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Introduction: The resolution of the skin's inflammatory response is only possible if its barrier function is restored. TRPV1 channel activation plays an important role during inflammation but the effect of this activation on the skin barrier under inflammatory conditions has not been clarified. We hypothesize that it could potentially aid the keratinocyte barrier by reducing inflammatory cytokine release and promoting tight junction development. Methods: To explore the role of TRPV1 activation in inflammation, we designed and optimized an in vitro model of keratinocytes with basal epidermal layer characteristics using HaCaT cells and TNFα to induce inflammation. Results: TNFα increased the gene expression of tight junction protein claudin 1 (CLDN1) by at least 2.60 ± 0.16-fold, in a concentration-dependent manner, over a 48 h period. The administration of a capsaicin pre-treatment reduced the CLDN1 expression to 1.51 ± 0.16-fold during the first 6 h after TNFα induction, whereas IL-8 cytokine release was reduced 0.64 ± 0.17-fold. After 48 h, CLDN1 protein levels increased by a factor of 6.57 ± 1.39 compared to cells only treated with TNFα. Discussion: These results suggest that activation of TRPV1 by capsaicin can potentiate the increase in CLDN1 expression and CLDN1 protein synthesis induced by TNFα in cultured keratinocytes, while reducing the release of IL-8. [ABSTRACT FROM AUTHOR]

Background: Skin photoaging induced by ultraviolet A (UVA) and ultraviolet B (UVB) radiation manifests as skin roughness, desquamation, pigmentation, and wrinkle formation. Current treatments, such as sunscreen, hormones, and antioxidants, have limitations and side effects. Traditional Chinese Medicine Hibisci Mutabilis Folium (HMF), or Mu-Fu-Rong-Ye in Chinese name, refers to the dried leaves of the plant Hibiscus mutabilis L., which belongs to the Malvaceae family. It has been used traditionally to treat acute mastitis, parotitis, neurodermatitis, burns. The reported activities of HMF include antiinflammatory and anti-oxidant effects. However, the therapeutic potential of HMF in preventing and treating UV-induced skin photoaging remains unexplored. Objective: This study aimed to investigate the protective effects of HMF extract (EHMF) against UV-induced skin photoaging and the underlying mechanisms of action, by using network pharmacology and experimental verification. Methods: Network pharmacology was employed to identify the effective chemical components of EHMF. Potential targets were identified via PPI network analysis. Representative compounds were characterized using UPLCMS/MS. In vitro validation involved assessing HaCaT cell viability, observing live/dead cell staining through fluorescence microscopy, and measuring inflammatory factors using ELISA. For in vivo validation, a UV-induced skin photoaging mice model was treated transdermally with EHMF or Methotrexate daily for 7 days. Dermatitis severity, skin morphology, and collagen fiber pathology were evaluated. Inflammatory cytokine and protein expression in dorsal skin lesions was confirmed using Elisa Kits, Western blot and immunohistochemistry. Results: A total of 22 active ingredients of EHMF were identified. GO enrichment and KEGG pathway analyses revealed a focus on inflammatory signaling pathways. In vitro experiments showed that EHMF significantly reduced UV-induced inflammatory factors in HaCaT cells and improved cell survival rates. In vivo, EHMF alleviated back skin lesions in UV-exposed mice, reducing epidermal and dermal thickening and pathological inflammatory cell infiltration. It also decreased abnormal MMP-9 expression and collagen fiber proliferation, along with levels of inflammatory factors like TNF-α, IL-6, IL-17, and EGFR. Western blot and immunohistochemistry results indicated that the over-activation of the AKTSTAT3 signaling pathway was inhibited. Conclusion: EHMF effectively reduced UV-induced skin damage, inflammation, and wrinkles, providing strong support for its clinical application as a dermatological agent. [ABSTRACT FROM AUTHOR]

Introduction: Atherosclerosis (AS) is considered the underlying cause of many diseases, particularly cardiovascular and cerebrovascular diseases. Inulin, a type of fructan, has shown potential in improving atherosclerosis, although there are conflicting findings. It is hypothesized that the polymerization degree of inulin may largely influence its therapeutic effectiveness. Therefore, this study aimed to investigate the effects and mechanisms of short-chain and long-chain inulin in AS. Methods: ApoE−/− mice fed a high fat diet (HFD) were used to establish an atherosclerosis model. These mice received daily oral administration of either short-chain or long-chain inulin for 12 weeks. Plasma lipid metabolism-related indices were measured using biochemical analysis, and plasma immunological indices were analyzed via ELISA. The aorta, aortic root regions, liver tissue, adipose tissue, and colon tissue were examined through various staining techniques, including ORO staining, hematoxylin and eosin staining, Alcian blue staining, and immunofluorescent or immunohistochemical assays. Microbiome analysis was conducted in the cecal content. Results: The results indicated that both short-chain and long-chain inulin substantially reduced the formation of atherosclerotic plaques. Inulin also improved plasma lipid concentrations and hepatic lipid metabolism, and partially alleviated both localized (atherosclerotic lesions) and systemic inflammation. Short-chain inulin was more effective than long-chain inulin in reducing atherosclerotic plaques formation, enhancing lipid metabolism and reducing inflammation. Additionally, both types of inulin showed similar effectiveness in enhancing intestinal epithelial barrier integrity, gut microbiota composition and functionality. Conclusion: These findings suggest that inulin has a protective role against atherosclerosis by enhancing lipid metabolism, reducing inflammation, and improving intestinal barrier and gut microbiota. As a dietary intervention, shortchain inulin is more effective than long-chain inulin, offering clinical implications for using inulin as a therapeutic agent for atherosclerosis. [ABSTRACT FROM AUTHOR]

Introduction: Nuclear factor kappa B (NF-κB) is a key regulator of immune and inflammatory responses. Glucocorticoid drugs (GC) act through the glucocorticoid receptor (GR) as immunosuppressant also in pediatric patients inhibiting NF-κB activity. The long non-coding RNA GAS5 interacts with the GR, influencing GC activity. No data on the role of GAS5 on GR-dependent inhibition of NF-κB activity have been published. Methods: This study investigated the impact of GAS5 on NF-κB activity in HeLa cells overexpressing GAS5, both under basal conditions and during GC treatment. The study used EMSA, RNA-immunoprecipitation (RIP), Western blotting, and bioinformatic analyses to assess NF-κB DNA binding, GAS5-p65 interaction, and NF-κB signaling pathway modulation. Results: GAS5 overexpression increased NF-κB DNA binding activity in untreated cells. RNA-IP confirmed a direct interaction between GAS5 and the NF-κB subunit p65, suggesting a potential regulatory mechanism. GAS5 overexpression led to downregulation of NF-κB target genes, TNF-a, and NR3C1. GC treatment reduced NF-κB DNA binding activity in GAS5-overexpressing cells, indicating a potential synergistic effect. Furthermore, GAS5 overexpression increased IκB levels and reduced p-p65/pan-p65 levels during GC treatment. Discussion: GAS5 appears to modulate NF-κB activity in a complex manner, influencing both basal and GC-induced signaling. The interaction between GAS5, GCs, and NF-κB is multi-faceted, and further research is needed to fully elucidate the underlying mechanisms. These findings suggest that GAS5 could be a potential target for personalized therapy, particularly in pediatric patients with inflammatory conditions. [ABSTRACT FROM AUTHOR]

Trisomy 21, characterized by the presence of an additional chromosome 21, leads to a set of clinical features commonly referred to as Down syndrome (DS). The pathological phenotypes observed in DS are caused by a combination of factors, such as mitochondrial dysfunction, neuroinflammation, oxidative stress, disrupted metabolic patterns, and changes in protein homeostasis and signal transduction, and these factors collectively induce neurological alterations. In DS, the triplication of chromosome 21 and the micronuclei arising from the missegregation of chromosomes are closely associated with inflammation and the development of redox imbalance. Autophagy, an essential biological process that affects cellular homeostasis, is a powerful tool to facilitate the degradation of redundant or dysfunctional cytoplasmic components, thereby enabling the recycling of their constituents. Targeting the autophagy process has been suggested as a promising method to balance intracellular inflammation and oxidative stress and improve mitochondrial dysfunction. In this review, we summarize the role of autophagy in regulating inflammation and redox homeostasis in DS and discuss their crosslinks. A comprehensive elucidation of the roles of autophagy in DS offers novel insights for the development of therapeutic strategies aimed at aneuploidy-associated diseases. [ABSTRACT FROM AUTHOR]

Background: Salidroside (SDS), a phenylpropanoid glycoside, is an antioxidant component isolated from the traditional Chinese medicine Rhodiola rosea and has multifunctional bioactivities, particularly possessing potent hepatoprotective function. Non-alcoholic steatohepatitis (NASH) is one of the most prevalent chronic liver diseases worldwide, but it still lacks efficient drugs. This study aimed to assess the preventive and therapeutic effects of SDS on NASH and its underlying mechanisms in a mouse model subjected to a methionine- and choline-deficient (MCD) diet. Methods: C57BL/6J mice were fed an MCD diet to induce NASH. During or after the formation of the MCD-induced NASH model, SDS (24 mg/kg/day) was supplied as a form of diet for 4 weeks. The histopathological changes were evaluated by H&E staining. Oil Red O staining and Sirius Red staining were used to quantitatively determine the lipid accumulation and collagen fibers in the liver. Serum lipid and liver enzyme levels were measured. The morphology of autophagic vesicles and autophagosomes was observed by transmission electron microscopy (TEM), and qRT-PCR and Western blotting were used to detect autophagy-related factor levels. Immunohistochemistry and TUNEL staining were used to evaluate the apoptosis of liver tissues. Flow cytometry was used to detect the composition of immune cells. ELISA was used to evaluate the expression of serum inflammatory factors. Transcript-proteome sequencing, molecular docking, qRT-PCR, and Western blotting were performed to explore the mechanism and target of SDS in NASH. Results: The oral administration of SDS demonstrated comprehensive efficacy in NASH. SDS showed both promising preventive and therapeutic effects on NASH in vivo. SDS could upregulate autophagy, downregulate apoptosis, rebalance immunity, and alleviate inflammation to exert anti-NASH properties. Finally, the results of transcript-proteome sequencing, molecular docking evaluation, and experimental validation showed that SDS might exert its multiple effects through targeting PPARα. Conclusion: Our findings revealed that SDS could regulate liver autophagy and apoptosis, regulating both innate immunity and adaptive immunity and alleviating inflammation in NASH prevention and therapy via the PPAR pathway, suggesting that SDS could be a potential anti-NASH drug in the future. [ABSTRACT FROM AUTHOR]

Metabolic compromise is crucial in aggravating age-associated chronic inflammation, oxidative stress, mitochondrial damage, increased LDL and triglycerides, and elevated blood pressure. Excessive adiposity, hyperglycemia, and insulin resistance due to aging are associated with elevated levels of damaging free radicals, inducing a proinflammatory state and hampering immune cell activity, leading to a malfunctioning cardiometabolic condition. The age-associated oxidative load and redox imbalance are contributing factors for cardiometabolic morbidities via vascular remodelling and endothelial damage. Recent evidence has claimed the importance of gut microbiota in maintaining regular metabolic activity, which declines with chronological aging and cardiometabolic comorbidities. Genetic mutations, polymorphic changes, and environmental factors strongly correlate with increased vulnerability to aberrant cardiometabolic changes by affecting key physiological pathways. Numerous studies have reported a robust link between biological aging and cardiometabolic dysfunction. This review outlines the scientific evidence exploring potential mechanisms behind the onset and development of cardiovascular and metabolic issues, particularly exacerbated with aging. [ABSTRACT FROM AUTHOR]

Introduction: Ischemic stroke (IS) is a serious threat to human life and health, and cerebral ischemia/reperfusion injury (CIRI) exacerbates IS by enhancing neuroinflammation and oxidative stress. Sweet tea (ST) comprises several bioactive components, such as phlorizin, trilobatin, and phloretin, with diverse pharmacological activities. However, it remains uncertain whether ST can confer protection against CIRI. In this study, we aimed to investigate the impact and potential underlying mechanism of ST in the context of CIRI. Methods: CIRI model were established in male sprague dawley (SD) rats. The neurobehavioral assessment, the volume of cerebral infarction and the morphology of neurons were measured to complete the preliminary pharmacodynamic study. The therapeutic targets and pathways of ST on IS were obtained by protein-protein interaction, molecular docking and Metascape database. The predicted results were further verified in vivo. Results: Our results revealed that ST treatment significantly ameliorated brain damage in rats subjected to CIRI by mitigating mitochondrial oxidative stress and neuroinflammation. Additionally, we identified the PI3K/AKT/NF-κB pathway and the NLRP3-mediated pyroptosis axis as crucial processes, with molecular docking suggested direct interactions between the main compounds of ST and NLRP3. Conclusion: ST safeguards against CIRI-induced neuronal loss, neuroinflammation and oxidative stress through the inhibition of the PI3K/AKT/NF-κB pathway and the regulation of NLRP3-mediated pyroptosis. [ABSTRACT FROM AUTHOR]

Pancreatic diseases such as pancreatitis and pancreatic cancer represent significant health challenges characterized by high mortality rates and limited survival durations. Autophagy, a crucial cellular catabolic process, has emerged as a focal point in understanding various pathological conditions, spanning inflammation-related disorders to malignant neoplasms. This comprehensive review aims to elucidate the biological intricacies of autophagy and its pivotal roles within two extensively researched pancreatic diseases, namely pancreatitis and pancreatic cancer, drawing upon recent scholarly contributions. The discussion will delve into the nuanced mechanisms underlying autophagy’s involvement in these diseases, shedding light on its potential as a therapeutic target. Furthermore, the review will explore cutting-edge therapeutic interventions leveraging autophagy regulation for managing pancreatitis and pancreatic cancer. Through this analysis, we endeavor to offer novel insights into the pathophysiology of pancreatic disorders and contribute to the development of innovative therapeutic modalities in this challenging clinical domain. [ABSTRACT FROM AUTHOR]

Introduction: Ischemic stroke (IS) is a serious threat to human life and health, and cerebral ischemia/reperfusion injury (CIRI) exacerbates IS by enhancing neuroinflammation and oxidative stress. Sweet tea (ST) comprises several bioactive components, such as phlorizin, trilobatin, and phloretin, with diverse pharmacological activities. However, it remains uncertain whether ST can confer protection against CIRI. In this study, we aimed to investigate the impact and potential underlying mechanism of ST in the context of CIRI. Methods: CIRI model were established in male sprague dawley (SD) rats. The neurobehavioral assessment, the volume of cerebral infarction and the morphology of neurons were measured to complete the preliminary pharmacodynamic study. The therapeutic targets and pathways of ST on IS were obtained by protein-protein interaction, molecular docking and Metascape database. The predicted results were further verified in vivo. Results: Our results revealed that ST treatment significantly ameliorated brain damage in rats subjected to CIRI by mitigating mitochondrial oxidative stress and neuroinflammation. Additionally, we identified the PI3K/AKT/NF-κB pathway and the NLRP3-mediated pyroptosis axis as crucial processes, with molecular docking suggested direct interactions between the main compounds of ST and NLRP3. Conclusion: ST safeguards against CIRI-induced neuronal loss, neuroinflammation and oxidative stress through the inhibition of the PI3K/AKT/NF-κB pathway and the regulation of NLRP3-mediated pyroptosis. [ABSTRACT FROM AUTHOR]

As a novel class of smart biomaterials with promising potentials, metal-organic frameworks (MOFs) are widely utilized in the field of biomedicine. Current researches indicate that the therapeutic strategies for osteoarthritis (OA) are highly limited to achieving symptom improvement and reducing both pain and inflammation. Together, the introduction of MOFs into the treatment of OA holds the potential to offer significant benefits. This is because MOFs not only have intrinsic biological activities, but also act as carriers to facilitate controlled drug delivery and prolong the duration in the management of OA. This paper presents a review of the recent studies that have explored the potential usage of MOFs as drugs or carriers in the treatment of OA, which also examines the progress of MOFs in tissue engineering for the treatment of OA. These studies are anticipated to not only enhance the comprehension of MOFs but also provide strong evidence in favor of their utilization in the treatment of OA. [ABSTRACT FROM AUTHOR]

Ion channels play an important role in mediating pain through signal transduction, regulation, and control of responses, particularly in neuropathic pain. Transient receptor potential channel superfamily plays an important role in cation permeability and cellular signaling. Transient receptor potential channel Melastatin 2 (TRPM2) subfamily regulates Ca2+ concentration in response to various chemicals and signals from the surrounding environment. TRPM2 has a role in several physiological functions such as cellular osmosis, temperature sensing, cellular proliferation, as well as the manifestation of many disease processes such as pain process, cancer, apoptosis, endothelial dysfunction, angiogenesis, renal and lung fibrosis, and cerebral ischemic stroke. Toll-like Receptor 4 (TLR4) is a critical initiator of the immune response to inflammatory stimuli, particularly those triggered by Lipopolysaccharide (LPS). It activates downstream pathways leading to the production of oxidative molecules and inflammatory cytokines, which are modulated by basal and store-operated calcium ion signaling. The cytokine production and release cause an imbalance of antioxidant enzymes and redox potential in the Endoplasmic Reticulum and mitochondria due to oxidative stress, which results from TLR-4 activation and consequently induces the production of inflammatory cytokines in neuronal cells, exacerbating the pain process. Very few studies have reported the role of TRPM2 and its association with Toll-like receptors in the context of neuropathic pain. However, the molecular mechanism underlying the interaction between TRPM2 and TLR-4 and the quantum of impact in acute and chronic neuropathic pain remains unclear. Understanding the link between TLR-4 and TRPM2 will provide more insights into pain regulation mechanisms for the development of new therapeutic molecules to address neuropathic pain. [ABSTRACT FROM AUTHOR]

The main bioactive components of agarwood, derived from Aquilaria sinensis, include sesquiterpenes, 2-(2-phenethyl) chromone derivatives, aromatic compounds, and fatty acids, which typically exert anti-inflammatory, antioxidant, immune-modulating, hypoglycemic, and antitumor pharmacological effects in the form of essential oils. Agarwood tree leaves, rich in flavonoids, 2-(2-phenethyl) chromone compounds, and flavonoid compounds, also exhibit significant anti-inflammatory, antioxidant, and immune-modulating effects. These properties are particularly relevant to the treatment of periodontitis, given that inflammatory responses, oxidative stress, and immune dysregulation are key pathological mechanisms of the disease, highlighting the substantial potential of agarwood and agarwood tree leaves in this therapeutic area. However, the low solubility and poor bioavailability of essential oils present challenges that necessitate the development of improved active formulations. In this review, we will introduce the bioactive components, extraction methods, pharmacological actions, and clinical applications of agarwood and agarwood tree leaves, analyzing its prospects for the treatment of periodontitis. [ABSTRACT FROM AUTHOR]

Hesperidin (Hes) protects different organs from damage by acting as a potent antioxidant and anti-inflammatory. This study aims to evaluate the gastroprotective effects of free hesperidin and its chitosan nanoparticles (HNPs) against ethanol-induced gastric ulcers in rats, hypothesizing that HNPs will enhance bioavailability and therapeutic efficacy due to improved solubility and targeted delivery. HNPs were synthesized via ion gelation and characterized using TEM, SEM, and zeta potential analyses. Key assessments included gastric acidity, histological analysis, and markers of inflammation, oxidative stress, and apoptosis. HNPs significantly decreased gastric acidity, reduced inflammatory and apoptotic markers, and enhanced antioxidant enzyme activities compared to free hesperidin and esomeprazole. Furthermore, Sirt-1, PGC-1α, HO-1, and FOXO1 gene expression were also evaluated. HNPs raised Sirt-1, PGC-1α, HO-1, and downregulated FOXO1, and they suppressed the activities of NF-κB p65, COX-2, IL-1β, CD86, FOXO1 P53, and caspase-3 and increased Sirt-1 activity. HNPs treatment notably restored antioxidant enzyme activity, reduced oxidative stress and inflammatory markers, and improved histological outcomes more effectively than free hesperidin and esomeprazole. These results indicate that chitosan nanoparticles significantly enhance the gastroprotective effects of hesperidin against ethanol-induced gastric ulcers, potentially offering a more effective therapeutic strategy. Further research should explore the clinical applications of HNPs in human subjects. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is a major pathological basis of coronary heart disease. However, the currently available medications are unable to effectively reduce the incidence of cardiovascular events in the majority of patients with AS. Therefore, naringin has been attracting considerable attention owing to its anti-AS effects. Naringin can inhibit the growth, proliferation, invasion, and migration of vascular smooth muscle cells, ameliorate endothelial cell inflammation and apoptosis, lower blood pressure, halt the cell cycle at the G1 phase, and impede growth via its antioxidant and free radical scavenging effects. These activities suggest the potential anti-AS effects of naringin. In this review article, we comprehensively summarized the latest findings on the anti-AS effects of naringin and their underlying mechanisms, providing a crucial reference for future research on the anti-AS potential of this agent. [ABSTRACT FROM AUTHOR]

Introduction: In this study, we aimed to examine the effects of chotosan, a traditional Japanese botanical drug, and its active component, Uncaria hook, on anxiety-like behaviors induced by systemic inflammation in mice. Methods: To induce systemic inflammation, the mice were treated with lipopolysaccharide (LPS), a bacterial endotoxin. Prior to LPS treatment, the mice were administered chotosan or Uncaria hook orally each day for 14 days. Anxiety-like behavior of the mice was evaluated using the light--dark test 24 h after LPS treatment. Results: Repeated administration of chotosan prevented anxiety-like behavior in both normal and LPS-treated mice. Similarly, administration of Uncaria hook suppressed LPS-induced anxiety-like behavior in mice. Furthermore, treatment with tandospirone, a 5-HT1A receptor agonist, alleviated anxiety-like behavior in mice, whereas treatment with DOI, a 5-HT2A receptor agonist, enhanced anxietylike behavior in mice. LPS treatment significantly increased serotonin (5-HT)2A receptor mRNA expression in the frontal cortex, whereas 5-HT1A receptor mRNA expression remained unchanged in the hippocampus. Notably, chotosan significantly suppressed the mRNA expression of 5-HT2A receptor. Discussion: These findings indicate that chotosan exerts anxiolytic-like effects in the context of inflammation-induced anxiety, potentially mediated by the inhibition of 5-HT2A receptor hyperfunction in LPS-treated mice. Consequently, we postulate that chotosan may be effective in managing inflammation-induced anxiety-like behaviors. [ABSTRACT FROM AUTHOR]

Background: Intervertebral disc degeneration (IDD) can lead to disc herniation and spinal instability, sometimes requiring surgical intervention. Currently, estrogen has a potential protective effect on IDD, and estrogen is associated with an increased risk of some cancers, such as breast and endometrial cancer. Therefore, it is important to identify natural compounds that estrogen analogues treat IDD while reducing the risk of tumor development. Objective: This study aims to explore a natural metabolic treatment strategy by targeting CRISP2 with the natural compound Hesperidin to mimic the protective effects of estrogen on IDD and reduce the risk of tumor development. Methods: Microarray data from healthy volunteers and IDD patients were extracted from the Gene Expression Omnibus (GEO) database, and RNA sequencing and clinical data from various cancer types were analyzed. Differentially expressed genes (DEGs) were identified using the Bioconductor Limma package, followed by principal component analysis, volcano plot, and heatmap visualization. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, CIBERSORT and ssGSEA immune cell infiltration assessments, survival analysis, metabolite enrichment analysis, and molecular docking were performed. Hesperidin's interaction with CRISP2 was further validated through molecular docking and experimental studies. Results: Hesperidin significantly reduced the expression of CRISP2, iNOS, and COX2 in IDD models, decreased reactive oxygen species (ROS) and apoptosis, and diminished inflammatory markers. CIBERSORT and ssGSEA analyses revealed a correlation between CRISP2 and immune cell infiltration. Survival analysis demonstrated that CRISP2 expression levels were associated with patient survival across various cancer types. Hesperidin was found to mimic estrogen's effects on IDD and reduce tumor progression. Cell culture and experimental validation confirmed Hesperidin's protective effects on nucleus pulposus cells (NPCs). Conclusion: Hesperidin, as a potential natural metabolic regulator, not only has therapeutic effects on IDD but may also synergize with estrogen therapy to promote spinal health without increasing cancer risk. This study presents a new clinical approach for IDD treatment and lays the foundation for further drug development and experimental research. [ABSTRACT FROM AUTHOR]

Background: Kawasaki disease (KD) is a self-limiting and acute systemic vasculitis of unknown etiology, mainly affecting children. Ferulic acid (FA), a natural phenolic substance, has multiple pharmacological properties, including antiinflammatory, anti-apoptosis, and anti-fibrosis, and so on. So far, the protective effects of FA on KD have not been explored. Methods: In this study, we established Candida albicans water soluble fraction (CAWS)-induced mouse coronary artery vasculitis of KD model and the tumor necrosis factor α (TNF-α)-induced human umbilical vein endothelial cells (HUVECs) injury model to investigate the anti-inflammatory and anti-apoptosis effects of FA on KD, and try to elucidate the underlying mechanism. Results: Our in vivo results demonstrated that FA exerted anti-inflammatory effects on KD by inhibiting the infiltration of CD45-positive leukocytes and fibrosis around the coronary artery. Additionally, FA downregulated the levels of inflammatory and chemotactic cytokines, alleviated splenomegaly, and exhibited anti-apoptotic effects on KD by reducing TUNEL-positive cells, downregulating BAX expression, and upregulating BCL-2 expression. In addition, Our in vitro findings showed that FA could effectively inhibit TNF-α-induced HUVEC inflammation like NF-κB inhibitor QNZ by downregulating the expression of pro-inflammatory cytokines as well as attenuated TNF-α-induced HUVEC apoptosis by reducing apoptotic cell numbers and the BAX/BCL-2 ratio, which could be reversed by the AMPK inhibitor compound c (CC). The further mechanistic study demonstrated that FA could restrain vascular endothelial cell inflammation and apoptosis in KD through activating the AMPK/mTOR/NF-κB pathway. However, FA alone is hard to completely restore KD into normal condition. Conclusion: In conclusion, FA has potential protective effects on KD, suggesting its promising role as an adjuvant for KD therapy in the future. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is the most prevalent cartilage degenerative and low-grade inflammatory disease of the whole joint. However, there are currently no FDAapproved drugs or global regulatory agency-approved treatments OA disease modification. Therefore, it’s essential to explore novel effective therapeutic strategies for OA. In our study, we investigated the effects of AFK-PD, a novel pyridone agent, on the development of OA induced by destabilization of the medial meniscus (DMM) in vivo, and its impact on the function of chondrocytes treated with IL-1β in vitro. Our results demonstrated AFK-PD alleviated OA progression through inhibiting cartilage degeneration, articular inflammation and osteophyte formation. Notably, AFK-PD inhibited chondrocyte inflammation and synovial macrophage M1 polarization, leading to the attenuation of articular inflammation. Additionally, AFK-PD promoted chondrocyte anabolism while mitigating catabolism and apoptosis, effectively inhibiting cartilage degeneration. Mechanistically, AFK-PD suppressed the expression of key signaling molecules involved in the MAPK pathway, such as p-ERK1/2 and p-JNK, as well as the NF-κB signaling molecule p-p65, in IL-1βinduced chondrocytes. These findings suggest AFK-PD ameliorates the development of OA by protecting chondrocyte functions and inhibiting articular inflammation in chondrocytes and synovial macrophages. Overall, our study highlights AFK-PD as a promising therapeutic candidate for the treatment of OA. [ABSTRACT FROM AUTHOR]

Programmed cell death (PCD) is essential for cellular homeostasis and defense against infections, with inflammatory forms like pyroptosis and necroptosis playing significant roles in cancer. Pyroptosis,mediated by caspases and gasdermin proteins, leads to cell lysis and inflammatory cytokine release. It has been implicated in various diseases, including cancer, where it can either suppress tumor growth or promote tumor progression through chronic inflammation. Necroptosis, involving RIPK1, RIPK3, and MLKL, serves as a backup mechanism when apoptosis is inhibited. In cancer, necroptosis can enhance immune responses or contribute to tumor progression. Both pathways have dual roles in cancer, acting as tumor suppressors or promoting a pro-tumorigenic environment depending on the context. This review explores the molecular mechanisms of pyroptosis and necroptosis, their roles in different cancers, and their potential as therapeutic targets. Understanding the context-dependent effects of these pathways is crucial for developing effective cancer therapies. [ABSTRACT FROM AUTHOR]

Daphnetin exerts certain pharmacological function on a variety of diseases, but its role in diabetic cognitive dysfunction has not been elucidated. In this study, we carried a series of pharmacological studies of GLP-1R with daphnetin. In rats and PC12 cells, we found that daphnetin could alleviate diabetic cognitive dysfunction and increase the expression level of GLP-1R. Additionally, the anti-diabetic cognitive dysfunction effect of DAP was accompanied by the inhibition of inflammation and oxidative stress. Further in-depth studies demonstrated that the inhibition GLP-1R enhanced the protective effect of daphnetin, whilst, the overexpression of GLP-1R weakened the protective effect of daphnetin. These results indicated that daphnetin protects diabetes cognitive dysfunction by regulating GLP-1R-mediated inflammation and oxidative stress, act as a GLP-1R agonist. The study further demonstrated that daphnetin has great value in preventing cognitive dysfunction in type 2 diabetes, and GLP-1R is a key potential target for the treatment of related diseases. [ABSTRACT FROM AUTHOR]

Background: Dexmedetomidine (DEX) is a commonly used sedative in the intensive care unit and has demonstrated cardioprotective properties against ischemia-reperfusion injury in preclinical studies. However, the protective effects of early treatment of DEX in patients with acute myocardial infarction (AMI) and its underlying mechanism are still not fully understood. This study aims to investigate the association between early DEX treatment and in-hospital mortality in patients with AMI, and to explore the potential mediating role of white blood cell (WBC) reduction in this relationship. Methods: A retrospective cohort analysis was conducted using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients with AMI were divided into the DEX and non-DEX group, based on whether they received DEX treatment in the early stage of hospitalization. The primary outcome measured was in-hospital mortality. The study evaluated the association between DEX use and in-hospital mortality using the Kaplan-Meier (KM) method and Cox proportional hazards model. Additionally, 1:1 propensity score matching (PSM) was conducted to validate the results. Furthermore, causal mediation analysis (CMA) was utilized to explore potential causal pathways mediated by WBC reduction between early DEX use and the primary outcome. Results: This study analyzed data from 2,781 patients, with 355 in the DEX group and 2,426 in the non-DEX group. KM survival analysis revealed a significantly lower in-hospital mortality rate in the DEX group compared to the non-DEX group. After adjusting for multiple confounding factors, the Cox regression model demonstrated a significant positive impact of DEX on the risk of in-hospital mortality in patients with AMI, with hazard ratios (HR) of 0.50 (95% confidence interval (CI): 0.35-0.71, p < 0.0001). PSM analysis confirmed these results, showing HR of 0.49 (95% CI: 0.31-0.77, p = 0.0022). Additionally, CMA indicated that 13.7% (95% CI: 1.8%-46.9%, p = 0.022) of the beneficial effect of DEX on reducing in-hospital mortality in patients with AMI was mediated by the reduction in WBC. Conclusion: The treatment of DEX was associated with a lower risk of in-hospital mortality in patients with AMI, potentially due to its anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a chronic degenerative disease mainly characterized by cartilage damage and synovial inflammation. Si Miao Powder, an herbal formula, was recorded in ancient Chinese medicine prescription with excellent anti-inflammatory properties. Based on the classical formula, the modified Si Miao Powder (MSMP) was developed with the addition of two commonly Chinese orthopedic herbs, which had the efficacy of strengthening the therapeutic effect for OA. Methods: In the in vivo experiments, thirty-six 8-week-old male C57BL/6mice were randomly divided into six groups: sham group, OA group, celecoxib group, low-MSMP group, middle-MSMP group, and high-MSMP group. OA mice were constructed by destabilization of medial meniscus (DMM) and treated with MSMP granules or celecoxib by gavage. The effects of MSMP on cartilage, synovitis and inflammatory factor of serum were tested. For in vitro experiments, control serum and MSMP-containing serum were prepared from twenty-five C57BL/6 mice. Macrophages (RAW264.7 cells) were induced by lipopolysaccharide (LPS) and then treated with MSMP-containing serum. The expression of inflammatory factors and the change of the NF-κB pathway were tested. Results: In vivo, celecoxib and MSMP alleviated OA progression in the treated groups compared with OA group. The damage was partly recovered in cartilage, the synovial inflammatory were reduced in synovium, and the concentrations of IL-6 and TNF-α were reduced and the expression of IL-10 was increased in serum. The function of the middle MSMP was most effective for OA treatment. The results of in vitro experiments showed that compared with the LPS group, the MSMP-containing serum significantly reduced the expression levels of pro-inflammatory (M1-type) factors, such as CD86, iNOS, TNF-α and IL-6, and promoted the expression levels of anti-inflammatory (M2-type) factors, such as Arg1 and IL-10. The MSMP-containing serum further inhibited NF-κB signaling pathway after LPS induction. Conclusion: The study demonstrated that MSMP alleviated OA progression in mice and MSMP-containing serum modulated macrophage M1/M2 phenotype by inhibiting the NF-κB signaling pathway. Our study provided experimental evidence and therapeutic targets of MSMP for OA treatment. [ABSTRACT FROM AUTHOR]

Background and Aim: Increased oxidative stress within the airways is associated to epithelial damage and amplification of inflammatory responses that in turn contribute to Chronic Obstructive Pulmonary Disease (COPD) progression. This study was aimed to identify whether a new formulation of N-acetylcisteine (NAC), carnitine, curcumin and B2 vitamin could counteract oxidative stress and downstream pro-inflammatory events promoted by cigarette smoke extract (CSE) exposure in primary bronchial epithelial cells (PBEC), both submerged/ undifferentiated (S-PBEC) and cultured at the air-liquid interface (ALI-PBEC). Methods: PBEC were exposed to CSE with/without the new formulation or NAC alone and ROS production, IL-8 and IL-6 gene expression and protein release were evaluated. Results: CSE increased ROS, IL-8 and IL-6 gene expression and protein release and the new formulation counteracted these effects. NAC alone was not effective on IL-8 and IL-6 release. The effects of a similar nutraceutical formulation were evaluated in COPD patients treated for six months. The results showed that the treatment reduced the concentration of IL-8 in nasal wash and improved quality of life. Conclusion: The tested formulation, exerting antioxidant and anti-inflammatory effects, can preserve airway epithelial homeostasis and improve clinical symptoms in COPD. [ABSTRACT FROM AUTHOR]

Mitochondria play a significant and varied role in inflammatory lung disorders. Mitochondria, known as the powerhouse of the cell because of their role in producing energy, are now recognized as crucial regulators of inflammation and immunological responses. Asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome are characterized by complex interactions between immune cells, inflammatory substances, and tissue damage. Dysfunctional mitochondria can increase the generation of reactive oxygen species (ROS), triggering inflammatory pathways. Moreover, mitochondrial failure impacts cellular signaling, which in turn affects the expression of molecules that promote inflammation. In addition, mitochondria have a crucial role in controlling the behavior of immune cells, such as their activation and differentiation, which is essential in the development of inflammatory lung diseases. Their dynamic behavior, encompassing fusion, fission, and mitophagy, also impacts cellular responses to inflammation and oxidative stress. Gaining a comprehensive understanding of the intricate correlation between mitochondria and lung inflammation is essential in order to develop accurate treatment strategies. Targeting ROS generation, dynamics, and mitochondrial function may offer novel approaches to treating inflammatory lung diseases while minimizing tissue damage. Additional investigation into the precise contributions of mitochondria to lung inflammation will provide significant knowledge regarding disease mechanisms and potential therapeutic approaches. This review will focus on how mitochondria in the lung regulate these processes and their involvement in acute and chronic lung diseases. [ABSTRACT FROM AUTHOR]

Autoimmune gastritis (AIG) is an autoimmune disorder characterized by the destruction of gastric parietal cells and atrophy of the oxyntic mucosa which induces intrinsic factor deficiency and hypo-achlorhydria. AIG predominantly affects the antral mucosa with AIG patients experiencing increased inflammation and a predisposition toward the development of gastric adenocarcinoma and type I neuroendocrine tumors. The exact pathogenesis of this autoimmune disorder is incompletely understood although dysregulated immunological mechanisms appear to major contributors. This review of autoimmune gastritis, an unmet medical need, summarizes current knowledge on pro- and anti-inflammatory cytokines and strategies for the discovery of novel biomarkers and potential pharmacological targets. [ABSTRACT FROM AUTHOR]

Background: The inflammatory factor YKL-40 is associated with various inflammatory diseases and is key to remodeling inflammatory cells and tissues. YKL-40 (Chi3l1) promotes the activation of tissue factor (TF), leading to intrahepatic vascular coagulation (IAOC) and liver injury. TF is a key promoter of the exogenous coagulation cascade and is also involved in several signaling involving cell proliferation, apoptosis, charring,migration and inflammatory diseases pathways. However, the effect of YKL-40-induced TF- PAR1 pathway on the expression of downstream chemokines remains unknown. Methods: We established a liver injury model using Concanavalin A (ConA) in C57 BL/6 mice. By adopting various experimental techniques, the effect of YKL-40 induced TF-PAR1 pathway on the expression of downstream chemokine ligand 2 (CCL2) and IP-10 was verified. Results: We found that overexpression of YKL-40 increased the expression of TF, protease-activated receptor 1 (PAR1), CCL2 and IP-10 inmice and exacerbated the severity of liver injury. However, blocking the expression of TF significantly reversed the extent of liver injury. Conclusion: We found that YKL-40 promotes the expression of downstream chemokines ligand 2 (CCL2) and IP-10 by activating the TF-PAR1 pathway, leading to increased recruitment of inflammatory cells and exacerbating the progression of liver injury. This provides a new approach for the clinical treatment of drug- induced liver injury. [ABSTRACT FROM AUTHOR]

Background: Considering the complex pathological mechanisms behind spinal cord injury (SCI) and the adverse effects of present non-approved drugs against SCI, new studies are needed to introduce novel multi-target active ingredients with higher efficacy and lower side effects. Polydatin (PLD) is a naturally occurring stilbenoid glucoside recognized for its antioxidative and anti-inflammatory properties. This study aimed to assess the effects of PLD on sensory-motor function following SCI in rats. Methods: Following laminectomy and clip compression injury at the thoracic 8 (T8)-T9 level of the spinal cord, rats were randomly assigned to five groups: Sham, SCI, and three groups receiving different doses of PLD treatment (1, 2, and 3 mg/kg). Over 4 weeks, behavioral tests were done such as von Frey, acetone drop, hot plate, Basso-Beattie-Bresnahan, and inclined plane test. At the end of the study, changes in catalase and glutathione activity, nitrite level, activity of matrix metalloproteinase 2 (MMP2) and MMP9 as well as spinal tissue remyelination/neurogenesis, were evaluated. Results: The results revealed that PLD treatment significantly improved the behavioral performance of the animals starting from the first week after SCI. Additionally, PLD increased catalase, and glutathione levels, and MMP2 activity while reduced serum nitrite levels and MMP9. These positive effects were accompanied by a reduction in the size of the lesion and preservation of neuronal count. Conclusion: In conclusion, PLD showed neuroprotective effects in SCI rats by employing anti-inflammatory and antioxidant effects, through which improve sensory and motor function. [ABSTRACT FROM AUTHOR]

Objectives: This study was conducted to examine the potential health benefits of thonningianin A (TA) on renal injury and interstitial fibrosis in diabetic nephropathy (DN) mice. Methods: In this study, a DN mice model was established using male C57BL/6 mice injected with streptozotocin (STZ, 50 mg/kg) intraperitoneally and treated with TA for 12 weeks. Firstly, the therapeutic and anti-fibrotic effects of TA on DN were evaluated. Secondly, the effect of TA on renal inflammation was evaluated and Western blot was used to detect the changes of NLRP3/ASC/Caspase-1 pathway-related protein expressions in kidney. Furthermore, the effect of TA on impairments in the intestinal mucosa barrier was evaluated and the changes of lipopolysaccharide (LPS) levels in feces and serum were detected by ELISA. Finally, 16S rRNA sequencing was used to detect alteration of gut microbiota diversity and abundance in mice after TA treatment. Results: The results showed that TA markedly mitigated blood glucose (Glu), decreased 24-h urinary total protein (24hUTP), improved renal dysfunction and kidney index (KI) in DN mice. Furthermore, TA significantly alleviated renal injury and interstitial fibrosis, repressing renal inflammation. Western blot results showed that the NLRP3/ASC/Caspase-1 signaling pathway-related proteins decreased after TA treatment. In addition, TA also ameliorated impairments in the intestinal mucosa barrier and restored the expressions of intestinal tight junction proteins (Claudin-1, Occludin and ZO-1). Subsequently, it reduced LPS levels of DN mice in fecal and serum. Furthermore, 16S rRNA high-throughput sequencing showed that TA modulated gut microbiota dysbiosis and decreased the abundance of Gram-negative bacteria (Proteobacteria and Escherichia-Shigella). Conclusion: This study suggested that TA might exert a beneficial effect on renal interstitial fibrosis in DN mice by modulating gut microbiota dysbiosis, ameliorating impairments in the intestinal mucosa barrier, reducing the production and release of LPS, inhibiting the activation of NLRP3/ASC/Caspase-1 signaling pathway, and repressing renal inflammatory. [ABSTRACT FROM AUTHOR]

Periodontal disease is more prevalent in patients with diabetes, and it has a negative impact on their quality of life. Inhibiting the infection and inflammation processes that cause periodontal disease can reduce the severity of the disease and chances of serious complications. In this study, we aimed to demonstrate the effectiveness of Clinacanthus nutans extract in reducing the inflammation in gingival fibroblast cells induced by Porphyromonas gingivalis lipopolysaccharide (LPS). Stimulation with LPS under high-glucose conditions led to increased inflammation compared to low-glucose conditions. Treatment of C. nutans extract significantly reduced the expression of these pro-inflammatory cytokines and chemokines. At a concentration of 50 μg/mL, it reduced the relative expression of IL6, IL8, and CXCL10 to 0.51 ± 0.09, 0.6 ± 0.19, and 0.09 ± 0.02, respectively, compared to the non-treatment control, accompanied by a decrease in secreted protein as measured by ELISA. Additionally, application of C. nutans extract markedly suppressed the NF-κB signaling pathway by reducing the phosphorylated form of IκBα, NF-κB p65, and nuclear translocation of NF-κB, along with a decrease in COX2, a key mediator in the inflammatory pathway. Furthermore, analysis of RNA sequencing data indicated that the extract clearly reversed the gene expression changes induced by LPS. This was particularly true for the signaling mediators and inflammatory genes in response to NF-κB, JAK/STAT, and TNF signaling pathways. Our finding highlights the potential of C. nutans extract to alleviate inflammation and suggests its potential as a treatment for periodontal disease in patients with diabetes. [ABSTRACT FROM AUTHOR]

Introduction: Galectin-3 is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. Selvigaltin (previously known as GB1211) is a novel orally active galectin-3 small molecule inhibitor that has high affinity for galectin-3 (human KD = 25 nM; rabbit KD = 12 nM) and high oral bioavailability in rabbits and man. In this study the efficacy of selvigaltin was investigated in a high fat diet (HFD) rabbit model of metabolic-associated steatohepatitis (MASH). Methods: Male New Zealand White rabbits were individually caged under standard conditions in a temperature and humidity-controlled room on a 12 h light/darkness cycle. After 1 week of regular diet (RD), rabbits were randomly assigned for 8 or 12 weeks to different groups: RD/vehicle, RD/selvigaltin, HFD (8 weeks), HFD/vehicle and HFD/selvigaltin (0.3, 1.0, 5.0 or 30 mg/kg selvigaltin with vehicle/selvigaltin p.o. dosed therapeutically q.d. 5 days per week from week 9 or 12). Liver inflammation, steatosis, ballooning, and fibrosis was measured via blood metabolic markers, histomorphological evaluation [Oil Red O, Giemsa, Masson's trichome, picrosirius red (PSR) and second harmonic generation (SHG)], and mRNA and protein expression. Results: Steatosis, inflammation, ballooning, and fibrosis were all increased from RD to HFD/vehicle groups. Selvigaltin demonstrated target engagement by significantly decreasing galectin-3 levels in the liver as measured via immunohistochemistry and mRNA analysis. Selvigaltin dose-dependently reduced biomarkers of liver function (AST, ALT, bilirubin), inflammation (cells foci), and fibrosis (PSR, SHG), as well as decreasing the mRNA and protein expression of several key inflammation and fibrosis biomarkers (e.g., IL6, TGFβ3, SNAI2, collagen). Doses of 1.0 or 5.0 mg/kg demonstrated consistent efficacy across most biological endpoints supporting the current clinical doses of selvigaltin being investigated in liver disease. Discussion: Selvigaltin significantly reduced hepatic inflammation and fibrosis in an HFD rabbit model of MASH following therapeutic dosing for 4 weeks in a dosedependent manner. These data support the human selvigaltin dose of 100 mg b.i.d. that has been shown to reduce key liver biomarkers during a clinical study in liver cirrhosis. [ABSTRACT FROM AUTHOR]

Treatments of inflammatory bowel disease (IBD) are diverse, but their efficacy is limited, and it is therefore urgent to find better therapies. Controlling mucosal inflammation is a must in IBD drug treatment. The occurrence of anti-tumor necrosis factor α (TNF-α) monoclonal antibodies has provided a safer and more efficacious therapy. However, this kind of treatment still faces failure in the form of loss of response. β-Carboline alkaloids own an anti-inflammatory pharmacological activity. While Kumujan B contains β-carboline, its biological activity remains unknown. In this study, we attempted to determine the antiinflammatory effects of Kumujan B using both the TNF-α-induced in vitro inflammation and DSS-induced in vivo murine IBD models. Our data show that Kumujan B attenuated the expression of interleukin 1β (IL-1β) and interleukin 6 (IL-6) induced by TNF-α in mouse peritoneal macrophages. Kumujan B suppressed c-Jun N-terminal protein kinases (JNK) signaling, especially c-Jun, for anti-inflammatory response. Furthermore, Kumujan B promoted K11-linked ubiquitination and degradation of c-Jun through the proteasome pathway. In an in vivo study, Kumujan B inhibited the expression of IL-1β, IL-6, and TNF-α and improved the colon barrier function in dextran sulfate sodium salt (DSS)-induced experimental mice colitis. Kumujan B exhibited in vivo and in vitro anti-inflammatory effects, making it a potential therapeutic candidate for treating IBD. [ABSTRACT FROM AUTHOR]

Severe COVID-19 cases often progress to life-threatening conditions such as acute respiratory distress syndrome (ARDS), sepsis, and multiple organ dysfunction syndrome (MODS). Gelsolin (GSN), an actin-binding protein with anti-inflammatory and immunomodulatory properties, is a promising therapeutic target for severe COVID-19. Plasma GSN levels are significantly decreased in critical illnesses, including COVID-19, correlating with dysregulated immune responses and poor outcomes. GSN supplementation may mitigate acute lung injury, ARDS, and sepsis, which share pathophysiological features with severe COVID-19, by scavenging actin, modulating cytokine production, enhancing macrophage phagocytosis, and stabilizing the alveolar-capillary barrier. Preliminary data indicate that recombinant human plasma GSN improves oxygenation and lung function in severe COVID-19 patients with ARDS. Although further research is needed to optimize GSN therapy, current evidence supports its potential to mitigate severe consequences of COVID-19 and improve patient outcomes. This review provides a comprehensive analysis of the biological characteristics, mechanisms, and therapeutic value of GSN in severe COVID-19. [ABSTRACT FROM AUTHOR]

Asthma is a common chronic inflammatory disease of the lungs and airway, yet its inflammatory subtypes and potential pathogenesis have not been completely elucidated and require further study. With advances in epigenetic development, methylation has emerged as a new direction for identifying and decoding the occurrence and subtype manifestations of asthma. N6-methyladenosine (m6A), an RNA methylation modification occurring in the N6-position of adenosine, is a prevalent epigenetic modification observed in eukaryotes. It exerts significant control over mRNA metabolism by regulating alternative splicing, stability, export, and translation. The dynamic process of m6A methylation plays a crucial role in the pathogenesis of asthma and is tightly regulated by three types of regulators: writers, readers, and erasers. This article provides a comprehensive review of the association between m6A regulators and the pathogenesis of inflammatory subtypes of asthma, such as involvement of inflammatory cells and related inflammatory response. Furthermore, the findings presented herein provide new insights and a solid foundation for further research on m6A mRNA methylation as biomarkers for the diagnosis and development of personalized treatment for different subtypes of asthma, particularly neutrophilic asthma and eosinophilic asthma. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a major reason for the high morbidity and mortality of cardiovascular diseases. Macrophage inflammation and foam cell formation are the key pathological processes of atherosclerosis. Ginsenoside compound K (CK) is a metabolite derived from ginseng. CK has anti atherosclerotic effect, but the molecular mechanism remains to be elucidated. We aim to explore the protective effect of CK against ox-LDL-induced inflammatory responses and foam cells formation in vitro and explore its potential mechanisms. Through the results of oil red O staining, Western blot, and qPCR, we found that CK significantly inhibited the foam cell formation, reduced the expression of SR-A1 and increased ABCA1 and ABCG1 expression. In addition, CK increased the number of autophagosomes and upregulated the LC3II/LC3I ratio and the expressions of ATG5 and Beclin-1 but decreased p62 expression. Moreover, CK significantly inhibited the NF-kB, p38, and JNK MAPK signaling pathway. Altogether, CK attenuated macrophage inflammation and foam cell formation via autophagy induction and by modulating NF-kB, p38, and JNK MAPK signaling. Thus, CK has potential as a therapeutic drug for atherosclerosis. [ABSTRACT FROM AUTHOR]

Objective: To investigate the anti-inflammatory activity and mechanism of Baicalin derivative (Baicalin butyl ester, BE). Methods: BE was synthesized and identified using UV-Vis spectroscopy, FT-IR spectroscopy, mass spectrometry (MS) and high-performance liquid chromatography (HPLC) methods. Its anti-inflammatory potential was explored by an in vitro inflammation model. Network pharmacology was employed to predict the anti-inflammatory targets of BE, construct proteinprotein interaction (PPI) networks, and analysis topological features and KEGG pathway enrichment. Additionally, molecular docking was conducted to evaluate the binding affinity between BE and its core targets. qRT-PCR analysis was conducted to validate the network pharmacology results. The organizational efficiency was further evaluated through octanol-water partition coefficient and transmembrane activity analysis. Results: UV-Vis, FT-IR, MS, and HPLC analyses confirmed the successfully synthesis of BE with a high purity of 93.75%. In vitro anti-inflammatory research showed that BE could more effectively suppress the expression of NO, COX-2, IL-6, IL-1ß, and iNOS. Network pharmacology and in vitro experiments validated that BE's anti-inflammatory effects was mediated through the suppression of SRC, HSP90AA1, PIK3CA, JAK2, AKT1, and NF-κB via PI3K-AKT pathway. Molecular docking results revealed that the binding affinities of BA to the core targets were lower than those of BE. The Log p-value of BE (1.7) was markedly higher than that of BA (-0.5). Furthermore, BE accumulated in cells at a level approximately 200 times greater than BA. Conclusion: BE exhibits stronger anti-inflammatory activity relative to BA, possibly attributed to its better lipid solubility and cellular penetration capabilities. The anti-inflammatory mechanism of BE may be mediated through the PI3K-AKT pathway. [ABSTRACT FROM AUTHOR]

Background: The primary constituent of ginseng, known as ginsenosides (GS), has been scientifically demonstrated to possess anti-fatigue, anti-hypoxia, antiinflammatory, and antioxidant properties. However, the effect and mechanisms of GS on tissue injury induced by high-altitude hypoxia still remain unclear. Aim of the study: This study aims to investigate the protective effect of GS on a high-altitude hypoxia model and explore its mechanism. Materials and methods: Sprague-Dawley rats were placed in a high-altitude simulation chamber for 48 h (equivalent to an altitude of 6,000 m) to establish a high-altitude hypoxia model. We assessed the anti-hypoxic efficacy of GS through blood gas analysis, complete blood count, and hemorheology analysis. We used H&E and hypoxia probe assays to evaluate the protective effect of GS on organ ischemia-induced injury. Further, we used ELISA and qPCR analysis to detect the levels of inflammatory factors and oxidative stress markers. Immunohistochemistry and immunofluorescence staining were performed to determinate protein expression of hypoxia inducible factor 1-alpha (HIF-1a), erythropoietin (EPO), and prolyl hydroxylase 2 (PHD2). Results: In the survival experiment of anoxic mice, 100 mg/kg of GS had the best anti-anoxic effect. GS slowed down the weight loss rate of rats in hypoxic environment. In the fluorescence detection of hypoxia, GS reduced the fluorescence signal value of lung and kidney tissue and alleviated the hypoxia state of tissue. Meanwhile GS improved blood biochemical and hematological parameters. We also observed that GS treatment significantly decreased oxidative stress damage in lung and kidney tissues. Further, the levels of inflammatory factors, IL-1β, IL-6, and TNF-α were reduced by GS. Finally, GS regulated the PHD2/HIF-1α/EPO signaling pathway to improve blood viscosity and tissue hyperemia damage. Conclusion: GS could alleviate high-altitude induced lung and kidney damage by reducing the level of inflammation and oxidative stress, improving blood circulation through the PHD2/HIF-1α/EPO pathway. [ABSTRACT FROM AUTHOR]

Introduction: Natural plants are valuable resources for exploring new bioactive compounds. Artemisia vulgaris L. is a traditional Chinese medicinal herb that has been historically used for treating multiple diseases. Active compounds isolated and extracted from A. vulgaris L. typically possess immunomodulatory and antiinflammatory properties. Artemvulactone E (AE) is a new sesquiterpene lactone isolated and extracted from A. vulgaris L. with unclear biological activities. Methods: The immunoregulatory effects of AE on macrophages were assessed by ELISA, RT-qPCR, immunofluorescence, and western blot assay. The effect of AE on lipopolysaccharide (LPS) -relates signaling pathways was examined by western blot assay. In zebrafish models, the larvae were yolk-microinjected with LPS to establish inflammation model and the effect of AE was evaluated by determining the survival rate, heart rate, yolk sac edema size, neutrophils and macrophages infiltration of zebrafish. The interaction between AE and Toll-like receptor 4 (TLR4) was examined by molecular docking and dynamic stimulation. Results: AE reduced the expression and secretion of pro-inflammatory cytokines (TNF-a and IL-6), inflammatory mediators iNOS and COX-2, as well as decreases the production of intracellular NO and ROS in LPS-stimulated macrophages. In addition, AE exerted its anti-inflammatory effect synergistically by inhibiting MAPK/JAK/STAT3-NF-B signaling pathways. Furthermore, AE enhanced the survival rate and attenuated inflammatory response in zebrafish embryos treated with LPS. Finally, the molecular dynamics results indicate that AE forms stable complexes with LPS receptor TLR4 through the Ser127 residue, thus completely impairing the subsequent activation of MAPK-NF-B signaling. Conclusion: AE exhibits notable anti-inflammatory activity and represents as a potential agent for treating inflammation-associated diseases. [ABSTRACT FROM AUTHOR]

Immune inflammation is one of the main factors in the pathogenesis of depression. It is an effective and active way to find more safe and effective anti-inflammatory depressant drugs from plant drugs. The purpose of this study is to explore the potential of marine plant Sargassum pallidum (Turn).C.Ag. (Haihaozi, HHZ) in the prevention and treatment of depression and to explain the related mechanism. Phytochemical analysis showed that alkaloids, terpenes, and organic acids are the main constituents. In vitro and in vivo activity studies showed the anti-neuroinflammatory and antidepressant effect of Sargassum pallidum, furthermore, confirmed that 7-Hydroxycoumarin, Scoparone, and Kaurenoic Acid are important plant metabolites in Sargasum pallidum for antineuroinflammation. Mechanism exploration showed that inhibition of ERK1/2/p38 inflammatory signaling pathway contributing to the antidepressant effect of Sargassum pallidum in reducing intestinal inflammatory levels. This study confirmed the value of Sargassum pallidum and its rich plant metabolites in anti-inflammatory depression, providing a new choice for the follow-up research and development of antidepressant drugs. [ABSTRACT FROM AUTHOR]

Depression is an inflammation-associated disease that results in major depression as inflammation increases and progresses. Ginsenoside Rg1 (Rg1), the major bioactive ingredient derived from ginseng, possesses remarkable anti-depressant and antiinflammatory effects. Our previous studies showed that the pathogenesis of depression was concomitant with the acceleration of connexin43 (Cx43) ubiquitin degradation, while Rg1 could upregulate Cx43 expression to attenuate depression. However, whether the ubiquitination of Cx43 is the specific correlation between depression and inflammation, and how Rg1 ameliorates neuroinflammation to attenuate depression, are still under investigation. In in vivo experiments, Rg1 treatment significantly ameliorated depression-like behaviors in rats subjected to chronic unpredictable stress (CUS). Moreover, these CUS rats treated with Rg1 exhibited attenuated neuroinflammation, together with the suppression of Cx43 ubiquitination. In in vitro experiments, Rg1 reduced the secretion of inflammatory cytokines and the ubiquitination of Cx43 in lipopolysaccharide-induced glial cells. Furthermore, treatment with ubiquitin-proteasome inhibitor MG132 suppressing the ubiquitination of Cx43 ameliorated lipopolysaccharide-induced neuroinflammation. The results suggest that Rg1 attenuates depression-like behavioral performances in CUSexposed rats; and the main mechanism of the antidepressant-like effects of Rg1 appears to involve protection against neuroinflammation via suppression of Cx43 ubiquitination. In conclusion, Rg1 could ameliorate neuroinflammation via suppression of Cx43 ubiquitination to attenuate depression, which represents the perspective of an innovative therapy of Rg1 in the treatment of inflammation-associated depression. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a recurring inflammatory bowel disease, in which oxidative stress plays a role in its progression, and regulation of the oxidative/ antioxidative balance has been suggested as a potential target for the treatment of UC. The aim of this study was to evaluate the protective effect of andrographolide against UC and its potential antioxidant properties by modulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. Dextran sulfate sodium (DSS) -induced UC mice and the LPS-induced HT29 inflammatory cell model were established to uncover the potential mechanisms of andrographolide. ML385, a Nrf2 inhibitor, was used in both models to assess whether andrographolide exerts a protective effect against UC through the Nrf2/HO-1 pathway. The in vivo experiment showed that andrographolide ameliorated the symptoms and histopathology of DSS-induced mice and restored the expressions of ZO-1, Occludin-1 and Claudin-1. Meanwhile, DSS-induced oxidative stress and inflammation were suppressed by andrographolide treatment, along with the upregulation of key proteins in the Nrf2/HO-1 pathway. In vitro experiments showed that andrographolide attenuated LPS-induced excessive generation of ROS in HT29 cells, reduced inflammatory factors, and upregulated the expression of proteins related to tight junctions and Nrf2/HO-1 pathway. In addition, ML385 abolished the beneficial effect of andrographolide. In conclusion, the protective effect of andrographolide against UC may involve the suppression of oxidative stress and inflammation via the Nrf2/HO-1 pathway. [ABSTRACT FROM AUTHOR]

Introduction: Preclinical studies suggest that cannabinoid receptor type 2 (CB2R) activation has a therapeutic effect in animal models on chronic inflammation and vascular permeability, which are key pathological features of diabetic retinopathy (DR). A novel CB2R agonist, triazolopyrimidine RG7774, was generated through lead optimization of a high-throughput screening hit. The aim of this study was to characterize the pharmacology, absorption, distribution, metabolism, elimination, and toxicity (ADMET) profile of RG7774, and to explore its potential for managing the key pathological features associated with retinal disease in rodents. Methods: The in vitro pharmacology of RG7774 was investigated for CB2R binding and receptor activation using recombinant human and mouse CB2R expression in Chinese hamster ovary cells, and endogenous CB2R expression in human Jurkat cells, and rat and mouse spleen cells. The ADMET profile was evaluated and the effects of RG7774 on retinal permeability, leukocyte adhesion, and choroidal neovascularization (CNV) were investigated in rodent models of retinal disease. Pharmacokinetic (PK) parameters and the exposure-response relationship were characterized in healthy animals and in animals with laserinduced CNV. Results: RG7774was found to be a potent (EC50: 2.8 nMand Ki: 51.3 nM), selective, and full CB2R agonist with no signs of cannabinoid receptor type 1 (CB1R) binding or activation. The ligand showed a favorable ADMET profile and exhibited systemic and ocular exposure after oral delivery. Functional potency in vitro translated from recombinant to endogenous expression systems. In vivo, orally administered RG7774 reduced retinal permeability and leukocyte adhesion in rodents with lipopolysaccharide (LPS)-induced uveitis and streptozotocin (STZ)-induced DR, and reduced lesion areas in rats with laser-induced CNV with an ED50 of 0.32 mg/kg. Anatomically, RG7774 reduced the migration of retinal microglia to retinal lesions. Discussion: RG7774 is a novel, highly selective, and orally bioavailable CB2R agonist, with an acceptable systemic and ocular PK profile, and beneficial effects on retinal vascular permeability, leukocyte adhesion, and ocular inflammation in rodent animal models. Results support the development of RG7774 as a potential treatment for retinal diseases with similar pathophysiologies as addressed by the animal models. [ABSTRACT FROM AUTHOR]

Background: Pain is a complex perception involving unpleasant somatosensory and emotional experiences. However, the underlying mechanisms that mediate its different components remain unclear. Sphingosine-1-phosphate (S1P), a metabolite of sphingomyelin and a potent lipid mediator, initiates signaling via G protein-coupled receptors (S1PRs) on cell surfaces. It serves as a second messenger in cellular processes such as proliferation and apoptosis. Nevertheless, the neuropharmacology of sphingolipid signaling in pain conditions within the central nervous system remains largely unexplored and controversial. Methods: Chronic nociceptive pain models were induced in vivo by intraplantar injection of 20 μL complete Freund's adjuvant (CFA) into the left hind paws. We assessed S1P and S1PR1 expression in the spinal cords of CFA model mice. Functional antagonists of S1PR1 or S1PR1-specific siRNA were administered daily following CFA model establishment. Paw withdrawal response frequency (PWF) and paw withdrawal latency (PWL) were measured to evaluate mechanical allodynia and thermal hyperalgesia, respectively. RT-PCR assessed interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels. Western blotting and immunofluorescence were used to analyze glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule (Iba1), STAT3, ERK, and p38 MAPK protein expression. Results: In the chronic nociceptive pain model induced by CFA, S1P and S1PR1 expression levels were significantly elevated, leading to activation of spinal cord glial cells. S1PR1 activation also promoted MMP2-mediated cleavage of mature IL-1β. Additionally, S1PR1 activation upregulated phosphorylation of STAT3, ERK, and p38 MAPK in glial cells, profoundly impacting downstream signaling pathways and contributing to chronic nociceptive pain. Conclusion: The S1P/S1PR1 axis plays a pivotal role in the cellular and molecular mechanisms underlying nociceptive pain. This signaling pathway modulates glial cell activation and the expression of pain-related genes (STAT3, ERK, p38 MAPK) and inflammatory factors in the spinal dorsal horn. These findings underscore the potential of targeting the S1P system for developing novel analgesic therapies. [ABSTRACT FROM AUTHOR]

The flavonoid-rich fraction of bergamot juice (BJe) has demonstrated anti-inflammatory and antioxidant activities. The aim of work was to test the beneficial effects of BJe on the modulation of the ileum inflammation caused by intestinal ischemia/reperfusion (I/R) injury in mice. To understand the cellular mechanisms by which BJe may decrease the development of intestinal I/R injury, we have evaluated the activation of signaling transduction pathways that can be induced by reactive oxygen species production. Superior mesenteric artery and celiac trunk were occluded for 30 min and reperfused for 1 h. The animals were sacrificed after 1 h of reperfusion, for both histological and molecular examinations of the ileum tissue. The experimental results demonstrated that BJe was able to reduce histological damage, cytokines production, adhesion molecules expression, neutrophil infiltration and oxidative stress by a mechanism involved both NF-kB and MAP kinases pathways. This study indicates that BJe could represent a new treatment against inflammatory events of intestinal I/R injury. [ABSTRACT FROM AUTHOR]

Background and aims: Recent studies suggest that empagliflozin reduces total and cardiovascular mortality in both diabetic and nondiabetic subjects. Although the exact mechanism is unclear, it is understood to positively affect myocardial energetics, including the metabolism of ketone bodies, lipids, and fatty acids. In this study, we compared empagliflozin effects on lipid metabolism in the heart and liver in a prediabetic rat model with severe dyslipidemia. Materials and methods: Wistar rats served as the control group, while hereditary hypertriglyceridemic (HHTg) rats were used as a nonobese, prediabetic model. Rats were treated with or without empagliflozin at a dose of 10 mg/kg body weight (BW) for 8 weeks. Results: In HHTg rats, empagliflozin decreased body weight and adiposity, improved glucose tolerance, and decreased serum triacylglycerols (TAGs) (p < 0.001). Empagliflozin decreased the activity and gene expression of the lipogenic enzyme SCD-1 (p < 0.001) in the myocardium, which may have led to a decrease in the ectopic accumulation of TAGs and lipotoxic diacylglycerols and lysophosphatidylcholines (p < 0.001). Changes in the myocardial phosphatidylcholine/phosphatidylethanolamine ratio (p < 0.01) and in the fatty acid profile of myocardial phospholipids may have contributed to the antifibrotic effects of empagliflozin. The anti-inflammatory effects of empagliflozin were evidenced by an increased IL-10/TNFa ratio (p < 0.001), a marked decrease in arachidonic acid metabolites (20-HETE, p < 0.001), and an increase in PUFA metabolites (14,15-EETs, p < 0.001) in the myocardium. However, empagliflozin did not significantly affect either the concentration or utilization of ketone bodies. In the liver, empagliflozin decreased lipogenesis and the accumulation of TAGs and lipotoxic intermediates. Its effect on arachidonic acid metabolites and alterations in n-3 PUFA metabolism was less pronounced than in the myocardium. Conclusion: Our findings suggest that empagliflozin treatment in the heart and liver reduced the accumulation of neutral lipids and lipotoxic intermediates and altered the metabolism of n-3 PUFA. In the heart, empagliflozin altered arachidonic acid metabolism, which is likely associated with the anti-inflammatory and antifibrotic effects of the drug. We assume that these alterations in lipid metabolism contribute to the cardioprotective effects of empagliflozin in prediabetic states with severe dyslipidemia. [ABSTRACT FROM AUTHOR]

Introduction: Excessive alcohol intake often results in hangovers and inflammatory liver damage, posing a significant health concern. Current treatment options for hangovers are still insufficient, highlighting the urgent need for new therapeutic approaches. Psyllium fiber (PF) is well-known for its gastrointestinal benefits, but its effect on hangovers is less explored. Methods: We utilized a mouse model with a single binge drinking (4 g/kg) to induce hangover and inflammatory liver injury. Intestine and liver injury were serologically and histologically estimated. Hangover symptoms were assessed using cylinder and footprint tests to objectively quantify hangover symptoms in mice. Results: Binge drinking significantly activated alcohol-metabolizing enzymes in the small intestine and liver, leading to inflammatory damage. Concurrently, there was a rise in alcohol metabolites such as acetaldehyde and acetone, which exhibited a positive correlation with hangover symptoms in mice. Interestingly, the oral administration of PF (100 mg/kg) alongside alcohol consumption significantly reduced the activity of these enzymes and lowered the levels of alcohol metabolites. Mice treated with PF exhibited a considerable improvement in hangover symptoms and a reduction in hepatic inflammation, compared to control groups. Furthermore, in vitro experiments using HepG2 cell lines and semipermeable membranes demonstrated that PF effectively inhibits alcohol absorption into the body. Discussion: In conclusion, PF demonstrates a potential protective effect against alcohol-induced hangover and liver injury by inhibiting the absorption of alcohol and lowering hangover-related alcohol metabolites. This study suggests that PF could serve as an effective therapeutic option for mitigating the adverse effects of excessive alcohol consumption. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a chronic condition that progressively worsens and continues to be a major financial burden and public health concern. The "gut-heart" axis provides an innovative perspective and therapeutic strategy for preventing and treating heart failure. Shenfu injection (SFI) is a Traditional Chinese Medicine-based treatment demonstrating potential as a therapeutic strategy for heart failure. However, the precise therapeutic mechanisms of SFI in heart failure are not completely characterized. In this study, HF models were established utilizing subcutaneous multipoint injection of isoproterenol (ISO) at a dosage of 5mg kg-1⋅d-1 for 7 days. Serum levels of inflammatory biomarkers were quantified using protein microarrays. Rat feces were analyzed using untargeted metabolomics research and 16S rRNA sequencing. The link between gut microbiota and metabolites was examined using a MetOrigin and Spearman correlation analysis. Our results show that Shenfu injection effectively enhances cardiac function in rats with ISO-induced heart failure by potentially modulating pro-/anti-inflammatory imbalance and reducing serum and urine Trimethylamine-N-oxide (TMAO) levels. Moreover, SFI significantly increases the abundance of Bacteroidota at the phylum level, thereby improving disrupted gut microbiota composition. Additionally, SFI supplementation enriches specific genera known for their capacity to produce short-chain fatty acids. SFI was found to be associated with three key metabolic pathways, as revealed by fecal metabonomics analysis, including the pentose phosphate pathway, pyrimidine metabolism, and purine metabolism. Metabolite tracing analysis revealed that Taurine and hypotaurine metabolism was found to be specific to the microbial community. The biosynthesis of Pyrimidine metabolism, Purine metabolism, beta-alanine metabolism, Naphthalene degradation, Pantothenate, and CoA biosynthesis were identified as co-metabolic pathways between microbes and host. The Spearman correlation analysis was also significantly correlated to differentially expressed metabolites regulated by SFI and the gut microbiota. These results suggest that SFI improves ISO-induced heart failure by modulating cometabolism and regulating the TMAO-inflammation axis. [ABSTRACT FROM AUTHOR]

Palmitoylethanolamide (PEA) is a pleiotropic lipid mediator with established anti-inflammatory and anti-hyperalgesic activity. Ultramicronized PEA (PEA-um) has superior oral efficacy compared to naïve (non-micronized) PEA. The aim of the present study was two-fold: (1) to evaluate whether oral PEA-um has greater absorbability compared to naïve PEA, and its ability to reach peripheral and central tissues under healthy and local inflammatory conditions (carrageenan paw edema); (2) to better characterize the molecular pathways involved in PEA-um action, particularly at the spinal level. Rats were dosed with 30 mg/kg of [13C]4-PEA-um or naïve [13C]4-PEA by oral gavage, and [13C]4-PEA levels quantified, as a function of time, by liquid chromatography/atmospheric pressure chemical ionization/mass spectrometry. Overall plasma levels were higher in both healthy and carrageenan-injected rats administered [13C]4-PEA-um as compared to those receiving naïve [13C]4-PEA, indicating the greater absorbability of PEA-um. Furthermore, carrageenan injection markedly favored an increase in levels of [13C]4-PEA in plasma, paw and spinal cord. Oral treatment of carrageenan-injected rats with PEA-um (10 mg/kg) confirmed beneficial peripheral effects on paw inflammation, thermal hyperalgesia and tissue damage. Notably, PEA-um down-regulated distinct spinal inflammatory and oxidative pathways. These last findings instruct on spinal mechanisms involved in the anti-hyperalgesic effect of PEA-um in inflammatory pain. [ABSTRACT FROM AUTHOR]

Background: Fexofenadine (FEX) is an antihistamine that acts as an inverse agonist against histamine (HIS) receptor 1 (H1R), which mediates the allergic reaction. Inverse agonists may be more potent than neutral antagonists, as they bind the same receptor as the agonist (HIS) but stabilize the inactive form and induce an opposite pharmacological response, suppressing the basal activity of H1R and preventing HIS from binding. This study aims to establish and validate a model of HIS-induced inflammation based on fully reconstituted human nasal epithelial tissue to assess the activity of FEX as an inverse agonist in this model and explore its link to clinical benefit. Methods: The model was developed using nasal MucilAir™ (Epithelix) in vitro epithelium challenged by HIS. Two conditions were assessed in a side-by-side comparison: tissue was exposed to HIS + FEX with or without FEX pre-treatment (one-hour prior to HIS challenge). Tissue functionality, cytotoxicity, H1R gene expression, and inflammatory cytokines were assessed. Results: HIS at 100 µM induced significant 3.1-fold and 2.2-fold increases for inflammatory biomarkers interleukin (IL)-8 and IL-6, respectively (p < 0.0001), as well as rapid upregulation of H1R mRNA. Inflammatory biomarkers were inhibited by FEX and H1R expression was significantly reduced (p < 0.0001). FEX alone decreased H1R expression at all doses tested. With one-hour FEX pre-treatment, there was significantly higher downregulation of IL-8 (p < 0.05) and further downregulation of H1R expression and IL-6 versus without FEX pre-treatment; the effects of FEX were improved from 22% to 40%. Conclusion: A model of HIS-induced airway inflammation was established based on IL-8, IL-6 and H1R gene expression and was validated with FEX. FEX works as an inverse agonist, with a higher effect when used before+during versus only during the HIS challenge. Taking FEX before+during allergen exposure, or when symptoms first occur, may reduce basal activity and H1R gene expression, providing stronger protection against the worsening of symptoms upon allergen exposure. [ABSTRACT FROM AUTHOR]

Phosphodiesterase 4 (PDE4) inhibitors are effective therapeutic agents for various inflammatory diseases. Roflumilast, apremilast, and crisaborole have been developed and approved for the treatment of chronic obstructive pulmonary disease psoriatic arthritis, and atopic dermatitis. Inflammation underlies many vascular diseases, yet the role of PDE4 inhibitors in these diseases remains inadequately explored. This review elucidates the clinical applications and anti-inflammatory mechanisms of PDE4 inhibitors, as well as their potential protective effects on vascular diseases. Additionally, strategies to mitigate the adverse reactions of PDE4 inhibitors are discussed. This article emphasizes the need for further exploration of the therapeutic potential and clinical applications of PDE4 inhibitors in vascular diseases. [ABSTRACT FROM AUTHOR]