PTP1B Inhibitory and Anti-Inflammatory Effects of Secondary Metabolites Isolated from the Marine-Derived Fungus Penicillium sp. JF-55

Abstract

Protein tyrosine phosphatase 1B (PTP1B) plays a major role in the negative regulation of insulin signaling, and is thus considered as an attractive therapeutic target for the treatment of diabetes. Bioassay-guided investigation of the methylethylketone extract of marine-derived fungus Penicillium sp. JF-55 cultures afforded a new PTP1B inhibitory styrylpyrone-type metabolite named penstyrylpyrone (1), and two known metabolites, anhydrofulvic acid (2) and citromycetin (3). Compounds 1 and 2 inhibited PTP1B activity in a dose-dependent manner, and kinetic analyses of PTP1B inhibition suggested that these compounds inhibited PTP1B activity in a competitive manner. In an effort to gain more biological potential of the isolated compounds, the anti-inflammatory effects of compounds 1–3 were also evaluated. Among the tested compounds, only compound 1 inhibited the production of NO and PGE2, due to the inhibition of the expression of iNOS and COX-2. Penstyrylpyrone (1) also reduced TNF-α and IL-1β production, and these anti-inflammatory effects were shown to be correlated with the suppression of the phosphorylation and degradation of IκB-α, NF-κB nuclear translocation, and NF-κB DNA binding activity. In addition, using inhibitor tin protoporphyrin (SnPP), an inhibitor of HO-1, it was verified that the inhibitory effects of penstyrylpyrone (1) on the pro-inflammatory mediators and NF-κB DNA binding activity were associated with the HO-1 expression. Therefore, these results suggest that penstyrylpyrone (1) suppresses PTP1B activity, as well as the production of pro-inflammatory mediators via NF-κB pathway, through expression of anti-inflammatory HO-1.

Marine Pharmacology in 2012–2013: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action

“…In a detailed study, Lee and colleagues investigated penstyrylpyrone ( 129 ), isolated from a marine-derived fungus Penicillium sp. JF-55, and determined that the inhibition of LPS-treated murine peritoneal macrophage production of NO, PGE 2 , TNF-α, IL-1β, was correlated with suppression of iκB-α and NF-κB and concomitant expression of heme oxygenase-1 [132]. Vilasi and colleagues extended the molecular pharmacology of the novel cyclic octapepetide perthamide C ( 130 ), isolated from the marine sponge Theonella swinhoei , by investigating its effect on the proteome of murine macrophages J774.A1 using two-dimensional proteomics, and determining differential effect on several cytosolic and ER-associated proteins, mainly involved in cellular folding processes, thus “shed(ding) more light on the…mechanisms of action” of this natural product [133].…”

Investigation of anti‐inflammatory and toxicity effects of mangrove‐derived Streptomyces rochei strain VITGAP173

“…51 Marine fungus has also been a source for few anti-inflammatory compounds such as mangicols A and B (sesterterpenes), mycoepoxidiene, penstyrylpyrone, and pyrenocine A. [52][53][54][55] However, the present study revealed the Table 5 and Figure 9A.…”

Inhibitors of Protein Tyrosine Phosphatase 1B from Marine Natural Products

“…JF‐55 cultures, along with two known metabolites, anhydrofulvic acid ( 87 ) and citromycetin ( 88 ). Compounds 86 and 87 were suggested to bind to the active site within PTP1B, exhibiting PTP1B inhibitory activity in a competitive manner with IC 50 values of 5.28 and 1.90 μ m , while compound 88 , which shared close structural features to 87 , did not show any inhibitory activity up to 25.8 μ m , which manifested that the linear tricyclic system and the position of the carbonyl groups in compound 87 might be important for the binding with active site of PTP1B …”