Multitargeted molecular docking and dynamics simulation studies of flavonoids and volatile components from the peel of Citrus sinensis L. (Osbeck) against specific tumor protein markers.

Citrus sinensis (L.) Osbeck (Rutaceae), commonly known as the sweet orange, is a popular and widely consumed fruit with several medicinal properties. The present study aimed to perform the in silico screening of 18 flavonoids and eight volatile components from the peel of C. sinensis against apoptotic and inflammatory proteins, metalloprotease, and tumor suppressor markers. Flavonoids obtained higher probabilities than volatile components against selected anti-cancer drug targets. Hence, the data from the binding energies against the essential apoptotic and cell proliferation proteins substantiate that they may be promising compounds in developing effective candidates to block cell growth, proliferation, and induced cell death by activating the apoptotic pathway. Further, the binding stability of the selected targets and the corresponding molecules were analyzed by 100 ns molecular dynamics (MD) simulations. Chlorogenic acid has the most binding affinity against the important anti-cancer targets iNOS, MMP-9, and p53. The congruent binding mode to different drug targets focused on cancer shown by chlorogenic acid suggests that it may be a compound with significant therapeutic potential. Moreover, the binding energy predictions indicated that the compound had stable electrostatic and van der Waal energies. Thus, our data reinforce the medicinal importance of flavonoids from C. sinensis and expand the need for more studies, seeking to optimize results and amplify the impacts of further in vitro and in vivo studies. Communicated by Ramaswamy H. Sarma.

The Use of Nanocarriers to Enhance the Anti-neuroinflammatory Potential of Dietary Flavonoids in Animal Models of Neurodegenerative Diseases: A Systematic Review.

BACKGROUND: Neurodegenerative diseases (NDs) have become a common and growing cause of mortality and morbidity worldwide, especially in older adults. The natural flavonoids found in fruits and vegetables have been shown to have therapeutic effects against many diseases, including NDs; however, in general, flavonoids have limited bioavailability to the target cells. One promising strategy to increase bioavailability is to entrap them in nanocarriers. OBJECTIVE: This article aims to review the potential role of nanocarriers in enhancing the anti-neuroinflammatory efficacy of flavonoids in experimentally induced ND. METHODS: A literature search was conducted in the scientific databases using the keywords "neurodegenerative", "anti-neuroinflammatory", "dietary flavonoids," "nanoparticles", and "therapeutic mechanisms". RESULTS: A total of 289 articles were initially identified, of which 45 articles reported on flavonoids. After completion of the selection process, five articles that met the criteria of the review were selected for analysis. Preclinical studies identified in this review showed that nanoencapsulated flavonoids attenuated cognitive impairment and seizure, improved behavioral patterns, and reduced levels of astrocytes. Importantly, they exhibited strong antioxidant properties, increasing the levels of antioxidant enzymes and reducing oxidative stress (OS) biomarkers. Moreover, nanocarrier-complexed flavonoids decreased the levels of the pro-inflammatory cytokines, interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nod-like receptor protein 3 inflammasome activation (NLRP3). They also had remarkable effects on important ND-related neurotransmitters, improved cognitive function via cholinergic neurotransmission, and increased prefrontal cortical and hippocampal norepinephrine (NE) and 5-hydroxytryptamine (5-HT). CONCLUSION: Nanoencapsulated flavonoids should, therefore, be considered a novel therapeutic approach for the treatment of NDs.

Cytotoxic activity of essential oil from Leaves of Myrcia splendens against A549 Lung Cancer cells.

BACKGROUND: Plants of the Myrcia genus have been widely used in folk medicine to treat various diseases, including cancer. Myrcia splendens species has a diverse chemical constitution, but the biological activities of its essential oil have not been well investigated. In this study to out the chemistry characterization of essential oil (EO) from the leaves of the species M. splendens from Brazil and evaluate cytotoxic effect in A549 lung cancer cells. METHODS: M. splendens EO was obtained by hydrodistillation and analyzed by Gas Chromatography-Mass Spectrometry (GC-MS). EO was isolated and evaluated for cellular viability in tumor cell lines by MTT assay. The evaluation of the formation of clones and the migratory capacity of the A549 cells treated with EO was done by the clonogenic assay and the wound healing assay. Morphological changes were observed in A549 cells by fluorescence using Phalloidin/FITC and DAPI. RESULTS: 22 compounds were identified in the chemical analysis of EO, corresponding to 88% of the sample. Major compounds were the sesquiterpenic hydrocarbons bicyclogermacrene (15.4%), germacrene D (8.9%) and E-caryophyllene (10.1%). The biological analysis of the EO showed high cytotoxic activity with an IC50 below 20 µg/ml in the THP-1, A549 and B16-F10 tumor cells. The treatment with EO reduced colony formation and inhibited the migratory capacity of A549 cells. Furthermore, apoptotic morphological changes in the nucleus and cytoplasm of A549 cells was observed after of treatment with EO. CONCLUSION: The findings of this study suggest that the M. splendens EO has cytotoxic compounds for the A549 lung cancer cells. Treatment with the EO decreased the colony formation and reduced the ability of lung cancer cells to migrate. Future studies may be used to isolate compounds from the EO for the study of lung cancer.

Anti-inflammatory natural products modulate interleukins and their related signaling markers in inflammatory bowel disease: A systematic review.

This review aims to identify in vivo studies investigating the potential of plant substances and their natural molecules in managing inflammatory bowel disease (IBD). Specifically, the objective is to examine the impact of these substances on interleukins and other key inflammatory signaling markers. Relevant articles published up to December 2022 were identified through a search of the PubMed, Scopus, Web of Science, and Embase databases. The search used keywords including "inflammatory bowel disease", "medicinal plants", "natural molecules", "anti-inflammatory", and "ulcerative colitis", and identified 1,878 potentially relevant articles, of which 89 were included in this review after completion of the selection process. This study provides preclinical data on natural products (NPs) that can potentially treat IBD, including ulcerative colitis. The main actions of these NPs relate to their effects on nuclear factor kappa B (NF-κB), the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, the regulation of T helper 17/regulatory T cells balance, and oxidative stress. The ability of these NPs to inhibit intestinal inflammation appears to be dependent on lowering levels of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, and IL-17, via the Jun N-terminal kinase (JNK)1, NF-κß-p65, and STAT3 pathways. In addition, NPs were shown to reduce oxidative stress and the severity of ulcerative colitis, as well as increase the activity of antioxidant enzymes. These actions suggest that NPs represent a promising treatment for IBD, and potentially have greater efficacy and safety than current treatments.

Chitosan-functionalized nanostructured lipid carriers containing chloroaluminum phthalocyanine for photodynamic therapy of skin cancer.

The objective of this study was to obtain optimized nanostructured lipid carriers (NLC) functionalized with chitosan containing chloroaluminum phthalocyanine (ClAlPc) as a photosensitizer. Initially, the optimization of the preparation method of the NLC was performed, where the influence of different surfactants such as PVA and Tween 80, as well as different solid lipids such as stearic acid and Glycerol Monostearate (GM) was evaluated. The formulation containing GM and PVA (NLC10) was considered promising. Following, by the adsorption method (NLC10q), the formulation was functionalized with chitosan and characterized. NLC10 and NLC10q presented sizes of 131.5 and 231.5 nm, and ZP of -24.30 and + 19.96 mV, respectively. The encapsulation efficiency of NLC10q was 96 %, higher than NLC10 (79 %). The formulations were able to promote significant cutaneous retention of ClAlPc, after 2 h and 4 h of the study, and showed to be non-toxic to fibroblasts (biocompatible). PDT in BF16-F10 melanoma resulted in reduced cell viability to 70 % and 50 % for NLC10 and NLCq, respectively. In view of the results obtained, NLC showed to be promising in the treatment of skin cancer through PDT. NLC10q showed higher encapsulation efficiency and stability than NLC10, but, contrary to what was expected, it presented lower photodynamic efficiency.

Health functions and related molecular mechanisms of ellagitannin-derived urolithins.

Ellagitannins are vital bioactive polyphenols that are widely distributed in a variety of plant-based foods. The main metabolites of ellagitannins are urolithins, and current research suggests that urolithins provide a variety of health benefits. This review focused on the role of the gut bacteria in the conversion of ellagitannins to urolithins. Based on the results of in vitro and in vivo studies, the health benefits of urolithins, including antioxidant, anti-inflammatory, anti-cancer, anti-obesity, anti-diabetic, anti-aging, cardiovascular protective, neuroprotective, kidney protective, and muscle mass protective effects, were thoroughly outlined, with a focus on their associated molecular mechanisms. Finally, we briefly commented on urolithins' safety. Overall, urolithins' diverse health benefits indicate the potential utilization of ellagitannins and urolithins in the creation of functional foods and nutraceuticals to treat and prevent some chronic diseases.

Anti-inflammatory natural products as potential therapeutic agents of rheumatoid arthritis: A systematic review.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease causing severe locomotor disability and deterioration in the quality of life. Existing treatments for RA mainly focus on the use of immunomodulators and the suppression of synovial inflammation, and many have significant side effects. Medicinal plants are regarded as important alternative sources for treating RA. PURPOSE: This review summarizes the bioactive compounds of medicinal plants, which have been shown to modulate the immune response by regulating interleukins in vitro and in vivo experimental models, and that may be promising substances for use in the treatment of RA. METHODS: Articles on natural products used for the management of arthritis were retrieved from PubMed, Embase, Scopus, and Web of Science through electronic and manual search in English. In total, 576 publications were identified, and 34 were included in this systematic review. RESULTS: Two articles presented findings on the role of natural components in the treatment of arthritis in both in vitro and in vivo studies. Nine reports defined the role of plant-derived natural molecules in the treatment of arthritis using cell lines, and 27 in vivo studies assessed the anti-arthritic efficacy and immunomodulation effects of phytoconstituents on interleukin production and inflammatory responses. CONCLUSION: This systematic review broadly reports that, in contrast to other classes of phytochemicals, flavonoids have the greatest therapeutic potential against arthritis by modulating the expression of pro-inflammatory TNF-α, IL-1ß, IL-6, IL-8, and IL-17, as well as anti-inflammatory IL-2 and IL-10 cytokines, through the suppression of dynamic inflammatory biomarkers.