Iranian Journal of Allergy, Asthma and Immunology

Metformin in Diabetes Management and Immune Modulation: A Comprehensive Review

Mehrangiz Ghafari — 2025-12-14

Metformin is a primary treatment for type 2 diabetes (T2D), well-known for its ability to lower blood glucose levels through both AMP-activated protein kinase (AMPK)-dependent and -independent pathways. Recent evidence suggests that metformin also possesses immunomodulatory properties, indicating its potential as a therapeutic agent that extends beyond metabolic regulation. This review summarizes the current understanding of metformin's dual roles in managing diabetes and modulating the immune system. It also explores the underlying mechanisms, clinical implications, and potential directions for future research.

Correlation between Component-resolved Diagnostics (CRD) and Clinical Symptoms in Allergic Children: A One-year Study at the Children's Medical Center (April 2023–March 2024)

Maedeh Khoshkam — 2025-12-14

Component- Resolved Diagnosis (CRD) is an effective tool in allergy diagnosis, that detects specific IgE to allergenic molecules. The ALEX (Allergy Explorer) test, commercially available since 2019, measures specific IgE to allergenic extracts and components associated with inhalant, food, animal, latex, and insect allergens. CRD results should be interpreted based on the patient's clinical history.

Since Children's Medical Center Hospital is one of the largest referral centers for allergic patients, we evaluated the results of the ALEX2 test in patients referred to this center and compared them with the patients’ clinical symptoms.

Clinical symptoms were concordant with positive CRD (ALEX2) test in 76.7% of cases. The overall agreement between positive allergen components and clinical symptoms was 58%.

These findings indicate that the ALEX2 test can improve diagnostic accuracy in allergic patients; however, positive test results should be interpreted in the context of the patient’s clinical history.

Evaluation of Salivary sIgA Levels in Hospitalized COVID-19 Patients with COVID-19 Disease Severity: A Cross-sectional Study

Zahra Valizadeh — 2025-12-14

Since late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) pandemic has dramatically affected public health worldwide. Although systemic antibodies like Immunoglobulin G (IgG) and Immunoglobulin M (IgM)have been widely studied in Coronavirus disease 2019 (COVID-19), the role of Immunoglobulin A (IgA) in mucosal immunity remains less understood. This study evaluated whether salivary IgA levels could serve as prognostic markers for disease severity, progression, and outcomes in hospitalized patients with COVID-19.

In this cross-sectional study, 61 hospitalized patients with COVID-19 were enrolled. After obtaining informed consent, saliva samples were collected at admission to measure IgA levels using an ELISA-based assay (Dlametra kit). Comprehensive clinical and laboratory data, including chest CT results, oxygen saturation, inflammatory markers, and clinical outcomes, were also recorded. Statistical tests were used to examine the association between salivary IgA levels and disease severity, progression, and outcomes.

We enrolled 61 hospitalized patients with COVID-19 (30 females, 31 males; mean age: 56.20±17.45 years; mean admission oxygen saturation: 89.98±5.77%). At admission, 39.3% of patients reported dyspnea, and 40% demonstrated severe lung involvement on chest CT scans. The mean salivary IgA level was 1729.69±391.35 mg/dL. No significant associations were found between salivary IgA levels and COVID-19 severity, disease progression, or clinical outcomes, including mortality.

Our findings show that salivary IgA levels did not significantly correlate with COVID-19 severity, disease progression, or clinical outcomes in hospitalized patients. Therefore, salivary IgA alone cannot be recommended as a prognostic biomarker for COVID-19. Further research is needed to identify more reliable immunological indicators for predicting COVID-19 severity and outcomes.

Investigating the Interplay between the Gut Microbiota and Host Immunity in Gastroenteric Disorders: The Potential of Combined Drug Therapies to Restore Microbial-immune Homeostasis

Yanlin Qiao — 2025-12-14

This study examines the interaction between the microbiota and the immune system in diseases of the gastrointestinal tract, with a special emphasis on the synergistic use of pharmacological agents.

This was a retrospective, observational study of 100 patients with moderate to severe gastrointestinal disorders, including irritable bowel syndrome and inflammatory bowel disease, receiving control, monotherapy, or combination therapy.

Over 12 weeks, combination therapy demonstrated superior efficacy in enhancing gut microbial diversity. Improvements were achieved in alpha diversity, and a decrease in inflammatory indices and a shift in the immune phenotype were observed. Patients experienced significant improvements in symptom severity, pain, and general health. In addition, the general health of patients also improved. Importantly, the combination therapy group had better responses compared with the other groups. With respect to the identified factors, regression analysis revealed that microbial diversity, immune system regulation, and inflammation had positive effects on disease symptom alleviation.

These findings therefore help support the perspective of combination therapy as a more comprehensive mode of approaching and treating gastroenteric diseases.

In Vitro Safety and Immunotoxicity Assessment of a Novel mRNA-LNP Vaccine against Cytomegalovirus: Insights into Safety and Immunomodulatory Profiles

Somayeh Mami — 2025-12-14

Predominantly a widespread beta herpesvirus, human cytomegalovirus (HCMV) triggers lifelong latent infection in most of the people, and HCMV vaccine development has been designated a high public health priority.

In the current study, the in vitro safety profile and potential immunotoxic effects of a novel messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccine designed against human cytomegalovirus (HCMV) were assessed. The aim was to measure inflammation, allergic reactions, complement activation, cytotoxicity, and hemolytic effects of the mRNA-LNP vaccine. Proinflammatory
cytokine secretion, evident in human peripheral blood mononuclear cells (hPBMCs) treated with unmodified mRNA-LNP, was markedly attenuated by incorporating modified nucleotides.

The vaccine appeared incapable of sparking allergic cytokine production or complement activation. Cell viability assays indicated no pronounced cytotoxicity, and hemolysis assays showed no notable hemolytic activity.

The findings suggest that the modified mRNA-LNP vaccine exhibits a promising in vitro safety profile, supporting further development of this vaccine candidate.

TREM1 Enhances Macrophage Proinflammatory Response to LPS by Promoting NF-κB Activation via an IL-26-mediated JAK/STAT Signaling Pathway

Liangliang Xie — 2025-12-15

Lipopolysaccharide (LPS)–induced inflammation in macrophages involves complex signaling pathways. This investigation explored the regulatory roles of triggering receptor expressed on myeloid cells-1 (TREM1) and interleukin (IL)-26 in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) and nuclear factor-kappa B (NF-κB) p65 pathways in LPS-stimulated RAW 264.7 macrophages.

RAW 264.7 cells were treated with LPS to assess TREM1 expression. TREM1 or IL-26 was silenced using short hairpin RNA (shRNA), while IL-26 was overexpressed via plasmid transfection. The JAK2 inhibitor AG490 was used to block JAK/STAT signaling. Western blot, reverse transcription–quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA) were employed to analyze the protein and mRNA levels of inflammatory markers and signaling molecules.

Results showed that LPS upregulated TREM1 expression. In addition, TREM1 knockdown suppressed p65 activation and reduced inflammatory cytokine levels. Moreover, silencing TREM1 inhibited IL-26 and JAK/STAT phosphorylation (p-JAK1, p-JAK2, p-STAT1, and p-STAT3). Similarly, IL-26 knockdown or AG490 treatment attenuated p65 activation and inflammation. Furthermore, IL-26 overexpression reversed the anti-inflammatory effects of TREM1 silencing.

Overall, TREM1 promoted LPS-induced macrophage inflammation via IL-26–mediated JAK/STAT and NF-κB pathway activation, suggesting that TREM1 and IL-26 are potential therapeutic targets.

Evaluation of the Effects of Newcastle Disease Virus as an Oncolytic Virus on the Expression of Apoptosis-related Genes in TC-1 Cell Line

Mohammad Ali Akbar Esfahani — 2025-12-15

TC-1 is a recognized cancer cell line derived from lung epithelial cells that have been altered using the oncogenic E6 and E7 genes of human papillomavirus (HPV). These TC-1 cells are frequently utilized in preclinical research focused on lung cancer and HPV-associated tumors. The incidence of lung cancer and HPV-related cancersis significantly increasing. Drug resistance and the lack of selectivity in current treatments reduce their effectiveness. Researchers are seeking new therapeutic methods, including targeted therapies, immunotherapy, and oncolytic virus and bacterial therapies, to improve treatment outcomes and decrease mortality associated with these diseases. In this context, the present original study aimed to evaluate the potency of wild-type Newcastle disease virus (NDV-WTS) on lactate dehydrogenase (LDH) secretion and the induction of apoptosis in TC-1 cells.

In this experimental study, the TC-1 cell lines were cultured under laboratory conditions. Subsequently, they were treated with different multiplicities of infection (MOIs) of NDV-WTS (1, 2,
and 4). Finally, the oncolytic effects of the virus were evaluated using laboratory assays, including MTT (cell viability), reactive oxygen species (ROS), LDH, survival rates, and the activities of Caspases 8 and 9.

The results indicated that NDV-WTS significantly decreased cell viability while increasing apoptosis, ROS levels, LDH release, and Caspase 8 and 9 activity compared to the control group. Molecular analyses further revealed that treatment of TC-1 cells with NDV significantly increased the expression of Bax, Casp8, and Casp9, while significantly decreasing Bcl2 expression relativeto the control group.

NDV-WTS demonstrated remarkable efficacy in treating lung cancer and HPV-associated tumors. Based on the results of the present study, the use of Newcastle disease virus in the treatment of lung cancer and HPV-associated tumors may be beneficial, which requires further studies and clinical trials.

Molecular Mechanisms of Pulmonary Fibrosis: The Interaction of Epithelial-mesenchymal Transition and AMPK Pathways in a Bleomycin-induced Model

Omid Sadatpour — 2025-12-15

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease marked by excessive extracellular matrix (ECM) deposition, largely mediated by activated fibroblasts. Epithelial-mesenchymal transition (EMT), regulated by transcription factors such as TGF-β, Twist1, and Snail, is a critical mechanism in fibrosis progression. AMP-activated protein kinase (AMPK) has been implicated in modulating fibrotic pathways, but its role in EMT remains unclear. This study aimed to explore the interaction between EMT and AMPK signaling in pulmonary fibrosis.

A bleomycin-induced pulmonary fibrosis mouse model was used. Histological analysis assessed fibrosis and inflammation, while gene expression (TGF-β, Twist1, Snail) was measured by qPCR. Protein levels of E-cadherin, α-SMA, and phosphorylated AMPK were analyzed using Western blotting to evaluate EMT and AMPK activity.

Bleomycin-treated mice showed significant lung inflammation and fibrosis, particularly in the lower region of the left lung. Gene expression analysis revealed elevated TGF-β, Twist1, and Snail in fibrotic areas. Protein analysis demonstrated increased α-SMA and decreased E-cadherin, confirming EMT induction. Notably, AMPK phosphorylation was significantly reduced in fibrotic regions, occurring concurrently with EMT activation.

These findings indicate an inverse relationship between AMPK signaling and EMT in pulmonary fibrosis. EMT may serve as a direct therapeutic target, either by inhibiting transcription factors such as Snail and Twist1 or by modulating upstream metabolic regulators including AMPK

Development and Validation of a Manganese-metabolism and Immune-integrated Gene Signature for Prognosis and Immune Contexture in Patients with Colorectal Cancer

Lei He — 2025-12-15

Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second leading cause of cancer-related mortality globally. Emerging evidence identifies manganese as an important trigger for the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, but prognostic signatures integrating manganese metabolism and immune pathways remain unexplored in CRC.

Through analysis of transcriptomic and clinical data from TCGA-CRC and GSE17538 cohorts, we established and validated an eleven-gene manganese metabolism and immune-related signature that robustly stratified CRC patients into distinct risk groups with significant survival differences.

High-risk patients exhibited suppressed immune microenvironments with enriched M2 macrophages and Tregs and activation of oncogenic pathways. Quantitative real-time polymerase chain reaction (qRT-PCR) validation confirmed dysregulation of eight signature genes in clinical CRC samples, indicating the model’s potential for prognostic prediction and immunotherapeutic stratification.

We established a novel MIRGs signature that accurately predicts CRC clinical outcome. Integration of manganese-based agents with immune checkpoint inhibitors (ICIs) represents a potential therapeutic strategy for immunotherapy-resistant CRC.

A Safer Lytic Alternative: Multi-omics and Immunoinformatics Reveal Reduced Inflammatory Impact of a Chimeric Endolysin Against Antibiotic-induced Immune Dysregulation

Atefeh Noori — 2025-12-15

Natural killer (NK) cells contribute to the development of Rheumatoid Arthritis (RA). Increased expression of programmed cell death protein 1 (PD-1), encoded by the PDCD1 gene, indicates NK cell exhaustion, a process that may be influenced by microRNAs (miRNAs). In this study, we examined PD-1 expression on NK cells from RA patients and evaluated whether miRNAs modulate this pathway.

Although antibiotics are critical for treating infections, they can provoke harmful immune responses by releasing bacterial components that overstimulate the immune system. Such responses may lead to excessive inflammation or cytokine storms. To address this risk, we assessed the immune safety of a newly designed chimeric endolysin, ZAM-MSC, and compared its effects with traditional antibiotics using transcriptomic, proteomic, and computational analyses.

We analyzed public gene and protein expression datasets from antibiotic-treated human cells and performed in silico studies on ZAM-MSC. Differential expression analysis and pathway enrichment were conducted, alongside structural modeling of the endolysin and its predicted interactions with immune receptors.

Antibiotic treatment strongly activated inflammatory genes and pathways, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). In contrast, ZAM-MSC minimally affected immune-related gene expression, with downregulation of interleukin-6 receptor (IL6R) and tumor necrosis factor receptor 1A (TNFRSF1A). Structural modeling showed weak interactions with Toll-like receptors, and epitope analysis predicted low immunogenicity. These results suggest ZAM-MSC may offer a safer antimicrobial alternative, though all protein-level findings are based on computational predictions and require experimental validation.

A Mendelian Randomization Study of Cardiovascular Proteins, Immune Cell Traits, and Lifestyle Factors

Hui Deng — 2025-12-16

We aimed to investigate the causal relationship between cardiovascular-related proteins and osteoporosis and to assess the influence of immune cell traits and lifestyle factors such as smoking and alcohol consumption on osteoporosis risk.

A two-sample Mendelian randomization (MR) approach was employed using publicly available genome-wide association study (GWAS) data. Univariable and multivariable MR analyses were conducted using the inverse variance weighted (IVW) method to evaluate causal effects. Additional sensitivity analyses were performed to validate findings.

Three cardiovascular proteins showed significant associations with osteoporosis and pathological fractures: TNF-related apoptosis-inducing ligand receptor 2 (OR=0.10), TNF-related activation-induced cytokine (OR=2.90), and C-C motif chemokine 4 (OR=1.12). Lifestyle factors, including household tobacco smoke exposure, daily smoking quantity, and alcohol consumption, were also significantly associated with increased osteoporosis risk. Immune cell traits were identified as potential mediators in the relationship between cardiovascular proteins and osteoporosis.

This study highlights a novel link between cardiovascular health and osteoporosis, suggesting that specific proteins increase risk, while immune traits mediate this effect, and lifestyle factors are independent risk factors. These findings underscore the importance of integrated strategies addressing inflammation and lifestyle in osteoporosis prevention and management.

miR-10a Delivered via MSC-derived Extracellular Vesicles Modulates Inflammation in a CCl4-induced Liver Fibrosis Model

Liang Wang — 2025-12-16

Liver fibrosis is a significant global health issue characterized by an abnormal accumulation of extracellular matrix proteins, that disrupts normal liver architecture and function. Mesenchymal stem cells (MSCs) show therapeutic potential by releasing extracellular vesicles (EVs) containing regulatory microRNAs like miR-10a.

This study evaluates miR-10a-enriched human umbilical cord MSC (hUCMSC)-EVs in a CCl₄-induced model of liver fibrosis, focusing on inflammatory marker modulation. Liver fibrosis was induced in experimental animals using CCl₄ administration. MSCs were isolated from the human umbilical cord and loaded with either a miR-10a mimic or a control sequence through Lipofectamine 3000. EVs were then isolated from the culture media of both miR-control and miR-10a-modified MSCs. The therapeutic potential of these miR-10a-loaded EVs was assessed by treating the CCl₄-induced fibrosis model with these vesicles. The efficacy of the treatment was evaluated by measuring two anti-inflammatory markers interleukin (IL)-10 and IL-4) and three pro-inflammatory markers (tumor necrosis factor-α (TNF-α), IL-6, and interferon-γ (IFN-γ)) using enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR) techniques.

The administration of miR-10a-loaded MSC-EVs resulted in a significant modulation of inflammatory markers. Our results revealed an increase in the levels of anti-inflammatory cytokines (IL-10 and IL-4) and a concurrent decrease in pro-inflammatory cytokines (TNF-α, IL-6, and IFN-γ) in the treated group compared to the control group.

The study demonstrates the therapeutic potential of MSC-EVs encapsulating miR-10a in ameliorating CCl₄-induced liver fibrosis. By modulating the balance between pro-inflammatory and anti-inflammatory cytokines, miR-10a-loaded EVs show promise as a targeted treatment approach for liver fibrosis.