Binary Nano-inhalant Formulation of Icariin Enhances Cognitive Function in Vascular Dementia via BDNF/TrkB Signaling and Anti-inflammatory Effects.

Vascular dementia (VaD) has a serious impact on the patients' quality of life. Icariin (Ica) possesses neuroprotective potential for treating VaD, yet its oral bioavailability and blood-brain barrier (BBB) permeability remain challenges. This research introduced a PEG-PLGA-loaded chitosan hydrogel-based binary formulation tailored for intranasal delivery, enhancing the intracerebral delivery efficacy of neuroprotective agents. The formulation underwent optimization to facilitate BBB crossing, with examinations conducted on its particle size, morphology, drug-loading capacity, in vitro release, and biodistribution. Using the bilateral common carotid artery occlusion (BCCAO) rat model, the therapeutic efficacy of this binary formulation was assessed against chitosan hydrogel and PEG-PLGA nanoparticles loaded with Ica. Post-intranasal administration, enhanced cognitive function was evident in chronic cerebral hypoperfusion (CCH) rats. Further mechanistic evaluations, utilizing immunohistochemistry (IHC), RT-PCR, and ELISA, revealed augmented transcription of synaptic plasticity-associated proteins like SYP and PSD-95, and a marked reduction in hippocampal inflammatory markers such as IL-1ß and TNF-α, highlighting the formulation's promise in alleviating cognitive impairment. The brain-derived neurotrophic factor (BDNF)/tropomyosin related kinase B (TrkB) pathway was activated significantly in the binary formulation compared with the other two. Our study demonstrates that the intranasal application of chitosan hydrogel loaded with Ica-encapsulated PEG-PLGA could effectively deliver Ica into the brain and enhance its neuroprotective effect.

Flavonoid Baicalein Suppresses Oral Biofilms and Protects Enamel Hardness to Combat Dental Caries.

The objectives of this study were to investigate the effects of a novel method using flavonoids to inhibit Streptococcus mutans (S. mutans), Candida albicans (C. albicans) and dual-species biofilms and to protect enamel hardness in a biofilm-based caries model for the first time. Several flavonoids, including baicalein, naringenin and catechin, were tested. Gold-standard chlorhexidine (CHX) and untreated (UC) groups served as controls. Optimal concentrations were determined by cytotoxicity assay. Biofilm MTT, colony-forming-units (CFUs), biofilm biomass, lactic acid and polysaccharide production were evaluated. Real-time-polymerase-chain reaction (qRT-PCR) was used to determine gene expressions in biofilms. Demineralization of human enamel was induced via S. mutans-C. albicans biofilms, and enamel hardness was measured. Compared to CHX and UC groups, the baicalein group achieved the greatest reduction in S. mutans, C. albicans and S. mutans-C. albicans biofilms, yielding the least metabolic activity, polysaccharide synthesis and lactic acid production (p < 0.05). The biofilm CFU was decreased in baicalein group by 5 logs, 4 logs, 5 logs, for S. mutans, C. albicans and S. mutans-C. albicans biofilms, respectively, compared to UC group. When tested in a S. mutans-C. albicans in vitro caries model, the baicalein group substantially reduced enamel demineralization under biofilms, yielding an enamel hardness that was 2.75 times greater than that of UC group. Hence, the novel baicalein method is promising to inhibit dental caries by reducing biofilm formation and protecting enamel hardness.

Therapeutic Potential of Flavonoids and Tannins in Management of Oral Infectious Diseases-A Review.

Medicinal plants are rich sources of valuable molecules with various profitable biological effects, including antimicrobial activity. The advantages of herbal products are their effectiveness, relative safety based on research or extended traditional use, and accessibility without prescription. Extensive and irrational usage of antibiotics since their discovery in 1928 has led to the increasing expiration of their effectiveness due to antibacterial resistance. Now, medical research is facing a big and challenging mission to find effective and safe antimicrobial therapies to replace inactive drugs. Over the years, one of the research fields that remained the most available is the area of natural products: medicinal plants and their metabolites, which could serve as active substances to fight against microbes or be considered as models in drug design. This review presents selected flavonoids (such as apigenin, quercetin, kaempferol, kurarinone, and morin) and tannins (including oligomeric proanthocyanidins, gallotannins, ellagitannins, catechins, and epigallocatechin gallate), but also medicinal plants rich in these compounds as potential therapeutic agents in oral infectious diseases based on traditional usages such as Agrimonia eupatoria L., Hamamelis virginiana L., Matricaria chamomilla L., Vaccinium myrtillus L., Quercus robur L., Rosa gallica L., Rubus idaeus L., or Potentilla erecta (L.). Some of the presented compounds and extracts are already successfully used to maintain oral health, as the main or additive ingredient of toothpastes or mouthwashes. Others are promising for further research or future applications.

A Review of Recent Developments in the Molecular Mechanisms of Bone Healing.

Between 5 and 10 percent of fractures do not heal, a condition known as nonunion. In clinical practice, stable fracture fixation associated with autologous iliac crest bone graft placement is the gold standard for treatment. However, some recalcitrant nonunions do not resolve satisfactorily with this technique. For these cases, biological alternatives are sought based on the molecular mechanisms of bone healing, whose most recent findings are reviewed in this article. The pro-osteogenic efficacy of morin (a pale yellow crystalline flavonoid pigment found in old fustic and osage orange trees) has recently been reported, and the combined use of bone morphogenetic protein-9 (BMP9) and leptin might improve fracture healing. Inhibition with methyl-piperidino-pyrazole of estrogen receptor alpha signaling delays bone regeneration. Smoking causes a chondrogenic disorder, aberrant activity of the skeleton's stem and progenitor cells, and an intense initial inflammatory response. Smoking cessation 4 weeks before surgery is therefore highly recommended. The delay in fracture consolidation in diabetic animals is related to BMP6 deficiency (35 kDa). The combination of bioceramics and expanded autologous human mesenchymal stem cells from bone marrow is a new and encouraging alternative for treating recalcitrant nonunions.

Higher intakes of flavonoids are associated with lower salivary IL-1ß and maintenance of periodontal health 3-4 years after scaling and root planing.

AIMS: Higher intakes of fruits and vegetables, and vitamin C are associated with improved periodontal healing post-scaling and root planing (SRP). This study determined if this association was sustained at 3-4 years post-SRP, and if flavonoid intake is associated with periodontal health. Whether reduced probing depth (PD) is sustained and whether PD is correlated with salivary IL-1ß, IL-6 and CRP at 3-4 years post-SRP were also studied. MATERIALS AND METHODS: Clinical periodontal outcomes, dietary intakes and salivary markers of inflammation were measured in patients (n = 43, 23 females, 37-93 years) who had undergone SRP 3-4 years earlier and had been part of a periodontal maintenance programme. RESULTS: Flavonoid intake was inversely associated with PD (p = .042) and salivary IL-1ß concentration (p = .015) after adjustment for multiple confounders. When changes in PD were considered, the association of flavonoid intake with reduced PD became borderline significant (p = .051) but persisted for IL-1ß (p = .018). PD at 3-4 years and 2-4 months post-SRP was similar. There was a positive correlation between PD and salivary IL-1ß (p = .005) but not with salivary CRP and IL-6. CONCLUSION: Higher flavonoid intake is associated with lower IL-1ß. Also, regular supportive periodontal therapy maintained the improved PD at 3-4 years post-SRP regardless of smoking status.

Factors adversely influencing neurodevelopment.

Neurodevelopment has been studied extensively, especially in respect to abuse, anoxia, nutritional status and prematurity/low birth weight. However, less attention has been paid to innate and environmental factors, as well as to inflammatory conditions that may adversely affect neurodevelopment and learning in children. These include heavy metals, herbicides and polyvinyl chlorides (PVCs), mycotoxins, viral infections and Lyme disease-associated pathogens, as well as number of conditions such as chronic inflammatory response syndrome (CIRS) and Mast cell activation syndrome (MCAS). Early recognition of factors/conditions that could interfere with neurodevelopment is critical. Corrective actions, including the use of some unique natural flavonoids, could have lasting beneficial results.

Magnetic chrysin silica nanomaterials behavior in an amyloidogenic environment.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with brain damage induced by ß-amyloid and tau accumulation. One of the hallmarks of amyloidogenesis, is the aggregation of amyloid proteins into a specific cross-ß sheet structure, which alters their biological activity thereby affecting neuronal connectivity and function. Despite significant progress in the management of AD over the recent years, the early diagnostic and treatment options still remain limited. Recently, great attention has been focused on the advancement of therapeutic strategies exploiting the antioxidant properties of naturally occurring compounds. Flavonoids, a major class of phytochemicals, have been found to possess a multiple range of health promoting effects, including neuroprotection. Chrysin (ChR) is a flavonoid of the flavone class with potent neuroprotective and anti-inflammatory activity. In addition, ChR improves cognitive decline by exerting anti-amyloidogenic and neurotrophic effects. Magnetic nanoparticles allow binding of drugs by entrapment on the particles, adsorption, or covalent attachment. In our study, well characterized ChR-loaded magnetic PEGylated silica nanospheres (MChRPNPs) were employed with potential enhanced protective characteristics against amyloid induced oxidative stress. The interactions of MChRPNPs with ß-amyloid were demonstrated in rat hippocampal cell cultures. Overall, the findings regarding the biological activity profile of MChRPNPs in a cellular amyloidogenic environment suggest an improved specificity of antioxidant properties counteracting amyloid mediated oxidative stress reactivity.

Development and characterization of morin hydrate-loaded micellar nanocarriers for the effective management of Alzheimer's disease.

The aim of this study was to prepare and characterise oral delivery of morin hydrate-loaded micellar nanocarriers using Pluronic P127 and Pluronic F123 for the effective management of Alzheimer's disease. After administration of formulation brain and blood drug concentration were found to be highest for optimised morin hydrate-loaded micellar nanocarriers as compared to plain morin hydrate. Significant (p < 0.05) reduction in assessed pharmacodynamic parameters was observed after administration of morin hydrate-loaded micellar nanocarriers as compared to disease control group. Chronic treatment with morin-loaded micelles significantly increased the memory in AlCl3 induced Alzheimer's disease in Wistar rats.

Myricetin Prevents Alveolar Bone Loss in an Experimental Ovariectomized Mouse Model of Periodontitis.

Periodontitis is a common chronic inflammatory disease, which leads to alveolar bone resorption. Healthy and functional alveolar bone, which can support the teeth and enable their movement, is very important for orthodontic treatment. Myricetin inhibited osteoclastogenesis by suppressing the expression of some genes, signaling pathways, and cytokines. This study aimed to investigate the effects of myricetin on alveolar bone loss in an ovariectomized (OVX) mouse model of periodontitis as well as in vitro osteoclast formation and bone resorption. Twenty-four healthy eight-week-old C57BL/J6 female mice were assigned randomly to four groups: phosphate-buffered saline (PBS) control (sham) OVX + ligature + PBS (vehicle), and OVX + ligature + low or high (2 or 5 mg∙kg(-1)∙day(-1), respectively) doses of myricetin. Myricetin or PBS was injected intraperitoneally (i.p.) every other day for 30 days. The maxillae were collected and subjected to further examination, including micro-computed tomography (micro-CT), hematoxylin and eosin (H&E) staining, and tartrate-resistant acid phosphatase (TRAP) staining; a resorption pit assay was also performed in vitro to evaluate the effects of myricetin on receptor activator of nuclear factor κ-B ligand (RANKL)-induced osteoclastogenesis. Myricetin, at both high and low doses, prevented alveolar bone resorption and increased alveolar crest height in the mouse model and inhibited osteoclast formation and bone resorption in vitro. However, myricetin was more effective at high dose than at low dose. Our study demonstrated that myricetin had a positive effect on alveolar bone resorption in an OVX mouse model of periodontitis and, therefore, may be a potential agent for the treatment of periodontitis and osteoporosis.

Evaluation of the in vitro trypanocidal activity of methylated flavonoid constituents of Vitex simplicifolia leaves.

BACKGROUND: Trypanosomiasis is a neglected tropical disease with complex clinical manifestations, tedious diagnosis, and difficult treatments. The drugs available for the treatment of this endemic disease are old, expensive, and associated with other problems including safety and drug resistant parasites. Therefore, there is an urgent need for the development of new, effective, cheap, and safe drugs for its treatment. Plants are potentially rich sources of leads for new drugs against trypanosomiasis. Vitex simplicifolia (Verbenaceae) is used traditionally for the treatment of tooth ache, edema, skin diseases, gout and trypanosomiasis in Nigeria. In a preliminary study, the methanol extract of Vitex simplicifolia was shown to exhibit a pronounced trypanocidal activity against T. b. rhodesiense. The present study was undertaken to investigate the active component responsible for the acclaimed activity of the leaves of Vitex simplicifolia in the traditional treatment of trypanosomiasis in Nigeria and other African countries. Our investigations aim at assessing the plant as a new source of potential trypanocidal compounds. METHODS: The crude extracts were prepared from the dried leaves using methanol, successive extraction with hexane, dichloromethane, ethylacetate and butanol was also done. The ethylacetate fraction was further fractionated and compounds isolated using preparative chromatographic technique and their structures were elucidated by NMR, mass spectrometry and comparison with literature data. Trypanocidal activities and cytotoxicity, using rat skeletal myoblast (L6) cells were investigated and their selectivity indices were determined. RESULTS: The chromatographic separations of the methanol extracts gave rise to seven compounds. The isolated compounds 2, 3, 6 and 7 exhibited promising trypanocidal activity with IC50 values ranging from 4.7-12.3 µg/ml and cytotoxicity in the range of 1.58- 46.20 µg/ml. Compound 6, however, showed the most selective trypanocidal activity with a selectivity index of 9.8. This is the first report of trypanocidal activity of flavonoids from this plant genus. CONCLUSIONS: The isolated compounds from Vitex simplicifolia exhibited noteworthy trypanocidal activities and hence may provide a source of new antitrypanosomal agents. These results also support the traditional use of Vitex simplicifolia in the treatment of trypanosomiasis. This is the first report of trypanocidal effect of flavonoids from this plant genus.

Biological activities and possible dental application of three major groups of polyphenols.

The present article reviewed the biological activities and possible dental application of three major polyphenols, i.e., lignin-carbohydrate complexes, tannins, and flavonoids, citing mostly our in vitro studies together with those from other groups. All these polyphenols showed much lower tumor-selective cytotoxicity against oral squamous cell carcinoma cells vs. normal oral cells (gingival fibroblast, pulp cell, periodontal ligament fibroblast), in comparison to popular chemotherapeutic antitumor drugs. Several compounds showing higher tumor-selectivity did not induce internucleosomal DNA fragmentation, a biochemical hallmark of apoptosis, in oral carcinoma cell lines. Lignin-carbohydrate complex protected the cells from the cytopathic effects of HIV infection and UV irradiation more efficiently than other polyphenols. Limited digestion of lignin-carbohydrate complex suggests that the lignin moiety is involved in the prominent anti-HIV activity, whereas the carbohydrate moiety may function in immunopotentiating activity through a cell surface receptor. Alkaline extract of plant leaf, which contains higher amounts of lignin-carbohydrate complex, showed potent anti-inflammatory action against IL-1ß-stimulated human gingival fibroblasts. Local application of lignin-carbohydrate complex through oral mucosa is recommended, considering its poor intestinal absorption.

Bilirubin/morin self-assembled nanoparticle-engulfed collagen/polyvinyl alcohol hydrogel accelerates chronic diabetic wound healing by modulating inflammation and ameliorating oxidative stress.

Chronic diabetic wounds pose a serious threat to human health and safety because of their refractory nature and high recurrence rates. The formation of refractory wounds is associated with wound microenvironmental factors such as increased expression of proinflammatory factors and oxidative stress. Bilirubin is a potent endogenous antioxidant, and morin is a naturally active substance that possesses anti-inflammatory and antioxidant effects. Both hold the potential for diabetic wound treatment by intervening in pathological processes. In this study, we developed bilirubin/morin-based carrier-free nanoparticles (BMn) to treat chronic diabetic wounds. In vitro studies showed that BMn could effectively scavenge overproduced reactive oxygen species and suppress elevated inflammation, thereby exerting a protective effect. BMn was then loaded into a collagen/polyvinyl alcohol gel (BMn@G) for an in vivo study to maintain a moist environment for the skin and convenient biomedical applications. BMn@G exhibits excellent mechanical properties, water retention capabilities, and in vivo safety. In type I diabetic mice, BMn@G elevated the expression of the anti-inflammatory factor IL-10 and concurrently diminished the expression of the proinflammatory factor TNF-α in the tissues surrounding the wounds. Furthermore, BMn@G efficiently mediated macrophage polarization from the M1-type to the M2-type, thereby fostering anti-inflammatory effects. Additionally, BMn@G facilitated the conversion of type III collagen fiber bundles to type I collagen fiber bundles, resulting in a more mature collagen fiber structure. This study provides a promising therapeutic alternative for diabetic wound healing.

Integrated microbiome and metabolomics revealed the protective effect of baicalin on alveolar bone inflammatory resorption in aging.

BACKGROUND: With the growing aging population and longer life expectancy, periodontitis and tooth loss have become major health concerns. The gut microbiota, as a key regulator in bone homeostasis, has gathered immense interest. Baicalin, a flavonoid compound extracted from Scutellaria baicalensis Georgi, has shown antioxidant and anti-inflammatory activities. PURPOSE: This study investigated, for the first time, the protective mechanism of baicalin against alveolar bone inflammatory resorption in aging mice by regulating intestinal flora and metabolites, as well as intestinal barrier function. METHODS: A ligature-induced periodontitis model was established in d-galactose (D-gal)-induced aging mice, and baicalin was administered at different dosages for 13 weeks. Body weight was measured weekly. The antioxidant and anti-inflammatory activity of baicalin were evaluated using serum superoxide dismutase (SOD), malonaldehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels. The immune capability was assessed by thymus and spleen indices. Histopathological changes were observed in the heart, liver, ileum, and periodontal tissues. Alveolar bone absorption of maxillary second molars was examined, and osteoclasts were counted by tartrate-resistant acid phosphatase (TRAP) staining. Furthermore, fecal samples were analyzed using 16S rRNA sequencing and non-targeted metabolomics to identify differences in intestinal bacterial composition and metabolites. RESULTS: Baicalin exhibited anti-aging properties, as evidenced by increased SOD activity and decreased levels of MDA, IL-6, and TNF-α in serum compared to the control group. Baicalin also ameliorated alveolar bone loss in the d-gal-induced aging-periodontitis group (p < 0.05). Furthermore, baicalin restored ileal permeability by up-regulating the expression of ZO-1 and occludin in aging-periodontitis groups (p < 0.05). Alpha diversity analysis indicated that baicalin-treated mice harbored a higher diversity of gut microbe. PCoA and ANOSIM results revealed significant dissimilarity between groups. The Firmicutes/Bacteroidetes (F/B) ratio, which decreased in periodontitis mice, was restored by baicalin treatment. Additionally, medium-dosage baicalin promoted the production of beneficial flavonoids, and enriched short-chain fatty acids (SCFAs)-producing bacteria. CONCLUSION: Intestinal homeostasis is a potential avenue for treating age-related alveolar bone loss. Baicalin exerts anti-inflammatory, antioxidant, and osteo-protective properties by regulating the gut microbiota and metabolites.

Eupatilin suppresses osteoclastogenesis and periodontal bone loss by inhibiting the MAPKs/Siglec-15 pathway.

Periodontitis is a widely prevalent oral disease around the world characterized by the disruption of the periodontal ligament and the subsequent development of periodontal pockets, as well as the loss of alveolar bone, and may eventually lead to tooth loss. This research aims to assess the suppressive impact of Eupatilin, a flavone obtained from Artemisia argyi, on osteoclastogenesis in vitro and periodontitis in vivo. We found that Eupatilin can efficiently obstruct the differentiation of Raw264.7 and bone marrow-derived macrophages (BMDMs) induced by RANKL, leading to the formation of mature osteoclasts. Consistently, bone slice resorption assay showed that Eupatilin significantly inhibited osteoclast-mediated bone resorption in a dose-dependent manner. Eupatilin also downregulated the expression of osteoclast-specific genes and proteins in Raw264.7 and BMDMs. RNA sequencing showed that Eupatilin notably downregulated the expression of Siglec-15. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses identified significantly enriched pathways in DEGs, including MAPK signaling pathway. And further mechanistic investigations confirmed that Eupatilin repressed MAPKs/NF-κBsignaling pathways. It was found that Siglec-15 overexpression reversed the inhibitory impact of Eupatilin on the differentiation of osteoclasts. Furthermore, activating MAPK signaling pathway reversed the downregulation of Siglec-15 and the inhibition of osteoclastogenesis by Eupatilin. To sum up, Eupatilin reduced the expression of Siglec-15 by suppressing MAPK signaling pathway, ultimately leading to the inhibition of osteoclastogenesis. Meanwhile, Eupatilin suppressed the alveolar bone resorption caused by experimentalperiodontitis in vivo. Eupatilin exhibits potential therapeutic effects in the treatment of periodontitis, rendering it a promising pharmaceutical agent.

Flavonol-containing phosphorylated pullulan may attenuate pulp inflammation.

AIM: To find possible reagents to minimize inflammatory responses by using an established pulpitis models for the purpose of developing new pulp-capping materials, and to test the possible use of phosphorylated pullulan as a carrier for such an anti-inflammatory reagent. METHODOLOGY: Co-culturing was performed using transwell systems. Inflammatory responses were evaluated by measuring cytokines produced by the cells. The effects of two flavonoids, luteolin and quercetin, as anti-inflammatory reagents, and phosphorylated pullulan, which potentially achieves a sufficient marginal sealing to hydroxyapatite and slowly releases luteolin, as a carrier for flavonoids, were tested. RESULTS: Flavonols, particularly luteolin, dramatically attenuated inflammatory cytokine production, which was augmented by co-cultures. Luteolin was successfully enclosed by phosphorylated pullulan. Finally, it was confirmed that luteolin released from phosphorylated pullulan was effective in reducing cytokine production by co-cultures. CONCLUSIONS: Combination of phosphorylated pullulan and luteolin could be potentially used in the treatment of dental pulp inflammation.

Chrysin loaded bilosomes improve the hepatoprotective effects of chrysin against CCl4 induced hepatotoxicity in mice.

In the present work, chrysin loaded bilosomes were formulated, characterized and evaluated to enhance the hepatoprotective activity of drug. Accordingly, chrysin loaded bilosomes were prepared by applying the thin film hydration method; also, fractional factorial design was used to optimize the production conditions of nanoformulations. The prepared formulations were subjected to different methods of characterization; then the hepatoprotective activity of the optimized one was evaluated in the CCl4 hepatointoxicated mice model. Optimized chrysin loaded bilosomes showed a spherical shape with a particle size of 232.97 ± 23 nm, the polydispersity index of 0.35 ± 0.01, the zeta potential of -44.5 ± 1.27 mv, the entrapment efficiency of 96.77 ± 0.18%, the drug loading % of 6.46 ± 0.01 and the release efficiency of 42.25 ± 1.04 during 48 h. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical-scavenging assay demonstrated the superiority of the anti-oxidant potential of chrysin loaded bilosomes, as compared to pure chrysin. This was in agreement with histopathological investigations, showing significant improvement in serum hepatic biomarkers of CCl4 intoxicated mice treated with chrysin loaded bilosomes, as compared with free chrysin. These results, thus, showed the potential use of bilosomes to enhance the hepatoprotective activity of chrysin via oral administration.

Skin regeneration after chemical burn under the effect of taxifolin-based preparations.

We studied the effect of liposome preparation containing taxifolin oligomers and taxifolin conjugates with carbonyl compounds on skin regeneration after chemical burn. The preparations containing flavonoid conjugates intensified regeneration processes and reparation of hair follicles and sebaceous glands after chemical burn. The preparation based on taxifolin conjugate with acetaldehyde was most effective; its activity was comparable with that of the wound-healing preparation Olasol. Taxifolin conjugates with carbonyl compounds can be used for the creation of combined wound- and burn-healing preparations.

Molecular insights and therapeutic implications of nanoengineered dietary polyphenols for targeting lung cancer: part II.

Flavonoids represent a major group of polyphenolic compounds. Their capacity to inhibit tumor proliferation, cell cycle, angiogenesis, migration and invasion is substantially responsible for their chemotherapeutic activity against lung cancer. However, their clinical application is limited due to poor aqueous solubility, low permeability and quick blood clearance, which leads to their low bioavailability. Nanoengineered systems such as liposomes, nanoparticles, micelles, dendrimers and nanotubes can considerably enhance the targeted action of the flavonoids with improved efficacy and pharmacokinetic properties, and flavonoids can be successfully translated from bench to bedside through various nanoengineering approaches. This review addresses the therapeutic potential of various flavonoids and highlights the cutting-edge progress in the nanoengineered systems that incorporate flavonoids for treating lung cancer.

A State-of-the-art Review and Prospective Therapeutic Applications of Prenyl Flavonoids as Chemosensitizers against Antifungal Multidrug Resistance in Candida albicans.

Multidrug resistance (MDR) in the opportunistic pathogen Candida albicans is defined as non-susceptibility to at least one agent in two or more drug classes. This phenomenon has been increasingly reported since the rise in the incidence of fungal infections in immunocompromised patients at the end of the last century. After the discovery of efflux pump overexpression as a principal mechanism causing MDR in Candida strains, drug discovery targeting fungal efflux transporters has had a growing impact. Chemosensitization aims to enhance azole intracellular concentrations through combination therapy with transporter inhibitors. Consequently, the use of drug efflux inhibitors combined with the antifungal agent will sensitize the pathogen. As a result, the use of lower drug concentrations will reduce possible adverse effects on the host. Through an extensive revision of the literature, this review aims to provide an exhaustive and critical analysis of the studies carried out in the past two decades regarding the chemosensitization strategy to cope with multidrug resistance in C. albicans. This work provides a deep analysis of the research on the inhibition of drug-efflux membrane transporters by prenylated flavonoids and the interactions of these phytocompounds with azole antifungals as an approach to chemosensitize multidrug-resistant C. albicans strains. We highlight the importance of prenylflavonoids and their particular chemical and pharmacological characteristics that make them excellent candidates with therapeutic potential as chemosensitizers. Finally, we propose the need for further research on prenyl flavonoids as inhibitors of drug-efflux mediated fungal resistance.

Baicalin clears inflammation by enhancing macrophage efferocytosis via inhibition of RhoA/ROCK signaling pathway and regulating macrophage polarization.

Effective efferocytosis of apoptotic polymorphonuclear leukocytes (PMNs) in the initiation and resolution of inflammation iscrucial for preventing progression to chronicinflammatorydisease. Baicalin, a bioactive flavonoid drug, exerts multiple anti-inflammatory effects; however, its underlying mechanism remains to be elucidated. Here, we investigated the role of baicalin in efferocytosis in vitro and in a Porphyromonas gingivalis lipopolysaccharide (LPS)-inducedmurinemodelofpleurisy. We found that the macrophage engulfment of apoptotic PMNs was significantly promoted by baicalin in an inflammatory environment with an effectiveness similar to that of N-acetylcysteine. Meanwhile, the production of reactive oxygen species was significantly blocked in P. gingivalis LPS-stimulated J774A.1 macrophages by baicalin, and the RhoA/ROCK signaling pathway was inhibited in the same way as the ROCK inhibitor, Y-27632. In addition, the M1/M2macrophage ratio and the proinflammatory cytokine TNF-α were downregulated, whereas the anti-inflammatory cytokine IL-10 was upregulated both in vitro and in vivo. Therefore, we propose that baicalin may increase efferocytosis by acting as an antioxidant via a RhoA-dependent pathway and regulate macrophage polarization, thus promoting inflammatory resolution.