Recent Advances in Inflammation & Allergy Drug Discovery - Online First

Lymphocytic Esophagitis (LyE) and Eosinophilic Esophagitis (EoE) share many clinical and endoscopic features. However, their treatment outcomes and prognoses differ significantly. LyE, the least recognized form of esophagitis, requires further research. This study compares symptoms, risk factors, and endoscopic findings in LyE and EoE patients.

This retrospective cohort study reviewed medical records, esophagogastroduodenoscopy (EGD) findings, and biopsy data. Patients with gastrointestinal symptoms who underwent EGD-guided segmental esophageal biopsies between March 2018 and January 2024 were included. Demographic data, clinical features, risk factors, and EGD findings were compared between LyE, EoE, non-specific esophagitis (NSE), and normal esophageal histology (NEH) groups. The LyE and EoE groups were compared and statistically analyzed with a third comparison group formed jointly by NSE and NEH subgroups.

The cohort included 11 LyE cases (1.25%), 79 EoE cases (8.96%), 447 NSE cases (50.68%), and 345 NEH cases (39.11%). LyE patients were older, with a mean age of 54.81 years, and 72.72% of them were female. In contrast, EoE patients were younger, with a mean age of 43.52 years, and had a male predominance. Cases of dysphagia, dyspepsia, and nausea or vomiting occurred in both groups. Food impaction was more frequent in EoE. Smoking, alcohol use, and autoimmune diseases (e.g., hypothyroidism and rheumatoid arthritis) were significant risk factors for LyE. Atopic conditions such as asthma and allergies were linked to EoE. Endoscopic findings often overlapped in LyE and EoE. Esophagitis and strictures were more common in LyE, while rings and furrows were more frequent in EoE. All endoscopic findings, including normal mucosa, were significant in LyE and EoE compared to the comparison group. However, rings, linear furrows, and exudates were not significant when comparing LyE to the comparison group.

This single-center study, limited by a small sample size and geographic scope, addresses the diagnostic challenges posed by overlapping features of Lymphocytic and Eosinophilic Esophagitis. Despite the lack of standardized definitions and variable diagnostic thresholds in previous literature, our use of uniform histopathological criteria (≥20 lymphocytes or eosinophils per HPF) and a large control group enhances the consistency and reliability of the findings.

LyE is a rare form of esophagitis with clinical and endoscopic features similar to EoE. Accurate histopathological diagnosis is essential for differentiation. LyE is more common in older females with autoimmune conditions, while EoE affects younger males with atopic conditions.

Phosphodiesterase 7 (PDE7) is a key enzyme in the PDE superfamily responsible for degrading cyclic adenosine monophosphate (cAMP) in pro-inflammatory and immunomodulatory cells. Elevated PDE7 activity is associated with inflammatory processes and various diseases. Suppression of PDE7 raises cAMP levels, reducing mucous secretion, cellular inflammation, and airway obstruction. This review provides an overview of the role of PDE7 in inflammatory disorders and highlights recent advances in the development of selective PDE7 inhibitors for therapeutic applications.

The review consolidates findings on the structure-activity relationships of PDE7 inhibitors. Key structural classes of small molecule inhibitors, including quinazolinone derivatives, thiadiazines, pyrimidines, and others, are discussed alongside preclinical and clinical data on selective inhibitors such as BRL50481 and OMS527.

Selective PDE7 inhibitors have shown exposed potential in animal models to reduce cAMP degradation, leading to decreased inflammation and airway obstruction. BRL50481 remains the only commercially available selective PDE7 inhibitor, while OMS527 has progressed to clinical trials, demonstrating promise in treating inflammatory, neurological disorders, and leukemias.

Selective PDE7 inhibitors represent a novel therapeutic class for inflammatory and neurodegenerative diseases. Further research is characterised by immune dysregulation.

Acute Respiratory Distress Syndrome (ARDS) is the pathophysiologic state of the inflammatory response to lung injury characterized by alveolar epithelial cell damage and increased cytokine production and accumulation in the lungs.

The current study was performed to identify the molecular mechanisms of ARDS related to the proteins elevated in the lung (PEL) and NF-κB pathway regulatory genes (GRNF). In addition, the phytocompounds were screened to inhibit the representative target genes and proteins associated with ARDS.

We implemented STRING v11.5 and Network Analyst 3.0 to construct the protein-protein interactions (PPI) network. CytoScape v3.8.2 and DisGeNet v7.3.0 were utilized to visualize and identify genes involved in respiratory diseases. The Cytohubba module was utilized to identify the hub genes from the constructed PPI network. Autodock Vina and Discovery Studio Visualizer v19.1.0.1828 were utilized for the molecular docking analysis.

The PPI network was constructed with the GRNF genes. Fifty-four genes are identified as biomarkers involved in respiratory diseases (BMRD). About 191 PEL were identified from the human protein atlas database and constructed the PPI network. The interactions between the PPI network of BMRD and PEL were analyzed. The top 100 hub genes and the signaling genes were identified. Based on the identified signaling genes through the PPI network of BMRD and PEL, the metabolic pathway was elucidated, which causes ARDS via NF-κB activation. The ARDS targets (ACVRL1, IKKβ, ITGAL, ITGB2, TGFβR1, and TGFβR2) were selected for the molecular docking study. One hundred and thirty-five chemical compounds from Allium sativum, Alstonia scholaris, Ammi visnaga, Artemisia vulgaris Linn., Houttuynia cordata, and Ocimum gratissimum Linn. were retrieved and used for docking against selected ARDS targets. Among them, genkdaphine from A. sativum inhibited ACVRL1 (binding affinity of -9.2 kcal/mol, and RMSD of 2.607Å), ITGAL (binding affinity of -9.1 kcal/mol, and RMSD of 1.69Å), ITGB2 (binding affinity of -7.9 kcal/mol, and RMSD of 2.184Å), TGFβRI (binding affinity of -8.5 kcal/mol, and RMSD of 1.807Å), and TGFβRII (binding affinity of -8.2 kcal/mol, and RMSD of 1.647Å). Edulisin III from A. visnaga inhibited the IKKβ (binding affinity of -7.4 kcal/mol, and RMSD of 2.223Å).

Genkdaphine and edulisin III may be the therapeutics for treating ARDS. However, further studies are needed to warrant the benefits of genkdaphine and edulisin III in treating ARDS. The study's findings may aid in developing new therapeutic approaches to improve the health status of ARDS-affected patients.

Basic helix-loop-helix protein 40 (BHLHE40) can function as both a transcriptional activator and repressor. Recent studies have reported its regulatory functions in T helper (Th)1 and Th17 immune responses. Rheumatoid arthritis (RA) is an autoimmune inflammatory disease in which joints are involved. Both Th1 and Th17 contribute to the pathogenesis of the disease. In the present study, the levels of BHLHE40, interleukin 17 (IL-17), and interferon-gamma (IFN-γ) were assessed in the RA patients.

Two groups, including RA patients and healthy individuals, were included in the study. The relative expression levels of BHLHE40, IL-17, and IFN-γ were quantified in peripheral blood mononuclear cells (PBMCs) using real-time PCR.

The results showed that the level of BHLHE40 was significantly higher in RA patients compared to the healthy control (P < 0.001) (11.1-fold increase). Accordingly, a significant increase in the levels of IL-17 (8.1 folds increase) (P < 0.021) and IFN-γ (12.7 folds) (P < 0.001) was observed.

Given the rapid pace of research showing the importance of Bhlhe40 in anti-tumor, anti-pathogen, and autoimmune responses, it is anticipated that Bhlhe40 might be leveraged either as a putative biomarker or as a candidate target for therapy in a variety of human diseases.

Evaluation of the expression level of BHLHE40 in RA patients showed a significant increase. In line with the elevated level of BHLHE40, a significant increase in the expression level of IL-17 and IFN-γ was also detected. These findings point to the possible role of BHLHE40 in the disease course or severity by elevating the levels of inflammatory cytokines, including IL-17 and IFN-γ. Therefore, BHLHE40 might be considered either as a putative biomarker or as a candidate for therapy in a variety of human diseases.

It is well known that acute or chronic kidney injury could be due to free radicals and pro-oxidants. This investigation aimed to monitor tacrolimus or cyclosporine blood trough levels and anti-oxidant capacity after kidney transplantation. Methods: There was no intervention in the routine management of transplant recipients. The sample size (n=70) included healthy individuals and kidney-transplanted recipients (n=25 on tacrolimus and n=10 on cyclosporine). The study population was matched for age. The attained information was examined by using the Statistical Package (SPSS Inc, Chicago, IL, USA). The significance level was considered as P ≤ 0.05.

In healthy individuals, the mean ± SD for the capacity of antioxidants was 91.9 ± 16.6 (u/ml), which was significantly higher when compared to the mean value of 28.5 ± 22.6 (u/ml) versus 24.7 ± 25.5 (u/ml), kidney recipients with tacrolimus versus cyclosporine (P ≤ 0.04) as immunosuppressive drugs. The mean value of tacrolimus levels was 14.6 ± 6.4 (ng/ml). The correlation between tacrolimus and cyclosporine trough levels and anti-oxidant capacity was 0.19 (P ≤ 0.14). There were no significant differences regarding age in cases and controls (P ≤ 42).

This study showed that the capacity of anti-oxidants in kidney transplant recipients, those on tacrolimus or cyclosporine, might be lower than in healthy individuals. Subsequent investigations are recommended to delve into the therapeutic consequences of the influence of antioxidant therapies on the clinical outcomes of transplanted recipients.

Inflammatory bowel diseases (IBD) necessitate cost-effective biomarkers for efficient management. This study aimed to explore the potential correlations of neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) with IBD disease activity. Additionally, we assessed their associations with other inflammatory markers.

We recruited 180 IBD patients with over 12 months of disease duration, categorized into two groups: Group 1 (active IBD) with 113 cases and Group 2 (inactive IBD) with 67 cases, alongside 200 group-matched healthy controls (Group 3). Hemogram, NLR, LMR, PLR, hs-CRP, ESR, fecal calprotectin (FC), and relevant parameters were recorded.

NLR and PLR were elevated, while LMR was decreased in active IBD patients compared to those in remission. The cutoff values for active IBD were determined as NLR > 1.98, LMR < 3.01, and PLR > 147, exhibiting sensitivity of 92%, 88%, and 91%, and specificity of 93%, 87%, and 89% respectively. Optimal cutoff values for IBD disease activity were CRP > 9.71, ESR > 24, and FC > 176. Multivariate logistic regression identified NLR, LMR, and PLR as robust parameters for discriminating IBD disease activity after adjusting for WBC, CRP, ESR, and FC markers (p < 0.05). NLR and PLR exhibited proportional increases with IBD severity, while LMR lacked such predictive capability.

NLR, PLR, and LMR emerge as simple, non-invasive, and cost-effective independent markers of IBD disease activity, complementing traditional markers like CRP and ESR.

Allergic rhinitis (AR) is a leading public health problem with high prevalence, but the therapies remain limited. Cang Er Zi Powder (CEZP), a Traditional Chinese Medicine formula, has been used for the clinical treatment of chronic rhinitis and allergic rhinitis in China for decades. However, the underlying mechanism is unclear.

In this study, we aimed to clarify the pharmacological mechanism of CEZP on allergic rhinitis

The active ingredients of CEZP were screened in the TCMSP (http://tcmspw.com/tcmsp.php) database. The targets related to “allergic rhinitis” were retrieved from MALACARDS, TTD, and DisGeNET disease target databases. The active ingredients and the candidate targets for AR were constructed and visualized using Cytoscape 3.7.2 software. The underlying mechanism involved in the treatment of CP against AR was analyzed using the WEB-based GEne SeT AnaLysis Toolkit. The effects of CEZP on levels of β-hexosaminidase, histamine, interleukin (IL)-4, and tumor necrosis factor (TNF)-α on DNP-IgE/HSA-stimulated rat basophilic leukemia cells were determined by enzyme-linked immunosorbent assay (ELISA) kits.

A total of 78 active ingredients in 9 Chinese herbs of CEZP and 90 target overlap targets from CEZP and AR were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggested that the inflammation response and NF-κB signaling pathway were responsible for the therapeutic targets of CEZP on AR, and CEZP could suppress mast cell degranulation via Toll-like receptor (TLR) and NF-κb signaling pathway.

Network pharmacology analysis and in vitro assays suggested that CEZP may exert therapeutic effects on AR by inhibiting the NF-κB signaling pathways.

Sepsis is a life-threatening condition responsible for high morbidity and mortality rates around the world and is characterized by a dysregulated host response to infection, resulting in multiple organ dysfunctions. Eugenol is a phenolic aromatic compound derived from clove oil. It has anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal, and anticancer characteristics, which have led to its extensive use in diverse fields, including cosmetology, medicine, and pharmacology. The ongoing study aimed to evaluate the efficacy of eugenol-loaded chitosan nanoparticles (EC-NPs) on sepsis-induced liver damage using the cecal ligation and puncture (CLP) model.

Thirty male albino rats were randomly divided into five groups: Sham, sepsis, and septic rats treated with chitosan, eugenol, or EC-NPs.

EC-NPs showed excellent antibacterial, antioxidant, and anti-inflammatory effects in vitro. EC-NP administration significantly improved liver function, as indicated by the decreased liver enzyme activities and C-reactive protein (CRP) level, as well as the increase of albumin content. Moreover, EC-NPs caused an increase in glutathione-reduced and antioxidant enzyme activities, as well as a reduction of malondialdehyde and nitric oxide formation. In addition, the EC-NP treatment reduced the DNA damage in septic rats; also, the EC-NP treatment repaired, to some extent, the abnormal architecture of the hepatic tissues of septic rats. Furthermore, the immunohistochemical examination showed a marked decrease in inflammation through the reduction of TNF-α and IL-1β expression.

In conclusion, EC-NPs attenuated liver injury in sepsis through its anti-inflammatory, anti-bacterial, and anti-oxidant activities and protection of DNA.