Combination of LC-Q-TOF-MS/MS, network pharmacology, and nanoemulsion approaches identifies active compounds of two Artemisia species responsible for tackling early diabetes-related metabolic complications in the liver.

INTRODUCTION: The chronicity of advanced glycation end-products (AGEs) imparts various damages resulting in metabolic dysfunction and diseases involving inflammation and oxidative stress. The use of plant extracts is of high interest in complementary medicine. Yet, extracts are multicomponent mixtures, and difficult to pinpoint their exact mechanism. OBJECTIVES: We hypothesise that network pharmacology and bioinformatics can help experimental findings depict the exact active components and mechanism of action by which they induce their effects. Additionally, the toxicity and variability can be lowered and standardised with proper encapsulation methods. METHODOLOGY: Here, we propose the formulation of phytoniosomes encapsulating two Artemisia species (Artemisia dracunculus and Artemisia absinthium) to mitigate AGEs and their induced cell redox dysregulation in the liver. Extracts from different solvents were identified via liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS/MS). Phytoniosomes were explored for their anti-glycating effect and modulation of AGE-induced damages in THLE-2 liver cells. Network pharmacology tools were used to identify possible targets and signalling pathways implicated. RESULTS: Data demonstrated that A. absinthium phytoniosomes had a significant anti-AGE effect comparable to reference molecules and higher than A. dracunculus. They were able to restore cell dysfunction through the restoration of tumour necrosis alpha (TNF-α), interleukin 6 (IL-6), nitric oxide, and total antioxidant capacity. Phytoniosomes were able to protect cells from apoptosis by decreasing caspase 3 activity. Network pharmacology and bioinformatic analysis confirmed the induction of the effect via Akt-PI3K-MAPK and AGE-RAGE signalling pathways through quercetin and luteolin actions. CONCLUSION: The current report highlights the potential of Artemisia phytoniosomes as strong contenders in AGE-related disease therapy.

Artemisia alleviates AGE-induced liver complications via MAPK and RAGE signaling pathways modulation: a combinatorial study.

Artemisia herba-alba (AHA) is a traditionally used plant to treat various diseases, including diabetes and metabolic dysfunctions. Plant extracts are generally explored empirically without a deeper assessment of their mechanism of action. Here, we describe a combinatorial study of biochemical, molecular, and bioinformatic (metabolite-protein pharmacology network) analyses to elucidate the mechanism of action of AHA and shed light on its multilevel effects in the treatment of diabetes-related advanced glycation end-products (AGE)-induced liver damages. The extract's polyphenols and flavonoids content were measured and then identified via LC-Q-TOF-MS/MS. Active compounds were used to generate a metabolite-target interaction network via Swiss Target Prediction and other databases. The extract was tested for its antiglycation and aggregation properties. Next, THLE-2 liver cells were challenged with AGEs, and the mechanistic markers were measured [TNF-α, IL-6, nitric oxide, total antioxidant capacity, lipid peroxidation (LPO), and caspase 3]. Metabolite and network screening showed the involvement of AHA in diabetes, glycation, liver diseases, aging, and apoptosis. Experimental confirmation showed that AHA inhibited protein modification and AGE formation. Additionally, AHA reduced inflammatory mediators (IL-6, TNFα), oxidative stress markers (NO, LPO), and apoptosis (Caspase 3). On the other hand, cellular total antioxidant capacity was restored to normal levels. The combinatorial study showed that AHA regulates AGE-induced liver damages through MAPK-AKT and AGE-RAGE signaling pathways. This report highlights the combination of experimental and network pharmacology for the exact elucidation of AHA mechanism of action as a multitarget option in the therapy of diabetes and AGEs-related diseases.

Zinc enhances carnosine inhibitory effect against structural and functional age-related protein alterations in an albumin glycoxidation model.

Age-related complications including protein alterations seen in diabetes and Alzheimer's disease are a major issue due to their accumulation and deleterious effects. This report aims to investigate the effect of zinc supplementation on the anti-glycoxidation activity of carnosine on the in vitro model of albumin-based protein modification. Besides, the therapeutic effect of this combination was tested through the addition of the molecules in tandem (co-treatment) or post initiation (post-treatment) of the protein modification process. Glycation was induced via the addition of glucose to which carnosine (5 mM) alone or with various zinc concentrations (125, 250, and 500 µM) were added either at 0 h or 24 h post-glycation induction. On the other hand, protein oxidation was induced using chloramine T (20 mM) and treated in the same way with carnosine and zinc. The different markers of glycation (advanced glycation end products (AGEs), dityrosine, and beta-sheet formation (aggregation)) and oxidation (AOPP, advanced oxidation protein products) were estimated via fluorescence and colorimetric assays. Zinc addition induced a significant enhancement of carnosine activity by reducing albumin modification that outperformed aminoguanidine both in the co- and post-treatment protocols. Zinc demonstrated a supplementary effect in combination with carnosine highlighting its potential in the protection against age-related protein modifications processes such as the ones found in diabetes.

Nanohybrid carriers: the yin-yang equilibrium between natural and synthetic in biomedicine.

Nanotechnology has seen an outburst in biomedicine applications through the use of nanoparticles of different sources in therapy and diagnostics. The needs of theranostics evolved through the years for the development of tailored treatments. In this regard, nanocarriers have shown a great impact on the field via the use of natural lipidic vesicles for drug delivery. This breakthrough allowed the medical field to protect the drug from undesired interactions in the bloodstream and lowered the drug load usually given to reach therapeutical doses. Nanocarriers further continued by using block polymers to create more stable structures with higher protection levels of their content. In this review, we introduce both lipidic and polymeric vesicles with their specific characteristics and discuss the advantages and disadvantages of each type which was taken as a base to introduce the newly known lipid-polymer hybrids that take the advantages from both sides to present an interesting approach to regulate the physicochemical features, pharmacokinetics and other parameters used in tailoring treatments for cancer therapy. In addition, from the many hybrids proposed we have focused our efforts in discussing two major groups that are lipid-polymer hybrid nanoparticles LPHNs (polymersomes inside liposomes), and capsosomes (liposomes inside polymersomes) showing the many potential benefits of combining lipids and polymers for biomedicine.