Protoberberine alkaloids: A review of the gastroprotective effects, pharmacokinetics, and toxicity.

BACKGROUND: Stomach diseases have become global health concerns. Protoberberine alkaloids (PBAs) are a group of quaternary isoquinoline alkaloids from abundant natural sources and have been shown to improve gastric disorders in preclinical and clinical studies. The finding that PBAs exhibit low oral bioavailability but potent pharmacological activity has attracted great interest. PURPOSE: This review aims to provide a systematic review of the molecular mechanisms of PBAs in the treatment of gastric disorders and to discuss the current understanding of the pharmacokinetics and toxicity of PBAs. METHODS: The articles related to PBAs were collected from the Web of Science, Pubmed, and China National Knowledge Infrastructure databases using relevant keywords. The collected articles were screened and categorized according to their research content to focus on the gastroprotective effects, pharmacokinetics, and toxicity of PBAs. RESULTS: Based on the results of preclinical studies, PBAs have demonstrated therapeutic effects on chronic atrophic gastritis and gastric cancer by activating interleukin-4 (IL-4)/signal transducer and activator of transcription 6 (STAT6) pathway and suppressing transforming growth factor-beta 1 (TGF-ß1)/phosphoinositide 3-kinase (PI3K), Janus kinase-2 (JAK2)/signal transducers and activators of transcription 3 (STAT3), and mitogen-activated protein kinase (MAPK) pathways. The major PBAs exhibit similar pharmacokinetic properties, including rapid absorption, slow elimination, and low bioavailability. Notably, the natural organ-targeting property of PBAs may account for the finding of their low blood levels and high pharmacological activity. PBAs interact with other compounds, including conventional drugs and natural products, by modulation of metabolic enzymes and transporters. The potential tissue toxicity of PBAs should be emphasized due to their high tissue accumulation. CONCLUSION: This review highlights the gastroprotective effects, pharmacokinetics, and toxicity of PBAs and will contribute to the evaluation of drug properties and clinical translational studies of PBAs, accelerating their transfer from the laboratory to the bedside.

Dietary gallic acid as an antioxidant: A review of its food industry applications, health benefits, bioavailability, nano-delivery systems, and drug interactions.

Gallic acid (GA), a dietary phenolic acid with potent antioxidant activity, is widely distributed in edible plants. GA has been applied in the food industry as an antimicrobial agent, food fresh-keeping agent, oil stabilizer, active food wrap material, and food processing stabilizer. GA is a potential dietary supplement due to its health benefits on various functional disorders associated with oxidative stress, including renal, neurological, hepatic, pulmonary, reproductive, and cardiovascular diseases. GA is rapidly absorbed and metabolized after oral administration, resulting in low bioavailability, which is susceptible to various factors, such as intestinal microbiota, transporters, and metabolism of galloyl derivatives. GA exhibits a tendency to distribute primarily to the kidney, liver, heart, and brain. A total of 37 metabolites of GA has been identified, and decarboxylation and dihydroxylation in phase I metabolism and sulfation, glucuronidation, and methylation in phase Ⅱ metabolism are considered the main in vivo biotransformation pathways of GA. Different types of nanocarriers, such as polymeric nanoparticles, dendrimers, and nanodots, have been successfully developed to enhance the health-promoting function of GA by increasing bioavailability. GA may induce drug interactions with conventional drugs, such as hydroxyurea, linagliptin, and diltiazem, due to its inhibitory effects on metabolic enzymes, including cytochrome P450 3A4 and 2D6, and transporters, including P-glycoprotein, breast cancer resistance protein, and organic anion-transporting polypeptide 1B3. In conclusion, in-depth studies of GA on food industry applications, health benefits, bioavailability, nano-delivery systems, and drug interactions have laid the foundation for its comprehensive application as a food additive and dietary supplement.

The antinociceptive and anti-inflammatory potential and pharmacokinetic study of significant alkamides ingredients from Asarum Linn.

ETHNOPHARMACOLOGICAL RELEVANCE: Asari Radix et Rhizoma (ARR), including 3 major plants of genus Asarum Linn, A. heterotropoides Fr. Schmidt var. mandshuricum (Maxim.) Kitag., A. sieboldii Miq. f. sieboldii and A. sieboldii Miq f. seoulense (Nakai) C. Y. Cheng et C. S. Yang, is one of the most important traditional herbal medicine in Asia with tremendous pharmacological activities. For a long time, researchers focus attention on studing asarinin and essential oils, the indicating ingredients of ARR, but paid less attention to another characteristic component, alkamides. The role of alkamides in the major efficacy of ARR medication remains to be elucidated. AIM OF THE STUDY: This study aims to investigate the contribution of alkamides in the efficacy of ARR according to the evaluation of antinociceptive and anti-inflammatory effects and in vivo pharmacokinetics processes. MATERIALS AND METHODS: For pharmacodynamic study, the analgesic and anti-inflammatory effects of alkamides-enriched fraction (ARRA) were comparatively evaluated by writhing test, hot plate test, and ear swelling test in mice after oral administration. For pharmacokinetic study, an UHPLC-MS/MS method was developed for the simultaneous determination of N-isobutyl-2E,4E,8Z,10Z/E-dodecatetraenamide (DDA) and other 6 major characteristic ingredients of ARR in rat plasma. The analytical method was validated and successfully applied to the pharmacokinetic study of ARR extract and DDA. RESULTS: Pharmacodynamic study show that the ARR and ARRA can significantly inhibit the writhing times of mice caused by acetic acid administration, increase the pain threshold of thermal stimulation, and inhibit xylene treated ear swelling degree by reduce PGE2 and TNF-α levels in the inflamed tissue. For pharmacokinetic study, the pharmacokinetic parameters of Vd/F and CL/F after intravenous administration in rats of DDA are 63.94 ± 32.12 L/kg and 0.33 ± 0.06 L/min/kg, respectively. The plasma drug concentration declined with the T1/2 value of 2.25 ± 0.96 h, and the MRT0-∞ was 2.23 ± 1.02 h. The absolute bioavailability of DDA after oral administration was calculated as 10.73%. DDA, methyleugenol, and asarinin have relatively high AUC0-∞ values when the ethanol and water extract of ARR is orally administered. CONCLUSIONS: ARRA is a kind of active ingredients with potential analgesic and anti-inflammatory effects that played a significant role in the major efficacy of ARR. DDA, the major compound of ARRA, has a high level of exposure in vivo, which could be is suitable for the pharmacokinetic marker or new quality marker of ARR.

A review on ß-carboline alkaloids and their distribution in foodstuffs: A class of potential functional components or not?

Pharmacologically active ß-carboline alkaloids (ßCs) such as harman, norharman and some others are naturally present in plants and occur in many foodstuffs. They have a lot of pharmacological properties, including antitumor, antioxidant, anti-inflammatory and antimicrobial effects, and possess the potential for treating Alzheimer's disease, Parkinson's disease, depression and other central nervous system diseases. Dietary intake is proven to be an important source of ßCs. Therefore, it is important to know the amounts of ßCs that can be gotten from daily diets. This review summarizes the pharmacological activities, toxicology and formation of ßCs, and gives collective information on contents of ßCs in different foodstuffs.

Hippocampal mRNA expression profiling in mice exposed to chronic unpredictable mild stress.

Depression is a state of low mood and aversion to activity, affecting a person's thoughts, behavior, motivation, feelings and sense of well-being, which is associated with dramatical gene expression changes in hippocampus. Rodents induced by chronic unpredictable mild stress (CUMS) demonstrate typical depression-like behaviors similar to clinical patients, therefore, are commonly used as a model for depression and antidepressant study. In order to enhance our understanding of the molecular mechanisms of the pathogenesis of depression, in the present study, the hippocampal mRNA expression profile of mice exposed to CUMS for 5 weeks was sequenced using Illumina HiSeq 4000 platform followed by enrichment analysis, including Hierarchical Cluster, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) network. Totally, 346 differently expressed mRNAs, including 208 downregulated and 138 upregulated, were identified in the hippocampus of the CUMS mice. KEGG biological pathway analysis showed that the upregulated and downregulated mRNAs were mostly enriched in 29 pathways and 8 pathways, respectively. PPI network analysis exposed that glyceraldehyde 3-phosphate dehydrogenase was the crucial node with high connectivity degree. Additionally, most of these genes in PPI network analysis have previously been linked to energy metabolism and corticosterone responses. Overall, our results indicate the possible novel molecular targets for the therapy of depression.