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Integrative Analyses Identify a cGAS‐STING Pathway‐Driven Signature With Context‐Dependent Roles in Systemic Lupus Erythematosus
The cGAS‐STING pathway is emerging as an essential driver in systemic lupus erythematosus (SLE). Here, we characterize the key signature of cGAS‐STING pathway and its roles in SLE by leveraging large‐scale transcriptomics, cell‐based assays, and two lupus‐like mouse models. We identify a STING‐dependent gene signature termed M7core, enabling quantitative assessment of cGAS‐STING pathway activity in SLE. M7core reveals widespread cGAS‐STING pathway activation in 70.4% of 3,180 SLE samples and predicts therapeutic response to STING antagonists in 74.1% of patients, with higher activity indicating greater sensitivity. Across ten independent cohorts, M7core outperforms interferon‐stimulated gene signatures (mean AUROC = 0.876) and correlates with disease activity, anti‐dsDNA antibodies, lymphopenia, and lupus nephritis. Hydroxychloroquine treatment reduces M7core expression and its clinical associations. Importantly, in cGAS‐STING pathway‐driven lupus‐like mice, STING antagonist administration ameliorates multiorgan pathology and suppresses M7core genes participating in promoting inflammation, type I interferon, and cell death, including ZBP1—an established cGAS‐STING pathway facilitator. Notably, ZBP1 deficiency phenocopies blocking cGAS‐STING pathway‐mediated autoimmune pathology exacerbation in pristane‐induced lupus‐like mice, underscoring its context‐dependent roles in lupus pathogenesis. Together, these findings define M7core as a robust diagnostic and mechanistic biomarker and highlight the necessity of assessing pathway activity before initiating STING‐targeted therapy in SLE. Zhang et al. identify M7core, a critical cGAS‐STING pathway‐driven gene signature that is activated in most lupus patients’ blood and links to lupus disease severity, lymphopenia, and lupus nephritis. They further reveal the diagnostic and pathogenic characteristics of M7core and emphasize the importance of assessing pathway activity before initiating STING antagonist therapy in lupus.
Journal Article
Sting and The Police : walking in their footsteps
In this critical study, Aaron West, a music critic and professional musician, explores the cultural and musical impact of Stewart Copeland, Andy Summers, and Sting--the band known as The Police. West details the distinctive hybrid character of The Police's musical output, and he shows how the band were pioneers in music video, modern label marketing, global activism, and the internationalization of pop music.--From publisher description.
Book
Ginkgetin Alleviates Inflammation and Senescence by Targeting STING
Ginkgo biloba extract is reported to have therapeutic effects on aging‐related disorders. However, the specific component responsible for this biological function and its mechanism of action remain largely unknown. This study finds that Ginkgetin, an active ingredient of Ginkgo biloba extract, can alleviate cellular senescence and improve pathologies in multiple tissues of aging mice. To reveal the molecular mechanism of Ginkgetin's anti‐aging effect, a graph convolutional network‐based drug “on‐target” pathway prediction algorithm for prediction is employed. The results indicate that the cGAS‐STING pathway may be a potential target for Ginkgetin. Subsequent cell biological and biophysical data confirmed that Ginkgetin directly binds to the carboxy‐terminal domain of STING protein, thereby inhibiting STING activation and signal transduction. Furthermore, in vivo pharmacodynamic data showed that Ginkgetin effectively alleviates systemic inflammation in Trex1−/− mice and inhibits the abnormally activated STING signaling in aging mouse model. In summary, this study, utilizing an artificial intelligence algorithm combined with pharmacological methods, confirms STING serves as a critical target for Ginkgetin in alleviating inflammation and senescence. Importantly, this study elucidates the specific component and molecular mechanism underlying the anti‐aging effect of Ginkgo biloba extract, providing a robust theoretical basis for its therapeutic use. An artificial intelligence algorithm is utilized to predict and confirm that STING serves as a critical target for Ginkgetin, an active ingredient of Ginkgo biloba extract, combined with pharmacological methods. In vivo experiments indicate that Ginkgetin effectively alleviates systemic inflammation in Trex1−/− mice and inhibits the aging phenotype and the abnormally activated STING signaling in aging mice.
Journal Article
Clinical complications in envenoming by Apis honeybee stings: insights into mechanisms, diagnosis, and pharmacological interventions
Envenoming resulting from Apis honeybee stings pose a neglected public health concern, with clinical complications ranging from mild local reactions to severe systemic manifestations. This review explores the mechanisms underlying envenoming by honeybee sting, discusses diagnostic approaches, and reviews current pharmacological interventions. This section explores the diverse clinical presentations of honeybee envenoming, including allergic and non-allergic reactions, emphasizing the need for accurate diagnosis to guide appropriate medical management. Mechanistic insights into the honeybee venom’s impact on physiological systems, including the immune and cardiovascular systems, are provided to enhance understanding of the complexities of honeybee sting envenoming. Additionally, the article evaluates emerging diagnostic technologies and therapeutic strategies, providing a critical analysis of their potential contributions to improved patient outcomes. This article aims to provide current knowledge for healthcare professionals to effectively manage honeybee sting envenoming, thereby improving patient care and treatment outcomes.
Journal Article
Recent Trends in Wasp Nest Removal and Hymenoptera Stings in South Korea
To better understand the impact of social wasps on the health of people in South Korea, we analyzed requests to emergency services call centers for the removal of social wasp nests and the effect of Hymenoptera stings on human health between 2010 and 2014.There were 483,233 calls requesting removal of wasp nests and Hymenoptera stings caused 78,860 injuries and 49 deaths. The strong relationships between both the number of emergency calls and injuries, and urban density reflect the sensitivity of densely populated areas to potential threats from wasp and the increased awareness of the wasp nest removal service communicated by public education programs. We found that the removed nests belonged to 17 species of social wasp, with Polistes rothneyi koreanus Vecht and Vespa velutina nigrithorax du Buysson being the most prevalent. Problems associated with the invasive V. v. nigrithorax increased as the species became more widely distributed across the country and more abundant in urban areas. Increases in the incidence of sting injuries among males aged 40–69 between July and September were likely due to increased exposure during outdoor activities involving less-fit adults. In total, 1.5% of victims required hospitalization, of which 98.5% were treated as outpatients. Total medical costs associated with wasp stings over the 5-yr period were approximately 3.2 million USD. Although most wasp sting–related injuries were minor, some were serious, including fatalities, and were probably attributable to lack of education on wasp attack behavior.
Journal Article
Dual Covalent Targeting of STING Cysteines 292/309 Disrupts Functional Oligomerization and Enables Potent Antagonist Development
Dysregulated STING activation is a well‐established driver of pathological inflammation in autoimmune and autoinflammatory diseases, underscoring the need for targeted therapeutic inhibition. Current STING antagonist development has predominantly relied on phenotypic screening strategies. In contrast, we introduce a rational design strategy that directly disrupts STING signaling at its structural origin by covalently targeting cysteine residues within the C‐terminal domain (CTD) to prevent functional oligomerization. Through covalent warhead repurposing, we identified P005091, previously known as a USP7 inhibitor, as a STING antagonist that operates via a non‐classical nucleophilic displacement mechanism. Mechanistic investigation demonstrated that inhibition by P005091 depends on its concurrent engagement of Cys292 and Cys309, as evidenced by the fact that its activity to block STING oligomerization was abolished only by the C292A/C309A double mutation. Functionally, P005091 potently suppressed STING signaling and type I interferon responses in vitro and in vivo. Structure‐guided optimization yielded the advanced compounds NTP14 and NTP16, which exhibit markedly enhanced cellular potency and robust efficacy in ameliorating type I interferon‐driven pathology in multiple preclinical models, including DSS‐induced colitis. Our work establishes dual covalent CTD targeting as a transformative strategy for STING antagonist development and opens a new therapeutic avenue for quenching STING‐driven inflammation at its source. We report a rational design strategy for STING antagonists by dual covalent targeting of Cys292/309 in its C‐terminal domain, directly preventing functional oligomerization. Through covalent warhead repurposing, we identified P005091 and revealed its unique dual‐cysteine mechanism. Optimized leads NTP14/16 show potent cellular & in vivo efficacy, suppressing interferon responses and ameliorating colitis, offering a novel strategy against STING‐driven inflammation.
Journal Article
Sting Stories: Firsthand Experiences of Fish Envenomation Through a Small-Scale Questionnaire
Stings from venomous bony and cartilaginous fishes are known to cause extreme pain in humans, and with changing migratory patterns and distributions due to climate change, human interactions with venomous fishes may increase. Therefore, developing a better understanding of venomous fish stings and the associated pain can provide better solutions for first aid and treatments, particularly in areas or within populations with a higher risk of being stung. Using the results from an online questionnaire, this study discusses the perspectives of 121 people with direct experience of fish stings, exploring the contexts in which fish stings occurred, their firsthand experiences of pain, sting pathophysiology, experiences with medical treatments, and the long-term consequences of fish stings. This small-scale survey has proved successful for the exploration of fish sting experiences, and as such, an approach of this nature should be considered to better understand victim’s experiences with other painful animal stings.
Journal Article
Scorpion Envenomation
Each year more than a million cases of scorpion envenomation occur worldwide, causing substantial morbidity and, among children, a risk of death. This brief review discusses the effects and treatment of scorpion envenomation.
Every year, more than 1 million cases of scorpion envenomation are reported worldwide.
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Although the resultant mortality is lower than that from snake envenomation, there is substantial morbidity and, among children, a risk of death. Almost all systemic scorpion envenomation causes pain at the site of the sting. A mixed autonomic excitation (neuroexcitatory) syndrome that is unique to scorpions follows; the syndrome varies in type and severity according to the type of scorpion.
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In addition, a cytotoxic envenomation syndrome has been reported in areas of Iran in which
Hemiscorpius lepturus
is endemic.
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Epidemiology
Although millions of scorpion stings occur . . .
Journal Article
Advances in Jellyfish Sting Mechanisms and Treatment Strategies
Jellyfish stings, as one of the most prevalent forms of marine injury, have increasingly become a subject of concern. Despite their simple morphology and structure, jellyfish possess a complex venom composition that can inflict varying degrees of damage on multiple human physiological systems. Consequently, the clinical symptoms associated with jellyfish stings are highly intricate. Although antivenoms have been developed for certain jellyfish species (e.g., C. fleckeri), specific antivenoms targeting the mechanisms of most jellyfish venoms remain understudied. To effectively prevent, treat, and cure jellyfish stings, we adhere to the principle of knowing their nature and their reasons. It is essential to investigate the emission mechanism of jellyfish nematocysts and the composition of their venom. Understanding these factors is crucial for the development of targeted treatment strategies. This review delves into the venom emission mechanism of jellyfish stinging cells, the symptoms resulting from jellyfish stings, and the comprehensive treatment strategies post-sting. It offers a scientific reference for comprehending jellyfish stings and establishes a theoretical foundation for subsequent research endeavors.
Journal Article