Neurofibromatosis type 1 (NF1) is an autosomal dominant human genetic disorder. The progression of benign plexiform neurofibromas to malignant peripheral nerve sheet tumors (MPNSTs) is a major cause of mortality in patients with NF1. Although elevated epidermal growth factor receptor (EGFR) expression plays a crucial role in the pathogenesis of MPNST, the cause of EGFR overexpression remains unclear. Here, we assessed EGFR expression levels in MPNST tissues of NF1 patients and NF1 patient-derived MPNST cells. We found that the expression of EGFR was upregulated in MPNST tissues and MPNST cells, while the expression of neurofibromin was significantly decreased. Manipulation of NF1 expression by NF1 siRNA treatment or NF1-GAP-related domain overexpression demonstrated that EGFR expression levels were closely and inversely correlated with neurofibromin levels. Notably, knockdown of the NF1 gene by siRNA treatment augmented the nuclear localization of phosphorylated SP1 (pSP1) and enhanced pSP1 binding to the EGFR gene promoter region. Our results suggest that neurofibromin deficiency in NF1-associated MPNSTs enhances the Ras/ERK/SP1 signaling pathway, which in turn may lead to the upregulation of EGFR expression. This study provides insight into the progression of benign tumors and novel therapeutic approaches for treatment of NF1-associated MPNSTs.

The rapid growth of the fisheries industry has resulted in numerous by-products, usually called waste, causing environmental and economic challenges. Recent advances in valorization techniques have highlighted the potential of these by-products as sources of bioactive compounds. This study aimed to investigate the antioxidant and anti-inflammatory activities of cutlassfish (Trichiurus lepturus) head peptone (CP) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. CP exhibited significant antioxidant activity, reducing ABTS and DPPH radical scavenging activity by up to 79.66% and 64.69%, respectively, with a maximum ferric-reducing antioxidant power (FRAP) value of 224.54 μM. CP enhanced macrophage proliferation (33.3%) and significantly mitigated LPS-induced oxidative and inflammatory responses, reducing nitric oxide (NO) production (60%) and reactive oxygen species levels (49.14%). CP suppressed the expression of inflammatory mediators, including inducible nitric oxide synthase (iNOS) and cyclooxygen-ase-2, and selectively inhibited the pro-inflammatory cytokines interleukin (IL)-1β and IL-6. Western blot analysis revealed that CP inhibited the phosphorylation of mitogen-activated protein kinases, including ERK, JNK, and p38, highlighting its role in modulating upstream inflammatory signaling pathways. CP exhibited significant antioxidant effects, particularly in scavenging ABTS and DPPH radicals, as well as reducing oxidative stress markers and inflammatory responses in LPS-stimulated macrophages. These findings suggest its potential not only as a therapeutic agent for conditions related to chronic inflammation, such as cardiovascular diseases and arthritis, but also as a functional ingredient in foods and nutraceuticals aimed at alleviating inflammation-related disorders.

Neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder, is caused by mutations in the NF1 gene, which encodes the GTPase-activating protein neurofibromin. The pathogenesis of the tumor progression of benign plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. Here, we found that interferon-induced transmembrane protein 1 (IFITM1) was downregulated in MPNST tissues compared to those in PN tissues from patients with NF1. Overexpression of IFITM1 in NF1-associated MPNST cells resulted in a significant decrease in Ras activation (GTP-Ras) and downstream extracellular regulatory kinase 1/2 (ERK1/2) phosphorylation, whereas downregulation of IFITM1 via treatment with small interfering RNA in normal Schwann cells had the opposite result, indicating that expression levels of IFITM1 are closely associated with tumor progression in NF1. Treatment of MPNST cells with interferon-gamma (IFN-γ) significantly augmented the expression of IFITM1, thereby leading to a decrease in Ras and ERK1/2 activation. Despite the small number of patient samples, these findings may potentially provide a new target for chemotherapy in patients with NF1-associated MPNSTs. In xenograft mice injected with MPNST cells, IFN-γ treatment successfully suppressed tumor progression with increased IFITM1 expression and decreased Ras and ERK1/2 activation in tumor tissues. Collectively, these results suggest that IFITM1 is closely involved in MPNST pathogenesis and that IFN-γ is a good candidate for the therapeutic treatment of MPNSTs in NF1.

Obesity, characterized by excessive adipose tissue accumulation, is an important risk factor for the development of several chronic conditions, including cardiovascular disease, type 2 diabetes mellitus, and hypertension. The present study aimed to investigate the effects of kukoamine B (KB), a major component of the Lycii Radicis Cortex (LRC), on adipogenesis and lipid accumulation in vitro and further assess its role in obesity in vivo. For the in vitro experiments, 3T3-L1 cells and primary-cultured adipose-derived stem cells were used. Lipid accumulation was measured using Oil Red O staining, and adipogenesis-related gene expression was assessed using quantitative reverse transcription polymerase chain reaction. For the in vivo experiments, LRC or KB was orally administered to ovariectomized and high-fat diet-induced obese mice. LRC exhibited antiadipogenic and antiobesity effects in vitro and in vivo experiments. Fractionation of the LRC extract identified KB as a bio-active component. KB treatment resulted in a dose-dependent reduction in lipid droplet formation and downregulation of adipogenesis-related genes, including Pparg, Cebpa, Srebp1, Fasn, and Plin2, in both cell types. Western blot analysis revealed that KB significantly suppressed the protein expression of key adipogenic factors, including phosphorylated CREB, CEBPB, PPARG, and CEBPA. In vivo, KB administration significantly reduced body weight gain, hepatic steatosis, and adipocyte hypertrophy in both mouse models. These results suggest that KB is a potential therapeutic agent for the prevention and treatment of obesity. Further rigorous investigations, including human clinical trials, are necessary to fully elucidate the safety profile, optimal dosing regimens, and long-term effects of KB.

Marine-derived natural products have attracted considerable attention as potential anti-inflammatory agents. Although the anticancer and pro-oxidative effects of heteronemin, a marine sponge-derived scalarane-type sesterterpenoid, have been reported, its direct regulatory effects on inflammatory mediator production in activated macrophages remain unclear. In this study, we aimed to investigate the anti-inflammatory effects of heteronemin in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Heteronemin significantly suppressed LPS-induced nitric oxide production at concentrations up to 10 μM with minimal effects on cell viability. In addition, heteronemin reduced the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), attenuated intracellular reactive oxygen species (ROS) accumulation, and downregulated pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). Furthermore, heteronemin treatment was associated with reduced phosphorylation of mitogen-activated protein kinases (MAPKs), including p38, JNK, and ERK, following prolonged LPS stimulation. In contrast to its previously reported ROS-inducing activity in cancer cells, heteronemin reduced inflammation-associated ROS accumulation and was associated with decreased MAPK phosphorylation in LPS-stimulated macrophages, suggesting that its effects on cellular redox responses may depend on the experimental context. Collectively, these findings suggest the therapeutic potential of heteronemin as a promising marine-derived lead compound for inflammatory diseases.