrated significant biological pathways differentially impacted by the presence of RAGE. We also observed evidence that the PI3K-Akt and NF-κB signaling pathways were significantly enriched in DEGs across multiple comparisons. These data collectively identify several opportunities to further dissect RAGE signaling in the context of SHS exposure and foreshadow possible therapeutic modalities. [ABSTRACT FROM AUTHOR]

Cardiac disorders in cancer patients pose significant challenges to disease prognosis. While it has been established that these disorders are linked to cancer cells, the precise underlying mechanisms remain elusive. In this study, we investigated the impact of cancerous ascites from the rat colonic carcinoma cell line RCN9 on H9c2 cardiomyoblast cells. We found that the ascites reduced mitochondrial volume, increased oxidative stress, and decreased membrane potential in the cardiomyoblast cells, leading to apoptosis and autophagy. Although the ascites fluid contained a substantial amount of high-mobility group box-1 (HMGB1), we observed that neutralizing HMGB1 with a specific antibody mitigated the damage inflicted on myocardial cells. Our mechanistic investigations revealed that HMGB1 activated both nuclear factor κB and phosphoinositide 3-kinases-AKT signals through HMGB1 receptors, namely the receptor for advanced glycation end products and toll-like receptor-4, thereby promoting apoptosis and autophagy. In contrast, treatment with berberine (BBR) induced the expression of miR-181c-5p and miR-340-5p while suppressing HMGB1 expression in RCN9 cells. Furthermore, BBR reduced HMGB1 receptor expression in cardiomyocytes, consequently mitigating HMGB1-induced damage. We validated the myocardial protective effects of BBR in a cachectic rat model. These findings underscore the strong association between HMGB1 and cancer cachexia, highlighting BBR as a promising therapeutic agent for myocardial protection through HMGB1 suppression and modulation of the signaling system. [ABSTRACT FROM AUTHOR]

Methylglyoxal (MGO) is a highly reactive α-dicarbonyl compound formed endogenously from 3-carbon glycolytic intermediates. Methylglyoxal accumulated in plasma and urine of hyperglycemic and diabetic individuals acts as a potent peptide glycation molecule, giving rise to advanced glycation end products (AGEs) like arginine-derived hydroimidazolone (MG-H1) and carboxyethyl-lysine (CEL). Methylglyoxal-derived AGEs exert their effects mostly via activation of RAGE, a cell surface receptor that initiates multiple intracellular signaling pathways, favoring a pro-oxidant environment through NADPH oxidase activation and generation of high levels of reactive oxygen species (ROS). Diabetic bladder dysfunction is a bothersome urological complication in patients with poorly controlled diabetes mellitus and may comprise overactive bladder, urge incontinence, poor emptying, dribbling, incomplete emptying of the bladder, and urinary retention. Preclinical models of type 1 and type 2 diabetes have further confirmed the relationship between diabetes and voiding dysfunction. Interestingly, healthy mice supplemented with MGO for prolonged periods exhibit in vivo and in vitro bladder dysfunction, which is accompanied by increased AGE formation and RAGE expression, as well as by ROS overproduction in bladder tissues. Drugs reported to scavenge MGO and to inactivate AGEs like metformin, polyphenols, and alagebrium (ALT-711) have shown favorable outcomes on bladder dysfunction in diabetic obese leptin-deficient and MGO-exposed mice. Therefore, MGO, AGEs, and RAGE levels may be critically involved in the pathogenesis of bladder dysfunction in diabetic individuals. However, there are no clinical trials designed to test drugs that selectively inhibit the MGO–AGEs–RAGE signaling, aiming to reduce the manifestations of diabetes-associated bladder dysfunction. This review summarizes the current literature on the role of MGO–AGEs–RAGE–ROS axis in diabetes-associated bladder dysfunction. Drugs that directly inactivate MGO and ameliorate bladder dysfunction are also reviewed here. [ABSTRACT FROM AUTHOR]

RAGE is a transmembrane receptor of immunoglobulin family that can bind various endogenous and exogenous ligands, initiating the inflammatory downstream signaling pathways, including inflammaging. Therefore, RAGE represents an attractive drug target for age‐related diseases. For the development of small‐molecule RAGE antagonists, we employed protein‐templated dynamic combinatorial chemistry (ptDCC) using RAGE′s VC1 domain as a template, the first application of this approach in the context of RAGE. The affinities of DCC hits were validated using microscale thermophoresis. Subsequent screening against AGE2 (glyceraldehyde‐modified AGE)‐sRAGE (solubleRAGE) (AGE2‐BSA/sRAGE) interaction using ELISA tests led to the identification of antagonists with micromolar potency. Our findings not only demonstrate the successful application of ptDCC on RAGE but also highlight its potential to address the pressing need for alternative strategies for the development of small‐molecule RAGE antagonists, an area of research that has experienced a slowdown in recent years. [ABSTRACT FROM AUTHOR]

Background: Through its capacity to intensify inflammatory pathways, Rheumatoid arthritis (RA) has been connected to the receptor for advanced glycation end products (RAGE). So, in those with rheumatoid arthritis, the RAGE gene polymorphism may be a significant indicator of disease activity. Our aim is illustration of the role of RAGE gene polymorphism (G82S) in susceptibility of rheumatoid arthritis.Methods: Thirty individuals were used in this case control study, which was conducted at the Zagazig University hospitals' Clinical Pathology, Rheumatology, and Rehabilitation departments after obtaining their written agreement for ethical reasons. The participants were split up into two groups: fifteen RA cases and fifteen healthy volunteers who acted as the control group. A molecular investigation of the RAGE gene's glycine-to-serine (G82S) polymorphism was done for genotyping. Results: Rheumatoid arthritis patients have allele G levels that are 7 times greater than those in the control group, with a 95% CI of 1.38 to 35.5. Significant difference: p=0.009.Conclusions: The RAGE gene polymorphism (G82S) with allele G was higher in rheumatoid arthritis patients than the control group. Sadly, we were unable to discover a link between gene variation and disease activity. [ABSTRACT FROM AUTHOR]

A growing body of literature has shown that type 1 diabetes (T1D) and high-fat diet (HFD) affect female reproductive function and may be involved in a chronic inflammatory state. Our previous studies indicated that T1D as well as HFD may evoke perturbations in the receptor for advanced glycation end products (RAGE) signaling pathway. The aim of the study was to determine the amount of RAGE protein and its proinflammatory ligands in uterine tissues harvested from T1D and HFD/pre-diabetic mice (n = 5 per group). We sought the impact of T1D and HFD on the activity of the RAGE signaling pathway in uterine tissues during the estrous cycle. The abundance of RAGE and its ligands were estimated using immunohistochemical staining. However, we also performed nerve conduction velocity studies to confirm diabetic neuropathy. The highest amount of RAGE and its ligands were observed in uterine tissues of T1D mice. Moreover, myometrial activity of the RAGE signaling pathway was increased in HFD in comparison to the control group (P≤0.05). We observed a strong relationship between RAGE, Nε-(carboxymethyl)lysine (CML) and tumor necrosis factor alpha (TNFα) proteins in mice myometrium. These data suggest that T1D and HFD could modulate the activity of RAGE and thus RAGE signaling pathway in uterine tissues during estrous cycle. Long-term diabetes and HFD may induce malfunctions in the uterine milieu. In the future RAGE protein may serve as a molecular marker in the diagnosis of malfunctions in pre- and diabetic uterus milieu. [ABSTRACT FROM AUTHOR]

A growing body of literature has shown that type 1 diabetes (T1D) and high-fat diet (HFD) affect female reproductive function and may be involved in a chronic inflammatory state. Our previous studies indicated that T1D as well as HFD may evoke perturbations in the receptor for advanced glycation end products (RAGE) signaling pathway. The aim of the study was to determine the amount of RAGE protein and its proinflammatory ligands in uterine tissues harvested from T1D and HFD/pre-diabetic mice (n = 5 per group). We sought the impact of T1D and HFD on the activity of the RAGE signaling pathway in uterine tissues during the estrous cycle. The abundance of RAGE and its ligands were estimated using immunohistochemical staining. However, we also performed nerve conduction velocity studies to confirm diabetic neuropathy. The highest amount of RAGE and its ligands were observed in uterine tissues of T1D mice. Moreover, myometrial activity of the RAGE signaling pathway was increased in HFD in comparison to the control group (P≤0.05). We observed a strong relationship between RAGE, Nε-(carboxymethyl)lysine (CML) and tumor necrosis factor alpha (TNFα) proteins in mice myometrium. These data suggest that T1D and HFD could modulate the activity of RAGE and thus RAGE signaling pathway in uterine tissues during estrous cycle. Long-term diabetes and HFD may induce malfunctions in the uterine milieu. In the future RAGE protein may serve as a molecular marker in the diagnosis of malfunctions in pre- and diabetic uterus milieu. [ABSTRACT FROM AUTHOR]

High mobility group protein 1 (HMGB1) plays a complex role in tumor biology. When released into the extracellular space, it binds to the receptor for advanced glycation end products (RAGE) located on the cell membrane, playing an important role in tumor development by regulating a number of biological processes and signal pathways. In this review, we outline the multifaceted functions of the HMGB1/RAGE axis, which encompasses tumor cell proliferation, apoptosis, autophagy, metastasis, and angiogenesis. This axis is instrumental in tumor progression, promoting tumor cell proliferation, autophagy, metastasis, and angiogenesis while inhibiting apoptosis, through pivotal signaling pathways, including MAPK, NF-κB, PI3K/AKT, ERK, and STAT3. Notably, small molecules, such as miRNA-218, ethyl pyruvate (EP), and glycyrrhizin exhibit the ability to inhibit the HMGB1/RAGE axis, restraining tumor development. Therefore, a deeper understanding of the mechanisms of the HMGB1/RAGE axis in tumors is of great importance, and the development of inhibitors targeting this axis warrants further exploration. [ABSTRACT FROM AUTHOR]

One of the hallmarks of Alzheimer’s disease (AD) is the accumulation of beta-amyloid peptide (Aβ) leading to formation of soluble neurotoxic Aβ oligomers and insoluble amyloid plaques in various parts of the brain. Aβ undergoes post-translational modifications that alter its pathogenic properties. Aβ is produced not only in brain, but also in the peripheral tissues. Such Aβ, including its post-translationally modified forms, can enter the brain from circulation by binding to RAGE and contribute to the pathology of AD. However, the transport of modified forms of Aβ across the blood–brain barrier (BBB) has not been investigated. Here, we used a transwell BBB model as a controlled environment for permeability studies. We found that Aβ42 containing isomerized Asp7 residue (iso-Aβ42) and Aβ42 containing phosphorylated Ser8 residue (pS8-Aβ42) crossed the BBB better than unmodified Aβ42, which correlated with dierent contribution of endocytosis mechanisms to the transport of these isoforms. Using microscale thermophoresis, we observed that RAGE binds to iso-Aβ42 an order of magnitude weaker than to Aβ42. Thus, post-translational modifications of Aβ increase the rate of its transport across the BBB and modify the mechanisms of the transport, which may be important for AD pathology and treatment [ABSTRACT FROM AUTHOR]

Aims Cyclophilin A (CyPA) induces leucocyte recruitment and platelet activation upon release into the extracellular space. Extracellular CyPA therefore plays a critical role in immuno-inflammatory responses in tissue injury and thrombosis upon platelet activation. To date, CD147 (EMMPRIN) has been described as the primary receptor mediating extracellular effects of CyPA in platelets and leucocytes. The receptor for advanced glycation end products (RAGE) shares inflammatory and prothrombotic properties and has also been found to have similar ligands as CD147. In this study, we investigated the role of RAGE as a previously unknown interaction partner for CyPA. Methods and results Confocal imaging, proximity ligation, co-immunoprecipitation, and atomic force microscopy were performed and demonstrated an interaction of CyPA with RAGE on the cell surface. Static and dynamic cell adhesion and chemotaxis assays towards extracellular CyPA using human leucocytes and leucocytes from RAGE-deficient Ager −/− mice were conducted. Inhibition of RAGE abrogated CyPA-induced effects on leucocyte adhesion and chemotaxis in vitro. Accordingly, Ager −/− mice showed reduced leucocyte recruitment and endothelial adhesion towards CyPA in vivo. In wild-type mice, we observed a downregulation of RAGE on leucocytes when endogenous extracellular CyPA was reduced. We furthermore evaluated the role of RAGE for platelet activation and thrombus formation upon CyPA stimulation. CyPA-induced activation of platelets was found to be dependent on RAGE, as inhibition of RAGE, as well as platelets from Ager −/− mice showed a diminished activation and thrombus formation upon CyPA stimulation. CyPA-induced signalling through RAGE was found to involve central signalling pathways including the adaptor protein MyD88, intracellular Ca2+ signalling, and NF-κB activation. Conclusion We propose RAGE as a hitherto unknown receptor for CyPA mediating leucocyte as well as platelet activation. The CyPA–RAGE interaction thus represents a novel mechanism in thrombo-inflammation. [ABSTRACT FROM AUTHOR]

Progress in the development of effective chemotherapy is producing a growing population of patients with acute and chronic painful chemotherapy-induced peripheral neuropathy (CIPN), a serious treatment-limiting side effect for which there is currently no US Food and Drug Administration-approved treatment. CIPNs induced by diverse classes of chemotherapy drugs have remarkably similar clinical presentations, leading to the suggestion they share underlying mechanisms. Sensory neurons share with immune cells the ability to detect damage associated molecular patterns (DAMPs), molecules produced by diverse cell types in response to cellular stress and injury, including by chemotherapy drugs. DAMPs, in turn, are ligands for pattern recognition receptors (PRRs), several of which are found on sensory neurons, as well as satellite cells, and cells of the immune system. In the present experiments, we evaluated the role of two PRRs, TLR4 and RAGE, present in dorsal root ganglion (DRG), in CIPN. Antisense (AS)-oligodeoxynucleotides (ODN) against TLR4 and RAGE mRNA were administered intrathecally before ('prevention protocol') or 3 days after ('reversal protocol') the last administration of each of three chemotherapy drugs that treat cancer by different mechanisms (oxaliplatin, paclitaxel and bortezomib). TLR4 and RAGE AS-ODN prevented the development of CIPN induced by all three chemotherapy drugs. In the reversal protocol, however, while TLR4 AS-ODN completely reversed oxaliplatin- and paclitaxel-induced CIPN, in rats with bortezomib-induced CIPN it only produced a temporary attenuation. RAGE AS-ODN, in contrast, reversed CIPN induced by all three chemotherapy drugs. When a TLR4 antagonist was administered intradermally to the peripheral nociceptor terminal, it did not affect CIPN induced by any of the chemotherapy drugs. However, when administered intrathecally, to the central terminal, it attenuated hyperalgesia induced by all three chemotherapy drugs, compatible with a role of TLR4 in neurotransmission at the central terminal but not sensory transduction at the peripheral terminal. Finally, since it has been established that cultured DRG neurons can be used to study direct effects of chemotherapy on nociceptors, we also evaluated the role of TLR4 in CIPN at the cellular level, using patch-clamp electrophysiology in DRG neurons cultured from control and chemotherapy-treated rats. We found that increased excitability of small-diameter DRG neurons induced by in vivo and in vitro exposure to oxaliplatin is TLR4-dependent. Our findings suggest that in addition to the established contribution of PRR-dependent neuroimmune mechanisms, PRRs in DRG cells also have an important role in CIPN. [ABSTRACT FROM AUTHOR]

Patients with acute myocardial infarction complicated with diabetes are more likely to develop myocardial ischemia/reperfusion (I/R) injury (MI/RI) during reperfusion therapy. Both HMGB1 and RAGE play important roles in MI/RI. However, the specific mechanisms of HMGB1 associated with RAGE are not fully clarified in diabetic MI/RI. This study aimed to investigate whether the HMGB1-RAGE axis induces diabetic MI/RI via regulating autophagy and apoptosis. A db/db mouse model of MI/RI was established, where anti-HMGB1 antibody and RAGE inhibitor (FPS-ZM1) were respectively injected after 10 min of reperfusion. The results showed that treatment with anti-HMGB1 significantly reduced the infarct size, serum LDH, and CK-MB level. Similar situations also occurred in mice administrated with FPS-ZM1, though the HMGB1 level was unchanged. Then, we found that treatment with anti-HMGB1 or FPS-ZM1 performed the same effects in suppressing the autophagy and apoptosis, as reflected by the results of lower LAMP2 and LC3B levels, increased Bcl-2 level, reduced BAX and caspase-3 levels. Moreover, the Pink1/Parkin levels were also inhibited at the same time. Collectively, this study indicates that the HMGB1-RAGE axis aggravated diabetic MI/RI via apoptosis and Pink1/Parkin mediated autophagy pathways, and inhibition of HMGB1 or RAGE contributes to alleviating those adverse situations. [ABSTRACT FROM AUTHOR]