Metabolic syndrome (MetS) is associated with a plethora of different comorbidities. Exploring its key molecular mechanisms, such as advanced glycation end product and its receptor (AGE/RAGE) pathway, holds great potential. Numerous sources agree that targeting the AGE/RAGE pathway is a potential therapeutic strategy for MetS. However, the regulation of AGE/RAGE by microRNAs (miRNAs) in the context of MetS is still poorly understood. This review aimed to provide a systematic picture of the influence of miRNAs on AGE/RAGE in the context of MetS, with a particular focus on its ligands and receptors. This review achieves this in two ways: through an inductive “bottom-up” approach realized by a classical descriptive literature search, and through a deductive/synthetic “top-down” approach based on carefully selected miRNA profiling studies in MetS and its comorbidities. Although the initial inductive approach allowed the identification of some miRNAs of interest, almost all articles on this topic focus on the regulation of processes exclusively involved in atherogenesis. The new deductive approach has broadened the research horizon: It has enabled the discovery of new promising miRNAs and allowed for ranking different comorbid pathologies in MetS according to the degree of miRNA dysregulation of AGE/RAGE. Thus, in addition to atherosclerosis, significant miRNA dysregulation of AGE/RAGE was also described in MetS, particularly in immune cells, as well as in subcutaneous adipose tissue in obesity. This review, along with the novel approaches to systematizing the data contained therein may contribute to the understanding of MetS pathogenesis and the search for targets for the treatment of MetS.

Sepsis involves a complex cascade of inflammatory reactions and immune system dysregulation. Neutrophils play a crucial role in modulating the anti-inflammatory response, which is vital for managing sepsis. Impaired chemotaxis of granulocytes can significantly impact the outcome of sepsis. Shenfu Decoction, by tonifying Qi and warming Yang, enhances the propelling function of Qi for promoting the chemotactic function of neutrophils. This study aimed to investigate the effects of Shenfu Decoction on the chemotactic function of neutrophils in septic mice and the underlying mechanisms.

Thirty 10-week-old specific-pathogen-free male C57BL/6J mice were randomly divided into five groups: sham operation, model, and low-, medium-, and high-dose Shenfu Decoction treatment groups (n = 6 in each group). Sepsis was induced using cecum ligation and puncture procedures. The sham-operated group served as the control. The drug was administered 6 h after surgery; the sham-operated and model groups received saline, while the treatment groups were gavaged every 12 h with the respective concentrations of Shenfu Decoction. Four hours after the last gavage, the mice were euthanized, and samples were collected to determine neutrophil counts and related indices. Primary neutrophils were extracted from the peripheral blood of septic mice and divided into blank control, sham-operated, low-dose, and high-dose groups. These cells were cultured with serum containing the respective treatments to measure neutrophil chemotactic distance, intracellular calcium ion concentration, and the expression levels of chemokine receptors and P2X1 receptors.

Compared with the sham-operated group, the total number of colonies and the number of neutrophils in the peritoneal lavage fluid were increased in the model group (P < 0.05). In the treatment groups, the number of neutrophils in the peritoneal lavage fluid was significantly increased (P < 0.05), while the number of neutrophils in the blood was decreased. Compared with the blank control group, the neutrophil chemotaxis distance was significantly prolonged in the sham-operated group. Additionally, the expression levels of P2X1 and FPR1 receptors were decreased, the expression levels of CXCR1 and CXCR2 receptors were increased (P < 0.05), and the calcium ion concentration was decreased (P > 0.05). Compared with the sham-operated group, the treatment groups exhibited a prolonged neutrophil chemotaxis distance, significantly decreased expression levels of P2X1 and FPR1 receptors, significantly increased expression levels of CXCR1 and CXCR2 receptors (P < 0.05), and significantly decreased calcium ion concentrations (P < 0.05). These effects were positively correlated with the Shenfu Decoction dosage.

Shenfu Decoction can improve the chemotactic function of neutrophils, possibly through the downregulation of P2X1 receptor expression. Its effects are positively correlated with the dosage.

Autoimmune hepatitis (AIH) is a severe immune-mediated liver disease with limited treatment options beyond immunosuppressants, which carry significant side effects. Existing evidence suggests that mesaconate (MSA) possesses immunomodulatory properties and may offer advantages over itaconate derivatives by avoiding succinate dehydrogenase inhibition. However, its specific role in AIH remains unclear. This study aimed to investigate the therapeutic effects of MSA on AIH and to elucidate its underlying mechanisms of action.

A murine AIH model was established via tail vein injection of concanavalin A (ConA, 20 mg/kg). MSA (250 mg/kg) was administered intraperitoneally 6 h before ConA exposure. Liver histology, serum transaminase levels, apoptosis markers, oxidative stress markers, and inflammatory cytokines were analyzed to assess the therapeutic efficacy of MSA. Additionally, RNA sequencing and Western blotting were performed to explore the mechanisms of MSA action. In vitro validation was conducted using RAW264.7 macrophages pretreated with MSA (1 mM) followed by interferon-gamma (IFN-γ, 50 ng/mL) stimulation.

MSA pretreatment effectively mitigated ConA-induced AIH by reducing inflammatory responses, oxidative stress, and apoptosis both in vivo and in vitro. The underlying protective mechanism involved MSA-mediated downregulation of IFN-γ expression and subsequent inhibition of the Janus tyrosine kinase 1/2–signal transducer and activator of transcription 1 signaling pathway. The involvement of this pathway in human AIH was also confirmed.

This study provides the first evidence that MSA ameliorates AIH by suppressing the IFN-γ–Janus tyrosine kinase 1/2–signal transducer and activator of transcription 1 signaling pathway, offering novel mechanistic insights and a promising therapeutic candidate for the future treatment of autoimmune disorders.

Metabolic dysfunction-associated fatty liver disease (MAFLD) poses a significant challenge in modern medicine due to its high prevalence. The pathogenesis of MAFLD involves a complex dysmetabolic process consistent with the “multiple-hit” hypothesis. This process includes excessive triglyceride (TC) accumulation within hepatocytes, lipotoxicity, insulin resistance (IR), chronic low-grade inflammation, and increased oxidative stress. The role of leptin in the liver has been extensively studied, demonstrating both direct effects on hepatic cells and indirect actions mediated through the central nervous system (CNS). In MAFLD, leptin modulates several physiological processes: it improves glucose metabolism by enhancing insulin sensitivity and lowering glucose levels; regulates lipid metabolism by promoting β-oxidation and TC export while inhibiting lipogenesis; and contributes to fibrogenesis by upregulating transforming growth factor-β (TGF-β) expression and activating hepatic stellate cells (HSCs) and the immune response. This review explores the structure of leptin, its primary physiological functions, its potential role in MAFLD pathogenesis, and its promise as a novel therapeutic target.

Liver failure syndromes are characterised by a dysregulated immune response leading to immune paralysis. Adrenomedullin (ADM) is a potent vasodilator and immunoregulator. This study aimed to explore the role of ADM in liver failure, hypothesising that there is a detrimental imbalance between ADM and adrenomedullin binding protein (AMBP)1 that promotes a switch of monocytes/macrophages towards a pro-restorative phenotype and function.

Consecutive patients with acute liver failure (ALF), acute-on-chronic liver failure (ACLF), and decompensated cirrhosis, as well as healthy controls (HC) were included between April 2020 and June 2024. Peripheral blood mononuclear cells/monocytes were isolated and used for RNA sequencing and cell culture. ADM and AMBP1 were measured by enzyme-linked immunosorbent assay.

Fifty-four patients with ALF, 25 with ACLF, 9 with decompensated cirrhosis, and 16 with HC were included. ADM expression in isolated monocytes was increased in ALF (log fold change = 5.88, p = 0.000216413) and ACLF (log fold change = 4.62, p = 0.00057122) compared to HC. Plasma ADM concentration was higher in ALF (1,684 ± 1,156 pg/mL) vs. ACLF (836.1 ± 765.2 pg/mL) and HC (164.8 ± 62.73 pg/mL). AMBP1 was significantly reduced in ALF (59.27 ± 44 µg/mL) vs. ACLF (126.3 ± 72.23 µg/mL) and HC (252.8 ± 159.7 µg/mL) (p < 0.0001, ALF vs. HC). Treatment with LPS increased ADM concentration in peripheral blood mononuclear cell supernatant (ALF n = 6; 561.4 ± 1,038 pg/mL vs. 259.2 ± 213.7 pg/mL, ACLF n = 4; 3,202 ± 491.2 vs. 1,757 ± 1,689 pg/mL). The percentage of CD14+ cells expressing Mer tyrosine kinase was reduced after culture with LPS (2.077 ± 0.87%); however, co-culture with ADM 100 nM restored the phenotype (3.852 ± 1.063%).

ADM is increased in liver failure, whereas AMBP1 is reduced. ADM affects monocyte function, increasing Mer Tyrosine Kinase and promoting a pro-restorative, anti-inflammatory phenotype.

Skin cancer, the most common global malignancy, is linked to ultraviolet (UV)-driven serum 25-hydroxyvitamin D (25(OH)D)synthesis, with its controversial role possibly reflecting cumulative UV exposure. This study aimed to assess the association and causality between 25(OH)D levels and skin cancer risk using the National Health and Nutrition Examination Survey (1999–2018) data and Mendelian randomization (MR) analyses, evaluating 25(OH)D as a screening biomarker.

We integrated data from the National Health and Nutrition Examination Survey (1999–2018; n = 21,357 U.S. adults, including 631 skin cancer cases) with MR analyses using genome-wide association study-derived genetic variants to assess the causal relationship between serum 25(OH)D levels and skin cancer risk.

Higher 25(OH)D levels were associated with increased risks of nonmelanoma skin cancer [odds ratio (OR) (95% confidence interval (CI)) = 2.94 (2.10, 4.20)], melanoma [OR (95% CI) = 2.94 (1.73, 5.28)], and other skin cancers [OR (95% CI) = 2.10 (1.36, 3.36)]. MR analyses supported a causal relationship for nonmelanoma skin cancer [OR (95% CI) = 1.01 (1.00, 1.02)] and melanoma [OR (95% CI) = 1.00 (1.00, 1.01)]. Risks were highest in males, older adults, and individuals with obesity.

Higher serum 25(OH)D levels are associated with increased skin cancer risk, likely reflecting cumulative UV exposure. Routine monitoring of 25(OH)D, combined with UV exposure management, is recommended for risk stratification in skin cancer screening, particularly among high-risk groups. Validation in multiethnic cohorts is needed to confirm these findings.

General transcription factor IIIC subunit 2 (GTF3C2) is one of the polymerase III transcription-related factors. Previous studies have revealed that GTF3C2 is involved in regulating cell proliferation. However, the role of GTF3C2 in hepatocellular carcinoma (HCC) remains unclear. This study aimed to determine its expression, biological function, and mechanism in HCC.

The expression of GTF3C2 in HCC and non-tumor tissues, along with its clinical significance, was investigated using public databases and clinical samples. Reverse transcription-quantitative polymerase chain reaction and Western blot assays were performed to detect the expression of GTF3C2, ubiquitin specific peptidase 21 (USP21), mitogen-activated protein kinase 2 (MEK2), extracellular signal-regulated kinase 1/2 (ERK1/2), and p-ERK1/2 in cells. A luciferase reporter assay was conducted to explore the regulatory effect of GTF3C2 on USP21 transcription. Cell Counting Kit-8, 5-ethynyl-2′-deoxyuridine, and colony formation assays were performed to assess HCC cell proliferation. Subcutaneous injection of HCC cells into nude mice was used to evaluate tumor growth in vivo.

GTF3C2 expression was upregulated in HCC tissues and was positively correlated with advanced tumor stages and high tumor grades. HCC patients with high GTF3C2 expression had significantly worse survival outcomes. Knockdown of GTF3C2 suppressed the proliferation of Hep3B and HCCLM3 cells, while overexpression of GTF3C2 facilitated the proliferation of SNU449 and Huh7 cells. GTF3C2 promoted USP21 expression by activating its transcription, which subsequently increased the levels of MEK2 and p-ERK1/2 in HCC cells. Overexpression of both USP21 and MEK2 counteracted the GTF3C2 knockdown-induced inactivation of the ERK1/2 pathway. Moreover, GTF3C2 promoted HCC cell proliferation in vitro and tumor growth in vivo by regulating the USP21/MEK2/ERK1/2 pathway.

Upregulation of GTF3C2 is frequently observed in HCC tissues and predicts poor prognosis. GTF3C2 promotes HCC cell proliferation via the USP21/MEK2/ERK1/2 pathway.

Infection control is essential for the success of prosthodontic and oral implant procedures, as microbial contamination can lead to serious complications such as denture stomatitis and peri-implantitis. While synthetic disinfectants like chlorhexidine are commonly used, they may cause side effects including irritation, toxicity, and the development of microbial resistance over time. Natural products derived from plants, animals, and minerals are currently being explored as safer alternatives. Compounds such as epigallocatechin gallate from green tea; eugenol from clove oil; quercetin, thymol, cinnamaldehyde, and flavonoids from propolis; and terpinen-4-ol from tea tree oil have shown strong antimicrobial and anti-biofilm properties. These natural agents are not only effective against harmful oral bacteria but also promote healing, are more biocompatible, environmentally friendly, and are often preferred by patients. However, challenges remain regarding their routine clinical use. The strength and composition of natural agents can vary, and there is a lack of consistent product standards, clinical trials, and comprehensive safety data. Currently, these products are not approved by the U.S. Food and Drug Administration for dental use and are only available as over-the-counter remedies. Production costs and scalability must also be evaluated in comparison with synthetic alternatives. Emerging technologies, such as nanocarriers and targeted delivery systems, are being developed to enhance the effectiveness of natural agents in dental applications. Further clinical research and the establishment of clear regulatory guidelines are necessary to support their integration into clinical practice. Natural disinfectants hold significant potential to become valuable, safe, and sustainable tools for maintaining hygiene in prosthodontics and oral implantology.

Emerging evidence implicates immune dysregulation and neuroinflammation in the pathogenesis of epilepsy, yet the causal mechanisms remain unclear. This study aimed to investigate the causal effects of immune cells and inflammatory proteins on epilepsy and evaluate the mediating role of inflammatory proteins.

This study utilized the largest available genome-wide association study data on immune cell phenotypes and inflammatory proteins as exposures, and epilepsy genome-wide association study data from the FinnGen dataset as outcomes. Five Mendelian randomization (MR) methods were applied within a two-sample MR framework to assess causal effects. Furthermore, a two-step MR analysis was conducted to quantify the proportion of epilepsy and its subtypes influenced by immune cells through inflammatory proteins.

The two-sample MR analysis identified 32 immune cell phenotypes associated with epilepsy risk (19 risk-increasing, e.g., CD19+ B cells; 13 protective, e.g., regulatory T cell subsets). Subtype analyses revealed 30 immune phenotypes associated with generalized epilepsy and 26 with focal epilepsy. Eight inflammatory proteins showed suggestive causal effects on epilepsy: C-C chemokine ligand 23, C-X-C motif chemokine ligand 6, C-X-C motif chemokine ligand 11, and vascular endothelial growth factor A increased epilepsy risk, while interleukin-13 (IL-13), leukemia inhibitory factor receptor, tumor necrosis factor, and osteoprotegerin conferred protection. Mediation analysis indicated that inflammatory proteins mediated 6.3–13.5% of the immune effects on epilepsy. Specifically, CD14+CD16+ monocytes increased epilepsy risk through elevated C-C chemokine ligand 23 levels (8.5% mediation), while effector memory double-negative (CD4−CD8−) T cells reduced epilepsy risk via upregulation of IL-13 (6.3%). Sensitivity analyses confirmed the robustness of these findings (P heterogeneity/pleiotropy > 0.05). Although no associations reached Bonferroni-corrected significance, the findings implicate B cells, monocytes, regulatory T cells, and cytokines (e.g., IL-13, leukemia inhibitory factor receptor) in the pathogenesis of epilepsy, with inflammatory proteins acting as partial mediators.

These results enhance our understanding of immune-inflammatory pathways in epilepsy and highlight potential therapeutic targets. Future studies should validate these findings across diverse populations and further elucidate the molecular mechanisms underlying the identified associations.