Two new aryltetralin lactone lignans, petasitesins A and B were isolated from the hot water extract of the leaves of butterbur (Petasites japonicus) along with six known compounds. The chemical structures of lignans 1 and 2 were elucidated on the basis of 1D and 2D nuclear magnetic resonance (NMR) spectroscopic data, electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra. Petasitesin A and cimicifugic acid D showed significant inhibitory effects on the production of both prostaglandin E2 (PGE₂) and NO in RAW264.7 macrophages. The expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were inhibited by compound 1 in RAW264.7 cells. Furthermore, compounds 1 and 3 exhibited strong affinities with both iNOS and COX-2 enzymes in molecular docking studies.

Neuroinflammation, which is mediated by microglia that release various inflammatory cytokines, is a typical feature of neurodegenerative diseases (NDDs), such as Alzheimer’s disease and Parkinson’s disease. Hence, alleviating neuroinflammation by downregulating pro-inflammatory action, and upregulating anti-inflammatory action of microglia is an efficient therapeutic target for NDDs. In this study, we evaluated whether trichosanthis semen (TS), a dried ripe seed of Trichosanthes kirilowii Maximowicz, reduces lipopolysaccharide (LPS)-induced neuroinflammation by regulating microglial responses in vitro and in vivo. Our results presented that TS reduced the release of pro-inflammatory mediators, such as nitric oxide (NO), inducible NO synthase, tumor necrosis factor-α, interleukin-1β, and interleukin-6 via inhibition of the nuclear factor kappa B (NF-κB) signaling pathway in LPS-treated BV2 microglial cells. Moreover, TS induced anti-inflammatory mediators, such as interleukin-10, found in inflammatory zone 1, and chitinase 3-like 3 by the upregulation of heme oxygenase 1 (HO-1). We further confirmed that TS administration suppressed microglial activation, but enhanced HO-1 expression in LPS-injected mice. These results suggest that TS has anti-neuroinflammatory effects via inhibition of NF-κB signaling through the activation of HO-1, and that TS may be a therapeutical candidate for NDDs treatment.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease, and is characterized by the accumulation of amyloid beta (Aβ) as a pathological hallmark. Aβ plays a central role in neuronal degeneration and synaptic dysfunction through the generation of excessive oxidative stress. In the present study, we explored whether leaves of Petasites japonicus (Siebold & Zucc.) Maxim. (PL), called butterbur and traditionally used in folk medicine, show neuroprotective action against Aβ_25–35 plaque neurotoxicity in vitro and in vivo. We found that PL protected Aβ_25–35 plaque-induced neuronal cell death and intracellular reactive oxygen species generation in HT22 cells by elevating expression levels of phosphorylated cyclic AMP response element-binding protein, heme oxygenase-1, and NAD(P)H quinine dehydrogenase 1. These neuroprotective effects of PL were also observed in Aβ_25–35 plaque-injected AD mouse models. Moreover, administration of PL diminished Aβ_25–35 plaque-induced synaptic dysfunction and memory impairment in mice. These findings lead us to suggest that PL can protect neurons against Aβ_25–35 plaque-induced neurotoxicity and thus may be a potential candidate to regulate the progression of AD.

Butterbur (Petasites japonicus (Siebold & Zucc.) Maxim) leaves are available to consumers in the marketplace, but there is no guarantee that they are safe for human consumption. Previously, we demonstrated that hot water extracts of P. japonicus leaves (KP-1) had anti-inflammatory properties and attenuated memory impairment. However, data regarding KP-1 toxicity are lacking. This study assessed the safety of KP-1 by examining oral and genotoxic effects using in vivo and in vitro tests, respectively. In a single oral dose toxicity and two-week repeated oral dose toxicity study, we observed no toxicologically significant clinical signs or changes in hematology, blood chemistry, and organ weights at any dose during the experiment. Following a thirteen-week repeated oral dose, toxicity, hyperkeratosis, and squamous cell hyperplasia of the limiting ridge in the stomach were observed. The no observable adverse effect level (NOAEL) was found to be 1250 mg/kg/day in male and female rats. However, hyperkeratosis and hyperplasia were not considered to be of toxicological significance when extrapolating the NOAEL to humans because the limiting ridge in the stomach is species-specific to rats. Therefore, in our study, the NOAEL was considered to be 5000 mg/kg/day when the changes in the stomach’s limiting ridge were discounted. Moreover, in vitro bacterial reverse mutations and chromosomal aberrations in Chinese hamster lung (CHL) cells and the in vivo micronucleus in Institute of cancer research (ICR) mice assays showed that KP-1 possessed no mutagenicity. Although additional research is required, these toxicological evaluations suggest that KP-1 could be safe for human consumption.

Background: Ultraviolet B (UVB) radiation accelerates skin aging by inducing oxidative stress, collagen degradation, and cellular senescence. Although Petasites japonicus is known for its antioxidant properties, its anti-photoaging potential remains underexplored. This research explored the protective properties of a hot water extract from P. japonicus leaves (KP-1) against photoaging caused by UVB exposure. Methods: Hairless mice were exposed to UVB three times per week and orally administered KP-1 for 13 weeks. Wrinkle formation, epidermal thickness, skin hydration, and collagen content were assessed. Protein expression related to MAPK/AP-1, TGF-β/Smad2/3, and p53/p21 pathways was analyzed by Western blotting. Results: KP-1 significantly reduced UVB-induced wrinkle area, epidermal and dermal thickening, and transepidermal water loss while restoring collagen density and skin hydration. KP-1 inhibited MMP-1 expression, enhanced COL1A1 levels, suppressed MAPK/AP-1 activation, and activated TGF-β/Smad2/3 signaling. It also balanced p53/p21 expression and restored cyclin D1 and CDK4 levels, thereby preventing UVB-induced senescence. Conclusions: The findings of this research revealed that KP-1 can serve as a promising natural substance for safeguarding the skin from damage and aging caused by UVB exposure.