Excessive Inflammation Research Articles

Sea food by-products valorization for biomedical applications: evaluation of their wound regeneration capabilities in an Ex vivo skin model

IntroductionThe skin is often exposed to harmful stimuli that might compromise its integrity and functionality. After an injury, the skin has a limited capability to restore its complex structure, and in the case of severe skin damage, surgical operations and rapid application of wound dressings are often required to promote optimal wound healing. Nowadays, collagen-based biomaterials are widely used in combination with bioactive molecules able to prevent excessive inflammation and possible infections. In line with a circular economy and blue biotechnology approach, it was recently demonstrated that both collagen and bioactive molecules (i.e., antioxidant compounds) can be sustainably obtained from sea food by-products and effectively used for biomaterial development. Herein, we describe and compare the application of two marine collagen-based wound dressings (CBWDs), produced with materials obtained from sea urchin food waste, for the treatment of skin lesions in a wound healing organ culture (WHOC) model.MethodsThe ex vivo WHOC model was set up starting from rat skin explants and the induced lesions were assigned into three different groups: control (CTRL) group, not treated, marine collagen wound dressing (MCWD) group, and antioxidants-enriched marine collagen wound dressing (A-MCWD) group. After 5 and 10 days, specimens were examined for organ maintenance and assessed for the healing process.ResultsImmunohistochemical results showed that both CBWDs were similarly successful in prolonging skin repair, preserving the epidermal barrier up to 5 days under static culture conditions. Histological and gene expression analysis highlighted that the A-MCWD might support and accelerate skin wound healing by exerting antioxidant activity and counteracting inflammation.DiscussionOverall, these findings underline the potential of sea urchin food waste as a novel resource for the development of functional medical devices for the treatment of skin wounds.

Porcine decellularized nerve matrix hydrogel attenuates neuroinflammation after peripheral nerve injury by inhibiting the TLR4/MyD88/NF-κB axis

Peripheral nerve injury causes severe neuroinflammation and has become a global medical challenge. Previous research has demonstrated that porcine decellularized nerve matrix hydrogel exhibits excellent biological properties and tissue specificity, highlighting its potential as a biomedical material for the repair of severe peripheral nerve injury; however, its role in modulating neuroinflammation post–peripheral nerve injury remains unknown. Here, we aimed to characterize the anti-inflammatory properties of porcine decellularized nerve matrix hydrogel and their underlying molecular mechanisms. Using peripheral nerve injury model rats treated with porcine decellularized nerve matrix hydrogel, we evaluated structural and functional recovery, macrophage phenotype alteration, specific cytokine expression, and changes in related signaling molecules in vivo. Similar parameters were evaluated in vitro using monocyte/macrophage cell lines stimulated with lipopolysaccharide and cultured on porcine decellularized nerve matrix hydrogel–coated plates in complete medium. These comprehensive analyses revealed that porcine decellularized nerve matrix hydrogel attenuated the activation of excessive inflammation at the early stage of peripheral nerve injury and increased the proportion of the M2 subtype in monocytes/macrophages. Additionally, porcine decellularized nerve matrix hydrogel negatively regulated the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB axis both in vivo and in vitro. Our findings suggest that the efficacious anti-inflammatory properties of porcine decellularized nerve matrix hydrogel induce M2 macrophage polarization via suppression of the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-?B pathway, providing new insights into the therapeutic mechanism of porcine decellularized nerve matrix hydrogel in peripheral nerve injury.

Abstract 4122249: Deletion of macrophage dynamin-related protein 1 exacerbates left ventricular remodeling after myocardial infarction by impairing mitochondrial quality maintenance machinery

Background: Macrophage-mediated inflammation plays an important role in the healing process after myocardial infarction (MI). We have previously reported in macrophages that inhibition of dynamin-related protein 1 (Drp1), which induces mitochondrial fission, restrains skewing toward inflammatory phenotype. It is, however, obscure whether macrophage Drp1 promotes left ventricular (LV) remodeling after MI. Aims: The aim of this study is to elucidate the role of macrophage Drp1 in the mechanisms of LV remodeling after MI. Methods: C57Bl/6J mice specifically deficient Drp1 in Lysozyme-M + macrophages (Drp1KO) were created by Cre/loxP technology and underwent ligation of the left anterior descending coronary artery at 8 to 12 weeks of age. Results: Deletion of macrophage Drp1 decreased LV ejection fraction (38±14 vs. 23±9% at day 28. N=9, p<0.05) and increased LV diameter (LVDd/Ds 5.7±0.4/4.8±0.3 vs. 4.6±0.2/3.7±0.3mm at day 28, N=9, p<0.05) (Figure). Survival rates until 28 days after MI were significantly lower in Drp1KO mice (25 vs. 64%. N=24 and 33, p<0.05). Deletion of Drp1 led to sustained macrophage accumulation and fibrosis of infarcted tissues. TEM revealed that mitophagosomes are decreased in Drp1-deficient macrophages in infarcted hearts. In ex vivo cultured macrophages, siRNA-mediated knockdown of Drp1 impaired mitochondrial fission and LC3-dependent mitophagy. In these macrophages, inhibition of Drp1 by Mdivi-1 for 96 hr, but not for 24 hr, induced mitochondrial DNA (mtDNA) leakage to the cytosol accompanied by increased expression of inflammatory cytokines. Hypoxia and starvation, in addition to Mdivi-1, induced leakage of mtDNA and expression of inflammatory cytokines at 24 hr. These results suggest that impairment of mitochondrial quality maintenance machinery causes leakage of mtDNA that induces inflammation. Conclusions: Macrophage Drp1 protects the heart from sustained inflammation and adverse cardiac remodeling after MI. Drp1-LC3-mediated mitophagy could be a mechanism that maintains mitochondrial quality and prevents excessive inflammation after MI.

Pyroligneous extract, a biomaterial derived from pyrolytic palm kernel shell wood vinegar, as a novel diabetic wound healing aid: an animal study

Objective Wound in diabetes is difficult to heal since it possesses excessive inflammation. The aim of the study was to evaluate wound healing activity of chitosan-based hydrogel containing pyroligneous acid in diabetic animals. Significance Pyroligneous acid, a byproduct of biochar production from palm kernel shell biomass, contained oxygenated compounds which, with extracting enrichment, could promote wound healing. Methods Streptozotocin-induced diabetic male jcl: ICR mice were subjected to create wounds and treat with hydrogel containing pyroligneous extract at dose strengths of 0 (placebo), 100 and 150 µg/g-gel. Commercial gel (Intrasite®) was used as an active comparator. On 3-, 7-, 10- and 14-day post-wounding, wound contraction was rated and wound site tissues were collected. The specimens were H&E stained and microscopically examined to evaluate histological responses. The underline wound healing related cytokine and polypeptide expressions were determined using real-time PCR and western blot. Results It was found that the extract accelerated the healing process in a dose-dependent manner where at dose strength of 150 µg/g-gel was as effective as active comparator. It increased gene expression of the cytokine and related proteins in TGF-β/SMAD signaling pathway and may further activate diabetic induced TGF-β downregulation to restore up to the level that healthy skin tissues express. It also enhanced the expressions of Akt, FAK, RhoA and Rac-1 and evidently activated phosphorylation of Akt and FAK. Conclusion The study demonstrated the extract could be a novel biomaterial for healing of such a chronic inflammatory wound as the wound in diabetes.

Single-cell RNA sequencing reveals common interactions between follicle immune cells and granulosa cells in premature ovarian insufficiency patients.

To investigate the follicle microenvironment of individuals with premature ovarian insufficiency (POI), normal ovarian reserve (normal) and advanced maternal age (AMA), and identify potential therapeutic targets. A total of 9 women, including 3 POI, 3 normal and 3 AMA women, underwent in vitro fertilization or intracytoplasmic sperm injection were included in this study. For each participant, the first punctured follicle not containing cumulus cells were submitted to single-cell RNA sequencing to explore the characteristics of the follicle microenvironment of POI, normal and AMA individuals. A total of 87,323 cells were isolated and grouped into six clusters: T cells, B cells, neutrophils, basophils, mononuclear phagocytes, and granulosa cells. Further analysis demonstrated that the population of granulosa cells in cluster 6 was increased in AMA and POI patients, whereas the population of gamma delta T (GDT)-cells was decreased. We also found that the genes that were differentially expressed between GDT cells and monocytes were enriched in ribosome- and endoplasmic reticulum (ER)-related pathways. In addition, it showed that VEGFA-FLT1 interaction between the monocytes and granulosa cells may be lost in the AMA and POI patients as compared with the normal group. Loss of the VEGFA-FLT1 interaction in monocytes and granulosa cells, along with enriched ER- and ribosome-related pathways, may drive excess inflammation, accelerating granulosa cell senility and contributing to infertility. This study provides new insights into the pathogenesis of POI and aging and highlights the VEGFA/FLT1 interaction may be a potential therapeutic target for reducing inflammation and treating POI.

A versatile natural gelatin-based hydrogel for emergency wound treatment through hemostasis, antibacterial, and anti-inflammation

Emergency wounds are often accompanied by bacterial infection, oxidative stress, and excessive inflammation due to the inability to quickly close and stop bleeding, resulting in chronic wounds that are difficult to heal. Clinically, surgical suturing is the fastest method for wound closure, but it is only suitable for wounds with small bleeding volumes and causes unsightly scar formation. Consequently, there is a critical need for hemostatic dressings versatile enough to address a spectrum of diverse and intricate wounds, especially in emergency scenarios. In this study, we constructed a unique versatile natural gelatin-based hydrogel with hemostasis, antibacterial, and anti-inflammation properties. The hydrogel was composed of 4-(4-(hydroxymethyl)-2-methoxy-5-nitrophenoxy) butyrylethylenediamine-modified methacrylated gelatin (GelMA-NB) and epigallocatechin gallate-grafted polylysine (EPL-EGCG), which imparts adhesion, antibacterial and antioxidant properties to the hydrogel. Simultaneously, the hydrogel was loaded with GelMA microspheres encapsulating natural resveratrol (RES@GM). This combination not only exhibited outstanding hemostatic capabilities but also preserved the anti-inflammatory potential of RES. In different animal models, the hydrogel exhibited outstanding hemostatic and wound healing effects, down-regulated the expression of IL-1βto promote inflammatory regulation and potential for angiogenesis and anti-scar. In conclusion, unique versatile natural gelatin-based hydrogel suitable for various complex wounds provides a promising strategy for emergency wound dressing applications.

3-Oxo-11αH-germacra-1(10) E,4Z-dien-12,6α-olide, a sesquiterpene from Artemisia sieversiana, attenuates lipopolysaccharide-induced inflammation via NF-κB/MAPK pathways and oxidative stress via ROS pathway in RAW264.7 cells.

Inflammation is a vital and normalphysiological response; however, excessive inflammation can contribute to the development of various diseases. Artemisia sieversiana, a traditional Chinese medicinal plant, contains a variety of chemical compounds. One such compound, 3-oxo-11αH-germacra-1(10)E,4Z-dien-12,6α-olide, a germacranolide sesquiterpenoid (germacranolide, GMO), has not been thoroughly investigated regarding its potential anti-inflammatory properties. In this study, the anti-inflammatory and antioxidant properties of GMO were investigated for the lipopolysaccharide (LPS)-induced inflammation in RAW264.7 cells. It was demonstrated that GMO effectively suppressed the production of inflammatory mediators, decreased the phosphorylation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) in RAW264.7 cells. Additionally, GMO exhibited the capacity to mitigate oxidative damage induced by LPS, as indicated by assessments of reactive oxygen species and mitochondrial membrane potential. In summary, GMO possesses significant anti-inflammatory effects by modulating the NF-κB/MAPK pathway and antioxidant effects by regulating ROS production.

Causal Effects of Gut Microbiota on Gout and Hyperuricemia: Insights from Genome-Wide Mendelian Randomization, RNA-Sequencing, 16S rRNA Sequencing, and Metabolomes.

This study investigated the causal relationship between gut microbiota (GM), serum metabolome, and host transcriptome in the development of gout and hyperuricemia (HUA) using genome-wide association studies (GWAS) data and HUA mouse model experiments. &#160;Methods: Mendelian randomization (MR) analysis of GWAS summary statistics was performed using an inverse variance weighted (IVW) approach to determine predict the causal role of the gut microbiota on gout. The HUA mouse model was used to characterize changes in the gut microbiome, host metabolome, and host kidney transcriptome by integrating cecal 16S rRNA sequencing, untargeted serum metabolomics, and host mRNA sequencing.</p> &#160;Results: Our analysis demonstrated causal effects of seven gut microbiota taxa on gout, including genera of Ruminococcus, Odoribacter, and Bacteroides. Thirty-eight, immune cell traits were associated with gout. Dysbiosis of Dubosiella, Lactobacillus,Bacteroides, Alloprevotella, and Lachnospiraceae_NK4A136_group genera were associated with changes in the serum metabolites and kidney transcriptome of the HUA model mice. The changes in the gut microbiome of the HUA model mice correlated significantly with alterations in the levels of serum metabolites such as taurodeoxycholic acid, phenylacetylglycine, vanylglycol, methyl hexadecanoic acid, carnosol, 6-aminopenicillanic acid, sphinganine, p-hydroxyphenylacetic acid, pyridoxamine, and de-o-methylsterigmatocystin, and expression of kidney genes such as CNDP2, SELENOP, TTR, CAR3, SLC12A3, SCD1, PIGR, CD74, MFSD4B5, and NAPSA.</p> &#160;Conclusion: Our study demonstrated a causal relationship between GM, immune cells, and gout. HUA development involved alterations in the vitamin B6 metabolism because of gut microbiota dysbiosis that resulted in altered pyridoxamine and pyridoxal levels, dysregulated sphingolipid metabolism, and excessive inflammation.</p>.

Inhibition of LPS-induced inflammatory response in RAW264.7 cells by natural Chlorogenic acid isomers involved with AKR1B1 inhibition

Inflammation is the physiological response of the immune system to injury or infection, typically manifested by local tissue congestion, swelling, heat, and pain. Prolonged or excessive inflammation can lead to tissue damage and the development of many diseases. The anti-inflammatory effects of natural ingredients have been extensively researched and confirmed. This study investigated the effects of Chlorogenic acid (CGA) isomers —— 3-Caffeolyquninic acid (3-CQA), 4-Caffeolyquninic acid (4-CQA), and 5-Caffeolyquninic acid (5-CQA) —— on the inflammatory response and oxidative stress reaction induced by LPS in RAW264.7 cells. Overall, 3-CQA exhibited the most significant reduction in levels of TNF-α, IL-6, NO, and ROS. 4-CQA showed superior inhibition of TNF-α compared to 5-CQA (p < 0.05), while no significant difference in other parameters. We further used DARTS and CETSA to demonstrate that CGA isomers have stable affinity with AKR1B1. As a positive control, the AKR1B1 antagonist epalrestat exhibited similar effects to the CGA isomers. 3-CQA having the smallest half-inhibitory concentration (IC50) for AKR1B1, while 4-CQA and 5-CQA have similar values. AutoDock simulations of the docking conformations revealed minimal differences in the average binding energies of the CGA isomers. The main differences were that VAL47 formed a hydrogen bond with 3-CQA, whereas GLN49 formed hydrogen bonds with 4-CQA and 5-CQA. Additionally, the number of hydrophobic bonds involving PHE122 and LEU300 varies. Our conclusion is that differences in non-covalent interactions result in the varying inhibitory abilities of CGA isomers on AKR1B1, which further affect the anti-inflammatory and antioxidant effects of CGA isomers.

Gypenosides alleviates HaCaT keratinocyte hyperproliferation and ameliorates imiquimod-induced psoriasis in mice.

Psoriasis is an autoimmune skin condition characterized by hyperproliferation of keratinocytes and chronic immune responses. Gypenosides (Gyp) exhibits anti-proliferative and anti-inflammatory effects on different diseases. However, its functioning and mechanism of Gyp on psoriasis remains unknown. To explore the effect and mechanism of Gyp on psoriasis. The impact and mechanism of Gyp on psoriasis in vitro and in vivo were probed through cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, reverse transcription quantitative polymerase chain reaction, hematoxylin and eosin staining, enzyme-linked immunosorbent serologic assay, immunofluorescence, and Western Blotting assays. Gyp inhibited cell proliferation and the release of inflammatory cytokinesin interleukin (IL-22)-induced spontaneously transformed human aneuploid immortal keratinocyte cell line (HaCaT). In addition, Gyp demonstrated enhancement in erythema and scaling as well as reductions in the thickness of epidermal layers, release of inflammatory factors, and Ki-67 (a nuclear protein) level in imiquimod (IMQ)-induced mice. Mechanistically, Gyp upregulated nuclear factor erythroid 2-related factor 2 (Nrf-2) expression and diminished the level of p-p65/p65 and p-STAT3/STAT3 in skin tissues from IMQ-induced mice and IL-22-induced HaCaT cells, which were reversed with the application of ML385, an inhibitor of Nrf2. In addition, the administration of ML385 reversed decrease in cell viability and reduced the expressions of IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) in IL-22-induced HaCaT cells caused by Gyp. In summary, Gyp reduced excessive cell growth and inflammation in psoriasis by suppressing nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) through activation of Nrf2.

γδ T Cells Mediate Protection against Neutrophil-associated Lung Inflammation in Pulmonary Melioidosis.

Pulmonary melioidosis is a severe tropical infection caused by Burkholderia pseudomallei and is associated with high mortality, despite early antibiotic treatment. γδ T cells have been increasingly implicated as drivers of the host neutrophil response during bacterial pneumonia, but their role in pulmonary melioidosis is unknown. Here, we report that in patients with melioidosis, a lower peripheral blood γδ T-cell concentration is associated with higher mortality, even when adjusting for severity of illness. γδ T cells were also enriched in the lung and protected against mortality in a mouse model of pulmonary melioidosis. γδ T-cell deficiency in infected mice induced an early recruitment of neutrophils to the lung, independent of bacterial burden. Subsequently, γδ T-cell deficiency resulted in increased neutrophil-associated inflammation in the lung as well as impaired bacterial clearance. In addition, γδ T cells influenced neutrophil function and subset diversity in the lung after infection. Our results indicate that γδ T cells serve a novel protective role in the lung during severe bacterial pneumonia by regulating excessive neutrophil-associated inflammation.

The oxidized hyaluronic acid hydrogels containing paeoniflorin microspheres regulates the polarization of M1/M2 macrophages to promote wound healing

Controlling excessive inflammation of acute wound is an effective means to shorten the healing time. Therefore, targeted control of the inflammatory response of the wound is a promising therapeutic strategy. In this study, paeoniflorin (Pae) was encapsulated in microspheres and combined with oxidized hyaluronic acid hydrogels to prepare the hydrogel loaded with Pae microspheres (Pae-MPs@OHA) to promote the healing of acute wounds in rats. The results demonstrated that the particle size of the Pae-MPs was 6.84 ± 0.51 μm, and the positive charge was 26.87 ± 1.51 mV. The uniform spherical structure of the Pae-MPs was observed by TEM. The Pae-MPs@OHA can maintain colloidal state in the range of 0.1–3.16 Hz. FTIR suggested that Pae could be effectively wrapped in MPs, and SEM indicated that the Pae-MPs@OHA had a uniform network pore structure. The Pae-MPs@OHA can realize the sustained release of Pae for 96 h. Biocompatibility experiments showed that the Pae-MPs@OHA hydrogels were safe and available. The Pae-MPs@OHA hydrogels can accelerate wound healing in rats. HE and masson staining suggested that the Pae-MPs@OHA could reduce inflammatory cell infiltration, promote re-epithelialization and collagen formation. The Pae-MPs@OHA could decrease the number of M1 and increase the number of M2 in macrophages, thus regulating the release of inflammatory factor TNF-α and IL-1β. The results of molecular docking and western blot results also confirmed that the Pae-MPs@OHA could reduce the expression of NF-κB, pNF-κB, NLRP3, ASC and pro-caspase-1. These findings suggest that the Pae-MPs@OHA has great potential for application in the treatment of inflammatory wound.

T Regulatory Cell Subsets Do Not Restore for One Year After Acute COVID-19.

COVID-19, caused by SARS-CoV-2, triggers a complex immune response, with T regulatory cells (Tregs) playing a crucial role in maintaining immune homeostasis and preventing excessive inflammation. The current study investigates the function of T regulatory cells during COVID-19 infection and the subsequent recovery period, emphasizing their impact on immune regulation and inflammation control. We conducted a comprehensive analysis of Treg subpopulations in peripheral blood samples from COVID-19 patients at different stages: acute infection, early convalescence, and long-term recovery. Flow cytometry was employed to quantify Tregs including "naïve", central memory (CM), effector memory (EM), and terminally differentiated CD45RA+ effector cells (TEMRA). Additionally, the functional state of the Tregs was assessed by the expression of purinergic signaling molecules (CD39, CD73). Cytokine profiles were assessed through multiplex analysis. Our findings indicate a significant decrease in the number of Tregs during the acute phase of COVID-19, which correlates with heightened inflammatory markers and increased disease severity. Specifically, we found a decrease in the relative numbers of "naïve" and an increase in EM Tregs, as well as a decrease in the absolute numbers of "naïve" and CM Tregs. During the early convalescent period, the absolute counts of all Treg populations tended to increase, accompanied by a reduction in pro-inflammatory cytokines. Despite this, one year after recovery, the decreased subpopulations of regulatory T cells had not yet reached the levels observed in healthy donors. Finally, we observed the re-establishment of CD39 expression in all Treg subsets; however, there was no change in CD73 expression among Tregs. Understanding these immunological changes across different T regulatory subsets and adenosine signaling pathways offers important insights into the disease's pathogenesis and provides a broader view of immune system dynamics during recovery.

A tranexamic acid-functionalized acellular dermal matrix sponge co-loaded with magnesium ions: Enhancing hemostasis, vascular regeneration, and re-epithelialization for comprehensive diabetic wound healing

Excessive inflammation, accumulation of wound exudate, and blood seepage are common in diabetic wounds, hindering cell proliferation and disrupting tissue remodeling, leading to delayed healing. This study presents a multifunctional sponge scaffold (P5T3@Mg) created by combining an acellular dermal matrix with tranexamic acid and MgO nanoparticles, designed for hemostatic and anti-inflammatory effects. The P5T3@Mg scaffold effectively absorbs wound fluid while promoting healing. In vivo and in vitro hemostasis experiments demonstrate that the P5T3@Mg sponge exhibits excellent hydrophilicity, enhancing blood absorption at the wound site, inhibiting fibrinolysis, and expediting hemostasis. Additionally, the sustained release of Mg2+ from the P5T3@Mg sponge promotes collagen deposition and angiogenesis in diabetic rat wounds, suppressing chronic inflammation and accelerating tissue remodeling and repair.

Effect of Bioplastic Material on Adhesion, Growth, and Proliferative Activity of Human Fibroblasts When Incubated in Solutions Mimic the Acidity of Wound an Acute and Chronic Inflammation.

: The aim of this study was to characterize the effect of bioplastic material based on collagen, hyaluronic acid, and elastin on the viability and proliferative activity of human fibroblasts in conditions simulating the acidity of acute and chronic wounds. : Bioplastic material was made according to the method described in RF patent no.2722744. Adhesive properties and proliferative activity of human fibroblasts were assessed visually using fluorescent microscopy. The number of apoptotic and necrotic cells was assessed by flow cytometry (BD FACSCanto II) using the commercial FITC Annexin V Apoptosis Detection Kit I (BD Pharmingen). The strength, Young's modulus, and elasticity of the gels were determined on a TA.XT-plus texture analyzer (Stable Micro Systems, Great Britain). : Using the methods of luminescent microscopy and flow cytometry, we found that the cell viability (namely, adhesive properties and proliferative activity) decreases after incubation on condition mimic of physiological acidosis. We found that bioplastic material contributes to the preservation of adhesive properties, viability, and proliferative activity of fibroblasts in physiological acidosis conditions. The results obtained indicate that bioplastic material based on soluble dermis components can be used as a biologically active component of wound dressings to increase the effectiveness of reparative regeneration, especially in cases of excessive acute inflammation.

Ethnic variations in post ST elevation myocardial infarction inflammatory kinetics

Abstract Introduction Sterile inflammation post myocardial infarction (MI) is essential to activation reparative mechanisms. However, excessive inflammation contributes to detrimental recovery and adverse outcomes(1). Several studies have reported an association between elevated leucocyte subpopulations and neutrophil-lymphocyte ratio (NLR) with poor prognosis after MI(2). In healthy volunteers, it is known that black individuals have a lower diurnal neutrophil, basophil, and monocyte count and the term ‘benign ethnic neutropenia’ has been used(3). However, the effect of ethnicity on leucocyte counts after MI is not known. Purpose We aimed to assess the interaction between ethnicity and leucocyte subpopulations and NLR. Understanding post-MI inflammation and its interaction with ethnicity is essential in providing personalised patient management and prognostication. Methods We conducted a single centre retrospective observational study of consecutive patients presenting with ST-segment elevation MI (STEMI) between 2016 and 2022. Patients were divided into white and other ethnic groups combined (‘ethnic minorities’) based on self-reported ethnicity. Leucocyte subpopulations, neutrophil and monocyte lymphocyte ratios (NLR and MLR, respectively) at baseline and for 4 days post admission were compared. Baseline variables were analysed with Shapiro-Wilk testing and presented as median (IQR). Area under the curve (AUC) was used to analyse magnitude of change in longitudinal analysis with smoothed conditional means (LOESS) to display trends in the data. Univariate and multivariate linear regression analyses were used to investigate for an association between ethnicity and baseline clinical variables. Results We included 1933 STEMI patients, of whom 1477 (76%) were white and 456 (24%) were from ethnic minority groups. Baseline neutrophils (7.73 [5.9-10] vs 9.04 [6.7-11.9] x109/L), monocytes (0.52 [0.38-0.69] vs 0.6 [0.44-0.82] x109/L), basophils (0.03 [0.02-0.04] vs 0.04 [0.02-0.06] x109/L), NLR (4.47 [2.93-7.19] vs 5.61 [3.64-8.89]) and MLR (0.3 [0.21-0.43] vs 0.36 [0.26-0.53]) were significantly lower (all p&amp;lt;0.001) in ethnic minority vs white patients. There were no differences in peak troponin T or CRP. Longitudinal assessment of leucocyte subgroups and NLR showed that white patients had a significantly higher AUC and difference between minimum and maximum values (delta) for neutrophils, monocytes, basophils and NLR (Panel 1). After correction, we observed a negative association between being in the ethnic minority group and baseline NLR (p=0.005) and basophil count (p&amp;lt;0.001). Conclusions Despite baseline differences in leucocyte subgroups and NLR according to ethnicity, there is a distinct interaction among patients with STEMI suggesting an ethnicity-specific inflammatory profile. Blunting of the magnitude and duration of leucocyte response is novel, and future work will focus on the implications for prognosis and tailored therapy.

Platelet Glycoprotein Ibα Cytoplasmic Tail Exacerbates Thrombosis During Bacterial Sepsis.

Septic patients, coupling severe disseminated intravascular coagulation (DIC) and thrombocytopenia, have poor prognoses and higher mortality. The platelet glycoprotein Ibα (GPIbα) is involved in thrombosis, hemostasis, and inflammation response. However, it remains unclear whether the GPIbα cytoplasmic tail regulates sepsis-mediated platelet activation and inflammation, especially in Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) infections. Using a mouse model of S. aureus-induced bacteremia, we found that both 10 amino acids of GPIbα C-terminal sequence deficiency and pharmacologic inhibition of protein kinase C (PKC) alleviated pathogenesis by diminishing platelet activation and aggregate formation. Furthermore, the GPIbα cytoplasmic tail promoted the phagocytosis of platelets by Kupffer cells in vivo. The genetically deficient GPIbα cytoplasmic tail also downregulated inflammatory cytokines and reduced liver damage, ultimately improving the survival rate of the septic mice. Our results illustrate that the platelet GPIbα cytoplasmic domain exacerbates excessive platelet activation and inflammation associated with sepsis through a PKC-dependent pathway. Thus, our findings provide insights for the development of effective therapeutic strategies using PKC inhibitor treatment against bacterial infection.

Evaluation of Rosmarinic Acid Attenuation Effect on Endoplasmic Reticulum Stress in Swiss-type Mice Affected With Nonalcoholic Steatohepatiti

Background and Objectives: Nonalcoholic steatohepatitis is a severe liver disease characterized by excess lipid accumulation (steatosis) and inflammation in the liver. Endoplasmic reticulum stress is considered one of the crucial factors in nonalcoholic steatohepatitis pathophysiology. Rosmarinic acid is a herbal medicine with antioxidant and anti-inflammatory properties. This study aimed to evaluate the effect of rosmarinic acid on reducing the endoplasmic reticulum stress induced by nonalcoholic steatohepatitis in male Swiss-type mice. Methods: The study animals were grouped into four: Saline, rosmarinic acid, nonalcoholic steatohepatitis, and nonalcoholic steatohepatitis-rosmarinic acid. Nonalcoholic steatohepatitis was induced by a diet without methionine-choline for 8 weeks, and rosmarinic acid was injected intraperitoneally daily for 8 weeks in mice. After 8 weeks, the animals were killed, and their liver samples were obtained. Real-time PCR was used for molecular studies. Data analyses were performed by one-way analysis of variance and Tukey's post hoc test. Results: Findings of this study showed that rosmarinic acid alleviated mRNA levels of GRP78, IRE-1, and PERK while increasing the Apo B expression. Conclusion: The results suggest that rosmarinic acid ameliorates endoplasmic reticulum stress parameters, upregulates Apo B expression as a key factor in triglyceride exit from the liver, and thereby improves nonalcoholic steatohepatitis in male Swiss-type mice.

Role of physicochemical properties in silica nanoparticle-mediated immunostimulation

Immunostimulation caused by nanoparticles may be beneficial or adverse depending on their intended application. Activation of immune cells is beneficial for indications targeting the immune system for therapeutic purposes, such as tumor microenvironment reprogramming, immunotherapy, and vaccines. When it is unwanted, however, immunostimulation may lead to excessive inflammation, cytokine storm, and hypersensitivity reactions. The increasing use of silica nanoparticles (SiNPs) for the delivery of drugs, imaging agents, and antigens warrants preclinical studies aimed at understanding carrier-mediated effects on the number, activation status, and function of immune cell subsets. Herein, we present an in vitro study utilizing primary human peripheral blood mononuclear cells (PBMC) to investigate the proinflammatory properties of four types of SiNPs varying in size and porosity. Cytokine analysis was performed in resting and LPS-primed PBMC cultures to understand the ability of silica nanoparticles to induce de novo and exaggerate preexisting inflammation, respectively. Changes in the number and activation status of lymphoid and myeloid cells were studied by flow cytometry to gain further insight into SiNP-mediated immunostimulation. Nonporous SiNPs were found to be more proinflammatory than mesoporous SiNPs, and larger-sized particles induced greater cytokine response. LPS-primed PBMC resulted in increased susceptibility to SiNPs. Immunophenotyping analysis of SiNP-treated PBMC resulted in T and B lymphocyte, natural killer cell, and dendritic cell activation. Additionally, a loss of regulatory T cells and an increase in γδ TCR T cell population were observed with all particles. These findings have implications for the utility of SiNPs for the delivery of drugs and imaging agents.

Distinct maternofetal immune signatures delineate preterm birth onset following urinary tract infection.

Preterm birth is the leading cause of infant mortality resulting in over one million neonatal deaths annually. Maternal urinary tract infection (UTI) during pregnancy increases risk for preterm birth; however, biological processes mediating UTI-associated preterm birth are not well-described. We established a murine maternal UTI model in which challenge with uropathogenic E. coli resulted in preterm birth in about half of dams. Dams experiencing preterm birth displayed excessive bladder inflammation and altered uteroplacental T cell polarization compared to non-laboring infected dams, with no differences in bacterial burdens. Additional factors associated with preterm birth included higher proportions of male fetuses and lower maternal serum IL-10. Furthermore, exogenous maternal IL-10 treatment absolved UTI-associated preterm birth but contributed to fetal growth restriction in this model. Using urine samples from a cohort of human pregnancies with or without UTI, we correlated urinary cytokines with birth outcomes and urine culture status. These analyses yielded a non-invasive, highly predictive three-model system for evaluating preterm birth risk implicating cytokines IL-10, IL-15, IL-1β, and IL-1RA. Our unique bimodal murine model coupled with patient samples provides a platform to investigate immunological and microbial factors governing UTI-associated preterm birth, revealing novel therapeutic opportunities to predict or prevent preterm birth.