Search Results (4,072)

L-arginine, a semi-essential amino acid, is well-documented for its role in nitric oxide (NO) synthesis, its anti-inflammatory properties, and its modulation of immune responses. Studies suggest it may improve gut barrier function and reduce inflammation in conditions such as colitis or sepsis. However, its specific efficacy in diabetic enteropathy (a complication of diabetes involving intestinal dysfunction, inflammation, and neuropathy) is less studied. To verify whether L-arginine and silkworm pupae components have a role in the treatment of diabetic enteropathy via the regulation of other cytokines and suppression of CD4+ T lymphocyte proliferation, a special medical-purpose formula containing both of these components was tested. For the first time, we have integrated L-arginine and silkworm pupae protein into enteral nutrition formulations for testing its anti-inflammatory potential. We have found that these formulations can improve the characteristics of diabetic intestinal inflammation through nutrient-modulating effects and nutritional efficacy. In addition, L-arginine (L-arginine, L-arg) enhances the immunomodulatory effects of special medical purpose formulas for diabetes mellitus. We utilized an oxidative stress model of small intestinal epithelial cells induced by high glucose and an inflammation model of the small intestine triggered by lipopolysaccharide in mice. The aim was to further investigate the protective effects of L-arginine and enteral nutritional preparations derived from silkworm pupae protein components on the intestinal tract. This research seeks to establish a theoretical foundation for understanding how L-arginine and these nutritional preparations regulate intestinal inflammation in vivo. Full article

Puccinia polysora Underw, the pathogen that causes southern corn rust (SCR), delivers effectors to manipulate host immune responses. However, the mechanisms by which these effectors modulate host defenses are not well characterized. In this study, we found that the P. polysora effector PpEX is highly upregulated during infection. PpEX suppresses plant immune responses that are initiated by chitin, including the activation of mitogen-activated protein kinases (MAPKs) and the expression of pathogenesis-related (PR) genes. Maize plants transiently expressing PpEX exhibited higher pathogen infection rates, larger colony areas, and greater fungal biomass on their leaves compared to the control group. By employing TurboID proximity labeling technology coupled with mass spectrometry analysis, we discovered potential target proteins of PpEX in maize. The split-luciferase system enabled us to identify ZmMPK3, a component of the MAPK signaling pathway, as an interacting partner of PpEX among the candidate proteins. This interaction was subsequently confirmed by co-immunoprecipitation (Co-IP) experiments. Additionally, we verified that ZmMPK3 plays a positive role in regulating maize resistance to SCR. Thus, PpEX may function as a virulence effector that dampens plant PTI immunity by interacting with ZmMPK3 and impeding the MAPK signaling pathway. Full article

Tazarotene, a retinoid derivative, is widely used in treating skin conditions such as psoriasis and acne. Recent studies have demonstrated its potential as a promising therapeutic agent for treating melanoma in situ. Its primary mechanism of action involves the selective activation of retinoic acid receptors (RAR-β and RAR-γ), which play important roles in regulating cell growth, differentiation, and apoptosis. By activating these receptors, tazarotene influences the expression of several downstream inducible genes, such as tazarotene-induced gene-1 (TIG1), TIG2, and TIG3. These genes play crucial roles in regulating melanoma cell proliferation, invasiveness, and immune responses in the tumor microenvironment. This review aims to provide a comprehensive overview of the current status of retinoid derivatives—particularly tazarotene—in melanoma treatment and the latest research regarding their molecular mechanisms. We will explore how tazarotene suppresses melanoma growth through gene regulation mechanisms and discuss its potential role in immune responses within the tumor microenvironment. Additionally, we assess the advantages and challenges of using tazarotene as a topical treatment and explore its future clinical applications. These studies contribute to a wider understanding of tazarotene’s antitumor mechanisms, providing a solid theoretical foundation for its potential as a therapeutic option for melanoma in situ. Full article

Non-muscle invasive bladder cancer (NMIBC) represents a significant clinical challenge due to its high recurrence rate and need for frequent monitoring. The current treatment modality is bacillus Calmette–Guérin (BCG) therapy combined with chemotherapy after transurethral resection of the bladder tumor (TURBT), which is highly effective in most patients. Yet, the cancer becomes resistant to these treatments in 30–40% of patients, necessitating the need for new treatment modalities. In the cancer world, the development of immune checkpoint inhibitors that target molecules, such as programmed cell death protein-1 (PD-1), its ligand, PD-L1, and Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), have revolutionized the treatment of many cancer types. PD-1/PD-L1 and CTLA-4 are shown to be upregulated in NMIBC in certain circumstances. PD-1/PD-L1 interactions play a role in immune evasion by suppressing T cell activity within the tumor microenvironment (TME), while the binding of CTLA-4 on T cells leads to downregulation of the immune response, making these pathways potential immunotherapeutic targets in NMIBC. This review seeks to understand the role of these therapies in treating NMIBC. We explore the cellular and non-cellular immune landscape in the TME of NMIBC, including Tregs, T effector cells, macrophages, B cells, and relevant cytokines. We also discuss the biological role of PD-1/PD-L1 and CTLA-4 while covering the rationale for these immunotherapies in NMIBC. Finally, we cover key clinical trials that have studied these treatments in NMIBC clinically. Such a study will be helpful for urologists and oncologists to manage patients with NMIBC more effectively. Full article

Hypercalcemia represents a rare complication of nontuberculous Mycobacterium (NTM) infections, particularly in individuals with human immunodeficiency virus (HIV) positivity. This systematic review examines NTM infections associated with hypercalcemia, including the presentation of a novel and illustrative case of Mycobacterium simiae. A meticulous literature search identified 24 cases relevant to this phenomenon (11 HIV-positive and 13 non-HIV), which were included in the analysis. Key clinical and laboratory findings reveal significant contrasts between HIV-positive and non-HIV patients. In the HIV-positive cohort, hypercalcemia is commonly developed after the initiation of highly active antiretroviral therapy (HAART) or treatment for NTM infections despite severe underlying immunosuppression. Conversely, in the non-HIV group, a spectrum of immunosuppressive conditions, including chronic renal failure and prolonged use of immunosuppressive drugs, was implicated in the pathogenesis of NTM infections with hypercalcemia. Two distinct mechanistic pathways likely underlie this association. In HIV-positive patients, immune restoration following HAART appears to drive granuloma formation and excessive 1,25-dihydroxyvitamin D production. In non-HIV individuals, prolonged immune suppression may facilitate macrophage activation associated with NTM infections, thereby contributing to hypercalcemia. Treatment strategies varied and included bisphosphonates, corticosteroids, and hemodialysis. Notably, bisphosphonates emerged as a safe and effective option in most cases. Antibiotic therapy was deemed unnecessary when hypercalcemia was the sole symptom of NTM infection. This review underscores the importance of recognizing hypercalcemia as a potential complication of NTM infections and tailoring management strategies to the patient’s underlying immunological status. Full article

Addressing the escalating global burdens of inflammatory bowel disease and antimicrobial resistance demanded innovative food-based approaches to fortify gut health and suppress pathogens. We introduced a novel edible probiotic, Enterococcus faecalis HY0110, isolated from marine Thunnus thynnus. Through comprehensive in vitro, in vivo, and metabolomic analyses, we demonstrated its superior antibacterial effects compared to Lactobacillus rhamnosus GG, along with significantly enhanced antioxidant and free-radical scavenging capacities. Notably, elevated acetic acid production strongly correlated with its antimicrobial efficacy (R ≥ 0.999). HY0110 also exerted antiproliferative effects on HT-29 colorectal cancer cells by attenuating β-catenin and BCL-2 expression while upregulating pro-apoptotic markers P62 and c-PARP. In a DSS-induced colitis model, HY0110 alleviated inflammation, restored gut microbial homeostasis, and enhanced deterministic processes in community assembly dynamics. Furthermore, fermenting Periplaneta americana powder with HY0110 triggered extensive metabolic remodeling, notably a 668.73-fold rise in astragaloside A, plus increases in L-Leucyl-L-Alanine, S-lactoylglutathione, and 16,16-dimethyl prostaglandin A1. These shifts diminished harmful components and amplified essential amino acids and peptides to bolster immune modulation, redox balance, and anti-inflammatory responses. This work established a transformative paradigm for utilizing marine probiotics and novel entomological substrates in functional foods, presenting strategic pathways for precision nutrition and inflammatory disease management. Full article

RNA viruses pose a significant global public health burden due to their high mutation rates, zoonotic potential, and ability to evade immune responses. A common aspect of their replication is the generation of defective interfering particles (DIPs), which contain truncated defective viral genomes (DVGs) that depend on full-length standard (STD) virus for replication. DVGs have gained recognition as they are increasingly detected in clinical samples from natural infections. While their role in modulating type I interferon (IFN-I) responses is well established, their impact on the complement (C′) system is not understood. In this study, we examined how DVGs influence C′-mediated lysis during parainfluenza virus 5 (PIV5) infection using real-time in vitro cell viability assays. Our results demonstrated that C′ effectively killed human lung epithelial cells infected with STD PIV5, whereas co-infection with DIP-enriched stocks significantly suppressed C′-mediated killing through mechanisms that were dependent on DVG replication but independent of IFN-I production. The titration of DI units in co-infection with STD PIV5 showed a strong linear relationship between DIP-mediated decreases in surface viral glycoprotein expression and the inhibition of C′-mediated lysis. Our findings reveal a previously unrecognized function of DVGs in modulating C′ pathways, shedding light on their potential role in viral persistence and immune evasion. Full article

Exosomes are actively produced extracellular vesicles, released from different cell types, that exert important regulatory roles in vital cellular functions. Tumor-derived exosomes (TDEs) have received increasing attention because they enable intercellular communication between the neoplastic and non-neoplastic cells present in the microenvironment of tumors, affecting important functions of different types of mesenchymal stem cells (MSCs) with the ability to self-renew and differentiate. MSC-derived exosomes (MSC-exos) carry a variety of bioactive molecules that can interact with specific cellular targets and signaling pathways, influencing critical processes in tumor biology, and exhibiting properties that either promote or inhibit tumor progression. They can regulate the tumor microenvironment by modulating immune responses, enhancing or suppressing angiogenesis, and facilitating tumor cells’ communication with distant sites, thus altering the behavior of non-cancerous cells present in the microenvironment. Herein, we explore the main functions of TDEs and their intricate interactions with MSC-exos, in terms of enhancing cancer progression, as well as their promising clinical applications as tumor microenvironment modulators. Full article

The cytokine storm, a hyperinflammatory response characterized by the excessive release of pro-inflammatory mediators such as TNFα, INFγ, IL-1β, IL-6, and GM-CSF, has been identified as a critical factor in the progression and severity of acute inflammatory conditions. Regulating these pathways is essential for mitigating systemic damage and improving outcomes. Natural products from tropical American plants have shown significant potential in modulating these hyperinflammatory responses. Key polyphenols, like quercetin and luteolin, found in plants such as Achyrocline satureioides and Mangifera indica demonstrate the downregulation of NF-κB and inhibition of pro-inflammatory cytokines. Alkaloids, such as berberine and mitraphylline, isolated from Berberis species and Uncaria tomentosa, respectively, have shown potent effects in suppressing nitric oxide production and regulating inflammasomes. Terpenoids, including parthenolide from Tanacetum parthenium and curcumol from Curcuma longa, exhibit multitarget activity, reducing cytokine levels and inhibiting key inflammatory enzymes like COX-2 and iNOS. These findings highlight the immense potential of bioactive compounds from tropical American plants as modulators of immune–inflammatory pathways, providing a foundation for developing effective therapeutic agents to counteract the severe effects of cytokine storms. Full article

Background: Glioblastoma is “cold”. Consequently, immune checkpoint blockade therapy has failed to improve patients‘ survival, which is negatively correlated with patients’ peripheral MDSC counts. AHR is known to mediate immune-suppressive functions of certain tryptophan metabolites such as kynurenine; yet, there lack of reports on how AHR agonists affect glioma immunity. Methods/Objectives: We hypothesized that ITE could synergize with PD1 antibody as AHR is one major node of immune-suppressive pathways, and tested it using an immune-competent mouse glioma model. Results: The combination of ITE+PD1 antibody glioma MDSC was significantly reduced, along with increased infiltration of the CD4−CD8+ and CD4+CD8+ T cells, leading to extended mouse survival. ITE treatment alone significantly reduces the infiltration of CD11b+Ly6G+Ly6Clo cells, namely PMN-MDSCs, and neutrophils, while the combination with PD1 antibody significantly reduces all MDSCs plus neutrophils. The presence of ITE inhibits the expression of IL11 and the in vitro induction of MDSCs from mouse PBMCs by IL11. The identification of the ITE-AHR-IL11-MDSC pathway provides more mechanistic insights into AHR’s effects. The fact that ITE, which is otherwise immune-suppressive, can activate immunity in glioma indicates that searching for drugs targeting AHR should go beyond antagonists. Full article

Small-cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid proliferation, early metastasis, and frequent recurrence, which contribute to a poor prognosis. SCLC is defined by the near-universal inactivation of key tumor suppressor genes, notably TP53 and RB1, which play central roles in its pathogenesis and resistance to therapy. The p53 family of proteins, including p53, p63, and p73, is essential to maintaining cellular homeostasis and tumor suppression. TP53 mutations are almost ubiquitous in SCLC, leading to dysregulated apoptosis and cell cycle control. Moreover, p73 shows potential as a compensatory mechanism for p53 loss, while p63 has a minimal role in this cancer type. In this review, we explore the molecular and functional interplay of the p53 family in SCLC, emphasizing its members’ distinct yet interconnected roles in tumor suppression, immune modulation, and therapy resistance. We highlight emerging therapeutic strategies targeting these pathways, including reactivating mutant p53, exploiting synthetic lethality, and addressing immune evasion mechanisms. Furthermore, this review underscores the urgent need for novel, isoform-specific interventions to enhance treatment efficacy and improve patient outcomes in this challenging disease. Full article

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease. The pathomechanism of RA depends on both B and T cells. Regulatory B cells (Breg) have been shown to suppress T-cell immune responses and play a key role in modulating autoimmune processes. We aimed to investigate the possibility of utilizing PD-L1⁺ Breg cells in downregulating the Th cells’ immune response in healthy individuals and RA patients. We hypothesized that the PD-1/PD-1L interaction plays a key role in this process, which may be defective in autoimmune diseases. We separated T and B cells from the peripheral blood of healthy volunteers and RA patients by magnetic cell sorting, and Th cells and Treg cells were isolated by fluorescence-activated cell sorting. The cytokine production by CD4⁺ Th cells was detected by intracellular flow cytometry. CpG and CD40L stimulations were applied to induce PD-L1^hi expressing Breg cells. We found that the frequency of PD-L1^hi cells is significantly lower in all B-cell subsets in RA compared to healthy controls. Functional analysis of induced PD-L1⁺ Breg cells in coculture with activated autologous Th cells has shown that healthy control samples containing higher levels of PD-L1^hi Breg cells significantly inhibit IFN-ү and IL-21 production by Th cells. In contrast, RA patients’ samples with lower levels of PD-L1^hi Breg cells failed to do so. Since the expression of PD-L1 on B cells can be modulated in vitro to induce Breg cell suppressive capacity, these data may provide new perspectives for future therapy for RA. Full article

Atopic dermatitis is caused by various factors, including complex interactions between immune responses and imbalances in T helper cells. In order to resolve the side effects of steroid-based treatment and rapidly improve atopy symptoms, the development of preventive substances for new treatments and as food supplements is essential. Pulsatilla koreana Nakai (PKN) is traditionally used as an effective herbal medicine for pain relief, anti-inflammation, and edema, and dried PKN is boiled and drunk as a tea to prevent them; however, its effect on skin manifestations such as atopy are unclear. Therefore, we investigated the in vivo and in vitro effects of PKN extract on improving symptoms of atopy as a potential treatment. By evaluating dermatitis scores and conducting histopathological analysis in mice with Dermatophagoides farina-induced atopy-like pathology, we demonstrated that PKN extract alleviated atopy symptoms. Moreover, PKN extract restored a reduction in the protein levels of skin barrier-related factors in skin tissue. Through in vitro analysis, we examined the impact of PKN on JAK/STAT signaling in IL-4/IL-13-stimulated human keratinocytes and elucidated the mechanisms that suppress the levels of skin barrier factors and inflammation. PKN extract inhibited JAK/STAT phosphorylation stimulated by IL-4/IL-13. Furthermore, docking analysis of PKN constituents indicated binding to JNK1/2 and STAT3/6 and a subsequent inhibition of signal transduction. Therefore, this suggests that PKN extract has potential not only as a treatment but also as a food supplement to improve atopic dermatitis by strengthening skin barrier factors and inhibiting key signaling molecules. Full article

Background/Objectives: Cutaneous melanoma (CM) is a highly aggressive malignancy with poor prognosis, necessitating novel biomarkers and therapeutic targets. Centromere protein F (CENPF), a mitotic regulator, has been implicated in tumor progression, but its role in melanoma remains unclear. This study aimed to investigate the clinical significance, biological function, and regulatory mechanisms of CENPF in melanoma. Methods: Public melanoma datasets (GSE46517, GSE3189, and GSE7553) were re-analyzed to identify differentially expressed genes (DEGs). CENPF expression was validated in clinical samples (n = 128), melanoma cell lines, and xenograft models. Functional assays (EdU, CCK-8, colony formation, wound healing, transwell, and flow cytometry) and bioinformatics analyses (GO, KEGG, GSEA, and SCENIC) were performed to assess proliferation, apoptosis, metastasis, and regulatory pathways. In vivo tumorigenesis and metastasis were evaluated in BALB/c nude mice. Results: CENPF was significantly upregulated in melanoma tissues and cell lines compared to controls (p < 0.05). High CENPF expression correlated with advanced Clark level (p = 0.006), ulceration (p = 0.04), and poor overall survival (p = 0.005). Knockdown of CENPF suppressed melanoma cell proliferation, migration, and invasion in vitro, while inducing G2/M phase arrest and apoptosis. In vivo, CENPF silencing reduced tumor growth and lung metastasis. Mechanistically, CENPF was transcriptionally activated by E2F3, and the E2F3-CENPF axis promoted cell cycle progression via G2/M checkpoint activation and P53 pathway suppression. Conclusions: CENPF serves as a prognostic biomarker and therapeutic target in melanoma. Its upregulation drives tumor progression through cell cycle dysregulation and immune evasion, while targeting the E2F3-CENPF axis may offer a novel strategy for melanoma treatment. These findings provide critical insights into melanoma pathogenesis and potential clinical applications. Full article

Rice false smut, caused by Ustilaginoidea virens, is one of the three major rice diseases in China. It not only seriously affects the rice yield and quality but also endangers human and animal health. Studying the pathogenic mechanism of U. virens has important theoretical significance and application value for clarifying the infection characteristics of the pathogen and cultivating disease-resistant varieties. Plant pathogenic fungi utilize secreted effectors to suppress plant immune responses, which can function in the apoplast or within host cells and are likely glycosylated. However, the posttranslational regulation of these effectors remains unexplored. Deletion of ΔUvALG led to the cessation of secondary infection hyphae growth and a notable decrease in virulence. We observed that ΔUvALG mutants triggered a significant increase in reactive species production within host cells, akin to ALG mutants, which plays a crucial role in halting the growth of infection hyphae in the mutants. ALG functions by sequestering chitin oligosaccharides to prevent their recognition by the rice chitin elicitor, thereby inhibiting the activation of innate immune responses, including reactive species production. Our findings reveal that ALG3 possesses three N-glycosylation sites, and the simultaneous Alg-mediated N-glycosylation of each site is essential for maintaining protein stability and chitin-binding activity, both of which are critical for its effector function. These outcomes underscore the necessity of the Alg-mediated N-glycosylation of ALG to evade host innate immunity. Full article