Search Results (284)

Background: The study evaluates the immunomodulatory potential of secukinumab (SECU) and honokiol (HONK) in a murine model of allergic asthma complicated by acute lung injury (ALI), with an emphasis on modulating key inflammatory pathways. The rationale is driven by the necessity to attenuate Th17-mediated cytokine cascades, wherein IL-17 plays a critical role, as well as to explore the adjunctive anti-inflammatory effects of HONK on Th1 cytokine production, including IL-6, TNF-α, and Th2 cytokines. Methods: Mice were sensitized and challenged with ovalbumin (OVA) and lipopolysaccharide (LPS) was administrated to exacerbate pulmonary pathology, followed by administration of SECU, HONK (98% purity, C₁₈H₁₈O₂), or their combination. Quantitative analyses incorporated OVA-specific IgE measurements, differential cell counts in bronchoalveolar lavage fluid (BALF), and extensive cytokine profiling in both BALF and lung tissue homogenates, utilizing precise immunoassays and histopathological scoring systems. Results: Both SECU and HONK, when used alone or in combination, display significant immunomodulatory effects in a murine model of allergic asthma concomitant with ALI. The combined therapy synergistically reduced pro-inflammatory mediators, notably Th1 cytokines, such as TNF-α and IL-6, as measured in both BALF and lung tissue homogenates. Conclusions: The combined therapy showed a synergistic attenuation of pro-inflammatory mediators, a reduction in goblet cell hyperplasia, and an overall improvement in lung histoarchitecture. While the data robustly support the merit of a combinatorial approach targeting multiple inflammatory mediators, the study acknowledges limitations in cytokine diffusion and the murine model’s translational fidelity, thereby underscoring the need for further research to optimize clinical protocols for severe respiratory inflammatory disorders. Full article

Topically applied TH1579 alleviated the psoriatic phenotype in the imiquimod-induced psoriasis mouse model by decreasing CD45⁺, Ly6b⁺, and CD3⁺ cell infiltration and downregulating the expression of the proliferation marker PCNA. Moreover, TH1579 strongly suppressed IL-17 expression in mouse skin, accompanied by reduced infiltration of IL-17-producing γδ-T cells. Furthermore, TH1579 decreased keratinocyte viability and proliferation. Mass spectrometry data analysis revealed the enrichment of proteins associated with nucleotide excision repair and cell cycle regulation. The key cell cycle regulatory protein F-box protein S-phase kinase-associated protein 2 (SKP2) was significantly downregulated, along with the psoriasis-associated proliferation marker WNT5a, identified as a SKP2 downstream target. The downregulation of SKP2 and WNT5a was confirmed in MTH1i-treated mouse skin. Our findings support the topical administration of MTH1i TH1579 as a psoriasis treatment. The therapeutic effects depended on the SKP2/WNT5a pathway, which mediates psoriatic hyperproliferation. This study introduces a conceptually innovative topical treatment for psoriasis patients with mild-to-moderate disease who have limited therapeutic options. Full article

Background: Chitosan, a family of polysaccharides composed of glucosamine and N-acetyl glucosamine, is a promising adjuvant candidate for eliciting potent immune response. Methods: This study compared the adjuvant effects of chitosan to those of empty lipid nanoparticles (eLNPs) and aluminum hydroxide (alum) following administration of recombinant SARS-CoV-2 spike immunogen in adult mice. Mice received the adjuvanted recombinant protein vaccine in a prime-boost regimen with four weeks interval. Subsequent analyses included serological assessment of antibody responses, evaluation of T cell activity, immune cell recruitment and cytokine profiles at injection site. Results: Compared to alum, chitosan induced a more balanced Th1/Th2 response, akin to that observed with eLNPs, demonstrating its ability to modulate both the humoral and cellular immune pathways. Chitosan induced a different proinflammatory cytokine (e.g., IL-1⍺, IL-2, IL-6, and IL-7) and chemokine (e.g., Eotaxin, IP-10, MIP-1a) profile compared to eLNPs and alum at the injection site and in the draining lymph nodes. Moreover, chitosan potentiated the recruitment of innate immune cells, with neutrophils accounting for about 40% of the infiltrating cells in the muscle, representing a ~10-fold increase compared to alum and a comparable level to eLNPs. Conclusions: These findings collectively indicate that chitosan has the potential to serve as an effective adjuvant, offering comparable, and potentially superior, properties to those of currently approved adjuvants. Full article

Background: Mycosis fungoides (MF), the most prevalent cutaneous T cell lymphoma, features clonal CD4⁺ T cell proliferation within a Th2-dominant microenvironment. Interleukin-4 (IL-4) promotes disease progression while Brentuximab Vedotin (BV), an anti-CD30 antibody–drug conjugate, shows efficacy but faces resistance challenges. Methods: We conducted a narrative literature review (2010–2024) synthesizing evidence on IL-4 signaling and BV’s efficacy in MF to develop a theoretical framework for combination therapy. Results: IL-4 may modulate CD30 expression and compromise BV’s effectiveness through immunosuppressive microenvironment remodeling. Theoretical mechanisms suggest that IL-4 pathway inhibition could reprogram the microenvironment toward Th1 dominance and restore BV sensitivity. However, no direct experimental evidence validates this combination, and safety concerns including potential disease acceleration require careful evaluation. Conclusions: The proposed IL-4/BV combination represents a biologically compelling but unproven hypothesis requiring systematic preclinical validation and biomarker-driven clinical trials. This framework could guide future research toward transforming treatment approaches for CD30-positive MF by targeting both malignant cells and their immunologically permissive microenvironment. Full article

Background: Alopecia areata (AA), an autoimmune condition causing non-scarring hair loss, often coexists with atopic dermatitis (AD) due to shared T-helper cell type 2 (Th2)-mediated pathways. Dupilumab, a monoclonal antibody inhibiting IL-4 and IL-13 signaling, is a cornerstone treatment for AD but has conflicting reports regarding its impact on AA, with some suggesting therapeutic benefits and others indicating AA induction. Methods: This retrospective study, utilizing the TriNetX Research Network’s de-identified data from over 300 million patient records, investigates the association between dupilumab use and AA risk in AD patients. Results: After propensity score matching, 23,782 dupilumab users were compared with an equal number of controls. Results revealed a statistically significant increased AA risk in dupilumab users (odds ratio: 1.436, 95% CI: 1.066–1.935, p = 0.0167) after 16 weeks. Cases occurring within 16 weeks were excluded. Conclusions: Potential mechanisms include immune rebalancing, with Th2 suppression possibly upregulating Th1/Th17 pathways or unmasking latent AA in predisposed individuals. These findings challenge dupilumab’s potential as an AA treatment and highlight the need for vigilant monitoring, including routine scalp examinations and patient education. Future research should focus on mechanistic pathways, risk stratification, and comparative studies with other biologics to optimize personalized treatment strategies for AD and AA. Full article

The two probiotic bacteria Lactobacillus helveticus MIMLh5 and L. acidophilus NCFM exhibit homology, are both equipped with an S-layer made up of highly homologous proteins and are capable of stimulating Th1-inducing signals in dendritic cells. In this study, we aimed to compare the two strains as regards the thickness of the S-layer and their capacity to induce the production of the two Th1-inducing cytokines IL-12 and IFN-β. For both bacteria, stimulation with an increasing number of bacteria led to the higher and prompter production of IL-12 and IFN-β, but at all MOIs tested, the IL-12 response induced by NCFM was always the strongest. For both bacteria, the induction of IL-12 peaked at a multiplicity of infection (MOI) of 2–5, while IL-10, known to inhibit the induction of IL-12 cytokines, was induced more slowly and continued to increase at a higher MOI. By employing specific inhibitors, MIMLh5 and NCFM were also shown to activate different MAP kinase pathways. Endocytosed MIMLh5 showed higher survival in the DCs compared to NCFM. In the presence of mannan, previously shown to accelerate endosomal killing of Gram-positive bacteria, the survival of MIMLh5 was strongly decreased, and IL-12 increased to a level close to that induced by NCFM without the addition of mannan, indicating the importance of rapid endosomal degradation for a strong IL-12 response. When measuring the S-layer thickness, MIMLh5’s S-layer appeared to be more than twice the thickness of NCFM and exhibited an elastic modulus approximately twice as high, which is a measure of a cell’s resistance to an applied mechanic stress. When the two strains were depleted of S-layer protein, the elastic modulus was comparable. Together, our data suggests that the thicker S-layer of MIMLh5 compared to NCFM may contribute to its endosomal survival, thus reducing its capacity to induce IL-12. This may constitute an important parameter in the selection of probiotic bacteria for specific purposes. Full article

Background: Doxorubicin (DOX) is a potent anti-cancer agent that is widely described in cancer treatment. However, its administration is often limited by its adverse effects, particularly its testicular toxicity, which can induce infertility in male patients. DOX-induced testicular damage is due to oxidative stress, apoptosis, and inflammation. Nanocurcumin (NCR) is a nano-formulated edition of curcumin with a higher therapeutic potential. NCR has demonstrated antioxidant and anti-inflammatory properties. Methods: This study is designed to inspect the potential validity of NCR on DOX-induced testicular damage in male rats. We used thirty-two Wistar albino rats (150–200 g) and divided them into four groups. NCR (80 mg/kg/ dissolved in 1% CMC) was given orally by oral gavage for 14 days. A single dose of DOX (15 mg/kg) (i.p.) was injected on the 7th day of the experiment. Results: DOX treatment reduced the sperm viability and motility rate, cellular antioxidants, and gonadal hormones; it led to higher levels of inflammatory mediators, necrosis, and sloughing in seminiferous tubules. Conversely, NCR treatment significantly alleviated these side effects by improving sperm count/motility and reducing sperm abnormalities. The testicular function recovery was likely driven by stimulating the cytoprotective SIRT1/NF-κB pathway, depressing the testicular level of oxidative indicators such as MDA, TNF-α, iNOS, IL-1β, and NO, and increasing levels of antioxidants such as GSH and SOD. In addition, NCR contradicted the apoptotic changes by downregulating the pro-apoptotic signals Bax and caspase-3, while inducing Bcl-2 upregulation. Moreover, NCR increased levels of gonadal hormones, attenuated histological abnormalities, and preserved testicular structure when compared with the DOX group. Conclusions: NCR treatment can effectively ameliorate DOX-induced testicular toxicity. Full article

Background: Cardiovascular disorders, especially atherosclerosis, have been associated with allergic inflammation. In addition to traditional inflammatory responses, there is evidence that the development and instability of coronary artery plaque may be influenced by effector cells of allergic inflammation. This review examines the phases of allergic pathology, the immunological mechanisms of atherosclerosis, and the clinical link between allergic diseases (asthma, atopic dermatitis, allergic rhinitis, and food allergy) and cardiovascular disease (CVD), along with future therapeutic perspectives. Material and Method: A literature search was conducted in PubMed, Google scholar; ScienceDirect, Scopus, and studies published between 2014–2024 were taken into consideration. Keywords included allergic inflammation, eosinophils, mast cells, reactive oxygen species, atherosclerosis, Th2 cells, and cytokines. Epidemiological studies and review articles were included. Results: Emerging evidence suggests that allergic inflammation contributes to atherosclerosis through interconnected mechanisms such as eosinophil activation, reactive oxygen species production, mast cell degranulation, and endothelial dysfunction. Th2-driven immune responses, which are mediated by cytokines such as IL-4, IL-5, and IL-13, as well as eosinophil activity and mast cell degranulation, play a crucial role in vascular inflammation and plaque progression. Additionally, changes in lipid metabolism contribute to this process. Epidemiological studies support this connection, indicating that patients with chronic allergic conditions such as asthma, allergic rhinitis, food allergy, and atopic dermatitis experience increased cardiovascular morbidity. However, most current data are observational, and our understanding of the underlying mechanisms in humans remains limited, often relying on insights gained from preclinical models. Conclusions: A potential mechanism for cardiovascular risk is suggested by the interaction between atherosclerosis and allergic inflammation. Promising alternatives for treating allergic inflammation and cardiovascular issues include novel treatments like cytokine inhibitors, mast cell stabilizers, and biologics that target certain pathways. Further research is necessary to see whether concentrating on allergy pathways could lead to innovative treatments for cardiovascular disorders or vice versa. Full article

Hidradenitis suppurativa (HS) and atopic dermatitis (AD) are both inflammatory dermatoses that can significantly impact patient quality of life, however, limited research exists regarding their association. The purpose of this comprehensive review is to compare the inflammatory pathogenesis of HS and AD, explore the associations between these diseases, and discuss standalone and concomitant disease treatment options. Although HS and AD are understood to be primarily driven by the Th1 and Th2 inflammation pathways, respectively, these conditions both utilize the Janus Kinase/Signal transducer and activator of transcription (JAK/STAT) pathway to promote inflammation. Newer research also suggests that IL-36 and IL-1 receptor-associated kinase 4 (IRAK4) may be two additional inflammatory signals shared between the HS and AD disease pathways. These shared mechanisms are reflected in patient presentations as HS and AD are often concomitantly present and demonstrate a bidirectional association in the current literature. Treatment options for concomitant disease are limited, but leverage the shared immune pathogenesis of both diseases. Dupilumab has been reported to improve both HS and AD symptoms in select patients. JAK inhibitors are currently FDA-approved for the treatment of AD, and early trials have suggested benefits from JAK inhibitors such as upadacitinib, povorcitinib, and topical ruxolitinib for HS. Possible future avenues for research on treating both HS and AD include IRAK-4 inhibitors such as zabedosertib and BAY1830839, and diet and gut microbiome modifications. Full article

Background: Seasonal influenza infection poses substantial risks to pregnant women, yet the immunological mechanisms underlying their heightened disease susceptibility remain incompletely characterized. Methods: This study employed multiparametric immunophenotyping and metabolic profiling to investigate cellular immunity, cytokine dynamics, and serum biomarkers in pregnant women infected with H3N2 across gestational stages. Through integrated flow cytometric analysis of peripheral blood mononuclear cells (PBMCs), multiple cytokine quantification, and LC-MS-based serum metabolomics, we compared immunological parameters, serum cytokines, and metabolites across trimesters in pregnant women infected and not infected with H3N2. Results: The results revealed reduced CD4⁺/CD8⁺ T cell ratios, a diminished CD27⁺ memory B cell population in pregnant women infected with H3N2, and elevated NK cells and Th2-skewed cytokines (IL-4, IL-6, IL-10) in severe influenza cases. Metabolomic profiling identified the dysregulation of the tryptophan–kynurenine (Trp–Kyn) pathway, with a 15-fold increase in the Kyn/Trp ratio in severe influenza compared to a normal pregnancy as a potential biomarker. Conclusions: These results elucidate synergistic pathophysiological axes-immune dysregulation and tryptophan metabolism alteration that potentially drive adverse outcomes. The identified biomarker panel (CD4/CD8 ratio, IL-6, Kyn/Trp ratio) shows potential clinical promise for early risk stratification in high-risk pregnancies with influenza infection. Full article

In sheep production, due to the limitations of breeding conditions, the uteri of ewes are often infected with bacteria, resulting in the failure of embryo implantation or loss, causing huge losses to the sheep industry. Therefore, in this study, by using RT-qPCR, Western blot, and immunofluorescence, we investigated the effects of LPS infusion on the immune microenvironment and endometrial receptivity, which play an important role in the process of embryo implantation in ruminants, during the three critical periods of embryo implantation in sheep. The results showed that LPS infusion at day 12, day 16, and day 20 significantly increased the expression of Th1 cytokines (TNF-α, IL-1β, IL-8, IL-6), while significantly decreasing the expression of Th2 cytokines (IL-4 and IL-10) and disrupting the expression of implantation factors, such as ITGB3, ITGB5, VEGF, and LIF, in the endometrial tissues of sheep. Additionally, the protein expression level of TLR4 and the phosphorylation level of ERK were significantly elevated at day 12, day 16, and day 20 after LPS infusion, suggesting that LPS may impair endometrial receptivity through the TLR4/ERK pathway. Validation was conducted in a receptive model of sEECs using TLR4 and ERK phosphorylation inhibitors. Compared with the LPS group, TLR4 and ERK phosphorylation inhibitors significantly reduced the expression of TLR4 and p-ERK, down-regulated Th1 cytokines, up-regulated Th2 cytokines, and alleviated the disruption of genes for attachment. Treatment with 50 μM PTE can significantly alleviate the abnormal expression of implantation genes caused by LPS, and its mechanism may be related to the regulation of the ERK signaling pathway. Full article

Psoriasis is a chronic immune-mediated inflammatory skin disorder characterized by keratinocyte hyperproliferation, impaired epidermal barrier function, and immune dysregulation. The Th17/IL-23 axis plays a central role in its pathogenesis, promoting the production of key pro-inflammatory cytokines such as IL-17, IL-23, and TNF-α, which sustain chronic inflammation and epidermal remodeling. Emerging evidence suggests that SARS-CoV-2 may trigger new-onset or exacerbate existing psoriasis, likely through viral protein-induced activation of toll-like receptors (TLR2 and TLR4). This leads to NF-κB activation, cytokine release, and enhanced Th17 responses, disrupting immune homeostasis. Erythrodermic psoriasis (EP), a rare and severe variant, presents with generalized erythema and desquamation, often accompanied by systemic complications, including infection, electrolyte imbalance, and hemodynamic instability. In a murine model of SARS-CoV-2 infection, we found notable cutaneous changes: dermal collagen deposition, hair follicle destruction, and subcutaneous adipose loss. Parallel findings were seen in a rare clinical case (only the third reported case) of EP in a patient with refractory psoriasis, who developed erythroderma after off-label initiation of dupilumab therapy. The patient’s histopathology closely mirrored the changes seen in the SARS-CoV-2 model. Histological evaluations also reveal similarities between psoriasis flare-ups following dupilumab treatment and cutaneous manifestations of COVID-19, suggesting a shared inflammatory pathway, potentially mediated by heightened type 1 and type 17 responses. This overlap raises the possibility of a latent connection between SARS-CoV-2 infection and increased psoriasis severity. Since the introduction of COVID-19 vaccines, sporadic cases of EP have been reported post-vaccination. Although rare, these events imply that vaccine-induced immune modulation may influence psoriasis activity. Our findings highlight a convergence of inflammatory mediators—including IL-1, IL-6, IL-17, TNF-α, TLRs, and NF-κB—across three triggers: SARS-CoV-2, vaccination, and dupilumab. Further mechanistic studies are essential to clarify these relationships and guide management in complex psoriasis cases. Full article

Atopic dermatitis (AD) is a chronic inflammatory skin disorder marked by intricate interplay among skin barrier dysfunction, immune dysregulation, and microbial dysbiosis. While therapeutic advancements targeting T helper 2 (Th2) cytokines, such as interleukin (IL)-4 and IL-13, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway have yielded promising outcomes, a significant proportion of patients still experience inadequate relief, particularly from persistent pruritus. Achieving minimal disease activity remains an unmet clinical priority and a cornerstone of effective AD management. This review provides an in-depth analysis of current therapeutic approaches and integrates findings from recent biologic studies, with a particular focus on innovative strategies under active investigation. These approaches include targeting components of the innate immune system, such as thymic stromal lymphopoietin (TSLP) and IL-1 family cytokines; the adaptive immune system, including OX40-OX40L interactions and Th17- and Th22-related cytokines; and mechanisms associated with pruritus, such as IL-31, histamine receptors, and neurokinin 1 receptor. Emerging insights underscore the transformative potential of personalized therapeutic regimens tailored to the distinct endotypes and severity of AD. Advances in deciphering the pathogenesis of AD are unlocking unprecedented opportunities for precision medicine, offering renewed hope for improved outcomes in this multifaceted and heterogeneous condition. Full article

Chronic inflammatory pain (IP) remains a therapeutic challenge under the worldwide prevalence of the high-fat dietary lifestyle. This study aimed at identifying mediators of the IP augmented by short-term high-fat diet (HFD). IP was induced on C57BL/6J mice by unilateral, intra-plantar, injection of Complete Freund’s Adjuvant (CFA). Von Frey test for mechanical hyperalgesia and Hargreaves’ test for thermal hyperalgesia were performed at pre-injection baseline and post-injection 6th h. and days 1/3/5/7/10/14. Ad libitum HFD feeding started 2 weeks pre-injection in assigned groups. Body weight and random blood glucose levels were measured. RT-qPCR and ELISA helped quantify expression levels of the selected candidate genes at manipulated hind-paws. After CFA injection, at 1400 W, a highly selective inducible nitric oxide synthase (iNOS) inhibitor was administered regularly to elicit differences in CFA-induced pain behaviors and gene expression in HFD-fed mice. Results showed that HFD-fed mice were heavier (p < 0.001) and relatively hyperglycemic (p = 0.013) at baseline. HFD aggravated CFA-induced mechanical and thermal pain (mechanical: p = 0.0004, thermal: p = 0.003), showing prolonged hyperalgesic durations and reduced pain thresholds at multiple timepoints. HFD-influenced paws showed accentuated overexpression of pro-inflammatory cytokines and iNOS (RT-qPCR for IL-1β: p = 0.015, IL-6: p = 0.019, TNF: p = 0.04; ELISA for iNOS: p = 0.011). At 1400 W, exertion of analgesic effects (mechanical: p < 0.0001, thermal: p < 0.0001) but pro-inflammatory (RT-qPCR for IL-1β: p = 0.004, IL-6: p = 0.03, TNF: p = 0.04) were exerted on the inflamed paw on day 5 post-injection. In conclusion, short-term HFD aggravated CFA-induced inflammatory pain. Pharmacological inhibition of iNOS attenuated the CFA-induced pain in HFD-fed mice. Future research might uncover signaling pathways mediating such effects, potentially benefiting obese patients with chronic IP. Full article

Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness, variable airflow obstruction, and persistent inflammation. While its pathophysiology is well established, growing evidence highlights significant sex-based differences in its prevalence, severity, and treatment response. Epidemiological studies indicate that asthma is more common in prepubertal boys but shifts toward a female predominance after puberty, with adult women experiencing higher morbidity and greater healthcare utilization. These disparities suggest a crucial role for sex hormones, genetic predisposition, and epigenetic regulation in asthma pathogenesis. Sex hormones modulate immune responses, contributing to disease progression. Estrogen enhances type 2 inflammation, increases eosinophilic infiltration, and upregulates IL-4 and IL-13 expression, leading to greater airway hyperreactivity in women. Additionally, progesterone fluctuations correlate with perimenstrual asthma exacerbations, while testosterone appears to exert a protective effect by dampening Th2-driven inflammation and airway remodeling. These hormonal influences contribute to sex-specific asthma phenotypes and treatment responses. Genetic and epigenetic factors further shape sex-related differences in asthma. The X chromosome harbors immune-regulatory genes, including TLR7 and TLR8, which amplify inflammatory responses in females. The sex-dependent expression of IL13 and ORMDL3 influences eosinophilic inflammation and airway remodeling. Epigenetic modifications, such as DNA methylation and microRNA regulation, further impact immune activation and corticosteroid responsiveness. For instance, Let-7 miRNAs modulate IL-13 expression, contributing to sex-specific inflammatory profiles. Environmental factors, including air pollution, obesity, and diet, interact with hormonal and genetic influences, exacerbating sex disparities in asthma severity. Obesity-related metabolic dysfunction promotes systemic inflammation, airway remodeling, and steroid resistance, disproportionately affecting women. Given these complex interactions, sex-specific approaches to asthma management are essential. Personalized treatment strategies targeting hormonal pathways, immune regulation, and metabolic health may improve outcomes for both men and women with asthma. Future research should focus on sex-based therapeutic interventions to optimize disease control and mitigate healthcare disparities. Full article