Apigenin (4′,5,7-trihydroxyflavone, flavonoid) is a phenolic compound that is known to reduce the risk of chronic disease owing to its low toxicity. The first study on apigenin analyzed its effect on histamine release in the 1950s. Since then, anti-mutation and antitumor properties of apigenin have been widely reported. In the present study, we evaluated the apigenin-mediated amelioration of skin disease and investigated its applicability as a functional ingredient, especially in cosmetics. The effect of apigenin on RAW264.7 (murine macrophage), RBL-2H3 (rat basophilic leukemia), and HaCaT (human immortalized keratinocyte) cells were analyzed. Apigenin (100 μM) significantly inhibited nitric oxide (NO) production, cytokine expression (interleukin (IL)-1β, IL6, cyclooxygenase (COX)-2, and inducible nitric oxide synthase [iNOS]), and phosphorylation of mitogen-activated protein kinase (MAPK) signal molecules, including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal protein kinase (JNK) in RAW264.7 cells. Apigenin (30 μM) also inhibited the phosphorylation of signaling molecules (Lyn, Syk, phospholipase Cγ1, ERK, and JNK) and the expression of high-affinity IgE receptor FcεRIα and cytokines (tumor necrosis factor (TNF)-α, IL-4, IL-5, IL-6, IL-13, and COX-2) that are known to induce inflammation and allergic responses in RBL-2H3 cells. Further, apigenin (20 μM) significantly induced the expression of filaggrin, loricrin, aquaporin-3, hyaluronic acid, hyaluronic acid synthase (HAS)-1, HAS-2, and HAS-3 in HaCaT cells that are the main components of the physical barrier of the skin. Moreover, it promoted the expression of human β-defensin (HBD)-1, HBD-2, HBD-3, and cathelicidin (LL-37) in HaCaT cells. These antimicrobial peptides are known to play an important role in the skin as chemical barriers. Apigenin significantly suppressed the inflammatory and allergic responses of RAW264.7 and RBL cells, respectively, and would, therefore, serve as a potential prophylactic and therapeutic agent for immune-related diseases. Apigenin could also be used to improve the functions of the physical and chemical skin barriers and to alleviate psoriasis, acne, and atopic dermatitis. Full article

Ultraviolet radiation (UV) is a major causative factor of DNA damage, inflammatory responses, reactive oxygen species (ROS) generation and a turnover of various cutaneous lesions resulting in skin photoaging. The purpose of this study is to investigate the protective effect of protocatechuic aldehyde (PA), which is a nature-derived compound, against UVA-induced photoaging by using human dermal fibroblast (HDF) cells. In this study, our results indicated that PA significantly reduced the levels of intracellular ROS, nitric oxide (NO), and prostaglandins-E₂ (PGE₂) in UVA-irradiated HDF cells. It also inhibited the levels of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression. Besides, PA significantly suppressed the expression of matrix metalloproteinases-1 (MMP-1) and pro-inflammatory cytokines and promoted collagen synthesis in the UVA-irradiated HDF cells. These events occurred through the regulation of activator protein 1 (AP-1), nuclear factor-κB (NF-κB), and p38 signaling pathways in UVA-irradiated HDF cells. Our findings suggest that PA enhances the protective effect of UVA-irradiated photoaging, which is associated with ROS scavenging, anti-wrinkle, and anti-inflammatory activities. Therefore, PA can be a potential candidate for the provision of a protective effect against UVA-stimulated photoaging in the pharmaceutical and cosmeceutical industries. Full article

Privileged structures have been widely used as an effective template for the research and discovery of high value chemicals. Coumarin is a simple scaffold widespread in Nature and it can be found in a considerable number of plants as well as in some fungi and bacteria. In the last years, these natural compounds have been gaining an increasing attention from the scientific community for their wide range of biological activities, mainly due to their ability to interact with diverse enzymes and receptors in living organisms. In addition, coumarin nucleus has proved to be easily synthetized and decorated, giving the possibility of designing new coumarin-based compounds and investigating their potential in the treatment of various diseases. The versatility of coumarin scaffold finds applications not only in medicinal chemistry but also in the agrochemical field as well as in the cosmetic and fragrances industry. This review is intended to be a critical overview on coumarins, comprehensive of natural sources, metabolites, biological evaluations and synthetic approaches. Full article

Metal-coordination polymeric gels are interesting areas as organic/inorganic hybrid supramolecular materials. The bispicolylamine (BPA) based gelator (1) showed excellent gelation with typical fibrillar morphology in acetonitrile. Upon complexing 1 with Zn²⁺, complexes ([1 + Zn + ACN]²⁺ and [1 + zinc trifluoromethanesulfonate (ZnOTf)]⁺) with four coordination numbers were formed, which determine the gel structure significantly. A gel-sol transition was induced, driven by the ratio of the two metal complexes produced. Through nuclear magnetic resonance analysis, the driving forces in the gel formation (i.e., hydrogen-bonding and π–π stacking) were observed in detail. In the absence and the presence of Zn²⁺, the intermolecular hydrogen-bonds and π–π stacking were the primary driving forces in the gel formation, respectively. In addition, the supramolecular gels exhibited a monolayer lamellar structure irrespective of Zn²⁺. Conclusively, the gels’ elasticity and viscosity reduced in the presence of Zn²⁺. Full article

Fibrinogen is a hexameric plasmatic glycoprotein composed of pairs of three chains (Aα, Bβ, and γ), which play an essential role in hemostasis. Conversion of fibrinogen to insoluble polymer fibrin gives structural stability, strength, and adhesive surfaces for growing blood clots. Equally important, the exposure of its non-substrate thrombin-binding sites after fibrin clot formation promotes antithrombotic properties. Fibrinogen and fibrin have a major role in multiple biological processes in addition to hemostasis and thrombosis, i.e., fibrinolysis (during which the fibrin clot is broken down), matrix physiology (by interacting with factor XIII, plasminogen, vitronectin, and fibronectin), wound healing, inflammation, infection, cell interaction, angiogenesis, tumour growth, and metastasis. Congenital fibrinogen deficiencies are rare bleeding disorders, characterized by extensive genetic heterogeneity in all the three genes: FGA, FGB, and FGG (enconding the Aα, Bβ, and γ chain, respectively). Depending on the type and site of mutations, congenital defects of fibrinogen can result in variable clinical manifestations, which range from asymptomatic conditions to the life-threatening bleeds or even thromboembolic events. In this manuscript, we will briefly review the main pathogenic mechanisms and risk factors leading to thrombosis, and we will specifically focus on molecular mechanisms associated with mutations in the C-terminal end of the beta and gamma chains, which are often responsible for cases of congenital afibrinogenemia and hypofibrinogenemia associated with thrombotic manifestations. Full article

Rice (Oryza sativa L.) is a widely cultivated food crop around the world, especially in Asia. However, rice seedlings often suffer from cold stress, which affects their growth and yield. Here, RNA-seq analysis and Meta-QTLs mapping were performed to understand the molecular mechanisms underlying cold tolerance in the roots of 14-day-old seedlings of rice (RPY geng, cold-tolerant genotype). A total of 4779 of the differentially expressed genes (DEGs) were identified, including 2457 up-regulated and 2322 down-regulated DEGs. The GO, COG, KEEG, and Mapman enrichment results of DEGs revealed that DEGs are mainly involved in carbohydrate transport and metabolism, signal transduction mechanisms (plant hormone signal transduction), biosynthesis, transport and catabolism of secondary metabolites (phenylpropanoid biosynthesis), defense mechanisms, and large enzyme families mechanisms. Notably, the AP2/ERF-ERF, NAC, WRKY, MYB, C2H2, and bHLH transcription factors participated in rice’s cold–stress response and tolerance. On the other hand, we mapped the identified DEGs to 44 published cold–stress-related genes and 41 cold-tolerant Meta-QTLs regions. Of them, 12 DEGs were the published cold–stress-related genes and 418 DEGs fell into the cold-tolerant Meta-QTLs regions. In this study, the identified DEGs and the putative molecular regulatory network can provide insights for understanding the mechanism of cold stress tolerance in rice. In addition, DEGs in KEGG term-enriched terms or cold-tolerant Meta-QTLs will help to secure key candidate genes for further functional studies on the molecular mechanism of cold stress response in rice. Full article

During development, starting from a pool of pluripotent stem cells, tissue-specific genetic programs help to shape and develop functional organs. To understand the development of an organ and its disorders, it is important to understand the spatio-temporal dynamics of the gene expression profiles that occur during its development. Modifications in existing genes, the de-novo appearance of new genes, or, occasionally, even the loss of genes, can greatly affect the gene expression profile of any given tissue and contribute to the evolution of organs or of parts of organs. The neocortex is evolutionarily the most recent part of the brain, it is unique to mammals, and is the seat of our higher cognitive abilities. Progenitors that give rise to this tissue undergo sequential waves of differentiation to produce the complete sets of neurons and glial cells that make up a functional neocortex. We will review herein our understanding of the transcriptional regulators that control the neural precursor cells (NPCs) during the generation of the most abundant class of neocortical neurons, the glutametergic neurons. In addition, we will discuss the roles of recently-identified human- and primate-specific genes in promoting neurogenesis, leading to neocortical expansion. Full article

Fish rely on their innate immune responses to cope with the challenging aquatic environment, with antimicrobial peptides (AMPs) being one of the first line of defenses. Piscidins are a group of fish specific AMPs isolated in several species. However, in the European sea bass (Dicentrarchus labrax), the piscidin family remains poorly understood. We identified six different piscidins in sea bass, performed an in-depth molecular characterization and evaluated their antimicrobial activities against several bacterial and parasitic pathogens. Sea bass piscidins present variable amino acid sequences and antimicrobial activities, and can be divided in different sub groups: group 1, formed by piscidins 1 and 4; group 2, constituted by piscidins 2 and 5, and group 3, formed by piscidins 6 and 7. Additionally, we demonstrate that piscidins 1 to 5 possess a broad effect on multiple microorganisms, including mammalian parasites, while piscidins 6 and 7 have poor antibacterial and antiparasitic activities. These results raise questions on the functions of these peptides, particularly piscidins 6 and 7. Considering their limited antimicrobial activity, these piscidins might have other functional roles, but further studies are necessary to better understand what roles might those be. Full article

For a long time, the tight junction (TJ) was known to form and regulate the paracellular barrier between epithelia and endothelial cell sheets. Starting shortly after the discovery of the proteins forming the TJ—mainly, the two families of claudins and TAMPs—several other functions have been discovered, a striking one being the surprising finding that some claudins form paracellular channels for small ions and/or water. This Special Issue covers numerous dedicated topics including pathogens affecting the TJ barrier, TJ regulation via immune cells, the TJ as a therapeutic target, TJ and cell polarity, the function of and regulation by proteins of the tricellular TJ, the TJ as a regulator of cellular processes, organ- and tissue-specific functions, TJs as sensors and reactors to environmental conditions, and last, but not least, TJ proteins and cancer. It is not surprising that due to this diversity of topics and functions, the still-young field of TJ research is growing fast. This Editorial gives an introduction to all 43 papers of the Special Issue in a structured topical order. Full article

Vanicosides A and B are the esters of hydroxycinnamic acids with sucrose, occurring in a few plant species from the Polygonaceae family. So far, vanicosides A and B have not been evaluated for anticancer activity against human malignant melanoma. In this study, we tested these two natural products, isolated from Reynoutria sachalinensis rhizomes, against two human melanoma cell lines (amelanotic C32 cell line and melanotic A375 cell line, both bearing endogenous BRAFV600E mutation) and two normal human cell lines—keratinocytes (HaCaT) and the primary fibroblast line. Additionally, a molecular docking of vanicoside A and vanicoside B with selected targets involved in melanoma progression was performed. Cell viability was studied using an MTT assay. A RealTime-Glo™ Annexin V Apoptosis and Necrosis assay was used for monitoring programmed cell death (PCD). Vanicoside A demonstrated strong cytotoxicity against the amelanotic C32 cell line (viability of the C32 cell line was decreased to 55% after 72 h incubation with 5.0 µM of vanicoside A), significantly stronger than vanicoside B. This stronger cytotoxic activity can be attributed to an additional acetyl group in vanicoside A. No significant differences in the cytotoxicity of vanicosides were observed against the less sensitive A375 cell line. Moreover, vanicosides caused the death of melanoma cells at concentrations from 2.5 to 50 µM, without harming the primary fibroblast line. The keratinocyte cell line (HaCaT) was more sensitive to vanicosides than fibroblasts, showing a clear decrease in viability after incubation with 25 µM of vanicoside A as well as a significant phosphatidylserine (PS) exposure, but without a measurable cell death-associated fluorescence. Vanicosides induced an apoptotic death pathway in melanoma cell lines, but because of the initial loss of cell membrane integrity, an additional cell death mechanism might be involved like permeability transition pore (PTP)-mediated necrosis that needs to be explored in the future. Molecular docking indicated that both compounds bind to the active site of the BRAFV600E kinase and MEK-1 kinase; further experiments on their specific inhibitory activity of these targets should be considered. Full article

Lysiphlebia japonica Ashmead (Hymenoptera, Braconidae) is an endophagous parasitoid and Aphis gossypii Glover (Hemiptera, Aphididae) is a major pest in cotton. The relationship between insect host-parasitoids and their hosts involves complex physiological, biochemical and genetic interactions. This study examines changes in the development and physiological metabolism of A. gossypii regulated by L. japonica. Our results demonstrated that both the body length and width increased compared to non-parasitized aphids. We detected significantly increases in the developmental period as well as severe reproductive castration following parasitization by L. japonica. We then used proteomics to characterize these biological changes, and when combined with transcriptomes, this analysis demonstrated that the differential expression of mRNA (up or downregulation) captured a maximum of 48.7% of the variations of protein expression. We assigned these proteins to functional categories that included immunity, energy metabolism and transport, lipid metabolism, and reproduction. We then verified the contents of glycogen and 6-phosphate glucose, which demonstrated that these important energy sources were significantly altered following parasitization. These results uncover the effects on A. gossypii following parasitization by L. japonica, additional insight into the mechanisms behind insect-insect parasitism, and a better understanding of host-parasite interactions. Full article

Brain injuries are devastating conditions, representing a global cause of mortality and morbidity, with no effective treatment to date. Increased evidence supports the role of neuroinflammation in driving several forms of brain injuries. High mobility group box 1 (HMGB1) protein is a pro-inflammatory-like cytokine with an initiator role in neuroinflammation that has been implicated in Traumatic brain injury (TBI) as well as in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Herein, we discuss the implication of HMGB1-induced neuroinflammatory responses in these brain injuries, mediated through binding to the receptor for advanced glycation end products (RAGE), toll-like receptor4 (TLR4) and other inflammatory mediators. Moreover, we provide evidence on the biomarker potential of HMGB1 and the significance of its nucleocytoplasmic translocation during brain injuries along with the promising neuroprotective effects observed upon HMGB1 inhibition/neutralization in TBI and EBI induced by SAH. Overall, this review addresses the current advances on neuroinflammation driven by HMGB1 in brain injuries indicating a future treatment opportunity that may overcome current therapeutic gaps. Full article

We have previously reported that the administration of Lactobacillus plantarum DR7 for 12 weeks reduced stress and anxiety in stressed adults as compared to the placebo group, in association with changes along the brain neurotransmitters pathways of serotonin and dopamine-norepinephrine. We now aim to evaluate the effects of DR7 on gut functions, gut microbiota compositional changes, and determine the correlations between microbiota changes and the pathways of brain neurotransmitters. The administration of DR7 prevented an increase of defecation frequency over 12 weeks as compared to the placebo (p = 0.044), modulating the increase of stress-induced bowel movement. Over 12 weeks, alpha diversity of gut microbiota was higher in DR7 than the placebo group across class (p = 0.005) and order (p = 0.018) levels, while beta diversity differed between groups at class and order levels (p < 0.001). Differences in specific bacterial groups were identified, showing consistency at different taxonomic levels that survived multiplicity correction, along the phyla of Bacteroides and Firmicutes and along the classes of Deltaproteobacteria and Actinobacteria. Bacteroidetes, Bacteroidia, and Bacteroidales which were reduced in abundance in the placebo group showed opposing correlation with gene expression of dopamine beta hydrolase (DBH, dopamine pathway; p < 0.001), while Bacteroidia and Bacteroidales showed correlation with tryptophan hydroxylase-II (TPH2, serotonin pathway; p = 0.001). A correlation was observed between DBH and Firmicutes (p = 0.002), Clostridia (p < 0.001), Clostridiales (p = 0.001), Blautia (p < 0.001), and Romboutsia (p < 0.001), which were increased in abundance in the placebo group. Blautia was also associated with TDO (p = 0.001), whereas Romboutsia had an opposing correlation with TPH2 (p < 0.001). Deltaproteobacteria and Desulfovibrionales which were decreased in abundance in the placebo group showed opposing correlation with DBH (p = 0.001), whereas Bilophila was associated with TPH2 (p = 0.001). Our present data showed that physiological changes induced by L. plantarum DR7 could be associated with changes in specific taxa of the gut microbiota along the serotonin and dopamine pathways. Full article

Abscisic acid (ABA) is well-known phytohormone involved in the control of plant natural developmental processes, as well as the stress response. Although in wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.) its role in mechanism of the tolerance to most common abiotic stresses, such as drought, salinity, or extreme temperatures seems to be fairly well recognized, not many authors considered that changes in ABA content may also influence the sensitivity of cereals to adverse environmental factors, e.g., by accelerating senescence, lowering pollen fertility, and inducing seed dormancy. Moreover, recently, ABA has also been regarded as an element of the biotic stress response; however, its role is still highly unclear. Many studies connect the susceptibility to various diseases with increased concentration of this phytohormone. Therefore, in contrast to the original assumptions, the role of ABA in response to biotic and abiotic stress does not always have to be associated with survival mechanisms; on the contrary, in some cases, abscisic acid can be one of the factors that increases the susceptibility of plants to adverse biotic and abiotic environmental factors. Full article

Blue light extensively regulates multiple physiological processes and secondary metabolism of plants. Although blue light quantity (fluence rate) is important for plant life, few studies have focused on the effects of different blue light intensity on plant secondary metabolism regulation, including tea plants. Here, we performed transcriptomic and metabolomic analyses of young tea shoots (one bud and two leaves) under three levels of supplemental blue light, including low-intensity blue light (LBL, 50 μmol m^–2 s^–1), medium-intensity blue light (MBL, 100 μmol m^–2 s^–1), and high-intensity blue light (HBL, 200 μmol m^–2 s^–1). The total number of differentially expressed genes (DEGs) in LBL, MBL and HBL was 1, 7 and 1097, respectively, indicating that high-intensity blue light comprehensively affects the transcription of tea plants. These DEGs were primarily annotated to the pathways of photosynthesis, lipid metabolism and flavonoid synthesis. In addition, the most abundant transcription factor (TF) families in DEGs were bHLH and MYB, which have been shown to be widely involved in the regulation of plant flavonoids. The significantly changed metabolites that we detected contained 15 lipids and 6 flavonoid components. Further weighted gene co-expression network analysis (WGCNA) indicated that CsMYB (TEA001045) may be a hub gene for the regulation of lipid and flavonoid metabolism by blue light. Our results may help to establish a foundation for future research investigating the regulation of woody plants by blue light. Full article