Tissue Inflammation Research Articles

GPCRs overexpression and impaired fMLP-induced functions in neutrophils from chronic kidney disease patients.

G-protein coupled receptors (GPCRs) expressed on neutrophils regulate their mobilization from the bone marrow into the blood, their half-live in the circulation, and their pro- and anti-inflammatory activities during inflammation. Chronic kidney disease (CKD) is associated with systemic inflammatory responses, and neutrophilia is a hallmark of CKD onset and progression. Nonetheless, the role of neutrophils in CKD is currently unclear. Blood and renal tissue were collected from non-dialysis CKD (grade 3 - 5) patients to evaluate GPCR neutrophil expressions and functions in CKD development. CKD patients presented a higher blood neutrophil-to-lymphocyte ratio (NLR), which was inversely correlated with the glomerular filtration rate (eGFR). A higher frequency of neutrophils expressing the senescent GPCR receptor (CXCR4) and activation markers (CD18+CD11b+CD62L+) was detected in CKD patients. Moreover, CKD neutrophils expressed higher amounts of GPCR formyl peptide receptors (FPR) 1 and 2, known as neutrophil pro- and anti-inflammatory receptors, respectively. Cytoskeletal organization, migration, and production of reactive oxygen species (ROS) by CKD neutrophils were impaired in response to the FPR1 agonist (fMLP), despite the higher expression of FPR1. In addition, CKD neutrophils presented enhanced intracellular, but reduced membrane expression of the protein Annexin A1 (AnxA1), and an impaired ability to secrete it into the extracellular compartment. Secreted and phosphorylated AnxA1 is a recognized ligand of FPR2, pivotal in anti-inflammatory and efferocytosis effects. CKD renal tissue presented a low number of neutrophils, which were AnxA1+. Together, these data highlight that CKD neutrophils overexpress GPCRs, which may contribute to an unbalanced aging process in the circulation, migration into inflamed tissues, and efferocytosis.

Role of gasdermin D in inflammatory diseases: from mechanism to therapeutics.

Inflammatory diseases compromise a clinically common and diverse group of conditions, causing detrimental effects on body functions. Gasdermins (GSDM) are pore-forming proteins, playing pivotal roles in modulating inflammation. Belonging to the GSDM family, gasdermin D (GSDMD) actively mediates the pathogenesis of inflammatory diseases by mechanistically regulating different forms of cell death, particularly pyroptosis, and cytokine release, in an inflammasome-dependent manner. Aberrant activation of GSDMD in different types of cells, such as immune cells, cardiovascular cells, pancreatic cells and hepatocytes, critically contributes to the persistent inflammation in different tissues and organs. The contributory role of GSDMD has been implicated in diabetes mellitus, liver diseases, cardiovascular diseases, neurodegenerative diseases, and inflammatory bowel disease (IBD). Clinically, alterations in GSDMD levels are potentially indicative to the occurrence and severity of diseases. GSDMD inhibition might represent an attractive therapeutic direction to counteract the progression of inflammatory diseases, whereas a number of GSDMD inhibitors have been shown to restrain GSDMD-mediated pyroptosis through different mechanisms. This review discusses the current understanding and future perspectives on the role of GSDMD in the development of inflammatory diseases, as well as the clinical insights of GSDMD alterations, and therapeutic potential of GSDMD inhibitors against inflammatory diseases. Further investigation on the comprehensive role of GSDM shall deepen our understanding towards inflammation, opening up more diagnostic and therapeutic opportunities against inflammatory diseases.

Interplay of co-cultured chimeric adipose and gingival tissues exacerbates inflammatory dysfunction relevant to periodontal and metabolic conditions

Adipose tissue dysfunction is a key feature of metabolic syndrome, which increases the risk of periodontitis, an inflammatory disease induced by bacteria that affects the gingiva and other components of periodontal tissue. Recent studies indicate that molecules from inflamed periodontal tissue contribute to adipose tissue dysfunction. However, the cellular mechanisms and interactions between adipose tissue and gingiva driving the progression of metabolic and periodontal conditions remain unclear. To address this, we developed a chimeric (mouse/human) co-culture tissue model (which identifies the origins of species-specific cytokines) to investigate these interactions. Using tissue-specific functional cells and immunocytes, we constructed equivalents of adipose tissue (ATE) and gingiva (GTE), co-cultivating them under inflammatory conditions induced by bacterial endotoxin, lipopolysaccharide (LPS). Our findings showed that exposure to LPS resulted in a notable reduction in lipid accumulation, GLUT4 expression, and adiponectin secretion in ATE, along with increased macrophage colonies forming around lipid droplets, as well as elevated levels of triglyceride, leptin, and IL-6. In GTE, LPS triggered significant inflammatory responses, characterized by increased macrophage accumulation, elevated COX-2 expression, and heightened secretion of inflammatory cytokines. LPS also reduced epithelial thickness and the expression of keratin 19 and collagen IV, indicating impaired barrier function and gingival integrity. Co-culturing ATE with GTE exacerbated these LPS-induced harmful effects in both tissues. In conclusion, our findings suggest that interplay between gingiva and adipose tissue can intensify the inflammatory and dysfunctional changes caused by LPS. This co-culture tissue model offers a valuable tool for future studies on periodontitis and metabolic syndrome.

Possible Role of NRF2 in Cell Response to OZOILE (Stable Ozonides) in Children Affected by Lichen Sclerosus of Foreskin.

Lichen sclerosus (LS) is a chronic inflammatory disease of the skin, and the gold standard for treatment is the use of the very potent topical steroids, but they can have side effects. Previously, we demonstrated that OZOILE (stable ozonides) were effective in children affected by LS, reducing the inflammatory process and stimulating tissue regeneration of the foreskin, showing a similar efficacy to steroid treatment. In this study, the modulation of inflammatory and oxidative stress pathways was evaluated by qRT-PCR and Western blotting in foreskins affected by LS removed from patients untreated or treated with OZOILE or corticosteroid cream formulations for 7 days before circumcision. OZOILE induced a significant increase in NRF2 and SOD2 levels, while it did not produce change in MIF, NF-kB subunits, and MMPs in comparison to untreated foreskins. Conversely, steroid topical treatment produced a significant reduction in the expression of p65, MIF, and MMP9, but it did not cause variation in NRF2 and SOD2 levels. These results demonstrate that the use of OZOILE as cream formulation exhibits effects on NRF2 signaling, and it does not induce NF-κB activation, unlike corticosteroids. On the basis of our biochemical data, further studies evaluating the role of NRF2 signaling cascade are necessary.

Combined endodontic and regenerative periodontal therapy for managing questionable mandibular anterior teeth with radicular cysts

Abstract Endodontic microsurgery (EMS) presents a great treatment option for unresolved periradicular pathologies, typically involving the removal of the apical root portion and adjacent inflamed tissues. This case report describes the management of persistent periapical lesions in the lower anterior teeth of a 32-year-old male. Root canal treatment was completed 4 years before presentation. The patient presented to the clinic with tooth mobility and mild discomfort and large radiographical periapical radiolucency. The case was diagnosed with previously treated with asymptomatic apical periodontitis. EMS was performed in conjunction with periodontal-guided tissue regeneration that includes bone graft and resorbable membrane and the teeth showed favorable resolution of the symptoms. Histopathological analysis showed the presence of a radicular cyst. After 3 years of follow-up, cone-beam computed tomography and periapical radiographs demonstrated substantial lesion regression and favorable outcome. This case report offering promising insights into the synergistic potential of combined endodontic and regenerative periodontal therapy in cases with unresolved periapical lesion with extensive bone destruction.

Myeloperoxidase-deficient mice exposed to Zymosan exhibit severe neutrophilia and anemia with enhanced granulopoiesis and reduced erythropoiesis, accompanied by pulmonary inflammation

We previously reported that myeloperoxidase-deficient (MPO-/-) mice develop more severe neutrophil-rich lung inflammation than wild-type mice following intranasal Zymosan administration. Interestingly, we found that these mutant mice with severe lung inflammation also displayed pronounced neutrophilia and anemia, characterized by increased granulopoiesis and decreased erythropoiesis in the bone marrow, compared to wild-type mice. This condition was associated with higher concentrations of granulocyte-colony stimulating factor (G-CSF) in both the lungs and serum, a factor known to enhance granulopoiesis. Neutrophils accumulating in the lungs of MPO-/- mice produced greater amounts of G-CSF than those in wild-type mice, indicating that they are a significant source of G-CSF. In vitro experiments using signal transduction inhibitors and Western blot analysis revealed that MPO-/- neutrophils express higher levels of G-CSF mRNA in response to Zymosan, attributed to the upregulation of the IκB kinase/nuclear factor (NF)-κB pathway and the extracellular-signal-regulated kinase/NF-κB pathway. These findings highlight MPO as a critical regulator of granulopoiesis and erythropoiesis in inflamed tissues.

Peculiarities of oral microbiota in patients with small and medium-sized dental defects and chronic periodontitis of moderate severity

BACKGROUND: Сhronic generalised periodontitis is one of the most widespread pathologies of the dento-mandibular system. To date, even if there is evidence of bacterial etiology, no biological markers have been developed to qualitatively assess the possibility of inflammation of periodontal tissues or its pathomorphosis to a more severe stage. AIMS: Study of peculiarities of oral microbiota in patients with acquired defects of dental rows in chronic generalised periodontitis of medium severity. MATERIALS AND METHODS: The study participants were 88 people with small/medium dental defects with no clinical signs of periodontal tissue inflammation (the first group) and chronic generalised periodontitis of medium severity (the second group). In order to assess the dental status, an index assessment of periodontal tissues and the intensity of tooth decay was carried out, and the degree of tooth mobility was determined. Using microbiological methods, biomaterial from the mucous membrane of the denture bed tissues was studied with determination of microorganisms composition. DNA of periodontal pathogens was detected and quantified by polymerase-chain reaction. Statistical analysis was performed using the Shapiro-Wilk criterion, t-criterion and χ2 criterion. RESULTS: The mean values of CFE and PMA indices in group 2 patients were 1.5 and 5.7 times higher, respectively, than in group 1. When analysing the composition of microorganisms in biological material from patients with chronic generalised periodontitis of moderate severity, Neisseria spp. were statistically significantly more common (p=0.002), Candida spp. (p=0.035), Enterobacterales (p=0.001), Enterococcus spp. (p=0.03) and statistically significantly lower Corynebacterium spp. (p=0.001) and S. salivarius (p=0.001). In the presence of partial defects of tooth rows in patients, the stated microorganisms formed persistent communities, the nature of symbiotic relations in which determined the clinical manifestations of inflammatory changes in the soft tissues of the periodontium. CONCLUSIONS: The increased incidence of Candida spp. and Enterobacterales in patients with acquired dental defects and periodontal soft tissue inflammation, as well as the formation of persistent relationships between them and antagonistic effects on oral autochthonous bacteria, is of interest for the development of targeted antimicrobial therapy in preparation for dental prosthetic treatment.

Imaging Identifies Superior Inflammation Targeting of M1 Macrophages for Cryo-Shocked Cell Pulmonary Drug Delivery to Treat Acute Lung Injury.

In the realm of combating acute lung injury (ALI) induced by a myriad of triggers including sepsis, pneumonia, aspiration, trauma, and pancreatitis, macrophages emerge as crucial players. However, traditional treatments such as systemic administration of glucocorticoids come with the baggage of severe side effects, curtailing their utility. Enter an innovative solution: a biomimetic drug delivery system fashioned from cryo-shocked macrophages, tailored for pulmonary drug delivery. Positron emission tomography (PET) imaging has shed light on the remarkable targeting abilities of live M1 macrophages, showcasing their unparalleled efficacy in homing in on local inflammatory foci when contrasted with naive, M1, and M2 macrophages. Building upon this foundation, liquid nitrogen-treated (LNT) M1 macrophages are developed, engineered to preserve their inflammation-targeting prowess while sidestepping the release of pro-inflammatory cytokines. This breakthrough allows for the delivery of glucocorticoids directly to inflamed lung tissues, efficiently quelling inflammation and mitigating pulmonary edema while drastically reducing systemic drug exposure. Inspired by the effectiveness of live M1 macrophages, the potential of glucocorticoid-loaded LNT M1 macrophages are harnessed, utilizing them as a stealthy "Trojan horse" in the battle against pneumonia-induced ALI. This innovative approach holds promise as a safe and potent treatment avenue for acute lung injury.

Serine protease inhibitor E2 protects against cartilage tissue destruction and inflammation in osteoarthritis by targeting NF-κB signalling.

OA is a chronic disease characterized by cartilage degeneration and inflammation, with no approved disease-modifying drugs. This study aimed to identify pathogenic genes and elucidate their mechanism in OA. We systematically identified pathogenic genes combined sing-cell and bulk transcriptome profiles of cartilage tissues in OA. Adenovirus carrying the serpin peptidase inhibitor clade E member 2 (serpinE2) or exogenous serpinE2 was injected into monosodium iodoacetate (MIA)-induced OA-model rats. Histological analysis, immunohistochemistry and Alcian blue staining were performed. In vitro, immunofluorescence, quantitative real-time PCR (RT-qPCR), ELISA and western blot assays were performed. serpinE2 exhibited elevated expression and hypomethylation, showing a positive association with collagen pathway activities in patients with OA. Silencing serpinE2 aggravated MIA-induced knee cartilage degeneration in OA-model rats. Conversely, the intra-articular injection of exogenous serpinE2 ameliorated articular cartilage degeneration, reduced pain-related behavioural responses and relieve synovitis in MIA-induced OA-model rats. Exogenous serpinE2 not only attenuated the elevation of NLRP3, IL-1β and caspase1 expression levels but also restored the reduction in cell viability induced by lipopolysaccharide (LPS) in chondrocytes. Mechanistically, we found that exogenous serpinE2 inhibited LPS-induced reactive oxygen species (ROS) release and NF-κB signalling activation. serpinE2 plays a protective role in cartilage and synovium tissues, suggesting that serpinE2 gene transfer or molecules that upregulate serpinE2 expression could be therapeutic candidates for OA.

Identification of a Novel Activated NK-Associated Gene Score Associated with Diagnosis and Biological Therapy Response in Ulcerative Colitis

Introduction: Natural killer (NK) cells are associated with the pathogenesis of ulcerative colitis (UC); however, their precise contributions remain unclear. The present study aimed to investigate the diagnostic value of the activated NK-associated gene (ANAG) score in UC and evaluate its predictive value in response to biological therapy. Methods: Bulk RNA-seq and scRNA-seq datasets were obtained from the Gene Expression Omnibus (GEO) and Single Cell Portal (SCP) databases. In the bulk RNA-seq, differentially expressed genes (DEGs) were screened by the “Batch correction” and “Robust rank aggregation” (RRA) methods. The immune infiltration landscape was estimated using single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT. DEGs that correlated with activated NK cells were identified as activated NK-associated genes (ANAGs). Protein-protein interaction (PPI) analysis and least absolute shrinkage and selection operator (LASSO) regression were used to screen key ANAGs and establish an ANAG score. The expression levels of the four key ANAGs were validated in human samples by real-time quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence. The potential therapeutic drugs for UC were identified using the DSigDB database. Through scRNA-seq data analysis, the cell scores based on the ANAGs were calculated by “AddModuleScore” and “AUCell.” Results: Immune infiltration analysis revealed a higher abundance of activated NK cells in noninflamed UC tissues (ssGSEA, p < 0.001; CIBERSORT, p < 0.01). Fifty-four DEGs correlated with activated NK cells were identified as ANAGs. The ANAG score was established using four key ANAGs (SELP, TIMP1, MMP7, and ABCG2). The ANAG scores were significantly higher in inflamed tissues (p < 0.001) and in biological therapy nonresponders (NR) tissues before treatment (golimumab, p < 0.05; ustekinumab, p < 0.001). The ANAG score demonstrated an excellent diagnostic value (AUC = 0.979). Patients with higher ANAG scores before treatment were more likely to experience a lack of response to golimumab or ustekinumab (golimumab, p < 0.05; ustekinumab, p < 0.001). Conclusion: This study established a novel ANAG score with the ability to precisely diagnose UC and distinguish the efficacy of biological treatment.

Adipose-derived stem cell-based anti-inflammatory paracrine factor regulation for the treatment of inflammatory bowel disease

Stem cell-based therapies offer promising avenues for treating inflammatory diseases owing to their immunomodulatory properties. However, challenges persist regarding their survival and efficacy in inflamed tissues. Our study introduces a novel approach by engineering adipose-derived stem cells (ADSCs) to enhance their viability in inflammatory environments and boost the secretion of paracrine factors for treating inflammatory bowel disease (IBD). An arginine-glycine-aspartate peptide-poly (ethylene glycol)-chlorin e6 conjugate (RPC) was synthesized and coupled with ADSCs, resulting in RPC-labeled ADSCs (ARPC). This conjugation strategy employed RGD-integrin interaction to shield stem cells and allowed visualization and tracking using chlorin e6. The engineered ARPC demonstrated enhanced viability and secretion of paracrine factors upon light irradiation, regulating the inflammatory microenvironment. RNA-sequencing analysis unveiled pathways favoring angiogenesis, DNA repair, and exosome secretion in ARPC(+) while downregulating inflammatory pathways. In in vivo models of acute and chronic IBD, ARPC(+) treatment led to reduced inflammation, preserved colon structure, and increased populations of regulatory T cells, highlighting its therapeutic potential. ARPC(+) selectively homed to inflammatory sites, demonstrating its targeted effect. Overall, ARPC(+) exhibits promise as an effective and safe therapeutic strategy for managing inflammatory diseases like IBD by modulating immune responses and creating an anti-inflammatory microenvironment.

Engineered hybrid carbon nanohorns-lipid platforms for the delivery of cisplatin to the colorectal cancer

Carbon nanostructures are considered distinctive multi-functional drug delivery platforms for cancer therapy. However, their potential biocompatibility is still a significant challenge and rational design of these carriers is a prospect in the context of efficient cancer therapy. Herein, we report on the synthesis of two bio-inspired carbon nanohorns (CNH) platforms with tumor targeting capabilities for the delivery of cisplatin. Oxidized CNH wrapped with either polyethylene glycol (PEG) and fusogenic lipids (PEG/DSPG CNH-CP) or glutamic acid-cisplatin complex (CNH-GA-CP), revealed nanosized dahlia-like structure approved by dynamic light scattering (DLS) and transmission electron microscopy (TEM) analysis. Further structure features analysis by using RAMAN, FTIR spectroscopy and TGA indicated CNH surface modification. Excitingly, the superior nanofeatures of the CNH platforms was due to the reduced hydrophobic interactions, and thus closely linked to the surface modifications. Both platforms preserved cisplatin toxicity in vitro on C26 cells. The PEGylated nanoplatform demonstrated elongated circulation time compared to the free drug, and showed a site-specific delivery to the tumor site, while reducing the accumulation within kidney. Following 3 i.v. doses at 3 mg/kg of cisplatin, PEGylated CNH significantly delayed tumor growth and improved the life span of C26-bearing BALB/c mice. These notable results were further approved by the histopathological data, demonstrating reduced degeneration, necrosis and inflammation in both kidney and liver tissues following PEGylated nanoplatform administration. In conclusion, our findings suggest that the systemic toxicity of cisplatin including nephrotoxicity can be resolved by delivering this chemotherapeutic through a rationally-fabricated surface-modified carbon nanoplatform to improve the cancer therapy outcome.

Cachexia-related consequences of glycemic metabolism: A multivariable and two-step Mendelian randomization study

BackgroundCachexia is a global burden that is caused by chronic diseases such as cancer. It is characterized by inflammation and progressive loss of muscle and adipose tissue, aggravating the patient’s health. Glycemic metabolism disorders exacerbate cachexia and mutually reinforce each other. Thus far, no research has established a connection between the two. Therefore, we aim to explore the influence of glucose metabolism on cachexia using Mendelian randomization (MR) and provide a theoretical basis for the early prediction of cachexia. MethodsWe used glycemic traits (type 2 diabetes (T2D), fasting glucose (FG), fasting insulin (FI), hemoglobin A1c (HbA1c), and 2-hour postprandial glucose (2hPG)) as exposures; and cachexia traits (hand grip strength (HGS), appendicular lean mass (ALM), and walking pace (WP)) as outcomes. 22 mediators were included for mediating effects. Multivariable and mediation MR were used to assess the impact of glycemic metabolism on cachexia. ResultsIn univariate MR, higher FI increased HGS (β = 0.113, 95% confidence interval (CI): 0.060–0.166) and WP (β = 0.066, 95% CI: 0.021–0.112). Higher HbA1c was associated with higher ALM (β = 0.067, 95% CI: 0.017–0.117). Higher 2hPG was associated with weaker HGS (β = −0.037, 95% CI: −0.054 to −0.021). In multivariable MR, only FI maintained a relationship with HGS after adjustments for T2D (β = 0.103, 95% CI: 0.026–0.181), FG (β = 0.101, 95% CI: 0.034–0.169), HbA1c (β = 0.115, 95% CI: 0.055–0.176), and 2hPG (β = 0.101, 95% CI: 0.033–0.169). In mediation MR, three mediators were found to be significant between FI and HGS: waist circumference (WC) (48.1%), lumbar spine bone mineral density (LSBMD) (21.3%) and insulin-like growth factor 1 (IGF-1) (6.7%). ConclusionsUsing multivariable and mediation MR, our finding suggests that higher FI increases HGS with an independent effect. WC, LSBMD, and IGF-1 mediate between FI and HGS. This study offers a theoretical framework for the early prediction and assessment of the prognosis of cachexia in cancer patients with glycemic metabolism disorders.

Immune suppression by human thymus-derived effector Tregs relies on glucose/lactate-fueled fatty acid synthesis

Regulatory Tcells (Tregs) suppress pro-inflammatory conventional T cell (Tconv) responses. As lipids impact cell signaling and function, we compare the lipid composition of CD4+ thymus-derived (t)Tregs and Tconvs. Lipidomics reveal constitutive enrichment of neutral lipids in Tconvs and phospholipids in tTregs. TNFR2-co-stimulated effector tTregs and Tconvs are both glycolytic, but only in tTregs are glycolysis and the tricarboxylic acid (TCA) cycle linked to a boost in fatty acid (FA) synthesis (FAS), supported by relevant gene expression. FA chains in tTregs are longer and more unsaturated than in Tconvs. In contrast to Tconvs, tTregs effectively use either lactate or glucose for FAS and rely on this process for proliferation. FASN and SCD1, enzymes responsible for FAS and FA desaturation, prove essential for the ability of tTregs to suppress Tconvs. These data illuminate how effector tTregs can thrive in inflamed or cancerous tissues with limiting glucose but abundant lactate levels.

Novel Nano Drug-Loaded Hydrogel Coatings for the Prevention and Treatment of CAUTI.

Catheter-associated urinary tract infection (CAUTI) is a prevalent type of hospital-acquired infection, affecting approximately 15% to 25% of patients with urinary catheters. Long-term use of the catheter can lead to colonization of microorganisms and biofilm formation, and may develop into bacterial CAUTI. However, the frequent replacement of catheters in clinical settings can result in tissue damage, inflammation, ulceration, and additional complications, causing discomfort and pain for patients. In light of these challenges, a novel nanodrug-supported hydrogel coating called NP-AM/FK@OMV-P/H has been developed in this study. Through in vitro experiments, it is confirmed that OMV nano-loaded liquid gel coating has an effective reaction against E.coli HAase and releases antibacterial drugs. This coating has also demonstrated strong inhibition of E.coli and has shown the ability to inhibit the formation of bacterial biofilm. These findings highlight the potential of the OMV nanoparticle gel coating in preventing and treating bacterial infections. Notably, NP-AM/FK@OMV-P/H has exhibited greater efficacy against multidrug-resistant E.coli associated with UTIs compared to coatings containing single antimicrobial peptides or antibiotics. Additionally, it has demonstrated good biosecurity. In conclusion, the NP-AM/FK@OMV-P/H coating holds great potential in providing benefits to patients with CAUTI.

Leveraging Chlorination-Based Mechanism for Resolving Subcellular Hypochlorous Acid.

Hypochlorous acid (HOCl) is crucial for pathogen defense, but an imbalance in HOCl levels can lead to tissue damage and inflammation. Existing HOCl indicators employ an oxidation approach, which may not truly reveal the chlorinative stress environment. We designed a suite of indicators with a new chlorination-based mechanism, termed HOClSense dyes, to resolve HOCl in sub-cellular compartments. HOClSense dyes allow the visualization of HOCl with both switch-on and switch-off detection modes with diverse emission colors, as well as a unique redshift in emission. HOClSense features a minimalistic design with impressive sensing performance in terms of HOCl selectivity, and our design also facilitates functionalization through click chemistry for resolving subcellular HOCl. As a proof of concept, we targeted plasma membrane and lysosomes with HOClSense for subcellular HOCl mapping. With utilizing HOClSense, we discovered the STING pathway-induced HOCl production and the abnormal HOCl production in Niemann-Pick diseases. To the best of our knowledge, this is the first chlorination-based HOCl indicator series for resolving subcellular HOCl.

Zinc finger-inspired peptide-metal-phenolic nanointerface enhances bone-implant integration under bacterial infection microenvironment through immune modulation and osteogenesis promotion

Orthopedic and dental implantations under bacterial infection microenvironment face significant challenges in achieving high-quality bone-implant integration. Designing implant coatings that incorporate both immune defense and anti-inflammation is difficult in conventional single-functional coatings. We introduce a multifunctional nanointerface using a zinc finger-inspired peptide-metal-phenolic nanocoating, designed to enhance implant osseointegration under such conditions. Abaloparatide (ABL), a second-generation anabolic drug for treating osteoporosis, can be integrated into the design of a zinc-phenolic network constructed on the implant surface (ABL@ZnTA). Importantly, the phenolic-coordinated Zn2+ ions in ABL@ZnTA can act as zinc finger motif to co-stabilize the configuration of ABL through multiple molecular interactions, enabling high bioactivity, high loading capacity (1.36 times), and long-term release (>7 days) of ABL. Our results showed that ABL@ZnTA can modulate macrophage polarization from the pro-inflammatory M1 towards the anti-inflammatory M2 phenotype, promoting immune osteogenesis with increased OCN, ALP, and SOD 1 expression. Furthermore, the ABL@ZnTA significantly reduces inflammatory fibrous tissue encapsulation and enhances the long-term stability of the implants, indicated by enhanced binding strength (6 times) and functional connectivity (1.5−3 times) in the rat bone defect model infected by S. aureus. Overall, our research offers a nano-enabled synergistic strategy that balances infection defense and osteogenesis promotion in orthopedic and dental implantations.

Eco-friendly nanotechnology in rheumatoid arthritis: ANFIS-XGBoost enhanced layered nanomaterials

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation and pain in the joints, which can lead to joint damage and disability over time. Nanotechnology in RA treatment involves using nano-scale materials to improve drug delivery efficiency, specifically targeting inflamed tissues and minimizing side effects. The study aims to develop and optimize a new class of eco-friendly and highly effective layered nanomaterials for targeted drug delivery in the treatment of RA. The study's primary objective is to develop and optimize a new class of layered nanomaterials that are both eco-friendly and highly effective in the targeted delivery of medications for treating RA. Also, by employing a combination of Adaptive Neuron-Fuzzy Inference System (ANFIS) and Extreme Gradient Boosting (XGBoost) machine learning models, the study aims to precisely control nanomaterials synthesis, structural characteristics, and release mechanisms, ensuring delivery of anti-inflammatory drugs directly to the affected joints with minimal side effects. The in vitro evaluations demonstrated a sustained and controlled drug release, with an Encapsulation Efficiency (EE) of 85% and a Loading Capacity (LC) of 10%. In vivo studies in a murine arthritis model showed a 60% reduction in inflammation markers and a 50% improvement in mobility, with no significant toxicity observed in major organs. The machine learning models exhibited high predictive accuracy with a Root Mean Square Error (RMSE) of 0.667, a correlation coefficient (r) of 0.867, and an R2 value of 0.934. The nanomaterials also demonstrated a specificity rate of 87.443%, effectively targeting inflamed tissues with minimal off-target effects. These findings highlight the potential of this novel approach to significantly enhance RA treatment by improving drug delivery precision and minimizing systemic side effects.

Alterations in one‑carbon metabolism and protein synthesis signals due to methionine supplementation and lipopolysaccharide challenge in Holstein fetal liver explants

One‑carbon metabolism (OCM) fueled by methionine (Met), choline, and folic acid is key for embryo development and fetal growth. We investigated effects of lipopolysaccharide (LPS) to induce inflammation in fetal liver tissue with or without Met on components of OCM and protein synthesis activity. Fetal liver harvested at slaughter from six multiparous pregnant Holstein dairy cows (37 ± 6 kg milk/d, 100 ± 3 d gestation) were incubated (0.2 ± 0.02 g) for 4 h at 37 °C with each of the following: ideal profile of amino acids (control; Lysine:Met 2.9:1), control plus LPS (1 μg/mL), increased Met supply (Met, Lys:Met 2.5:1), and Met+LPS. Data were analyzed as a 2 × 2 factorial (PROC MIXED, SAS 9.4). Ratios of mechanistic target of rapamycin (p-mTOR:mTOR) and eukaryotic elongation factor 2 (p-eEF2:eEF2) protein were lowest (P < 0.0 5) with LPS and highest with Met. Tissue amino acid concentrations were lowest (P < 0.0 5) with Met regardless of LPS suggesting enhanced use via mTOR. The marked increase (P = 0.02) in phosphorylation of S6 ribosomal protein (p-RPS6) with LPS suggested a pro-inflammatory response that was partly alleviated with Met+LPS. No effect (P = 0.4 5) on methionine adenosyl transferase 1 A (MAT1A) protein abundance was detected. Activity of betaine-homocysteine S-methyltransferase (BHMT) was greatest with Met, but Met+LPS dampened this effect (P = 0.0 5). Overall, fetal liver responds to inflammatory challenges and Met supply. The latter can stimulate protein synthesis via mTOR and alter some OCM reactions while having a modest anti-inflammatory effect.

CXCR3-Expressing T Cells in Infections and Autoimmunity.

The chemokine receptor CXCR3 and its ligands (MIG/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11) play a central role in the generation of cellular inflammation, both in the protective responses to invading pathogens, and in different pathological conditions associated with autoimmunity. It is worth noting that CXCR3 is highly expressed on innate and adaptive lymphocytes, as well as on various cell subsets that are localized in non-immune organs and tissues. Our review focuses exclusively on CXCR3-expressing T cells, including Th1, Th17.1, Tfh17, Tfh17.1, CXCR3+ Treg cells, and Tc1 CD8+ T cells. Currently, numerous studies have highlighted the role of CXCR3-dependent interactions in the coordination of inflammation in the peripheral tissues, both to increase recruitment of CD4+ and CD8+ T cells that upregulate inflammation, and also for recruitment of CXCR3+ T regulatory cells to dampen overexuberant responses. Understanding the role of CXCR3 and its ligands might help to apply them as new and effective therapeutic targets in a wide range of diseases.