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The continuous activation of macrophages play a critical role in the pathogenesis of cytokine storm (CS). Considering that CS results from the participation of multiple cytokines, the therapeutic effect of a single cytokine or its receptor-targeted blockade therapy remains uncertain. Melittin, which can systematically suppress the overexpression of proinflammatory mediators via inhibiting the mitogen-activated protein kinase and nuclear factor kappa-B pathways in activated macrophages, shows great potential in alleviating CS and acute inflammatory injury (AII). However, its clinical application is limited by its hemolytic activity, non-specific cytotoxicity and lack of targeting. In this study, a folic acid-modified and melittin stable-loaded solid lipid nanoparticle (Fa-MpG@LNP) with a core–shell structure was developed for CS control via targeted inhibition of the overproduction of proinflammatory mediators in activated macrophages with specific expression of folate receptor-β. The resultant Fa-MpG@LNP showed ideal physicochemical properties and stability, low hemolytic activity and non-specific cytotoxicity, and it can specifically bind to lipopolysaccharide (LPS)-stimulated macrophages and effectively reduce the elevated levels of proinflammatory mediators. After intravenous administration, the Fa-MpG@LNP accumulated at inflamed tissue and significantly downregulate the overproduction of proinflammatory cytokines in tissue-infiltrated macrophages, resulting in a significant decrease of cytokine concentration in inflamed tissue and serum in LPS-induced acute pneumonia mice, and finally alleviate AII with undetectable toxic side effects. These results indicate the clinical application potential of Fa-MpG@LNP in alleviating CS and its related symptoms. [Display omitted] • The folate-modified and melittin stable-loaded solid lipid nanoparticles Fa-MpG@LNP was successfully developed. • The Fa-MpG@LNP exhibits almost no hemolytic activity and non-specific cytotoxicity. • The Fa-MpG@LNP can significantly downregulate the overexpression of proinflammatory cytokines in activated macrophages. • The MpG@LNP can remarkably alleviate cytokine storm and acute inflammatory injury with negligible toxicities. [ABSTRACT FROM AUTHOR]

Casein kinase II (CK2) has recently emerged as a pivotal mediator in the propagation of inflammation across various diseases. Nevertheless, its role in the pathogenesis of sepsis remains unexplored. Here, we investigated the involvement of CK2 in sepsis progression and the potential beneficial effects of silmitasertib, a selective and potent CK2α inhibitor, currently under clinical trials for COVID-19 and cancer. Sepsis was induced by caecal ligation and puncture (CLP) in four-month-old C57BL/6OlaHsd mice. One hour after the CLP/Sham procedure, animals were assigned to receive silmitasertib (50 mg/kg/i.v.) or vehicle. Plasma/organs were collected at 24 h for analysis. A second set of experiments was performed for survival rate over 120 h. Septic mice developed multiorgan failure, including renal dysfunction due to hypoperfusion (reduced renal blood flow) and increased plasma levels of creatinine. Renal derangements were associated with local overactivation of CK2, and downstream activation of the NF-ĸB-iNOS-NO axis, paralleled by a systemic cytokine storm. Interestingly, all markers of injury/inflammation were mitigated following silmitasertib administration. Additionally, when compared to sham-operated mice, sepsis led to vascular hyporesponsiveness due to an aberrant systemic and local release of NO. Silmitasertib restored sepsis-induced vascular abnormalities. Overall, these pharmacological effects of silmitasertib significantly reduced sepsis mortality. Our findings reveal, for the first time, the potential benefits of a selective and potent CK2 inhibitor to counteract sepsis-induced hyperinflammatory storm, vasoplegia, and ultimately prolonging the survival of septic mice, thus suggesting a pivotal role of CK2 in sepsis and silmitasertib as a novel powerful pharmacological tool for drug repurposing in sepsis. [Display omitted] • CK2 is overactivated during CLP-induced sepsis, thus triggering NF-ĸB-iNOS-NO axis. • Silmitasertib attenuates CK2 activation, reducing local and systemic inflammatory storm. • Silmitasertib reduces NO levels, leading to improved renal perfusion and restoring responsiveness to vasoconstrictors. • Silmitasertib mitigates multiorgan dysfunction and enhances the survival of septic mice. [ABSTRACT FROM AUTHOR]

Cytokines regulate immune responses essential for maintaining immune homeostasis, as deregulated cytokine signaling can lead to detrimental outcomes, including inflammatory disorders. The antioxidants emerge as promising therapeutic agents because they mitigate oxidative stress and modulate inflammatory pathways. Antioxidants can potentially ameliorate inflammation-related disorders by counteracting excessive cytokine-mediated inflammatory responses. A comprehensive understanding of cytokine-mediated inflammatory pathways and the interplay with antioxidants is paramount for developing natural therapeutic agents targeting inflammation-related disorders and helping to improve clinical outcomes and enhance the quality of life for patients. Among these antioxidants, curcumin, vitamin C, vitamin D, propolis, allicin, and cinnamaldehyde have garnered attention for their anti-inflammatory properties and potential therapeutic benefits. This review highlights the interrelationship between cytokines-mediated disorders in various diseases and therapeutic approaches involving antioxidants. [Display omitted] • Cytokines, produced by immune cells, are pivotal players in many health conditions. • The imbalance of cytokines results in an excessive immune response. • Antioxidants provide therapeutic benefits in inflammatory conditions. • Antioxidants combined with radiotherapy can be an effective therapeutic option. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a significant global burden of morbidity and mortality, with lung injury being the primary cause of death in affected patients. The pathogenesis of lung injury, however, remains a complex issue. In recent years, the role of the immune system in lung injury has attracted extensive attention worldwide. Despite advancements in our understanding of various lung injury subtypes, significant limitations persist in both prevention and treatment. This review investigates the immunopathogenesis of ALI/ARDS, aiming to elucidate the pathological processes of lung injury mediated by dendritic cells (DCs), natural killer (NK) cells, phagocytes, and neutrophils. Furthermore, the article expounds on the critical contributions of gut microbiota, inflammatory pathways, and cytokine storms in the development of ALI/ARDS. [Display omitted] • Damage to lung tissue caused by immune cell dysfunction. • The ecological stability of intestinal flora is important in protecting lung tissue. • The inflammatory pathway plays a crucial role in regulating and mediating lung injury. • The impact of cytokine storm on lung injury is severe. [ABSTRACT FROM AUTHOR]

Stroke is a prevalent cerebrovascular condition with a global impact, causing significant rates of illness and death. Despite extensive research, the available treatment options for stroke remain restricted. Hence, it is crucial to gain a deeper understanding of the molecular mechanisms associated with the onset and advancement of stroke in order to establish a theoretical foundation for novel preventive and therapeutic approaches. NF-κB, also known as nuclear factor κB, is a transcription factor responsible for controlling the expression of numerous genes and plays a crucial role in diverse physiological processes. NF-κB is triggered and regulates neuroinflammation and other processes after stroke, promoting the generation of cytokine storms and contributing to the advancement of ischemic stroke (IS). Therefore, NF-κB could potentially play a vital role in stroke by regulating diverse pathophysiological processes. This review provides an overview of the functions of NF-κB in stroke and its governing mechanisms. In addition, our attention is directed towards various potential therapies that aim to inhibit the NF-κB signaling pathway in order to offer valuable insights for the advancement of innovative treatment approaches for stroke. [Display omitted] ● NF-κB plays a key role in neuroinflammation following ischemic stroke. ● NF-κB is involved in regulating the pathological mechanisms of ischemic stroke. ● A series of therapies exert neuroprotective effects on ischemic stroke via inhibiting NF-κB signalling pathway. [ABSTRACT FROM AUTHOR]

The use of natural compounds, such as curcumin, to treat infections caused by bacteria, viruses, fungi, parasites, inflammatory diseases, and various types of cancer is an active and dynamic area of research. Curcumin has a long history of use in the food industry, and there is currently a growing interest in its therapeutic applications. Numerous clinical trials have consistently shown that curcumin, a polyphenolic compound, is safe and well-tolerated even at high doses. There is no toxicity limit. However, the clinical efficacy of curcumin has been limited by its constraints. However, scientific evidence indicates that the use of adjuvants and carriers, such as nanoparticles, exosomes, micelles, and liposomes, can help overcome this limitation. The properties, functions, and human benefits of using nanocurcumin are well-supported by scientific research. Recent evidence suggests that nanocurcumin may be a beneficial therapeutic modality due to its potential to decrease gene expression and secretion of specific inflammatory biomarkers involved in the cytokinestorm seen in severe COVID-19, as well as increase lymphocyte counts. Nanocurcumin has demonstrated the ability to improve clinical manifestations and modulate immune response and inflammation in various autoinflammatory diseases. Additionally, its efficacy, affordability, and safety make it a promising replacement for residual cancer cells after tumor removal. However, further studies are necessary to evaluate the safety and efficacy of nanocurcumin as a new therapeutic in clinical trials, including appropriate dosage, frequency, and duration. In Brief • Curcumin has a wide range of pharmacological effects against a variety of pathologies with limitations such as poor aqueous solubility, extensive metabolism and rapid elimination. • Nanoscale techniques have been used to overcome these pharmacokinetic limitations, with encouraging results in both laboratory experiments and in vivo. • The observed decrease in gene expression and secretion of inflammatory biomarkers (implicated in the cytokine storm seen in severe COVID-19 cases), as well as the increase in lymphocyte count, have provided evidence for the therapeutic potential of nanocurcumin. [Display omitted] [ABSTRACT FROM AUTHOR]