Lipid-Based Nanoparticulate Systems for the Ocular Delivery of Bioactives with Anti-Inflammatory Properties

The complexity of the eye structure and its physiology turned ocular drug administration into one of the most challenging topics in the pharmaceutical field. Ocular inflammation is one of the most common ophthalmic disorders. Topical administration of anti-inflammatory drugs is also commonly used as a side treatment in tissue repair and regeneration. The difficulty in overcoming the eye barriers, which are both physical and chemical, reduces drug bioavailability, and the frequency of administration must be increased to reach the therapeutic effect. However, this can cause serious side effects. Lipid nanoparticles seem to be a great alternative to ocular drug delivery as they are composed from natural excipients and can encapsulate both hydrophilic and lipophilic drugs of different sources, and their unique properties, as their excellent biocompatibility, safety and adhesion allow to increase the bioavailability, compliance and achieve a sustained drug release. They are also very stable, easy to produce and scale up, and can be lyophilized or sterilized with no significant alterations to the release profile and stability. Because of this, lipid nanoparticles show a great potential to be an essential part of the new therapeutic technologies in ophthalmology to deliver synthetic and natural anti-inflammatory drugs. In fact, there is an increasing interest in natural bioactives with anti-inflammatory activities, and the use of nanoparticles for their site-specific delivery. It is therefore expected that, in the near future, many more studies will promote the development of new nanomedicines resulting in clinical studies of new drugs formulations.     

Potential Anti-Inflammatory and Chondroprotective Effect of Luzula sylvatica

(1) Interest in the Juncaceae family has risen as some members have shown anti-inflammatory properties and interesting compounds. In this regard, we decided to investigate the antioxidant and anti-inflammatory properties of Luzula sylvatica, a Juncaceae not yet extensively studied, in the context of osteoarthritis. (2) The Luzula sylvatica Ethanol extract (LS-E) was used to test the production of reactive oxygen species (ROS) by leucocytes, the IL1β and PGE2 production by peripheral blood mononuclear cells (PBMCs), the production of EP4, and the activation of NFκB in THP-1, as well as the IL1β-activated normal human knee articular chondrocytes (NHAC-Kn) gene expression, grown in monolayers or maintained in alginate beads. (3) Organic acids, caffeoylquinic acids, quercetin and luteolin, compounds frequently found in this family were identified. The LS-E exhibited inhibited ROS formation. The LS-E did not affect NFκB activation and IL1β secretion but dampened the secretion of PGE2 by PBMCs and the presence of EP4 in THP-1. It also modulated the expression of NHAC-Kn in both models and inhibited the expression of several proteases and inflammatory mediators. (4) Luzula sylvatica might supply interesting antioxidant protection against cartilage damages and lessen joint inflammation, notably by decreasing PGE2 secretion in the synovial fluid. Moreover, it could act directly on chondrocytes by decreasing the expression of proteases and, thus, preventing the degradation of the extracellular matrix.     

柚类黄酮抗氧化作用的研究

对柚子不同部位进行类黄酮的提取,同时对柚子类黄酮提取液的抗氧化活性进行了研究。结果表明：柚果皮中类黄酮的含量较柚果肉中类黄酮的含量要高。柚类黄酮提取液具有明显的清除羟自由基和超氧阴离子自由基作用,清除率与浓度之间存在着量效关系。柚类黄酮抗氧自由基的能力强于VC,证明了柚类黄酮是一种很强的抗氧化剂。     

Role of Renin-Angiotensin-Aldosterone System and Cortisol in Endometriosis: A Preliminary Report

Endometriosis is a chronic inflammatory disease associated with pelvic pain, infertility, and increased cardiovascular risk. Recent studies suggest a possible role of aldosterone as a pro-inflammatory hormone in the pathogenesis of the disease. Cortisol is also an important mediator of stress reaction, but its role is controversial in endometriosis. The aim of this study was to evaluate aldosterone and cortisol levels and blood pressure values in women with endometriosis. We measured blood pressure, plasma aldosterone, renin, cortisol, and dehydroepiandrosterone sulfate (DHEAS) in 20 women with untreated minimal or mild pelvic endometriosis compared with 20 healthy controls matched for age and body mass index. Aldosterone values were similar in the two groups, while renin was significantly lower and the aldosterone to renin ratio was significantly higher in patients with endometriosis than in controls. Systolic blood pressure was in the normal range, but significantly higher in patients with endometriosis. Morning plasma cortisol was normal, but significantly lower in patients with endometriosis compared with controls, while DHEAS to cortisol ratio was similar in the two groups. These preliminary results are evidence of increased biological aldosterone activity and dysregulation of the hypothalamic-pituitary-adrenal axis in early stages of endometriosis. These alterations could play a role in disease development, suggesting new therapeutic targets for aldosterone receptor blockers.     

Anti-Inflammatory Activity of Mulberry Leaf Flavonoids In Vitro and In Vivo

Mulberry (Morus alba L.) is a flowering tree traditionally used in Chinese herbal medicine. Mulberry leaf flavonoids (MLFs) have been reported to exert important anti-inflammatory and antioxidant properties. The purpose of this study was to select the MLF with the best anti-inflammatory and antioxidative activities from MLFs eluted by different ethanol concentrations (30%, 50%, and 75%) and explore its pharmacological properties. Three types of MLFs inhibited the production of nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and inflammatory cytokines in lipopolysaccharide (LPS)-induced RAW 264.7 cells. All MLFs boosted the antioxidative capacity by decreasing the reactive oxygen species (ROS) production and the scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals and improving the metal ion chelating activity and reducing power. The results revealed that the MLFs eluted by 30% ethanol exhibited the best anti-inflammatory and antioxidative activities. A nontargeted metabolomic analysis was used to analyze 24 types of differential flavonoids between the MLFs. Quercetin, kaempferol, and their derivatives in 30%MLF were more abundant than the other two MLFs. Furthermore, we evaluated the pharmacological activities of 30%MLF in dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) mice. The 30%MLF could alleviate the clinical symptoms, reduce the secretion of inflammatory cytokines, and inhibit the activation of the inflammatory pathway in DSS-induced colitis mice. This study will provide valuable information for the development of MLFs eluted by 30% ethanol as a functional food.     

葛根内生菌的分离及其发酵产物抗氧化活性的初步研究

从健康葛根植株的根、茎、叶中分离到11株内生菌,通过聚酰胺薄层层析检测到其中有两株内生菌（S1和S2）的乙醇提取液分别有2条和1条层析带与葛根乙醇提取物的层析带比移值相当,并以总还原力等体外抗氧化模型分别测定了内生菌S1和S2乙醇提取液的抗氧化性,得出结果：内生菌S1的抗氧化性较S2强。     

Anti-Eryptotic Activity of Food-Derived Phytochemicals and Natural Compounds

Human red blood cells (RBCs), senescent or damaged due to particular stress, can be removed by programmed suicidal death, a process called eryptosis. There are various molecular mechanisms underlying eryptosis. The most frequent is the increase in the cytoplasmic concentration of Ca²⁺ ions, later exposure of erythrocytes to oxidative stress, hyperosmotic shock, ceramide formation, stimulation of caspases, and energy depletion. Phosphatidylserine (PS) exposed by eryptotic RBCs due to interaction with endothelial CXC-Motiv-Chemokin-16/Scavenger-receptor, causes the RBCs to adhere to vascular wall with consequent damage to the microcirculation. Eryptosis can be triggered by various xenobiotics and endogenous molecules, such as high cholesterol levels. The possible diseases associated with eryptosis are various, including anemia, chronic kidney disease, liver failure, diabetes, hypertension, heart failure, thrombosis, obesity, metabolic syndrome, arthritis, and lupus. This review addresses and collates the existing ex vivo and animal studies on the inhibition of eryptosis by food-derived phytochemicals and natural compounds including phenolic compounds (PC), alkaloids, and other substances that could be a therapeutic and/or co-adjuvant option in eryptotic-driven disorders, especially if they are introduced through the diet.     

Benzoylpaeoniflorin Activates Anti-Inflammatory Mechanisms to Mitigate Sepsis in Cell-Culture and Mouse Sepsis Models

Xuebijing injection (XBJI) (comprising of five herbs) is a widely used traditional Chinese medicine for sepsis treatment. However, the bioactive components of XBJI and the mechanisms responsible for its sepsis-mitigating action have not been experimentally determined. One of the main bioactive compounds in XBJI—benzoylpaeoniflorin (BPF)—inhibits the expressions of key mediators of inflammation such as nuclear factor kappa B (NF-κB), cyclooxygenase-1 (COX-1), and COX-2. However, its effects on sepsis have not been determined yet. Therefore, here, we investigated the immunomodulatory effect of BPF on severely inflamed endothelial cells, THP-1 macrophages, peritoneal macrophages, and mice. Human umbilical vein endothelial cells (HUVECs) and THP-1-macrophages were activated using lipopolysaccharide (LPS) after pretreatment with BPF. Subsequently, changes in the expression profiles of pro-inflammatory molecules including inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were determined using quantitative real-time polymerase chain reaction (qPCR) and Western blot analysis. Furthermore, we monitored the phosphorylation of NF-kB and mitogen-activated protein kinases (MAPKs) to determine their activation levels. Using the LPS-induced mouse model of sepsis, we studied the effects of BPF on inflammatory cytokine production, pulmonary histopathology, and survival rates. Finally, we evaluated whether BPF protects against cecal ligation and puncture (CLP)-induced sepsis, as it closely mimics human sepsis. BPF pretreatment inhibited LPS-induced increase in mRNA and protein levels of iNOS, TNF-α, and IL-6 in HUVECs and THP-1-macrophages. It also suppressed LPS-mediated phosphorylation of p65, p38, JNK, and ERK. Mice with LPS-induced-sepsis who were treated with BPF had lower serum levels of IL-6, TNF-α, IL-1β, CXCL1, and CXCL2 than the control mice treated with BPF. Histopathology revealed that BPF treatment alleviated LPS-induced lung damage. In addition, in mice given a lethal dose of LPS, BPF treatment showed a dose-dependent improvement in survival rates. BPF treatment dose-dependently inhibited the LPS-induced IL-6, TNF-α, and CXCL1 production in peritoneal macrophages. BPF treatment also dose-dependently improved the survival rates in mice with CLP-induced sepsis. These results show that BPF alleviates LPS-stimulated septic conditions and protects mice from CLP-induced sepsis. Our research marks BPF as a potential drug in the treatment of sepsis and various inflammatory diseases.     

Anti-Inflammatory Mechanisms of Dietary Flavones: Tapping into Nature to Control Chronic Inflammation in Obesity and Cancer

Flavones are natural phytochemicals broadly distributed in our diet. Their anti-inflammatory properties provide unique opportunities to control the innate immune system and inflammation. Here, we review the role of flavones in chronic inflammation with an emphasis on their impact on the molecular mechanisms underlying inflammatory diseases including obesity and cancer. Flavones can influence the innate immune cell repertoire restoring the immune landscape. Flavones impinge on NF-κB, STAT, COX-2, or NLRP3 inflammasome pathways reestablishing immune homeostasis. Devoid of adverse side effects, flavones could present alternative opportunities for the treatment and prevention of chronic inflammation that contributes to obesity and cancer.     

叶下花黄酮抗氧化活性研究

采用3种体外模型,通过与Vc和芦丁进行比较,研究了叶下花黄酮成分的抗氧化活性。结果表明,叶下花黄酮具有较强的还原力和抗氧化活性,二者的变化关系具有一致性,并呈现很好的量效关系;羟基自由基清除率最高可达82.58%。三者比较,还原力和抗氧化活性顺序均为抗坏血酸≈叶下花黄酮>芦丁;三者的SC50分别为39.17、66.50、91.06 mg/L。为从叶下花黄酮中分离提取具有较高活性的新型天然抗氧化剂奠定基础。     

Plasma Concentration of Cortisol Negatively Associates with Platelet Reactivity in Older Subjects

The interaction of platelets with steroid hormones is poorly investigated. Age is one of the factors that increase the risk of pathological platelet reactivity and thrombosis. The aim of this study was to assess whether there were associations between platelet reactivity and plasma cortisol levels in volunteers aged 60–65 years. For this purpose, impedance aggregometry in whole blood measured after arachidonic acid, collagen, or ADP stimulation was used to estimate platelet reactivity and mass spectrometry was used to measure peripheral plasma cortisol concentration. Statistically significant negative correlations were observed between cortisol concentration and platelet reactivity in response to arachidonic acid and ADP, but not to collagen. The presented results suggest for the very first time that cortisol is a new endogenous modulator of platelet reactivity in the elderly population.     

Senescence-Independent Anti-Inflammatory Activity of the Senolytic Drugs Dasatinib,Navitoclax, and Venetoclax in Zebrafish Models of Chronic Inflammation

Telomere shortening is the main molecular mechanism of aging, but not the only one. The adaptive immune system also ages, and older organisms tend to develop a chronic pro-inflammatory status with low-grade inflammation characterized by chronic activation of the innate immune system, called inflammaging. One of the main stimuli that fuels inflammaging is a high nutrient intake, triggering a metabolic inflammation process called metainflammation. In this study, we report the anti-inflammatory activity of several senolytic drugs in the context of chronic inflammation, by using two different zebrafish models: (i) a chronic skin inflammation model with a hypomorphic mutation in spint1a, the gene encoding the serine protease inhibitor, kunitz-type, 1a (also known as hai1a) and (ii) a non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) model with inflammation induced by a high-fat diet. Our results show that, although these models do not manifest premature aging, the senolytic drugs dasatinib, navitoclax, and venetoclax have an anti-inflammatory effect that results in the amelioration of chronic inflammation.     

饿蚂蝗中黄酮类化合物的抗氧化活性的研究

提取了饿蚂蝗中的黄酮化合物,并研究了其含量及与体外抗氧化活性关系。用体积分数为75%的乙醇提取饿蚂蝗全草黄酮化合物,并采用HPD-100大孔树脂对粗提液进行精制,利用NaNO2-Al（ NO3）3-NaOH显色法和可见分光光度法测定精制黄酮的含量。采用DPPH和ABTS自由基测定法,对饿蚂蝗黄酮化合物的抗氧化活性进行评价。结果表明：在自由基清除实验中,精制饿蚂蝗黄酮类化合物自由基清除能力高于未精制的乙醇提取物。饿蚂蝗黄酮类化合物的体外抗氧化活性与黄酮含量呈正相关性。     

猕猴桃根总黄酮的超声提取及抗氧化活性研究

以湘西“米良猕猴桃”根为原料,采用超声波辅助乙醇提取总黄酮, 通过单因素及正交实验优化提取工艺条件,考察总黄酮对羟基自由基清除效果及对油脂氧化的抑制作用,并与常用抗氧化剂作比较。结果表明,以60%乙醇按照料液比1∶30 (g∶mL) 在60 ℃水浴中超声提取40 min后,猕猴桃根中总黄酮得率为1.5%。该提取物对羟基自由基清除效果随浓度的增大而升高,对食用油脂的氧化有很好的抑制作用。     

响应面法优化闪式提取罗汉松总黄酮及抗氧化活性研究

本研究对罗汉松总黄酮提取工艺及其抗氧化活性进行了研究,采用闪式提取法提取罗汉松总黄酮,并通过单因素法和响应面优化方法,同时考察了罗汉松总黄酮对DPPH•、O2-•和•OH自由基清除作用。结果表明,闪式提取罗汉松总黄酮最佳工艺条件为：乙醇浓度71 %、料液比1:36 (g·mL-1)、提取时间53 s、提取电压为75 V时,罗汉松总黄酮提取率为8.147 %。罗汉松总黄酮对DPPH•、O2-•和•OH具有明显的清除能力,最大清除率分别达到87.13%、58.24%和67.56%,为罗汉松的综合开发利用提供了参考。     

Antioxidant Activity and Healthy Benefits of Natural Pigments in Fruits: A Review

Natural pigments, including carotenoids, flavonoids and anthocyanidins, determine the attractive color of fruits. These natural pigments are essential secondary metabolites, which play multiple roles in the whole life cycle of plants and are characterized by powerful antioxidant activity. After decades of research and development, multiple benefits of these natural pigments to human health have been explored and recognized and have shown bright application prospects in food, medicine, cosmetics and other industries. In this paper, the research progress of natural fruit pigments in recent years was reviewed, including the structural characteristics and classification, distribution in fruits and analysis methods, biosynthetic process, antioxidant capacity and mechanism, bioaccessibility and bioavailability, and health benefits. Overall, this paper summarizes the recent advances in antioxidant activity and other biological functions of natural fruit pigments, which aims to provide guidance for future research.     

TGF-β Signalling Mediates the Anti-Inflammatory Activity of Enamel Matrix Derivative In Vitro

Enamel matrix derivative (EMD) prepared from extracted porcine fetal tooth material can support the regrow of periodontal tissues. Previous findings suggest that EMD has anti-inflammatory properties and TGF-β activity in vitro. However, the anti-inflammatory activity of EMD is mediated via TGF-β has not been considered. To this aim, we first established a bioassay to confirm the anti-inflammatory activity of EMD. The bioassay was based on the RAW 264.7 macrophage cell line and proven with primary macrophages where EMD significantly reduced the forced expression of IL-6. We then confirmed the presence of TGF-β1 in EMD by immunoassay and by provoking the Smad2/3 nuclear translocation in RAW 264.7 macrophages. Next, we took advantage of the TGF-β receptor type I kinase-inhibitor SB431542 to block the respective signalling pathway. SB431542 reversed the anti-inflammatory activity of EMD and TGF-β in a bioassay when IL-6 and CXCL2 expression was driven by the LPS stimulation of RAW 264.7 macrophages. This central observation was supported by showing that SB431542 reversed the anti-inflammatory activity of EMD using IL-1β and TNF-α-stimulated ST2 bone marrow stromal cells. Together, these findings implicate that the TGF-β activity mediates at least part of the anti-inflammatory activity of EMD in vitro.     

Anti-Inflammatory Effect of Allicin Associated with Fibrosis in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling. Recent evidence supports that inflammation plays a key role in triggering and maintaining pulmonary vascular remodeling. Recent studies have shown that garlic extract has protective effects in PAH, but the precise role of allicin, a compound derived from garlic, is unknown. Thus, we used allicin to evaluate its effects on inflammation and fibrosis in PAH. Male Wistar rats were divided into three groups: control (CON), monocrotaline (60 mg/kg) (MCT), and MCT plus allicin (16 mg/kg/oral gavage) (MCT + A). Right ventricle (RV) hypertrophy and pulmonary arterial medial wall thickness were determined. IL-1β, IL-6, TNF-α, NFκB p65, Iκβ, TGF-β, and α-SMA were determined by Western blot analysis. In addition, TNF-α and TGF-β were determined by immunohistochemistry, and miR-21-5p and mRNA expressions of Cd68, Bmpr2, and Smad5 were determined by RT-qPCR. Results: Allicin prevented increases in vessel wall thickness due to TNF-α, IL-6, IL-1β, and Cd68 in the lung. In addition, TGF-β, α-SMA, and fibrosis were lower in the MCT + A group compared with the MCT group. In the RV, allicin prevented increases in TNF-α, IL-6, and TGF-β. These observations suggest that, through the modulation of proinflammatory and profibrotic markers in the lung and heart, allicin delays the progression of PAH.