Platelet-activating Factor Research Articles

Winery By-Products In Vitro and In Vivo Effects on Atherothrombotic Markers: Focus on Platelet-Activating Factor.

Platelet aggregation and inflammation play a crucial role in atherothrombosis. Wine contains micro-constituents of proper quality and quantity that exert cardioprotective actions, partly through inhibiting platelet-activating factor (PAF), a potent inflammatory and thrombotic lipid mediator. However, wine cannot be consumed extensively due to the presence of ethanol. Alternatively, winery by-products are abundant in similar-to-wine micro-constituents that could be used in food fortification and dietary supplements. Also, the vinification process produces millions of tons of by-products worldwide, posing an environmental matter of waste management. Therefore, the purpose of this literature review is to update the existing data concerning the in vitro anti-platelet and anti-inflammatory properties of winery by-product extracts and their possible health effects through controlled clinical trials in humans, specifically focused on their effects on PAF's actions. Data from in vitro studies report that winery by-product compounds are able to inhibit platelet aggregation against several aggregation factors, as well as to downregulate inflammatory markers. Among their actions, extracts or phenolic compounds present in winery by-products inhibit PAF's actions, a potent inflammatory and thrombotic mediator. Similar conclusions have been drawn from human supplementation studies, which suggest that winery by-product extracts may have beneficial biological effects on the cardiovascular system. Evidence from long-term studies shows that consumption may lower total and low density lipoprotein (LDL) cholesterol, improve insulin sensitivity, decrease lipid and protein oxidative damage, enhance antioxidant capacity, and have mild anti-inflammatory action toward reducing cytokine expression and levels. Data from the limited postprandial studies report that the acute consumption of winery by-product extracts improves glycemic response and reduces platelet reactivity to aggregatory stimuli. Although wine extracts and phenolic compounds have been reported to inhibit PAF's actions and reduce the activity of its biosynthetic enzymes, no data exist concerning the influence of winery by-product extracts. In the future, additional long-term randomized controlled trials or postprandial studies are needed to draw definitive conclusions and establish a viable cardioprotective strategy that incorporates the sustainable use of winery by-products.

Ameliorative effects of squid phospholipids from Todarodes pacificus on atopic dermatitis-like lesions in NC/Nga mice.

Atopic dermatitis (AD), also known as eczema, is a chronic or relapsing inflammatory skin disease characterized by repeated exacerbations and remissions. Here, we investigated the effects of squid phospholipids (PLs) extracted from Todarodes pacificus on AD. The composition of squid PLs was analyzed using thin-layer chromatography and high-performance liquid chromatography, and the effects of PLs on AD were investigated using a rat paw edema model and an AD-like mouse model (NC/Nga mice). Squid PLs mainly consist of phosphatidylethanolamine (PE), phosphatidylcholine (PC), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid, which are bound at the sn-2 positions of PE and PC. Squid PLs inhibited rat paw edema induced by platelet-activating factor, a highly potent pro-inflammatory mediator. In an AD mouse model (NC/Nga mice), the topical application of squid PLs (1% or 5%) improved dermatitis of the ears and reduced thickness of the ears and epidermis in dermatitis, but 1.2% DHA or 1% soybean PC did not affect them. There results suggest that squid PLs, which mainly consist of PC and PE, and contain DHA, EPA, and ARA at the sn-2 position, may be useful for the prevention and treatment of AD.

Sleeve gastrectomy improves HDL function examined by Apo-A1 and atherogenic indices in non-diabetic obese patients.

Dysregulation of lipid metabolism can be one of the pathophysiological mechanisms linking high-density lipoprotein cholesterol (HDL-C) dysfunction to obesity. The aim of the study is to show possible changes in lipid metabolism with atherogenic indices in obese patients after sleeve gastrectomy (SG) surgery. Thirty patients who had SG surgery for obesity were included in the prospective study. The atherogenic risk indices were calculated pre-operatively, at 3 and 6 months post-operatively. Furthermore, serum paraoxonase-1 (PON-1), apolipoprotein-A1 (Apo-A1), and platelet-activating factor acetylhydrolase (PAF-AH) levels, amount of oxidized low-density lipoprotein (Ox-LDL) was measured. We observed improvement in atherogenic risk indices and improved HDL-C functionality after SG. Increases were observed in HDL-C and HDL-C-related Apo-A1 levels 6 months after obesity surgery. Besides, the amount of serum triglycerides (TGs), PON-1 activity, and atherogenic risk indices decreased significantly within 6 months. As far as we know, there is no study in the literature examining the dynamic changes in SG and PON-1, PAF-AH, Apo-A1, and Ox-LDL parameters. This preliminary study dynamically detected improvement in HDL-C function and reduction in atherogenic risk indices after SG.

Clinical values of serum platelet-activating factor in hypertensive disorders complicating pregnancy.

Serum platelet-activating factor (PAF) was proven to be associated with gestational hypertension. However, the predictive value of serum PAF at early pregnancy for the occurrence and outcomes of hypertensive disorders complicating pregnancy (HDCP) remained unclear. The demographic and clinical characteristics of patients were compared among the different subgroups. The serum PAF level was determined using an enzyme-linked immunosorbent assay. The predictive value of serum PAF for the occurrence and outcomes of HDCP was evaluated using receiver operating characteristic curve analysis. The correlation of serum PAF with blood pressure was assessed using Spearman analysis. Both systolic blood pressure and diastolic blood pressure were significantly higher in HDCP patients, as well as the serum levels of TNF-α and IL-1β at diagnosis/enrollment, while serum levels of IL-10 showed the opposite trend. Serum PAF levels were significantly higher in patients with HDCP compared to normal pregnant women. Furthermore, serum PAF levels were higher in HDCP patients with mild preeclampsia compared to those with gestational hypertension and even more elevated in HDCP patients with severe preeclampsia at the early pregnancy stage and at diagnosis. In HDCP patients, increased serum PAF levels at early pregnancy and at diagnosis were associated with poor outcomes. Additionally, serum PAF levels could predict the occurrence of HDCP and poor outcomes. Serum PAF from HDCP patients at both the early pregnancy and diagnosis stages could effectively predict the occurrence and outcome of HDCP.

Relevance of the Platelet-activating factor system in chemical warfare agents-induced effects.

The threats to chemical warfare-associated agents (CWA), including nitrogen mustard, are increasing, and no direct antidote is currently available to mitigate the deleterious cutaneous and systemic responses to prevent mortality. Though most of these agents act as alkylating agents, a significant knowledge gap exists in the molecular mechanisms of how these vesicants cause toxic effects. Studies, including ours, have shown that exposure to reactive oxygen species (ROS)-generating stimuli, including alkylating chemotherapeutic agents, and thermal burn injuries with ethanol produce the potent family of lipid mediators, Platelet-activating factor (PAF) agonists that induce local inflammation, and multi-system organ dysfunction (MOD). Notably, nano-sized microvesicle particles (MVPs), released from cells in response to stimuli, carry PAF-agonists and act as potent signaling agents to induce the local (cutaneous) and systemic responses. The current review highlights mechanistic insights and applicable approaches to mitigate CWA-induced local and systemic toxic responses with implications in cellular senescence and aging.

Platelet-activating factor: a potential therapeutic target to improve cancer immunotherapy.

The tumor microenvironment (TME) fosters cancer progression by supporting the differentiation and proliferation of myeloid-derived suppressor cells (MDSCs), which play a critical role in suppressing immune responses and facilitating tumor growth. Recent findings by Dahal etal. reveal that platelet-activating factor (PAF), a lipid mediator elevated in the TME, contributes to the differentiation of neutrophils into immunosuppressive neutrophils. They showed that inhibiting PAF signaling reduces MDSC-mediated immunosuppression, thereby enhancing cytotoxic T-cell activity. This approach may improve cancer immunotherapy outcomes, particularly when combined with checkpoint blockade therapies, suggesting a promising avenue for therapeutic development.

Maternal high fat diet exposure modifies amniotic fluid metabolites and expands group 3 innate lymphoid cells dependent on the maternal microbiome and MyD88-signaling.

Maternal high fat diet (mHFD) exposure expands IL-17 producing group 3 innate lymphoid cells (IL17+ve ILC3) in the small intestine of neonatal murine offspring and increases their susceptibility to intestinal inflammation. How mHFD modulates innate immunity in the fetal offspring remains unclear. Dams were exposed to 60% high fat diet or maintained on regular diet (RD) prior to and during mating. Amniotic fluid (AF) was collected during mid-pregnancy and metabolites examined by global non-targeted mass spectrometry in conventional wild-type (WT) and germ-free pregnant dams. Offspring were delivered by C-section or vaginally and fecal contents examined for major bacterial phyla and small intestinal lamina propria cells (LP) by flow cytometry. Susceptibility to intestinal inflammation was determined using a lipopolysaccharide and platelet-activating factor model (LPS/PAF) in WT, germ-free and MyD88 deficient offspring. Neonatal germ-free pups were exposed to HFD or RD AF by gavage and LP examined by flow cytometry. We identified differentially produced metabolites in mHFD AF when compared to RD AF in conventionally raised mice, with no difference seen in germ-free mice. C-section delivery maintained the mHFD phenotype of expansion of IL17+ve ILC3 and increased susceptibility to inflammation in neonatal offspring. In addition, mHFD offspring had expansion of IL17+ve ILC3 at birth and 2 weeks of life, which was not seen in germ-free and MyD88 KO mice exposed to mHFD. Germ-free and MyD88 KO mice were protected from mHFD induced LPS/PAF injury and IL17+ve ILC3 expansion, demonstrating that the maternal microbiome and MyD88 are prenatally necessary for the expansion of IL17+ve ILC3 in mHFD offspring. Furthermore, introduction of mHFD AF to neonatal germ-free pups by gavage was sufficient to expand IL17+ve ILC3 in the small intestine. Our findings indicate that mHFD interacts with the maternal microbiome to modify AF metabolites and signal via MyD88 to expand IL17+ve ILC3 in murine neonatal offspring.

Exploring the Effect of Resveratrol, Tyrosol, and Their Derivatives on Platelet-Activating Factor Biosynthesis in U937 Cells.

Platelet-activating factor (PAF) is a potent lipid mediator, involved in thrombosis, inflammation, and atherosclerosis. The protective effect of wine and olive oil against atherosclerotic diseases is largely attributed to their phenolic compounds and mostly to resveratrol and tyrosol. Both compounds have been reported to inhibit PAF biosynthesis in interleukin-1β (IL-1β)-stimulated monocytes and also to attenuate PAF biosynthesis in cell lysates. The aim of this study was to investigate the effects of resveratrol, tyrosol, and their derivatives on unstimulated U937 cells and to explore the intracellular messaging pathways that participate in the activation of PAF biosynthesis in the same cell line. Tyrosol and its derivatives did not exert any substantial effect on PAF biosynthesis. Resveratrol (50 and 100 μM), as well as its methoxy derivative (5-20 μM), caused a reduction in the PAF biosynthetic enzymes' activity by 20-43% after 24 h of incubation. On the other hand, lower resveratrol concentration (10 μM) and higher concentration of the methoxy derivative (50 μM) increased the Ca2+-dependent lyso-PAF acetyltransferase (LysoPAF-ATC) activity by 28-45% after half-hour incubation via p38 mitogen-activated protein kinase (p38-MAPK) action. IL-1β activated PAF biosynthetic pathways via different signaling pathways, with phospholipase C-β (PLC-β) being a key enzyme.

Abstract C043: Alprazolam abrogates the secretion of proinflammatory cytokines in PDAC CAFs

Abstract The present study sets out to determine how commonly prescribed triazolobenzodiazepines (triazoloBZDs) modulate the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC), and how this can be leveraged therapeutically to improve patient outcomes. PDAC is one of the most lethal cancer subtypes with a 5-year survival rate of ∼13%. The poor prognosis of this disease is, in part, attributable to the dense, fibrotic tumor microenvironment (TME), and lack of durable responses to standard-of-care treatment options. A recent study from our lab reported that over 40% of PDAC patients at Roswell Park are prescribed benzodiazepines (BZDs) to manage anxiety, nausea, and other disease-related side effects. Importantly, survival outcomes in these patients varied in a compound-specific manner, as the usage of the n-unsubstituted BZD lorazepam was associated with poorer outcomes, while usage of the n-substituted triazoloBZD alprazolam was associated with improved progression-free survival. In vitro and in vivo data from the aforementioned study suggested that these findings may be a result of BZD-specific regulation of interleukin-6 (IL6), a proinflammatory cytokine with a known role in PDAC pathogenesis. More specifically, alprazolam-treated cancer-associated fibroblasts (CAFs) exhibited a potent reduction in IL6 transcription and secretion, while lorazepam treatment increased IL6 production. Based on these data, we hypothesized that triazoloBZDs may uniquely reduce intratumoral inflammation to alleviate immunosuppression in PDAC. We now find that triazoloBZDs such as alprazolam suppress the secretion of several proinflammatory cytokines (IL6, CCL2, CXCL12, IL8) by CAFs, the stromal components of the PDAC TME responsible for fibrosis and exclusion of immune infiltrates. Furthermore, we have observed that this phenotype is likely a result of triazoloBZD-mediated inhibition of the platelet- activating factor (PTAFR) signaling cascade. Investigations are currently underway to determine the impact of triazoloBZDs on regulating the immune landscape of the PDAC TME in vivo. Altogether, these findings provide a basis to inform clinical selection of BZDs for symptom management and present a novel therapeutic opportunity to repurpose FDA-approved compounds for treatment of PDAC. Citation Format: Hunter D. Reavis, Arwen A. Tisdale, Kathryn E. Maraszek, Michael E. Feigin. Alprazolam abrogates the secretion of proinflammatory cytokines in PDAC CAFs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C043.

Syringin ameliorates dextran sulphate colitis via alteration oxidative stress, inflammation NF-κB signalling pathway and gut microbiota.

The objective of the current study was to investigate the potential effects of syringin against dextran sulphate colitis (DSS)-induced ulcerative colitis (UC) in mice. In vitro study was performed on the RAW 264.7 cells and cytokines and inflammatory level were estimated. The oxidative stress, inflammatory cytokines, apoptosis and inflammatory parameters were estimated. The mRNA expression and faecal samples were estimated in the colon tissue. Syringin treatment enhanced the body weight, colon length and reduced the disease activity index (DAI), spleen index. Syringin treatment remarkably suppressed the level of nitric oxide (NO), myeloperoxidase (MPO), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) along with alteration of antioxidant parameters. Syringin treatment also altered level of cytokines in the serum and colon tissue; inflammatory parameters viz., platelet-activating factor (PAF), cyclooxygenase-2 (COX-2), prostaglandin (PGE2), inducible nitric oxide synthetase (iNOS), nuclear factor κ-B (NF-κB); matrix metalloproteinases (MMP) level. Syringin significantly (p < 0.001) enhanced the level of nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase-1 (HO-1). Syringin remarkably altered the relative abundance of gut microbiota like Firmicutes, Bacteroidetes, F/B ratio, Verrucomicrobia and Actinobacteria. Syringin exhibited the protective effect against DSS-induced UC in mice via alteration of NF-κB signalling pathway.

Antibacterial chitosan/organic rectorite nanocomposite-conjugated gelatin/β-cyclodextrin hydrogels with improved hemostasis performance for wound repair

Bacterial infections and severe bleeding continue to pose significant challenges in wound repair. There is an urgent need for innovative, nature-inspired hydrogel dressings with antibacterial and hemostatic properties. A Ge-β-CD-CS-OREC conjugate hydrogel was developed by grafting β-CD and CS-OREC nanocomposites into a Ge matrix using EDC/NHS crosslinking, as confirmed by FT-IR and EDX analyses. Compared to single Ge-β-CD cross-linked hydrogels, the addition of CS-OREC enhanced the hydrogel's properties, including increased pore size (60 ± 14 μm), improved wettability (WCA = 28.82 ± 0.6°), enhanced tensile strength (41.3 ± 3.56 KPa), and strong tissue adhesion. Furthermore, this hydrogel demonstrated excellent cytocompatibility when co-cultured with keratinocytes (Kcs) and vascular endothelial cells (VECs). The incorporation of CS chains into OREC interlayers allowed the hydrogel to specifically target bacteria and increase membrane permeability in Pseudomonas aeruginosa (PA), Klebsiella pneumoniae (KP), and Staphylococcus aureus (SA), effectively reducing the bacterial load in infected wounds by 50.24–73.92 % compared to controls in vivo. Further, the hydrogel exhibited superior hemostatic efficiency (78 ± 10 s) over commercial gauze and other gels by enhancing platelet activation and coagulation factor secretion. The hydrogel accelerated tissue regeneration by promoting epithelial maturation and blood vessel regeneration, indicating its clinical potential as promising wound dressing.

Role of Platelet-Activating Factor in the Pathogenesis of Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria (CSU) is a debilitating condition characterized by mast cell activation. Platelet-activating factor (PAF) is produced by various immune cells, including mast cells, basophils, lymphocytes, and eosinophils, which play crucial roles in CSU pathogenesis. It induces mast cell degranulation, increases vascular permeability, and promotes the chemotaxis of inflammatory cells. These effects result in the release of inflammatory mediators, the development of edema, and the persistence of inflammation, which are key features of CSU. Notably, elevated PAF levels have been linked to heightened disease activity and resistance to antihistamine treatment in CSU patients. Despite these findings, the precise role of PAF in CSU pathogenesis remains unclear. Rupatadine, an antihistamine, and heat shock protein 10, a natural anti-inflammatory peptide that selectively inhibits PAF-induced mast cell degranulation, have demonstrated anti-PAF activity. Furthermore, with the molecular structure of the PAF receptor now identified, several experimental PAF receptor antagonists have been synthesized. However, there remains a significant need for the development of therapeutic options targeting PAF in CSU management.

Study on the Pilot-Scale Technology of Ginkgolide B Synthesis by Coprinus comatus

Ginkgo biloba extract (EGB) has been approved by the Food and Drug Administration in the United States for clinical studies on memory disorders. Ginkgolide B (GB) is the major terpene lactone component of EGB and is a specific and potent antagonist of platelet-activating factor (PAF). In a previous study, we reported the medium composition for the conversion of ginkgolides to GB by Coprinus comatus. In the present study, we applied the response surface methodology (RSM) to optimize the conversion conditions in a 20 L fermenter and applied HPLC-MS/MS, circular dichroism (CD) and infrared (IR) spectroscopy analyses, and nuclear magnetic resonance (NMR) to further confirm the sample structure. The optimal conversion conditions consisted of 12.7 L/min of ventilation, a 156 h conversion time, a 132 rpm rotating speed, a 0.04 MPa fermenter pressure, and a 27.8 °C conversion temperature. Under the optimal conditions, the GB conversion rate was 98.62%, and the GB content of the sample was higher than 98%. HPLC-MS/MS, CD, IR, and NMR analyses showed that the molecular formula of the sample was C20H24O10 and the chemical structure of the sample was in good agreement with the standard GB. Our current study lays the groundwork for the industrial production of GB.

Study on the Role of Platelet-Activating Factor in Promoting Relapse of Multiple Myeloma after CAR-T Therapy

Study on the Role of Platelet-Activating Factor in Promoting Relapse of Multiple Myeloma after CAR-T Therapy

Platelet-activating Factor (PAF) in Urinary Bladder Smooth Muscle (UBSM): Its Novel Role as a Potential Inducer of Detrusor Overactivity and the Mechanisms Underlying Its Effects in Enhancing UBSM Mechanical Activities

Platelet-activating factor (PAF), a phospholipid mediator, was discovered in 1972 as an inducer of platelet aggregation. Subsequent studies have revealed that PAF has a variety of biological functions, such as its role as a potent proinflammatory mediator. Additionally, PAF regulates the contractile functions of various types of smooth muscle (SM), such as the (1) endothelium-dependent relaxation of vascular SM; (2) contraction and epithelium-dependent relaxation of airway SM; (3) contraction of gastrointestinal SM; and (4) contraction of uterine SM, which occurs more strongly in pregnant females. PAF is produced in platelets, monocytes, neutrophils, and macrophages, which are cells related to thrombus formation and inflammation/immune responses. Furthermore, PAF is produced in various other cells throughout the body. Interestingly, recent studies have focused on the urinary bladder (UB) as a PAF-producing organ since the accumulation of this phospholipid is enhanced in patients with bladder cancer and interstitial cystitis/bladder pain syndrome, especially those who smoke. Therefore, in UB tissue, PAF may play a substantial role as an inducer or enhancer of cancers and inflammatory diseases. However, the effects of PAF on the immediate mechanical activities of UBSM have not been investigated to date. In this regard, we recently discovered that PAF strongly enhances mechanical activities (muscle tone and spontaneous contractile activity) in UBSM tissues isolated from guinea pigs and mice. In this review article, we present our data on these PAF effects together with the possible underlying mechanisms. We also discuss the potential pathophysiological roles of this phospholipid in UB diseases and disorders.

Lysophosphatidylcholine Acyltransferase 2 Contributes to Increased Allergic and Irritant Inflammation in Mice.

Platelet-activating factor (PAF) is an important chemical mediator in the field of inflammation, but its function in the skin is unclear. To unravel the role of PAF, we focused on lysophosphatidylcholine acyltransferase 2 (LPCAT2 also called LPLAT9), a biosynthetic enzyme involved in PAF production, and investigated the role of PAF in allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD). We measured the amount of PAF in the skin and investigated the ear swelling responses and leukocyte infiltration into the skin following the application of 2,4,6-trinitro-1-chlorobenzene (TNCB) or croton oil in wild-type (WT) and LPCAT2 knockout (LPCAT2-KO) mice. The amount of PAF was increased in the skin of WT mice after TNCB or croton oil application but not detected in LPCAT2-KO mice. The ear swelling response was decreased in LPCAT2-KO mice compared with that in WT mice. In the ACD model, the numbers of lymphocytes, eosinophils, macrophages, mast cells and neutrophils were smaller in LPCAT2-KO mice than in WT mice. In the ICD model, the ear swelling response was also decreased in LPCAT2-KO mice compared with that in WT mice. When double staining of each inflammatory cell type and LPCAT2 was performed in ACD tissue, marked co-staining of the eosinophil marker and LPCAT2 was observed. In addition, LPCAT2 expression was observed in the epidermis. These results indicate that PAF is involved in the infiltration of several cell types into the sites of allergic and non-allergic skin inflammation. Furthermore, eosinophils and keratinocytes are primarily responsible for PAF production in skin inflammation.

Hyperexpression of PTAFR and PF4 as Possible Platelet Risk Biomarkers in Patients With COVID-19.

SARS-CoV-2 infection presents different severity levels that suggest the influence of genetic factors on the clinical outcome of the disease. In cases of severe COVID-19, the presence of elevated coagulation markers, increased platelet activation and aggregation and the risk of thrombotic complications are described. Given the participation of these cells in several serious viral infections and their negative role when associated with a prothrombotic response, it is important to understand the mechanistic role of SARS-CoV-2 in platelet physiology. This study evaluated the hyperexpression of platelet-activating factor receptor (PTAFR) and platelet factor 4 (PF4) in unvaccinated and hospitalized patients with COVID-19. The study included 43 COVID-19 patients stratified according to WHO guidelines. Subsequently, the expression of the PTAFR and PF4 genes were evaluated using the real-time quantitative PCR and their possible correlation with the severity of the disease and clinical variables including hospitalization, outcome, sex, age and laboratory parameters (platelet count, INR and D-dimer). The analysis demonstrated a significant (p<0.05) hyperexpression of these genes COVID-19 patients (n=43) compared to healthy controls. Expression of these genes in patients was not statistically significant (p>0.05) different between patients stratified according to clinical variables. The expression of PTAFR and PF4 suggests an important molecular pathway in the pathophysiology of the disease and may be valuable platelet biomarkers to indicate increased risk in patients with COVID-19 who require hospital care, contributing to personalized intervention strategies and improving their clinical management.

Zinc signaling controls astrocyte-dependent synapse modulation via the PAF receptor pathway.

Astrocytes are important regulators of neuronal development and activity. Their activation plays a key role in the response to many central nervous system (CNS) pathologies. However, reactive astrocytes are a double-edged sword as their chronic or excessive activation may negatively impact CNS physiology, for example, via abnormal modulation of synaptogenesis and synapse function. Accordingly, astrocyte activation has been linked to neurodegenerative and neurodevelopmental disorders. Therefore, the attenuation of astrocyte activation may be an important approach for preventing and treating these disorders. Since zinc deficiency has been consistently linked to increased pro-inflammatory signaling, we aimed to identify cellular zinc-dependent signaling pathways that may lead to astrocyte activation using techniques such as immunocytochemistry and protein biochemistry to detect astrocyte GFAP expression, fluorescent imaging to detect oxidative stress levels in activated astrocytes, cytokine profiling, and analysis of primary neurons subjected to astrocyte secretomes. Our results reveal a so far not well-described pathway in astrocytes, the platelet activation factor receptor (PAFR) pathway, as a critical zinc-dependent signaling pathway that is sufficient to control astrocyte reactivity. Low zinc levels activate PAFR signaling-driven crosstalk between astrocytes and neurons, which alters excitatory synapse formation during development in a PAFR-dependent manner. We conclude that zinc is a crucial signaling ion involved in astrocyte activation and an important dietary factor that controls astrocytic pro-inflammatory processes. Thus, targeting zinc homeostasis may be an important approach in several neuroinflammatory conditions.

Lipopolysaccharide aggravating anaphylactoid reactions caused by traditional Chinese Medicine injections via p38/ERK/NF-κB signaling pathways

Ethnopharmacological relevanceCurrently, adverse reactions limit the development of traditional Chinese medicine injections (TCMI), and severe anaphylactoid shock is one of the serious adverse reactions, which presents a significant challenge. The presence of abnormal inflammatory mediators before the administration of TCMI will most likely result in severe anaphylactoid reactions. Not only that, the lack of clinically relevant safety evaluations impedes the widespread use of TCMI, and there is an urgent need for studies to reveal the mechanisms of anaphylactoid shock caused by TCMI. Aim of the studyTo investigate the effects and underlying mechanisms of lipopolysaccharide (LPS)-induced inflammation, which aggravates anaphylactoid reactions caused by TCMI, utilizing a guinea pig model. MethodsThe dose and duration of LPS administration and different doses of compound 48/80 (C48/80) were examined by using guinea pigs as a model. Shuanghuanglian (SHLI) and Qingkailing (QKLI) injections, these two representative TCMI, were used for validation. The plasma biochemical indices, including histamine, 5-hydroxytryptamine, tumor necrosis factor-α, interleukin 6, immunoglobulin E, C5a, tryptase, and platelet activating factor, as well as the pathological characteristics of the lung, were analyzed. Futhermore, plasma metabolomics was employed to reveal changes in metabolic pathways in vivo when inflammation co-exists with TCMI. In addition, Western blot analysis was conducted to assess the expression of critical signaling pathways. ResultsStimulation with 2 mg/kg of LPS for 12 h induced inflammatory responses in the guinea pig model. C48/80 (3.0 mg/kg) in combination with LPS resulted in an increase in anaphylactoid-related indicators in the plasma. High doses of SHLI and QKLI aggravated plasma indices and lung histological injury caused by LPS-induced inflammation. A total of 36 and 63 differential metabolites were significantly altered after LPS stimulation in the SHLI-and QKLI-treated guinea pig groups, respectively. The associated metabolic pathways include central carbon metabolism in cancer, the tricarboxylic acid cycle, glyoxylate and dicarboxylate metabolism. The p38/ERK/NF-κB signal pathway may be significantly affected by TCMI in vivo after LPS stimulation. ConclusionLPS-induced inflammation aggravated anaphylactoid reactions caused by SHLI and QKLI, with a correlation to dosage. After the presence of LPS, the administration of TCMI interferes with the immune response by over-activating the p38/ERK/NF-κB signaling pathway. This activation leads to an excessive release of inflammatory factors and anaphylactoid mediators. These results present a new direction for mitigating adverse clinical reactions associated with TCMI.

Unwinding the Threads of Mesoporous Silica Nanoparticles as Cutting-Edge for the Management of Inflammation: An Updated Review.

Inflammation serves as a protective response to combat cellular and tissue damage. There is currently a wide array of synthetic and traditional therapies available for the treatment of inflammatory diseases. However, it is necessary to create a drug delivery system based on nanotechnology that can improve the solubility, permeability, and bioavailability of current treatments. Mesoporous silica nanoparticles (MSNPs) are inorganic materials known for their organised porous interiors, high pore volumes, substantial surface area, exceptional selectivity, permeability, low refractive index, and customisable pore sizes. This review offers concise insights into the progression of the pathophysiology of inflammation, as well as the inducers, mediators, and effectors that are involved in the inflammatory pathway. This study focuses on the growing significance of MSNPs in the treatment of neuroinflammation, inflammatory bowel disease, arthritic inflammation, lung inflammation, and wound healing applications. This review also presents the latest information on the crucial role of MSNPs in delivering herbal medicines for the treatment of inflammation. A comprehensive literature search was conducted for this aim, utilising the Google Scholar, PubMed, and ScienceDirect databases. A systematic review was undertaken utilising scholarly articles published in peer-reviewed journals from 2000 to 2024. The inflammatory mediators involved in the pathophysiology of inflammation include platelet-activating factor, lipoxygenase, cyclooxygenase, Interferon-α, interleukin-6, interleukin- 1β, matrix metalloproteinases, inducible nitric oxide synthase, nuclear factor-κB, prostaglandins, nitric oxide, and phospholipase A2. MSNPs have the potential to be used in the treatment of neuroinflammation, inflammatory bowel disease, arthritic inflammation, lung inflammation, and wound healing. The investigation of the MSNPs of plant-based compounds such as berberine, tetrahydrocannabinol, curcumin, and resveratrol has shown successful results in recent years for the purpose of managing inflammation. This review demonstrates that MSNPs have a strong potential to play a positive role in delivering synthetic and plant-based therapies for the treatment of inflammatory illnesses.