Protective Role of St. John's Wort and Its Components Hyperforin and Hypericin against Diabetes through Inhibition of Inflammatory Signaling: Evidence from In Vitro and In Vivo Studies

Abstract

Diabetes mellitus is a very common chronic disease with progressively increasing prevalence. Besides the well-known autoimmune and inflammatory pathogenesis of type 1 diabetes, in many people, metabolic changes and inappropriate lifestyle favor a subtle chronic inflammatory state that contributes to development of insulin resistance and progressive loss of β-cell function and mass, eventually resulting in metabolic syndrome or overt type 2 diabetes. In this paper, we review the anti-inflammatory effects of the extract of Hypericum perforatum L. (St. John's wort, SJW) and its main active ingredients firstly in representative pathological situations on inflammatory basis and then in pancreatic β cells and in obese or diabetic animal models. The simultaneous and long-lasting inhibition of signal transducer and activator of transcription (STAT)-1, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPKs)/c-jun N-terminal kinase (JNK) signaling pathways involved in pro-inflammatory cytokine-induced β-cell dysfunction/death and insulin resistance make SJW particularly suitable for both preventive and therapeutic use in metabolic diseases. Hindrance of inflammatory cytokine signaling is likely dependent on the hyperforin content of SJW extract, but recent data reveal that hypericin can also exert relevant protective effects, mediated by activation of the cyclic adenosine monophosphate (cAMP)/protein kinase cAMP-dependent (PKA)/adenosine monophosphate activated protein kinase (AMPK) pathway, against high-fat-diet-induced metabolic abnormalities. Actually, the mechanisms of action of the two main components of SJW appear complementary, strengthening the efficacy of the plant extract. Careful quantitative analysis of SJW components and suitable dosage, with monitoring of possible drug-drug interaction in a context of remarkable tolerability, are easily achievable pre-requisites for forthcoming clinical applications.

Keywords: St. John’s wort; cytokines; diabetes; hyperforin; hypericin; inflammatory signaling; insulin resistance; metabolic syndrome; obesity; pancreatic beta cells.

Figure 1

Protective mechanisms of St. John’s wort and hyperforin against cytokine-induced signaling pathways in pancreatic β cells. Abbreviations: TNF-α, tumor necrosis factor α; IL-1β, interleukin-1β; INF-γ, interferon-γ; SJW, St. John’s wort; HPF, hyperforin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; MAPK, mitogen-activated protein kinase; STAT, signal transducer and activator of transcription; ER, endoplasmic reticulum.

Figure 2

Protective mechanisms of St. John’s wort against development of obesity, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes due to a chronic low-grade inflammation state. Other diseases sharing, at least partially, an inflammatory pathogenesis are indicated as putative targets of SJW treatment. Abbreviations: SJW, St. John’s wort; M1-macrophages, classically activated M1 macrophages; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; JNK, c-jun N-terminal kinase; PTP1B, protein tyrosine phosphatase 1B; TNF-α, tumor necrosis factor α; IL-1, interleukin-1; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein-1; FFA, free fatty acids; NO, nitric oxide; AMPK, adenosine monophosphate-activated protein kinase; PXR, pregnane X receptor. ↑: increase; ↓: decrease.