juglanin and Inflammation

Arthritis is characterized by irreversible joint destruction and presents a global health burden. Natural alternatives to synthetic drugs have been gaining popularity for their safety and effectiveness. Juglanin has demonstrated a range of anti-inflammatory effects in various tissues and cell types. However, the pharmacological function of Juglanin in arthritis and chondrocytes has been little studied. ATDC5 cells were treated with 1 μg/mL lipopolysaccharide (LPS) in the presence or absence of juglanin (2.5, 5 μM) for 24 h. The effects of juglanin on cellular nucleotide-binding domain leucin-rich repeat receptor 3 (NLRP3) inflammasome complex and endproduct interleukin 1β (IL-1β) and interleukin (IL-18) were assessed by reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and Western blot experiments. The oxidative stress was measured by super oxide dismutase (SOD) activity and NADPH oxidase 4 (NOX4) expression. The dependent effect of juglanin on silent information regulator 2 homolog 1 (SIRT1) was evaluated by siRNA knockdown approach. Juglanin significantly reduced cellular oxidative stress by downregulating NOX4 expression production and rescuing the decreased activity of total SOD induced by LPS. Juglanin inhibited the activation of the TxNIP/NLRP3/ASC/caspase-1 axis, and decreased production of IL-1β and IL-18. Moreover, juglanin rescued the LPS-induced decrease in SIRT1 expression. SIRT1 silencing abolished the anti-NLRP3 inflammasome effect of juglanin, indicating that the effects of juglanin are dependent on its amelioration on SIRT1 expression. Juglanin possesses an anti-inflammatory and anti-ROS capacity in chondrocytes, and this study provides available evidence that juglanin may be of use in the treatment of arthritis.

Topics: Anti-Inflammatory Agents; Antioxidants; Cell Line; Chondrocytes; Cytokines; Glycosides; Humans; Inflammation; Kaempferols; Lipopolysaccharides; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Reactive Oxygen Species; Signal Transduction; Sirtuin 1

Idiopathic pulmonary fibrosis (IPF), characterized by excessive collagen deposition, is a progressive and typically fatal lung disease without effective therapeutic strategies. Juglanin, as a natural product mainly isolated from green walnut husks of Juglans mandshuric, has various bioactivities, including anti-oxidative, anti-inflammatory and anti-fibrotic effects. Stimulator of interferon genes (Sting) is a signaling molecule and plays an essential role in meditating fibrosis. However, the effects of Jug and Sting on pulmonary fibrosis are not fully understood. In this study, we investigated the role of Jug in bleomycin (BLM)-induced inflammation and fibrosis mouse model, as well as the underlying molecular mechanism. The results here indicated that Jug-treated mice exhibited a definitively improved survival rate than that of the BLM-challenged mice. Jug administration significantly alleviated neutrophil alveolar infiltration, lung vascular permeability and pro-inflammatory response in BLM mice. Subsequently, the pulmonary fibrosis induced by BLM was markedly attenuated by Jug through reducing the expression of fibrotic hallmarks, including transforming growth factor-β1 (TGF-β1), fibronectin, matrix metallo-proteinase-9 (MMP-9), α-smooth muscle actin (α-SMA) and collagen I. Importantly, we found that BLM mice showed higher expression levels of Sting in lung tissues, which were notably restrained by Jug treatment. The role of Jug in suppressing Sting was confirmed in TGF-β-incubated cells. Notably, the in vitro analysis further showed that Sting knockdown could ameliorate TGF-β-triggered collagen accumulation. In contrast, TGF-β-induced fibrosis was accelerated by Sting over-expression. Therefore, BLM may induce lung fibrosis through activating Sting signaling, and Jug could be used therapeutically to improve tissue repair and attenuate the intractable disease.

Topics: Actins; Animals; Bleomycin; Collagen Type I; Fibronectins; Gene Knockdown Techniques; Glycosides; Inflammation; Kaempferols; Male; Matrix Metalloproteinase 9; Membrane Proteins; Mice; Pulmonary Fibrosis; Signal Transduction; Survival Rate; Transforming Growth Factor beta1

Osteoarthritis (OA) is one of the most characterized joint diseases associated with chondrocyte apoptosis. Juglanin has been reported to have anti-inflammation activity. This study aimed to evaluate the protective anti-inflammatory effects of juglanin in human OA chondrocytes. Human OA chondrocytes were pretreated with juglanin (10, 20 and 40 μM) for 2 h and subsequently stimulated with IL-1β for 24 h. Nitric oxide (NO) production was determined using the Griess method and prostaglandin E2 (PGE2), matrix metalloproteinase-3, -9 and -13 (MMP-3, MMP-9 and MMP-13), TNF-α, and IL-6 were assessed using ELISA. The expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), a disintegrin and metalloproteinase with thrombospondin motifs-4 and -5 (ADAMTS-4 and ADAMTS-5) were detected by qRT-PCR and western blot analysis. NF-κB signalling molecules were detected by western blot analysis. The results showed that juglanin dose-dependently suppressed PGE2, NO, MMP-1, MMP3, MMP13, TNF-α and IL-6 production induced by IL-1β. The expression of COX-2, iNOS, ADAMTS-4 and ADAMTS-5 induced by IL-1β were also suppressed by juglanin pretreatment. Western blot analysis showed that juglanin suppressed IL-1β-induced NF-κB activation. Taken together, we found that juglanin inhibits IL-1β-induced inflammation through the regulation of NF-κB signalling. Juglanin might be used as a therapeutic agent for treating OA.

Topics: ADAMTS4 Protein; ADAMTS5 Protein; Anti-Inflammatory Agents; Cell Survival; Chondrocytes; Dinoprostone; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Glycosides; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Kaempferols; Matrix Metalloproteinases; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Tumor Necrosis Factor-alpha

Parkinson's disease (PD) is a common neuro-degenerative disorder, and novel therapeutic targets are required for the treatment of PD. Juglanin is a natural compound extracted from the crude Polygonum aviculare, exhibiting anti-inflammatory, anti-oxidant and anti-cancer activities. In our study, PD in mice was induced by systemic LPS treatment as evidenced by enhanced α-synuclein and reduced tyrosine hydroxylase (TH), which were reversed by juglanin treatment. Moreover, juglanin administration attenuated LPS-caused behavioral and memory impairments and reduced LPS-induced enhancement of neuro-degenerative markers, including amyloid β (Aβ) and p-Tau. Additionally, juglanin ameliorated synaptic functionality through promoting the expression of synaptic markers, such as SYP, PSD-95 and SNAP-25. Toll-like receptor 4 (TLR4) signaling in brain regulates neuroinflammation, contributing to neurodegenerative diseases. Furthermore, LPS induced neuroinflammation through the acceleration of various pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-18 (IL-18) and Cyclooxygenase-2 (COX-2), via activating TLR4/nuclear factor (NF)-κB pathway in hippocampus of mice and microglia cells. Juglanin significantly reduced LPS-induced production of pro-inflammatory cytokines and blocked TLR4/NF-κB pathway. We also found that LPS-induced astrocytes (AST) activity was prevented by juglanin through down-regulating glial fibrillary acidic protein (GFAP) and Iba1 in vivo and in vitro. Together, our results indicated that juglanin ameliorated neuroinflammation-related memory impairment, and neurodegeneration through impeding TLR4/NF-κB, indicating its potential for PD prevention.

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Behavior, Animal; Cells, Cultured; Cytokines; Glycosides; Hippocampus; Inflammation; Kaempferols; Lipopolysaccharides; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Microglia; NF-kappa B; Parkinsonian Disorders; Signal Transduction; Toll-Like Receptor 4

Acute lung injury in children is a complication showing devastating disorders linked to fibrosis progression and inflammation response. Fibrosis and inflammation response are two markers for acute lung injury. Juglanin is a natural product mainly isolated from green walnut husks of Juglans mandshurica, which isconsidered as the functional composition among a series of compounds. It exhibited effective role in various diseases by inhibiting inflammation response. In our study, the protective effects and anti-inflammatory activity of juglanin were investigated in mice and lung cells treated by lipopolysaccharide (LPS) to reveal the possible mechanism by which juglanin attenuates acute lung injury. The mice were separated into four groups. The mouse model was established with 15 mg/kg LPS injection. Juglanin dramatically reduced the inflammation of cell infiltration. Compared to mice only treated with LPS, LPS-treated mice in the presence of juglanin developed less lung fibrosis with lower levels of α-smooth muscle-actin (α-SMA), collagen type I, collagen type III, and transforming growth factor-β1 (TGF-β1). Additionally, juglanin markedly downregulated inflammatory cytokine secretion and phosphorylated nuclear factor-κB (NF-κB) expression via inhibiting IKKα/IκBα signaling pathway. Our results indicate that juglanin has a protective role in LPS-triggered acute lung injury via suppression of fibrosis and inflammation response by NF-κB signaling pathways inactivation. Thus, juglanin may be a potential candidate as dietary supplement for acute lung injury for children in future.

Topics: Acute Lung Injury; Animals; Collagen Type I; Glycosides; Inflammation; Kaempferols; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Pulmonary Fibrosis; Signal Transduction; Transforming Growth Factor beta1

Ultraviolet (UV) radiation induces skin injury, and is associated with the development and formation of melanoma, which is a highly lethal form of skin cancer. Juglanin is a natural product, which is predominantly extracted from Polygonum aviculare, and is considered a functional component among its various compounds. Juglanin has been reported to exert marked protective effects in various diseases via the inhibition of inflammation and tumor cell growth. The present study aimed to explore the effects of juglanin on human skin cancer induced by UV and to reveal the underlying molecular mechanism. In the present study, immunohistochemical analysis, western blot analysis, RT-qPCR analysis and flow cytometry assays were mainly used in vivo and/or in vitro. The results indicated that in mice, UVB exposure increased susceptibility to carcinogens, and accelerated disease pathogenesis. Conversely, juglanin was able to ameliorate this condition via inhibition of inflammation, suppression of cell proliferation and induction of apoptosis via p38/c‑Jun N‑terminal kinase (JNK) blockage, nuclear factor (NF)‑κB inactivation and caspase stimulation in vivo. In addition, in vitro, the present study demonstrated that treatment of UVB‑stimulated B16F10 melanoma cells with juglanin resulted in a dose‑dependent decrease in cell viability, as well as increased apoptosis via the upregulation of caspase expression and poly (ADP‑ribose) polymerase cleavage. In addition, juglanin markedly attenuated p38/JNK signaling, inactivated the phosphoinositide 3‑kinase/protein kinase B pathway and suppressed UVB‑induced NF‑κB activation. Taken together, these results indicated the possibility of applying juglanin in combination with UVB as a potential therapeutic strategy for preventing skin cancer.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Carcinogenesis; Caspases; Cell Proliferation; Enzyme Activation; Glycosides; Humans; Inflammation; Kaempferols; Male; MAP Kinase Signaling System; Melanoma, Experimental; Mice; Poly(ADP-ribose) Polymerases; Skin Neoplasms; Ultraviolet Rays

High fructose-feeding is an essential causative factor leading to the development and progression of hepatitis associated with high levels of endotoxin (LPS). Juglanin, as a natural compound extracted from the crude Polygonum aviculare, displayed inhibitory activity against inflammation response and cancer growth. However, researches about its role on anti-inflammation and apoptosis are far from available. Here, it is the first time that juglanin was administrated to investigate whether it inhibits fructose-feeding-induced hepatitis in rats and to elucidate the possible mechanism by which juglanin might recover it. Fructose-feeding rats were orally administrated with juglanin of 5, 10 and 20mg/kg for 6 weeks, respectively. Juglanin exerted prevention of fructose-feeding-stimulated increased LPS levels, accelerated alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) and up-regulated inflammatory cytokines expression in serum, mainly including tumor necrosis factor-alpha (TNF-a), Interleukin 1beta (IL-1β), Interleukin 6 (IL-6) and Interleukin 18 (IL-18). Meanwhile, toll-like receptor 4 (TLR4)-modulated mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) and apoptosis-related Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway are involved in the progression of hepatic injury and inflammation. And juglanin was found to suppress fructose-feeding-induced activation of these signaling pathways compared with the model group administrated only with fructose. These results indicate that juglanin represses inflammatory response and apoptosis via TLR4-regulated MAPK/NF-κB and JAK2/STAT3 signaling pathway respectively in rats with hepatitis induced by LPS for fructose-feeding. Treatment of juglanin might be an effective therapeutic strategy for preventing hepatitis.

Topics: Animals; Apoptosis; Cytokines; Feeding Behavior; Fructose; Glycosides; Hepatitis; Inflammation; Janus Kinase 2; Kaempferols; Liver; Male; Mitogen-Activated Protein Kinases; NF-kappa B; Phosphorylation; Protective Agents; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor; Toll-Like Receptor 4