Chem. Pharm. Bull.(オピニオン)

The naphthoquinone pigment, shikonin, isolated from Lithospermum erythrorhizon Sieb. et Zucc.(Boraginaceae) and its derivatives are the active components isolated from the Chinese herbal therapeutic, Zicao. Historically, Zicao root extracts have been used to treat macular eruption, measles, sore-throat, carbuncles and burns. Multiple pharmacological actions have been attributed to shikonin, e.g. antiinflammatory, antigonadotropic and anti-HIV-1 activity. In this review, several therapeutic applications of shikonin will be summarized including its pleiotropic, antiinflammatory and antitumour effects. Widely diverse and sometimes conflicting activities have been attributed to shikonin, e.g. wound healing, enhanced granuloma formation, suppression of local acute inflammatory reactions, inhibition of angiogenesis, inhibition of select chemokine ligands, inhibition of DNA topoisomerase activity, inhibition of platelet activation and antimicrobial activity. Comparison of the various reported mechanisms of action for shikonin lead us to hypothesize that shikonin is an effective inhibitor of protein-protein interaction with multiple targets in both the intracellular and extracellular compartments. This general inhibitory effect can account for the broad spectrum of shikonin biological and pharmacological activities.

Cellular pharmacology studies of shikonin derivatives.

The pharmacology of resveratrol in animals and humans.

The non-communicable disease, cancer, is one of the major causes of death across the world and is forecast to increase by 75% to reach close to 25 million cases over the next two decades. Radiotherapy and surgical approaches have been unsuccessful in controlling the incidence of most cancers. The development of chemotherapeutic strategies involving novel small molecule antitumour agents has therefore been the focus area of cancer chemotherapy for several decades as another strategy to combat and control the incidence of cancer. Many natural products as well as several synthetic drugs have a naphthoquinone chromophore. The anticancer activities of naphthoquinones have been the focus of much research to discover novel anticancer agents. The naturally occurring 1,2-naphthoquinone-based compound, β-lapachone (ARQ 761), is currently being assessed for its anti-tumour activity against advanced solid tumours. This review describes the most recent applications of naphthoquinones and their derivatives in cancer drug discovery. The biology relevant to the design of novel naphthoquinone anticancer agents is also discussed. Furthermore, the discussion of the biology will contribute to understanding cancer as well as the applications of naphthoquinones as anticancer agents.

/pdf/understanding-cancer-and-the-anticancer-activities-of-4os2fxxzqo.pdf

Understanding cancer and the anticancer activities of naphthoquinones – a review

Alzheimer's disease (AD) is a progressive and neurodegenerative disorder of the cortex and hippocampus, which eventually leads to cognitive impairment. Although the etiology of AD remains unclear, the presence of β-amyloid (Aβ) peptides in these learning and memory regions is a hallmark of AD. Therefore, the inhibition of Aβ peptide aggregation has been considered the primary therapeutic strategy for AD treatment. Many studies have shown that resveratrol has antioxidant, anti-inflammatory, and neuroprotective properties and can decrease the toxicity and aggregation of Aβ peptides in the hippocampus of AD patients, promote neurogenesis, and prevent hippocampal damage. In addition, the antioxidant activity of resveratrol plays an important role in neuronal differentiation through the activation of silent information regulator-1 (SIRT1). SIRT1 plays a vital role in the growth and differentiation of neurons and prevents the apoptotic death of these neurons by deacetylating and repressing p53 activity; however, the exact mechanisms remain unclear. Resveratrol also has anti-inflammatory effects as it suppresses M1 microglia activation, which is involved in the initiation of neurodegeneration, and promotes Th2 responses by increasing anti-inflammatory cytokines and SIRT1 expression. This review will focus on the antioxidant and anti-inflammatory neuroprotective effects of resveratrol, specifically on its role in SIRT1 and the association with AD pathophysiology.

/pdf/neuroprotective-mechanisms-of-resveratrol-in-alzheimer-s-27o7g989a7.pdf

Neuroprotective Mechanisms of Resveratrol in Alzheimer's Disease: Role of SIRT1.

In vitro antifungal activities of naphtoquinone-derivatives, which are constituents of Shikon, roots of Lithospermum erythrorhizon, were investigated against several fungal pathogens. When the biological activity of these compounds was tested against fungi, a wide range of sensitivity was recorded. Shikonin was found to have a stronger than fluconazole against yeast-like fungi: four-fold against Candida krusei (minimal inhibitory concentration (MIC); 4 μg/ml) and two-fold (MIC; 4 μg/ml) against Saccharomyces cerevisiae, though it showed the same potency as fluconazole against C. glabrata. Deoxyshikonin also exhibited four-fold stronger activity against C. krusei (MIC; 4 μg/ml) and three-fold (MIC; 2 μg/ml) stronger against S. cerevisiae. Acetylshikonin and β-hydroxyisovaleryl shikonin showed lower activities against all fungal pathogens except for C. krusei compared with the standard. Against the filamentous fungus, Trichosporon cutaneum, all naphthoquinones were found to have a range of activity with lower potency than standard. This result provides a rational basis for the clinical use of shikon and shows the possibility of its use in medicinal treatment as an anti-inflammatory agent with antifungal activity.

/pdf/in-vitro-antifungal-activity-of-naphthoquinone-derivatives-4n6wbqrowd.pdf

In vitro antifungal activity of naphthoquinone derivatives.

Neuroimaging evidence showed structural and/or functional abnormalities existing in the central nervous system, especially the hippocampus, in chronic fatigue syndrome (CFS) patients. However, its pathophysiologic mechanisms are unclear in part due to the lack of an applicable animal model. We established a chronic fatigue murine model by six repeated injections of Brucella abortus antigen to mice, which was manifested as reduced daily running activity and hippocampal atrophy. Thereafter, resveratrol, a polyphenolic activator of sirtuin 1, was used for treatment in this model. Daily running activity was increased by more than 20%, and the hippocampus was enlarged after 4-week resveratrol therapy. Furthermore, resveratrol inhibited neuronal apoptosis and expression of hippocampal acetylated p53 in the fatigue mice. Resveratrol also improved neurogenesis and expression of brain-derived neurotrophic factor mRNA in the hippocamous. We concluded that repeated injection of B. abortus antigen could induce hypoactivity and hippocampal atrophy in mice. Resveratrol may be effective for improving fatigue symptoms and enlarging the atrophic hippocampus by repressing apoptosis and promoting neurogenesis.

https://www.jstage.jst.go.jp/article/bpb/34/3/34_3_354/_pdf

Resveratrol improves hippocampal atrophy in chronic fatigue mice by enhancing neurogenesis and inhibiting apoptosis of granular cells.

We investigated the effects of water and ethyl acetate extracts of Citrus unshiu peel (Aurantii Nobilis pericarpium) on hepatitis C virus (HCV) absorption in MOLT-4 cells (a human lymphoblastoid leukemia cell line). By reverse transcription polymerase chain reaction (RT-PCR), we showed that both the ethyl acetate layer of Citrus unshiu peel extract and fraction 7 decreased HCV absorption in MOLT-4 cells. Furthermore, we demonstrated that 3',4',5,6,7,8-hexamethoxyflavone (nobiletin) is the active ingredient that markedly inhibited HCV infection in MOLT-4 cells.

Anti-hepatitis C virus effect of citrus unshiu peel and its active ingredient nobiletin.

From the aerial parts of Clinopodium chinense var. parviflorum, nine new phenylpropanoids, clinopodic acids A-I (2-10), were isolated together with a known phenylpropanoid, rosmarinic acid (1). The structures of these new compounds were elucidated on the basis of spectroscopic analysis. Clinopodic acid C (4) showed MMP-2 inhibitory activity (IC(50) 3.26 microM).

Matrix metalloproteinase-2 inhibitors from Clinopodium chinense var. parviflorum.

A tyrosinase inhibitor was isolated from the peel of Citrus fruit by activity-guided fractionation, and identified as 3',4',5,6,7,8-hexamethoxyflavone (nobiletin) by comparison with reported spectral data. Nobiletin (IC50 of; 46.2 microM) exhibited more potency than Kojic acid (IC50; 77.4 microM) used as a positive control, and it was found to be potentially an effective inhibitor of the production of melanin.

/pdf/nobiletin-as-a-tyrosinase-inhibitor-from-the-peel-of-citrus-4obmydxq6n.pdf

Kenroh Sasaki

Papers

In vitro antifungal activity of naphthoquinone derivatives.

Resveratrol improves hippocampal atrophy in chronic fatigue mice by enhancing neurogenesis and inhibiting apoptosis of granular cells.

Anti-hepatitis C virus effect of citrus unshiu peel and its active ingredient nobiletin.

Matrix metalloproteinase-2 inhibitors from Clinopodium chinense var. parviflorum.

Nobiletin as a tyrosinase inhibitor from the peel of Citrus fruit.