Maternal colonization with Group B Streptococcus (GBS) disrupts the vaginal microbiota, potentially affecting infant microbiota assembly and growth. While the gut microbiota's importance in infant growth is recognized, the specific effects of maternal GBS on growth remain unclear. This study aimed to explore the effects of maternal vaginal GBS during pregnancy on early infant growth, microbiome, and metabolomics.

We recruited and classified 453 pregnant women from southern China into GBS or healthy groups based on GBS vaginal colonization. Their infants were categorized as GBS-exposed or GBS-unexposed groups. We comprehensively analyzed infant growth, gut microbiota, and metabolites during early life, along with maternal vaginal microbiota during pregnancy, using 16S rDNA sequencing and targeted metabolomics.

GBS-exposed infants exhibited lower length-for-age z-scores (LAZ) than GBS-unexposed infants, especially at 2 months. Altered gut microbiota and metabolites in GBS-exposed infants correlated with growth, mediating the impact of maternal GBS on infant LAZ. Changes in the vaginal microbiota of the GBS group during the third trimester correlated with infant LAZ. Additionally, differences in neonatal gut microbiota, metabolites, and vaginal microbiota during pregnancy were identified between infants with overall LAZ<-1 within 8 months after birth and their counterparts, enhancing the discriminatory power of fundamental data for predicting the occurrence of LAZ<-1 during the first 8 months of life.

GBS exposure is associated with decreased infant length growth, with altered microbiota and metabolites potentially mediating the effects of maternal GBS on offspring length growth, offering potential targets for predicting and addressing growth impairment.

The gut microbiota is a crucial link between diet and cardiovascular disease (CVD). Using fecal metaproteomics, a method that concurrently captures human gut and microbiome proteins, we determined the crosstalk between gut microbiome, diet, gut health, and CVD. Traditional CVD risk factors (age, BMI, sex, blood pressure) explained < 10% of the proteome variance. However, unsupervised human protein-based clustering analysis revealed two distinct CVD risk clusters (low-risk and high-risk) with different blood pressure (by 9 mmHg) and sex-dependent dietary potassium and fiber intake. In the human proteome, the low-risk group had lower angiotensin-converting enzymes, inflammatory proteins associated with neutrophil extracellular trap formation and auto-immune diseases. In the microbial proteome, the low-risk group had higher expression of phosphate acetyltransferase that produces SCFAs, particularly in fiber-fermenting bacteria. This model identified severity across phenotypes in heart failure patients and long-term risk of cardiovascular events in a large population-based cohort. These findings underscore multifactorial gut-to-host mechanisms that may underlie risk factors for CVD.

Vascular calcification significantly contributes to cardiovascular morbidity and mortality, particularly in high-risk populations like chronic kidney disease (CKD) patients. Calprotectin, a heterodimeric protein with pro-inflammatory and pro-calcific properties, has emerged as a key molecule in vascular pathology. This review highlights the mechanisms linking calprotectin to vascular calcification, its clinical relevance, and its potential as a therapeutic target.

Vascular calcification is an active, cell-mediated process involving vascular smooth muscle cell (VSMC) dysfunction, inflammation, matrix remodeling, and cellular senescence. Calprotectin is strongly associated with cardiovascular disease and vascular calcification, particularly in CKD. Mechanistic studies reveal that calprotectin promotes calcification through the activation of RAGE and TLR4 signaling pathways, driving inflammatory cascades. Preclinical studies demonstrate that pharmacological inhibition of calprotectin attenuates vascular calcification in animal models, supporting its potential as a therapeutic target.

Calprotectin is emerging as a promising biomarker and therapeutic target in vascular calcification, particularly in CKD and aging-related vascular diseases. However, further studies are required to clarify its mechanisms and assess the long-term efficacy and safety of calprotectin-targeted therapies. A deeper understanding of calprotectin's multifaceted role could pave the way for innovative therapeutic strategies targeting both inflammation and mineralization in calcification-related vascular diseases.

Geniposide (GE) has potential efficacy in treating ulcerative colitis (UC). However, its reactivity can be affected by rapid degradation after oral administration. Furthermore, increasing oral doses may lead to hepatotoxicity. Thus, We used enema administration, characterized by smaller dose and higher localized concentration in the lesion, to improve the above situation.

We aimed to confirm that enema administration is a better modality than oral administration for GE against UC and to explore its mechanism.

We established UC mouse model, monitoring Disease Activity Index (DAI), inflammatory cytokines levels, and histopathology. Macrogenomics and bile acid (BAs) metabolomics analysed the major intestinal flora and BAs. Simultaneouslly, we conducted quantitative proteomics analysis and screened core proteins and pathway. In vitro validation was taken by qPCR, immunofluorescence and immunoblotting experiments.

GE via enema alleviate UC by inhibiting inflammatory factor production through downregulating S100A8/S100A9/NF-κB pathway. Analysis of the intestinal flora and BAs revealed that the enhanced abundance of Lachnospiraceae, which improves the ratio of primary to secondary BAs, and the reduced abundance of Provocaceae, which increases intestinal permeability and promotes inflammation, favored the restoration of the intestinal barrier. In addition, in vitro experiments confirmed that the key BA metabolites (mainly UDCA, DCA, and LCA) stimulated TGR5 signal to inhibit the assembly of the NLRP3 inflammasome and alleviated inflammation.

We firstly confirmed that GE alleviates UC via the enema route in a better manner than the oral route, through enhancing the intestinal barrier, restoring intestinal flora and BAs homeostasis, and inhibiting inflammatory injury. This study initially revealed that GE can alleviate UC through elevating UDCA, DCA, and LCA levels at the colonic site to activate TGR5 receptor for inhibiting the NLRP3 inflammasome, in addition to downregulating the S100A8/S100A9/-TLR4-NF-κB pathway related inflammatory response directly. The evidences offer a promising strategy and profround meaning for UC treatment.

Celiac disease (CD) is a very common immune-mediated enteropathy resulting from the interaction between dietary gluten and the immune system in genetically predisposed individuals. The immune response leads to intestinal damage, malabsorption and, ultimately, to a broad spectrum of both intestinal and extra-intestinal symptoms. According to current criteria, a proper diagnosis of CD requires an initial phase consisting of clinical case identification and serological screening that, over time, has increased in importance. In most adults and in selected children, the diagnosis is subsequently defined by histological evidence of intestinal damage as a confirmatory test, which usually returns to normal after a suitable period of a gluten-free diet (GFD). The clinical remission and disappearance of circulating antibodies after a GFD further confirm the diagnosis and represent a goal to be achieved to improve the quality of life and reduce the risk of long-term complications. However, although the diagnostic criteria for CD are well defined and described in specific guidelines, the monitoring of CD patients undergoing GFD has been less studied and, consequently, specific guidelines for this phase are still lacking. The aim of this report was to evaluate the classical tools used to monitor the adherence and response to GFD, other non-invasive biomarkers that have been proposed for CD monitoring, and the histological follow-up of CD patients in order to provide a starting point for future discussions on this specific topic.

Liver injury and uveitis pose severe threats to human health. Owing to the close relationship of physiology and pathology between the liver and the eyes, cases in which both conditions occur simultaneously are not uncommon in clinical settings, significantly complicating treatment. However, no suitable comorbid animal model has been reported, and research on the pathological mechanisms of this comorbidity is lacking. Prunella vulgaris L., a well-known traditional Chinese medicine renowned for its liver-clearing and eye-brightening properties. Prunella vulgaris polyphenols (PVPs) hold promise for improving liver injury and uveitis. However, research exploring their dual therapeutic effects within a single organism remains lacking, leaving the key active components and mechanisms of action largely uninvestigated.

This exploratory study aimed to establish a rat model of liver injury combined with uveitis and investigated its pathological mechanisms, evaluating the therapeutic efficacy of PVPs in alleviating liver injury combined with uveitis in rats. Additionally, it explored the mechanism of action and identified key active ingredients of PVPs, offering potential new directions for the development of clinical therapeutic drugs.

A rat model of liver injury with uveitis was established through intraperitoneal d-GalN/LPS injection. Metabolomics and proteomics were applied to investigate pathological mechanisms, followed by validation using acylcarnitine and S100A9 inhibitors. PVPs were administered to evaluate therapeutic effects and explore mechanisms involved in alleviating liver injury and uveitis. Network pharmacology combined with molecular docking identified critical active components in PVPs. Subsequent animal experiments verified the efficacy of the representative component in improving liver injury and uveitis.

d-GalN/LPS (150 mg/kg : 1 mg/kg) induced significant liver injury and uveitis in rats. Metabolomics analysis pointed to acylcarnitine as a key metabolite, and its inhibition reduced inflammation. Proteomics analysis implicated S100A9 in inflammation and immunity. Then, we intervened with S100A9 inhibitors in the model rats. The results suggested that the pathological mechanism of liver injury and uveitis caused by d-GalN/LPS involved the upregulation of S100A9 expression, an increase in PP2A activity, the inhibition of AMPK phosphorylation, and the downregulation of CPT1A, leading to the accumulation of acylcarnitine and promoting the inflammatory response in the liver and retina. Further, experiments involving PVPs demonstrated dose-dependent improvements in liver injury and uveitis caused by d-GalN/LPS. The underlying mechanism of action involved suppression of S100A9 expression, reduction of PP2A activity, activation of AMPK, upregulation of CPT1A, and subsequent reduction in acylcarnitine accumulation in both the liver and retina. This mechanism effectively alleviated the inflammatory effects induced by d-GalN/LPS. Network pharmacology and molecular docking analyses pinpointed several key active components of PVPs-namely, rosmarinic acid, salviaflaside, esculetin, 2-hydroxycinnamic acid, 3,4-dihydroxybenzaldehyde, and 7,8-dihydroxycoumarin-that play significant roles in mitigating liver injury and uveitis. Follow-up experiments using the representative active component rosmarinic acid in rats confirmed its efficacy in improving symptoms of d-GalN/LPS-induced liver injury and uveitis, further validating the therapeutic potential of these key active components.

This study successfully established a rat model of liver injury combined with uveitis and confirmed the efficacy of PVPs in alleviating this condition. Furthermore, it determined that the underlying mechanism involves regulation of the S100A9-PP2A-AMPK pathway, with rosmarinic acid identified as a key active compound. These findings provide a basis for clinical studies on liver-eye comorbidities and offer critical evidence for further research and drug development of PVPs in liver-clearing and eye-brightening.

Mitophagy regulates cellular homeostasis and liver inflammation; however, it is inhibited in acute-on-chronic liver failure (ACLF), which drives disease progression. The JianPi LiShi YangGan formula (YGF) has the potential to improve inflammatory responses and reduce mortality in patients with ACLF. However, the precise mechanisms underlying these effects remain unknown.

We investigated the role of S100A9/RAGE signaling in mitophagy and the protective effects of traditional Chinese medicinal compounds on ACLF.

An ACLF mouse model was established using carbon tetrachloride, lipopolysaccharide, and d-galactose. Hematoxylin and eosin staining and enzyme-linked immunosorbent assay were employed to evaluate the hepatoprotective effect of YGF in ACLF mice. Mitochondrial damage was assessed using transmission electron microscopy. Protein levels of mitophagy-related indicators were assessed through immunohistochemistry and western blotting, and immunofluorescence staining was performed to observe Lamp2 and COX-IV co-localization.

The hepatocytes of ACLF mice contained damaged mitochondria, decreased mitophagy-related protein (Pink1, Parkin, and LC3B) expression and activated S100A9/RAGE signaling. Inhibiting S100A9 or RAGE improved liver injury in ACLF mice and enhanced Lamp2-COX-IV co-localization. In alpha mouse liver 12 (AML12) cells overexpressing RAGE, recombinant S100A9 protein inhibited mitophagy induced by 3-chlorocarbonyl benzoyl chloride. YGF reduced mitochondrial damage, increased Pink1, Parkin, and LC3B levels, and enhanced mitophagy while inhibiting S100A9/RAGE activation in the hepatocytes of ACLF mice.

This study found that S100A9/RAGE pathway activation impairs mitophagy, and YGF alleviates liver injury by downregulating S100A9 and RAGE signaling, which may be a novel therapeutic strategy for ACLF.

Peptide 3 is an 18-amino acid linear peptide binding with sub-micromolar affinity to the inflammation marker calprotectin. Its application in point-of-care diagnostic assays has shown promising results, yet improving its affinity for calprotectin could facilitate the development of sensitive and robust assays. Herein, a detailed structure-activity relationship analysis of Peptide 3 is reported to better understand the importance of each individual amino acid for the binding to calprotectin. Moreover, two different approaches have been followed here, one based on prolonging the peptide with random sequences and phage display selection, and one on screening chemically synthesized peptide variants containing non-canonical amino acids, to increase its binding affinity. Combining several mutations that enhance affinity by small factors yielded Peptide 4 binding human calprotectin with a KD of 39 ± 5 nM measured by surface plasmon resonance spectroscopy, which is a five-fold improvement compared to the previously reported Peptide 3.

Inflammatory bowel disease (IBD) is a relapsing-remitting illness requiring proactive monitoring of gut inflammation. We aimed to determine the correlations of plasma myeloperoxidase (pMPO) and calprotectin (pCal), two neutrophil proteins, with existing measures of disease activity.

Adults with IBD undergoing ileocolonoscopy were recruited prospectively. Baseline assessments included blood tests (pMPO, pCal, and C-reactive protein ([CRP]), symptom questionnaires, and endoscopic indices (simple endoscopic score for CD [SES-CD] and UC endoscopic index of severity [UCEIS]). Active IBD was defined as SES-CD > 2 and UCEIS ≥ 2. Spearman's rank correlations assessed the associations between blood markers and endoscopic activity. The area under the receiver operating characteristics curves (AUROC) and univariable logistic regression assessed the ability of blood markers (at optimal thresholds) to identify active disease.

In total, 170 participants were included (female, n = 92; Crohn's disease [CD], n = 99; median age 46 years, IQR 35-58). Plasma biomarkers more accurately identified active IBD in individuals with UC (AUROCpMPO = 0.76, P < .001; AUROCpCal = 0.66, P < .05; AUROCCRP = 0.73, P < .001) than in CD (AUROCpMPO = 0.62, P > .05; AUROCpCal = 0.65, P < .01; AUROCCRP = 0.66, P < .01). In all patients with IBD, the addition of pCal (AUROC = 0.73, P < .001) and pMPO (AUROC = 0.73, P < .001) to CRP added benefit compared to CRP (AUROC = 0.70, P < .001) alone. Plasma myeloperoxidase > 13.86 ng/mL (odds ratio [OR] = 10.13, 3.4-30.16) and pCal > 961.72 ng/mL (OR = 3.38, 1.21-9.4) were associated with an increased odds of having endoscopically active UC.

Plasma MPO shows promise as a potential blood-based biomarker of IBD activity, especially in UC. The combined use of pMPO and CRP adds diagnostic utility in discriminating between active versus quiescent IBD.

Iron is an essential dietary micronutrient for both humans and microorganisms. Disruption of iron homeostasis is closely linked, as both a cause and an effect, to the development and progression of gut microbiota dysbiosis and multiple diseases. Iron absorption in humans is impacted by diverse environmental factors, including diet, medication and microbiota-derived molecules. Accordingly, treatment outcomes for iron-associated diseases may depend on an individual patient's microbiome. Here we describe various iron acquisition strategies used by the host, commensal microorganisms and pathogens to benefit or outcompete each other in the complex gut environment. We further explore recently discovered microbial species and metabolites modulating host iron absorption, which represent potential effectors of disease and therapeutic targets. Finally, we discuss the need for mechanistic studies on iron-host-microbiome interactions that can affect disease and treatment outcomes, with the ultimate aim of supporting the development of microbiome-based personalized medicine.

Respirable silica exposure adversely affects lung tissue immunopathology, triggering oxidative bursts in macrophages and neutrophils, releasing Damage-associated molecular patterns (DAMPs), including calprotectin proteins, S100A8, and S100A9. Calprotectin constitutes up to 45% of these innate immune cells, and serum levels of these alarmins correlate with inflammation, fibrosis, remodelling, and drug response in chronic diseases, including inflammatory bowel disease, asthma, and cystic fibrosis. The consequence of releasing calprotectin protein could trigger the pro-fibrotic effect of silicosis. This study aimed to investigate the role of calprotectin (S100A8/S100A9) as a pro-inflammatory and pro-fibrotic mediator in silica-induced lung fibrosis and evaluated the therapeutic potential of the calprotectin inhibitor, paquinimod. Using a mouse model of silicosis, silica exposure significantly elevated calprotectin expression, lung inflammation, and fibrosis, as evidenced by increased levels of epithelial-to-mesenchymal transition (EMT) markers, collagen deposition, and matrix metalloproteinases (MMPs). In vitro, stimulation of human bronchial fibroblasts with S100A8/S100A9 upregulated fibrotic markers (COL1A1 and α-SMA), which were reduced by inhibitors of TLR4 and RAGE receptors, as well as by paquinimod. Treatment with paquinimod effectively reduced these pathological changes, normalized calprotectin levels, decreased fibrosis scores, and attenuated NF-κB activation. These findings highlighted calprotectin's pivotal role in silica-induced lung fibrosis and inflammation, suggesting that its inhibition could be a promising therapeutic approach for silicosis and other fibro-inflammatory lung diseases. Further research is warranted to explore the precise mechanisms linking calprotectin to lung fibrosis and its potential as a biomarker and therapeutic target.

Coronavirus 2019 (COVID-19) leads to substantial morbidity and excess mortality all over the world which may be aggravated by the propensity of Severe Acute Respiratory Syndrome Coronavirus 2 to mutate. Mechanisms for development of severe COVID-19 are poorly understood. The air we exhale contains endogenous proteins and represents a highly accessible yet unexploited biological sample that can be collected without use of invasive procedures. We collected exhaled breath condensate samples from 28 patients hospitalised due to COVID-19 at admission and discharge using RTubes™. Bottom-up proteomic analysis of tandem mass-tag-labelled single exhaled breath samples was performed in 25 exhaled breath samples collected at admission and 13 samples collected at discharge using discovery-based nano-liquid chromatography-tandem mass spectrometry. In total, 232 proteins were identified in the exhaled breath samples after stringent data filtering. Most of the exhaled proteins were related to the immune systems function and regulation. The levels of four proteins, KRT77, DCD, CASP14 and SERPINB12 decreased from admission to discharge as patients generally recovered from the infection. These proteins are expressed in lung epithelium or macrophages and are associated with the regulation of inflammation drivers in COVID-19. In particular, the alarmins S100A8 and S100A9 accounted for 8% of the exhaled breath proteins. In conclusion, our study demonstrates that analysis of the exhaled breath protein composition can give insights into mechanisms related to inflammation and response to infections, and hereby also of severe COVID-19.Clinical Trial No: NCT04598620.

Inflammatory Bowel Disease (IBD), a chronic condition characterized by gastrointestinal inflammation, is influenced by genetic and environmental factors. Emerging evidence suggests a "mouth-gut axis," with the oral cavity reflecting extra-intestinal manifestations of IBD. This study evaluated the oral health status of IBD patients and the potential of salivary calprotectin (SCP) as a biomarker for assessing IBD activity and oral health.

Oral health was assessed in 100 IBD patients [60 with Crohn's disease (CD) and 40 with ulcerative colitis (UC)] and 14 controls. Evaluations included the Decayed, Missing, and Filled Teeth (DMFT) Score, Periodontal Diagnosis and the need for dental or prosthetic treatment. Saliva and stool samples were collected to measure SCP and faecal calprotectin (FCP) levels using the Elia Calprotectin 2 Test. IBD activity was evaluated with FCP, the Harvey-Bradshaw Index for CD, and the Partial Mayo Score for UC.

The DMFT index mean was comparable between IBD patients (mean 7.99, SD 7.73) and controls (mean 10.00, SD 6.49). However, periodontal disease was significantly more prevalent in IBD patients (57% in CD, 70% in UC) than in controls (29%), with severe cases (stages III/IV) more frequent in IBD. Additionally, 89% of IBD patients required dental treatment, and 39% needed prosthetic rehabilitation. SCP levels showed no significant correlation with disease activity or oral health status, while FCP correlated with C-reactive protein and erythrocyte sedimentation rate.

This study underscores the need for improved oral health management in IBD patients and suggests that SCP may not be a reliable biomarker for monitoring IBD or periodontal disease.

Not applicable.

Pneumonia is a major threat to the health of children, especially those under the age of five. Mycoplasma  pneumoniae infection is a core cause of pediatric pneumonia, and the incidence of severe mycoplasma pneumoniae pneumonia (SMPP) has increased in recent years. Therefore, there is an urgent need to establish an early warning model for SMPP to improve the prognosis of pediatric pneumonia.

The study comprised 597 SMPP patients aged between 1 month and 18 years. Clinical data were selected through Lasso regression analysis, followed by the application of eight machine learning algorithms to develop early warning model. The accuracy of the model was assessed using validation and prospective cohort. To facilitate clinical assessment, the study simplified the indicators and constructed visualized simplified model. The clinical applicability of the model was evaluated by DCA and CIC curve.

After variable selection, eight machine learning models were developed using age, sex and 21 serum indicators identified as predictive factors for SMPP. A Light Gradient Boosting Machine (LightGBM) model demonstrated strong performance, achieving AUC of 0.92 for prospective validation. The SHAP analysis was utilized to screen advantageous variables, which contains of serum S100A8/A9, tracheal computed tomography (CT), retinol-binding protein(RBP), platelet larger cell ratio(P-LCR) and CD4+CD25+Treg cell counts, for constructing a simplified model (SCRPT) to improve clinical applicability. The SCRPT diagnostic model exhibited favorable diagnostic efficacy (AUC > 0.8). Additionally, the study found that S100A8/A9 outperformed clinical inflammatory markers can also differentiate the severity of MPP.

The SCRPT model consisting of five dominant variables (S100A8/A9, CT, RBP, PLCR and Treg cell) screened based on eight machine learning is expected to be a tool for early diagnosis of SMPP. S100A8/A9 can also be used as a biomarker for validity differentiation of SMPP when medical conditions are limited.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory disease of the bladder for which no effective therapy is currently available. Understanding the pathogenesis of IC/BPS and identifying effective intervention targets are of great clinical importance for its effective treatment. Our work focuses on elucidating the key targets and underlying mechanisms of IC/BPS.

We established an experimental autoimmune cystitis (EAC) mouse model and generated gene knockout mice to elucidate key mediators triggering chronic inflammatory damage in IC/BPS through using single-cell RNA sequencing, proteomic sequencing, and molecular biology experiments.

Our study revealed that the infiltration and activation of macrophages, T cells, and mast cells exacerbated inflammatory bladder damage in both IC/BPS and EAC mice. Notably, cell-cell communication among bladder immune cells was significantly enhanced in EAC mice. Macrophages, as the main cell types altered in EAC mice, received and transmitted the most intensity signalling. Mechanistically, macrophages synthesized and secreted S100A9, which in turn facilitated macrophage polarization and promoted the production of pro-inflammatory cytokines. S100A9 emerged as an important pro-inflammatory and pathogenic molecule in IC/BPS and EAC. Further analysis demonstrated that S100A9 activation enhanced the inflammatory response and exacerbated bladder tissue damage in IC/BPS patients and EAC mice via TLR4/NF-κB and TLR4/p38 signalling pathways. Importantly, inhibition of S100A9 with paquinimod, as well as genetic knockout of S100A9, significantly attenuated the pathological process.

S100A9 is an important pro-inflammatory and pathogenic molecule in IC/BPS and EAC. Targeting S100A9-initiated signalling pathways may offer a novel therapeutic strategy for IC/BPS.

The gut microbiome is altered in MS and may contribute to disease by disrupting the intestinal barrier. The colonic mucus barrier, which is primarily composed of mucin protein 2 (MUC2), plays a crucial role in providing a barrier between colonic epithelial cells and the microbiome. Disruption of intestinal epithelial and mucus barriers has been reported in inflammatory bowel disease (IBD) and Parkinson's disease (PD) but has not been studied in the context of the microbiome in multiple sclerosis (MS).

We investigated the epithelial tight junction protein zonulin occludins 1 (ZO-1), mucus protein MUC2, inflammatory stool markers (calprotectin), and gut microbiota composition in a cohort of subjects with relapsing and progressive MS.

MUC2 was decreased in stool of subjects with both relapsing and progressive MS. ZO-1 was elevated in the serum of subjects with progressive MS but was not altered in the stool. Inflammatory markers typically elevated in IBD and PD, including calprotectin, were not altered in MS stool, suggesting disease specificity of altered gut physiology in MS. Microbiota with known mucus degrading capacity were elevated in the stool of subjects with MS and negatively correlated with mucus protein levels.

Taken together, these findings suggest reduced gut barrier function in MS which is linked to increased mucin degrading bacteria.

This work was supported by grants from the National MS Society, the NIH/NINDS, the Nancy Davis Race to Erase MS Young Investigator Award, the Water Cove Charitable Foundation, and the Clara E. and John H. Ware Jr.

Obefazimod is an oral small molecule that selectively enhances the expression of a single micro-RNA (miRNA), miR-124. Obefazimod has demonstrated safety and efficacy in patients with moderate-to-severely active ulcerative colitis (UC) in a phase 2b induction trial. This analysis presents the 2-year outcome data of the open-label maintenance (OLM) study.

Patients received placebo or obefazimod 25, 50, or 100 mg once-daily (od) during the induction trial and, irrespective of their clinical response, could enter the 96-week OLM study with obefazimod 50 mg od. Safety was monitored through monthly visits in the first year and quarterly visits in the second year. Efficacy was assessed at weeks 48 and 96 using nonresponder imputation (NRI) for missing data.

Of 222 eligible patients, 217 were enrolled and 164 (75.6%) completed week 96 of the OLM study. Clinical response was achieved at weeks 48 and 96 in 177 (81.6%) and 158 (72.8%) patients and clinical remission in 119 (54.8%) and 114 (52.5%) of patients. A total of 133 (61.3%) and 128 (59.0%) patients showed endoscopic improvement, and 72 (33.2%) and 78 (35.9%) endoscopic remission. In total, 148/217 patients (68.2%) reported at least 1 treatment-emergent adverse event (TEAE). The most frequent TEAEs were COVID-19 (14.3%), headache (11.5%), UC (7.8%), and nasopharyngitis (6.9%). No new safety risks emerged over 96 weeks.

The 96-week OLM study supports the long-term efficacy and favorable safety profile of obefazimod 50 mg od. A phase 3 program with obefazimod in patients with moderate-to-severe UC is ongoing.

A phase 2b, open-label, efficacy and safety study of ABX464 as maintenance therapy in patients with moderate-to-severe UC. NCT04023396.

The protein heterodimer calprotectin and its component proteins, S100A8 and S100A9, play important antibacterial and pro-inflammatory roles in the mammalian innate immune response. Gaining mechanistic insights into the regulation and biological function of calprotectin will help facilitate patient diagnostics and therapy for inflammation and further our understanding of the host-microbe interface. Recent literature has identified zebrafish s100a10b as zebrafish calprotectin based on sequence similarity, genomic context, and transcriptional upregulation during the immune response to bacterial infections. The field would benefit from expanding the breadth of calprotectin studies into a zebrafish innate immunity model. Here, we carefully evaluated the possibility that zebrafish possess a calprotectin ortholog or a paralog that convergently evolved similar function. Using careful bioinformatics approaches, we found that zebrafish do not have an ortholog of either mammalian S100A8 or S100A9. To look for paralogs with convergent function, we identified four zebrafish s100 proteins-including s100a10b-that are expressed in immune cells and upregulated during the immune response. We recombinantly expressed and purified these proteins and measured their antimicrobial activity. None of the zebrafish proteins exhibited activity comparable to mammalian calprotectin. We also generated structural models of all homodimers and heterodimers of all annotated zebrafish s100 genes. None of these complexes were predicted to have an antimicrobial transition metal binding site equivalent to calprotectin. Finally, we measured the ability of our four purified zebrafish s100 proteins to activate inflammation via Toll-like receptor 4, a key feature of human S100A9; none of the proteins activated the receptor. Our work demonstrates conclusively that zebrafish have no ortholog of calprotectin and suggests that similar proteins have not convergently evolved analogous functions.

Evidence for a potential link between dietary inflammatory potential and inflammatory bowel disease is limited, and the moderating role of genetic susceptibility remains to be assessed.

To evaluate energy-adjusted dietary inflammatory index (E-DII) for the associations with incident Crohn's disease (CD) and ulcerative colitis (UC) and the role of genetic susceptibility.

A total of 205,706 UK Biobank participants who were aged 39-72 years and had no known CD or UC at baseline (2006-2010) were included. The E-DII score was calculated based on energy-adjusted average intakes of 33 food or nutrient items derived from up to five 24-hour dietary recalls. Multivariable Cox regression models were used estimate hazard ratios (HRs) with 95% confidence interval (CI) for incident CD and UC.

During a median 12.3 years of follow-up, 382 incident CD and 798 incident UC cases were ascertained. A higher E-DII score was not associated with risk of CD (HR Q4 VS. Q1 = 1.28, 95% CI: 0.94-1.74; P-trend = 0.09) or UC (HR Q4 VS. Q1 = 1.10, 95% CI: 0.90-1.36; P-trend = 0.17). There was an interaction between the E-DII and the polygenic risk score (PRS) for CD on incident CD (P-interaction = 0.023), with an association only among participants with a high PRS (HR Q4 VS. Q1 = 1.64, 95% CI: 1.03-2.61) (P-interaction = 0.023). As compared with the participants with a low PRS for CD and a low E-DII score, participants with high levels of both scores had a particularly higher risk of CD (HR = 3.12; 95% CI: 1.74-5.60).

The association of dietary inflammatory potential with incident CD appears to be amplified by high genetic susceptibility to CD.

Crohn's disease is a chronic, transmural inflammatory disease of the human gut. Changes in the fecal microbial composition and dysbiosis are consistent features in studies of Crohn's disease patients, but whether dysbiosis is a cause or consequence of inflammation remains unresolved. Genetic susceptibility plays a role in the development of Crohn's disease and has been linked to genes involved in recognition of intestinal bacteria by the mononuclear phagocyte system. The earliest visible lesions in Crohn's disease are aphthous ulcers, overlying Peyer's patches and lymphoid follicles. To identify mechanisms underlying the earliest stages of disease we compared gene expression in aphthous ulcers, Peyer's patches, inflamed and endoscopically normal mucosa from patients and controls using total RNA-seq. The resulting data were subjected to network analysis to identify coregulated gene expression signatures of cell types and processes. These results were compared to single-cell RNA-seq analysis of intestinal macrophages in normal and diseased mucosa. The analysis of aphthous ulcers revealed signatures of epithelial stress and antimicrobial defense, plasma cell activation and immunoglobulin production, monocyte recruitment, inflammatory gene expression and induction of interferon-γ. These signatures were not present in the normal appearing mucosa adjacent to aphthous ulcers, which were similar to healthy control mucosa. Given the role of Peyer's patches and lymphoid follicles in sampling the luminal contents, these findings suggest the initial lesion in Crohn's disease arises from the uptake of bacteria and the activation of multiple host defense pathways rather than the breakdown of epithelial barrier integrity and widespread bacterial translocation.

Hepatocellular carcinoma (HCC) represents the third deadliest cancer worldwide with limited treatment options. Immune checkpoint inhibitors (ICIs) have revolutionized HCC therapy, but immune suppression within the tumor microenvironment remains a major challenge. Therefore, in this study, we aimed to define novel ICI molecules arising on T cells during aggressive HCC development.

Using autochthonous HCC models, we performed microarray analyses followed by in vivo RNA interference screen and identified several new ICI molecules on CD4 and CD8 T lymphocytes in HCC-bearing mice. Short hairpin RNA (shRNA)-mediated knockdown of the ICI molecules was performed to validate their functional role in T cell activity and survival of HCC-bearing mice. Finally, we searched for the presence of the defined ICI molecules in HCC patients.

We identified neutrophilic granule protein (Ngp), hemoglobin subunit alpha-1 (Hba-a1), and S100 calcium-binding protein a8 (S100a8) as novel inhibitory molecules of T cells in HCC. The specific shRNA-based knockdown of these inhibitory targets was safe, led to a downregulation of classical ICI molecules (PD-1, PD-L1, 4-1BBL, CD160), and kept liver parameters under control in murine HCC. Besides, we detected upregulation of S100A8 and S100A9 in blood and liver tissues in HCC patients, supporting their clinical relevance.

The obtained results pave the way for the use of the newly defined ICI molecules Ngp, Hba-a1, and S100a8 as novel immunotherapeutic targets in further preclinical and clinical studies in HCC patients.

Arachidonic acid levels are elevated in the colonic mucosa of patients with inflammatory bowel disease (IBD). Fecal metabolites are emerging as valuable diagnostic tools for IBD. This study aimed to investigate associations between 31 fecal fatty acids, including arachidonic acid, to identify potential correlations with disease severity. Among the 31 fatty acids analyzed in feces, dihomo-γ-linolenic acid, arachidonic acid, and adrenic acid were significantly increased in patients with IBD compared to controls. In contrast, levels of linoleic acid and γ-linolenic acid, the precursors of arachidonic acid, were similar between both groups. No significant differences in fatty acid levels were observed between patients with Crohn's disease and ulcerative colitis. Arachidonic acid and adrenic acid levels positively correlated with fecal calprotectin, a clinically established marker of IBD severity, but showed no association with stool consistency or the Gastrointestinal Symptom Rating Scale. This suggests that these fatty acids are linked to disease severity rather than disease-related symptoms. Current IBD-specific medications had no significant impact on the fecal levels of any of the 31 fatty acids. In summary, this study demonstrates elevated fecal levels of dihomo-γ-linolenic acid, arachidonic acid, and adrenic acid in IBD patients. Normal levels of precursor fatty acids suggest that impaired downstream metabolism may contribute to the accumulation of these n-6 polyunsaturated fatty acids.

Diabetic foot is a complex condition with high incidence, recurrence, mortality, and disability rates. Current treatments for diabetic foot ulcers are often insufficient. This study was conducted to identify potential therapeutic targets for diabetic foot.

Datasets related to diabetic foot and diabetic skin were retrieved from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified using R software. Enrichment analysis was conducted to screen for critical gene functions and pathways. A protein interaction network was constructed to identify node genes corresponding to key proteins. The DEGs and node genes were overlapped to pinpoint target genes. Plasma and chronic ulcer samples from diabetic and non-diabetic individuals were collected. Western blotting, immunohistochemistry, and enzyme-linked immunosorbent assays were performed to verify the S100 calcium binding protein A9 (S100A9), inflammatory cytokine, and related pathway protein levels. Hematoxylin and eosin staining was used to measure epidermal layer thickness.

In total, 283 common DEGs and 42 node genes in diabetic foot ulcers were identified. Forty-three genes were differentially expressed in the skin of diabetic and non-diabetic individuals. The overlapping of the most significant DEGs and node genes led to the identification of S100A9 as a target gene. The S100A9 level was significantly higher in diabetic than in non-diabetic plasma (178.40 ± 44.65 ng/mL vs. 40.84 ± 18.86 ng/mL) and in chronic ulcers, and the wound healing time correlated positively with the plasma S100A9 level. The levels of inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1, and IL-6) and related pathway proteins (phospho-extracellular signal regulated kinase [ERK], phospho-p38, phospho-p65, and p-protein kinase B [Akt]) were also elevated. The epidermal layer was notably thinner in chronic diabetic ulcers than in non-diabetic skin (24.17 ± 25.60 μm vs. 412.00 ± 181.60 μm).

S100A9 was significantly upregulated in diabetic foot and was associated with prolonged wound healing. S100A9 may impair diabetic wound healing by disrupting local inflammatory responses and skin re-epithelialization.

Crohn's disease (CD) is a chronic and recurrent inflammatory condition. Histologic healing is associated with better outcomes in CD, while less is known regarding the assessment of histological condition. Recently, a study has examined the discordance between endoscopic and histopathologic assessment in ileal CD, revealing a poor correlation between endoscopic and histologic evaluations in assessing mucosal inflammation and disease activity. However, the involvement of CD can span the entire gastrointestinal tract, as well as numerous clinical manifestations and extraintestinal complications, and the patchy nature of transmural inflammation is a well-established characteristic of this disease. The diagnosis of CD relies on a comprehensive evaluation that includes clinical, biochemical, stool, endoscopic, cross-sectional imaging, and histological investigations due to the incomplete understanding of its etiology and pathogenesis. Upon diagnosis, complimentary investigations should focus on markers of disease activity. Since transmural inflammation can only be assessed in resections, therefore, we primarily focused on the evaluation value of clinical aspects, histological scoring systems, particular in vivo imaging evaluation such as computed tomography enterography, magnetic resonance elastography, scintigraphy, sonographically measurement, endoscopic ultrasonography, and advanced endoscopic imaging techniques.

Mucosal healing in Crohn's disease (CD) has been established as a crucial target of treatment, leading to long term remission and decrease in complication rates. Endoscopy still serves as the gold standard for assessment, particularly in the small bowel where balloon or capsule enteroscopy is frequently needed. However, these modalities are often unavailable, expensive, and invasive, posing risks to patients. Consequently, the identification of accessible and reliable biomarkers, especially in small intestinal CD, remains a challenge. The study by Ohno et al, published in this issue, further illuminates this field. It confirms the potential role of fecal biomarker leucine-rich α2 glycoprotein (LRG) and validates findings from previous smaller trials. Comparing to other markers LRG showed a much higher predictive value for mucosal healing of the small bowel, making it a useful option for small intestinal CD follow up. In this editorial, we explore the optimal marker of inflammation or mucosal healing in CD, particularly in the small bowel. We provide an overview of available conventional biomarkers and introduce several novel biomarkers, including an update on emerging technologies and innovations.

Environmental enteric dysfunction (EED), a subclinical intestinal disorder, is characterized by chronic fecal-oral exposure to entero-pathogens and could be diagnosed by measuring non-invasive biomarkers. Escherichia coli is the one of the key bacterial enteric pathogens that drives EED, but there is a lack of information on the E. coli pathotypes in relation to the biomarkers of EED in malnourished adults. Here, we intended to measure the possible association of these pathotypes with EED biomarkers and nutritional status of adults residing in a slum in Bangladesh.

Fecal samples were collected from 524 malnourished adults (BMI ≤18.5 kg/m2) living in a slum-setting in Dhaka from March 2016 to September 2019 and analyzed by TaqMan Array Card assays to evaluate the presence of E. coli pathotypes and other entero-pathogens. The multivariable linear regression model was used to assess the association.

In these malnourished adults, the most prevalent pathotype of E. coli was EAEC (61.7%) and the least prevalent was STEC (6.7%). The prevalence of atypical EPEC, ETEC and Shigella/EIEC were 52%, 48.9% and 45.1% respectively. The infection with atypical EPEC had significant positive association with levels of Myeloperoxidase (b = 0.38; 95% CI = 0.11, 0.65; p-value = 0.006). Similarly, a significantly higher concentration of alpha-1-antitrypsin (b = 0.13; 95% CI = 0.03, 0.22; p-value = 0.011) was found in the STEC-infected adults. However, no notable association was found between the E. coli pathotypes and nutritional status of these adult participants. Moreover, Plesiomonas infected adults were more likely to be infected with EAEC (p-value = 0.017), ETEC (p-value <0.001) and STEC (pvalue = 0.002). Significant coinfection was also detected among the pathotypes and other entero-pathogens such as Giardia, Ascaris, Campylobacter, Salmonella, Enterocytozoon bieneusi, and Adenovirus.

The study results imply that there is an influence of particular E. coli pathotypes (EPEC and STEC) on intestinal inflammation and gut permeability of the malnourished Bangladeshi adults, but no association with nutritional status is found. Potential pathogenicity of the E. coli pathotypes is also observed when co-infection with other pathogens exists in these adults.

Short-chain fatty acids (SCFAs), mainly produced by gut microbiota through the fermentation process of dietary fibers and proteins, are crucial to human health, with butyrate, a famous four-carbon SCFA, standing out for its inevitably regulatory impact on both gut and immune functions. Within this narrative review, the vital physiological functions of SCFAs were examined, with emphasis on butyrate's role as an energy source for colonocytes and its ability to enhance the gut barrier while exhibiting anti-inflammatory effects. Knowledge of butyrate synthesis, primarily generated by Firmicutes bacteria, can be influenced by diets with specifically high contents of resistant starches and fiber. Butyrate can inhibit histone deacetylase, modulate gene expression, influence immune functionality, and regulate tight junction integrity, supporting the idea of its role in gut barrier preservation. Butyrate possesses systemic anti-inflammatory properties, particularly, its capacity to reduce pro-inflammatory cytokines and maintain immune homeostasis, highlighting its therapeutic potential in managing dysbiosis and inflammatory diseases. Although butyrate absorption into circulation is typically minimal, its broader health implications are substantial, especially regarding obesity and type 2 diabetes through its influence on metabolic regulation and inflammation. Furthermore, this narrative review thoroughly examines butyrate's growing recognition as a modulator of neurological health via its interaction with the gut-brain axis. Additionally, butyrate's neuroprotective effects are mediated through activation of specific G-protein-coupled receptors, such as FFAR3 and GPR109a, and inhibition of histone deacetylases (HDACs). Research indicates that butyrate can alleviate neurological disorders, including Alzheimer's, Parkinson's, autism spectrum disorder, and Huntington's disease, by reducing neuroinflammation, enhancing neurotransmitter modulation, and improving histone acetylation. This focus will help unlock its full therapeutic potential for metabolic and neurological health, rather than exclusively on its well-known benefits for gut health, as these are often interconnected.

Diabetes Mellitus type 2 (DM2) is thought to have a bidirectional relationship with Periodontitis (PD). However, the complex molecular interactions between DM2 and PD remain unclear. This study aimed to explore the shared genes and common signatures of DM2 and PD via bioinformatic analysis.

Firstly, using bioinformatic methods to investigate common genes. The series matrix files of GSE6751 for DM and GSE15932 for PD were downloaded from the Gene Expression Omnibus (GEO) database. The data was normalized using the R package, and the limma package was utilized to identify the Differentially Expressed Genes (DEGs). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of DEGs were performed using the "clusterProfiler" package in the R software. The protein-protein network was constructed to analyze the potential relationship among the proteins. CytoHubba, a plugin for the Cytoscape software, was used to identify the hub genes. The validation datasets selected for DM2 and PD were GSE10334 and GSE7014, respectively. Receiver Operating Characteristic (ROC) curve analysis was performed to obtain the area under the ROC curve. Lipopolysaccharide (LPS) +  high glucose-induced DM-related PD was simulated to verify the three hub genes through quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western blot (WB).

In total, 44 common DEGs were identified. ITGAM, H2BC21, S100A9 was identified as he hub genes of DM2 and PD, with all of them were up-regulated. In addition, the area under the curve of all three hub genes was more than 0.65. In-vitro experiments revealed that the relative expression of S100A9 was increased after the treatment with LPS +  high glucose. Besides, TLR4 and p-NF-κB levels were also improved in model group.

S100A9 was identified as the hub gene of DM2 and PD. S100A9 could trigger TLR4 signaling way to promote disease development, which can be the potential targets for diagnosis and treatment.

Norovirus infection is the second most frequent viral agent causing gastroenteritis worldwide. Asymptomatic norovirus infection is prevalent in children and is associated with growth failure. Evaluating the intestinal inflammation of asymptomatic norovirus infection is pivotal to overcoming malnutrition, especially in resource-limited settings. The current study aimed to compare the level of fecal neopterin and calprotectin, as the well-established biomarker for intestinal inflammation, in malnourished children with symptomatic and asymptomatic norovirus infections.

In total 78 stool samples from children under five years old were analyzed in this comparative study. The 67 of the participants were malnourished children, with 24 had asymptomatic (ANV) and 18 had symptomatic norovirus infection (SNV), while 25 had no infections (Mal). We assigned 11 healthy children without any infection as control (Healthy). We assessed the fecal neopterin and calprotectin from the stools samples collected during viral diarrhea surveillance in Surabaya, East Java, Indonesia, using commercially ELISA kit from BT Lab (Zhejiang, China) for human neopterin and calprotectin. The statistical differences were tested using Kruskal-Wallis nonparametric test.

The level of fecal neopterin (mean ± SD, 15.46 ± 1.75 nmol/L and 15.12 ± 2.41 nmol/L; p-value: 0.744) and calprotectin (mean ± SD, 184.35 ± 35.09 ng/ml and 177.95 ± 49.55 ng/ml; p-value: 0.457) between ANV and SNV was comparable, also between Mal and Healthy groups. Meanwhile, the level of both biomarkers was significantly different in norovirus positive group and norovirus negative group (p-value < 0.000).

Norovirus infection, regardless of the presence of symptoms, triggered intestinal inflammation, represented by the increased of fecal neopterin and calprotectin level.

ObjectivesThis study aimed to identify risk factors for postoperative recurrence in patients with perianal fistulizing Crohn's disease and assess the predictive value of fecal calprotectin and serum miRNA6086.MethodsFrom 105 patients with perianal fistulizing Crohn's disease, blood and fecal samples as well as clinical data were collected. Analysis of blood tests, C-reactive protein, miRNA6086, and fecal calprotectin revealed postoperative recurrence risk factors. Receiver operating characteristic curve analysis assessed the predictive accuracy of miRNA6086 and fecal calprotectin for perianal fistulizing Crohn's disease recurrence and determined their optimal cutoff values, sensitivity, and specificity.ResultsOf the 105 patients with perianal fistulizing Crohn's disease, 33 (31.4%) experienced recurrence. Anal fistula type, preoperative miRNA6086, and fecal calprotectin levels were identified as independent risk factors for postoperative recurrence. Receiver operating characteristic curve analysis revealed that miRNA6086 had a cutoff value of 0.3195, sensitivity of 65.28%, specificity of 66.67%, and area under curve value of 0.6589 (95% confidence interval, 0.5503-0.7674). Fecal calprotectin had a cutoff value of 0.6073, sensitivity of 81.94%, specificity of 78.79%, and area under curve value of 0.8224 (95% confidence interval, 0.5503-0.7674). Combined miRNA6086 and fecal calprotectin detection had a cutoff value of 0.7121, sensitivity of 83.33%, specificity of 87.88%, and area under curve value of 0.9146 (95% confidence interval, 0.8547-0.9744).ConclusionAnal fistula type, preoperative miRNA6086, and fecal calprotectin levels are independent risk factors for perianal fistulizing Crohn's disease recurrence. Combined detection of miRNA6086 and fecal calprotectin levels enhances predictive accuracy for postoperative recurrence.

Background: Peripheral arterial disease (PAD) is a chronic atherosclerotic disease characterized by atheromatous plaque buildup within arteries of the lower limbs. It can lead to claudication, skin ulcerations, and, in severe cases, chronic limb-threatening ischemia, requiring amputation. There are several plasma protein biomarkers that have been suggested as prognostic markers for adverse events, including major adverse cardiovascular and limb events. However, the clinical benefit and ability to clinically adapt these biomarkers remains uncertain due to inconsistent findings possibly related to heterogenous study designs and differences in methodology. Objectives: This review aims to evaluate the current literature on the prognostic value of plasma protein biomarkers for PAD, their predictive ability for PAD-related adverse outcomes, and their potential roles in guiding PAD management. Methods: To address these challenges, we conducted a systematic review of MEDLINE, Embase, and Cochrane CENTRAL libraries of the current literature (2010-2024). Results: We found 55 studies that evaluated the prognostic value of 44 distinct plasma proteins across various pathophysiological processes. These included markers of immunity and inflammation, markers of metabolism, cardiac biomarkers, markers of kidney function, growth factors and hormones, markers of coagulation and platelet function, extracellular matrix and tissue remodeling proteins, and transport proteins. This review summarizes the existing evidence for prognostic protein plasma biomarkers for PAD and their association with adverse events related to PAD. Conclusions: With this review, we hope to provide a comprehensive list of the prognostic markers and their value as prognostic biomarkers to guide clinical decision making in these patients.

Prognostic biomarkers have been widely studied in COVID-19, but their levels may be influenced by treatment strategies. This study examined plasma biomarkers and proteomic survival prediction in two unvaccinated hospitalized COVID-19 cohorts receiving different treatments. In a derivation cohort (n = 126) from early 2020, we performed plasma proteomic profiling and evaluated innate and complement system immune markers. A proteomic model based on differentially expressed proteins predicted 30-day mortality with an area under the curve (AUC) of 0.81. The model was tested in a validation cohort (n = 80) from late 2020, where patients received remdesivir and dexamethasone, and performed with an AUC of 0.75. Biomarker levels varied considerably between cohorts, sometimes in opposite directions, highlighting the impact of treatment regimens on biomarker expression. These findings underscore the need to account for treatment effects when developing prognostic models, as treatment differences may limit their generalizability across populations.

Ulcerative colitis (UC) is a chronic, nonspecific inflammatory disorder characterized by symptoms such as abdominal pain, diarrhea, hematochezia, and urgency during defecation. While the primary site of involvement is the colon, UC can extend to encompass the entire rectum and colon. The causes and development mechanisms of UC are still not well understood; nonetheless, it is currently held that factors including environmental influences, genetic predispositions, intestinal mucosal integrity, gut microbiota composition, and immune dysregulation contribute to its development. Dysregulated immune responses are pivotal in the pathophysiology of UC, and these aberrant responses are considered key contributors to the disease onset. In patients with UC, immune cells become hyperactive and erroneously target normal intestinal tissue, resulting in inflammatory cascades and damage to the intestinal mucosa. The therapeutic strategies currently employed for UC include immunosuppressive agents such as aminosalicylates and corticosteroids. However, these treatments often prove costly and carry significant adverse effects - imposing a considerable burden on patients. Traditional Chinese Medicine (TCM) has attracted worldwide attention because of its multi-target approach, minimal side effects, cost-effectiveness, and favorable efficacy profiles. In this review, the ways in which TCM modulates inflammatory responses in the treatment of ulcerative colitis have been outlined. Research into TCM modalities for modulating inflammatory pathways in the treatment of UC, which has yielded promising advancements, including individual herbs, herbal formulations, and their derivatives, has been summarized. TCM has been utilized to treat UC and the immune system plays a key role in regulating intestinal homeostasis. It is imperative to facilitate large-scale evidence-based medical research and promote the clinical application of TCM in the management of UC.

Sepsis is the body's response to infection, which can result in multiple organ failure. The immune imbalance in patients with sepsis leads to high mortality. Recent research has greatly advanced our understanding of sepsis pathophysiology, especially in the regulation of inflammatory pathways and immune suppression. S100A9, an alarmin, plays a critical role in modulating the immune response during sepsis and is associated with the potential for multiple organ dysfunction. In the early stage of sepsis, S100A9 can represent the occurrence of inflammation, while in the late stage of sepsis, S100A9 is related to immune suppression. This review summarizes the latest developments in S100A9 research, including its biological functions, role in immune responses, effects on organ damage across different systems during sepsis, and potential clinical applications. It provides insights into the interactions between S100A9 and the immune response and explores S100A9's involvement in sepsis-associated organ injuries. Additionally, this review outlines a framework for future applications of targeted S100A9 interventions and therapeutic strategies to reduce organ injury in sepsis.

Esophagitis is a frequent, but at the molecular level poorly characterized condition with diverse underlying etiologies and treatments. Correct diagnosis can be challenging due to partially overlapping histological features. By proteomic profiling of routine diagnostic FFPE biopsy specimens (n = 55) representing controls, Reflux- (GERD), Eosinophilic-(EoE), Crohn's-(CD), Herpes simplex (HSV) and Candida (CA)-esophagitis by LC-MS/MS (DIA), we identified distinct signatures and functional networks (e.g. mitochondrial translation (EoE), immunoproteasome, complement and coagulations system (CD), ribosomal biogenesis (GERD)), and pathogen-specific proteins for HSV and CA. Moreover, combining these signatures with histological parameters in a machine learning model achieved high diagnostic accuracy (100% training set, 93.8% test set), and supported diagnostic decisions in borderline/challenging cases. Applied to a young patient representing a use case, the external GERD diagnosis could be revised to CD and ICAM1 was identified as highly abundant therapeutic target. This resulted in CyclosporinA as a personalized treatment recommendation by the local multidisciplinary molecular inflammation board. Our integrated AI-assisted morphoproteomic approach allows deeper insights in disease-specific molecular alterations and represents a promising tool in esophagitis-related precision medicine.