Myconoside and Calceolarioside E Restrain UV-Induced Skin Photoaging by Activating NRF2-Mediated Defense Mechanisms.

Chronic and excessive ultraviolet (UVA/UVB) irradiation exposure is known as a major contributor to premature skin aging, which leads to excessive reactive oxygen species generation, disturbed extracellular matrix homeostasis, DNA damage, and chronic inflammation. Sunscreen products are the major preventive option against UVR-induced photodamage, mostly counteracting the acute skin effects and only mildly counteracting accelerated aging. Therefore, novel anti-photoaging and photopreventive compounds are a subject of increased scientific interest. Our previous investigations revealed that the endemic plant Haberlea rhodopensis Friv. (HRE) activates the antioxidant defense through an NRF2-mediated mechanism in neutrophiles. In the present study, we aimed to investigate the photoprotective potential of HRE and two of its specialized compounds-the phenylethanoid glycosides myconoside (MYC) and calceolarioside E (CAL)-in UVA/UVB-stimulated human keratinocytes in an in vitro model of photoaging. The obtained data demonstrated that the application of HRE, MYC, and CAL significantly reduced intracellular ROS formation in UVR-exposed HaCaT cells. The NRF2/PGC-1α and TGF-1ß/Smad/Wnt signaling pathways were pointed out as having a critical role in the observed CAL- and MYC-induced photoprotective effect. Collectively, CAL is worth further evaluation as a potent natural NRF2 activator and a promising photoprotective agent that leads to the prevention of UVA/UVB-induced premature skin aging.

Multi-omics identification of a key glycosyl hydrolase gene FtGH1 involved in rutin hydrolysis in Tartary buckwheat (Fagopyrum tataricum).

Rutin, a flavonoid rich in buckwheat, is important for human health and plant resistance to external stresses. The hydrolysis of rutin to quercetin underlies the bitter taste of Tartary buckwheat. In order to identify rutin hydrolysis genes, a 200 genotypes mini-core Tartary buckwheat germplasm resource was re-sequenced with 30-fold coverage depth. By combining the content of the intermediate metabolites of rutin metabolism with genome resequencing data, metabolite genome-wide association analyses (GWAS) eventually identified a glycosyl hydrolase gene FtGH1, which could hydrolyse rutin to quercetin. This function was validated both in Tartary buckwheat overexpression hairy roots and in vitro enzyme activity assays. Mutation of the two key active sites, which were determined by molecular docking and experimentally verified via overexpression in hairy roots and transient expression in tobacco leaves, exhibited abnormal subcellular localization, suggesting functional changes. Sequence analysis revealed that mutation of the FtGH1 promoter in accessions of two haplotypes might be necessary for enzymatic activity. Co-expression analysis and GWAS revealed that FtbHLH165 not only repressed FtGH1 expression, but also increased seed length. This work reveals a potential mechanism behind rutin metabolism, which should provide both theoretical support in the study of flavonoid metabolism and in the molecular breeding of Tartary buckwheat.

Avian influenza overview September-December 2023.

Between 2 September and 1 December 2023, highly pathogenic avian influenza (HPAI) A(H5) outbreaks were reported in domestic (88) and wild (175) birds across 23 countries in Europe. Compared to previous years, the increase in the number of HPAI virus detections in waterfowl has been delayed, possibly due to a later start of the autumn migration of several wild bird species. Common cranes were the most frequently affected species during this reporting period with mortality events being described in several European countries. Most HPAI outbreaks reported in poultry were primary outbreaks following the introduction of the virus by wild birds, with the exception of Hungary, where two clusters involving secondary spread occurred. HPAI viruses identified in Europe belonged to eleven different genotypes, seven of which were new. With regard to mammals, the serological survey conducted in all fur farms in Finland revealed 29 additional serologically positive farms during this reporting period. Wild mammals continued to be affected mostly in the Americas, from where further spread into wild birds and mammals in the Antarctic region was described for the first time. Since the last report and as of 1 December 2023, three fatal and one severe human A(H5N1) infection with clade 2.3.2.1c viruses have been reported by Cambodia, and one A(H9N2) infection was reported from China. No human infections related to the avian influenza detections in animals in fur farms in Finland have been reported, and human infections with avian influenza remain a rare event. The risk of infection with currently circulating avian H5 influenza viruses of clade 2.3.4.4b in Europe remains low for the general population in the EU/EEA. The risk of infection remains low to moderate for occupationally or otherwise exposed people to infected birds or mammals (wild or domesticated); this assessment covers different situations that depend on the level of exposure.

Maackiain Mimics Caloric Restriction through aak-2-Mediated Lipid Reduction in Caenorhabditis elegans.

Obesity prevalence is becoming a serious global health and economic issue and is a major risk factor for concomitant diseases that worsen the quality and duration of life. Therefore, the urgency of the development of novel therapies is of a particular importance. A previous study of ours revealed that the natural pterocarpan, maackiain (MACK), significantly inhibits adipogenic differentiation in human adipocytes through a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent mechanism. Considering the observed anti-adipogenic potential of MACK, we aimed to further elucidate the molecular mechanisms that drive its biological activity in a Caenorhabditis elegans obesity model. Therefore, in the current study, the anti-obesogenic effect of MACK (25, 50, and 100 µM) was compared to orlistat (ORST, 12 µM) as a reference drug. Additionally, the hybrid combination between the ORST (12 µM) and MACK (100 µM) was assessed for suspected synergistic interaction. Mechanistically, the observed anti-obesogenic effect of MACK was mediated through the upregulation of the key metabolic regulators, namely, the nuclear hormone receptor 49 (nhr-49) that is a functional homologue of the mammalian PPARs and the AMP-activated protein kinase (aak-2/AMPK) in C. elegans. Collectively, our investigation indicates that MACK has the potential to limit lipid accumulation and control obesity that deserves future developments.

Resequencing of global Lotus corniculatus accessions reveals population distribution and genetic loci, associated with cyanogenic glycosides accumulation and growth traits.

BACKGROUND: Lotus corniculatus is a widely distributed perennial legume whose great adaptability to different environments and resistance to barrenness make it an excellent forage and ecological restoration plant. However, its molecular genetics and genomic relationships among populations are yet to be uncovered. RESULT: Here we report on a genomic variation map from worldwide 272 L. corniculatus accessions by genome resequencing. Our analysis suggests that L. corniculatus accessions have high genetic diversity and could be further divided into three subgroups, with the genetic diversity centers were located in Transcaucasia. Several candidate genes and SNP site associated with CNglcs content and growth traits were identified by genome-wide associated study (GWAS). A non-synonymous in LjMTR was responsible for the decreased expression of CNglcs synthesis genes and LjZCD was verified to positively regulate CNglcs synthesis gene CYP79D3. The LjZCB and an SNP in LjZCA promoter were confirmed to be involved in plant growth. CONCLUSION: This study provided a large number of genomic resources and described genetic relationship and population structure among different accessions. Moreover, we attempt to provide insights into the molecular studies and breeding of CNglcs and growth traits in L. corniculatus.

Comparative and population genomics of buckwheat species reveal key determinants of flavor and fertility.

Common buckwheat (Fagopyrum esculentum) is an ancient crop with a world-wide distribution. Due to its excellent nutritional quality and high economic and ecological value, common buckwheat is becoming increasingly important throughout the world. The availability of a high-quality reference genome sequence and population genomic data will accelerate the breeding of common buckwheat, but the high heterozygosity due to the outcrossing nature has greatly hindered the genome assembly. Here we report the assembly of a chromosome-scale high-quality reference genome of F. esculentum var. homotropicum, a homozygous self-pollinating variant of common buckwheat. Comparative genomics revealed that two cultivated buckwheat species, common buckwheat (F. esculentum) and Tartary buckwheat (F. tataricum), underwent metabolomic divergence and ecotype differentiation. The expansion of several gene families in common buckwheat, including FhFAR genes, is associated with its wider distribution than Tartary buckwheat. Copy number variation of genes involved in the metabolism of flavonoids is associated with the difference of rutin content between common and Tartary buckwheat. Furthermore, we present a comprehensive atlas of genomic variation based on whole-genome resequencing of 572 accessions of common buckwheat. Population and evolutionary genomics reveal genetic variation associated with environmental adaptability and floral development between Chinese and non-Chinese cultivated groups. Genome-wide association analyses of multi-year agronomic traits with the content of flavonoids revealed that Fh05G014970 is a potential major regulator of flowering period, a key agronomic trait controlling the yield of outcrossing crops, and that Fh06G015130 is a crucial gene underlying flavor-associated flavonoids. Intriguingly, we found that the gene translocation and sequence variation of FhS-ELF3 contribute to the homomorphic self-compatibility of common buckwheat. Collectively, our results elucidate the genetic basis of speciation, ecological adaptation, fertility, and unique flavor of common buckwheat, and provide new resources for future genomics-assisted breeding of this economically important crop.

Anti-Adipogenic Activity of Rhaponticum carthamoides and Its Secondary Metabolites.

Besides their common use as an adaptogen, Rhaponticum carthamoides (Willd.) Iljin. rhizome and its root extract (RCE) are also reported to beneficially affect lipid metabolism. The main characteristic secondary metabolites of RCE are phytoecdysteroids. In order to determine an RCE's phytoecdysteroid profile, a novel, sensitive, and robust high-performance thin-layer chromatography (HPTLC) method was developed and validated. Moreover, a comparative analysis was conducted to investigate the effects of RCE and its secondary metabolites on adipogenesis and adipolysis. The evaluation of the anti-adipogenic and lipolytic effects was performed using human Simpson-Golabi-Behmel syndrome cells, where lipid staining and measurement of released glycerol and free fatty acids were employed. The HPTLC method confirmed the presence of 20-hydroxyecdysone (20E), ponasterone A (PA), and turkesterone (TU) in RCE. The observed results revealed that RCE, 20E, and TU significantly reduced lipid accumulation in human adipocytes, demonstrating their anti-adipogenic activity. Moreover, RCE and 20E were found to effectively stimulate basal lipolysis. However, no significant effects were observed with PA and TU applications. Based on our findings, RCE and 20E affect both lipogenesis and lipolysis, while TU only restrains adipogenesis. These results are fundamental for further investigations.

The Triterpenoid Nrf2 Activator, CDDO-Me, Decreases Neutrophil Senescence in a Murine Model of Joint Damage.

The synthetic 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a potent activator of the erythroid 2-p45-derived factor 2, Nrf2, a leucine-zipper regulator of the antioxidant response. Herein, we investigated the effect of CDDO-Me on neutrophil function in a murine model of joint damage. Collagenase-induced osteoarthritis (CIOA) was initiated by the intra-articular injection of collagenase in the knee-joint cavity of Balb/c mice. CDDO-Me was administrated intra-articularly twice a week starting at day 7 post-CIOA, and its effect was evaluated at day 14. Neutrophils in blood and bone marrow (BM), cell apoptosis, necrosis, expression of C-X-C chemokine receptor 4 (CXCR4), beta-galactosidase (ß-Gal), and Nrf2 levels were measured by flow cytometry. In vitro, CDDO-Me promoted cell survival, reduced cell necrosis, and increased Nrf2 levels by 1.6 times. It decreased surface CXCR4 expression and reduced the frequency of senescent ß-Gal+CXCR4+ neutrophils by three times. In vivo, the degree of knee-joint damage in CIOA was correlated with upregulated CXCR4 on CD11b+ neutrophils. CDDO-Me improved the disease histological score, increased the levels of Nrf2, and downregulated surface CXCR4 on mature BM cells. Our data suggest that CDDO-Me may act as a potent regulator of neutrophil senescence during the progression of knee-joint damage.

Crocus sativus Extract as a Biological Agent for Disease-Modifying Therapy of Collagenase-Induced Mouse Model of Osteoarthritis.

OBJECTIVES: Osteoarthritis (OA) is an age-related joint disease that involves the degeneration of cartilage and is the most prevalent form of arthritis, affecting a large part of the population. OA is a multifactorial disorder, and no single etiological mechanism has been found to be common to all forms of the disease. Currently used therapies for control of the disease are mainly nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroid medications. The aim of this study was to investigate the extract from Crocus sativus as a biological disease-suppressing therapy agent. METHODS: Balb/c mice were injected intra-articularly with Clostridium histolyticum type IA for induction of osteoarthritis. The mice were randomized to five groups: control group, I group (CIOA untreated), II group (CIOA + 100 mg/kg/daily saffron), III group (CIOA + 50 mg/kg/daily saffron), IV group (CIOA + 25 mg/kg/daily saffron). Flow-cytometry analysis was used to study the splenocytes' phenotype isolated from the treated animals. The serum levels of inflammatory and anti-inflammatory cytokines were analyzed with ELISA. The histological assessment was used to analyze the saffron extract effect on histopathological alterations. RESULTS: Saffron treatment significantly decreased osteoarthritis-associated joint histological manifestations and decreased serum TNFα levels. The flow-cytometry analysis showed a decrease in pro-inflammatory immune cell subtypes in the spleen. CONCLUSIONS: The results obtained suggest that saffron affected the disease progression and could be a potential therapeutic approach in osteoarthritic patients' therapy.

Multiomics analysis reveals the molecular mechanisms underlying virulence in Rhizoctonia and jasmonic acid-mediated resistance in Tartary buckwheat (Fagopyrum tataricum).

Rhizoctonia solani is a devastating soil-borne pathogen that seriously threatens the cultivation of economically important crops. Multiple strains with a very broad host range have been identified, but only 1 (AG1-IA, which causes rice sheath blight disease) has been examined in detail. Here, we analyzed AG4-HGI 3 originally isolated from Tartary buckwheat (Fagopyrum tataricum), but with a host range comparable to AG1-IA. Genome comparison reveals abundant pathogenicity genes in this strain. We used multiomic approaches to improve the efficiency of screening for disease resistance genes. Transcriptomes of the plant-fungi interaction identified differentially expressed genes associated with virulence in Rhizoctonia and resistance in Tartary buckwheat. Integration with jasmonate-mediated transcriptome and metabolome changes revealed a negative regulator of jasmonate signaling, cytochrome P450 (FtCYP94C1), as increasing disease resistance probably via accumulation of resistance-related flavonoids. The integration of resistance data for 320 Tartary buckwheat accessions identified a gene homolog to aspartic proteinase (FtASP), with peak expression following R. solani inoculation. FtASP exhibits no proteinase activity but functions as an antibacterial peptide that slows fungal growth. This work reveals a potential mechanism behind pathogen virulence and host resistance, which should accelerate the molecular breeding of resistant varieties in economically essential crops.

Targeting PI3K/AKT signaling pathway in obesity.

Obesity is a disorder with an increasing prevalence, which impairs the life quality of patients and intensifies societal health care costs. The development of safe and innovative prevention strategies and therapeutic approaches is thus of great importance. The complex pathophysiology of obesity involves multiple signaling pathways that influence energy metabolism in different tissues. The phosphatidylinositol 3-kinases (PI3K)/protein kinase B (AKT) pathway is critical for the metabolic homeostasis and its function in insulin-sensitive tissues is described in the context of health, obesity and obesity-related complications. The PI3K family participates in the regulation of diverse physiological processes including but not limited to cell growth, survival, differentiation, autophagy, chemotaxis, and metabolism depending on the cellular context. AKT is downstream of PI3K in the insulin signaling pathway, and promotes multiple cellular processes by targeting a plethora of regulatory proteins that control glucose and lipid metabolism. Natural products are essential for prevention and treatment of many human diseases, including obesity. Anti-obesity natural compounds effect multiple pathophysiological mechanisms involved in obesity development. Numerous recent preclinical studies reveal the advances in using plant secondary metabolites to target the PI3K/AKT signaling pathway for obesity management. In this paper the druggability of PI3K as a target for compounds with anti-obesity potential is evaluated. Perspectives on the strategies and limitations for clinical implementation of obesity management using natural compounds modulating the PI3K/AKT pathway are suggested.

The International Natural Product Sciences Taskforce (INPST) and the power of Twitter networking exemplified through #INPST hashtag analysis.

BACKGROUND: The development of digital technologies and the evolution of open innovation approaches have enabled the creation of diverse virtual organizations and enterprises coordinating their activities primarily online. The open innovation platform titled "International Natural Product Sciences Taskforce" (INPST) was established in 2018, to bring together in collaborative environment individuals and organizations interested in natural product scientific research, and to empower their interactions by using digital communication tools. METHODS: In this work, we present a general overview of INPST activities and showcase the specific use of Twitter as a powerful networking tool that was used to host a one-week "2021 INPST Twitter Networking Event" (spanning from 31st May 2021 to 6th June 2021) based on the application of the Twitter hashtag #INPST. RESULTS AND CONCLUSION: The use of this hashtag during the networking event period was analyzed with Symplur Signals (https://www.symplur.com/), revealing a total of 6,036 tweets, shared by 686 users, which generated a total of 65,004,773 impressions (views of the respective tweets). This networking event's achieved high visibility and participation rate showcases a convincing example of how this social media platform can be used as a highly effective tool to host virtual Twitter-based international biomedical research events.

Rewiring of the seed metabolome during Tartary buckwheat domestication.

Crop domestication usually leads to the narrowing genetic diversity. However, human selection mainly focuses on visible traits, such as yield and plant morphology, with most metabolic changes being invisible to the naked eye. Buckwheat accumulates abundant bioactive substances, making it a dual-purpose crop with excellent nutritional and medical value. Therefore, examining the wiring of these invisible metabolites during domestication is of major importance. The comprehensive profiling of 200 Tartary buckwheat accessions exhibits 540 metabolites modified as a consequence of human selection. Metabolic genome-wide association study illustrates 384 mGWAS signals for 336 metabolites are under selection. Further analysis showed that an R2R3-MYB transcription factor FtMYB43 positively regulates the synthesis of procyanidin. Glycoside hydrolase gene FtSAGH1 is characterized as responsible for the release of active salicylic acid, the precursor of aspirin and indispensably in plant defence. UDP-glucosyltransferase gene FtUGT74L2 is characterized as involved in the glycosylation of emodin, a major medicinal component specific in Polygonaceae. The lower expression of FtSAGH1 and FtUGT74L2 were associated with the reduction of salicylic acid and soluble EmG owing to domestication. This first large-scale metabolome profiling in Tartary buckwheat will facilitate genetic improvement of medicinal properties and disease resistance in Tartary buckwheat.

Icariin Improves Stress Resistance and Extends Lifespan in Caenorhabditis elegans through hsf-1 and daf-2-Driven Hormesis.

Aging presents an increasingly significant challenge globally, driven by the growing proportion of individuals aged 60 and older. Currently, there is substantial research interest in pro-longevity interventions that target pivotal signaling pathways, aiming not only to extend lifespan but also to enhance healthspan. One particularly promising approach involves inducing a hormetic response through the utilization of natural compounds defined as hormetins. Various studies have introduced the flavonoid icariin as beneficial for age-related diseases such as cardiovascular and neurodegenerative conditions. To validate its potential pro-longevity properties, we employed Caenorhabditis elegans as an experimental platform. The accumulated results suggest that icariin extends the lifespan of C. elegans through modulation of the DAF-2, corresponding to the insulin/IGF-1 signaling pathway in humans. Additionally, we identified increased resistance to heat and oxidative stress, modulation of lipid metabolism, improved late-life healthspan, and an extended lifespan upon icariin treatment. Consequently, a model mechanism of action was provided for icariin that involves the modulation of various players within the stress-response network. Collectively, the obtained data reveal that icariin is a potential hormetic agent with geroprotective properties that merits future developments.

Betulinic acid counteracts the lipid accumulation in Caenorhabditis elegans by modulation of nhr-49 expression.

Obesity is an ingrained health problem with а multifactorial origin and а long history, thereby innovations in the treatment strategies are of great importance. In the search of a remedy for excessive weight gain, we have directed our investigations to phytochemicals as valuable bioactive compounds. Betulinic acid (BA), among the other triterpenoids, is known for its anti-inflammatory and anti-neoplastic properties. In addition, a previous study of ours has demonstrated а potent anti-adipogenic effect of BA in human adipocytes. Therefore, we aimed here to further verify the anti-obesogenic effect of BA in vivo in Caenorhabditis elegans. Induction of lipid accumulation in the nematodes was modelled with glucose-supplemented media, followed by treatment with BA (10-50 µM) or orlistat (12 µM) as a control anti-obesity medication. Oil red O and Nile red staining were applied to provide quantification of accumulated lipids. Analysis of the relative expression of genes, related to lipid metabolism suggested molecular mechanism of lipid-reducing action of BA in C. elegans. Treatment of nematodes with BA significantly decreased the lipid accumulation, downregulated desaturases involved in lipogenesis (fat-5, fat-6 and fat-7), modulated key transcription factors (nhr-49 and hlh-11) and microRNAs (miR-60, lin-4, let-7 and miR-786) associated with the lipid metabolism. Collectively, the current research provides additional insight on the molecular mechanism of the BA's anti-obesogenic effect in vivo. Furthermore, it validates the potential of BA as a candidate compound in obesity management by reducing lipid accumulation.

Crisis Preparedness Exercise on Rift Valley Fever Introduction into Europe under a One Health Approach.

Crisis preparedness training programmes are substantial for the effective management of contingency plans. Rift Valley Fever (RVF) was chosen as the vector transmitted zoonosis for a crisis preparedness exercise co-organised in 2021 by the European Food Safety Authority (EFSA) and the Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise "G. Caporale" (IZS-Teramo). The online table-top simulation exercise was planned to strengthen the network of Mediterranean countries on rapid risk assessment, risk/crisis management and risk communication during a human/animal health crisis, adopting the 'One Health' approach. Italy, Spain, Portugal, France, Greece, Albania, Croatia, Montenegro and Turkey were the beneficiary countries, while European Commission (EC), European Centre for Disease Prevention and Control (ECDC), World Health Organisation (WHO), World Organisation for Animal Health (WOAH) and Food and Agricultural Organisation (FAO) were the designated observers who were actively involved along the entire capacity building process. The simulation exercise was based on a fictional case study in which the zoonotic mosquito-borne disease, not currently present in Europe, was accidentally introduced into the European Union via the accidental transfer of infected vectors from a RVF-endemic country. The training activity was positively assessed by the participants and useful suggestions were given to address further future similar initiatives.

Chemical Composition and Histochemical Localization of Essential Oil from Wild and Cultivated Rhaponticum carthamoides Roots and Rhizomes.

Rhaponticum carthamoides (Willd.) Iljin is not only a source of phytosteroids and flavonoids, but is also source of essential oil (EO). This study evaluated the volatile metabolic constituents and histochemical localization of root and rhizome essential oils (EOs) from R. carthamoides populations wild-grown in Russia and cultivated in Bulgaria. The performed histochemical analysis confirmed the presence of lipophilic substances in the secretory ducts of the examined roots and rhizomes. Both EOs were obtained by hydrodistillation and further analyzed by gas chromatography with mass detection. The results showed differences between the chemical compositions of both EOs. Forty-six components were tentatively identified in R. carthamoides oil from the wild population, with ß-selinene (4.77%), estragole (6.32%), D-carvone (6.37%), cyperene (8.78%), and ledene oxide (11.52%) being the major constituents. In the EO isolated from cultivated R. carthamoides, twenty-three compounds were tentatively identified, with humulene (7.68%), ß-elemene (10.76%), humulene-1,2-epoxide (11.55%), ledene oxide (13.50%), and δ-elemene (19.08%) predominating. This is the first report describing the histolocalization and chemical profile of EO from R. carthamoides cultivated in Bulgaria. Further research on the cultivation of R. carthamoides in Bulgaria would affect the relationship between its chemical composition and pharmacological effects.