Shikonin, a naphthalene ingredient: Therapeutic actions, pharmacokinetics, toxicology, clinical trials and pharmaceutical researches

Systematic reviews and meta-analyses are essential to summarise evidence relating to efficacy and safety of healthcare interventions accurately and reliably. The clarity and transparency of these reports, however, are not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users. Since the development of the QUOROM (quality of reporting of meta-analysis) statement—a reporting guideline published in 1999—there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realising these issues, an international group that included experienced authors and methodologists developed PRISMA (preferred reporting items for systematic reviews and meta-analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions. The PRISMA statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this explanation and elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA statement, this document, and the associated website (www.prisma-statement.org/) should be helpful resources to improve reporting of systematic reviews and meta-analyses.

Shikonin is the major bioactive component extracted from the roots of Lithospermum erythrorhizon which is also known as "Zicao" in Traditional Chinese Medicine (TCM). Recent studies have shown that shikonin demonstrates various bioactivities related to the treatment of cancer, inflammation, and wound healing. This review aimed to provide an updated summary of recent studies on shikonin. Firstly, many studies have demonstrated that shikonin exerts strong anticancer effects on various types of cancer by inhibiting cell proliferation and migration, inducing apoptosis, autophagy, and necroptosis. Shikonin also triggers Reactive Oxygen Species (ROS) generation, suppressing exosome release, and activate anti-tumor immunity in multiple molecular mechanisms. Examples of these effects include modulating the PI3K/AKT/mTOR and MAPKs signaling; inhibiting the activation of TrxR1, PKM2, RIP1/3, Src, and FAK; and regulating the expression of ERP57, MMPs, ATF2, C-MYC, miR-128, and GRP78 (Bip). Next, the anti-inflammatory and wound-healing properties of shikonin were also reviewed. Furthermore, several studies focusing on shikonin derivatives were reviewed, and these showed that, with modification to the naphthazarin ring or side chain, some shikonin derivatives display stronger anticancer activity and lower toxicity than shikonin itself. Our findings suggest that shikonin and its derivatives could serve as potential novel drug for the treatment of cancer and inflammation.

Abstract Coronaviruses are contagious pathogens primarily responsible for respiratory and intestinal infections. Research efforts to develop antiviral agents against coronavirus demonstrated the main protease (Mpro) protein may represent effective drug target. X-ray crystallographic structure of the SARS-CoV2 Mpro protein demonstrated the significance of Glu166, Cys141, and His41 residues involved in protein dimerization and its catalytic function. We performed in silico screening of compounds from Curcuma longa L. (Zingiberaceae family) against Mpro protein inhibition. Employing a combination of molecular docking, scoring functions, and molecular dynamics simulations, 267 compounds were screened by docking on Mpro crystallographic structure. Docking score and interaction profile analysis exhibited strong binding on the Mpro catalytic domain with compounds C1 (1E,6E)-1,2,6,7-tetrahydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione) and C2 (4Z,6E)‐1,5‐dihydroxy‐1,7‐bis(4‐hydroxyphenyl)hepta‐4,6‐dien‐3‐one as lead agents. Compound C1 and C2 showed minimum binding score (–9.08 and –8.07 kcal/mole) against Mpro protein in comparison to shikonin and lopinavir (≈ −5.4 kcal/mole) a standard Mpro inhibitor. Furthermore, principal component analysis, free energy landscape and protein-ligand energy calculation studies revealed that these two compounds strongly bind to the catalytic core of the Mpro protein with higher efficacy than lopinavir, a standard antiretroviral of the protease inhibitor class. Taken together, this structure based optimization has provided lead on two natural Mpro inhibitors for further testing and development as therapeutics against human coronavirus. Communicated by Ramaswamy H. Sarma