Infection Inflammation Research Articles

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.

The possibility of using synovial C-reactive protein, interleukin-6 and presepsin in the diagnosis of periprostheticjoint infection.

The diagnosis of infectious complications in joint prosthetics remains a pressing issue, especially in cases where pathogens do not grow during the seeding of biological material. This study analyzed the potential use of synovial biomarkers for the diagnosis of periprosthetic infections (PPI), based on literature data. The aim was to determine the significance of synovial C-reactive protein (CRP), interleukin-6 (IL-6), and presepsin in diagnosing PPI. Materials and methods: A prospective, single-center, blinded study was conducted on patients undergoing revision arthroplasty for both infectious and aseptic inflammation in the endoprosthetic area. The study included 66 patients, divided into two groups: Group I included 17 patients with periprosthetic infection diagnosed according to the ICM Philly criteria of 2018; and Group II included 49 patients with aseptic inflammation in the endoprosthetic region.Synovial fluid samples from all participants were analyzed for bacteriological and cytological analysis to determine the levels of CRP, IL-6, and presepsin. Receiver operating characteristic (ROC) analysis was performed to determine sensitivity, specificity, and accuracy, as well as thresholds for laboratory data. Results: The greatest reliability for diagnosing infectious and aseptic inflammations was shown for the number of leukocytes in synovial fluids, with an area under the curve (AUC) of 0,928 (95% confidence interval [CI]: 0,837-0,977; p0,0001), as well as for synovial CRP with an AUC of 0,776 (95% CI: 0,656-0,87; p=0,0004), and IL-6 with an AUC of 0,712 (95% CI: 0,583-0,82, p=0,0048). While the presepsin level was significantly different between groups, AUC was 0,582 (95% CI: 0,453-0,703, p=0,3344). Threshold values were calculated for CRP at 5,6 mg/L and presepsin – 1212,0 pg/mL and IL-6 – 988,5 pg/mL. The sensitivity, specificity, and accuracy of the diagnosis of PPI were 62,5%, 85,71%, and 80%, respectively for CRP; 68,5%, 63,04%, and 68,7% for IL-6; and 43,75%, 79,59%, and 70,77% for presepsin. Conclusion: IL-6 has the highest sensitivity for PPI, but it has lower accuracy and specificity than CRP. Presepsin has the lowest sensitivity, specificity and accuracy for the diagnosis of PPI.

OA26 Atypical Multisystem Inflammation related to infection or just plain old polyarteritis nodosa?

Abstract Introduction We present the case of a 5-year-old boy with episodes of pyrexia of unknown origin associated with polyarthritis, central neuroinflammation and mucocutaneous manifestations. His skin biopsy demonstrated a nodular vasculitis which could be consistent with polyarteritis nodosa. Interestingly though, he had additional atypical rashes, ocular inflammation and evidence of acute and past streptococcal infection and his fever and CRP normalised prior to corticosteroid initiation. Case description A five-year-old British African male presented with five-week history of persistent fever, headaches, joint pain and bilateral eye pain. He was transferred to a tertiary paediatric infectious disease’s unit due to unrelenting fever with no fixed pattern, despite nine days of broad-spectrum intravenous antibiotics. He was diagnosed with neuroinflammation of uncertain aetiology, evidenced by leptomeningeal enhancement and bilateral papillitis on brain MRI. CSF microbiology and autoimmune profiles were negative. There was no evidence of primary malignancy. The fever resolved with pulsed IV methylprednisolone and the child was discharged home on a weaning regime of oral prednisolone. After stopping steroid treatment, he represented with high-grade fever, limping, anterior uveitis and new-onset non tender cutaneous lesions, plaques over eyelids and cheek and annular lesions over arms, legs and buttocks. Repeat MRI of the brain and spine showed resolution of previous neuroinflammation. Blood tests revealed raised ANA, IgG and ASOT titre, and his throat swab was positive for Group A Streptococcus. He completed 10 days of intravenous antibiotics and oral high dose ibuprofen (10 mg/kg TDS). On review by tertiary paediatric rheumatology, he was identified to have pleomorphic skin rash and subcutaneous nodules. Skin and deep tissue biopsy confirmed lobular and septal panniculitis with necrotising vasculitis, consistent with a nodular vasculitis. Treatment with high-dose steroid and mycophenolate mofetil (MMF) was initiated, but his CRP and fever had resolved prior to his first dose. He experienced improvement in systemic symptoms and arthritis; however, skin lesions persisted, with appearance of new lesions and hyperpigmentation, on reduction of steroid dose. His course was complicated by acute varicella infection, requiring oral aciclovir. Further treatment trials included topical tacrolimus and topical corticosteroids for his skin lesions. At one biopsy site, he experienced significant delay in wound healing. The genetic panel for primary immunodeficiency panel (R15) demonstrated no pathological variants. Discussion This case report highlights that, whilst the biopsy may be consistent with nodular vasculitis, such as PAN, the clinical manifestations are not perfectly aligned. Discussion within the rheumatology community would support optimal patient care. Childhood-onset Polyarteritis Nodosa (c-PAN) is a rare systemic vasculitis. Although the aetiology is unknown, associations with infections like group A streptococcus and hepatitis B suggest a postinfectious autoimmune response. There are no clear genetic links to PAN, but PAN-like vasculitis is part of reported monogenic autoinflammatory conditions. Key atypical features in this case include uveitis at presentation, nonspecific central neuroinflammation, unusual cutaneous lesion morphology, improvement of acute phase reactants before immunomodulatory treatment, and delayed biopsy wound healing. While ocular findings in PAN may include episcleritis, scleritis, keratitis, retinal vascular occlusions, and ocular ischemic syndrome, uveitis has not been reported in c-PAN. The patient also showed nonspecific inflammatory changes on initial MRI. Neurological involvement in c-PAN typically includes cerebrovascular accidents, cranial nerve palsies, and mononeuritis multiplex, with meningeal involvement being less common (reported 4% in a study of 69 children). Additionally, the patient experienced delayed wound healing following the biopsy, which is undocumented in c-PAN, but may be related to immune modulating treatment. A positive streptococcal throat swab could suggest an immune reaction as part of bacterial tonsilitis, or Acute Rheumatic Fever. However, he did not meet Jones Criteria, there was no response to prolonged antibiotics and the chronic remitting nature made these less likely. An autoinflammatory disorder, Deficiency of Adenosine Deaminase 2 (DADA2), was also considered but he had no evidence of livedo racemosa, strokes and no CECR1 mutation was identified. Our case has been discussed within a multidisciplinary team and we speculate that it could represent a previously undefined immune sensitivity within the autoimmune, autoinflammatory and immune deficiency spectrum giving an exaggerated response to infection. Key learning points • This case presents a significant diagnostic challenge due to its atypical clinical features and inconclusive extensive investigations, including immunologic testing, tissue biopsy, and genetic analysis. • While the patient’s symptoms improved with high-dose steroids and MMF, the recurrence of symptoms upon tapering steroids underscores the persistent inflammatory nature of the disease. • The detection of group A Streptococcus in the patient’s throat swab suggests a potential postinfectious autoimmune trigger, highlighting the role infections can play in the pathogenesis of vasculitis. The negative results from the R15 Primary Immunodeficiency panel suggest that more advanced genetic and immunologic testing may be beneficial. • We invite discussion on whether additional genetic or immunologic testing could optimise this patient’s care and contribute to the broader understanding of atypical vasculitis syndromes.

Antimicrobial peptide LyeTx I mn∆K labeled with 68Ga is a potential PET radiopharmaceutical for molecular imaging of infections

BackgroundAntimicrobial peptides have been radiolabeled and investigated as molecular diagnostic probes due to their propensity to accumulate in infectious sites rather than aseptic inflammatory lesions. LyeTx I is a cationic peptide from the venom of Lycosa erythrognatha, exhibiting significant antimicrobial activity. LyeTx I mn∆K is a shortened derivative of LyeTx I, with an optimized balance between antimicrobial and hemolytic activities. This study reports the first 68Ga-radiolabeling of the DOTA-modified LyeTx I mn∆K and primarily preclinical evaluations of [68Ga]Ga-DOTA(K)-LyeTx I mn∆K as a PET radiopharmaceutical for infection imaging. MethodsDOTA(K)-LyeTx I mn∆K was radiolabeled with freshly eluted 68Ga. Radiochemical yield (RCY), radiochemical purity (RCP), and radiochemical stability (in saline and serum) were evaluated using ascending thin-layer chromatography (TLC) and reversed-phase high-performance liquid chromatography (RP-HPLC). The radiopeptide's lipophilicity was assessed by determining the logarithm of the partition coefficient (Log P). Serum protein binding (SBP) and binding to Staphylococcus aureus (S. aureus) cells were determined in vitro. Ex vivo biodistribution studies and PET/CT imaging were conducted in healthy mice (control) and mice with infection and aseptic inflammation to evaluate the potential of [68Ga]Ga-DOTA(K)-LyeTx I mn∆K as a specific PET radiopharmaceutical for infections. Results[68Ga]Ga-DOTA(K)-LyeTx I mn∆K was obtained with a high RCY (>90 %), and after purification through a Sep-Pak C18 cartridge, the RCP exceeded 99 %. Ascending TLC and RP-HPLC showed that the radiopeptide remained stable for up to 3.0 h in saline solution and up to 1.5 h in murine serum. [68Ga]Ga-DOTA(K)-LyeTx I mn∆K exhibited hydrophilic characteristics (Log P = −2.4 ± 0.1) and low SPB (ranging from 23.3 ± 0.4 % at 5 min of incubation to 10.5 ± 1.1 % at 60 min of incubation). The binding of [68Ga]Ga-DOTA(K)-LyeTx I mn∆K to S. aureus cells was proportional to bacterial concentration, with binding percentages of 8.8 ± 0.5 % (0.5 × 109 CFU.mL−1), 16.2 ± 1.4 % (1.0 × 109 CFU.mL−1), and 62.2 ± 0.6 % (5.0 × 109 CFU.mL−1). Ex vivo biodistribution studies and PET/CT images showed higher radiopeptide uptake at the infection site compared to the aseptic inflammation site; the latter was similar to the control group. Target-to-non-target (T/NT) ratios obtained by ex vivo biodistribution data were approximately 1.0, 1.3, and 3.0 at all investigated time intervals for the control, aseptic inflammation, and infection groups, respectively. Furthermore, T/NT ratios obtained from PET/CT images were 1.1 ± 0.1 for the control group and 1.4 ± 0.1 for the aseptic inflammation group. For the infection group, T/NT ratio was 5.0 ± 0.3, approximately 5 times greater compared to the former groups. ConclusionsThe results suggest the potential of [68Ga]Ga-DOTA(K)-LyeTx I mn∆K as a PET radiopharmaceutical for molecular imaging of infections.

Detection of C-reactive protein using a label-free NIR fluorescent aptasensor with a large Stokes shift based on an AIEE anthracene derivative

BackgroundC-reactive protein (CRP), one of the classic biomarkers of inflammation, is closely related to infectious inflammation, cardiovascular disease, cancer, and other diseases. Therefore, timely and accurate detection of CRP in human blood is crucial for the discovery, diagnosis, and treatment of the aforementioned diseases. Herein, a novel label-free NIR fluorescence aptasensor with a large Stokes shift based on an AIEE anthracene derivative B and a molybdenum disulfide (MoS2) platform was developed and used for the high sensitivity and specificity detection of CRP. ResultsCompound B could emit near-infrared (NIR) fluorescence with a large Stokes shift (190 nm). Notably, this compound could bind with the aptamer of CRP (CRP-Apt) through electrostatic attraction to form a B/CRP-Apt complex, generating an aggregation-induced emission enhancement effect and enhancing the fluorescent intensity of B. B/CRP-Apt could be adsorbed on the surface of MoS2 with the addition of MoS2 to its solution, and the fluorescence of Compound B was quenched. CRP was then added to the above solution. CRP-Apt had a substantially higher affinity for CRP than MoS2. Therefore, B/CRP-Apt detached from the surface of MoS2 and bound to CRP, thereby restoring the fluorescence of B. Experimental results showed a good linear relationship between the fluorescent recovery intensity of B and the concentration of CRP in the concentration range of 0.3–70 ng mL−1, with a limit of detection as low as 0.1 ng mL−1. Significance and NoveltyThe aptasensor integrates the advantages of high sensitivity of NIR fluorescence, high specificity of aptamers, good water-solubility and AIEE effect of Compound B. And it could be applied to the determination of CRP in human serum samples, while most of the reported methods can only determine CRP in spiked human serum samples.

The multiple roles of macrophages in peritoneal adhesion

AbstractPeritoneal adhesion (PA) refers to the abnormal adhesion of the peritoneum either with the peritoneum itself or with tissues and organs that is caused by abdominopelvic surgery, abdominal infection or peritoneal inflammation. PA is associated with various clinical complications, such as abdominal pain and distension, intestinal obstruction, gastrointestinal disorders and female infertility, and adversely affects the quality of life of patients. Macrophages are essential for PA formation and can undergo polarization into classically activated macrophages (M1) and alternatively activated macrophages (M2), which are influenced by the peritoneal microenvironment. By releasing proinflammatory cytokines and reactive oxygen species, M1 macrophages promote peritoneal inflammatory reactions and the resultant formation of adhesion. In contrast, M2 macrophages secrete anti‐inflammatory cytokines and growth factors to inhibit PA formation and to promote repair and healing of peritoneal tissues, and thereby play a significant anti‐inflammatory role. This review comprehensively explores the function and mechanism of macrophages and their subtypes in PA formation to gain insight into the prevention and treatment of PA based on the modulation of macrophages.

Infection and Inflammation in the Cystic fibrosis (CF) airway.

Cystic fibrosis (CF) airway disease is characterized by chronic infection and neutrophil-driven inflammation, leading to progressive airway damage and early mortality. Infection with Pseudomonas aeruginosa significantly impacts morbidity and mortality, requiring early detection and aggressive antibiotic treatment. Controlling inflammation remains difficult due to the limited availability of effective anti-inflammatory treatments. CFTR modulators show potential in reducing inflammation, but further research is needed. Effective management of CF lung disease requires a comprehensive approach addressing both infection and inflammation.

The Detection of Chlamydia pneumoniae, Helicobacter pylori and Cytomegalovirus in Non-Atherosclerotic Arteries of Patients with Coronary Artery Disease

Atherosclerotic coronary artery disease (ACAD) is a major cause of global morbidity and mortality, characterized as an inflammatory process due to damage to blood vessel walls by risk factors like aging, hyperlipidemia, hypertension, smoking, and diabetes. Infectious agents, including Chlamydia pneumoniae (Cpn), Cytomegalovirus (CMV), and Helicobacter pylori (HP), have been implicated in ACAD’s pathophysiology. A study with 56 subjects undergoing coronary artery bypass grafting (CABG) aimed to detect Cpn, CMV, and HP DNA in unaffected artery segments and explore associations with disease progression and inflammation markers. The study found infectious agents’ DNA in 21.4% of samples, HP in eight samples, and CMV and Cpn in four samples each. Significant correlations were observed between HP and overweight or obese subjects, as well as between the presence of infectious agents and inflammation marker values. An association between HP and renal function was also noted. The findings reaffirm previous discoveries of infectious agents in non-clinically affected arteries used as CABG grafts. Correlations identified between the presence of HP, CMV, and Cpn DNA in grafts and several biomarkers of inflammation and obesity emphasize the potential role of these infectious agents in ACAD pathogenesis.

Bioinformatics and network pharmacology discover the molecular mechanism of Liuwei Dihuang pills in treating cerebral palsy.

A collection of chronic central motor, postural, and activity restriction symptoms are referred to as cerebral palsy (CP). Previous research suggests that a number of perinatal variables, including hypoxia, may be linked to CP. And the pathophysiological process that causes brain injury in growing fetuses is mostly caused by amniotic fluid infection and intra-amniotic inflammation. Still, there is still much to learn about the molecular mechanism of CP. The goal of this study was to identify the molecular mechanism of Liuwei Dihuang pill (LWDHP) in the treatment of CP using network pharmacology and bioinformatics. The Chinese medicine database provided the LWDHP components and targets, the CP illness gene data set was gathered from a disease, and the expression profile of children with CP was chosen from anther database. Using the Kyoto Encyclopedia of Genes and Genomes and gene ontology databases, a network of interactions between proteins was created, and functional enrichment analysis was carried out. Analysis of traditional Chinese medicine found that the key active ingredients of LWDHP are quercetin, Stigmasterol and kaempferol. Through enrichment analysis, it was found that the hub genes for LWDHP treatment of CP are CXCL8, MMP9, EGF, PTGS2, SPP1, BCL2L1, MMP1, and AR. K EGG analysis found that LWDHP treatment of CP mainly regulates PI3K-Akt signaling pathway, IL-17 signaling pathway, Jak-STAT signaling pathway, NF-kappa B signaling pathway, etc. To summarize, LWDHP regulates immunological and inflammatory variables through a variety of components, targets, and signaling pathways, which plays a significant role in the development and management of CP.

Systematisation of the causes that required revision hip replacement, methods of their solution, treatment results in Ukraine

BackgroundThe objective of this study is to organise data on complications following total hip replacement (THA) over a span of 10 years, specifically focussing on cases that necessitated revision endoprosthetic surgeries. The objective is to create a recommendation for an All-Ukrainian registry of initial and repeated hip arthroplasty (HA) and standardise the terminology used to define “revision of total hip replacement surgery”.MethodsThe retrospective analysis examined 236 instances of revision hip arthroplasty (rTHA) performed at the Institute of Traumatology and Orthopaedics Centre between January 2005 and December 2021. The primary factors for revision were identified through an analysis of the patient’s medical records, laboratory results, visual inspection, and the state of the previously implanted prosthesis. Demographic information, primary and revision HA dates, diagnoses, and causes of complications were recorded. The statistical analysis was conducted using the Statistica package (StatSoft), version 12.6 (2015), with a significance level of p < 0.05.ResultsOut of the 364 patients who were diagnosed with complications, 236 of them (55.17%) needed a procedure called 1rTHA. Among these cases, 152 (41.76%) were specifically diagnosed with aseptic component instability. Significant factors for mechanical loosening were a high body mass index (BMI ≥ 30) and older age, with respective t-values of 2.08 (p = 0.004) and 2.59 (p = 0.045). Osteoporosis significantly contributed to aseptic loosening and fractures around the implant. The occurrence of infectious complications was frequently linked to chronic infectious diseases (t = 3.37, p = 0.001). The overall percentage of need for 2rTHA was 27.22% (43 cases), with one case of infectious lesion following the revision.ConclusionsThe study emphasises the urgent requirement for standardised terminology and a comprehensive registry for hip arthroplasty procedures. Primary results indicate that cement-free fixation is more effective than cement-based fixation for revision in patients with aseptic instability and that two-stage arthroplasty is effective for treating infectious inflammation. Furthermore, the most effective treatment for femoral fractures with periprosthetic involvement was determined to be open repositioning and osteosynthesis with metal retainers. The aforementioned observations emphasise the need to create a comprehensive registry across Ukraine to support patient care, enable evidence-based practices, and enhance the overall effectiveness of hip arthroplasty operations.Clinical trial numberNot applicable.

NIR-II Image-Guided Wound Healing in Hypoxic Diabetic Foot Ulcers: The Potential of Ergothioneine-Luteolin-Chitin Hydrogels.

Hypoxic diabetic foot ulcers (HDFUs) pose a challenging chronic condition characterized by oxidative stress damage, bacterial infection, and persistent inflammation. This study introduces a novel therapeutic approach combining ergothioneine (EGT), luteolin (LUT), and quaternized chitosan oxidized dextran (QCOD) to address these challenges and facilitate wound healing in hypoxic DFUs. In vitro, assessments have validated the biosafety, antioxidant, and antimicrobial properties of the ergothioneine-luteolin-chitin (QCOD@EGT-LUT) hydrogel. Furthermore, near-infrared II (NIR-II) fluorescence image-guided the application of QCOD@EGT-LUT hydrogel in simulated HDFUs. Mechanistically, QCOD@EGT-LUT hydrogel modulates the diabetic wound microenvironment by reducing reactive oxygen species (ROS). In vivo studies demonstrated increased expression of angiogenic factors mannose receptor (CD206)and latelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), coupled with decreased inflammatory factors tumor necrosis factor-α (TNF-α) and Interleukin-6 (IL-6), thereby promoting diabetic wound healing through up-regulation of transforming growth factor β-1 (TGF-β1).

D-[5-11C]-Glutamine Positron Emission Tomography Imaging for Diagnosis and Therapeutic Monitoring of Orthopedic Implant Infections.

Orthopedic implant infections (OIIs) present diagnostic and therapeutic challenges, owing to the lack of methods to distinguish between active infection and sterile inflammation. To address this unmet need, d-amino-acid-based radiotracers with unique metabolic profiles in microorganisms have emerged as a novel class of infection-specific imaging agents. Given the pivotal role of d-glutamine in bacterial biofilm formation and virulence, herein, we explored the potential of positron emission tomography (PET) imaging with d-[5-11C]-Glutamine (d-[5-11C]-Gln) for early detection and treatment monitoring of OIIs. In vitro studies confirmed an active uptake of d-[5-11C]-Gln by Staphylococcus aureus (S. aureus) biofilm commonly associated with OIIs. In vivo evaluations included PET imaging comparisons with d-[5-11C]-Gln vs l-[5-11C]-Gln or 2-deoxy-2-[18F]-fluoroglucose ([18F]-FDG) in a rat OII model with tibial implantation of sterile or S. aureus-colonized stainless-steel screws before and after treatment. These studies demonstrated that the uptake of d-[5-11C]-Gln was significantly higher in the infected screws than that in sterile screws (∼3.4-fold, p = 0.008), which displayed significantly higher infection-to-background muscle uptake ratios (∼2-fold, p = 0.011) with d-[5-11C]-Gln as compared to l-[5-11C]-Gln. Following a 3 week vancomycin treatment, imaging with d-[5-11C]-Gln showed a significant reduction in uptake at the infected sites (∼3-fold, p = 0.0008). Further regression analyses revealed a superior correlation of residual infection-associated radiotracer uptake with the postimaging ex vivo bacterial counts for d-[5-11C]-Gln (k = 0.473, R2 = 0.796) vs [18F]-FDG (k = 0.212, R2 = 0.434), suggesting that d-[5-11C]-Gln PET had higher sensitivity for detecting residual bacterial burden than [18F]-FDG PET. Our results demonstrate the translational potential of d-[5-11C]-Gln PET imaging for noninvasive detection and treatment monitoring of OIIs.

Comparative analysis of Seabuckthorn and its significant component in enhancing fish mucosal immunity

Seabuckthorn and its significant component, gallic acid, were found to alleviate foodborne enteritis in zebrafish, a model species. To investigate the protective effects on mucosal immunity in cultured fish, seabuckthorn or gallic acid was added to soybean meal feed in a study conducted on juvenile grass carp. After a 5-week feeding trial, histopathology, enteritis-related gene expression, transcriptomics, and 16S rRNA gene sequencing were performed on the hindgut and liver tissues. The results showed that dietary inclusion of seabuckthorn (9.5 g/kg) or gallic acid (1.2 g/kg) prevented enteritis, evidenced by an increase in intestinal villi length and a decrease in goblet cell numbers. The gallic acid group showed benefits in preserving villi length, while seabuckthorn was advantageous in controlling goblet cells. On the molecular level, downregulation of pro-inflammatory genes and upregulation of anti-inflammatory genes were observed. Specifically, seabuckthorn was more effective in controlling cytokine expression, while gallic acid better protected the epithelial barrier function. Omics analysis revealed an upregulated hepatic “PPAR signaling pathway” in the seabuckthorn group and downregulated intestinal “platelet activation” in the gallic acid group, suggesting reduced inflammation and improved immune homeostasis. Regarding intestinal microbiota, both groups showed reduced pathogenic Campilobacterota and Aeromonas, and increased Bacteroides and Cetobacteria, potentially enhancing mucosal immunity. For anti-inflammatory processes, hepatic “fatty acid degradation”, “tryptophan metabolism”, and “FoxO signaling pathway” were elevated only in the seabuckthorn group. Gallic acid was advantaged with more “mitophagy” and “autophagy”. Fish-fed seabuckthorn or gallic acid were challenged with Aeromonas hydrophila to assess impacts on other mucosal surfaces. In the gill, compared to the soybean meal group, significantly higher survival rates, reduced CD4 inflammatory signals, and increased filament space were observed. Comparing seabuckthorn with its active component, seabuckthorn performed better in lipid metabolism, resistance to A. hydrophila, anti-inflammation, and probiotic abundance, while gallic acid mainly showed benefits for mucosal barrier protection, such as increased gill filament space. In summary, seabuckthorn and gallic acid improved mucosal immunity in fish, particularly in the gut and gills, enhancing resistance to bacterial infection and foodborne inflammation. Thus, gallic acid and seabuckthorn may be optimal phytotherapy choices in aquaculture.

Selenium-doped carbon dots inhibit ferroptosis by multi-hierarchy iron chelation and mitochondrial homeostasis regulation to control inflammation

Ferroptosis has been identified as a prevalent pathological process in both infectious and non-infectious inflammation. Multiregional iron accumulation within extracellular, cytoplasmic, and subcellular compartments, particularly into mitochondria, can trigger lipid peroxidation and subsequent ferroptosis. Meanwhile, mitochondrial dysfunction, as a hallmark feature of ferroptosis, also exacerbates ferroptosis and inflammation. Here, a strategy of multi-hierarchy iron chelation coupled with mitochondrial homeostasis regulation is proposed to inhibit ferroptosis and relieve inflammation based on selenium-doped carbon dots (SeCDs). SeCDs with reactive oxygen species (ROS) scavenging capacity can be efficiently internalized into cells and enriched in mitochondria. Through the multi-hierarchy chelation for extracellular, cytoplasmic, and mitochondrial iron, iron overload is remarkably inhibited. Meanwhile, promoting glutathione peroxidase 4 (GPX4) expression and activating the AMPK pathway can restrain the metabolism of glycerophospholipids and polyunsaturated fatty acids and lipid peroxidation. Importantly, SeCDs restore mitochondrial homeostasis by chelating mitochondrial iron, scavenging mtROS, and increasing the level of GPX4, thereby enhancing ferroptosis suppression. Further, SeCDs rescue the osteogenic differentiation potential of stem cells, which is generally weakened by ferroptosis. In vivo experiments prove that SeCDs can significantly inhibit ferroptosis and inflammation, and facilitate tissue regeneration. Thus, this multifunctional nanosystem provides a promising therapeutic strategy to inhibit ferroptosis and ease inflammation.

Bioenergetic-active photoluminescent bioactive Nanodressing for proangiogenic MRSA infected wound repair and microenviroment monitoring

Multidrug-resistant bacterial infected wound repair and real-time microenvironment monitoring are still critical challenges, due to the infection-induced inflammation and poor angiogenesis capacity, as well as the complicate wound microenvironment. Herein, we report a multifunctional photoluminescent bioactive hydrogel (GMCB) with cell bioenergy-supplying and excellent antioxidant activities for achieving infection inflammation wound repair and microenvironment monitoring. GMCB was constructed through a bioenergy-supplying poly(citrate-borate) nanomicelle, antioxidant myricetin and gelatin matrix. GMCB possesses injectable, adhesive, photoluminescent and biodegradable properties, demonstrating excellent cellular biocompatibility. GMCB also shows a pH-responsive photoluminescent change based on the reversible crosslinking between borate and myricetin, which would have the potential to monitoring the pH values of wounds. GMCB significantly promotes the cell migration, upregulates the expression of angiogenesis-related genes, efficiently clears reactive oxygen species, and inhibits the expression of inflammatory factors. Importantly, GMCB could release citrate to accelerate the cellular bioenergetics by enhancing mitochondrial membrane potential and ATP levels providing energy for multiple biological activities of cells. GMCB accelerates the repair of methicillin-resistant Staphylococcus aureus (MRSA) infected inflammatory wounds by inhibiting early-stage inflammation, promoting neovascularization and collagen deposition. This work provides a feasible strategy to design bioenergy-reinforcing and intelligent dressing for wound repair-monitoring integration.

A new antibacterial with anti-inflammatory properties promotes wound healing through inhibiting cGAS/STING/NF-κB/IRF3 pathway

Benzothiazole-urea hybrid 8l was found to be a potent anti-bacterial agent against methicillin-resistant Staphylococcus aureus (MRSA2858) (MIC = 0.78 μM, Eur J Med Chem. 2022,236:114333). Herein, 8l was further evaluated to remedy the MRSA-infected scald with bacterial infection and severe inflammation. In scalded skin model with MRSA infection, 8l not only effectively reduced bacterial load, but also decreased pro-inflammatory cytokines secretion and promoted collagen deposition to effectively reverse the progression of wound infection and inflammation by blocking cGAS/STING/NF-κB/IRF3 signaling pathway. In vitro model of RAW264.7 cells verified that 8l can inhibit MRSA-induced inflammation via regulating this pathway. All in all, dual anti-bacterial and anti-inflammatory agent 8l could heal MRSA-infected refractory scald by regulating cGAS/STING/NF-κB/IRF3 pathway.

Dynamics of perifocal reactions to the application of antimicrobial gel in one-stage hip replacement under conditions of staphylococcal infection in the experiment

Background. Local antibacterial therapy in the treatment of osteomyelitis significantly increases the effectiveness of surgical debridement.The aim of the work. To assess in an in vivo experiment the dynamics of perifocal tissue reactions to the application of an original polyvinylpyrrolidone-based antimicrobial gel in a one-stage treatment of implant-associated infection in the hip joint in rabbits.Methods. Implant-associated infection was modeled by inserting Staphylococcus aureus-infected wires into the medullary canal of the femur of rabbits (n = 12). On the day 14, we removed the wire and performed radical surgical treatment of the suppurative focus and hip replacement. The animals were divided into two groups: experimental group – with application of the original antimicrobial gel at the stage of hip replacement (n = 6); comparison group – without gel application (n = 6). For morphological studies, animals were sacrificed on the days 10, 45 and 90 after hip replacement, changes in soft tissues and the bone marrow canal were assessed, and cell populations were counted with statistical data processing.Results. The application of the original antimicrobial gel causes statistically significant decrease in the number of neutrophils in the soft tissues surrounding the implant in the comparison group at all stages. Moreover, in the experimental group, at early stages the number of lymphocytes, plasmacytes and macrophages was statistically significantly higher; on the day 45, a statistically significantly larger number of lymphocytes was registered, and on the day 90 – a statistically significantly larger number of multinucleated and epithelioid cells.Conclusion. The experiment histologically confirmed the effectiveness of application of the original antimicrobial gel to stop infectious inflammation in soft tissues and the bone marrow canal during surgical debridement of an osteomyelitic lesion followed by hip replacement. A pronounced giant cell reaction aimed at removing the polyvinylpyrrolidone-based gel requires further research in terms of its outcomes.

Leptin reduces LPS‐induced A1 reactive astrocyte activation and inflammation via inhibiting p38‐MAPK signaling pathway

AbstractNeurotoxic A1 reactive astrocytes are induced by inflammatory stimuli. Leptin has been confirmed to have neuroprotective properties. However, its effect on the activation of A1 astrocytes in infectious inflammation is unclear. In the current study, astrocytes cultured from postnatal day 1 Sprague–Dawley rats were stimulated with lipopolysaccharide (LPS) to induce an acute in vitro inflammatory response. Leptin was applied 6 h later to observe its protective effects. The viability of the astrocytes was assessed. A1 astrocyte activation was determined by analyzing the gene expression of C3, H2‐D1, H2‐T23, and Serping 1 and secretion of pro‐inflammatory cytokines IL‐6 and TNF‐α. The levels of phospho‐p38 (pp38) and nuclear factor‐κB (NF‐κB) phosphor‐p65 (pp65) were measured to explore the possible signaling pathways. Additionally, an LPS‐induced inflammatory animal model was established to investigate the in vivo effects of leptin on A1 astrocytic activation. Results showed that in the in vitro culture system, LPS stimulation caused elevated expression of A1 astrocyte‐specific genes and the secretion of pro‐inflammatory cytokines, indicating the activation of A1 astrocytes. Leptin treatment significantly reversed the LPS induced upregulation in a dose‐dependent manner. Similarly, LPS upregulated pp38, NF‐κB pp65 protein and inflammatory cytokines were successfully reduced by leptin. In the LPS‐induced animal model, the amelioratory effect of leptin on A1 astrocyte activation and inflammation was further confirmed, showed by the reduced sickness behaviors, A1 astrocyte genesis and inflammatory cytokines in vivo. Our results demonstrate that leptin efficiently inhibits LPS‐induced neurotoxic activation of A1 astrocytes and neuroinflammation by suppressing p38‐MAPK signaling pathway.

Low-dose pro-resolving mediators temporally reset the resolution response to microbial inflammation

BackgroundSpecialized pro-resolving mediators (SPMs) promote resolution of inflammation, clear infections and stimulate tissue regeneration. These include resolvins, protectins, and maresins. During self-resolving acute inflammation, SPMs are produced and have key functions activating endogenous resolution response for returning to homeostasis. Herein, we addressed whether infections initiated with ongoing inflammation alter resolution programs, and if low-dose repetitive SPM regimen re-programs the resolution response.MethodsInflammation was initiated with zymosan (1 mg/mouse) followed by E. coli (105 CFU/mouse) infections carried out in murine peritonitis, and exudates collected at 4-72 h. Leukocytes were enumerated using light microscopy, percentages of PMN, monocytes and macrophages were determined using flow cytometry, and resolution indices calculated. Lipid mediators and SPM profiles were established using mass spectrometry-based metabololipidomics. Repetitive dosing with a SPM panel consisting of RvD1, RvD2, RvD5, MaR1 and RvE2 (0.1 ng/mouse each, i.p.) was given to mice, followed by zymosan challenge. Leukocyte composition, resolution indices and RNA-sequencing were carried out for the repetitive SPM treatments.ResultsE. coli infections initiated acute inflammation-resolution programs with temporal SPM production in the infectious exudates. Zymosan-induced inflammation prior to E. coli peritonitis shifted exudate resolution indices and delayed E. coli clearance. Lipid mediator metabololipidomics demonstrated that E. coli infection with ongoing zymosan-induced inflammation shifted the time course of exudate SPMs, activating a SPM cluster that included RvD1, RvD5 and MaR1 during the initiation phase of infectious inflammation (0-4 h); RvD5 and MaR1 were present also in the resolution phase (24-48 h). To emulate daily SPM regimens used in humans, a repetitive subthreshold dosing of the SPM panel RvD1, RvD2, RvD5, MaR1 and RvE2 each at 0.1 ng per mouse was administered. This low-dose SPM regimen accelerated exudate PMN clearance following zymosan-induced inflammation, and shortened the resolution interval by > 70%. These low-dose SPMs regulated genes and pathways related to immune response, chemokine clearance and tissue repair, as demonstrated by using RNA-sequencing.ConclusionsInfections encountered during ongoing inflammation in mice reset the resolution mechanisms of inflammation via SPM clusters. Low-dose SPMs activate innate immune responses and pathways towards the resolution response that can be reprogrammed.

Intact FGF23 and Markers of Iron Homeostasis, Inflammation, and Bone Mineral Metabolism in Acute Pediatric Infections.

We intend to evaluate the association of intact Fibroblast Growth Factor 23 (i-FGF23), a phosphaturic hormone that contributes to anemia of inflammation, with markers of iron homeostasis, inflammation, and bone mineral metabolism in acute pediatric infections. Seventy-nine children, aged 1 month-13 years, out of which forty-two were males and thirty-seven females, participated in this study. Children with diseases and nutrient deficiencies causing anemia were excluded. Twenty-six patients had bacterial infections, twenty-six had viral infections, and twenty-seven children served as healthy controls. Complete blood count, markers of inflammation, iron and mineral metabolism, serum hepcidin, and i-FGF23 were compared between the groups. Thirty-nine percent of patients with bacterial infection and twelve percent of patients with viral infection presented characteristics of anemia of inflammation (p < 0.001). Ninety-two percent of patients with bacterial infection and eighty-one percent of patients with viral infection had functional iron deficiency (p < 0.001). Hepcidin was significantly positively correlated with the duration of fever, markers of inflammation, and negatively with iron, mineral metabolism parameters, and i-FGF23. i-FGF23 was positively correlated with iron metabolism parameters and negatively with the duration of fever, markers of inflammation, and hepcidin. Hepcidin levels increase, whereas i-FGF23 levels decrease in acute pediatric infections. Further research is required to understand the role of FGF23 in the hepcidin-ferroportin axis and for hepcidin in the diagnosis of bacterial infections and mineral metabolism.