Search Results (42)

Plastic pollution is acknowledged as a serious problem for ecosystems. Among these plastics, polystyrene nanoplastics (PS-NPs) are emerging environmental pollutants, and their biological effects on hepatotoxicity are the least explored. Therefore, the present work examined the effect of PS-NPs on the hepatic transcription of the antioxidant genes Hmox1 and Sod3 in mice (n = 6, treatment (PS-NPs) vs. vehicle group (Veh)), mediated by RORγ and epigenetic modifications. The results show that PS-NP mice had significantly reduced body weight; increased activity of adenosine triphosphate (ATP), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH), and Complexes I, III, and V in the liver; and increased Alanine Transaminase (ALT), Aspartate Transaminase (ASP), Alkaline Phosphatase (ALP), malondialdehyde (MDA) and reactive oxygen species (ROS) compared to the Veh group. Furthermore, PS-NPs resulted in considerably lower relative mRNA expression of Hmox1, Sod3, and RORγ in the liver than the Veh group. Likewise, when compared to Veh, PS-NPs significantly reduced the enrichment of RORγ, as well as the occupancies of the key components of the transcriptional activation pathway (P300, SRC1, Pol II, Ser5-Pol II, and Ser2-Pol II) at the loci of Hmox1 and Sod3. In comparison to Veh, PS-NPs showed downregulated occupancies of the histone active marks H3K9ac and H3K18ac, while H3K4me3 and H3K27me3 were higher at the target loci of Hmox1 and Sod3. In conclusion, the present study highlights that PS-NPs induce oxidative stress by modifying Hmox1 and Sod3 in mice’s livers through histone changes and nuclear receptor RORγ modulation. Full article

Teleost fish are the first evolutionary group to exhibit an innate and adaptive immune system. Within the mechanisms of adaptive immunity, fish possess, among others, T-helper cells (CD4-like) and their differentiation machinery, regulated by the master transcription factors T-bet, GATA3, Foxp3, and RORγ. Many studies support the existence of a non-neuronal cholinergic system involved in the immune response, named after the ability of leukocytes to synthesize de novo acetylcholine (ACh). Organophosphorus pesticides (OPs), such as diazoxon (DXN), are examples of compounds that act as cholinergic disruptors with immunotoxic effects. The present study aimed to evaluate the expression of transcription factors in leukocytes (spleen mononuclear cells, SMNCs) of Nile tilapia by modulating cholinergic pathways in immune cells using agonists, antagonists, and diazoxon (DXN), an anticholinesterase substance. The obtained data showed a significant increase in RORγ mRNA expression upon stimulation with the nicotinic agonist, whereas activation of the muscarinic receptor with its agonist increased T-bet mRNA expression. An alteration in RORγ expression levels induced by DXN exposure was also observed. The results suggest a probable directing of the immune response towards a pro-inflammatory profile orchestrated mainly by RORγ and T-bet transcription factors in response to cholinergic stimuli. Full article

Nuclear receptors (NRs) are transcription factors regulated by ligands that direct metabolism, development, and immunity. The NR superfamily constitutes a principal category of pharmacological targets for human ailments. Retinoic acid receptor-related orphan receptors (RORs) α, β, and γ are part of the nuclear receptor superfamily. They are nevertheless classified as “orphan” receptors due to the contentious nature of identifying their endogenous ligands. RORγ nuclear receptor protein further consists of two isoforms, namely RORγ1 and RORγ2 or RORγt. RORγt is largely found in immune cells and has been primarily associated with chronic inflammatory conditions. The expression of STAT3 is a major driver of Th17 differentiation and induces RORγt expression through the JAK-STAT pathway. Type 3 innate lymphoid cells (ILC3s), Th17 cells, and γδT cells express RORγt, the master transcription regulator for the pro-inflammatory cytokine interleukin IL-17. In chronic inflammatory skin disorders, a significant increase in IL-17 has been observed, which plays a key role in both immune cell recruitment to the site of inflammation and the propagation of tissue damage. In this review, we will discuss how RORγt regulates IL-17-driven inflammation and explore potential strategies to target the RORγt-IL-17 axis as a viable therapeutic intervention in chronic inflammatory skin disorders. Full article

Nuclear receptors are involved in multiple biological processes, among which RORγ can regulate the expression of inflammation-related genes and is thus frequently used as a therapeutic target for cancer. Canine mammary cancer is one of the most common tumor diseases in dogs, with a relative incidence rate of 46.71% for CMT in China over the past five years, severely threatening the life and health of dogs. Therefore, the search for novel drugs targeting canine mammary cancer is of great significance. This study aims to investigate how the RORγ inhibitors W6134 and XY018 affect the expression of inflammatory genes through histone modifications in CMT-N7 cells. These results show that W6134 and XY018 can upregulate signaling pathways related to inflammation and apoptosis and influence the expression of associated genes. The close link between RORγ and inflammation-related genes further confirms that RORγ may serve as a therapeutic target for canine cancer. Additionally, ChIP-qPCR was used to detect the enrichment of histone markers such as P300, H3K27ac, H3K4me1, H3K9la, and H3K9bhb at the target loci of CXCL10 and MECOM genes. Collectively, our findings provide molecular evidence for the protective role of RORγ in canine mammary cancer, potentially by regulating inflammatory pathways via histone modifications, offering new insights for improving the cure rate and survival of affected dogs. Full article

Cardiac glycosides (CGs), a class of plant- and animal-derived compounds historically used to treat heart failure, have garnered renewed interest for their diverse pharmacological properties beyond Na⁺/K⁺-ATPase (NKA) inhibition. Recent studies reveal that CGs modulate key signaling pathways—such as NF-κB, PI3K/Akt, JAK/STAT, and MAPK—affecting processes central to cancer, viral infections, immune regulation, and neurodegeneration. In cancer, CGs induce multiple forms of regulated cell death, including apoptosis, ferroptosis, pyroptosis, and immunogenic cell death, while also inhibiting angiogenesis, epithelial–mesenchymal transition, and cell cycle progression. They demonstrate broad-spectrum antiviral activity by disrupting viral entry, replication, and mRNA processing in viruses such as HSV, HIV, influenza, and SARS-CoV-2. Immunologically, CGs regulate Th17 differentiation via RORγ signaling, although both inhibitory and agonistic effects have been reported. In the nervous system, CGs modulate neuroinflammation, support synaptic plasticity, and improve cognitive function in models of Alzheimer’s disease, epilepsy, and multiple sclerosis. Despite their therapeutic potential, clinical translation is hindered by narrow therapeutic indices and systemic toxicity. Advances in drug design and nanocarrier-based delivery are critical to unlocking CGs’ full potential as multi-target agents for complex diseases. This review synthesizes the current knowledge on the emerging roles of CGs and highlights strategies for their safe and effective repurposing. Full article

The current definition of a postbiotic is a “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”. Postbiotics can be mainly classified as metabolites, derived from intestinal bacterial fermentation, or structural components, as intrinsic constituents of the microbial cell. Secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) are bacterial metabolites generated by the enzymatic modifications of primary bile acids by microbial enzymes. Secondary bile acids function as receptor ligands modulating the activity of a family of bile-acid-regulated receptors (BARRs), including GPBAR1, Vitamin D (VDR) receptor and RORγT expressed by various cell types within the entire human body. Secondary bile acids integrate the definition of postbiotics, exerting potential beneficial effects on human health given their ability to regulate multiple biological processes such as glucose metabolism, energy expenditure and inflammation/immunity. Although there is evidence that bile acids might be harmful to the intestine, most of this evidence does not account for intestinal dysbiosis. This review examines this novel conceptual framework of secondary bile acids as postbiotics and how these mediators participate in maintaining host health. Full article

Background: It is true that vitamin D did not earn its title as the “sunshine vitamin” for nothing. In recent years, however, there has been a shift in the perception surrounding vitamin D to a type of hormone that boasts countless bioactivities and health advantages. Historically, vitamin D has been known to take care of skeletal integrity and the calcium–phosphorus balance in the body, but new scientific research displays a much larger spectrum of actions handled by this vitamin. Materials and Methods: A systematic literature search was performed using the following electronic databases: PubMed, Scopus, Web of Science, Embase, and Cochrane Library. Results: Many emerging new ideas, especially concerning alternative hormonal pathways and vitamin D analogs, are uniformly challenging the classic “one hormone–one receptor” hypothesis. To add more context to this, the vitamin D receptor (VDR) was previously assumed to be the only means through which the biologically active steroid 1,25-dihydroxyvitamin D3 could impact the body. Two other molecules apart from the active hormonal form of 1,25(OH)2D3 have gained interest in recent years, and these have reinvigorated research on D3 metabolism. These metabolites can interact with several other nuclear receptors (like related orphan receptor alpha—RORα, related orphan receptor gamma—RORγ, and aryl hydrocarbon receptor—AhR) and trigger various biological responses. Conclusions: This paper thus makes a case for placing vitamin D at the forefront of new holistic and dermatological health research by investigating the potential synergies between the canonical and noncanonical vitamin D pathways. This means that there are now plentiful new opportunities for manipulating and understanding the full spectrum of vitamin D actions, far beyond those related to minerals. Full article

Background: Within the past few years, many new therapies have emerged for psoriasis and psoriatic arthritis (PsA). Current topical therapies—including corticosteroids, vitamin D analogs, tapinarof, and roflumilast—remain the mainstay for mild disease, while oral systemic and biologic options are for moderate to severe cases. Biologics—such as Tumor necrosis factor-alpha (TNF-alpha), Interleukin 12/23 (IL-12/23), Interleukin-17 (IL-17), and Interleukin-23 (IL-23)—have revolutionized care by providing highly effective and safer alternatives. Oral small molecules, including Janus kinase (JAK) and tyrosine kinase 2 (TYK2) inhibitors, further expand the therapeutic options. Objectives: The goal for this review article was to examine current and latest treatments for psoriasis and PsA and discuss whether these emerging therapeutic options address the unmet needs of current treatments. Methods: The search for this review article included PubMed, Google Scholar, and ClinicalTrials.gov for relevant articles and current clinical trials using keywords. Results: A wide range of novel psoriatic and PsA therapies are currently undergoing clinical trials. These include selective JAK inhibitors, TYK2 inhibitors, retinoic acid-related orphan receptor (RORγT) inhibitors, oral IL-23 receptor inhibitors, oral IL-17A inhibitors, nanobody products, sphingosine-1-phosphate (S1P1R) antagonists, A3 adenosine receptor (A3AR) agonists, heat shock protein (HSP) 90 inhibitors, and rho-associated protein kinases (ROCK-2) inhibitors. Conclusions: These different mechanisms of action not only expand treatment options but may offer potential solutions for patients who do not achieve adequate response with existing therapies. However, the safety and contraindications of these newer agents remain an important consideration to ensure appropriate patient selection and minimize potential risks. Certain mechanisms may pose increased risks for infection, cardiovascular manifestations, malignancy, or other immune-related adverse events, necessitating careful monitoring and individualized treatment decisions. Ongoing clinical research aims to address unmet needs for patients who do not respond to previous agents to achieve sustained remission, monitor long-term safety outcomes, and assess patient preferences for delivery, including a preference for oral delivery. Oral IL-23 inhibitors hold potential due to their robust safety profiles. In contrast, oral IL-17 inhibitors and TYK-2 inhibitors are effective but may present side effects that could impact their acceptability. It is essential to balance efficacy, safety, and patient preferences to guide the selection of appropriate therapies. Full article

Retinoic-acid-related orphan receptors (RORs) are transcription factors belonging to the nuclear receptor subfamily consisting of RORα, RORβ, and RORγ. By binding to the ROR response elements (ROREs) on target gene promoters, RORs regulate a wide variety of cellular processes, including autophagy, mitophagy, oxidative stress, and inflammation. The regulatory roles of RORs are observed in cardiac cells, hepatocytes, pulmonary epithelial cells, renal cells, immune cells, and cancer cells. A growing body of clinical and experimental evidence suggests that ROR expression levels are markedly reduced under different pathological and stress conditions, suggesting that RORs may play a critical role in the pathogenesis of a variety of disease states, including myocardial infarction, immune disorders, cancer, and metabolic syndrome. Reductions in RORs are also associated with inhibition of autophagy, increased reactive oxygen species (ROS), and increased cell death, underscoring the importance of RORs in the regulation of these processes. Herein, we highlight the relationship between RORs and homeostatic processes that influence cell viability. Understanding how these intricate processes are governed at the cellular level is of high scientific and clinical importance to develop new therapeutic strategies that modulate ROR expression and disease progression. Full article

Heat stress (HS) is a significant concern in broiler chickens, which is vital for global meat supply in the dynamic field of poultry farming. The impact of heat stress on the ileum and its influence on the redox homeostatic genes in chickens remains unclear. We hypothesized that adding zinc to the feed of heat-stressed broilers would improve their resilience to heat stress. However, this study aimed to explore the effects of organic zinc supplementation under HS conditions on broiler chickens’ intestinal histology and regulation of HS index genes. In this study, 512 Xueshan chickens were divided into four groups: vehicle, HS, 60 mg/kg zinc, and HS + 60 mg/kg zinc groups. Findings revealed that zinc supply positively increased the VH and VH: CD in the ileum of the broilers compared to the HS group, while CD and VW decreased in Zn and HS+Zn supplemented broilers. Zn administration significantly increased superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and decreased the enzymatic activities of reactive oxygen species (ROS) and malondialdehyde (MDA) compared to the HS group. In addition, Zn administration significantly increased relative ATP, complex I, III, and V enzyme activity compared to the HS group. Furthermore, the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), lactate transporter 3 (LPCAT3), peroxiredoxin (PRX), and transferrin receptor (TFRC) in the protein levels was extremely downregulated in HS+Zn compared to the HS group. Zn supply significantly decreased the enrichment of RORγ, P300, and SRC1 at target loci of ACSL4, LPCAT3, and PRX compared to the HS group. The occupancies of histone active marks H3K9ac, H3K18ac, H3K27ac, H3K4me1, and H3K18bhb at the locus of ACSL4 and LPCAT3 were significantly decreased in HS+Zn compared to the HS group. Moreover, H3K9la and H3K18la at the locus of ACSL4 and LPCAT3 were significantly decreased in HS+Zn compared to the HS group. This study emphasizes that organic Zn is a potential strategy for modulating the oxidative genes ACSL4, LPCAT3, PRX, and TFRC in the ileum of chickens via nuclear receptor RORγ regulation and histone modifications. Full article

Global fire activities, which are getting worse due to climate change, cause both environmental and human health hazards. Firefighters, being the first responders, are frequently exposed to heat which may impact their immune system and overall health. However, the nature of the impact of chronic heat exposure on immune function has not been studied in-depth in firefighters. In this study, 22 firefighters exposed to “heavy-smoke fires (structural fires)”, categorized as the “high-exposure group” (>0.15 structural fires/week) and “low-exposure group” (<0.15 structural fires/week), were sampled. Peripheral blood was examined for immune cell profile based on total and differential cell counts, immune function based on the transcriptional expression of drivers of innate and adaptive immunity and key inflammation mediators, and heat stress marker HSP70. The white blood cell (WBC) count, mean corpuscular volume, mean corpuscular hemoglobin, and absolute and segmented neutrophil counts decreased below the normal range in both exposure groups. The gene transcript levels for toll-like receptors (TLR2, TLR4, but not TLR7) and their adaptor protein MYD88 were lower whereas those for T-cell transcription factors (RORC/RORγ, FoxP3) and inflammatory mediators (TNF-α, Granzyme-B) were higher in the “high-exposure group”, indicating mixed response; however, the ratios between pro-inflammatory and anti-inflammatory transcription factors of adaptive immunity, namely T-bet/FoxP3 (Th1/Treg) and RORC/FoxP3 (Th17/Treg), were lower. Collectively, decreased immune cell landscape, downregulated key innate immunity receptors, and Tregs’ dominance suggested that chronic heat exposure in firefighters dysregulated innate and adaptive immunity, skewed towards an overall immunosuppressive condition with inflammation. Full article

Granulomatous Mycosis Fungoides (GMF) is a rare form of mycosis fungoides (MF) characterized by a granulomatous infiltrate associated with the neoplastic lymphoid population and is considered to have a worse prognosis compared with regular MF. The upregulation of the T helper (Th) axis, especially Th17, plays an important role in the pathogenesis of several inflammatory/infectious granulomatous cutaneous diseases, but its role in GMF is still not elucidated to date. In this study, we evaluated the immunohistochemical expression of Th1 (Tbet), Th2 (GATA-3), Th17 (RORγT), T regulatory (Foxp3), and immune checkpoint (IC) (PD-1 and PD-L1) markers in a cohort of patients with GMF and MF with large cell transformation (MFLCT). Skin biopsies from 49 patients (28 GMF and 21 MFLCT) were studied. Patients with GMF were associated with early clinical stage (p = 0.036) and lower levels of lactate dehydrogenase (p = 0.042). An increased percentage of cells positive for Tbet (p = 0.017), RORγT (p = 0.001), and PD-L1 (p = 0.011) was also observed among the GMF specimens, while a stronger PD-1 intensity was detected in cases of MFLCT. In this cohort, LCT, RORγT < 10%, Foxp3 < 10%, age, and advanced stage were associated with worse overall survival (OS) in univariate analysis. GMF demonstrated Th1 (cellular response) and Th17 (autoimmunity) phenotype, seen in early MF and granulomatous processes, respectively, which may be related to the histopathological appearance and biological behavior of GMF. Further studies involving larger series of cases and more sensitive techniques are warranted. Full article

Patients with active ulcerative colitis (UC) display a misalignment of the circadian clock, which plays a vital role in various immune functions. Our aim was to characterize the expression of clock and inflammation genes, and their mutual regulatory genes in treatment-naïve pediatric patients with UC. Using the Inflammatory Bowel Disease Transcriptome and Metatranscriptome Meta-Analysis (IBD TaMMA) platform and R algorithms, we analyzed rectal biopsy transcriptomic data from two cohorts (206 patients with UC vs. 20 healthy controls from the GSE-109142 study, and 43 patients with UC vs. 55 healthy controls from the GSE-117993 study). We compared gene expression levels and correlation of clock genes (BMAL1, CLOCK, PER1, PER2, CRY1, CRY2), inflammatory genes (IκB, IL10, NFκB1, NFκB2, IL6, TNFα) and their mutual regulatory genes (RORα, RORγ, REV-ERBα, PGC1α, PPARα, PPARγ, AMPK, SIRT1) in patients with active UC and healthy controls. The clock genes BMAL1, CLOCK, PER1 and CRY1 and the inflammatory genes IκB, IL10, NFκB1, NFκB2, IL6 and TNFα were significantly upregulated in patients with active UC. The genes encoding the mutual regulators RORα, RORγ, PGC1α, PPARα and PPARγ were significantly downregulated in patients with UC. A uniform pattern of gene expression was found in healthy controls compared to the highly variable expression pattern in patients with UC. Among the healthy controls, inflammatory genes were positively correlated with clock genes and they all showed reduced expression. The difference in gene expression levels was associated with disease severity and endoscopic score but not with histological score. In patients with active UC, clock gene disruption is associated with abnormal mucosal immune response. Disrupted expression of genes encoding clock, inflammation and their mutual regulators together may play a role in active UC. Full article

The reduced burden of helminth parasites in industrialized countries is probably one of the reasons for the increased prevalence of autoimmune disorders such as multiple sclerosis (MS). The current study aimed to evaluate the potential preventive effects of hydatid cyst fluid (HCF) on the disease severity in an EAE mouse model of MS. EAE-induced mice were treated with HCF before and after EAE induction. An RT-PCR-based evaluation of IFN-γ, IL-1β, TNF, T-bet, IL-4, GATA3, IL-17, RoRγ, TGF-β, and FOXP3 expression levels in splenocytes and an ELISA-based analysis of IFN-γ and IL-4 levels in cell culture supernatant of splenocytes were performed. Histopathological examinations of mice during the study were also conducted. The expression levels of T-bet, IL-4, GATA3, TGF-β, and FOXP3 in EAE + HCF mice were significantly higher compared to EAE + PBS mice. In the EAE + HCF group, the expression levels of IFN-γ, IL-1β, and TNF were significantly lower than in the EAE + PBS group. The histopathological results showed significantly reduced inflammation and demyelination in EAE + HCF mice compared to EAE + PBS mice. Our study provides proof-of-concept in the EAE mouse model of MS that helminth-derived products such as HCF have a potential prophylactic effect on MS development and present a novel potential therapeutic strategy. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by impaired communication, reciprocal social interactions, restricted sociability deficits, and stereotyped behavioral patterns. Environmental factors and genetic susceptibility have been implicated in an increased risk of ASD. Aflatoxin B₁ (AFB₁) is a typical contaminant of food and feed that causes severe immune dysfunction in humans and animals. Nevertheless, the impact of ASD on behavioral and immunological responses has not been thoroughly examined. To investigate this phenomenon, we subjected BTBR T⁺Itpr3^tf/J (BTBR) mice to AFB₁ and evaluated their marble-burying and self-grooming behaviors and their sociability. The exposure to AFB₁ resulted in a notable escalation in marble-burying and self-grooming activities while concurrently leading to a decline in social contacts. In addition, we investigated the potential molecular mechanisms that underlie the impact of AFB₁ on the production of Th1 (IFN-γ, STAT1, and T-bet), Th9 (IL-9 and IRF4), Th17 (IL-17A, IL-21, RORγT, and STAT3), Th22 (IL-22, AhR, and TNF-α), and T regulatory (Treg) (IL-10, TGF-β1, and FoxP3) cells in the spleen. This was achieved using RT-PCR and Western blot analyses to assess mRNA and protein expression in brain tissue. The exposure to AFB₁ resulted in a significant upregulation of various immune-related factors, including IFN-γ, STAT1, T-bet, IL-9, IRF4, IL-17A, IL-21, RORγ, STAT3, IL-22, AhR, and TNF-α in BTBR mice. Conversely, the production of IL-10, TGF-β1, and FoxP3 by CD4⁺ T cells was observed to be downregulated. Exposure to AFB₁ demonstrated a notable rise in Th1/Th9/Th22/Th17 levels and a decrease in mRNA and protein expression of Treg. The results above underscore the significance of AFB₁ exposure in intensifying neurobehavioral and immunological abnormalities in BTBR mice, hence indicating the necessity for a more comprehensive investigation into the contribution of AFB₁ to the development of ASD. Full article