BACKGROUND: Allergic rhinitis (AR) is a non-infectious chronic inflammation of the nasal mucosa mainly mediated by immunoglobulin E (IgE) in atopic individuals after exposure to allergens. The application of AR guideline-recommended pharmacotherapies can rapidly relieve symptoms of AR but with poor long-term efficacy, and many of these therapies have side effects. Many natural products and their derivatives have shown potential therapeutic effects on AR with fewer side effects.
OBJECTIVE: This review aims to expand understanding of the roles and mechanisms of natural compounds in the treatment of AR and to highlight the importance of utilizing natural products in the treatment of AR.
METHODS: We conducted a systematic literature search using PubMed, Web of Science, Google Scholar, and Clinical Trials. The search was performed using keywords including natural products, natural compounds, bioproducts, plant extracts, naturally derived products, natural resources, allergic rhinitis, hay fever, pollinosis, nasal allergy. Comprehensive research and compilation of existing literature were conducted.
RESULTS: This article provided a comprehensive review of the potential therapeutic effects and mechanisms of natural compounds in the treatment of AR. We emphasized that natural products primarily exert their effects by modulating signalling pathways such as NF-κB, MAPKs, STAT3/ROR-γt/Foxp3, and GATA3/T-bet, thereby inhibiting the activation and expansion of allergic inflammation. We also discussed their toxicity and clinical applications in AR therapy.
CONCLUSIONS: Taken together, natural products exhibit great potential in the treatment of AR. This review is also expected to facilitate the application of natural products as candidates for treating AR. Furthermore, drug discovery based on natural products has a promising prospect in AR treatment.

Acute lung injury (ALI) is a life-threatening disease characterized by severe inflammatory response, which has no pharmacological therapy in clinic. In this study, we found that eupalinolide B (EB), a sesquiterpene lactone isolated from Eupatorium lindleyanum, significantly ameliorated lipopolysaccharide (LPS)-induced ALI in mice, which manifests as reduction in lung injury score, activity of myeloperoxidase, and release of cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). In RAW264.7 murine macrophages, EB effectively inhibited LPS-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) by down-regulating the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2), respectively. Mechanistically, EB not only blocked LPS-induced phosphorylation of inhibitor of nuclear factor kappa B kinase-α/β (IKKα/β), phosphorylation and degradation of inhibitor of nuclear factor-kappa B alpha (IκBα), and phosphorylation and nuclear translocation of nuclear factor-kappa B (NF-κB) P65, but also suppressed LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs) in vitro or in vivo. Through cellular thermal shift assay and western blotting, EB was demonstrated to target and inactivate transforming growth factor β activated kinase-1 (TAK1), which is an important upstream kinase for the activation of NF-κB and MAPKs pathways. Additionally, EB-mediated actions were markedly abolished by dithiothreitol in LPS-exposed RAW264.7 cells, suggesting a crucial role of the α,γ-unsaturated lactone for the anti-inflammatory activity of EB. In conclusion, our findings showed that EB could effectively alleviate ALI in mice, and attenuate inflammatory response by inhibiting the activation of TAK1, and TAK1-mediated activation of NF-κB and MAPKs cascades.

Alzheimer\'s disease (AD) is a neurodegenerative disease with a complicated pathogenesis. F-box and WD-40 domain protein 11 (FBXW11), as a component of the SCF (Skp1-Cul1-F-box) E3 ubiquitin ligase complex, regulates multiple different signaling pathways. However, the effects of FBXW11 on AD progression and the underlying mechanisms have not been studied. In this study, we found that FBXW11 expression was markedly increased in microglial cells stimulated by amyloid-β (Aβ). Immunofluorescence staining showed that FBXW11 was co-localized with Iba-1 in microglial cells, suggesting its potential in regulating neuroinflammation. Meanwhile, significantly elevated expression of FBXW11 was detected in hippocampus of AD mouse models. Then, our in vitro studies showed that FBXW11 deletion considerably ameliorated inflammatory response in Aβ-incubated microglial cells through suppressing nuclear transcription factor κB (NF-κB) signaling. We further found that FBXW11 physically interacted with apoptosis signal-regulating kinase 1 (ASK1) and promoted its ubiquitination, which led to the aberrant activation of NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways. Importantly, promoting ASK1 significantly abolished the effects of FBXW11 knockdown to repress inflammation and MAPKs/NF-κB activation in Aβ-treated microglial cells. Subsequently, our in vivo experiments demonstrated that hippocampus-specific knockout of FBXW11 dramatically alleviated Aβ plaque load, neuronal death, and microglial activation in AD mice. Furthermore, hippocampal deficiency of FBXW11 markedly mitigated neuroinflammation in AD mice through restraining ASK1/MAPKs/NF-κB signaling, along with alleviated cognitive deficits. Together, our findings demonstrated that FBXW11 may be a functionally important mediator of ASK1 activation, which could be a novel molecular target for AD treatment.

Hederacoside-C (HDC) is a biological active ingredient, extracted from the leaves of Hedera helix. It has been reported to have anti-inflammatory properties. However, the effects of HDC on Staphylococcus aureus (S. aureus)-induced mastitis have not been reported yet. Here, we evaluated the anti-inflammatory effects of HDC on S. aureus-induced mastitis both in vivo on mammary gland tissues and in vitro on RAW 264.7 cells. The ascertained histopathological changes and MPO activity revealed that HDC defended mammary glands from tissue destruction and inflammatory cell infiltration induced by S. aureus. The results of ELISA, western blot, and qRT-PCR indicated that HDC significantly inhibited the expressions IL-6, IL-1β, and TNF-α and enhanced the IL-10 by downregulating and upregulating their relevant genes, respectively. Furthermore, HDC markedly suppressed the TLR2 and TLR4 expressions by attenuating the MAPKs (p38, ERK, JNK) and NF-κB (p65 and IκBα) pathways followed by decreasing the phosphorylation of p38, ERK, JNK, p65, and IκBα. The above parameters enhanced the mammary gland defense and reduced inflammation. These findings suggested that HDC may have the potential to be an effective anti-inflammatory drug for the S. aureus-induced mice mastitis and in RAW 264.7 cells.

Spinal cord injury (SCI) is a devastating neurological condition that results in progressive tissue loss, secondary to vascular dysfunction and inflammation. Lack of effective pharmacotherapies for SCI is mainly attributable to an incomplete understanding of its pathogenesis. Stimulator of interferon gene (Sting), also known as Transmembrane protein 173 (TMEM173), activates the type I interferon-regulated innate immune response, playing crucial role in modulating inflammation. However, the mechanism underlying Sting activation in SCI is still unclear. Here, we reported that Sting functioned as a positive regulator of SCI. Sting expression was increased in the injured spinal cord samples of SCI mice, along with significantly up-regulated levels of pro-inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6. Suppressing Sting expression in lipopolysaccharide-incubated mouse microglia markedly reduced the activation of nuclear factor-κB (NF-κB) and mitogen activated protein kinases (MAPKs) signaling pathways, as illustrated by the decreased phosphorylation of IKKβ, IκBα, NF-κB/p65, p38, ERK1/2 and JNK. Furthermore, LPS-stimulated release of pro-inflammatory cytokines in microglial cells was also reversed by Sting knockdown. In contrast, LPS-induced inflammation was further accelerated in microglial cells with Sting over-expression through potentiating NF-κB and MAPKs signaling. Mechanistically, Sting directly interacted with the TANK-binding kinase 1 (TBK1), thus promoting its phosphorylation and the activation of down-streaming NF-κB and MAPKs signaling pathways. Notably, the effects of Sting on SCI progression were verified in mice. Consistently, Sting knockout alleviated inflammatory response and facilitated recovery after SPI in mice through blocking TBK1 activation and subsequent NF-κB and MAPKs phosphorylation. In summary, our findings may provide a novel strategy for prevention and treatment of SCI by targeting Sting.