Branched-Long-Chain Monomethyl Fatty Acids: Are They Hidden Gems?

Branched-long-chain monomethyl fatty acids (BLCFA) are consumed daily in significant amounts by humans in all stages of life. BLCFA are absorbed and metabolized in human intestinal epithelial cells and are not only oxidized for energy. Thus far, BLCFA have been revealed to possess versatile beneficial bioactivities, including cytotoxicity to cancer cells, anti-inflammation, lipid-lowering, reducing the risk of metabolic disorders, maintaining normal ß cell function and insulin sensitivity, regulation of development, and mitigating cerebral ischemia/reperfusion injury. However, compared to other well-studied dietary fatty acids like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), BLCFA has received disproportionate attention despite their potential importance. Here we outlined the major food sources, estimated intake, absorption, and metabolism in human cells, and bioactive properties of BLCFA with a focus on the bioactive mechanisms to advocate for an increased commitment to BLCFA investigations. Humans were estimated to absorb 6-5000 mg of dietary BLCFA daily from fetus to adult. Notably, iso-15:0 inhibited the growth of prostate cancer, liver cancer and T-cell non-Hodgkin lymphomas in rodent models at the effective doses of 35-105 mg/kg/day, 70 mg/kg/day, and 70 mg/kg/day, respectively. Feeding formula prepared with 20% w/w BLCFA mixture to neonatal rats with enterocolitis mitigated the intestine inflammation. Iso-15:0 at doses of 10, 40, and 80 mg/kg relieved brain ischemia/reperfusion injury in rats. In the future, it is crucial to conduct research to establish the epidemiology of BLCFA intake and their impacts on health outcomes in humans as well as to fully uncover the underlying mechanisms for their bioactivities.

Multi-effective components and their target mechanism of Ziziphi Spinosae Semen in the treatment of insomnia.

Insomnia is a common and refractory disease. Since more than 2000 years ago, people have been using Ziziphi Spinosae Semen (ZSS). However, there are lack of molecular mechanisms of sleep promotion effects of ZSS. The purpose of this study is to clarify the active ingredients in ZSS that are used to treat insomnia. Using a method called cellular label-free integrative pharmacology (CLIP), we established five insomnia-related target models, including serotonin (5HT2A and 5HT1A), melatonin (MT1), dopamine (D2) and epinephrine (ß2) receptors. The one-dimensional (1D) fractions of ZSS extract were prepared on a RZC18 column and assayed on five models. Subsequently, the active fraction was further analyzed, fractionated and quantified using a two-dimensional (2D) liquid phase method coupled with a charged aerosol detector (CAD), This CAD-coupled 2D-LC method requires micro-fractions from the 1D separation and thus it greatly saves sample amounts and corresponding preparation time, and quickly conduct activity screening. The composition of the active 2D fractions was then determined using three-dimensional (3D) HPLC-MS, and molecular docking was separately carried out for the described compounds on the targets for activity prediction. Seven compounds were predicted to be active on 5HT2A, and two compounds on D2. We experimentally verified the prediction and found that vitexin exhibited D2 agonistic activity, and nuciferine exhibited 5HT2A antagonistic activity. This study revealed the effective components and their targets of ZSS in the treatment of insomnia, also highlighted the potential of the CLIP technique and bioactivity guided multi-dimensional HPLC-MS in molecular mechanism elucidation for traditional Chinese medicines.

Ferroptosis: A Double-Edged Sword in Gastrointestinal Disease.

Ferroptosis is a novel form of regulated cell death (RCD) that is typically accompanied by iron accumulation and lipid peroxidation. In contrast to apoptosis, autophagy, and necroptosis, ferroptosis has unique biological processes and pathophysiological characteristics. Since it was first proposed in 2012, ferroptosis has attracted attention worldwide. Ferroptosis is involved in the progression of multiple diseases and could be a novel therapeutic target in the future. Recently, tremendous progress has been made regarding ferroptosis and gastrointestinal diseases, including intestinal ischemia/reperfusion (I/R) injury, inflammatory bowel disease (IBD), gastric cancer (GC), and colorectal cancer (CRC). In this review, we summarize the recent progress on ferroptosis and its interaction with gastrointestinal diseases. Understanding the role of ferroptosis in gastrointestinal disease pathogenesis could provide novel therapeutic targets for clinical treatment.

Computational study of novel natural inhibitors targeting aminopeptidase N(CD13).

OBJECTIVES: To screen and identify ideal leading compounds from a drug library (ZINC15 database) with potential inhibition of aminopeptidase N(CD13) to contribute to medication design and development. RESULTS: Two novel natural compounds, ZINC000000895551 and ZINC000014820583, from the ZINC15 database were found to have a higher binding affinity and more favorable interaction energy binding with CD13 with less rodent carcinogenicity, Ames mutagenicity, and non-inhibition with cytochrome P-450 2D6. Molecular dynamics simulation analysis suggested that the 2 complexes, ZINC000000895551-CD13 and ZINC000014820583-CD13, have favorable potential energy, and exist stably in the natural circumstances. CONCLUSION: This study discovered that ZINC000000895551 and ZINC000014820583 were ideal leading compounds to be inhibitions targeting to CD13. These compounds were selected as safe drug candidates as CD13 target medication design and improvement. MATERIALS AND METHOD: Potential inhibitors of CD13 were identified using a series of computer-aided structural and chemical virtual screening techniques. Structure-based virtual screening was carried out to calculate LibDock scores, followed by analyzing their absorption, distribution, metabolism, and excretion and toxicity predictions. Molecule docking was employed to reveal binding affinity between the selected compounds and CD13. Molecular dynamics simulation was applied to evaluate stability of the ligand-CD13 complex under natural environment.

Co-administration of combretastatin A4 nanoparticles and sorafenib for systemic therapy of hepatocellular carcinoma.

Effective systemic therapy is highly desired for the treatment of hepatocellular carcinoma (HCC). In this study, a combination of nanoparticles of poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4 sodium salt (CA4-NPs) plus sorafenib is developed for the cooperative systemic treatment of HCC. The CA4-NPs leads to the disruption of established tumor blood vessels and extensive tumor necrosis, however, inducing increased expression of VEGF-A and angiogenesis. Sorafenib reduces the VEGF-A induced angiogenesis and further inhibits tumor proliferation, cooperating with the CA4-NPs. A significant decrease in tumor volume and prolonged survival time are observed in the combination group of CA4-NPs plus sorafenib compared with CA4-NPs or sorafenib monotherapy in subcutaneous and orthotopic H22 hepatic tumor models. Seventy-one percent of the mice are alive without residual tumor at 96 days post tumor inoculation for the subcutaneous models treated with CA4-NPs 30 or 35 mg·kg-1 plus sorafenib 30 mg·kg-1. Our findings suggest that co-administration of sorafenib and CA4-NPs possesses significant antitumor efficacy for HCC treatment. STATEMENT OF SIGNIFICANCE: Effective systemic therapy is highly desired for the treatment of hepatocellular carcinoma (HCC). Herein, we demonstrate that a combination of nanoparticles of poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4 sodium salt (CA4-NPs) plus sorafenib is a promising synergistic approach for systemic treatment of HCC. The CA4-NPs leads to the disruption of established tumor blood vessels and extensive tumor necrosis, however, inducing increased expression of VEGF-A and angiogenesis. Sorafenib reduces the VEGF-A induced angiogenesis and further inhibits tumor proliferation, cooperating with the CA4-NPs.